OA12189A - Vitronectin receptor antagonists. - Google Patents

Abstract

Pharmaceutically active compounds which inhibit the vitronectin receptor and are useful for the treatment of inflammation, cancer and cardiovascular disorders, such as atherosclerosis and restenosis, and diseases wherein bone resorption is a factor, such as osteoporosis.

Description

012189

TITLE

Vitronectin Receptor Antagonists

FIELD OF THE INVENTION

This invention relates to pharmaceutically active compounds which inhibit thevitronectin receptor and are useful for the treatment of inflammation, cancer andcardiovascular disorders, such as atherosclerosis and restenosis, and diseases wherein bonerésorption is a factor, such as osteoporosis.

BACKGROUND OF THE INVENTION

Integrins are a superfamily of cell adhesion receptors, which are transmembraneglycoproteins expressed on a variety of cells. These cell surface adhesion receptors includegpllb /Ilia (the fibrinogen receptor) and av&3 (the vitronectin receptor). The fibrinogenreceptor gpllb /Ilia is expressed on the platelet surface, and médiates platelet aggregationand the formation of a hemostatic clôt at the site of a bleeding wound. Philips, et al.,

Blood., 1988, 71, 831. The vitronectin receptor avB3 is expressed on a number of cells,including endothélial, smooth muscle, osteoclast, and tumor cells, and, thus, it has a varietyof functions. The avB3 receptor expressed on the membrane of osteoclast cells médiates theadhesion of osteoclasts to the bone matrix, a key step in the bone résorption process. Ross,et al., J. Biol. Chem., 1987, 262, 7703. A disease characterized by excessive bonerésorption is osteoporosis. The ανββ receptor expressed on human aortic smooth musclecells médiates their migration into neointima, a process which can lead to restenosis afterpercutaneous coronary angioplasty. Brown, et al., Cardiovascular Res., 1994,28,1815.Additionally, Brooks, et al., Cell, 1994, 79, 1157 has shown that an ctyBj antagonist is ableto promote tumor régression by inducing apoptosis of angiogenic blood vessels. Thus,agents that block the vitronectin receptor would be useful in treating diseases, such asosteoporosis, restenosis and cancer.

The vitronectin receptor is now known to refer to three different integrins,designated avB|, ayfij and ανβ5· Horton, et al., Int. J. Exp. Pathol., 1990, 71,741. avBjbinds fibronectin and vitronectin. otyBj binds a large variety of ligands, including fibrin,fibrinogen, laminin, thrombospondin, vitronectin, von Willebrand's factor, osteopontin andbone sialoprotein I. oCyBj binds vitronectin. The vitronectin receptor avB5 has been shownto be involved in cell adhesion of a variety of cell types, including microvascularendothélial cells, (Davis, et al., J. Cell. Biol., 1993, 57, 206), and its rôle in angiogenesishas been confirmed. Brooks, et al., Science, 1994,264,569. This integrin is expressed onblood vessels in human wound granulation tissue, but not in normal skin.

The vitronectin receptor is known to bind to bone matrix proteins which contain thetri-peptide Arg-Gly-Asp (or RGD) motif. Thus, Horton, et al., Exp. Cell Res. 1991, 795, -2- 012189 368, disclose that RGD-containing peptides and an anti-vitronectin receptor antibody(23C6) inhibit dentine résorption and cell spreading by osteoclasts. In addition, Sato, et al.,J. Cell Biol. 1990,111,1713 discloses that echistatin, a snake venom peptide whichcontains the RGD sequence, is a potent inhibitor of bone résorption in tissue culture, andinhibits attachment of osteoclasts to bone.

It has now been discovered that certain compounds are potent inhibitors of theΟγββ and 0^65 receptors. In particular, it has been discovered that such compounds aremore potent inhibitors of the vitronectin receptor than the fîbrinogen receptor.

SUMMARY OF THE INVENTION

This invention comprises compounds of the formula (I) as described hereinafter,which hâve pharmacological activity for the inhibition of the vitronection receptor and areuseful in the treatment of inflammation, cancer and cardiovascular disorders, such asatherosclerosis and restenosis, and diseases wherein bone résorption is a factor, such as.osteoporosis.

This invention is also a pharmaceutical composition comprising a compoundaccording to formula (I) and a pharmaceutically carrier.

This invention is also a method of treating diseases which are mediated by thevitronectin receptor. In a particular aspect, the compounds of this invention are useful fortreating atherosclerosis, restenosis, inflammation, cancer and diseases wherein bonerésorption is a factor, such as osteoporosis.

DETAELED DESCRIPTION

This invention comprises novel compounds which are more potent inhibitors of thevitronectin receptor than the fîbrinogen receptor. This invention comprises compounds offormula (I): R* (I) wherein: R* is R'

R

R

X

-CH or

Xis CR’R’, NR’,OorS; 012189 Y is CR’R’, NR’, O or S; A is H, halo, -ORS, -SRS, -CN, -NRSRk, -NO2, -CF3, -S(O)rCF3, -CO2RS, -CORS,-CONRS2 -Ci-6alkyl, -Cg^alkyl-Ar, -Co^alkyl-Het, -Co_6alkyl-C3-6cycloalkyl, -S(O)kRS,or CH2N(Rf)2; 5 R1 is -C0.6alkyl-Het-, -C0.6alkyl-Ar, -Cj^alkyl, -H, -CN, -CH=CH2, -CSCH or, -S(O)kRS; R^ is 10

(?)u

^^^(CR’^-W

R" y T QV°3 NR'1—CR'2—W- • Il 3-Q4

Q <>8 Λυ

NR"—CR’2 —W

.NRM

or 15 W is -(CHRS)a-U-(CHRS)b-; U is absent or CO, CRS2, C(=CRS2), S(O)k, O, NRS, CRSORS, CRS(ORk)CRS2, CRS2CRS(ORk), C(O)CRS2, CRS2C(O), CONR', NR'CO, OC(O), C(O)O, C(S)O, OC(S),C(S)NR8, NRSC(S), S(O)2NRS, NRSS(O)2 N=N, NRSNRS, NRSCRS2, CRS2NRS, CRS2O,OCRS2, C sC , CRS=CRS, Ar or Het; 20 G is NRe, S or O; RS is H, Ci.6alkyl, Het-Co-galkyl, C3-7cycloalkyl-C0_6alkyl or Ar-C0.6alkyl;

Rk is RS, -C(O)RS, or -C(O)ORf; R1 is is H, Cj.galkyl, Het-Cg^alkyl, C3-7cycloalkyI-Co.6alkyl, Ar- C^galkyl, orC j.galkyl substituted by one to three groups chosen from halogen, CN, NRS2, ORS, SRS, 25 CO2RS, and CON(R8)2;

Rf is H, Cj.^alkyl or Ar-C0_6alkyl;

Re is H, Cj.^alkyl, Ar-C0.6alkyl, Het-Co^alkyl, C3-7cycloalkyl-C0_6alkyl, or(CH2)kCO2RS;

Rb and Rc are independently selected from H, Cj.6alkyl, Ar-C0.6alkyl, Het-C0. 30 galkyl, or C3-6cycloalkyl-C0.6alkyl, halogen, CF3, ORf, S(O)kRf, CORf, NO2, N(Rf)2, -4- 012189 CO(NRf>2, CH2N(Rf>2, or Rb and Rc are joined together to form a five or six memberedaromatic or non-aromatic carbocyclic or heterocyclic ring, optionally substituted by up tothree substituents chosen from halogen, CF3, Cj^alkyl, ORf, S(O)j<rA CORf, CO2Rf, OH,NO2, N(R^2, CO(NRf)2, and C^NfR^; or methylenedioxy; Q1, Q2. Q3 and Q4 are independently N or C-RY, provided that no more than one ofQl, Q2, Q3 and Q4 is N; R’is H, Cj-éalkyl, Ar-Co-galkyl or C3-6cycloalkyl-Co-6alkyl; R" is R’, -C(O)R’ or -C(O)OR’; RY is H, halo, -ORS, -SRS, -CN, -NRSRk, -NO2, -CF3, CF3S(O)r-, -CO2RS, -CORSor -CONRS2, or Ci.6alkyl optionally substituted by halo, -ORS, -SRS, -CN, -NRSR", -NO2,-CF3, R*S(O)r-, -CO2RS, -CORS or -CONRS2; a is 0,1 or 2;b is 0,1 or 2;k is 0, 1 or 2;r is 0,1 or 2;s is 0, 1 or 2;u is 0 or 1; andv is 0 or 1; or a pharmaceutically acceptable sait thereof.

Suitably, this invention comprises formula (I) compounds of formula (la): R’ wherein:

Xis CRR’, NR’, O or S; Y is CRR’, NR’, O or S; A is H, halo, -ORS, -SRS, -CN, -NRSRk, _νο2, -CF3, -S(O)rCF3, -CO2RS, -CORS, -CONRS2 -C].6alkyl, -C0.6alkyl-Ar, -Cg^alkyl-Het, -C0_6alkyl-C3-6cycloalkyl, -SCO^RS,orCH2N(Rf)2; R1 is -Co.6alkyl-Het-, -C^galkyl-Ar, H, -CN or -SfO^RS; R2 is

ÿ— NR"—CR’2—W R’ -5- 012189 R’ «?>, R'

(CR’2)V—w M NR"—CR’,—W-

Q

bk ^NR”—CR’, —W W is -(CHRg)a-U-(CHRg)b-; U is absent or CO, CRg2, C(=CRg2), S(O)k, O, NRë, CRêORS, CRg(ORk)CRS2,CRg2CRg(ORk), C(O)CRg2, CRg2C(O), CONR>, NR'CO, OC(O), C(O)O, C(S)O, OC(S),C(S)NRg, NRgC(S), S(O)2NRg, NRgS(O)2 N=N, NRgNRg, NRgCRg2, CRg2NRg, CRg2O,OCRg2, C —C , CRg=CRg, Ar or Het; G is NRe, S or O;

Rg is H, Cj.^alkyl, Het-Co^alkyl, C3_7cycloalkyl-Co_6alkyl or Ar-Co^alkyl;

Rk is Rg, -C(O)Rg, or -C(O)ORf; R' is is H, Ci.^alkyl, Het-Cg^alkyl, C3-7cycloalkyl-CQ.galkyl, Ar- C^galkyl, orCj.^alkyl substituted by one to three groups chosen from halogen, CN, NRg2, ORg, SRg,CO2Rg, and CON(Rg)2;

Rf is H, Cj^alkyl or Ar-C^galkyl;

Re is H, Cj^alkyl, Ar-CQ^alkyl, Het-Co^alkyl, C3-7cycloalkyl-C0_6alkyl, or(CH2)kCO2Rg;

Rb and Rc are independently selected from H, C^galkyl, Ar-Cg^alkyl, Het-Cg,galkyl, or C3-6cycloalkyl-CQ„6alkyl, halogen, CF3, ORf, S(O)kRf, CORf, NO2, N(Rf)2>CO(NRf)2, CH2N(Rf)2, or Rb and Rc are joined together to form a five or six memberedaromatic or non-aromatic carbocyclic or heterocyclic ring, optionally substituted by up tothree substituents chosen from halogen, CF3, Cj^alkyl, ORf, S(O)kRf, CORf, CO2Rf, OH,NO2, N(Rf)2j CO(NRf)2, and CH2N(Rf)2; or methylenedioxy; Q1, Q^, Q3 and Q4 are independently N or C-RÏ, provided that no more than one ofQ1» Q2, Q2 and Q4 is N; R’ is H, Cpéalkyl, Ar-Co-6aIkyl or C3_6cycloalkyl-Co-6alkyl; R” is R’, -C(O)R’ or -C(O)OR’; RV is H, halo, -ORg, -SRg, -CN, -NRgRk, -NO2, -CF3, CF3S(O)r-, -CO2Rg, -CORgor -CONRg2, or Ci^alkyl optionally substituted by halo, -ORg, -SRg, -CN, -NRgR", -NO2,-CF3, R’S(O)r-, -CO2Rg, -CORg or -CONRg2; -6- 012189 a is 0,1 or 2;b is 0,1 or 2;k is 0, 1 or 2;r is 0,1 or 2;s is 0,1 or 2;u isOor 1; andvisOor 1; or a pharmaceutically acceptable sait thereof.

Also included in this invention are pharmaceutically acceptable addition salts and complexes of the compounds of this invention. In cases wherein the compounds of thisinvention may hâve one or more chiral centers, unless specified, this invention includes. each unique nonracemic compound which may be synthesized and resolved byconventional techniques. In cases in which compounds hâve unsaturated carbon-carbondouble bonds, both the cis (Z) and trans (E) isomers are within the scope of this invention.In cases wherein compounds may exist in tautomeric forms, such as keto-enol tautomers, OR’

O such as and and each tautomeric form is contemplated as being included within this invention whether existing in equilibrium or locked in one form by appropriatesubstitution with R’.

The compounds of formula (I) inhibit the binding of vitronectin and other RGD-containing peptides to the vitronectin receptor. Inhibition of the vitronectin receptor onosteoclasts inhibits osteoclastic bone résorption and is useful in the treatment of diseaseswherein bone résorption is associated with pathology, such as osteoporosis andosteoarthritis.

In another aspect, this invention is a method for stimulating bone formation whichcomprises administering a compound which causes an increase in osteocalcin release.Increased bone production is a clear benefit in disease States wherein there is a defîciencyof mineralized bone mass or remodeling of bone is desired, such as fracture healing and theprévention of bone fractures. Diseases and metabolic disorders which resuit in loss of bonestructure would also benefit from such treatment. For instance, hyperparathyroidism,Paget’s disease, hypercalcemia of malignancy, osteolytic lésions produced by bonemetastasis, bone loss due to immobilization or sex hormone defîciency, Behçet's disease,osteomalacia, hyperostosis and osteopetrosis, could benefit from administering a compoundof this invention.

Additionally, since the compounds of the instant invention inhibit vitronectinreceptors on a number of different types of cells, said compounds would be useful in thetreatment of inflammatory disorders, such as rheumatoid arthritis and psoriasis, andcardiovascular diseases, such as atherosclerosis and restenosis. The compounds of Formula 012189 (I) of the présent invention may be useful for the treatment or prévention of other diseasesincluding, but not limited to, thromboembolie disorders, asthma, allergies, adult respiratorydistress syndrome, graft versus host disease, organ transplant rejection, septic shock,eczema, contact dermatitis, inflammatory bowel disease, and other autoimmune diseases.

The compounds of the présent invention may also be useful for wound healing.

The compounds of the présent invention are also useful for the treatment, includingprévention, of angiogenic disorders. The term angiogenic disorders as used herein includesconditions involving abnormal neovascularization. Where the growth of new blood vesselsis the cause of, or contributes to, the pathology associated with a disease, inhibition ofangiogenisis will reduce the deleterious effects of the disease. An example of such adisease target is diabetic retinopathy. Where the growth of new blood vessels is required tosupport growth of a deleterious tissue, inhibition of angiogenisis will reduce the bloodsupply to the tissue and thereby contribute to réduction in tissue mass based on bloodsupply requirements. Examples include growth of tumors where neovascularization is acontinuai requirement in order that the tumor grow and the establishment of solid tumormétastasés. Thus, the compounds of the présent invention inhibit tumor tissueangiogenesis, thereby preventing tumor metastasis and tumor growth.

Thus, according to the methods of the présent invention, the inhibition ofangiogenesis using the compounds of the présent invention can ameliorate the symptoms ofthe disease, and, in some cases, can cure the disease.

Another therapeutic target for the compounds of the instant invention are eyediseases chacterized by neovascularization. Such eye diseases include comeal neovasculardisorders, such as comeal transplantation, herpetic keratitis, luetic keratitis, pterygium andneovascular pannus associated with contact lens use. Additional eye diseases also includeage-related macular degeneration, presumed ocular histoplasmosis, retinopathy ofprematurity and neovascular glaucoma.

This invention further provides a method of inhibiting tumor growth whichcomprises administering stepwise or in physical combination a compound of formula (I)and an antineoplastic agent, such as topotecan and cisplatin.

With respect to formula (I) and (la):

Suitably R2 is -8- 012189 QKN\/NR —CR’-W- Q<x Jq4 θ ,wherein Q1, Q2, and Q3 are each CRy, Q4 is CRy or N and u is 0, and preferably, each R’ is H, R"is H or Ci^alkyl, W is -(CH2)l-4-, Q4isCRyandRyis H.

Altemately R2 is <?>« R’

R* T Y Q<· Z-Q3 θ ,wherein Q1, Q2, and Q3 are each CH and u is 0, and preferably, each R’ is H, R" is H or Cj.galkyl, W is -CH2-CH2- and v is 0.

Altemately R2 is 10 jJ NR"—CR’2—W- , wherein G is NH and Rb and Rc are each H, and preferably, W is -CH2-CH2-.Altemately R2 is

,b

G NR"—CR’Z—W- N u , wherein G is NH and RD and Rc are 15 joined together to form a five or six membered aromatic or non-aromatic carbocyclic orheterocyclic ring, optionally substituted by up to three substituents chosen from halogen,CF3, C1.4alkyl, ORf, S(O)kRf, CORf, CO2Rf, OH, NO2, N(Rf)2, CO(NRf)2, andCH2N(Rf)2; or methylenedioxy. Preferably, Rb and Rc are joined together to form a sixmembered aromatic carbocyclic or heterocyclic ring and W is -CH2-CH2-. 20 Altemately R2 is ( Y !

Os\XNR9 , wherein each R’ is H, R" is H or Ci-ôalkyl,RS is H or Cj.galkyl and s is 0,1 or 2 and, preferably, W is -CH2-CH2-.

Altemately, R2 is -9- 012189

wherein v is 0 and W is -CH2-CH2-.

With respect to formula (I), suitably R1 is is phenyl, benzyl, pyridyl, imidazolyl,oxazolyl or thiazolyl. Preferably, R1 is phenyl. Suitably, Y is O or CH2 and X is NH orCH2- Preferably, Y is O.

Représentative of the novel compounds of this invention are the compounds namedin Examples 1-43 hereinafter.

In cases wherein the compounds of this invention may hâve one or more chiralcenters, unless specified, this invention includes each unique nonracemic compound whichmay be synthesized and resolved by conventional techniques. According to the présentinvention, the (S) configuration of the formula (I) compounds is preferred.

In cases in which compounds hâve unsaturated carbon-carbon double bonds, boththe cis (Z) and trans (E) isomers are within the scope of this invention. The meaning of anysubstituent at any one occurrence is independent of its meaning, or any other substituent’smeaning, at any other occurrence.

Also included in this invention are prodrugs of the compounds of this invention.Prodrugs are considered to be any covalently bonded carriers which release the activeparent drug according to formula (I) in vivo. Thus, in another aspect of this invention arenovel prodrugs, which are also intermediates in the préparation of formula (la) compounds,

wherein:

Xis CR’R’, NR’, O or S; Y is CR’R’, NR’, O or S; A is H, halo, -ORS, -SRS, -CN, -NRgRk, -NO2, -CF3, -S(O)rCF3, -CO2RS, -CORS,-CONRS2 -Ci-6alkyl, -C0.6alkyl-Ar, -Co^alkyl-Het, -C0.6alkyl-C3_6cycloalkyl, -S(O)kRS,or CH2N(Rf)2; R1 is -C0.6alkyl-Het-, -C0_6alkyl-Ar, H, -CN or -S(O)kRS; R^ is - 10- 012189

jf NR" CR’2—W (?)u

(O)u •N\/(CR’À—W-

NR"—CR’— W

NR"—CR' — W- W is -(CHRg)a-U-(CHRg)b-; U is absent or CO, CRg2, C(=CRg2), S(O)k, O, NRg, CRgORg, CRg(ORk)CRg2,CRg2CRg(ORk), C(O)CRg2, CRg2C(O), CONR1, NR'CO, OC(O), C(O)O, C(S)O, OC(S),C(S)NRg, NRgC(S), S(O)2NRg, NRgS(O)2 N=N, NRgNRg, NRgCRg2, CRg2NRg, CRg2O,OCRg2, C =C , CRg=CRg, Ar or Het; G is NRe, S or O;

Rg is H, Ci.galkyl, Het-C0.galkyl, C3-7cycloalkyl-Co_6alkyl or Ar-C^galkyl;

Rk is Rg, -C(O)Rg, or -C(O)ORf; R* is is H, Cj.galkyl, Het-C^galkyl, C3-7cycloalkyl-Co^alkyl, Ar- C^galkyl, orCj.galkyl substituted by one to three groups chosen from halogen, CN, NRg2, ORg, SRg,CO2Rg, and CON(Rg)2;

Rf is H, Cj.galkyl or Ar-Co^alkyl;

Re is H, Cj^alkyl, Ar-Cg^alkyl, Het-CQ.^alkyl, C3-7cycloalkyl-Co.6alkyl, or(CH2)kCO2Rg·,

Rb and Rc are independently selected from H, Cj.galkyl, Ar-C^galkyl, Het-Cg.galkyl, or C3-6cycloalkyl-Co_6alkyl, halogen, CF3, ORf, S(O)kRf, CORf, NO2, N(Rf)2(CO(NRf)2, CH2N(Rf)2, or Rb and Rc are joined together to form a five or six memberedaromatic or non-aromatic carbocyclic or heterocyclic ring, optionally substituted by up tothree substituents chosen from halogen, CF3, Cj^alkyl, ORf, S(O)kRf, CORf, CO2Rf, OH,NO2, N(Rf)2j CO(NRf)2, and CH2N(Rf)2; or methylenedioxy; Q1, Q2, Q3 and Q4 are independently N or C-Ry, provided that no more than one ofQJ,Q2, Q3 and Q4 is N; R’ is H, Ci-6alkyl, Ar-Co-6alkyl or C3„6cycloalkyl-Co-6alkyl; R" is R’, -C(O)R’ or -C(O)OR’; -11 - 012189

Ry is H, halo, -ORg, -SRg, -CN, -NRgRk, -NO2, -CF3, CF3S(O)r-, -CO2Rg, -CORgor -CONRg2, or C].6alkyl optionally substituted by halo, -ORg, -SRg, -CN, -NRgR", -NO2, -CF3, R’S(O)r-, -CO2Rg, -CORg or -CONRg2; a is 0, 1 or 2;b is 0, 1 or 2;k is 0, 1 or 2;r is 0, 1 or 2;s is 0, 1 or 2;u is 0 or 1 ; andv is 0 or 1 ; or a pharmaceutically acceptable sait thereof.

In yet another aspect of this invention are novel intermediates of formula (III):

(III) wherein: X is CRR’, NR’, O or S;

Yis CRR’, NR’, O or S; A is H, halo, -ORS, -SRg, -CN, -NRgRk, -NO2, -CF3, -S(O)rCF3, -CO2Rg, -CORg,-CONRg2 -Ci^alkyl, -Cg^alkyl-Ar, -C0.galkyl-Het, -C0_6alkyl-C3-6cycloalkyl, -S(O)kRg,orCH2N(Rf)2; R1 is -Co-galkyl-Het-, -C0_6alkyl-Ar, H, -CN or -S(O)kRg; W is -(CHRg)a-U-(CHRg)b-; U is absent or CO, CRg2, C(=CRg2), S(O)k, O, NRg, CRgORg, CRg(ORk)CRg2,CRg2CRg(ORk), C(O)CRg2, CRg2C(O), CONR’, NR’CO, OC(O), C(O)O, C(S)O, OC(S),C(S)NRg, NRgC(S), S(O)2NRg, NRgS(O)2 N=N, NRgNRg, NRgCRg2, CRg2NRg, CRg2O,OCRg2, C =C , CRg=CRg, Ar or Het;

Rg is H, Cj.galkyl, Het-CQ_galkyl, C3-7cycloalkyl-Co_6alkyl or Ar-CQ^alkyl;

Rk is Rg, -C(O)Rg, or -C(O)ORf; R1 is is H, Cj.galkyl, Het-C().6alkyl, C3-7cycloalkyl-C0„6aIkyl, Ar- C0.6alkyl, orCj.6alkyl substituted by one to three groups chosen from halogen, CN, NRg2, ORg, SRg,CO2Rg, and CON(Rg)2;

Rf is H, Cj.galkyl or Ar-Co_6alkyl; - 12- 01 2 18 9 Q1, Q2, Q3 and Q4 are independently N or C-RY, provided that no more than one ofQ1, Q2, Q3 and Q4 is N; R’ is H, Ci-6alkyl, Ar-Co-6alkyl or C3-6cycloalkyl-Co.6alkyl; R" is R’, -C(O)R’ or -C(O)OR’; RY is H, halo, -ORS, -SRS, -CN, -NRgRk, -NO2, -CF3, CF3S(O)r-, -CO2Rg, -CORSor -CONRS2, or Ci_6alkyl optionally substituted by halo, -ORS, -SRS, -CN, -NRSR", -NO2,-CF3, R’S(O)r-, -CO2RS, -CORS or -CONRS2; a is 0,1 or 2; andb is 0,1 or 2; or a pharmaceutically acceptable sait thereof.

Abbreviations and symbols commonly used in the peptide and Chemical arts areused herein to describe the compounds of this invention. In general, the amino acidabbreviations follow the IUPAC-IUB Joint Commission on Biochemical Nomenclature asdescribed in Eur. J. Biochem., 158, 9 (1984). C^alkyl as applied herein means an optionally substituted alkyl group of 1 to 4carbon atoms, and includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl.Cj.galkyl additionally includes pentyl, n-pentyl, isopentyl, neopentyl and hexyl and thesimple aliphatic isomers thereof. C^alkyl and C^alkyl additionally indicates that noalkyl group need be présent (e.g., that a covalent bond is présent).

Any Cj.4alkyl or Cj.^ alkyl, C2_g alkenyl, C2.g alkynyl or Cj.g oxoalkyl may beoptionally substituted with the group Rx, which may be on any carbon atom that résulte in astable structure and is available by conventional synthetic techniques. Suitable groups forRx are C^alkyl, OR’, SR’, Cj^alkylsulfonyl, Cj^alkylsulfoxyl, -CN, N(R )2) CH2N(R )2,-NO2, -CF3, -CO2R’-CON(R’)2, -COR’, -SO2N(R’)2, -NR’C(O)R’, F, Cl, Br, I, orCF3S(O)r-,wherein r is 0,1 or 2.

Halogen or halo means F, Cl, Br, and I.

Ar, or aryl, as applied herein, means phenyl or naphthyl, or phenyl or naphthylsubstituted by one to three substituents, such as those defined above for alkyl, especiallyC^alkyl, Cj^alkoxy, Cj^alkthio, CF3, NH2, OH, F, Cl, Br or I.

Het, or heterocycle, indicates an optionally substituted five or six memberedmonocyclic ring, or a nine or ten-membered bicyclic ring containing one to threeheteroatoms chosen from the group of nitrogen, oxygen and sulfur, which are stable andavailable by conventional Chemical synthesis. Illustrative heterocycles are benzofuran,benzimidazole, benzopyran, benzothiophene, benzothiazole, furan, imidazole, indoline,morpholine, piperidine, piperazine, pyrrole, pyrrolidine, tetrahydropyridine, pyridine,thiazole, oxazole, thiophene, quinoline, isoquinoline, and tetra- and perhydro- quinolineand isoquinoline. Any accessible combination of up to three substituents on the Het ring, - 13 - 012189 such as those defined above for alkyl that are available by Chemical synthesis and are stableare within the scope of this invention. C3-7cycloalkyl refers to an optionally substituted carbocyclic System of three toseven carbon atoms, which may contain up to two unsaturated carbon-carbon bonds.

Typical of C3-7cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl,cyclohexyl, cyclohexenyl and cycloheptyl. Any combination of up to three substituents,such as those defined above for alkyl, on the cycloalkyl ring that is available byconventional Chemical synthesis and is stable, is within the scope of this invention.

When Rb and Rc are joined together to form a five- or six-membered aromatic ornon-aromatic carbocyclic or heterocyclic ring fused to the ring to which Rb and Rc areattached, the ring formed will generally be a five- or six-membered heterocycle selectedfrom those listed above for Het, or will be a phenyl, cyclohexyl or cyclopentyl ring.

Preferably R^ and Rc will be -D1=D2-D3=D4 wherein DI - D4 are independently CH, N orC-Rx with the proviso that no more than two of DI - D4 are N. Most preferably, when Rband Rc are joined together they form the group -CH=CH-CH=CH-.

Certain radical groups are abbreviated herein. t-Bu refers to the tertiary butylradical, Boc refers to the t-butyloxycarbonyl radical, Fmoc refers to thefluorenylmethoxycarbonyî radical, Ph refers to the phenyl radical, Cbz refers to thebenzyloxycarbonyl radical, Bn refers to the benzyl radical, Me refers to methyl, Et refers toethyl, Ac refers to acetyl, Alk refers to Cj^alkyl, Nph refers to 1- or 2-naphthyl and cHexrefers to cyclohexyl. Tet refers to 5-tetrazoIyl.

Certain reagents are abbreviated herein. DCC refers to dicyclohexylcarbodiimide,DMAP refers to dimethylaminopyridine, DIEA refers to diisopropylethyl amine, EDCrefers to l-(3-dimethylaminopropyl)-3-ethylcarbodiimide, hydrochloride. HOBt refers to1-hydroxybenzotriazole, THF refers to tetrahydrofuran, DIEA refers to diisopropylethylamine, DEAD refers to diethyl azodicarboxylate, PPI13 refers to triphenylphosphine, DIAD refers to diisopropyl azodicarboxylate, DME refers to dimethoxyethane, DMF refers to dimethylformamide, NBS refers to N-bromosuccinimide,Pd/C refers to a palladium on carbon catalyst, PPA refers to polyphosphoric acid, DPPArefers to diphenylphosphoryl azide, BOP refers to benzotriazol-l-yloxy-tris(dimethyl-amino)phosphonium hexafluorophosphate, HF refers to hydrofluoric acid, TEA refers totriethylamine, TFA refers to trifluoroacetic acid, PCC refers to pyridinium chlorochromate.

The compounds of formula (la) are generally prepared by reacting a compound offormula (IV) with a compound of formula (V): - 14- 012189 HO.

A

R2-L1 (V) wherein Rl, R2, A and X are as defined in formula (la), with any reactivefunctional groups protected, and iJ is OH or halo; and thereafter removing any protecting groups, and optionally forming apharmaceutically acceptable sait.

Suitably, certain compounds of formula (la) are prepared by reacting a compoundof formula (IV), as defined hereinbefore, with a compound of formula (VI): O-

^N+ ^NR“— CR’S

-W-OH

Q (VI)

,.Q wherein R’, R", W, Qb Q2, Q3 and Q4 are as defined in formula (la), with anyreactive functional groups protected; and thereafter removing any protecting groups, and optionally forming apharmaceutically acceptable sait.

Preferably, for formula (VI) compounds, Q1, Q2, Q3 and Q4 are CH, W is-(CH2)l-4-, R’ is H and R" is H or Cj^alkyl. Suitably, the reaction between a compoundof formual (IV) with a compound of formula (VI) is carried out in the presence of diethylazodicarboxylate and triphenylphosphine in an aprotic solvent.

Additionally, certain compounds of formula (la) are prepared by reacting acompound of formula (IV), as defined hereinbefore, with a compound of formula (VU): O-

wherein R’, R", W, Q1, Q2, Q3 and v are as defined in formula (la), with any reactive functional groups protected; - 15- 012189 and thereafter removing any protecting groups, and optionally forming apharmaceutically acceptable sait.

Preferably, for formula (VII) compounds, Q1, Q2 and Q3 are CH, W is -CH2-CH2-, R’ is H and R" is H or Cj.galkyl. Suitably, the reaction between a compound of formula 5 (IV) with a compound of formula (VII) is carried out in the presence of diethylazodicarboxylate and triphenylphosphine in an aprotic solvent.

Compounds of this invention, including formula (I) and (la) compounds, areprepared by the general methods described in Schemes I-XVI.

The préparation of compounds wherein Y is O and X is CH2 is described in10 Schemel. -16-

Scheme I 012189

7 (a) EtOAc/LiN(TMS)2, THF; (b) Et3SiH, BF3 · OEt2, CH2C12; (c) H2> 10% Pd/C, EtOH;5 (d) EtSH, A1C13, CH2C12; (e) 2-[(3-hydroxy-l-propyl)amino]pyridine-N-oxide, DIAD, (Ph)3P, DMF; (f) cyclohexene, 10% Pd/C, 2-propanol; (g) 1.0 N LiOH, THF, H2O, thenacidification. - 17- 012189

An appropriately substituted deoxybenzoin dérivative, such as 2-(4-methoxyphenyl)-l-phenylethanone (Chem. Ber. 1958, 97, 755-759), is reacted in an aldol-type reaction with the enolate of ethyl acetate, which can be generated from ethyl acetate onexposure to an appropriate amide base, for instance lithium diisopropylamide (LDA) orlithium bis(trimethylsilyl)amide (LiN(TMS)2), to afford 1-2. Frequently, THF is thesolvent of choice for an aldol reaction, although THF in the presence of various additives,for instance HMPA or TMEDA, is often used. Reaction of 1-2 with triethylsilane (Et3SiH)in the presence of boron trifluoride etherate (BF3 · OEt2) according to the general protocolof Orphanopoulos and Smonu (Synth. Commun. 1988, 833) for the réduction of tertiarybenzylic alcohols affords 1-3, together with the olefinic product derived from β-eliminationof the alcohol. The olefinic product can be conveniently converted to 1-3 by hydrogénationover a palladium catalyst, such as palladium métal on activated carbon (Pd/C), in anappropriate inert solvent, for instance methanol, éthanol, or ethyl acetate. Removal of themethyl ether of 1-3 to give 1-4 can be accomplished by reaction with ethanethiol (EtSH) inthe presence of a Lewis acid catalyst, preferably anhydrous aluminum trichloride (AICI3),in an inert solvent, for instance CH2CI2· Other useful methods for removal of a methylether are described in Greene, "Protective Groupe in Organic Synthesis" (published byWiley-Interscience). Compound 1-4 is reacted with 2-[(3-hydroxy-l- propyl)amino]pyridine-N-oxide in a Mitsunobu-type coupling reaction (Organic Reactions1992,42, 335-656; Synthesis 1981, 1-28) to afford 1-5. The reaction is mediated by thecomplex formed between an azodicarboxylate diester, such as diethyl azodicarboxylate ordiisopropyl azodicarboxylate, and triphenylphosphine, and is conducted in an aproticsolvent, for instance THF, CH2CI2, or DMF. The pyridine-N-oxide moiety of 1-5 isreduced to the corresponding pyridine 1-6 under transfer hydrogénation conditions using apalladium catalyst, preferably palladium métal on activated carbon, in an inert solvent, forinstance methanol, éthanol, or 2-propanol. Cyclohexene, 1,4-cyclohexadiene, formic acid,and salts of formic acid, such as potassium formate or ammonium formate, are commonlyused as the hydrogen transfer reagent in this type of reaction. The ethyl ester of 1-6 ishydrolyzed using aqueous base, for example, LiOH in aqueous THF or NaOH in aqueousmethanol or éthanol, and the intermediate carboxylate sait is acidified with a suitable acid,for instance TFA or HCl, to afford the carboxylic acid 1-7. Altematively, the intermediatecarboxylate sait can be isolated, if desired, or a carboxylate sait of the free carboxylic acidcan be prepared by methods well-known to those of skill in the art.

An alternative method for preraing formula (I) compounds is described in Scheme II.

Scheme II -18- 012189

(a) NaH, 2-[N-(3-methanesulfonyloxy-1 -propyl)-N-(ierr-butoxycarbonyI)amino]pyridine-N-oxide, DMSO; (b) TFA, CH2CI2; (c) see Scheme I. 5

Compound II-l, prepared as described in Scheme I, is reacted with a base, suitablyan alkali métal hydride such as sodium hydride or potassium hydride, in a polar, aproticsolvent, generally THF, DMF, DMSO, or mixtures thereof, to afford the correspondingalkali métal phenoxide. Altematively, an alkali métal amide, for instance LDA, or the

10 lithium, sodium, or potassium sait of hexamethyldisilazane, can be used for deprotonation.The intermediate phenoxide is generally not isolated, but is reacted in situ with anappropriate electrophile, for instance 2-[N-(3-methanesulfonyloxy-l-propyl)-N-(rerr-butoxycarbonyl)amino]pyridine-N-oxide, to afford the coupled product II-2. The tert-butoxycarbonyl protecting group in II-2 is removed under acidic conditions, such as 4 M 15 HCl in 1,4-dioxane or TFA in CH2CI2, to afford Π-3. Conditions for removal of the tert- butoxycarbonyl protecting group are well-known to those of skill in the art, and several useful methods are described in standard reference volumes such as Greene "Protective

Groups in Organic Synthesis". II-3 is subsequently converted to II-4 following the protocol outlined in Scheme I. 20

Scheme III 012189

5 (a) Tf2O,2,6-lutidine, ΟΗ2α2; (b) CO, KOAc, Pd(OAc)2, dppf, DMSO; (c) 2-[(2-amino- 5 l-ethyl)amino]pyridine dihydrochloride, EDC, HOBt · H2O, Et3N, CH3CN; (d) LiOH,THF, H2O, then acidification.

Phénol III-l, prepared as described in Scheme I, is converted to itstrifluoromethanesulfonate ester III-2 by reaction with trifluoromethanesulfonic anhydride 10 (Tf2O) in the presence of a suitable non-nucleophilic amine base, such as 2,6-lutidine, in aninert solvent, generally CH2C12. ΠΙ-2 reacts with carbon monoxide (CO) in the presenceof potassium acetate, l,l’-bis(diphenylphosphino)ferrocene (dppf), and a palladiumcatalyst, for instance palladium acetate (Pd(OAc)2), in a suitable solvent, preferablyDMSO, according to the general method described by Cacchi and Lupi (Tet. Lett. 1992,33, 15 3939) for the carboxylation of aryl trifluoromethanesulfonates. The carboxylic acid of the resulting compound (III-3) is converted to an activated form using, for example, EDC andHOBt, or SOCI2, and the activated form is subsequently reacted with an appropriate amine, -20- 012189 for instance 2-[(2-amino-l-ethyl)amino)pyridine dihydrochloride, in a suitable solvent suchas DMF, CH2CI2, or CH3CN, to afford ΙΠ-4. Depending on whether acid neutralization isrequired, an added base, such as triethylamine (ΕίβΝ), diisopropylethylamine ((i-Pr)2NEt),or pyridine, may be used. Many additional methods for converting a carboxylic acid to an 5 amide are known, and can be found in standard reference books, such as "Compendium ofOrganic Synthetic Methods", Vol. I - VI (published by Wiley-Interscience), or Bodansky, "The Practice of Peptide Synthesis" (published by Springer-Verlag). The ethyl ester of ΪΙΙ-4 is hydrolyzed using aqueous base, for example, LiOH in aqueous THF or NaOH inaqueous methanol or éthanol, and the intermediate carboxylate sait is acidified with a 10 suitable acid, for instance TFA or HCI, to afford the carboxylic acid III-5. Altematively,the intermediate carboxylate sait can be isolated, if desired, or a carboxylate sait of the freecarboxylic acid can be prepared by methods well-known to those of skill in the art. -21 - 012189

Scheme IV

(a) CBr4, Ph3P, THF; (b) 2-(tert-butoxyamino)pyridine, NaH, DMF; (c) H2, Pd/C, EtOAc; 5 (d) PhCHO, MgSO4, CH2C12; (e) BrZnCH2CO2t-Bu, BF3 · OEt2, THF; (f) TFA, CH2C12.

The commercially available alcohol IV-1 is converted to an activated species, forexample the corresponding bromide IV-2, using carbon tetrabromide andtriphenylphosphine in an inert solvent, preferably THF. Many other conditions are 10 available for converting an alcohol to an activated species, such as the corresponding bromide, chloride, iodide, mesylate, or triflate, and are well-known to those of skill in theart. The bromide IV-2 is alkylated with a suitable 2-aminopyridine dérivative, for instance2-(tert-butoxyamino)pyridine, to afford the alkylated dérivative IV-3. The reaction ismediated by an appropriate base, such as an alkali métal halide, and is conducted in a polar, 15 aprotic solvent, generally THF, DMF, DMSO, or mixtures thereof. Réduction of the nitro -22- 012i89 group of IV-3 can be accomplished by a variety of methods well-known to those of skill inthe art, Preferably, the réduction is accomplished by hydrogénation in the presence of apalladium catalyst, for instance palladium on activated charcoal, in a suitable solvent, suchas EtOAc, MeOH, EtOH, i-PrOH, or mixtures thereof. The resulting aniline IV-4 reacts 5 with a suitable aldéhyde, such as benzaldehyde, in an inert solvent such as CH2CI2, benzene, or toluene, to afford the corresponding aldimine IV-5. If desired, a dehydratingagent, such as MgSO4, can be used to remove the H2O formed during the reaction. Thealdimine is subsequently reacted in an aldol-type reaction with an appropriate enolate of anacetic acid ester to afford IV-6. The reaction is generally mediated by a Lewis acid, for 10 instance BF3 · OEt2, and is usually conducted in an ethereal solvent, such as THF or DME.As described in Scheme I, the enolate can be generated from ethyl acetate on exposure to anappropriate amide base, for instance lithium diisopropylamide (LDA) or lithiumbis(trimethylsilyl)amide (LiN(TMS)2)· Altematively, the enolate can be generated fromtert-butyl bromoacetate on exposure to zinc métal, according to the procedure of Orsoni and 15 coworkers (Tetrahedron 1984,40, 2781 - 2787). The tert-butoxycarbonyl group and thetert-butyl ester of IV-6 are removed simultaneously under acidic conditions, such as 4 MHCl in 1,4-dioxane or TFA in CH2CI2, to afford IV-7. Conditions for deprotection of tert-butyl carbamates and tert-butyl esters are well-known to those of skill in the art, and severaluseful methods are described in standard reference volumes such as Greene "Protective 20 Groupe in Organic Synthesis" (published by Wiley-Interscience). -23- 012189

Scheme V

5 (a) BnCl, K2CO3, acetone; (b) L1AIH4, THF; (c) Swem oxidation; (d) Ph3p=CHCO2CH3, THF; (e) H2, Pd/C, MeOH; (f) 6-(methylamino)-2-pyridylethanol, DIAD, (Ph)3P, THF; (g)LiOH, THF, H2O, then acidification.

The phénol group of commercially available methyl 4-hydroxyphenyIacetate (V-l) 10 is protected with a suitable protecting group, for instance a methyl ether, a benzyl ether, ora triisopropylsilyl ether. Protection of phénols is well-known to those of skill in the art, andreprésentative protecting groupe are described in standard reference volumes such asGreene "Protective Groups in Organic Synthesis" (published by Wiley-Interscience).. Theester group of V-2 is reduced to the corresponding primary alcohol using lithium aluminum 15 hydride. Many other methods exist for the réduction of carboxylic acids and esters toalcohols, and are described in standard reference volumes, such as "Compendium ofOrganic Synthetic Methods" (published by Wiley-Interscience). The alcohol in V-3 isoxidized to the corresponding aldéhyde using the well-know Swem conditions (J. Org. 01218 Çhem* 1978,43,2480). Many other methods exist for the oxidation of alcohols to *aldéhydes, and are described in standard référencé volumes, such as "Compendium ofOrganic Synthetic Methods" (published by Wiley-Interscience). Aldéhyde V-4 isconverted to the α,β-unsaturated ester V-5 through the well-known Wittig reaction.Optimally, the reaction is conducted using (carbomethoxymethylene)triphenylphosphoranein a polar, aprotic solvent, such as DMSO, THF, or mixtures thereof. Réduction of theolefin group of V-5 is optimally accomplished by hydrogénation in the presence of apalladium catalyst, for instance palladium on activated charcoal, in a suitable solvent, suchas EtOAc, MeOH, EtOH, i-PrOH, or mixtures thereof. If a benzyl ether is used to protectthe phénol group, it is simultaneously cleaved to liberate the free phénol. If anotherprotecting group is used, suitable conditions are employed for its removal. For instance, ifa methyl ether is used, it can be cleaved with ethanethiol (EtSH) and aluminum trichloride(AICI3) as described in Scheme I, or with boron tribromide (BBrç), in an inert solvent,preferably CH2CI2. Altematively, if a triisopropylsilyl group is used, it can be cleavedusing, for example, tetrabutylammonium fluoride, in a neutral solvent such as THF. Otheruseful methods for removal of phenolic protecting groups are described in Greene,"Protective Groups in Organic Synthesis" (published by Wiley-Interscience). The resultingphénol V-6 is reacted with 6-(methylamino)-2-pyridylethanol in a Mitsunobu-type couplingreaction (Organic Reactions 1992,42, 335-656; Synthesis 1981, 1-28) to afford V-7. Thereaction is mediated by the complex formed between an azodicarboxylate diester, such asdiethyl azodicarboxylate or diisopropyl azodicarboxylate, and triphenylphosphine, and isconducted in an aprotic solvent, for instance THF, CH2CI2, or DMF. V-7 is subsequentlyconverted to V-8 according to the protocol described in Scheme III. -25- 012189

Scheme VI

5 (a) (vinyl)MgBr, CuBr · DMS, THF; (b) TBAF, THF; (c) 6-(methylamino)-2- pyridylethanol, DIAD, (Ph)3P, DMF; (d) LiOH, THF, H2O, then acidification.

The α,β-unsaturated ester VI-1, prepared as described in Scheme V, is reacted witha cuprate reagent to effect a conjugate addition reaction. For example, reaction of VI-1 10 with the cuprate reagent derived from vinylmagnesium bromide and copper (I) bromide-dimethylsulfide complex, in an aprotic solvent such as Et2O or THF, gives the conjugateaddition product VI-2. Many procedures hâve been reported for the formation andconjugate addition reactions of a wide array of cuprate and organocopper reagents, andseveral excellent reviews hâve been published (for example, see Posner, Organic Reactions 15 1972,19, 1 - 113; Lipshutz and Sengupta, Organic Reactions 1992,41,135 - 631). The triisopropylsilyl group of VI-2 is removed as described in Scheme V, and the resultingphénol VI-3 is converted to VI-4 according the methods described in Scheme V. -26-

Scheme VII 012189

5 (a) PhOH, Cu, K2CO3; (b) sulfur, morpholine; (c) KOH, H2O, i-PrOH; (d) L1AIH4, THF; (e) Swem oxidation; (f) Ph3P=CHCO2CH3, THF; (g) H2, Pd/C, MeOH; (h) BBr3,CH2C12; (i) 6-(methylamino)-2-pyridylethanol, DEAD, (Ph)3P, CH2C12; (j) 1.0 N NaOH,MeOH, then acidification. 10 Commercially available 2-fluoro-4-methoxyacetophenone (VII-1) reacts with an alcohol, for example phénol, in the presence of copper métal and a suitable base, forinstance K2CO3, to afford the diaryl ether VII-2. On treatment with sulfur and anappropriate primary or secondary amine, preferably morpholine, according to the generalmethod of Harris (J. Med. Chem. 1982, 25, 855), VII-2 is converted to VII-3 in a classical 15 Willgerodt-Kindler reaction. The thioamide thus obtained is hydrolyzed to the corresponding carboxylic acid VII-4 by reaction with an alkali métal hydroxide, suitably -27- 012189 KOH, in an aqueous alcoholic-solvent, such as aqueous MeOH, EtOH, or i-PrOH. VII-4 issubsequently converted to VII-9 according to the general protocol described in Scheme V.

Scheme VIII

(a) LiN(TMS)2, THF, then 4-methoxybenzyl chloride; (b) 1.0 N NaOH, MeOH, thenacidification; (c) SOC12; (d) CH2N2, Et2O; (e) AgOBz, MeOH; (f) BBr3, CH2C12; (g) 6-(N-Boc-N-methylamino)-2-pyridylethanol, DEAD, (PIO3P, CH2C12; (h) HCl/dioxane; (i)1.0 N NaOH, MeOH, then acidification. 10 -28- 012189 2-Thiophënèacetic acid methyl ester (VHI-1) is deprotonated with a suitable base,generally an alkali métal amide such as LDA or lithium bis(trimethylsilyl)amide, andwithout isolation the intermediate ester enolate is reacted with an appropriate benzyl halide,for instance 4-methoxybenzyl chloride, to afford the alkylation product VIII-2. Generally, a 5 polar aprotic solvent such as THF, or THF in the presence of various additives, for instance HMPA or TMEDA, is preferred for this reaction. The methyl ester of VIII-2 is hydrolyzedusing aqueous base, for example, LiOH in aqueous THF or NaOH in aqueous MeOH orEtOH, and the intermediate carboxylate sait is acidified with a suitable acid, for instanceTFA or HCl, to afford the carboxylic acid VIII-3. This is converted to an activated form of 10 the carboxylic acid using, for example, SOCI2, and the activated form is subsequentlyreacted with diazomethane in a suitable solvent, such as EtjO or a mixture of Et2O andCH2CI2, to afford the diazoketone VIII-4. On treatment with a suitable silver sait, forinstance silver benzoate or silver triflate, in an alcoholic solvent, generally MeOH or EtOH,VIII-4 undergoes a classical Amdt-Eistert reaction to afford the ester VIII-5. Deprotection 15 of the methyl ether according to the general conditions described in Scheme V gives VIII-6, which is converted to VHI-7 by reaction with 6-(N-Boc-N-methylamino)-2-pyridylethanol'in a Mitsunobu reaction according to the conditions described in Scheme V.

The tert-butoxycarbonyl group of VIII-7 is removed under acidic conditions, such as 4 MHCl in 1,4-dioxane or TFA in CH2CI2, to afford VIII-8. Conditions for deprotection of 20 tert-butyl carbamates are well-known to those of skill in the art, and several useful methodsare described in standard référencé volumes such as Greene "Protective Groups in OrganicSynthesis". Saponification of the according to the general methods described in Scheme IIIaffords VIII-9. -29- 01 2189

Scheme IX

(a) 4-methoxybenzylmagnesium chloride, Cul, TMEDA, TMSC1, THF; (b) BBrç, CH2CI2;

5 (c) 6-(N-Boc-N-methylamino)-2-pyridylethanol, DIAD, (Ph^P, CH2CI2; (d) 4 N HCl/dioxane; (e)1.0 N NaOH, EtOH, then acidification. A suitable dérivative of acrylic acid, for instance ethyl 4-bromocinnamate (IX-1),is converted to dérivative IX-2 by reaction with selected benzyl cuprate reagents according 10 to the general method of Van Heerden (Tetrahedron 1996,52,12313). As described in

Scheme VI, many additional procedures hâve been reported for the formation and conjugateaddition reactions of a wide array of cuprate and organocopper reagents. The additionproduct IX-2 is then converted to IX-5 by the general protocol described in Scheme VIII. -30- 012189

Scheme X <

(a) methyl 3-(benzyloxycarbonyl)-3-butenoate, Pd(OAc)2, P(tol)3, (i-Pr)2NEt,propionitrile; (b) H2,10% Pd/C, MeOH, EtOAc; (c) CDI, (CH3O)2CHCH2NH2, CH2Cl2;(d) 6 N HCl, THF; (e) I2, PPh3, Et3N, CH2Cl2; (f) BBr3, CH2C12; (g) 6-(methylamino)-2-pyridylethanol, DIAD, (Ph)3P, THF; (h) LiOH, THF, H2O, then acidification. A suitable haloaromatic dérivative, for instance 4-bromoanisole (X-l), reacts with 10 methyl 3-(benzyloxycarbonyl)-3-butenoate in a Heck-type reaction (see Heck, Org.Reactions 1982,27, 345) to afford X-2. The reaction is mediated by a palladium(O)species, and generally is conducted in an inert solvent, such as CH3CN, propionitrile, ortoluene, in the presence of an appropriate acid scavenger, such as triethylamine (Et3N) ordiisopropylethylamine ((i-Pr^NEt). Typical sources of the palladium(O) species include 15 palladium (II) acetate (Pd(OAc)2) and palladium(II) chloride (PdCl2), and oftentimesphosphine ligands, for instance triphenylphosphine (PPh3) or tri-ortho-tolylphosphine(P(tol)3), are included. The α,β-unsaturated ester X-2 is reduced to the saturatedcompound X-3 by reaction with hydrogen gas in the presence of a suitable catalyst,preferably palladium métal on activated carbon (Pd/C), in an inert solvent, generally 20 MeOH, EtOH, EtOAc, or mixtures thereof. The benzyl ester in X-2 is cleaved -31 - 012189 simultaneously under these conditions to liberate the corresponding carboxylic acid. Thecarboxylic acid of X-3 is converted to an activated form using, for example, EDC andHOBt, SOCI2, or Ι,Γ-carbonyldiimidazole (CDI), and the activated form is subsequentlyreacted with an appropriate amine, for instance aminoacetaldehyde dimethyl acetal, in a 5 suitable solvent, such as CH2CI2, to afford X-4. Depending on whether acid neutralizationis required, an added base, such as triethylamine (Et3N), diisopropylethylamine ((i-Pr)2NEt), or pyridine, may be used. Many additional methods for converting a carboxylicacid to an amide are known, and can be found in standard reference books, such as"Compendium of Organic Synthetic Methods", Vol. I - VI (published by Wiley- 10 Interscience), or Bodansky, "The Practice of Peptide Synthesis" (published by Springer-Verlag). The dimethyl acetal of X-4 is cleaved to the corresponding aldéhyde (X-5) underacidic conditions, preferably with hydrochloric acid in THF or dioxane. Other methods forconverting a dimethyl acetal to an aldéhyde are described in standard reference volumes,such as Greene, "Protective Groups in Organic Synthesis" (published by Wiley- 15 Interscience). The amidoaldehyde X-5 is cyclized to the oxazole X-6 according to themethodology of Rovnyak (J. Med. Chem. 1997,40, 24-34). X-6 is then converted to X-7according to the protocol described in Scheme V. -32- 012189

Scheme XI

(a) BnCl, K2CO3, acetone; (b) (CH3O)NHCH3 · HCl, AICI3, toluene; (c) 2-bromopyridine,tert-BuLi, THF; (d) (EtO)2P(O)CH2CO2Et, NaH, THF; (e) H2, Pd/C, EtOH; (f) 6-(methylamino)-2-pyridylethanol, DIAD, (Ph)3P, THF; (g) LiOH, THF, Η2Ο, thenacidification. 10 The phénol group of commercially available methyl 4-hydroxyphenylacetate (XI- 1) is protected as its benzyl ether as described in Scheme V. The resulting compound (XI- 2) reacts with Ν,Ο-dimethylhydroxylamine hydrochloride in the presence of AICI3 in aninert solvent, preferably toluene, according to the general method of Weinreb (Synth.Commun. 1982,12, 989), to afford XI-3. This compound reacts with suitable Grignard or 15 organolithium reagents to afford ketones according to the general procedure of Weinreb(Tet. Lett. 1981,22, 3815). For example, 2-lithiopyridine, prepared from 2-bromopyridineand tert-butyllithium, reacts with XI-3 in an ethereal solvent, such as THF or DME, toafford the ketone dérivative XI-4. This ketone reacts in a Wittig-type reaction with triethy 1phosphonoacetate in the presence of a suitable base, for instance LiN(TMS)2 or NaH, in a -33- 012189 polar, aprotic solvent, preferably THF, to afford the α,β-unsaturated ester XI-5. As described in Scheme V, hydrogénation of XI-5 reduces the olefin and simultaneouslyremoves the benzyl ether to afford XI-6. This compound is then converted to XI-7 by theprotocol described in Scheme V.

Scheme XII

(a) NaH, 4-methoxybenzyl chloride, DMF; (b) BBrç, CH2CI2; (c) 6-(N-Boc-N- 10 methylamino)-2-pyridylethanol, DIAD, (Ph^P, CH2CI2; (d) 4 N HCl/dioxane; (e) 1.0 NNaOH, EtOH, then acidification. A suitably N-functionalized amino acid dérivative, for instance N-phenylglycine(XII-1), is reacted with an appropriately functionalized benzyl halide, for example 4-

15 methoxybenzyl chloride, to afford XII-2. The reaction is mediated by a base, such as NaH or LiN(TMS)2, and is conducted in a polar, aprotic solvent, generally THF, DMF, or mixtures thereof. The product XII-2 is subsequently converted to XII-5 according the protocol described in Scheme VIII. -34-

012189

Scheme XIII

5 (a) glycine methyl ester hydrochloride, NaBH3CN, 3Â sieves, MeOH; (b) 6-(N-Boc-N- methylamino)-2-pyridylethanol, DIAD, (Ph)3P, CH2CI2; (c) 4 N HCVdioxane; (d)1.0 NNaOH, MeOH, THF, then acidification. A suitably functionalized aromatic aldéhyde such as 4-hydroxy-2-10 methoxybenzaldehyde (XIII-1), is reacted with an amino acid dérivative, for instance glycine methyl ester hydrochloride, under reductive amination conditions, to afford XIII-2.Reductive amination involves the reaction of an aldéhyde or ketone with an amine in thepresence of a suitable reducing agent, generally sodium cyanoborohydride (NaB^CN) orsodium triacetoxyborohydride (NaB(OAc)3H), oftentimes in the presence of an acid 15 catalyst, generally acetic acid or hydrochloric acid. The reaction proceeds through anintermediate imine, which reacts in situ with the reducing agent to afford the amine.Altematively, the imine can be prepared as a discreet entity, and reduced in a subséquentstep. Typical solvents for this reaction include CH2CI2, DMF, or an alcohol such as MeOHor EtOH. A dehydrating reagent, such as molecular sieves, MgSO^ or trimethyl 20 orthoformate, can be used to react with the water liberated during the course of the reaction.The product XIII-2 is subsequently converted to XIII-4 according the protocol described inScheme VIII. -35- 01218g P50757

Scheme XIV

5 (a) Triisopropylsiîyl chloride, imidazole, DMF; (b) methyl 3-(benzyloxycarbonyl)-3- butenoate, Pd(OAc)2, P(tol)3, (i-Pr)2NEt, propionitrile; (c) H2, 10% Pd/C, i-PrOH, EtOAc; -36- 012189 (d) serine benzyl ester, EDC, HOBt · H2O, EtjN, DMF; (e) Burgess reagent, THF; (f) C^CBr, DBU, CH2CI2; (g) TBAF, THF; (h) 6-(methylamino)-2-pyridylethanol, DIAD, (Ph)3P, THF; (i) LiOH, THF, H2O, then acidification. 5 A halophenol dérivative, for instance 4-bromophenol (XIV-1), is converted to a suitably protected dérivative, for instance 4-bromo-l-(triisopropylsilyloxy)benzene (XIV-2). The protecting group for the phénol must be compatible with subséquent chemistry, andalso must be able to be removed selectively when desired. Methods for the protection ofphénols are described in standard reference volumes, such as Greene, "Protective Groups in 10 Organic Synthesis" (published by Wiley-Interscience). XIV-2 is converted to XIV-4 andsubsequently to XIV-5 according to the general methods described in Scheme X. XIV-5 isthen converted to the oxazole dérivative XIV-7. Several methods are known for theconversion of amidoalcohols to oxazoles (Meyers, Tetrahedron 1994,50, 2297-2360; Wipf, J. Org. Chem. 1993,58,3604-3606). For example, the amidoalcohol XIV-5 can be 15 converted first to the oxazoline XIV-6. This transformation is generally accomplishedunder dehydrating conditions, such as reaction with Burgess reagent in THF. OxazolineXIV-6 is then oxidized to oxazole XIV-7 using, for instance, bromtrichloromethane andDBU in CH2CI2 (Williams, Tetrahedron Letters 1997,38, 331-334) or CuBrç and DBU inan appropriate solvent, such as EtOAc/CHCl3 or CH2CI2 (Barrish, J. Org. Chem. 1993,58, 20 4494-4496). Removal of the silyl protecting group affords phénol XFV-8, which is converted to XIV-10 as described in Scheme V. -37-

Scheme XV 012189

5 (a) H2,10% Pd/C, EtOH; (d) Me2NH · HCl, EDC, HOBt · H2O, Et3N, DMF; (c) LiOH, THF, H2O, then acidification.

Compound XV-1, prepared as described in Scheme XIV, is converted to thecarboxylic acid dérivative XV-2 by hydrogénation in the presence of a suitable catalyst, 10 preferably palladium métal on activated carbon (Pd/C), in an inert solvent, generally

MeOH, EtOH, EtOAc, or mixtures thereof. XV-2 is converted to the amide dérivative XV- 3 according to the general methods for formation of amides from carboxylic acids described in Scheme X. Saponification as described in Scheme V gives XV-4. -38- 012189

\ 'W Scheme XVI

(a) (COC1)2, DMF, CH2CI2; (b) (ΡΙίβΡ^ΟιΒΗψ (Ph)3P, acetone; (c) dimethyl-l-diazo-2-oxopropylphosphonate, K2CO3, MeOH; BBrç, CH2CI2; (d) 6-(N-Boc-N-methylamino)-2-pyridylethanol, DEAD, (Ph)3P, CH2CI2; (d) 4 N HCl/dioxane; (e)1.0 N NaOH, MeOH,then acidification.

Compound XVI-1, prepared as described in Scheme X, is converted to aldéhydedérivative XVI-2, preferably by the method of Fleet and Harding (Tet. Lett. 1979,11, 975-978). This method involves initial conversion of the carboxylic acid moiety of XVI-1 tothe corresponding acid chloride under standard conditions well-known to those of skill inthe art, followed by réduction to the aldéhyde using (Pl^P^CuBH^ Other methods areknown for the sélective conversion of a carboxylic acid to an aldéhyde in the presence of acarboxylic ester, and can be found in standard reference volumes, such as Compendium ofOrganic Synthetic Methods (published by Wiley-Interscience). The aldéhyde XVI-2 issubsequently transformed into the acetylene dérivative XVI-3 by the procedure of Muller,et al. (Syn. Lett. 1996, 521-522). Thus, XVI-2 is reacted with dimethyl-l-diazo-2-oxopropylphosphonate in the presence of a suitable base, generally K2CO3, in anappropriate solvent, such as methanol. Additional methods for the conversion of analdéhyde to an acetylene are known, and can be found in standard reference volumes, suchas Compendium of Organic Synthetic Methods (published by Wiley-Interscience). Theproduct XVI-3 is subsequently converted to XVI-S according the general protocoldescribed in Scheme VIII. -39- 012189

Amide coupling reagents as used herein dénoté reagents which may be used toform peptide bonds. Typical coupling methods employ carbodiimides, activatedanhydrides and esters and acyl halides. Reagents such as EDC, DCC, DPPA, BOP reagent, HOBt, N-hydroxysuccinimide and oxalyl chloride are typical.

Coupling methods to form peptide bonds are generally well known to the art. Themethods of peptide synthesis generally set forth by Bodansky et al., THE PRACTICE OFPEPTIDE SYNTHESIS, Springer-Verlag, Berlin, 1984, Ali et al. in J. Med. Chem., 29, 984(1986) and J. Med. Chem., 30, 2291 (1987) are generally illustrative of the technique andare incorporated herein by reference.

Typically, the amine or aniline is coupled via its free amino group to an appropriatecarboxylic acid substrate using a suitable carbodiimide coupling agent, such as N,N’dicyclohexyl carbodiimide (DCC), optionally in the presence of catalysts such as 1-hydroxybenzotriazole (HOBt) and dimethylamino pyridine (DMAP). Other methods, suchas the formation of activated esters, anhydrides or acid halides, of the free carboxyl of asuitably protected acid substrate, and subséquent reaction with the free amine of a suitablyprotected amine, optionally in the presence of a base, are also suitable. For example, aprotected Boc-amino acid or Cbz-amidino benzoic acid is treated in an anhydrous solvent,such as methylene chloride or tetrahydrofuran(THF), in the presence of a base, such as N-methyl morpholine, DMAP or a trialkylamine, with isobutyl chloroformate to form the"activated anhydride", which is subsequently reacted with the free amine of a secondprotected amino acid or aniline.

Useful intermediates for preparing formula (I) compounds in which R2 is abenzimidazole are disclosed in Nestor et al, J. Med. Chem. 1984, 27, 320. Représentativemethods for preparing benzimidazole compounds useful as intermediates in the présentinvention are also common to the art and may be found, for instance, in EP-A 0 381 033.

Acid addition salts of the compounds are prepared in a standard manner in asuitable solvent from the parent compound and an excess of an acid, such as hydrochloric,hydrobromic, hydrofluoric, sulfuric, phosphoric, acetic, trifluoroacetic, maleic, succinic ormethanesulfonic. Certain of the compounds form inner salts or zwitterions which may beacceptable. Cationic salts are prepared by treating the parent compound with an excess ofan alkaline reagent, such as a hydroxide, carbonate or alkoxide, containing the appropriatecation; or with an appropriate organic amine. Cations such as Li+, Na+, K+, Ca++, Mg++and NH4+ are spécifie examples of cations présent in pharmaceutically acceptable salts.

This invention also provides a pharmaceutical composition which comprises acompound according to formula (I) and a pharmaceutically acceptable carrier.

Accordingly, the compounds of formula (I) may be used in the manufacture of amédicament. Pharmaceutical compositions of the compounds of formula (I) prepared ashereinbefore described may be formulated as solutions or lyophilized powders for -40- 012189 parentéral administration. Powders may be reconstituted by addition of a suitable diluentor other pharmaceutically acceptable carrier prior to use. The liquid formulation may be abuffered, isotonie, aqueous solution. Examples of suitable diluents are normal isotoniesaline solution, standard 5% dextrose in water or buffered sodium or ammonium acetatesolution. Such formulation is especially suitable for parentéral administration, but may alsobe used for oral administration or contained in a metered dose inhaler or nebulizer forinsufflation. It may be désirable to add excipients such as polyvinylpyrrolidone, gelatin,hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodiumcitrate.

Altemately, these compounds may be encapsulated, tableted or prepared in aémulsion or syrup for oral administration. Pharmaceutically acceptable solid or liquidcarriers may be added to enhance or stabilize the composition, or to facilitate préparation ofthe composition. Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba,magnésium stéarate or stearic acid, talc, pectin, acacia, agar or gelatin. Liquid carriersinclude syrup, peanut oil, olive oil, saline and water. The carrier may also include asustained release material such as glyceryl monostearate or glyceryl distearate, alone orwith a wax. The amount of solid carrier varies but, preferably, will be between about 20mg to about 1 g per dosage unit. The pharmaceutical préparations are made following theconventional techniques of pharmacy involving milling, mixing, granulating, andcompressing, when necessary, for tablet forms; or milling, mixing and fïlling for hardgelatin capsule forms. When a liquid carrier is used, the préparation will be in the form ofa syrup, élixir, émulsion or an aqueous or non-aqueous suspension. Such a liquidformulation may be administered directly p.o. or filled into a soft gelatin capsule.

For rectal administration, the compounds of this invention may also be combinedwith excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols and moldedinto a suppository.

The compounds described herein are antagonists of the vitronectin receptor, and areuseful for treating diseases wherein the underlying pathology is attributable to ligand or cellwhich interacts with the vitronectin receptor. For instance, these compounds are useful forthe treatment of diseases wherein loss of the bone matrix créâtes pathology. Thus, theinstant compounds are useful for the treatment of ostoeporosis, hyperparathyroidism,

Paget’s disease, hypercalcemia of malignancy, osteolytic lésions produced by bonemetastasis, bone loss due to immobilization or sex hormone deficiency. The compounds ofthis invention are also believed to hâve utility as antitumor, anti-angiogenic, antiinflammatory and anti-metastatic agents, and be useful in the treatment of atherosclerosis and restenosis.

The compound is administered either orally or parenterally to the patient, in amanner such that the concentration of drug is sufficient to inhibit bone résorption, or other -41 - 012189 such indication. The pharmaceutical composition containing the compound is administeredat an oral dose of between about 0.1 to about 50 mg/kg in a manner consistent with thecondition of the patient. Preferably the oral dose would be about 0.5 to about 20 mg/kg.

For acute therapy, parentéral administration is preferred. An intravenous infusion of the 5 peptide in 5% dextrose in water or normal saline, or a similar formulation with suitableexcipients, is most effective, although an intramuscular bolus injection is also useful.Typically, the parentéral dose will be about 0.01 to about 100 mg/kg; preferably between0.1 and 20 mg/kg. The compounds are administered one to four times daily at a level toachieve a total daily dose of about 0.4 to about 400 mg/kg/day. The précisé level and 10 method by which the compounds are administered is readily determined by one routinelyskilled in the art by comparing the blood level of the agent to the concentration required tohâve a therapeutic effect.

This invention further provides a method for treating osteoporosis or inhibitingbone loss which comprises administering stepwise or in physical combination a compound 15 of formula (I) and other inhibitors of bone résorption, such as bisphosphonates (i.e., allendronate), hormone replacement therapy, anti-estrogens, or calcitonin. In addition, thisinvention provides a method of treatment using a compound of this invention and ananabolic agent, such as the bone morphogenic protein, iproflavone, useful in the préventionof bone loss and/or to increase bone mass. 20 ' Additionally, this invention provides a method of inhibiting tumor growth which comprises administering stepwise or in physical combination a compound of formula (I)and an antineoplastic agent. Compounds of the camptothecin analog class, such astopotecan, irinotecan and 9-aminocamptothecin, and platinum coordination complexes,such as cisplatin, ormaplatin and tetraplatin, are well known groups of antineoplastic 25 agents. Compounds of the camptothecin analog class are described in U.S. Patent Nos.5,004,758,4,604,463, 4,473,692,4,545,880 4,342,776,4,513,138,4,399,276, EP PatentApplication Publication Nos. 0 418 099 and 0 088 642, Wani, et al., J. Med. Chem., 1986,29, 2358, Wani, et al., J. Med. Chem., 1980, 23, 554, Wani, et al., J. Med. Chem., 1987, 30,VH 4, and Nitta, et al., Proc. 14th International Congr. Chemotherapy., 1985, Anticancer 30 Section I, 28, the entire disclosure of each which is hereby incorporated by reference. Theplatinum coordination complex, cisplatin, is available under the name Platinol® fromBristol Myers-Squibb Corporation. Useful formulations for cisplatin are described in U.S.Patent Nos. 5,562,925 and 4,310,515, the entire disclosure of each which is herebyincorporated by reference. 35 In the method of inhibiting tumor growth which comprises administering stepwise or in physical combination a compound of formula (I) and an antineoplastic agent, theplatinum coordination compound, for example cisplatin, can be administered using slowintravenous infusion. The preferred carrier is a dextrose/saline solution containing -42- 012189 mannitol. The dose scheduleof the platinum coordination compound may be on the basisof from about 1 to about 500 mg per square meter (mg/m^) of body surface area per courseof treatment. Infusions of the platinum coordiation compound may be given one to twotimes weekly, and the weekly treatments may be repeated several times. Using acompound of the camptothecin analog class in a parentéral administration, the course oftherapy generally employed is from about 0.1 to about 300.0 mg/m^ of body surface areaper day for about five consecutive days. Most preferably, the course of therapy employedfor topotecan is from about 1.0 to about 2.0 mg/m^ of body surface area per day for aboutfive consecutive days. Preferably, the course of therapy is repeated at least once at about aseven day to about a twenty-eight day interval.

The pharmaceutical composition may be formulated with both the compound offormula (I) and the antineoplastic agent in the same container, but formualtion in differentcontainers is preferred. When both agents are provided in solution form, they can becontained in an infusion/injection System for simultaneous administration or in a tandemarrangement.

For convenient administration of the compound of formula (I) and theantineoplastic agent at the same or different times, a kit is prepared, comprising, in a singlecontainer, such as a box, carton or other container, individual bottles, bags, vials or othercontainers each having an effective amount of the compound of formula (I) for parentéraladministration, as described above, and an effective amount of the antineoplastic agent forparentéral administration, as described above. Such kit can comprise, for example, bothpharmaceutical agents in separate containers or the same container, optionally aslyophilized plugs, and containers of solutions for reconstitution. A variation of this is toinclude the solution for reconstitution and the lyophilized plug in two chambers of a singlecontainer, which can be caused to admix prior to use. With such an arrangement, theantineoplastic agent and the compound of this invention may be packaged separately, as intwo containers, or lyophilized together as a powder and provided in a single container.

When both agents are provided in solution form, they can be contained in aninfusion/injection System for simultaneous administration or in a tandem arrangement. Forexample, the compound of formula (I) may be in an i.v. injectable form, or infusion baglinked in sériés, via tubing, to the antineoplastic agent in a second infusion bag. Using sucha System, a patient can receive an initial bolus-type injection or infusion of the compoundof formula (I) followed by an infusion of the antineoplastic agent.

The compounds may be tested in one of several biological assays to détermine theconcentration of compound which is required to hâve a given pharmacological effect. -43- 012189

Inhibition of vitronectin binding

Solid-Phase [3 H]-SK&amp;F-107260 Binding to ανβ^: Human placenta or human plateletανβ3 (0.1-0.3 mg/mL) in bufferT (containing 2 mM CaCl2 and 1% octylglucoside) wasdiluted with buffer T containing 1 mM CaCl2, 1 mM MnCl2, 1 mM MgCl2 (buffer A) and0.05% NaN3, and then immediately added to 96-well ELISA plates (Corning, New York,NY) at 0.1 mL per well. 0.1 - 0.2 pg of ανβ3 was added per well. The plates wereincubated ovemight at 4°C. At the time of the experiment, the wells were washed oncewith buffer A and were incubated with 0.1 mL of 3.5% bovine sérum albumin in the samebuffer for 1 hr at room température. Following incubation the wells were aspiratedcompletely and washed twice with 0.2 mL buffer A.

Compounds were dissolved in 100% DMSO to give a 2 mM stock solution, whichwas diluted with binding buffer (15 mM Tris-HCl (pH 7.4), 100 mM NaCl, 1 mM CaCl2,1mM MnCl2, 1 mM MgCl2) to a final compound concentration of 100 μΜ. This solution isthen diluted to the required final compound concentration. Various concentrations ofunlabeled antagonists (0.001 - 100 μΜ) were added to the wells in triplicates, followed bythe addition of 5.0 nM of [3H]-SK&amp;F-107260 (65 - 86 Ci/mmol).

The plates were incubated for 1 hr at room température. Following incubation thewells were aspirated completely and washed once with 0.2 mL of ice cold buffer A in awell-to-well fashion. The receptors were solubilized with 0.1 mL of 1% SDS and thebound [3H]-SK&amp;F-107260 was determined by liquid scintillation counting with theaddition of 3 mL Ready Safe in a Beckman LS Liquid Scintillation Counter, with 40%efficiency. Nonspecific binding of [3H]-SK&amp;F-107260 was determined in the presence of2 pM SK&amp;F-107260 and was consistently less than 1% of total radioligand input. TheIC50 (concentration of the antagonist to inhibit 50% binding of [3H]-SK&amp;F-107260) wasdetermined by a nonlinear, least squares curve-fitting routine, which was modified from theLUNDON-2 program. The Kj (dissociation constant of the antagonist) was calculatedaccording to the équation: Kj = Ιθ5θ/(1 + L/Kd), where L and K<j were the concentrationand the dissociation constant of [3H]-SK&amp;F-107260, respectively.

Compounds of the présent invention inhibit vitronectin binding to SK&amp;F 107260 inthe concentration range of about 10 to about 0.01 micomolar.

Compounds of this invention are also tested for in vitro and in vivo bone résorptionin assays standard in the art for evaluating inhibition of bone formation, such as the pitformation assay disclosed in EP 528 587, which may also be performed using humanosteoclasts in place of rat osteoclasts, and the ovarectomized rat model, described byWronski et al., Cells and Materials 1991, Sup. 1,69-74.

Vascular smooth muscle cell migration assay -44- 012189 > i r Rat or human sortie smooth muscle cells were used. The cell migration was monitored in a Transwell cell culture chamber by using a polycarbonate membrane with pores of 8 um (Costar). The lower surface of the filter was coated with vitronectin. Cells were suspended in DMEM supplemented with 0.2% bovine sérum albumin at a 5 concentration of 2.5 - 5.0 x 10^ cells/mL, and were pretreated with test compound at various concentrations for 20 min at 20°C. The solvent alone was used as control. 0.2 mLof the cell suspension was placed in the upper compartment of the chamber. The lowercompartment contained 0.6 mL of DMEM supplemented with 0.2% bovine sérum albumin.Incubation was carried out at 37°C in an atmosphère of 95% air/5% CO2 for 24 hr. After 10 incubation, the non-migrated cells on the upper surface of the filter were removed by gentlescraping. The filter was then fixed in methanol and stained with 10% Giemsa stain.

Migration was measured either by a) counting the number of cells that had migrated to thelower surface of the filter or by b) extracting the stained cells with 10% acetic acidfollowed by determining the absorbance at 600 nM. 15

Thyroparathyroidectomized rat model

Each experimental group consiste of 5-6 adult male Sprague-Dawley rats (250-400g bodyweight). The rats are thyroparathyroidectomized (by the vendor, Taconic Farms) 7 days prior touse. Ail rats receive a replacement dose of thyroxine every 3 days. On receipt of the rats, 20 circulating ionized calcium levels are measured in whole blood immediately after it has beenwithdrawn by tail venipuncture into heparinized tubes. Rats are included if the ionized Ca level(measured with a Ciba-Coming model 634 calcium pH analyzer) is <1.2 mM/L. Each rat is fittedwith an indwelling venous and arterial cathéter for the delivery of test material and for bloodsampling respectively. The rats are then put on a diet of calcium-free chow and deionized water. 25 Baseline Ca levels are measured and each rat is administered either control vehicle or humanparathyroid hormone 1-34 peptide (hPTHl-34, dose 1.25 ug/kg/h in saline/0.1% bovine sérumalbumin, Bachem, Ca) or a mixture of hPTHl-34 and test material, by continuous intravenousinfusion via the venous cathéter using an extemal syringe pump. The calcémie response of eachrat is measured at two-hourly intervals during the infusion period of 6-8 hours. 30

Human osteoclast résorption and adhesion assays

Pit résorption and adhesion assays hâve been developed and standardized using normal human osteoclasts derived from osteoclastoma tissue. Assay 1 was developed forthe measurement of osteoclast pit volumes by laser confocal microscopy. Assay 2 was 35 developed as a higher throughput screen in which collagen fragments (released duringrésorption) are measured by competitve ELISA.

Assay 1 (using laser confocal microscopy) -45- 012189 • Aliquots of humanosteoclastoma-derived cell suspensions are removed from liquidnitrogen strorage, warmed rapidly at 37°C and washed xl in RPMI-1640 medium bycentrifugation (lOOOrpm, 5 mins at 4°C). • The medium is aspirated and replaced with murine anti-HLA-DR antibody thendiluted 1:3 in RPMI-1640 medium. The suspension is incubated for 30 mins on ice andmixed frequently. • The cells are washed x2 with cold RPMI-1640 followed by centrifugation (1000rpm, 5 mins at 4°C) and the cells are then transferred to a stérile 15 ml centrifuge tube.

The number of mononuclear cells are enumerated in an improved Neubauer countingchamber. • Sufficient magnetic beads (5 / mononuclear cell), coated with goat anti-mouse IgG(Dynal, Great Neck, NY) are removed from their stock bottle and placed into 5 ml offresh medium (this washes away the toxic azide preservative). The medium is removedby immobilizing the beads on a magnet and is replaced with fresh medium. • The beads are mixed with the cells and the suspension is incubated for 30 mins onice. The suspension is mixed frequently. • The bead-coated cells are immobilized on a magnet and the remaining cells(osteoclast-rich fraction) are decanted into a stérile 50 ml centrifuge tube. • Fresh medium is added to the bead-coated cells to dislodge any trapped osteoclasts.

This wash process is repeated xlO. The bead-coated cells are discarded. • The viable osteoclasts are enumerated in a counting chamber, using fluoresceindiacetate to label live cells. A large-bore disposable plastic pasteur pipet is used to addthe sample to the chamber. • The osteoclasts are pelleted by centrifugation and the density adjusted to theappropriate number in EMEM medium (the number of osteoclasts is variable fromtumor to tumor), supplemented with 10% fêtai calf sérum and 1.7g/liter of sodiumbicarbonate. • 3ml aliquots of the cell suspension (per compound treatment) are decanted into15ml centrifuge tubes. The cells are pelleted by centrifugation. • To each tube, 3ml of the appropriate compound treatment are added (diluted to 50uM in the EMEM medium). Also included are appropriate vehicle Controls, a positivecontrol (anti-vitronectin receptor murine monoclonal antibody [87MEM1] diluted to100 ug/ml) and an isotype control (IgG2a diluted to 100 ug/ml). The samples areincubated at 37°C for 30 mins. • 0.5ml aliquots of the cells are seeded onto stérile dentine slices in a 48-well plateand incubated at 37°C for 2 hours. Each treatment is screened in quadruplicate. -46- 012189 • The slices are washed in six changes of warmPBS (10 ml ! well in a 6-welI plate)and then placed into fresh medium containing the compound treatment or controlsamples. The samples are incubated at 37°C for 48 hours.

Tartrate résistant acid phosphatase (TRAP) procedure (sélective stainfor cells of theosteoclast lineage) • The bone slices containing the attached osteoclasts are washed in phosphatebuffered saline and fixed in 2% gluteraldehyde (in 0.2M sodium cacodylate) for 5 mins. • They are then washed in water and are incubated for 4 minutes in TRAP buffer at37°C (0.5 mg/ml naphthol AS-BI phosphate dissolved in Ν,Ν-dimethylformamide andmixed with 0.25 M citrate buffer (pH 4.5), containing 10 mM sodium tartrate. • Following a wash in cold water the slices are immersed in cold acetate buffer (0.1M, pH 6.2) containing 1 mg/ml fast red gamet and incubated at 4°C for 4 minutes. • Excess buffer is aspirated, and the slices are air dried following a wash in water. • The TRAP positive osteoclasts (brick red/ purple precipitate) are enumerated bybright-fîeld microscopy and are then removed from the surface of the dentine bysonication. • Pit volumes are determined using the Nikon/Lasertec ILM21W confocalmicroscope.

Assay 2 (using an ELISA readout)

The human osteoclasts are enriched and prepared for compound screening asdescribed in the initial 9 steps of Assay 1. For clarity, these steps are repeated hereinbelow. • Aliquots of human osteoclastoma-derived cell suspensions are removed from liquidnitrogen strorage, warmed rapidly at 37°C and washed xl in RPMI-1640 medium bycentrifugation (lOOOrpm, 5 mins at 4°C). • The medium is aspirated and replaced with murine anti-HLA-DR antibody thendiluted 1:3 in RPMI-1640 medium. The suspension is incubated for 30 mins on ice andmixed frequently. • The cells are washed x2 with cold RPMI-1640 followed by centrifugation ( 1000rpm, 5 mins at 4°C) and the cells are then transferred to a stérile 15 ml centrifuge tube.

The number of mononuclear cells are enumerated in an improved Neubauer countingchamber. • Sufficient magnetic beads (5 / mononuclear cell), coated with goat anti-mouse IgG(Dynal, Great Neck, NY) are removed from their stock bottle and placed into 5 ml offresh medium (this washes away the toxic azide preservative). The medium is removedby immobilizing the beads on a magnet and is replaced with fresh medium. -47- 012189 • The beads are mixed with the cells’and the suspension is incubated for 30 mins onice. The suspension is mixed frequently. • The bead-coated cells are immobilized on a magnet and the remaining cells(osteoclast-rich fraction) are decanted into a stérile 50 ml centrifuge tube. • Fresh medium is added to the bead-coated cells to dislodge any trapped osteoclasts.This wash process is repeated xlO. The bead-coated cells are discarded. • The viable osteoclasts are enumerated in a counting chamber, using fluoresceindiacetate to label live cells. A large-bore disposable plastic pasteur pipet is used to addthe sample to the chamber. • The osteoclasts are pelleted by centrifugation and the density adjusted to theappropriate number in EMEM medium (the number of osteoclasts is variable fromtumor to tumor), supplemented with 10% fêtai calf sérum and 1.7g/liter of sodiumbicarbonate.

In contrast to the method desribed above in Assay 1, the compounds are screened at 4 doses to obtain an IC50, as outlined below: • The osteoclast préparations are preincubated for 30 minutes at 37°C with testcompound (4 doses) or Controls. • They are then seeded onto bovine cortical bone slices in wells of a 48-well tissueculture plate and are incubated for a further 2 hours at 37°C. • The bone slices are washed in six changes of warm phosphate buffered saline(PBS), to remove non-adherent cells, and are then retumed to wells of a 48 well platecontaining fresh compound or Controls. • The tissue culture plate is then incubated for 48 hours at 37°C. • The supematants from each well are aspirated into individual tubes and arescreened in a compétitive ELISA that detects the c-telopeptide of type I collagen whichis released during the résorption process. This is a commercially available ELISA(Osteometer, Denmark) that contains a rabbit antibody that specifîcally reacts with an 8-amino acid sequence (Glu-Lys-Ala-His- Asp-GIy-Gly-Arg) that is présent in thecarboxy-terminal telopeptide of the al-chain of type I collagen. The results areexpressed as % inhibition of résorption compared to a vehicle control.

Human osteoclast adhesion assay

The human osteoclasts are enriched and prepared for compound screening asdescribed above in the inital 9 steps of Assay 1. For clarity, these steps are repeatedhereinbelow. • Aliquots of human osteoclastoma-derived cell suspensions are removed from liquidnitrogen strorage, warmed rapidly at 37°C and washed xl in RPMI-1640 medium bycentrifugation (lOOOrpm, 5 mins at 4°C). -48- 012189 • The medium is aspirated and replaced with murine anti-HLA-DR antibody thendiluted 1:3 in RPMI-1640 medium. The suspension is incubated for 30 mins on ice andmixed frequently. • The cells are washed x2 with cold RPMI-1640 followed by centrifugation (1000rpm, 5 mins at 4°C) and the cells are then transferred to a stérile 15 ml centrifuge tube.

The number of mononuclear cells are enumerated in an improved Neubauer countingchamber. • Sufficient magnetic beads (5 Z mononuclear cell), coated with goat anti-mouse IgG(Dynal, Great Neck, NY) are removed from their stock bottle and placed into 5 ml offresh medium (this washes away the toxic azide preservative). The medium is removedby immobilizing the beads on a magnet and is replaced with fresh medium. • The beads are mixed with the cells and the suspension is incubated for 30 mins onice. The suspension is mixed frequently. • The bead-coated cells are immobilized on a magnet and the remaining cells(osteoclast-rich fraction) are decanted into a stérile 50 ml centrifuge tube. • Fresh medium is added to the bead-coated cells to dislodge any trapped osteoclasts.

This wash process is repeated xlO. The bead-coated cells are discarded. • The viable osteoclasts are enumerated in a counting chamber, using fluoresceindiacetate to label live cells. A large-bore disposable plastic pasteur pipet is used to addthe sample to the chamber. • The osteoclasts are pelleted by centrifugation and the density adjusted to theappropriate number in EMEM medium (the number of osteoclasts is variable fromtumor to tumor), supplemented with 10% fêtai calf sérum and 1.7g/liter of sodiumbicarbonate. • Osteoclastoma-derived osteoclasts are preincubated with compound (4 doses) orControls at 37°C for 30 minutes. • The cells are then seeded onto osteopontin-coated slides (human or rat osteopontin,2.5ug/ml) and incubated for 2 hours at 37°C. • Non adhèrent cells are removed by washing the slides vigorously in phosphatebuffered saline and the cells remaining on the slides are fixed in acetone. • The osteoclasts are stained for tartrate-resistant acid phosphatase (TRAP), asélective marker for cells of this phenotype (see steps 15-17), and are enumerated bylight microscopy. The results are expressed as % inhibition of adhesion compared to avehicle control.

Cell Adhesion Assay

Cells and Cell Culture

Human embryonic kidney cells ( HEK293 cells) were obtained from ATCC (Catalog No. CRL 1573). Cells were grown in Earl’s minimal essential medium (EMEM) -49- 01 2189 medium containing Earl’s salts, 10% fêtai bovine sérum, 1% glutamine and 1% Penicillin-Steptomycin.

Constructs and Transfections A 3.2 kb EcoRI-Kpnl fragment of the av subunit and a 2.4 kb Xbal- Xhol fragment 5 of the ββ subunit were inserted into the EcoRI - EcoRV cloning sites of the pCDN vector(Aiyar et al., 1994 ) which contains a CMV promoter and a G418 selectable marker byblunt end ligation. For stable expression, 80 x 10 6 HEK 293 cells were electrotransformedwith αν+ββ constructs (20 μg DNA of each subunit) using a Gene Puiser (Hensley et al., 1994 ) and plated in 100 mm plates (5x10^ cells/plate). After 48 hr, the growth medium 10 was supplemented with 450 μg/mL Geneticin (G418 Sulfate, GIBCO-BRL, Bethesda, MD).

The cells were maintained in sélection medium until the colonies were large enough to beassayed.

Immunocytochemical analysis of transfected cells

To détermine whether the HEK 293 transfectants expressed the vitronectin 15 receptor, the cells were immobilized on glass microscope slides by centrifugation, fixed inacetone for 2 min at room température and air dried. Spécifie reactivity with 23C6, amonoclonal antibody spécifie for the ανββ compîex was demonstrated using a standardindirect immunofluorescence method. 20 Cell Adhesion Studies

Corning 96-well ELIS A plates were precoated ovemight at 4°C with 0.1 mL ofhuman vitronectin (0.2 μgZmL in RPMI medium). At the time of the experiment, the plates .were washed once with RPMI medium and blocked with 3.5% BSA in RPMI medium for 1hr at room température. Transfected 293 cells were resuspended in RPMI medium, 25 supplemented with 20 mM Hepes, pH 7.4 and 0.1% BSA at a density of 0.5 x 10^ cells/mL. 0.1 mL of cell suspension was added to each well and incubated for 1 hr at 37°C, in thepresence or absence of various ανββ antagoniste. Following incubation, 0.025 mL of a10% formaldéhyde solution, pH 7.4, was added and the cells were fixed at roomtempérature for 10 min. The plates were washed 3 times with 0.2 mL of RPMI medium 30 and the adhèrent cells were stained with 0.1 mL of 0.5% toluidine blue for 20 min at roomtempérature. Excess stain was removed by extensive washing with deionized water. Thetoluidine blue incorporated into cells was eluted by the addition of 0.1 mL of 50% éthanolcontaining 50 mM HCl. Cell adhesion was quantitated at an optical density of 600 nm on amicrotiter plate reader (Titertek Multiskan MC, Sterling, VA). 35

Solid-Phase ανβ§ Binding Assay: -50- 012189

The vitronectin receptor ανβ5 was purifïed from human placenta. Receptorpréparation was diluted with 50 mM Tris-HCl, pH 7.5,100 mM NaCl, 1 mM CaCb, 1 mMMnCl2,1 mM MgCh (buffer A) and was immediately added to 96-well ELIS A plates at 0.1ml per well. 0.1-0.2 gg of Ογββ was added per well. The plates were incubated ovemight at4°C. At the time of the experiment, the wells were washed once with buffer A and wereincubated with 0.1 ml of 3.5% bovine sérum albumin in the same buffer for 1 hr at roomtempérature. Following incubation the wells were aspirated completely and washed twicewith 0.2 ml buffer A.

In a [3H]-SK&amp;F-107260 compétition assay, various concentrations of unlabeledantagoniste (0.001-100 μΜ) were added to the wells, followed by the addition of 5.0 nM of[3H]-SK&amp;F-107260. The plates were incubated for 1 hr at room température. Followingincubation the wells were aspirated completely and washed once with 0.2 ml of ice coldbuffer A in a well-to-well fashion. The receptors were solubilized with 0.1 ml of 1% SDSand the bound [3H]-SK&amp;F-107260 was determined by liquid scintillation counting with theaddition of 3 ml Ready Safe in a Beckman LS 6800 Liquid Scintillation Counter, with 40%efficiency. Nonspecifïc binding of [3H]-SK&amp;F-107260 was determined in the presence of 2μΜ SK&amp;F-107260 and was consistently less than 1% of total radioligand input. The IC50(concentration of the antagonist to inhibit 50% binding of [3H]-SK&amp;F-107260) wasdetermined by a nonlinear, least squares curve-fïtting routine, which was modified from theLUNDON-2 program. The Kj (dissociation constant of the antagonist) was calculatedaccording to Cheng and Prusoff équation: Ki = IC50/ (1 + L/K<j), where L and Kj were theconcentration and the dissociation constant of [3H]-SK&amp;F-107260, respectively.

Inhibition of RGD-mediated GPIIb-IIIa binding

Purification of GPIIb-IIIa

Ten units of outdated, washed human platelets (obtained from Red Cross) werelyzed by gentle stirring in 3% octylglucoside, 20 mM Tris-HCl, pH 7.4, 140 mM NaCl, 2mM CaCl2 at 4°C for 2 h. The lysate was centrifuged at 100,000g for 1 h. The supematantobtained was applied to a 5 mL lentil lectin sepharose 4B column (E.Y. Labs)preequilibrated with 20 mM Tris-HCl, pH 7.4, 100 mM NaCl, 2 mM CaCl2, 1%octylglucoside (buffer A). After 2 h incubation, the column was washed with 50 mL coldbuffer A. The lectin-retained GPIIb-IIIa was eluted with buffer A containing 10% dextrose.AU procedures were performed at 4°C. The GPIIb-IIIa obtained was >95% pure as shownby SDS polyacrylamide gel electrophoresis. - 51 - 012189

Incorporation of GPIIb-IIIa in Liposomes. A mixture of phosphatidylserine (70%) and phosphatidylcholine (30%) (AvantiPolar Lipids) were dried to the walls of a glass tube under a stream of nitrogen. PurifiedGPIIb-IIIa was diluted to a final concentration of 0.5 mg/mL and mixed with thephospholipids in a protein:phospholipid ratio of 1:3 (w:w). The mixture was resuspendedand sonicated in a bath sonicator for 5 min. The mixture was then dialyzed ovemight using12,000-14,000 molecular weight cutoff dialysis tubing against a 1000-fold excess of 50mM Tris-HCl, pH 7.4,100 mM NaCl, 2 mM CaC12 (with 2 changes). The GPIIb-IIIa-containing liposomes wee centrifuged at 12,000g for 15 min and resuspended in the dialysisbuffer at a final protein concentration of approximately 1 mg/mL. The liposomes werestored at -70C until needed.

Compétitive Binding to GPIIb-IIIa

The binding to the fibrinogen receptor (GPIIb-IIIa) was assayed by an indirectcompétitive binding method using [3H]-SK&amp;F-107260 as an RGD-type ligand. Thebinding assay was performed in a 96-well filtration plate assembly (Millipore Corporation,Bedford, MA) using 0.22 um hydrophilic durapore membranes. The wells were precoatedwith 0.2 mL of 10 pg/mL polylysine (Sigma Chemical Co., St. Louis, MO.) at roomtempérature for 1 h to block nonspecific binding. Various concentrations of unlabeledbenzazepines were added to the wells in quadruplicate. [3H]-SK&amp;F-107260 was applied toeach well at a final concentration of 4.5 nM, followed by the addition of 1 pg of the purifiedplatelet GPIIb-IIIa-containing liposomes. The mixtures were incubated for 1 h at roomtempérature. The GPIIb-IIIa-bound [3H)-SK&amp;F-107260 was seperated from the unboundby filtration using a Millipore filtration manifold, followed by washing with ice-cold buffer(2 times, each 0.2 mL). Bound radioactivity remaining on the filters was counted in 1.5 mLReady Solve (Beckman Instruments, Fullerton, CA) in a Beckman Liquid ScintillationCounter (Model LS6800), with 40% efficiency. Nonspecific binding was determined in thepresence of 2 pM unlabeled SK&amp;F-107260 and was consistently less than 0.14% of thetotal radioactivity added to the samples. Ail data points are the mean of quadruplicatedéterminations.

Compétition binding data were analyzed by a nonlinear least-squares curve fittingprocedure. This method provides the IC50 of the antagonists (concentration of theantagonist which inhibits spécifie binding of [3H]-SK&amp;F-107260 by 50% at equilibrium).The IC50 is related to the equilibrium dissociation constant (Ki) of the antagonist based onthe Cheng and Prusoff équation: Ki = IC5Q/(1+L/Kd), where L is the concentration of [3H]-SK&amp;F-107260 used in the compétitive binding assay (4.5 nM), and Kd is the dissociationconstant of [3HJ-SK&amp;F-107260 which is 4.5 nM as determined by Scatchard analysis. -52- 012189

Preferred compounds of this invention hâve an affinity for the vitronectin receptorrelative to the fibrinogen receptor of greater than 10:1. Most preferred compounds hâve aratio of activity of greater than 100:1.

The efficacy of the compounds of formula (I) alone or in combination with anantineoplastic agent may be determined using several transplantable mouse tumor models.

See U. S. Patent Nos. 5,004,758 and 5,633,016 for details of these models

The examples which follow are intended in no way to limit the scope of thisinvention, but are provided to illustrate how to make and use the compounds of thisinvention. Many other embodiments will be readily apparent to those skilled in the art.

General

Proton nuclear magnetic résonance (^H NMR) spectra were recorded at either 250,300, or 400 MHz. Chemical shifts are reported in parts per million (δ) downfield from theinternai standard tetramethylsilane (TMS). Abbreviations for NMR data are as follows:s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, dd=doublet of doublets, dt=doubletof triplets, app=apparent, br=broad. J indicates the NMR coupling constant measured inHertz. CDCI3 is deuteriochloroform, DMSO-d6 is hexadeuteriodimethylsulfoxide, andCD3OD is tetradeuteriomethanol. Infrared (IR) spectra were recorded in transmissionmode, and band positions are reported in inverse wavenumbers (cm*1). Mass spectra wereobtained using electrospray (ES) or FAB ionization techniques. Elemental analyses wereperformed either in-house or by Quantitative Technologies Inc., Whitehouse, NJ. Meltingpoints were taken on a Thomas-Hoover melting point apparatus and are uncorrected. Ailtempératures are reported in degrees Celsius. Analtech Silica Gel GF and E. Merck SilicaGel 60 F-254 thin layer plates were used for thin layer chromatography. Both flash andgravity chromatography were carried out on E. Merck Kieselgel 60 (230-400 mesh) silicagel. Analytical and préparative HPLC were carried out on Rainin or Beckmanchromatographs. ODS refers to an octadecylsilyl derivatized silica gel chromatographiesupport. 5 μ Apex-ODS indicates an octadecylsilyl derivatized silica gel chromatographiesupport having a nominal particle size of 5 μ, made by Jones Chromatography, Littleton,Colorado. YMC ODS-AQ® is an ODS chromatographie support and is a registeredtrademark of YMC Co. Ltd., Kyoto, Japan. PRP-1® is a polymeric (styrene- divinylbenzene) chromatographie support, and is a registered trademark of Hamilton Co.,Reno, Nevada. Celite® is a filter aid composed of acid-washed diatomaceous silica, and isa registered trademark of Manville Corp., Denver, Colorado. -53- 012189

Préparation 1

Préparation of 2-f(3-hydroxv-l-propyl)amino1pyridine-N-oxide a) 2- [(3-Hydroxy-1 -propyl)amino]pyridine-N-oxide A mixture of 2-chloropyridine-N-oxide hydrochloride (16.6 g, 0.1 mole), 3-amino- 1-propanol (15.3 mL, 0.2 mole), NaHCC>3 (42 g, 0.5 mole), and tert-amyl alcohol (100 mL)was heated to reflux. After 21 hr, the reaction was cooled, diluted with CH2CI2 (300 mL),and suction filtered to remove insoluble materials. The filtrate was concentrated andreconcentrated from toluene to leave a yellow oil. Silica gel chromatography (20%MeOH/CHCl3) gave the title compound (15.62 g, 93%) as a yellow solid: TLC (20%MeOH/CHCl3) Rf 0.48; !h NMR (250, CDCI3) δ 8.07 (dd, J = 6.6,1.2 Hz, 1 H), 7.34 (br t,1 H), 7.10 - 7.30 (m, 1 H), 6.64 (dd, J = 8.5, 1.4 Hz, 1 H), 6.40 - 6.60 (m, 1 H), 4.49 (br s, 1H), 3.65 - 3.90 (m, 2 H), 3.35 - 3.60 (m, 2 H), 1.75 - 2.00 (m, 2 H); MS (ES) m/e 169 (M+H)+.

Préparation 2

Préparation of 6-(methylamino)-2-pyridylethanol a) 2-(ierr-Butoxycarbonylamino)-6-picoline A solution of 2-amino-6-picoline (21.63 g, 200 mmole) and di-ierr-butyldicarbonate (52.38 g, 240 mmole) in CH2CI2 (200 mL) was concentrated on the rotavap at50 °C, and the resulting residue was allowed to rotate on the rotavap at 50 °C undervacuum. After 21.5 hr, the reaction was diluted with hexanes (400 mL) and filteredthrough silica gel (hexanes followed by 20% EtOAc/hexanes). Concentration left the titlecompound (41.84 g, quantitative) as a light yellow oil which gradually solidified onstanding: iH NMR (250 MHz, CDCI3) δ 7.71 (d, J = 8.3 Hz, 1 H), 7.40 - 7.65 (m, 2 H),6.80 (d, J = 7.5 Hz, 1 H), 2.43 (s, 3 H), 1.50 (s, 9 H); MS (ES) m/e 153 (M + H - C4Hg)+. b) 2-[(tert-Butoxycarbonyl)methylamino]-6-picoline

NaH (60% in minerai oil, 3.60 g, 90 mmole) was added in portions over severalmin to a solution of 2-(reri-butoxycarbonylamino)-6-picoline (15.62 g, 75 mmole) andiodomethane (9.3 mL, 150 mmole) in anhydrous DMSO (75 mL) at 15 °C (cool waterbath). The internai température rose to 35 °C. When gas évolution had subsided, the coolwater bath was removed and the reaction was allowed to stir at RT. After 0.5 hr, the darkyellow mixture was poured onto iceÆ^O (300 mL) and extracted with Et2Û (3 x 300 mL).The combined organic layers were washed sequentially with H2O (2 x 75 mL) and brine -54- 012189 (75 mL). Drying (MgSC>4) and concentration left a yellow oil which was chromatographedon silica gel (7% EtOAc/hexanes). The title compound (13.01 g, 78%) was obtained as afaintly yellow oil: NMR (250 MHz, CDC13) δ 7.51 (app t, 1 H), 7.37 (d, J = 8.2 Hz, 1 H), 6.86 (d, J = 7.2 Hz, 1 H), 3.38 (s, 3 H), 2.49 (s, 3 H), 1.50 (s, 9 H); MS (ES) m/e 223 (M+ H)+. c) Ethyl-6-[(iÉ’ri-butoxycarbonyl)methylamino]-2-pyridylacetate LDA was prepared at 0 °C under argon from diisopropylamine (19.5 mL, 139.14mmole) and 2.5 M n-BuLi in hexanes (46.4 mL, 115.95 mmole) in dry THF (350 mL).

This solution was cooled to -78 °C and a solution of 2-[(tert- butoxycarbonyl)methylamino]-6-picoline (10.31 g, 46.38 mmole) in dry THF (46 mL) wasadded dropwise over 10 min. Additional dry THF (2 mL) was used in transfer. The orangesolution was stirred at -78 °C for 15 min, then diethyl carbonate (6.2 mL, 51.02 mmole)was added rapidly. The red solution was stirred at -78 °C for 15 min, then was quenchedwith half-saturated NH4CI (175 mL). The mixture was warmed to +5 °C and extractedwith EtOAc (175 mL) then with CH2CI2 (2 x 100 mL). The combined organics werewashed with brine (100 mL), dried (MgSC>4), and concentrated. The cloudy yellow oil waschromatographed on silica gel (15% EtOAc/hexanes) to afford the title compound (10.72 g,79%) as a light yellow oil: ^H NMR (250 MHz, CDC13) δ 7.51 - 7.63 (m, 2 H), 6.91 - 7.03(m, 1 H), 4.19 (q, J = 7.1 Hz, 2 H), 3.77 (s, 2 H), 3.38 (s, 3 H), 1.27 (t, J = 7.1 Hz, 3 H), 1.51 (s, 9 H); MS (ES) m/e 295 (M + H)+. d) 6-[(rerr-Butoxycarbonyl)methylamino]-2-pyridylethanol A solution of 2 N LiBH4 in THF (7 mL, 14 mmole) was added via syringe to astirred solution of ethyl-6-[(ierr-butoxycarbonyl)methylamino]-2-pyridylacetate (6.97 g,23.7 mmole) in anhydrous THF (30 mL) under argon. The reaction was then slowly heatedto reflux (initial exotherm). After 16 h at reflux, the reaction was cooled to 0 °C andcarefully quenched with water (50 mL). The mixture was extracted with EtOAc (150 mL),and the organic layer was washed with brine, dried (Na2SÛ4), and concentrated.Purification by flash chromatography on silica gel (35% EtOAc/hexane) gave the titlecompound (5.26 g, 88%) as a clear oil: JH NMR (400 MHz, CDCI3) δ 7.57 (m, 2 H), 6.88(d, J = 7.2 Hz, 1 H), 4.01 (t, 2 H), 3.39 (s, 3 H), 3.00 (t, 2 H), 1.53 (s, 9 H); MS (ES) m/e253.2 (M + H)+. e) 6-(Methylamino)-2-pyridylethanol

To 6-[(iert-butoxycarbonyl)methylamino]-2-pyridylethanol (17.9 g, 71 mmole) wasadded a solution of 4N HCl in dioxane (200 mL). The reaction was stirred at roomtempérature for 1 h (gentle gas évolution was observed) then was concentrated to dryness. -55- 012189

The product as the hydrochlaride sait solidified under vacuum. The solid was dissolved inNaCl-saturated 1.0 N NaOH solution (75 mL), and the solution was extracted with Et2Û (2x 200 mL). The combined organic layers were washed with brine, dried (Na2SC>4), andconcentrated to afford the title compound (9.12 g, 85%) as a waxy solid: NMR (400 MHz, CDCI3) δ 7.37 (t, 1 H), 6.42 (d, J = 7.3 Hz, 1 H), 6.27 (d, J = 8.3 Hz, 1 H), 4.62 (br s, 1 H), 3.96 (t, 2 H), 2.90 (d, J = 5.2 Hz, 3 H), 2.84 (t, 2 H); MS (ES) m/e 153 (M + H)+

Préparation 3

Préparation of ethyl (i)-4-(4-hydroxyphenyl)-3-phenylbutanoate a) Ethyl (±)-3-hydroxy-4-(4-methoxyphenyl)-3-phenylbutanoate

Anhydrous EtOAc (4.3 mL, 44 mmole) was added dropwise over 5-6 min to asolution of lithium bis(trimethylsilyl)amide (1.0 M in THF, 40 mL, 40 mmole) in dry THF(60 mL) in a flame-dried flask at -78 °C under argon. The yellow solution was stirred at -78 °C for 0.5 hr, then a solution of 2-(4-methoxyphenyl)-l-phenylethanone (Chem. Ber. 1958, 91, 755-759; 4.53 g, 20 mmole) in dry THF (20 mL) was added dropwise over 12min. Additional THF (2 mL) was used in transfer. After 0.5 hr, The reaction was quenchedwith saturated NH4CI (120 mL) and warmed to RT. EtOAc extraction, drying (MgSO4),concentration, and silica gel chromatography (20% EtOAc/hexanes) gave the titlecompound (6.13 g, 96%) as a light yellow oil: TLC Rf (20% EtOAc/hexanes) 0.34; MS(ES) m/e 315.2 (M + H)+. b) Ethyl (±)-4-(4-methoxyphenyl)-3-phenylbutanoate

Boron trifluoride etherate (4.8 mL, 39 mmole) was added dropwise over 3 min to asolution of ethyl (±)-3-hydroxy-4-(4-methoxyphenyl)-3-phenylbutanoate(6.13 g, 19.5mmole) and triethylsilane (6.2 mL, 39 mmole) in anhydrous CH2CI2 (49 mL) at 0 °C underargon. The reaction was stirred at RT ovemight, then was quenched with 5% NaHCO3(100 mL). The mixture was stirred briskly for 10 min, then was separated. The aqueouslayer was extracted with CH2CI2 (100 mL), and the combined organic layers were dried(Na2SÛ4) and concentrated. The residue was reconcentrated from hexanes (to removeCH2CI2) to leave a yellow oil. This was dissolved in absolute EtOH (100 mL), and 10%

Pd/C (775 mg, 1.95 mmole) was added. The mixture was shaken on a Parr apparatus at RTunder H2 (50 psi) for 2 hr, then was filtered through celite®. The fîltrate was concentrated,and the residue was chromatographed on silica gel (15 % EtOAc/hexanes). The titlecompound (5.27 g, 91 %) was obtained as a colorless oil: TLC Rf (15% EtOAc/hexanes) 0.40; MS (ES) m/e 299.2 (M + H)+. -56- 01 21 8 9 c) Ethyl (±)-4-(4-hydroxyphenyl)-3-phenylbutarioate

Anhydrous aluminum trichloride (4.49 g, 33.7 mmole) was added ail at once tosolution of ethyl (±)-4-(4-methoxyphenyl)-3-phenylbutanoate(2.01 g, 6.74 mmole) andethanethiol (2.5 mL, 33.7 mmole) in anhydrous CH2CI2 (67 mL) at 0 °C under argon. Theyellow solution was warmed to RT and stirred for 3 hr, then was recooled to 0 °C andquenched with cold 3 N HCl (67 mL). The mixture was stirred for 5 min, then wasseparated. The aqueous layer was extracted with CH2Cl2(2 x 100 mL), and the combinedorganic layers were dried (Na2SC>4) and concentrated. Silica gel chromatography (25%EtOAc/hexanes) gave the title compound (1.84 g, 96%) as a colorless oil: TLC Rf (30%EtOAc/hexanes) 0.47; MS (ES) m/e 285.2 (M + H)+.

Préparation 4

Préparation of 2-[(2-amino-l-ethyl)amino1pyridine dihydrochloride a) 2-[[2-(tert-Butoxycarbonyl)amino-1 -ethyljamino]-1 -oxopyridine A mixture of N-Boc-ethylenediamine (5.83 g, 36.39 mmole), 2-chloropyridine-N-oxide hydrochloride (7.25 g, g, 43.67 mmole), NaHCOj (15.29 g, 182 mmole), and tert-amyl alcohol (36 mL) was heated at reflux. After 47 hr, the dark brown mixture wascooled, diluted with CH2CI2 (100 mL), and suction filtered. The filtrate was concentratedand the residue was reconcentrated from toluene. Silica gel chromatography (10%MeOH/CH2Cl2) gave the title compound (8.23 g, 89%) as a yellow solid: NMR (250 MHz, CDCI3) δ 8.16 (dd, J = 6.5, 1.3 Hz, 1 H), 7.05 - 7.30 (m, 2 H), 6.68 (br d, J = 8.6 Hz, 1 H), 6.50 - 6.65 (m, 1 H), 5.70 - 5.95 (m, 1 H), 3.25 - 3.60 (m, 4 H), 1.44 (s, 9 H); MS (ES)m/e 254 (M + H)+. b) 2-[[2-(tert-Butoxycarbonyl)amino-l-ethyl]amino]pyridine A mixture of 2-[[2-(tert-butoxycarbonyl)amino-l-ethyl]amino]-l-oxopyridine (7.00g, 27.64 mmole), 10% Pd/C (5.88 g, 5.53 mmole), cyclohexene (28 mL, 276.4 mmole), andisopropanol (110 mL) was heated at reflux. After 17 hr, the reaction was filtered throughcelite®, and the filtrate was concentrated. The yellow residue was reconcentrated fromtoluene, then was chromatographed on silica gel (5% MeOH/CHCl3). The title compound(5.09 g, 78%) was obtained as a yellow oil: ÎH NMR (400 MHz, CDCI3) δ 8.05 - 8.12 (m, 1 H), 7.37 - 7.46 (m, 1 H), 6.53 - 6.61 (m, 1 H), 6.41 (d, J = 8.3 Hz, 1 H), 5.12 (br s, 1 H),4.86 (br s, 1 H), 3.26 - 3.51 (m, 4 H), 1.44 (s, 9 H); MS (ES) m/e 238 (M + H)+. c) 2-[(2-Amino-l-ethyl)amino]pyridine dihydrochloride -57- 012189 4 N HCl/dioxane (54 mL) was added in a stream to a solution of 2-[[2-(tert-butoxycarbonyl)amino-l-ethyl]amino]pyridine (5.09 g, 21.45 mmole) in anhydrousCH2CI2 (54 mL) at 0 °C under argon, then the mixture was warmed to RT. After 2 hr, themixture was cooled to 0 °C and suction filtered. The solid was washed extensively withanhydrous Et2Û and dried in high vacuum at 40 °C to afford the title compound (4.27 g, 95%) as an off-white, somewhat hygroscopic solid: NMR (400 MHz, CD3OD) δ 7.99 - 8.07 (m, 1 H), 7.92 - 7.98 (m, 1 H), 7.19 (d, J = 9.1 Hz, 1 H), 6.98 - 7.04 (m, 1 H), 3.76 (t, J= 6.2 Hz, 2 H), 3.27 (t, J = 6.2 Hz, 2 H, partially obscured by residual solvent signal); MS(ES) m/e 138 (M + H)+.

Préparation 5

Préparation of 2-f(3-hydroxv- l-propyl)amino1-4-methylpyridine-N-oxide a) 2-Chloro-4-methylpyridine

Sodium nitrite (13.88 g, 200 mmole) was added slowly at 0 °C to a solution of 2-amino-4-picoline (15.0 g, 139 mmole) in conc. HCI (200 mL). The reaction mixture wasallowed to warm to RT and was stirred for 16 hr, then was poured onto ice (500 g). The pHwas adjusted to 8.0 with conc. NH4OH, and the mixture was extracted with ether (3 x 300mL). The combined ether layers were washed sequentially with H2O (2 x 200 mL) andbrine (200 mL). Drying (MgSOzp and concentration gave the title compound (10.3 g, 58%)as a faintly yellow oil: MS (ES) m/e 127.8 (M + H)+. b) 2-Chloro-4-methylpyridine-N-oxide hydrochloride A mixture of 2-chloro-4-methylpyridine (10.0 g, 78.3 mmole) and 34% peraceticacid (76.05 g, 91.0 mmole) in glacial AcOH (10 mL) was heated at 70°C for 3 hr. Thereaction mixture was cooled, conc. HCl (35 mL) was added, and the mixture wasconcentrated on the rotavap. Recrystallization from n-butanol followed by trituration withether gave the title compound (7.16 g, 51%) as a white solid: MS (ES) m/e 143.9 (M + H)+. c) 2-[(3-Hydroxy-l-propyl)amino]-4-methylpyridine-N-oxide A mixture of 2-chloro-4-methylpyridine-N-oxide hydrochloride (7.16 g, 39mmole), 3-aminopropanol (6.01 g, 80 mmole), and NaHCO3 (16-8 g, 200 mmole) in tert-amyl alcohol (50 mL) was heated at reflux for 19 hr. The reaction mixture was diluted withCH2CI2 (200 mL) and filtered, and the filtrate was concentrated on the rotavap.Recrystallization from C^C^Æ^O gave the title compound (5.41 g, 75%) as a yellowsolid: TLC (15% MeOH/CH2Cl2) Rf 0.44; iH NMR (400, CDCI3) δ 7.92 (d, J = 6.7,1 H), -58- 012189 7.28 (br t, 1 H), 6.43 (s, 1 H), 6.33 (dd, J = 6.6,2.1 Hz, 1 H), 3.73 (t, J=5.7 Hz, 2 H), 3.47(q, H=6.3 Hz, 2 H), 2.29 (s, 3 H), 1.82 - 1.88 (m, 2 H); MS (ES) m/e 183 (M+ H)+.

Préparation 6

Préparation of 2-i(3-bromo-l-propvl)amino1pyridine-N-oxide hydrobromide a) 2-[(3-Bromo-l-propyl)amino]pyridine-N-oxide hydrobromide A solution of SOBrç (5.0 mL, 64.5 mmole) in CH2CI2 (20 mL) was added dropwise over 15-20 min to a solution of 2-[(3-hydroxy-l-propyl)amino]-4- methylpyridine-N-oxide (10.0 g, 54.87 mmole) in CH2CI2 (100 mL) at 0 °C. The reactionwas warmed to RT and stirred for 2 hr, then Et2O (200 mL) was added slowly. Thesolvents were decanted away from the gummy precipitate, and the precipitate was washedwith additional CH2Cl2/Et2O (several times). The resulting brownish-yellow residuesolidified on standing in a refrigerator ovemight. This solid was collected and washed withEt2Û to afford the title compound (15.07 g) as a yellow solid. Additional title compound(2.05 g) was obtained as white needles by concentration of the combined organic layers.

The total yield of title compound was 17.89 g (96%): MS (ES) m/e 245 and 247 (M + H)+.

Préparation 7

Préparation of 2-i(5-hydroxv-l-pentyl)amino1pyridine-N-oxide a) 2-[(5-Hydroxy-1 -pentyI)amino]pyridine-N-oxide A suspension of 2-chloropyridine N-oxide hydrochloride (1.00 g, 6.03 mmole) and

NaHCÛ3 (2.53 g, 30.1 mmole) in tert-amyl alcohol (20 mL) was heated to reflux for 18 h.

The reaction was cooled to RT, diluted with CH2CI2, and filtered. The filtrate wasconcentrated to give a pale green oil. Radial chromatography (10% MeOH/CHCl3, silicagel, 6 mm plate) gave the title compound (0.52 g) as a clear oil: NMR (300 MHz, CDCI3) δ 8.10 (d, J = 6.5 Hz, 1 H), 7.18 (t, J = 7.3 Hz, 1 H), 6.85 (br s, 1 H), 6.50 (m, 2 H),3.65 (t, J = 6.2 Hz, 2 H), 3.23 (m, 2 H), 2.20 (br s, 1 H), 1.85 - 1.40 (m, 6H).

Préparation 8

Préparation of 2-rN-(tert-butoxycarbonvl)-N-methylaminol-5-pvridylethanol a) 5-Bromo-2-[(tert-butoxycarbonyl)amino]pyridine -59- 012189 A solution of 2-amino-5-bromopyridine (5.67 g, 32.7 nlmole)and di-tert-butyldicarbonate(8.57 g, 38.3 mmole) in CH2CI2 (50 mL) was concentrated on the rotavap at50°C, and the resulting residue was allowed to rotate on the rotavap at 50 °C under vacuumovemight. After 20 hr, the reaction was chromatographed on silica gel (5%

MeOH/hexanes) to afford the title compound (6 g, 67% )as a white solid: MS (ES) m/e273 (M + H)+. b) 5-Bromo-2-[N-(tert-butoxycarbonyl)-N-methylamino]pyridine

To a solution of 5-bromo-2-[(tert-butoxycarbonyl)amino]pyridine (6 g, 21.9mmole) in dry DMF (50 mL) under nitrogen was added in portions 80% NaH (0.8 g, 26.3mmol ) at 0 °C The reaction mixture was stirred at 0 °C for 15 min ,then iodomethane (3mL, 43.8 mmole) was added in a stream. The reaction was stirred at RT ovemight, thenwas concentrated in vacuum. The residue was diluted with water and extracted withCH2CI2· Drying (MgSO/p, concentration, and flash chromatography on silica gel (5%EtOAc/hexanes) gave the title compound ( 2.2 g 35%) as an oil: MS (ES) m/e 286.9 (M +H)+. c) 2-[N-(tert-Butoxycarbonyl)-N-methylamino]-5-vinylpyridine

To a solution of 5-bromo-2-[N-(tert-butoxycarbonyl)-N-methylamino]pyridine (2.2g, 7.69 mmol ) and vinyltributyltin ( 3.4 mL 11.5 mmol ) in toluene at RT was addedtetrakis(triphenylphosphine)palladium(0) (346 mg, 0.3 mmol ). The solution was degassedunder vacuum for 10 min, then was heated at reflux. After 5 hr, the reaction was cooled,concentrated in vacuum, and flash chromatographed on silica gel (5% EtOAc/hexanes) toafford the title compound (1.0 g, 65%) as a colorless oil: MS (ES) m/e 235 (M + H )+.Unchanged 5-bromo-2-[N-(tert-butoxycarbonyl)-N-methylamino]pyridine (0.3 g) was alsorecovered. d) 2-[N-(tert-Butoxycarbonyl)-N-methylamino]-5-pyridylethanol

To a solution of 2-[N-(tert-butoxycarbonyl)-N-methylamino]-5-vinylpyridine (1.1g, 4.7 mmole) in dry THF (20 mL) was added borane-tetrahydrofuran complex (1.0 M inTHF, 3 mL, 3 mmole) at 0 °C. The reaction was heated for 1 hr, then was concentrated invacuum. The crude product was dissolved in THF (5 mL), and NaOAc (770 mg, 9.4mmole) was added, followed by 30% H2O2 (1.56 mL). The reaction was stirred at RT for1 hr, then was partly concentrated in vacuum. The residue was treated with saturated NaCl(mL) and the mixture was extracted with CH2CI2. Drying (MgSOzp, concentration, andflash chromatography on silica gel (1:1 EtOAc/hexanes) gave the title compound (230 mg,21%) as a colorless oil: MS (ES) m/e 253 (M + H )+. -60- 012189 ~ . Préparation 9

Préparation of 2-rN-(3-methanesulfonvloxv-l-propyl)-N-(ferf- butoxycarbonvl)aminolpyridine-N-oxide 5 a) 2-[N-(3-Hydroxy-l-propyl)-N-(tert-butoxycarbonyl)amino3pyridine-N-oxide A solution of 2-[(3-hydroxy-l-propyl)amino]pyridine-N-oxide (8.0 g, 47.6 mmole)in tert-BuOH (80 mL) was treated with di-ferf-butyl dicarbonate (11.4 g, 55.3 mmole).

After 18h, the solution was concentrated and the residue was triturated with hexane. The 10 resulting solid was dried in vaciio to give the title compound (12.5 g, 98%) as an off-whitesolid: MS (ES) m/e 269.3 (M + H)+. b) 2-[N-(3-Methanesulfonyloxy-l-propyl)-N-(tert-butoxycarbonyl)amino]pyridine-N-oxide 15 Methanesulfonyl chloride (0.17 mL, 2.20 mmole) was added dropwise to a solution of 2-[N-(3-hydroxy-l-propyl)-N-(ferf-butoxycarbonyl)amino]pyridine-N-oxide (0.50 g, 1.86 mmole) and pyridine (0.23 mL, 2.84 mmole) in CHCI3 (5 mL, dried over K2CO3) at0°C. When complété by ILC, the reaction was diluted with CHCI3, washed with ice water,dried (Na2SC>4), and concentrated. Silica gel chromatography (10% MeOH/CHCl3) gave 20 the title compound (0.41 g, 64%) as a colorless oil: NMR (250 MHz, CDCI3) δ 8.25 (dd, J = 6.0,1.9 Hz, 1 H), 7.25 (m, 4 H), 4.35 (t, J = 6.2 Hz, 2 H), 3.75 (t, J = 6.6 Hz, 2 H),3.00 (s, 3 H), 2.00 (m, 2 H), 1.40 (s, 9 H). Unchanged 2-[N-(3-hydroxy-l-propyl)-N-(rerz-butoxycarbonyl)amino]pyridine-N-oxide (0.18 g, 36%) could also be recovered from thechromatographie purification. 25

Préparation 10

Préparation of (±)-ethvl 4-(4-carboxyphenyl)-3-phenvlbutanoate 30 a) Ethyl (±)-3-phenyl-4-[4-(trifluoromethanesulfonyloxy)phenyl]butanoate

Trifluoromethanesulfonic anhydride (1.4 mL, 8.4 mmole) was added rapidly dropwise to a solution of ethyl (±)-4-(4-hydroxyphenyl)-3-phenylbutanoate (1.84 g, 6.47mmole) and 2,6-lutidine (1.5 mL, 12.9 mmole) in anhydrous CH2CI2 (32 mL) at -78°Cunder argon. After 0.5 hr, the yellow solution was warmed to RT and stirred for 1 hr. The 35 reaction was diluted with Et2Û (150 mL) and washed sequentially with 1.0 N HCl (15 mL),5% NaHCC>3 (15 mL), and saturated brine(15 mL). Drying (MgSO^, concentration, andsilica gel chromatography (15% EtOAc/hexanes) gave the title compound (2.62 g, 97%) asa nearly colorless oil: TLC Rf (20% EtOAc/hexanes) 0.55; MS (ES) m/e 417.0 (M + H)+. -61 - 012189 b) Ethyl (±)-4-(4-carboxyphenyl)-3-phenylbutanoate A mixture of ethyl (±)-3-phenyl-4-[4- (trifluoromethanesulfonyloxy)phenyl]butanoate (2.62 g, 6.29 mmole), anhydrous KOAc(2.47 g, 25.16 mmole), Pd(OAc)2 (70.6 mg, 0.31 mmole), dppf (697.4 mg, 1.26 mmole),and anhydrous DMSO (31 mL) was purged with carbon monoxide (three évacuation/carbon monoxide purge cycles, followed by bubbling carbon monoxide through the mixturefor 5 min), then was heated at 70°C under a balloon of carbon monoxide. After 3.5 hr, thereaction was diluted with HjO (31 mL), cooled in ice, and acidified with 1.0 N HCl (25mL). CH2CI2 extraction (2 x 100 mL), drying (MgSO4), concentration, andreconcentration from toluene left a reddish-orange liquid. Silica gel chromatography (1%

AcOH in 7:3 toluene/EtOAc) gave the title compound (1.78 g, 91%) as a cream-coloredsolid: TLC Rf (1% AcOH in 7:3 toluene/EtOAc) 0.47; MS (ES) m/e 313.2 (M + H)+.

Préparation 11 HPLC séparation of the enantiomers of ethyl (±)-4-(4-hydroxyphenvl)-3-phenvlbutanoate a) Ethyl (S)-(-)-4-(4-hydroxyphenyl)-3-phenylbutanoate and ethyl (R)-(+)-4-(4-hydroxyphenyl)-3-phenylbutanoate

Ethyl (±)-4-(4-hydroxyphenyl)-3-phenylbutanoate was resolved into itsenantiomers using the following conditions: Daicel Chiralcel AD® column (21.2 mm x250 mm), 5% éthanol in hexane mobile phase, 15 mL/min flow rate, uv détection at 254nm, 40 mg injection; tR for ethyl (S)-(-)-4-(4-hydroxyphenyl)-3-phenylbutanoate = 19.8min.; tR for ethyl (R)-(+)-4-(4-hydroxyphenyl)-3-phenylbutanoate = 23.0 min.

Préparation 12

Préparation of methyl 4-(4-hydroxyphenyl)butanoate a) Methyl 4-benzyloxyphenylacetate

To a suspension of K2CO3 (20.7 g, 150 mmoles) in acetone (50 mL) was addedmethyl 4-hydroxyphenyl acetate (5.0 g, 30 mmoles) and benzyl chloride (10.4 mL, 90mmoles) and the mixture was heated to reflux. After 24 hr the mixture was cooled to RT,filtered, and concentrated. The residue was chromatographed on silica gel (10%

EtOAc/hexanes) to afford the title compound (7.7 g, 100%) as a white solid: iH NMR (300MHz, CDCI3) δ 7.40 (m, 5 H), 7.21 (d, J = 6.6 Hz, 2 H), 6.95 (d, J = 6.6 Hz, 2 H), 5.05 (s, 2H), 3.70 (s, 3 H), 3.59 (s, 2 H). -62- 012189 b) 4-Benzyloxyphenethyl alcohol

To a solution of methyl 4-benzyloxyphenylacetate (1.5 g, 5.85 mmoles) in dry THF(30 mL) was added L1AIH4 (244 mg, 6.44 mmoles) at 0 °C. After 2 hr the mixture wasquenched by dropwise addition of 1.0 N NaOH until white solid aluminum salts hadformed. The mixture was diluted with EtOAc (100 mL), dried over MgSC>4, filtered, andconcentrated to give the title compound (1.35 g, quantitative) which was used withoutpurification. NMR (300 MHz, CDCI3) δ 7.40 (m, 5 H), 7.15 (d, J = 6.6 Hz, 2 H), 6.90(d, J = 6.6 Hz, 2 H), 5.05 (s, 2 H), 3.82 (t, 2 H), 2.81 (t, 2 H). c) 4-Benzyloxyphenylacetaldehyde

To a solution of DMSO (0.83 mL, 11.7 mmoles) in CH2CI2 (20 mL) was addedoxalyl chloride (0.51 mL, 5.85 mmoles) at -78 °C. After 10 min, a solution of 4-(benzyloxy)phenethyl alcohol (1.35 g, 5.85 mmoles) in CH2CI2 (10 mL) was added. After30 min ΕΐβΝ (2.69 mL, 19.3 mmoles) was added and the mixture was warmed to RT. After30 min the mixture was washed sequentially with 10 mL each H20,10% HCl, and H2O,then the resulting organic layer was dried over MgSC>4, filtered, and concentrated. Theresidue was used immediately in the next step without purification. d) Methyl 4-(4-benzyloxyphenyl)crotonate

To a solution of 4-benzyloxyphenylacetaldehyde (5.85 mmoles) in dry THF (30mL) was added methyl (triphenylphosphoranylidene)acetate (2.4 g, 7.02 mmoles). After 18hr the mixture was concentrated. The residue was taken up in 1:1 Et2O/hexanes (200 mL)and filtered. The filtrate was concentrated and the residue was chromatographed on silicagel (10% EtOAc/hexanes) to afford the title compound (780 mg, 47% from b) as a yellowoil: JH NMR (300 MHz, CDCI3) δ 7.35 (m, 5 H), 7.05 (m, 2 H), 6.90 (m, 3 H), 5.80 (d, J =15 Hz, 1H), 5.05 (s, 2 H), 3.79 (s, 3 H), 3.47 (d, J = 6.0 Hz, 2 H). e) Methyl 4-(4-hydroxyphenyl)butanoate

To a suspension of 10% Pd/C (113 mg) in absolute EtOH (15 mL) was addedmethyl 4-(4-benzyloxyphenyl)crotonate (300 mg, 1.06 mmoles). The mixture wasdeoxygenated (3 x évacuation/^ purge cycles) then was charged with H2 (50 psi). After 2hr the H2 was removed and the mixture was filtered through a pad of celite®. The filtratewas concentrated and the residue was chromatographed on silica gel (30% EtOAc/hexanes)to afford the title compound (180 mg, 87%) as a colorless oil: JH NMR (300 MHz, CDCI3) δ 7.05 (m, 2 H), 6.90 (m, 2 H), 3.68 (s, 3 H), 2.69 (t, 2 H), 2.30 (t, 2 H), 1.90 (m, 2H). -63- 012189

Préparation 13

Préparation of methyl (±)-4-(4-hvdroxvphenvl)-3-vinylbutanoate a) Methyl 4-(triisopropylsiloxy)phenylacetate

To a solution of methyl 4-hydroxyphenylacetate (5.0 g, 30 mmoles) and imidazole(4.08 g, 60 mmoles) in dry DMF (80 mL) was added triisopropylsilyl chloride (9.6 mL, 45mmoles). After 18 hr the mixture was poured into H2O (500 mL) and extracted withhexanes (3 x 300 mL). The combined organic layers were dried over MgSO^ filtered, andconcentrated. The residue was chromatographed on silica gel (5% EtOAc/hexanes) to givethe title compound (9.03 g, 93%) as a colorless oil: NMR (300 MHz, CDCI3) δ 7.10 (d, J = 6.6 Hz, 2 H), 6.80 (d, J = 6.6 Hz, 2 H), 3.66 (s, 3 H), 3.51 (s, 2 H), 1.23 (m, 3 H), 1.08(d, J = 7.5 Hz, 18 H). b) 4-(Triisopropylsiloxy)phenethyl alcohol

To a solution of methyl 4-(triisopropyIsiloxy)phenylacetate (9.03 g, 28 mmoles) indry THF (100 mL) was added LÎA1H4 (1.17g, 30.8 mmoles) at 0 °C. After 1 hr themixture was quenched by dropwise addition of 1.0 N NaOH until white solid aluminumsalts had formed. The mixture was diluted with EtOAc (100 mL), dried over MgSOz},filtered, and concentrated to give the title compound (8.02 g, 97%) which was used withoutpurification: JH NMR (300 MHz, CDCI3) δ 7.10 (d, J = 6.6 Hz, 2 H), 6.80 (d, J = 6.6 Hz, 2H), 3.80 (t, 2 H), 2.79 (t, 2 H), 1.23 (m, 3 H), 1.08 (d, J = 7.5 Hz, 18 H). c) 4-(TriisopropyIsiloxy)phenylacetaldehyde

To a solution of DMSO (3.83 mL, 54 mmoles) in (¾¾ (100 mL) was addedoxalyl chloride (2.36 mL, 27 mmoles) at -78 °C. After 10 min, a solution of 4-(triisopropylsiloxy)phenethyl alcohol (8.02 g, 27 mmoles) in CH2CI2 (25 mL) was added.After 1 hr Et3N (12.5 mL, 89.8 mmoles) was added and the mixture was warmed to RT.After 1.5 hr the mixture was washed sequentially with 50 mL each H2O, 10% HCl, andH2O, then the resulting organic layer was dried over MgSÜ4, filtered, and concentrated.The residue was used immediately in the next step without purification. d) Methyl 4-[(4-triisopropylsiloxy)phenyl]crotonate

To a solution of 4-(triisopropylsiloxy)phenylacetaldehyde (27 mmoles) in drybenzene (100 mL) was added methyl (triphenylphosphoranylidene)acetate (18.1 g, 54mmoles). After 96 hr the mixture was concentrated. The residue was taken up in Et2Û(500 mL) and filtered. The filtrate was concentrated and the residue was chromatographedon silica gel (2:1 hexanes/CH2Cl2) to afford the title compound (3.39 g, 36% from b) as a -64- 012189 yellow oil: NMR (300 MHz, CDC13) δ 7.09 (m, 1 H), 6.99 (d, J = 6.6 Hz, 2 H), 6.79 (d, J = 6.6 Hz, 2 H), 5.78 (d, J = 15 Hz, 1 H), 3.71 (s, 3 H), 3.42 (d, J = 7.1 Hz, 2 H), 1.23 (m, 3H), 1.08 (d, J = 7.5 Hz, 18 H). e) Methyl (±)-4-[(4-triisopropylsiloxy)phenyl]-3-vinylbutanoate

To a suspension of CuBr-DMS complex (647 mg, 3.0 mmoles) in dry THF (10 mL)was added vinyl magnésium bromide (6.0 mL, 6.0 mmoles) dropwise at -78 °C. After 15min, a solution of methyl 4-[(4-triisopropylsiloxy)phenyl]crotonate (350 mg, 1.0 mmoles)in dry THF (3 mL) was added dropwise. After 1.5 hr the mixture was quenched with H2O(10 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were driedover MgSÛ4, filtered, and concentrated. The residue was chromatographed on silica gel(3:1 hexanes/CH2Cl2) to give the title compound (224 mg, 59%) as a yellow oil: ^H NMR(300 MHz, CDCI3) δ 6.99 (d, J = 6.6 Hz, 2 H), 6.79 (d, J = 6.6 Hz, 2 H), 5.69 (m, 1 H), 4.95 (m, 2 H), 3.60 (s, 3 H), 2.80 (m, 1 H), 2.59 (m, 2 H), 2.32 (m, 2 H), 1.23 (m, 3 H), 1.08(d, J = 7.5 Hz, 18 H). f) Methyl (±)-4-(4-hydroxyphenyl)-3-vinylbutanoate

To a solution of methyl (±)-4-[(4-triisopropylsiloxy)phenyl]-3-vinylbutanoate (224mg, 0.59 mmoles) in dry THF (5 mL) was added a solution of TB AF in THF (1.0 M, 0.65mL, 0.65 mmoles). After 1 hr the mixture was diluted with H2O (10 mL) and extractedwith EtOAc (3 x 20 mL). The combined organic layers were dried over MgSO4, filtered,and concentrated. The residue was chromatographed on silica gel (30% EtOAc/hexane) togive the title compound (92.5 mg, 71%) as a yellow oil: ^H NMR (300 MHz, CDCI3) δ7.00 (d, J = 6.6 Hz, 2 H), 6.74 (d, J = 6.6 Hz, 2 H), 5.70 (m, 1 H), 4.99 (m, 2 H), 4.75 (bs, 1H), 3.62 (s, 3 H), 2.80 (m, 1 H), 2.59 (m, 2 H), 2.32 (m, 2 H).

Préparation 14

Préparation of ethvl (±)-4-(4-hydroxyphenvl)-3-(pyridin-2-vl)butanoate a) 4-Benzyloxy-N-methoxy-N-methylphenylacetamide

To a suspension of Ν,Ο-dimethylhydroxylamine hydrochloride (761 mg, 7.8mmoles) in dry toluene (20 mL) was added trimethylaluminum (7.8 mL, 7.8 mmoles) atRT. After 1 hr methyl 4-(benzyloxy)phenylacetate (1.0 g, 3.9 mmoles) was added and themixture was heated to reflux. After 2 hr the mixture was cooled to RT and stirred for 18 hr,then was quenched by the slow addition of 10% HCl (20 mL) and extracted with EtOAc (3x 30 mL). The combined organic layers were dried over MgSÛ4, filtered, and -65- 012189 concentrated. The residue was chromatographed on silica gel (75% EtOAc/hexanes) togive the title compound (473 mg, 43%) as an orangish solid: MS (ES) m/e 286 (M + H)+. b) 2-[4-(Benzyloxy)phenyl]-l-(pyridin-2-yl)ethanone

To a solution of 2-bromopyridine (0.08 mL, 0.8 mmoles) in dry THF (2 mL) wasadded t-BuLi (0.94 mL, 1.6 mmoles) at -78 °C. After 10 min, a solution of 4-benzyloxy-N-methoxy-N-methylphenylacetamide (115 mg, 0.4 mmoles) in dry THF (2 mL) was added.

The mixture was allowed to warm as the bath warmed. After 18 hr the mixture wasquenched with saturated NH4CI (20 mL) and extracted with EtOAc (3 x 20 mL). Thecombined organic layers were dried over MgSC>4, filtered, and concentrated. The residuewas chromatographed on silica gel (15% EtOAc/hexanes) to give the title compound (80mg, 66%) as an orangish solid: MS (ES) m/e 304 (M + H)+. c) Ethyl (±)-4-[4-(benzyloxy)phenyl]-3-(pyridin-2-yl)crotonate

To a suspension of NaH (21 mg, 0.53 mmoles) in dry THF (2 mL) was addedtriethyl phosphonoacetate (0.11 mL, 0.53 mmoles) dropwise at RT. After 10 min, asolution of 2-[4-(benzyloxy)phenyl]-l-(pyridin-2-yl)ethanone (80 mg, 0.26 mmoles) in dryTHF (2 mL) was added dropwise. After 4 hr the mixture was concentrated. The residuewas chromatographed on silica gel (30% EtOAc/hexanes) to give the title compound (82mg, 84%) as a mixture of olefin isomers: MS (ES) m/e 374 (M + H)+. d) Ethyl (±)-4-(4-hydroxyphenyl)-3-(pyridin-2-yl)butanoate

To a suspension of 10% Pd/C (69 mg) in 1:1 EtOAc/i-PrOH (10 mL) was addedethyl (±)-4-[4-(benzyloxy)phenyl]-3-(pyridin-2-yl)crotonate (243 mg, 0.65 mmoles). Themixture was deoxygenated (3 x evacuation/N2 purge cycles) then was charged with H2 (50psi). After 4 hr the H2 was removed and the mixture was filtered through a pad of celite®.

The filtrate was concentrated to afford the title compound as an oil (90 mg, 49%) whichwas used without purification: ^H NMR (300 MHz, CDCI3) δ 8.55 (d, 1 H), 7.48 (t, 1 H), 7.08 (m, 1 H), 6.95 (m, 3 H), 6.80 (m, 3 H), 3.98 (q, 2 H), 3.55 (m, 1 H), 2.90 (m, 2 H), 2.62 (m,2H), 1.09 (t, 3 H).

Préparation 15

Préparation of methvl (±)-4-(4-hydroxyphenyl)-3-(oxazol-2-yl)butanoate a) Methyl 3-(benzyloxycarbonyl)-3-butenoate

Diisopropyl azodicarboxylate (32.8 mL, 166 mmole) was added to a solution of methyl 3-carboxy-3-butenoate (20 g, 139 mmole), benzyl alcohol (17.2 mg, 166 mmole), -66- 012189 and triphenylphôsphine (43.7 g, 166 mmole) in anhydrous THF (500 mL) at 0 °C. Themixture was allowed to warm as the bath warmed to RT. After 3 hr the mixture wasconcentrated and the residue was chromatographed on silica gel (10% EtOAc/hexanes).

The title compound (29.46 g, 91%) was obtained as a colorless oil: NMR (300 MHz, CDC13) δ 7.35 (m, 5 H), 6.48 (s, 1 H), 5.71 (s, 1 H), 5.20 (s, 2 H), 3.63 (s, 3 H), 3.37 (s, 2H). b) Methyl (±)-4-(4-methoxyphenyl)-3-carboxybutanoate A solution of 4-bromoanisole (3.35 mL, 26.7 mmoles), methyl 3-(benzyloxycarbonyl)-3-butenoate (12.5 g, 53.4 mmoles), Pd(OAc)2 (599 mg, 2.67mmoles), P(o-tolyl)3 (1.63 g, 5.34 mmoles), and (i-Pr)2NEt (9.3 mL, 53.4 mmoles) inpropionitrile (100 mL) was deoxygenated (3 x évacuation/^ purge cycles) then was heatedto reflux. After 24 hr the mixture was concentrated, and the residue was chromatographedon silica gel (15% EtOAc/hexanes) to give a yellow oil. The oil was taken up in 20%EtOAc/hexanes (100 mL), and the solution was allowed to stand at RT. After 18 hr themixture was filtered and the fîltrate was concentrated to give the title compound as amixture of olefin isomers. This was used immediately in the next step.

To a suspension of 10% Pd/C (2.8 g) in 1:1 EtOAc/i-PrOH (100 mL) was added theabove olefin mixture. The mixture was deoxygenated (3 x évacuation/^ purge cycles)then was charged with H2 (50 psi). After 4 hr the H2 was removed and the mixture wasfiltered through a pad of celite®. The fîltrate was concentrated to afford the title compound(5.81 mg, 86% from 4-bromoanisole) as a yellow oil: NMR (300 MHz, CDCI3) δ 7.09 (d, J = 6.8 Hz, 2 H), 6.81 (d, J = 6.8 Hz, 2 H), 3.78 (s, 3 H), 3.64 (s, 3 H), 3.08 (m, 2 H), 2.68 (m, 2 H), 2.40 m, 1 H). c) Methyl (±)-4-(4-methoxyphenyl)-3-[(2,2-dimethoxyethyl)aminocarbonyl]butanoate

To a solution of methyl (±)-4-(4-methoxyphenyl)-3-carboxybutanoate (300 mg, 1.19 mmoles) in CH2CI2 (5 mL) was added Ι,Γ-carbonyl diimidazole (289 mg, 1.78mmoles). After 1 hr aminoacetaldehyde dimethyl acetal (0.2 mL, 1.78 mmoles) was added.After 72 hr the mixture was concentrated. The residue was chromatographed on silica gel(50% EtOAc/hexanes) to give the title compound (287 mg, 71%) as a clear oil: MS (ES)m/e 340 (M + H)+. d) Methyl (±)-4-(4-methoxyphenyl)-3-(oxazol-2-yl)butanoate

To a solution of methyl 4-(4-methoxyphenyl)-3-[(2,2-dimethoxyethyl)aminocarbonyl]butanoate (287 mg, 0.85 mmoles) in THF (5 mL) wasadded 6.0 N HCl (5 mL). After 1 hr the mixture was extracted with EtOAc (3x10 mL).

The combined organic layers were dried over MgSÜ4, filtered, and concentrated. The -67- 012189 residue was taken up in CH2CI2 (5 mL) and added to a solution of PPI13 (267 mg, 1.02mmoles), I2 (259 mg, 1.02 mmoles), and EtgN (0.24 mL, 1.02 mmoles) in CH2CI2 (5 mL).After 18 hr the mixture was concentrated. The residue was chromatographed on silica gel(50% EtOAc/hexanes) to give the title compound (95 mg, 41%) as a yellow oil: MS (ES)m/e 276 (M + H)+. e) Methyl (±)-4-(4-hydroxyphenyl)-3-(oxazol-2-yl)butanoate

To a solution of methyl (±)-4-(4-methoxyphenyl)-3-(oxazol-2-yl)butanoate (314mg, 1.14 mmoles) in CH2CI2 (5 mL) was added BBrç (3.42 mL, 3.42 mmoles) at -20 °C.After 1 hr the mixture was carefully quenched with 10% HCl in MeOH (10 mL), and thesolution was allowed to warm to RT. After 18 hr the mixture was concentrated. Theresidue was taken up in saturated NaHCO3 (20 mL) and extracted with Et2Ü (3 x 20 mL).The combined organic layers were dried over MgSCty, filtered, and concentrated. Theresidue was chromatographed on silica gel (50% EtOAc/hexanes) to give the titlecompound (163 mg, 55%) as a yellow oil: MS (ES) m/e 262 (M + H)+.

Préparation 16

Préparation of ethvl (i)-4-(4-hvdroxyphenvl)-3-(thiazol-2-yl)butanoate a) 2-[4-(Benzyloxy)phenylJ-l-(thiazol-2-yl)ethanone

To a solution of n-BuLi (0.98 mL, 2.44 mmoles) in dry Et2Û (5 mL) was added 2-bromothiazole (0.21 mL, 2.34 mmoles) dropwise at -78 °C. After 20 min methyl 4-(benzyloxy)phenylacetate (0.5 g, 1.95 mmoles) in dry Et20 (5 mL) was added dropwise.After 1 hr the mixture was quenched with saturated NH4CI (10 mL), warmed to RT, andextracted with Et20 (3 x 20 mL). The combined organic layers were dried over MgSC>4,filtered, and concentrated. The residue was chromatographed on silica gel (20%EtOAc/hexanes) to give the title compound (485 mg, 80%) as a brownish-yellow solid. MS(ES) m/e 310 (M + H)+. b) Ethyl (±)-4-[4-(benzyloxy)phenyl]-3-(thiazol-2-yl)crotonate

To a suspension of NaH (111 mg, 2.78 mmoles) in dry THF (5 mL) was addedtriethyl phosphonoacetate (0.56 mL, 2.78 mmoles) dropwise at RT. After 15 min, asolution of 2-[4-(benzyloxy)phenyl]-l-(thiazol-2-yl)ethanone (430 mg, 1.39 mmoles) in dryTHF (5 mL) was added dropwise. After 6 hr the mixture was quenched with saturatedNH4CI (10 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers weredried over MgSÛ4, filtered, and concentrated. The residue was chromatographed on silica -68- 012189 ««. gel (20% EtOAc/hexanes) to give the title compound (356 mg, 67%) as a mixture of olefinisomers: MS (ES) m/e 380 (M + H)+. c) Ethyl (±)-4-(4-hydroxyphenyl)-3-(thiazol-2-yl)butanoate 5 To a suspension of 10% Pd/C (100 mg) in absolute EtOH (5 mL) was added ethyl (±)-4-[4-(benzyloxy)phenyl]-3-(thiazol-2-yl)crotonate (356 mg, 0.94 mmoles). Themixture was deoxygenated (3 x evacuation/N2 purge cycles) then was charged with H2 (50psi). After 4 hr the H2 was removed and the mixture was filtered through a pad of celite®.

The fîltrate was concentrated. The reaction was repeated three times. The residue was 10 chromatographed on silica gel (35% EtOAc/hexanes) to afford the title compound (155 mg,57%) as an oil: MS (ES) m/e 292 (M + H)+.

Préparation 17 15 Préparation of ethyl (i)-4-(4-hvdroxyphenvl)-3-methylbutanoate a) Ethyl (±)-4-(4-methoxyphenyl)-3-methylcrotonate

According to the procedure of Préparation 16 (b), except substituting 4-methoxyphenylacetone for the of 2-[4-(benzyloxy)phenyl]-l-(thiazol-2-yl)ethanone, the 20 title compound (5.2 g, 74%) was prepared: NMR (300 MHz, CDCI3) δ 7.08 (d, J = 8.7

Hz, 2 H), 6.85 (d, J = 8.7 Hz, 2 H), 5.66 (narrow m, 1 H), 4.14 (q, J = 7.1 Hz, 2 H), 3.80 (s, 3 H), 3.37 (s, 2 H), 2.12 (d, J = 1.2 Hz, 3 H), 1.27 (t, J = 7.1 Hz, 3 H). b) Ethyl (±)-4-(4-methoxyphenyl)-3-methylbutanoate 25 According to the procedure of Préparation 16 (c), except substituting ethyl (±)-4- (4-methoxyphenyl)-3-methylcrotonate for the ethyl (±)-4-[4-(benzyloxy)phenyl]-3-(thiazol-2-yl)crotonate, the title compound (5.1 g, 97%) was prepared as a colorless oil: ^H NMR(300 MHz, CDCI3) δ 7.07 (d, J = 8.5 Hz, 2 H), 6.83 (d, J = 8.5 Hz, 2 H), 4.11 (q, J = 7.1Hz, 2 H), 3.79 (s, 3 H), 2.00 - 2.60 (m, 5 H), 1.25 (t, J = 7.1 Hz, 3 H), 0.93 (d, J = 6.3 Hz, 3 30 H). c) Ethyl (±)-4-(4-hydroxyphenyl)-3-methylbutanoate

According to the procedure of Préparation 15 (e), except substituting ethyl (±)-4-(4-methoxyphenyl)-3-methylbutanoate for the methyl (±)-4-(4-methoxyphenyl)-3-(oxazol- 35 2-yl)butanoate, the title compound (3.2 g, 70%) was prepared as a yellow oil: ^H NMR(250 MHz, CDCI3) δ 7.00 (d, 2 H), 6.76 (d, 2 H), 5.95 - 6.15 (m, 1 H), 4.13 (q, 2 H), 2.05 -2.60 (m, 5 H), 1.25 (t, 3 H), 0.93 (d, 3 H). -69- 012189

Préparation 18

Préparation of methyl 4-(4-methoxyphenyl)crotonate a) 4-Methoxyphenylacetaldehyde A solution of 4-methoxyphenethyl alcohol (1.14 g, 7.49 mmole) in CH2CI2 (30mL) was added dropwise to a suspension of PCC (2.45 g, 11.37 mmole) and NaOAc (1.85g, 22.55 mmole) in CH2CI2 (50 mL) at 0 °C under argon. After 1 hr, the mixture wasfiltered, and both celite® and activated charcoal were added to the filtrate. This mixturewas filtered, and the filtrate was concentrated on the rotavap. The residue was dissolved inEt2O, and both MgSC>4 an<^ activated charcoal were added. Filtration and concentrationgave the title compound (1.1 g, 98%) as a colorless oil. This material was usedimmediately in the next step without further purification. b) Methyl 4-(4-methoxyphenyl)crotonate A solution of 4-methoxyphenylacetaldehyde (1.1 g, 7.33 mmole) and methyl(triphenylphosphoranylidene)acetate (2.99 g, 8.94 mmole) in THF (50 mL) was stirred atRT ovemight, then was concentrated in vacuum. The residue was dissolved in Et20, andthe solution was treated with celite® and activated charcoal. Filtration, concentration, andsilica gel chromatography (5% EtOAc/hexanes) gave the title compound (0.5 g, 33%):NMR (300 MHz, CDC13) δ 7.00 - 7.20 (m, 3 H), 6.85 (d, J = 8.6 Hz, 2 H), 5.79 (d, J = 15.5Hz, 1 H), 3.79 (s, 3 H), 3.71 (s, 3 H), 3.46 (d, J = 6.7 Hz, 2 H). c) Methyl 4-(4-hydroxyphenyl)crotonate BBrç (1.0 M in CH2CI2,4.0 mL, 4.0 mmole) was added dropwise to a solution ofmethyl 4-(4-methoxyphenyl)crotonate (0.75 g, 3.64 mmole) in CH2CI2 (30 mL) at 0 °Cunder argon. The reaction was stirred at 0 °C for 2 hr, then additional BBrg (1.0 M inCH2CI2, 1.0 mL, 1.0 mmole) was added. After another 1 hr, the reaction was quenchedcarefully by slow addition of MeOH. The solution was concentrated, and the residue wasreconcentrated from MeOH (2x). The resulting residue was flash chromatographed onsilica gel (1% MeOH/ 0¾¾) to afford the title compound (0.46 g, 66%): ^H NMR (300MHz, CDC13) δ 6.95 - 7.25 (m, 3 H), 6.80 (d, J = 8.4 Hz, 2 H), 5.82 (d, J = 15.6 Hz, 1 H),5.08 (s, 1 H), 3.75 (s, 3 H), 3.48 (d, J = 6.8 Hz, 2 H). -70- 012189

Préparation 19

Préparation of methyl (±)-4-(4-hydroxvphenyl)-3-(thiophen-2-yl)butanoate a) Ethyl (±)-3-(4-methoxyphenyl)-2-(thiophen-2-yl)propionate

Lithium hexamethyldisilazide (1.0 M in THF, 14 mL, 14.0 mmole) was added to a solution of ethyl 2-thiopheneacetate (2.268 g, 13.32 mmole) in dry THF (10 mL) at -78 °Cunder argon. After 1 hour, 4-methoxybenzyl chloride (2.0 mL, 14.75 mmole) was added.

The reaction was kept at -78 °C for another 15 min, then was allowed to warm to RT. After18 hours, the reaction was diluted with EtOAc and the solution was washed with 1.0 N HCl(2x) followed by 1.0 N NaHCO3 (2x). Drying (MgSC>4), concentration, and flashchromatography on silica gel (gradient: 5% EtOAc/hexanes, then 10% EtOAc/hexanes,then 20% EtOAc/hexanes) gave the title compound (2.71 g, 66%) as a clear colorless oil: *H NMR (300 MHz, CDCI3) δ 7.16 - 7.14 (m, 1 H), 7.04 (d, J = 8.7 Hz, 2 H), 7.02 - 6.87(m, 2 H), 6.76 (d, J = 8.7 Hz, 2 H), 4.14 - 4.02 (m, 3 H), 3.71 (s, 3 H), 3.30 (dd, J = 13.6, 8.9 Hz, 1 H), 3.04 (dd, J = 13.7,6.7 Hz, 1 H), 1.12 (t, J = 7.2, 3 H). b) (±)-1 -Diazo-4-(4-methoxyphenyl)-3-(thiophen-2-yl)-2-butanone 1.0 N NaOH (10 mL, 10 mmole) was added to a solution of ethyl (±)-3-(4- methoxyphenyl)-2-(thiophen-2-yl)propionate (2.71 g, 8.84 mmole) in MeOH (10mL), and the resulting bright yellow mixture was further diluted with MeOH andTHF to dissolve a precipitated oil. After 18 hr at RT, the reaction was neutralizedwith 1.0 N HCl (10 mL), and the volatile organics were removed in vacuum. Theremaining aqueous layer was acidified with 1.0 N HCl and extracted with EtOAc.The combined organic layers were dried (MgSO4), fîltered and concentrated invacuum. The residue was dissolved in excess SOCI2, and the solution was heated atreflux for 1 hr. The reaction was concentrated in vacuum and the residue wasreconcentrated from toluene (2x). The resulting residue was dissolved in THF, anddiazomethane, generated from Diazald (2.0077 g, 9.4 mmole), was added at RT.More diazomethane from Diazald (1.4420g, 6.7 mmole) was added, and the reactionwas left stirring at RT ovemight. The resulting orange reaction was concentrated invacuum and the residue was adsorbed onto silica gel. This was loaded onto a drysilica gel column. Flash chromatography (gradient: 5% EtOAc/hexanes, then 10%EtOAc/hexanes, then 20% EtOAc/hexanes) gave the title compound (707.6 mg,30%) as an oil: ^H NMR (300 MHz, CDCI3) δ 7.25 - 7.19 (m, 1 H), 7.03 (d, J = 8.6Hz, 2 H), 6.94 - 6.85 (m, 2 H), 6.77 (d, J = 8.7 Hz, 2 H), 5.18 (s, 1 H), 3.75 (s, 3 H),3.41 (dd, J = 13.8,7.9 Hz, 1 H), 3.00 (dd, J = 13.8, 7.2 Hz, 1 H). -71 - 012189 c) Methyl (±)-4-(4-methoxyphenyl)-3-(thiophen-2-yl)butanoate A solution of silver benzoate (744.2 mg, 3.25 mmole) in triethylamine (3 mL, 21.6mmole) was added to a solution of (±)-l-diazo-4-(4-methoxyphenyl)-3-(thiophen-2-yl)-2-butanone (707.6 mg, 2.47 mmole) in MeOH (20 mL) at RT. Gas évolution was observed,and the reaction mixture became black in color. After 30 min, the reaction was heated toreflux. After 1 hr at reflux, the reaction was filtered through celite® and the filtrate wasconcentrated in vacuum. The residue was adsorbed onto silica gel and was loaded onto adry silica gel column. Flash chromatography (gradient: 5% EtOAc/hexanes, then 10%EtOAc/hexanes) gave the title compound (453.4 mg, 48.0%) as a light yellow oil: NMR (300 MHz, CDC13) δ 7.16 - 7.14 (m, 1 H), 7.04 (d, J = 8.5 Hz, 2 H), 6.91 - 6.89 (m, 1H), 6.81 (d, J = 8.5 Hz, 2 H), 6.77 - 6.76 (m, 1 H), 3.78 (s, 3 H), 3.74 - 3.72 (m, 1 H), 3.61(s, 3 H), 2.97 - 2.92 (m, 2 H), 2.71 - 2.65 (m, 2 H). d) Methyl (±)-4-(4-hydroxyphenyl)-3-(thiophen-2-yî)butanoate

Boron tribromide (1.0 M in CH2CI2, 8 mL, 8 mmole) was added to a solution ofmethyl (±)-4-(4-methoxyphenyl)-3-(thiophen-2-yl)butanoate (453.4 mg, 1.56 mg) inCH2CI2 (10 mL) at 0 °C under argon. After 1 hr, the reaction was quenched with absoluteMeOH and concentrated in vacuum. Reconcentration from toluene (several times)followed by drying in high vacuum gave the title compound (449.6 mg, quantitative) as anoil: !h NMR (300 MHz, CDCI3) δ 7.30 - 7.14 (m, 2 H), 7.04 (d, J = 8.2 Hz, 2 H), 6.95 -6.89 (m, 1 H), 6.74 (d, J = 8.4 Hz, 2 H), 6.14 (br s, 1 H), 3.74 - 3.71 (m, 1 H), 3.62 (s, 3 H),2.95 - 2.89 (m, 2 H), 2.72 - 2.66 (m, 2 H).

Préparation 20

Préparation of ethyl 2-ÎN-benzyl-N-(4-hydroxybenzyl)amino1acetate a) Ethyl 2-[N-benzyl-N-(4-methoxybenzyl)amino]acetate

To a solution of 4-methoxybenzyl chloride (1.00 mL, 7.38 mmole) in DMF (14mL) at 0 °C was added ethyl 2-benzylaminoacetate (1.20 mL, 6.40 mmole) followed byNaH (0.38 g, 60% dispersion in oil, 9.50 mmole). The ice bath was removed and thereaction was allowed to stir at RT for 18 h. The reaction was quenched by pouring intosaturated NaHCO3, and the mixture was extracted with EtOAc. The combined organicextracts were dried over Na2SC>4 and concentrated to give a yellow oil. Radialchromatography (10% EtOAc/hexanes, silica gel, 6 mm plate) gave the title compound(0.40 g) as a clear oil: MS (ES) m/e 314.1 (M + H)+. -72- 012189 b) Ethyl 2-[N-benzyl-N-(4-hydroxybenzyl)amino]acetate A solution of ethyl 2-[N-benzyl-N-(4-methoxybenzyl)amino]acetate (0.40 g, 1.27mmole) in CH2CI2 (2 mL) was added dropwise to a solution of BBrç (3.80 mL, 1.0 M inCH2CI2,3.80 mmole) at 0 °C. After 1 h at 0 °C, the reaction was carefully quenched withMeOH (2 mL). The solvent was removed under reduced pressure and the residue wasazeotroped from MeOH (2x). Radial chromatography (30% EtOAc/hexanes, silica gel, 6mm plate) gave the title compound (0.19 g) as a white solid: MS (ES) m/e 300.1 (M + H)+.

Préparation 21

Préparation of methyl 2-ÎN-(4-hvdroxvbenzvl)-N-phenylamino1acetate a) Methyl 2-[N-(4-methoxybenzyl)-N-phenylamino]acetate

To a solution of methyl 2-(phenylamino)acetate hydrochloride (0.19 g, 0.96mmole) in DMF (3 mL) was added 4-methoxybenzyl chloride (0.52 mL, 3.84 mmole)followed by NaH (0.11 g, 60% dispersion in oil, 2.75 mmole). After 18 h at RT, thereaction was poured into saturated NaHCO3, and the mixture was and extracted withEtOAc. The combined organic extracts were washed with 50% brine, dried over Na2SÛ4,and concentrated to give a yellow oil. Radial chromatography ( 20% EtOAc/hexane, silicagel, 6 mm plate) gave the title compound (0.13 g) as a clear oil·. MS (ES) m/e 286.1 (M +H)+. b) Methyl 2-[N-(4-hydroxybenzyl)-N-phenylamino]acetate A solution of methyl 2-[N-(4-methoxybenzyl)-N-phenylamino]acetate (0.13 g, 0.47mmole) in CH2CI2 was added dropwise to a solution of ΒΒτβ (1.40 mL, 1.0 M in CH2CI2,1.40 mL) at 0 °C. After 45 min at 0 °C, the reaction was carefully quenched by the additionof MeOH (2 mL). The solvent was removed under reduced pressure and the residue wasazeotroped from MeOH (2x). The residue was dissolved in saturated NaHCOj, and thesolution was extracted with EtOAc. The combined organic extracts were dried overNa2SO4 and the solvent was removed under reduced pressure to give a pale yellow oil.Radial chromatography (30% EtOAc/hexane, silica gel, 2 mm plate) gave the titlecompound (39 mg) as a pale yellow solid: MS (ES) m/e 272.2 (M + H)+. -73- 012189

Préparation 22

Préparation of methyl 2-f(4-hydroxy-2-methoxvbenzyl)amino1acetate a) Methyl 2-[(4-hydroxy-2-methoxybenzyl)amino]acetate

To a suspension of 4-hydroxy-2-methoxybenzaldehyde (2.00 g, 13.1 mmole) and glycine methyl ester hydrochloride (6.60 g, 52.6 mmole) in dry MeOH (100 mL) was added4 Â molecular sieves (ca. 2 g) and ΝύΒΗβΟΝ (0.83 g, 13.2 mmole). After 18 hr at RT, thereaction mixture was filtered through a bed of celite® and the solvent was removed underreduced pressure to leave a white residue. Flash chromatography on silica gel (10%MeOH/CHCl3) gave the title compound (1.27 g) as a clear oil: MS (ES) m/e 226.0 (M +H)+.

Préparation 23

Préparation of methyl 2-(4-hydroxv-2-phenoxyphenvl)acetate a) 2-(4-Methoxy-2-phenoxyphenyl)-1 -morpholin-4-ylethan-1 -thione

According to the procedure of Harris, T. W., et al. (7. Med. Chem. 1982, 25(7), 855- 858), 4-methoxy-2-phenoxyacetphenone (1.69 g, 6.98 mmole), sulfur (0.36 g, 11.2mmole), and morpholine (0.98 mL, 11.2 mmole) were reacted to give the title compound(1.24 g) as a white solid: MS (ES) m/e 344.0 (M + H)+. b) 2-(4-Methoxy-2-phenoxyphenyl)acetic acid

To a solution of 2-(4-methoxy-2-phenoxyphenyl)-l-morpholin-4-ylethan-l-thione(0.35 g, 1.02 mmole) in i-PrOH (15 mL) and H2O (15 mL) was added KOH (0.57 g, 10.2mmole). The reaction was heated at reflux for 18 hr, then was cooled to RT, diluted withH2O, and washed with Et20. The aqueous layer was acidified to pH « 4 with conc. HCland was extracted with CHCI3. The combined extracts were dried over MgSC>4 andconcentrated to give the title compound (0.22 g) as a white solid. This was used withoutfurther purification: MS (ES) m/e 259.0 (M + H)+. c) Methyl 2-(4-methoxy-2-phenoxyphenyl)acetate

To a solution of 2-(4-methoxy-2-phenoxyphenyl)acetic acid (0.22 g, 0.85 mmole)in MeOH (10 mL) was added conc. H2SO4 (1 drop). The reaction was heated at reflux for18 hr, then was allowed to cool to RT. The bulk of the MeOH was removed under reducedpressure, and the remaining solution was poured into saturated NaHCO3· The aqueouslayer was extracted with EtOAc, and the combined organic extracts were washed with brine -74- 012189 and dried over Na2SC>4. The solvent was removed under reduced pressure to give the titlecompound (0.22 g) as a pale yellow oil. This was used without further purification: MS(ES) m/e 273.0 (M + H)+. d) Methyl 2-(4-hydroxy-2-phenoxyphenyl)acetate

To a solution of BBrç (1.0 M in CH2CI2,4.0 mL, 4 mmole) at 0 °C was addeddropwise a solution of methyl 2-(4-methoxy-2-phenoxyphenyl)acetate (0.22 g, 0.81 mmole)in CH2CI2 (1 mL). After 20 min, the solvent was removed under reduced pressure and theresidue was azeotroped from MeOH (2 x). The residue was then dissolved in saturatedNaHCC>3, and the solution was extracted with EtOAc. The combined extracts were driedover Na2SC>4 and concentrated to give the title compound (0.19 g) as a pale yellow oil.

This was used without further purification: MS (ES) m/e 259.0 (M + H)+.

Préparation 24

Préparation of methyl 2-(2-phenoxy-4-hydroxv)phenylbutanoate a) 2-(2-Phenoxy-4-methoxy)phenylethan-1 -ol

To a solution of 2-(4-methoxy-2-phenoxyphenyl)acetic acid (0.24 g, 0.93 mmole)in THF (5 mL) at 0 °C was added lithium aluminum hydride (0.11 g, 2.79 mmole). After 1hr at 0 °C, the reaction was diluted with toluene (10 mL), and NaF (0.47 g) and H2O (0.15mL) were added sequentially. The mixture was stirred vigorously at 0 °C for 30 min. Theresulting precipitate was removed by filtration and rinsed with Et2Û. The filtrate wasconcentrated to give the title compound (0.16 g) as a clear oil. The material was usedwithout further purification: NMR (300 MHz, CDCI3) δ 7.30 (m, 3 H), 7.08 (t, J = 7.4

Hz, 1 H), 6.95 (d, J = 7.6 Hz, 2 H), 6.66 (dd, J = 8.4, 2.5 Hz, 1 H), 6.45 (d, J = 2.6 Hz, 1 H),3.82 (q, J = 6.4 Hz, 2 H), 3.73 (s, 3 H), 2.85 (t, J = 6.6 Hz, 2 H). b) 2-(2-Phenoxy-4-methoxy)phenylacetaldehyde

Oxalyl chloride (0.06 mL, 0.69 mmole) was added to a solution of DMSO (0.09mL, 1.27 mmole) in CH2CI2 (1.2 mL) at -78 °C. After 10 min, a solution of 2-(2-phenoxy-4-methoxy)phenylethan-l-ol (0.16 g, 0.64 mmole) in CH2CI2 (1.2 mL) was added. Thereaction was stirred at -78°C for an additional 1 hr, then Et3N (0.27 mL, 1.94 mmole) wasadded, and the -78 °C bath was removed. After an additional 20 min, the reaction wasdiluted with CH2CI2 and washed sequentially with 1.0 N HCl, saturated NaHCÜ3, an^brine, then was dried over Na2SC>4. The solvent was removed under vacuum to give thetitle compound (0.13 g) as a pale yellow oil. The material was used without furtherpurification: *H NMR (300 MHz, CDCI3) δ 9.71 (t, J = 1.9 Hz, 1 H), 7.30 (m, 2 H), 7.10 -75- 012189 (m, 2 H), 6.95 (d, J = 7.7 Hz, 2 H), 6.66 (dd, J = 8.4, 2.5 Hz, 1 H), 6.45 (d, J = 2.5 Hz, 1 H), 3.71 (s, 3 H), 3.64 (s, 2 H). c) Methyl 2-(2-phenoxy-4-methoxy)phenylbut-2-enoate A solution of 2-(2-phenoxy-4-methoxy)phenylacetaldehyde (0.13 g, 0.53 mmole)and methyl (triphenylphosphoranyiidene)acetate (0.35 g, 1.05 mmole) in THF (3 mL) washeated at reflux to 5 hr, then was allowed to cool to RT. The reaction was poured into H2Oand the mixture was extracted with Et2O. The organic extracts were dried over Na2SC>4and the solvent was removed under reduced pressure. Radial chromatography (20%EtOAc/hexane, silica gel, 6 mm plate) gave the title compound (0.12 g) as a mixture ofolefin stéréo- and regio-isomers. This was used in the next step without furtherpurification: MS (ES) m/e 299.1 (M + H)+. d) Methyl 2-(2-phenoxy-4-methoxy)phenylbutanoate A Parr hydrogénation vessel was charged with methyl 2-(2-phenoxy-4-methoxy)phenylbut-2-enoate (0.12 g, 0.39 mmole), 10% Pd/C (50 mg), and MeOH (50mL), and the mixture was shaken under an atmosphère of hydrogen at 50 psi. After 18 hr,the catalyst was removed by filtration and the filtrate was concentrated under reducedpressure. Flash chromatography on silica gel (15% EtOAc/hexanes) gave the titlecompound (0.09 g) as a clear oil: MS (ES) m/e 300.9 (M + H)+. e) Methyl 2-(2-phenoxy-4-hydroxy)phenylbutanoate A solution of methyl 2-(2-phenoxy-4-methoxy)phenylbutanoate (0.09 g, 0.30mmole) in CH2CI2 (2 mL) was added to BBrç (1.0M in CH2CI2, 1.50 mL, 1.50 mmole) at0 °C. After 1 hr at 0 °C, the reaction was quenched by dropwise addition of MeOH (2 mL).

The solvent was removed under reduced pressure and the residue was azeotroped fromMeOH (2x). A solution of saturated ΝβΗΟΟβ was added to the residue and the aqueouslayer was extracted with EtOAc. The combined extracts were dried over Na2SO4 andconcentrated to give the title compound (0.08 g) as a pale yellow oil. This material wasused in the next step without further purification: NMR (300 MHz, CDCI3) δ 7.25 (m, 2 H), 7.05 (m, 2 H), 6.93 (d, J = 7.6 Hz, 2 H), 6.54 (dd, J = 8.2, 2.5 Hz, 1 H), 6.35 (d, J = 2.5 Hz, 1 H), 5.45 (s, 1 H), 3.62 (s, 3 H), 2.59 (t, J = 7.5 Hz, 2 H), 2.32 (t, J = 7.5 Hz, 2 H), 1.90 (m,2H). -76-

Preparation 25 012189

Préparation of 2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)-1 -éthanol a) 2-Methyl-8-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro-1,8-naphthyridine A mixture of 2-methyl-l,8-naphthyridine (J. Chem. Soc. (C) 1966, 315; 5.13 g,35.58 mmole), 10% Pd/C (1.14 g, 1.07 mmole), and absolute EtOH (70 mL) wasdeoxygenated through three évacuation/^ purge cycles, then was stirred briskly under aballoon 01¾. After 18.5 hr, the mixture was filtered through celite®, and the filter padwas washed sequentially with absolute EtOH and EtOAc. The filtrate was concentrated todryness, and the residue was reconcentrated from EtOAc to leave an off-white solid (5.25g)· A solution of the above material (5.25 g), di-tert-butyl dicarbonate (15.53 g, 71.16mmole), and CH2CI2 (10 mL) was concentrated on the rotavap to remove the solvent, andthe oily residue was heated under N2 in an oil bath set at 55 - 60 °C. After 45 hr, thereaction was cooled to RT, and the residue was flash chromatographed on silica gel (40%EtOAc/hexanes). The title compound (4.90 g, 55%) was obtained as a light yellow solid:*H NMR (300 MHz, CDCI3) δ 7.27 (d, J = 7.6 Hz, 1 H), 6.81 (d, J = 7.6 Hz, 1 H), 3.69 -3.79 (m, 2 H), 2.65 - 2.75 (m, 2 H), 2.48 (s, 3 H), 1.83 - 1.98 (m, 2 H), 1.52 (s, 9 H); MS(ES) m/e 249 (M + H)+. b) Ethyl [8-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl]acetate

To a solution of diisopropylamine (7.24 mL, 55.3 mmole) in dry THF (50 mL) wasadded n-BuLi (2.5 M in hexanes, 22 mL, 55.3 mmole) dropwise at 0 °C. After 15 min, thissolution was added dropwise to a solution of 2-methyl-8-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro-l,8-naphthyridine (4.9 g, 19.7 mmole) and diethylcarbonate (8.86 mL, 73.0mmole) in dry THF (50 mL) at -78 °C. After 30 min, the mixture was quenched withsaturated NH4CI (100 mL), warmed to RT, and extracted with EtOAc (3 x 200 mL). Thecombined organic extracts were dried over MgSO4, filtered, and concentrated underreduced pressure. The residue was chromatographed on silica gel (40% EtOAc/hexanes) togive the title compound (5.72 g, 91%) as a light yellow oil: MS (ES) m/e 321 (M + H)+. c) 2-(5,6,7,8-Tetrahydro-1,8-naphthyridin-2-y 1)-1 -éthanol

To a solution of ethyl [8-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl]acetate (5.72 g, 17.85 mmole) in dry THF (80 mL) at RT was added LiBH4 (2.0 M inTHF, 10.7 mL, 21.42 mmole), and the resulting mixture was heated to reflux. After 18 hr,the mixture was cooled to 0 °C and carefully quenched with H2O (100 mL). After 10 min,the mixture was extracted with EtOAc (3 x 100 mL). The combined organic extracts were -77- 012189 dried over MgSC>4, filtered, and çoncentrated under reduced pressure.

The above residue (4.9 g) was dissolved in CH2CI2 (10 mL). To this was added 4N HCl in dioxane (20 mL) ail at once at RT. After 4 , the mixture was concentrated underreduced pressure. The residue was taken up in a 1:1 mixture of 1.0 N NaOH and saturatedNaCl (100 mL) and extracted with CH2CI2 (3 x 100 mL). The combined organic extractswere dried over MgSÜ4, filtered, and concentrated under reduced pressure. The residuewas chromatographed on silica gel (10% MeOH in 1:1 EtOAc/CHC^) to give the titlecompound (2.09 g, 66%) as a yellow solid: MS (ES) m/e 179 (M + H)+.

Préparation 26 HPLC séparation of the enantiomers of methvl (±)-4-(4-hydroxyphenyl)-3-(thiazol-2- vPbutanoate a) Methyl (S)-(-)-4-(4-hydroxyphenyl)-3-(thiazol-2-yl)butanoate and methyl (R)-(+)-4-(4-hydroxyphenyl)-3-(thiazol-2-yl)butanoate

Methyl (+)-4-(4-hydroxyphenyl)-3-(thiazol-2-yl)butanoate was resolved into itsenantiomers using the following conditions: Daicel Chiralcel OJ® column (21.2 x 250mm), 20 % éthanol in hexane mobile phase, 12 mL/min flow rate, uv détection at 320 nm,25 mg injection; tR for methyl (S)-(-)-4-(4-hydroxyphenyl)-3-(thiazol-2-yl)butanoate = 14.5 min; tR for methyl (R)-(+)-4-(4-hydroxyphenyl)-3-(thiazol-2-yl)butanoate = 17.2 min.

Préparation 27 HPLC séparation of the enantiomers of ethyl (±)-4-(4-methoxyphenyl)-3-phenylbutanoate a) Ethyl (-)-4-(4-methoxyphenyl)-3-phenylbutanoate and ethyl (+)-4-(4-methoxyphenyl)- 3-phenylbutanoate

Ethyl (±)-4-(4-methoxyphenyl)-3-phenylbutanoate was resolved into its enantiomers using the following conditions: Daicel Chiralcel OJ® column (21.2 x 250 mm), 15 % éthanol in hexane mobile phase, 15 mL/min flow rate, uv détection at 254 nm,

100 mg injection; tR for ethyl (-)-4-(4-methoxyphenyl)-3-phenylbutanoate = 9.0 min; tR for ethyl (+)-4-(4-methoxyphenyl)-3-phenylbutanoate = 12.2 min. -78- 012189

Preparation28

Préparation of methyl (±~)-3-(furan-2-vl')-4-(4-hvdroxvphenvl)butanoate a) Methyl 3-(furan-2-yl)acrylate H2SO4 (0.5 mL, 9.39 mmole) was added to a solution of 3-(2-furanyl)acrylic acid(5.0 g, 36.2 mmole) in MeOH (30 mL). The reaction was heated at reflux for 22 hr, thenwas concentrated on the rotavap. The residue was diluted with H2O (100 mL) andextracted with ether (2 x 70 mL). The organic layers were combined and washedsequentially with saturated NaHCC>3 (30 mL) and H2O (30 mL). Drying (Na2SO4) andconcentration on the rotavap gave the title compound (4.86 g, 88%) as a light brown oil:TLC Rf (10% EtOAc/hexanes) 0.50; MS (ES) m/e 479.0 (3M + Na)+. b) Methyl (±)-3-(furan-2-yl)-4-(4-methoxyphenyl)butanoate TMEDA (2.18 mL, 14.47 mmole) was added slowly to a mixture of Cul (2.51 g, 13.16mmole) in THF (35 mL) at RT under argon. After 10 min at RT, the reaction mixture wascooled to -78 °C, and a solution of 4-methoxybenzylmagnesium chloride in THF (0.5 M,26.32 mL, 13.16 mmole) was added slowly. The reaction was stirred for 15 min, then asolution of TMSC1 (4.17 mL, 32.89 mmole) and methyl 3-(furan-2-yl)acrylate (1.0 g, 6.58mmole) in THF (20 mL) was injected, and the température was allowed to rise to -30 °C.After 18 hr, the reaction wa$ quenched with saturated NH4CI/NH4OH (30 mL), and stirringwas continued to an ambient température. H2O (20 mL) was added, and the mixture wasextracted with ether (2 x 70 mL). The combined organic layers were washed with H2O (2 x50 mL) an dried (Na2SC>4). Concentration and silica gel chromatography (8 %EtOAc/Hexanes) gave the title compound (0.85 g, 93%) as a clear oil: TLC Rf (8 %EtOAc/Hexanes) 0.38; MS (ES) m/e 297 (M + Na)+. c) Methyl (±)-3-(furan-2-yl)-4-(4-hydroxyphenyl)butanoate A solution of methyl (±)-3-(furan-2-yl)-4-(4-methoxyphenyl)butanoate (0.82 g, 2.99 mmole) in CH2CI2 (10 mL) was added dropwise to a solution of BBrç in CH2CI2 (1.0Μ, 11.97 mL, 11.97 mmole) at 0 °C ^nder argon. After 30 min, the reaction was quenchedwith MeOH (5 mL). The solution was stirred for 10 min then was concentrated on therotavap. The residue was partitioned between EtOAc (50 mL) and 5% NaHCÛ3 (30 mL).The layers were separated and the organic layer was washed with H2O (20 mL) and dried(Na2SO4). Concentration and silica gel chromatography (40% EtOAc/Hexanes) gave thetitle compound (0.12 g, 15%) as a light yellow greenish residue: TLC Rf (50%EtOAc/hexanes) 0.36; MS (ES) m/e 542.8 (2M + Na)+. -79- 012189

Préparation 29

Préparation of (±)-3-i l-(dimethylaminosulfonyl)imidazol-2-yll-4-(4- hydroxyphenyDbutanoate 5 a) 1 -(Dimethylaminosulfonyl)imidazole

To a solution of imidazole (1.63 g, 24 mmole) in CH2CI2 (100 mL) was addedΕΐβΝ (3.35 mL, 24 mmole), followed by dimethylaminosulfonyl chloride (2.15 mL, 20mmole) at RT. After 24 hr the mixture was concentrated. The residue was taken up in 10 EtOAc (200 mL) and filtered through a pad of siîica gel. The filtrate was concentrated togive the title compound (2.89 g, 82%) as a white solid: MS (ES) m/e 176 (M + H)+. b) 2-(4-Benzyloxyphenyl)-l-[l-(dimethylaminosulfonyl)imidazol-2-yl]ethanone

According to the procedure of Préparation 16 (a), except substituting 1-15 (dimethylaminosulfonyl)imidazole (410 mg, 2.34 mmole) for the 2-bromothiazole, the title compound (364 mg, 47%) was prepared as a white solid following silica gelchromatography (35% EtOAc/hexanes): MS (ES) m/e 400 (M + H)+. c) Ethyl (±)-4-(4-benzyloxyphenyl)-3-( 1 -(dimethylaminosulfonyl)imidazol-2-yl]crotonate 20 According to the procedure of Préparation 16 (b), except substituting 2-(4- benzyloxyphenyl)-l-[l-(dimethylaminosulfonyl)imidazol-2-yl]ethanone (564 mg, 1.41mmole) for the 2-[4-(benzyloxy)phenyl]-l-(thiazol-2-yl)ethanone, the title compound (589mg of a mixture of olefin isomers, 89%) was prepared as an orange oil following silica gelchromatography (35% EtOAc/hexanes): MS (ES) m/e 470 (M + H)+. 25 d) Ethyl (±)-3-[l-(dimethylaminosulfonyl)imidazol-2-yI]-4-(4-hydroxyphenyl)butanoate

According to the procedure of Préparation 16 (c), except substituting ethyl (±)-4-(4-benzyloxyphenyl)-3-[l-(dimethylaminosulfonyl)imidazol-2-yl]crotonate (589 mg, 1.25mmole) for the ethyl (±)-4-[4-(benzyloxy)phenylJ-3-(thiazol-2-yl)crotonate, the title 30 compound (436 mg, 91%) was prepared as a white solid: MS (ES) m/e 382 (M + H)+. -80- 012189

Préparation 30

Préparation of ethyl (±)-3-(benzothiazol-2-yl)-4-(4-hydroxyphenvI)butanoate a) 1 -(Benzothiazol-2-yl)-2-(4-benzyloxyphenyl)ethanone

According to the procedure of Préparation 16 (a), except substituting benzothiazole(0.26 mL, 2.34 mmole) for the 2-bromothiazole, the title compound (570 mg, 81%) wasprepared as a pale yellow solid following trituration with hexanes: MS (ES) m/e 360 (M + H)+. b) Ethyl (±)-3-(benzothiazol-2-yl)-4-(4-benzyloxyphenyl)crotonate

According to the procedure of Préparation 16 (b), except substituting 1-(benzothiazol-2-yl)-2-(4-benzyloxyphenyl)ethanone (570 mg, 1.59 mmole) for the 2-[4-(benzyloxy)phenyl]-l-(thiazol-2-yl)ethanone, the title compound was prepared as a mixtureof olefin isomers. The crude product was used without further purification. c) Ethyl (±)-3-(benzothiazol-2-yl)-4-(4-benzyloxyphenyl)butanoate

Ethyl (±)-3-(benzothiazol-2-yl)-4-(4-benzyloxyphenyl)crotonate (1.59 mmole,crude) was hydrogenated (50 psi H2) using 10% Pd/C (1.00 g) in 1:1 EtOH/EtOAc (20 mL)for 5 hr. The mixture was fîltered through a pad of celite®, and the filtrate wasconcentrated. The crude residue was used without further purification. d) Ethyl (±)-3-(benzothiazol-2-yl)-4-(4-hydroxyphenyl)butanoate

To a solution of ethyl (±)-3-(benzothiazol-2-yl)-4-(4-benzyloxyphenyl)butanoate(1.59 mmole, crude) in EtSH (1.95 mL) at RT was added BF3 · OEt2 (1.95 mL). After 48hr, additional BF3 · OEt2 (1.95 mL) was added. After another 18 hr, the mixture wascooled to 0 °C and carefully quenched with saturated NaHCO3- The resulting mixture wasextracted with CH2CI2 (3 x 25 mL). The combined organic layers were dried over MgSÛ4and concentrated. The residue was chromatographed on silica gel (30% EtOAc/hexanes) togive the title compound (391 mg, 72% over 3 steps) as a foam: MS (ES) m/e 342 (M + H)+. -81 - 012189

Préparation 31

Préparation of ethyl (i)-3-(4-methylthiazol-2-yl)-4-(4-hydroxyphenyl)butanoate a) 2-(4-Benzyloxyphenyl)-1 -(4-methylthiazol-2-yl)ethanone

According to the procedure of Préparation 16 (a), except substituting 4-methylthiazole (0.21 mL, 2.34 mmole) for the 2-bromothiazole, the title compound (303mg, 48%) was prepared as a pale yellow solid following silica gel chromatography (15%EtOAc/hexanes): MS (ES) m/e 324 (M + H)+. b) Ethyl (±)-3-(4-methylthiazol-2-yl)-4-(4-benzyloxyphenyl)crotonate

According to the procedure of Préparation 16 (b), except substituting 2-(4-benzyloxyphenyl)-l-(4-methylthiazol-2-yl)ethanone (300 mg, 0.93 mmole) for the 2-[4-(benzyloxy)phenyl]-l-(thiazol-2-yl)ethanone, the title compound was prepared as a mixtureof olefin isomers. The crude product was used without further purification. c) Ethyl (±)-3-(4-methyIthiazol-2-yl)-4-(4-benzyloxyphenyl)butanoate

Ethyl (±)-3-(4-methylthiazol-2-yl)-4-(4-benzyloxyphenyl)crotonate (0.93 mmole,crude) was dissolved in MeOH (10 mL), and magnésium tumings (113 mg, 4.65 mmole)were added at RT. After 18 hr the mixture was poured into 10% HCl (75 mL) andextracted with CH2CI2 (3 x 50 mL). The combined organic layers were dried over MgSÛ4and concentrated. The residue was used in the next step without purification. d) Ethyl (±)-3-(4-methylthiazol-2-yl)-4-(4-hydroxyphenyl)butanoate

To a solution of ethyl (±)-3-(4-methylthiazol-2-yl)-4-(4-benzyloxyphenyl)butanoate (0.93 mmole, crude) in EtSH (10 mL) was added BF3 · OEt2(2.29 mL) at RT. After 24 hr, more BF3 · 0Et2 (1.00 mL) was added. After 72 hr themixture was cooled to 0 °C and carefully quenched with saturated NaHCO3- The resultingmixture was extracted with CH2CI2 (3 x 25 mL). The combined organic layers were driedover MgSC>4 and concentrated. The residue was cîiromatographed on silica gel (30%EtOAc/hexanes) to give the title compound (216 mg, 80% over 3 steps) as a white solid:MS (ES) m/e 292 (M + H)+. -82- Οι 218 9

Préparation 32

Préparation of methyl (±)-4-(4-hvdroxvphenyl)-3-i4-(benzvloxycarbonyl)l,3-oxazol-2- vllbutanoate a) 4-Bromo-1 -(triisopropylsilyloxy )benzene

To a solution of 4-bromophenol (2.00 g, 11.56 mmole) in dry DMF (20 mL) at RTwas added imidazole (1.57 g, 23.12 mmole), followed by triisopropylsilyl chloride (3.71mL, 17.34 mmole). After 4 hr the mixture was diluted with H2O (50 mL) and extractedwith hexanes (3 x 75 mL). The combined organic layers were dried over MgSC>4 andconcentrated to give the title compound (4.00 g, 100%) as a clear oil which was usedwithout purification: NMR (300 MHz, CDCI3) δ 7.29 (d, J = 6 Hz, 2 H), 6.71 (d, J = 6

Hz, 2 H), 1.22 (m, 3 H), 1.09 (m, 18 H). b) Methyl (±)-3-carboxy-4-[4-(triisopropylsilyloxy)phenyl]butanoate

According to the procedure of Préparation 15 (b), except substituting 4-bromo-l-(triisopropylsilyloxy)benzene (2.19 g, 6.66 mmole) for the 4-bromoanisole, the titlecompound (2.24 g, 85% over 2 steps) was prepared as a clear oil: ^H NMR (300 MHz,CDCI3) δ 7.01 (d, J = 6 Hz, 2 H), 6.80 (d, J = 6 Hz, 2 H), 3.62 (s, 3 H), 3.05 (m, 2 H), 2.65(m, 1 H), 2.40 (m, 2 H), 1.21 (m, 3H), 1.09 (m, 18H). c) (±)-N-[2-[4-(Triisopropylsilyloxy)benzyl]-3-(carbomethoxy)propionyl]serine benzylester

To a solution of methyl (±)-3-carboxy-4-[4-(triisopropylsilyloxy)phenyl]butanoate(1.00 g , 2.53 mmole) in dry DMF (10 mL) at RT was added serine benzyl esterhydrochloride (704 mg, 3.04 mmole), HOBt (411 mg, 3.04 mmole), Et3N (1.06 mL, 7.60mmole), and EDC (583 mg, 3.04 mmole). After 18 hr the mixture was concentrated. Theresidue was chromatographed on silica gel (80% EtOAc/hexanes) to give the titlecompound (834 mg, 58%) as a pale yellow oil: MS (ES) m/e 572 (M + H)+. d) Methyl (±)-3-[4-(benzyloxycarbonyl)-l,3-oxazolin-2-yl]-4-[4- (triisopropylsilyloxy)phenyl]butanoate

To a solution of (±)-N-[2-[4-(triisopropylsilyïoxy)benzyl]-3-(carbomethoxy)propionyl] serine benzyl ester (834 mg, 1.46 mmole) in dry THF (10 mL)was added Burgess reagent (417 mg, 1.75 mmole), then the mixture was heated to reflux.After 2 hr the mixture was cooled to RT and concentrated. The residue was -83- 01 21 8 y chromatographéft on silica gel (35% EtOAc/hexanes) to give the title compound (633 mg,78%) as a clear oil: MS (ES) m/e 554 (M + H)+. e) Methyl (±)-3-[4-(benzyloxycarbonyI)-l,3-oxazol-2-yl]-4-[4- (triisopropylsilyloxy)phenyl]butanoate

To a solution of methyl (±)-3-[4-(benzyIoxycarbonyl)-l,3-oxazolin-2-yl]-4-[4-(triisopropylsilyloxy)phenyl]butanoate (633 mg, 1.14 mmole) in CH2CI2 (6 mL) at 0 °Cwas added DBU (0.19 mL, 1.25 mmole), followed by bromotrichloromethane (0.12 mL,1.25 mmole). The mixture was allowed to warm to RT as the bath warmed. After 18 hr themixture was concentrated. The residue was chromatographed on silica gel (20%EtOAc/hexanes) to give the title compound (427 mg, 68%) as a clear oil: MS (ES) m/e 552(M + H)+. f) Methyl (±)-3-[4-(benzyloxycarbonyl)-1,3-oxazol-2-yl]-4-(4-hydroxyphenyl)butanoate

To a solution of methyl (±)-3-[4-(benzyloxycarbonyl)-l,3-oxazol-2-yl]-4-(4-(triisopropylsilyloxy)phenyl]butanoate (427 mg, 0.77 mmole) in dry THF (5 mL) at 0 °Cwas added a solution of TBAF in THF (1.0 M, 1.16 mL, 1.16 mmole). After 2 hr themixture was diluted with saturated NH4CI (10 mL) and extracted with CH2CI2 (3x15mL). The combined organic layers were dried over MgSO4 and concentrated. The residuewas chromatographed on silica gel (40% EtOAc/hexanes) to give the title compound (268mg, 88%) as an off-white foam: MS (ES) m/e 396 (M + H)+.

Préparation 33

Préparation of methyl (±)-3-f4-carboxy-l,3-oxazol-2-vH-4-f4-f2-f6-(methylamino)pvridin- k 2-vn-l-ethoxvlphenyllbutanoate a) Methyl (±)-3-[4-(benzyloxycarbonyl)-l ,3-oxazol-2-yl]-4-[4-[2-[6- (methy lamino)pyridin-2-yl]-1 -ethoxy ]phenyl]butanoate

Ditsopropyl azodicarboxylate (0.27 mL, 1.36 mmole) was added to a solution ofmethyl (±)-3-[4-(benzyloxycarbonyl)-1,3-oxazol-2-yl]-4-(4-hydroxyphenyl)butanoate (268mg, 0.68 mmole), 2-[(6-methylamino)pyridin-2-yl)]ethanol (207 mg, 1.36 mmole), andtriphenylphosphine (357 mg, 1.36 mmole) in anhydrous THF (4 mL) at 0 °C. The mixturewas allowed to warm to RT as the bath warmed. After 18 hr the mixture was concentratedand the residue was chromatographed on silica gel (50% EtOAc/toluene) to give the titlecompound (284 mg, 79%) as a clear oil: MS (ES) m/e 530 (M + H)+. -84- 012189 b) Methyl (±)-3-[4-carboxy-l,3-oxazol-2-yll-4-[4-[2-[6-(methylamino)pyridin-2-yl]-l-ethoxy]phenyl]butanoate A mixture of methyl (±)-3-[4-(benzyloxycarbonyl)-l,3-oxazol-2-yl]-4-[4-[2-[6-(methylamino)pyridin-2-yl]-l-ethoxy]phenyl]butanoate (234 mg, 0.44 mmole) and 10% 5 PdZC (100 mg) in EtOH (5 mL) was deoxygenated (3 x vacuum/N2), then was stirredbriskly under H2 (balloon pressure). After 4 hr the mixture was filtered through a pad ofcelite® and concentrated to give the title compound (165 mg, 85%) as a white foam: MS(ES) m/e 440 (M + H)+. 10 Préparation 34

Préparation of methyl (±)-3-(4-hydroxybenzyl)pent-4-ynoate a) Methyl (±)-3-formyl-4-(4-methoxyphenyl)butanoate 15 To a solution of methyl (±)-4-(4-methoxyphenyl)-3-carboxybutanoate (prepared as described in Préparation 15,0.45 g, 1.80 mmole) in CH2CI2 (10 mL) was added oxalylchloride (0.24 mL, 2.75 mmole) and DMF (1 drop). After 1.5 hr, the solvent was removedunder reduced pressure and the residue was azeotroped from toluene (2x). The crude acidchloride was dissolved in acetone (2 mL) and the solution was added dropwise to a rapidly 20 stirring suspension of (PlrçP^CuBIfy (1.14 g, 1.89 mmole) and Pl^P (0.99 g, 3.78 mmole)in acetone (4 mL). After lh àt RT, the reaction mixture was filtered through celite®, andthe filter pad was further rinsed with EtOAc. The combined organic filtrâtes wereconcentrated to give a yellow residue. Radial chromatography on silica gel (6 mm plate, 20% EtOAc/hexane) gave the title compound (0.25 g) as a clear oil: *Η NMR (300 MHz, 25 CDCI3) δ 9.79 (s, 1 H), 7.11 (d, J = 8.6 Hz, 2 H), 6.84 (d, J = 8.6 Hz, 2 H), 3.79 (s, 3 H), 3.65 (s, 3 H), 3.10 (m, 2 H), 2.70 (m, 2 H), 2.38 (dd, J = 16.8, 5.1 Hz, 1 H). b) Methyl (±)-3-(4-methoxybenzyl)pent-4-ynoate

To a solution of methyl (±)-3-formyl-4-(4-methoxyphenyl)butanoate (0.14 g, 0.61 30 mmole) in dry MeOH (5 mL) was added K2CO3 (0.17 g, 1.21 mmole), followed by dropwise addition of a solution of dimethyl-l-diazo-2-oxopropylphosphonate (0.13 g, 0.67mmole) in MeOH (5 mL). After 18 hr at RT, the reaction was poured into sat. NaHCÛ3and extracted with Et2Û. The combined organic extracts were washed with brine and driedover MgSÛ4. The solvent was removed under reduced pressure to give a clear oil. Radial 35 chromatography on silica gel (2 mm plate, 20% EtOAc/hexanes) gave the title compound(0.06 g) as a clear oil: NMR (300 MHz, CDCI3) δ 7.23 (d, J = 8.4 Hz, 2 H), 6.92 (d, J = -85- 012189 8.4 Hz, 2 H),. 3.87 (s, 3 H), 3.77 (s, 3 H), 3.20 (m, 1 H), 2.85 (m, 2 H), 2.56 (d, 6.7 Hz, 2H), 2.17 (d, J = 2.0 Hz, 1 H). c) Methyl (±)-3-(4-hydroxybenzyl)pent-4-ynoate

To a solution of BBrç in CH2CI2 (1.0 M, 0.85 mL, 0.85 mmole) at 0 °C was added a solution of methyl (±)-3-(4-methoxybenzyl)pent-4-ynoate (66 mg, 0.28 mmole) inCH2CI2 (0.60 mL). After 3 hr at 0 °C, the reaction was quenched by careful addition ofMeOH (1 mL). The solvent was removed under reduced pressure and the residue wasazeotroped from MeOH (2x). Sat. NaHCO3 was added to the residue and the aqueous layerwas extracted with EtOAc. The combined organic extracts were washed with brine anddried over Na2SO4. The solvent was removed under reduced pressure to give a clear film.Radial chromatography on silica gel (2 mm plate, 20% EtOAc/hexanes) gave the titlecompound (25 mg) as a clear film: JH NMR (300 MHz, CDCI3) δ 7.15 (d, J = 8.5 Hz, 2H), 6.83 (d, J = 8.5 Hz, 2 H), 3.79 (s, 3 H), 3.69 (s, 3 H), 3.10 (m, 1 H), 2.75 (m, 2 H), 2.45(m,2H), 2.11 (d, J = 2.2 Hz, 1 H).

Préparation 35

Préparation of methyl (±)-4-(4-hydroxyphenyl)-3-(phenvlethyl)butanoate a) (±)-2-(4-Methoxybenzyl)-4-phenylbutanoic acid

A reaction flask was charged with diisopropylamine (1.0 mmole, 7.5 mmole), NaH (60% in minerai oil, 0.33 g, 8.5 mmole), and THF (40 mmole). To the stirred mixture wasadded a solution of phenylbutyric acid (1.23 g, 7.5 mmole) in THF (10 mmole) over 5minutes. The hydrogen évolution was completed by heating the mixture to reflux for 10minutes. The reaction was cooled to 10 °C, and a solution of n-BuLi (2.5 M in hexanes, 3.0mmole, 7.5 mmole) was added. After 15 minutes at that température the mixture washeated to 30 °C for 15 min. The turbid solution was cooled to 0 °C and 4-methoxybenzylchloride (1.2 g, 7.5 mmole) was added over 10 minutes. After 20 minutes at thattempérature the mixture was stirred at RT ovemight. The reaction was kept at or below 15°C while H2O (50 mL) was added. The mixture was partly concentrated in vacuum, dilutedwith water, and extracted with ether (2 x 50 mL). The aqueous layer was acidified with 6 NHCl to Congo red and extracted with Et20 (3 x 30 mL). The combined extracts were driedover anhydrous MgSC>4, filtered and concentrated to give the title compound (1.6 g, 56%)as a yellow oil: TLC Rf (1% MeOH/CH2Cl2) 0.37. b) (±)-1 -Diazo-4-(4-methoxyphenyl)-3-(2-phenylethyl)-2-butanone -86- 012189 A solution of (±)-2-(4-methoxybenzyl)-4-phenylbutanoic acid (1.5 g, 5.26 mmole)in CH2CI2 (30 mL) was treated with oxalyl chloride (0.92 mL, 10.5 mmole). The reactionwas stirred at RT ovemight, then was concentrated in vacuum. The residue was dissolvedin Et20, and Et3N was added, followed by excess diazomethane (generated from 1-methyl-3 nitro-l-nitroguanidine and NaOH). The reaction was stirred at RT ovemight then wasconcentrated in vacuum to afford the title compound (1.5 g, 94%) as a yellow oil: MS (ES)m/e 309 (M + H)+. c) Methyl (±)-4-(4-methoxyphenyl)-3-(2-phenylethyl)butanoate A solution of silver benzoate (0.9 g 3.9 mmole) in Et3N (8 mL, 55.6 mL) wasadded to a solution of (±)-l-diazo-4-(4-methoxyphenyl)-3-(phenylethyl)-2-butanone (0.3 g, 0.97 mmole) in MeOH (20 mL) at RT. Gas évolution was observed, and the reactionmixture became black in color. After 30 min, the reaction was heated to reflux. After 1 hrat reflux, the reaction was cooled to RT and filtered through celite®, and the filtrate wasconcentrated in vacuum. The residue was adsorbed onto silica gel and was loaded onto adry silica gel column. Flash chromatography (5% EtOAc/hexanes) gave the title compound(0.1 g, 57%) as a light yellow oil: TLC Rf (5% EtOAc/hexanes) 0.63. d) Methyl (±)-4-(4-hydroxyphenyl)-3-(phenylethyl)butanoate

Boron tribromide (1.0 M in CH2CI2,4.8 mL, 4.8 mmole) was added to a solutionof methyl (±)-4-(4-methoxyphenyl)-3-(2-phenylethyl)butanoate (1.0 g, 3.21 mmole) inCH2CI2 (10 mL) at 0 °C under argon. After 1 hr, the reaction was quenched with absoluteMeOH and concentrated in vacuum. Reconcentration from toluene (several times)followed by drying in high vacuum gave the title compound (0.7 g, 73% ) as an oil: TLCRf (15% EtOAc/hexanes) 0.26.

Préparation 36

Préparation of methyl (±)-4-(4-hvdroxyphenvl)-3-benzylbutanoate a) (±)-2-(4-Methoxybenzyl)-3-phenylpropionic acid

According to the procedure of Préparation 35 (a), except substituting phenylpropionic acid for the phenylbutyric acid, the title compound (60%) was obtained asyellow oil: TLC Rf ( 1 % MeOH/C^C^) 0.38. -87- 012189 b) (±)- l-Diazo-3-(4-methoxyphenyl)-3-(benzyl)-2-butanone

According to the procedure of Préparation 35 (b), except substituting (±)-2-(4-methoxybenzyl)-3-phenylpropionic acid for the (±)-2-(4-methoxybenzyl)-4-phenylbutanoicacid, title compound (100%) was obtained as yellow oil: MS (ES) m/e 289 (M + H)+. c) Methyl (±)-4-(4-methoxyphenyl)-3-benzylbutanoate

According to the procedure of Préparation 35 (c), except substituting (±)-l-diazo-3-(4-methoxyphenyl)-3-(benzyl)-2-butanone for the (±)-l-diazo-4-(4-methoxyphenyl)-3-(phenylethyl)-2-butanone, the title compound (80%) was prepared as a slightly yellowfoam: TLC Rf (5% EtOAc/hexanes) 0.33. d) Methyl (±)-4-(4-hydroxyphenyl)-3-benzylbutanoate

According to the procedure of Préparation 35 (d), except substituting methyl (±)-4-(4-methoxyphenyl)-3-benzylbutanoate for the methyl (±)-4-(4-methoxyphenyl)-3-(2-phenylethyl)butanoate, the title compound (24%) was prepared: TLC Rf (20%EtOAc/hexanes) 0.33.

Préparation 37

Préparation of methyl (+)-4-(4-hydroxyphenyl)-3-cyclopropylbutanoate a) (±)-2-(4-Methoxybenzyl)-2-cyclopropyl acetic acid

According to the procedure of Préparation 35 (a), except substitutingcyclopropylacetic acid for the phenylbutyric acid, the title compound (60%) was obtainedas yellow oil: TLC Rf (10% MeOH/CH2Cl2) 0.42. b) (±)-1 -Diazo-3-(4-methoxyphenyl)-3-cyclopropy 1-2-butanone

According to the procedure of Préparation 35 (b), except substituting (±)-2-(4-methoxybenzyl)-2-cyclopropyl acetic acid for the (±)-2-(4-methoxybenzyl)-4-phenylbutanoic acid, title compound (100%) was prepared as a yellow oil: MS (ES) m/e245 (M + H)+. c) Methyl (±)-4-(4-methoxyphenyl)-3-cyclopropylbutanoate

According to the procedure of Préparation 35 (c), except substituting (±)-l-diazo-3-(4-methoxyphenyl)-3-cyclopropyl-2-butanone for the (±)-l-diazo-4-(4-methoxyphenyl)-3-(phenylethyl)-2-butanone, the title compound (60%) was prepared as a slightly yellow film:TLC Rf (10% EtOAc/hexanes) 0.21. -88- 012189 d) Methyl (±)-4-(4-hydroxyphenyl)-3-cyclopropylbutanoate

According to the procedure of Préparation 35 (d), except substituting methyl (±)-4-(4-methoxyphenyl)-3-cyclopropylbutanoate for the methyl (±)-4-(4-methoxyphenyl)-3-(2- 5 phenylethyl)butanoate, the title compound (20%) was prepared as a slightly yellow film: TLC Rf (10% EtOAc/hexanes) 0.11.

Préparation 38 10 Préparation of ethvl 4-(4-hydroxvphenyl)-3-methvl-3-butenoate a) Ethyl 4-(4-methoxyphenyl)-3-methyl-3-butenoate

To a suspension of NaH (60% in minerai oil, 2.1 g, 54 mmole) in toluene (40 mL)was added triethyl phosphonoacetate (11.1g, 49.4 mmole) in toluene (50 mL). The 15 reaction was stirred at RT for 20 min, then a solution of 4-methoxyphenylacetone (7.4 g, 44.9 mmole) in toluene (40 mL) was added dropwise. The reaction was heated at reflux for5 hr, then was concentrated. Flash chromatography on silica gel (5% EtOAc/hexanes) gavethe title compound (1.0 g) as a colorless oil: TLC Rf (5% EtOAc/hexanes) 0.23. 20 b) Ethyl 4-(4-hydroxyphenyl)-3-methyl-3-butenoate

According to the procedure of Préparation 35 (d), except substituting ethyl 4-(4- methoxyphenyl)-3-methyl-3-butenoate for the methyl (±)-4-(4-methoxyphenyl)-3-(2-phenylethyl)butanoate, the title compound (34%) was prepared as a colorless oil: TLC Rf(10% EtOAc/hexanes) 0.13. 25

The following compounds illustrate methods for preparing the biologically activecompounds of this invention from intermediate compounds such as described in theforegoing Préparations. -89- 012189

Example 1

Préparation of (+)-3-phenyl-4-[4-i3-(pvridin-2-yl)amino-l-propyloxylphenvl1butanoic acid a) Ethyl (±)-3-phenyl-4-[4-[3-( 1 -oxopyridin-2-yl)amino-1 -propyloxy]phenyl]butanoate

Diisopropyl azodicarboxylate (0.44 mL, 2.25 mmole) was added over 45 sec to asolution of ethyl (±)-4-(4-hydroxyphenyI)-3-phenylbutanoate (426.5 mg, 1.5 mmole), 2-[(3-hydroxy-l-propyl)amino]pyridine-N-oxide (378.5 mg, 2.25 mmole), and triphenylphosphine (590.2 mg, 2.25 mmole) in anhydrous DMF (22.5 mL) at 0 °C underargon. The yellow solution was kept at 0 °C for 10 min, then was warmed to RT. After 23hr, the reaction was concentrated and the residue was reconcentrated from xylenes (2x).Silica gel chromatography (gradient: EtOAc, then 5% MeOH/CHCl3) gave the titlecompound (445.7 mg, 68%) as a yellow oil: TLC Rf (5% MeOH/CHCl3) 0.41; NMR(250 MHz, CDC13) Ô 8.11 (dd, J = 6.5, 1.3 Hz, 1 H), 7.05 - 7.35 (m, 5 H), 6.85 - 7.05 (m, 1H), 6.94 (d, J = 8.6 Hz, 2 H), 6.76 (d, J = 8.6 Hz, 2 H), 6.62 (dd, J = 8.5, 1.5 Hz, 1 H), 6.48 -6.59 (m, 1 H), 3.90 - 4.10 (m, 4 H), 3.50 (q, J = 6.5 Hz, 2 H), 3.25 - 3.45 (m, 1 H), 2.85 (d, J= 7.4 Hz, 2 H), 2.50 - 2.72 (m, 2 H), 2.05 - 2.22 (m, 2 H), 1.11 (t, J = 7.1 Hz, 3 H); MS(ES) m/e 435.1 (M + H)+. b) Ethyl (±)-3-phenyl-4-[4-[3-(pyridin-2-yl)amino-1 -propyloxy]phenyl]butanoate A mixture of ethyl (+)-3-phenyl-4-[4-[3-(l-oxopyridin-2-yl)amino-l-propyloxy]phenyl]butanoate (445.7 mg, 1.03 mmole), cyclohexene (1 mL, 10 mmole), 10%Pd/C (110 mg, 0.10 mmole), and isopropanol (10 mL) was heated at reflux under argon.After 3 hr, more Pd/C (110 mg) was added. The mixture was heated at reflux for another20.5 hr, then was hot-filtered through celite®. The filter pad was washed with hot 1:1MeOH/CHC13, and the combined filtrâtes were concentrated. The residue wasreconcentrated from toluene, then was chromatographed on silica gel (5% MeOH/CHC^)to afford the title compound (332.5 mg, 77%) as a colorless oil: TLC Rf (5%MeOH/CHCl3) 0.43; !H NMR (250 MHz, CDCI3) δ 8.02 - 8.12 (m, 1 H), 7.32 - 7.45 (m, 1 H), 7.06 - 7.32 (m, 5 H), 6.94 (d, J = 8.6 Hz, 2 H), 6.75 (d, J = 8.6 Hz, 2 H), 6.50 - 6.60(m, 1 H), 6.39 (d, J = 8.4 Hz, 1 H), 4.65 - 4.82 (m, 1 H), 3.88 - 4.10 (m, 4 H), 3.48 (q, J =6.4 Hz, 2 H), 3.28 - 3.45 (m, 1 H), 2.84 (d, J = 7.4 Hz, 2 H), 2.50 - 2.62 (m, 2 H), 2.00 - 2.15 (m, 2 H), 1.10 (t, J = 7.1 Hz, 3 H); MS (ES) m/e 419.1 (M + H)+. -90- 012189 c) (±)-3-Phenyl-4-[4-[3-(pyridin-2-yl)amino-1 -propyloxy]phéhÿl]butanoic acidA mixture of ethyl (±)-3-phenyl-4-[4-[3-(pyridin-2-yl)amino-l- propyloxy]phenyl]butanoate (332.5 mg, 0.79 mmole), 1.0 N LiOH (1.2 mL, 1.2 mmole), THF (4 mL), and H2O (2.8 mL) was stirred at RT for 4 hr, then was warmed in an oil bathset at 45 - 50 °C. After 17.5 hr, the resulting homogeneous, nearly colorless solution wascooled to RT and extracted with Et2Û (2x8 mL). The Et20 layers were discarded. Theaqueous layer was stirred with gentle warming under vacuum to remove residual organicsolvents, then was filtered. The resulting aqueous solution was stirred at RT while the pHwas slowly and carefully adjusted to 5.5 - 6.0 with 1.0 N HCl. The mixture was stirred for0.5 hr, then the solid was collected by suction filtration and washed with plenty of H2O.

Drying in high vacuum at 60 °C gave the title compound (232.3 mg, 74%) as a glassy solid: HPLC (Hamilton PRP-1®, 35% CH3CN/H2O containing 0.1% TFA) K’ = 2.4; !h NMR(400 MHz, CD3OD) Ô 7.75 - 7.95 (m, 1 H), 7.48 (app t, 1 H), 7.07 - 7.27 (m, 5 H), 6.90 (d, J = 8.5 Hz, 2 H), 6.72 (d, J = 8.5 Hz, 2 H), 6.50 - 6.70 (m, 2 H), 4.01 (t, J = 6.0 Hz, 2 H), 3.44 (t, J = 6.7 Hz, 2 H), 3.20 - 3.40 (m, 1 H, obscured by residual solvent signal), 2.87 (dd, J = 13.6, 6.6 Hz, 1 H), 2.79 (dd, J = 13.6, 8.1 Hz, 1 H), 2.48 - 2.70 (m, 2 H), 1.98 - 2.11 (m, 2 H); MS (ES) m/e 391.0 (M + H)+. Anal. Calcd for C24H26N2O3 · 0.33 H2O: C, 72.72; H, 6.78; N, 7.07. Found: C, 72.68; H, 6.69; N, 6.96.

Example 2

Préparation of (i)-3-phenvl-4-f4-f2-i6-(methvlamino)pyridin-2-yll-1- ethoxylphenvllbutanoic acid a) Ethyl (±)-3-phenyl-4-[4-[2-[6-(methylamino)pyridin-2-yl]-1 -ethoxy]phenyl]butanoateDiisopropyl azodicarboxylate (0.44 mL, 2.25 mmole) was added over 2 min to a solution of ethyl (±)-4-(4-hydroxyphenyl)-3-phenylbutanoate (427 mg, 1.5 mmole), 6-(methylamino)-2-pyridylethanol (343 mg, 2.25 mmole), and triphenylphosphine (590 mg, 2.25 mmole) in anhydrous THF (22.5 mL) at 0 °C under N2. The yellow solution was keptat 0 °C for 10 min, then was warmed to RT. After 24 hr, the reaction was concentrated andthe residue was chromatographed on silica gel (4:1 Et2Û/hexanes). The title compound(479.5 mg, 76%) was obtained as a colorless oil: TLC Rf (4:1 Et2O/hexanes) 0.50; ^HNMR (250 MHz, CDCI3) δ 7.38 (app t, 1 H), 7.07 - 7.30 (m, 5 H), 6.93 (d, J = 8.6 Hz, 2 H), 6.76 (d, J = 8.6 Hz, 2 H), 6.54 (d, J = 7.3 Hz, 1 H), 6.24 (d, J = 8.3 Hz, 1 H), 4.42 - 4.58 (m, 1 H), 4.26 (t, J = 7.0 Hz, 2 H), 3.98 (q, J = 7.1 Hz, 2 H), 3.25 - 3.42 (m, 1 H), 3.05 (t, J = 7.0Hz, 2 H), 2.89 (d, J = 5.3 Hz, 3 H), 2.74 - 2.92 (m, 2 H), 2.50 - 2.72 (m, 2 H), 1.10 (t, J = 7.1 Hz, 3 H); MS (ES) m/e 419.1 (M + H)+. -91 - ΰ ι 2189 b) (±)-3-Phenyl-4-[4-[2-[6-(methylamino)pyridin-2-yl]-l-ethoxy]phenyl]butanoic acid 1.0 N NaOH (1.15 mL, 1.15 mmole) was added dropwise to a cooled (15 °C)solution of ethyl (±)-3-phenyl-4-[4-[2-[6-(methylamino)pyridin-2-yl]-l-ethoxy]phenyl]butanoate (479.5 mg, 1.15 mmole) in dioxane (4.6 mL). The resultingmixture was stirred at RT for 2.5 hr, then was warmed in an oil bath set at 40 °C. After 24hr, the reaction was cooled to RT and stirred for 3 days, then was diluted with H2O (3.4mL) and extracted with Et2Û (3x5 mL). The Et2Û layers were discarded. Since a solidprecipitate separated from the aqueous layer, 1.0 N NaOH (1.0 mL), dioxane (5 mL), andEt20 (10 mL) were added to afford a homogeneous solution. The pH was adjusted to 5.5 -6.0 with 1.0 N HCl, and the organic solvents were removed on the rotavap. The aqueoussolution was decanted away from the gummy precipitate, and the precipitate was driedthoroughly in vacuum. The residue was recrystallized from CH3CN, and the solid wasdried in vacuum at 60 °C for several days to afford the title compound (331.0 mg, 74%) asa white, crystalline solid: HPLC (Hamilton PRP-1®, 35% CH3CN/H2O containing 0.1%TFA) K’ = 2.9; ÏH NMR (300 MHz, DMSO-d6) δ 7.05 - 7.40 (m, 6 H), 6.95 (d, J = 8.4 Hz, 2 H), 6.76 (d, J = 8.4 Hz, 2 H), 6.42 (d, J = 7.1 Hz, 1 H), 6.30 - 6.50 (m, 1 H), 6.26 (d, J = 8.3 Hz, 1 H), 4.21 (t, J = 6.7 Hz, 2 H), 3.12 - 3.30 (m, 1 H), 2.92 (t, J = 6.7 Hz, 2 H), 2.60 -2.90 (m, 2 H), 2.73 (d, J = 4.8 Hz, 3 H), 2.40 - 2.60 (m, 2 H, partially obscured by residualsolvent signal); MS (ES) m/e 391.2 (M + H)+. Anal. Calcd for C24H26N2O3: C, 73.82; H, 6.71; N, 7.17. Found: C, 73.43; H, 6.72; N, 7.40.

Example 3

Préparation of (i)-3-phenyl-4-f4-ff2-(pyridin-2-yl)amino-l- ethylaminolcarbonyllphenyllbutanoic acid a) Ethyl (±)-3-phenyl-4-[4-[[2-(pyridin-2-yl)amino-l- ethylamino]carbonyl]phenyl]butanoate

To a suspension of ethyl (±)-(4-carboxyphenyl)-3-phenylbutanoate (312 mg, 1.0mmoles), 2-[(2-amino-l-ethyl)amino]pyridine dihydrochloride (252 mg, 1.2 mmoles), andHOBt (162 mg, 1.2 mmoles) in CH3CN (5 mL) was added (i-Pr)2NEt (0.87 mL, 5.0mmoles) then EDC (230 mg, 1.2 mmoles). After 18 hr the mixture was concentrated. Theresidue was chromatographed on silica gel (5% MeOH in 1:1 CHC^/EtOAc) to give thetitle compound (380 mg, 88%) as a brownish foam: MS (ES) m/e 432 (M + H)+. -92- 012189 b) (±)-3-Phenyl-4-(4-[[2-(pyridin-2-yl)amino-l-ethylamino]carbonyl]phenyl]butanoic acidTo a solution of ethyl (±)-3-phenyl-4-[4-[[2-(pyridin-2-yl)amino-l- ethylamino]carbonyl]phenyl]butanoate (380 mg, 0.88 mmoles) in 1:1 THF/H2O (5 mL)was added 1.0 N LiOH (1.3 mL, 1.3 mmoles). After 24 hr the mixture was concentrated toremove the THF. The resulting aqueous solution was cooled to 0 °C and acidified to pH 6using 10% HCl. The precipitate was collected by filtration and dried in vacuo to give thetitle compound (213 mg, 60%) as a white solid: MS (ES) m/e 404 (M + H)+. Anal. Calcdfor C24H25N3O3 · 0.25 H2O: C, 70.66; H, 6.30; N, 10.30. Found: C, 70.92; H, 6.44; N, 10.14.

Example 4

Préparation of (±)-3-phenvl-3-r4-r4-(pvridin-2-vl)amino-1 -butyllphenvlaminolpropanoic acid a) 1 -Bromo-4-(4-nitrophenyl)butane

To a solution of 4-(4-nitrophenyl)-l-butanol (1.0 g, 5.12 mmoles) in dry THF (10mL) was added PPI13 (1.61 g, 6.14 mmoles) and CBty (2.04 g, 6.14 mmoles). After 4 hrthe mixture was concentrated. The residue was chromatographed on silica gel (10%EtOAc/hexanes) to afford the title compound (1.22 g, 92%) as a pale yellow oil: ^H NMR(300 MHz, CDCI3) ? 8.18 (d, J = 6.5 Hz, 2 H), 7.36 (d, J = 6.5 Hz, 2 H), 3.48 (t, 2H), 2.80(t, 2 H), 1.9 (m,4H). b) l-[N-(tert-Butoxycarbonyl)-N-(pyridin-2-yl)amino]-4-(4-nitrophenyl)butane

To a suspension of NaH (170 mg, 4.25 mmoles) in dry DMF (10 mL) was added 2-(tert-butoxycarbonylamino)pyridine (750 mg, 3.86 mmoles) at 0 °C. After 5 min themixture was warmed to RT. After 15 min the mixture was cooled to 0 °C and l-bromo-4-(4-nitrophenyl)butane (1.22 g, 4.73 mmoles) in dry DMF (5 mL) was added. The mixturewas allowed to warm to RT as the bath warmed. After 18 hr the mixture was concentrated.The residue was taken up in H2O (50 mL) and extracted with EtOAc (3 x 50 mL). Thecombined organic layers were dried over MgSOzj, filtered, and concentrated. The residuewas chromatographed on silica gel (15% EtOAc/hexanes) to give the title compound (1.25g, 87%) as a pale yellow oil: MS (ES) m/e 372 (M + H)+. c) l-[N-(tert-Butoxycarbonyl)-N-(pyridin-2-yl)amino]-4-(4-aminophenyl)butane

To a suspension of 10% Pd/C (358 mg) in absolute EtOH (15 mL) was added 1-[N-(tert-butoxycarbonyl)-N-(pyridin-2-yl)amino]-4-(4-nitrophenyl)butane (1.25 g, 3.37mmoles). The mixture was deoxygenated (3 x evacuation/N2 purge cycles) then charged -93- 012189 with H2 (50 psi). After 2 hr the H2 was removed and the mixture filtered through a pad ofcelite®. The filtrate was concentrated to give the title compound (1.14 g, 99%) as a yellowoil which was used without purification: MS (ES) m/e 342 (M + H)+. 5 d) tert-Butyl (±)-3-phenyl-3-[4-[4-[N-(tert-butoxycarbony)-N-(pyridin-2-yl)amino]-l-butyl]phenylamino]propanoate

To a suspension of MgSC>4 (7.0 g) in CH2CI2 (20 mL) was added l-[N-(tert-butoxycarbonyl)-N-(pyridin-2-yl)amino]-4-(4-aminophenyl)butane (560 mg, 1.64 mmoles)then benzaldehyde (0.2 mL, 1.97 mmoles). After 18 hr the mixture was filtered and the 10 filtrate was concentrated. The residue was taken up in dry THF (10 mL) and cooled to -78°C. To this mixture was added BF3 · 0Et2 (0.4 mL, 3.28 mmoles) dropwise. After 15 min,the Reformatsky reagent prepared from zinc métal and tert-butyl bromoacetate in THF(Tetrahedron 1984,40, 2781; 818 mg, 2.46 mmoles) was added. The mixture was allowedto warm to RT over 5 hr as the bath warmed. The mixture was diluted with H2O (20 mL) 15 and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried overMgSO4, filtered, and concentrated. The residue was chromatographed on silica gel (15%EtOAc/hexanes) to give the title compound (350 mg, impure): MS (ES) m/e 546 (M + H)+.This was used in the next step without further purification. 20 e) (±)-3-Phenyl-3-[4-[4-(pyridin-2-yl)amino-l-butyl]phenylamino]propanoic acid tert-Butyl (±)-3-phenyl-3-[4-[4-[N-(tert-butoxycarbony)-N-(pyridin-2-yl)amino]-1 - butyl]phenylamino]propanoate (350 mg, impure) was dissolved in 1:1 TFA/CH2CI2 (10mL). After 2 hr the mixture was concentrated. The residue was dissolved in 1.0 M NaOH(10 mL) and extracted with EtOAc (2x10 mL). The aqueous layer was acidified to pH 6 25 using 10% HCl. The solid was collected by filtration and dried in vacuo at 50 °C for 18 hrto give the title compound (74 mg, 12%) as an off-white powder: MS (ES) m/e 390 (M +H)+. Anal. Calcd for C24H27N3O2 · 0.50 H2O: C, 72.34; H, 7.08; N, 10.54. Found: C,72.29; H, 6.92; N, 10.37. -94- 012189 e Example 5 ? · 7

Préparation of 4-r4-f2-r6-(methvlamino)pvridin-2-yl]-l-ethoxylphenvl1butanoic acid a) Methyl 4-[4-[2-[6-(methylamino)pyridin-2-yl]-l-ethoxy]phenyl]butanoate

Diisopropyl azodicarboxylate (0.3 mL, 1.4 mmole) was added to a solution ofmethyl 4-(4-hydroxyphenyl)butanoate (180 mg, 0.93 mmole), 6-(methylamino)-2-pyridylethanol (212 mg, 1.4 mmole), and triphenylphosphine (367 mg, 1.4 mmole) inanhydrous THF (10 mL) at 0 °C. The mixture was allowed to warm to RT as the bathwarmed. After 24 hr the mixture was concentrated and the residue was chromatographedon silica gel (Et2O). The title compound (160 mg, 52%) was obtained as a pale yellow oil: !h NMR (300 MHz, CDC13) ? 7.39 (t, 1 H), 7.05 (d, J = 6.6 Hz, 2 H), 6.82 (d, J = 6.6 Hz, 2H), 6.52 (d, J = 8 Hz, 1 H), 6.13 (d, J = 8.0 Hz, 1 H), 4.51 (br s, 1 H), 4.28 (t, 2 H), 3.72 (t, 2 H), 3.65 (s, 3 H), 3.06 (t, 2 H), 2.89 (d, J = 6.0 Hz, 3 H), 2.55 (t, 2 H), 2.30 (t, 2 H), 1.88(m,2H). b) 4-[4-[2-[6-(Methylamino)pyridin-2-yl]-1 -ethoxy]phenyl]butanoic acid

To a solution of methyl 4-[4-[2-[6-(methylamino)pyridin-2-yl]-l- .ethoxy]phenyl]butanoate (160 mg, 0.49 mmoles) in 1:1 THF/H2O (1.5 mL) was added 1.0N LiOH (0.58 mL, 0.58 mmoles). After 5 hr the mixture was concentrated to remove THF.

The resulting aqueous solution was cooled to 0 °C and acidified to pH 6 using 10% HCl.

The title compound (94 mg, 61%) was collected by filtration and dried in vacuo at 50 °Cfor 18 hr: MS (ES) m/e 315 (M + H)+. Anal. Calcd for C18H22N2O3: C, 68.77; H, 7.05; N, 8.91. Found: C, 68.75; H, 7.06; N, 8.74.

Example 6

Préparation of (±)-4-f4-f2-Î6-(methvlamino)pvridin-2-yll-l-ethoxy1phenvn-3- vinvlbutanoic acid a) Methyl (±)-4-[4-[2-[6-(methylamino)pyridin-2-yl]-1 -ethoxy]phenyl]-3-vinylbutanoate

Diisopropyl azodicarboxylate (0.17 mL, 0.84 mmole) was added to a solution ofmethyl (±)-4-(4-hydroxyphenyl)-3-vinylbutanoate (92.5 mg, 0.42 mmole), 6-(methylamino)-2-pyridylethanol (128 mg, 0.84 mmole), and triphenylphosphine (220 mg, O. 84 mmole) in anhydrous THF (2 mL) at 0 °C. The mixture was allowed to warm to RT asthe bath warmed. After 24 hr the mixture was concentrated and the residue waschromatographed on silica gel (3:1 Et2O/hexanes). The title compound (100 mg, 67%) wasobtained as a pale yellow oil: MS (ES) m/e 355 (M + H)+. -95- 012189 b) (±)-4-[4-[2-[6-(Methylamino)pyridin-2-yl]-l-ethoxy]phenyl]-3-vinylbutanoic acidTo a solution of methyl (±)-4-[4-[2-[6-(methylamino)pyridin-2-yl]-l- ethoxy]phenyl]-3-vinylbutanoate (100 mg, 0.28 mmoles) in 1:1 THF/H2O (1.5 mL) wasadded 1.0 N LiOH (0.34 mL, 0.34 mmoles). After 18 hr the mixture was acidified to pH 6using 10% HCl and extracted with EtOAc (3x10 mL). The combined organic layers weredried over MgSC>4, filtered, and concentrated. The residue was lyophilized from HOAc (10mL) to give the title compound (50 mg, 52%) as a yellow oil: MS (ES) m/e 341 (M + H)+.Anal. Calcd for C20H24N2O3 2.75 CH3CO2H: C, 60.58; H, 6.98; N, 5.54. Found: C,60.55; H, 6.91; N, 5.47.

Example 7

Préparation of (±)-4-i4-i2-f6-(methylamino)pyridin-2-vn-l-ethoxylphenyll-3-(pyridin-2- yPbutanoic acid a) Ethyl (±)-4-[4-[2-[6-(methyIamino)pyridin-2-yl]-l-ethoxy]phenyl]-3-(pyridin-2-yl)butanoate

Diisopropyl azodicarboxylate (0.12 mL, 0.62 mmole) was added to a solution ofethyl (±)-4-(4-hydroxyphenyl)-3-(pyridin-2-yl)butanoate (90 mg, 0.31 mmole), 6-(methylamino)-2-pyridylethanol (95 mg, 0.62 mmole), and triphenylphosphine (163 mg,0.62 mmole) in anhydrous THF (2 mL) at 0 °C. The mixture was allowed to warm to RT asthe bath warmed. After 24 hr the mixture was concentrated and the residue waschromatographed on silica gel (10% hexanesÆ^O). The title compound (71 mg, 55%) wasobtained as a colorless oil; MS (ES) m/e 420 (M + H)+. b) (±)-4-(4-[2-[6-(Methylamino)pyridin-2-yl]-l-ethoxy]phenyl]-3-(pyridin-2-yl)butanoicacid

To a solution of ethyl (±)-4-[4-[2-[6-(methylamino)pyridin-2-yl]-l-ethoxy}phenyl]- 3-(pyridin-2-yl)butanoate (71 mg, 0.17 mmoles) in 1:1 THF/H2O (2 mL) was added 1.0 NLiOH (0.34 mL, 0.34 mmoles). After 18 hr the mixture was acidified to pH 6 using 10%HCl and extracted with CHCI3 (3 x 10 mL). The combined organic layers were dried overMgSÜ4, filtered, and concentrated. The residue was chromatographed on silica gel (10%MeOH/CHCl3) to give the title compound as a yellowish foam. MS (ES) m/e 392 (M +H)+. Anal. Calcd for C23H25N3O3 · 0.75 H2O: C, 68.21; H, 6.60; N, 10.38. Found: C,68.50; H, 6.39; N, 10.24.

Example 8 -96- 012189

Préparation of (±)-4-r4-f2-f6-(methvlamino)pvridin-2-yll-l-ethoxvlDhenvn-3-(oxazol-2- vl)butanoic acid a) Methyl (±)-4-[4-[2-[6-(methylamino)pyridin-2-yl]-l-ethoxy]phenyl]-3-(oxazol-2- 5 yl)butanoate

Diisopropyl azodicarboxylate (0.24 mL, 1.24 mmole) was added to a solution ofmethyl (±)-4-(4-hydroxyphenyl)-3-(oxazol-2-yl)butanoate (163 mg, 0.62 mmole), 6-(methylamino)-2-pyridylethanol (190 mg, 1.24 mmole), and triphenylphosphine (325 mg,1.24 mmole) in anhydrous THF (4 mL) at 0 °C. The mixture was allowed to warm as the 10 bath warmed to RT. Afiter 24 hr the mixture was concentrated and the residue was chromatographed on silica gel (50% EtOAc/CHClj). The title compound (167 mg, 68%)was obtained as an orangish oil: MS (ES) m/e 396 (M + H)+. b) (±)-4-[4-[2-[6-(Methylamino)pyridin-2-yl]-1 -ethoxy]phenyl]-3-(oxazol-2-yl)butanoic 15 acid

To a solution of methyl (±)-4-[4-[2-[6-(methylamino)pyridin-2-yl]-l-ethoxy]phenyl]-3-(oxazol-2-yl)butanoate (167 mg, 0.42 mmoles) in 1:1 THF/H2O (4 mL)was added 1.0 N LiOH (0.63 mL, 0.63 mmoles). After 18 hr the mixture was washed withEt2Û (2x2 mL). The aqueous layer was concentrated to remove residual THFÆ^O then 20 was acidified to pH 6 using 10% HCl. The title compound (114 mg, 71%) was collected asa white solid by filtration and dried in vacuo at 50 °C for 18 hr. MS (ES) m/e 382 (M + H)+. Anal. Calcd for C21H23N3O4 · 0.50 H2O: C, 64.60; H, 6.20; N, 10.76. Found: C,64.33; H, 6.12; N, 10.38. -97- 012189

Example 9

Préparation of (±)-4-r4-i2-[6-(methylamino)pyridin-2-yn-l-ethoxv1phenyn-3-(thiazol-2- yDbutanoic acid a) Ethyl (±)-4-[4-[2-[6-(methylamino)pyridin-2-yl]-l-ethoxy]phenyl]-3-(thiazol-2-yl)butanoate

Diisopropyl azodicarboxylate (0.21 mL, 1.06 mmole) was added to a solution ofethyl (±)-4-(4-hydroxyphenyl)-3-(thiazol-2-yl)butanoate (155 mg, 0.53 mmole), 6-(methylamino)-2-pyridylethanol (163 mg, 1.06 mmole), and triphenylphosphine (278 mg, 1.06 mmole) in anhydrous THF (5 mL) at 0 °C. The mixture was allowed to warm to RT asthe bath warmed. After 24 hr the mixture was concentrated and the residue waschromatographed on silica gel (50% EtOAc/CHClj). Fractions containing the productwere concentrated and rechromatographed on silica gel (60% EtOAc/hexanes). Fractionsfrom the second chromatography which contained the product were further purifîed bypréparative TLC (60% EtOAc/hexanes). The title compound (106 mg, 47%) was obtainedas an oil: MS (ES) m/e 426 (M + H)+. b) (±)-4-[4-[2-[6-(Methylamino)pyridin-2-yl]-l-ethoxy]phenyl]-3-(thiazol-2-yl)butanoicacid

To a solution of ethyl (±)-4-[4-[2-[6-(methylamino)pyridin-2-yl]-l-ethoxy]phenyl]- 3-(thiazol-2-yl)butanoate (106 mg, 0.25 mmoles) in 1:1 THF/H2O (5 mL) was added 1.0 NLiOH (0.37 mL, 0.37 mmoles). After 18 hr the mixture was extracted with Et2Û (2x5mL), and the Et2O layers were discarded. The aqueous layer was concentrated to removeresidual organic solvents, then was acidifîed to pH 6 using 10% HCl. CH3CN (0.5 mL)was added to the mixture to dissolve ail solids. The solution was purified by C18-bond/elute chromatography (H2O, then 20% CH3CN/H2O). Fractions containing theproduct were lyophilized to give the title compound (53 mg, 53%) as a white powder: MS(ES) m/e 398 (M + H)+. Anal. Calcd for C21H23N3O3S: C, 63.46; H, 5.83; N, 10.57.Found: C, 63.17; H, 6.00; N, 10.37. -98- 012189 · - Example 10 ” ;

Préparation of (±)3-methvl-4-i4-f3-(pvridin-2-vl)amino-l-propyloxylphenvl1butanoic acid a) Ethyl (±)-3-methyl-4-(4-[3-(l-oxopyridin-2-yl)amino-l-propyloxy]phenyl)butanoate

Diisopropyl azodicarboxylate (0.3 mL, 1.5 mmole) was added over 45 sec to asolution of ethyl (±)-4-(4-hydroxyphenyl)-3-methylbutanoate (220 mg, 1.0 mmole), 2-[(3-hydroxy-l-propyl)amino]pyridine-N-oxide (252 mg, 1.5 mmole), and triphenylphosphine(390 mg, 1.5 mmole) in anhydrous DMF (22.5 mL) at 0 °C under argon. The yellowsolution was kept at 0 °C for 10 min, then was warmed to RT. After 23 hr, the reaction wasconcentrated and the residue was reconcentrated from xylenes (2x). Silica gelchromatography (1% MeOH/CH2Cl2) gave the title compound (200 mg, 54%) as a yellowoil: MS (ES) m/e 373 (M + H)+. b) Ethyl (±)-3-methyî-4-[4-[3-(pyridin-2-yl)amino-1 -propyloxy]phenyl]butanoate A mixture of ethyl (±)-3-methyl-4-[4-[3-(l-oxopyridin-2-yl)amino-l-propyloxy]phenyl]butanoate (200 mg, 0.54 mmole), cyclohexene (0.6 mL, 0.54 mmole), 10% Pd/C (55 mg, 00.5 mmole), and isopropanol (10 mL) was heated at reflux underargon.. The mixture was heated at reflux for another 20.5 hr, then was hot-fîltered throughcelite®. The filter pad was washed with hot 1:1 MeOHZCHCl3 and the filtrate wasconcentrated. The residue was reconcentrated from toluene, then was chromatographed onsilica gel (1% MeOH/CH2Cl2) to afford the title compound (150 mg, 78%) as a colorlessoil: MS (ES) m/e 357 (M + H)+. c) (±)-3-Methyl-4-[4-[3-(pyridin-2-yl)amino-1 -propyloxy]phenyl]butanoic acid A mixture of ethyl (±)-3-methyl-4-[4-[3-(pyridin-2-yl)amino-l-propyloxy]phenyl]butanoate (150 mg, 0.42 mmole), 1.0N LiOH (1.2 mL, 1.2 mmole), THF(4 mL), and H2O (2.8 mL) was stirred at RT for 4 hr, then was warmed in an oil bath set at45 - 50 °C. After 17.5 hr, the resulting homogeneous, nearly colorless solution was cooledto RT and extracted with Et20 (2x8 mL). The Et2Û layers were discarded. The aqueouslayer was stirred with gentle warming under vacuum to remove residual organic solvents,then was filtered. The resulting aqueous solution was stirred at RT while the pH wasslowly and carefully adjusted to 5.5 - 6.0 with 1.0 N HCl. The mixture was stirred for 0.5hr, then the solid was collected by suction filtration and washed with plenty of H2O.

Drying in high vacuum at 60 °C gave the title compound (90 mg, 65%) as a glassy solid: MS (ES) m/e 328 (M + H)+. Anal. Calcd for C19H24N2O3 · 0.25 H2O: C, 68.54; H, 7.13; N, 8.35. Found: C, 68.55; H, 7.42; N, 8.41. -99- 012189

Example 11

Préparation of (±)-3-methvl-4-i4-12-f6-(methvlamino)pvridin-2-yn-l- ethoxylphenyllbutanoic acid a) Ethyl (±)-3-methyl-4-[4-[2-[6-(methylamino)pyridin-2-yl]-l-ethoxy]phenyl]butanoate

Diisopropyl azodicarboxylate (0.44 mL, 2.25 mmole) was added over 2 min to asolution of ethyl (±)-4-(4-hydroxyphenyl)-3-methylbutanoate (378 mg, 2.25 mmole), 6-(methylamino)-2-pyridylethanol (343 mg, 2.25 mmole), and triphenylphosphine (590 mg,2.25 mmole) in anhydrous THF (22.5 mL) at 0 °C under N2. The yellow solution was keptat 0 °C for 10 min, then was warmed to RT. After 24 hr, the reaction was concentrated andthe residue was chromatographed on silica gel (6:4 EtOAc/hexanes). The title compound(200 mg, 76%) was obtained as a colorless oil: MS (ES) m/e 357 (M + H)+. b) (+)-3-Methyî-4-[4-[2-[6-(methylamino)pyridin-2-yl]-1 -ethoxy]phenyl]butanoic acid 1.0 N NaOH (1 mL, 0.898 mmole) was added dropwise to a cooled (15 °C) solutionof ethyl (±)-3-methyl-4-[4-[2-[6-(methylamino)pyridin-2-yl]-1 -ethoxy]phenyl]butanoate(160 mg, 0.449 mmole) in THF (3 mL), and the mixture was stirred at RT for 24 hr. Theresulting solution was concentrated in vacuum and the residue was dissolved in H2O (5mL). The pH was adjusted to 7 with 1.0 N HCl, and the supematant was decanted awayfrom the gummy precipitate.. Thorough drying in vacuum at 60 °C for several days gavethe title compound (120 mg, 82%) as a white, foamy solid: MS (ES) m/e 328 (M + H)+.Anal. Calcd for ^9^4^03: C,69.49; H, 7.37; N, 8.53. Found: C, 69.03; H, 7.27; N,8.40.

Example 12

Préparation of (i)-3-methyI-4-f4-f2-f2-(methylamino)pyridin-5-vn-l- ethoxylphenyllbutanoic acid a) Ethyl (±)-3-methyl-4-[4-[2-[2-(methylamino)pyridin-5-y 1]-1 -ethoxyJphenyl]butanoateDiisopropyl azodicarboxylate (0.18 mL, 0.913 mmole) was added over 2 min to asolution of ethyl (+)-4-(4-hydroxyphenyl)-3-methylbutanoate (133 mg 0.6 mmole), 2-[N- (tert-butoxycarbonyl)-N-methylamino]-5-pyridylethanol (230 mg, 0.913 mmole), andtriphenylphosphine (239 mg, 0.913 mmole) in anhydrous THF (5 mL) at 0 °C under N2.The yellow solution was kept at 0 °C for 10 min, then was warmed to RT. After 24 hr, thereaction was concentrated and the residue was chromatographed on silica gel (1% - 100- 012189

MeOH/CH2Cl2). The title compound (200 mg, 73%) waiis obtained as a colorless oil: MS(ES) m/e 456 (M + H)+. b) (±)-3-Methyl-4-[4-[2-[2-(methylamino)pyridin-5-yl]-l-ethoxy]phenyl]butanoic acid

Ethyl (±)-3-methyl-4-[4-(2-[2-(methylamino)pyridin-5-yl]-1 -ethoxy]phenyl]butanoate (200 mg, 0.44 mmole) was suspended in 1.0 M HCl/dioxane (5mL). After 2 hr., the reaction was concentrated in vacuum and the residue wasreconcentrated from toluene (3 x 10 mL). The remaining residue was taken up in 5%Na2CC>3 solution and extracted with CH2CI2· The extracts were dried over MgSC>4,filtered, and concentrated leave an oil (50 mg). This was taken up in THF (3 mL), 1.0 NLiOH (0.28 mL, 0.28 mmole) was added, and the mixture was stirred at RT for 24 hr. Theresulting solution was concentrated in vacuum and the residue was dissolved in H2O (5mL). The pH was adjusted to 7 with 1.0 N HCl, and the supematant was decanted awayfrom the gummy precipitate. Thorough dry.ing in vacuum at 60 °C for several days gavethe title compound (5 mg) as a white, foamy solid: MS (ES) m/e 328 (M + H)+.

Example 13

Préparation of (i)-4-r4-f2-f6-(methylamino)pyridin-2-yn-l-ethoxvlphenvn-3-(thiophen-2- vllbutanoic acid a) Methyl (±)-4-[4-[2-[6-[N-(tert-butoxycarbonyl)-N-methylamino)pyridin-2-yl]-1-ethoxy]phenyl]-3-(thiophen-2-yl)butanoate A solution of methyl (±)-4-(4-hydroxyphenyl)-3-(thiophen-2-yl)butanoate (245.1mg, 0.89 mmole) and PPI13 (237.6 mg, 0.91 mmole) in CH2CI2 was added slowly to asolution of 6-[N-(tert-butoxycarbonyl)-N-methylamino]-2-pyridylethanol (244.1 mg, 0.97mmole) and DEAD (0.14 mL, 0.89 mmole) in CH2CI2 at 0 °C. The reaction was allowedto warm to RT as the bath warmed. After 24 hours, the reaction was concentrated invacuum, and the residue was chromatographed on silica gel (gradient: 10% EtOAc/hexanes,then 20% EtOAc/hexanes, then 50% EtOAc/hexanes) to afford the title compound (122.1mg, 26.9%): MS (ES) m/e 510.9 (M + H)+. - 101 - 0 ι 2 I 8 9 b) (±)-4-[4-[2-[6-(Methylamino)pyridin-2-yl]-l-ethoxy]phenyl]-3-(thiophen-2-yl)butanoicacid

Methyl (±)-4-[4-[2-[6-[N-(tert-butoxycarbonyl)-N-methylamino)pyridin-2-yl]-l-ethoxy]phenyl]-3-(thiophen-2-yl)butanoate (122.1 mg, 0.24 mmole) was stirred with 4 NHCl/dioxane for 2.5 hr at RT, then the reaction was concentrated, and the residue wasreconcentrated from toluene (2x). Since the Boc group had not been completely removed,the residue was resubmitted to the reaction conditions. After another 1.5 hr, the reactionwas concentrated, and the residue was reconcentrated from toluene. This material wasdissolved in dioxane (3 mL) and THF (3 mL), and 1.0 N NaOH (2 mL, 2.0 mmole) wasadded. The reaction was stirred at RT for 24 hr, then was concentrated. Since ester wasstill présent, the residue was resubmitted to the reaction conditions. After an additional 20hr at RT, the reaction was neutralized with 1.0 N HCl and concentrated. Again, ester wasstill présent, so the residue was resubmitted to the reaction conditions, this time withwarming at 60 °C. After 18 hours, the reaction was neutralized with 1.0 N HCl andconcentrated in vacuum. The solid residue was reconcentrated from toluene (2x), then wastaken up in 0.1% TFA/H2O. The white precipitate that separated was collected and washedwith more 0.1 % TFA/ H2O. Drying in vacuum gave the title compound (92.5 mg, 83%) asa white powder: MS (ES) m/e 397.1 (M + H)+. Anal. Calcd for C22H24N2O3S · 0.5 TFA• 0.5 H2O: C, 59.73; H, 5.56; N, 6.06. Found: C, 59.62; H, 5.40; N, 6.14.

Example 14

Préparation of 2-[N-benzvl-N-f4-i2-[6-(methyIamino)pyridin-2-yn-l- ethoxvlbenzyllaminolacetic acid a) Ethyl 2-[N-benzyl-N-[4-[2-[6-[N-(tert-butoxycarbonyl)-N-methylamino]pyridin-2-yl]-l-ethoxy]benzyl]amino]acetate A solution of 6-[N-(tert-butoxycarbonyl)-N-methylamino]-2-pyridylethanol (0.17g, 0.69 mmole) and diethyl azodicarboxylate (0.11 mL, 0.70 mmole) in CH2CI2 (1.5 mL)was added dropwise to a solution of ethyl 2-[N-benzyl-N-(4-hydroxybenzyl)amino]acetate(0.14 g, 0.46 mmole) and PI13P (0.18 g, 0.69 mmole) in CH2CI2 (1.5 mL) at 0 °C. The icebath was removed and the reaction was allowed to warm to RT. After 24 h, the solvent wasremoved under reduced pressure. Radial chromatography (20% EtOAc/hexane, silica gel, 6mm plate) gave the title compound (0.14 g) as a clear oil: MS (ES) m/e 534.1 (M + H)+. - 102- 012189 b) 2-[N-benzyl-N-[4-[2-[6-(methylamino)pyridin-2-yl]-l-ethoxy]benzyl]amino]acetic acidEthyl 2-[N-benzyl-N-[4-[2-[6-[N-(tert-butoxycarbonyl)-N-methylamino]pyridin-2-yl]-l-ethoxy]benzyl]amino]acetate (0.14 g, 0.27 mmole) was dissolved in 4 N HCl/dioxane (5 mL). The reaction was stirred for 5.5 h at RT, then the solvent was removed underreduced pressure. The residue was suspended in 1.0 N NaOH (2 mL) and MeOH (2 mL).The reaction was stirred for 18 h at RT, then the solvent was removed under reducedpressure. The residue was dissolved in H2O and the solution was acidified to pH « 5 with1.0 N HCl. The solvent was removed under reduced pressure. Purification by préparativeHPLC (Hamilton PRP-1 column, 20% CH3CN/H2O containing 0.1% TFA) gave the titlecompound (0.40 g) as a white powder: MS (ES) m/e 406.0 (M + H)+. Anal. Calcd forC24H27N3O3 · 2.5 TFA · 1.5 H2O: C, 48.54; H, 4.56; N, 5.86. Found: C, 48.69; H, 4.24;N, 5.78.

Example 15

Préparation of 2-rN-f4-f2-i6-(methylamino)pyridin-2-yn-l-ethoxy1benzvn-N- phenvllaminolacetic acid a) Methyl 2-[N-[4-[2-[6-[N’-(tert-butoxycarbonyl)-N’-methylamino]pyridin-2-yl]-1 -ethoxy]benzyl]-N-phenyl]amino]acetate

According to the procedure of Example 14 (a), except substituting methyl 2-[N-(4-hydroxybenzyl)-N-phenylamino]acetate (39 mg, 0.14 mmole) for the ethyl 2-[N-benzyl-N-(4-hydroxybenzyl)amino]acetate, the title compound (8 mg) was obtained as a clear filmfollowing radial chromatography (20% EtOAc/hexane, silica gel, 2 mm plate): MS (ES)m/e 506.0 (M + H)+. b) 2-[N- [4- [2- [6-(methylamino)pyridin-2-y 1]-1 -ethoxyjbenzyl]-N-pheny 1] amino] aceticacid A solution of 4 N HCl in dioxane (5 mL) was added to methyl 2-[N-[4-[2-[6-(methylamino)pyridin-2-yl]-l-ethoxy]benzyI]-N-phenyl]amino]acetate (8 mg, 0.016mmole). The reaction was stirred for 5.5 h at RT, then the solvent was removed underreduced pressure to leave a clear film. This was dissolved in 1.0 N NaOH (2 mL) andMeOH (2 mL). The reaction was stirred for 18 h at RT, then the solvent was removedunder reduced pressure. Flash chromatography on a C-18 Bond Elut® column (stepgradient: H2O containing 0.1% TFA, then 20% CH3CN/H2O containing 0.1% TFA, then50% CH3CN/H2O containing 0.1% TFA) gave the title compound (1.5 mg) as ahygroscopic, dark solid: MS (ES) m/e 392.0 (M + H)+. - 103- 01218ç

Example 16

Préparation of 2-rN-f2-methoxv-4-[2-[6-(methylamino)pyridin-2-vl]-l- ethoxylbenzyllaminolacetic acid a) Methyl 2-[N-[2-methoxy-4-[2-[6-[N’-(tert-butoxycarbonyl)-N’-methylamino]pyridin-2-yl]-l-ethoxy]benzyl]amino]acetic acid

According to the procedure of Example 14 (a), except substituting methyl 2-[(4-hydroxy-2-methoxybenzyl)amino]acetate (0.48 g, 2.14 mmole) for the ethyl 2-[N-benzyl-N-(4-hydroxybenzyl)amino]acetate, the title compound (0.14 g) was obtained as a clear oilafter flash chromatography on silica gel (40% EtOAc/hexane) folio wed by radialchromatography (5% MeOH/ CHCI3, silica gel, 6 mm plate): MS (ES) m/e 506.0 (M +H)+. b) Methyl 2-[N-[2-methoxy-4-[2-[6-(methylamino)pyridin-2-yl]-l- ethoxy]benzyl]amino]acetate A solution of 4 N HCl in dioxane (15 mL) was added to methyl 2-[N-[2-methoxy- 4-[2-[6-[N’-(tert-butoxycarbonyl)-N’-methylamino]pyridin-2-yl]-l-ethoxy]benzyl]amino]acetic acid (0.14 g, 0.30 mmole). The reaction was stirred for 2 hr atRT, then the solvent was removed under reduced pressure to leave a clear residue. Thiswas dissolved in saturated NaHCO3, and the solution was extracted with 10%MeOH/EtOAc. The combined organic extracts were washed with brine, dried overNa2SC>4, and concentrated to give a pale yellow oil. Flash chromatography on silica gel(5% MeOH/ CHCI3) gave the title compound (0.11 g) as a clear oil: MS (ES) m/e 350.4(M + H)+. c) 2-[N-[2-Methoxy-4-[2-[6-(methylamino)pyridin-2-yl]-l-ethoxy]benzyl]amino]aceticacid

To a solution of methyl 2-[N-[2-methoxy-4-[2-[6-(methylamino)pyridin-2-yl]-l-ethoxy]benzyllamino]acetate (0.11 g, 0.30 mmole) in MeOH (3 mL) was added 1.0 NNaOH (3 mL). The reaction was stirred for 15 min at RT, then the solvent was removedunder reduced pressure. The residue was dissolved in H2O and the solution was acidifiedto pH « 3 with conc HCl. The solvent was removed to leave a white residue. Flashchromatography on a Waters Sep-PaK® C-18 column (step gradient: H2O, then 15%CH3CN/H2O) gave the title compound (0.11 g) as a very hygroscopic white solid: MS(ES) m/e 346.4 (M + H)+. !h NMR (300 MHz, DMSO-d6) δ 7.70 (m, 1 H), 7.40 (d, J =8.3 Hz, 1 H), 6.80 - 6.55 (m, 4 H), 4.35 (m, 2 H), 4.05 (s, 2 H), 3.80 (s, 3 H), 3.67 (s, 2 H), 3.15 (m, 2 H), 2.95 (s, 3 H). - 104- 0121

Example 17

Préparation of 2-phenoxy-4-i5-(pyridin-2-vl)amino-l-pentyloxvlphenvlacetic acid a) Methyl 2-phenoxy-4-[5-( 1 -oxopyridin-2-yl)amino-1 -pentyloxy]phenylacetate

According to the procedure of Example 14 (a), except substituting methyl 2-(4-hydroxy-2-phenoxyphenyl)acetate (0.19 g, 0.74 mmole) for the ethyl 2-[N-benzyl-N-(4-hydroxybenzyl)amino]acetate, the title compound (0.35 g) was obtained as a pale yellow oilfollowing radial chromatography (50% EtOAc/hexane, silica gel, 6 mm plate): MS (ES)m/e 506.0 (M + H)+. b) Methyl 2-phenoxy-4-[5-(pyridin-2-yl)amino-1 -pentyloxy]phenylacetate

To a solution of methyl 2-phenoxy-4-[5-(l-oxopyridin-2-yl)amino-l-pentyloxy]phenylacetate (0.35 g, 0.81 mmole) and cyclohexene (0.81 mL, 8.00 mmole) inEtOH (4 mL) was added 10% Pd/C (10 mg). After 18 h at reflux, the reaction was allowedto cool to RT and the catalyst was removed by filtration. The solvent was removed underreduced pressure to leave a clear oil. Radial chromatography (5% to 10% MeOH/CHClj,silica gel, 6 mm plate) gave the title compound (0.23 g) as a clear oil: MS (ES) m/e 421.1(M + H)+. c) 2-Phenoxy-4- [5-(pyridin-2-yl)amino-1 -pentyloxyJphenylacetic acid

To a solution of methyl 2-phenoxy-4-[5-(pyridin-2-yl)amino-l-pentyloxyjphenylacetate (0.23 g, 0.55 mmole) in MeOH (2.5 mL) was added 1.0 N NaOH(2.5 mL). The reaction was stirred for 18 h at RT, then the solvent was removed underreduced pressure. The residue was dissolved in H2O, and the solution was acidified to pH= 4 with conc. HCl. The aqueous layer was extracted with EtOAc and the combinedorganic extracts were dried over Na2SO4- The solvent was removed to give a pale yellowoil. Flash chromatography on silica gel (10% MeOH/ CHCI3) gave the title compound (81mg): MS (ES) m/e 407.0 (M + H)+. *H NMR (300 MHz, CDCI3) δ 7.78 (d, J = 4.1 Hz, 1H), 7.50 (dt, J = 8.7, 1.6 Hz, 1 H), 7.20 (m, 3 H), 6.95 (m, 3 H), 6.50 (m, 4H), 3.77 (t, J = 6.4 Hz, 2 H), 3.59 (s, 2 H), 3.13 (t, J = 6.6 Hz, 2 H), 1.80 - 1.50 (m, 6 H). - 105 - 012189

Example 18

Préparation of 4-i4-i6-(methylamino)pvridin-2-yll- l-ethoxvl-2-phenoxyphenyllbutanoic acid a) Methyl 4-[4-[6-(methylamino)pyridin-2-yl]-l-ethoxy]-2-phenoxyphenyl]butanoate A solution of 2-[(6-methylamino)-2-pyridinyl]ethanol (0.07 g, 0.43 mmole) anddiethyl azodicarboxylate (0.07 mL, 0.44 mmole) in CH2CI2 (3 mL) was added in adropwise manner to a solution of PhjP (0.11 g, 0.43 mmole) and 2-phenoxy-4-[5-(pyridin-2-yl)amino-l-pentyloxy]phenylacetic acid (0.08 g, 0.29 mmole) in CH2CI2 (3 mL) at 0 °C.The cooling bath was removed and the reaction was allowed to warm to RT. After 18 hr,the solvent was removed under reduced pressure and the residue was purified by radialchromatography (30% to 50% EtOAc/hexanes, silica gel, 6 mm plate) to afford the titlecompound (0.14 g) as an oil: MS (ES) m/e 420.9 (M + H)+. b) 4-[4-[6-(methylamino)pyridin-2-yl]-1 -ethoxy]-2-phenoxyphenyllbutanoic acid A solution of methyl 4-[4-[6-(methylamino)pyridin-2-yl]-l-ethoxy]-2-phenoxyphenyljbutanoate (0.1 g, 0.34 mmole) and 1.0 N NaOH (2 mL) in MeOH (2 mL)and THF (sufficient to afford a homogeneous solution) was stirred at RT. After 18h, thesolvent was removed under reduced pressure. The residue was suspended in H2O, and themixture was acidified to pH = 3 with conc HCl. The aqueous phase was extracted withEtOAc and the combined extracts were dried over Na2SÛ4· The solvent was removedunder reduced pressure to leave a white foam. Flash chromatography on silica gel (EtOActo 10% MeOH/EtOAc) gave the title compound (0.07 g) as a white foam: MS (ES) m/e 406.9 (M + H)+. Anal. Calcd for C24H26N2O4 · 0.75 H2O: C, 68.64; H, 6.60; N, 6.67.Found: C, 68.33; H, 6.09; N, 6.54.

Example 19

Préparation of (R)-3-phenvl-4-f4-i3-(pyridin-2-vl)amino-l-propyloxy1phenynbutanoic acid a) Ethyl (+)-3-phenyl-4-[4-[3-( 1 -oxopyridin-2-yl)amino-1 -propyloxy]phenyl]butanoateDiisopropyl azodicarboxylate (0.40 mL, 2 mmole) was added over 45 sec to a solution of ethyl (R)-4-(4-hydroxyphenyl)-3-phenylbutanoate (0.39 g, 1.4 mmole), 2-[(3-hydroxy-l-propyl)amino]pyridine-N-oxide (0.35 g, 2 mmole), and triphenylphosphine(0.54 g, 2 mmole) in anhydrous DMF (20 mL) at 0 °C under argon. The yellow solutionwas kept at 0 °C for 10 min, then was warmed to RT. After 23 hr, the reaction was -106- 012189 concentrated. Silica gel chromatography (gradient: 1%- 4% MeOH/CHC^) gave the titlecompound (0.30 g, 51%) as a yellow oil: MS (ES) m/e 434.9 (M + H)+. b) Ethyl (R)-3-phenyl-4-[4-[3-(pyridin-2-yl)amino-1 -propyloxyjphenyl]butanoate A mixture of ethyl (R)-3-phenyl-4-[4-[3-(l-oxopyridin-2-yl)amino-l-propyloxy]phenyl]butanoate (0.30 g, 0.69 mmole), cyclohexene (1 mL, 10 mmole), 10%Pd/C (93 mg, 0.09 mmole), and isopropanol (5 mL) was heated at reflux under argon.

After 3 hr, more Pd/C (110 mg) was added. The mixture was heated at reflux for another20.5 hr, then was hot-filtered through celite®. The fîlter pad was washed with hot EtOAc,and the combined filtrâtes were concentrated to afford the title compound (0.25 g, 87%) asa pale yellow oil: MS (ES) m/e 419.1 (M + H)+. c) (R)-3-Phenyl-4-[4-[3-(pyridin-2-yl)amino-1 -propyloxy]phenyl]butanoic acid A mixture of ethyl (R)-3-phenyl-4r[4-[3-(pyridin-2-yl)amino-l-propyloxy]phenyl)butanoate (0.25 g, 0.6 mmole)and lithium hydroxide monohydrate (32mg, 0.76 mmole) in THF (5 mL) and H2O (3 mL) was stirred at RT for 18 hr, then wasconcentrated, and the residue was dissolved in H2O. The resulting aqueous solution wasstirred at RT while the pH was slowly and carefully adjusted to 5.5 - 6.0 with 1.0 N HCl.

The mixture was stirred for 0.5 hr, then the solid was collected by suction filtration andwashed with plenty of H2O. Drying in high vacuum at 60 °C gave the title compound (100mg, 43%) as a glassy solid: MS (ES) m/e 390.7 (M + H)+. Anal. Calcd for C24H26N2O3 ·0.25 H2O: C, 73.82; H, 6.71; N, 7.17. Found: C, 72.98; H, 6.76; N, 7.09.

Example 20

Préparation of (S)-3-phenvl-4-i4-f2-f6-(methvlamino)pyridin-2-yll-l- ethoxylphenyllbutanoic acid a) Ethyl (S)-3-phenyl-4-[4-[2-[6-(methylamino)pyridin-2-yl]-1 -ethoxy]phenyl]butanoate

Diisopropyl azodicarboxylate (0.16 mL, 0.80 mmole) was added over 2 min to asolution of ethyl (S)-4-(4-hydroxyphenyl)-3-phenylbutanoate (0.19 g, .66 mmole), 6-(methylamino)-2-pyridylethanol (0.12 g, 0.80 mmole), and triphenylphosphine (0.20 g 0.80mmole) in anhydrous CH2CI2 (5 mL) at 0 °C under N2. The yellow solution was kept at 0°C for 10 min, then was warmed to RT. After 24 hr, the reaction was concentrated and theresidue was chromatographed on silica gel (gradient: 10% - 30% EtOAc/hexanes). Thetitle compound (0.26 g, 93%) was obtained as a colorless oil: MS (ES) m/e 419.0 (M + H)+. - 107- 012189 b) (S)-3-Phenyl-4-[4-[2-[6-(methylamino)pyridin-2-yl]-l-ethoxy]phenyl]butanoic acid

Lithium hydroxide monohydrate (29 mg, 0.69 mmole) in H2O (2 mL) was added toa solution of ethyl (S)-3-phenyl-4-[4-[2-[6-(methylamino)pyridin-2-yl]-l-ethoxy]phenyl]butanoate (0.25 g, 0.62 mmole) in THF ( 5 mL). The resulting mixture wasstirred at RT for 18 hr, then was concentrated. The residue was dissolved in H2O, and thepH was adjusted to 5.5 - 6.0 with 1.0 N HCl. The aqueous solution was decanted awayfrom the gummy precipitate, which was dried in vacuum at 60 °C for several days to affordthe title compound (0.10g, 41%) as a white solid: MS (ES) m/e 391.0 (M + H)+. Anal.Calcd for C24H26N2O3: C, 73.82; H, 6.71; N, 7.17. Found: C, 73.62; H, 6.80; N, 6.98.

Example 21

Préparation of (S)-3-phenvl-4-f4-i3-(pvridin-2-yl)amino-l-propyloxylphenyllbutanoic acid a) Ethyl (S)-3-phenyl-4-[4-[3-(l-oxopyridin-2-yl)Boc-amino-l- propyloxy]phenyl]butanoate

Sodium hydride (80% in minerai oil, 66 mg, 2.2 mmole) was added to a solution ofethyl (S)-4-(4-hydroxyphenyl)-3-phenylbutanoate (0.60 g, 2 mmole) in anhydrous DMSO(6 mL) at 23 °C under argon. After the mixture became homogeneous, 2-[N-(3-methanesulfonyloxy-l-propyl)-N-(tert-butoxycarbonyl)aminoJpyridine-N-oxide (0.35 g, 2mmole) was added. The resulting solution was stirred at room température for 5 days, thenwas then partitioned between EtOAc and H2O. The organic phase was washed twice withH2O and once with brine, dried (MgSOzj), and concentrated. Silica gel chromatography(gradient: 0.5%- 4% MeOH/CH2Cl2) gave the title compound (0.30 g, 55% based onrecovered starting material) as a yellow oil: MS (ES) m/e 535.0 (M + H)+. Unchangedethyl (S)-4-(4-hydroxyphenyl)-3-phenylbutanoate (0.30 g) was recovered. b) Ethyl (S)-3-phenyl-4-[4-[3-( 1 -oxopyridin-2-yl)amino-1 -propyloxy]phenyl]butanoate A solution of ethyl (S)-3-phenyl-4-[4-[3-(l-oxopyridin-2-yl)Boc-amino-l-propyloxy]phenyl]buanoate (0.30 g, 0.56 mmole), CH2CI2 (5 mL), and TFA (5 mL) wasstirred at 0 °C for 1 hr, then was allowed to warm to RT. After an additional 2 hr, thesolution was concentrated to afford the title compound (0.15 g) as a pale yellow oil: MS(ES) m/e 435.2 (M + H)+. c) Ethyl (S)-3-phenyl-4-[4-[3-(pyridin-2-yl)amino-l-propyloxy)phenyl]butanoate A mixture of ethyl (S)-3-phenyl-4-[4-[3-(l-oxopyridin-2-yl)amino-l-propyloxyjphenyl)butanoate (0.15 g, 0.35 mmole), cyclohexene (0.5 mL, 5 mmole), 10%Pd/C (80 mg, 0.075 mmole), and isopropanol (5 mL) was heated at reflux under argon. -108- 012189

After 20.5 hr, themixture was hot-filtered through celite®. The fîlter pad was washed withhot EtOAc, and the combined filtrâtes were concentrated to afford the title compound (0.1g, 43%) as a pale yellow oil: MS (ES) m/e 419.2 (M + H)+. d) (S)-3-Phenyl-4-[4-[3-(pyridin-2-yl)amino-1 -propyloxy]phenyl]butanoic acid A mixture of ethyl (S)-3-phenyl-4-[4-[3-(pyridin-2-yl)amino-l-propyloxy]phenyl]butanoate (0.10 g, 0.24 mmole)and lithium hydroxide monohydrate (12mg, 0.29 mmole) in THF (5 mL) and H2O (2 mL) was stirred at RT for 18 hr, then wasconcentrated. The residue was dissolved in H2O, and the resulting aqueous solution wasstirred at RT while the pH was slowly and carefully adjusted to 5.5 - 6.0 with 1.0 N HCl.

The mixture was stirred for 0.5 hr, then the solution was decanted away from the solid.

Drying in high vacuum at 60 °C gave the title compound (40 mg, 43%) as a glassy solid: MS (ES) m/e 390.7 (M + H)+. Anal. Calcd for C24H26N2O3 · 1.7 HCl: C, 63.72; H, 6.17; N, 6.19. Found: C, 63.56; H, 6.22; N, 6.10.

Example 22

Préparation of (±)-3-(4-bromophenvl)-4-f4-f2-f6-(methvlamino)pvridin-2-yn-1 - ethoxylphenvllbutanoic acid a) Ethyl (±)-3-(4-bromophenyl)-4-[4-[2-[6-[N-(tert-butoxycarbonyl) -N- methy lamino]pyridin-2-y 1]-1 -ethoxy ]pheny l]butanoate

Diisopropyl azodicarboxylate (0.24 mL, 1.24 mmole) was added slowly to asolution of ethyl (±)-3-(4-bromophenyl)-4-(4-hydroxyphenyl)butanoate (0.30 g, 0.82mmole), 6-[N-(tert-butoxycarbonyl)-N-methylamino]-2-pyridylethanol (0.31 g, 1.24mmole), and triphenylphosphine (0.32 g, 1.24 mmole) in anhydrous CH2CI2 (10 mL) at 0°C under argon. The yellow solution was kept at 0 °C for 10 min, then was warmed to RT.After 39 hr, the reaction was concentrated and the residue was chromatographed on silicagel (20% EtOAc/hexanes) gave the title compound (0.32 g, 65%) as a clear oil: TLC Rf(20% EtOAc/hexanes) 0.44; MS (ES) m/e 349.1 (M + Na)+, 674.9 (2M + Na)+. b) Ethyl (±)-3-(4-bromophenyl)-4-[4-[2-[6-(methylamino)pyridin-2-yl]-1- ethoxy]phenyl]butanoate A solution of ethyl (±)-3-(4-bromophenyl)-4-[4-[2-[6-[N-(tert-butoxycarbonyl)-N-methylamino]pyridin-2-yl]-l-ethoxy]phenyl]butanoate (0.32 g, 0.53 mmole) in 4 N HCl indioxane (15 mL) was stirred at RT for 1.5 hr. Concentration and reconcentration fromCH2CI2 and hexanes afforded the title compound as a white syrup which was carriedforward without further purification. - 109- 012189 c) (±)-3-(4-Bromophenyl)-4-[4-[2-[6-(methylamino)pyridin-2-yl]-1 - ethoxy]phenyl]butanoic acid 1.0 N NaOH ( 1.44 mL, 1.44 mmole) was added dropwise to a solution of ethyl (±)- 3-(4-bromophenyl)-4-[4-[2-[6-(methylamino)pyridin-2-yl]-l-ethoxy]phenyl]butanoate(0.26 g, 0.48 mmole) in dioxane (10 mL) and H2O (5.0 mL). The resulting mixture wasstirred at 50 °C for 3 hr, then was concentrated. The residue was diluted with H2O (5 mL),and the solution was neutralized with 1.0 N HCl. The precipitated solid was collected anddried to afford the title compound (0.20 g, 81 %) as a white, crystalline solid: HPLC(Hamilton PRP-1®, gradient over 20 min: 10% - 80% CH3CN/H2O containing 0.1% TFA)K’= 13.28; Anal. Calcd for C24H25N2O3Br · 1.5 HCl · 0.25 H2O: C, 54.54; H.5.15; N,5.30. Found: C, 54.49; H, 4.97; N, 5.10.

Example 23

Préparation of (i)-3-(4-isopropylphenvl)-4-i4-i2-f6-(methylamino)pvridin-2-yll-l- ethoxylphenyllbutanoic acid a) Methyl (±)-3-(4-isopropylphenyl)-4-[4-[2-[6-(methylamino)pyridin-2-yl]-1 -ethoxy]phenyl]butanoate

According to the procedure of Example 22 (a), except substituting methyl (±)-4-(4-hydroxyphenyl)-3-(4-isopropylphenyl)butanoate for the ethyl (±)-3-(4-bromophenyl)-4-(4-hydroxyphenyl)butanoate, and substituting 6-(methylamino)-2-pyridylethanol for the 6-[N-(tert-butoxycarbonyl)-N-methylamino]-2-pyridylethanol, the title compound was obtainedfollowing silica gel chromatography (30% EtOAc/hexanes): MS (ES) m/e 447.0 (M + H)+. b) (±)-3-(4-Isopropylphenyl)-4-[4-[2-[6-(methylamino)pyridin-2-yl]-l- ethoxy]phenyl]butanoic acid

According to the procedure of Example 22 (c), except substituting methyl (±)-3-(4-isopropylphtenyl)-4-[4-[2-[6-(methylamino)pyridin-2-yl]-l-ethoxy]phenyl]butanoate for theethyl (±)-3-(4-bromophenyl)-4-[4-[2-[6-(methylamino)pyridin-2-yl)-1 - ethoxy]phenyl]butanoate, the title compound was obtained: HPLC (Hamilton PRP-1®,gradient over 20 min: 10% - 80% CH3CN/H2O containing 0.1% TFA) K’ = 14.19; MS(ES) m/e 435.5 (M + H)+.

Example 24 -no- 012189

Préparation of (±)-3-(4-isopropvlphenyl)-4-f4-f3-(4-methylpyndÎn-2-vnamino-l- propyloxylphenvllbutanoic acid a) Methyl (±)-3-(4-isopropylphenyl)-4-[4-[3-(4-methyl-1 -oxopyridin-2-yl)amino-1 - 5 propyloxy]phenyl]butanoate

NaOH (0.14 g, 3.37 mmole) was added to a solution of 2-[(3-bromo-l-propyl)amino]pyridine-N-oxide (0.37 g, 1.13 mmole) and methyl (±)-4-(4-hydroxyphenyl)- 3-(4-isopropylphenyl)butanoate (0.32 g, 1.02 mmole) in anhydrous CH3CN (15 mL). Afterstirring at RT under argon for 20 hr, the reaction was filtered and concentrated on the 10 rotavap. Silica gel chromatography (5% MeOH/CH2Cl2) gave the title compound (0.31 g, 64 %) as a clear oil: MS (ES) m/e 477.1 (M + H)+. b) Methyl (±)-3-(4-isopropylphenyl)-4-[4-[3-(4-methylpyridin-2-yl)amino-1 -propyloxy]phenyl]butanoate 15 A mixture of methyl (±)-3-(4-isopropylphenyl)-4-[4-[3-(4-methyl-1 -oxopyridin-2- yl)amino-l-propyloxy]phenyl]butanoate (0.31 g, 0.65 mmole), 10% Pd/C (0.31 g, 0.29mmole), cyclohexene (0.66 mL, 6.51 mmole), and isopropanol (15 mL) was heated atreflux for 16 hr, then the catalyst was removed by filtration through celite®. Concentrationand silica gel chromatography (5% MeOH/CH2Cl2) gave the title compound (0.25 g, 83%) 20 as a light yellow oil: MS (ES) m/e 460.9 (M + H)+. c) (±)-3-(4-Isopropylphenyl)-4-[4-[3-(4-methylpyridin-2-yl)amino-1 -propyloxy]phenyl]butanoic acid

According to the procedure of Example 22 (c), except substituting methyl (±)-3-(4- 25 isopropylphenyl)-4-[4-[3-(4-methylpyridin-2-yl)amino-l-propyloxy]phenyl]butanoate forthe ethyl (±)-3-(4-bromophenyl)-4-[4-[2-[6-(methylamino)pyridin-2-yl]-1 -ethoxy]phenyl]butanoate, the title compound was obtained: HPLC (Hamilton PRP-1®,gradient over 20 min: 10% - 80% CH3CN/H2O containing 0.1 % TFA) K’ = 14.57; MS(ES) m/e 447.5 (M + H)+. 30

Example 25

Préparation of 4-i4-r2-r6-(methylamino)pyridin-2-vll-l-ethoxylphenynbut-3-enoic acid 35 a) Methyl 4-(4-[2-[6-(methylamino)pyridin-2-yl]-l-ethoxy]phenyl]crotonate

According to the procedure of Example 5 (a), except substituting methyl 4-(4- hydroxyphenyl)crotonate (0.46 g, 2.39 mmole) for the methyl 4-(4- - 111 - 012189 hydroxyphenyl)butanoate, the title compound (0.6 g, 76%) was prepared: MS (ES) m/e327 (M + H)+. b) 4-[4-[2-[6-(Methylamino)pyridin-2-yl]-1 -ethoxy]phenyl]but-3-enoic acid 1.0 N NaOH (1.8 mL, 1.8 mmole) was added to a solution of methyl 4-[4-[2-[6- (methylamino)pyridin-2-yl}-l-ethoxy]phenyl]crotonate (0.3 g, 0.92 mmole) in MeOH (5mL). The reaction was stirred at RT ovemight, then was concentrated in vacuum. Flashchromatography on silica gel (gradient: CH2CI2, then 1 % MeOH/CH2Cl2> then 1 %MeOH/CH2Cl2 containing 0.5% HCO2H) to afford the title compound (0.09 g, 31%) as aslightly yellow solid: MS (ES) m/e 313 (M + H)+; !h NMR (360 MHz, DMSO-d6) ? 7.85(app t, 1 H), 7.33 (d, J = 8.7 Hz, 2 H), 6.84 - 6.96 (m, 4 H), 6.81 (d, I = 7.2 Hz, 1 H), 6.40(d, J = 16.0 Hz, 1 H), 6.08 - 6.18 (m, 1 H), 4.22 - 4.35 (m, 2 H), 3.09 - 3.29 (m, 4 H), 2.96(s, 3 H). Anal. Calcd for Ci8H20N2O3 · 1.0 HCO2H: C, 63.68; H, 6.19: N, 7.82. Found:C, 63.84; H, 6.42; N 7.98.

Example 27

Préparation of (S)-3-phenyI-4-f4-i2-(5,6.7.8-tetrahvdro-1,8-naphthyridin-2-yl)-1 - ethoxylphenyllbutanoic acid a) Ethyl (S)-3-phenyl-4-(4-[2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)-1 - ethoxy]phenyl]butanoate

Diisopropyl azodicarboxylate (0.25 mL, 1.25 mmole) was added to a solution ofethyl (S)-3-phenyl-4-(hydroxyphenyl)butanoate (178 mg, 0.63 mmole), 2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)ethanol (223 mg, 1.25 mmole), and triphenylphosphine(328 mg, 1.25 mmole) in anhydrous THF (5 mL) at 0 °C. The mixture was allowed towarm as the bath warmed to RT. After 18 hr the mixture was concentrated and the residuewas chromatographed on silica gel (4.5:1 Et2O/hexanes) to give the title compound (197mg, 71%) as a clear oil. MS (ES) m/e 445 (M + H)+. b) (S)-3-Phenyl-4-[4-[2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)-1 - ethoxy]phenyl]butanoic acid

To a solution of ethyl (S)-3-phenyl-4-[4-[2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)-l-ethoxy]phenyl]butanoate (197 mg, 0.44 mmole) in 1:1 THF/H2O (2 mL) was addedIN LiOH (0.66 mL, 0.66 mmole). After 18 hr the mixture was heated to 50 °C. After 18 hrthe mixture was cooled to RT and washed with Et2O (2x5 mL). The aqueous layer wasconcentrated to remove residual THF/Et2O then acidified to pH 6 using 10% HCl. Thesolid was collected by filtration and dried under vacuum at 50 °C to give the title compound - 112- 012189 as a white powder (136 mg, 74%). MS (ES) m/e 417 (M + H)+. Anal. Calcd for C26H28N2°3 · °·5 H2O: C, 73.39; H, 6.87; N, 6.58. Found: C, 73.14; H, 6.64; N, 6.26.

Example 28

Préparation of (±)-3-fl-(dimethylaminosulfonvl)imidazol-2-vn-4-f4-r2-f6- (methylamino)pvridin-2-yll-1 -ethoxylphenvllbutanoic acid a) Ethyl (±)-3-[l-(dimethylaminosulfonyl)imidazol-2-yl]-4-[4-[2-[6- (methy lamino)pyridin-2-yl]-1 -ethoxy ]phenyl]butanoate

According to the procedure of Example 9 (a), except substituting ethyl (±)-3-[l-(dimethylaminosulfonyl)imidazol-2-yl]-4-(4-hydroxyphenyl)butanoate (436 mg, 1.14mmole) for the ethyl (±)-4-(4-hydroxyphenyl)-3-(thiazol-2-yl)butanoate, the titlecompound (411 mg, 70%) was prepared as a light orange oil: MS (ES) m/e 516 (M + H)+. b) (±)-3-[ 1 -(Dimethylaminosulfonyl)imidazol-2-yl]-4-[4-[2-[6-(methylamino)pyridin-2-yl]-1-ethoxy ]phenyl]butanoic acid

According to the procedure of Example 9 (b), except substituting ethyl (±)-3-[l-(dimethylaminosulfonyl)imidazol-2-yl]-4-[4-[2-[6-(methylamino)pyridin-2-yl]-l-ethoxyjphenyljbutanoate (200 mg, 0.39 mmole) for the ethyl (±)-4-[4-[2-[6-(methylamino)pyridin-2-yl]-l -ethoxy]phenyl]-3-(thiazol-2-yl)butanoate, the title compound(70 mg, 37%) was prepared as a white solid: MS (ES) m/e 488 (M + H)+. Anal. Calcd forC23H29N5O5S · 0.5 H2O HCl: C, 51.83; H, 5.86; N, 13.14. Found: C, 51.88; H, 5.69; N, 12.75. - 113- 012189

Example 29

Préparation of (±)-3-(imidazol-2-yl')-4-r4-r2-f6-(methylamino)pvridin-2-yn-l- ethoxylphenyllbutanoic acid a) (±)-3-(Imidazol-2-yl)-4-[4-[2-[6-(methylamino)pyridin-2-yl]-1 -ethoxy]phenyl]butanoicacid

Ethyl (±)-3-[l-(dimethylaminosulfonyl)imidazol-2-yl]-4-[4-[2-[6-(methylamino)pyridin-2-yl]-l-ethoxy]phenyl]butanoate (200 mg, 0.39 mmoîe) wasdissolved in 2.0 M HCl (10 mL) and the solution was heated to reflux. After 6 hr themixture was cooled to RT and the pH was adjusted to 6 using 1.0 N NaOH. The resultingsolution was concentrated to approximately 2 mL, and was chromatographed on a C-18bond/elute column (H2O then 20% CH3CN/H2O). Fractions containing the product werecombined and lyophilized to give the title compound (80 mg, 54%) as a white powder: MS(ES) m/e 381 (M + H)+. Anal. Calcd for C21.H24N4O3 · 0.85 HCl: C, 61.31; H, 6.09; N,13.62. Found: C, 61.26; H, 6.09; N, 13.62.

Example 30

Préparation of (S)-4-f4-r2-f6-(methylamino)pyridin-2-yfl-1 -ethoxylphenyll-3-(thiazol-2- vDbutanoic acid a) Ethyl (S)-4-[4-[2-[6-(methylamino)pyridin-2-yl)-1 -ethoxy]phenyl]-3-(thiazol-2-yl)butanoate

According to the procedure of Example 9 (a), except substituting ethyl (S)-4-(4-hydroxyphenyl)-3-(thiazol-2-yl)butanoate (200 mg, 0.69 mmole) for the ethyl (±)-4-(4-hydroxyphenyl)-3-(thiazol-2-yl)butanoate, the title compound (262 mg, 89%) was preparedas a pale orange oil foliowing silica gel chromatography (35% THF in 1:1 toluene/hexanes): MS (ES) m/e 426 (M + H)+. b) (S)-4-[4-[2-[6-(Methylamino)pyridin-2-yl]-l-ethoxy]phenyl]-3-(thiazol-2-yl)butanoicacid

According to the procedure of Example 9 (b), except substituting ethyl (S)-4-[4-[2-[6-(methylamino)pyridin-2-yl]-l-ethoxy]phenyl)-3-(thiazol-2-yl)butanoate (262 mg, 0.62mmole) for the ethyl (±)-4-[4-[2-(6-(methylamino)pyridin-2-yl]-l-ethoxy]phenyl]-3-(thiazol-2-yl)butanoate, the title compound (112 mg, 45%) was prepared as a white solid: - 114- 012189

JfS (ES) m/e 398 (M + H)+. Anal. Calcd for C2iH23N3O3 · 0.75 H2O: C,€1.3^ H, 6.01;N, 10.22. Found: C, 61.51; H, 5.89; N, 10.18.

Example 31 5

Préparation of (R)-4-f4-f2-f6-(methvïamino)pvridin-2-vn-l-ethoxy1phenvn-3-(thiazoI-2- vllbutanoic acid a) Ethyl (R)-4-[4-[2-[6-(methylamino)pyridin-2-yl]- l-ethoxy]phenyl]-3-(thiazol-2- 10 yl)butanoate

According to the procedure of Example 9 (a), except substituting ethyl (R)-4-(4-hydroxyphenyl)-3-(thiazol-2-yl)butanoate (200 mg, 0.69 mmole) for the ethyl (±)-4-(4-hydroxyphenyl)-3-(thiazol-2-yl)butanoate, the title compound (265 mg, 90%) was preparedas a pale orange oil following silica gel chromatography (35% THF in 1:1 15 toluene/hexanes): MS (ES) m/e 426 (M + H)+. b) (R)-4-[4-[2-[6-(Methylamino)pyridin-2-yl]-1 -ethoxy]phenyl]-3-(thiazol-2-yl)butanoicacid

According to the procedure of Example 9 (b), except substituting ethyl (R)-4-[4-[2-20 [6-(methylamino)pyridin-2-yl]-l-ethoxy]phenyl]-3-(thiazol-2-yl)butanoate (265 mg, 0.62 mmole) for the ethyl (±)-4-[4-[2-[6-(methylamino)pyridin-2-yl]-l-ethoxy]phenyl]-3-(thiazol-2-yl)butanoate, the title compound (98 mg, 40%) was prepared as a white solid: MS (ES) m/e 398 (M + H)+. Anal. Calcd for C2iH23N3O3 0.5 H2O: C, 62.05; H, 5.95;N, 10.34. Found: C, 62.25; H, 5.80; N, 10.37. 25

Example 32

Préparation of (±')-3-(benzothiazol-2-vl)-4-f4-f2-f6-(methylamino)pyridin-2-vll-1 - ethoxylphenvllbutanoic acid30 a) Ethyl (±)-3-(benzothiazol-2-yl)-4-[4-[2-[6-(methylamino)pyridin-2-yl]-l-ethoxy]phenyl]butanoate

According to the procedure of Example 9 (a), except substituting ethyl (±)-3-(benzothiazol-2-yl)-4-(4-hydroxyphenyl)butanoate (200 mg, 0.59 mmole) for the ethyl (±)- 35 4-(4-hydroxyphenyl)-3-(thiazol-2-yl)butanoate, the title compound (220 mg, 78%) wasprepared as a clear oil following silica gel chromatography (60% EtOAc/hexanes): MS(ES) m/e 476 (M + H)+. - 115- 012189 b) (±)-3-(Benzothiazol-2-yl]-4-[4-[2-[6-(methylamino)pyridin-2-yl]-l- ethoxy]phenyl]butanoic acid

According to the procedure of Example 9 (b), except substituting ethyl (±)-3-(benzothiazol-2-yl)-4-[4-[2-[6-(methylamino)pyridin-2-yl]-l-ethoxy ]phenyl]butanoate (220mg, 0.46 mmole) for the ethyl (±)-4-[4-[2-[6-(methylamino)pyridin-2-yl]-l- ethoxy]phenyl]-3-(thiazol-2-yl)butanoate, the title compound (125 mg, 61%) was obtainedas a white solid: MS (ES) m/e 448 (M + H)+. Anal. Calcd for C25H25N3O3S · 0.75 H2O:C, 65.13; H, 5.79; N, 9.11. Found: C, 65.22; H, 5.49; N, 8.92.

Example 33

Préparation of (S)-4-f4-f2-(5,6,7,8-tetrahydro-l'8-naphthvridin-2-yl)-l-ethoxvlphenvn-3- (thiazol-2-yl)butanoic acid a) Ethyl (S )-4- [4- [2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-y 1)-1 -ethoxy]phenyl]-3-(thiazol-2-yl)butanoate

According to the procedure of Example 27 (a), except substituting ethyl (S)-4-(4-hydroxyphenyl)-3-(thiazol-2-yl)butanoate (200 mg, 0.69 mmole) for the ethyl (S)-3-phenyl- 4-(hydroxyphenyl)butanoate, the title compound (371 mg, impure) was obtained as aclearoil following silica gel chromatography (40% THF in 1:1 CHCl3/hexanes): MS (ES) m/e452 (M + H)+. b) (S)-4-[4-[2-(5,6,7,8-Tetrahydro-l,8-naphthyridin-2-yl)-l-ethoxy]phenyl]-3-(thiazol-2-yl)butanoic acid

Ethyl (S)-4-[4-[2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)-1 -ethoxy]phenyl}-3-(thiazol-2-yl)butanoate (371 mg, impure) was dissolved in 1:1 THF/H2O (5 mL). To thissolution was added 1.0 N LiOH (1.04 mL, 1.04 mmole) and the mixture was heated to 50°C. After 18 hr the mixture was cooled to RT and washed with Et2O (2x5 mL). Theaqueous layer was concentrated under vacuum to remove residual organic solvents, thenwas acidified to pH 6 using 10% HCl. The solid was collected by filtration and dried undervacuum at 50 °C to give the title compound (106 mg, 36% over 2 steps) as a white powder:MS (ES) m/e 424 (M + H)+. Anal. Calcd for C23H25N3O3S · 0.33 HCl: C, 63.42; H, 5.86; N, 9.65. Found: C, 63.19; H, 5.61; N, 9.45.

Example 34 - 116- 012189

Préparation of (i)-3-(4-Methylthiazol-2-vl)-4-f4-Î2-f6-(methvlamino)pvridin-2-vI1-1 - ethoxvlphenvllbutanoic acid a) Ethyl (±)-3-(4-methylthiazol-2-yl)-4-[4-[2-[6-(methylamino)pyridin-2-yl]-1 - ethoxy]phenyl]butanoate

According to the procedure of Example 9 (a), except substituting ethyl (±)-3-(4-methylthiazol-2-yl)-4-(4-hydroxyphenyl)butanoate (216 mg, 0.74 mmole) for the ethyl (±)- 4-(4-hydroxyphenyl)-3-(thiazol-2-yl)butanoate, the title compound (395 mg, impure) wasprepared as a clear oil following silica gel chromatography (50% EtOAc/hexanes): MS(ES) m/e 426 (M + H)+. b) (±)-3-(4-Methy lthiazol-2-y l]-4- [4- [2-(6-(methylamino)pyridin-2-y 1]-1 - ethoxy]phenyl]butanoic acid

Impure ethyl (±)-3-(4-methylthiazol-2-yl)-4-[4-[2-[6-(methylamino)pyridin-2-yl]-l-ethoxy]phenyl]butanoate (395 mg) was dissolved in 1:1 THF/H2O (5 mL). To thissolution was added 1.0 N LiOH (1.11 mL, 1.11 mmole), and the mixture was heated at 50°C. After 18 hr the mixture was cooled to RT and washed with Et2O (2x5 mL). Theaqueous layer was concentrated under vacuum to remove residual organic solvents, thenwas acidified to pH 6 using 10% HCl. The solid was collected by filtration and dried undervacuum at 50 °C to give the title compound (88 mg, 29% over 2 steps) as a pale yellowpowder: MS (ES) m/e 412 (M + H)+. Anal. Calcd for C22H25N3O3S 0.25 HCl: C, 62.82; H, 6.05; N, 9.99. Found: C, 62.94; H, 5.95; N, 9.95.

Example 35

Préparation of (±)-3-[4-carboxy-l,3-oxazol-2-vn-4-f4-r2-f6-(methvlamino)pyridin-2-vll-l- ethoxvlphenyllbutanoic acid a) (±)-3-[4-Carboxy-1,3-oxazol-2-yl]-4-[4-[2-[6-(methylamino)pyridin-2-yl]-1 - ethoxy]phenyl]butanoic acid

To a solution of methyl (±)-3-[4-(benzyloxycarbonyl)-l,3-oxazol-2-yl]-4-[4-[2-[6-(methylamino)pyridin-2-yl]-l-ethoxy]phenyl]butanoate (50 mg, 0.09 mmole) in 1:1THF/H2O (1 mL) at RT was added 1.0 N LiOH (0.28 mL, 0.28 mmole). After 72 hr themixture was acidified to pH 6 using 10% HCl then was concentrated to dryness. Theresidue was purified by reverse-phase HPLC (gradient: 10-80% CH3CN/H2O containing0.1% TFA). The fractions containing the product were combined and concentrated toremove CH3CN. The resulting aqueous solution was lyophilized to give the title - 117 - 012189 compound (36 mg, 94%) as a white solid: MS (ES) m/e 426 (M + H)+. Anal. Calcd for c22h23n3°6 ·17 tfa·. c>49·26;H’ 4O2’> N>6·79· Found: c- 49·3θ;H’4·24;N’ 6·97·

Example 36

Préparation of (i)-3-14-(Aminocarbonyl)-L3-oxazol-2-vn-4-f4-r2-f6- (methvlamino)pvridin-2-yll-l-ethoxvlphenynbutanoic acid a) Methyl (±)-3-[4-(aminocarbonyl)-l,3-oxazol-2-yl]-4-[4-[2-[6-(methylamino)pyridin-2-y 1 ] -1 -ethoxy ]phenyl]butanoate

To a solution of methyl (±)-3-[4-carboxy-l,3-oxazol-2-yl]-4-[4-[2-[6-(methylamino)pyridin-2-yl]-l-ethoxy]phenyl]butanoate (82 mg, 0.19 mmole) in dry DMF(2 mL) at RT was added NH4CI (30 mg, 0.56 mmole), HOBt (30 mg, 0.22 mmole), Et3N(0.08 mL, 0.56 mmole), and EDC (42 mg, 0.22 mmole). After 18 hr the mixture wasconcentrated. The residue was taken up in H2O (10 mL) and extracted with CH2CI2 (3 x30 mL). The combined organic layers were dried over MgSC>4 and concentrated to give thetitle compound (46 mg, 55%) as a light yellow oil: MS (ES) m/e 439 (M + H)+. b) (±)-3-[4-(Aminocarbonyl)oxazol-2-yl]-4-[4-[2-[6-(methylamino)pyridin-2-yl]-l-ethoxy]phenyl]butanoic acid

According to the procedure of Example 35 (a), except substituting methyl(±)-3-[4-(aminocarbonyl)-l,3-oxazol-2-yl]-4-[4-[2-[6-(methylamino)pyridin-2-yl]-l-ethoxy]phenyl]butanoate (46 mg, 0.1 mmole) for the methyl (±)-3-[4- (benzyloxycarbonyl)-l,3-oxazol-2-yl]-4-[4-[2-[6-(methylamino)pyridin-2-yl]-l-ethoxy ]phenyl]butanoate, the crude product was prepared. This was purified byreverse-phase HPLC (gradient: 15-50% CH3CN/H2O containing 0.1% TFA). Thefractions containing the product were combined and concentrated to removeCH3CN. The resulting aqueous solution was lyophilized to give the title compound(19 mg, 45%) as a white solid: MS (ES) m/e 425 (M + H)+. Anal. Calcd forC22H24N4O5 · 2.5 TFA, 1.0 H2O: C, 44.58; H, 3.95; N, 7.70. Found: C, 44.24; H, 3.60; N, 7.83.

Example 37

Préparation of (±)-3-f4-(dimethylaminocarbonyl)-L3-oxazol-2-vll-4-r4-i2-[6- (methylamino)pvridin-2-yn-l-ethoxylphenyllbutanoic acid - 118- 012189 a) MethyL (±)-3-[4-(dimethylaminocarbonyl)-1,3-oxazol-2-yl]-4-[4-[2-[6- ί (methy lamino)pyridin-2-yl]-1 -ethoxy Jpheny IJbutanoate

To a solution of methyl (±)-3-[4-carboxy-l,3-oxazol-2-yl]-4-[4-[2-[6-(methylamino)pyridin-2-yl]-l-ethoxy]phenyl]butanoate (82 mg, 0.19 mmole) in dry DMF 5 (2 mL) at RT was added dimethylamine hydrochloride (46 mg, 0.56 mmole), HOBt (30 mg, 0.22 mmole), EtjN (0.08 mL, 0.56 mmole), and EDC (42 mg, 0.22 mmole). After 18 hr themixture was concentrated. The residue was taken up in H2O (10 mL) and extracted withCH2CI2 (3 x 30 mL). The combined organics were dried over MgSC>4 and concentrated tothe title compound (79 mg, 89%) as a light yellow oil: MS (ES) m/e 439 (M + H)+. 10 b) (±)-3-[4-(Dimethylaminocarbonyl)-l,3-oxazol-2-yl]-4-[4-[2-[6-(methylamino)pyridin-2-yl]-l-ethoxy]phenyl]butanoic acid

According to the procedure of Example 35 (a), except substituting methyl(±)-3-[4-(dimethylaminocarbonyl)-1,3-oxazol-2-yl]-4-[4-[2-[6- 15 (methylamino)pyridin-2-yl]-1 -ethoxy]phenyl]butanoate (79 mg, 0.17 mmole) for the methyl (±)-3-[4-(benzyloxycarbonyl)-1,3-oxazol-2-yl]-4-[4-[2-[6-(methylamino)pyridin-2-yl]-l-ethoxy]phenyl]butanoate, the crude product wasprepared. This was purified by reverse-phase HPLC (gradient: 10-80% CH3CN/H2O containing 0.1% TFA). The fractions containing the product were 20 combined and concentrated to remove CH3CN. The resulting aqueous solution waslyophilized to give the title compound (48 mg, 62%) as a white solid: MS (ES) m/e453 (M + H)+. Anal. Calcd for C24H28N4O5 · 1.8 TFA: C, 50.44; H, 4.57; N, 8.52. Found: C, 50.19; H, 4.79; N, 8.88. -119- 012189

Example 38

Préparation of (S)-3-phenvl-4-f4-[3-(3.4,5,6-tetrahydropyrimidin-2-yl)amino-l- propyloxylphenyllbutanoic acid a) Ethyl (S)-3-phenyl-4-[4-[3-(tert-butoxycarbonyl)amino-1 -propyloxy]phenyl]butanoate A solution of 3-N-(tert-butoxycarbonyl)amino-l-propanol (499 mg, 2.85 mmole )and diisopropyl azodicarboxylate (0.561 mL, 2.85 mmole) in anhydrous CH2CI2 (14 mL)was added dropwise over 10 min to a solution of ethyl (S)-3-pheny 1-4-(4- hydroxyphenyl)butanoate (323 mg, 1.14 mmole) and triphenylphosphine (747 mg, 2.85mmole) in anhydrous CH2CI2 (5.7 mL) at 0 °C under argon. The yeliow solution was keptat 0 °C for 10 min, then was warmed to RT. After 23 hr, the reaction was concentrated onthe rotavap and the residue was flash chromatographed on silica gel (15% EtOAc/hexanes)to afford the title compound (378 mg, 75%) as a white solid: ^H NMR (300 MHz, CDCI3)δ 7.28 - 7.10 (m, 5 H), 6.95 - 6.90 (d, 2 H), 6.76 - 6.72 (d, 2 H), 6.84 - 4.70 (br s, 1 H), 4.01- 3.94 (dd, 4 H), 3.38 - 3.27 (m, 3 H), 2.85 - 2.83 (d, 2 H), 2.63 - 2.58 (t, 2 H), 1.96 - 1.92(m, 2 H), 1.43 (s, 9 H), 1.12 - 1.08 (t, 3 H). b) Ethyl (S)-3-phenyl-4-[4-(3-amino- l-propyloxy)phenyl]butanoate 4 N HCl in dioxane HCl (4.25 mL, 17 mmole) was added dropwise to a solution ofethyl (S)-3-phenyl-4-[4-[3-(tert-butoxycarbonyl)amino-l-propyloxy]phenyl]butanoate (377mg, 0.85 mmole) at RT, and the resulting mixture was stirred for 2 hr. The solvent wasremoved on the rotavap and the residue was triturated with ether to afford the titlecompound a white solid: MS (ES) m/e 341.9 (M + H)+. c) Ethyl (S)-3-phenyl-4-[4-(3-(pyrimidin-2-y l)amino-1 -propyloxy]phenyl]butanoate A mixture of ethyl (S)-3-phenyl-4-[4-(3-amino-l-propyloxy)phenyl]butanoate(0.85 mmole, crude), 2-bromopyrimidine (177 mg, 1.11 mmole), and NaHCC>3 (357 mg,4.25 mmole) in EtOH (10 mL) was heated at reflux for 22 hr. The mixture was cooled toRT and the salts were removed by filtration. The filter cake was washed with EtOH. Thecombined fîltrate and washings were concentrated on the rotavap and the residue was flashchromatographed on silica gel (25% EtOAc/hexanes) to give the title compound (289 mg,80%, 2 steps): MS (ES) m/e 419.9 (M + H)+. - 120- 012189 d) Ethyl (S)-3-phenyl-4-[4-[3-(3,4,5,6-tetrahydropyrimidin-2-yl)amino-1 - propyloxy]phenyl]butanoate A mixture of ethyl (S)-3-phenyl-4-[4-[3-(pyrimidin-2-yl)amino-l-propyloxy]phenyl]butanoate (286 mg, 0.68 mmole), glacial HOAc (10 mL), conc. HCl(0.113 mL, 1.36 mmole), and 10% Pd/C (72 mg, 0.068 mmole) was shaken at RT under H2(45 psi) on a Parr apparatus. After 4 hr, the reaction was filtered and concentrated to yieldthe title compound (240 mg, 83%): MS (ES) m/e 423.8 (M + H)+. e) (S)-3-Pheny 1-4- [4-[3-(3,4,5,6-tetrahydropyrimidin-2-yl)amino-1 - propyloxy]phenyljbutanoic acid A mixture of ethyl (S)-3-phenyl-4-[4-[3-(3,4,5,6-tetrahydropyrimidin-2-yl)amino-l-propyloxy]phenyl]butanoate (240 mg, 0.56 mmole), 1.0 N NaOH (1.15 mL, 1.12 mmole), THF (4 mL), and EtOH (4 mL) was stirred in an oil bath set at 35 °C. After 18 hr, themixture was cooled to RT and washed with Et20 (2x5 mL). The Et20 washings werediscarded. The remaining aqueous layer was concentrated briefly on the rotavap to removeresidual organic solvents, then was filtered, and the filtrate was acidified to pH 5 with 30% TFA. Préparative HPLC (Hamilton PRP-1®, 250 x 21.5 mm, 35% CH3CN/H2Ocontaining 0.1% TFA) followed by lyophilization gave the title compound (80 mg) as awhite powder: MS (ES) m/e 395.9 (M + H)+. Anal. Calcd for C23H29N3O3 · TFA: C, 58.93; H, 5.93; N,8.25. Found: C, 58.63; H, 5.59; N, 7.99.

Example 39

Préparation of (±)-3-i4-f2-[6-(methvlamino)pyridin-2-ynethoxylbenzynpent-4-ynoic acid a) Methy 1 (±)-3- [4- [2- [6- [N-(tert-butoxycarbonyl)methylamino]pyridin-2- yl]ethoxy]benzyl]pent-4-ynoate

To a solution of methyl (±)-3-(4-hydroxybenzyl)pent-4-ynoate (25 mg, 0.12mmole), 6-[(tert-butoxycarbonyl)methylamino]-2-pyridylethanol (43 mg, 0.17 mmole),

Ph3P (45 mg, 0.17 mmole) in CH2CI2 (5 mL) at 0 °C was added dropwise DEAD (0.03mL, 0.19 mmole). The reaction was allowed to warm to RT. After 2 days, the solvent wasremoved under reduced pressure. Radial chromatography on silica gel (2 mm plate, 20%EtOAc/hexane) gave the title compound (30 mg) as a clear oil: MS(ES) m/e 453.1 (M + H)+. - 121 - 012189 b) (±)-3-[4-[2-[6-(Methylamino)pyridin-2-yl]ethoxy]benzyl]pent-4-ynoic acid A solution of 4 N HCl/dioxane (1 mL) was added to methyl (±)-3-[4-[2-[6-[N-(tert-butoxycarbonyl)methylamino]pyridin-2-yl]ethoxy]benzyl]pent-4-ynoate (30 mg, 0.06mmole). After 8 hr, the solvent was removed under reduced pressure to give a pale yellowresidue. A solution of this residue, 1.0 N NaOH (0.5 mL), MeOH (0.5 mL), and THF (1drop) was stirred at RT for 18 hr, then was concentrated to dryness under reduced pressure.

The residue was dissolved in H2O (3 mL), and the pH was adjusted to 6 with 1.0 N HCl.

The aqueous layer was extracted with 10% MeOH/CHCl3. The combined organic extractswere dried over Na2SC>4 and the solvent was removed. The residue was lyophilized fromwater to give the title compound (21 mg) as a white powder. NMR (300 MHz, CDCI3)δ 7.57 (m, 1 H), 7.12 (d, J = 8.5 Hz, 2 H), 6.76 (d, J = 8.5 Hz, 2 H), 6.55 (d, J = 7.2 Hz, 1H), 6.40 (d, J = 8.8 Hz, 1 H), 4.2 (m, 2 H), 3.70 (m, 2 H), 3.15 (m, 2 H), 2.88 (s, 3 H), 2.80(m, 1 H), 2 70 (m, 1 H), 2.50 (m, 2 H), 2.01 (d, J = 2.3 Hz, 1 H). MS (ES) m/e 339.2 (M +H)+.

Example 40

Préparation of (±)-4-[4-i2-[6-(methylamino)pyridin-2-yn-1 -ethoxvlphenvH-3-(2- phenylethyDbutanoic acid a) Methyl (±)-4-[-4-[2-[6-(methylamino)pyridin-2-yl]-l-ethoxy]phenyl]-3-(2-phenylethyl)butanoate

According to the procedure of Example 2 (a), except substituting methyl (+)-4-(4-hydroxyphenyl)-3-(phenylethyl)butanoate for the ethyl (+)-4-(4-hydroxyphenyl)-3-phenylbutanoate, the title compound (59%) was obtained as a clear film following silica gelchromatography (20% EtOAc/hexanes): MS (ES) m/e 433 (M + H)+. b) (±)-4-[-4-[2-[6-(Methylamino)pyridin-2-yl]-1 -ethoxy]phenyl]-3-(2- phenylethyl)butanoic acid

According to the procedure of Example 2 (b), except substituting methyl (±)-4-[-4-[2-[6-(methylamino)pyridin-2-yl]- l-ethoxy]phenyl]-3-(2-phenylethyl)butanoate for theethyl (±)-3-phenyl-4-[4-[2-[6-(methylamino)pyridin-2-yl]-l-ethoxy]phenyl]butanoate, thetitle compound (70%) was obtained as a white foam: MS (ES) m/e 419 (M + H)+. Anal.Calcd for C26H30N2O3 · 1.1 H2O: C, 71.24; H, 7.40; N, 6.39. Found: C, 71.29; H, 7.19;N, 6.33.

Example 41 - 122- 012189

Préparation of (±)-3-benzyl-4-r4-r2-r6-(methvlamino)pyridin-2-yn-l- ethoxylphenyllbutanoic acid a) Methyl (±)-3-benzyl-4-[4-[2-[6-(methylamino)pyridin-2-yl]-1 -ethoxy ]phenyl]butanoate

According to the procedure of Example 2 (a), except substituting methyl (±)-4-(4-hydroxyphenyl)-3-benzylbutanoate for the ethyl (±)-4-(4-hydroxyphenyl)-3-phenylbutanoate, the title compound (47%) was obtained as a clear film followingchromatography on silica gel (20% EtOAc/hexanes): MS (ES) m/e 419 (M + H)+. b) (±)-4-(-4-[2-[6-(Methylamino)pyridin-2-yl]-l-ethoxy]phenyl]-3-(2-benzyl)-butanoicacid

According to the procedure of Example 2 (b), except substituting methyl (±)-3-benzyl-4-[4-[2-[6-(methylamino)pyridin-2-yl]-l-ethoxy]phenyl]butanoate for the ethyl (±)- 3-phenyl-4-[4-[2-[6-(methylamino)pyridin-2-yl]-l-ethoxy]phenyl]butanoate, the titlecompound (47%) was obtained as a light yellow foam: MS (ES) m/e 405 (M + H)+. Anal.Calcd for C25H28N2O3 · 1.0 HCl · 0.45 H2O: C, 66.87; H, 6.71; N, 6.24. Found: C,66.68; H, 6.62; N, 6.64.

Example 42

Préparation of (±)-4-f4-i2-f6-(methylamino)pyridin-2-yn-l-ethoxvlphenvn-3-(2- cvclopropyl)-butanoic acid a) Methyl (±)-4-[4-[2-[6-(methylamino)pyridin-2-yl]-l-ethoxy]phenyl]-3-(2-cyclopropyl)-butanoate

According to the procedure of Example 2 (a), except substituting methyl (±)-4-(4-hydroxyphenyl)-3-cyclopropylbutanoate for the ethyl (±)-4-(4-hydroxyphenyl)-3-phenylbutanoate, the title compound (64%) was obtained as a clear film followingchromatography on silica gel (20% EtOAc/hexanes): MS (ES) m/e 369 (M + H)+. b) (±)-4-[4-[2-[6-(Methylamino)pyridin-2-yl]-l-ethoxy]phenyl]-3-(2-cyclopropyl)-butanoic acid

According to the procedure of Example 2 (b), except substituting methyl (±)-4-[4-[2-[6-(methylamino)pyridin-2-yl]-1 -ethoxy]phenyl]-3-(2-cyclopropy l)-butanoate for theethyl (±)-3-phenyl-4-[4-[2-[6-(methylamino)pyridin-2-yl]-l-ethoxy Jphenyl]butanoate, thetitle compound was obtained (9 mg) as a light yellow foam: MS (ES) m/e 355 (M + H)+. - 123- 012189

Example 43

Préparation of 3-methyl-4-i4-r2-f6-(methylarnino)pyridin-2-vn-l-ethoxy1phenvll-3- butenoic acid a) Methyl 3-methyl-4-[4-[2-[6-(methylamino)pyridin-2-yl]-l-ethoxy]phenyl]-3-butenoate

According to the procedure of Example 2 (a), except substituting ethyl 4-(4-hydroxyphenyl)-3-methyl-3-butenoate for the ethyl (±)-4-(4-hydroxyphenyl)-3-phenylbutanoate, the title compound (96%) was obtained as a clear film followingchromatography on silica gel (20% EtOAc/hexanes): MS (ES) m/e 355 (M + H)+. b) 3-Methyl-4-[4-[2-[6-(methyîamino)pyridin-2-yl]-l-ethoxy]phenyl]-3-butenoic acid

According to the procedure of Example 2 (b), except substituting methyl 3-methyl- 4-[4-[2-[6-(methylamino)pyridin-2-yl]-l-ethoxy]phenyl]-3-butenoate for the ethyl (±)-3-phenyl-4-[4-[2-[6-(methylamino)pyridin-2-yl]-l-ethoxy]phenyl]butanoate, the titlecompound (30 mg) was obtained as a yellow foam: MS (ES) m/e 327 (M + H)+. Anal.Calcd for C19H22N2O3 · 0.60 HCl 0.55 H2O: C, 63.71; H, 6.67; N, 7.82. Found: C,63.41; H, 6.78; N, 8.14.

Example 44

Parentéral Dosage Unit Composition A préparation which contains 20 mg of the compound of Example 1 as a stérile drypowder is prepared as follows: 20 mg of the compound is dissolved in 15 mL of distilledwater. The solution is filtered under stérile conditions into a 25 mL multi-dose ampouleand lyophilized. The powder is reconstituted by addition of 20 mL of 5% dextrose in water(D5W) for intravenous or intramuscular injection. The dosage is thereby determined by theinjection volume. Subséquent dilution may be made by addition of a metered volume ofthis dosage unit to another volume of D5W for injection, or a metered dose may be addedto another mechanism for dispensing the drug, as in a bottle or bag for IV drip infusion orother injection-infusion System. - 124- 012189

Example 45

Oral Dosage Unit Composition 5 A capsule for oral administration is prepared by mixing and milling 50 mg of the compound of Example 1 with 75 mg of lactose and 5 mg of magnésium stéarate. Theresulting powder is screened and filled into a hard gelatin capsule.

Example 46 10

Oral Dosage Unit Composition A tablet for oral administration is prepared by mixing and granulating 20 mg ofsucrose, 150 mg of calcium sulfate dihydrate and 50 mg of the compound of Example 1 15 with a 10% gelatin solution. The wet granules are screened, dried, mixed with 10 mgstarch, 5 mg talc and 3 mg stearic acid; and compressed into a tablet.

The above description fully discloses how to make and use the présent invention.However, the présent invention is not limited to the particular embodiments described 20 hereinabove, but includes ail modifications thereof within the scope of the following daims. The various references to joumals, patents and other publications which are cited _herein comprises the State of the nrt nnd arc incoi-pnimwl lierpin hy reft»rf>nr.t> as thnngh fully set forth.

Claims (42)

1. - 125- What is claimed is:

   1. A compound according to formula (I): „2 „ A

   (I) wherein: R* is 012189

   X is CRR’, NR’, O or S; Yis CRR’, NR’, O or S; A is H, halo, -ORg, -SRg, -CN, -NRgRk, -NO2, -CF3, -S(O)rCF3, -CO2Rg, -CORg,-CONRg2 -Ci.galkyl, -CQ^alkyl-Ar, -C0_6alkyl-Het, -C0_6alkyl-C3-6cycloalkyl, -S(O)kRg,orCH2N(Rf)2; R1 is -C()_6alkyl-Het-, -C0_6alkyl-Ar, -C1.6alkyl, -H, -CN, -CH=CH2, -C=CH or,-S(O)kRg; R^ is

   (?>u R’ /NX^N\/(cr’2)v-w R" Γ Tq’ q3 Q q1>N NR"-CR’-W-Q2^ 3-Q4 xq3 r y Osx^nr9 N. „ NR"—- CR’2 — W N. .N. /(CR’)—W

   or W is -(CHRg)a-U-(CHRg)b-; - 126- 01 21 8 U is absent or CO, CRg2, C(=CRg2), S(O)k, O, NRg, CRgORg, CRg(ORk)CRg2,CRg2CRg(ORk), C(O)CRg2, CRg2C(O), CONR», NR‘CO, OC(O), C(O)O, C(S)O, OC(S),C(S)NRg, NRgC(S), S(O)2NRg, NRgS(O)2 N=N, NRgNRg, NRgCRg2, CRg2NRg, CRg2O,OCRg2, CsC , CRg=CRg, Ar or Het; G is NRe, S or O; Rg is H, Cj.^alkyl, Het-Cg.galkyl, C3-7cycloalkyl-Co_6alkyl or Ar-C^galkyl; Rk is Rg, -C(O)Rg, or -C(O)ORf; R’ is is H, C^galkyl, Het-Co^alkyl, C3_7cycloalkyl-CQ_6alkyl, Ar- Cg^alkyl, orCi_galkyl substituted by one to three groups chosen from halogen, CN, NRg2, ORg, SRS,CO2Rg, and CON(Rg)2; Rf is H, Cj.^alkyl or Ar-Cg^alkyl; Re is H, Cj.galkyl, Ar-Co^alkyl, Het-C^galkyl, C3-7cycloalkyl-CQ_6alkyl, or(CH2)kCO2Rg; Rb and Rc are independently selected from H, Cj^alkyl, Ar-Cg^alkyl, Het-Cfl.galkyl, or C3-6cycloalkyl-CQ.6alkyl, halogen, CF3, ORf, S(O)kRf, CORf, NO2, N(Rf)2)CO(NRf)2,CH2N(Rf)2, or Rb and Rc are joined together to form a five or six memberedaromatic or non-aromatic carbocyclic or heterocyclic ring, optionally substituted by up tothree substituents chosen from halogen, CF3, C^alkyl, ORf, S(O)kRf, CORf, CO2Rf, OH,NO2, N(Rf)2> CO(NRf)2, and CH2N(Rf)2; or methylenedioxy; Q1, Q^, Q3 and are independently N or C-Ry, provided that no more than one ofQ’,Q2, Q3andQ4isN; --R* is H, Ci-ealkyl, Ar-Co-^alkyl or C3-fecyclualkyl-Co-6alkyI; R" is R’, -C(O)R’ or -C(O)OR’; RY is H, halo, -ORg, -SRg, -CN, -NRgRk, -NO2, -CF3, CF3S(O)r-, -CO2Rg, -CORgor -CONRg2, or Cj.galkyl optionally substituted by halo, -ORg, -SRg, -CN, -NRgR", -NO2,-CF3, R'S(O)r-, -CO2R8, -CORg or -CONRg2; a is 0, 1 or 2;b is 0, 1 or 2;k is 0, 1 or 2;r is 0, 1 or 2;s is 0, 1 or 2;u is 0 or 1 ; andv is 0 or 1 ; or a pharmaceutically acceptable sait thereof. - 127- 012189
2. 2. A compound according to formula (la): A

   X CO-H wherein: X is CRR’, NR’, O or S; Yis CRR’, NR’, O or S; A is H, halo, -ORS, -SRS, -CN, -NRSRk, -NO2, -CF3, -S(O)rCF3, -CO2RS, -CORS, -CONRS2 -Ci-ealkyl, -Cg^alkyl-Ar, -Cg^alkyl-Het, -CQ_^alkyl-C3_6cycloalkyl, -S(O)kR8,orCH2N(Rf)2; R1 is -C0.6alkyl-Het-, -C0.6alkyl-Ar, H, -CN or -S(O)kRS; R^ is R'

   G NR»—cr,2—w- (9) (9), R’

   Q' Q' ,or N NR"—CR’ — W Q'

   W is -(CHRS)a-U-(CHRS)b-; U is absent or CO, CRS2, C(=CRS2), S(O)k, O, NRS, CRSORS, CRS(ORk)CRS2,CRS2CR8(ORk), C(O)CRS2, CRS2C(O), CONRÎ, NR’CO, OC(O), C(O)O, C(S)O, OC(S),C(S)NRS, NRSC(S), S(O)2NRS, NR8S(O)2 N=N, NRSNRS, NRSCRS2, CRS2NRS, CRS2O,OCRS2> C=C , CRS=CRS, Ar or Het; G is NRe, S or O; RS is H, Cj.galkyl, Het-Cg^alkyl, C3-7cycloalkyl-CQ.6alkyl or Ar-Cg^alkyl; Rk is RS, -C(O)RS, or -C(O)ORf; - 128- 012189 R' is is H, Cpgalkyl, Het-C^galkyl, C3-7cycloalkyl-Co.6alkyl, Ar- C^galkyl, or' Cj.6alkyl substituted by one to three groups chosen from halogen, CN, NRS2, ORS, SRS, CO2RS, and CON(RS)2; Rf is H, Cj.^alkyl or Ar-Co^alkyl; Re is H, Cj.galkyl, Ar-CQ-galkyl, Het-C^galkyl, C3-7cycloalkyl-Co_6alkyl, or(CH2)kCO2RS; Rb and Rc are independently selected from H, Cj.galkyl, Ar-C^galkyl, Het-C0_galkyl, or C3-6cycloalkyl-Co_6alkyl, halogen, CF3, ORf, S(O)kRf, CORf, NO2, N(Rf)2)CO(NRf)2, CH2N(Rf)2, or Rb and Rc are joined together to form a fîve or six memberedaromatic or non-aromatic carbocyclic or heterocyclic ring, optionally substituted by up tothree substituents chosen from halogen, CF3, C^alkyl, ORf, S(O)kRf, CORf, CO2Rf, OH,NO2, N(Rf)2, CO(NRf)2, and CH2N(Rf)2; or methylenedioxy; Q1, Q2, Q3 and Q4 are independently N or C-Ry, provided that no more than one ofQ1, Q2, Q3 and Q4 is N; R’ is H, Ci-6alkyl, Ar-Co.6alkyl or C3-6cycIoalkyl-Co-6alkyl; R" is R’, -C(O)R’ or -C(O)OR’; Ry is H, halo, -ORS, -SRS, -CN, -NRSRk, -NO2, -CF3, CF3S(O)r-, -CO2RS, -CORSor -CONRS2, or Ci-6alkyl optionally substituted by halo, -ORS, -SRS, -CN, -NRSR", -NO2,-CF3, R’S(O),.-, -CO2R8, -CORS or -CONRS2; a is 0,1 or 2;b is 0,1 or 2;k is 0, 1 or 2;ris 0,1 or 2;s is 0,1 or 2;u is 0 or 1 ; andv is 0 or 1 ; or a pharmaceutically acceptable sait thereof.
3. 3. A compound according to daims 1 or 2 in which R2 is

   ,wherein Q1, Q2, and Q3 are each CRy, Q4 is CRy or N and u is 0. r <· i2’ 01218 9 " 4. A compound according to claim 3 in which each R’ is H, R"is H or Ci.6alkyl, W is -(CH2)l-4-, Q4 is CRY and RY is H.
4. 5. A compound according to daims 1 or 2 in which R2 is
5. 6. A compound according to claim 5 in which each R’ is H, R" is H orCj.éalkyl, v is 0 and W is -CH2-CH2-.
6. 7. A compound according to daims 1 or 2 in which R2 is NR”-CR’2—W- r^-N , wherein G is NH and R*5 and Rc are each H.
7. 8. A compound according to claim 7 in which W is -CH2-CH2-.
8. 9. A compound according to daims 1 or 2 in which R2 is NR"-CR’ -W- , wherein G is NH and Rb and Rc arejoined together to form a five or six membered aromatic or non-aromatic carbocyclic orheterocyclic ring, optionally substituted by up to three substituents chosen from halogen,CF3, CMalkyl, ORf, S(O)kRf, CORf, CO2Rf, OH, NO2, N(Rf)2, CO(NRf)2, andCH2N(Rf)2‘> θΓ methylenedioxy.
9. 10. A compound according to claim 9 in which Rb and Rc are joined togetherto form a six membered aromatic carbocyclic ring.
10. 11. A compound according to claim 10 in which W is -CH2-CH2· - 130- 012189
11. 12. A compound according to claim 9 in which Rb and Rc are joined togetherto form a six membered aromatic heterocyclic ring.
12. 13. A compound according to claim 12 in which W is -CH2-CH2-.
13. 14. A compound according to claims 1 or 2 in which R2 is .N. NR"—CR’?~W- ( Y ».x^NR» , wherein each R’ is H, R" is H or Ci-6alkyl, . RS is H or Cj.galkyl and s is 0, 1 or 2.
14. 15. A compound according to claim 14 in which W is -CH2-CH2-.
15. 16. A compound according to claims 1 or 2 in which R1 is phenyl, benzyl, pyridyl, imidazolyl, oxazolyl or thiazolyl.
16. 17. A compound according to claims 1 or2 in which Y is O or CH2.
17. 18. A compound according to claims 1 or 2 in which X is NH or CH2.
18. 19. A compound according to claim 1 in which R2 is

    wherein v is 0 and W is -CH2-CH2-.
19. 20. A compound which is: (±)-3-phenyl-4-[4-[3-(pyridin-2-yl)amino-1 -propyloxy]phenyl]butanoic acid;(±)-3-phenyl-4-[4-[2-[6-(methylamino)pyridin-2-yl]-l-ethoxy]phenyl]butanoic acid; (±)-3-phenyl-3-[4-[4-(pyridin-2-yl)amino-1 -butyl]phenylamino]propanoic acid; 4-[4-[2-[6-(methyIamino)pyridin-2-yl]-l-ethoxy]phenyl]butanoic acid;(S)-3-phenyl-4-[4-[3-(pyridin-2-yl)amino-î-propyloxy]phenyl]butanoic acid;2-phenoxy-4-[5-(pyridin-2-yl)amino-1 -pentyloxyjphenylacetic acid; 4-[4-[6-(methylamino)pyridin-2-yl]-l-ethoxy]-2-phenoxyphenyl]butanoic acid;(±)-4-[4-[6-(methylamino)pyridin-2-yl]-l-ethoxy]phenyl]-3-vinylbutanoic acid; - 131 - 012189 (±)-3-methyl-4-[4-[3-(pyridin-2-yl)amino-1 -propyloxy]phenyl]butanoic acid; (R) -3~phenyl-4-[4-[3-(pyridin-2-yl)amino-l-propyloxy]phenyl]butanoic acid;(±)-4-[4-[2-[6-(methylamino)pyridin-2-yl]-l-ethoxy]phenyl]-3-(pyridin-2- yl)butanoic acid; (±)-3-methyl-4-[4-[2-[2-(methylamino)pyridin-5-yl]-l-ethoxy]phenyl]butanoic acid; 2-[N-benzyl-N-[4-[2-[6-(methylamino)pyridin-2-yl]-l-ethoxy]benzyl]amino]acetic acid; (±)-4-[4-[2-[6-(methylamino)pyridin-2-yl]-l-ethoxy]phenyl]-3-(thiophen-2-yl)butanoic acid; 2-[N-[4-[2-[6-(methylamino)pyridin-2-yI]-l-ethoxy]benzyl]-N-phenyl]amino]-acetic acid; (±)-3-(4-bromophenyl)-4-[4-[2-[6-(methylamino)pyridin-2-yl]-l-ethoxy]phenyl]-butanoic acid; (±)-3-methyl-4-[4-[2-[6-(methylamino)pyridin-2-yl]-l-ethoxy]phenyl]butanoic acid; (S) -3-phenyl-4-[4-[2-[6-(methylamino)pyridin-2-yl]-l-ethoxy]phenyl]butanoic acid; (±)-3-(4-isopropylphenyl)-4-[4-[2-[6-(methylamino)pyridin-2-yl]-l-ethoxy]-phenyl]butanoic acid; (±)-3-(4-isopropylphenyl)-4-[4-[3-(4-methylpyridin-2-yl)amino-l-propyloxy]phenyl]butanoic acid; (±)-4-[4-[2-[6-(methylamino)pyridin-2-yl]-l-ethoxy]phenyl]-3-(oxazol-2-yl)butanoic acid; 2- {N-[2-methoxy-4-[2-[6-(methylamino)pyridin-2-yl]-1 -ethoxy]-benzyl]amino]acetic acid; 4-[4-[2-[6-(methylamino)pyridin-2-yl]-l-ethoxy]phenylJbut-3-enoic acid;(±)-4-[4-[2-[6-(methylamino)pyridin-2-yl]-l-ethoxy]phenyl]-3-(thiazol-2- yl)butanoic acid; (±)-3-phenyl-4-[4-[[2-(pyridin-2-yl)amino-l-ethylamino]carbonyI]phenyl]butanoic acid; (±)-3-(furan-2-yl)-4-[4-[2-[6-(methylamino)pyridin-2-yl]-l-ethoxy]phenyl]-butanoic acid; (±)-4-[4-[2-[6-(methylamino)pyridin-2'yl]-l-ethoxy]phenyl]-3-(2-phenylethyl)-butanoic acid; (S)-3-phenyl~4-[4-[2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)-l-ethoxy]-phenyl]butanoic acid; 3- methyl-4-[4-[2-[6-(methylamino)pyridin-2-yl]-l-ethoxy]phenyl]-3-butenoic acid; - 132- 012189 (±)-3-[ 1 -(dimethylaminosulfonyl)imidazol-2-yl]-4-[4-[2-[6-(methylamino)pyridin-2-yl]-1 -ethoxy]phenyl]butanoic acid; (±)-3-benzyl-4-[4-[2-[6-(methylamino)pyridin-2-yl]-l-ethoxy]phenyllbutanoic acid; (±)-3-(imidazol-2-yl)-4-[4-[2-[6-(methylamino)pyridin-2-yl]-l-ethoxy]phenyl]-butanoic acid (S)-4-[4-[2-[6-(methylamino)pyridin-2-yl]-l-ethoxy]phenyl]-3-(thiazol-2-yl)butanoic acid; (R) -4-[4-[2-[6-(methylamino)pyridin-2-yl]-l-ethoxyJphenyl]-3-(thiazol-2-yl)butanoic acid; (S) -3-phenyl-4-[4-[3-(3,4,5,6-tetrahydropyrimidin-2-yl)amino-l-propyloxy]-phenyljbutanoic acid; (±)-3-cyclopropyl-4-[4-[2-[6-(methylamino)pyridin-2-yl]-l-ethoxy]phenyl]-butanoic acid; (±)-3-(benzothiazol-2-yl)-4-[4-[2-[6-(methylamino)pyridin-2-yl]-l-ethoxy]phenyl]-butanoic acid; (S)-4-[4-[2-(5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl)-l-ethoxy]phenyl]-3-(thiazol-2-yl)-butanoic acid; (±)-3-(4-methylthiazol-2-yl)-4-[4-[2-[6-(methylamino)pyridin-2-yl]-l-ethoxy]-phenyljbutanoic acid; (±)-3-[4-carboxy-l,3-oxazol-2-yl]-4-[4-[2-[6-(methylamino)pyridin-2-yl]-l-ethoxy]phenyl]butanoic acid; (±)-3-[4-(aminocarbonyl)-l,3-oxazol-2-yl]-4-[4-[2-[6-(methylamino)pyridin-2-yl]-l-ethoxy]phenyl]butanoic acid; (±)-3-[4-(dimethylaminocarbonyl)-l,3-oxazol-2-yl]-4-[4-[2-[6-(methylamino)-pyridin-2-yl]- l-ethoxy]phenyl]butanoic acid; (±)-3-[4-[2-[6-(methylamino)pyridin-2-yl]ethoxy]benzyl]pent-4-ynoic acid;or a pharmaceutically acceptable sait thereof.
20. 21. A pharmaceutical composition which comprises a compound according todaims 1-20 and a pharmaceutically acceptable carrier.
21. 22. A pharmaceutical composition which comprises a compound according todaims 1-20, an antineoplastic agent and a pharmaceutically acceptable carrier.
22. 23. The pharmaceutical composition according to daim 22 wherein theantineoplastic agent is topotecan or cisplatin. - 133- 01 2189
23. 24. A pharmaceutîêal composition which comprises a compound according toclaim 1, an inhibitor of bone résorption and a pharmaceutically acceptable carrier.
24. 25. A method of treating a disease State in which antagonism of the ανββreceptor is indicated which comprises administering to a subject in need thereof acompound according to claim 1.
25. 26. A method of treating a disease State in which antagonism of the avfi5receptor is indicated which comprises administering to a subject in need thereof acompound according to claim 1.
26. 27. A method of treating osteoporosis which comprises administering to asubject in need thereof a compound according to claim 1.
27. 28. A method for inhibiting angiogenesis, tumor growth or tumor metastasiswhich comprises administering to a subject in need thereof a compound according to claim1.
28. 29. A method of treating atherosclerosis, restenosis or inflammation whichcomprises administering to a subject in need thereof a compound according to claim 1.
29. 30. A method of inhibiting tumor growth which comprises administeringstepwise or in physical combination a compound according to claim 1 and an antineoplasticagent.
30. 31. The method according to claim 30 wherein the antineoplastic agent istopotecan or cisplatin.
31. 32. A method of treating osteoporosis or inhibiting bone loss which comprisesadministering stepwise or in physical combination a compound according to claim 1 and aninhibitor of bone résorption. - 134-
32. 33. A compound according to formula (H): Ri-y

    CO^^alkyl (Π) 012189 wherein: Xis CRR’, NR’, O or S; Y is CRR’, NR’, O or S; A is H, halo, -ORS, -SRg, -CN, -NRgRk, -NO2, -CF3, -S(O)rCF3, -CO2Rg, -CORg, -CONRg2 -Ci-6alkyl, -C^galkyl-Ar, -C^galkyl-Het, -Co.6alkyl-C3-6cycloalkyl, -S(O)kRg,orCH2N(Rf)2; R1 is -CQ.galkyl-Het-, -CQ^alkyl-Ar, H, -CN or -S(O)kRg; R^ is R’ R' NR”—CR’,—W (9),

    Q'

    N NR"—CR’, —W-

    W is -(CHRg)a-U-(CHRg)b-; U is absent or CO, CRg2, C(=CRg2), S(O)k, O, NRg, CRgORg, CRg(ORk)CRg2,CRg2CRg(ORk), C(O)CRg2, CRg2C(O), CONR‘, NR‘CO, OC(O), C(O)O, C(S)O, OC(S),C(S)NRg, NRgC(S), S(O)2NRg, NRgS(O)2 N=N, NRSNRg, NRgCRg2, CRS2NRg, CRg2O,OCRg2, C=C , CRg=CRg, Ar or Het; G is NRe, S or O; Rg is H, Cj.galkyl, Het-Cg^alkyl, C3-7cycloalkyl-C0_6alkyl or Ar-C^galkyl; Rk is Rg, -C(O)Rg, or -C(O)ORf; - 135- 012189 R’ is is H, Cj.galkyl, Het-Cg^alkyl, C3-7cycloalkyl-Cg_6alkyl, Ar- Cg^alkyl, or Cj.galkyl substituted by one to three groups chosen from halogen, CN, NRg2, ORg, SRS, CO2Rg, and CON(RS)2; Ri is H, Cj.galkyl or Ar-Cg.galkyl; 5 Re is H, Cj.galkyl, Ar-Cg^alkyl, Het-Cg^alkyl, C3_7cycloalkyl-Cg_6alkyl, or (CH2)kCO2Rg; Rb and Rc are independently selected from H, Cj.galkyl, Ar-Cg.galkyl, Het-Cg.galkyl, or C3-6cycloalkyl-Cg_6alkyl, halogen, CF3, ORf, S(O)kRf, CORf, NO2, N(Rf)2)CO(NRf)2, CH2N(Rf)2, or Rb and Rc are joined together to form a five or six membered 10 aromatic or non-aromatic carbocyclic or heterocyclic ring, optionally substituted by up tothree substituents chosen from halogen, CF3, C^alkyl, ORf, S(O)kRf, CORf, CO2Rf, OH,NO2, N(Rf)2i CO(NRf)2, and CH2N(Rf)2; or methylenedioxy; Q1, Q2, q3 and Q4 are independently N or C-Ry, provided that no more than one ofQ’.Q2, Q3 andQ4isN; 15 R’ is H, Cj.6alkyl, Ar-Co-6alkyl or C3_6cycloalkyl-Co-6alkyl; R" is R’, -C(O)R’ or -C(O)OR’; RV is H, halo, -ORg, -SRg, -CN, -NRgRk, -NO2, -CF3, CF3S(O)r-, -CO2Rg, -CORgor -CONRg2, or Cj^alkyl optionally substituted by halo, -ORg, -SRg, -CN, -NRgR", -NO2,-CF3, R’S(O)r-, -CO2Rg, -CORg or -CONRg2; 20 a is 0, 1 or 2; b is 0, 1 or 2;k is 0, 1 or 2;r is 0, 1 or 2;s is 0, 1 or 2; 25 u is 0 or 1 ; and v is 0 or 1 ; or a pharmaceutically acceptable sait thereof; or a compound according to formula (III):30 O-

    (ΠΙ) wherein: X is CRTV, NR’, O or S; -136- 012189 . Y is CRR’, NR’, O or S; A is H, halo, -ORS, -SRS, -CN, -NRSRk, -NO2, -CF3, -S(O)rCF3, -CO2RS, -CORS,-CONRS2 -Ci-6alkyl, -C^alkyl-Ar, -Co^alkyl-Het, -C^galkyl-Cs-écycloalkyl, -S(O)kRS,orCH2N(Rf)2; R1 is -Co.6alkyl-Het-, -C0.6alkyl-Ar, H, -CN or -S(O)kRS; W is -(CHRS)a-U-(CHRS)b-; U is absent or CO, CRS2, C(=CRS2), S(O)k, O, NRS, CR8ORS, CRS(ORk)CRS2,CRS2CR8(ORk), C(O)CRS2, CRS2C(O), CONR>, NRÎCO, OC(O), C(O)O, C(S)O, OC(S),C(S)NRS, NRSC(S), S(O)2NRS, NRSS(O)2 N=N, NRSNR8, NRSCRS2, CRS2NRS, CR82O,OCRS2, C=C ,CRS=CRS, ArorHet; RS is H, Ci.galkyl, Het-Co-^alkyl, C3-7cycloalkyl-CQ.galkyl or Ar-Cg^alkyl; Rk is RS, -C(O)RS, or -C(O)ORf; R’ is is H, Cj-galkyl, Het-CQ^alkyl, C3-7cycloalkyl-CQ_5alkyl, Ar- C^galkyl, orCj.galkyl substituted by one to three groups. chosen from halogen, CN, NRS2, ORS, SRS,CO2RS, and CON(RS)2; Rfis H, Cj.galkyl or Ar-Co^alkyl; Q1, Q2. Q3 and Q4 are independently N or C-Ry, provided that no more than one ofQ1, Q2, Q3 and Q4 is N; R’ is H, Cj-éalkyl, Ar-Co-ôalkyl or C3-6cycloalkyl-Co-6alkyl; R" is R’, -C(O)R’ or -C(O)OR’; Ry is H, halo, -ORS, -SRS, -CN, -NRSRk, -NO2, -CF3, CF3S(O)r-, -CO2RS, -CORSor -CONRS2, or Cj^alkyl optionally substituted by halo, -ORS, -SRS, -CN, -NRSR", -NO2,-CF3, R’S(O)r-, -CO2RS, -CORS or -CONRS2; a is 0,1 or 2; andb is 0, 1 or 2; or a pharmaceutically acceptable sait thereof.
33. 34. A process for preparing a compound of the formula (la) as defined in claim2, which process comprises reacting a compound of formula (IV) with a compound offormula (V): X (IV) CO2C^alkyl R2-Ll (V) - 137- 012189 wherein Rl, A and X are as defined in formula (la), with any reactive functionalgroups protected, and lJ is OH or halo; and thereafter removing any protecting groups, and optionally forming apharmaceutically acceptable sait.
34. 35. A process for preparing a compound of the formula (la) as defined in claim2, which process comprises reacting a compound of formula (IV) with a compound offormula (VI):

    Ο- Ι V NR“— CR*2-W - OH • IIQ%s. g,Q4 Q (VI) wherein Ri, A, X, R’, R", W, Q1, Q2, Q3 and Q4 are as defined in formula (la),with any reactive functional groups protected; and thereafter removing any protecting groups, and optionally forming apharmaceutically acceptable sait; or a process for preparing a compound of the formula (la) as defined in claim2, which process comprises reacting a compound of formula (IV) with a compound offormula (VII):

    O-

    (VII) wherein R1, A, X, R’, R", W, Q1, Q2, Q3 and v are as defined in formula (la), withany reactive functional groups protected; and thereafter removing any protecting groups, and optionally forming apharmaceutically acceptable sait. - 138- 012189
35. 36. A compound according to any one of daims 1 to 20 for use as amédicament.
36. 37. The use of a compound of the formula (I) as defîned in claim 1 in the 5 manufacture of a médicament for the treatment of diseases in which antagonism of the ανββ receptor is indicated.
37. 38. The use of a compound of the formula (I) as defîned in claim 1 in themanufacture of a médicament for the treatment of diseases in which antagonism of the 10 0^85 receptor is indicated.
38. 39. The use of a compound of the formula (I) as defîned in claim 1 in themanufacture of a médicament for the treatment of osteoporosis.
39. 40. The use of a compound of the formula (I) as defîned in claim 1 in the manufacture of a médicament for the inhibition of angiogenesis, tumor growth or tumormetastasis.
40. 41. The use of a compound of the formula (I) as defîned in claim 1 in the 20 manufacture of a médicament for the treatment of atherosclerosis, restenosis or inflammation.
41. 42. The use of a compound of the formula (I) as defîned in claim 1 and anantineoplastic agent in the manufacture of a médicament for the inhibition of tumor growth 25 in physical combination or for stepwise administration.
42. 43. The use according to claim 43 wherein the antineoplastic agent is topotecanor cisplatin.