MXPA00008847A - 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

VITRONECTINE RECEPTOR ANTAGONISTS FIELD OF THE INVENTION This invention relates to pharmaceutically active compounds that inhibit the vitronectin receptor, and are useful for the treatment of inflammation, cancer and cardiovascular disorders, such as atherosclerosis and restenosis, and diseases in which bone resorption is a factor, such as in osteoporosis. * 10 BACKGROUND OF THE INVENTION Integrins are a superfamily of cell adhesion receptors that are transmembrane glycoproteins expressed in a variety of cells. These cell surface adhesion receptors include gpllb / llla (the fibrinogen receptor) and avß3 (the vitronectin receptor). The fibrinogen receptor gpllb / llla is expressed on the surface of platelets and intervenes in platelet aggregation and in the formation of a hemostatic clot at the site of a bleeding wound. Philips and others, Blood, 1988, 71, 831. The avr3 vitronectin receptor is expressed in several cells that include endothelial cells, smooth muscle cells, osteoclasts and tumor cells, and therefore have a variety of functions. The avß3 receptor expressed on the membrane of osteoclast cells intervenes in the adhesion of osteoclasts to the bone matrix, a key step in the process of bone resorption. Ross et al., J. Biol. Chem., 1987, 262, 7703. A disease characterized by excessive bone resorption is osteoporosis. The vß3 receptor expressed in human smooth muscle aortic cells intervenes in its migration to neointima, a process that can lead to restenosis after percutaneous coronary angioplasty. Brown et al., Cardiovascular Res., 1994, 28, 1815. In addition, Brooks et al., Cell, 1994, 79, 1157, have shown that a vß3 antagonist is capable of promoting tumor regression by inducing apoptosis of angiogenic blood vessels. In this way, agents that block the vitronectin receptor would be useful in the treatment of diseases such as osteoporosis, restenosis and cancer. It is now known that the vitronectin receptor refers to three different integrins, designated as avß ?, avß3 and avßs. Horton et al., Int. J. Exp. Pathol., 1990, 71, 741. The av? it binds to fibronectin and vitronectin. Avß3 binds to a wide variety of ligands, including fibrin, fibrinogen, laminin, thrombospondin, vitronectin, von Willebrand factor, osteopontin, and bone sialoprotein I. The avßs binds to vitronectin. The vitronectin avßs receptor has been shown to be involved in cell adhesion of a variety of cell types, including microvascular endothelial cells (Davis et al., J. Cell, Biol., 1993, 51, 206), and confirmed its role in angiogenesis. Brooks et al., Science, 1994, 264, 569. This integrin is expressed in blood vessels in human tissue of injured granulation, but not in normal skin. It is known that the vitronectin receptor binds to bone matrix proteins containing the tripeptide motif Arg-Gly-Asp (or RGD). Thus, Horton et al., Exp. Cell Res., 1991, 195, 368, disclose that peptides containing RGD and an anti-vitronectin receptor antibody (23C6) inhibit dentin resorption and cell dissemination by osteoclasts. In addition, Sato et al., J. Cell Biol., 1990, 111, 1713, disclose that echistatin, a snake venom peptide containing the RGD sequence, is a potent inhibitor of bone resorption in tissue culture, and inhibits osteoclast fixation to bone. It has now been discovered that certain compounds are potent inhibitors of avß3 and avßs receptors. In particular, it has been found that such compounds are more potent inhibitors of the vitronectin receptor than the fibrinogen receptor.

BRIEF DESCRIPTION OF THE INVENTION This invention comprises compounds of the formula (I) described below, which have pharmacological activity for the inhibition of the vitronectin receptor and are useful in the treatment of inflammation., cancer and cardiovascular disorders such as atherosclerosis and restenosis, and diseases in which bone resorption is a factor, such as in osteoporosis. This invention is also a pharmaceutical composition comprising a compound according to formula (I) and a pharmaceutical carrier. This invention is also a method of treating diseases in which the vitronectin receptor intervenes. In a particular aspect, the compounds of this invention are useful for the treatment of atherosclerosis, restenosis, inflammation, cancer and diseases in which bone resorption is a factor, such as in osteoporosis.

DETAILED DESCRIPTION OF THE INVENTION This invention comprises novel compounds that are inhibitors of the vitronectin receptor more potent than the fibrinogen receptor. This invention comprises compounds of formula (I): (Or where: R * is X is CR'R \ NR \ O or S; And it is CR'R ', NR \ O or S; A is H, halogen, -OR9, -SR9, -CN, -NR9Rk, -NO2, -CF3I -S (O) rCF3I -CO2R9, -COR9, -CONRValkyl of C? -dl-Co-6-Ar alkyl , -Co-6-Het alkyl, -C 6 -cycloalkyl C 3-6 alkyl, -S (O) kR 9, or CH 2 N (Rf) 2; R1 is -Co-6-Het alkyl, -Co-e-Ar alkyl, -C6 -6 alkyl, -H, -CN, -CH = CH2l -C = CH or -S (O) kR9; R2 is H W is - (CHR9) a-U- (CHR9) b-; U is absent or is CO, CRg2, C (= CR92), S (O) k, O, NRg, CR9OR9, CR9 (ORk) CR92, CR92CR9 (ORk), C (O) CR92, CR92C (O), CONR , • NR'CO, OC (O), C (0) 0, C (S) 0, OC (S), C (S) NRg, NRgC (S), S (0) 2NR9, NRgS (O) 2 N = N, NRgNR9, NR9CRg2, CRg2NR9, CR92O, OCR92, C? C, CR9 = CR9, Ar or Het; G is NRe, S or O; R9 is H, C-? 6 alkyl, Het-alkyl of Co-6, cycloalkyl of C3_-C06 alkyl- or Ar-C06 alkyl; * Rk is Rg, -C (O) R9 or -C (O) ORf; R1 is H, C1-6 alkyl, Het-alkyl of Co-β, cycloalkyl of C3_7-alkyl of C0_6-, Ar-alkyl of C0_6; or C? _6 alkyl substituted with one to three groups selected from halogen, CN, NR92, OR9, SR9, CO2R9 and CON (R9) 2; Rf is H, C 1 -β alkyl or Ar-C 0 -β alkyl; 15 Re is H, C? _6 alkyl, Ar-Co-? Alkyl, Het-alkyl of Co-β, C3_7 cycloalkyl-C0_? Alkyl or (CH2) kCO2R9; Rb and Rc are independently selected from H, C? _ß alkyl, Ar-β-alkyl, Het-alkyl from Co-β, or cycloalkyl from C3_6-alkyl from Co-β, halogen, CF3, ORf, S ( O) kRf, CORf, N02, N (Rf) 2, CO (NRf) 2, CH2N (Rf) 2, or Rb and 20 Rc are joined to form a five or six membered aromatic or non-aromatic carbocyclic or heterocyclic ring, optionally substituted with up to three substituents selected 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; Q \ Q2, Q3 and Q4 are independently N or C-Ry, with the proviso that not more than one of Q1, Q2, Q3 and Q4 is N; R 'is H, C6_6 alkyl, Ar_C06 alkyl or C3_6 cycloalkylC06 alkyl; R "is R \ -C (O) R 'or -C (O) OR'; Ry is H, halogen, -OR9, -SR9, -CN, -NR9Rk, -NO2, -CF3, CF3S (O) r , -CO2R9, -COR9 or -CONR92, or d.6 alkyl optionally substituted with halogen, -OR9, -SR9, -CN, -NR9R ", -N02, -CF3, R'S (0) r, - CO2R9, - COR9 or -CONR92; 10 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; 15 u is 0 or 1; and v is 0 or 1; or a pharmaceutically acceptable salt thereof. Conveniently, this invention comprises compounds of formula (I) having the formula (Ia): (la) where: X is CR'R ', NR', O or S; And it is CR'R ', NR', O or S; A is H, halogen, -OR9, -SR9, -CN, -NR9Rk, -N02, -CF3, -S (0) rCF3, -C02R9, -COR9, -CONRg2-alkyl, of, -C06 alkyl-Ar , -alkyl of Co-ß-Het, -Calkyl-cycloalkyl of C3.6, -S (O) kR9, or CH2N (Rf) 2; R1 is -C0_6-Het alkyl, -C0-ß-Ar alkyl, H, -CN or -S (0) kR9; R2 is W is - (CHRg) a-U- (CHRg) b-; U is absent or is CO, CR92, C (= CR92), S (O) k, O, NR9, CR9OR9, CR9 (ORk) CR92, CR92CR9 (ORK), C (O) CR92, CR92C (O), CONR , NR'CO, OC (O), C (0) 0, C (S) O, OC (S), C (S) NR9, NRgC (S), S (O) 2NRg, NR9S (O) 2 N = N, NR9NR9, NR9CR92, CR92NRg, CR92O, OCR92, C? C, CR9 = CR9, Ar or Het; • G is NRe, S or O; R9 is H, C? _6 alkyl, Het-C0-6 alkyl, C3.7-cycloalkyl-Co-? - alkyl or Ar-C6-alkyl; Rk is R9, -C (0) R9 or -C (O) ORf; R1 is H, C6-6alkyl Het-C0-6alkyl, C7-cycloalkyl-Co-βalkyl, Coalkylalkyl or C6-6alkyl substituted with one to three / 10 groups selected from halogen, CN, NR92, OR9, SR9, CO2R9 and CON (R9) 2; Rf is H, alkyl of d_6 or Ar-alkyl of C0-β; Re is H, C? _6 alkyl, Ar-C0-b alkyl, Het-alkyl of Co-β, cycloalkyl of C3_7-C0_ß alkyl or (CH2) kCO2R9; Rb and Rc are independently selected from H, d-β alkyl, Ar-alkyl of Co-β, Het-alkyl of Co-β, or cycloalkyl of C3.β-C0_6 alkyl, halogen, CF3, ORf, S (O) kRf, CORf, NO2, N (Rf) 2, CO (NRf) 2, CH2N (Rf) 2, or Rb and Rc are joined to form a five or six membered aromatic or non-aromatic carbocyclic or heterocyclic ring, optionally substituted with up to three substituents selected from halogen, CF3, C ^ alkyl, ORf, 20 S (0) kRf, CORf, C02Rf, OH, NO2 >; N (Rf) 2, CO (NRf) 2 and CH 2 N (Rf) 2; or methylenedioxy; Q1, Q2, Q3 and Q4 are independently N or C-Ry, with the proviso that no more than one of Q1, Q2, Q3 and Q4 is N; R 'is H, d-β alkyl, Ar-C0_6 alkyl or C3.6 cycloalkyl-Co-β alkyl; R "is R", -C (O) R 'or -C (O) OR'; Ry is H, halogen, -OR9, -SR9, -CN, -NR9Rk, -NO2, -CF3, 5CF3S (O) r-, -CO2R9, -COR9 or -CONR92, or alkyl of optionally substituted with halogen, -OR9, -SR9, -CN, -NR9R ", -NO2, -CF3, R'S (O) r, -CO 2 R 9, -COR 9 or -CONR 92, a is 0, 1 or 2, b is 0, 1 or 2; 10 k is 0, 1 or 2, r is 0, 1 or 2, s is 0, 1 or 2, u is 0 or 1, and v is 0 or 1, or a pharmaceutically acceptable salt thereof. this invention addition salts and pharmaceutically acceptable complexes of the compounds of this invention In cases where the compounds of this invention may have one or more chiral centers, unless otherwise specified, this invention or includes each unique non-racemic compound that it can be synthesized and resolved by conventional techniques.In cases where the compounds have unsaturated carbon-carbon double bonds, both the cis (Z) isomer and the trans (E) isomer are within the scope of this invention. cases in which compounds may exist in tautomeric forms, such as keto-enol tautomers as it is contemplated that each tautomeric form is included within this invention, whether it exists in equilibrium or closed in some way by appropriate substitution with R '. The compounds of formula (I) inhibit the binding of vitronectin and other RGD-containing peptides to the vitronectin receptor. The inhibition of the vitronectin receptor on osteoclasts inhibits the resorption of osteoclastic bone, and is useful in the treatment of diseases in which bone resorption is associated with pathology, such as in osteoporosis and osteoarthritis. In another aspect, this invention is a method for stimulating bone formation which comprises administering a compound that causes an increase in the release of osteocalcin. Increased production of bone is a clear benefit in pathological states in which there is a deficiency of mineralized bone mass or in which bone remodeling is sought, such as in the healing of fractures and the prevention of bone fractures. Such treatment would also be of benefit for metabolic diseases and disorders that result in loss of bone structure. For example, administration of a compound of this invention would be beneficial for hyperparathyroidism, Paget's disease, hypercalcemia of malignancy, osteolytic lesions caused by bone metastasis, bone loss due to immobilization or deficiency of sexual hormone, Behcet's disease, osteomalacia, hyperostosis. and osteopetrosis. Additionally, since the compounds of the present invention inhibit vitronectin receptors in several different types of cells, said compounds would be useful in the treatment of inflammatory disorders such as rheumatoid arthritis and psoriasis, and cardiovascular diseases such as atherosclerosis and restenosis. The compounds of formula (I) of the present invention may be useful for the treatment or prevention of other diseases including, but not limited to, thromboembolic disorders, asthma, allergies, respiratory distress syndrome in adults, graft versus host disease. , rejection of organ transplant, septic shock, eczema, contact dermatitis, inflammatory bowel disease, and other autoimmune diseases. The compounds of the present invention may also be useful for wound healing. The compounds of the present invention are also useful for the treatment, including prevention, of angiogenic disorders. The term "angiogenic disorders" as used herein, includes conditions that involve abnormal neovascularization. Where the growth of new blood vessels is the cause of, or contributes to, the pathology associated with a disease, the inhibition of angiogenesis will reduce the detrimental effects of the disease. An example of such a white disease is diabetic retinopathy. When the growth of new blood vessels is required to sustain the growth of a noxious tissue, the inhibition of angiogenesis will reduce the supply of blood to the tissue, and thereby contribute to the reduction of the tissue mass based on the blood supply requirements. Examples include the growth of tumors in which neovascularization is a continuous requirement for tumor growth and for the establishment of solid tumor metastases. In this manner, the compounds of the present invention inhibit angiogenesis of tumor tissue, thus preventing tumor metastasis and tumor growth. Therefore, in accordance with the methods of the present invention, the inhibition of angiogenesis using the compounds of the present invention can improve the symptoms of the disease, and in some cases, it can cure the disease. Another therapeutic target for the compounds of the present invention are diseases of the eye characterized by neovascularization. Such eye diseases include neovascular corneal disorders such as corneal transplantation, herpetic keratitis, luteal keratitis, pterygium and neovascular cloth associated with the use of contact lenses. Additional eye diseases also include age-related macular degeneration, presumed ocular histoplasmosis, pre-maturation retinopathy, and neovascular glaucoma. This invention further provides a method of inhibiting tumor growth which comprises administering gradually or in physical combination a compound of formula (I) and an antineoplastic agent such as topotecan and cisplatin. With respect to the formula (I) and (the): Conveniently R2 is 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 C? _6 alkyl, W is - (CH2)? - 4- , Q4 is CRy and Ry is H. Alternatively, R2 is wherein Q1, Q2 and Q3 are each CH and u is 0, and preferably each R 'is H, R "is H or alkyl of d_6, W is -CH2-CH2-, and v is 0. Alternatively, R2 is wherein G is NH and Rb and Rc are each H, and preferably W is -CH2-CH2-. Alternatively, R2 is wherein G is NH and Rb and Rc are linked to form a five or six membered aromatic or non-aromatic carbocyclic or non-aromatic heterocyclic ring, optionally substituted with up to three substituents selected from halogen, CF3, C1.4 alkyl, ORf, S ( O) kRf, CORf, CO2Rf, OH, NO2, N (Rf) 2, CO (NRf) 2, and CH2N (Rf) 2; or methylenedioxy. Preferably, Rb and Rc are joined to form a six-membered aromatic carbocyclic or heterocyclic ring and W is -CH2-CH2-. Alternatively, R2 is wherein each R 'is H, R "is H or C? _6 alkyl, R9 is H or alkyl of _6 and s is 0, 1 or 2 and, preferably, W is -CH2-CH2-. Alternatively, R2 is H .N, _. (CR'2) -W- where v is 0 and W is -CH2-CH2-. With respect to formula (I), R1 is conveniently phenyl, benzyl, pyridyl, imidazolyl, oxazolyl or thiazolyl. Preferably, R1 is phenyl.

Conveniently, Y is O or CH2 and X is NH or CH2. Preferably, Y is O. The compounds referred to in Examples 1-43 below are representative of the novel compounds of this invention. In cases where the compounds of this invention may have one or more chiral centers, unless specified, this invention includes a single non-racemic composite face that can be synthesized or resolved by conventional techniques. In accordance with the present invention, the (S) configuration of the compounds of formula (I) is preferred. In cases where the compounds have unsaturated carbon-carbon double bonds, both the cis (Z) and the trans (E) isomer are within the scope of this invention. The meaning of any substituent in any occurrence is independent of its meaning, or any other meaning of substituent, in any other occurrence. The prodrugs of the compounds of this invention are also included in this invention. The prodrugs are considered to be any covalently bonded vehicle that releases the original active drug in vivo according to formula (I). Thus, another aspect of this invention are novel prodrugs, which are also intermediates in the preparation of compounds of formula (la), having the formula (II): (II) where: X is CR'R ', NR \ O or S; And it is CR'R ', NR', O or S; A is H, halogen, -OR9, -SR9, -CN, -NR9Rk, -NO2, -CF3, -S (O) rCF3, -CO2R9, -COR9, -CONRg2-alkyl of d.6, -alkyl of C0 -6-Ar, -alkyl of Co-β-Het, -C0.6-cycloalkyl of C3-β, -S (O) kR9, or CH2N (Rf) 2; R1 is -C0-e-Het alkyl, -C0.e-Ar alkyl, H, -CN or -S (0) kR9; R2 is W is - (CHR9) a-U- (CHR9) b-; U is absent or is CO, CR92, C (= CR92), S (O) k, O, NR9, CR9ORg, CR9 (ORk) CR92, CR92CR9 (ORk), C (O) CR92, CR92C (O), CONR , NRCO, OC (O), C (O) O, C (S) O, OC (S), C (S) NR9, NRgC (S), S (O) 2NR9, NRgS (O) 2N = N, NR9NR9, NR9CR92, CR92NR9, CR92O, OCR92, C? C, CR9 = CR9, Ar or Het; G is NRe, S or O; R9 is H, C? _ Alquilo alkyl, Het-alkyl of Co-β, cycloalkyl of C3-7-alkyl of Co-β- or Ar-alkyl of Co-β; Rk is R9, -C (O) Rg or -C (O) ORf; R1 is H, C? .ß alkyl, Het-alkyl of Co-β, cycloalkyl of C3_ -alkyl of C0_β-, Ar-alkyl of C0- β; or C? _6 alkyl substituted with one to three chosen halogen groups, CN, NR92, OR9, SR9, CO2R9 and CON (Rg) 2; Rf is H, alkyl of d-e or Ar-alkyl of C0_6; Re is H, C? _ß alkyl, Ar-β-alkyl, Het-alkyl of Co-β, cycloalkyl of C3.7-alkyl of C 0 β or (CH 2) kCO R 9; Rb and Rc are independently selected from H, C? _6 alkyl, Ar-alkyl of Co-β, Het-alkyl of Co-e, or cycloalkyl of de-alkyl of C0_6, halogen, CF3, ORf, S (O) kRf, CORf, NO2, N (Rf) 2, CO (NRf), CH2N (Rf) 2, or Rb and Rc are joined to form a five- or six-membered aromatic or non-aromatic carbocyclic or heterocyclic ring, optionally substituted with up to three substituents selected 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, with the proviso that no more than one of Q1, Q2, Q3 and Q4 is N; R 'is H, C? _-Alkyl, Ar-C de-alkyl or C3-C ciclo-cycloalkyl-Co alquiloß alkyl; R "is R ', -C (O) R' or -C (O) OR '; Ry is H, halogen, -OR9, -SR9, -CN, -NRgRk, -N02, -CF3, CF3S (O) r-, -CO2R9, -COR9 or -CONR92, or d.6 alkyl optionally substituted with halogen, -OR9, -SR9, -CN, -NR9R ", -NO2, -CF3, R'S (O), -CO2R9, -COR9 or -CONR92; 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; and v is 0 or 1; or a pharmaceutically acceptable salt thereof. Another aspect of this invention are the novel intermediates of formula (III): (lll) where: X is CR'R ', NR', O or S; And it is CR'R ', NR', O or S; A is H, halogen, -OR9, -SR9, -CN, -NR9Rk, -NO2, -CF3, -S (O) rCF3, -CO2R9, -COR9, -CONR92-alkyl of d6, -alkyl of Co-β -Ar, -Cal-ß-Het alkyl, -C3-cycloalkyl-C3.6 alkyl, -S (O) kR9, or CH2N (Rf) 2; R1 is -C0-β-Het alkyl, -Co-e-Ar alkyl, H, -CN or -S (O) kR9; W is - (CHRg) a-U- (CHR9) b-; U is absent or is CO, CRg2, C (= CR92), S (O) k, O, NR9, CR9OR9, CR9 (ORk) CR92, CRg2CR9 (ORk), C (0) CR92, CR92C (0), CONR , NRCO, OC (O), C (O) O, C (S) O, OC (S), C (S) NR9, NR9C (S), S (O) 2NR9, NR9S (O) 2 N = N, NR9NRg, NRgCR92, CR92NR9, CR92O, OCR92, C = C, CR9 = CRg, Ar or Het; Rg is H, alkyl of d-β, Het-alkyl of Co-β, cycloalkyl of C3-7-alkyl of C0_ß- or Ar-alkyl of Co_β; Rk is Rg, -C (O) R9 or -C (O) ORf; R 'is H, alkyl of d-β, Het-alkyl of C0-β, cycloalkyl of C3_7-alkyl of Co-β-, Ar-alkyl of Co-β! or C-alkyl substituted with one to three groups selected from halogen, CN, NR92, ORg, SR9, CO R9 and CON (R9); Rf is H, C? _ Alquiloalkyl or Ar-C alquilo alquiloalkyl; Q1, Q2, Q3 and Q4 are independently N or C-Ry, with the proviso that no more than one of Q1, Q2, Q3 and Q4 is N; R 'is H, C? _6 alkyl, Ar-C de-alkyl or C 3 e-C de_ß-cycloalkyl; R "is R \ -C (O) R 'or -C (O) OR'; Ry is H, halogen, -OR9, -SR9, -CN, -NR9Rk, -NO2, -CF3, CF3S (O), -CO2R9, -COR9 or -CONR92, or d6 alkyl optionally substituted with halogen, -OR9, -SR9, -CN, -NRgR ", -NO2, -CF3, R'S (O) r, -C02R9, -COR9 or - CONR92; a is 0, 1 or 2; and b is 0, 1 or 2; or a pharmaceutically acceptable salt thereof. Abbreviations and symbols commonly used in the chemical and peptide techniques are used herein to describe the compounds of this invention. In general, the abbreviations of amino acids follow the nomenclature of the Joint IUPAC-IUB Commission on Biochemical Nomenclature as described in Eur. J. Biochem., 158, 9 (1984). C 1-4 alkyl as used herein means an optionally substituted alkyl group having from 1 to 4 carbon atoms, and includes methyl, ethyl, n-propyl, n-butyl, isobutyl and t-butyl. Alkyl of C? _6 additionally includes pentyl, n-pentyl, isopentyl, neopentyl and hexyl and the simple aliphatic isomers thereof. C0-4 alkyl and Co-6 alkyl further indicate that the alkyl group is not required to be present (e.g., that a covalent bond is present).

Any C 1-4 alkyl or C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or d-β oxoalkyl, may be optionally substituted with the R x group, which may be on any carbon atom that • originates a stable structure and is available through conventional synthetic techniques. Suitable groups for Rx are C 1 -4 alkyl, OR ", SR ', C 1 -4 alkylsulfonyl, CM alkylsulfoxyl, -CN, N (R') 2, CH 2 N (R ') 2, -NO 2, - CF 3 , -CO2R ', -CON (R') 2, -COR ', -SO2N (R') 2, -NR'C (O) R ', F, Cl, Br, I or CF3S (O) r, in where r is 0, 1 or 2. Halogen or halo means F, Cl, Br and I. Ar or aryl, as used herein, means phenyl or naphthyl, or phenyl or naphthyl substituted with one to three substituents such as those defined above for alkyl, especially C ?4 alkyl, C ?4 alkoxy, C? _4 alkylthio, CF 3, NH 2, OH, F, Cl, Br or I. Het or heterocycle denotes a five or six monocyclic ring members optionally substituted, or a nine- or ten-membered bicyclic ring containing one to three heteroatoms selected from the group of nitrogen, oxygen and sulfur, which are stable and available by conventional chemical synthesis. Exemplary 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 perhydroquinoline and isoquinoline. Any accessible combination of up to three substituents on the Het ring, such as those defined above for alkyl, which is available by chemical synthesis and is stable, is within the scope of this invention. C3_7 cycloalkyl refers to a substituted carbocyclic system • optionally three to seven carbon atoms, which can contain up to two unsaturated carbon-carbon bonds. Typical cycloalkyl of C3_7 are cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl and 'cycloheptyl. Any combination of up to three substituents on the cycloalkyl ring, such as those defined above for alkyl, which is available by chemical synthesis and is stable, is within the scope of • 10 this invention. When Rb and Rc are joined to form a five or six membered aromatic or non-aromatic carbocyclic or heterocyclic ring fused to the ring to which Rb and Rc are attached, the ring formed will generally be a five or six membered heterocycle selected from those HE mentioned above for Het, or it will be a ring of phenyl, cyclohexyl or cyclopentenyl. Preferably, Rb and Rc will be -D1 = D2-D3 = D4, where D1- • D4 are independently CH, N or C-Rx, with the proviso that not more than two of D1-D4 are N. Preferably, when Rb and Rc are united they form the group -CH = CH-CH = CH-. 20 Certain radical groups are abbreviated here. t-Bu refers to the tertiary butyl radical, Boc refers to the t-butoxycarbonyl radical, Fmoc refers to the fluorenylmethoxy radical, Ph refers to the phenyl radical, Cbz refers to the benzyloxycarbonyl radical, Bn refers to the benzyl radical, Me refers to a methyl, Et refers to ethyl, Ac refers to acetyl, Alk refers to C 4 alkyl, Nph refers to 1- or 2-naphthyl and cHex refers to cyclohexyl. Tet refers to 5-tetrazolyl. Certain reagents are abbreviated here. DCC refers to dicyclohexylcarbodiimide, DMAP refers to dimethylaminopyridine, DIEA refers to diisopropylethylamine, EDC refers to 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, HOBt refers to 1-hydroxybenzotriazole, THF refers to tetrahydrofuran, DEAD refers to diethyl azodicarboxylate, PPh3 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 catalyst of palladium on carbon, PPA refers to polyphosphoric acid, DPPA refers to diphenylphosphoryl azide, BOP refers to benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, HF refers to hydrofluoric acid, TEA refers to triethylamine, TFA refers to trifluoroacetic acid, PCC refers to pyridinium chlorochromate. The compounds of formula (la) are generally prepared by reacting a compound of formula (IV) with a compound of formula (V): (IV) (V) wherein R1, R2, A and X are as defined in formula (la), with any protected reactive functional group, and L1 is OH or halogen; and then removing any protecting group, and optionally forming a pharmaceutically acceptable salt. Conveniently, certain compounds of formula (la) are prepared by reacting a compound of formula (IV) as defined above, with a compound of formula (VI): (SAW) wherein R ", R", W, Q1, Q2, Q3 and Q4 are as defined in formula (la), with any protected reactive functional group; and then removing any protecting group, and optionally forming a pharmaceutically acceptable salt. Preferably, for compounds of formula (VI), Q1, Q2, Q3 and Q4 are CH, W is - (CH ^ -, R 'is H and R "is H or alkyl of d.6.

Conveniently, the reaction between a compound of formula (IV) with a compound of formula (VI) is carried out in the presence of diethyl azodicarboxylate and triphenylphosphine in an aprotic solvent.

Additionally, certain compounds of formula (la) are prepared by reacting a compound of formula (IV) as defined above, with a compound of formula (VII): wherein R ', R ", W, Q1, Q2, Q3 and v are as defined in formula (la), with any protected reactive functional group, and then remove any protecting group, and optionally form a pharmaceutically acceptable salt. , for compounds of formula (VII), Q1, Q2 and Q3 are CH, W is -CH2-CH2-, R 'is H and R "is H or Ci-e alkyl-Conveniently, the reaction between a compound of formula (IV) with a compound of formula (VII), is carried out in the presence of diethyl azodicarboxylate and triphenylphosphine in an aprotic solvent. The compounds of this invention, which include the compounds of formula (I) and (Ia), are prepared by means of the general methods described in Schemes I-XVI. Scheme I describes the preparation of compounds in which Y is O and X is CH2.

SCHEME I (a) EtOAc / LiN (TMS) 2, THF; (b) Et 3 SiH, BF 3 -OEt 2, CH 2 Cl 2; (c) H2, Pd 10% / C, EtOH; (d) EtSH, AICI3, CH2Cl2; (e) N - oxide of 2 - [(3-hydroxy-1-propyl) amino] pyridine, DIAD, (Ph) 3P, DMF; (f) cyclohexene, Pd 10% / C, 2-propanol; (g) 1.0 N LiOH, THF, H2O, then acidification. An appropriately substituted deoxybenzoin derivative, such as for example 2- (4-methoxyphenyl) -1-phenylethanone (Vhem Ber., 1958, 91, J55-759), is reacted in an aldol-type reaction with the ethyl acetate enolate, which can be generated from ethyl acetate by exposure to an appropriate amide base, for example lithium diisopropylamide (LDA) or lithium bis (trimethylsilyl) amide (LiN (TMS) 2), to produce -2. Frequently, the solvent of choice for an aldol reaction is THF, although THF is frequently used in the presence of various additives, for example HMPA or TMEDA. The reaction of 1-2 with triethylsilane (Et3SiH) in the presence of boron trifluoride etherate (BF3-OEt2) according to the general protocol of Orphanopoulos and Smonu (Synth Commun. 1988, 833) for the reduction of tertiary benzylic alcohols, produces I-3 together with the olefinic product derived from the alcohol-elimination. The olefinic product can be conveniently converted to I-3 by hydrogenation over a palladium catalyst, such as palladium metal on activated carbon (Pd / C) in a suitable inert solvent such as methanol, ethanol or ethyl acetate. Removal of the methyl ether from I-3 to give I-4 can be effected by reaction with ethanethiol (EtSH) in the presence of a Lewis acid catalyst, preferably anhydrous aluminum trichloride (AICI3), in an inert solvent, for example , CH2Cl2. Other useful methods for the removal of a methyl ether in Greene, "Protective Groups in Organic Synthesis" -protective groups in organic synthesis- (published by Wiley-lnterscience) are described. Compound 1-4 is reacted with 2 - [(3-hydroxy-1-propyl) amino] pyridine N-oxide in a Mitsunobu-type coupling reaction (Organic Reactions, 1992, 42, 335-656; Synthesis 1981 , 1-28) to produce I-5. The reaction is mediated by the complex formed between an azodicarboxylate diester, such as diethyl azodicarboxylate or diisopropyl azodicarboxylate, and triphenylphosphine, and is carried out in an aprotic solvent, for example, THF, CH2Cl2, or DMF. The pyridine N-oxide portion of 1-5 is reduced to the corresponding pyridine 1-6 under transfer hydrogenation conditions using a palladium catalyst, preferably palladium on activated carbon metal, in an inert solvent such as methanol, ethanol or 2-propanol As a hydrogen transfer reagent, they are commonly used in this type of reaction, cyclohexene, 1,4-cyclohexadiene, formic acid and salts of formic acid such as potassium formate or ammonium formate. The ethyl ester of I-6 is hydrolyzed using aqueous base, for example LiOH in aqueous THF or NaOH in methanol or aqueous ethanol, and the intermediate carboxylate salt is acidified with a suitable acid, for example TFA or HCl, to produce the acid carboxylic 1-7. Alternatively, if desired, the carboxylate intermediate salt can be isolated, or a carboxylate salt of the free carboxylic acid can be prepared by methods well known to the person skilled in the art.

Scheme II describes an alternative method for preparing compounds of formula (I).

SCHEME II (a) NaH, 2- [N- (3-methanesulfonyloxy-1-propyl) -N- (tert-butoxycarbonyl) amino] pyridine N-oxide, DMSO; (b) TFA, CH2CI2, (c) see scheme I.

Compound 11-1, prepared as described in Scheme I, is reacted with a base, conveniently an alkali metal hydride such as sodium hydride or potassium hydride, in a polar aprotic solvent, generally THF, DMF, DMSO or mixtures thereof, to produce the corresponding alkali metal phenoxide. Alternatively, an alkali metal amide, for example LDA, or the lithium, sodium or potassium salt of hexamethyldisilizan can be used for deprotonation. Generally the intermediate phenoxide is not isolated, but is reacted in situ with a suitable electrophile, for example 2- [N- (3-methanesulfonyloxy-1-propyl) -N- (tert-butoxycarbonyl) N-oxide. ) amino] pyridine, to produce the coupled product 11-2. The tert-butoxycarbonyl protecting group in 11-2 is removed under acidic conditions, such as for example 4 M HCl in 1,4-dioxane or TFA in CH 2 Cl 2, to produce II-3. The conditions for the removal of the terbutoxycarbonyl protecting group are well known to those skilled in the art, and various methods useful in standard reference volumes are described such as in Greene, "Protective Groups in Organic Synthesis" (published by W iley-lnterscience) . Subsequently, II-3 is converted to II-4 following the protocol indicated in scheme I.

SCHEME III (a) Tf20, 2,6-lutidine, CH2Cl2; (b) CO, KOAc, Pd (OAc) 2, dppf, DMSO; (c) 2 - [(2-amino-1-ethyl) amino] pyridine hydrochloride, EDC, HOBfH2O, Et3N, CH3CN; (d) LiOH, THF, H2O, then acidification.

Phenol 111-1, prepared as described in Scheme I, is converted to its trifluoromethanesulfonate ester III-2 by reaction with trifluoromethanesulfonic anhydride (TF2O) in the presence of a suitable non-nucleophilic amine base such as 2.6 -lutidine, in an inert solvent, generally CH2Cl2. 111-2 reacts with carbon monoxide (CO) in the presence of potassium acetate, 1, 1'-bis (diphenylphosphino) ferrocene (dppf), and a palladium catalyst, for example palladium acetate (Pd (OAc) 2) in a suitable solvent, preferably DMSO, according to the general method described by Cacchi and Lupi (Tet. Lett, 1992, 33, 3939) for the carboxylation of aryltrifluoromethanesulfonates. The carboxylic acid of the resulting compound (III-3) is converted to an activated form using for example EDC and HOBt, or SOCI2, and the activated form is subsequently reacted with a • Appropriate amine, for example 2 - [(2-amino-1-ethyl) amino] pyridine dihydrochloride, in a suitable solvent such as DMF, CH2Cl2, or CH3CN, to produce III-4. Depending on whether neutralization of the acid is required, an added base such as triethylamine (Et3N), diisopropylethylamine ((1-Pr) 2NEt), or pyridine can be used. Many other methods are known to convert a carboxylic acid to an amide, and can be found in standard reference books such as "Compendium of Organic Synthetic • Methods "-Compendium of synthetic organic methods-, Vol. I-VI (published by Wiley-lnterscience), or Bodansky," The Practice of Peptide Synthesis "(published by Springer-Verlag). The ester Ethyl of 111-4 is hydrolyzed using an aqueous base, for example LiOH in aqueous THF or NaOH in methanol or aqueous ethanol, and the intermediate carboxylate salt is acidified with a suitable acid, for example TFA or HCl, to produce the acid carboxylic 111-5. Alternatively, if desired, the intermediate carboxylate salt can be isolated, or a carboxylate salt of the free carboxylic acid can be prepared by methods well known to those skilled in the art.

SCHEME IV (a) CBr4, Ph3P, THF; (b) 2- (tert-butoxyamino) pyridine, NaH, DMF; (c) H2, Pd / C, EtOAc; (d) PhCHO, MgSO 4, CH 2 Cl 2; (e) BrZnCH2C02t-Bu, BF3OEt2, THF; (f) TFA, CH2Cl2. • The alcohol IV-1, commercially available, is converted into an activated species, for example the corresponding bromide IV-2, using carbon tetrabromide and triphenylphosphine in an inert solvent, preferably THF. Many other conditions are available to convert an alcohol into an activated species, such as the corresponding bromide, chloride, • 10 iodide, mesylate or triflate, and are well known to the person skilled in the art. Bromide IV-2 is alkylated with a suitable derivative of 2-aminopyridine, for example 2- (tert-butoxyamino) pyridine, to produce the alkylated derivative IV-3. The reaction is mediated by an appropriate base such as an alkali metal halide, and is carried out in an aprotic polar solvent, generally THF, DMF, DMSO, or mixtures thereof. The reduction of the nitro group of IV-3 can be effected by a variety of methods well known to the person skilled in the art. Preferably, the reduction is effected by hydrogenation in the presence of a palladium catalyst, for example palladium on activated carbon, in a suitable solvent such as EtOAc, MeOH, EtOH, I-Pr-OH, or mixtures thereof. The resulting aniline IV-4 reacts with a suitable aldehyde such as benzaldehyde, in an inert solvent such as CH2Cl2, benzene or toluene, to produce the corresponding IV-5 aldimine. If desired, a dehydrating agent such as MgSO4 may be used to remove the H2O formed during the reaction. Subsequently, the aldimine is reacted in an aldol-type reaction with an appropriate enolate of an acetic acid ester to produce IV-6. Generally, the reaction is mediated • by a Lewis acid, for example BF OEt2) and usually carried out in an ethereal solvent such as THF or DME. As described in scheme I, the enolate can be generated from ethyl acetate by exposure to an appropriate amide base, for example lithium diisopropylamide (LDA) or lithium bis (trimethylsilyl) amide (LiN (TMS) 2. , the enolate can be generated from tert-butyl bromoacetate by exposure to metal • 10 zinc, according to the procedure of Orsoni et al. (Tetrahedron 1984, 40, 2781-2J8J). The tert-butoxycarbonyl group and the tert-butyl ester of IV-6 are simultaneously stirred under acidic conditions, such as 4 M HCl in 1,4-dioxane or TFA in CH 2 Cl 2, to produce IV-7. The conditions for the deprotection of tert-butyl carbamates and tert-butyl esters are well known to the person skilled in the art, and various useful methods are described in standard reference volumes such as in Greene, "Protective Groups in Organic Synthesis" (published by Wiley-lnterscience).

SCHEME V H (a) BnCI, K2CO3 > acetone; (b) LIAIH4, THF; (c) Swern oxidation; (d) Ph3P = CHCO2CH3, THF; (e) H2, Pd / C, MeOH; (f) 6- (methylamino) -2-pyridylethanoI, DIAD, (Ph) 3P, THF; (g) LiOH, THF, H2O, then acidification.

The phenol group of commercially available methyl 4-hydroxyphenylacetate (V-1) is protected with a suitable protecting group, for example a methyl ether, a benzyl ether or a triisopropylsilyl ether. The protection of phenols is well known to those skilled in the art and representative protective groups are described in standard reference volumes such as Greene's, "Protective Groups in Organic Synthesis" (published by Wiley-Interscience). The ester group of V-2 is reduced to the corresponding primary alcohol using lithium aluminum hydride. There are many other methods for the reduction of carboxylic acids and esters to alcohols, and are described in standard reference volumes such as "Compendium of Organic Synthetic Methods" (published by Wiley-lnterscience). The alcohol in V-3 is oxidized to the corresponding aldehyde using the well-known conditions of Swern (J. Org. Chem., 1978, 43, 2480). There are many other methods for the oxidation of alcohols to aldehydes, and are described in standard reference volumes such as "Compendium of Organic Synthetic Methods" (Compendium of Organic Synthetic Methods) (published by Wiley-lnterscience). The aldehyde V-4 is converted to the α, β-unsaturated ester V-5 by the well-known Wittig reaction. Optimally, the reaction is carried out using (carbomethoxymethylene) triphenylphosphorane in an aprotic polar solvent such as DMSO, THF or mixtures thereof. The reduction of the olefin group of V-5 is optimally performed by hydrogenation in the presence of a palladium catalyst, for example palladium on activated carbon, in a suitable solvent such as EtOAc, MeOH, EtOH, i-PrOH, or mixtures thereof. If a benzyl ether is used to protect the phenol group, it is simultaneously removed to release the free phenol. If another protective group is used, the appropriate conditions are used for its removal. For example, if a methyl ether is used, it can be separated with ethanethiol (EtSH) and aluminum trichloride (AICI3), as described in Scheme I, or with boron tribromide (BBr3) in an inert solvent, preferably CH2Cl2 . Alternatively, if a triisopropylsilyl group is used, it can be separated using for example tetrabutylammonium fluoride in a neutral solvent such as THF. Other useful methods for the removal of phenolic protective groups are described in Greene, "Protective Groups in Organic Synthesis" (published by Wiley-lnterscience). The resulting phenol V-6 is reacted with 6- (methylamino) -2-pyridylethanol in a coupling reaction of Mitsunobu type (Organic Reactions, 1992, 42, 335-656; Synthesis, 1981, 1-28) to produce V-7. The reaction is mediated by the complex formed between an azodicarboxylate diester such as diethyl azodicarboxylate or diisopropyl azodicarboxylate, and triphenylphosphine, and is carried out in an aprotic solvent, for example THF, CH2Cl2 or DMF. Subsequently, V-7 is converted into V-8 according to the protocol described in scheme III.

SCHEME VI (a) (vinyl) MgBr, CuBrDMS, 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 with a cuprate reagent to effect a conjugate addition reaction. For example, the reaction of VI-1 with the cuprate reagent derived from vinylmagnesium bromide and the copper bromide (l) -dimethyl sulfoxide complex, in an aprotic solvent such as EÍ2O or THF, gives the conjugate addition product VI -2. Many procedures have been reported for the formation and conjugate addition reactions of a broad set of cuprate and organocopper reagents, and several excellent reviews have been published (see, for example, Posner, Organic Reactions, 1972, 19, 1-1 13 Lipshutz and Sengupta, Organic Reactions, 1992, 41, 135-631). The triisopropylsilyl group of VI-2 is removed as described in the scheme • V, and the resulting phenol VI-3 is converted to VI-4 according to the methods described in scheme V.

SCHEME VII twenty (a) PhOH, Cu, K2CO3; (b) sulfur, morpholine; (c) KOH, H2O, -PrOH; (d) LiAIH4, THF; (e) Swern oxidation; (f) Ph3P = CHC02CH3, THF; (g) H2, Pd / C, MeOH; (h) BBr3, CH2Cl2, (i) 6- (methylamino) -2-pyridylethanol, DEAD, (Ph) 3P, CH2Cl2; 0) 1.0 N NaOH, MeOH, then acidification.

The commercially available 2-fluoro-4-methoxyacetophenone (VII-1) reacts with an alcohol, for example phenol, in the presence of copper metal and a suitable base, for example K2CO3, to produce the diaryl ether VII-2. By treatment with sulfur and an appropriate primary or secondary amine, preferably morpholine, according to the Harris general method (J. Med. Chem., 1982, 25, 855), VII-2 is converted to VII-3 in a classic reaction of Willgerodt-Kindler. The thioamide thus obtained is hydrolyzed to the corresponding carboxylic acid VI by reaction with an alkali metal hydroxide, conveniently KOH, in an aqueous alcoholic solvent such as aqueous MeOH, EtOH or i-PrOH. Subsequently, it is converted to VII-4 in 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, then acidification; (c) SOCI2; (d) CH2N2, Et2O; (e) AgOBz, MeOH; (f) BBr3, CH2Cl2; (g) 6- (N-Boc-N-methylamino) -2-pyridylethanol, DEAD, (Ph) 3P, CH2Cl2; (h) HCl / dioxane; (i) 1.0 N NaOH, MeOH, then acidification.

Methyl ester of 2-thiophenacetic acid (VIII-1) is deprotonated with a suitable base, generally an alkali metal amide such as LDA or lithium bis (trimethylsilyl) amide and, without isolation, the intermediate enolate ester is reacted with a halide of suitable benzyl, for example 4-methoxybenzyl chloride, to produce the alkylation product VIII-2. A polar aprotic solvent such as THF or THF in the presence of various additives, for example HMPA or TMEDA, is generally preferred for this reaction. The methyl ester of VIII-2 is hydrolyzed using an aqueous base, for example LiOH in aqueous THF or NaOH in MeOH or aqueous EtOH, and the intermediate carboxylate salt is acidified with a suitable acid, for example TFA or HCl, to produce the carboxylic acid VIII-3. This is converted to an activated form of the carboxylic acid using for example SOCI2, and the activated form is subsequently reacted with diazomethane in a suitable solvent such as Et20 or a mixture of Et 0 and CH 2 Cl 2, to produce the diazoketone VIII-4. By treatment with a suitable silver salt, for example silver benzoate or silver triflate, in an alcohol solvent, generally MeOH or EtOH, VIII-4 undergoes a classical Arndt-Eistert reaction to produce the ester VIII-5. The deprotection of the methyl ether according to the general conditions described in scheme V, gives VIII-6, which is converted to VIII-7 by reaction with 6- (N-Boc-N-methylamino) -2-pyridylethanol in a reaction of Mitsunobu according to the conditions described in scheme V. The tert-butoxycarbonyl group of VIII-7 is removed under acidic conditions, such as 4 M HCl in 1,4-dioxane or TFA in CH 2 Cl 2, to produce VHI-8. The conditions for the deprotection of tert-butyl carbamates are well known to those skilled in the art, and several useful methods are described in standard reference volumes such as Greene's, "Protective Groups in Organic Synthesis". Saponification in accordance with the general methods described in scheme III, produces VIII-9.

SCHEME IX (a) 4-methoxybenzylmagnesium chloride, Cul, TMEDA, TMSCI, THF; (b) BBr3, CH2Cl2; (c) 6- (N-Boc-N-methylamino) -2-pyridylethanol, DIAD, (Ph) 3P, CH2Cl2; (d) 4 N HCl / dioxane; (e) 1.0 N NaOH, EtOH, then acidification. • A suitable derivative of acrylic acid, for example ethyl 4-bromocinamate (IX-1), is converted to its IX-2 derivative by reaction with selected benzyl cuprate reagents, according to the general method of Van Heerden (Tetrahedron 1996 , 52, 12313). As described in scheme VI, many additional procedures have been reported for the reactions of formation and conjugate addition of a large set of cuprate and organocopper reagents. Then, the addition product IX-2 is converted to IX-5 by means of the general protocol described in Scheme VIII.

SCHEME X ,, CH2Cl2; (d) 6 N HCl, THF; (e) 12, PPh 3, Et 3 N, CH 2 Cl 2; (f) BBr3, CH2Cl2; (g) 6- (methylamino) -2-pyridylethanol, DIAD, (Ph) 3P, THF; (h) LiOH, THF, H20, then acidification.

A suitable haloaromatic derivative, for example 4-bromoanisole (X-1), reacts with methyl 3- (benzyloxycarbonyl) -3-butenoate in a Heck reaction (see Heck, Org Reactions, 1982, 27, 345) to produce X-2. The reaction is mediated by a palladium (0) species and is generally carried out in an inert solvent such as CH3CN, propionitrile or toluene, in the presence of an appropriate acid scavenger such as triethylamine (Et3N) or diisopropylethylamine ((-Pr ^ NEt). Typical sources of palladium (0) species include palladium (II) acetate (Pd (OAc) 2) and palladium (II) chloride (PdC), and phosphine ligands are often included, example triphenylphosphine (PPh3) or tri-ortho-tolylphosphine (P (tol) 3) The ester, -unsaturated X-2 is reduced to the saturated compound X-3 by reaction with hydrogen gas in the presence of a suitable catalyst, preferably metal palladium on activated carbon (Pd / C), in an inert solvent, generally MeOH, EtOH, EtOAc, or mixtures thereof. The benzyl ester in X-2 decomposes simultaneously under these conditions to release the corresponding carboxylic acid. The carboxylic acid of X-3 is converted to an activated form using for example EDC and HOBt, SOCI2 or 1, 1'-carbonyldiimidazole (CDI), and the activated form is subsequently reacted with an appropriate amine, for example aminoacetaldehyde dimethylacetal, in a • inert solvent such as CH2CI2, to produce X-4. Depending on whether acid neutralization is required, an added base such as triethylamine (Et3N), diisopropylethylamine ((i-Pr) 2NEt), or pyridine can be used. HE Many other methods are known to convert a carboxylic acid into an amide, and can be found in standard reference books such as the "Compendium of Organic Synthetic Methods", Vol. I-VI (published by Wiley-Interscience), or Bodansky, "The Practice of Peptide Synthesis" (published by Springer-Verlag). The dimethylacetal of X-4 is decomposed in the corresponding aldehyde (X-5) under acidic conditions, preferably with hydrochloric acid in THF or dioxane. Other methods for converting a dimethylacetal to an aldehyde are described in standard reference volumes, such as Green's, "Protective Groups in Organic Synthesis" (published by Wiley-lnterscience). Amidoaldehyde X-5 is cyclized to oxazole X-6 according to the methodology of Rovnyak (J. Med. Chem., 1997, 40, 24-34). Then, X-6 is converted to X-7 according to the protocol described in scheme V. 10 SCHEME XI (a) BnCl, K2C03, acetone; (b) (CH30) NHCH3? CI, AICI3, toluene; (c) 2-bromopyridine, ter-BuLi, THF; (d) (EtO) 2P (0) CH2C02Et, NaH, THF; (e) H2, Pd / C, EtOH; (f) 6- (methylamino) -2-pyridylethanol, DIAD, (Ph) 3P, THF; (g) LiOH, THF, H2O, then acidification.

The phenol group of methyl 4-hydroxyphenylacetate (XI-1), commercially available, is protected as its benzyl ether as described in Scheme V. The resulting compound (XI-2) reacts with N-hydrochloride., O-dimethylhydroxylamine in the presence of AICI3 in an inert solvent, preferably toluene, according to the general method of Weinreb (Synth Commun., 1982, 12, 989), to produce XI-3. This compound reacts with suitable Grignard or organolithium reagents to produce ketones according to the general procedure of Weinreb (Tet. Lett., 1981, 22, 3815). For example, 2-lithiopyridine, prepared from 2-bromopyridine and tert-butyllithium, reacts with XI-3 in an ethereal solvent such as THF or DME, to produce the ketone derivative XI-4. This ketone reacts in a Wittig type reaction with triethyl phosphonoacetate in the presence of a suitable base, for example LiN (TMS) or NaH, in a polar aprotic solvent, preferably THF, to produce the ester, β-unsaturated XI-5. As described in scheme V, the hydrogenation of XI-5 reduces the olefin and simultaneously removes the benzyl ether to produce XI-6. This compound is then converted to XI-7 by means of the protocol described in scheme V.

SCHEME XII (a) NaH, 4-methoxybenzyl chloride, DMF; (b) BBr3, CH2Cl2; (c) 6- (N-Boc-N-methylamino) -2-pyridylethanol, DIAD, (Ph) 3 P, CH 2 Cl 2; (d) 4N HCl / dioxane; (e) 1.0 N NaOH, EtOH, then acidification.

A suitably N-functionalized amino acid derivative, for example N-phenylglycine (XII-1), is reacted with an appropriately functionalized benzyl halide, for example 4-methoxybenzyl chloride, to produce XII-2. The reaction is mediated by a base such as NaH or LiN (TMS) 2, and is carried out in an aprotic polar solvent, generally THF, DMF or mixtures thereof. The product XII-2 is subsequently converted to XII-5 according to the protocol described in scheme VIII.

SCHEME XIII (a) glycine methyl ester hydrochloride, NaBH 3 CN, 3 A sieves, MeOH; (b) '6- (N-Boc-N-methylamino) -2-pyridylethanol, DIAD, (Ph) 3P, CH2Cl2; (c) 4 N HCl / dioxane; (d) 1.0 N NaOH, MeOH, THF, then acidification.

A suitably functionalized aromatic aldehyde, such as 4-hydroxy-2-methoxybenzaldehyde (XIII-1), is reacted with an amino acid derivative, for example glycine methyl ester hydrochloride, under reductive amination conditions, to produce XIII-2 . Reductive amination involves the reaction of an aldehyde or ketone with an amine in the presence of a suitable reducing agent, generally 5% cyanoborohydride. sodium (NaBH3CN) or sodium triacetoxyborohydride (NaB (OAc) 3H), often in the presence of an acid catalyst, usually acetic acid or hydrochloric acid. The reaction proceeds through an intermediate imine that reacts in situ with the reducing agent to produce the amine. Alternatively, the imine can be prepared as a discrete entity and can be reduced in a subsequent step. Typical solvents for this reaction include CH2Cl2, DMF or an alcohol such as MeOH or EtOH. A dehydrating reagent such as molecular sieve, MgSO4 or trimethyl orthoformate can be used to react with the water released during the reaction. Subsequently, the product XIII-2 is converted to XIII-4 according to the protocol described in scheme VIII.

SCHEME XIV (a) Triisopropylsilyl chloride, imidazole, DMF; (b) methyl 3- (benzyloxycarbonyl) -3-butenoate, Pd (OAc) 2, P (tol) 3, (i-Pr) 2NEt, propionitrile; (c) H2, Pd 10% / C, i-PrOH, EtOAc; (d) serine benzyl ester, EDC, HOBt? 20, Et3N, • DMF; (e) Burgess reagent, THF; (f) CI3CBr, DBU, CH2Cl2; (g) TBAF, THF; (h) 6- (methylamino) -2-pyridylethanol, DIAD, (Ph) 3P, THF; (i) LiOH, THF, H20, then acidification.

A haiophenol derivative, for example 4-bromophenol (XIV-1), is converted to a suitably protected derivative, for example 4-bromo-1-10 (triisopropylsilyloxy) benzene (XIV-2). The protective group for phenol must be compatible with the subsequent chemistry, and must also be capable of being selectively removed at the desired time. Methods for the protection of phenols are described in standard reference volumes such as Green's "Protective Groups in Organic Synthesis" (published by Wiley-lnterscience). X1V-2 is converted to XIV-4 and subsequently to XIV-5 according to the general methods described in Scheme X. Next, XIV-5 is converted to the oxazole derivative XIV-7. Various methods are known for the conversion 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 converted first to the oxazoline XIV-6. This transformation is generally carried out under dehydrating conditions, such as those of the reaction with the Burgess reagent in THF. The oxazoline XIV-6 is then oxidized to oxazole XIV-7 using, for example, bromotrichloromethane and DBU in CH CI2 (Williams, Tetrahedron Letters, 1997, 38, 331-334) or CuBr2 and DBU in a suitable solvent such as EtOAc / CHC or CH2Cl2 (Barrish, J. Org. Chem., 1993, 58, 4494-4496). The • Removal of the silyl protecting group produces the phenol XIV-8, which is converted to XIV-10 as described in scheme V.

SCHEME XV twenty (a) H2, Pd 10% / C, EtOH; (b) Me2NH HCI, EDC, HOBt H20, Et3N, DMF; (c) LiOH, THF, H20, then acidification.

Compound XV-1, prepared as described in Scheme XIV, is converted to the carboxylic acid derivative XV-2 by hydrogenation in the presence of a suitable catalyst, preferably palladium on activated carbon (Pd / C) metal, in a inert solvent, generally MeOH, EtOH, EtOAc, or mixtures thereof. XV-2 is converted to the amide derivative XV-3 according to the general methods described in Scheme X for the formation of amides from carboxylic acids. The saponification as described in scheme V gives XV-4.

SCHEME XVI (a) (COCI) 2, DMF, CH2Cl2; (b) (Ph3P) 2CuBH4, (Ph) 3P, acetone; (c) dimethyl 1-diazo-2-oxopropylphosphonate, K2CO3, MeOH, BBr3, CH2Cl2; (d) 6- (N-Boc-N-methylamino) -2-pyridylethanol, DEAD, (Ph) 3P, CH2Cl2; (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 the aldehyde derivative XVI-2, preferably by the method of Fleet and Harding (Tet. Lett., 19J9, 11, 975-978). This method includes the initial conversion of the carboxylic acid portion of XVI-1 into the corresponding acid chloride under standard conditions well known to those skilled in the art, followed by reduction to the aldehyde using (Ph3P) 2CuBH4. Other methods are known for the selective conversion of a carboxylic acid to an aldehyde in the presence of a carboxylic ester, and can be found in standard reference volumes, such as the "Compendium of Organic Synthetic Methods" (published by Wiley-Interscience). The aldehyde XVI-2 is subsequently converted to the acetylene derivative XVI-3 by the method of Muller et al. (Syn. Lett., 1996, 521-522). In this manner, XVI-2 is reacted with dimethyl 1-diazo-2-oxopropylphosphonate in the presence of a suitable base, generally K 2 C 3, in an appropriate solvent such as methanol. Additional methods for the conversion of an aldehyde into an acetylene are known, and can be found in standard reference volumes such as the "Compendium of Organic Synthetic Methods" (published by Wiley-Interscience). The product XVI-3 is subsequently converted to XVI-5 according to the general protocol described in scheme VIII. Amide coupling reagents, as used herein, denote reagents that can be used to form peptide bonds. Typical coupling methods employ carbodiimides, anhydrides and activated esters and acyl halides. Reagents such as EDC are typical DCC, DPPA, BOP reagent, HOBt, N-hydroxysuccinimide and oxalyl chloride. Coupling methods for forming peptide bonds are generally well known in the art. In general, the peptide synthesis methods outlined in general terms by Bodansky and others are illustrative in THE PRACTICE OF PEPTIDE SYNTHESIS - Peptide Synthesis Practice -, Springer-Verlag, Berlin, 1984, Ali and others in J. Med. Chem., 29, 984 (1986) and J. Med. Chem., 30, 2291 (1987), and are incorporated herein by reference. Typically, the amine or aniline is coupled via its free amino group with a suitable carboxylic acid substrate using a suitable carbodiimide coupling agent, such as N, N'-dichlohexylcarbodiimide (DCC), optionally in the presence of catalysts such as 1-hydroxybenzotriazole (HOBt) and dimethylaminopyridine (DMAP). Other methods are also suitable such as the formation of activated esters, anhydrides or halides of acid, of the free carboxyl of a suitably protected acid substrate, and subsequent reaction with the free amine of a suitably protected amine, optionally in the presence of a base.

For examplea protected Boc-amino acid or Cbz-protected amidinobenzoic acid is treated with isobutyl chloroformate in an inert solvent such as methylene chloride or tetrahydrofuran (THF), in the presence of a base such as N-methylmorpholine, DMAP or a trialkylamine, for forming the "activated anhydride", which is subsequently reacted with the free amine of a second protected amino acid or aniline. Useful intermediates for the preparation of compounds of formula (I) wherein R 2 is a benzimidazole are described in Nestor et al., J. Med. Chem., 1984, 27, 320. Representative methods are also common in the art. preparing benzimidazole compounds useful as intermediates in the present invention, and can be found, for example, in EP-A-0 381 033. The acid addition salts of the compounds are prepared in a normal manner in a suitable solvent starting from the original compound and an excess of acid such as hydrochloric, hydrobromic, hydrofluoric, sulfuric, phosphoric, acetic, trifluoroacetic, maleic, succinic or methanesulfonic. Some of the compounds form internal salts or zwitterions that may be acceptable. The cationic salts are prepared by treating the original compound with an excess of an alkaline reagent such as a hydroxide, carbonate or alkoxide, containing the appropriate cation; or with an appropriate organic amine. Cations such as Li +, Na +, K +, Ca ++, Mg ++ and NH +, are specific examples of cations present in pharmaceutically acceptable salts.

This invention also provides a pharmaceutical composition comprising a compound according to formula (I) and a pharmaceutically acceptable carrier. Therefore, the compounds of formula (I) can be used in the manufacture of a medicament. The pharmaceutical compositions of the compounds of formula (I) prepared as described hereinabove can be formulated as lyophilized solutions or powders for parenteral administration. The powders can be reconstituted before use by the addition of a suitable diluent or other pharmaceutically acceptable carrier. The liquid formulation can be an isotonic buffered aqueous solution. Examples of suitable diluents are saline solution, standard solution of 5% dextrose in water or buffered sodium or ammonium acetate solution. Said formulation is especially suitable for parenteral administration, but it can also be used for oral administration or dosages for insufflation can be packaged in an inhaler or nebulizer. It may be convenient to add excipients such as polyvinylpyrrolidone, gelatin, hydroxycellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate. Alternatively, these compounds can be encapsulated, tableted or prepared in an emulsion or syrup for oral administration. Pharmaceutically acceptable solid or liquid carriers can be added to improve or stabilize the composition, or to facilitate the preparation of the composition. Solid carriers include starch, lactose, calcium sulfate dihydrate, gypsum, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin. Liquid vehicles include syrup, peanut oil, olive oil, saline and water. The vehicle can also include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The amount of solid carrier varies, but will preferably be between about 20 mg to about 1 g per unit dose. The pharmaceutical preparations are made following conventional pharmacy techniques, including grinding, mixing, granulation and compression, when necessary, for tablet forms; or grinding, mixing and filling for hard gelatin capsule forms. When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension. Said liquid formulation can be administered directly orally or it can be supplied in a soft gelatin capsule. For rectal administration, the compounds of this invention can also be combined with excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols, and molded into the form of a suppository. The compounds described herein are antagonists of the vitronectin receptor and are useful for treating diseases in which the fundamental pathology is attributable to the ligand or cell that interacts with the vitronectin receptor. For example, these compounds are useful for the treatment of diseases in which the loss of bone matrix creates a pathology. Thus, the present compounds are useful for the treatment of osteoporosis, hyperparathyroidism, Paget's disease, hypercalcemia or malignancy, osteolytic lesions caused by bone metastasis, bone loss due to immobilization or sexual hormone deficiency. As well • it is considered that the compounds of this invention have utility as antitumor, antiangiogenic, anti-inflammatory and antimetastatic agents, and may be useful in the treatment of atherosclerosis and restenosis. The compound is administered to the patient either orally or parenterally such that the concentration of drug is sufficient to inhibit bone resorption, or other such indication. The pharmaceutical composition containing the compound is administered in an oral dose of between about 0.1 and about 50 mg / kg in a manner consistent with the condition of the patient. Preferably, the oral dose would be from about 0.5 to about 20 mg / kg. For acute therapy, parenteral administration is preferred. It is more effective intravenous infusion of the peptide in 5% dextrose in water or in normal saline, or a similar formulation with suitable excipients; however, an intramuscular bolus injection is also useful. Typically, the parenteral dose will be from about 0.01 to about 100 mg / kg, preferably between 0.1 and 20 mg / kg. The compounds are administered one to four times a day at a level sufficient to achieve a total daily dose of about 0.4 to about 400 mg / kg / day. The precise level and method in which the compounds are administered can be readily determined by a person skilled in the art by comparing the blood level of the agent with the concentration required to have a therapeutic effect. This invention also provides a method for treating osteoporosis or inhibiting bone loss, comprising administering by step 5 or in physical combination a compound of formula (I) and other bone resorption inhibitors, such as bisphosphonates (ie, alendronate) , hormone replacement therapy, antiestrogen or calcitonin. In addition, this invention provides a method of treatment useful in the prevention of bone loss and / or to increase bone mass, using a compound of this invention and • an anabolic agent such as bone morphogenic protein or iproflavone. In addition, this invention provides a method of inhibiting tumor growth which comprises administering in step or in physical combination a compound of formula (I) and an antineoplastic agent. Compounds of the class of camptothecin analogs, such as topotecan, irinotecan and 9-aminocamptothecin, and platinum coordination complexes such as cisplatin, ormaplatin, and tetraplatin, are well-known groups of • antineoplastic agents. Compounds of the class of camptothecin analogs are described in the U.S. Patents. Nos. 5,004,758, 4,604,463, 4,473,692, 4,545,880, 4,342,776, 4,513,138, 4,399,276, the patent application publications EP 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, 1774. , and Nitta et al., Proc. 14th International Congr. Chemotherapy, 1985, Anticancer Section 1, 28, the complete descriptions of which are incorporated herein by reference. The platinum coordination complex, cisplatin, is available under the brand name Platinol® from Bristol Myers-Squibb Corporation. They describe • Useful formulations for cisplatin in the patents of E.U.A. Nos. 5,562,925 5 and 4,310,515, the complete descriptions of which are incorporated herein by reference. In the tumor growth inhibition method comprising administering in step or in physical combination a compound of formula (I) and an antineoplastic agent, the compound of • the coordination of platinum, for example cisplatin, using slow intravenous infusion. The preferred vehicle is a dextrose / saline solution containing mannitol. The dose regimen of the platinum coordination compound may be on the basis of about 1 to about 500 mg per square meter (mg / m2) of body surface area per course of treatment. Infusions of the platinum coordination compound can be given once or twice a week and weekly treatments are • can repeat several times. Using a compound of the class of camptothecin analogs in a parenteral administration, the course of therapy employed is generally from about 0.1 to about 300.0 mg / m2 body surface area per day for approximately five consecutive days. Preferably, the course of therapy employed for topotecan is from about 1.0 to about 2.0 mg / m2 of body surface area per day for approximately five consecutive days. Preferably, the course of the therapy is repeated at least once in a range of from about seven days to about twenty-eight days. The pharmaceutical composition can be formulated with the compound of formula (I) and the antineoplastic agent in the same container; however, the formulation in different containers is preferred. When both agents are provided in solution form, they can be contained in an infusion / injection system for simultaneous administration or in a tandem arrangement. For the convenient administration of the compound of formula (I) and the antineoplastic agent at the same time or at different times, an equipment is prepared comprising, in a single container such as a box, cardboard or other container, bottles, bags, flasks or other individual containers each having an effective amount of the compound of formula (I) for parenteral administration as described above, and an effective amount of the antineoplastic agent for parenteral administration as described above. Said equipment may comprise, for example, both pharmaceutical agents in separate containers or in the same container, optionally as lyophilized tablets, and containers of solutions for reconstitution. A variation of this is to include the solution for reconstitution and the lyophilized tablet in two chambers of a single container, which can be made to mix before use. With such an arrangement the antineoplastic agent and the compound of this invention can be packaged separately, as in two containers, or they can be lyophilized together as a powder and provided in a single container. When both agents are provided in solution form, they can be contained in an infusion / injection system for simultaneous administration or in a tandem arrangement. For example, the compound of formula (I) can be in an injectable form i.v., or infusion bag attached in series, by tubing, to the antineoplastic agent in a second infusion bag. Using such a system, a patient may receive a bolus injection or initial infusion of the compound of formula (I), followed by an infusion of the antineoplastic agent. To determine the concentration of compound that is required to obtain a given pharmacological effect, the compounds can be tested in one of several biological assays.

Inhibition of vitronectin binding Union of [3H] -SK &F-107260 aaz in solid phase: Avβ3 of human placenta or human platelets (0.1-0.3 mg / ml) was diluted in buffer T (containing 2 mM CaC and 1% octylglucoside), with T buffer containing 1 mM CaCl, 1 mM MnCl 2, 1 mM MgCl 2 (buffer A) and 0.05% NaN 3, and then immediately added to 96-well ELISA plates (Corning, New York, New York) at 0.1 ml per well. 0.1 - 0.2 μg of avß3 was added per well. The plates were incubated overnight at 4 ° C. At the time of the experiment, the wells were washed once with buffer A and incubated with 0.1 ml of 3.5% bovine serum albumin in the same buffer for 1 hour at room temperature. After the incubation, the wells were completely aspirated and washed twice with 0.2 ml of buffer A. The compounds were dissolved in 100% DMSO to give a 2 mM supply solution, which was diluted with binding buffer (Tris. 15 mM HCl (pH 7.4), 100 mM NaCl, 1 mM CaCl 2, 1 mM MnCl 2, 1 mM MgCl 2) to a final compound concentration of 100 μM. This solution was then diluted to the required final concentration of the compound. Several concentrations of unlabeled antagonists (0.001-100 μM) in triplicate were added to the wells, followed by the addition of 5.0 nM of [3 H] -SK &F-107260 (65-86 Ci / mmol). The plates were incubated for 1 hour at room temperature. After incubation the wells were completely aspirated and washed once with 0.2 ml of cold buffer A as ice, from well to well. The receptors were solubilized with 0.1 ml of SDS 1%, and the [3H] -SK &F-107260 ligated was determined by liquid scintillation counting with the addition of 3 ml of Ready Safe in a liquid scintillation counter Beckman LS , with 40% efficiency. The non-specific binding of [3 H] -SK &F-107260 was determined in the presence of 2 μM SK & F-107260, and was consistently less than 1% of the total radioligand input. The IC50 (concentration of the antagonist to inhibit 50% binding of [3H] -SK &F-107260) was determined by means of a least squares non-linear curve fitting routine that was modified from the LUNDON-2 program. The K, (antagonist dissociation constant) was calculated according to the equation: K, = IC50 / (1 + L / Kd), where L and Kd were the concentration and the constant of • dissociation of [3 H] -SK &F-107260, respectively. The compounds of the present invention inhibited the binding of vitronectin with SK &F-107260 in a concentration range of about 10 to about 0.01 micromolar. The compounds of this invention can also be tested in vitro and in vivo to determine bone resorption in standard assays of the art to evaluate the inhibition of bone formation, such as the pit formation test described in the document. EP 528 587, which can also be made using human osteoclasts instead of rat osteoclasts, and the ovariectomized rat model described by Wronski et al., Cells and Materials, 1991, Sup. 1, 69-74. 15 Migration test of vascular smooth muscle cells Rat or human aortic smooth muscle cells were used. Cell migration was monitored in a Transwell cell culture chamber using a polycarbonate membrane with pores of 8 μm (Costar). The lower surface of the filter was coated with vitronectin. The cells were suspended in DMEM supplemented with 0.2% bovine serum albumin at a concentration of 2.5 - 5.0 x 10 6 cells / ml, and pretreated with the test compound at various concentrations for 20 minutes at 20 ° C. It was used as a solvent control alone. 0.2 ml of the cell suspension was placed in the upper compartment of the chamber. The lower compartment contained 0.6 ml of DMEM supplemented with 0.2% bovine serum albumin. It was incubated at 37 ° C in a 95% air / C02 5% atmosphere for 24 hours. After incubation, the cells that did not migrate were gently scraped off the upper surface of the filter. The filter was then fixed in methanol and stained with 10% Giemsa stain. The emigration was measured a) by counting the number of cells that had migrated to the lower surface of the filter, or b) extracting the stained cells with 10% acetic acid followed by the determination of the absorbance at 600 nm.

Model of thyroparathyroidectomized rat Each experimental group consists of 5-6 adult male Sprague-Dawley rats (250-400 g of body weight). The rats are thyroparathyroidectomized 7 days before use (by the seller, Taconic Farms). All rats receive a thyroxine replacement dose every 3 days. Upon receiving the rats, the levels of circulating ionized calcium in whole blood are measured immediately after being extracted by venipuncture of the tail in heparinized tubes. Rats with an ionized Ca level (measured with calcium pH analyzer Ciba-Corning model 634) < 1.2 mM / l. Each rat is conditioned with an internal venous and arterial catheter for the release of test material and for blood sampling, respectively. Afterwards, the rats are placed on a diet of calcium-free food and deionized water. The basal levels of Ca are measured and each rat is administered control vehicle or peptide 1-34 of human parathyroid hormone (hPTH1-34, dose of 1.25 g / kg / h in solution • saline / bovine serum albumin 0.1%, Bachem, Ca) or a mixture of hPTH1-34 and test material, by continuous intravenous infusion through the venous catheter, using an external syringe pump. The calcemic response of each rat is measured at two-hour intervals during the infusion period of 6-8 hours. io Human osteoclast resorption and adhesion tests Hoop resorption and adhesion tests have been developed and standardized using normal human osteoclasts derived from osteoclastoma tissue. Test 1 was developed for the measurement of osteoclast hole volumes by means of confocal laser microscopy. HE developed test 2 as a higher performance screen in which fragments of collagen (released during resorption) were measured by competitive ELISA.

Test 1 (using confocal laser microscopy) 20 • Aliquots of cell suspensions derived from human osteoclastoma were removed from storage in liquid nitrogen; they were rapidly heated to 37 ° C and washed 1x in RPMI-1640 medium by centrifugation (1000 rpm, 5 minutes at 4 ° C). • The medium was aspirated and replaced with murine anti-HLA- • DR antibody; then it was diluted 1: 3 in RPMI-1640 medium. The suspension was incubated for 30 minutes on ice and mixed frequently. • The cells were washed x2 with cold RPMI-1640, followed by centrifugation (1000 rpm, 5 minutes at 4 ° C), and the cells were then transferred to a sterile 15 ml centrifuge tube. The number of mononuclear cells was counted in an improved Neubauer counting chamber. • sufficient magnetic beads (5 / mononuclear cell), coated with goat anti-IgG (Dynal, Great Neck, New York), were removed from their supply container, and were placed in 5 ml of new medium (this washes the toxic preservative of azide). The medium was removed by immobilizing the globules on a magnet and replaced with fresh medium. • The blood cells were mixed with the cells and the suspension for 30 minutes on ice. The suspension was mixed frequently. • The cells that coated the beads were immobilized on a magnet, and the remaining cells (osteoclast-rich fraction) were decanted into a sterile 50 ml centrifuge tube. • New medium was added to the cells that coated the blood cells to dislodge any trapped osteoclasts. This washing procedure was repeated x 10. The cells coating the beads were discarded. • Viable osteoclasts were counted in a counting chamber using fluorescein diacetate to label living cells. A plastic Pasteur pipette was used • 10 large-bore disposable to add the sample to the camera. • The osteoclasts were pelleted by means of centrifugation and the density was adjusted to the appropriate value in EMEM medium (the number of osteoclasts is variable tumor to tumor), supplemented with 10% fetal calf serum and 1.7 g / liter of sodium bicarbonate. • 3 ml aliquots of the cell suspension (by treatment compound) were decanted into 15 ml centrifuge tubes. The cells were pelleted by centrifugation.

• To each tube was added 3 ml of the appropriate treatment compound (diluted to 50 uM in the EMEM medium). Appropriate vehicle controls were also included, a positive control (murine vitronectin anti-receptor monoclonal antibody [87MEM1] diluted at 100 ug / ml) and an isotype control (IgG2a diluted at 100 ug / ml). The samples were incubated at 37 ° C for 30 minutes. • 0.5 ml aliquots of the cells were seeded onto pieces of sterile dentin in a 48-well plate and incubated at 37 ° C for 2 hours. Each treatment was screened in quadruplicate. • The pieces were washed in six changes of hot PBS (10 ml / well in a 6-well plate) and then placed in The new medium containing the treatment compound or control samples. The samples were incubated at 37 ° C for 48 hours.

Tartrate-resistant acid phosphatase (TRAP) procedure (selective staining for osteoclast lineage cells) • The pieces of bone containing the adhered osteoclasts were washed in phosphate buffered saline and fixed in 2% glutaraldehyde (in cacodylate sodium 0.2 M) for 5 minutes. • They were then washed in water and incubated for 4 minutes in TRAP buffer at 37 ° C (0.5 mg / ml naphthol phosphate AS-B1 dissolved in N, N-dimethylformamide) and mixed with 0.25 M citrate buffer (pH 4.5) containing 10 mM sodium tartrate. • After washing in cold water, the pieces will be • submerged in cold acetate buffer (0.1 M, pH 6.2) containing 1 mg / ml of fast red garnet and incubated at 4 ° C for 4 minutes. • The excess cushion was sucked and the pieces were air dried after a wash with water. • Positive TRAP osteoclasts (red brick / purple precipitate) were counted by bright field microscopy and then removed from the surface of the dentin by sonication. • The void volumes were determined using the Nikon / Lasertec ILM21W confocal microscope. 15 Test 2 (using ELISA reading) The human osteoclasts were enriched and prepared for compound selection as described in the initial 9 steps of test 1. For clarity, these steps are repeated here. 20 • Aliquots of suspensions of cells derived from human osteoclastoma were removed from storage in liquid nitrogen; they were rapidly heated to 37 ° C and washed x1 in RPMI-1640 medium by centrifugation (1000 rpm, 5 minutes at 4 ° C). • The medium was aspirated and replaced with murine anti-HLA- • DR antibody; then it was diluted 1: 3 in RPMI-1640 medium. The suspension was incubated for 30 minutes on ice and mixed frequently. • The cells were washed x2 with cold RPMI-1640, followed by centrifugation (1000 rpm, 5 minutes at 4 ° C), and the cells were then transferred to a sterile 15 ml centrifuge tube. The number of mononuclear cells was counted in an improved Neubauer counting chamber. • sufficient magnetic beads (5 / mononuclear cell), coated with goat anti-IgG (Dynal, Great Neck, New York), were removed from their supply container, and were placed in 5 ml of fresh medium (this washes the toxic azide preservative). The medium was removed by immobilizing the globules on a magnet and replaced with fresh medium. • The globules were mixed with the cells and the suspension was incubated for 30 minutes on ice. The suspension was mixed frequently. • The cells that coated the beads were immobilized on a magnet, and the remaining cells (osteoclast-rich fraction) were decanted into a sterile 50 ml centrifuge tube. • New media was added to the cells that coated the blood cells to dislodge any trapped osteoclasts. This washing procedure was repeated x 10. The cells coating the beads were discarded. • Viable osteoclasts were counted in a counting chamber using fluorescein diacetate to label living cells. A large-size disposable plastic Pasteur pipette was used to add the sample to the chamber. • Osteoclasts were pelleted by centrifugation and the density was adjusted to the appropriate value in EMEM medium (the number of osteoclasts is variable from tumor to tumor), supplemented with 10% fetal calf serum and 1.7 g / liter of bicarbonate of sodium.

In contrast to the method described above in test 1, the compounds are screened at 4 doses as indicated below, to obtain an IC50: • The osteoclast preparations were preincubated for 30 minutes at 37 ° C with the test compound (4 doses) or with controls.

They were then seeded onto pieces of bovine cortical bone in wells of a 48-well tissue culture plate and incubated for a further 2 hours at 37 ° C. The pieces of bone were washed in six changes of buffered phosphate buffered saline (PBS) to remove the non-adherent cells, and then returned to wells of a 48-well plate containing compound or new controls. The tissue culture plate was then incubated for 48 hours to 37 ° C. Supernatants from each well were aspirated into individual tubes and screened in a competitive ELISA that detects type I collagen c-telopeptide that is released during the resorption process. This is an ELISA commercially available (Osteometer, Denmark) which contains a rabbit antibody that specifically reacts with a sequence of 8 amino acids (Glu- • Lys-Ala-His-Asp-Gly-Gly-Arg) which is present in the carboxy terminal telopeptide of the a1 chain of collagen type I. The results are expressed as% inhibition of resorption compared to a vehicle control.

Adhesion test of human osteoclasts Human osteoclasts were enriched and prepared for screening compounds as described above in the initial 9 steps of test 1. For clarity, these steps are repeated here: • 5 • Aliquots of cell suspensions were removed derived from human osteoclastoma storage in liquid nitrogen; they were rapidly heated to 37 ° C and washed x1 in RPMI-1640 medium by centrifugation (1000 rpm, 5 minutes at 4 ° C). • The medium was aspirated and replaced with murine anti-HLA-v * DR antibody; then it was diluted 1: 3 in RPMI-1640 medium. The suspension was incubated for 30 minutes on ice and mixed frequently. • The cells were washed x2 with cold RPMI-1640, followed by centrifugation (1000 rpm, 5 minutes at 4 ° C), and the cells were then transferred to a sterile 15 ml centrifuge tube. The number of mononuclear cells in a chamber was counted • Improved Neubauer count. • 20 magnetic beads (5 / mononuclear cell), coated with goat anti-lgG (Dynal, Great Neck, New York), were removed from their supply container and placed in 5 ml of fresh medium (this lava the toxic preservative of azide). The medium was removed by immobilizing the globules on a magnet and replaced with fresh medium. The globules were mixed with the cells and the suspension was • incubated for 30 minutes on ice. The suspension was mixed frequently. The cells that coated the beads were immobilized on a magnet, and the remaining cells (osteoclast-rich fraction) were decanted into a 50 ml sterile centrifuge tube. • 10 New media was added to the cells that coated the blood cells to dislodge any trapped osteoclasts. This washing procedure was repeated x 10. The cells coating the beads were discarded. The viable osteoclasts were counted in a chamber count using fluorescein diacetate to label the living cells. A large-size disposable plastic Pasteur pipette was used to add the sample to the chamber. Osteoclasts were pelleted by means of This was followed by centrifugation and the density was adjusted to the appropriate value in EMEM medium (the number of osteoclasts is variable from tumor to tumor), supplemented with 10% fetal calf serum and 1.7 g / liter of sodium bicarbonate.

• The osteoclasts derived from osteoclastoma were preincubated with compound (4 doses) or control at 37 ° C for 30 minutes. • The cells were then seeded on ice-coated osteopontin (human or rat osteopontin, 2.5 ug / ml) slides and incubated for 2 hours at 37 ° C. • Non-adherent cells were removed by washing the slides vigorously in phosphate-buffered saline, and the remaining cells on the slides were • 10 fixed in acetone. • Osteoclasts were stained for tartrate-resistant acid phosphatase (TRAP), a selective marker for cells of this phenotype (see steps 15-17) and counted by light microscopy. The results are expressed as% inhibition of adhesion compared to a vehicle control.

Cell adhesion test Cells and cell culture 20 Human embryonic kidney cells were obtained (cells HEK293) from ATCC (Catalog No. CRL 1573). The cells were grown in Earl's minimal essential medium (EMEM) containing Earl's salts, 10% fetal bovine serum, 1% glutamine and 1% penicillin-streptomycin.

Constructs and transfections A 3.2 kb fragment of EcoRI-Kpnl from the av subunit and a 2.4 kb fragment of Xbal-Xhol from the β3 subunit were inserted into the EcoRI-EcoRV cloning sites of the pCDN vector (Aiyar et al., 1994) , what • contained a CMV promoter and a G418 selectable marker by ligation of shaved ends. For a stable expression, 80 x 106 HEK293 cells were electrotransformed with v + β3 constructs (20 μg of DNA from each subunit) using a Gene Pulser pulsator (Hensley et al., 1994) and seeded on 100 mm plates (5 x 105 cells / plate). After 48 After 10 hours, the growth medium is supplemented with 450 μg / ml Geneticin (G418 Sulfate, GIBCO-BRL, Bethesda, Maryland). The cells were kept in selection medium until the colonies were large enough to be tested.

Immunocytochemistry analysis of transfected cells To determine whether the HEK293 transfectants expressed the vitronectin receptor, the cells were immobilized on microscope glass slides by centrifugation, fixed in acetone for 2 minutes at room temperature and air dried. The specific reactivity with 23C6, a monoclonal antibody specific for the avß3 complex, using an indirect standard method of immunofluorescence.

Cell adhesion studies 96-well Corning ELISA plates were coated overnight at 4 ° C with 0.1 ml human vitronectin (0.2 μg / ml in RPMI medium) overnight. At the time of the experiment, the plates were washed Wf once with RPMI medium and blocked with 3.5% BSA in RPMI medium for 1 hour at room temperature. The transfected 293 cells were resuspended in RPMl medium, supplemented with 20 mM Hepes pH 7.4 and 0.1% BSA at a density of 0.5 x 10 6 cells / ml. 0.1 ml of the cell suspension was added to each well and incubated for 1 hour at 37 ° C, in presence or absence of several vß3 antagonists. After incubation, 0.025 ml of a 10% formaldehyde solution, pH 7.4, was added and the cells were fixed at room temperature for 10 minutes. The plates were washed 3 times with 0.2 ml of RPMI medium and the adherent cells were stained with 0.1 ml of 0.5% toluidine blue for 20 minutes at room temperature. Excess dye was removed by extensive washing with deionized water. The toluidine blue incorporated into the cells was eluted by the addition of 0.1 ml of 50% ethanol containing 50 mM HCl. Cell adhesion was quantified at an optical density of 600 nm on a microtiter plate reader (Titertek Multiskan MC, Sterling, Virginia). Assay of binding of a and g in solid phase The vitronectin avßs receptor of human placenta was purified. The receptor preparation was diluted with 50 mM tris-HCl, pH 7.5, 100 mM NaCl, 1 mM CaC, 1 mM MnCl 2, 1 mM MgC (buffer A), and immediately added to 96-well ELISA plates, at 0.1 ml per well. 0.1-0.2 μg of vß3 was added per well. The plates were incubated overnight at 4 ° C. At the time of the experiment, the wells were washed once with buffer A and incubated with 0.1 ml of 3.5% bovine serum albumin in the same buffer for 1 hour at room temperature. After incubation, the wells were completely aspirated and washed twice with 0.2 ml of buffer A. In a competition assay of [3H] -SK &; F-107260, several concentrations of unlabeled antagonists (0.001-100 μM) were added to the wells, followed by the addition of 5.0 nM of [3 H] -SK &F-107260. The plates were incubated 1 hour at room temperature. After incubation, the wells were completely aspirated and washed once with 0.2 ml of cold buffer A as ice in a well-to-well manner. The receptors were solubilized with 0.1 ml of 1% SDS and the [3H] -SK &F-107260 ligated was determined by liquid scintillation counting with the addition of 3 ml of Ready Safe in a Beckman LS liquid scintillation counter 6800, with 40% efficiency. The non-specific binding of [3 H] -SK &F-107260 was determined in the presence of 2 μM SK & F-107260 and was consistently less than 1% of the total radioligand input. The IC50 (concentration of the antagonist to inhibit 50% of the binding of [3H] -SK &F-107260) was determined by means of a least-squares non-linear curve fitting routine that was modified from the LUNDON-2 program. The K i (antagonist dissociation constant) was calculated according to the Cheng and Prusoff equation: K, = IC5o / (1 + L / Kd), where L and Kd were the concentration and the dissociation constant of [ 3H] -SK &F-107260, respectively.

Inhibition of GPIIb-llla binding mediated by RGD Purification of GPIIb-llla. Ten units of washed, antiquated human platelets (obtained from Red Cross) were lysed, by gentle agitation in 3% octylglucoside, 20 mM Tris-HCl, pH 7.4, 140 mM NaCl, 2 mM CaCl 2, at 4 ° C. for 2 hours. The lysate was centrifuged at 100,000g for one hour. The obtained supernatant was applied to a 5 ml Sepharose 4B lentil lectin column (E.Y. Labs), pre-equilibrated with 20 mM TrisHCI, pH 7.4, 100 mM NaCl, 2 mM CaCl2, 1% octylglucoside (buffer A). After 2 hours of incubation, the column was washed with 50 ml of cold buffer A. The GPIIb-llla retained by lectin was eluted with buffer A containing 10% dextrose. All procedures were performed at 4 ° C. The GPIIb-llla obtained was > 95% pure as shown by polyacrylamide gel electrophoresis-SDS.

Incorporation of GPIIb-llla into liposomes. A mixture of phosphatidylserine (70%) and phosphatidylcholine (30%) (Avanti Polar Lipids) was dried on the walls of a glass tube under a stream of nitrogen. Purified GPIIb-llla was diluted to a final concentration of 0.5 mg / ml, and mixed with the phospholipids at a protein: phospholipid ratio of 1: 3 (p: p). The mixture was resuspended and subjected to sonication for 5 minutes in a bath sonicator. The mixture was then dialyzed overnight using 12,000-14,000 molecular weight cut dialysis tubing against a 1000-fold excess of 50 mM Tris-HCl, pH 7.4, 100 mM NaCl, 2 mM CaCl 2 (with 2 changes). The liposomes containing GPIIb-llla were centrifuged at 12,000g for 15 minutes and resuspended in the dialysis buffer at a final protein concentration of approximately 1 mg / ml. The liposomes were stored at -70 ° C until needed.

Competitive union to GPIIb-llla. Fibrinogen receptor binding (GPIIb-Illa) was tested by means of an indirect method of competitive binding using [3 H] -SK &F-107260 as a ligand of type RGD. The binding test was performed on a 96-well filtration plate assembly (Millipore Corporation, Bedford, Massachusetts) using durapore hydrophilic membranes of 0.22 um. The wells were pre-coated with 0.2 ml of 10 μg / ml polylysine (Sigma Chemical Co., St. Louis Missouri) at room temperature for 1 hour to block nonspecific binding. Four concentrations of unlabeled benzazepines were added to the wells in quadruplicate. [3H] -SK &F-107260 was applied to each well at a final concentration of 4.5 nM, followed by the addition of 1 g of the liposomes containing purified platelet GPIIb-llla. The mixtures were incubated 1 hour at room temperature. [3H] -SK & F-107260 bound to GPIIb-llla was separated from unbound by filtration, using a Millipore filtration manifold, followed by washing with cold buffer 5 as ice (2 times, each with 0.2 ml). The bound radioactivity remaining in the filters was counted in 1.5 ml of Ready Solve (Beckman Instruments, Fullerton, California) in a Beckman liquid scintillation counter (l LS6800), with 40% efficiency. Nonspecific binding was determined in the presence of 2 μM of SK & F-107260 unlabelled, and was consistently less than 0.14% of the total radioactivity added to the • samples. All data points are the average of quadrupled determinations. Competitive binding data was analyzed by a least-squares non-linear curve fitting procedure. East The method provides the IC 50 of the antagonists (concentration of antagonists that inhibits the specific binding of [3 H] -SK &F-107260 by 50% at equilibrium). The IC50 is related to the equilibrium dissociation constant (K1) of the antagonist ft based on the Cheng and Prusoff equation: K¡ = IC50 / (1 + L / Kd), where L is the concentration of [3H ] -SK &F-107260 used in the test of competitive binding (4.5 nM), and Kd is the dissociation constant of [3H] -SK &; F-107260, which is 4.5 nM as determined by Scatchard analysis. Preferred compounds of this invention have an affinity for the vitronectin receptor with respect to the fibrinogen receptor of more than 10: 1. The highly preferred compounds have an activity ratio greater than 100: 1. The efficacy of the compounds of formula (I) alone or in combination with an antineoplastic agent can be determined using several models of mouse transplantable tumor. See the patents of E.U.A. Nos. 5,004,758 and 5,633,016 for details of these models.

The examples that follow are in no way intended to limit the scope of this invention, but are provided to illustrate how ft 10 prepare and use the compounds of this invention. Many other modalities will be apparent to the person skilled in the art.

General Nuclear magnetic resonance spectra of protons (1 H NMR) at 250, 300 or 400 MHz. Chemical shifts are reported in parts per million (d) to the lower part of the internal standard tetramethylsilane (TMS). The abbreviations of the NMR data are as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublets, dt = doublet of triplets, ap = apparent, br = broad . J indicates the NMR coupling constant measured in Hertz. CDCI3 is deuteriochloroform, DMSO-d6 is hexadeuterium dimethylsulfoxide, and CD3OD is tetradeuteriomethanol. Infrared (IR) spectra were recorded in transmission mode and band positions were reported in inverse wave numbers (cm "1) Mass spectra were obtained using electroaspersion (ES) or FAB ionization techniques. Within the organization or by Quantitative Technologies Inc., Whitehouse, New Jersey, melting points were taken on a 5 ft. melting point Thomas-Hoover apparatus, and are not corrected.All temperatures are reported in degrees Celsius. Silica gel thin film silicates Analtech Silica Gel GF and E. Merck Silica Gel 60 F-254 were used to perform thin layer chromatography, and flash chromatography was performed on an E. Merck Kieselgel 60 silica gel (mesh). 230-400) Analytical and preparative HPLC was performed on Rainin or Beckman chromatographs ODS refers to a silica gel chromatographic support derived from octadecylsilyl Apex-ODS 5μ indi a silica gel chromatographic support derived from octedecylsilyl having a nominal particle size of 5 μ, made by Jones Chromatography, Littleton, Colorado. YMC ODS-AQR is an ODS chromatographic support and is a registered trademark of YMC Co., Ltd., Kyoto, Japan. PRP-1R is a polymeric chromatographic support (styrene-divinylbenzene), and is a registered trademark of Hamilton Co., Reno, Nevada. CeliteR is a filter aid composed of diatomaceous silica washed with acid, and is a registered trademark of Manville Corp., Denver, Colorado.

PREPARATION 1 Preparation of 2-r (3-hydroxy-1-propyl) amino-1-pyridine 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 was heated to reflux. -propanol (15.3 ml, 0.2 moles), NaHC? 3 (42 g, 0.5 moles), and ione-amyl alcohol (100 ml). After 21 hours, the reaction was cooled, diluted with CH2Cl2 (300 mL), and filtered by suction to remove the insoluble materials. The toluene filtrate was concentrated and reconcentrated to leave a yellow oil. Chromatography on silica gel (20% MeOH / CHCl3) gave the title compound (15.62 g, 93%) as a yellow solid: TLC (20% MeOH / CHCl3) Rf 0.48; 1 H NMR (250, CDCl 3) d 8. 07 (dd, J = 6.6, 1.2 Hz, 1H), 7.34 (br t, 1 H), 7.10-7.30 (m, 1H), 6.64 (dd, J = 8.5, 1.4 Hz, 1 H), 6.40-6.60 (m, 1 H), 4.49 (br s, 1 H), 3.65-3.90 (m, 2H), 3.35-3.60 (m, 2H), 1 J5-2.00 (m, 2H); MS (ES) m / e 169 (M + H) +.

PREPARATION 2 Preparation of 6- (methylamido) -2-pyridylethanol a) 2- (tert-Butoxycarbonylamino) -6-picoline A solution of 2-amino-6-p-choline (21.63 g, 200 mmol) and di-t-butyl dicarbonate (52.38 g, 240 mmol) was concentrated in CH2CI2 (200 ml) was added to the rotary evaporator at 50 ° C, and the resulting residue was allowed to rotate in a rotary evaporator at 50 ° C under vacuum. After 21.5 hours, the reaction was diluted with hexane (400 mL) and filtered through silica gel (hexane followed by 20% EtOAc / hexane). Concentration left the title compound (41.84 g, • 5 quantitative) as a light yellow oil that solidified gradually upon standing: H NMR (250 MHz, CDCl 3) d 7.71 (d, J = 8.3 Hz, 1 H), 7.40-7.65 (m, 2H), 6.80 (d, J = 7.5 Hz, 1H), 2.43 (s, 3 H), 1.50 (s, 9 H); MS (ES) m / e 153 (M + H-C4H8) +. b) 2 - [(fer-Butoxycarbonyl) methylamino] -6-picoline NaH (60% in mineral oil, 3.60 g, 90 mmol) was added in portions over several minutes to a solution of 2- (tert-butoxycarbonylamino) - 6-picoline (15.62 g, 75 mmol) and iodomethane (9.3 ml, 150 mmol) in anhydrous DMSO (75 ml), at 15 ° C (cold water bath). internal temperature increased to 35 ° C. When the evolution of gas had ceased, the water bath was removed and the reaction was allowed to stir at room temperature. After 5 hours, the dark yellow mixture was emptied on ice / H2? (300 ml) and extracted with Et2? (3 x 300 ml). The combined organic layers were washed sequentially with H2O (2 x 75 ml) and brine (75 ml). Drying (MgSO 4) and concentration gave a yellow oil which was chromatographed on silica gel (7% EtOAc / hexane). The title compound was obtained (13.01 g, 78%) as a slightly yellow oil: "? NMR (250 MHz, CDCl 3) d 7.51 (t ap, 1 H), 7.37 (d, J = 8.2 Hz, 1H), 6.86 (d, J = 7.2 Hz, 1H), 3.38 (s, 3 H), 2.49 (s, 3 H), 1.50 (s, 9 H), MS (ES) m / e 223 (M + H) + > ft c) Ethyl 6 - [(ery-butoxycarbonyl) methylamino] -2-pyridylacetate LDA was prepared at 0 ° C under argon from diisopropylamine (19.5 ml, 139.14 mmol) and n-BuL 2.5 M in hexane (46.4 ml, 115.95 mmol) in dry THF (350 ml). This solution was cooled to -78 ° C and a solution of 2 - [(fer-butoxycarbonyl) methylamino] -6-picoline (10.31 g, 46.38 10 mmol) in dry THF (46 ml) was added dropwise during 10 minutes. Additional dry THF (2 ml) was used in the transfer. The orange solution was stirred at -78 ° C for 15 minutes and then diethyl carbonate (6.2 ml, 51.02 mmol) was added rapidly. The red solution was stirred at -78 ° C for 15 minutes, then quenched with half-saturated NH4CI (175 ml). The mixture warmed to + 5 ° C and extracted with EtOAc (175 ml), then with CH 2 Cl 2 (2 x 100 ml). The combined organic extracts were washed with brine (100 ml), dried (MgSO 4) and concentrated. The turbid yellow oil was chromatographed on silica gel (15% EtOAc / hexane) to give the title compound (10.72 g, 79%) as a light yellow oil: "? RMN (250 MHz, CDCl 3) d 7.51-7.63 (m, 2 H), 6.91-7.03 (m, 1 H), 4.19 (q, J = 7.1 Hz, 2 H), 3J7 (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) +. (a2S? 4) and concentrated to yield the title compound (9.12 g, 85%) as a waxy solid: 1 H NMR (400 MHz, CDCl 3) d 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) +.

PREPARATION 3 Preparation of (±) -4- (4-hydroxyphenyl) -3-phenylbutanoate ethyl a) (±) -3-Hydroxy-4- (4-methoxyphenyl) -3-phenylbutanoate ethyl 10.5 Anhydrous EtOAc (4.3 ml, 44 mmol) was added dropwise over a 5-6 minute solution to an (trimethylsilyl) lithium amide (1.0 M in THF, * 40 ml, 40 mmol) 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 hour; then a solution of 2- (4-methoxyphenyl) -1-phenylethanone (Chem. Ber., 1958, 91, 755-759; 4.53 g, 20 mmol) in dry THF was added dropwise over 12 minutes. 20 ml). Additional THF (2 ml) was used in the transfer. After 0.5 hours, the reaction was quenched with saturated NH 4 Cl (120 mL) and warmed to room temperature. By extraction with EtOAc, drying (MgSO 4), concentration and chromatography on silica gel (20% EtOAc / hexane), the title compound (6.13 g, 96%) was obtained as a light yellow oil: TLC Rf (20% EtOAc / hexane) 0.34; EM (ES) m / e 315. 2 (M + H) +. b) (±) -4- (4-Methoxyphenyl) -3-phenylbutanoate ethyl. Boron trifluoride-etherate (4.8 ml, 39 mmol) was added dropwise to a solution of (±) -3 for 3 minutes. ethylhydroxy-4- (4-methoxyphenyl) -3-phenylbutanoate (6.13 g, 19.5 mmol) and triethylsilane (6.2 ml, 39 mmol) in anhydrous CH2Cl2 (49 ml), at 0 ° C under argon. The reaction was stirred at room temperature overnight and then quenched with 5% NaHC 3 3 (100 mL). The mixture was stirred vigorously for 10 minutes; then it separated. The aqueous layer was extracted with CH2Cl2 (100 mL) and the combined organic layers were dried (Na2S4) and concentrated. The residue was reconcentrated from hexane (to remove CH2Cl2), to leave a yellow oil.

This was dissolved in absolute EtOH (100 ml), and 10% Pd / C (775 mg, 1.95 mmol) was added. The mixture was stirred on a Parr apparatus at room temperature under H2 (3.5 kg / cm ^) for 2 hours, and then filtered through celite ^. The filtrate was concentrated, and the residue was chromatographed on silica gel (15% EtOAc / hexane). The title compound was obtained (5.27 g, 91%) as a colorless oil: TLC Rf (15% EtOAc / hexane) 0.40; EM (ES) m / e 299.2 (M + H) +. c) (±) -4- (4-Hydroxyphenyl) -3-phenylbutanoate ethyl. Anhydrous aluminum trichloride (4.49 g, 33.7 mmol) was added, all at once, to a solution of (±) -4- ( 4-methoxyphenyl) -3-phenylbutanoate (2.01 g, 6.74 mmol) and ethanethiol (2.5 mL, 33.7 mmol) in anhydrous CH 2 Cl 2 (67 mL), at 0 ° C under argon. The yellow solution was warmed to room temperature and stirred for 3 hours; then it was cooled again to 0 ° C and quenched with cold 3N HCl (67 ml). The mixture was stirred 5 minutes; • then separated. The aqueous layer was extracted with CH2Cl2 (2 x 100 ml) and the combined organic layers were dried (Na2S4) and concentrated. Chromatography on silica gel (25% EtOAc / hexane) gave the title compound (1.84 g, 96%) as a colorless oil: TLC Rf (30% EtOAc / hexane) 0. 47; MS (ES) m / e 285.2 (M + H) +. ft 10 PREPARATION 4 Preparation of 2-r (2-amino-1-etH) amino.pyridine dihydrochloride a) 2 - [[2- (fer-Butoxycarbonyl) amino-1-ethyl] aminoj-1-oxopyridine A mixture of N-Boc-ethylenediamine (5.83 g, 36.39 mmoles), 2-chloropyridine N-oxide hydrochloride (7.25 g, 43.67 mmol), NaHCO 3 (15.29 g, 182 mmol), and fer-amyl alcohol (36 ml). After 47 hours, the dark brown mixture was cooled, diluted with CH2CI2 (100 ml) and filtered by suction. The filtrate was concentrated and the residue was concentrated again from toluene. Chromatography on silica gel (MeOH 10% / CH2Cl2) gave the title compound (8.23 g, 89%) as a solid yellow: 1 H NMR (250 MHz, CDCl 3) d 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), 5.70-595 (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- (fer-Butoxycarbonyl) amino-1-ethyl] amino] pyridine ft A mixture of 2 - [[2- (fer-butoxycarbonyl) amino-1-ethyl] amino] -1-oxopyridine (7.00 g, 27.64 mmol), Pd 10% / C (5.88 g, 5.53 mmol) was refluxed. ), cyclohexene (28 ml, 276.4 mmol) and isopropanol (110 ml). After 17 hours, the reaction was filtered through celite® and the filtrate was concentrated. The yellow residue was reconcentrated from toluene and then subjected to chromatography on silica gel (MeOH • 10 5% / CHC.3). The title compound (5.09 g, 78%) was obtained as an oil yellow: 1 H NMR (400 MHz, CDCl 3) d 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-1-ethyl) amino] pyridine dihydrochloride. A 4 N HCl / dioxane (54 ml) was added in a stream at 0 ° C under argon to a solution of 2 - [[ 2- (I-butoxycarbonyl) amino-1-ethyl] amino] pyridine (5.09 g, 21.45 mmol) in anhydrous CH 2 Cl 2 (54 mL); then, the mixture was heated to room temperature. After 2 hours, the mixture was cooled to 20 0 C and filtered by suction. The solid was washed extensively with Et2? anhydrous and dried under high vacuum at 40 ° C to yield the title compound (4.27 g, 95%) as a whitish solid, somewhat hygroscopic: "? NMR (400 MHz, CD3OD) d 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); ES) m / e 138 (M + H) +.

PREPARATION 5 Preparation of 2-r (3-hydroxy-1-propyl) aminol-4-methylpyridine N-oxide a) 2-Chloro-4-methylpyridine Sodium nitrite (13.88 g, 200 mmol) was slowly added at 0 ° C to a solution of 2-amino-4-picoline (15.0 g, 139 mmol) in conc HCl. . (200 ml). The reaction mixture was allowed to warm to room temperature and was stirred for 16 hours; then it was emptied on ice (500 g). The pH was adjusted to 8.0 with conc. NH4OH, and the mixture was extracted with ether (3 x 300 ml). The combined ether layers were washed sequentially with H2O (2 x 200 ml) and brine (200 ml). Drying (MgSO 4) and concentration gave the title compound (10.3 g, 58%) as a slightly 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 mmol) and 34% peracetic acid was heated at 70 ° C for 3 hours ( 76.05 g, 91.0 mmol) in glacial AcOH (10 mL). The reaction mixture was cooled, conc. HCl was added. (35 ml), and the mixture was concentrated in the rotary evaporator. By recrystallization of n-butanol, followed by trituration with ether, the title compound (7.16 g, 51%) was obtained as a white solid: MS (ES) m / e 143.9 (M + H) +. • c) N - Oxide of 2 - [(3-hydroxy-1-propyl) amino] -4-methylpyridine A mixture of 2-chloro-4-methylpyridine N-oxide hydrochloride was refluxed for 19 hours. (7.16 g, 39 mmol), 3-aminopropanol (6.01 g, 80 mmol), and NaHCO 3 (16.8 g, 200 mmol) in fer-amyl alcohol (50 ml). The reaction mixture was diluted with CH2Cl2 (200 ml) and filtered; he The filtrate was concentrated in the rotary evaporator. The recrystallization of CH2Cl2 / Et2? it gave the title compound (5.41 g, 75%) as a yellow solid: TLC (MeOH % / CH2Cl2) Rf 0.44; 1 H NMR (400, CDCl 3) d 7.92 (d, J = 6J, 1 H), 7.28 (brt, 1 H), 6.43 (s, 1 H), 6.33 (dd, J = 6.6, 2.1 Hz, 1 H), 3 J3 (t, J = 5 J 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 m / e 183 (M + H) +. 15 PREPARATION 6 ft Preparation of 2-r N-oxide hydrobromide (3-bromo-1-propyaminaminopyridine a) 2 - [(3-Bromo-1-propyI) amino] pyridine N-oxide hydrobromide A solution of SOBr2 (5.0 ml, 64.5 mmol) in CH2Cl2 (20 ml) was added dropwise, over 15-20 minutes, to a solution of 2 - [(3-hydroxy-1-propyl) amino] -4-methy1pyridine N-oxide (10.0 g, 54.87 mmol) in CH2CI2 (100 ml) at 0 ° C. The reaction was warmed to room temperature and stirred for 2 hours; then Et ^ O (200 ml) was added slowly. The solvents were separated by decanting the gummy precipitate and this precipitate was washed with CH2Cl2 / Et2? additional (several times). The resulting yellow-brown residue solidified upon standing in a refrigerator overnight. This solid was collected and washed with Et? to produce the title compound (15.07 g) as a yellow solid. More title compound (2.05 g) was obtained as white needles by concentration of the combined organic layers. The total yield of the title compound was 17.89 g (96%): MS (ES) m / e 245 and 247 (M + H) +.

PREPARATION 7 Preparation of 2-r.5-hydroxy-1-pentyl) aminolpyridine N-oxide a) 2 - [(5-Hydroxy-1-pentyl) amino] pyridine N-oxide A suspension of 2-chloropyridine N-oxide hydrochloride (1.00 g, 6.03 mmoles) and NaHC? 3 (2.53 g, 30.1 mmol) in ethyl-amyl alcohol (20 ml). The reaction was cooled to room temperature, diluted with CH2Cl2 and filtered. The filtrate was concentrated to give a pale green oil. Radial chromatography (10% MeOH / CHCl3, silica gel, 6 mm plate) gave the title compound (0.52 g) as a clear oil: 1 H NMR (300 MHz, CDCl 3) 8.10 (d, J = 6.5 Hz, 1 HOUR), 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).

PREPARATION 8 Preparation of 2-rN- (tert-butoxycarbonyl) -N-methylamino-1-5-pyridylethanol a) 5-Bromo-2 - [(tert-butoxycarbonyl) amino] pyridine A solution of 2-amino-5-bromopyridine (5.67 g, 32.7 mmol) and di-tert-butyl dicarbonate (8.57 g, 38.3 mmol) ) in CH2CI2 (50 ml), was concentrated in the rotary evaporator at 50 ° C, and the resulting residue was allowed to rotate in the rotary evaporator overnight at 50 ° C under vacuum. After 20 hours, the reaction was chromatographed on silica gel (5% MeOH / hexane) to give the title compound (6 g, 67%) as a white solid: MS (ES) m / e 273 (M + H) +. b) 5-Bromo-2- [N- (fer-butoxycarbonyl) -N-methylamino] pyridine To a solution of 5-bromo-2 - [(fer-butoxycarbonyl) amino] pyridine (6 g, 21.9 mmoles) in dry DMF (50 ml), under nitrogen, was added in portions 80% NaH (0.8 g, 26.3 mmoles) at 0 ° C. The reaction mixture was stirred at 0 ° C for 15 minutes and then iodomethane (3 ml, 43.8 mmol) was added in a stream. The reaction was stirred overnight at room temperature and then concentrated in vacuo. The residue was diluted with water and extracted with CH2Cl2. Drying (MgSO4), concentration and flash chromatography on silica gel (5% EtOAc / hexane), gave the title compound (2.2 g, 35%) as an oil: MS (ES) m / e 286.9 (M + H) +. c) 2- [N- (Ier-Butoxycarbonyl) -N-methylamino] -5-vinylpyridine To a solution of 5-bromo-2- [N- (ery-butoxycarbonyl) -N-methylaminojpyridine (2.2 g , 7.69 mmoles) and vinyltributyltin (3.4 ml, 11.5 mmoles) in toluene, at room temperature, was added tetrakis (triphenylphosphine) palladium (0) (346 mg, 0.3 mmoles). The solution was degassed under vacuum for 10 minutes and then heated to reflux. After 5 hours, the reaction was cooled, concentrated in vacuo and chromatographed on silica gel (5% EtOAc / hexane) to give the title compound (1.0 g, 65%) as a colorless oil: MS ( ES) m / e 235 (M + H) +. Also recovered was 5-bromo-2- [N- (fer-butoxycarbonyl) -N-methylaminojpyridine (0.3 g) not transformed. d) 2- [N- (Ier-Butoxycarbonyl) -N-methylamino] -5-pyridylethanol To a solution of 2- [N- (ery-butoxycarbonyl) -N-methylamino] -5-vinylpyridine (1.1 g, 4.7 mmol ) in dry THF (20 ml) was added borane-tetrahydrofuran complex (1.0 M in THF, 3 ml, 3 mmol) at 0 ° C. The reaction was heated for 1 hour and then concentrated in vacuo. The crude product was dissolved in THF (5 ml) and NaOAc (770 mg, 9.4 mmol) was added, followed by 30% H2O2 (1.56 ml). The reaction was stirred at temperature environment for 1 hour and then partially concentrated in vacuo. The residue was treated with saturated NaCl (ml), and the mixture was extracted with CH2Cl2. ft For drying (MgS? 4), concentration and flash chromatography on gel silica (EtOAc / hexane 1: 1), the title compound was obtained (230 mg, 21%) as a colorless oil: MS (ES) m / e 253 (M + H) +.

PREPARATION 9 Preparation of 2-rN- (3-methanesulfonyl-1-propyl) -N- (fer- • 10-butoxycarboniPaminolpyridine N-oxide) a) N-Oxide of 2- [N- (3-hydroxy-1-propyl) -N- (ér-butoxycarbonyl) amino] pyridine A solution of 2 - [(3-hydroxy-1-propyl) N-oxide amino] pyridine (8.0 g, 47.6 mmol) in fer-BuOH (80 mL) was treated with di-butyl-15-dicarbonate (11.4 g, 55.3 mmol). After 18 hours, the solution was concentrated and the residue was triturated with hexane. The resulting solid was dried in vacuo to give the title compound (12.5 g, 98%) as an off white solid: MS (ES) m / e 269.3 (M + H) +.

B) N-Oxide of 2- [N- (3-methanesulfonyloxy-1-propyl) -N- (tert-butoxycarbonyl) amino] pyridine. Methanesulfonyl chloride (0.17 ml, 2.20 mmol) was added dropwise. a solution of 2- [N- (3-hydroxyl-1-propyl) -N- (1-butoxycarbonyl) amino] pyridine N-oxide (0.50 g, 1.86 mmol) and pyridine (0.23 mL, 2.84 mmole) in CHCl3 (5 ml, dried over K2CO3), at 0 ° C. When the reaction was finished, according to CCF, it was diluted with CHCl3, washed with ice water, dried ft (Na2S? 4), and concentrated. Chromatography on silica gel (MeOH 10% / CHCl3) gave the title compound (0.41 g, 64%) as a colorless oil: 1 H NMR (250 MHz, CDCl 3) d 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), 3J5 (t, J = 6.6 Hz, 2 H), 3.00 (s, 3 H), 2.00 (m, 2 H), 1.40 (s, 9 H). It was also possible to recover from the chromatographic purification N-oxide of 2- [N- (3-hydroxy-1-propyl) -N- (rt-butoxycarbonyl) amino] pyridine (0.18 g, 36%) not transformed.

PREPARATION 10 Preparation of ethyl (±) -4- (4-carboxyphenyl) -3-phenylbutanoate a) (±) -3-Phenyl-4- [4- (trifluoromethanesulfonyloxy) phenyl] butanoate ethyl Trifluoromethanesulfonic anhydride (1.4 ml, 8.4 mmol) was rapidly added dropwise to a solution of (±) - 4- (4-hydroxyphenyl) -3-phenylbutanoate (1.84 g, 6.47 mmol) and 2,6-lutidine (1.5 mL, 12.9 mmol) in anhydrous CH 2 Cl 2 (32 mL), at -78 ° C under argon. After After 0.5 hour, the yellow solution was warmed to room temperature and stirred for 1 hour. The reaction was diluted with Et2? (150 ml) and washed sequentially with 1.0 N HCl (15 ml), 3% NaHC 3 (15 ml), and saturated brine (15 ml). Drying (MgSO 4), concentration and chromatography on silica gel (15% EtOAc / hexane), gave the title compound (2.62 g, 97% o) as an almost colorless oil: TLC Rf (20% EtOAc / hexane) 0.55; EM (ES) m / e 417.0 (M + H) +. b) (±) -4- (4-carboxyphenyl) -3-phenylbutanoate ethyl A mixture of ethyl (±) -3-phenyl-4- [4- (trifluoromethanesulfonyloxy) phenyl] butanoate (2.62 g, 6.29 mmole) , Anhydrous KOAc (2.47 g, 25.16 mmol), Pd (OAc) 2 (70.6 mg, 0.31 mmol), dppf (697.4 mg, 1.26 mmol) and anhydrous DMSO (31 mL), purged with carbon monoxide (three cycles of evacuation / purging of carbon monoxide, followed by bubbling of carbon monoxide through the mixture for 5 minutes); then it was heated to 70 ° C under a carbon monoxide balloon. After 3.5 hours, the reaction was diluted with H2O (31 mL), cooled on ice, and acidified with 1.0 N HCl (25 mL). Extraction with CH2Cl2 (2 x 100 ml), drying (MgSO4), concentration and reconcentration of toluene left an orange-red liquid. Chromatography on silica gel (AcOH 1% in toluene / EtOAc 7: 3) gave the title compound (1.78 g, 91%) as a cream solid: CCF Rf (AcOH 1% in toluene / EtOAc 7: 3) 0.47; MS (ES) m / e 313.2 (M + H) +.

PREPARATION 11 HPLC separation of the enantiomers of ethyl (±. 4- (4-hydroxyphenyl) -3-phenylbutanoate) a) (S) - (-) - ethyl 4- (4-hydroxyphenyl) -3-phenylbutanoate and ethyl (R) - (+) - 4- (4-hydroxyphenyl) -3-phenylbutanoate Resolved (±) -4- (4-hydroxy-phenyl) -3-phenylbutanoate ethyl in its enantiomers using the following conditions: Diacel Chiralcel Column ADR (21.2 mm x 250 mm), mobile phase of 5% ethanol in hexane, flow rate 15 ml / min, detection in uv at 254 nm, injection of 40 mg; IR for (S) - (-) - ethyl 4- (4-hydroxyphenyl) -3-phenylbutanoate = 19.8 min; IR for (R) - (+) - ethyl 4- (4-hydroxyphenyl) -3-phenylbutanoate = 23.0 min.

PREPARATION 12 Preparation of methyl 4- (4-hydroxyphenyl) butanoate a) Methyl 4-benzyloxyphenylacetate To a suspension of K2CO3 (20.7 g, 150 mmol) in acetone (50 ml), methyl 4-hydroxyphenylacetate (5.0 g, 30 mmol) and benzyl chloride (10.4 ml, 90 mmol) were added, and the mixture was heated to reflux. After 24 hours, the mixture was cooled to room temperature, filtered and concentrated. The residue was chromatographed on silica gel (10% EtOAc / hexane) to give the title compound (7.7 g, 100%) as a white solid: "? NMR (300 MHz, CDCl 3) d 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, 2 H), 3.70 (s, 3 H), 3.59 (s, 2 H). b) 4-benzyloxyphenethyl alcohol To a solution of methyl 4-benzyloxyphenylacetate (1.5 g, 5.85 mmol) in dry THF (30 mL), L.AIH4 (244 mg, 6.44 mmol) was added to 0 ° C. After 2 hours, the mixture was quenched by the dropwise addition of 1.0 N NaOH to the formation of solid aluminum salts. The mixture was diluted with EtOAc (100 mL), dried over MgSO 4, filtered and concentrated to give the title compound (1.35 g, quantitative), which was used without purification. 1 H NMR (300 MHz, CDCl 3) 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 mmol) in CH2Cl2 (20 ml), oxalyl chloride (0.51 ml, 5.85 mmol) was added at -78 ° C. After 10 minutes, a solution of 4- (benzyloxy) phenethyl alcohol (1.35 g, 5.85 mmol) in CH2Cl2 (10 mL) was added. After 30 minutes, Et ^ N (2.69 ml, 19.3 mmol) was added and the mixture was warmed to room temperature. After 30 minutes, the mixture was washed sequentially with H 2 O, 10% HCl and H 2 ?, 10 ml of each, and then the resulting organic layer was dried over MgSO 4, filtered and concentrated. The residue was used immediately in the next step without purification. d) 4- (4-benzyloxyphenyl) methyl crotonate To a solution of 4-benzyloxyphenylacetaldehyde (5.85 mmol) in dry THF (30 ml), methyl (methyl triphenylphosphoranylidene) acetalate (2.4 g, 7. 02 mmoles). After 18 hours, the mixture was concentrated. The residue was taken in Et2? / Hexane 1: 1 (200 ml) and filtered. The filtrate was concentrated and the residue was chromatographed on silica gel (10% EtOAc / hexane) to yield the title compound (780 mg, 47% from b) as a yellow oil: 1 H NMR (300 MHz, CDCl 3) d 7.35 (m, 5 H), 7.05 (m, 2 H), 6.90 (m, 3 H), 5.80 (d, J = 15 Hz, 1 H), 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), methyl 4- (4-benzyloxyphenyl) crotonate (300 mg, 1.06 mmol). The mixture was deoxygenated (3 x evacuation / purge cycles of N2) and then it was charged with H2 (3.5 kg / cm ^). After 2 hours the H2 was removed and the mixture was filtered through a pad of celite®. The filtrate was concentrated and the residue was chromatographed on silica gel (30% EtOAc / hexane) to give the title compound (180 mg, 87%) as a colorless oil: 1 H NMR (300 MHz, CDCl 3) d 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, 2 H).

PREPARATION 13 Preparation of methyl (±) -4- (4-hydroxyphenyl) -3-vinylbutanoate a) Methyl 4- (Triisopropylsiloxy) phenylacetate To a solution of methyl 4-hydroxyphenylacetate (5.0 g, 30 mmol) and imidazole (4.08 g, 60 mmol) in dry DMF (80 ml), triisopropylsilyl chloride ( 9.6 ml, 45 mmol). After 18 hours, the mixture was poured into H2O (500 ml) and extracted with hexane (3 x 300 ml). The combined organic layers were dried over MgSO 4, filtered and concentrated. The residue was chromatographed on silica gel (5% EtOAc / hexane) to give the title compound (9.03 g, 93%) as a colorless oil: 1 H NMR (300 MHz, CDCl 3) d 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- (Trisopropylsiloxy) phenethyl alcohol To a solution of methyl 4- (triisopropylsiloxy) phenylacetate (9.03 g, 28 mmol) in dry THF (100 ml), L1? IH4 (1.17 g, 30.8 mmol) was added to 0 ° C. After 1 hour, the mixture was quenched by the addition, dropwise, of 1.0 N NaOH until the formation of solid aluminum salts. The mixture was diluted with EtOAc (100 mL), dried over MgSO 4, filtered and concentrated to give the title compound (8.02 g, 97%), which was used without purification: H NMR (300 MHz, CDCI3) d 7.10 (d, J = 6.6 Hz, 2 H), 6.80 (d, J = 6.6 hz, 2 H), 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- (Triisopropylsiloxy) phenylacetaldehyde To a solution of DMSO (3.83 ml, 54 mmol) in CH 2 Cl 2 (100 ml), oxalyl chloride (2.36 ml, 27 mmol) was added at -78 ° C. After 10 minutes, a solution of 4- (triisopropylsilyoxy) phenethyl alcohol (8.02 g, 27 mmol) in CH2Cl2 (25 mL) was added. After 1 hour Et3N (12.5 ml, 89.8 mmol) was added and the mixture was warmed to room temperature. After 1.5 hours, the mixture was washed sequentially with H2O, 10% HCl and H2O, 50 ml of each, and then the resulting organic layer was dried over MgSO4, 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 mmol) in dry benzene (100 ml), methyl (triphenylphosphoranylidene) acetate (18.1 g, 54 mmoles). After 96 hours, the mixture was concentrated. The residue was taken in Et2? (500 ml) and filtered. The filtrate was concentrated and the residue was chromatographed on silica gel (2: 1 hexane / CH 2 Cl 2) to yield the title compound (3.39 g, 36% from b) as a yellow oil: 1 H NMR (300 MHz, CDCl 3 ) d 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, 3 H), 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 mmol) in dry THF (10 mL) was added dropwise to drop, vinylmagnesium bromide (6.0 ml, 6.0 mmol) at -78 ° C. After 15 minutes, a solution of methyl 4 - [(4-triisopropylsilyloxy) phenyl] crotonate (350 mg, 1.0 mmol) in dry THF (3 ml) was added dropwise. After 1.5 hours, the mixture was quenched with H2O (10 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel (hexane / CH2C-2 3: 1) to give the title compound (224 mg, 59%) as a yellow oil: H NMR (300 MHz, CDCl 3) d 6.99 ( d, J = 6.6 Hz, 2 H), 6J9 (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) (±) -4- (4-Hydroxyphenyl) -3-methyl vinylbutanoate To a solution of methyl (±) -4 - [(4-triisopropylsiloxy) phenyl] -3-vinylbutanoate (224 mg, 0.59 mmol) in dry THF (5 ml), a solution of TBAF in THF (1.0 M, 0.65 ml, 0.65 mmole) was added. After 1 hour, the mixture was diluted with H2O (10 mL) and extracted with 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) to give the title compound (92.5 mg, 71%) as a yellow oil: 1 H NMR (300 MHz, CDCl 3 d 7.00 (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 (br, 1 H), 3.62 (s, 3 H) ), 2.80 (m, 1 H), 2.59 (m, 2 H), 2.32 (m, 2 H).

PREPARATION 14 Preparation of ethyl (±) -4- (4-hydroxy-phenyl) -3- (pyridin-2-yl) butanoate a) 4-Benzyloxy-N-methoxy-N-methylphenylacetamide To a suspension of N, O-dimethylhydroxylamine hydrochloride (761 mg, 7.8 mmol) in dry toluene (20 ml) was added trimethylaluminum (7.8 ml, 7.8 g). mmoles) at room temperature. After 1 hour, methyl 4- (benzyloxy) phenylacetate (1.0 g, 3.9 mmol) was added and the mixture was heated to reflux. After 2 hours, the mixture was cooled to room temperature and stirred for 18 hours; then it was quenched by the slow addition of 10% HCl (20 ml) and extracted with EtOAc (3 x 30 ml). The combined organic layers were dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel (75% EtOAc / hexane) to give the title compound (473 mg, 43%) as an orange solid: MS (ES) m / e 286 (M + H) +. b) 2- [4- (Benzyloxy) phenyl] -1- (pyridin-2-yl) ethanone To a solution of 2-bromopyridine (0.08 ml, 0.8 mmol) in dry THF (2 ml), was added t- BuLi (0.94 ml, 1.6 mmol) at -78 ° C. After 10 minutes, a solution of 4-benzyloxy-N-methoxy-N-methylphenylacetamide (115 mg, 0.4 mmol) in dry THF (2 ml) was added. The mixture was allowed to warm up as the bath heated. After 18 hours, the mixture was quenched with NH 4 Cl (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over MgSO 4, filtered and concentrated. The residue was chromatographed on silica gel (15% EtOAc / hexane) to give the title compound (80 mg, 66%) as an orange solid: MS (ES) m / e 304 (M + H) +. c) (±) -4- [4- (benzyloxy) phenyl] -3- (pyridin-2-yl) ethyl crotonate To a suspension of NaH (21 mg, 0.53 mmol) in dry THF (2 ml), added drop depletes triethyl phosphonoacetate (0.11 ml, 0.53 mmol) at room temperature. After 10 minutes, a solution of 2- [4- (benzyloxy) phenyl] -1- (pyridin-2-yl) ethanone (80 mg, 0.26 mmol) in dry THF (2 ml) was added dropwise. After 4 hours, the mixture was concentrated. The residue was chromatographed on silica gel (30% EtOAc / hexane) to give the title compound (82 mg, 84%) as a mixture of olefin isomers: MS (ES) m / e 374 (M + H ) + d) (±) -4- (4-hydroxyphenyl) -3- (pyridin-2-yl) ethyl butanoate To a suspension of Pd 10% / C (69 mg) in EtOAc / i-PrOH 1: 1 (10 ml) was added (±) -4- [4- (benzyloxy) phenyl] -3- (pyridin-2-yl) ethyl crotonate (243 mg, 0.65 mmol). The mixture was deoxygenated (3 x evacuation / purge cycles of N2) and then charged with H2 (3.5 kg / cm2). After 4 hours, the H2 was removed and the mixture was filtered through a pad of ce! iteR. The filtrate was concentrated to yield the title compound as an oil (90 mg, 49%), which was used without purification: 1 H NMR (300 MHz, CDCl 3) d 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, 2 H), 1.09 (t, 3 H).

PREPARATION 15 Preparation of methyl (±) -4- (4-hydroxyphenyl) -3- (oxazol-2-yl) butanoate a) Methyl 3- (benzyloxycarbonyl) -3-butenoate Diisopropyl azodicarboxylate (32.8 ml, 166 mmol) was added to a solution of methyl 3-carboxy-3-butenoate (20 g, 139 mmol), benzyl alcohol (17.2 mg, 166 mmol) and triphenylphosphine (43J g, 166 mmol) in anhydrous THF (500 mL), at 0 ° C. The mixture was allowed to warm up as the bath warmed to room temperature. After 3 hours, the mixture was concentrated and the residue was chromatographed on silica gel (10% EtOAc / hexane). The title compound (29.46 g, 91%) was obtained as a colorless oil: 1 H NMR (300 MHz, CDCl 3) d 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, 2 H). b) (±) -4- (4-Methoxyphenyl) -3-carboxybutanoate methyl 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, 2.67 mmole), P (o-tolyl) 3 (1.63 g, 5.34 mmole) and (i-Pr ^ NEt (9.3 ml, 53. 4 mmoles) in propionitrile (100 ml), was deoxygenated (3 x evacuation / purge cycles of N2) and then heated to reflux. After 24 hours, the mixture was concentrated and the residue was chromatographed on silica gel (15% EtOAc / hexane) to give a yellow oil. The oil was taken in 20% EtOAc / hexane (100 ml), and the solution was allowed to stand at room temperature. After 18 hours, the mixture was filtered and the filtrate was concentrated to give the title compound as a mixture of olefin isomers. This was used immediately in the next step. To a suspension of Pd 10% / C (2.8 g) in EtOAc / i-PrOH 1: 1 (100 ml), the above olefin mixture was added. The mixture was deoxygenated (3 x evacuation / purge cycles of N2) and then loaded with H2 (3.5 kg / cm2). After 4 hours, the H2 was removed and the mixture was filtered at through a pad of celiteR. The filtrate was concentrated to yield the title compound (5.81 mg, 86% 4-bromoanisole) as a yellow oil: 1 H NMR (300 MHz, CDCl 3) d 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) (±) -4- (4-methoxyphenyl) -3 - [(2,2-dimethoxyethyl) aminocarbonyl] -butanoate methyl To a solution of (±) -4- (4-methoxyphenyl) -3-carboxybutanoate of methyl (300 mg, 1.19 mmol) in CH2Cl2 (5 mL), was added 1,1-carbonyldiimidazole (289 mg, 1.78 mmol). After 1 hour, aminoacetaldehyde dimethylacetal (0.2 ml, 1.78 mmol) was added. After 72 hours, the mixture was concentrated. The residue was chromatographed on silica gel (50% EtOAc / hexane) to give the title compound (287 mg, 71%) as a clear oil: MS (ES) m / e 340 (M + H) +. d) (±) -4- (4-methoxyphenyl) -3- (oxazol-2-yl) butanoate methyl To a solution of 4- (4-methoxyphenyl) -3 - [(2,2-dimethoxyethyl) aminocarbonyl] Methyl butanoate (287 mg, 0.85 mmol) in THF (5 ml), 6.0 N HCl (5 ml) was added. After 1 hour, the mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over MgSO 4, filtered and concentrated. The residue was taken up in CH2CI2 (5 ml) and a solution of PP .3 (267 mg, 1.02 mmol), I2 (259 mg, 1.02 mmol) and Et ^ N (0.24 ml, 1.02 mmol) in CH2Cl2 ( 5 ml). After 18 hours, the mixture was concentrated. The residue was chromatographed on silica gel (50% EtOAc / hexane) to give the title compound (95 mg, 41%) as a yellow oil: MS (ES) m / e 276 (M + H) +. e) (±) -4- (4-Hydroxyphenyl) -3- (oxazol-2-yl) butanoate methyl To a solution of (±) -4- (4-methoxyphenyl) -3- (oxazol-2-yl) Methyl butanoate (314 mg, 1.14 mmol) in CH2Cl2 (5 ml), BBr3 (3.42 ft ml, 3.42 mmol) was added at -20 ° C. After 1 hour, the mixture was carefully quenched with 10% HCl in MeOH (10 mL), and the solution was allowed to warm to room temperature. After 18 hours, the mixture was concentrated. The residue was taken up in saturated NaHC 3 3 (20 ml) and extracted with Et2? (3 x 20 ml). The combined organic layers were dried over MgSO4, filtered and concentrated. The residue was subjected to gel chromatography Of silica (50% EtOAc / hexane) to give the title compound (163 mg, 55%) as a yellow oil: MS (ES) m / e 262 (M + H) +.

PREPARATION 16 Preparation of ethyl (±) -4- (4-hydroxyphenyl) -3- (thiazole-2-yl) butanoate 15 a) 2- [4- (Benzyloxy) phenyl] -1 - (thiazol-2-yl) ) Ethanone To a solution of n-BuLi (0.98 ml, 2.44 mmole) in Et2? dry (5 ml), 2-bromothiazole (0.21 ml, 2.34 mmol) was added dropwise to -78.

° C. After 20 minutes, 4- (benzyloxy) phenylacetate was added dropwise Methyl (0.5 g, 1.95 mmol) in dry E.2O (5 mL). After 1 hour, the mixture was quenched with saturated NH 4 Cl (10 mL), warmed to room temperature and extracted with E 2 O (3 x 20 mL). The combined organic layers were dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel (20% EtOAc / hexane) to give the title compound (485 mg, 80%) as a brown-yellow solid. EM (ES) m / e 310 (M + H) +. b) (±) -4- [4- (Benzyloxy) phenyl] -3- (thiazol-2-yl) ethyl crotonate To a suspension of NaH (111 mg, 2.78 mmol) in dry THF (5 ml), he added dropwise triethyl phosphonoacetate (0.56 ml, 2.78 mmol) at room temperature. After 15 minutes, a solution of 2- [4- (benzyloxy) phenyl] -1- (thiazol-2-yl) ethanone (430 mg, 1.39 mmol) in dry THF (5 ml) was added dropwise. After 6 hours, the mixture was quenched with saturated NH 4 Cl (10 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over MgSO 4, filtered and concentrated. The residue was chromatographed on silica gel (20% EtOAc / hexane) to give the title compound (356 mg, 67%) as a mixture of olefin isomers: MS (ES) m / e 380 (M + H ) + c) (±) -4- (4-Hydroxyphenyl) -3- (thiazol-2-yl) ethyl butanoate To a suspension of Pd 10% / C (100 mg) in absolute EtOH (5 ml), was added (±) -4- [4- (benzyloxy) phenyl] -3- (thiazol-2-yl) ethyl crotonate (356 mg, 0.94 mmol). The mixture was deoxygenated (3 x evacuation / purge cycles of N2) and then charged with H2 (3.5 kg / cm2). After 4 hours, the H2 was removed and the mixture filtered through a pad of celite®. The filtrate was concentrated. The reaction was repeated three times. The residue was chromatographed on silica gel (35% EtOAc / hexane) to give the title compound (155 mg, 57%) as an oil: MS (ES) m / e 292 (M + H) +.

PREPARATION 17 Preparation of (±) -4- (ethyl 4-hydroxyphenid-3-methylbutanoate) a) (±) -4- (4-Methoxyphenyl) -3-methylcryotonate of ethyl The title compound was prepared (5.2 g, 74%) according to the preparation procedure 16 (b), but was replaced with 4- methoxyphenylacetone 2- [4- (benzyloxy) phenyl] -1- (thiazol-2-yl) ethanone: 1 H NMR (300 MHz, CDCl 3) d 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) (±) -4- (4-Methoxyphenyl) -3-methylbutanoate ethyl The title compound was prepared as a colorless oil (5.1 g, 97%) according to the preparation procedure 16 (c), but substituted with ethyl (±) -4- (4-methoxyphenyl) -3-methylcrotonate ethyl (±) -4- [4- (benzyloxy) phenyl] -3- (thiazol-2-yl) crotonate: 1 H NMR (300 MHz, CDCI3) d 7.07 (d, J = 8.5 Hz, 2.H), 6.83 (d, J = 8.5 Hz, 2 H), 4.11 (q, J = 7.1 Hz, 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 H). c) (±) -4- (4-Hydroxyphenyl) -3-methylbutanoate ethyl The title compound was prepared as a yellow oil (3.2 g, 70%) according to the preparation procedure 15 (e), but Substituted with methyl (±) -4- (4-methoxyphenyl) -3-methylbutanoate methyl (±) -4- (4-methoxyphenyl) -3- (oxazol-2-yl) butanoate: H NMR (250 MHz , CDCI3) d 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).

PREPARATION 18 Preparation of methyl 4- (4-methoxyphenyl) crotonate a) 4-Methoxyphenylacetaldehyde A solution of 4-methoxyphenethyl alcohol (1.14 g, 7.49 mmol) in CH 2 Cl 2 (30 ml) was added dropwise to a suspension of PCC (2.45 g, 11.37 mmol) and NaOAc (1.85 g, 22.55 mmol). ) in CH2CI2 (50 ml) at 0 ° C under argon. After 1 hour, the mixture was filtered, and celite.RTM. And activated carbon was added to the filtrate. This mixture was filtered and the filtrate was concentrated in the rotary evaporator. The residue was dissolved in EtpO and MgS? 4 and activated charcoal were added. Filtration and concentration gave the title compound (1.1 g, 98%) as a colorless oil. This material was used immediately in the next step without further purification. b) Methyl 4- (4-methoxyphenyl) crotonate A solution of 4-methoxyphenylacetaldehyde (1.1 g, 7.33 mmol) and methyl (triphenylphosphoranylidene) acetate (2.99 g, 8.94 mmol) in THF (50 ml) was stirred at room temperature overnight and then concentrated in vacuo. The residue was dissolved in Et, 2? and the solution was treated with celite® and activated carbon. Filtration, concentration and chromatography on silica gel (5% EtOAc / hexane) gave the title compound (0.5 g, 33%): 1 H NMR (300 MHz, CDCl 3) d 7.00-7.20 (m, 3 H) ), 6.85 (d, J = 8.6 Hz, 2 H), 5.79 (d, J = 15.5 Hz, 1 H), 3J9 (s, 3 H), 3.71 (s, 3 H), 3.46 (d, j = 6.7 Hz, 2 H). c) 4- (4-Hydroxyphenyl) methyl crotonate BBr3 (1.0 M in CH2Cl2, 4.0 mL, 4.0 mmol) was added dropwise to a solution of methyl 4- (4-methoxyphenyl) crotonate (0.05 g, 3.64 mmol). ) in CH2CI2 (30 ml) at 0 ° C under argon. The reaction was stirred at 0 ° C for 2 hours and then more BBr3 was added (1.0 M in CH 2 Cl 2, 1.0 ml, 1. 0 mmol). After another hour, the reaction was carefully quenched by the slow addition of MeOH. The solution was concentrated and the residue was reconcentrated from MeOH (2x). The resulting residue was subjected to flash chromatography on silica gel (1% MeOH / CH2C-2) to produce the Compound title (0.46 g, 66%): 1 H NMR (300 MHz, CDCl 3) d 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).

PREPARATION 19 Preparation of methyl (±) -4- (4-hydroxyphenyl) -3- (thiophen-2-yl) butanoate a) (±) -3- (4-Methoxy-phenyl) -2- (thiophene-2-yl) -ethyl propionate Lithium hexamethyldisilazide (1.0 M in THF, 14 ml, 14.0 mmol) was added to a solution of 2 ml. ethyl -thiopheneacetate (2268 g, 13.32 mmol) in dry THF (10 ml) at -78 ° C under argon. After 1 hour, 4-methoxybenzyl chloride (2.0 ml, 14.75 mmol) was added. The reaction was maintained at -78 ° C for a further 15 minutes and then allowed to warm to room temperature. After 18 hours, the reaction was diluted with EtOAc and the solution was washed with 1.0 N HCl (2x), followed by 1.0 N NaHC (2x). Drying (MgSO 4), concentration and flash chromatography on silica gel (gradient: 5% EtOAc / hexane, then 10% EtOAc / hexane, then 20% EtOAc / hexane), the title compound (2.71 g, 66%) was obtained as a clear, colorless oil: 1 H NMR (300 MHz, CDCl 3 ) d 7.16-7.14 (m, 1 H), 7.04 (d, J = 8 J Hz, 2 H), 7.02-6.87 (m, 2 H), 6.76 (d, J = 8 J 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). 3 b) (±) -1-Diazo-4- (4-methoxyphenyl) -3- (thiophen-2-yl) -2-butanone 1.0 N NaOH (10 mL, 10 mmol) was added to a solution of (±) Ethyl -3- (4-methoxyphenyl) -2- (thiophen-2-yl) propionate (2.71 g, 8.84 mmol) in MeOH (10 mL), and the resulting bright yellow mixture was subsequently diluted with MeOH and THF to dissolve a precipitated oil. After 18 hours at room temperature, the reaction was neutralized with 1.0 N HCl (10 ml) and the volatile organic fractions were removed in vacuo. The remaining aqueous layer was acidified with 1.0 N HCl and extracted with EtOAc. The combined organic layers were dried (MgSO 4), filtered and concentrated in vacuo. The residue was dissolved in excess of SOCI2 and the solution was heated to reflux for 1 hour. The reaction was concentrated in vacuo and the residue reconcentrated from toluene (2x). The resulting residue was dissolved in THF, and diazomethane, generated from Diazald (2.0077 g, 9.4 mmol) was added at room temperature. Additional diazomethane from Diazald (1.4420 g, 6.7 mmol) was added and the reaction was allowed to stir overnight at room temperature. The resulting orange reaction mixture was concentrated in vacuo and the residue was adsorbed on silica gel. This was loaded onto a dry column of silica gel. Flash chromatography (gradient: 5% EtOAc / hexane, then 10% EtOAc / hexane, then 20% EtOAc / hexane) gave the title compound (707.6 mg, 30%) as an oil: 1 H NMR (300 MHz, CDCl 3 ) d 7.25-7.19 (m, 1 H), 7.03 (d, J = 8.6 Hz, 2 H), 6.94-6.85 (m, 2 H), 6J7 (d, J = 8J 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). c) (±) -4- (4-Methoxyphenyl) -3- (thiophene-2-yl) methyl butanoate A solution of silver benzoate (744.2 mg, 3.25 mmol) in triethylamine (3 ml, 21.6 mmol) was added to a solution of (±) -1-diazo-4- (4-methoxyphenyl) -3- (thiophen-2-yl) -2-butanone (707.6 mg, 2.47 mmol) in MeOH (20 ml) at room temperature. Gas evolution was observed and the reaction mixture turned black. After 30 minutes, the reaction was heated to reflux. After 1 hour at reflux, the reaction was filtered through celite® and the filtrate was concentrated in vacuo. The residue was adsorbed on silica gel and loaded onto a dry column of silica gel. Flash chromatography (gradient: 5% EtOAc / hexane, then 10% EtOAc / hexane) gave the title compound (453.4 mg, 48.0%) as a light yellow oil: 1 H NMR (300 MHz, CDCl 3) d 7.16- 7.14 (m, 1 H), 7.04 (d, J = 8.5 Hz, 2 H), 6.91-6.89 (m, 1 H), 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) (±) -4- (4-Hydroxyphenyl) -3- (thiophene-2-yl) methyl butanoate Boron tribromide (1.0 M in CH2Cl2, 8 ml, 8 mmol) was added to a solution of (±) Methyl -4- (4-methoxyphenyl) -3- (thiophen-2-yl) butanoate (453.4 mg, 1.56 mg) in CH2Cl2 (10 mL) at 0 ° C under argon. After 1 hour, the reaction was quenched with absolute MeOH and concentrated in vacuo. Reconcentration of toluene (several times), followed by ng under high vacuum, gave the title compound (449.6 mg, quantitative) as an oil: 1 H NMR (300 MHz, CDCl 3) d 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).

PREPARATION 20 Preparation of ethyl 2-rN-benzyl-N- (4-hydroxybenzyl) amino-1-acetate a) 2- [ethyl N-benzyl-N- (4-methoxybenzyl) amino] acetate To a solution of 4-methoxybenzyl chloride (1.00 ml, 7.38 mmol) in DMF (14 ml) at 0 ° C, added ethyl 2-benzylaminoacetate (1.20 ml, 6.40 mmol), followed by NaH (0.38 g, 60% dispersion in oil, 9.50 mmol). The ice bath was removed and the reaction was allowed to stir at room temperature for 18 hours. The reaction was quenched by emptying it in saturated NaHCO 3 and the mixture was extracted with EtOAc. The combined organic extracts were dried over Na 2 SO 4 and concentrated to give a yellow oil. Radial chromatography (10% EtOAc / hexane, silica gel, 6 mm plate) gave the title compound (0.40 g) as a clear oil: MS (ES) m / e 314.1 (M + H) +. b) 2- [N-Benzyl-N- (4-hydroxybenzyl) amino] ethyl acetate A solution of ethyl 2- [N-benzyl-N- (4-methoxybenzyl) amino] acetate (0.40 g, 1.27 mmol) in CH 2 Cl 2 (2 mL) was added dropwise to a solution of BBr 3 (3.80 mL, 1.0 M in CH 2 Cl 2, 3.80 mmol) at 0 ° C. After 1 hour at 0 ° C, the reaction was carefully quenched with MeOH (2 mL). The solvent was removed under reduced pressure and the residue was azeotropically distilled from MeOH (2x). Radial chromatography (30% EtOAc / hexane, silica gel, 6 mm plate) gave the title compound (0.19 g) as a white solid: MS (ES) m / e 300.1 (M + H) +.

PREPARATION 21 Preparation of methyl 2-fN- (4-hydroxybenzyl) -N-phenylamino-1-acetate a) 2- [N- (4-Methoxybenzyl) -N-phenylamino] methyl acetate To a solution of methyl 2- (phenylamino) acetate hydrochloride (0.19 g, 0.96 mmol) in DMF (3 mL), added 4-methoxybenzyl chloride (0.52 ml, 3.84 mmol), followed by NaH (0.11 g, 60% dispersion in oil, 2.75 mmol). After 18 hours at room temperature, the reaction was poured into saturated NaHC 3 3 and the mixture was extracted with EtOAc. The combined organic extracts were washed with 50% brine, dried over Na 2 SO 4 and concentrated to give a yellow oil. Radial chromatography (20% EtOAc / hexane, silica gel, 6 mm plate) gave the title compound (0.13 g) as a clear oil: MS (ES) m / e 286.1 (M + H) +. b) 2- [N- (4-Hydroxybenzyl) -N-phenylamino] methyl acetate A solution of methyl 2- [N- (4-methoxybenzyl) -N-phenylamino] acetate (0.13 g, 0.47 mmole) in CH2Cl2 was added dropwise to a solution of BBr3 (1.40 ml, 1.0 M in CH2Cl2, 1-40 ml) at 0 ° C. After 45 minutes at 0 ° C, the reaction was carefully quenched by the addition of MeOH (2 mL). The solvent was removed under reduced pressure and the residue was azeotropically distilled from MeOH (2x). The residue was dissolved in saturated NaHC 3 3 and the solution was extracted with EtOAc. The combined organic extracts were dried over Na 2 SO 4 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 title compound (39 mg) as a light yellow solid: MS (ES) m / e 272.2 (M + H) + .

PREPARATION 22 Preparation of methyl 2-α- (4-hydroxy-2-methoxybenzyl) amino-1-acetate a) Methyl 2 - [(4-hydroxy-2-methoxybenzyl) amino] acetate To a suspension of 4-hydroxy-2-methoxybenzaldehyde (2.00 g, 13. 1 mmol) and glycine methyl ester hydrochloride (6.60 g, 52.6 mmol) in dry MeOH (100 ml), were added molecular sieves of 4 Á (approximately 2 g) and NaBH 3 CN (0.83 g, 13.2 mmol). After 18 hours at room temperature, the reaction mixture was filtered through a pad of celite® and the solvent was removed under reduced 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) +.

PREPARATION 23 Preparation of methyl 2- (4-hydroxy-2-phenoxyphenyl) acetate a) 2- (4-Methoxy-2-phenoxyphenyl) -1-morpholin-4-yl-ethane-1-thione Reacted 4-methoxy-2-phenoxyacetophenone (1.69 g, 6.98 mmol), sulfur (0.36 g, 11.2 mmoles) and morpholine (0.98 ml, 11.2 mmoles), according to the procedure of Harris TW et al (J. Med. Ft 10 Chem., 1982, 25 (7), 855-858), to give the compound of title (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) -1-morpholin-4-yl-ethane-1-thione (0.35 g, 1.02 mmoles) in i-PrOH (15 ml) and H 2 O (15 ml), KOH (0.57 g, 10.2 mmol) was added. The reaction was heated to reflux for 18 hours and then cooled to room temperature, diluted with H2O and washed with Et2 ?. The aqueous layer was acidified to pH «4 with conc. HCl. and extracted with CHCl3. The combined extracts were dried over MgSO4 and concentrated to give the title compound (0.22 g) as a white solid. This was used without further 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 H2SO4 conc. (1 drop) The reaction was heated to reflux for 18 hours and then allowed to cool to room temperature. Most of the MeOH was removed under reduced pressure and the remaining solution was poured into saturated NaHCO 3. The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with brine and dried over Na 2 SO 4. The solvent was removed under reduced pressure to give the title compound (0.22 g) as a light 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 BBr3 (1.0 M in CH2Cl2, 4.0 ml, 4 mmol), at 0 ° C, a solution of 2- was added dropwise. Methyl (4-methoxy-2-phenoxyphenyl) acetate (0.22 g, 0.81 mmol) in CH 2 Cl 2 (1 mL).

After 20 minutes, the solvent was removed under reduced pressure and the residue was azeotropically distilled from MeOH (2x). Then, the residue was dissolved in saturated NaHC 3 3 and the solution was extracted with EtOAc. The combined extracts were dried over Na 2 SO 4 and concentrated to give the title compound (0.19 g) as a light yellow oil. This was used without further purification: MS (ES) m / e 259.0 (M + H) +.

PREPARATION 24 Preparation of methyl 2- (2-phenoxy-4-hydroxy-phenylphenylbutanoate) a) 2- (2-Phenoxy-4-methoxy) phenylethan-1-ol 5 To a solution of 2- (4-methoxy-2-phenoxyphenyl) acetic acid (0.24 g, 0.93 mmol) in THF (5 ml) a 0 ° C, lithium aluminum hydride (0.11 g, 2J9 mmoles) was added. After 1 hour at 0 ° C, the reaction was diluted with toluene (10 ml), and NaF (0.47 g) and H2O (0.15 ml) were added sequentially. The mixture was stirred vigorously at 0 ° C for 30 minutes. The resulting ft 10 precipitate was removed by filtration and rinsed with Et 2 ?. The filtrate was concentrated to give the title compound (0.16 g) as a clear oil. The material was used without further purification: ^ H NMR (300 MHz, CDCl 3) d 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, 15 J = 6.6 Hz, 2 H). ft b) 2- (2-Phenoxy-4-methoxy) phenylacetaldehyde Oxalyl chloride (0.06 ml, 0.69 mmole) was added to a solution of DMSO (0.09 ml, 1.27 mmole) in CH2Cl2 (1.2 ml) at -78 ° C . 20 After 10 minutes, was added a solution of 2- (2-phenoxy-4-methoxy) phenylethane-1-ol (0.16 g, 0.64 mmol) in CH2CI2 (1.2 ml). The reaction was stirred at -78 ° C for an additional 1 hour, then added (0.27 ml, 13 1. 94 mmoles) and the bath was removed from -78 ° C. After an additional 20 minutes, the reaction was diluted with CH2Cl2 and washed sequentially with 1.0 N HCl, saturated NaHCO3 and brine; then dried over Na 2 SO 4. The solvent was removed under vacuum to give the title compound (0.13 g) as a light yellow oil. The material was used without further purification: H NMR (300 MHz, CDCl3) d 9.71 (t, J = 1.9 Hz, 1H), 7.30 (m, 2 H), 7. 10 (m, 2 H), 6.95 (d, J = 7J 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-butenoate A solution of 2- (2-phenoxy-4-methoxy) phenylacetaldehyde (0.13 g, 0.53 mmole) and methyl (triphenylphosphoranylidene) acetate ( 0.35 g, 1.05 mmol) in THF (3 ml), was heated to reflux for 5 hours and then allowed to cool to room temperature. The reaction was poured into H2O and the mixture was extracted with Et2 ?. The organic extracts were dried over Na2SO4 and 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 of stereo- and regioisomers olefin. This was used in the next step without further purification: MS (ES) m / e 299.1 (M + H) +. d) Methyl 2- (2-phenoxy-4-methoxy) phenylbutanoate A Parr hydrogenation vessel was charged with methyl 2- (2-phenoxy-4-methoxy) phenylbut-2-enoate (0.12 g, 0.39 mmol) ), Pd 10% / C (50 mg) and MeOH (50 ml), and the mixture was stirred under a hydrogen atmosphere at 3.5 kg / cm2. After 18 hours, the catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. Flash chromatography on silica gel (15% EtOAc / hexane) gave the title compound (0.09 g) as a clear oil: MS (ES) m / e 300.9 (M + H) +. e) Methyl 2- (2-phenoxy-4-id roxy) phen-ilbutanoate A solution of methyl 2- (2-phenoxy-4-methoxy) phenylbutanoate (0.09 g, 0.30 mmol) in CH2Cl2 (2 ml), was added to BBr3 (1.0 M in CH2CI2, 1. 50 ml, 1.5 mmol) at 0 ° C. After 1 hour 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 azeotropically distilled from MeOH (2x). A saturated solution of NaHCO 3 was added to the residue and the aqueous layer was extracted with EtOAc. The combined extracts were dried over Na2SO4 and concentrated to give the title compound (0.08 g) as a light yellow oil. This material was used in the next step without further purification: 1H NMR (300 MHz, CDCl3) d 7.25 (m, 2H), 7.05 (m, 2H), 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, 2 H).

PREPARATION 25 Preparation of 2- (5,6,7,8-tetrahydro-1,8-naphthyrid? N-2-yl) -1-ethanol a) 2-Methyl-8- (7e-butoxycarbonyl) -5,6,7,8-tetrahydro-1,8-naphthyridine A mixture of 2-methyl-1,8-naphthyridine (J. Chem. Soc. C) 1966, 315; 5.13 g, 35.58 mmol), Pd 10% / C (1.14 g, 1.07 mmol) and absolute EtOH (70 ml), was deoxygenated by three cycles of evacuation / purge of H2; it was then stirred vigorously under a H2 balloon. After 18.5 hours, the mixture was filtered through celite® and the filter pad was washed sequentially with absolute EtOH and EtOAc. The filtrate was concentrated to dryness and the residue was reconcentrated from EtOAc to leave an off-white solid (5.25 g). A solution of the above material (5.25 g), di-fer-butyl dicarbonate (15.53 g, 71.16 mmol) and CH2CI2 (10 mL) was concentrated in the rotary evaporator to remove the solvent, and the oily residue was heated under N2 in an oil bath set at 55-60 ° C. After 45 hours, the reaction was cooled to room temperature and the residue was subjected to flash chromatography on silica gel (40% EtOAc / hexane). The title compound was obtained (4.90 g, 55%) as a light yellow solid: 1 H NMR (300 MHz, CDCl 3) d 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) [8- (fer-Butoxycarbonyl) -5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl] ethyl acetate To a solution of diisopropylamine (7.24 ml, 55.3 mmoles) in THF Dry (50 ml) was added dropwise n-BuLi (2.5 M in hexane, 22 ml, 55.3 mmol) at 0 ° C. After 15 minutes, this solution was added dropwise to a solution of 2-methyl-8- (fer-butoxycarbonyl) -5,6,7,8-tetrahydro-1,8-naphthyridine (4.9 g, 19.7 mmol) and diethyl carbonate (8.86 ml, 73.0 mmol) in dry THF (50 ml) at -78 ° C. After 30 minutes, the mixture was quenched with saturated NH 4 Cl (100 mL), warmed to room temperature and extracted with EtOAc (3 x 200 mL). The combined organic extracts were dried over MgSO 4, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel (40% EtOAc / hexane) to give the title compound (5J2 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-yl) -1-ethanol To a solution of [8- (fer-butoxycarbonyl) -5,6,7,8 ethyl-tetrahydro-1, 8-naphthyridin-2-yl] acetate (5.72 g, 17.85 mmol) in dry THF (80 ml) at room temperature, was added LBH4 (2.0 M in THF, 10.7 ml, 21.42 mmol) , and the resulting mixture was heated to reflux. After 18 hours, the mixture was cooled to 0 ° C and carefully quenched with H2O (100 mL).

After 10 minutes, the mixture was extracted with EtOAc (3 x 100 ml). The combined organic extracts were dried over MgSO 4, filtered and concentrated under reduced pressure.

The above residue (4.9 g) was dissolved in CH2Cl2 (10 ml). To this was added all at once 4N HCl in dioxane (20 ml) at room temperature. After 4 [], the mixture was concentrated under reduced pressure. He • residue was taken in a 1: 1 mixture of 1.0 N NaOH and saturated NaCl (100 ml) and extracted with CH2Cl2 (3 x 100 ml). The combined organic extracts were dried over MgSO 4, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel (10% MeOH in EtOAc / CHCl 3 1: 1) to give the title compound (2.09 g, 66%) as a yellow solid: MS (ES) m / e 179 (M + H) +. 10 PREPARATION 26 HPLC separation of the enantiomers of methyl (±) -4- (4-hydroxyphenyl) -3- (thiazol-2-yl) butanoate a) (S) - (-) - Methyl 4- (4-hydroxyphenyl) -3- (thiazol-2-yl) butanoate and (R) - (+) - 4- (4-ft hydroxyphenyl) -3 Methyl (thiazol-2-yl) butanoate Methyl (±) -4- (4-hydroxyphenyl) -3- (thiazol-2-yl) butanoate was resolved in its enantiomers using the following conditions: Diacel Chiralcel OJR column ( 21.2 x 250 mm), mobile phase of 20% ethanol in hexane, flow rate 12 ml / min, uv detection at 320 nm, injection of 25 mg; IR for (S) - (-) - methyl 4- (4-hydroxyphenyl) -3- (thiazol-2-yl) butanoate = 14.5 min; IR for (R) - (+) - methyl 4- (4-hydroxyphenyl) -3- (thiazol-2-yl) butanoate = 17.2 min.

PREPARATION 27 HPLC separation of the enantiomers of ethyl (±) -4- (4-methoxyphenyl) -3-phenylbutanoate a) (-) - Ethyl 4- (4-methoxyphenyl) -3-phenylbutanoate and ethyl (+) - 4- (4-methoxyphenyl) -3-phenylbutanoate Resolved (±) -4- (4-methoxyphenyl) Ethyl-3-phenylbutanoate in its enantiomers using the following conditions: Diacel Chiralcel OjR column (21.2 x 250 mm), mobile phase of 15% ethanol in hexane, flow rate 15 ml / min, uv detection at 254 nm, injection of 100 mg; IR for (-) - ethyl 4- (4-methoxyphenyl) -3-phenylbutanoate = 9.0 min; IR for (+) - ethyl 4- (4-methoxyphenyl) -3-phenylbutanoate = 12.2 min.

PREPARATION 28 Preparation of methyl (±) -3- (furan-2l) -4- (4-hydroxy-phenyl) butanoate a) 3- (Furan-2-yl) methyl acrylate H2SO4 (0.5 ml, 9.39 mmol) was added to an acid solution 3- (2-furanyl) acrylic (5.0 g, 36.2 mmol) in MeOH (30 mL). The reaction was heated to reflux for 22 hours and then concentrated in the rotary evaporator. The residue was diluted with H2O (100 ml) and extracted with ether (2 x 70 ml). The organic layers were combined and washed sequentially with saturated NaHC 3 (30 ml) and H 2 O (30 ml). By drying (Na 2 S 4) and concentration in the rotary evaporator, the title compound (4.86 g, 88%) was obtained as a light brown oil: TLC Rf (10% EtOAc / hexane) 0.50; EM (EN) m / e 479.0 (3M + Na) +. b) (±) -3- (Furan-2-yl) -4- (4-methoxyphenyl) butanoate of methyl. TMEDA (2.18 ml, 14.47 mmol) was added slowly to a mixture of Cul (2.51 g, 13.16 mmol) in THF (35 ml) at room temperature under argon. After 10 minutes at room temperature, the reaction mixture was cooled to -78 ° C and a solution of 4-methoxybenzylmagnesium chloride in THF (0.5 M, 26.32 mL, 13.16 mmol) was added slowly. The reaction was stirred for 15 minutes and then a solution of TMSCI (4.17 ml, 32.89 mmol) and methyl 3- (furan-2-yl) acrylate (1.0 g, 6.58 mmol) in THF (20 ml) was injected, and the temperature was allowed to rise to -30 ° C. After 18 hours, the reaction was quenched with NH 4 Cl / saturated NH 4 OH (30 ml) and the reaction was continued to room temperature. H2O (20 ml) was added and the mixture was extracted with ether (2 x 70 ml). The combined organic layers were washed with H2O (2 x 50 ml) and dried (Na2S4). Concentration and chromatography on silica gel (8% EtOAc / hexane) gave the title compound (0.85 g, 93%) as a clear oil: TLC Rf (8% EtOAc / hexane) 0.38; MS (ES) m / e 297 (M + Na) +. c) (±) -3- (Furan-2-yl) -4- (4-hydroxyphenyl) butanoate methyl A solution of (±) -3- (furan-2-yl) -4- was added dropwise. Methyl (4-methoxyphenyl) butanoate (0.82 g, 2.99 mmol) in CH2Cl2 (10 mL) a • a solution of BBr3 in CH2Cl2 (1.0 M, 11.97 ml, 11.97 mmol) at 0 ° C under argon. After 30 minutes, the reaction was quenched with MeOH (5 ml). The solution was stirred for 10 minutes and then concentrated in the rotary evaporator. The residue was partitioned between EtOAc (50 mL) and 3% NaHC 3 (30 mL). The layers were separated and the organic layer was washed with H2O (20 ml) and dried (Na2SO4). By concentration and chromatography on silica gel (40% EtOAc / hexane), obtained the title compound (0.12 g, 15%) as a light greenish yellow residue: TLC Rf (EtOAc 50% / hexane) 0.36; EM (ES) m / e 542.8 (2M + Na) +.

PREPARATION 29 15 Preparation of (±) -3-M - (dimethylaminosulfonyl) imidazole-2-in-4- (4-hydroxy-phenyl-butanoate) a) 1 - (Dimethylaminosulfonyl) imidazole To a solution of imidazole (1.63 g, 24 mmol) in CH2CI2 8100 ml), E.3N (3.35 ml, 24 mmol) was added, followed by dimethylaminosulfonyl chloride (2.15 ml, 20 mmol) at room temperature. After 24 hours, the mixture was concentrated. The residue was taken up in EtOAc (200 ml) and filtered through a pad of silica gel. The filtrate was concentrated to give the title compound (2.89 g, 82%) as a white solid: MS (ES) m / e 176 (M + H) +. b) 2- (4-Benzyloxyphenyl) -1 - [1- (dimethylaminosulfonyl) imidazol-2-yl] ethanone The title compound was prepared (364 mg, 47%) according to the preparation procedure 16 (a) , but was substituted with 1- (dimethylaminosulfonyl) imidazole (410 mg, 2.34 mmol) 2-bromothiazole, obtaining as a white solid after chromatography on silica gel (EtOAc 35% / hexane): MS (ES) m / e 400 (M + H) +. c) (±) -4- (4-Benzyloxy-phenyl) -3- [1- (dimethylaminosulfonyl) imidazol-2-yl] ethyl crotonate The title compound was prepared (589 mg of a mixture of olefin isomers, 89% ) according to the preparation procedure 16 (b), but was substituted with 2- (4-benzyloxyphenyl) -1- [1- (dimethylaminosulfonyl) imidazol-2-yl] ethanone (564 mg, 1.41 mmol) at 2 ° C. - [4- (benzyloxy) phenyl] -1- (thiazol-2-yl) ethanone, obtained as an orange oil after chromatography on silica gel (35% EtOAc / hexane): MS (ES) m / e 470 (M + H) +. d) (±) -3- [1- (dimethylaminosulfonyl) imidazol-2-yl] -4- (4-hydroxyphenyl) butanoate of ethyl The title compound (436 mg, 91%) was prepared as a white solid in accordance with the preparation procedure 16 (c), but was substituted with ethyl (±) -4- (4-benzyloxyphenyl) -3- [1- (dimethylaminosulfonyl) imidazoI-2-ylchcrotonate (589 mg, 1.25 mmol) on ( ±) -4- [4- (benzyloxy) phenyl] -3- (thiazole-2-yl) ethyl crotonate: MS (ES) m / e 382 (M + H) +.

PREPARATION 30 Preparation of (±) -3- (benzothiazol-2-yl) -4- (4-hydroxyphenyl, ethyl butanoate a) 1 - (Benzothiazol-2-yl) -2- (4-benzyloxyphenyl) ethanone The title compound was prepared (570 mg, 81%) according to the preparation procedure 16 (a), but was replaced with benzothiazole (0.26 mL, 2.34 mmol) 2-bromothiazole, obtaining as a pale yellow solid after trituration with hexane: MS (ES) m / e 360 (M + H) +. b) (±) -3- (Benzothiazol-2-yl) -4- (4-benzyloxyphenyl) ethyl crotonate The title compound was prepared as a mixture of olefin isomers according to the preparation procedure 16 (b) , but was substituted with 1- (benzothiazol-2-yl) -2- (4-benzyloxyphenyl) ethanone (570 mg, 1.59 mmol) 2- [4- (benzyloxy) phenyl] -1 - (thiazo-2-yl); I) ethanone. The crude product was used without further purification. c) (±) -3- (BenzothiazoI-2-yl) -4- (4-benzyloxyphenyl) butanoate of ethyl It was hydrogenated (at 3.5 kg / cm2 of H2) (±) -3- (benzothiazol-2-yl) -4- (4-benzyloxyphenyl) ethyl crotonate (1.59 mmoles, crude) using Pd 10% / C (1.00 g) in EtOH / EtOAc 1: 1 (20 ml) for 5 hours. The mixture was filtered through a pad of celite and the filtrate was concentrated. The crude residue was used without further purification. d) (±) -3- (Benzothiazdl-2-yl) -4- (4-hydroxyphenyl) butanoate ethyl To a solution of (±) -3- (benzothiazol-2-yl) -4- (4-benzyloxyphenyl) ethyl butanoate (1.59 mmol, crude) in EtSH (1.95 ml), at room temperature, BF3-OEÍ2 (1.95 ml) was added. After 48 hours, more BF3-OEÍ2 (1.95 ml) was added. After a further 18 hours, the mixture was cooled to 0 ° C and quenched carefully with saturated NaHC 3. The resulting mixture was extracted with CH2Cl2 (3 x 25 ml). The combined organic layers were dried over MgSO4 and concentrated. The residue was chromatographed on silica gel (30% EtOAc / hexane) to give the title compound (391 mg, 72% by the 3 steps) as a foam: MS (ES) m / e 342 (M + H ) + PREPARATION 31 Preparation of ethyl (± .3- (4-methylthiazol-2-yl) -4- (4-hydroxyphenyl) butanoate a) 2- (4-Benzyloxyphenyl) -1 - (4-methylthiazol-2-yl) ethanone The title compound was prepared (303 mg, 48%) according to the preparation procedure 16 (a), but was replaced with 4-methylthiazole (0.21 ml, 2.34 mmol) 2-bromothiazole, obtaining as a pale yellow solid after chromatography on silica gel (15% EtOAc / hexane): MS (ES) m / e 324 (M + H) +. b) (±) -3- (4-Methylthiazol-2-yl) -4- (4-benzyloxyphenyl) ethyl crotonate The title compound was prepared as a mixture of olefin isomers according to the preparation procedure 16 ( b), but was substituted with 2- (4-benzyloxyphenyl) -1- (4-methithiazol-2-yl) ethanone (300 mg, 0.93 mmole) 2- [4- (benzyloxy) phenyl] -1- (thiazol-2-yl) ethanone. The crude product was used without further purification. c) (±) -3- (4-Methylthiazol-2-yl) -4- (4-benzyloxyphenyl) butanoate of ethyl (±) -3- (4-Methylthiazol-2-yl) -4- (4 -benzyloxyphenyl) ethyl crotonate (0.93 mmole, crude) in MeOH (10 ml), and magnesium swarf (113 mg, 4.65 mmol) was added at room temperature. After 18 hours, the mixture was drained in 10% HCl (75 mL) and extracted with CH2Cl2 (3 x 50 mL). The combined organic layers were dried over MgSO 4 and concentrated. The residue was used in the next step without purification. d) (±) -3- (4-Methylthiazol-2-yl) -4- (4-hydroxyphenyl) butanoate of ethyl To a solution of (±) -3- (4-methylthiazol-2-yl) -4- Ethyl (4-benzyloxyphenyl) butanoate (0.93 mmol, crude) in EtSH (10 ml), was added BF3-OEÍ2 (2.29 ml) at room temperature. After 24 hours, it he added more BF3-OEÍ2 (1.00 ml). After 72 hours, the mixture was cooled to 0 ° C and quenched with saturated NaHC 3 3. The resulting mixture was extracted with CH2Cl2 (3 x 25 ml). The combined organic layers were dried over MgSO 4 and concentrated. The residue was chromatographed on silica gel (30% EtOAc / hexane) to give the title compound (216 mg, 80% by 3 steps) as a white solid: MS (ES) m / e 292 (M + H) +.

PREPARATION 32 Preparation of (±) -4- (4-hydroxyphenyl) -3-r4- (benzyloxycarbonyl) -1,3-oxazole-2-methylbutanoate methyl a) 4-Bromo-1 - (triisopropylsilyloxy) benzene To a solution of 4-bromophenol (2.00 g, 1.56 mmol) in dry DMF (20 ml) at room temperature, imidazole (1.57 g, 23.12 mmol) was added, followed by triisopropylsilyl chloride (3J1 ml, 17.34 mmol).

After 4 hours, the mixture was diluted with H2O (50 ml) and extracted with hexane (3 x 75 ml). The combined organic layers were dried over MgSO 4 and concentrated to give the title compound (4.00 g, 100%) as a clear oil, which was used without purification: ^ H NMR (300 MHz, CDCl 3) d 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) (±) -3-Carboxy-4- [4- (triisopropylsilyloxy) phenyl] butanoate methyl The title compound (2.24 g, 85% by 2 steps) was obtained as a clear oil according to the procedure of Preparation 15 (b), but was replaced with 4-bromo-1- (triisopropylsilyoxy) benzene (2.19 g, 6.66 mmoles) 4-bromoanisole. 1 H NMR (300 MHz, CDCl 3) d 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, 3 H), 1.09 (m, 18 H). c) Benzyl ester of (±) -N- [2- [4- (tri isopropylsilyloxy] benzyl] -3- (carbomethoxy) propionyl] serine To a solution of (±) -3-carboxy-4- [4 - methyl (triisopropylsilyloxy) phenyl] butanoate (1.00 g, 2.53 mmol) in dry DMF (10 ml) at room temperature, was added benzyl ester hydrochloride serine (704 mg, 3.04 mmol), HOBt (411 mg, 3.04 g) mmoles), EtjN (1.06 ml, 7.60 mmoles) and EDC (583 mg, 3.04 mmoles). After 18 hours, the mixture was concentrated. The residue was chromatographed on silica gel (80% EtOAc / hexane) to give the title compound (834 mg, 58%) as a pale yellow oil: MS (ES) m / e 572 (M + H) + . d) (±) -3- [4- (Benzyloxycarbonyl) -1,3-oxazolin-2-yl] -4- [4- (triisopropylsilyloxy) phenyl] butanoate methyl To a solution of benzyl ester of (±) - N- [2- [4- (Trisopropylsilyloxy) benzyl] -3- (carbomethoxy) propionyl] serine (834 mg, 1.46 mmol) in dry THF (10 mL) was added with Burgess reagent (417 mg, 1 mg). J5 mmoles) and then the mixture was heated to reflux. After 2 hours, the mixture was cooled to room temperature and concentrated. The residue was chromatographed on silica gel (36% EtOAc / hexane) to give the title compound (633 mg, 78%) as a clear oil: MS (ES) m / e 554 (M + H) +. e) (±) -3- [4- (benzyloxycarbonyl) -1,3-oxazol-2-yl] -4- [4- (triisopropylsilyoxy) phenyl] butanoate methyl To a solution of (±) -3- [ 4- (Benzyloxycarbonyl) -1,3-oxazolin-2-yl] -4- [4- (triisopropylsilyloxy) phenyl] butanoate methyl (633 mg, 1.14 mmol) in CH 2 Cl 2 (6 mL) at 0 ° C, added DBU (0.19 ml, 1.25 mmol), followed by bromotrichloromethane (0.12 ml, 1.25 mmol). The mixture was allowed to warm to room temperature as the bath warmed. After 18 hours, the mixture was concentrated. The residue was chromatographed on silica gel (20% EtOAc / hexane) to give the title compound (427 mg, 68%) as a clear oil: MS (ES) m / e 552 (M + H) +. f) (±) -3- [4- (Benzyloxycarbonyl) -1,3-oxazol-2-yl] -4- (4-hydroxyphenyl) butanoate methyl To a solution of (±) -3- [4- ( benzyloxycarbonyl) -1,3-oxazol-2-yl] -4- [4- (triisopropylsilyloxy) phenyl] butanoate (427 mg, 0.77 mmol) in dry THF (5 ml) at 0 ° C, added a solution of TBAF in THF (1.0 M, 1.16 ml, 1.16 mmol). After 2 hours, the mixture was diluted with saturated NH 4 Cl (10 mL) and extracted with CH 2 Cl 2 (3 x 15 mL). The combined organic layers were dried over MgSO 4 and concentrated. The residue was chromatographed on silica gel (40% EtOAc / hexane) to give the title compound (268 mg, 88%) as a whitish foam: MS (ES) m / e 396 (M + H) +.

PREPARATION 33 Preparation of (±, -3-r4-carboxy-1,3-oxazol-2-ip-4-r4-.2-r6- (methylamino) pyridin-2-n-1-ethoxylphen Methyl nbutanoate a) (±) -3- [4- (Benzyloxycarbonyl) -1, 3-oxazol-2-yl] -4- [4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy Methyl] phenyl] butanoate Diisopropyl azodicarboxylate (0.27 ml, 1.36 mmol) was added to a solution of (±) -3- [4- (benzyloxycarbonyl) -1,3-oxazol-2-yl] -4- (4 -hydroxyphenyl) methyl butanoate (268 mg, 0.68 mmol), 2 - [(6-methylamino) pyridin-2-yl)] ethanol (207 mg, 1.36 mmol), and triphenylphosphine (357 mg, 1.36 mmol) in anhydrous THF (4 ml) at 0 ° C. The mixture was allowed to warm to room temperature as the bath warmed. After 18 hours, the • mixture was concentrated and the residue was chromatographed on silica gel (50% EtOAc / toluene) to give the title compound (284 mg, 79%) as a clear oil: MS (ES) m / e 530 (M + H) +. b) (±) -3- [4-Carboxy-1, 3-oxazol-2-yl] -4- [4- [2- [6- (methylamino) pyridin-2-yl] -1 - methyl ethoxy] phenyl] butanoate? or A mixture of (±) -3- [4- (benzyloxycarbonyl) -1, 3-oxazol-2-yl] -4- [4- [2- [6- (methylamino)] methyl pyridin-2-yl] -1-ethoxy] phenyljbutanoate (234 mg, 0.44 mmol) and 10% Pd / C (100 mg) in EtOH (5 ml), deoxygenated (3x vacuum / N2), and then stirred vigorously under H2 (balloon pressure). After 4 hours, the mixture was filtered through a pad of celite® and concentrated to give the title compound (165 mg, 85%) as a white foam: MS • (ES) m / e 440 (M + H) +.

PREPARATION 34 Preparation of Methyl (±. 3- (4-hydroxybenzyl) pent-4-enoate 20 a) (±) -3-Formyl-4- (4-methoxyphenyl) butanoate To a solution of (±) Methyl 4- (4-methoxyphenyl) -3-carboxybutanoate (prepared as described in Preparation 15, 0.45 g, 1.80 mmol) in CH2Cl2 (10 mL), oxalyl chloride (0.24 mL, 2.75 mmol) was added. and DMF (1 drop). After 1.5 hours, the solvent was removed under reduced pressure and the residue was azeotropically distilled from toluene (2x). The crude acid chloride was dissolved in acetone (2 ml) and the solution was added dropwise to a rapidly stirred suspension of (Ph3P) 2CuBH4 (1.14 g, 1. 89 mmoles) and Ph3P (0.99 g, 3.78 mmoles) in acetone (4 ml). After 1 hour at room temperature, the reaction mixture was filtered through celite® and the filter pad was further rinsed with EtOAc. The combined organic filtered ft were concentrated to give a yellow residue.

Radial chromatography on silica gel (6 mm plate, EtOAc % / hexane) gave the title compound (0.25 g) as a clear oil: ^ H NMR (300 MHz, CDCl 3) d 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 = 16.8.51 Hz, 1 H). 15 • b) (±) -3- (4-Methoxybenzyl) pent-4-enoate methyl To a solution of methyl (±) -3-formyl-4- (4-methoxyphenyl) butanoate (0.14 g, 0.61 mmol) ) in dry MeOH (5 ml), K2CO3 (0.17 g, 1.21 mmol) was added, followed by the dropwise addition of a solution of dimethyl diazo-2-oxopropylphosphonate (0.13 g, 0.67 mmol) in MeOH (5 ml). After 18 hours at room temperature, the reaction was emptied into saturated aHC? 3 and extracted with Et2 ?. The combined organic extracts were washed with brine and dried over MgSO 4. The solvent was removed under reduced pressure to give a clear oil. Radial chromatography on silica gel (2 mm plate, 20% EtOAc / hexane) gave the title compound (0.06 g) as a clear oil: 1 H NMR (300 MHz, CDCl 3) d 7.23 (d, J = 8.4 Hz, 2 H), 6.92 (d, J = 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, 2 H), 2.17 (d, J = 2.0 Hz, 1 H). c) (±) -3- (4-Hydroxybenzyl) pent-4-enoate methyl To a solution of BBr3 in CH2CI2 (1.0 M, 0.85 ml, 0.85 mmole) at 0 ° C, a solution of (± ) -3- (4-methoxybenzyl) pent-4-enoate methyl (66 mg, 0.28 mmole) in CH2Cl2 (0.60 ml). After 3 hours at 0 ° C, the reaction was quenched by the careful addition of MeOH (1 ml). The solvent was removed under reduced pressure and the residue was azeotropically distilled from MeOH (2x). Saturated NaHCO3 was added to the residue and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine and dried over Na 2 S 4. The solvent was removed under reduced pressure to give a clear film. Radial chromatography on silica gel (2 mm plate, 20% EtOAc / hexane) gave the title compound (25 mg) as a clear film: 1 H NMR (300 MHz, CDCl 3) d 7.15 (d, J = 8.5 Hz, 2 H), 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, 2 H), 2.11 (d, J = 2.2 Hz, 1 H).

PREPARATION 35 Preparation of methyl (±) -4- (4-hydroxyphenyl) -3- (phenylethyl) butanoate a) (±) -2- (4-methoxybenzyl) -4-phenylbutanoic acid A reaction flask was charged with diisopropylamine (1.0 mmoles, 7.5 mmoles), NaH (60% in mineral oil, 0.33 g, 8.5 mmoles) and THF (40 mmol). To the stirred mixture was added a solution of phenylbutyric acid (1.23 g, 7.5 mmol) in THF (10 mmol) for 5 minutes. The evolution of hydrogen was completed by heating the mixture to reflux for 10 minutes. The reaction was cooled to 10 ° C and a solution of n-BuLi (2.5 M in hexane, 3.0 mmol, 7.5 mmol) was added. After 15 minutes at that temperature, the mixture was heated at 30 ° C for 15 minutes. The cloudy solution was cooled to 0 ° C and 4-methoxybenzyl chloride (1.2 g, 7.5 mmol) was added over 10 minutes. After 20 minutes at that temperature, the mixture was stirred at room temperature overnight. The reaction was maintained at 15 ° C or less while H2O (50 ml) was added. The mixture was partially concentrated in vacuo, diluted with water and extracted with ether (2 x 50 ml). The aqueous layer was acidified with 6N HCl to Congo red and extracted with Et2? (3 x 30 ml). The combined extracts were dried over anhydrous MgSO 4, filtered and concentrated to give the title compound (1.6 g, 56%) as a yellow oil: TLC Rf (MeOH 1% / CH 2 Cl 2) 0.37. b) (±) -1-Diazo-4- (4-methoxyphenyl) -3- (2-phenylethyl) -2-butanone A solution of (±) -2- (4-methoxybenzyl) -4-phenylbutanoic acid (1.5) g, 5.26 mmol) in CH2Cl2 (30 ml), was treated with oxalyl chloride (0.92 ml, 10.5 mmol). The reaction was stirred at room temperature overnight and then concentrated in vacuo. The residue was dissolved in Et2? and Et3 was added, followed by excess diazomethane (generated from 1-methyl-3-nitro-1-nitroguanidine and NaOH). The reaction was stirred at room temperature overnight and then concentrated in vacuo to give the title compound (1.5 g, 94%) as a yellow oil: MS (ES) m / e 309 (M + H) +. 10 c) (±) -4- (4-Methoxyphenyl) -3- (2-phenylethyl) butanoate methyl A solution of silver benzoate (0.9 g, 3.9 mmol) in EtßN (8 mL, 55.6 mL) was added to a solution of (±) -1-diazo-4- (4-methoxyphenyl) -3- (phenylethyl) -2-butanone (0.3 g, 0.97 mmol) in MeOH (20 mL). ml) at temperature atmosphere. Gas evolution was observed and the reaction mixture turned black. After 30 minutes, the reaction was heated to reflux. After 1 hour at reflux, the reaction was cooled to room temperature and filtered through celite®; the filtrate was concentrated in vacuo. The residue was adsorbed on silica gel and loaded onto a dry gel column of silica. Flash chromatography (5% EtOAc / hexane) gave the title compound (0.1 g, 57%) as a light yellow oil: TLC Rf (5% EtOAc / hexane) 0. 63 d) (±) -4- (4-Hydroxyphenyl) -3- (phenylethyl) butanoate methyl. Boron tribromide (1.0 M in CH2Cl2, 4.8 ml, 4.8 mmol) was added to a solution of (±) -4- ( Methyl 4-methoxyphenyl) -3- (2-phenylethyl) butanoate (1.0 g, 3.21 mmol) in CH 2 Cl 2 (10 mL) at 0 ° C under argon. After 1 hour, the reaction was quenched with absolute MeOH and concentrated in vacuo. By reconcentration of toluene (several times), followed by drying under high vacuum, the title compound (0.7 g, 73%) was obtained as an oil: TLC Rf (EtOAc 15% / hexane) 0.26.

PREPARATION 36 Preparation of methyl (±) -4- (4-hydroxyphenyl) -3-benzylbutanoate a) (±) -2- (4-Methoxybenzyl) -3-phenylpropionic acid The title compound was obtained as a yellow oil (60%) according to the preparation procedure 35 (a), but was replaced with phenylpropionic acid Phenylbutyric acid: CCF Rf (MeOH 1% / CH2Cl2) 0.38. b) (±) -1-Diazo-3- (4-methoxyphenyl) -3- (benzyl) -2-butanone The title compound was obtained as a yellow oil (100%) according to the preparation procedure 35 ( b), but was replaced by (±) -2- (4-methoxybenzyl) -3-phenylpropionic acid (±) -2- (4-methoxybenzyl) -4-phenylbutanoic acid: EM (ES) m / e 289 (M + H) +. c) (±) -4- (4-Methoxyphenyl) -3-benzylbutanoate methyl The title compound was prepared as a slightly yellow foam (80%) according to the preparation procedure 35 (c), but was replaced with (+) - 1-diazo-3- (4-methoxyphenyl) -3- (benzyl) -2-butanone (±) -1-diazo-4- (4-methoxyphenyl) -3- (phenylethyl) -2- butanone: TLC Rf (EtOAc 5% / hexane) 0.33. d) (±) -4- (4-Hydroxyphenyl) -3-benzylbutanoate methyl The title compound (24%) was prepared according to the preparation procedure 35 (d), but was replaced with (±) -4 Methyl (4-methoxyphenyl) -3-benzylbutanoate methyl (±) -4- (4-methoxyphenyl) -3- (2-phenylacetyl) butanoate: TLC Rf (20% EtOAc / hexane) 0.33.

PREPARATION 37 Preparation of methyl (±) -4- (4-hydroxyphenyl) -3-cyclopropylbutanoate a) (±) -2- (4-Methoxybenzyl) -2-cyclopropylacetic acid The title compound was obtained as a yellow oil (60%) according to preparation procedure 35 (a), but was replaced with cyclopropylacetic acid phenylbutyric acid: CCF Rf (10% MeOH / CH2Cl2) 0.42. b) (±) -1-Diazo-3- (4-methoxyphenyl) -3-cyclopropyl-2-butanone The title compound was prepared as a yellow oil (100%) according to the preparation procedure 35 (b) , but (±) -2- (4-methoxybenzyl) -2-cyclopropylacetic acid (±) -2- (4-methoxybenzyl) -4-phenylbutanoic acid: MS (ES) m / e 245 (M + H) +. c) (±) -4- (4-Methoxyphenyl) -3-cyclopropylbutanoate methyl The title compound was prepared as a slightly yellow film (60%) according to the preparation procedure 35 (c), but was replaced with (±) -1-diazo-3- (4-methoxyphenyl) -3-cyclopropyl-2-butanone (±) -1-diazo-4- (4-methoxyphenyl) -3- (phenylethyl) -2- butanone: CCF Rf (10% EtOAc / hexane) 0.21. d) (±) -4- (4-Hydroxyphenyl) -3-cyclopropylbutanoate methyl The title compound was prepared as a slightly yellow film (20%) according to the preparation procedure 35 (d), but was replaced with (±) -4- (4-methoxyphenyl) -3-cyclopropylbutanoate methyl (±) -4- (4-methoxyphenyl) -3- (2-phenylethyl) butanoate: CCF Rf (EtOAc % / hexane) 0.11.

PREPARATION 38 Preparation of ethyl 4- (4-hydroxyphenyl-3-methyl-3-butenoate a) Ethyl 4- (4-methoxyphenyl) -3-methyl-3-butenoate To a suspension of NaH (60% in mineral oil, 2.1 g, 54 mmol) in toluene (40 ml), phosphonoacetate was added triethyl (11.1 g, 49.4 mmoles) in toluene (50 ml). The reaction was stirred at room temperature for 20 minutes and then a solution of 4-methoxyphenylacetone (7.4 g, 44.9 mmol) in toluene (40 ml) was added dropwise. The reaction was refluxed for 5 hours and then concentrated. Flash chromatography on silica gel (5% EtOAc / hexane) gave the title compound (1.0 g) as a colorless oil: TLC Rf (5% EtOAc / hexane) 0.23. b) ethyl 4- (4-hydroxyphenyl) -3-methyl-3-butenoate The title compound was prepared as a colorless oil (34%) according to preparation procedure 35 (d), but was replaced with Ethyl 4- (4-methoxyphenyl) -3-methyl-3-butenoate methyl (±) -4- (4-methoxyphenyl) -3- (2-phenylethyl) butanoate: TLC Rf (10% EtOAc / hexane) 0.13.

The following examples illustrate methods for preparing the biologically active compounds of this invention from intermediates such as those described in the preceding preparations.

EXAMPLE 1 Preparation of (±) -3-phenyl-4-r4-r3- (pyridin-2-yl) amino-1-propyloxylphenylbutanoic acid a) (±) -3-Phenyl-4- [4- [3- (1-oxopyridin-2-yl) amino-1-propyloxyphyphenyl] -butanoate ethyl Diisopropyl azodicarboxylate (0.44 ml, 2.25 mmol) was added over 45 seconds to a solution of ethyl (±) -4- (4-hydroxyphenyl) -3-phenylbutanoate (426.5 mg, 1.5 mmol), 2 - [(3-hydroxy-1-propyl) amino] pyridine N-oxide (378 mg, 2.25 mmol) and triphenylphosphine (590.2 mg, 2.25 mmol) in anhydrous DMF (22.5 ml) at 0 ° C under argon. The yellow solution was kept at 0 ° C for 10 minutes and then warmed to room temperature. After 23 hours, the reaction was concentrated and the residue was reconcentrated from xylene (2x). Chromatography on silica gel (gradient: EtOAc, then 5% MeOH / CHCl3) gave the title compound (445.7 mg, 68%) as a yellow oil: TLC Rf (MeOH 5% / CHCl3) 0.41; 1 H NMR (250 MHz, CDCI3) d 8.11 (dd, J = 6.5.1.3 Hz, 1 H), 7.05-7.35 (m, 5 H), 6.85-7.05 (m, 1 H), 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) (±) -3-Phenyl-4- [4- [3- (pyridin-2-yl) amino-1-propyloxy] phenyl] butanoate ethyl A mixture of (±) -3-phenyl-4 - [Ethyl 4- [3- [3- (1-oxopyridin-2-yl) amino] -1-propyloxykhyphenyljbutanoate (445.7 mg, 1.03 mmol), cyclohexene (1 mL, 10 mmol), Pd 10% / C (110 mg) , 0.10 mmole) and isopropanol (10 ml), was heated to reflux under argon. After 3 hours, more Pd / C (110 mg) was added. The mixture was refluxed for another 20.5 hours and then filtered hot through celite.RTM. The filter pad was washed with MeOH / CHCl3 1: 1 hot and the combined filtrates were concentrated. The residue was reconcentrated from toluene and then chrographed on silica gel (5% MeOH / CHCl3) to yield the title compound (332.5 mg, 77%) as a colorless oil: TLC Rf (MeOH 5% / CHCl3) 0.43; 1 H NMR (250 MHz, CDCl 3) d 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), 6J5 (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) +. c) Acid (±) -3-phenyl-4- [4- [3- (pyridin-2-yl) amino-1-propyloxy] phenyl] butanoic A mixture of (±) -3-phenyI-4- [4 - ethyl [3- (pyridin-2-yl) amino-1-propyloxy] phenyl] butanoate (332.5 mg, 0J9 mmol), 1.0 N LiOH (1.2 ml, 1.2 mmol), THF (4 ml) and H2O (2.8 ml), was stirred at room temperature for 4 hours and then heated in an oil bath set at 45-50 ° C. After 17.5 hours, the resulting homogeneous, almost colorless solution was cooled to room temperature and extracted with Et2? (2 x 8 ml). The Et2? Layers were discarded. The aqueous layer was stirred with gentle heating under vacuum to remove residual organic solvents, and then filtered. The resulting aqueous solution was stirred at room temperature while slowly and carefully adjusting its pH to 5.5-6.0 with 1.0 N HCl. The mixture was stirred for 0.5 hour and then the solid was collected by suction filtration and washed with abundant H2O. Drying in high vacuum at 60 ° C gave the title compound (232.3 mg, 74%) as a crystalline solid: HPLC (Hamilton PRP-1 R CH3CN / H20 with 1% TFA) K '= 2.4; 1 H NMR (400 MHz, CD3OD) d 7.75-7 95 (m, 1 H), 7.48 (t ap, 1 H), 7.07-7.27 (m, 5 H), 6.90 (d, J = 8.5 Hz, 2 H), 6J2 (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. Cale, for C24H26 2O3.O.33 H2O: C, 72.72; H, 6J8; N, 7.07. Found: C, 72.68; H, 6.69; N, 6.96. ft EXAMPLE 2 Preparation of Acid (±. 3-phenyl-4-r4-r2-r6- (methylamino.pyridin-2-iri-1-ethoxyphenylbutanoic a) (±) -3-Fenii-4- [4- [ Ethyl 2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] phenyl] butanoate Diisopropyl azodicarboxylate (0.44 ml, 2.25 mmol) was added over 2 minutes to a solution of (±) -4- (4-hydroxyphenyl) -3-phenylbutanoate (427 mg, 1.5 mmol), 6- (methylamino) -2-pyridylethanol (343 mg, 2.25 mmol) and triphenylphosphine (590 mg, 2.25 mmol) in anhydrous THF (22.5 ml) ), at 0 ° C under N2- The yellow solution was maintained at 0 ° C for 10 minutes and then warmed to room temperature. After 24 hours, the reaction was concentrated and the residue was chrographed on silica gel (Et2? / Hexane 4: 1). The title compound was obtained (479.5 mg, 76%) as a colorless oil: TLC Rf (Et2? / hexane 4: 1) 0.50; 1 H NMR (250 MHz, ft CDCl 3) d 7.38 (t ap, 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 = 7.0 Hz, 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) +. b) Acid (±) -3-phenyl-4- [4- [2- [6- (methylamino) pyridin-2-yI] -1-ethoxy] phenyl] butane • 1.0 N NaOH (1.15 mL, 1.15 mmol) was added dropwise to a cold (15 ° C) solution of (±) -3-phenyl-4- [4- [2- [6- (methylamino) p. Ridin-2-yl] -1- ethyl ethoxyphyphenylbutanoate (479.5 mg, 1.15 mmoles) in dioxane (4.6 ml). The resulting mixture was stirred at room temperature for 2.5 hours and Then it was heated in an oil bath set at 40 ° C. After 24 hours, the reaction was cooled to room temperature and stirred for 3 days; then it was diluted with H2O (3.4 ml) and extracted with Et2? (3 x 5ml). The layers of Et2? They were discarded. As a solid precipitate was separated from the aqueous layer, 1.0 N NaOH (1.0 ml), dioxane (5 ml) and Et2 were added thereto. (10 ml) to obtain a homogeneous solution. The pH was adjusted to 5.5-6.0 with HCl 1. 0 N and the organic solvents were removed in the rotary evaporator. The solution The aqueous phase was separated by decanting the gummy precipitate and this precipitate was completely dried under vacuum. The residue was recrystallized from CH3CN and the solid was dried under vacuum at 60 ° C for several days to yield the title compound (331.0 mg, 74%) as a white crystalline solid: HPLC (Hamilton • PRP-1 R, CH3CN 35% / H20 with 0.1% TFA) K '= 2.9; 1 H NMR (300 MHz, (DEMO-d6) d 7.05-7.40 (m, 6 H), 6.95 (d, J = 8.4 Hz, 2 H), 6.76 (d, J = 8.4 Hz, 2H), 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), 2J3 (d, J = 4.8 Hz, 3 H), 2.40-2.60 (m, 2 H, partially obscured by residual solvent signal, MS (ES) m / e 391.2 (M + H) + Anal Cale, for 15 C24H26N2O3: C, 73.82; H, 6.71; N, 7.17 Found: C, 73.43; H, 6.72; N, • 7.40.

EXAMPLE 3 Preparation of Acid (±) -3-phenyl-4-r4-IT2- (pyridin-2-yl) amino-1-ethylaminolcarbonylphenylbutanoic acid a) (±) -3-Phenyl-4- [4 - [[2- (pyridin-2-yl) amino-1-ethylamino] carbonyl] phenyl] butanoate ethyl To a suspension of (±) - (4- carboxyphenyl) -3-phenylbutanoate (312 mg, 1.0 mmol), 2 - [(2-amino-1-ethyl) amino] pyridine dihydrochloride (252 mg, 1.2 mmol) and HOBt (162 mg, 1.2 mmol) in CH3CN (5 ml) was added (i-Pr) 2NEt (0.87 ml, 5.0 mmol) and then EDC (230 mg, 1.2 mmol). After 18 hours, the mixture was concentrated. The residue was chromatographed on silica gel (5% MeOH in CHCl3 / EtOAc 1: 1) to give the title compound (380 mg, 88%) as a brownish foam: MS (ES) m / e 432 (M + H) +. b) Acid (±) -3-phenyl-4- [4 - [[2- (pyridin-2-yl) amino-1-ethylamino] carbonyl] phenyl] butanoic To a solution of (±) -3-phenyl- 4- [4 - [[2- (pyridin-2-yl) amino-1-ethylamino] carbonyl] phenyljbutanoate (380 mg, 0.88 mmol) in THF / H2O 1: 1 (5 mL), 1.0 N LiOH (1.3 mL, 1.3 mmol) was added. After 24 hours, the mixture was concentrated to remove the THF. The resulting aqueous solution was cooled to 0 ° C and acidified to pH 6 using 10% HCl. The precipitate was collected by filtration and dried in vacuo to give the title compound (213 mg, 60%) as a white solid: MS (ES) m / e 404 (M + H) +. Anal. cale, for C 24 H 25 N 3 O 3 O 25 H 2 O: C, 70.66; H, 6.30; N, 10.30.

Found: C, 70.92; H, 6.44; N, 10.14.

EXAMPLE 4 Preparation of Acid (±) -3-phenyl-3-r4-r4- (pyridin-2-yl) amino-1-butylphenylaminolpropanoic acid a) 1 -Bromo-4- (4-nitrophenyl) butane To a solution of 4- (4-nitrophenyl) -1-butanol (1.0 g, 5.12 mmol) in dry THF (10 ml), PPh3 (1.61 g) was added. g, 6.14 mmoles) and CBr4 (2.04 g, 6. 14 mmol). After 4 hours, the mixture was concentrated. The residue was chromatographed on silica gel (10% EtOAc / hexane) to give the title compound (1.22 g, 92%) as a pale yellow oil: 1 H NMR (300 MHz, CDCl 3) d 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) 1- [N- (Ier-Butoxycarbonyl) -N- (pyridin-2-yl) amino] -4- (4-nitrophenol) butane To a suspension of NaH (170 mg, 4.25 mmol) in dry DMF (10 ml), 2- (tert-butoxycarbonylamino) pyridine (750 mg, 3.86 mmol) was added at 0 ° C. After 5 minutes, the mixture was warmed to room temperature. After 15 minutes, the mixture was cooled to 0 ° C and added 1-Bromo-4- (4-nitrophenyl) butane (1.22 g, 4.73 mmol) in dry DMF (5 mL). The mixture was allowed to warm to room temperature as the bath warmed. After 18 hours, the mixture was concentrated. The residue was taken up in H2O (50 ml) and extracted with EtOAc (3 x 50 ml). The combined organic layers were dried over MgSO 4, filtered and concentrated. The residue was chromatographed on silica gel (15% EtOAc / hexane) to give the title compound (1.25 g, 87%) as a pale yellow oil: MS (ES) m / e 372 (M + H) +. c) 1- [N- (rer-Butoxycarbonyl) -N- (pyridin-2-yl) amino] -4- (4-aminophenyl) butane To a suspension of Pd 10% / C (358 mg) in absolute EtOH ( 15 ml) was added 1- [N- (fer-butoxycarbonyl) -N- (pyridin-2-yl) amino] -4- (4-nitrophenyl) butane (1.25 g, 3.37 mmol). The mixture was deoxygenated (3 x evacuation cycles / N2) and then loaded with H2 (3.5 kg / cm2). After 2 hours, the H2 was removed and the mixture was filtered through a pad of celiteR. The filtrate was concentrated to give the title compound (1.14 g, 99%) as a yellow oil, which was used without purification: MS (ES) m / e 342 (M + H) +. d) (±) -3-Phenyl-3- [4- [4- [N- (ér-butoxycarbonyl) -N- (pyridin-2-yl) amino] -1-butyl] phenyl-amino-propanoate fer -butyl To a suspension of MgS 4 (7.0 g) in CH 2 Cl 2 (20 ml), was added 1- [N- (1er-butoxycarbonyl) -N- (pyridin-2-yl) amino] -4- (4 -amniphenyl) butane (560 mg, 1.64 mmol), and then benzaldehyde (0.2 ml, 1.97 mmol). After 18 hours, the mixture was filtered and the filtrate was concentrated. The residue was taken in dry THF (10 ml) and cooled to -78 ° C. BF3-EÍ2 (0.4 ml, 3.28 mmol) was added dropwise to this mixture. After 15 minutes, Reformatsky reagent, prepared from zinc metal and urea-butyl bromoacetate in THF (Tetrahedron 1984, 40, 2781, 818 mg, 2.46 mmol) was added. The mixture was allowed to warm to room temperature for 5 hours as the bath was heated. The mixture was diluted with H2O (20 ml) and extracted with EtOAc (3 x 20 ml). The combined organic layers were dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel (15% EtOAc / hexane) 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. e) Acid (±) -3-phenyl-3- [4- [4- (pyridin-2-yl) amino-1-butyI] phenylamino] propanoic (±) -3-phenyl was dissolved -3- [4- [4- [N-fer-butoxycarbonyl) -N- (pyridin-2-yl) amino] -1-butyl] phenylamino] -erbutyl propanoate (350 mg, impure) in TFA / CH2Cl2 1: 1 (10 ml). After 2 hours, the mixture was concentrated. The residue was dissolved in 1.0 M NaOH (10 mL) and extracted with EtOAc (2 x 10 mL). The aqueous layer was acidified to pH 6 using 10% HCl. The solid was collected by filtration and dried under vacuum at 50 ° C for 18 hours to give the title compound (74 mg, 12%) as an off-white powder: MS (ES) m / e 390 (M + H) + . Anal. Cale, for C24H2JN3O2-0.50 H2O: C, 72.34; H, 7.08; N, 10.54. Found: C, 72.29; H, 6.92; N, 10.37.

EXAMPLE 5 Preparation of 4-r 4 -r 2 -6- (methylamino) pyridin-2-ill-1-ethoxylphenylbutanoic acid a) Methyl 4- [4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] phenyl] butanoate Diisopropyl azodicarboxylate (0.3 ml, 1.4 mmol) was added to a solution of Methyl (4-hydroxyphenyl) butanoate (180 mg, 0.93 mmol), 6- (methylamino) -2-pyridylethanol (212 mg, 1.4 mmol) and triphenylphosphine (367 mg, 1.4 mmol) in anhydrous THF (10 mL) at 0 ° C. The mixture was allowed to warm to room temperature as the bath warmed. After 24 hours, the mixture was concentrated and the residue was chromatographed on silica gel (Et2?). The title compound (160 mg, 52%) was obtained as a pale yellow oil: H NMR (300 MHz, CDCl 3) d 7.39 (t, 1 H), 7.05 (d, J = 6.6 Hz, 2 H), 6.82 (d, J = 6.6 Hz, 2 H), 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, 2H), 2.30 (t, 2 H), 1.88 (m, 2 H). b) 4- [4- [2- [6- (Methylamino) pyridin-2-yl] -1-ethoxy] phenyl] butanoic acid To a solution of 4- [4- [2- [6 Methyl (methyl (methylamino) pyridin-2-yl) -1-ethoxy] phenyl] butanoate (160 mg, 0.49 mmol) in THF / H2O 1: 1 (1.5 ml), 1.0 N LiOH (0.58 ml, 0.58) was added. mmoles). After 5 hours, 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 under vacuum at 50 ° C for 18 hours: MS (ES) m / e 315 (M + H) +. Anal. cale, for C18H22N203: C, 68.77; H, 7.05; N, 8.91. Found: C, 68.75; H, 7.06; N, 8.74.

EXAMPLE 6 Preparation of acid (±) -4-r4-r2-rß- (methylamino) pyridin-2-ip-1-ethoxypfenH1-3-vinylbutanoic acid a) (±) -4- [4- [2- [6- (Methylamino) pyridin-2-yl] -1-ethoxy] phenyl] -3-vinylbutanoate Methyl azodicarboxylate was added of diisopropyl (0.17 ml, 0.84 mmol) to a solution of methyl (±) -4- (4-hydroxyphenyl) -3-vinylbutanoate (92.5 mg, 0.42 mmol), 6- (methylamino) -2-pyridylethanol ( 128 mg, 0.84 mmol), and triphenylphosphine (220 mg, 0.84 mmol) in anhydrous THF (2 mL) at 0 ° C. The mixture was allowed to warm to room temperature as the bath warmed. After 24 hours, the mixture was concentrated and the residue was chromatographed on silica gel (Et2? / Hexane 3: 1). The title compound (100 mg, 67%) was obtained as a pale yellow oil: MS (ES) m / e 355 (M + H) +. b) Acid (±) -4- [4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] phenyl] -3-vinylbutanoic To a solution of (±) -4- [4 - [2- [6- (Methylamino) pyridin-2-yl] -1-ethoxy] phenyl] -3-vinylbutanoate methyl (100 mg, 0.28 mmole) in THF / H2O 1: 1 (1.5 ml), 1.0 N LiOH (0.34 ml, 0.34 mmol) was added. After 18 hours, the mixture was acidified to pH 6 using 10% HCl and extracted with EtOAc (3 x 10 ml). The combined organic layers were dried over MgSO4, filtered and concentrated. The residue was lyophilized from HOAc (10 mL) to give the title compound (50 mg, 52%) as a yellow oil: MS (ES) m / e 341 (M + H) +. Anal. cale, for C2oH24N2? 3-2J5 CH3CO2H: C, 60.58; H, 6.98; N, 5.54. Found: C, 60.55; H, 6.91; N, 5.47.

EXAMPLE 7 Preparation of Acid (±) -4-r4-r2-rß- (methylamino) pyr8din-2-H1-1-etoxpfenip-3- (pyridin-2-yl) butanoic acid a) (±) -4- [4- [2- [6- (Methylamino) pyridin-2-yl] -1-ethoxy] pheny] -3- (pyridin-2-yl) butanoate ethyl Diisopropyl azodicarboxylate (0.12 ml, 0.62 mmol) was added to a solution of ethyl (±) -4- (4-hydroxyphenyl) -3- (pyridin-2-yl) butanoate (90 mg, 0.31 mmol), - (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 room temperature as the bath warmed. After 24 hours, the mixture was concentrated and the residue was chromatographed on silica gel (10% hexane / Et2?). The title compound (71 mg, 55%) was obtained as a colorless oil: MS (ES) m / e 420 (M + H) +. b) Acid (±) -4- [4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] phenyl] -3- (pyridin-2-yl) butanoic To one solution of (±) -4- [4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] phenyl] -3- (pyridin-2-yl) ethyl butanoate (71 mg, 0.17) mmoles) in THF / H2O 1: 1 (2 ml), 1.0 N LiOH (0.34 ml, 0.34 mmol) was added. After 18 hours, the mixture was acidified to pH 6 using 10% HCl and extracted with CHCl 3 (3 x 10 ml). The combined organic layers were dried over MgSO4, 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. cale, for C23H25N3? 3-0.75 H2O: C, 68.21; H, 6.60; N, 10.38. Found: C, 68.50; H, 6.39; N, 10.24.

EXAMPLE 8 Preparation of acid f ±) -4-r4-r2-rß- (methylamine pyridin-2-p-, 1-ethoxypfenin-3- (oxazole-2-ii) butanoic acid a) (±) -4- [4- [2- [6- (Methylamino) pyridin-2-yl] -1-ethoxy] phenyl] -3- (oxazol-2-yl) butanoate methyl azodicarboxylate was added diisopropyl (0.24 ml, 1.24 mmole) to a solution of methyl (±) -4- (4-hydroxyphenyl) -3- (oxazol-2-yl) butanoate (163 mg, 0.62 mmol), 6- (methylamino) - 2-pyridifethanol (190 mg, 1.24 mmol), and triphenylphosphine (325 mg, 1.24 mmol) in anhydrous THF (4 mL) at 0 ° C. The mixture was allowed to warm up as the bath warmed to room temperature. After 24 hours, the mixture was concentrated and the residue was chromatographed on silica gel (50% EtOAc / CHCl3). The title compound (167 mg, 68%) was obtained as an orange oil: MS (ES) m / e 396 (M + H) +. b) Acid (±) -4- [4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] phenyl] -3- (oxazol-2-yl) butanoic To a solution of ( ±) -4- [4- [2- [6- (Methylamino) pyridin-2-yl] -1-ethoxy] phenyl] -3- (oxazol-2-yl) butanoate methyl (167 mg, 0.42 mmol) ) in THF / H2O 1: 1 (4 mL), 1.0 N LiOH (0.63 mL, 0.63 mmol) was added.

After 18 hours, the mixture was washed with Et ^ O (2 x 2 ml). The aqueous layer was concentrated to remove residual THF / EI20 and then acidified to pH 6 using 10% HCl. The title compound (114 mg, 71%) was collected as a white solid by means of filtration and dried under vacuum at 50 ° C for 18 hours: MS (ES) m / e 382 (M + H) +. Anal. cale, for C21 H23N3O4O.5O H20: C, 64. 60; H, 6.20; N, 10.76. Found: C, 64.33; H, 6.12; N, 10.38.

EXAMPLE 9 Preparation of Acid (±) -4-r4-r2-r6- (methylamino) pyridin-2-yn-1-ethoxypfenin-3- (thiazol-2-yl) butanoic acid a) (±) -4- [4- [2- [6- (Methylamino) pyridin-2-yl] -1-ethoxy] phenyl] -3- (thiazole-2-1l) ethyl butanoate was added azodicarboxylate diisopropyl (0.21 ml, 1.06 mmol) to a solution of ethyl (±) -4- (4-hydroxyphenyl) -3- (thiazol-2-yl) butanoate (155 mg, 0.53 mmol), 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 up as the bath warmed to room temperature. After 24 hours, the mixture was concentrated and the residue was chromatographed on silica gel (50% EtOAc / CHCl3). The fractions containing the product were concentrated and re-chromatographed on silica gel (60% EtOAc / hexane). The fractions from the second chromatography containing the product were further purified by preparative TLC (60% EtOAc / hexane). The title compound (106 mg, 47%) was obtained as an oil: MS (ES) m / e 426 (M + H) +. b) Acid (±) -4- [4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] phenyl] -3- (thiazol-2-yl) butanoic To a solution of ( ±) -4- [4- [2- [6- (Methylamino) pyridin-2-yl] -1-ethoxy] phenyl] -3- (thiazol-2-yl) ethyl butanoate (106 mg, 0.25 mmol) ) in THF / H2O 1: 1 (5 mL), 1.0 N LiOH (0.37 mL, 0.37 mmol) was added. After 18 hours, the mixture was extracted with Et2? (2 x 5 ml) and the layers of Et2? They were discarded. The aqueous layer was concentrated to remove residual organic solvents and then acidified to pH 6 using 10% HCl. CH3CN (0.5 ml) was added to dissolve all solids. The solution was purified by C18 / elution chromatography (H2O, then CH3CN 20% / H2O). The fractions containing the product were lyophilized to give the title compound (53 mg, 53%) as a white powder: MS (ES) m / e 398 (M + H) +. Anal. cale, for C21H23N3O3S: C, 63.46; H, 5.83; N, 10.57. Found: C, 63.17; H, 6.00; N, 10.37.

EXAMPLE 10 Preparation of Acid (±) -3-methyl-4-r4-f3- (pyridin-2-yl) amino-1-propyloxy-phenylbutanoic acid a) (±) -3-Methyl-4- [4- [3- (1-oxopyridin-2-yl) amino-1-propyloxy] phenyl] butanoate ethyl Diisopropyl azodicarboxylate (0.3 ml, 1.5 mmol) was added ) for 45 seconds, to a solution of ethyl (±) -4- (4-hydroxyphenyl) -3-methylbutanoate (220 mg, 1.0 mmol), 2 - [(3-hydroxy-1-propyl) N-oxide amino] pyridine (252 mg, 1.5 mmol), and triphenylphosphine (390 mg, 1.5 mmol) in anhydrous DMF (22.5 ml) at 0 ° C under argon. The yellow solution was kept at 0 ° C for 10 minutes and then warmed to room temperature. After 23 hours, the reaction was concentrated and the residue was reconcentrated from xylene (2x). Chromatography on silica gel (1% MeOH / CH2Cl2) gave the title compound (200 mg, 54%) as a yellow oil: MS (ES) m / e 373 (M + H) +. b) (±) -3-Methyl-4- [4- [3- (pyridin-2-yl) amino-1-propyloxy] phenol] ethyl butanoate A mixture of (±) -3-methyl -4- [4- [3- (1-oxopyridin-2-yl) amino-1-propyloxy] phenyl] butanoate ethyl (200 mg, 0.54 mmol), cyclohexene (0.6 ml, 0. 54 mmoles), Pd 10% / C (55 mg, 00.5 mmol) and isopropanol (10 ml), was heated to reflux under argon. The mixture was refluxed for another 20.5 hours and then filtered through hot celite. The filter pad was washed with warm 1: 1 MeOH / CHCl3 and the filtrate was concentrated. The residue was reconcentrated from toluene and then chromatographed on silica gel (1% MeOH / CH2Cl2) to yield the title compound (150 mg, 78%). as a colorless oil: MS (ES) m / e 357 (M + H) +. c) Acid (±) -3-methyl-4- [4- [3- (pyridin-2-yl) amino-1-propyloxy] phenyl] butanoic A mixture of (±) -3-methyl-4- [4 - [Ethyl 3- (pyridin-2-yl) amino-1-propyloxy] phenyl] butanoate (150 mg, 0.42 mmol), 1.0 N LiOH (1.2 mL, 1.2 mmol), THF (4 mL) and H2O (2.8 ml), was stirred at room temperature for 4 hours and then heated in an oil bath set at 45-50 ° C.

After 17.5 hours, the resulting homogeneous, almost colorless solution was cooled to room temperature and extracted with Et2? (2 x 8 ml). The layers of Et2? They were discarded. The aqueous layer was stirred with gentle heating under vacuum to remove residual organic solvents, and then filtered. The resulting aqueous solution was stirred at room temperature while slowly and carefully adjusting the pH to 5.5 - 6.0 with 1.0 N HCl. The mixture was stirred for 0.5 hour and then the solid was collected by suction filtration and washed with abundant H2O. By drying under high vacuum at 60 ° C, the title compound (90 mg, 65%) was obtained as a crystalline solid: MS (ES) m / e 328 (M + H) +. Anal. cale, for C? H24N2? 3-0.25H2 ?: C, 68.54; H, 7. 13; N, 8.35. Found: C, 68.55; H, 7.42; N, 8.41.

EXAMPLE 11 Preparation of (±) -3-methyl-4-r4-r2-r6- (methylamino) pyridin-2-ill-1-ethoxylphenylbutanoic acid a) (±) -3-Methyl-4- [4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] phenyl] ethyl butanoate Diisopropyl azodicarboxylate (0.44) ml, 2.25 mmol) for 2 minutes, to a solution of ethyl (±) -4- (4-hydroxyphenyl) -3-methylbutanoate (378 mg, 2.25 mmol), 6- (methylamino) -2-pyridylethanol (343 mg, 2.25 mmol), and triphenylphosphine (590 mg, 2.25 mmol) in THF was anhydrous (22.5 ml) at 0 ° C under N2- The yellow solution was kept at 0 ° C for 10 minutes and then warmed to room temperature. After 24 hours, the reaction was concentrated and the residue was chromatographed on silica gel (EtOAc / hexane 6: 4). The title compound (200 mg, 76%) was obtained as a colorless oil: MS (ES) m / e 357 (M + H) +. 15 b) Acid (±) -3-methyl-4- [4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy-phenyljbutanoic 1.0 N NaOH (1 ml, 0.898 mmol) was added dropwise. ) to a cold (15 ° C) solution of ethyl (±) -3-methyl-4- [4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] phenyl] butanoate ( 160 mg, 0.449 mmol) in THF (3 ml), and the The mixture was stirred at room temperature for 24 hours. The resulting solution was concentrated in vacuo and the residue was dissolved in H2O (5 ml). The pH was adjusted to 7 with 1.0 N HCl and the supernatant was separated by decanting the gummy precipitate. By complete drying under vacuum at 60 ° C for several days, the title compound (120 mg, 82%) was obtained as a white foamy solid: MS (ES) m / e 328 (M + H) +. Anal. cale, for C ^ gH24N2? 3: C, 69.49; H, 7.37; N, 8.53. Found: C, 69.03; H, 7.27; N, 8.40. ft EXAMPLE 12 Preparation of (±) -3-methyl-4-r4-r2-f2- (methylamino) pyridin-5-in-1-ethoxylphenylbutanoic acid a) (±) -3-MetiI-4- [4- [2- [2- (methylamino) pyridin-5-yl] -1-ethoxy] phenyl] ethyl butanoate 10 Diisopropyl azodicarboxylate (0.18 ml, 0.913 mmoles) for 2 minutes, to a solution of ethyl (±) -4- (4-hydroxyphenyl) -3-methylbutanoate (133 mg, 0.6 mmol), 2- [N- (fer-butoxycarbonyl) -N-methylamino ] -5-pyridylethanol (230 mg, 0.913 mmol), and triphenylphosphine (239 mg, 0.913 mmol) in anhydrous THF (5 ml) at 0 ° C under N2. The yellow solution is kept at 0 ° C for 10 minutes and then warmed to temperature • ambient. After 24 hours, the reaction was concentrated and the residue was chromatographed on silica gel (1% MeOH / CHCl3). The title compound (200 mg, 73%) was obtained as a colorless oil: MS (ES) m / e 456 (M + H) +. 20 b) Acid (±) -3-methyl-4- [4- [2- [2- (methylamino) pyridin-5-yl] -1-ethoxy] phenyl] butanoic was suspended (±) -3-methyl- Ethyl 4- [4- [2- [2- (methylamino) pyridin-5-yl] -1-ethoxy] phenyl] butanoate (200 mg, 0.44 mmol) in 1.0 M HCl / dioxane (5 mL). After 2 hours, the reaction was concentrated in vacuo and the residue reconcentrated from toluene (3 x 10 ml). The remaining residue was taken in 5% Na 2 C 3 solution and extracted with CH 2 Cl 2. The extracts were dried over MgSO4, filtered and concentrated, leaving an oil (50 mg). This was taken up in THF (3 ml), 1.0 N LiOH (0.28 ml, 0.28 mmol) was added thereto, and the mixture was stirred at room temperature for 24 hours. The resulting solution was concentrated in vacuo and the residue was dissolved in H2O (5 ml). The pH was adjusted to 7 with 1.0 N HCl and the supernatant was separated by decanting the gummy precipitate. Complete drying under vacuum at 60 ° C for several days, gave the title compound (5 mg) as a white foamy solid: MS (ES) m / e 328 (M + H) +. EXAMPLE 13 Preparation of (±) -4-r4-r2-r6- (methylamino) pyridin-2-ip-1-ethoxy-phenyl-3- (thiophen-2-yl) butanoic acid a) (±) -4- [4- [2- [6- [N- (Ier-Butoxycarbonyl) -N-methylamino) pyridin-2-yl] -1-ethoxy] phenyl] -3- methyl (thiophene-2-yl) butanoate A solution of methyl (±) -4- (4-hydroxyphenyl) -3- (thiophen-2-yl) butanoate (245.1 mg, 0.89 mmol) and PPh3 (237.6 mg, 0.91 mmol) in CH2Cl2, was added slowly to a solution of 6- [N- (fer-butoxycarbonyl) -N-methylamino] -2-pyridylethanol (244.1 mg, 0.97 mmol) and DEAD (0.14 mL, 0.89 mmol) in CH2Cl2 at 0 ° C. The reaction was allowed to warm to room temperature as the bath warmed. After 24 hours, the reaction was concentrated in vacuo and the residue was chromatographed on silica gel (gradient: 10% EtOAc / hexane, then 20% EtOAc / hexane, then 50% EtOAc / hexane) to give the title compound. title (122.1 mg, 26.9%): y > (ES) m / e 510.9 (M + H) +. b) Acid (±) -4- [4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] phenyl] -3- (thiophen-2-yl) butanoic It was stirred (±) -4- [4- [2- [6- [N- (fer-butoxycarbonyl) -N-methylamino) pyridin-2-yl] -1-ethoxy] phenyl] -3- (thiophen-2-yl) butanoate methyl (122.1 mg, 0.24 mmol) with 4 N HCl / dioxane for 2.5 hours at room temperature; then the reaction was concentrated and the residue was reconcentrated from toluene (2x). Since the Boc group had not been completely removed, the residue was re-subjected to the reaction conditions. After another 1.5 hours, the reaction was concentrated and the residue reconcentrated from toluene.

This material was dissolved in dioxane (3 ml) and THF (3 ml) and 1.0 N NaOH (2 ml, 2.0 mmol) was added. The reaction was stirred at room temperature ft for 24 hours and then concentrated. As there was still ester present, the residue was again subjected to the reaction conditions. After a further 20 hours at room temperature, the reaction was neutralized with 1.0 N HCl and concentrated. Again, there was ester present, so the residue was re-subjected to the reaction conditions, this time with heating at 60 ° C. After 18 hours, the reaction was neutralized with 1.0 N HCl and concentrated in vacuo. The solid residue was reconcentrated from toluene (2x) and then taken in 0.1% TFA / H2 ?. The white precipitate that separated was collected and washed with more 0.1% TFA / H2 ?. Vacuum drying afforded the title compound fRk (92.5 mg, 83%) as a white powder: MS (ES) m / e 397. 1 (M + H) +. Anal. cale, for C22H24N2O3S-O.5TFA-O.5H2O: C, 59.73; H, 5.56; N, 6.06. Found: C, 59.62; H, 5.40; N, 6.14.

EXAMPLE 14 Preparation of Acid 2-fN-benzyl-N-r4-r2-r6- (metHamino) pyridin-2-p-1-ethoxylbenzipaminoacetic acid 10 a) 2- [N-Benzyl] - [4- [2- [6- [N- (Ier-butoxycarbonyl) -N-methylamino] pyridin-2-yl] -1- ethoxy] benzyl] amino] ethyl acetate A solution of 6- [N- (fer- butoxycarbonyl) -N-methylamino] -2- pyridylethanol (0.17 g, 0.69 mmole) and diethyl azodicarboxylate (0.11 ml, 0.70 mmol) 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 mmol) and Ph3P (0.18 g). , 0.69 mmole) in CH2CI2 (1.5 ml) at 0 ° C. The ice bath was removed and the reaction allowed to warm to room temperature. After 24 hours, the solvent was removed under reduced pressure. Radial chromatography (EtOAc -20% / hexane, silica gel, 6 mm plate) gave the title compound (0.14 g) as a clear oil: MS (ES) m / e 534.1 (M + H) +. b) 2- [N-Benzyl-N- [4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] benzyl] amino] acetic acid 2- [N-benzyl] N was dissolved - [4- [2- [6-N- (fer-butoxycarbonyl) -N-methylamino] pyridin-2-yl] -1-ethoxy] benzyl] amino] ethyl acetate (0.14 g, 0.27 mmol) in HCl 4 N / dioxane (5 ml). The reaction was stirred for 5.5 hours at room temperature and then the solvent was removed under reduced pressure. The residue was suspended in 1.0 N NaOH (2 mL) and MeOH (2 mL). The reaction was stirred for 18 hours at room temperature and then the solvent was removed under reduced pressure. The residue was dissolved in H2O and the solution was acidified to pH «5 with 1.0 N HCl. The solvent was removed under reduced pressure. Purification by preparative HPLC (Hamilton PRP-1 R column, 20% CH 3 CN / H 2 O with 0.1% TFA) gave the title (0.40 g) as a white powder: MS (ES) m / e 406.0 (M + H) +. Anal. cale, for 024 ^ 7 ^ 03-2.5 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 Preparation of 2-rN-r4-r2-r6- (methylamino) pmdin-2-ip-1-ethoxylbencip-N-phenylaminoacetic acid a) 2- [N- [4- [2- [6- [N, - (Ier-Butoxycarbonyl) -N, -methylamino] pyridin-2-yl] -1-ethoxy] benzyl] -N-phenyl] amino ] methyl acetate The title compound (8 mg) was obtained according to the procedure of example 14 (a), but was replaced with methyl 2- [N- (4-hydroxybenzyl) -N-phenylamine] acetate (39). mg, 0.14 mmol) ethyl 2- [N-benzyl-N- (4-hydroxybenzyl) amino] acetate, obtaining as a clear film after 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-yl] -1-ethoxy] benzyl] -N-phenyl] amino] acetic acid A solution of 4 N HCl in dioxane ( 5 ml), was added to methyl 2- [N- [4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] benzyl] -N-phenyl] amino] acetate ( 8 mg, 0.016 mmol). The reaction was stirred for 5.5 hours at room temperature and then the solvent was removed under reduced pressure to leave a clear film. This was dissolved in 1.0 N NaOH (2 mL) and MeOH (2 mL). The reaction was stirred for 18 hours at room temperature and then the solvent was removed under reduced pressure. By flash chromatography on a Bond Elut ^ C-18 column (gradient in steps: H2O with 0.1% TFA, then 20% CH3CN / H2? With 0.1% TFA, then 50% CH3CN / H2? With TFA 0.1%), the title compound (1.5 mg) was obtained as a dark hygroscopic solid: MS (ES) m / e 392.0 (M + H) +.

EXAMPLE 16 Preparation of 2-rN-r2-methoxy-4-r2-f- (methylamino) pyridin-2-in-1-ethoxylbenzylaminoacetic acid a) Methyl-2- [N- [2-methoxy] -4- [2- [6- [N '- (fer-butoxycarbonyl) -N * -methylamino] pyridin-2-yl] -1-ethoxy] benzyl] amino] acetic The title compound (0.14 g) was obtained according to the procedure of example 14 (a), but was replaced with methyl 2 - [(4-hydroxy-2-methoxybenzyl) amino] acetate (0.48) g, 2.14 mmol) ethyl 2- [N-benzyl-N- (4-hydroxybenzyl) amino] acetate, obtaining as a clear oil after flash chromatography on silica gel (40% EtOAc / hexane), followed by chromatography radial (MeOH 5% / CHCl3, gel silica, 6 mm plate): MS (ES) m / e 506.0 (M + H) +. b) 2- [N- [2-methoxy-4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] benzyl] amino] methyl acetate A solution of 4 N HCl in dioxane (15 ml) was added to methyl-2- [N- [2-methoxy-4- [2- [6- [N '- (fer-butoxycarbonyl) -N'-methylamino] pyridin-2-yl] -1-ethoxy] benzyl] amino] acetic acid (0.14 g, 0.30 mmol). The reaction was stirred for 2 hours at room temperature and then the solvent was removed under reduced pressure to leave a clear residue. This was dissolved in saturated NaHCO3 and the solution was extracted with 10% MeOH / EtOAc. The combined organic extracts were washed with brine, dried over Na 2 SO 4 and concentrated to give a pale yellow oil. Flash chromatography on silica gel (5% MeOH / CHCl3) 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] -1-ethoxy] benzyl] amino] acetic acid To a solution of 2- [N - [2-Methoxy-4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy-3-benzyl] amino] -acetic acid methyl ester (0.11 g, 0.30 mmol) in MeOH (3 mL), he added 1.0 N NaOH (3 ml). The reaction was stirred for 15 minutes at room temperature and then the solvent was removed under reduced pressure. The residue was dissolved in H2O and the solution was acidified to pH «3 with HCl conc. The solvent was removed to leave a white residue. By flash chromatography on a Waters Sep-PaK ^ C-18 column (gradient in steps: H2O, then CH3CN 15% / H2?) The title compound (0.11 g) was obtained as a very hygroscopic white solid: MS (ES) m / e 346.4 (M + H) +. "? NMR (300 MHz, DMSO-de) d 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).

EXAMPLE 17 Preparation of 2-phenoxy-4-r5- (pyridin-2-yl) amino-1-pentyloxy phenylacetic acid ft. a) Methyl 2-phenoxy-4- [5- (1-oxopyridin-2-yl) amino-1-pentyloxy] phenylacetate The title compound (0.35 g) was obtained according to the procedure of example 14 (a) , but it was substituted with methyl 2- (4-hydroxy-2-phenoxyphenyl) acetate (0.19 g, 0.74 mmol) the ethyl 2- [N-benzyl-N- (4-hydroxybenzyl) amino] acetate, obtaining as a yellow oil pale after 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 2-phenoxy-4- [5- (1-oxopyridin-2-yl ) amino-1- 15 methyl pentyloxyphenylacetate (0.35 g, 0.81 mmol) and cyclohexene (0.81 mL, 8.00 mmol) in EtOH (4 mL), was added Pd 10% / C (10 mg). After 18 hours at reflux, the reaction was allowed to cool to room temperature and the catalyst was removed by filtration. The solvent was removed under reduced pressure to leave a clear oil. Radial chromatography (5% MeOH a 10% / CHCl 3, 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-pentyloxy] phenylacetic acid To a solution of 2-phenoxy-4- [5- (pyridin-2-yl) amino-1- methyl pentyloxyphenylacetate (0.23 g, 0.55 mmole) in MeOH (2.5 ml), 1.0 N NaOH (2.5 ml) was added. The reaction was stirred for 18 hours at room temperature and then the solvent was removed under reduced pressure. The residue was dissolved in H2O and the solution acidified to pH »4 with Concentrated HCl. The aqueous layer was extracted with EtOAc and the combined organic extracts were dried over Na2SO4. The solvent was removed to give a pale yellow oil. Flash chromatography on silica gel (10% MeOH / CHCl3) gave the title compound (81 mg): MS (ES) m / e 407. 0 (M + H) +. 1 H NMR (300 MHz, CDCl 3) d 7.78 (d, J = 4.1 Hz, 1 H), 7.50 (dt, J = 8J, 1.6 Hz, 1 H), 7.20 (m, 3 H), 6.95 (m, 3 H), 6.50 (m, 4 H), 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).

EXAMPLE 18 Preparation of 4-r4-rβ-Fmethylamino) pyridin-2-yn-1-ethoxy1-2-phenoxyphenylbutanoic acid a) Methyl 4- [4- [6- (Methylamino) pyridin-2-yl] -1-ethoxy] -2-phenoxyphenyl] butanoate A solution of 2 - [(6-methylamino) -2-pyridinyl] ethanol (0.07 g, 0.43 mmol) and diethyl azodicarboxylate (0.07 ml, 0.44 mmol) in CH2Cl2 (3 ml), was added dropwise to a solution of Ph3P (0.11 g, 0.43 mmol) and 2-phenoxy-4 acid. - [5- (pyridin-2-yl) amino-1-pentyloxy] phenylacetic (0.08 g, 0.29 mmol) in CH2Cl2 (3 mL) at 0 ° C. The cooling bath was removed and the reaction was allowed to warm to room temperature. After 18 hours, the solvent was removed under reduced pressure and the residue was purified by radial chromatography (30% to 50% EtOAc / hexane, silica gel, 6 mm plate), to yield the title compound (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-phenoxyphenyl] butanoic acid A solution of 4- [4- [6- (methylamino) pyridin-2-yl) ] -1-ethoxy.] -2-phenoxyphenyl-1,3-butanoate (0.1 g, 0.34 mmol) and 1.0 N NaOH (2 mL) in MeOH (2 mL), and THF (sufficient to produce a homogeneous solution), stirred at room temperature ambient. After 18 hours, the solvent was removed under reduced pressure. The residue was suspended in H2O and the mixture was acidified to pH = 3 with concentrated HCl. The aqueous phase was extracted with EtOAc and the combined extracts were dried over Na 2 S 4. The solvent was removed under reduced pressure to leave a white foam. Flash chromatography on silica gel (10% EtOAc / MeOH / EtOAc) gave the title compound (0.07 g) as a white foam: MS (ES) m / e 406.9 (M + H) +. Anal. cale, for C 24 H 26 N 2 O 4 -O.75.H 2 O: C, 68.64; H, 6.60; N, 6.67.

Found: C, 68.33; H, 6.09; N, 6.54.

EXAMPLE 19 Preparation of (R) -3-phenyl-4-r4-r3- (pyridin-2-yl) amino-1-propyloxy-phenylbutanoic acid a) (+) - 3-PheniI-4- [4- [3- (1-oxopyridin-2-yl) amino-1-propyloxy] phenyl] butanoate ethyl Diisopropyl azodicarboxylate (0.40 ml, 2 mmol) ) for 45 seconds, to a solution of ethyl (R) -4- (4-hydroxyphenyl) -3-phenylbutanoate (0.39 g, 1.4 mmol), 2 - [(3-hydroxy-1-propyl) N-oxide amino] pyridine (0.35 g, 2 mmol), and triphenylphosphine (0.54 g, 2 mmol) in anhydrous DMF (20 ml) was at 0 ° C under argon. The yellow solution was kept at 0 ° C for 10 minutes and then warmed to room temperature. After 23 hours, the reaction was concentrated. Chromatography on silica gel (gradient: 1% -4% MeOH / CHCl3) gave the title compound (0.30 g, 51%) as an oil yellow: MS (ES) m / e 434.9 (M + H) +. 15 b) (R) -3-Phenyl-4- [4- [3- (pyridin-2-yl) amino-1-propyloxy] phenyl] butanoate ethyl A mixture of (R) -3-phenyl-4- Ethyl [4- [3- (1-oxopyridin-2-yl) amino-1-propyloxy] phenyl] butanoate (0.30 g, 0.69 mmol), cyclohexene (1 mL, 10 mmol), Pd 10% / C (93 mg, 0.09 mmol) and isopropanol (5 ml), was heated to Reflux under argon. After 3 hours, more Pd / C (110 mg) was added. The mixture was refluxed for another 20.5 hours and then filtered through hot celite. The filter pad was washed with hot EtOAc and the combined filtrates were concentrated to give the title compound (0.25 g, 87%) as a 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 (R) -3-phenyl-4- [4- [3- (pyridin-2-yl) amino-1-propyloxyphyphenyljbutanoate (0.25 g, 0.6 mmol) and lithium hydroxide monohydrate (32 mg, 0.76 mmol) in THF (5 mL) and H2O (3 mL), stirred at room temperature environment for 18 hours; it was then concentrated and the residue was dissolved in H2O. The resulting aqueous solution was stirred at room temperature while slowly and carefully adjusting the pH to 5.5 - 6.0 with 1.0 N HCl. The mixture was stirred for 0.5 hour and then the solid was collected by suction filtration and washed with abundant H2O. Drying in high vacuum at 60 ° C gave the title compound (100 mg, 43%) as a crystalline solid: MS (ES) m / e 390.7 (M + H) +. Anal. cale, for C24H26N2? 3-0.25H2O: C, 73.82; H, 6.71; N, 7.17. Found: C, 72.98; H, 6.76; N, 7.09.

EXAMPLE 20 Preparation of (S) -3-phenyl-4-r4-r2-r- (methylamino) pyridin-2-yn-1-ethoxylphene II butanoic acid a) (S) -3-Phenyl-4- [4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] phenol] ethyl butanoate Diisopropyl azodicarboxylate ( 0.16 ml, 0.80 mmol) for 2 minutes, to a solution of ethyl (S) -4- (4-hydroxyphenyl) -3-phenylbutanoate (0.19 g, 0.66 mmol), 6- (methylamino) -2-pyridylethanol ( 0.12 g, 0.80 mmol), and triphenylphosphine (0.20 g, 0.80 mmol) in anhydrous CH 2 Cl 2 (5 mL) at 0 ° C under N 2. The yellow solution was maintained at 0 ° C during minutes and then warmed to room temperature. After 24 hours, the reaction was concentrated and the residue was chromatographed on silica gel (gradient: 10% -30% EtOAc / hexane). The title compound (0.26 g, 93%) was obtained as a colorless oil: MS (ES) m / e 419.0 (M + H) +. b) (S) -3-Phenyl-4- [4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] phenyl] butanoic Lithium hydroxide monohydrate (29 mg, 0.69 mmol) was added ) in H2O (2 ml), to a solution of ethyl (S) -3-phenyl-4- [4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] phenyl] butanoate (0.25 g, 0.62 mmol) in THF (5 mL). The resulting mixture was stirred at room temperature for 18 hours and then concentrated. The residue was dissolved in H2O and the pH was adjusted to 5.5 - 6.0 with 1.0 N HCl. The aqueous solution was separated by decanting the gummy precipitate, which was dried under vacuum at 60 ° C for several days to yield the title compound ( 0.10 g, 41%) as a white solid: MS (ES) m / e 391.0 (M + H) +. Anal. cale, for C 24 H 26 N 2 O 3: C, 73.82; H, 6.71; N, 7.17. Found: C, 73.62; H, 6.80; N, 6.98.

EXAMPLE 21 Preparation of (S) -3-phenyl-4-r4-r3- (p8ridin-2-y-amino-1-propyloxy-phenylbutanoic acid) a) (S) -3-Phenyl-4- [4- [3- (1-oxopyridin-2-yl) Boc-amino-1-propyloxy] phenol] ethyl butanoate Sodium hydride ( 80% in mineral oil, 66 mg, 2.2 mmol) to a solution of ethyl (S) -4- (4-hydroxyphenyl) -3-phenylbutanoate (0.60 g, 2 mmol) in anhydrous DMSO (6 ml) at 23 ° C. C under argon. After the mixture became homogeneous, 2- [N- (3-methanesulfonyloxy-1-propyl) -N- (tert-butoxycarbonyl) amino] pyridine N-oxide (0.35 g, 2%) was added. mmoles). The resulting solution was stirred at room temperature for 5 days and then partitioned between EtOAc and H2O. The organic phase was washed twice with H2O and once with brine; dried (MgSO 4) and concentrated. Chromatography on silica gel (gradient: 0.5% -4% MeOH / CH2Cl2) gave the title compound (0.30 g, 55% based on the recovered starting material) as a yellow oil: MS (ES) m / e 535.0 (M + H) +. Sodium (S) -4- (4-hydroxyphenyl) -3-phenylbutanoate (0.30 g) not recovered was recovered. b) (S) -3-Phenyl-4- [4- [3- (1-oxopyridin-2-yl) amino] -1-propyloxy] phenyl] butanoate A solution of (S) - was stirred Ethyl 3-phenyl-4- [4- [3- (1-oxopyridin-2-yl) Boc-amino-1-propyloxy] phenyl] butanoate (0.30 g, 0.56 mmol), CH2Cl2 (5 mL) and TFA ( 5 ml), at 0 ° C for 1 hour; then it was allowed to warm to room temperature. After 2 more hours, the solution was concentrated to give the title compound (0.15 g) as a pale yellow oil: MS (ES) m / e 435. 2 (M + H) +. c) (S) -3-Phenyl-4- [4- [3- (pyridin-2-yl) amino-1-propyloxy] phenyl] butanoate ethyl A mixture of (S) -3-phenyl-4- [ 4- [3- (1-oxopyridin-2-yl) amino-1-propyloxy-yl-phenyl) -butanoate (0.15 g, 0.35 mmol), cyclohexene (0.5 mL, 5 mmol), Pd 10% / C (80 mg, 0.075 mmol) and isopropanol (5 ml), was heated to ft 10 reflux under argon. After 20.5 hours, the mixture was filtered hot through celite ^. The filter pad was washed with hot EtOAc and the combined filtrates were concentrated to yield the title compound (0.1 g, 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 ft A mixture of (S) -3-phenyl-4- [4- [3- (pyridin-2-yl) amino-1-propyloxy-phenyl-1,3-butanoate (0.10 g, 0.24 mmol) and lithium hydroxide monohydrate (12 mg, 0.29 mmol) in THF (5 mL) and HO (2 mL) was stirred at room temperature for 18 hours and then concentrated. The residue 20 was dissolved in H2O and the resulting aqueous solution was stirred at room temperature while slowly and carefully adjusting the pH to 5.5 - 6.0 with 1.0 N HCl. The mixture was stirred for 0.5 hour and then the solution was separated from the solid by decanting Drying the solid under high vacuum at 60 ° C, gave the title compound (40 mg, 43%) as a crystalline solid: MS (ES) m / e 390.7 (M + H) +. Anal. cale, for C24H26N203-1 JHCI: C, 63.72; H, 6.17; N, 6.19. Found: C, 63.56; H, 6.22; N, 6.10. • EXAMPLE 22 Preparation of the acid (±) -3- (4-bromophenyl-4-r2-r6- (methylamino) pyridin-2-ill-1-ethoxyphenylbutanoic acid • a) (±) -3- (4-Bromophenyl) -4- [4- [2- [6- [N- (fer-butoxycarbonyl) -N-methylamino] pyridin-2-yl] -1-ethoxy ] ethyl phenyl] butanoate Diisopropyl azodicarboxylate (0.24 ml, 1. 24 mmole) to a solution of ethyl (±) -3- (4-bromophenyl) -4- (4-hydroxyphenyl) butanoate (0.30 g, 0.82 mmol), 6- [N- (eer-butoxycarbonyl) -N- methylamino] -2-pyridylethanol (0.31 g, 1.24 mmol), and triphenylphosphine (0.32 g, 1.24 mmole) in anhydrous CH 2 Cl 2 (10 ml), at 0 ° C under argon. The yellow fc solution was kept at 0 ° C for 10 minutes and then warmed to room temperature. After 39 hours, the reaction was concentrated and the residue was chromatographed on silica gel (20% EtOAc / hexane) to give the title compound (0.32 g, 65%) as a clear oil: TLC Rf (20% EtOAc / hexane) 0.44; MS (ES) m / e 349.1 (M + Na) +, 674.9 (2M + Na) +. b) (±) -3- (4-Bromophenyl) -4- [4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] phenyl] butanedioate ethyl A solution of ( ±) -3- (4-bromophenyl) -4- [4- [2- [6- [N- (fer-ft-butoxycarbonyl) -N-methylamino] pyridin-2-yl] -1-ethoxy] phenyl] butanoate of ethyl (0.32 g, 0.53 mmol) in 4 N HCl in dioxane (15 ml) was stirred at room temperature for 1.5 hours. By concentration and re-concentration of CH2Cl2 and hexane, the title compound was obtained as a white syrup, which was passed to the next step without further purification. c) Acid (±) -3- (4-bromophenyl) -4- [4- [2- [6- (methylamino) pyridin-2-yl] -1- ethoxy-phenyl-butanoic acid 1.0 N NaOH was added dropwise. (1.44 ml, 1.44 mmole) to a solution of (±) -3- (4-bromophenyl) -4- [4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] phenyl] Ethyl butanoate (0.26 g, 0.48 mmol) in dioxane (10 ml) and H2O (5.0 ml). The resulting mixture was stirred at 50 ° C for 3 hours and then concentrated. The residue was diluted with H2O (5 ml) and the solution was neutralized with HCl 1.0 N. The solid precipitate was collected and dried to yield the title compound (0.20 g, 81%) as a white crystalline solid: HPLC (Hamilton PRP-1 R, gradient for 20 minutes: CH3CN 10% -80% / H2? With TFA 0.1%) K "= 13.28 Anal cale, for C24H25N2O3BM.5HCIO.25H2O: C, 54.54; H, 5.15; N, 5.30 Found: C, 54.49; H, 4.97; N, 5.10.

EXAMPLE 23 Preparation of (±) -3- (4-isopropylphenyl) -4-r4-r2-r6- (methylamino) pyridin-2? I1-1-ethoxylphenylbutanoic acid a) (±) -3- (4-lsopropylphenyl) -4- [4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy-phenyl-phenylbutanoate The title compound was obtained in accordance with procedure of Example 22 (a), but was replaced with methyl (±) -4- (4-hydroxyphenyl) -3- (4-isopropylphenyl) butanoate (±) -3- (4-bromophenyl) -4- ( Ethyl 4-hydroxyphenyl) butanoate, and substituting 6- (N-methoxycarbonyl) -N-methylamino] -2-pyridylethanol with 6- (methylamino) -2-pyridylethanol, obtaining after chromatography on silica gel ( 30% EtOAc / hexane): MS (ES) m / e 447.0 (M + H) +. b) Acid (±) -3- (4-isopropylphenyl) -4- [4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] phenyl] butanoic The title compound was obtained according to the procedure of example 22 (c), but was substituted with (±) -3- (4-isopropylphenyl) -4- [4- [2- [6- (methylamino) pyridin-2-yl] -1 methyl-ethoxy] phenyl] butanoate (±) -3- (4-bromophenyl) -4- [4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] phenyl] ethyl butanoate: HPLC (Hamilton PRP-1 R, gradient for 20 minutes: CH3CN 10% -80% / H2O with 0.1% TFA) K '= 14.19. MS (ES) m / e 435.5 (M + H) +.

EXAMPLE 24 Preparation of (±) -3- (4-? -propyl-phenyl) -4-r4-r3- (4-methyl-pyridin-2-yl) amino-1-propyloxy-phenyl-n-butanoic acid a) (±) -3- (4-lsopropyl-phenyl) -4- [4- [3- (4-methyl-1-oxopyridin-2-yl) amino-1-propyloxy-phenyl-1,3-butanoate methyl ester NaOH (0.14 g, 3.37 mmol) to a solution of N - oxide of 2 - [(3-bromo-1-propyI) amino] pyridine (0.37 g, 1.13 mmol) and (±) -4- (4-hydroxypheni) -3- (4-isopropylphenyl) butanoate methyl (0.32 g, 1.02 mmoles) in ft 10 anhydrous CH3CN (15 ml). After stirring at room temperature under argon for 20 hours, the reaction was filtered and concentrated in the rotary evaporator. Chromatography on silica gel (5% MeOH / CH2Cl2) gave the title compound (0.31 g, 64%) as a clear oil: MS (ES) m / e 477.1 (M + H) +. b) (±) -3- (4-lsopropylphenyl) -4- [4- [3- (4-methylpyridin-2-yl) amino-1-propyloxy] phenyl] -butanoate methyl A mixture of (±) -3- (4-isopropylphenyl) -4- [4- [3- (4-methyl-1-oxopyridin-2-yl) amino-1-propyloxy] phenyl] butanoate methyl (0.31 g, 0.65 mmol), Pd 10% / C (0.31 g, 0.29 mmol), cyclohexene (0.66 ml, 6.51 mmol) and isopropanol (15 ml), heated to reflux for 16 hours; the catalyst was then removed by filtration through celite.RTM. Concentration and chromatography on silica gel (5% MeOH / CH2Cl2) gave the title compound (0.25 g, 83%) as a light yellow oil: MS (ES) m / e 460.9 (M + H) +. c) Acid (±) -3- (4-isopropylphenyl) -4- [4- [3- (4-methylpyridin-2-yl) amino-1-propyloxy] -phenylbutanoic acid The compound of the title according to the procedure of example 22 (c), but was substituted with (±) -3- (4-isopropylphenyl) -4- [4- [3- (4-methylpyridin-2-yl) amino-1- methyl propyloxy] phenyl] butanoate ethyl (±) -3- (4-bromopheni) -4- [4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] phenyl] butanoate HPLC (Hamilton PRP-1 R, gradient for 20 minutes: CH3CN 10% - • 10 80% / H2O with 0.1% TFA) K '= 14.57. MS (ES) m / e 447.5 (M + H) +.

EXAMPLE 25 Preparation of 4-r4-r2-r6- (methylamino) pyridin-2-yn-1-ethoxyphenin-3-butenoic acid 15 ft a) Methyl 4- [4- [2- [6- (Methylamino) pyridin-2-yl] -1-ethoxy] phenyl] crotonate The title compound was prepared (0.6 g, 76%) according to the procedure of example 5 (a), but was substituted with methyl 4- (4-hydroxyphene) crotonate (0.46 g, 2.39 mmol) on 4- (4- Methyl hydroxyphenyl) butanoate: MS (ES) m / e 327 (M + H) +. b) 4- [4- [2- [6- (Methylamino) pyridin-2-yl] -1-ethoxy] phenyl] -3-butenoic acid A solution of 1.0 N NaOH (1.8 ml, 1.8 mmol) was added to a solution of methyl 4- [4- [2- [6- (methylamino) pyridn-2-yl] -1-ethoxy] phenyl] crotonate (0.3 g, 0.92 mmol) in MeOH (5 ml ). The reaction was stirred overnight at room temperature and then concentrated in vacuo. By flash chromatography on silica gel (gradient: CH2CI2, after MeOH 1% CH2Cl2, then MeOH 1% / CH2Cl2 with HC02H 0.5%) gave the title compound (0.09 g, 31%) as a slightly yellow solid: MS (ES) m / e 313 (M + H) +; ^ H NMR (360 MHz, (DMSO-d6) d 7.85 (t ap, 1 H), 7. 33 (d, J = 8J Hz, 2 H), 6.84-6.96 (m, 4 H), 6.81 (d, J = 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. Cale, for C? ßH2? 2? 3-1.0 HCO2H: C, 63.68; H, 6.19: N, 7.82. Found: C, 63.84; H, 6.42; N 7.98.

EXAMPLE 26 Preparation of (S) -3-phenyl-4-r4-r2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) -1-ethoxyphenylbutanoic acid a) (S) -3-Phenyl-4- [4- [2- (5,6J, 8-tetrahydro-1,8-naphthyridin-2-yl) -1-ethoxy] phenyl] -butanoic acid ethyl ester diisopropyl azodicarboxylate (0.25 ml, 1.25 mmol) to a solution of ethyl (S) -3-phenyl-4- (hydroxyphenyl) butanoate (178 mg, 0.63 mmol), 2- (5,6,7,8-tetrahydro) -1,8-naphthyridin-2-yl) ethanol (223 mg, 1.25 mmol) and triphenylphosphine (328 mg, 1.25 mmol) in anhydrous THF (5 ml) at 0 ° C. The mixture was allowed to warm up as the bath warmed to room temperature. After 18 hours, the mixture was concentrated and the residue was chromatographed on silica gel (Et2? / Hexane 4.5: 1) to give the title compound (197 mg, 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 one solution of (S) -3-phenyl-4- [4- [2- (5,6J, 8-tetrahydro-1, 8-naphthyridin-2-yl) -1-ethoxy] phenyl] ethyl butanoate (197 mg 0.44 mmole) in THF / H2O 1: 1 (2 ml) was added 1N LiOH (0.66 ml, 0.66 mmole). After 18 hours, the mixture was heated to 50 ° C. After 18 hours, the mixture was cooled to room temperature and washed with Et2? (2 x 25 ml). The aqueous layer was concentrated to remove residual THF / Et2O and then acidified to pH 6 using 10% HCl. The solid was collected by filtration and dried under vacuum at 50 ° C to give the title compound as a white powder (136 mg, 74%). MS (ES) m / e 417 (M + H) +. Anal. cale, for C26H28N2? 3-0.5H2O: C, 73.39; H, 6.87; N, 6.58. Found: C, 73.14; H, 6.64; N, 6.26.

EXAMPLE 27 Preparation of (±) -3-y1- (dimethylaminosulfonyl) imidazol-2-n-4-r4-y2-r6- (methylamino) pyridin-2-yn-1-ethoxy-p-p-n-butanoic acid a) (±) -3- [1- (Dimethylaminosulfonyl) imidazol-2-yl] -4- [4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] phenyl] butanoate ethyl The title compound (411 mg, 70%) was prepared as a light orange oil, according to the procedure of example 9 (a), but was replaced with (±) -3- [1- (dimethylaminosulfonyl) ethyl imidazoI-2-yl] -4- (4-hydroxyphenyl) butanoate (436 mg, 1.14 mmol) ethyl (±) -4- (4-hydroxyphenyl) -3- (thiazol-2-yl) butanoate: MS (ES) m / e 516 (M + H) +. b) Acid (±) -3- [1 - (dimethylaminosulfonyl) imidazol-2-yl] -4- [4- [2- [6- (methylamino) -pyridin-2-yl] -1-ethoxy] phenyl] butanoic The title compound (70 mg, 37%) was prepared as a white solid according to the procedure of example 9 (b), but was replaced with (±) -3- [1- (dimethylaminosulfonyl) imidazole-2 il] -4- [4- [2- [6- (Methylamino) pyridin-2-yl] -1-ethoxy] phenyl] -butanoate (200 mg, 0.39 mmol) (±) -4- [4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] phenyl] -3- (thiazol-2-yl) ethyl butanoate: MS (ES) m / e 488 (M + H). +. Anal. cale, for C23H2gN5? 5S-0.5H2? -HCI: C, 51.83; H, . 86; N, 13.14. Found: C, 51.88; H, 5.69; N, 1275.

EXAMPLE 28 Preparation of (±) -3-flmidazole-2-8D-4-r4-r2-r6- (methylamino) pyridin-2-yl-1-ethoxyphenylbutanoic acid a) Acid (±) -3- (midazol-2-yl) -4- [4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] phenyl] -butanoic It was dissolved ( ±) -3- [1 - (dimethylaminosulfonyl) imidazol-2-yl] -4- [4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] phenyl] butanoate ethyl (200 mg, 0.39 mmol) in 2.0 M HCl (10 mL), and the solution was heated to reflux. After 6 hours, the mixture was cooled to room temperature and the pH adjusted to 6 using 1.0 N NaOH. The resulting solution was concentrated to approximately 2 ml and subjected to chromatography on a C-18 binding / elution column ( H2O, then CH3CN 20% / H2?). The fractions containing the product were combined and lyophilized to give the title compound (80 mg, 54%) as a white powder: MS (ES) m / e 381 (M + H) +. Anal. cale, for C21 H24N4O3-O.85-.CI: C, 61.31; H, 6.09; N, 13.62. Found: C, 61.26; H, 6. 09; N, 13.62.

EXAMPLE 29 Preparation of (S) -4-r4-r2-r6- (methylamino) pyridin-2-yn-1-ethoxy-1-phenyl-3- (thiazol-2-yl, butanoic acid a) (S) -4- [4- [2- [6- (Methalamino) pyridin-2-yl] -1-ethoxy] phenyl-3- (thiazol-2-yl) ethyl butanoate The compound of the title (262 mg, 89%) according to the procedure of Example 9 (a), but was replaced with ethyl (S) -4- (4-hydroxyphenyl) -3- (thiazol-2-yl) butanoate (200 mg, 0.69 mmol) ethyl (±) -4- (4-hydroxyphenyl) -3- (thiazol-2-yl) butanoate, obtaining as a pale orange oil after chromatography on silica gel (THF) 35% in toluene / hexane 1: 1): MS (ES) m / e 426 (M + H) +. b) (S) -4- [4- [2- [6- (Methylamino) pyridin-2-yl] -1-ethoxy] phenyl] -3- (thiazol-2-yl) -butanoic acid. title compound (112 mg, 45%) as a white solid, according to the procedure of example 9 (b), but was replaced with (S) -4- [4- [2- [6- (methylamino) pyridine -2-yl] -1-ethoxy] phenyl] -3- (thiazol-2-yl) butanoate (262 mg, 0.62 mmol) (±) -4- [4- [2- [6- (methylamino) ) pyridin-2-yl] -1-ethoxy] phenyl] -3- (thiazol-2-yl) ethyl butanoate: MS (ES) m / e 398 (M + H) +. Anal. cale, for C2iH23N3? 3-0J5H2O: C, 61.37; H, 6.01; N, 10.22. Found: C, 61.51; H, 5.89; N, 10.18.

EXAMPLE 30 Preparation of (R) -4-r4-r2-r6- (methylamino) pyridin-2-ip-1-etoxpfenip-3- (thiazol-2-yl) butanoic acid a) (R) -4- [4- [2- [6- (Methylamino) pyridin-2-yl] -1-ethoxy] phenyl] -3- (thiazoI-2-yl) ethyl butanoate prepared the title compound (265 mg, 90%) according to the procedure of example 9 (a), but was substituted with (R) -4- (4-hydroxyphenyl) -3- (thiazol-2-yl) butanoate of ethyl (200 mg, 0.69 mmol) ethyl (±) -4- (4-ft-10-hydroxyphenyl) -3- (thiazol-2-yl) butanoate, obtaining as a pale orange oil after gel chromatography of silica (THF 35% in toluene / hexane 1: 1): MS (ES) m / e 426 (M + H) +. b) (R) -4- [4- [2- [6- (Methylamino) pyridin-2-yl] -1-ethoxy] phenyl] -3- (thiazol-2-yl) -15-butanoic acid. title compound (98 mg, 40%) as a white solid, according to the procedure of example 9 (b), but was substituted with (R) -4- [4- [2- [6- (methylamino) pyridine -2-yl] -1-ethoxy] phenyl] -3- (thiazol-2-yl) butanoate (265 mg, 0.62 mmol) (±) -4- [4- [2- [6- (methylamino) ) pyridin-2-yl] -1- 20 ethoxy] phenyl-3- (thiazol-2-yl) ethyl butanoate: MS (ES) m / e 398 (M + H) +. Anal. cale, for C21 H23N3O3O.5H2O: C, 62.05; H, 5.95; N, 10.34. Found: C, 62. 25; H, 5.80; N, 10.37.

EXAMPLE 31 Preparation of acid (±) -3- (benzothiazol-2-yl) -4-r4-r2-r6- (methylamino) pyridin-2-ylM-ethoxyphenylbutanoic acid a) (±) -3- (Benzothiazol-2-yl) -4- [4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] phenyl] -butanoate ethyl The title compound (220 mg, 78%) was prepared according to the procedure of example 9 (a), but was replaced with (±) -3- (benzothiazol-2-yl) -4- (4-hydroxyphenyl) ) ethyl butanoate (200 mg, 0.59 mmol) ethyl ether (±) -4- (4-hydroxyphenyl) -3- (thiazol-2-yl) butanoate, obtained as a clear oil after gel chromatography of silica (EtOAc 60% / hexane): MS (ES) m / e 476 (M + H) +. b) Acid (±) -3- (benzothiazol-2-yl) -4- [4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy-phenyl] -15-butanoic The compound was obtained of the title (125 mg, 61%) as a white solid, according to the procedure of example 9 (b), but was substituted with (±) -3- (benzothiazol-2-yl) -4- [4- [ 2- [6- (Methylamino) pyridin-2-yl] -1-ethoxy] phenyl] -ethyl butanoate (220 mg, 0.46 mmol) (±) -4- [4- [2- [6- (methylamino) pyridin- 2-yl] -1-ethoxy] phenyl] -3- (thiazol-2-yl) butanoate: MS (ES) m / e 448 (M + H) +.

Anal. cale, for C25H25N3O3S-0.75H2O: C, 65.13; H, 5.79; N, 9.11.

Found: C, 65.22; H, 5.49; N, 8.92.

EXAMPLE 32 Preparation of (S) -4-r 4 -r 2 - (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) -1- etoxpfen-p-3-.thiazol-2-yl acid. butanoic a) (ethyl SH-μ-p-id.dJ.d-tetrahydro-I .S-naphthyridin-1-yl-ethoxyJphenyl-S-ithiazol-yl) -butanoate The title compound was obtained (371 mg , impure) according to the procedure of example 27 (a), but was replaced with ethyl (S) -4- (4-hydroxyphenyl) -3- (thiazol-2-yl) butanoate (200 mg, 0.69 mmol) ethyl (S) -3-phenyl-4- (hydroxyphenyl) butanoate, obtained as a clear oil after chromatography on silica gel (THF 40% in CHCl3 / hexane 1: 1): MS (ES) m / e 452 (M + H) +. b) (S) -4- [4- [2- (5,6,7,8-Tetrahydro-1,8-naphthridin-2-yl) -1-ethoxy] phenyl-3- (thiazole-) acid 2-yl) butanoic was dissolved (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) in THF / H2O 1: 1 (5 ml). To this solution was added 1.0 N LiOH (1.04 mL, 1.04 mmol), and the mixture was heated to 50 ° C. After 18 hours, the mixture was cooled to room temperature and washed with Et2? (2 x 5 ml). The aqueous layer was concentrated under vacuum to remove residual organic solvents and then acidified to pH 6 using 10% HCl. The solid was collected by filtration and dried under vacuum at 50 ° C to give the title compound (106 mg, 36% by 2 steps) as a white powder: MS (ES) m / e 424 (M + H) +. Anal. cale, for C23H25N3O3SO.33HCI: C, 63.42; H, 5.86; N, 9.65. Found: C, 63.19; H, 5.61; N, 9.45.

EXAMPLE 33 Preparation of acid (±, -3- (4-methylthiazol-2-yl) -4-r4-r2-r6- (met8-lanyl) pyridin-2-ip-1-ethoxy-1-phenylbutanoic acid a) (±) -3- (4-Methylthiazol-2-yl) -4- [4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] phenyl] -butanoate ethyl The title compound (395 mg, impure) was prepared according to the procedure of example 9 (a), but substituting (±) -3- (4-methylthiazol-2-yl) -4- (4-hydroxyphenyl) ethyl butanoate (216 mg, 0.74 mmol) ethyl (±) -4- (4-hydroxyphenyl) -3- (thiazol-2-yl) butanoate, obtained as a clear oil after chromatography on silica gel ( EtOAc 50% / hexane): MS (ES) m / e 426 (M + H) +. b) Acid (±) -3- (4-methylthiazol-2-yl) -4- [4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy-phenyl] -butanoic It was dissolved (±) -3- (4-Met.IthiazoI-2-yl) -4- [4- [2- [6- (methylamino) pyridn-2-yl] -1-ethoxy] pheni'i ] impure ethyl butanoate (395 mg) in THF / H2O 1: 1 (5 ml). To this solution was added 1.0 N LiOH (1.11 mL, 1.11 mmol), and the mixture was heated to 50 ° C. After 18 hours, the mixture was cooled to room temperature and washed with Et2? (2 x 5ml). The aqueous layer was concentrated under vacuum to remove residual organic solvents and then acidified to pH 6 using 10% HCl. The solid was collected by filtration and dried under • vacuum at 50 ° C to give the title compound (88 mg, 29% by the 2 steps) as a pale yellow powder: MS (ES) m / e 412 (M + H) +. Anal. cale, for C22H25N3O3SO.25HCI: C, 62.82; H, 6.05; N, 9.99. Found: C, 62.94; H, 5.95; N, 9.95.

EXAMPLE 34 Preparation of (±) -3-r4-carboxy-1,3-oxazol-2-p-4-r4-.2-r6- (methylamino) pyridin-2-p-1-ethoxy-pfenipbutane acid co a) Acid (±) -3- [4-carboxy-1, 3-oxazol-2-yl] -4- [4- [2- [6- (methylamino) pyridin-2-yl] -1- ethoxy] phenyl] butanoic 15 To a solution of (±) -3- [4- (benzyloxycarbonyl) -1, 3-oxazol-2-yl] -4- ft [4- [2- [6- (methylamino) pyridin-2] methyl] -1-ethoxy] phenyl] butanoate (50 mg, 0.09 mmol) in THF / H2O 1: 1 (1 ml) at room temperature, LiOH was added 1. 0 N (0.28 ml, 0.28 mmol). After 72 hours, the mixture was acidified to pH 6 using 10% HCl, and then dried to dryness. The residue is purified by reverse phase HPLC (gradient: CH3CN 10-80% / H2? With TFA 0.1%). The fractions containing the product were combined and concentrated to remove CH3CN. The resulting aqueous solution was lyophilized to give the title compound (36 mg, 94%) as a white solid: MS (ES) m / e 426 (M + H) +. Anal. cale, for C22H23N3? 6-1 J TFA: C, 49.26; H, 4.02; N, 6.79. Found: C, 49.30; H, 4.24; N, 6.97.

EXAMPLE 35 Preparation of (±) -3-r4- (aminocarbonyl) -1.3-oxazole-2-yn-4-r4-r2-r6- (methylamino) pyridin-2-ip-1-ethoxy-1-phenylbutanoic acid a) (±) -3- [4- (Aminocarbonyl) -1, 3-oxazol-2-yl] -4- [4- [2- [6- (methylamino) pyridin-2-yl] - Methyl 1-ethoxy] phenyl] butanoate To a solution of (±) -3- [4-carboxy-1,3-oxazol-2-yl] -4- [4- [2- [6- (methylamino) pyridine] -2-iI] -1-ethoxy] phenyl] butanoate (82 mg, 0.19 mmol) in dry DMF (2 mL) at room temperature, NH4Cl (30 mg, 0.56 mmol), HOBt (30 mg, 0.22 mmole), Et ^ N (0.08 ml, 0.56 mmole) and EDC (42 mg, 0.22 mmole). After 18 hours, the mixture was concentrated. The residue was taken up in H2O (10 ml) and extracted with CH2Cl2 (3 x 30 ml). The combined organic layers were dried over MgSO 4 and concentrated to give the title compound (46 mg, 55%) as a light yellow oil: MS (ES) m / e 439 (M + H) +. b) Acid (±) -3- [4- (aminocarbonyl) oxazol-2-yl] -4- [4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] phenyl] butanoic acid The crude product was prepared according to the procedure of Example 35 (a), but substituting (±) -3- [4- (aminocarbonyl) -1,3-oxazol-2-yl] -4- [4- [2- [6- (Methylamino) pyridin-2-yl] -1-ethoxy] phenyl] butanoate methyl (46 mg, 0.1 mmol) (±) -3- [4- (benzyloxycarbonyl) -1, 3- oxazol-2-yl] -4- [4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] phenyl] butanoate methyl. The crude product was purified by reverse phase HPLC (gradient: CH3CN 15-50% / H2? With TFA 0.1%). The fractions containing the product were combined and concentrated to remove CH3CN. 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. cale, for C22H24N4? 5-2.5TFA, 1.0 H2O: C, 44.58; H, 3.95; N, 7.70. Found: C, 44.24; H, 3.60; N, 7.83.

EXAMPLE 36 Preparation of (±) -3-r4- (dimethylaminocarbonyl) -1,3-oxazole-2-yn-4-r4-r2-r6- (methylamino) pyridin-2-yn-1-ethoxylphenylbutanoic acid a) (±) -3- [4- (Dimethylaminocarbonyl) -1, 3-oxazol-2-yl] -4- [4- [2- [6- (methylamino) pyridin-2-yl] -1 methyl-ethoxy] phenyl] butanoate To a solution of (±) -3- [4-carboxy-1,3-oxazol-2-yl] -4- [4- [2- [6- (methylamine) pyridine- 2-yl] -1-ethoxy] phenol] butanoate (82 mg, 0.19 mmol) in dry DMF (2 ml) at room temperature, dimethylamine hydrochloride (46 mg, 0.56 mmol), HOBt ( 30 mg, 0.22 mmole), Et ^ N (0.08 ml, 0.56 mmole) and EDC (42 mg, 0.22 mmole). After 18 hours, the mixture was concentrated. The residue was taken up in H2O (10 ml) and extracted with CH2Cl2 (3 x 30 ml). The combined organic extracts were dried over MgSO4 and concentrated to give the title compound (79 mg, 89%) as light yellow oil: MS (ES) m / e 439 (M + H) +. b) Acid (±) -3- [4- (dimethylaminocarbonyl) -1, 3-oxazoI-2-yl] -4- [4- [2- [6- (methylamino) -pyridin-2-yl] -1 -ethoxy] phenyl] butanoic The crude product was prepared according to the procedure of Example 35 (a), but substituting (±) -3- [4- (dimethylaminocarbonyl) -1, 3-oxazol-2-yl] - 4- [4- [2- [6- (Methylamino) pyridin-2-yl] -1-ethoxyphenyl-methylbutanoate (79 mg, 0.17 mmol) (±) -3- [4- (benzyloxycarbonyl) -1, 3 methyl -oxazol-2-yl [] - 4- [4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] phenyl] butanoate. The crude product was purified by reverse phase HPLC (gradient: CH3CN 10-80% / H2O with TFA 0.1%). The fractions containing the product were combined and concentrated to remove CH3CN. The resulting aqueous solution was lyophilized to give the title compound (48 mg, 62%) as a white solid: MS (ES) m / e 453 (M + H) +. Anal. cale, for C 24 H 28 N 4 O 5 -L 8 TFA: C, 50.44; H, 4.57; N, 8.52. Found: C, 50.19; H, 4.79; N, 8.88.

EXAMPLE 37 Preparation of (S) -3-phenyl-4-r4-r3- (3,4,5,6-tetrahydropyrimidin-2-yl) amino-1-propyloxy-pheninb-tanoic acid a) (S) -3-Phenyl-4- [4- [3- (i.e.-butoxycarbonyl) amino-1-propyloxy] phenyl] butanoate ethyl A solution of 3-N- (1er-butoxycarbonyl) amino-1 -propanol (499 mg, 2.85 mmol) and diisopropyl azodicarboxylate (0.561 ml, 2.85 mmol) in anhydrous CH 2 Cl 2 (14 ml), was added dropwise over 10 minutes at one ft 10 (S) -3-phenyl- 4- (4-hydroxyphenyl) butanoate (323 mg, 1.14 mmol) and triphenylphosphine (747 mg, 2.85 mmol) in anhydrous CH 2 Cl 2 (5.7 mL) 0 ° C under argon. The yellow solution was kept at 0 ° C for 10 minutes and then warmed to room temperature. After 23 hours, the reaction was concentrated in the rotary evaporator and the residue was subjected to chromatography flash on silica gel (15% EtOAc / hexane) to produce the • title compound (378 mg, 75%) as a white solid: 1 H NMR (300 MHz, CDCl 3) d 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, 2H), 1.43 (s, 9 H), 1.12-1.08 (t, 3 H). 20 b) (S) -3-Phenyl-4- [4- (3-amino-1-propyloxy) phenyl] butanoate of ethyl 4N HCl in dioxane (4.25 ml, 17 mmol) was added dropwise to a solution of ethyl (S) -3-phenyl-4- [4- [3- (i.e-butoxycarbonyl) amino-1-propyloxy] phenyl] butanoate (377 mg, 0.85 mmol) at room temperature, and the resulting mixture it was stirred for 2 hours. The solvent was removed in the rotary evaporator and the residue was triturated with ether to yield the title compound as a white solid: MS (ES) m / e 341.9 (M + H) +. c) (S) -3-Phenyl-4- [4- [3- (pyrimidin-2-yl) amino] -1-propyloxy] phenyl] butanoate A mixture of (S) -3-phenyl -4- [4- (3-amino-1-propyloxy) phenyl] butanoate of ethyl (0.85 mmol, crude), 2-bromopyrimidine (177 mg, 1.11 mmol) and NaHC? 3 (357 mg, 4.25 mmol) in EtOH (10 ml), was heated to reflux for 22 hours. The mixture was cooled to room temperature and the salts were removed by filtration. The filter cake was washed with EtOH. The combined filtrate and washings were concentrated in the rotary evaporator, and the residue was subjected to flash chromatography on silica gel (25% EtOAc / hexane) to give the title compound (289 mg, 80%, 2 steps): MS ( ES) m / e 419.9 (M + H) +. d) (S) -3-Phenyl-4- [4- [3- (3,4,5,6-tetrahydropyrimidin-2-yl) amino-1-propyloxy] phenyl] -butanoate ethyl A mixture of (S) Ethyl) -3-phenyl-4- [4- [3- (pyrimidin-2-yl) amino-1-propyloxy] phenyl] butanoate (286 mg, 0.68 mmol), glacial HOAc (10 ml), Concentrated HCl (0.113 ml, 1.36 mmol) and 10% Pd / C (72 mg, 0.068 mmol), was stirred at room temperature under H2 (3.15 kg / cm2) in a Parr apparatus.

After 4 hours, the reaction was filtered and concentrated to yield the title compound (240 mg, 83%): MS (ES) m / e 423.8 (M + H) +. e) (S) -3-phenyl-4- [4- [3- (3,4,5,6-tetrahydropyrimidin-2-yl) amino-1-propyloxy] -phenyl-butanoic acid A mixture of (S) -3 ethyl-phenyl-4- [4- [3- (3,4,5,6-tetrahydropyrimidin-2-yl) amino-1-propyloxy] phenyl] butanoate (240 mg, 0.56 mmol), 1.0 N NaOH (1.15 ml, 1.12 mmol), THF (4 ml) and EtOH (4 ml) was stirred in an oil bath set at 35 ° C. After 18 hours, the mixture was cooled to room temperature and washed with Et2O (2 x 5 ml). The washes of Et2? They were discarded. The remaining aqueous layer was slightly concentrated in the rotary evaporator to remove residual organic solvents; it was then filtered and the filtrate was acidified to pH 5 with 30% TFA. Preparative HPLC (Hamilton PRP-1R, 250 x 21.5 mm, CH3CN 35% / H20 with 0.1% TFA), followed by lyophilization, gave the title compound (80 mg) as a white powder: MS (ES) m / e 395.9 (M + H) +. Anal. cale, for C23H29N3O3-TFA: C, 58.93; H, 5.93; N, 8.25. Found: C, 58.63; H, 5.59; N, 7.99.

EXAMPLE 38 Preparation of acid (±.-3-r4-r2-r6- (methylamino) pyridin-2-ipetoxflbenzyl-4-pentynoic acid a) (±) -3- [4- [2- [6- [N- (fe? -Butoxycarbonyl) methylamino] pyridin-2-yl] ethoxy] benzyl] -4-methyl pentynoate A a solution of methyl (±) -3- (4-hydroxybenzyl) -4-pentynoate (25 mg, 0.12 mmol), 6 - [(etr-butoxycarbonyl) methylamino] -2-pyridylethanol (43 mg, 0.17 mmol), Pl P (45 mg, 0.17 mmol) in CH 2 Cl 2 (5 mL) at 0 ° C was added dropwise DEAD (0.03 mL, 0.19 mmol). The reaction was allowed to warm to room temperature. After 2 days, the solvent was removed 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) +. 15 b) (+) - 3- [4- [2- [6- (methylamino) pyridin-2-yl] ethoxy] benzyl] -4-pentynoic acid A solution of 4 N HCl / dioxane was added (1 mL) a (±) -3- [4- [2- [6- [N- (tert-butoxycarbonyl) methylamino) pyridin-2-yl] ethoxy] benzyl] -4-methyl pentynoate (30 mg, 0.06 mmoles). After 18 hours, the solvent was removed under reduced pressure to give a pale yellow residue. A solution of this residue was stirred with 1.0 N NaOH (0.5 ml), MeOH (0.5 ml) and THF (1 drop) at room temperature for 18 hours; it was then 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 extracts were dried over Na2SO4 and the solvent was removed. The residue was lyophilized from water to give the title compound (21 mg) as a white powder. 1 H NMR (300 MHz, CDCl 3) d 7.57 (m, 1 H), 7.12 (d, J = 8.5 Hz, 2 H), 6J6 (d, J = 8.5 Hz, 2 H), 6.55 (d, J = 7.2 Hz, 1 H), 6.40 (d, J = 8.8 Hz, 1 H), 4.2 (m, 2 H), 3J0 (m, 2 H), 3.15 (m, 2 H), 2.88 (s, 3 H), 2.80 (m, 1 H), 2J0 (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 39 Preparation of (±) -4-r4-r2-r6- (methylamino) pyridin-2-p-1-ethoxy-1-phenyl-3- (2-phenylethyl) butanoic acid a) (±) -4- [4- [2- [6- (Methylamino) pyridin-2-yl] -1-ethoxy] phenyl] -3- (2-phenylethyl) butanoate methyl The title compound was obtained (59%) according to the procedure of Example 2 (a), but substituting methyl (±) -4- (4-hydroxyphenyl) -3- (phenylethyl) butanoate with (±) -4- (4-hydroxyphenyl) Ethyl) -3-phenylbutanoate, obtained as a clear film after chromatography on silica gel (20% EtOAc / hexane): MS (ES) m / e 433 (M + H) +. b) Acid (±) -4- [4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] phenyl] -3- (2-phenylethyl) -butanoic The compound was obtained of the title (70%) as a white foam, according to the procedure of example 2 (b), but substituting • with (±) -4- [4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] phenyl] -3- (2-phenylethyl) butanoate methyl (±) -3 ethyl phenyl-4- [4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] phenyl] butanoate: MS (ES) m / e 419 (M + H) +. Anal. cale, 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 40 Preparation of (±) -3-benzyl-4-r4-r2-r6- (methylamino) pyridin-2-yn-1-ethoxyphenylbutanoic acid a) (+) - methyl 3-Benzyl-4- [4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] pheny] butanoate The title compound was obtained ( 47%) according to the Mk procedure of Example 2 (a), but substituting methyl (±) -4- (4-hydroxyphenyl) -3-benzylbutanoate with ethyl (±) -4- (4-hydroxyphenyl) -3-phenylbutanoate, obtaining as a clear film after chromatography on silica gel (30% EtOAc / hexane): MS (ES) m / e 419 (M + H) +. 20 b) Acid (±) -4- [4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] phenyl] -3- (2-benzyl) -butanoic Obtained the title compound (47%) as a light yellow foam, according to the procedure of example 2 (b), but substituting with (±) -3-benzyl-4- [4- [2- [6- (Methylamino) pyridin-2-yl] -1-ethoxy] -phenyl] -butanoate methyl (±) -3-phenyl-4- [4- [2- [6- (methylamino) pyridin-2-yl] -1- ethyl ethoxyphiylbutanoate: MS (ES) m / e 405 (M + H) +. Anal. cale, for C25H28N2O3-I .OHCI-O.45 H2O: C, 66.87; H, 6.71; N, 6.24. Found: C, 66.68; H, 6.62; N, 6.64.

EXAMPLE 41 Preparation of (±) -4-r4-r2-r6- (methylamino) pyridin-2-yn-1-ethoxypfenin-3- (2-cyclopropyl) butanoic acid a) (±) -4- [4- [2- [6- (Methylamino) pyridin-2-yl] -1-ethoxy] phenyl] -3- (2-cyclopropyl) butanoate methyl The title compound was obtained (64%) according to the procedure of Example 2 (a), but substituting (±) -4- (4-hydroxyphenyl) -3-cyclopropylbutanoate methyl (±) -4- (4-hydroxyphenyl) -3 ethyl phenylbutanoate, obtained as a clear film after chromatography on silica gel (20% EtOAc / hexane): MS (ES) m / e 369 (M + H) +. b) Acid (±) -4- [4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] phenyl] -3- (2-cyclopropyl) -butanoic The title compound was obtained (9 mg) as a light yellow foam, according to the procedure of example 2 (b), but substituting with (±) -4- [4- [2- [6- (methylamino) pyridin-2-yl) (1) -3-phenyl-4- [4- [2- [6- (methylamine) pyridin-2-yl] methyl] -1-ethoxy] phenyl] -3- (2-cyclopropyl) butanoate Ethyl-1-ethoxy] phenyl] butanoate: MS (ES) m / e 355 (M + H) +.

• EXAMPLE 42 Preparation of 3-methyl-4-r4-r2-r6- (methylamino) pyridin-2-in-1-ethoxy-phenin-3-butenoic acid a) Methyl 3-Methyl-4- [4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] phenyl] -3-butenoate The title compound (96%) was obtained from according to the procedure of Example 2 (a), but substituting ethyl 4- (4-hydroxyphenyl) -3-methyl-3-butenoate with (±) -4- (4-hydroxyphenyl) -3-phenylbutanoate of ethyl, being obtained as a clear film after chromatography on gel of silica (20% EtOAc / hexane): MS (ES) m / e 355 (M + H) +.

B) 3-Methyl-4- [4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] phenyl] -3-butenoic acid The title compound (30 mg) was obtained as a yellow foam, according to the procedure of example 2 (b), but substituting 3-methyl-4- [4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] phenyl] Methyl-3-butenoate the (±) -3-phenyl-4- [4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] phenol] butanoate Ethyl: MS (ES) m / e 327 (M + H) +. Anal. cale, for C-i9H22N2O3-O.6OHCI-O.55 H20: C, 63.71; H, 6.67; N, 7.82. Found: C, 63.41; H, 6.78; N, 8.14.

EXAMPLE 43 Composition of parenteral unit dose • A preparation containing 20 mg of the compound of Example 1 was made as a sterile dry powder, in the following manner: 20 mg of the compound was dissolved in 15 ml of distilled water. The solution was filtered under sterile conditions in a 25 ml multi-dose ampule and lyophilized. The powder can be reconstituted by the addition of 20 ml of 5% dextrose in water (D5W) for intravenous or intramuscular injection. • 10 With this the dosage is determined by the injection volume. Subsequent dilution can be done by adding a measured volume of this unit dose to another volume of D5W for injection, or a metered dose can be added to another mechanism to dispense the drug, such as in a bottle or IV infusion bag. or another injection-15 infusion system. ft EXAMPLE 44 Composition of oral unit dose A capsule was prepared for oral administration by mixing and milling 50 mg of the compound of Example 1 with 75 mg of lactose and 5 mg of magnesium stearate. The resulting powder was screened and used to fill a hard gelatin capsule.

EXAMPLE 45 Composition of oral unit dose A tablet was prepared for oral administration by mixing and granulating 20 mg of sucrose, 150 mg of calcium sulfate dihydrate and 50 mg of the compound of Example 1, with a 10% gelatin solution. The wet granulate was sieved, dried and mixed with 10 mg of starch, 5 mg of talc and 3 mg of stearic acid, and then compressed into a tablet. ft 10 The foregoing description fully discloses how to make and use the present invention. However, this invention is not limited to the particular embodiments described above, but includes all modifications thereof within the scope of the following claims. The various references to journals, patents and other publications cited herein, comprise the state of the art and are incorporated by reference as if they were fully disclosed. twenty

Claims (3)

1. NOVELTY OF THE INVENTION CLAIMS 1. - A compound according to formula (I): (I) ft 10 where: R * is X is CR'R ', NR', O or S; And it is CR'R ', NR', O or S; A is H, halogen, -ORg, -SRg, -CN, -NRgRk, -NO2, -CF3, -S (O) rCF3, -CO2R9, -COR9, -CONRg2-C6-6 alkyl, -alkyl Co-6-Ar, -C0-6-Het alkyl, -C3-C-cycloalkyl alkyl. 6, -S (O) kR9, or CH2N (Rf) 2; R1 is -C0-6-Het alkyl, -C06-Ar alkyl, -d-e alkyl, -H, -CN, -CH = CH2, -C = CH or -S (0) kR9; R2 is 20 ft 10 W is - (CHR9) a-U- (CHR9) b-; U is absent or is CO, CRg2, C (= CR92), S (0) k, O, NR9, CRgORg, CR9 (ORk) CR92, CR92CR9 (ORk), C (O) CR92 > CR92C (O), CONR, NR'CO, OC (O), C (0) 0, C (S) 0, OC (S), C (S) NR9, NR9C (S), S (0) 2NR9 , NR9S (O) 2N = N, NRgNR9, NR9CRg2, CR92NR9, CRg2O, OCR92, C = C, CR9 = CR9, Ar or Het; G is NRe, S or O; R9 is H, alkyl of d-e, Het-alkyl of C0-e, C3_7-cycloalkyl-C0_6- alkyl or Ar -C1-alkyl; Rk is R9, -C (O) R9 or - C (0) ORf; R1 is H, C6_6alkyl, Het-C0_6alkyl, C3.7-cycloalkylC06-6alkyl, Ar -Br_alkyl; or C? _6 alkyl substituted with one to three chosen groups of halogen, CN, NRg2, OR9, SR9, CO2R9 and CON (R9) 2; Rf is H, C? _6 alkyl or Ar-C? -alkyl; Re is H, C? -6 alkyl, Ar-alkyl 20 Co-e, Het-alkyl of Co-e, cycloalkyl of C3.7-C0-6 alkyl or (CH2) kC02R9; Rb and Rc are independently selected from H, C1-6 alkyl, Ar-Co6 alkyl, H6-C06 alkyl, or C3-6 cycloalkyl-Co-β alkyl, halogen, CF3, ORf, S (0) kRf, CORf, N02, N (Rf) 2, CO (NRf) 2, CH2N (Rf) 2, or Rb and Rc are linked to form a five or six membered aromatic or non-aromatic carbocyclic or heterocyclic ring, optionally substituted with up to three substituents chosen from halogen, CF3 > C1- alkyl. ORf, S (0) kRf, CORf, C02Rf, OH, N02, N (Rf) 2, CO (NRf) 2 and CH2N (Rf) 2; or methylenedioxy; Q1, Q2, Q3 and Q4 are independently N or C-Ry, with the proviso that no more than one of Q1, Q2, Q3 and Q4 is N; R 'is H, C? _6 alkyl, Ar-C6-alkyl or C3.6-cycloalkyl-C0_e alkyl; R "is R ', -C (0) R' or -C (O) OR '; Ry is H, halogen, -OR9, -SRg, -CN, -NRgRk, -N02, -CF3, CF3S (0) r, -C02R9, -COR9 or -CONR92, or C6-6 alkyl optionally substituted with halogen, -OR9, -SR9, -CN, -NR9R ", -ft 10 NO2, -CF3, R'S (O), -C02R9 , -COR9 or -CONR92; 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; and v is 0 or 1; or a pharmaceutically acceptable salt thereof.
2. 2. A compound according to formula (la): (the) where: X is CR'R ', NR \ O or S; And it is CR'R ', NR', O or S; A is H, halogen, -ORg, -SR9, -CN, -NR9Rk, -N02, -CF3, -S (0) rCF3, -C02Rg, -COR9, -CONR92- C6-6 alkyl, -alkyl C0-6-Ar, -C0_6-Het alkyl, -C0-6-cycloalkyl of C3_e, -S (0) kR9, or CH2N (Rf) 2; R1 is -Co-e-Het alkyl, -Co-e-Ar alkyl, H, -CN or -S (0) kR9; R2 is • W is - (CHR9) a-U- (CHRg) b-; U is absent or is CO, CR92, C (= CR92), S (0) kl O, NR9, CR9OR9, CRg (ORk) CR92, CR92CR9 (ORk), C (0) CR92, CR92C (0), 15 CONR, NRCO, OC (O), C (0) 0, C (S) 0, OC (S), C (S) NR9, NR9C (S), S (0) 2NR9, NRgS (O) 2N = N, NRgNRg, NR9CRg2, CRg2NR9, CR92O, OCR92, CC, CRg = CRg, ft Ar or Het; G is NRe, S or O; Rg is H, Ct.6 alkyl, Het-C0.6 alkyl, C3.7 cycloalkyl-Co-β- alkyl or Ar-Co-βalkyl; Rk is R9, -C (0) R9 or -C (0) ORf; R1 is H, C6_6 alkyl, Het-C06 alkyl, C3_7- cycloalkylC06- alkyl, Ar -C1- alkyl; or C? _6 alkyl substituted with one to three chosen groups of halogen, CN, NRg2, OR9, SR9, CO2R9 and CON (R9) 2; Rf is H, C? _6 alkyl or Ar-C? -alkyl; Re is H, alkyl of Ar-alkyl of Co-6, Het-alkyl of CO_6, cycloalkyl of C3-7-alkyl of CO_6 or (CH2) kCO2Rg; Rb and Rc are independently selected from H, C? _6 alkyl, Ar-C6 alkyl, H6-C06 alkyl, or C3_6 cycloalkyl-Co-β alkyl, halogen, CF3, ORf, S ( 0) kRf, CORf, N02, N (Rf) 2) CO (NRf) 2, CH2N (Rf) 2, or Rb and Rc are joined to form a five or six membered aromatic or non-aromatic carbocyclic or heterocyclic ring, substituted optionally with up to three substituents chosen from halogen, CF3, Ct_alkyl, ORf, S (0) kRf, CORf, C02Rf, 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, with the proviso that no more than one of Q1, Q2, Q3 and Q4 is N; R 'is H, alkyl of d-6, Ar-alkyl of Co-β or cycloalkyl of Cs-e-C0-6 alkyl; R "is R *, -C (0) R 'or -C (0) OR'; Ry is H, halogen, -ORg, -SR9, -CN, -NRgRk, -N02, -CF3, CF3S (0) r, -C02R9, -COR9 or -CONR92, or C6-6 alkyl optionally substituted with halogen, -ORg, -SR9, -CN, -NR9R ", -N02, -CF3, R'S (0), -C02Rg, - COR9 or -CONR92; 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; and v is 0 or 1; or a pharmaceutically acceptable salt thereof.
3. 3. A compound according to claim 1 or 2, further characterized in that R2 is where Q \ Q2 and Qó are each CRy, Q4 is CRy or N, and u is 0. 4. - A compound according to claim 3, further characterized in that each R 'is H, R "is H or Ci-β alkyl, W is - (CH2)? - 4-, Q4 is CRy, and Ry is H. 5. A compound according to claim 1 or 2, further characterized in that R2 is 10 wherein Q1, Q2 and Q3 are each CH and u is 0. 6. A compound according to claim 5, further characterized in that each R 'is H, R "is H or C? _6 alkyl, v is 0 and W is -CH2-CH2- 7. '- A compound according to claim 1 or 2, 15 further characterized because R2 is wherein G is NH and Rb and Rc are each H. 8. A compound according to claim 7, further characterized in that W is -CH2-CH2-. 9. A compound according to claim 1 or 2, further characterized in that R2 is wherein G is NH and Rb and Rc are linked to form a five or six membered aromatic or non-aromatic carbocyclic or non-aromatic heterocyclic ring, optionally substituted with up to three substituents chosen from halogen, CF3, d-4 alkyl, ORf, S (0) kRf, CORf, C02Rf, OH, N02, N (Rf) 2, CO (NRf) 2 and CH2N (Rf) 2; or methylenedioxy. 10. A compound according to claim 9, further characterized in that Rb and Rc are joined to form a six-membered aromatic carbocyclic ring. 11. A compound according to claim 10, further characterized in that W is -CH2-CH2-. 12. A compound according to claim 9, further characterized in that Rb and Rc are joined to form a six-membered aromatic heterocyclic ring. 13. A compound according to claim 12, further characterized in that W is -CH2-CH2-. 14. A compound according to claim 1 or 2, further characterized in that R2 is wherein each R 'is H, R "is H or C? -6 alkyl, R9 is H or Ci-β alkyl and s is 0, 1 or 2. 15. A compound according to claim 14, characterized also because W is -CH2-CH2- 16.- A compound according to claim 1 or 2, further characterized in that R1 is phenyl, benzyl, pyridyl, imidazolyl, oxazolyl or thiazolyl 17.- A compound according to claims 1 or 2, further characterized in that Y is O or CH2 18. A compound according to claim 1 or 2, further characterized in that X is NH or CH2 19. A compound according to claim 1, characterized also because R2 is H where v is 0 and W is -CH2-CH2-. 20. A compound characterized in that it is: (±) -3-phenyl-4- [4- [3- (pyridin-2-yl) amino-1-propyloxy] pheny] butanoic acid; (±) -3-phenyl-4- [4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] phenyl] butanoic acid; (±) -3-phenyl-3- [4- [4- (pyridin-2-yl) amino-1-butyl] phenylamino] propanoic acid; 4- [4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] phenyl] butanoic acid; (S) -3-phenyl-4- [4- [3- (pyridn-2-yl) amino-1-propyloxy] phenyl] butanoic acid; 2-phenoxy-4- [5- (pyridin-2-yl) amino-1-pentyloxy] phenylacetic acid; 4- [4- [6- (methylamino) pyridin-2-yl] -1-ethoxy] -2-phenoxyphenyl] butanoic acid; (+) - 4- [4- [6- (methylamino) pyridin-2-yl] -1-ethoxy] phenyl] -3-vinylbutanoic acid; ## STR10 ## (±) -3-methyl-4- [4- [3- (pyridin-2-yl) amino-1-propyloxy] phenyl] butanoic acid; 5 (R) -3-phenyl-4- [4- [3- (pyridin-2-yl) amino-1-propyloxy] phenyl] butanoic acid; (±) -4- [4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] phenyl] -3- (pyridin-2-yl) -butanoic acid; (±) -3-methyl-4- [4- [2- [2- (methylamino) pyridin-5-yl] -1-ethoxy] phenyl] butanoic acid; 2- [N-benzyl-N- [4, [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] benzyl] amino] -10-acetic acid; (±) -4- [4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] phenyl] -3- (thiophen-2-yl) -butanoic acid; 2- [N- [4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] benzyl] -N-phenyl] amino] -acetic acid; (±) -3- (4-bromophenyl) -4- [4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] phenyl] -butanoic acid; • (±) -3-Methyl-4- [4- [2- [6- (methylamino) pyridin-2-ylj-1-ethoxy] phenyl] butanoic acid; (S) -3-phenyl-4- [4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] phenyl] butanoic acid; (±) -3- (4-Isopropylphenyl) -4- [4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] phenyl] -20-butanoic acid; (±) -3- (4-isopropylphenyl) -4- [4- [3- (4-methyl-pyridin-2-yl) amino-1-propyloxy] phenyl] -butanoic acid; (±) -4- [4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] phenyl] -3- (oxazoI-2-yl) -butanoic acid; 2- [N- [2-methoxy] -4- [2- [6- (methylamino) pyridin-2-ylj-1-ethoxy] benzyl] amino] -phthaletic acid; 5 4- [4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] phenyl] -3-butenoic acid; (±) -4- [4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] phenyl] -3- (thiazol-2-yl) -butanoic acid; (±) -3-phenyl-4- [4 - [[2- (pyridin-2-yl) amino-1-ethylamino] carbonyl] phenyl] butanoic acid; (±) -3- (furan-2-yl) -4- [4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] phenyl] butanoic acid; 10 (±) -4- [4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] phenyl] -3- (2-phenylethyl) -butanoic acid; (S) -3-phenyl-4- [4- [2- (5,6J, 8-tetrahydro-1,8-naphthyridin-2-yl) -1-ethoxy] phenyl-butanoic acid; 3-methyl-4- [4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] phenyl] -3-butenoic acid; 15 (±) -3- [1 - (dimethylaminosulfonyl) imidazol-2-yl] -4- [4- [2- [6- (methylamino) pyridin-2-yl] -1- acid ethoxy] phenyl] butanoic; • (±) -3-Benzyl-4- [4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] phenyl] butanoic acid; (±) -3- (imidazol-2-yl) -4- [4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] phenyl] -butanoic acid; 20 (S) -4- [4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] phenyl] -3- (thiazol-2-yl) -butanoic acid; (R) -4- [4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] phenyl] -3- (thiazol-2-yl) -butanoic acid; (S) -3-phenyl-4- [4- [3- (3,4,5,6-tetrahydropyrimidin-2-yl) amino) -1-propyloxy] -phenyl-butanoic acid; (±) -3-Cyclopropyl-4- [4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] phenyl] butanoic acid; (±) -3- (Benzothiazol-2-yl) -4- [4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] phenyl] -5-butanoic acid; (S) -4- [4- [2- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) -1-ethoxy] phenyl] -3- (thiazole-2-yl) acid ) butanoic; (±) -3- (4-Methyltol-2-yl) -4- [4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy] phenyl] -butanoic acid; ft 10 acid (±) -3- [4-carboxy-1, 3-oxazol-2-l3-4- [4- [2- [6- (methylamino) pyridin-2-yl] -1- ethoxy] phenyl] butanoic; (±) -3- [4- (aminocarbonyl) -1,3-oxazol-2-yl] -4- [4- [2- [6- (methylamino) pyridin-2-yl] -1-ethoxy-phenyl-butanoic acid; (±) -3- [4- (dimethylaminocarbonyl) -1, 3-oxazol-2-yl] -4- [4- [2- [6- (methylamino) -15 pyridin-2-yl] -1- acid ethoxy] phenyl] butanoic; (±) -3- [4- [2- [6- (methylamino) pyridin-2-yl] ethoxy] benzyl] -4-pentenoic acid; ft or a pharmaceutically acceptable salt thereof. 21. A pharmaceutical composition comprising a compound according to claims 1-20, and a pharmaceutically acceptable carrier. 22. A pharmaceutical composition comprising a compound according to claims 1-20, an antineoplastic agent and a pharmaceutically acceptable carrier. 23. - The pharmaceutical composition according to claim 22, further characterized in that the antineoplastic agent is topotecan or cisplatin. 24. A pharmaceutical composition comprising a compound according to claim 1, a bone resorption inhibitor and a pharmaceutically acceptable carrier. 25. A compound according to formula (II): (II) where: X is CR'R ', NR', O or S; And it is CR'R ', NR', O or S; A is H, halogen, -OR9, -SRg, -CN, -NRgR-NO2, -CF3, -S (O) rCF3, -CO2Rg, -COR9, -CONR92- C6-6 alkyl, -C06 alkyl -Ar, -C0-6-Het alkyl, -C0-6 alkyl- C3-e cycloalkyl, -S (0) kRg, or CH2N (Rf) 2; R1 is -C06 alkyl-Het, -alkyl W is - (CHR9) a-U- (CHR9) b-; U is absent or is CO, CR92, C (= CRg2), S (0) k, O, NR9, CR9OR9, CRg (ORk) CRg2, CR92CR9 (ORk), C (0) CRg2, CR92C (0), CONR , NRCO, OC (O), C (0) 0, C (S) 0, OC (S), C (S) NR9, NR9C (S), S (0) 2NR9, NRgS (0) 2N = N, NR9NRg, NRgCR92, CR92NR9, CRg20, OCR92, CC, CR9 = CR9, Ar or Het; G is NRe, S or O; Rg is H, alkyl of d_6, Het-alkyl of C0-e, cycloalkyl of C3-7-alkylo of C0-6- or Ar-alkyl of C0-6; Rk is R9, -C (0) R9 or -C (0) ORf; R1 is H, C? -6 alkyl, Het-C06 alkyl, C3.7 cycloalkyl-Co-6- alkyl, C0-e-alkyl; or d-β alkyl substituted with one to three chosen halogen groups, CN, NRg2, OR9, SRg, C02RS and CON (Rg) 2; Rf is H, C ?_6 alkyl or Ar_C de_6 alkyl; Re is H, C? _6 alkyl, Ar-Co-e alkyl, Het-C0-6 alkyl, C3_ cycloalkyl-C0-e alkyl or (CH2) kC02R9; Rb and Rc are independently selected from H, C6 alkyl, ArC6 alkyl. Het-C0-6alkyl, or C3.6-cycloalkyl-C0-6alkyl, halogen, CF3, ORf, S (O) kRf, CORf, NO2, N (Rf) 2, CO (NRf) 2, CH2N (Rf) 2, or Rb and Rc are joined to form a five or six membered aromatic or nonaromatic carbocyclic or aromatic heterocyclic ring, optionally substituted with up to three substituents selected from halogen, CF3, C ^ alkyl, ORf, S (0 ) kRf, CORf, C02Rf, OH, N02, N (Rf) 2, CO (NRf) 2 and CH2N (Rf) 2; or methylenedioxy; Q1, Q2, Q3 and Q4 are independently N or C-Ry, with the proviso that no more than one of Q1, Q2, Q3 and Q4 is N; R 'is H, C? _6 alkyl, C0.6 alkyl aryl or C3.6 cycloalkyl-C06 alkyl; R "is R ', -C (0) R' or -C (0) OR '; Ry is H, halogen, -OR9, -SR9, -CN, -NRgRk, -N02, -CF3, CF3S (0) r, -C02R9, -COR9 or -CONR92, or C6-6 alkyl optionally substituted with halogen, -ORg, -SR9, -CN, -NR9R ", - N02, -CF3, R'S (0) r, -C02R9, -COR9 or -CONR92; 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; and v is 0 or 1; or a pharmaceutically acceptable salt thereof; or a compound according to formula (III): (III) where: X is CR'R ', NR', O or S; And it is CR'R ', NR', O or S; A is H, halogen, -OR9, -SRg, -CN, -NR9Rk, -N02, -CF3, -S (0) rCF3, -C02Rg, -COR9, -CONR92-C6_6 alkyl, -C6_alkyl -Ar, -C0-6-Het alkyl, -C6-6-cycloalkyl alkyl, -S (O) kRg, or CH2N (Rf) 2; R1 is -Co-e-Het alkyl, -Co-e-Ar alkyl, H, -CN or -S (O) kRg; W is - (CHRg) a-U- (CHR9) b-; U is absent or is CO, CRg2, C (= CRg2), S (O) k, O, NR9, CR9OR9, CR9 (ORk) CRg2, CR92CR9 (ORk), C (0) CR92, CRg2C (0), CONR ¡, NR¡CO, OC (O), C (0) 0, C (S) 0, OC (S), C (S) NRg, NRgC (S), S (0) 2NR9, NR9S (0) 2N = N, NR9NRg, NR9CRg2, CRg2NRg, CR920, OCRg2, CC, CRg = CR9, Ar or Het; Rg is H, alkyl of d-e, Het-alkyl of Co-β, cycloalkyl of C3.7-alkyl of Co-β- or Ar-alkyl of Co-6. Rk is R9, -C (0) R9 or -C (0) ORf; R1 is H, alkyl of d-6, Het-alkyl of C0_6, cycloalkyl of C3. -alkyl of Co-β-, Ar-alkyl of Co-β; or C? -6 alkyl substituted with one to three groups selected from halogen, CN, NR92, OR9, SR9, C02R9 and CON (R9) 2; Rf is H, alkyl of d_6 or Ar-alkyl of C0-e. Q1, Q2, Q3 and Q4 are independently N or C-Ry, with the proviso that no more than one of Q1, Q2, Q3 and Q4 is N; R 'is H, C? _6 alkyl, C0-e Ar-alkyl or C3.6 cycloalkyl-C06 alkyl; R "is R ', -C (0) R' or -C (0) OR"; Ry is H, • halogen, -OR9, -SR9, -CN, -NR9Rk, -N02, -CF3, CF3S (0) r, -C02Rg, -COR9 or-CONR92, or C1-6 alkyl optionally substituted with halogen, -OR9, -SR9, -CN, -NR9R ", -N02, -CF3, R'SÍO ^, -C02Rg, -COR9 or -CONR92, a is 0, 1 or 2, and b is 0, 1 or 2, or a pharmaceutically salt acceptable thereto 26. A process for preparing a compound of formula (la) as claimed in claim 2, characterized in that • 10 comprises reacting a compound of formula (IV) with a compound of formula (V): 15 (V) (IV) wherein R1, A and X are as defined in formula (la), with any protected reactive functional group, and L1 is OH or halogen; and then removing any protecting group, and optionally forming a pharmaceutically salt 20 acceptable. 27. A process for preparing a compound of formula (la) as claimed in claim 2, characterized in that it comprises reacting a compound of formula (IV) with a compound of formula (VI): (IV) (VI) where R1, A, X, R ', R ", W, Q1, Q2, Q3 and Q4 are as defined in formula (la), with any protected reactive functional group, and then ft 10 remove any protecting group, and optionally forming a pharmaceutically acceptable salt, or a process for preparing a compound of formula (la) as claimed in claim 2, characterized in that it comprises reacting a compound of formula (IV) with a compound of formula (VII) : (IV) (Vil) Wherein R1, A, X, R ', R ", W, Q1, Q2, Q3 and v are as defined in formula (la), with any protected reactive functional group, and then remove any protecting group, and optionally form a pharmaceutically acceptable salt. 28. - The use of a compound of formula (I) as claimed in claim 1, in the manufacture of a medicament for the treatment of diseases in which antagonism of the avß3- 5 receptor is indicated 29.- The use of a compound of formula (I) as claimed in claim 1, in the manufacture of a medicament for the treatment of diseases in which antagonism of the vßs-30 receptor is indicated. The use of a compound of formula (I) like the one that It claims in claim 1, in the manufacture of a medicament for the treatment of osteoporosis. 31. The use of a compound of formula (I) as claimed in claim 1, in the manufacture of a medicament for the inhibition of angiogenesis, tumor growth or tumor metastasis. 15. The use of a compound of formula (I) as claimed in claim 1, in the manufacture of a medicament for the treatment of atherosclerosis, restenosis or inflammation. 33. The use of a compound of formula (I) as claimed in claim 1, and an antineoplastic agent, in the manufacture of a medicament for the inhibition of tumor growth in physical combination or for administration in stages . 34. The use according to claim 33, wherein the antineoplastic agent is topotecan or cisplatin. 35. The use of a compound of formula (I) as claimed in claim 1, and an inhibitor of bone resorption, in the manufacture of a medicament for treating osteoporosis or for inhibiting bone loss.