MX2008006704A - Calcilytic compounds - Google Patents

Abstract

Novel calcilytic compounds, pharmaceutical compositions, methods of synthesis and methods of using them are provided.

Description

CALCILITIC COMPOUNDS FIELD OF THE INVENTION The present invention relates to novel calcilytic compounds, pharmaceutical compositions containing these compounds, processes for their preparation and their use as calcium receptor antagonists. In mammals, extracellular Ca2 + is under rigid homeostatic control and regulates various processes such as blood coagulation, excitability of the nerve and muscle, and proper formation of the bones. Extracellular Ca2 + inhibits the secretion of the parathyroid form ("PTH") of parathyroid cells, inhibits bone resorption by means of osteoclasts, and stimulates the secretion of calcitonin from C cells. Calcium receptor proteins allow certain specialized cells to respond to changes in the concentration of extracellular Ca2 +. PTH is the main endocrine factor that regulates Ca2 + homeostasis in blood and extracellular fluids. PTH, by acting on the bone and kidney cells, increases the level of Ca + in the blood. This increase is extracellular Ca2 + then acts as a negative feedback signal, decreasing the secretion of PTH. The reciprocal relationship between extracellular Ca2 + and PTH secretion forms an important mechanism that maintains Ca2 + homeostasis bodily.

Extracellular Ca2 + acts directly on parathyroid cells to regulate PTH secretion. The existence of a parathyroid cellular surface protein that detects changes in extracellular Ca2 + has been confirmed. See Brown et al., Nature 366: 574, 1993. In parathyroid cells, this protein, the calcium receptor, acts as a receptor for extracellular Ca2 +, detects changes in the concentration of extracellular Ca2 + ions, and initiates a functional cellular response , PTH secretion. Extracellular Ca2 + influences several cellular functions, reviewed in Nemeth et al., Cell Calcium 11: 319, 1990. For example, extracellular Ca2 + performs a function in parafollicular (C cells) and parathyroid cells. See, Nemeth, cell Calcium 11: 323, 1990. The function of extracellular Ca2 + in bone osteoclasts has also been studied. See Zaidi, Bioscience Reports 10: 493, 1990. Several compounds known to mimic the effects of extracellular Ca2 + on a calcium receptor molecule. Calcilytics are compounds capable of inhibiting calcium receptor activity, thereby causing a decrease in one or more calcium receptor activities evoked by extracellular Ca2 +. Calcilytics are useful as guide molecules in the discovery, development, design, modification and / or construction of useful calcium modulators, which are active in Ca2 + receptors. Said calcilytics are useful in the treatment of various disease states characterized by abnormal levels of one or more components, for example, polypeptides such as hormones, enzymes or growth factors, expression and / or secretion of which is regulated or affected by activity in one or more Ca2 + receptors. Diseases or disorders that are considered the target for calcilytic compounds include diseases involving bone and mineral homeostasis. Abnormal calcium homeostasis is characterized by one or more of the following activities: an abnormal increase or decrease in serum calcium; an abnormal increase or decrease in urinary calcium excretion; an abnormal increase or decrease in bone calcium levels (for example, as assessed by bone mineral density measurements); an abnormal absorption of dietary calcium; an abnormal increase or decrease in the production and / or release of messengers that affect serum calcium levels such as levels such as PTH and calcitonin; and an abnormal change in the response produced by messengers that affect serum calcium levels. Thus, calcium receptor antagonists offer a unique approach to the pharmacotherapy of diseases associated with abnormal bone or mineral homeostasis, such as hypoparathyroidism, osteosarcoma, periodontal disease, fracture healing, osteoarthritis, rheumatoid arthritis, Pager's disease, hypercalcemia. humoral associated with malignancy and healing of the fracture, and osteoporosis.

BRIEF DESCRIPTION OF THE INVENTION The present invention comprises novel calcium receptor antagonists represented by formula (I) and formula (II) below, formulations comprising the present compounds, and their use as calcium receptor antagonists in the treatment of a variety of associated diseases with bone or mineral homeostasis, including but not limited to hypoparathyroidism, osteosarcoma, periodontal disease, fracture healing, osteoarthritis, rheumatoid arthritis, Pager's disease, humoral hypercalcemia associated with malignancy and fracture healing, and osteoporosis. The present invention further provides a method for antagonizing calcium receptors in an animal, including humans, comprising administering to an animal in need thereof an effective amount of a compound of formula (I) or (II), indicated below. The present invention further provides a method for increasing serum parathyroid levels in an animal, including humans, comprising administering to an animal in need thereof an effective amount of a compound of formula (I) or (II), indicated later.

DETAILED DESCRIPTION OF THE INVENTION The present invention involves novel compounds according to formula (I) below: where X is O or S; R1 and R2 are independently selected from the group consisting of H, halogen, CN, CMO alkyl, C2.6 alkenyl, cycloalkyl, cycloalkyl-C6_6alkyl, aryl, arylalkyl of C6.6, heterocyclyl, heteroaryl, (CR10R ??)? NR5R6, C (O) OR5, C (O) NR5R6, NR5C (O) R6, (CR10Rn)? OR5 and NC (O) R5, optionally substituted, except for H, halogen and CN , one to three times, independently, by halogen, CN, C? _4 alkyl, aryl, heteroaryl, C (O) OR19, O- (CR? 9R) qO, C (O) R19, CF3, OCF3 > NO2, C (O) NR19R20, (CR? 0R ??) zORi9, (CR10R ??) zNR? 9R20 and C (R10Rn)? S (O) mR19; or R1 and R2 together form an optionally substituted 5 to 8 membered ring, optionally containing one to three heteroatoms selected from N, O and S, wherein the optional substituents are selected, independently, at each occurrence, one to three times, from the a group consisting of halogen, C? _4 alkyl, (CR? or R?) zS (O) mR5, (CR10Rn) zOR5, (CR10R ??) zNR5R6, C (O) R5 and C (O) OR5; or R1 and R2 together form an optionally substituted heteroaryl ring, wherein the optional substituents are selected, independently, at each occurrence, one to three times, from the group consisting of halogen, C? _ alkyl, (CR? or Rn) zS (0) mR5, (CR? ORn) zOR5, (CR10R ??) zNR5R6, C (O) R5 and C (O) OR5; or, when R1 is NR5R6, R5 and R6 together can be joined to form a 5- to 7-membered ring, optionally substituted by C? alkyl. 4 or halogen; R5 and Re represent, independently, in each occurrence, H, C? _ Alkyl, cycloalkyl, C? _6 cycloalkyl-alkyl, C2_6-alkenyl, heterocyclyl, C6-6 heterocyclylalkyl, aryl, d6-lactyl, heteroaryl, or heteroaryl-C? _6 alkyl, where each portion, except H, is optionally substituted, independently, one to three times, by halogen or C? _ alkyl. Rio and R11, independently represent, in each occurrence, H or C? _ Alkyl. R19 and R20 represent, independently, in each occurrence, H, C? _ Alkyl, cycloalkyl, cycloalkyl-C de _5 alkyl, > C 2-6 alkenyl, heterocyclyl, C 1-6 heterocyclylalkyl, aryl, C? -6 arylalkyl, heteroaryl, or a heteroaryl-C? .6 alkyl moiety, wherein each portion, except H, can be substituted, independently , one to three times, by halogen or C? -4 alkyl; R3 represents aryl or heteroaryl, optionally substituted, independently, one to three times, by C? - alkyl, halogen, CN or CF3; R4 is selected from the group consisting of the group consisting of cycloalkyl-C?-Alkyl, heteroaryl, heterocyclyl, aryl, heteroarylalkyl of C ?2, heterocyclylalkyl of C? -2, cycloalkyl-alkenyl of C2, aryl-alkenyl of C2 , C2 heteroaryl-alkenyl, and C2 heterocyclyl-alkenyl, wherein each portion is optionally, independently, substituted one to three times, by alkyl m is O, 1 or 2; x is O, 1, 2 or 3; q is 1, 2 or 3; and z is 0, 1, 2, 3 or 4; or a pharmaceutically acceptable salt thereof. As used herein, "alkyl" refers to a straight or branched saturated hydrocarbon group containing from 1 to 10 carbon atoms. Examples of such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, n-pentyl, isopentyl, neopentyl or hexyl and the like. As used herein, "cycloalkyl" refers to a saturated monocyclic hydrocarbon ring of 3 to 7 carbon atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. As used herein, "heterocyclyl" refers to a ring 4 to 8 membered monocyclic or a bicyclic ring of 8 to 12 membered fused which can be saturated or partially unsaturated containing from 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur. Examples of such monocyclic rings include pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiazolidinyl, and the like. Examples of bicyclic heterocyclyl rings include indolinyl, isoindolinyl, benzopyranyl, tetrahydrobenzazepinyl, tetrahydrobenzothienyl, tetrahydroisoquinolinyl and the like. As used herein, "heterocyclylalkyl" refers to a heterocyclyl-C 1 -2 alkyl group, wherein heterocyclyl and C 2 -alkyl are as defined herein. As used herein, "aryl" refers to a monocyclic hydrocarbon ring of C8 or bicyclic C5-? 2 wherein at least one ring is aromatic. Examples of such groups include phenyl, naphthyl, indenyl or tetrahydronaphthyl and the like. As used herein, "arylalkyl" refers to an aryl-C 1-6 alkyl group wherein aryl and C 1 alkyl are as defined herein. As used herein, "heteroaryl" refers to a fused 5- to 6-membered monocyclic aromatic ring or 8-10 membered bicyclic aromatic ring containing 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur. Examples of such monocyclic aromatic rings include thienyl, furyl, furazinyl, pyrrolyl, thiazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazolyl, pyrimidyl, pyridazinyl, pyrazinyl, pyridyl, and the like.

Examples of such aromatic rings include isoquinolinyl, quinazolinyl, quinoxalinyl, indolyl, isoindolyl, indazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisothiazolyl, and the like. As used herein, "heteroarylalkyl" refers to a heteroaryl-C 1 -2 alkyl group wherein heteroaryl and C 2 -2 alkyl are as defined herein. As used herein, "alkenyl" refers to a straight or branched hydrocarbon group containing one or more carbon-carbon double bonds having from 2 to 6 carbon atoms. Examples of such groups include ethenyl, propenyl, butenyl, pentenyl, or hexenyl and the like. As used herein, "alkoxy" refers to an alkyl group -O-C? _4 wherein C? -4 alkyl is as defined herein. Examples of such groups include methoxy, ethoxy, propoxy, butoxy, pentoxy or hexoxy and the like. As used herein, "halogen" or "halo" refers to F, Cl, Br or l. As used herein, "optionally substituted", unless otherwise indicated, means substituted, independently, at each occurrence, one to three times, by such groups as halogen, CN, C? -4 alquilo alkyl, C2 alkenyl .4, cycloalkyl of C? .6, heterocyclyl, aryl, heteroaryl, CO (O) R5-, O- (CH2) nO, C (O) R5, CF3, OCF3, NO2, C (0) NR5-R6- , (CR? R? R) 2-OR5-, (CR10'R? V) z'NR5'R6 ', and (CR10'R? R) z'S (O) m R5', in such a way the optional substituents are they can additionally replace, except for halogen and CN, one to three times, independently, by halogen or alkyl of C? -4. As used herein, R5 and R6 'represent, independently, in each occurrence, an H, d3 alkyl, cycloalkyl, cycloalkyl-alkyl of d. 3, C2 alkenyl, heterocyclyl, heterocyclyl-C1-4alkyl, aryl, aryl-C1-3alkyl, heteroaryl or a heteroaryl-C1_3 alkyl moiety, wherein each portion, except H, is optionally substituted, independently, one to three times, by halogen or C1.3 alkyl. As used herein, R 10 'and Rir represent, in each occurrence, independently, H or C 1-3 alkyl. As used herein, m 'is 0, 1 or 2. As used herein, n' is 1, 2 or 3. As used herein, z 'is 0, 1, 2 or 3. Suitably, X is O or S. Preferably , X is O. Suitably, R1 and R2 are independently selected from the group consisting of H, halogen, CN, CM O alkyl, C2.6 alkenyl, cycloalkyl, cycloalkyl-C6-alkyl) aryl, aryl-alkyl of d. 6, heterocyclyl, heteroaryl, (CR10R ??) xNR5R6, C (O) OR5, C (O) NR5R6, NR5C (O) R6, (CR? 0R ??)? OR5 and NC (O) R5, optionally substituted, except for H, halogen and CN, one to three times, independently, by halogen and CN, C1-4 alkyl, aryl, heteropole, C (O) OR19, O- (CR19R20) qO, C (O) R19, CF3 , OCF3, NO2, C (O) NR19R20, (CR? ORn) zOR? 9l (CR10Rn) 2NR? 9R2o, and (CR? OR ??) xS (O) mR? G.

In one embodiment, R1 and R2 are independently selected from the group consisting of H, halogen, CN, C? -10 alkyl, C2_6 alkenyl, C? _4 cycloalkyl, C1_3 cycloalkyl, aryl, C1-3 arylalkyl, heterocyclyl, heteroaryl, (CR10R ??)? NR5R6, NH2, C (O) OR5, NR5C (O) C1-4 alkyl, C1.4 alkoxy, and (CR10R ??)? OR5 , optionally substituted, one to three times, except for H, halogen and CN, independently, by halogen, CN, C? -2 alkyl, aryl, heteroaryl, C (0) ORi9, O- (CH2) qO, C ( 0) R? G, CF3, OCF3, NO2, C (O) NR19R20, (CH2) xOR19, (CH2) xNR19R2o, and (CR? OR ??)? S (O) mR? 9, such that the optional substituents, except for halogen and CN, can be further substituted, once or twice, independently, by halogen or C? _2 alkyl. In another embodiment, R1 and R2 are independently selected from the group consisting of H, halogen, CN, C2.3 alkenyl, C (O) OH, phenethyl, pyrrolidinyl, N-propyl, NHC (O) alkyl d .3 and C (O) CH3. In another embodiment, R and R2 are, independently, selected from the group consisting of C? _6 alkyl, C3-5 cycloalkyl and C3_4 cycloalkyl-C1_2alkyl, wherein each portion is optionally substituted, independently, one to three times, for alkyl d_2 or halogen. In another embodiment, R1 and R2 independently represent phenyl, optionally substituted, independently, one to three times, by an optional substituent selected from the group consisting of F, OH, methyl, CN, OCF3, CF3, NH2, CH2OH, N -dimethyl, ethoxy, phenyl NO2, methylsulfonyl, isopropoxy and CH2N-C? -2 alkyl. In another embodiment, R1 and R2 independently represent piperidinyl, optionally substituted by C? _3 alkyl. In another embodiment, R1 and R2 independently represent an amine moiety, optionally substituted by C? _ Alkyl. In another embodiment, R1 and R2 independently represent an ether portion, substituted by C3_3 alkyl or benzyl. In another embodiment, R1 and R2 independently represent a heteroaryl portion selected from the group consisting of furyl, pyrizinyl, pyridyl, indanyl, thienyl, pyrrolyl, and thiazolyl, wherein the heteroaryl portion is optionally substituted, independently, once or twice times, by a substituent selected from the group consisting of methyl, chloro, CH2NH2, CN, CH2OH, phenyl, CH2NHCH3 and 1, 3,4-oxadiazolyl. In another embodiment, R1 and R2 independently represent a bicyclic heterocyclyl selected from the group consisting of quinolinyl, tetrahydroquinolinyl, methyltetrahydroquinolinyl, dihydrobenzodioxinyl, 3-benzothiophenyl, benzodioxolyl, benzothienyl, benzothiophenyl, benzofuranyl, indolyl and thiazolyl, wherein the bicyclic portion it can be optionally substituted, independently, one to three times, by a substituent selected from the group consisting of methyl, phenyl, chloro and thiazolyl. In another embodiment, R1 and R2 are independently selected from the group consisting of hydrogen, I, Cl, Br, F, CN, methyl, ethyl, isobutyl, propyl, butyl, isopropyl, hexyl, 2-methyl butyl, 3-methyl butyl, 2-hydroxyl, 2-methyl-2-propene, 2-methyl? l-1-propenyl, 1-propenyl, cyclopentyl, cyclopropyl, cyclobutylethyl, cyclobutylmethyl, cyclopropylmethyl, phenyl, 2,4-d? fluorophenyl, 3,4-difluorophenyl, 4-fluorophenyl, 2- fluorophenol, 3-fluorophenyl, 3-methylen, 4-hydroxyphenyl, 2-c? anophenol, 4-c? anophenol, 4-tpfluoromet? lphene, 3-hydroxymethylphenyl, 3- H? drox? phenol, 4-N, Nd? methyl?, 4-ethoxy? phenol, 4-b? phenol, 4-? sopropox? phenol, 5-methylsulfon ? lfen? lo, 3-ethoxy? phenol, 2-ethoxy? phenol, 3-cyanophenyl, 4-tp? uoromethoxy? phenol, 3-t?? uoromethoxy? phenol, 3-dimethylaminomethylphenyl, 3-N, Nd Methylbenzene, 4-t-butyl, 4-isopropylphenyl, 3-N, Nd? met? lmethyl, 3-nitrophenol, carboxylic acid, pyrrohodynyl , morpholinyl, azetidinyl, phenpropyl, phenethyl, 3,4-d? chlorophenetheyl, ethylamino, methylethiobutylamino, diethylamino, dimethylamino, 2,2-dimethylpropanamide, NH2, NN-dimethylamm, aniline, N-propyl, methylmethylether, benzylethylether, methylethylether, ethyl ether, isopropyl ether, N, 2-d? Met? Lpropanam? Da, 2-methylpropanamide, pyrazinyl, 3-p? P? Lo, 2-fuplo , 3-fuplo, 2-? Ndan? Lo, 3-met? L-2-thienyl, 4-met? L-2-t? En? Lo, 5-met? L-2-t? En? Lo, 3-t? En? Lo, 2-t? Enilo, 5-chloro-2-t? In? Lo, 2-pyrrole, 1-met? L-2-p ?rol? Lo, 5-met? L -3-t? On ?, 5-methylam? No-2-t? On ?, 5-h? Drox? Met? L-2-t? On ?, 4,5-d? Met? -2-t? In? Lo, 5-c? Ano-2-t? In? Lo, 5-phen? L-2-t? In? Lo, 2-met? L-1, 3-t? Azol -5-? Lo, 1, 3-t? Azol-2-? Lo, 5-acet? L-2-t? En? Lo, 4,5-d? Met? L-1, 3-t? Azol -2-yl, 4-methyl-1, 3-t-azol-2-? Lo, 5-methyl-1, 3,4-oxad? Azole-2-yl, quino nile, 1, 2,3,4-tetrahydroquinoline nyl, 1, 2,3,4-methylenetetrahydroquinone, 2,3-d? -hydro-1,4-benzodioxinyl, 3-benzot? Ofen It, 1, 3-benzod? oxol-5-? lo, 4-benzot? in? lo, 2-benzofuranyl, 4,5,6,7-tetrahydrobenzot ?, in it, 1-met? l? ndol-5-? lo, 5- (2-phen? l-1, 3- thiazol-5-yl), 5-chloro-3-methyl-1-benzothien-2-yl, 2-benzothiophenyl, 1-methylindol-2-yl, and 5- (2-methyl-1,3-thiazole-4 -yl) -2-thienyl. In another embodiment, R1 is selected from the group consisting of isobutyl, ethyl, phenyl, furanyl, quinolinyl, halogen, tetrahydroquinolinyl, pyrrolidinyl, thiophenyl, morpholinyl, cyclopentyl, isopropyl, amino, pyrazinyl, indolyl, thiazolyl, piperidinyl, N-acyl, benzothiophenyl and benzothiazolyl, all portions may optionally be substituted, independently, one to three times, by C 4 alkyl or halogen. Preferably, R1 is selected from the group consisting of isobutyl, phenyl, thiazolyl and thienyl, optionally substituted by methyl. In another embodiment, R 2 is selected from the group consisting of methyl, methoxymethyl, piperidinyl, ethyl, methoxyethyl, benzyloxyethyl, phenyl, pyrrolidinyl, amino, alkylamino, propyl, phenethyl, phenpropyl, butyl, isobutyl, cyclobutylethyl, 3-methylbutyl, dimethylaminomethyl, piperidinylmethyl, and alkylaminomethyl, all portions may optionally be substituted, independently, one to three times, by C ?4 alkyl or halogen. Preferably, R2 is methyl, ethyl or propyl. More preferably, R2 is methyl. Suitably, R1 and R2 together form an optionally substituted 5- to 8-membered ring, optionally containing one to three heteroatoms selected from N, O, and S, wherein the optional substituents are independently selected at each occurrence, one to three times, from the group consisting of halogen, d-4 alkyl, (CR10R ??)? S (O) mR3, (CR10R ??) zOR5, (CR10R ??) zNR5R6, C (O) R5 and C (O) OR5. Suitably, R1 and R2 together form an optionally substituted heteroaryl ring, wherein the optional substituents are selected, independently, at each occurrence, one to three times, from the group consisting of halogen, C1-4 alkyl, (CR? Or R? ?) zS (O) mR5, (CR10Rn) zOR5, (CR10R ??) zNR5R6, C (O) R5 and C (O) OR6. Suitably, R1 is NR5R6, R5 and Re together are joined to form a 5- to 7-membered ring, optionally substituted by C1-alkyl. 4 or halogen. In one embodiment, R1 and R2 combine to form, together with the adjacent ring, a portion selected from the group consisting of pyrimidinonyl, quinazolinyl, pyrridolpyrimidinecarboxyl, pyrimidoazepinyl, cyclooctapyrimidinonyl, tetrahydropyrrolopyrimidinecarboxyl, and pyrazolopyrimidinonyl, optionally substituted, independently, once or twice times, by a substituent selected from the group consisting of methyl, ethyl, benzyl, acetyl, methylsulfonyl, COCH 2 C (CH 3) 2 and C (0) OCH 2 C (CH 3) 2. In another embodiment, R1 and R2 combine to form, together with the adjacent ring, a portion selected from the group consisting of azepinyl, cyclohexyl, cycloheptyl, tetrahydrooxepinyl, tetrahydropyridinyl, tetrahydropyrrolidinyl, pyrazolyl and cyclooctyl, all portions may be optionally substituted, independently, one to three times, by C1.4 alkyl or halogen. In another embodiment, R1 and R2 combine to form, together with the adjacent ring, a portion selected from the group consisting of 6-phenylmethyl-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidin-4 (3H) -onyl, 5,6,7,8-tetrahydro- 4 (3H) -quinazolinonyl, 6,6-dimethyl-4a, 5,6,7,8,8a-hexahydro-4 (-3H) -quinazolinonyl, 3,5,6,7,8,9-hexahydrocycloheptapyrimidin-4 -onyl, ethyl 3,5,7,8-tetrahydropyridolpyrimidine-6-carboxylyl, 3,5,6,7,8,9-hexahydropyrimido-4,5-azepin-4-onyl, 7-benzyl-3,5, 6,7,8,9-hexahydropyrimid-4,5-azepin-4-onyl, 7-acetyl-3,5,6,7,8,9-hexahydropyrimido-4,5-azepine-4-onyl, 7-Methylsulfonyl-3,5,6,7,8,9-hexahydropyrimido-4,5-azepin-4-ynyl, 6 (3-methylbutanoyl) -5,6,7,8-tetrahydropyrimido-4-onyl, 3 -methylbutyryl-3,5,7,8-tetrahydropyridopyrimidine-6-carboxylyl, 5,6,7,8-tetrahydropyridopyrimidin-4 (3H) -onyl, 5-methyl-5,6,7,8-tetrahydropyridopyrimidin-4 ( 3H) -onyl, 5-ethyl-5,6,7,8-tetrahydropyridopyrimidin-4 (3H) -onyl, 1,1-dimethylethyl-3,4,5,7-tetrahydropyrrolopyrimidine-6-carboxylate, 1- methyl-1, 5-dihydro-4-pyrrazolopyrimidin-4 (3H) -onyl, and 5,6,7,8,9,10-hexahydrocyclooctapyrimidin-4 (3H) -onyl. Preferably, when R1 and R2 form a ring, the ring is cyclohexyl or dimethylcyclohexyl. Suitably, R3 represents aryl or heteroaryl, optionally substituted, independently, one to three times, by C? - alkyl, halogen, CN or CF3. In one embodiment, R3 represents an aryl or heteroaryl portion, optionally substituted, independently, one to three times, by a substituent selected from F, OH and Cl. In another embodiment, R3 is selected from the group consisting of phenyl, pyrrolyl, thienyl, pyrridolyl, furanyl, imidazolyl, and furyl, optionally substituted, independently, once or twice, with a substituent selected from the group consisting of OH, F, methoxy and OCH2phenyl. In another embodiment, R3 is selected from the group consisting of 2-hydroxy-4-fluorophenyl, 2-hydroxy-3-fluorophenyl, 3-hydroxy-2-fluorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 2,3-dihydroxyphenyl, 2-fluorophenyl, 2-hydroxy-3-fluorophenyl, 2-methoxyphenyl, 3-fluoro-2 (phenylmethyl) oxyphenyl, 2-pyrrolyl, 2-thienyl, 2-pyrrodilyl, 2-furanyl, 2-imidazolyl, 2-furyl, and thienyl. Suitably, R 4 is selected from the group consisting of cycloalkyl-alkyl of d. , heteroaryl, heterocyclyl, aryl, heteroaryl C alquilo -2 -2alkyl, heterocyclyl-C alquilo?-2alkyl, cycloalkylidenyl of C2, aryl-alkenyl of C2, heteroaryl-alkenyl of C2, and heterocyclic-alkenyl of C2, in wherein each portion is optionally substituted, independently, once to three times, by C- | alkyl. , F, CF3 or Cl. In another embodiment, R4 is selected from the group consisting of phenyl-alkyl of d2, cyclohexyl-C2-2alkyl, cyclopentyl-C1.2alkyl, thienyl-C2-2alkyl, pyranyl-C alquilo .2 alkyl, indenyl-C de .2 alkyl and piperidinyl-alkyl of d.2, optionally substituted, independently, once or twice, by F, CF3 or CI. In another embodiment, R4 is selected from the group consisting of phenyl-C2-alkyl, cyclohexyl-alkenyl of C2, cyclopentyl-alkenyl of C2, thienyl-alkenyl of C2, pyranyl-alkenyl of C2, indenyl-alkenyl of C2, and indenyl -C2 alkenyl.

In another embodiment, R 4 is selected from the group consisting of 3-fluorophenyl-C 1 -2 alkyl, phenyl-C 2,2-alkyl, 2-fluorophenyl-C 1, 2, 3-trifluoromethylphenyl-C alkyl. _2, 2-chlorophenyl-C1_2-alkyl, cyclopentyl-C2_2-alkyl, cyclohexyl-C2_2-alkyl, 2-thienyl-C2_2_3-alkyl, 3-thienyl-C2_2 alkyl, pyranyl -alkyl of d.2, indenyl-alkyl of C? _2 and piperidinyl-alkyl of C? _2. Preferably, R 4 is selected from the group consisting of phenethyl, 3-fluorophenethyl, 4-fluorophenethyl, 2-fluorophenethyl, 2-thienylethyl, phenylethyl, dihydroindenyl, coclohexylethyl, 3-chlorophenethyl, 3-trifluoromethylphenethyl, cyclopentylethyl and tetrahydropyranylethyl. More preferably, R 4 is phenethyl, optionally substituted, once or twice, independently, by F. Suitably, R 0 and R n, independently, represent hydrogen or C 4 alkyl. In one embodiment, O- (CR5R6) q-O represents 1,3-benzodioxinyl or 1,4-benzodioxinyl. In another embodiment, q is 2 or 3. An alternate embodiment of the present invention involves a compound according to formula (II) below: where: R1 and R2 are independently selected from the group consisting of H, halogen, C? _8 alkyl, aryl, heterocyclyl, and heteroaryl, optionally substituted, except for H, and halogen, one to three times, independently, by halogen, CN, C? _4 alkyl, aryl, heteroaryl, -O- (CH2) nO-, CF3, and OCF3; or R1 and R2 together form a 5- to 8-membered ring, optionally containing one to three heteroatoms selected from N, O and S, optionally substituted, independently, once or twice, by methyl; R 14 represents F or H; R4 represents aryl-C de -2 alquiloalkyl, optionally substituted, independently, one to three times, by F, CF or Cl; and N is 1, 2 or 3; or a pharmaceutically acceptable salt thereof. Unless otherwise specified, all definitions belonging to formula (I) are applicable to formula (II). Suitably, R1 and R2 are independently selected from the group consisting of H, halogen, C, .8 alkyl, aryl, heterocyclyl, and heteroaryl, optionally substituted, except for H, and halogen, one to three times, independently, by halogen, CN, alkyl of d.4, aryl, heteroaryl, -O- (CH2) nO, CF3 and OCF3. In one embodiment, R1 is selected from the group consisting of d-haloalkyl, dihydrobenzodioxy, N-pyrrolyl, benzothienyl, benzothiazolyl. In another embodiment, R1 represents phenyl, optionally substituted, independently, once or twice, by F, Cl and CN. In another embodiment, R1 represents thienyl, optionally substituted, independently, once or twice, by F, methyl or CN. In another embodiment, R1 represents thiazlolyl, optionally substituted by methyl. Preferably, R1 is selected from the group consisting of chloro, propyl, isobutyl, 2-thienyl, 5-methyl-2-thienyl, 3-cyano-2-thienyl, 4-methyl-2-thienyl, 3-cyano-2- thienyl, 2-cyanophenyl, 3-cyanophenyl, 3,5-difluorophenyl, dihydrobenzodioxyl, benzothienyl, benzothiazolyl, 2-methylthiazolyl, N-pyrrolyl and 2-methylthiazolyl. More preferably, R1 is selected from the group consisting of isobutyl, thienyl, 4-methyl-2-thienyl, phenyl and thiazolyl. Suitably, R1 and R2 together form a 5- to 8-membered ring, optionally containing one to three heteroatoms selected from N, O and S, optionally substituted, independently, once or twice by methyl. Preferably, when R1 and R2 form a ring, the ring is selected from the group consisting of cyclohexyl and dimethylcyclohexyl. Preferably, R2 is methyl, ethyl or propyl. More preferably, R2 is methyl. Suitably, R 14 represents F or H.

Preferably, R14 is F. Suitably, R4 represents aryl-alkyl of d-2, optionally substituted, independently, one to three times, by F, CF3 or Cl. Preferably, R4 is phenethyl, optionally substituted by F. More preferably, R4 It is 3-fluorophenethyl. Suitably, n is 1, 2 or 3. Preferably, n is 1 or 2. Preferred compounds of the present invention include but are not limited to: 2- (2-Fluoro-3-hydroxyphenyl) -6-methyl-5- ( 2-methylpropyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (3-Hydroxyphenyl) -6-methyl-5- (2-methylpropyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (2,3-Dihydroxyphenyl) -6-methyl-5- (2-methylpropyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 6-Methyl-5- (2-methylpropyl) -3- (2-phenylethyl) -2- (1 H -pyrrol-2-yl) -4 (3 H) -pyrimidinone; 6-Methyl-5- (2-methylpropyl) -3- (2-phenylethyl) -2- (2-thienyl) -4 (3H) -pyrimidinone; 6-Methyl-5- (2-methylpropyl) -3- (2-phenylethyl) -2- (2-pyridinyl) -4 (3H) -pyrimidinone; 2- (2-Furanyl) -6-methyl-5- (2-methylpropyl) -3- (2-phenylethyl) -4 (3H- pyrimidinone; 2- (1 H-imidazol-2-yl) -6-methyl-5- (2-methylpropyl) -3- (2-phenylethyl) -4 (3 H) -pyrimidinone; 5-Ethyl-2- (2-fluoro-3-hydroxyphenyl) -3- [2- (3-fluorophenyl) ethyl] -6-methyl-4 (3H) -pyrimidinone; 5-Ethyl-3- [2- (3-fluorophenyl) ethyl] -6-methyl-2- (1 H -pyrrol-2-yl) -4 (3 H) -pyrimidinone; 5-Bromo-2-. { 3-fluoro-2 - [(phenylmethyl) oxy] phenyl} -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5-Bromo-2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- (6-quinolinyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- (1, 2,3,4-tetrahydro-6-quinolinyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-5- (1-methyl-1, 2,3,4-tetrahydro-6-quinolinyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -5- (2-furanyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-5-phenyl-3- [2- (2-thienyl) ethyl] -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- (1-pyrrolidinyl) -4 (3H) -pyrimidinone; - (5-Chloro-2-thienyl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5-bromo-6-methyl-3- (2-phenylethyl) -2-. { 2 - [(phenylmethyl) oxy] phenyl} -4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -3- (2-phenylethyl) -6- (1-p -peridinylmethyl) -4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -6-. { [methyl (2-methylpropyl) amino] methyl} -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -6-methyl-5 - [(1-methylethyl) oxy] -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- (2-Furanyl) -2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- (2-thienyl) -4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -6-methyl-5- (4-morpholinyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone, 5-Ethyl-2- (3-fluoro-2-hydroxyphenyl) -3- [2- (3-fluorophenyl) ethyl] -6- (1-piperidinyl) -4 (3H) -pyrimidinone; 5-Ethyl-1 - [2- (3-fluorophenyl) ethyl] -2- [2- (methyloxy) phenyl] -6-oxo-1,6-dihydro-4-pyrimidinecarboxylic acid; 5-Ethyl-2- (2-hydroxyphenyl) -6-methyl-3 - [(E) -2-phenylethenyl] -4 (3H) -pyrimidinone; 2- (3,6-Difluoro-2-hydroxyphenyl) -5-ethyl-3- [2- (3-fluorophenyl) ethyl] -6-methyl- 4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-5-propyl-3- [2- (2-thienyl) ethyl] -4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -5,5-dimethyl-3- [2- (2-thienyl) etl] -5,6,7,8-tetrahydro-4 (3H) -quinazolinone; 3- [2- (2-Fluorophenyl) ethyl] -2- (2-hydroxyphenyl) -5,5-dimethyl-5,6,7,8-tetrahydro-4 (3H) -quinazolinone; 2- (2-Hydroxyphenyl) -3- (2-phenylethyl) -3,5,6,7,8,9-hexahydro-4H-cyclohepta [d] pyrimidin-4-pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -3- (2-phenylethyl) -5,6,7,8-tetrahydro-4 (3H) -quinazolinone; 5-Cyclopentyl-2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- (2,3-Dihydro-1,4-benzodioxin-6-yl) -6-methyl-3- (2-phenylethyl)) - 2- (2-thienyl) -4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -6 - [(methyloxy) methyl] -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -6 - [(methyloxy) methyl] -5- (2-methylpropyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2-. { 3-Fluoro-2 - [(phenylmethyl) oxy] phenyl} -5- (2-hydroxyethyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5-propyl-4 (3H) -pyrimidinationa; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-5-phenyl-3- (2-phenylethyl) -4 (3H) -pyrimidinationa; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-5- (2-methylpropyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinationa; 3- (2,3-Dihydro-1 H-inden-2-i) -2- (2-hydroxyphenyl) -6-methyl-5- (1-methyl-ethyl) -4 (3H) -pyrimidinone; 5,6-Dieityl-2- (3-fluoro-2-hydroxyphenyl) -3- [2- (2-fluorophenyl) ethyl] -4 (3H) -pyrimidinone; 6- (2-Cyclohexylethyl) -5-ethyl-2- (3-fluoro-2-hydroxyphenyl) -3- [2- (2-fluorophenyl) ethyl] -4 (3H) -pyrimidinone; 6- [2- (3,4-Dichlorophenyl) ethyl] -5-ethyl-2- (3-fluoro-2-hydroxyphenyl) -3- [2- (2-fluorophenyl) ethyl] -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -3- [2- (2-fluorophenyl) ethyl] -6methyl-5- (2-methylpropyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-5- (2-methylpropyl) -3- [2- (2-thienyl) ethyl] -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -3- [2- (4-fluorophenyl) ethyl] -6-methyl-5- (2-methylpropyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -3- [2- (3-fluorophenyl) ethyl] -6-methyl-5- (2-methylpropyl) -4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -7-methyl-3- (2-phenylethyl) -3,5,6,7,8,9-hexahydro-4H-pyrimido [4,5-d] azepin-4-one; 7-Acetyl-2- (2-hydroxyphenyl) -3- (2-phenylethyl) -3,5,6,7,8,9-hexahydro-4H- pyrimido [4,5-d] azepin-4-one; 2- (2-Hydroxyphenyl) -7- (methylsulfonyl) -3- (2-phenylethyl) -3,5,6,7,8,9-hexahydro-4H-pyrimido [4,5-d] azepin-4- ona; 5-Bromo-2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -5-iodo-6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5-Chloro-3- (2-cyclohexylethyl) -2- (2-hydroxyphenyl) -6-methyl-4 (3H) -pyrimidinone; 5-Chloro-2- (2-hydroxyphenyl) -6-methyl-3- [2- (2-thienyl) ethyl] -4 (3H) -pyrimidinone; 5-Chloro-2- (2-hydroxyphenyl) -6-methyl-3- (2-phenolletyl) -4 (3H) -pyrimidinationa; 5-Bromo-2- (3-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (3-Hydroxyphenyl) -6-methyl-5-phenyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (2-hydroxyphenyl) -6-methyl-5- (phenylamino) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- (1-Azetidinyl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxypheni)) - 6-methyl-3- (2-phenylethyl) -5- (propylamino) -4 (3H) -pyrimidinone; 2- (2-Fluoro-3-hydroxyphenyl) -6-methyl-5-phenyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- (3-thienyl) -4 (3H) -pyrimidinone; 5- (3-Furanyl) -2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- (4-Biphenylyl) -2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- (1, 3-Benzodioxol-5-yl) -2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- (2-fluorophenyl) -2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5-. { 4- (trifluoromethyl) phenyl] -4 (3H) -pyrimidinone; 5- (3-Fluorophenyl) -2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- (2,4-Difluorophenyl) -2- (2-hydroxy-phenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- [4- (Dimethylamino) phenyl] -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- [4- (Ethyloxy) phenyl] -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- (1-Benzothien-3-yl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- (1-Benzothien-4-yl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2- phenylethyl) -4 (3H) -pyrimidinone; 2- [2- (3-Fluoro-2-hydroxyphenyl) -4-methyl-6-oxo-1- (2-phenylethyl) -1,6-dihydro-5-pyrimidinyl-benzonitrile; 4- [2- (3-fluoro-2-hydroxyphenyl) -4-methyl-6-oxo-1- (2-phenylethyl) -1,6-dihydro-5-pyrimidinyl] benzonitrile; 5- [2- (Ethyloxy) phenyl] -2- (3-fluoro-2-hydroxyphenyl) -6-methyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- [3- (Ethyloxy) phenyl] -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- (1-Benzofuran-2-yl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- (1 H -pyrrol-2-yl) -4 (3 H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -5- [3- (hydroxymethyl) phenyl] -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-5- [3- (methylsulfonyl) phenyl] -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- [3- (trifluoromethyl) phenyl] -4 (3H) -pyrimidinone; 5- (3,4-Difluorophenyl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- [4- (1, 1-Dimethylethyl) phenyl] -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; - (5-Acetyl-2-thienyl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5-. { 3 - [(trifluoromethyl) oxy] phenyl} -4 (3H) -pyrimidinone; 5-. { 3-. { (Dimethylamino) methyl] phenyl} -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 3- [2- (3-Fluoro-2-hydroxyphenyl) -4-methyl-6-oxo-1- (2-phenylethyl) -1,6-dihydro-5-pyrimidinyl] -N, N-dimethylbenzamide; 5- (4,5-Dimethyl-2-thienyl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- [2- (3-Fluoro-2-hydroxyphenyl) -4-methyl-6-oxo-1- (2-phenylethyl) -1,6-dihydro-5-pyrimidinyl] -2-thiophenecarbonitrile; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-5- (1-methyl-1 H -pyrrol-2-yl) -3- (2-phenylethyl) -4 (3 H) -pyrimidinone; 2- (3-fluoro-2-hydroxyphenyl) -6-methyl-5- (1-methyl-1 H -indol-2-yl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- (1,3-thiazol-2-yl) -4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- (3-pyridinyl) -4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- (2-pyrazinyl) -4 (3H) -pyrimidinone; 6-Methyl-2- [2- (methyloxy) phenyl] -3- (2-phenylethyl) -5- (2-thienyl) -4 (3H) - pyrimidinone; 2- (2-Hydroxyphenyl) -6-methyl-5-phenyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- (4-Fluorophenyl) -2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -6-methyl-5- (3-methylphenyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-5- (1-methyl-1 H -indol-5-yl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5-. { 4 - [(trifluoromethyl) oxy] phenyl} -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-5-. { 4 - [(1-methylethyl) oxy] phenyl} -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- (6-quinolinyl) -4 (3H) -pyrimidinone; 5- (2,3-Dihydro-1,4-benzodioxin-6-yl) -2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- (5-Chloro-3-methyl-1-benzothien-2-yl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-5- [5- (1, 3-oxazol-5-yl) -2-thienyl] -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5-Fluoro-2- (2-hydroxyphenii) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -6-methyl-5- (2-methylpropyl) -3- (2-phenylethyl) -4 (3H) - pyrimidinone; 2- (2-Hydroxyphenyl) -6-methyl-5- (2-methyl-2-propen-1-yl) -3- (2-phenylethyl) -4 (3 H) -pyrimidinone; 5- (Cyclobutylmethyl) -6-methyl-2- [2- (methyloxy) phenyl] -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- (Cyclobutylmethyl) -2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -6,6-dimethyl-3- (2-phenylethyl) -4a, 5,6,7,8,8a-hexahydro-4 (3H) -quinazolinone; 5- (Cyclopropylmethyl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5-Cyclopropyl-2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-5- (3-methylbutyl)) - 3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- (2-Cyclohexylethyl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-prienylethyl) -4 (3H) -pyrimidinone; 5- (Cyclohexylmethyl) -2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-metii-3- (2-phenylethyl) -5- (phenylmethyl) -4 (3H) -pyrimidinone; 5-Amino-2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- (1-piperidinii) -4 (3H) -pyrimidinone; 5- (Dimethylamino) -2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; N- [2- (2-Hydroxyphenyl) -4-methyl-6-oxo-1- (2-phenylethyl) -1,6-dihydro-5-pyrimidinyl] -2,2-dimethylpropanamide; N- [2- (2-Hydroxyphenyl) -4-methyl-6-oxo-1- (2-phenylethyl) -1,6-dihydro-5-pyrimidinyl] -2-methylpropanamide; N- [2- (2-hydroxyphenyl) -4-methyl-6-oxo-1- (2-phenylethyl) -1,6-dihydro-5-pyrimidinyl] -N, 2-dimethylpropanamide; 5- (Dipropylamino) -2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- (Diethylamino) -2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- (Etylamino) -2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -5- (2-methylpropyl) -3- (2-phenylethyl) -6-propyl-4 (3H) -pyrimidinone; 6-Ethyl-2- (2-hydroxyphenyl) -5- (2-methylpropyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 6-Butyl-2- (2-hydroxyphenyl) -5- (2-methylpropyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -5- (2-methylpropyl) -3- (2-phenylethyl) -6-. { 2- [(phenylmethyl) oxy] ethyl} -4 (3H) -pyrimidinone; 6- (2-Hydroxyethyl) -2- (2-hydroxypheni)) - 5- (2-methylpropyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 6- [2- (methyloxy) ethyl] -5- (2-methyl-1-propen-1-yl) -3- (2-phenylethyl) -4 (3 H) -pyrimidinone; 2- (2-hydroxyphenyl) -6- [2- (methyloxy) ethyl] -5- (2-methylpropyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- (dimethylamino) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- (Dimethylamino) -2- (2-fluoro-3-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 6-Methyl-2,5-diphenyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (2-Fluorophenyl) -6-methyl-5-phenyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 3- [2- (2-Chlorophenyl) ethyl] -2- (2-hydroxyphenyl) -5,6,7,8-tetrahydro-4 (3H) -quinazolinone; 3- [2- (3-Fluorophenyl] ethyl) -2- (2-hydroxyphenyl) -5,5-dimethyl-5,6,7,8-tetrahydro-4 (3H) -quinazolinone; 3- (2-Cyclohexylethyl) -2- (2-hydroxyphenyl) -5,5-dimethyl-5,6,7,8-tetrahydro-4 (3H) -quinazolinone; 3- [2- (3-Fluorophenyl) ethyl] -2- (2-furanyl) -5,6,7,8-tetrahydro-4 (3H) -quinazolinone; 3- [2- (3-Fluorophenyl) ethyl] -2- (2-thienyl) -5,6,7,8-tetrahydro-4 (3H) -quinazolinone; Ethyl 2- (2-hydroxyphenyl) -4-methyl-6-oxo-1- (2-phenylethyl) -1,6-dihydro-5-pyrimidinecarbonitrile; 2- (2-Hydroxyphenyl) -4-methyl-6-oxo-1- (2-phenylethyl) -1,6-dihydro-5-pyrimidinecarboxylate ethyl; 2- (2-Hydroxyphenyl) -6-methyl-5- (1-methylpropyl) -3- [2- (2-thienyl) ethyl] -4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -6-methyl-5- (1-methylpropyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-5- (1-methylpropyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5-Butyl-2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -6-methyl-5-pentyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5-Hexyl-2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5-Butyl-2- (2-hydroxyphenyl) -6-methyl-3- [2- (2-thienyl) ethyl] -4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -6-methyl-5-pentyl-3- [2- (2-thienyl) ethyl] -4 (3H) -pyrimidinone; 5-Hexyl-2- (2-hydroxyphenyl) -6-methyl-3- [2- (2-thienyl) ethyl] -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -3- [2- (3-fluorophenyl) ethyl] -5,6,7,8-tetrahydro-4 (3H) -quinazolinone; 2- (3-Fluoro-2-hydroxyphenyl) -3- [2- (3-fluorophenyl) ethyl] -3,5,6,7,8,9- hexahydro-4H-cyclohepta [d] pyrimidin-4-one; 2- (2-Hydroxyphenyl) -4-oxo-3- (2-phenylethyl) -3,5,7,8-tetrahydropyrido [4,3-d] pyrimidine-6 (4H) -carboxylic acid ethyl ester; (2-Hydroxyphenyl) -6- (3-methylbutanoyl) -3- (2-phenylethyl) -5,6,7,8-tetrahydropyrido [4,3-d] pyrimidin-4 (3H) -one; 5-Ethyl-2- (2-hydroxyphenyl) -6-methyl-3- [2- (2-thienyl) ethyl] -4 (3H) -pyrimidinone; 5-lsopropyl-2- (2-hydroxy-phenyl) -6-methyl-3- (2-thiophen-2-yl-ethyl) -3H-pyrimidin-4-one; 5-lsopropyl-2- (2-hydroxy-phenyl) -6-methyl-3- (2-cyclohexyl-ethyl) -3H-pyrimidin-4-one; 5-Ethyl-2- (2-hydroxy-3-fluorophenyl) -6-methyl-3- (2-fluorophenylethyl) -3H-pyrimidin-4-one; 5-Propenyl-2 (2-hydroxy-3-fluorophenyl) -6-methyl-3- (3-fluorophenylethyl) -3H-pyrimidin-4-one; 3- (2-Cyclohexylethyl) -2- (2-hydroxyphenyl) -5,6,7,8-tetrahydro-4 (3H) -quinazolinone; 3- (2-Thiophene-2-yl-ethyl) -2- (2-hydroxy-phenyl) -5,6,7,8-tetrahydro-3H-quinazolin-4-one; 3- (2-Thiophene-2-yl-ethyl) -2- (2-hydroxy-3-fluorophenyl) -5,6,7,8-tetrahydro-3H-quinazolin-4-one; 3- (2-Thiophene-3-yl-ethyl) -2- (2-hydroxy-phenyl) -5,6,7,8-tetrahydro-3H-quinazolin-4-one; 3- (3-Chloro-phenethyl) -2- (2-hydroxy-phenyl) -5,6,7,8-tetrahydro-3H-quinazolin-4-one; 3- (2-Cyclopentylethyl) -2- (2-hydroxy-phenyl) -5,6,7,8-tetrahydro-3H-quinazolin-4-one; 3- (3-Trifluoromethyl-phenethyl) -2- (2-hydroxy-phenyl) -5,6,7,8-tetrahydro-3H-quinazolin-4-one; 2- (2-Hydroxyphenyl) -3- (2-phenylethyl) -5,6,8,9-tetrahydrooxepino [4,5-d] pyrimidin-4 (3H) -one; 3- (2-Cyclohexyl-ethyl) -2- (2-hydroxy-phenyl) -3,5,6,7,8,9-hexahydro-cycloheptapyrimidin-4-one; 2- (2-Hydroxyphenyl) -3- (2-phenylethyl) -6- (phenylmethyl) -5,6,7,8-tetrahydropyrido [4,3-d] pyrimidin-4 (3H) -one; 2-Methylpropyl-2- (2-hydroxyphenyl) -4-oxo-3- (2-phenylethyl) -3,5,7,8-tetrahydropyrido [4,3-djpyrimidine-6 (4H) -carboxylate; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-5- [5- (2-methyl-1,3-thiazol-4-yl) -2-thienyl] -3- (2-phenylethyl) - 4 (3H) -pyrimidinone; 2- [2- (Hydroxy) phenyl] -3- (2-phenylethyl) -5,6,7,8-tetrahydropyrido [3,2-d] pyrimidin-4 (3H) -one; 2- (2-Hydroxyphenyl) -5-methyl-3- (2-phenylethyl) -5,6,7,8-tetrahydropyrido [3,2- d] pyrimidin-4 (3H) -one; 5-Ethyl-2- [2-hydroxyphenyl] -3- (2-phenylethyl) -5,6,7,8-tetrahydropyrido [3,2-d] pyrimidin-4 (3H) -one; 2- (2-Hydroxyphenyl) -4-oxo-3- (2-phenylethyl) -3,4,5,7-tetrahydro-6H- pyrrolo [3,4-d] pyrimidine-6-carboxylic acid 1,1-dimethylethyl ester; 5- (2-Methylpropyl-2-yl) -2- (2-hydroxy-phenyl) -6-methyl-3- (2-phenethyl) -3H-pyrimidin-4-one; 5- [2- (3-Fluorophenyl) ethyl] -6- (2-hydroxyphenyl) -1-methyl-1,5-dihydro-4H-pyrazolo [3,4-d] pyrimidin-4-one; 5-Ethyl-2- (3-fluoro-2-hydroxyphenyl) -3- [2- (3-fluorophenyl) ethyl] -6-phenyl-4 (3H) -pyrimidinone; 6- [3,4-Bis (methyloxy) phenyl] -5-ethyl-2- (3-fluoro-2-hydroxyphenyl) -3- [2- (3-fluorophenyl) ethyl] -4 (3H) -pyrimidinone; 5-Ethyl-2- (3-fluoro-2-hydroxyphenyl) -3- [2- (3-fluorophenyl) ethyl] -6- (3-nitrophenyl) -4 (3H) -pyrimidinone; 5-Ethyl-3- [2- (3-fluorophenyl) ethyl] -2- (2-hydroxyphenyl) -6- (1-pyrrolidinyl) -4 (3H) -pyrimidinone; 6- (Dimethylamino) -5-ethyl-3- [2- (3-fluorophenyl) ethyl] -2- (2-hydroxyphenyl) -4 (3H) -pyrimidinone; 5-Ethyl-3- [2- (3-fluorophenyl) ethyl] -2- (2-hydroxyphenyl) -6- (methylamino) -4 (3H) -pyrimidinone; 5-Cyclopentyl-3- [2- (3-fluorophenyl) ethyl] -2- (2-hydroxyphenyl) -6-methyl-4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -6-methyl-5- (2-methylpropyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -6-methyl-5- (2-methylpropyl) -3- [2- (2-thienyl) eti)] - 4 (3H) -pyrimidinone; -Et? L-2- (2-h? Drox? -fen? L) -6-et? L-3-phen? Let? L-3H-p? R? M? D? N-4-one , 5-Et? L-2- (2-h? Drox? -fen? L) -6-prop? L-3-phen? Let? L-3H-p? Pm? D? N-4-one, 5-Et? L-2- (3-fluoro-2-hydrox? -fen? L) -6- (2-phen? Let? L) -3- (2-fluoro-phen? Let? L) -3H-p? R? M? D? N-4-one, 5-Et? L-2- (3-fluoro-2-h? Drox? -fen? L) -6-prop? L-3- (2-fluoro-phenol? L) -3H-p? Pm? D? N-4-one, 5-Et? L-2- (3-fluoro-2-hydrox? -fen? L) -6- (3-phenol-propyl) -3- (2-fluoro-phenolyl) -3H-p? R? M? D? N-4-one, 5-Et? L -2- (3-fluoro-2-hydrox? -phen?) -6-but? L-3- (2-fluoro-phenol? L) -3H-p? Pm? D? N- 4- ona, 5-Et? L-2- (3-fluoro-2-hydrox? -fen? L) -6- (2-met? L-prop? L) -3- (2-fluoro- phen? let? l) -3H-p? pm? d? n-4-one, 5-Et? l-2- (3-fluoro-2-hydrox? -fen? l) -6- (3 -met? l-but? l) -3- (2-fluoro-phenol? l) -3H-p? pm? d? n-4-one, 5-Et? l-2- (3-fluoro) -2-h? Drox? -fen? L) -6- (2-c? Clobut? L-et? L) -3- (2-fluoro-phen? Let? L) -3H-p? Pm? D n-4-one, 5-Et? l-2- (3-fluoro-2-hydrox? -fen? l) -6- (3,4-d? chlorophenet? l) -3- (2 -fluoro-phenol? l) -3H-p? pm? d? n-4-one, 5-Et? l-2- (4-fluoro-2-hydrox? phen?) -6- met? l-3- (2-phen? le? l) -4 (3H) -pipmidinone, 6-Met? l-5- (2-m) et? l-1, 3-t? azol-5-? l) -3- (2-phen? let? l) -2-. { 2 - [(fen? Lmet? L) ox?] Phen? L} -4 (3H) -p? Pm? Donone, 2- (2-H? Drox? Phen?) -6-met? L-5-. { 5-met? L-2-t? In? L) -3- (2-phen? Let? L) -4 (3H) - pyrimidinone; 2- (2-Hydroxyphenyl) -6-methyl-5- (5-methyl-3-thienyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-5- (5-methyl-3-thienyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- (4,5-Dimethyl-2-thienyl) -2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -6-methyl-5- [5- (1,3-oxazol-5-yl) -2-thyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -6-methyl-5- (4-methyl-2-thyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- [2- (2-Hydroxyphenyl) -4-methyl-6-oxo-1- (2-phenylethyl) -1,6-dihydro-5-pyrimidinyl] -2-thiophenecarbonitrile; 2- (2-Hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- [5- (1 H-tetrazol-5-yl) -2-thienyl] -4 (3H) -pyrimidinone; 5- [5- (Aminomethyl) -2-thienyl] -2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -6-methyl-5-. { 5 - [(methylamino) methyl] -2-thienyl} -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- [5- (Hydroxymethyl) -2-thienyl] -2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- (4,5,6,7-tetrahydro-1-benzothien-2-yl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- (2-phenyl-1,3-thiazol-5-yl) -4 (3 H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -5- (4-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -5- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -5- (3-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -6-methyl-5- (2-methylpropyl) -3- [2- (1-piperidinyl) ethyl] -4 (3H) -pyrimidinone; 5-Ethyl-3- [2- (2-fluorophenyl) ethyl] -2- (3-hydroxyphenyl) -6-methyl-4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -6-methyl-5- [5- (5-methyl-1, 3,4-oxadiazol-2-yl) -2-thienyl] -3- (2-phenylethyl) -4 ( 3H) -pyrimidinone; 5- (2,3-Dhydro-1,4-benzodioxin-6-yl) -2- (2-hydroxyphenyl) -6- [(methyloxy) methyl] -3- (2-phenylethyl) -4 (3H ) -pyrimidinone; 2- (2-Hydroxyphenyl) -6 - [(methyloxy) methyl] -5- (4-methyl-2-thienyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -6 - [(methyloxy) methyl] -5- (5-methyl-2-thienyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5-Bromo-6 - [(dimethylamino) methyl] -2- (2-hydroxyphenyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 6 - [(Dimethylamino) methyl] -2- (2-hydroxyphenyl) -3- (2-phenylethyl) -4 (3H) - pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-5- (5-methyl-3-thienyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- (4,5-Dimethyl-1, 3-thiazol-2-yl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-5- (4-methyl-1,3-thiazol-2-yl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- (1, 3-Benzodioxol-5-yl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 3- (2,3-Dihydro-1 H -inden-2-yl) -2- (2-hydroxyphenyl) -6-methyl-5- (5-methyl-2-thienyl) -4 (3H) -pyrimidinone; 3- [1- (2,3-Dihydro-1 H -inden-2-yl) -2- (2-hydroxyphenyl) -4-methyl-6-oxo-1,6-dihydro-5-pyrimidinyl] benzonitrile; 3- (2,3-Dihydro-1 H -inden-2-yl) -5- (4,5-dimethyl-1,3-triazol-2-yl) -2- (2-hydroxyphenyl) -6-methyl -4 (3H) -pyrmidinone; 3- (2-Cyclohexylethyl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-5- (5-methyl-2-thienyl) -4 (3H) -pyrimidinone; 3- (2-Cyclohexylethyl) -5- (4,5-dimethyl-1,3-thiazol-2-yl) -2- (3-fluoro-2-hydfoxyphenyl) -6-methyl-4 (3H) -pyrimidinone; 3- (2-Cyclohexylethyl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-5- (2-methyl-1,3-thiazol-5-yl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-5- (5-methyl-2-thienyl) -3- [2- (2-thienyl) ethyl] -4 (3H) -pyrimidinone; - (4,5-Dimethyl-1, 3-thiazol-2-yl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- [2- (2-thienyl) ethyl] -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-5- (5-methyl-2-thienyl) -3- [2- (tetrahydro-2H-pyran-4-yl) ethyl] -4 (3H ) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -3- [2- (2-fluorophenyl) ethyl] -6-methyl-5- (5-methyl) -2-thienyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -3- [2- (3-fluorophenyl) ethyl] -6-methyl-5- (5-methyl-2-thienyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -3- [2- (4-fluorophenyl) ethyl] -6-methyl-5- (5-methyl-2-thienyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-5- (3-methyl-2-thinyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -3- (2-phenylethyl) -5,6,7,8,9,10-hexahydrocycloocta [d] pyrimidin-4 (3H) -one; 5- (1-Benzothien-2-yl) -3- (2,3-dihydro-1 H -inden-2-yl) -2- (2-hydroxyphenyl) -6-methyl-4 (3 H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-5- (2-methylpropyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -5,5-dimethyl-3- (2-phenylethyl) -5,6,7,8-tetrahydro-4 (3H) -quinazolinone; 5-Chloro-2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 3- [2- (3-Fluorophenyl) ethyl] -2- (2-hydroxyphenyl) -5,6,7,8-tetrahydro-4 (3H) -quinazolinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-5- (5-methyl-2-thienyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 3- [2- (3-Fluoro-2-hydroxyphenyl) -4-methyl-6-oxo-1- (2-phenylethyl) -1,6-dihydro-5-pyrimidinyl] benzonitrile; 5- (2,3-Dihydro-1,4-benzodioxin-6-yl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- (3,5-Difluorophenyl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-5- (4-methyl-2-thienyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone, 5- (1-Benzothien- 2-yl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- (3-thienyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- (5-phenyl-2-thienyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- (2-thienyl) -4 (3H) -pyrimidinone; 5- (1, 3-Benzothiazol-2-yl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl)) - 4 (3H) -pyrimidinone; 5- (1-Benzothien-2-yl) -2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -6-methyl-5- (2-methyl-1,3-thiazol-5-yl) -3- (2-phenylethyl) - 4 (3H) -pyrimidinone; 5- [2- (2-Hydroxyphenyl) -4-methyl-6-oxo-1- (2-phenylethyl) -1,6-dihydro-5-pyrimidinyl] -2-thiophenecarbonitrile; 3- [2- (2-Hydroxyphenyl) -4-methyl-6-oxo-1- (2-phenylethyl) -1,6-dihydro-5-pyrinnidinyl-benzonitrile; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-5-phenyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5-propyl-4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-5- (2-methyl-1,3-thiazol-5-yl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; and 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- (1 H -pyrrol-1-yl) -4 (3 H) -pyrimidinone; or a pharmaceutically acceptable salt thereof. More preferred compounds useful in the present invention include but are not limited to: 2- (3-fluoro-2-hydroxyphenyl) -6-methyl-5- (2-methylpropyl) -3- (2-phenylethyl) -4 (3H ) -pyrimidinone; 2- (2-hydroxyphenyl) -5,5-dimethyl-3- (2-phenylethyl) -5,6,7,8-tetrahydro-4 (3H) -quinazolinone; 5-chloro-2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 3- [2- (3-Fluorophenyl) ethyl] -2- (2-hydroxyphenyl) -5,6,7,8-tetrahydro-4 (3H) -quinazolinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-5- (5-methyl-2-thienyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 3- [2- (3-Fluoro-2-hydroxyphenyl) -4-methyl-6-oxo-1- (2-phenylethyl) -1,6-dihydro-5-pyrimidinyl] benzonitrile; 5- (2,3-dihydro-1,4-benzodioxin-6-yl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- (3,5-Difluorophenyl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (3-fluoro-2-hydroxyphenyl) -6-methyl-5- (4-methyl-2-thienyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- (1-benzothien-2-yl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- (2-thienyl) -4 (3H) -pyrimidinone; 5- (1, 3-Benzothiazol-2-yl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- (1-Benzothien-2-yl) -2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -6-methyl-5- (2-methyl-1,3-thiazol-5-yl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- [2- (2-Hydroxyphenyl) -4-methyl-6-oxo-1- (2-phenylethyl) -1,6-dihydro-5-pyrimidinyl] -2-thiophenecarbonitrile; 3- [2- (2-hydroxyphenyl) -4-methyl-6-oxo-1- (2-phenylethyl) -1,6-dihydro-5- pyrimidinylbenzonitrile; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-5-phenyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5-propyl-4 (3H) -pyrimidinone; and 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- (1 H -pyrrol-1-yl) -4 (3 H) -pyrimidinone; or a pharmaceutically acceptable salt thereof. As used herein, the term "pharmaceutically acceptable" refers to a compound that is suitable for pharmaceutical use. The salts and solvates of compounds of the invention which are suitable for use in medicine are those in which the counter-ion or associated solvent is pharmaceutically acceptable. However, salts and solvates having non-pharmaceutically acceptable counterions are within the scope of the present invention, for example, to be used as intermediates in the preparation of other compounds of the invention and their pharmaceutically acceptable salts and solvates. Those with experience in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they react or from which they precipitate or crystallize. These complexes are known as "solvates". For example, a complex with water is known as a "hydrate". Solvates of the compound of the invention are within the scope of the invention.

With respect to stereoisomers, the present compounds may have one or more asymmetric carbon atoms and may occur as racemates, racemic mixtures and as individual enantiomers or distereomers. All such isomeric forms are included within the present invention, including their mixtures. In addition, some of the crystalline forms of the present compounds may exist as polymorphs, which are included in the present invention. Due to its potential use in medicine, the salts of the compounds of formula (I) and (II) are preferably pharmaceutically acceptable. Suitable pharmaceutically acceptable salts can include acid or base addition salts. A pharmaceutically acceptable acid addition salt can be formed by the reaction of a compound of formula (I) or (II) with a suitable inorganic or organic acid (such as hydrobromic, hydrochloric, sulfuric, nitric, phosphoric, succinic acid) , maleic, formic, acetic, propionic, fumaric, citric, tartaric, lactic, benzoic, salicylic, glutamic, aspartic, p-toluenesulfonic, benzenesulfonic, methanesulfonic, ethanesulfonic, naphthalenesulfonic, such as 2-naphthalenesulfonic, or hexanoic), optionally in a suitable solvent such as an organic solvent, to provide the salt which is normally isolated for example by means of crystallization and filtration. An acceptable acid addition salt of a compound of formula (I) or (II) may comprise or be for example a hydrobromide, hydrochloride, sulfate, nitrate, phosphate, succinate, maleate, fomat, acetate, propionate, fumarate, citrate, tartrate, lactate, benzoate, salicylate, glutamate, aspartate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, ethanesulfonate, naphthalenesulfonate (eg , 2-naphthalenesulfonate) or hexanoate salt. A pharmaceutically acceptable base addition salt can be formed by the reaction of a compound of formula (I) or (II) with a suitable inorganic or organic base (e.g., triethylamine, ethanolamine, triethanolamine, choline, arginine, lysine or histidine), optionally in a solvent such as an organic solvent, to give the base addition salt which is normally isolated eg by crystallization and filtration. Other suitable pharmaceutically acceptable salts include pharmaceutically acceptable metal salts, for example pharmaceutically acceptable alkali metal or alkaline earth metal salts such as sodium, potassium, calcium or magnesium salts; in particular pharmaceutically acceptable metal salts of one or more carboxylic acid moieties which may be present in the compound of formula (I) or (II). Other non-pharmaceutically acceptable salts, for example, oxalates, can be used, for example in the isolation of compounds of the invention, and are included within the scope of this invention. The invention includes within its scope all possible stoichiometric and non-stoichiometric forms of the salts of the compounds of formula (I) or (II).

Synthetic schemes The general synthetic methods are detailed later in schemes 1-4. The present schemes are intended to be illustrative of the present invention and not to limit it in any way. Although particular substituents are described, other variables can be made with the present schemes.

SCHEME 1 (with or without solvent.

Treatment of a β-keto amide such as 1 with an amide in the presence of a Lewis acid such as Ti (O-iPr) provides the pyrimidinone 2 as outlined in scheme 1.

SCHEME 2 NaOEi, EtOH 4 Alternatively, as shown in scheme 2, the treatment of a β-keto ester such as 3 with an amidine in the presence of a base such as sodium methoxide or sodium ethoxide provides the pipmidinone 4 Alkylation of 4 with, and alkylating agent in the presence of a common basis for the technique such as lithium hydride provides the protected pipmidinone that during the deprotection of the protective group of phenol, common to the technique, can be achieved by means of a variety of also common methods for the technique to provide analogues desired 5 SCHEME 3 6 wherein: Rie represents an alkyl group of d-2, benzyl or acetyl in scheme 3. Y is a displacement group selected from F, Cl, Br and I. R4 is selected from the group consisting of phenethyl, 3- fluorophenethyl, 4-fluorophenethyl, 2-fluorophenethyl, 2-thienylethyl, phenylethyl, dihydroindenyl, cyclohexylethyl, 3-chlorophenethyl, 3-trifluoromethylphenethyl, cyclopentylethyl and tetrahydropyranylethyl. As described in scheme 3, the treatment of an appropriately protected 3-fluoro-2-alkoxybenzoic acid 6 with thionyl chloride provides corresponding acyl chloride which reacts with methyl 3-aminocrotonate in the presence of a common base for the technique such as pyridine provides mixtures of geometric isomers such as (2E, Z) -3-. { [2-benzyloxy) -3-fluorobenzoyl] amino} but-2-enoate 7. Cyclization of 7 in the presence of Mß3AI and amine provides the protected pyrimidinone 8. Selective bromination of 8 at the C-5 position under conditions common to the technique such as NBS provides 9. Bromide 9 then it can be coupled with 5-methyl-2-thiophene boronic acid under standard Suzuki reaction conditions to generate 10 that during deprotection of the phenol protecting group using HBr in acetic acid, common to the art, provides the desired compound 11. Scheme 3 describes a novel method of converting an enamide according to 7 to a pyrimidinone according to 8. The novel intermediates include compounds 7, 8, 9 and 10 in scheme 3.

SCHEME 4 3-fl? O? O-2-l) i? L? ox¡l > e? Z? n) i < l.? Fenetilomino Ti (/ PrO) 4, Reflux Y < EtzO, Reflow 43% 93% 9 10 11 12 As shown in the scheme 4 a-substituted-ß-keto-amides such as 14 can be prepared by means of a microwave-assisted thermal addition of an amine to a β-keto-ester such as 13. The enol triflate 15 form under conditions common to the art such as trifluoromethanesulfonic acid anhydride in the presence of a base such as triethyl amine. Subsequent treatment of enol triflate with a benzamide in the presence of a palladium catalyst and inorganic base such as cesium carbonate provides enamide 16. Common standard conditions for the technique are used to affect cyclization to fully functionalized pyrimidinone 17. In order to use a compound of formula (I) or (II) or a salt Pharmaceutically acceptable thereof for the treatment of humans and other mammals, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition. Calcilytic compounds can be administered by means of different routes including intravenous, intraperitoneal, subcutaneous, intramuscular, oral, topical (transdermal), or transmucosal administration. For systemic administration, oral administration is preferred. For oral administration, for example, the compounds can be formulated in conventional oral dosage forms such as capsules, tablets, and liquid preparations such as syrups, elixirs, and concentrated drops. Alternatively, the injection (parenteral administration) can be used, for example, for intramuscular, intravenous, intraperitoneal, and subcutaneous administration. For injection, the compounds of the invention are formulated in liquid solutions, preferably, in pH regulators or physiologically compatible solutions, such as saline solution, Hank's solution, or Ringer's solution. In addition, the compounds can be formulated in solid form and re-dissolved or suspended immediately before use. Lyophilized forms can also be produced. Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, appropriate penetrants for the barrier to be penetrated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, bile salts and fusidic acid derivatives. In addition, detergents can be used to facilitate penetration. Transmucosal administration, for example, can be through nasal sprays, rectal suppositories, or vaginal suppositories. For topical administration, the compounds of the invention can be formulated into ointments, balm, gels, or creams, as is generally known in the art. The amounts of various calcilytic compounds to be administered can be determined by standard procedures considering factors such as the IC50 of the compound, EC50, the biological half-life of the compound, the age, size and weight of the patient, and the disease or disorder associated with the patient. The importance of these and other factors to be considered are known to those skilled in the art. Amounts administered also depend on the routes of administration and the degree of oral bioavailability. For example, for compounds with low oral bioavailability, relatively higher doses will have to be administered. Preferably, the composition is in a unit dosage form. For oral application, for example, a tablet, or capsule can be administered, for nasal application, a dosed aerosol dose can be administered, for transdermal application, a topical formulation or patch can be administered and for delivery Transmucosal, a mouth patch can be administered. In each case, the dosage is such that the patient can be administered with a single dose. Each dosage unit for oral administration suitably contains 0.01 to 500 mg / kg, and preferably 0.1 to 50 mg / kg, of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, is calculated as the free base. The daily dosage for parenteral, nasal, oral, transmucosal or transdermal inhalation routes suitably contains from? 0.01 mg to 100 mg / kg of a compound of formula (I) or (II). A topical formulation suitably contains 0.01 to 5.0% of a compound of formula (I) or (II). The active ingredient can be administered, for example, from 1 to 6 times per day, preferably once, sufficient to exhibit the desired activity, as is readily apparent to a person skilled in the art. As used herein, "treatment" of a disease includes, but is not limited to prevention, delay and prophylaxis of the disease. Diseases and disorders that can be treated or prevented, based on the affected cells, including diseases related to bones or minerals; hypoparathyroidism; those of the central nervous system such as seizures, stroke, brain trauma, spinal cord injury, nerve cell damage induced by hypoxia, such as occurs in cardiac arrest or neonatal insufficiency, epilepsy, neurodegenerative diseases such as Alzheimer's disease, of Huntington and Parkinson's disease, dementia, tension muscle, depression, anxiety, panic disorder, obsessive-compulsive disorder, post-traumatic stress disorder, schizophrenia, neuroleptic malignant syndrome, and Tourette's syndrome; diseases involving excess water re-absorption by the kidney, such as inappropriate ADH secretion syndrome (SIADH), cirrhosis, congestive heart failure, and nephrosis; hypertension; prevention and / or reduction of renal toxicity of cationic antibiotics (for example, aminoglycoside antibiotics); intestinal motility disorders such as diarrhea and spastic colon; ulcer diseases Gl; Gl diseases with excessive calcium absorption such as sarcoidosis; autoimmune diseases and organ transplant rejection; squamous cell carcinoma; and pancreatitis. In a preferred embodiment of the present invention, the present compounds are used to increase levels of serum parathyroid hormone ("PTH"). Increasing serum PTH levels may be useful in the treatment of diseases such as hypoparathyroidism, osteosarcoma, periodontal disease, fracture, osteoarthritis, rheumatoid arthritis, Paget's disease, hypercalcemia humoral malignancy and osteoporosis. Another aspect of the present invention describes a method for the treatment of a patient comprising administering to the patient an amount of a present compound sufficient to increase the serum PTH level. Preferably, the method is carried out by administering an amount of the effective compound to cause a increase in the duration and / or amount of serum PTH level sufficient to have a therapeutic effect. In various embodiments, the compound administered to a patient causes an increase in serum PTH lasting for up to one hour, approximately one to approximately 24 hours, approximately one to approximately 12 hours, approximately one to approximately six hours, approximately one to about five hours, about one to about four hours, about two to about five hours, about two to about four hours, or about three to about six hours. In an alternate embodiment of the present invention, the compound administered to a patient causes an increase in serum PTH that lasts for more than about 24 hours provided it is co-administered with an anti-resorbing agent. In further different embodiments, the compound administered to a patient causes an increase in serum PTH by up to two times, two to five times, five to ten times, and at least 10 times, more than the maximum serum PTH in the patient. The maximum serum level is measured with respect to a patient who does not undergo treatment. In a preferred embodiment of the present invention, the present compound is co-administered with an anti-resorbing agent. Suitable anti-resorptive agents for co-administration include, but are not limited to estrogen, 1a, 25- (OH) 2D3, 1a- (OH) D3, calcitonin, selective estrogen receptor modulators, vitronectrin receptor antagonists, V-H + -ATPase inhibitors, SH2 src antagonists, bio-phosphonates and cathepsin K inhibitors. The composition of formula (I) or (II) and its pharmaceutically acceptable salts, which are active when delivered orally, can be formulated as syrups, tablets, capsules and lozenges. A syrup formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier eg, ethanol, peanut oil, olive oil, glycerin or water with a flavoring or coloring agent. When the composition is in the form of a tablet, any pharmaceutical carrier routinely used for the preparation of solid formulations can be used. Examples of such carriers include magnesium stearate, gypsum, talc, gelatin, acacia, stearic acid, starch, lactose and sucrose. When the composition is in the form of a capsule, any routine encapsulation is suitable, for example using the carriers mentioned above in a hard gelatin capsule shell. When the composition is in the form of a soft gelatin shell capsule, any pharmaceutical carrier used routinely for the preparation of dispersions or suspensions may be considered, for example, aqueous gums, celluloses, silicates or oils, and incorporated in a coating of soft gelatin capsule. Typical parenteral compositions consist of a solution or suspension of a compound or salt in a sterile aqueous or non-aqueous carrier optionally containing a parenterally acceptable oil, for example, polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil or sesame oil. Typical compositions for inhalation are in the form of a solution, suspension or emulsion which can be administered as a dry powder or in the form of an aerosol using a conventional propellant such as dichlorodifluoromethane or trichlorofluoromethane. A typical suppository formulation comprises a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof which is active when administered in this manner, with a binder and / or lubricant, for example, polymeric glycols, gelatins , cocoa butter or other vegetable waxes of low melting point or fats or their synthetic analogues. The dermal and transdermal formulations comprise a conventional aqueous or non-aqueous vehicle, for example, a cream, ointment, lotion or paste or are in the form of a medicated poultice, patch or membrane. Preferably the composition is in the unit dosage form, for example, a tablet, capsule or dosage dosed in aerosol, so that the patient can take a single dose. Acceptable toxicological effects are expected when the compounds of the present invention are administered in accordance with present invention. The biological activity of the compounds of formula (I) and (II) are demonstrated by the following tests: (I) Calcium receptor inhibitor assay Calcilytic activity is measured by determining the IC50 of the test compound to block the increases of intracellular Ca2 + produced by extracellular Ca2 + in HEK 293 4.0-7 cells stably expressing the human calcium receptor. HEK 293 4.0-7 cells are constructed as described by Rogers et al., J. Bone Miner. Res. 10 Suppl. 1: S483, 1995 (incorporated therefore for reference herein). Increases in intracellular Ca2 + are produced by increasing extracellular Ca2 + from 1 to 7.5 mM. Intracellular Ca2 + is measured using fluo-3, a fluorescent calcium indicator. The procedure is as follows: 1. Cells are maintained in T-150 flasks in selection medium (DMEM supplemented with 10% fetal bovine serum and 200 ug / ml hygromycin B), low CO2 5%; 95% air at 37 ° C and develop up to 90% confluence. 2. The medium is decanted and the cell monolayer is washed twice with saline with pH regulated phosphate (PBS) which is maintained at 37 ° C. After the second wash, 6 ml of 0.02% EDTA in PBS is added and incubated for 4 minutes at 37 ° C. Following the incubation, the cells Disperse by means of gentle agitation. 3. The cells of 2 or 3 flasks are grouped and formed into pellets (100 x g). The cell pellet is resuspended in 10-15 ml of SPF-PCB + and pelletized again by centrifugation. This washing is done twice. The phosphate and sulfate-free parathyroid cell pH regulator (SPF-PCB) contains 20 mM Na-Hepes, pH 7.4, 126 mM NaCl, 5 mM KCI and 1 mM MgCl 2. SPF-PCB is composed and stored at 4 ° C. On the day of use, SPF-PCB is supplemented with 1 mg / ml D-glucose and 1 mM CaCl2 and then divided into two fractions. To a fraction, bovine serum albumin (BSA, fraction V, ICN) is added in 5 mg / ml (SPF-PCB +). This pH regulator is used for washing, loading and maintaining the cells. The free fraction of BSA is used to dilute the cells in the test tube for fluorescence measurements. 4. The pellet is resuspended in 10 ml of SPF-PCB + containing 2. 2 μ fluo-3 (Molecular Probes) and incubate at room temperature for 35 minutes. 5. After the incubation period, the cells are pelleted by centrifugation. The resulting pellet is washed with SPF-PCB +. After this washing, the cells are resuspended in SPF-PCB + at a density of 1-2 x 10 6 cells / ml. 6. For the recording of fluorescent signals, 300 ul of cell suspension is diluted in 1.2 ml of pH regulator SPF containing 1 mM CaCl2 and 1 mg / ml D-glucose. Fluorescence measurements are made at 37 ° C with constant agitation using a spectrofluorimeter. The excitation and emission wavelengths are measured at 485 and 535 nm, respectively. To calibrate the fluorescence signals, digitonin (5 mg / ml in ethanol) is added to obtain Fmax, and the apparent Fmin is determined by adding Tris-EGTA (2.5 M Tris-base, 0.3 M EGTA). The intracellular calcium concentration is calculated using the following equation: Intracellular Calcium = (F-Fm¡n / Fmá?) X Kd; where Kd = 400 nM. 7. To determine the potential catalytic activity of the test compounds, the cells are incubated with the test compound (or vehicle as a control) for 90 seconds before increasing the extracellular Ca 2+ concentration from 1 to 2 mM. The calcilytic compounds are detected by their ability to block, in a concentration-dependent manner, increases in the concentration of intracellular Ca2 + produced by extracellular Ca2. In general, those compounds that have lower IC50 values in the calcium receptor inhibitor assay are more preferred compounds. Compounds that have an IC50 greater than 30 μ are considered to be inactive. Preferred compounds are those that have an IC50 of 10 μ or lower. The present examples are analyzed except for examples 11, 20, 28, 44 and 107. All the compounds analyzed are found to be active, except for examples 27, 46, 100, 123, 127, 214, 215 and 216 in the concentrations used.

(II) Calcium receptor binding assay HEK 293 4.0-7 cells stably transfected with the human parathyroid calcium receptor ("HuPCaR") are progressively increased in T180 tissue culture flasks. Plasma membrane is obtained by polytron homogenization or douncing glass in pH regulator (50 mM Tris-HCl pH 7.4, 1 mM EDTA, 3 mM MgCl2) in the presence of a protease inhibitor cocktail containing 1 uM leupeptin, 0.04 ppm pepstatin. uM, and PMSF mM. Membrane in aliquots is rapidly frozen and stored at -80 ° C. A compound labeled with 3 H is radiolabelled for a radio-specific activity of 44 Ci / mmol and added in aliquots and stored in liquid nitrogen for radiochemical stability. A typical reaction mixture contains a 3H 2 nM compound ((R, R) -N-4'-methoxy-t-3-3'-methyl-1'-ethylphenyl-1- (1-naphthyl) ethylamine), or compound 3H (R) -N- [2-hydroxy-3- (3-chloro-2-cyano-2-cyanophenoxy) propyl] -1,1-diethyl-2- (4-methoxyphenyl) ethylamine 4-10 ug membrane in homogenization pH regulator containing 0.1% gelatin and 10% EtOH in a 0.5 ml reaction volume. Incubation is carried out in 12 x 75 polyethylene tubes in an ice water bath. To each tube 25 ul of test sample in 100% EtOH is added, followed by 400 ul of cold incubation buffer, and 25 ul of 40 nM 3 H compound in 100% EtOH for a final concentration of 2 nM. The binding reaction is initiated by the addition of 50 ul of 80-200 ug / ml of HEK 293 4.0-7 membrane diluted in pH buffer of incubation, allowed to incubate at 4 ° C for 30 minutes. The pH regulator of Washing is 50 mM Tris-HCl containing 0.1% PEI. The non-specific binding is determined by the addition of a 100-fold excess of unlabelled homologous ligand, and is generally 20% of total binding. The binding reaction is terminated by rapid filtration on pre-treated PEI 1% GF / C filters using a Brandel Harvestor. The filters are placed in scintillation fluid and radioactivity valued by liquid scintillation counting. Preferred compounds are those having an IC 0 of 10 uM or lower. The present examples are discussed except for examples 11, 20, 28, 44 and 107. All the compounds tested are found to be effective.

(III) Oral administration in dog and rat Dog Animals (male beagle dogs) are fed a "certified canine diet" diet # 5007. Approximately 300-500 grams per day. Water is provided at pleasure. During the days of dosing, the animals are kept fasting (they do not feed in the morning), and the animals are fed after 240 minutes of the time point of blood collection. For the first 2 hours of these studies the dogs are placed in restriction slings for dosing and blood collection purposes. They return to their cages after 2 hours of the time point and are individually restricted for all time points of posterior blood collection.

Experimental procedures A square Latin design 4 x 4 (4 treatments, 4 experimental days, 1 animal / treatment / day) is followed where the treatments are assigned randomly before the first experiment. The total experiment is completed in 4 separate days following the subsequent summary. In each of these days of study, an animal receives vehicle or compound, so that at the conclusion of the study, all animals are exposed to all treatments. 4 x 4: Latin square design Group ratings On each study day, 3 dogs receive compound 1, 2 or 3 in X mg [6 ml] / kg, and 1 dog receives vehicle in a dose volume of 6ml / kg. The compounds are prepared in Cavitron 20% and DMSO 1%. The formulation is a suspension in all three doses. The pH is measured and adjusted if necessary and documented after drug formulation. All animals are dosed via an oral probe using a 24 French feeding tube attached to a three-way stopcock. After introduction of the feeding tube into the stomach, approximately 10 ml of a 20 ml water purge is tube-fed to ensure proper placement of the dosing tube. The dose is then administered in Xmg [6 ml] / kg. After dosing the rest of the water purge (approximately 10 ml) is tube-fed to clean the dosing tube. Blood samples (approximately 3 ml) are obtained from the cephalic or saphenous vein using a 20 gauge catheter and an injection obturator or a 23 gauge needle and syringe. The catheter is blocked with a glucose heparin retainer (prepared by the LAS department) between samples. Blood samples are obtained just before dosing and at 5, 10, 15, 30, 60, 90, 120, 240 and 360 minutes after the dose. Whole blood is placed in a heparinized sodium vacutainer tube and gently shaken until vortex effect is obtained to inhibit coagulation and proper mixing of the sample. From each sample collected, a 100 μl aliquot is used to determine blood ionized calcium using the Medica Easylyte calcium analyzer. In addition, a 25 μl blood sample is transferred immediately to a properly marked tube. Nanopure water (25 μl) is added to this tube and then stirred until vortex effect is obtained (this is done in duplicate). This sample is allowed to stir for approximately 0.5 minutes at room temperature to allow lysis of the blood cells, and then placed on dry ice. The concentrations of compounds are quantified by HPLC / MS / MS by means of the DMPK MMPD CEDD department. An aliquot of whole blood (~ 200 μl) and approximately 5 mg of compound are quantified. The rest of the whole blood is centrifuged and plasma is separated for determination of PTH1-84.

Rat 1. Experimental procedures Compounds are prepared weekly by wetting the appropriate amount of compound in 1% DMSO. Subsequently cavitron 40% (total volume 20%) is added, followed by sterile water to bring the solution to the appropriate volume. The final pH for each compound and vehicle is measured and adjusted if necessary. Any adjustment to the pH is made before the addition of deionized water and documented. The animals are weighed and dosed. The volumes are adjusted so that each rat receives 8 ml / kg as an oral dose. Blood withdrawals (300 μl) occur before dosing and at 2, 5, 15, 30, 45, 60, 120, 180 and 240 minutes after the dosage. An aliquot of 25 μl of the collected whole blood sample is shaken until vortex effect with 25 μl of nanopure water and placed on dry ice for evaluation of drug levels. This sample is allowed to stir for approximately 0.5 minutes at room temperature to allow for lysis of blood cells, and then placed on dry ice. The concentrations of the compound (s) are quantified by means of HPLC / MS / MS. An aliquot of whole blood (-200 μl) and approximately 5 mg of compound are quantified. The remaining blood is centrifuged and the plasma collected for PTH 1-84 analysis. The blood is replaced at the end of each experiment (it is collected from a donor animal on the same day and heparinized slightly, approximately 5 lU / ml). The amount of blood replaced equals the total amount taken from the animal during the study. 4 x 4: Latin square design Group ratings * Only reported data of dose of 3 mg / kg All the compounds described in Examples 249 to 253 and 255 to 269, according to Formula (II) of the present invention, are analyzed and found to be active for the above assays. A compound appears to be active if there is a significant release of PTH produced relative to the vehicle. In the rat test, a compound appears to be active in > 50 pg / ml. In the dog test, a compound appears to be active > 15 pg / ml.

EXAMPLES Nuclear magnetic resonance spectra are recorded at 300 or 400 MHz using, respectively, a Broker ARX 300 or Broker AVANCE 400 spectrometer. CDCI3 is deuteriochloroform, DMSO-d6 is hexadeuteriodimethylsulfoxide, and CD3OD is tatradeuteriomethanol. Chemical shifts are reported in parts per million (?) Downfield of the internal standard tetramethylsilane. The abbreviations for the NMR data are as follows: s = singlet, d = doublet, t = triplet, q = cuartete, m = multiplote, dd = doublet of doublets, dt = doublet of triplets, app = apparent, br = broad. J indicates the NMR coupling constant measured in Hertz. Fourier transform infrared (FTIR) spectra are recorded on a Nicolet 510 infrared spectrometer. FTIR spectra are recorded in transmission mode, and band positions are reported at inverse wave numbers (cm "1). masses are taken in a SCIEX5 or Micromass instrument, using electro-spraying ionization (ES) techniques.The elemental analyzes are obtained using a Perkin-Elmer 240C elemental analyzer.The melting points are taken in a Thomas melting point apparatus -Hoover and they are not corrected.All temperatures are reported in Celsius, thin-film plates Analtech silica gel GF and E. GF and E. Merck silica gel 60 F-254 are used for thin-layer chromatography. Gravity is carried out on silica gel E. Merck Kieselgel 60 (230-400 mesh) Analytical and preparative HPLC is carried out in Rainin or Beckman chromatographies ODS refers to a chromatographic support of silica gel d octadecylsilyl. Apex-ODS 5 μ indicates a silica gel chromatographic support derived from octadecylsilyl having a nominal particle size of 5 μ, prepared by Jones Chromatography, Littieton, Colorado. YMC ODS-AQ® is an ODS chromatographic support and is a registered trademark of YMC Co. Ltd., Kyoto, Japan. PRP-1® is a polymeric chromatographic support (styrene-divinylbenzene), and is a registered trademark of Hamilton Co., Reno, Nevada.

Celite® is a filter aid composed of diatomaceous silica washed with acid, and is a registered trademark of Manville Corp., Denver, Colorado. The following examples are intended to be illustrative only and are not limited in any way: EXAMPLE 1 Preparation of 2- (2-fluoro-3-hydroxyphenyl) -6-methyl-5- (2-methylpropyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone to. Ethyl 2-Acetyl-4-methyl-4-pentenoate To a solution of ethyl 3-oxobutanoate (5.8 g, 0.05 mol) in dry acetonitrile is added 3-bromo-2-methyl-1-propene (6.75 g, 0.05 g). mmol) and K2CO3. The reaction mixture is stirred at room temperature for 62 hours. The solid is filtered and the filtrate is concentrated. The crude residue is purified by flash column chromatography using 10% EtOAc in hexanes to give 4.29 g of the desired product in 52% yield. b. 2-Acetyl-4-methyl-N- (2-phenylethyl) -4-pentamide To a solution of ethyl 2-acetyl-4-methyl-4-pentanoate (0.25 g, 1.35 mmol) in DME (2.7 ml) is added phenethylamine (0.057 ml, 0.45 mmol) in a microwave reaction vessel. This mixture is irradiated at 180 ° C for 800 seconds. The reaction mixture is diluted with EtOAc and washed with 1 N HCl. The organic layer is separated and dried over Na2SO, filtered, concentrated and purified by chromatography on silica gel (Biotage, 0-40% ethyl acetate / hexane) to produce pure amide (0.21 g) with a yield of 60%. c. 2-Acetyl-4-methyl-N- (2-phenylethyl) pentamide To a solution of 2-acetyl-4-methyl-N- (2-phenylethyl) -4-pentamide (2.0 g, 7.69 mmol) in a mixture of solvents of equal volume of EtOH and EtOAc (100 ml) is added Pd / C 10% (0.1 g). This mixture is placed under a hydrogen atmosphere and stirred for 12 hours. The reaction mixture is filtered through a pad of celite, and the concentrated filtrate is used in the next step without purification. d. 2-r2-Fluoro-3- (methyloxy) phenyl-6-methyl-5- (2-methylpropyl) -3- (2-phenylethyl) -4- (3H) -pyrimidinone 2-acetyl is taken 4-Methyl-N- (2-phenylethyl) pentamide (1.00 g, 3.82 mmol) in dry xylene (38 ml). To this is added 2-fluoro-3-methoxybenzamide (0.65 g, 3.82 mmol) and titanium isopropoxide (4.47 ml, 0.015 mol) consecutively. The reaction is heated to reflux until all the starting material is consumed. The reaction mixture is concentrated and diluted with dichloromethane and washed with 3N HCl. The organic layer is separated and dried Na2SO, filtered, concentrated and purified by chromatography on silica gel (Biotage, 0-40% ethyl acetate / hexane) to yield the pure product (0.57 g) in 38% yield. e, 2- (2-Fluoro-3-hydroxyphenyl) -6-meth »l-5- (2-methylpropyl) -3- (2-phenylethyl) -4- (3H) -pyrimidinone 2- [2- Fluoro-3- (methyloxy) phenyl] -6-methyl-5- (2-methylpropyl) -3- (2-phenylethyl) -4- (3H) -pyrimidinone (0.10 g, 0.25 mmol) in 1.0 ml of dichloromethane was added. cool to 0 ° C. BBr3 is then added and the reaction mixture is warmed to room temperature and stirred for 12 hours. The reaction mixture is diluted with dichloromethane and aqueous NaHCO3 then added. The organic layer is separated and washed with H2O, brine and dried over Na2SO, filtered, concentrated and purified by chromatography on silica gel (Biotage, 0-60% ethyl acetate / hexane) to yield the pure compound (0.043 g) with a yield of 45%. MS (m / z): 371.2 [M + H] +.

EXAMPLE 2 Preparation of 2- (3-hydroxyphenyl) -6-methyl-5- (2-methylpropyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone The title compound is prepared by substituting 3-methoxybenzamide for 2-methoxy-3-fluorobenzamide in Example 1d: MS (m / z): 363.4 [M + H] +.

EXAMPLE 3 Preparation of 2- (2,3-dihydroxyphenyl) -6-methyl-5- (2-methylpropyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone The title compound is prepared by substituting 2,3-dimethoxybenzamide for 2-methoxy-3-fluorobenzamide in Example 1d: MS (m / z): 379.2 [M + H] +.

EXAMPLE 4 Preparation of 6-methyl-5- (2-methylpropyl) -3- (2-phenylethyl) -2- (1 H -pyrrol-2-yl-4 (3H) -pyrimidinone 2-Acetyl-4-methyl-N- (2-phenylethyl) pentanamide from example 1c is taken up in titanium isopropoxide (3.96 mmol, 11.74 ml). To this is added 1 H-pyrrolo-2-carboxamide (0.5 g, 4.58 mmol) and the reaction is refluxed for 48 hours. During completion, the reaction is diluted with dichloromethane and washed with 3N HCl. The organic layer is separated and dried over Na2SO4, filtered, concentrated and purified by chromatography on silica gel (Biotage, 0-50% ethyl acetate / hexane) to yield the title compound (0.42 g). with a yield of 42%. MS (m / z): 336.2 [M + H] +.

EXAMPLE 5 Preparation of 6-methyl-5-f2-methylpropyl) -3-f2-phenylethyl) -2- (2-thienyl) -4 (3H) -pyrimidinone to. 6-Methyl-5- (2-methyl-2-propen-1-yl) -3- (2-phenylethyl) -2- (2-thienyl) -4 (3H) -pyrimidinone 2-Acetyl-4-methyl- N- (2-phenylethyl) pentanamide from example 1b (0.52 g, 1.98 mmol) is taken up in titanium isopropoxide (2.57 mmol, 7.56 ml). To this is added thiophene-2-carboxamide (0.38 g, 2.97 mmol) and the reaction is refluxed for 48 hours. During completion, the reaction is diluted with dichloromethane and washed with 3N HCl. The organic layer is separated and dried over Na2SO4. The crude compound is taken in the next step without purification. b, 6-Methyl-5- (2-methylpropyl) -3- (2-phenylethyl) -2- (2-thienyl) -4 (3H) -pyrimidinone 6-Methyl-5- (2-methyl-2-propen -1-yl) -3- (2-phenylethyl) -2- (2-thienyl) -4 (3H) -pyrimidinone is taken up in ethanol (4.0 ml). To this is added 0.1 g of 10% Pd / C and placed under a hydrogen atmosphere for 16 hours. The mixture of The reaction is filtered through a pad of celite, and the concentrated filtrate is purified by reverse phase HPLC to yield (0.17 g) of the final compound in 25% yield. MS (m / z): 453.2 [M + H] +.

EXAMPLE 6 Preparation of 6-methyl-5- (2-methylpropyl) -3- (2-phenyletin-2- (2-pyridinyl) -4 (3H) -pyrimidinone The title compound is prepared by substituting 2-pyridinecarboxamide for thiophene-2-carboxamide of example 5a: MS (m / z): 348.2 [M + H] +.

EXAMPLE 7 Preparation of 2- (2-furanyl) -6-methyl-5- (2-methylpropin-3- (2-phenylethyl) -4 (3H) -pyrimidinone The title compound is prepared by substituting furan-2-carboxamide for thiophene-2-carboxamide of example 5a: MS (m / z): 337.2 [M + H] +.

EXAMPLE 8 Preparation of 2- (1 H-imidazol-2-yl) -6-methyl-5- (2-methylpropyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone 2-Acetyl-4-methyl-N- (2-phenylethyl) -4-pentanamide from example 1c (0.26 g, 0.99 mmol) is taken up in titanium isopropoxide (12.89 mmol, 3.82 ml). To this is added 1 H-imidazole-2-carboxamide (0.17 g, 1.49 mmol) and the mixture is refluxed for 48 hours. The reaction mixture is concentrated and diluted with dichloromethane and washed with 3N HCl. The organic layer is separated and Dry over Na 2 SO 4, filter, concentrate and purify by reverse phase HPLC to yield the pure title compound in 15% yield (0.051 g). MS (m / z): 337.2 [M + H] +.

EXAMPLE 9 Preparation of S-ethyl-2- (2-fluoro-3-hydroxyphenyl) -3-r2- (3-fluorophenyl) etn-6-methyl-4 (3H) -pyrimidinone to. 2- (2-Methyl-1,3-dioxolan-2-yl) butanoate A commercially available ethyl ester of 2-ethyl-3-oxo-butyric acid (54 g, 0.34 mol), ethylene glycol (23.3 g, 0.375 mol), and p-toluenesulfonic acid (0.2 g) in toluene (500 ml) is heated at 120 ° C for 4 hours under a Dean-Stark apparatus. The reaction mixture is cooled to room temperature, the solvent is removed, and the residue is partitioned between ethyl acetate and NaHCO3. The layers are separated, and the aqueous portion is extracted three times with ethyl acetate. The organic portions are pooled, dried (MgSO) and concentrated to give the cyclic ketal product as a colorless oil in 91% yield (63 g) b. 2- (2-Methyl-1,3-dioxolan-2-yl) butanoic acid To a solution of ethyl 2- (2-methyl-1, 3-dioxolan-2-yl) butanoate (60 g, 0.297 mol) previously provided in EtOH (750 ml) is added 85% KOH solution in water (30 ml), and the mixture is stirred at reflux overnight. The reaction mixture is cooled to room temperature, the solvent is evaporated, and the residue is partitioned between CH2Cl2 and 2N HCl. After separating the layers, the aqueous portion is extracted 3 times with CH2Cl2. The organic portions are pooled, dried (Na2SO), and concentrated to give the acidic product as a yellow oil (27 g, 52% yield). c. N-r2- (3-fluorophenyl) ethyll-2- (2-methyl-1,3-dioxolan-2-yl) butanamide To a cold (0 ° C) solution of 2- (2-methyl-1, 3) acid -dioxolan-2-yl) butanoic acid (32.89 g, 0.19 mol) in CH2Cl2 (30 ml) is added oxalyl chloride (60.0 ml) dropwise. After 15 minutes at 0 ° C, the mixture is allowed to stir at room temperature for 2 hours. The excess oxalyl chloride and solvent is removed to give an oil, which is taken up in fresh CH 2 Cl 2 and cooled to 0 ° C. A solution of pyridine (20 ml) of [2- (3-fluorophenyl) ethyl] amine (44 ml, 0.34 mol) is added dropwise, and the resulting solution is allowed to warm to room temperature while stirring overnight. The reaction mixture is partitioned between CH 2 Cl 2 and 1 N HCl. After separating the layers, the organic portion is washed with water and aqueous NaHC 3. The aqueous portion is pooled, dried (Na2SO) and concentrated in vacuo to give the crude amide product (35.0 g) which is used in the next reaction without further purification. d. 2-Ethyl-N-'2- (3-fluorophenyl) etp-3-oxobutanamide To a solution of N- [2- (3-fluorophenyl) ethyl] -2- (2-methyl-1,3-dioxolan -2-yl) butanamide (35.0 g, 0.12 mol) in acetone and water (250 ml / 5 ml) is added p-toluenesulfonic acid (36.1 g, 0.19 mol). This mixture is stirred and heated at 95 ° C for 4 hours. After cooling to room temperature, the solvent is removed and the residue is partitioned between CH 2 Cl 2 and aqueous Na 2 C 3. After separating the layers, the aqueous layer is extracted twice with fresh CH2CI2, and the combined organic portions are dried (Na2SO4), filtered and concentrated to provide a white solid. The solid is triturated with hexanes / diethyl ether 1: 1 to give 24.5 g (85%). and. 5-Ethyl-2- (2-fluoro-3-hydroxyphenyl) -3-r2- (3-fluorophenyl) ethyl-6-methyl-4 (3H) -pyrimidinone The title compound is prepared by the general procedure described briefly in example 1 and by substituting 2-ethyl-N- [2- (3-fluorophenyl) ethyl] -3-oxobutanamide for 2-acetyl-4-methyl-N- (2-phenylethyl) pentamide in step 1d: MS (m / z): 371.2 [M + H] +.

EXAMPLE 10 Preparation of 5-ethyl-3-r2- (3-fluorophenyl) -etin-6-methyl-2- (1 H -pyrrol-2-yl-4 (3H) -pyrimidinone Ethyl-N- [2- (3-fluorophenyl) ethyl] -3-oxobutanamide (0.5 g, 2.14 mmol) of example 9d is taken up in titanium isopropoxide (2.78 mmol, 8.5 ml). To this is added 1 H-pyrrolo-2-carboxamide (0.35 g, 3.21 mmol) and the reaction is refluxed for 48 hours. During completion, the reaction is diluted with dichloromethane and washed with 3N HCl. The organic layer is separated and dried over Na2SO4, filtered, concentrated and purified by chromatography on silica gel (Biotage, 0-50% ethyl acetate / hexane) to yield the title compound (0.42 g). with a yield of 42%. MS (m / z): 326.2 [M + H] +.

EXAMPLE 11 Preparation of 5-bromo-3-f3-fluoro-2-r (phenylmethyl) oxylphenol) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone rf 3 f) < ? «? or 2 liMl? x¡l > ei] z.? iM? l.? f (-IHilil.illl ill? £ *: A, efi ?, 0 T «/ PrO)«. Reflux to. 3-Fluoro-2-hydroxybenzoate methyl The hydroxy acid (10 g, 0.064 mol) is taken in anhydrous methanol (215 ml). A catalytic amount of sulfuric acid is added thereto and the reaction is heated to reflux for 16 hours. The reaction is concentrated and the crude product is taken in the next step without purification. b. 3-Fluoro-2-hydroxybenzamide The methyl ester is placed in a reaction vessel under pressure. To this 2N ammonia in methanol (125 ml) is added and the reaction is heated at 110 ° C for 16 hours. The reaction is concentrated and taken up in dichloromethane. The undissolved material is filtered. The reaction is concentrated and dissolved in a large amount of methanol and decolorized. The methanol solution is partially concentrated during which the crystalline solid (pale brown) is broken. The solid is filtered and used in the next stage. c. 3-Oxo-N- (2-phenylethyl) butanamide Dice-tene (10.0 g, 0.12 mole) is taken in anhydrous ether (240 ml). To this is added phenethylamine (14.93 ml, 0.12 mol) dropwise via a dropping funnel. Upon completion of the amine addition the reaction is heated to reflux for 3 hours. The crude mixture is taken in a separatory funnel, and washed with 5% HCl and the organic layer is separated, dried over sodium sulfate and concentrated to give 22.78 grams in 93% yield. d, 2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone 3-Oxo-N- (2-phenylethyl) butanamide (10 g , 0.049 moles) is placed in a 500 ml round bottom flask. To this is added titanium isopropoxide (214 ml, 0.73 mol). Although the reaction is stirred, 3-fluoro-2-hydroxybenzamide (11.42 g, 0.098 mol) is added, a condenser is placed and the The reaction is heated to reflux (oil bath temperature = 150 ° C). The 2-hydroxy-3-fluorobenzamide dissolves slowly and provides a homogeneous brown solution for some time at elevated temperatures. The reaction is run for 36 hours and cooled to room temperature and diluted with dichloromethane. 3N HCl is added slowly until all the solid that was initially formed has dissolved. The organic layer is separated and the aqueous layer is further extracted with dichloromethane. The combined organic layer is dried over sodium sulfate and filtered and concentrated. The crude reaction mixture is taken up in EtOAc and hexanes are added to break the product. The solid (6.79 g, 43%) is filtered and taken in the next step without purification. and. 2-. { 3-Fluoro-2-((phenylmethyl) oxylphenyl > -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone ( 6.0 g, 0.019 mol) is dissolved in dry DMF (92 ml). To this is added potassium carbonate (3.83 g, 0.028 moles) and benzyl bromide (2.64 ml, 0.028 moles) consecutively. The reaction is heated to 60 ° C and stirred for 16 hours. The reaction mixture is cooled to room temperature, filtered and diluted with EtOAc. This is washed successively with 5% HCl and saturated sodium chloride solution. The organic layer is dried over sodium sulfate and concentrated to give the product (7.12 g) in 93% yield.

F. 5-Bromo-2- (3-fluoro-2-r (phenylmethyl) oxylphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone 2-. { 3-fluoro-2 - [(phenylmethyl) oxy] phenyl} -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone (6.0 g, 0.0145 moles) is taken in glacial acetic acid (100 ml). To this is added bromine (0.74 ml, 0.0145 moles) dropwise by means of a syringe. The reaction is stirred for 16 hours. Ethyl acetate and acetic acid are added and washed with saturated sodium bicarbonate. The organic layer is further washed with saturated sodium sulfite / sodium metabisulfite solution and dried over sodium sulfate. Sodium sulfate is filtered and the organic layer is concentrated. The crude product is purified by chromatography on silica gel (Biotage) using ethyl acetate and hexane mixtures (10-50%) to obtain the desired product (7.06 g) in 98% yield. MS (m / z): 495.2 [M + H] +.

EXAMPLE 12 Preparation of 5-bromo-2- (3-f1uoro-2-hydroxyphenyl) -β-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone to. 3-Fluoro-2- (methyloxy) benzamide To a solution of 2-hydroxy-3-fluorobenzoic acid (30.0 g, 0.19 mol) in dry DMF (320 ml) is added K2CO3 (66.4 g, 0.48 mol) and iodomethane (30.0 g). ml, 0.48 mol) consecutively. The reaction is heated to 60 ° C and stirred for 16 hours. During cooling, the reaction mixture is diluted with EtOAc and washed with 1 N HCl, 5% NaHCO3 and brine. The organic layer is dried over Na2SO, filtered and concentrated. The resulting methyl ester is placed in a reaction vessel. To this is added 2N NH3 in methanol and the reaction is heated at 110 ° C for 16 hours. During cooling, the reaction mixture is filtered and concentrated to give the desired amide (26.3 g) with an overall yield of 81%. b. 3-Oxo-2-phenyl-N-r2- (2-thienyl) ethyllbutanamide To a solution of ethyl 3-oxo-2-phenylbutanoate (5.0 g, 0.024 mol) in DME (21 ml) is added [2- ( 2-thienyl) ethyl] amine (0.057 ml, 0.45 mmol) in a microwave reaction vessel. A few drops of ethanol are added to the reaction mixture which is irradiated at 180 ° C for 800 seconds. The reaction mixture is diluted with EtOAc and washed with 1 N HCl. The organic layer is separated and dried over Na2SO. It is filtered, concentrated and purified by means of chromatography on silica gel (Biotage 0-40% ethyl acetate / hexane) to yield the pure amide (3.42 g) with a yield of 49%. c. 5-Bromo-2-r3-fluoro-2- (methyloxy) phenyl-6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone The title compound is prepared by the general procedure briefly described in Example 1 by substituting 3-fluoro-2-methoxybenzamide for 3-fluoro-2-hydroxybenzamide in step 1d. d. 5-Bromo-2- (3-bromo-2-hydroxyphenyl-6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone 5-Bromo-2- [3-fluoro-2- (methyloxy) phenyl) ] -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone (0.065 g, 0.16 mmol) in 2 ml of dichloromethane is cooled to 0 ° C. 1M DCM solution of BBr3 (0.8 ml, 0.78 mmol) is then added and the reaction mixture is warmed to room temperature and stirred for 16 hours. hours. The reaction mixture is diluted with dichloromethane and aqueous NaHCO3 is then added. The organic layer is separated and washed with H 2 O, brine and dried over Na 2 SO 4, filtered, concentrated and purified by chromatography on silica gel (Biotage, 0-60% ethyl acetate / hexane) produce the pure compound (0.022 g) with a yield of 35%. MS (m / z): 405.0 [M + H] +.

EXAMPLE 13 Preparation of 2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- (6-quinolinyl) -4 (3H) -pyrimidinone To a solution of 5-bromo-2- [3-fluoro-2 - [(phenylmethyl) oxy] phenyl} -5-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone (0.20 g, 0.4 mmol) in dioxane (3 ml) is added 6-quinolinylboronic acid (0.14 g, 0.8 mmol) dissolved in mixture of solvents of 0.5 ml of ethanol and 0.5 ml of dioxane, and 0.5 ml of aqueous sodium carbonate (0.09 g, 0.8 mmol) in a microwave reaction vessel and irradiated at 150 ° C for 2400 seconds. The reaction mixture is filtered through a syringe filter (Acrodisc CR25mm with PTFE membrane 0.2 Dm). The filtrate is diluted with EtOAc and washed with brine, separated, Dry over sodium sulfate, filter, concentrate in vacuo and purify the residue by chromatography on silica gel (Biotage, 0-60% ethyl acetate / hexane) to yield the desired compound (0.12 g) with a 66% yield. MS (m / z): 452.4 [M + H] +.

EXAMPLE 14 Preparation of 2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- (1, 2.3.4-tetrahydro-6-quinolinyl) -4 (3H) -pyrimidinone To a solution of 2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- (6-quinolinyl) -4 (3H) -pyrimidinone of Example 13 found (0.33 g, 0.073 mmol) in ethanol is added 10% Pd / C (0.01 g). This mixture is placed under a hydrogen atmosphere and stirred for 12 hours. The reaction mixture is filtered through a pad of celite and concentrated and purified by chromatography on silica gel (Biotage, 0-60% ethyl acetate / hexane) to yield the desired product (0.020 g) with a yield of 60%.

MS (m / z): 456.2 [M + H] +.

EXAMPLE 15 Preparation of 2- (3-fluoro-2-hydroxyphenyl) -6-methyl-5- (1-methyl-1.2.3.4-tetrahydro-6-quinolinyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone To a solution of example 14 (0.02 g, 0.044 mol) in methanol, formaldehyde (0.018 ml, 0.66 mmol) and NaCNBH3 (8.15 mg, 0.13 mmol) were added consecutively. The reaction is stirred for 48 hours at room temperature. The reaction mixture is concentrated and diluted with dichloromethane and washed with water and brine. The organic layer is separated, dried over sodium sulfate, filtered and concentrated. The residue is purified by reverse phase HPLC to produce the desired product (7 mg) in 34% yield. MS (m / z): 470.2 [M + H] +.

EXAMPLE 16 Preparation of 2- (3-fluoro-2-hydroxyphenyl) -5- (2-furanyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone to. 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- (2-thienyl) -4 (3H) -pyrimidinone To a solution containing 5-bromo-2-. { 3-fluoro-2 - [(phenylmethyl) oxy] phenyl} -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone (1.0 g, 2.02 mol) of example 11 in deoxygenated dioxane is added Pd (tBu3P) 2 (0.10 g, 0.20 mol), cesium fluoride (0.67 g, 4.5 mol) and tributyl (2-furanyl) stannane (0.6 ml, 2.22 mol) are added consecutively. The reaction is heated at 90 ° C for 16 hours and concentrated. The crude residue is diluted with dichloromethane and washed with saturated aqueous potassium fluoride, water and brine. The organic layer is separated, dried over Na 2 SO 4, filtered and concentrated. The crude material is purified by chromatography on silica gel (Biotage, 0-50% ethyl acetate / hexane) to yield the desired product (0.81 g) with a 81% yield. b. 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- (2-thienyl) -4 (3H) -primidinone 2- (3-Fluoro-2-hydroxyphenyl) - 6-Methyl-3- (2-phenylethyl) -5- (2-thienyl) -4 (3H) -primidinone (0.81 g, 1.63 mol) is placed in a round bottom flask equipped with a stir bar and a condenser . To this is added HBr in acetic acid (10 ml), water (1.0 ml) and stirred for 5 hours. The reaction is quenched with saturated NaHCO 3 and extracted with dichloromethane. The combined organic layers are dried over Na 2 SO 4, filtered and concentrated. The crude residue is purified by chromatography on silica gel (Biotage, 0-50% ethyl acetate / hexane) to yield the desired product (0.61 g) with a yield of 91%. MS (m / z): 391.2 [M + H] +.

EXAMPLE 17 Preparation of 2- (3-f1uoro-2-hydroxyphenyl) -6-methyl-5-phenyl-3-r2- (2-thienyl) etn-4 (3H) -pyrimidinone to. 3-Oxo-phenyl-N-r2- (2-thienyl) ethyllbutanamide To a solution of ethyl 3-oxo-2-phenylbutanoate (5 g, 0.24 mol) in DME (21 ml) is added 2- (2- thienyl) ethylamine (2.92 g, 0.023 mol) in a microwave reaction vessel. Add a few drops of ethanol to the reaction mixture and irradiate at 180 ° C for 1200 seconds. The reaction mixture is diluted with EtOAc and washed with 1 N HCl. The organic layer is separated and dried over Na2SO. It is filtered, concentrated and purified by chromatography on silica gel to produce pure amide (3.42 g) in 49% yield. b. Trifluoromethanesulfonate of (1Z) -1-methyl-3-oxo-phenyl-3-. { [2- (2-thienyl) ethyl-amino) -1-propen-1-yl To a solution of 3-oxo-2-phenyl-N- [2- (2-thienyl) ethyl] butanamide (3.42 g, 0.012 mol) in dry dichloromethane (50 ml) is cooled to -78 ° C. To this is added trifluoromethanesulfonic anhydride (2.2 ml, 0.013 mol) and triethyl amine (2.49 ml, 0.018 mol) consecutively and stir while heating the reaction at 0 ° C. The reaction is concentrated and purified by chromatography on silica gel (Biotage, 0-40% ethyl acetate / hexane) to produce triflate (3.55 g) in 71% yield. c. 3-Fluoro-N - ((1Z) -1-methyl-3-oxo-2-phenyl-3- (r2- (2-thienyl) ethylamino) -1-propen-1-yl) -2- (methyloxy) benzamide To a solution of (1Z) -1-methyl-3-oxo-2-phenyl-3-trifluoromethanesulfonate. { [2- (2-thienyl) ethyl] amino} -1-propen-1-yl in dry deoxygenated dioxane is added 3-fluoro-2-methoxybenzamide (0.48 g, 2.82 mmol), cesium carbonate (1.19 g, 3.67 mol), Pd2 (dba) 3 (0.06 g, 0.065) mmol) and xanthophos (0.113 g, 0.2 mmol). The reaction is heated to reflux for 16 hours. The cooled reaction mixture is filtered through a pad of celite and concentrated. The purification is purified by chromatography on silica gel (Biotage) to provide enamide with a 62% yield. d. 2-f3-Fluoro-2- (methyloxy) phenyl-6-methyl-5-phenyl-3-r2- (2-thienyl) ethyl-4 (3H) -pyrimidinone 3-Fluoro-N - ((1Z) -1 -methyl-3-oxo-2-phenyl-3 { [2- (2-thienyl) ethyl] amino.} -1-propen-1-yl) -2- (methyloxy) benzamide (0.74 g, 1.69 mol) is dissolved in ethanol (10 ml). To this is added 10 ml of 25% aqueous potassium hydroxide (w / v) and refluxed for 16 hours. The crude reaction mixture is acidified with 6N HCl to pH ~ 1 and extracted with dichloromethane. The combined organic layers are washed with brine and concentrated. The crude residue is purified by chromatography on silica gel (Biotage) to provide the desired product (0.33 g) with a yield of 46%. and. 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-5-phenyl-3-f2- (2-thienyl) etn-4 (3H) -pyrimidinone 2- [3-Fluoro-2- (methyloxy ) phenyl] -6-methyl-5-phenyl-3- [2- (2-thienyl) ethyl] -4 (3H) -pyrimidinone (0.33 g, 0.81 mmol) in 3 ml of dichloromethane is cooled to 0 ° C. BBr 3 in dichloromethane (1.62 ml) is then added and the reaction mixture is warmed to room temperature. At the termination the reaction mixture is diluted with dichloromethane and aqueous NaHCO3 then added. The organic layer is separated and washed with H2O, brine and dried over Na2SO4. After filtration the reaction mixture is concentrated and purified by chromatography on silica gel (Biotage, 0-60% ethyl acetate / hexane) to yield the pure compound (0.186 g) in 46% yield.

MS (m / z): 407.2 [M + H] +.

EXAMPLE 18 Preparation of 2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- (1-pyrrolidinyl) -4 (3H) -pyrimidinone to. 2-r3-Fluoro-2- (methyloxy) pheny1-5-iodo-6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone 2- [3-fluoro-2- (methyloxy ) phenyl] -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone (4.78 g, 0.014 mol) of example 12c is taken in glacial acetic acid (283 ml). To this is added 1 M dichloromethane solution of iodine monochloride (71 ml, 0.071 mmol) and the reaction is stirred for 16 hours. Ethyl acetate is added and acetic acid is washed with saturated sodium carbonate. The organic layer is dried over sodium sulfate. Sodium sulfate is filtered and the organic layer is concentrated. The crude product is purified by chromatography on silica gel (Biotage) using ethyl acetate and hexane mixtures (20-50%) to obtain the desired product (2.1 g) in 32% yield. b. 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- (1-pyrrolidinyl) -4 (3H) -pyrimidinone To a solution of 2- [3-Fluoro] -2- (methyloxy) phenyl] -5-iodo-6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone (0.3 g, 0.65 mol) in deoxygenated toluene (3.2 ml) is added xanthophos (0.06) g, 0.096 mmol), Pd2 (dba) 3 (0.59 g, 0.032 mmol) and NaOtBu (0.09 g, 0.91 mmol) in a microwave container. The reaction is stirred for 5 minutes and pyrrolidine (0.064 ml, 0.08 mmol) is added, the reaction vessel is capped and irradiated on a Smith synthesizer at 150 ° C for 1000 seconds. The reaction mixture is concentrated and purified by chromatography on silica gel (Biotage) using EtOAc and hexane mixtures (5-30%) to obtain the desired product (0.32 g) containing small amount of impurity. The subsequent deprotection is carried out using BBr3 as described in example 1e yields the title compound: MS (m / z): 394.4 [M + H] +.

EXAMPLE 19 Preparation of 5- (5-chloro-2-thienyl) -2- (3-f1uoro-2-hydroxy-phenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone to. 5- (5-Chloro-2-thienyl) -2- (3-fluoro-2 -, (phenylmethyl) oxylphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone To a solution of 5-bromo-2-. { 3-fluoro-2 - [(phenylmethyl) oxy] phenyl} -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone (0.5 g, 1.01 mmol) 11 in deoxygenated dioxane is added 2-chloro-5-bromothiophene (0.2 g, 1.01 mmol), tetrakistriphenylphosphine (0.18) g, 0.1 mmol) and hexamethylditine (0.21 ml, 1.01 mmol). The reaction is refluxed for 48 hours and concentrated. The crude residue is purified by chromatography on silica gel (Biotage) using ethyl acetate and hexane mixtures (0-60%) to obtain the desired product (0.031 g) in 6% yield. b. 5- (5-Chloro-2-thienyl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone In a flask of Round bottom equipped with a stir bar and a condenser is placed 5- (5-chloro-2-thienyl) -2-. { 3-fluoro-2- [(phenylmethyl) oxy] phenol} -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone (0.031 g, 0.06 mmol). To this is added 2 ml of 45% HBr in acetic acid and the reaction is stirred at room temperature for 3 hours. The crude residue is diluted with dichloromethane and extracted with saturated sodium carbonate and brine. The organic layer is concentrated and purified by reverse phase HPLC to give the pure product (11 mg) in 42% yield: MS (m / z): 441.2 [M + H] +.

EXAMPLE 20 Preparation of 5-bromo-6-methyl-3- (2-phenylethyl) -2-. { 2-f (phenylmethyl) oxy] phenyl > - 4 (3H) -pyrimidinone The title compound is prepared following the methods described for example 11 except that 2-hydroxybenzamide is replaced by 3-fluoro-2-hydroxybenzamide in step 1d: MS (m / z): 477.2 [M + H] +.

EXAMPLE 21 Preparation of 2- (2-hydroxyphenyl) -3- (2-phenylethyl-6- (1-piperidinylmethyl PH) -pyrimidinone a, 6-Methyl-3- (2-phenylethyl) -2- (2-r (phenylmethyl) oxy-phenyl) -4 (3H) -pyrimidinone 6-Methyl-3- (2-phenylethyl) -2-. { 2 - [(phenylmethyl) oxy] phenyl} -4 (3H) -pyrimidinone is prepared according to the procedures described in Example 11d except that 3-fluoro-2-hydroxybenzamide is replaced with 2-hydroxybenzamide. b. 5-Iodo-6-methyl-3- (2-phenylethyl) -2- (2-f (phenylmethyl) oxylphenyl) -4 (3H) -pyrimidinone Methyl-3- (2-phenylethyl) -2-. { 2 - [(phenylmethyl) oxy] phenyl} -4 (3H) -pyrimidinone (4.23 g, 10.7 mmol) is taken in glacial acetic acid (107 ml). To this is added 1 M dichloromethane solution of iodine monochloride (31 ml, 32.1 mmol) and the reaction is stirred for 16 hours. Ethyl acetate is added and acetic acid is washed with saturated sodium carbonate. The organic layer is dried over sodium sulfate. Sodium sulfate is filtered and the organic layer is concentrated. The crude product is purified by chromatography on silica gel (Biotage) using ethyl acetate and hexane mixtures (20-50%) to obtain the desired product (2.5 g) in 45% yield. c. 3- (2-phenylethyl) -2- (2-f (phenylethyl) oxy1phenyl) -6- (1-piperidinylmethyl) -4 (3H) -pyrimidinone To a solution of 5-iodo-6- methyl-3- (2-phenylethyl) -2-. { 2 - [(phenylmethyl) oxy] phenyl} -4 (3H) -pyrimidinone (0.1 g, 0.19 mmol) in 3 ml of piperidine is added 1-ethyl-3-methylimidazolium hexafluorophosphate. The reaction is irradiated on a Smith synthesizer at 200 ° C for 1200 seconds. The reaction mixture is concentrated and purified by chromatography on silica gel (Biotage) using ethyl acetate and mixtures of hexane (0-50%) followed by MeOH and dichloromethane (0-10%) to obtain the desired product (0.07 g) with 77% yield. d. 2- (2-Hydroxyphenyl) -3- (2-phenylethyl) -6- (1-piperidinylmethyl) -4 (3H) -pyrimidinone To a solution of 3- (2-phenylethyl) -2-. { 2 - [(phenylmethyl) oxy] phenyl} -6- (1-piperidinylmethyl) -4 (3H) -pyrimidinone (0.12 g, 0.25 mmol) in ethanol (2 ml) is add Pd / C 10% (0.03 g). This mixture is placed under a hydrogen atmosphere and stirred for 12 hours. The reaction mixture is filtered through a pad of celite and concentrated and purified by chromatography on silica gel (Biotage) using (0-50%) ethyl acetate and hexane mixtures (0-50%) followed by MeOH (0-10%) and dichloromethane to obtain the desired product (0.7 g) with a yield of 69%. MS (m / z): 390.4 [M + H] +.

EXAMPLE 22 Preparation of 2- (2-hydroxyphenyl) -6-. { [methyl (2-methylpropyl) amino] methyl] -3- (2-phenylmethyl) -4 (3H) -pyrimidinone The title compound is prepared by substituting methyl (2-methylpropyl) amine for piperidine from Example 21: MS (m / z): 392.4 [M + H] +.

EXAMPLE 23 Preparation of 2- (2-hydroxyphenyl) -6-methyl-5 - [(1-methylethyl) oxy] -3- (2-phenylethyl) -4 (3H) -pyrimidinone To a solution of 5-iodo-6-methyl-3- (2-phenylethyl) -2-. { 2 - [(phenylmethyl) oxy] phenyl} -4 (3H) -pyrimidinone (0.13 g, 0.25 mmol) of Examples 21 in 3 mL of toluene is added copper iodide (0.16 g, 0.50 mmol). The reaction mixture is stirred for 5 minutes and isopropyl alcohol is added and heated at reflux for 16 hours. The reaction is concentrated and purified by chromatography on silica gel (Biotage) using ethyl acetate and hexane mixtures (0-30%) to obtain the desired product (0.094 g) in 84% yield. Catalytic hydrogenolysis as previously described provides the title compound: MS (m / z): 365 [M + H] +.

EXAMPLE 24 Preparation of 5- (2-furanyl) -2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone to. 5- (2-Furanyl) -6-methyl-2- [2- (methyloxy) phenin-3- (2-phenylethyl) -4 (3H) -pyrimidinone To a solution containing 5-chloro-6-methyl-2 - [2- (Methyloxy) phenyl] -3- (2-phenylethyl) -4 (3H) -pyrimidinone (0.06 g, 0.000176 mol) in deoxygenated dioxane is added Pd (tBu3P) 2 (5.3 mg, 0.01 mmol), fluoride of cesium (0.06 g, 0.00039 mol) and tributyl (2-furanyl) stannane (0.06 ml, 0.000176 mol) is added consecutively. The reaction is heated at 90 ° C for 16 hours and concentrated. The crude residue is diluted with dichloromethane and washed with saturated aqueous potassium fluoride, water and brine. The organic layer is separated, dried over Na 2 SO 4, filtered and concentrated. The crude material is purified by chromatography on silica gel (0-50% ethyl acetate / hexane) to yield the desired product (6.6 mg) in 10% yield. MS (m / z): 373.4 [M + H] +.

EXAMPLE 25 Preparation of 2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- (2-thienyl) ^ (3H) -pyrimidinone to. 6-Methyl-2-r2- (methyloxy) phenyl-3- (2-phenylethyl) -5- (2-thienyl) -4 (3H) -pyrimidinone To a solution containing 5-chloro-6-methyl-2- [2- (methyloxy) phenyl] -3- (2-phenylethyl) -4 (3H) -pyrimidinone (0.32 g, 0.000903 mol) from example 26 in deoxygenated dioxane is added Pd (tBu3P) 2 (0.028 mg, 0.054 mmol) , cesium fluoride (0.30 g, 0.00198 mol) and tributyl (2-furanyl) stannane (0.32 ml, 0.00099 mol) is added consecutively. The reaction is heated at 90 ° C for 16 hours and concentrated. The crude residue is diluted with dichloromethane and washed with saturated aqueous potassium fluoride, water and brine. The organic layer is separated, dried over Na 2 SO 4, filtered and concentrated. The crude material is purified by chromatography on silica gel (0-50% ethyl acetate / hexane) to yield the desired product (0.2 g) in 54% yield.

MS (m / z): 403 [M + H] +. 2- (2-Hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- (2-thienyl) -4 (3H) -pyrimidinone In a 5 ml microwave container is charged with 6-methyl-2 - [2- (methyloxy) phenyl] -3- (2-phenylethyl) -5- (2-thienyl) -4 (3H) -pyrimidinone (0.1 g, 0.25 mmol), 1.0 ml of AcOH and 2 ml of HBr. The reaction mixture is sealed and irradiated on a Smith synthesizer at 150 ° C for 600 seconds. The reaction mixture is diluted with dichloromethane and washed with NaHCO 3, brine and dried over Na 2 SO 4. Sodium sulfate is filtered and concentrated. The crude product is purified by flash column chromatography (0-50% ethyl acetate / hexane) to yield the product (0.27 g) in 28% yield. MS (m / z): 389.2 [M + H] +.

EXAMPLE 26 Preparation of 2- (2-hydroxyphenyl) -6-methyl-5- (4-morpholinyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone to. 2- (Methyloxy) benzenecarboximidamide To anhydrous ether at 0 ° C is introduced into a flask under argon, LiHMDS (94 ml, 93.9 mmol) is introduced and stirred for 5 minutes. 2-Methoxy-benzonitrile (5g, 37.6 mmol) is then added and the mixture is stirred at room temperature for 3 days. When all the starting material is consumed, the reaction mixture is concentrated and 200 ml of cold 1N HCl is added and stirred for 0.5 hours. The aqueous layer is extracted with diethyl ether and then the pH of the aqueous layer is adjusted to 13 with the addition of 6N NaOH. The 2- (methoxy) benzenecarboximidamide free base is extracted with dichloromethane (X 3). The combined organic layers are dried over Na2SO4 and concentrated to give the pure product in 91% yield. b. 5-Chloro-6-methyl-2- [2- (methyloxy) phenyl-4 (1 H) -pyrimidinone To a solution of 2- (methyloxy) benzenecarboximidamide (4.76 g, 0.032 mol) in 150 ml of solvent mixture of MeOH (Dioxane (1/5) NaOMe (2.56 g) is added and the mixture is stirred for 15 minutes, ethyl 2-chloro-3-oxobutanoate (7.82 g, 0.048 mol) is introduced and the reaction mixture is heated to reflux for 16 hours During the termination the reaction mixture is concentrated, diluted with dichloromethane and dilute HCl is added.The dichloromethane layer is separated and washed with brine, dried over Na2SO4, and in the filtration and concentration, the crude product is dried. purify by flash column chromatography (30% ethyl acetate / hexane) to give the product (3.09 g) in 39% yield. c, 5-Chloro-6-methyl-2-y2- (methyloxy) phenyl1-3- (2-phenylethyl) -4 (3H) -pyrimidinone To a solution of 5-chloro-6-methyl-2- [ 2- (methyloxy) phenyl] -4 (1 H) -pyrimidinone (3.2 g, 0.013 mol) in dry DMF is added LiH (0.122 g, 0.015 mol) and stirred for 10 minutes at room temperature. Then (2-bromoethyl) benzene is added and stirred overnight. The reaction mixture is quenched by the addition of ice and 6N HCl. This mixture is extracted with EtOAc and the organic layer is washed with aqueous NaHCO3, brine and dried over Na2SO4. The sodium sulfate is filtered and concentrated. The crude product is purified by flash column chromatography (30% ethyl acetate / hexane) to give the product (2.13 g) in 47% yield. d. 2- (2-Hydroxyphenyl) -6-methyl-5- (4-morpholinyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone To a solution of 5-chloro-6-methyl-2- [2- (Methyloxy) phenyl] -3- (2-phenylethyl) -4 (3H) -pyrimidinone (0.07 g, 0.2 mmol) in 3 ml of dioxane is added Pd2 (dba) 3 (0.009 mg, 0.001 mmol), dicyclohexylphosphino-2 '(N, N-dimethylaminobiphenyl) (0.008 g, 0.02 mmol), NaOtBu (0.26 g, 0.27 mmol) and morpholine (0.024 ml). The reaction mixture is irradiated at 180 ° C for 2400 seconds. The reaction is concentrated and diluted with dichloromethane and washed with 5% HCl and brine. The reaction mixture is dried over sodium sulfate, filtered, concentrated and purified by means of flash column chromatography MeOH / dichloromethane (0-5%) to obtain the product desired (0.20 g) with 37% yield. The resulting product is deprotected as described in Example 1e to give the title compound: MS (m / z): 392.4 [M + H] +.

EXAMPLE 27 Preparation of 5-ethyl-2- (3-f1uoro-2-hydroxyphenyl) -3-r2- (3-fluorophenyl) etl-6- (1-piperidinyl) -4 (3H) -pyrimidinone A 3 a T to. 2-chloro-6-fluorophenyl phenylmethyl ether 2-chloro-6-fluoro-phenol (2.0 g, 13.6 mmol) is dissolved in DMF 68 ml. To this solution is added Cs 2 CO 3 (6.67 g, 20.5 mmol) and benzyl bromide (1.78 ml, 15 mmol) consecutively and stirred for 12 hours. The The reaction mixture is diluted with EtOAc and washed with brine (3 x 100 ml). The organic layer is dried over Na 2 SO 4, filtered and concentrated to give 2.97 g of product in 92% yield. b. 3-Fluoro-2-f (phenylmethyl) oxy-1-benzonitrile To the solution of 1-benzyloxy-2-chloro-6-fluoro-benzene (200 mg, 0.42 mmol) in 8 ml of dry DMF is added Zn (CN) 2 (110 mg, 0.93 mmol) and Pd (t-Bu3P) 2 (86 mg, 0.08 mmol) and the mixture is placed in a microwave reactor (150 ° C, 20 minutes). The reaction mixture is diluted with EtOAc and washed with brine. The organic layer is dried over Na2SO, filtered and concentrated. The crude product is purified by flash column chromatography (0 to 20% EtOAc / hexane) to yield the desired product (0.8 g) in 83% yield. a 3-Fluoro-N-r2- (3-fluorophenyl) etn-2-r (phenylmethyl) oxy! benzenecarboximidamide A round bottom flask is charged with [2- (3-fluorophenyl) ethyl] amine ( O.Odg, 0.59 mmol) and 5 ml of toluene and cooled to 0 ° C. Me3AI (2.0 M in hexane, 0.88 ml, 0.18 mmol) is added dropwise over 30 minutes and the resulting mixture is stirred at 0 ° C for 0.5 hour and heated at room temperature for 4 hours. Then 3-fluoro-2 - [(phenylmethyl) oxy] benzonitrile (200 mg, 0.88 mmol) is added portionwise at room temperature and heated at 80 ° C under argon overnight. After cooling to room temperature, the mixture is slowly poured into a suspension of silica gel in CHCl3 and stirred for 30 minutes. The mixture is filtered and rinsed with 20% MeOH in chloroform (x 3). The filtrate is concentrated and purified by flash column chromatography (50% EtOAc / hexane to 10% MeOH / dichloromethane and 0.1% NH3) to yield the desired product (0.054 mg) in 25% yield. d. 5-Ethyl-3-f2- (3-fluorophenyl) ethyn-2- (3-fluoro-2-r (phenylmethyl) oxy-phenyl) -6-hydroxy-4 (3H) -pyrimidinone To a cold solution (-78) ° C) of 3-Fluoro-N- [2- (3-fluorophenyl) ethyl] -2- [(phenylmethyl) oxy] benzenecarboximidamide in THF (0.28 g, 0.00077 mol) is added NaHMDSA (0.768 ml, 0.00077 mol) and Stir for 10 minutes. Ethyl malonyl chloride (0.143 ml, 0.00084 mol) is added dropwise via a cannula. After stirring overnight while heating to room temperature, the reaction mixture is diluted with EtOAc and washed with brine. The organic layer is separated, dried and concentrated. The crude product is purified by flash column chromatography (30% EtOAc / hexane) to yield the desired product (0.12 g) in 42% yield. and. 5-Ethyl-1- [2- (3-fluorophenyl) etyl-6-oxo-2- trifluoromethanesulfonate. { 2 - [(Phenylmethyl) oxyphenyl) -1,6-hydroxy-4-pyrimidinyl 5-Ethyl-3- [2- (3-fluorophenyl) ethyl] -2-. { 3-fluoro-2 - [(phenylmethyl) oxy] phenyl} -6-hydroxy-4 (3H) -pyrimidinone (0.14 g, 2.94 mmol) is taken in DCM (5 ml) and cool to -78 ° C. To this is added colidin (0.057 ml, 4.31 mmol) and the reaction is stirred for 5 minutes. At this time, trifluoromethanesulfonic anhydride (0.066 ml, 3.96 mmol) is added and the reaction is warmed to 0 ° C and stirred overnight. The reaction mixture is diluted with EtOAc and washed with H0, brine and dried (Na SO4) and concentrated. The crude product is purified by flash column chromatography (30% EtOAc / hexane) to yield the desired product (0.081 g) in 47% yield.

F. 5-Ethyl-2- (3-fluoro-2-hydroxyphenyl) -3- [2- (3-fluorophenyl) ethyl-6- (1-piperidinyl) -4 (3H) -pyrimidinone To the solution of trifluoromethanesulfonate of 5- ethyl-1- [2- (3-fluorophenyl) ethyl] -6-oxo-2-. { 2 - [(phenylmethyl) oxy] phenyl} -1,6-dihydro-4-pyrimidinyl (30 mg, 0.07 mmol) in dry dioxane is added (7.7 ul, 0.08 mmol) and CS2CO3 (31 mg, 0.1 mmol). The reaction mixture is heated at 105 ° C overnight. The reaction mixture is concentrated and purified by flash column chromatography (0 to 50% EtOAc / hexane) to yield the desired product (25.5 mg) in 74% yield. The title compound is prepared by performing deprotection using the catalytic hydrogenolysis protocol: MS (m / z): 440.4 [M + H] +.

EXAMPLE 28 Preparation of 5-ethyl-1- [2- (3-fluorophenyl) ethyl] -2-f2- (methyloxy) phenan-6-oxo-1,6-dihydro-4-pyrimidine acid -carboxylic ? dichloride «le eiil- CN propane diol THF, -78 * C NaHMDSA to. 5-Ethyl-1- [2- (3-fluorophenyl) etyl-6-oxo-2- (2 - [(phenylmethyl) oxy-phenyl) -1,6-dihydro-4-pyrimidinyl trifluoromethanesulfonate The title compound is prepare by following the general procedure briefly described in Example 27 except that 2-methoxybenzonitrile is substituted for 3-fluoro-2 - [(denylmethyl) oxy] benzonitrile in steps 27c. b. 5-Ethyl-1-f2- (3-fluorophenyl) etyl-2-y2- (methyloxy) phenyl-1-6-oxo-1,6-dihydro-4-pyrimidinecarbonitrile To the solution of trifluoromethanesulfonate of 5-ethyl-1- [ 2- (3- fluorophenyl) ethyl] -6-oxo-2-. { 2 - [(phenylmethyl) oxy] phenyl} -1,6-dihydro-4-pyrimidinyl (0.1 g, 0.20 mmol) in 2 ml of dry DMF is added Zn (CN) 2 (0.026 g, 0.22 mmol) and Pd (Ph3P) 4 (0.023 g, 0.02 mmol) and the mixture is placed in a microwave reactor (150 ° C, 2500 seconds). The reaction mixture is diluted with EtOAc and washed with brine. The organic layer is dried over Na2SO4, filtered and concentrated. The crude product is purified by flash column chromatography (0 to 20% EtOAc / hexane) to yield the desired product (0.06 g) in 83% yield. c. 5-Ethyl-1- [2- (3-fluorophenyl) etyl-2-f2- (methyloxy) phenyl-6-oxo-1 acid, 6-dihydro-4-pyrimidine-carboxylic acid To a solution of 5-ethyl-1- [2- (3-fluorophenyl) ethyl] -2- [2- (methyloxy) phenyl] -6-oxo-1, 6- Dihydro-4-pyrimidinecarbonitrile (0.29 g, 0.77 mmol) in ethylene glycol (7 ml) is added KOH (0.22 g, 3.84 mmol) and the reaction is heated at 190 ° C for 16 hours. Part of the solvent is removed under reduced pressure at elevated temperatures. The remaining reaction mixture is diluted with dichloromethane and acidified to pH ~ 5 with 1N HCl. The organic layer is separated, dried over Na2SO, filtered and concentrated. The crude product is purified by flash column chromatography using MeOH (0 to 20%) in dichloromethane (saturated with ammonia) to yield the desired product (0.15 g) in 52% yield. MS (m / z): 397.2 [M + H] +.

EXAMPLE 29 Preparation of 5-ethyl-2- (2-hydroxyphenyl) -6-methyl-3-r (E) -2-phenyletenyl-4 (3H) -pyrimidinone to. 5-Ethyl-6-methyl-2- [2- (methyloxy) phenyl-1-4 (1 H) -pyrimidinone A solution of NaOMe in methanol (58.6 ml) is added to a solution at 0 ° C of 2- (methoxy) benzenecarboxamidine (2.0 g, 0.013 mol) and ethyl 2-ethyl-3-oxobutanoate (3.16 g, 0.02 mol) in methanol (125 ml) and 1,4-dioxane (25 ml). The resulting mixture is heated to reflux overnight. The solvents are removed and the residue is diluted with H2O and pH is adjusted to 8 with acetic acid. The layers are separated and the aqueous layer is extracted with dichloromethane 3 times. The combined organic portions are dried over Na2SO and purified by flash column chromatography (0 to 100% EtOAc / hexanes) to yield a pure product. b. 5-Ethyl-6-methyl-2-r2- (methyloxy) phenyl-3-f (E) -2-phenyletenyl-4 (3H) -pyrimidinone To a solution of the intermediate 5-Ethyl-6-methyl-2 - [2- (Methyloxy) phenyl] -4 (1 H) -pyrimidinone (0.1 g, 0.41 mmol) in dry DMF (1 mL) is added KH (0.016 g, 0.41 mmol and stirred for 5 minutes. ) -2-bromoethenyl] benzene (0.053 ml, 0.41 mmol) and Cul (0.078 g, 0.41 mmol) are added to the reaction consecutively and heated at 130 ° C for 16 hours.The reaction is cooled, diluted with EtOAc and The organic layer is dried over Na 2 SO 4, filtered and concentrated The crude product is purified by flash column chromatography (0 to 20% EtOAc / hexanes) to yield the desired product (0.05 g) with 36% of performance.

-Ethyl-2- (2-hydroxyphenyl) -6-methyl-3-r (E) -2-phenyletenyl-4 (3H) -pyrimidinone Deprotection of 5-Ethyl-6-methyl-2- [2- ( methyloxy) phenyl] -3 - [(E) -2-phenylethenyl] -4 (3H) -pyrimidinone is carried out using BBr3 as detailed in example 1e to provide the title compound: MS (m / z): 333.4 [ M + H] +.

EXAMPLE 30 Preparation of 2- (3,6-difluoro-2-hydroxyphenyl) -5-ethyl-3-r2- (3-fluorophenyl) ethyn-6-methyl (3H) -pyrimidinone scheme to. (2Z) -3-amino-2-ethyl-N- [2- (3-fluorophenyl) -etin-2-butanamide A solution of 2-ethyl-N- [2- (3-fluorophenyl) ethyl] -3-oxobutanamide (3.1 g, 0.012 mol) of Example 9 in dry diethyl ether (350 mL) at 0 ° C is saturated with gaseous ammonia for 3 hours. ACI3 (2.0 g) is added, and the mixture is added to warm to room temperature while stirring overnight. The resulting suspension is filtered, and the filtrate is concentrated to provide the product as a colorless oil (2.1 g) with a yield of 68%. b. 3,6-Difluoro-2- acid. { [(methoxy) methoxy) benzoic This compound is prepared according to the procedure reported in the literature (Eur. J. Org. Chem. 2001, 15, 2911-2915). c. 3.6-Difluoro-N-r (1Z) -2 - ((f2- (3-fluorophenyl) etillamino) carbonyl) -1- 1 -methyl-buten-1 -H-2-. { [(methyloxy) methyloxy) benzamide To a solution of 3,6-difluoro-2- acid. { [(methyloxy) methyl] oxy} Benzoic acid (0.2 g, 0.91 mmol) and (2Z) -3-amino-2-ethyl-N- [2- (3-fluorophenyl) ethyl] -2-butenamide (0.22 g, 0.87 mmol) in dry THF is added EDC (0.21 g, 1.09 mmoles), HOBt (0.15 g, 1.09 mmol) and TEA (0.51 ml, 3.65 mmol) consecutively. The reaction is stirred at room temperature for 48 hours. The reaction is diluted with EtOAc and washed with dilute HCl, 5% NaHCO3 and brine. The organic layer is separated, dried over Na2SO, filtered and concentrated. The crude product is purified by flash column chromatography (30% EtOAc / hexanes) to yield the desired product 28c (0.081 g). d. 2- (3,6-difluoro-2-r ((methyloxy) methyloxy) phenyl) -5-ethyl-6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone 3,6-Difluoro-N- [ (1Z) -2- ( { [2- (3-fluorophenyl) ethyl] amino.} Carbonyl) -1-methyl-1-buten-1-yl] -2-. { [(methyloxy) methyl] oxy} Benzamide (0.39 g, 0.87 mmol) is taken up in ethanol (7 ml) and 5 ml of 25% KOH are added and the reaction is heated at reflux overnight. After the reaction is cooled to temperature environment the pH is adjusted to ~ 1 with 3N HCl and extracted with dichloromethane. The combined organic layers are dried over Na 2 SO 4, filtered and concentrated. The crude product is purified by flash column chromatography (30% EtOAc / hexanes) to yield the desired product (0.32 g) together with some impurities. and. 2- (3,6-D-fluoro-2-hydroxyphenyl) -5-ethyl-3- [2- (3-fluorophenyl) ethyl-6-methyl-4 (3H) -pyrimidinone The mixture of the product obtained from the previous step is dissolved in dry dichloromethane and to this is added TFA (2 ml) and the reaction is stirred for 3 hours. Upon completion of the reaction, it is concentrated, diluted with dichloromethane and washed with 5% NaHC03, brine and dried over Na2SO4. The crude product is purified by flash column chromatography (30% EtOAc / hexanes) to yield the desired product (0.048 g) with an overall yield of 15%. MS (m / z): 389.2 [M + H] +.

EXAMPLE 31 Preparation of 2- (3-fluoro-2-hydroxyphenyl) -6-methyl-5-propyl-3-r2- (2-thienyl) etn-4 (3H) -pyrimidinone Tr (PrO), 3-fluor or-2-hydroxy benzamide The title compound is prepared according to the general procedures briefly described in Example 1 except that allyl bromide is replaced by 3-bromo-2-methyl-1-propene in step 1a, 2-thienylenthylamine by phenethylamine in Stage 1 by 3-fluoro-2-hydroxybenzamide by 2-fluoro-3-methoxybenzamide in step 1d. MS (m / z): 373.2 [M + H] +.

EXAMPLE 32 Preparation of 2- (2-hydroxyphenyl) -5,5-dimethyl-3-r 2 - (2-thienyl) etin-5,6,7,8-tetrahydro-4 (3 H) -quinazoline The title compound is prepared according to the procedures described in Example 26 except that methyl 2,2-dimethyl-6-oxocyclohexanecarboxylate is replaced by ethyl 2-chloro-3-oxobutanoate and 2- (2-bromoethyl) thiophene by (2-bromoethyl) benzene: 1 H NMR (400 MHz, CHCl 3 -d) d ppm 1.42-1.46 (m, 6 H), 1.66 -1.72 (m, 2 H), 1.82-1.90 (m, 2 H), 2.75 (t, J = 6.06 Hz, 2 H), 3.15 (t, J = 7.07 Hz, 2 H), 4.18 - 4.25 (m, 2H), 6.54 (d, J = 3.28 Hz, 1 H), 6.75 ( d, J = 8.34 Hz, 1 H), 6.82 - 6.92 (m, 3 H), 7.12 (d, J = 5.05 Hz, 1 H), 7.32 - 7.39 (m, 1 H).

EXAMPLE 33 Preparation of 3-r2- (2-fluorophenyl) ethyl-2- (hydroxyphenyl) -5,5-dimethyl-5,6,7,8-tetrahydro-4 (3H) -quinazoline The title compound is prepared according to the procedures of Example 26 except that methyl 2,2-dimethyl-6-oxocyclohexanecarboxylate is replaced by ethyl 2-chloro-3-oxobutanoate and 2-fluorophenethylbromide by (2-bromoethyl) ) benzene: 1 H NMR (400 MHz, CHCl 3 -d) d ppm 1.25 - 1.37 (m, 2 H), 1.38 -1.47 (m, 6 H), 1.59 - 1.71 (m, 2 H), 1.77 - 1.85 (m , 2 H), 2.61 (t, J = 6.32 Hz, 2 H), 3.06 (t, J = 7.33 Hz, 2 H), 4.32 - 4.41 (m, 2 H.) 6.92 - 7.04 (m, 4 H) , 7.14 -7.24 (m, 1 H) 7.27 - 7.36 (m, 3 H).

EXAMPLE 34 Preparation of 2- (2-hydroxy-phenyl) -3- (2-phenylethyl) -3,5,6,7,8,9-hexahydro-4H-cyclohepta [d] pyrimidin-4-one The title compound is prepared according to the procedures of Example 26 except that methyl 2-oxocycloheptanecarboxylate is replaced by ethyl 2-chloro-3-oxobutanoate: MS (m / z): 361.2 [M + H] +.

EXAMPLE 35 Preparation of 2- (3-fluoro-2-hydroxyphenyl) -3- (2-phenylethyl) -5.6.7.8-tetrahydro-4 (3H) -quinazoline to. 3-Fluoro-2- (methyloxy) benzonitrile This compound is prepared by following the general procedures briefly described in Example 27 and substituting methyl iodide in place of benzyl bromide in step 1a. b. 3-Fluoro-2- (methyloxy) benzenecarboximidamide 3-fluoro-2-methoxybenzonitrile (4.9 g, 0.032 mol) is added to a solution at 0 ° C of LiHMDS (81 ml, 1 M in hexanes, 0.081 mol) in Et2O anhydride (65 ml, 0.5 M) under N2. After warming to room temperature, the mixture is stirred for three days. The resulting reaction mixture is quenched with the addition of 1 N HCl. The layers are separated and the aqueous is extracted 2 times with Et2O. The aqueous layer is cooled in an ice bath, adjusted to pH 12, and extracted 3 times with dichloromethane. The organic portions are pooled, dried over Na2SO4, and concentrated to a brown oil which solidifies to a brown solid under vacuum (5.0 g, yield 93%): check with YL. p 2- [3-Fluoro-2- (methyloxy) phenyl-5,6,7,8-tetrahydro-4 (1 H) -quinazolinone Solution 25% (w / v) of NaOMe (3.68 ml, 0.0257 mol) is add to a 0 ° C solution of 3-fluoro-2- (methyloxy) benzenecarboxisamide (1.32 g, 0.0117 mol) and methyl 2-oxocyclohexanecarboxylate (2.0 g, 0.0117 mol) in methanol (70 ml) and 1,4-dioxane (20 ml). The resulting mixture is heated to reflux overnight. The solvents are removed and the residue is taken up in ethyl acetate and 1 N HCl. The layers are separated and the aqueous layer is extra with dichloromethane 3 times. The combined organic portions are dried over Na2SO and purified by flash column chromatography to give 2.05 g of product (75% yield). d. 2-r3-Fluoro-2- (methyloxy) phenin-3- (2-phenylethyl) -5,6,7,8-tetrahydro-4 (3H) -quinazolinone LiH (0.032 g, 4.0 mmol) and LiBr (0.52, 6.0 mmol) ) is added to a solution at 0 ° C of 2- [3-fluoro-2- (methyloxy) phenyl] -5,6,7,8-tetrahydro-4 (1 H) -quinazolinone (0.55 g, 2.0 mmol) in DMF (10 ml) and stirred at 0 ° C for 30 minutes Bromoethyl benzene (1.36 ml, 10 mmol) is added and the resulting mixture is stirred at room temperature for 40 hours. The reaction is quenched by the addition of ethyl acetate (15 ml) and water (15 ml). The layers are separated and the organic portion is washed 3 times with water, dried over NaSO 4, filtered and concentrated. Flash column chromatography (30% ethyl acetate / hexanes) provides pure product. and. 2- (3-Fluoro-2-hydroxyphenyl) -3- (2-phenylethyl) -5.6.7.8-tetrahydro-4 (3H) -quinazolinone To a solution of dichloromethane at 0 ° C of the 2- [3-Fluoro- 2- (methyloxy) phenyl] -3- (2-phenylethyl) -5,6,7,8-tetrahydro-4 (3H) -quinazolinone (0.12 g, 0.32 mmol) is added BBr3 (1.6 ml, 1 M in dichloromethane ) drops. The resulting solution is allowed to warm to room temperature while stirring overnight. The reaction is quenched with the addition of Na2CO3 and dichloromethane. The layers are separated and the organic portion is dried over MgSO 4, filtered and concentrated. The crude residue is purified by flash column chromatography to give the title compound. MS (m / z): 365.2 [M + H] +.

EXAMPLE 36 Preparation of 5-cyclopentyl-2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone The title compound is prepared following the general procedure briefly described in Example 35 except that ethyl α-acetylcyclopentanoacetate for methyl 2-oxocyclohexanecarboxylate is substituted. MS (m / z): 393.2 [M + H] +.

EXAMPLE 37 Preparation of 5- (2,3-dihydro-1,4-benzodioxin-6-yl) -6-methyl-3- (2-phenylethyl) -2- (2-thienyl) -4 (3H) -pyrimidinone 150 ° C. 3000 & to. 5-Bromo-6-methyl-3- (2-phenylethyl) -2- (2-thienyl) -4 (3H) -pyrimidinone The title compound is prepared according to the procedure of example 11 except that it is substituted -thiophenecarboxamide by 3-fluoro-2-hydroxybenzamide in step 11d. b. 5- (2,3-Dihydro-1,4-benzodioxin-6-yl) -6-methyl-3- (2-phenylethyl) -2- (2-thienyl) -4 (3H) -pyrimidinone To a solution of 5-Bromo-6-methyl-3- (2-phenylethyl) -2- (2-thienyl) -4 (3H) -pyrimidinone (0.20 g, 0.53 mmol) in dioxane is added 1,4-benzodioxane-6- boronic (0.19 g, 1.06 mmol) dissolved in a solvent mixture of 0.5 ml of dioxane, and 0.5 ml of aqueous sodium carbonate (0.09 g, 0.8 mmol) in a microwave reaction vessel. To this is added Pd (PPh3) (0.12 g, 0.11 mmol) and irradiated at 150 ° C for 3000 seconds. The reaction mixture is filtered through a syringe filter (Acrodisc CR25 mm with 0.2 dm PTFE membrane). The filtrate is diluted with EtOAc and washed with brine, separated, dried over sodium sulfate, filtered, concentrated in vacuo and the residue purified by reverse phase HPLC to give the desired product. MS (m / z): 431.2 [M + H] +.

EXAMPLE 38 Preparation of 2- (2-hydroxyphenyl) -6-r (methyloxy) methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone to. 6 - [(Methyloxy) methan-2-. { 2 - [(phenylmethyl) oxylphenyl) -4 (1 H) -pyrimidinone The title compound is prepared following the general procedure briefly described in Example 35 except that 2- [(phenylmethyl) oxy] benzenecarboximidamide is substituted for 3-fluoro-2- (methyloxy) benzenecarboximidamide and 4- (methyloxy) -3-oxobutanoate of methyl by 2-oxocyclohexanecarboxylate in step 35c. b, 2- (2-Hydroxyphenyl) -6-r (methyloxy) methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone 6 - [(Methyloxy) methyl] -2-. { 2 - [(phenylmethyl) oxy] phenyl] -4 (1 H) -pyrimidinone (0.05 g, 0.11 mmol) dissolved in ethanol is added Pd / C 10% (0.01 g). This mixture is placed under a hydrogen atmosphere and stirred for 12 hours. The reaction mixture is filtered through a pad of celite and Concentrate to produce the desired product (0.021 g) with a yield of 56%. MS (m / z): 337.0 [M + H] +.

EXAMPLE 39 Preparation of 2- (2-hydroxyphenyl) -6-r (methyloxy) methyl-5- (2-methylpropyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone -Bromo-6-r (methyloxy) methyl-3- (2-phenylethyl) -2- (2- (phenylmethyl) oxylphenyl) -4- (3H) -pyrimidinone 6 - [(Methyloxy) methyl] - 3- (2-Phenylethyl) -2- {2 - [(phenylmethyl) oxy] phenyl} -4- (3H) -pyrimidinone (0.8 g, 1.9 mmol) from Example 38 is taken in glacial acetic acid.

To this bromine (0.144 ml, 2.8 mmol) is added dropwise by means of a syringe. The reaction is stirred for 16 hours. Ethyl acetate is added and acetic acid is washed with saturated sodium bicarbonate. The organic layer is further wash with saturated sodium sulfite / sodium metabisulfite solution and dry over sodium sulfate. Sodium sulfate is filtered and the organic layer is concentrated. The crude product is purified by chromatography on silica gel (Biotage) to obtain the desired product. b. 6-α (Methyloxy) methyl-5- (2-methyl-1-propen-1-yl) -3- (2-phenylethyl) -2- (2 - [(phenylmethyl) oxylphenyl) -4 (3H) -pyrimidinone To a solution of 5-bromo-6 - [(methyloxy) methyl] -3- (2-phenylethyl) -2-. { 2 - [(phenylmethyl) oxy] phenyl} -4 (3H) -pyrimidinone (0.50 g, 0.99 mmol) in dioxane was added 2,2-dimethylethylboronic acid (0.20 g, 1.98 mmol) dissolved in a mixture of 0.5 ml of ethanol and 0.5 ml of dioxane, and 0.5 ml of aqueous sodium carbonate (0.09 g, 0.8 mmol) in a microwave reaction vessel. To this is added Pd (PPh3) 4 (0.172 g, 0.15 mmol) and irradiated at 150 ° C for 1000 seconds. The reaction mixture is filtered through a syringe filter (Acrodisc CR25 mm with 0.2 dm PTFE membrane). The filtrate is diluted with EtOAc and washed with brine, separated, dried over sodium sulfate, filtered, concentrated in vacuo and the residue purified by chromatography on silica gel (Biotage) to yield the desired product. 2- (2-Hydroxyphenyl) -6-r (methyloxy) metin-5- (2-methylpropyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone To a solution of 6 - [(methyloxy) ) methyl] -5- (2-methyl-1-propen-1-yl) -3- (2-phenylethyl) -2-. { 2 - [(phenylmethyl) oxy] phenyl} -4 (3H) -pyrimidinone (0.409 g, 0.81 mmol) in acetic acid (30 ml) 10% Pd / C (0.10 g) is added. This mixture is placed under a hydrogen atmosphere (3.4 atm) for 72 hours. The reaction mixture is filtered through a pad of celite and concentrated to give the desired product. MS (m / z): 393.2 [M + H] +.

EXAMPLE 40 Preparation of 2- (3-fluoro-2-hydroxyphenyl) -6-methyl-5-f2- (methyloxy) etp-3- (2-phenylethyl) -4 (3H) -pyrimidinone to. 5-Ethenyl-2- (3-fluoro-2-r (phenylmethyl) oxy-phenyl-1-6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone To a solution of 5-bromo-2- {3-fluoro-2 - [(phenylmethyl) oxy] phenyl} -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone (1.5 g, 0.003 mol) in dioxane (10 ml) 2,4,6-trivinylcycloboraxane pyridine complex (0.88 g, 0.0036 mmol) is added dissolved in a solvent mixture of 0.5 ml of ethanol and 0.5 ml of dioxane, and 0.5 ml of aqueous sodium carbonate (0.64 g, 0.0061 mol) in a microwave reaction vessel. This mixture is irradiated at 150 ° C for 700 seconds. The reaction mixture is filtered through a syringe filter (Acrodisc CR25 mm with 0.2 dm PTFE membrane). The filtrate is diluted with EtOAc and washed with brine, separated, dried over sodium sulfate, filtered, concentrated in vacuo and the residue purified by chromatography on silica gel (Biotage, 0-60% ethyl acetate / hexane) to produce the desired product (0.86 g) with 64% yield. b. 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-5- [2- (methoxy) etn-3- (2-phenylethyl) -4 (3H) -pyrimidinone To a solution of 5- etenil-2-. { 3-Fluoro-2 - [(phenylmethyl) oxy] phenyl] -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone (0.19 g, 0.45 mmol) in dry THF is added 0.5M solution of 9 -BBN (1.07 ml, 0.54 mmol) and the reaction is refluxed for 1 hour. An additional ml of 9-BBN is added and the reaction is continued at reflux for another two hours. The reaction mixture is cooled and 14 ml of 3N NaOH and 2 ml of 30% H 2 O 2 are added and stirred for 6 hours. The crude reaction mixture is extracted with EtOAc dried over Na2SO4. The crude product is purified by flash column chromatography (40% EtOAc / hexane) to yield the desired product (0.10 g) in 57% yield. c. 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-5-r2- (methyloxy) ethyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone To a solution of 2- (3-Fluoro- 2-hydroxyphenyl) -6-methyl-5- [2- (methyloxy) ethyl] -3- (2-phenylethyl) -4 (3H) -pyrimidinone (0.22 g, 0.48 mmol) in dry THF is added with NaH (0.029 g) , 0.71 mol) and stirred for 2 minutes. Iodomethane (0.059 ml, 0.95 mmol) is added and the reaction is warmed to 50 ° C and stirred for 6 hours. The reaction is quenched with 1 N HCl and extracted with EtOAc. The organic layer is separated and dried over Na2SO. The crude product is purified by flash column chromatography (40% EtOAc / hexane) to yield the desired product (0.17 g) in 77% yield. Removal of the benzyl protecting group through catalytic hydrogenolysis as previously described provides the title compound: MS (m / z): 383.2 [M + H] +.

EXAMPLE 41 Preparation of 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5-propyl-4 (3 H-pyrimidinationa) to. 2-Acetyl-N- (2-phenylethyl) pentanamide To a solution of ethyl 2-acetylpentanoate (1.0 g, 5.81 mmol) of Example 31 in DME (21 ml) is added phenethylamine (0.7 g, 5.23 mmole) in a vessel of microwave reaction. Some drops of ethanol are added to the reaction mixture and irradiated at 180 ° C for 1200 seconds. The reaction mixture is diluted with EtOAc and washed with 1 N HCl. The organic layer is separated and dried over Na2SO. It is filtered, concentrated and purified by chromatography on silica gel (Biotage, 0-40% ethyl acetate / hexane) to yield the pure amide (0.6 g) in 42% yield. MS (m / z): 248.2 [M + H] +. b. 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5-propyl-4 (3H) -pyrimidinone The oxo-N- (2-phenylethyl) butanamide (6.2 g, 0.025 mol) is placed in a 500 ml round bottom flask and 251 ml of m-xylene are added followed by titanium isopropoxide (74 ml, 0.25 mol). While the reaction is stirred 3-fluoro-2-hydroxybenzamide (3.92 g, 0.025 mol) is added, a condenser is placed and the reaction is heated to reflux (oil bath temperature = 150 ° C). The 2-hydroxy-3-fluorobenzamide dissolves slowly and gives a homogeneous brown solution for some time at elevated temperature. The reaction is run for 36 hours and cooled to room temperature and diluted with dichloromethane. 3N HCl is added slowly until all the solid that initially formed has dissolved. The organic layer is separated and the aqueous layer is extracted additionally with dichloromethane. The combined organic layer is dried over sodium sulfate and filtered and concentrated. The crude reaction mixture is purified by EtOAc / hexanes and followed by MeOH in dichloromethane to give the pure product in 46% yield (4.21 g). 1 H NMR (400 MHz, CHCl 3) d ppm 1.04 (t, J = 7.4 Hz, 2 H), 1.55-1.61 (m, 2 H) 5 2.27 (s, 3 H), 2.52-2.56 (m, 2 H), 2.88 (t, J = 7.4 Hz, 2H), 4.17 (t, J = 7.4 Hz, 2H), 6.85-6.89 (m, 5 H), 7.04-7.19 (m, 3 H), 9.98 (brs, 1 H) ). MS (m / z): 367.2 [M + H] +. c. 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5-propyl-4 (3H) -pyrimidinationa To a sealed tube containing 2- (3-Fluoro-2-hydroxyphenyl) ) -6-methyl-3- (2-phenylethyl) -5-propyl-4 (3H) -pyrimidinone (0.1 g, 0.27 mmol) in dry toluene (2.0 ml) is added Lawesson's reagent (0.32 g, 0.82 mmol) and pyridine (0.065 ml, 0.82 mol). The sealed tube is closed and heated at 120 ° C for 16 hours after which it is allowed to cool to room temperature. The resulting solid is filtered and crude product is purified by chromatography on silica gel (Biotage) using (0-50%) EtOAc / hexane to provide the title compound (0.037 g) in 36% yield: MS (m / z) ): 383.2 [M + H] +.

EXAMPLE 42 Preparation of 2- (3-fluoro-2-hydroxyphenyl) -6-methyl-5-phenyl-3- (2-phenylethyl) -4 (3H) -pyrimidinationa to. 3-Oxo-2-phenyl-N- (2-phenylethyl) butanamide To a solution of ethyl 3-oxo-2-phenylbutanoate (5g, 0.24 mol) in DMF (21 ml) is added 2-thiophene-ethylamine (2.92). g, 0.023 mol) in a microwave reaction vessel. Some drops of ethanol are added to the reaction mixture and irradiated at 180 ° C for 1200 seconds. The reaction mixture is diluted with EtOAc and washed with 1 N HCl. The organic layer is separated and dried over Na 2 SO 4. It is filtered, concentrated and purified by chromatography on silica gel by chromatography on silica gel to give pure amide (3.42 g) with a yield of 49%.b. Trifluoromethanesulfonate of (1Z) -1-methyl-3-oxo-2-phenyl-3-f (2-phenylethiPaminoM -propen-1-yl To a solution of 3-oxo-2-phenyl-N- (2-phenylethyl) butanamide () 17.26 g, 0.061 mol) in dry dichloromethane is cooled to -78 ° C. To this is added trifluoromethanesulfonic anhydride (12.36 ml, 0.073 mol) and triethyl amine (12.80. ml, 0.092 mol) consecutively and stirred while the reaction is warmed to 0 ° C. The reaction is concentrated and purified by chromatography on silica gel (Bíotage, 0-40% ethyl acetate / hexane) to yield the triflate (14.3 g) in 56% yield. c. 3-Fluoro-N - ((1Z) -1-methyl-3-oxo-2-phenyl-3-f (2-phenylethyl) aminol-1-propen-1-yl.} -2- (methyloxy) benzamide To a solution of (1Z) -1-methyl-3-oxo-2-phenyl-3 - [(2-phenylethyl) amino] -1-propene-1-yl trifluoromethanesulfonate (13.2 g, 32 mmol) in deoxygenated dioxane dry 3-fluoro-2-hydroxybenzamide (5.49 g, 35 mmol), cesium carbonate (14.7 g, 45 mol), Pd2 (dba) 3 (0.74 g, 0.081 mmol) and xanthophos (1.40 g, 2.4 mmol) are added. The reaction is heated at reflux for 16 hours.The cooled reaction mixture is filtered through a pad of celite and concentrated.The purification is carried out by chromatography on silica gel (Biotage) to provide enamide (7.56 g) with a yield of 56%. d. 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-5-phenyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone 3-Fluoro-N - ((1Z) -1-methyl- 3-oxo-2-phenyl-3 { [2- (2-thienyl) ethyl] amino.} -1-propen-1-yl) -2- (methyloxy) benzamide (7.56 g, 0.018 mol) dissolve in ethanol (100 ml). To this is added 20 ml of 25% aqueous potassium hydroxide (w / v) and heated at reflux for 16 hours. The crude reaction mixture is acidified with 6N HCl to pH ~ 1 and extracted with dichloromethane.

The combined organic layers are washed with brine and concentrated. The crude residue is purified by chromatography on silica gel (Biotage) followed by recrystallization from EtOAc to provide the desired product (6.3 g) in 88% yield. MS (m / z): 401.2 [M + H] +. 1 H NMR (400 MHz, CHCl 3) d ppm 2.29 (s, 3 H), 3.01 (t, J = 7.8 Hz, 2H), 4.28 (t, J = 7.8 Hz, 2H), 6.94-7.09 (m, 4H) , 7.11-7.39 (m, 4 H), 7.41-7.51 (m, 5 H). and. 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-5-phenyl-3- (2-phenylethyl) -4 (3H) -pyrimidinethione The title compound is prepared according to the procedure briefly described in Example 47 except that 2- (3-fluoro-2-hydroxyphenyl) -6-methyl-5-phenyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone is replaced by 2- (3-fluoro- 2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5-propyl-4 (3H) -pyrimidinone. MS (m / z): 417.2 [M + H] +.

EXAMPLE 43 Preparation of 2- (3-fluoro-2-hydroxyphenyl) -6-methyl-5- (2-methylpropyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinationa to. Acetyl-4-methylpentanoate To a suspension of NaOMe (12.78 g, 0.24 mol) in dry methanol (4300 ml) is added methyl acetoacetate (25 g, 0.22 mol) and stirred for 15 minutes and heated to gentle reflux. 1-Bromo-2-methylpropane (29.5 g, 0.22 mol) is added in portions in two hours and the heating is continued overnight. The reaction is concentrated and diluted with NH 4 Cl and extracted with diethyl ether. The ether layer is dried and concentrated. The residue is purified by flash column chromatography (10% EtOAc / hexanes) to provide 2 g (5%) of the title compound. b. 2- (3-Fluoro-2-r (phenylmethyl) oxylphenyl) -6-methyl-5- (2-methylpropin-4 (1 H) -pyrimidinone To a solution of sodium methoxide (3.08 g) is added 3-fluoro -2 - [(Phenylmethyl) oxy] benzenecarboximidamide (3.95 g, 1.6 mmol) This mixture is kept at room temperature for 15 minutes after which 2- keep at room temperature for 15 minutes after which methyl 2-acetyl-4-methylpentanoate (2.23 g, 13 mmol) is added. This mixture is heated to reflux overnight after which it is cooled to room temperature and quenched with NH 4 Cl. The residue is diluted with EtOAc and washed with brine. The aqueous layer is extracted again with EtOAc and the combined organic layers are dried, filtered and concentrated. The residue is purified by flash column chromatography (30% EtOAc / hexanes) to provide 0.9 g (19%) of the title compound. c. 2- (3-Fluoro-2 - [(phenylmethyl) oxylphenyl) -6-methyl-5- (2-methylpropyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone To a solution of 2-. { 3-Fluoro-2 - [(phenylmethyl) oxy] phenyl} -6-methyl-5- (2-methylpropyl) -4 (1 H) -pyrimidinone (0.9 g, 2.46 mmol) in DMF (25 mL) is added titanium hydride (0.039 g, 4.91 mmol) and lithium bromide ( 0.64 g, 7.37 mmol). This mixture is stirred at room temperature for 15 minutes after which phenethyl bromide (2.27 g, 12.3 mmol) is added. This mixture is kept at room temperature for 12 hours after which it is diluted with EtOAc, washed with brine (3x's) and concentrated. Column chromatography of the residue (25% EtOAc / hexanes) provides 0.323 g (28%) of the title compound. d, 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-5- (2-methylpropyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone To a solution at 0 ° C of 2- [3-fluoro-2 - [(phenylmethyl) oxy] phenyl} -6-methyl-5- (2-methylpropyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone (0.323 g, 0.68 mmol) is added BBr3 (2.0 ml of 1 M DCM solution, 2.06 mmol). This mixture is allowed to warm to room temperature overnight after which methanol is added and the mixture is concentrated. Column chromatography of the residue (0-30% EtOAc / hexanes) provides 0.22 g (85%) of the title compound. MS (El) 381.2 [M + H] +. 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-5- (2-methylpropyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinationa The title compound is prepared as described in according to the procedure briefly described in example 45 except substituting 2- (3-fluoro-2-hydroxyphenyl) -6-methyl-5- (2-methylpropyl) -3- (2-phenylethyl) -4 (3H) - pyrimidinone by 2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5-propyl-4 (3H) -pyrimidinone: MS (m / z) 397.2 [M + H ] +.

EXAMPLE 44 Preparation of 3- (2,3-dihydro-1 H -inden-2-yl) -2- (2-hydroxyphenyl) -6-methyl-5-f 1 -methylethyl) -4 (3H) -pyrimidinone to. 2-Acetyl-N- (2,3-dihydro-1 H -inden-2-yl) -3-methylbutanamide The title compound is prepared using procedures briefly described in Example 1 except that 2-acetyl-3 is substituted ethyl methylbutanoate by ethyl 2-acetyl-4-methyl-4-pentanoate and phenethylamine by 2,3-dihydro-inden-1 H-2-ylamine in step 11 b. b. 3- (2,3-Dihydro-1H-inden-2-yl) -2- (2-hydroxyphenyl) -6-methyl-5- (1-methylethyl) -4 (3H) -pyrimidinone La 2 -acetyl-N- (2,3-dihydro-1 H -inden-2-yl) -3-methylbutanamide (1.2 g, 0.0046) is placed in a 100 ml round bottom flask. To this is added titanium isopropoxide (13.62 ml). While the reaction is stirred, salicylamide (0.956 g, 0.069 mol) is added, a condenser is placed and the reaction is heated to reflux (oil bath temperature = 150 ° C). The The reaction is run for 36 hours and cooled to room temperature and diluted with dichloromethane. 3N HCl is added slowly until all the solid that was initially formed has dissolved. The organic layer is separated and the aqueous layer is further extracted with dichloromethane. The combined organic layer is dried over sodium sulfate and filtered and concentrated. The crude solid is purified by reverse phase HPLC to produce the pure product. MS (m / z) 361.2 [M + H] +.

EXAMPLE 45 Preparation of 5.6-dethyl-2- (3-fluoro-2-hydroxyphenyl) -3-r2- (2-fluorophenyl) etn-4 (3H) -pyrimidinone to. (2Z) -3-aminoi-2-ethyl-N-r2- (2-fluorophenyl) etyl-2-butenamide The title compound is prepared following the procedure briefly described in Example 30 except that 2-fluorophenethylamine is replaced by 3- fluorofenetylamine in step 30a. b. 3-Fluoro-N-α (1Z) -2 - (([2- (2-fluorophenyl) ethamino) carbonyl) -1-methyl-1-buten-1-ill-2-hydroxybenzamide To a solution of ( 2Z) -3-amino-2-ethyl-N- [2- (2-fluorophenyl) ethyl] -2-butanamide (4.48 g, 0.0179 mol) and 3-fluoro-2-hydroxybenzoic acid (5.60 g, 0.038) in Dry THF is added EDC (4.13 g, 0.022 mol), HOBt (2.91 g, 0.022 mol) and TEA (0.8 ml) consecutively. The reaction is stirred at room temperature for 48 hours. The reaction is diluted with EtOAc and washed with dilute HCl, 5% NaHCO3 and brine. The organic layer is separated, dried over Na2SO, filtered and concentrated. The crude product is purified by flash column chromatography (30% EtOAc / hexane) to yield the desired product (4.0 g) in 57% yield. c. 5-Ethyl-2- (3-fluoro-2-hydroxyphenyl) -3-r2- (2-fluorophenyl) ethyl-6-methyl-4 (3H) -pyrimidinone 3-fluoro-N - [(1Z) - 2- ( { [2- (2-fluorophenyl) ethyl] amino.} Carbonyl) -1-methyl-1-buten-1-yl] -2-hydroxybenzamide (4.00 g, 0.01 mol) is taken in ethanol (60 ml) and 50 ml of 25% KOH is added and the reaction is heated to reflux overnight. After the reaction is cooled to room temperature the pH is adjusted to -1 with 3N HCl and extracted with dichloromethane. The combined organic layers are dried over Na2SO4, filtered and concentrated. The crude product is purified by flash column chromatography (30% EtOAc / hexane) yields the desired product (1.37 g) in 36% yield. d, 5-Ethyl-2- (3-fluoro-2 - ([(methyloxy) methyloxy) phenyl) -3-r2- (2-fluorophenyl) ethyll-6-methyl-4 (3H) -pyrimidinone A solution of 5-ethyl-2- (3-fluoro-2-hydroxyphenyl) -3- [2- (2-fluorophenyl) ethyl] -6-methyl-4 (3H) -pyrimidinone (1.37 g, 3.7 mmol) in dichloromethane Dry MOMCI (0.28 ml, 4.1 mmol) and TEA (0.57 ml, 4.1 mmol) are added and the mixture is refluxed overnight. The reaction mixture is diluted with EtOAc and washed with dilute HCl and brine. The organic layer is dried over Na2SO, filtered and concentrated. The residue is purified by flash column chromatography using 30% EtOAc in hexanes to provide the product (1.28 g) in 84% yield. e, 5,6-diethyl-2- (3-fluoro-2- (f (methyloxy) methyloxy) phenyl) -3-r2- (2-fluorophenyl) etl1-4 (3H) -pyrimidinone A solution at -78 ° C 5-ethyl-2- (3-fluoro-2-. {[[(methyloxy) methyl] oxy} phenyl) -3- [2- (2-fluorophenyl) ethyl] -6 -methyl-4 (3H) -pyrimidinone (0.2 g, 0.48 mmol) in THF is added 2M LDA (0.25 mL) in THF, mixed solvents of hexane and ethyl benzene and the reaction is stirred for 1 h. Iodomethane (0.03 ml) is added and the reaction is stirred until the starting material is completely consumed. The reaction is quenched by NH4CI, extracted with EtOAc. The organic layer is washed with brine, dried over Na 2 SO 4, filtered and concentrated. The residue is purified by flash column chromatography (20% EtOAc / hexane) to provide the product (0.08 g) in 43% yield.

F. 5,6-diethyl-2- (3-fluoro-2-hydroxyphenyl) -3- [2- (2-fluorophenyl) ethyl-4 (3H) -pyrimidinone To a solution of 5,6-diethyl-2- (3 -fluoro-2- { [[methyloxy) methyl] oxy} phenyl) -3- [2- (2-fluorophenyl) etl] -4 (3H) -pyrimidinone (0.08 g, 0.18 mmol) in dichloromethane at 0 ° C TFA (0.3 ml, 9.3 mmol) is added and the reaction is stirred for 1 h. The reaction mixture is diluted with EtOAc and washed with NaHC 3 and brine. The EtOAc layer is dried over Na2SO4, filtered and concentrated. The residue is purified by flash column chromatography (30% EtOAc / hexane) to give the product (0.05 g) in 73% yield.

MS (m / z): 385.0 [M + H] +.

EXAMPLE 46 Preparation of 6- (2-cyclohexyl-ethyl) -5-ethyl-2- (3-fluoro-2-hydroxyphenyl) -3-r2- (2-fluorophenyl) -etin-4 (3H) -pyrimidinone The compound of! title is prepared according to the procedures of Example 45 except substituting cyclohexylmethyl bromide for iodomethane in step 45e. MS (m / z): 467.4 [M + H] +.

EXAMPLE 47 Preparation of 6-r2- (3,4-dichlorophenyl) ethyl-5-ethyl-2- (3-fluoro-2-hydroxyphenyl) -3-r2- (2-fluorophenyl) ethyl-4 (3H) -pyrimidinone The title compound is prepared according to the procedures of Example 45 except substituting 3,4-dichlorobenzyl bromide for iodomethane for step 45e. MS (m / z): 529.4 [M + H] +.

EXAMPLE 48 Preparation of 2- (3-fluoro-2-hydroxyphenyl) -3-F2- (2-fluorophenypipetin-6-methyl-5- (2-methylpropyl) -4 (3H) -pyrimidinone to. Methyl 2-acetyl-4-methylpentanoate 3-Bromo-2-methyl-1-propene (6.75 g, 0.05 mol) and potassium carbonate (4.84 g, 0.035 mol) are added to a stirred solution of methyl acetoacetate in ACN (500 ml). The resulting heterogeneous mixture is stirred for 4 days and the solid is removed by filtration. Et2O is added and washed with H2O and brine. The organic layer is dried (Na SO4), filtered and concentrated. The crude residue is purified by flash chromatography (10% EtOAc / hexanes) to yield the product (4.29 g). The subsequent catalytic hydrogenolysis produces the product. b. 2-l3-fluoro-2- (methyloxy) phenyl-1-6-methyl-5- (2-methylpropyl) -4 (1 H) -pyrimidinone NaOMe (3.58 g, 0.068 mol) is added to a solution at 0 ° C. 3-fluoro-2- (methyloxy) benzenecarboximidamide (5.07 g, 0.03 mol) and methyl 2-acetyl-4-methylpentanoate (6.23 g, 0.036 mol) in methanol (75 ml) and 1,4-dioxane (15 ml) . The resulting mixture is heated to reflux overnight. The solvents are removed and the residue is quenched with NH 4 Cl and EtOAc. The layers are separated and the aqueous layer is extracted with dichloromethane 3 times. The combined organic portions are dried over Na2SO and purified by flash column chromatography (30% EtOAc / hexanes) to provide 3.46 g of the product in 40% yield. c. 2- [3-fluoro-2- (methoxy) phenyl-3-r2- (2-fluorophenyl) ethyll-6-methyl-5- (2-methylpropyl) -4 (3H) -pyrimidinone To a solution of 2 - [3-Fluoro-2- (methyloxy) phenyl] -6-methyl-5- (2-methylpropyl) -4 (1 H) -pyrimidinone (0.80 g, 0.0027 mol) in dry DMF is added LiH (0.044 g, 0.0055 mol), LiBr (0.72 g, 0.0083 mol) and stirred for 10 minutes at room temperature. Then 2-fluorophenethyl bromide (1.68 g, 0.0083 mol) is added and the mixture is stirred overnight. The reaction mixture is quenched by the addition of ice and 6N HCl. This mixture is extracted with EtOAc and the organic layer is washed with aqueous NaHC 3, brine and dried over Na 2 SO 4. The sodium sulfate is filtered and concentrated. The crude product is purified by flash column chromatography (25% ethyl acetate / hexane) to give the product (0.207 g) in 18% yield. d. 2- (3-fluoro-2-hydroxyphenyl) -3-r2- (2-fluorophenyl) ethyl-6-methyl-5- (2-methylpropyl) -4 (3H) -pyrimidinone 2- [3-fluoro- 2- (methyloxy) phenyl] -3- [2- (2-fluorophenyl) etl] -6-methyl-5- (2-methylpropyl) -4 (3H) -pyrimidinone (0.274 g, 0.67 mmol) in 2.0 ml of dichloromethane is cooled to 0 ° C. DCM 1 M solution of BBr3 (3.0 ml, 0.33 mmol) is then added and the reaction mixture is warmed to room temperature and stirred for 12 hours. The reaction mixture is diluted with dichloromethane and aqueous NaHC 3 and then added. The organic layer is separated and washed with H2O, brine and dried over Na2SO, filtered, concentrate and purify by chromatography on silica gel (Biotage, 25% ethyl acetate / hexane) to yield the pure compound (0.221 g) in 82% yield. MS (m / z). 399.2 [M + H] +.

EXAMPLE 49 Preparation of 2- (3-f1uoro-2-hydroxyphenyl) -6-methyl-5- (2-methylpropyl) -3-r2- (2-thienyl) etin-4 (3H) -pyrimidinone The title compound is prepared according to the procedures of Example 48 except substituting 2- (2-bromoethyl) thiophene for 1- (2-bromoethyl) -2-fluorobenzene in step 48c. MS (m / z) 387.4 [M + H] +.

EXAMPLE 50 Preparation of 2- (3-fluoro-2-hydroxyphenyl) -3-r2- (4-fluorophenyl) ethyne-6-methyl-5- (2-methylpropyl) -4 (3H) -pyrimidinone The title compound is prepared according to the procedures of Example 48 except substituting 1- (2-bromoethyl) -4-fluorobenzene for 1- (2-bromoethyl) -2-fluorobenzene in step 48c. MS (m / z): 399.2 [M + H] P EXAMPLE 51 Preparation of 2- (3-fluoro-2-hydroxy-phenyl-3-r2- (3-fluorophenyl) -6-methyl-5- (2-methylpropyl) -4 (3H) -pyrimidinone The title compound is prepared according to the procedures of Example 48 except substituting 1- (2-bromoethyl) -3- fluorobenzene by 1- (2-bromoethyl) -2-fluorobenzene in step 48c. MS (m / z): 399.2 [M + H] +.

EXAMPLE 52 Preparation of 2- (2-hydroxyphenyl) -7-methyl-3- (2-phenylethyl) -3,5,6,7,8,9-hexahydro-4H-pyrimido [4,5-d] azepin-4-one to. 4-ethyl-5-oxohexahydro-1 H-azepine-1,4-dicarboxylic acid 1- (1,1-dimethylethyl) synthesis is carried out as reported in the literature (Synth Commun., 1992, 22 (9) , 1249-1258). ^ 2- [2- (methyloxy) phenyl-4-oxo-1, 4,5,6, 8,9-hexahydro-7H-pyrimido (4,5-d) azepine-7-carboxylate 1,1-dimethylethyl NaOMe (0.98 g, 0.018 mol) is added to the solution at 0 ° C and 4-ethyl-5-oxohexahydro-1 H-azepine-1,4-dicarboxylic acid 1- (1,1-dimethylethyl) (2.58 g, 0.0091 mol) in methanol (45 ml) and 1,4-dioxane (45 ml). The resulting mixture is heated to reflux overnight. The solvents are removed and the residue is quenched with NH CI and EtOAc. The layers are separated and the aqueous layer is extracted with dichloromethane 3 times. The combined organic potions are dried over Na2SO and purified by flash column chromatography to provide 2.75 g of the product in 81% yield. c. 2-r2- (methyloxy) phenan-4-oxo-3- (2-phenylethyl) -3,4,5,6,8,9-hexahydro-7H-pyrimido [4,5-d1azepine-7-carboxylate] of 1, 1 -dimethylethyl To a solution of 2- [2- (methyloxy) phenyl] -4-oxo-1, 4,5,6,8,9-hexahydro-7H-pyrimido [4,5-d] azepine -7-carboxylic acid 1,1-dimethylethyl ester (2.75 g, 0.0074 mol) in dry DMF is added LiH (0.118 g, 0.015 mol), LiBr (1.93 g, 0.022 mol) and stirred for 10 minutes at room temperature. Then (2-bromoethyl) benzene (6.85 g, 0.037 mol) is added and the mixture is stirred overnight. The reaction mixture is quenched by the addition of ice and 6N HCl. This mixture is extracted with EtOAc and the organic layer is washed with aqueous NaHCO3, brine, and dried over Na2SO. The sodium sulfate is filtered and concentrated. The crude product is purified by flash column chromatography (30% ethyl acetate / hexane) to give the product (2.15 g) in 61% yield d. 2-γ2- (methyloxy) phenyl-3- (2-phenylethyl) -3,5,6,7,8,9-hexahydro-4H-pyrimido [4,5-d1azepin-4-one 2- [2- (methyloxy) phenyl] 4-Oxo-3- (2-phenylethyl) -3,4,5,6,8,9-hexahydro-7H-pyrimido [4,5-d] azepine-7-carboxylic acid 1,1-dimethylethyl ester (2.33 g, 4.9 mmol) is taken up in dichloromethane and to this is added trifluoroacetic acid (5.58 g, 49 mmol). The reaction is neutralized by aqueous NaOh and extracted with dichloromethane. The dichloromethane layer is washed with brine and dried over sodium sulfate. The reaction mixture is filtered and concentrated in vacuo to yield the free amine (1.79 g, 97%). and. 2- (2-hydroxyphenyl) -7-methyl-3- (2-phenylethyl) -3,5.6,7,8,9-hexahydro-4H-pyrimido [4,5-d1azepin-4-one To a solution of 2 - [2- (methyloxy) phenyl] -3- (2-phenylethyl) -3,5,6,9,8,8-hexahydro-4H-pyrimido [4,5-d] azepin-4-one (1.0 g , 2 mmol) in methanol at 0 ° C is added formaldehyde (2.3 ml, 30 mmol) and sodium cyanoborohydride (0.39 g, 6 mmol). The reaction mixture is stirred overnight. The reaction is quenched with water, extracted with dichloromethane and the dichloromethane is dried over sodium sulfate. The filtrate is concentrated in vacuo and the residue is purified by flash chromatography (0-30% ethyl acetate / hexane) to yield the product (0.4 g, 50%). Subsequent demethylation using BBr3 previously described yields the title compound.

MS (m / z): 376.4 [M + H] +.

EXAMPLE 53 Preparation of 7-acetyl-2- (2-hydroxyphenyl) -3- (2-phenylethyl) -3.5.6.7.8.9- hexahydro-4H-pyrimido [4,5-d1azepin-4-one] To a solution of 2- [2- (methyloxy) phenyl] -3- (2-phenylethyl) -3,5,6,9,8,8-hexahydro-4H-pyrimido [4,5-d] azepin-4 -one (0.94 g, 1.9 mmol) of Example 52 in dichloromethane is added acetyl chloride (0.45 g, 5.8 mmol) and triethylamine (0.58 g, 5.8 mmol). The reaction mixture is stirred until all the starting material is consumed. The reaction is quenched with saturated sodium carbonate, the dichloromethane layer is washed with brine and dried over sodium sulfate. The filtrate is concentrated in vacuo and the residue is purified by flash chromatography (0-30% ethyl acetate / hexane) to yield the product (0.27 g, 34%). Subsequent demethylation using BBr3 previously described yields the title product (0.18 g, 69%). MS (m / z): 404.2 [M + H] +.

EXAMPLE 54 Preparation of 2- (2-hydroxyphenyl) -7- (methylsulfonyl) -3- (2-phenylethyl) -3.5.6.7.8.9- hexahydro-4H-pyrimido [4,5-d1azepin-4-one The title compound is prepared according to the procedure of Example 53 except substituting methylsulfonyl chloride for acetyl chloride. MS (m / z) 440.2 [M + H] +.

EXAMPLE 55 Preparation of 5-bromo-2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone To a solution of 6-methyl-2- [2- (methyloxy) phenyl] -3- (2-phenylethyl) -4 (3H) -pyrimidinone (0.16 g, 0.5 mmol) in 50 ml of acetic acid is added bromine (0.08 g, 0.5 mmol) dropwise. The reaction is quenched with saturated sodium carbonate and the pH is adjusted to ~8 at 0 ° C. The reaction mixture is extracted with dichloromethane and the combined organic layers are washed with brine and dry over sodium sulfate. The organic layer is filtered, concentrated in vacuo and the residue is purified by flash chromatography (0-20% ethyl acetate / hexane) to yield the product (0.2 g) in 98% yield. Subsequent demethylation using BBr3 as previously described yields the title compound (0.15 g) in 79% yield. MS (m / z): 384.8 [M + H] +.

EXAMPLE 56 Preparation of 2- (2-hydroxyphenyl) -5-vodo-6-methyl-3- (2-phenylethyl) ^ (3H) -pyrimidine 6-Methyl-2- [2- (methyloxy) phenyl] -3- (2-phenylethyl) -4 (3H) -pyrimidinone (0.21 g, 0.66 mmol) is taken in glacial acetic acid (13 ml). To this is added 1 M dichloromethane solution of iodine monochloride (0.72 ml, 0.72 mmol) and the reaction is stirred for 16 hours. Ethyl acetate and acetic acid are added and washed with saturated sodium carbonate. The organic layer is dried over sodium sulfate. Sodium sulfate is filtered and the organic layer is concentrated. The crude product is purified by chromatography on silica gel (Biotage) using mixtures of ethyl acetate and hexanes (20-50%) to obtain the desired product (0.058 g) in 20% yield. Deprotection using BBr3 as detailed previously yields the title compound. MS (m / z) 433.0 [M + H] +.

EXAMPLE 57 Preparation of 5-chloro-3- (2-cyclohexylethyl) -2- (2-hydroxyphenyl) -β-methyl-4 (3H) -pyrimidinone to. 6-methyl-2- [2- (methyloxy) phenyl-1-4 (1 H) -pyrimidinone NaOMe (3.95 g, 0.073 mol) is added to a solution at 0 ° C of 2- (methoxy) benzenecarboxamide (5.49 g, 0.0366). mol) and methylacetoacetate (4.24 g, 0.0366 mol) in methanol (45 ml) and 1,4-dioxane (15 ml). The resulting mixture is heated to reflux overnight. The solvents are removed and the residue dilute with H2O and the pH is adjusted to 8 with acetic acid. The layers are separated and the aqueous layer is extracted with dichloromethane 3 times. The combined organic portions are dried over Na2SO and purified by flash column chromatography to provide 2.98 g of the product. b. 5-Chloro-6-methyl-2- [2- (methyloxy) phenylH-4 (1 H) -pyrimidinone To a solution of 6-methyl-2- [2- (methyloxy) phenyl] -4 (1 H) ) -pyrimidinone (0.043 g, 0.2 mmol) in 1: 1 acetone / water is added chloramine-T (0.045 g, 0.2 mmol) and sulfuric acid (0.020 g, 0.2 mmol). The reaction mixture is heated to reflux overnight. Upon cooling, the reaction mixture is diluted with ethyl acetate, washed with saturated sodium carbonate, brine, dried over sodium sulfate. The filtrate is concentrated in vacuo and the residue is purified by flash chromatography (0-50% ethyl acetate / hexane) to yield 5-chloro-6-methyl-2- [2- (methyloxy) phenyl] -4 ( 1 H) -pyrimidinone (0.017 g) in 34% yield. c. 5-chloro-3- (2-cyclohexylethyl) -2- (2-hydroxyphenyl) -6-methyl-4 (3H) -pyrimidinone To a solution of chloro-6-methyl-2- [2- (methyloxy) phenyl] -4 (1 H) -pyrimidinone (0.42 g, 1.7 mmol) in DMF is added lithium hydride (0.027 g, 3.4 mmol), lithium bromide (0.436 g, 5.0 mmol), and 2-cyclohexylethyl bromide (1.6 g). 8.4 mmol). While stirring overnight at room temperature, the reaction is quenched with saturated ammonium chloride, extracted with ethyl acetate. The Combined organic layers are washed with brine, dried over sodium sulfate, filtered, concentrated in vacuo and the residue purified by flash chromatography (0-30% ethyl acetate / hexane) to provide the desired product (0.23 g). , 38%). Subsequent deprotection using BBr3 is performed to produce the title compound (0.2 g, 90%). MS (m / z): 347.2 [M + H] +.

EXAMPLE 58 Preparation of 5-chloro-2- (2-hydroxyphenyl) -6-methyl-3-r2- (2-thienyl) ethyl (3H) -pyrimidinone The title compound is prepared according to the procedure briefly described in Example 57 except substituting 2-thiophenethyl bromide for 2-cyclohexylethyl bromide. MS (m / z): 347.2 [M + H] +.

EXAMPLE 59 Preparation of 5-chloro-2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinationa A mixture of 5-chloro-6-met? L-2- [2- (met? Lox?) Phen? L] -3- (2-phenet? L) -4 (3H) -p? Pm? D? Example 26c (036 g, 10 mmol) and phosphorus pentasulfide (0.73 g, 5 mmol) in dioxane is heated in a sealed tube at 120 ° C overnight The mixture is concentrated in vacuo and the residue is concentrated in vacuo. purify by flash chromatography (ethyl acetate / hexane = 10-25%) to yield 016 g. Demethylation using BBr3 (3 eq) in dichloromethane as detailed previously yields the title compound (0 083 g, 54%) MS ( m / z) 357 2 [M + H] + EXAMPLE 60 Preparation of 5-bromo-2- (3-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone The title compound is prepared by the procedures described briefly in Example 11 and substituting 3-methoxybenzamide for 2-hydrox-3-fluorobenzamide in step 11d. Subsequent deprotection with BBr3 as previously described provides the product. MS (m / z) 386.0 [M + H] +.

EXAMPLE 61 Preparation of 2- (3-hydroxyphenyl) -6-methyl-5-phenyl-2-f2-phenylethyl-4 (3H-pyrimidinone The title compound is prepared according to the procedure briefly described in Example 13 except substituting phenylboronic acid for 6-quinolinylboronic acid and 5-bromo-6-methyl-2- [3- (methyloxy) phenyl] -3- (2 phenylethyl) -4 (3H) -pyrimidinone by 5-bromo-2- (3-fluoro-2 - [(phenylmethyl) oxy] phenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) - pyrimidinone. Subsequent deprotection with BBr3 as previously described provides the product. MS (m / z) 383.2 [M + H] +.

EXAMPLE 62 Preparation of 2- (2-hydroxyphenyl) -6-methyl-5- (phenylamino) -3- (2-phenylethyl) -4 (3H) -pyrimidinone To a solution of 5-bromo-6-methyl-3- (2-phenylethyl) -2-. { 2 - [(phenylmethyl) oxy] phenyl} -4 (3H) -pyrimidinone (0.10 g, 0.21 mmol) of Example 20 in dioxane (5 mL) is added aniline (0.027 g, 0.30 mmol), xanthous (0.037 g, 0.06 mmol) and cesium carbonate (0.096 g, 0.30 mmol) in microwave reaction vessel. After bubbling the nitrogen for 10 minutes, tris (dibenzyldenoacetone) dipalladium (0.019 g, 0.02 mmol) is added. The mixture in the sealed container radiates at 150 ° C for 1000 seconds. The reaction mixture is filtered through a syringe filter (Acrodisc CR25 mm with 0.2 μm PTFE membrane). The vessel and the filter are washed with ethyl acetate. And the combined organic layers are combined with the filtrate and washed with brine, dried over sodium sulfate, filtered, concentrated in vacuo and the residue purified by flash chromatography (0-50% ethyl acetate / hexane) to yield the desired product (0.087 g, 85%). Debencylation using palladium on activated carbon as previously described provides the title compound (0.056 g, 79%). MS (m / z): 398.2 [M + H] +.

EXAMPLE 63 Preparation of 5- (1-azetidinyl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone The title compound is prepared according to the procedure of Example 62 except substituting azetidine (10 eq) for aniline. During the course of the reaction partial debenzylation occurs eliminating the subsequent hydrogenolysis step and producing the title compound directly (0.1 g, 53%). MS (m / z): 380.2 (M + H).

EXAMPLE 64 Preparation of 2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- (propylamino) -4 (3H) -pyrimidinone To a solution of 5- (1-azetidinyl) -2-. { 3-fluoro-2 - [(phenylmethyl) oxy] phenol} -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone (0.15 g, 0.32 mmol) in ethanol and 10% Pd / C (0.02 g) is added. This mixture is placed under a hydrogen atmosphere and stirred for 18 hours. The reaction mixture is filtered through a pad of celite and concentrated and purified by chromatography on silica gel (Biotage) to produce the desired product. MS (m / z): 382.0 [M + H] +.

EXAMPLE 65 Preparation of 2- (2-fluoro-3-hydroxyphenyl) -6-methyl-5-phenyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone 3-fluoro-2-methoxybenzamide Ti. { íPr?) 4, reflux a, 2-2 2-fluoro-3- (methyloxy) phenyl-1-6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone 3-oxo-N- (2-phenylethyl) butanamide (2.09 g, 0.01 mmol) is taken up in dry xylene (38 ml). To this is added 2-fluoro-3- (methyloxy) benzamide (2.58 g, 0.015 mmol) and titanium isopropoxide (0.15 mol) consecutively. The reaction is heated to reflux until all the starting material is consumed. The reaction mixture is concentrated and diluted with dichloromethane and washed with 3N HCl. The organic layer is separated and dried over Na 2 SO 4, filtered, concentrate and purify by chromatography on silica gel (Biotage, ethyl acetate / hexane 0-40%) to yield 1.5 g of the crude product. b. 5-bromo-2-f2-fluoro-3- (methyloxy) phenyl-6-methyl-3- (2-phenyletin-4 (3H) -pyrimidinone 2- [2-fluoro-3- (methyloxy) phenyl] -6 -methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone (1.5 g, 0.0044 mol) is taken in glacial acetic acid, to which bromine (0.34 ml, 0.0066 mol) is added dropwise by syringe. The reaction is stirred for 16 hours, ethyl acetate is added and acetic acid is washed with saturated sodium bicarbonate.The organic layer is further washed with saturated sodium sulfite / sodium metabisulfite solution and dried over sodium sulfate. The sodium sulfate is filtered and the organic layer is concentrated, the crude product is purified by chromatography on silica gel (Biotage) to obtain the desired product. c. 2-2 2-fluoro-3- (methyloxy) phenyl-6-methyl-5-phenyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone To a solution of 5-bromo-2- [2-fluoro- 3- (methyloxy) phenyl] -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone (0.75 g, 1.8 mmol) in dioxane is added phenylboronic acid (0.44 g, 3.6 mol), 2 ml of ethanol, and 2 ml of aqueous sodium carbonate (0.38 g, 3.6 mmol) in a microwave reaction vessel: after bubbling nitrogen for 10 minutes tetrakis (triphenylphosphine) palladium (0.21 g, 0.18 mmol) is added and the reaction it covers irradiate at 150 ° C for 700 seconds. The reaction mixture is filtered through a syringe filter (Acrodisc CR25 mm with 0.2 μm PTFE membrane). The vessel is filtered and washed with ethyl acetate. The combined EtOAc with filtrate is washed with brine, separated, dried over sodium sulfate. The filtrate is concentrated in vacuo and the residue is purified by flash chromatography (0-40% ethyl acetate / hexane) to yield the desired product (0.61 g, 82%). d. 2- (2-fluoro-2-hydroxyphenyl) -6-methyl-5-phenyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone 2- [2-fluoro-3- (methyloxy) phenyl] -6 -methyl-5-phenyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone (0.81 g, 1.94 mmol) in dichloromethane is cooled to 0 ° C. Then BBr3 (9.71 mmol) is added and the reaction mixture is warmed to room temperature and stirred for 12 hours. The reaction mixture is diluted with dichloromethane and aqueous NaHCO3 then added. The organic layer is separated and washed with H2O, brine and dried over Na2SO, filtered, concentrated and purified by reverse phase HPLC (ACN / H2O, 0.1% TFA) to yield the pure product (0.64 g) in 89% yield. MS (m / z): 400.8 [M + H] +.

EXAMPLE 66 Preparation of 2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- (3-thienyl) - (3H) -pyrimidinone To a solution of 5-iodo-6-met? L-3- (2-phen? Let? L) -2- [2 - [(phen? Lmet? L) ox?] Phen? L] -4 (3H ) -p? r? m? d? none (0 20 g, 0 38 mmol) of Example 21 in dioxane (5 ml) is added t? ofeno-3-boron? co (0 098 g, 0 76 mmol) , 0 5 ml of ethanol, and 0 5 ml of aqueous sodium carbonate (0 081 g, 0 76 mmol) in microwave reaction vessel After 10 minutes of deoxygenation, tetraqu? S (tpfen? Lfosf? Na) is added. palladium (0 044 g, 0 04 mmol) The mixture in the sealed container is irradiated at 150 ° C for 700 seconds The reaction mixture is filtered through a syringe filter (Acrodisc CR25 mm with 0 2 μm membrane PTFE) The vessel and filter are washed with ethyl acetate The layers of ethyl acetate are combined and filtered and washed with brine, separated, dried over sodium sulfate, they are filtered and concentrated in vacuo and the residue is purified by flash chromatography (0-40% ethyl acetate / hexane) to yield 6-methyl-3- (2-phenylethyl) -2-. { 2 - [(phenylmethyl) oxy] phenyl-5- (3-thienyl) -4 (3H) -pyrimidinone (0.17 g, 93%). 6-methyl-3- (2-phenylethyl) -2-. { 2 - [(phenylmethyl) oxy] phenyl} -5- (3-thienyl) -4 (3H) -pyrimidinone is debenzylated using palladium on activated carbon under a hydrogen atmosphere overnight to provide the title compound. MS (m / z): 389.4 [M + H] +.

EXAMPLE 67 Preparation of 5- (3-furanyl) -2- (2-hydroxyphenyl) -6-metJI-3- (2-phenylethyl) -4 (3H) -pyrimidinone The title compound is prepared according to the procedures briefly described in Example 66 except substituting 3-furanboronic acid for thiophene-3-boronic acid. MS (m / z) 373.0 [M + H] +.

EXAMPLE 68 Preparation of 5- (4-biphenylyl) -2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone The title compound is prepared according to the procedures briefly described in Example 66 except substituting 4-biphenylboronic acid for thiophene-3-boronic acid. MS (m / z) 459.2 [M + H] +.

EXAMPLE 69 Preparation of 5- (1,3-benzodioxol-5-yl) -2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone The title compound is prepared according to the procedures briefly described in Example 66 except substituting 3,4-methylenedioxyphenylboronic acid by thiophene-3-boronic acid. MS (m / z) 427.2 [M + H] +.

EXAMPLE 70 Preparation of 5- (2-fluorophenyl) -2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4- (3H) -pyrimidinone The title compound is prepared according to the procedures briefly described in Example 66 except substituting 2-fluorophenylboronic acid for thiophene-3-boronic acid. MS (m / z) 401.2 [M + H] +.

EXAMPLE 71 Preparation of 2- (2-hydroxyphenyl-6-methyl-3- (2-phenylethyl-5-r4- (trifluoromethyl) phenyl] -4 (3H) -pyrimidinone The title compound is prepared according to the procedures of Example 66 except substituting 5-bromo-6-met? L-3- (2-phen? Let? L) -2-. { 2 - [(fen? Lmet? L) ox?] Phen? L} -4 (3H) -p? Pm? D? None (example 20) by 5-iodo-6-met? L-3- (2-phen? Let? L) -2-. { 2 - [(fen? Lmet? L) ox?] Phen? L} -4 (3H) -p? Pm? Donone and 4-tpfluoromethylbenzeneboronic acid by t? Ofeno-3-boron? Co of the title compound MS (m / z) 451 2 [M + H] + EXAMPLE 72 Preparation of 5- (3-fluorophenyl) -2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone The title compound is prepared according to the procedures of Example 66 except substituting 5-bromo-6-methyl-3- (2-phenylethyl) -2-. { 2 - [(phenylmethyl) oxy] phenyl} -4 (3H) -pyrimidinone (example 20) by 5-iodo-6-methyl-3- (2-phenylethyl) -2-. { 2 - [(phenylmethyl) oxy] phenyl} -4 (3H) -pyrimidinone and 3-fluorophenylboronic acid by thiophene-3-boronic acid. MS (m / z): 401.2 [M + H] +.

EXAMPLE 73 Preparation of 5- (2,4-difluorophenyl) -2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone The title compound is prepared according to the procedures of Example 66 except substituting 5-bromo-6-methyl-3- (2- phenylethyl) -2-. { 2 - [(phenylmethyl) oxy] phenyl} -4 (3H) -pyrimidinone (example 20) by 5-iodo-6-methyl-3- (2-phenylethyl) -2-. { 2 - [(phenylmethyl) oxy] phenyl} -4 (3H) -pyrimidinone and 2,4-difluorophenylboronic acid by thiophene-3-boronic acid. MS (m / z): 419.2 [M + H] +.

EXAMPLE 74 Preparation of 5-r4- (dimethylamino) phenyI-2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone To a solution of 5-bromo-2- (3-fluoro-2 - [(phenylmethyl) oxy] phenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone (0.20 g, 0.41 mmol ) of example 11 in dioxane (5 ml) is added 4- (N, N-dimethylamino) phenylboronic acid (0.134 g, 0.81 mmol), 0.5 ml of ethanol and 0.5 ml of aqueous sodium carbonate (0.089 g, 0.81 mmol) in microwave reaction vessel. After 10 minutes of deoxygenation, tetrakis (triphenylphosphine) palladium (0.070 g, 0.06 mmol) is added. The mixture in a sealed container is irradiated at 150 ° C for 2400 seconds. The reaction mixture is filtered through a syringe filter (Acrodisc CR25 mm with 0.2 μm PTFE membrane). The vessel and the filter are washed with ethyl acetate. EtOAc combined with the filtrate is washed with brine, separate, dry over sodium sulfate. The filtrate is concentrated in vacuo and the residue is purified by flash chromatography (0-40% ethyl acetate / hexane) to yield the title compound (0.13 g, 72%). MS (m / z): 444.2 [M + H].

EXAMPLE 75 Preparation of 5-r4- (ethyloxy) phenyl-2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone The title compound is prepared according to the procedures briefly described in Example 74 except substituting 4-ethoxyphenylboronic acid for 4- (N, N-dimethylamino) phenylboronic acid. MS (m / z): 445.4 [M + H] +.

EXAMPLE 76 Preparation of 5- (1-benzothien-3-yl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- [2-phenylethyl] -4 (3H) -pyrimidinone The title compound is prepared according to the procedures briefly described in Example 74 except substituting t-phthalic-3-boronic acid for 4- (N, N-dimethylamino) phenylboronic acid. MS (m / z): 457.2 [M + H] +.

EXAMPLE 77 Preparation of 5- (1-benzothien-4-yl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone The title compound is prepared according to the procedures briefly described in Example 74 except substituting tianaphthene-4-boronic acid by 4- (N, N-dimethylamino) phenylboronic acid. MS (m / z): 457.2 [M + H] +.

EXAMPLE 78 Preparation of 2- [2- (3-fluoro-2-hydroxyphenyl) -4-methyl-6-oxo-1- (2-phenylethi) -1,6-dihydro-5-pyrimidinebenzonitrile The title compound is prepared according to the procedures briefly described in Example 74 except substituting 2-cyanophenylboronic acid for 4- (N, N-dimethylamino) phenylboronic acid. MS (m / z): 426.2 [M + H] +.

EXAMPLE 79 Preparation of 4-r2- (3-fluoro-2-hydroxyphenyl) -4-methyl-6-oxo-1- (2-phenylethyl) -1,6-dihydro-5-pyrimidinebenzoate The title compound is prepared according to the procedures briefly described in Example 74 except substituting 3-cyanophenylboronic acid for 4- (N, N-dimethylamino) phenylboronic acid. MS (m / z): 426.2 [M + H] +.

EXAMPLE 80 Preparation of 5-r2- (ethyloxy) phenin-2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone The title compound is prepared according to the procedures briefly described in Example 74 except substituting 2-ethoxyphenylboronic acid by 4- (N, N-dimethylamino) phenylboronic acid; MS (m / z): 445.4 [M + H] +.

EXAMPLE 81 Preparation of 5-r3- (ethyloxy) phenin-2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3-f2-phenylethyl) -4 (3H) -pyrimidinone The title compound is prepared according to the procedures briefly described in Example 74 except substituting 3-ethoxyphenylboronic acid for 4- (N, N-dimethylamino) phenylboronic acid. MS (m / z): 445.4 [M + H] +.

EXAMPLE 82 Preparation of 5- (1-benzofuran-2-yl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone The title compound is prepared according to the procedures briefly described in Example 74 except substituting 2-benzenefuranboronic acid for 4- (N, N-dimethylamino) phenylboronic acid. MS (m / z): 441.2 [M + H] +.

EXAMPLE 83 Preparation of 2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- (1 H -pyrrol-2-yl) -4 (3 H) -pyrimidinone The title compound is prepared according to the procedures briefly described in Example 74 except substituting N-Boc-pyrrole-2-boronic acid by 4- (N, N-dimethylamino) phenylboronic acid. MS (m / z): 390.2 [M + H] +.

EXAMPLE 84 Preparation of 2- (3-fluoro-2-hydroxyphenyl) -5-f3- (hydroxymethyl) phenan-6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone The title compound is prepared according to the procedures briefly described in Example 74 except substituting [3- (hydroxymethyl) phenyl] boronic acid for 4- (N, N-dimethylamino) phenylboronic acid. MS (m / z): 431.2 [M + H] +.

EXAMPLE 85 Preparation of 2- (3-fluoro-2-hydroxyphenyl) -6-methyl-5- [3- (methylsulfonyl) pheyp-3- (2-phenylethyl) -4 (3H) -pyrimidinone The title compound is prepared according to the procedures briefly described in Example 74 except substituting 3-methanesulfonylphenylboronic acid for 4- (N, N-dimethylamino) phenylboronic acid. MS (m / z): 479.2 [M + H] +.

EXAMPLE 86 Preparation of 2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5-f3- (trifluoromethyl) phen-4 (3H) -pyrimidinone The title compound is prepared according to the procedures briefly described in Example 74 except substituting 3-trifluoromethylphenylboronic acid by 4- (N, N-dimethylamino) phenylboronic acid. MS (m / z): 469.2 [M + H] +.

EXAMPLE 87 Preparation of 5- (3,4-difluorophenyl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone The title compound is prepared according to the procedures briefly described in Example 74 except substituting 3,4-difluorophenylboronic acid for 4- (N, N-dimethylamino) phenylboronic acid. MS (m / z): 437.2 [M + H] +.

EXAMPLE 88 Preparation of 5-r4- (1,1-dimethylethyl) phenyl1-2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone The title compound is prepared according to the procedures briefly described in Example 74 except substituting 4-t-butylphenylboronic acid for 4- (N, N-dimethylamino) phenylboronic acid. MS (m / z): 457.2 [M + H] +.

EXAMPLE 89 Preparation of 5- (5-acetyl-2-thienyl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl (3H) -pyrimidinone The title compound is prepared according to the procedures briefly described in Example 74 except substituting -acetylthiophen-2-boronic acid by 4- (N, N-dimethylamino) phenylboronic acid. MS (m / z): 449.2 [M + H] +.

EXAMPLE 90 Preparation of 2- (3-f1uoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5-. { 3- r (trifluoromethyl) oxy-phenyl) -4 (3H) -pyrimidinone The title compound is prepared according to the procedures briefly described in Example 74 except substituting 4- (N, N-dimethylamino) phenylboronic acid for 4- (trifluoromethoxy) benzeneboronic acid. MS (m / z): 485.2 [M + H] +.

EXAMPLE 91 Preparation of 5-. { 3 - [(dimethylamino) metinphenyl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl (3H) -pyrimidinone The title compound is prepared according to the procedures briefly described in Example 74 except substituting N, N-dimethylaminomethyl) phenyl-3-boronic acid pinacol for 4- (N, N-dimethylamino) phenylboronic acid. MS (m / z): 458.2 [M + H] +.

EXAMPLE 92 Preparation of 3-r2- (3-fluoro-2-hydroxyphenyl) -4-methyl-6-oxo-1- (2-phenylethyl) -1,6-dihydro-5-pyrimidinin-N.N-dimethylbenzamide The title compound is prepared according to the procedures briefly described in Example 74 except substituting 3- (N, N-dimethylamino) phenylboronic acid for 3- (dimethylcarbamoyl) phenyl boronic acid. MS (m / z): 472.2 [M + H] +.

EXAMPLE 93 Preparation of 5- (4,5-dimethyl-2-thienyl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3-. { 2-phenylethyl (3H) -pyrimidinone The title compound is prepared according to the procedures briefly described in Example 74 except substituting (4,5-dimethyl-2-thienyl) borinate ethyl by 4- (N, N-dimethylamino) phenylboronic acid. MS (m / z): 435.2 [M + H] +.

EXAMPLE 94 Preparation of 5-r2- (3-fluoro-2-hydroxyphenyl) -4-methyl-6-oxo-1-β-phenylethyl-1,6-dihydro-5-pyrimidinyl-2-thiophenecarbonitrile The title compound is prepared according to the procedures of Example 74 except substituting 5-cyanothiophene-2-boronic acid for 4- (N, N-dimethylamino) phenylboronic acid and bis- (tri-t-butylphosphite) palladium for tetrakis ( triphenylphosphine) palladium. Microwave irradiation at 150 ° C for 2400 seconds produces the desired compound. The debenzylation using hydrobromic acid in acetic acid as detailed previously yields the title product. MS (m / z): 432.2 [M + H] +.

EXAMPLE 95 Preparation of 2- (3-fluoro-2-hydroxyphenyl) -6-methyl-5- (1-methyl-1 H -pyrrol-2-yl) -3- (2-phenylethyl-4 (3H) - pyrimidinone to. 2- (3-fluoro-2-r (phenylmethyl) oxylphenyl) -6-methyl-3- (2-phenylethyl) -5- (1 H-pyrrol-2-yl) -4 (3 H) -pyrimidinone To one solution of 5-bromo-2- [3-fluoro-2 - [(phenylmethyl) oxy] phenyl] -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone (0.60 g, 1.2 mmol) of the example In dioxane, N-Boc-pyrrole-2-boronic acid (0.51 g, 2.4 mmol), 0.5 ml of ethanol, and 0.5 ml of aqueous sodium carbonate (0.26 g, 2.4 mmol) are added in a microwave reaction vessel. . After 10 minutes of dehydrogenation, tetrakis (triphenylphosphine) paldium (0.14 g, 0.12 mmol) is added. The mixture in a sealed container is irradiated at 150 ° C for 700 seconds. The reaction mixture is filtered through a syringe filter (Acrodisc CR25 mm with 0.2 μm PTFE membrane). The container and filter are washed with acetate of ethyl. EtOAc is combined with the filtrate washed with brine, separated, dried over sodium sulfate. The filtrate is concentrated in vacuo and the residue is purified by flash chromatography to yield the title compound (0.285 g). b. 2- (3-fluoro-2-hydroxyphenyl) -6-methyl-5- (1-methyl-1 H -pyrrol-2-yl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone A 2- . { 3-fluoro-2-. { (phenylmethyl) oxy} phenyl } -6-methyl-3- (2-phenylethyl) -5- (1 H -pyrrol-2-yl) -4 (3H) -pyrimidinone (0.29 g, 0.59 mmol) in DMF cesium carbonate (0.39 g) is added g, 1.2 mmol) and methyl iodide (0.17 g, 1.2 mmol). The reaction is quenched with water and diluted with ethyl acetate. The ethyl acetate is separated, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo and the residue is purified by flash chromatography (ethyl acetate / 0-40% hexane) to yield 0.19 g. (47%) 2- performance. { 3-fluoro-2 - [(phenylmethyl) oxy] phenyl} 6-methyl-5- (1-methyl-1 H -pyrrol-2-yl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone. Catalytic hydrogenolysis produces the title product. MS (m / z): 404.2 [M + H] +.

EXAMPLE 96 Preparation of 2- (3-fluoro-2-hydroxyphenyl) -6-methyl-5- (1-methyl-1 H -indol-2-yl) -3- (2-phenylethyl) -4 (3H) - pyrimidinone The compound is prepared according to the procedure of Example 95 except substituting N-Boc-indole-2-boronic acid for 4- (N, N-dimethylamino) phenylboronic acid. MS (m / z): 454.0 [M + H] +.

EXAMPLE 97 Preparation of 2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- (1, 3-thiazol-2-yl) -4 (3H) -pyrimidinone To a solution of 5-bromo-2- [3-fluoro-2 - [(phenylmethyl) oxy] phenyl] -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone (0.20 g, 0.41 mmol ) of example 11 in dioxane (5 ml) is added cesium fluoride (0.154 g, 1 mmol). After 10 minutes of deoxygenation, bis (tri-t-phosphine) palladium (0.021 g, 0.04 mmol) and 2- (tributylstannanyl) thiazole are added. The mixture in the sealed container is heated to 120 ° C overnight. The reaction mixture is filtered through celite and diluted with ethyl acetate. The filtrate is washed with 10% w / v potassium fluoride, separated, dried over sodium sulfate, filtered, concentrated in vacuo and the residue purified by flash chromatography (ethyl acetate / 0-40 hexane). %) to produce 0.16 g in 79% yield. The catalytic hydrogenolysis followed by HPLC separation of Reverse phase produces the title compound (0.095 g, 72%). MS (m / z): 408.2 [M + H] +.

EXAMPLE 98 Preparation of 2- (2-hydroxy-phenyl) -6-methyl-3- (2-phenylethyl) -5- (3-pyridinyl) -4 (3H) -pyrimidinone To the solution of 5-chloro-6-methyl-2- [2- (methyloxy) phenyl] -3- (2-phenylethyl) -4 (3H) -pyrimidinone from example 26 (0.15 g, 0.42 mmol) in 10 ml of dioxane is added Pd (t-Bu3P) 2 (0.022 g, 0.04 mmol), 3-pyridinboronic acid (0.05 g, 0.47 mmol) and Cs2CO3 (0.17 g, 0.51 mmol). The reaction is degassed for 10 minutes and then heated at 90 ° C for 12 hours. The reaction mixture is cooled to room temperature, concentrated and the crude product is subjected to flash silica gel column chromatography using 30% EtOAc / hexanes to provide 6-methyl-2- [2- (methyloxy) phenyl. ] -3- (2-phenylethyl) -5- (3-pyridinyl) -4 (3H) -pyrimidinone. MS (ES) m / e 398 [M + H] +. Subsequent deprotection with BBr3 as previously described by the title compound MS (ES) m / e 348 [M + H] +.

EXAMPLE 99 Preparation of 2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- (2-pyrazinyl) -4 (3H) -pyrimidinone a, 5-chloro-2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone 5-chloro-6-methyl-2- [2- (methyloxy) phenyl] -3- (2-Phenylethyl) -4 (3H) -pyrimidinone (0.23 g, 0.65 mmol) from Example 26 in dichloromethane is cooled to 0 ° C. BBr3 1 M in dichloromethane (0.8 ml) is then added and the mixture is allowed to stir at this temperature until the starting material is consumed. On completion the reaction mixture is diluted with dichloromethane and aqueous NaHCO and then added. The nic layer is separated and washed with H2O, brine and dried over NaSO. After filtration the reaction mixture is mixed and purified by chromatography on silica gel (40% ethyl acetate / hexane) to yield the pure compound (0.10 g) in 45% yield. b. 2- (2-Hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- (2-pyrazinyl) -4 (3H) -pyrimidinone To a solution of 5-chloro-2- (2-hydroxyphenyl) ) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone (0.17 g, 0.50 mmol) in dioxane under argon atmosphere is added Pd (tBu3P) 2 (0.015 g, 0.029 mmol) and CsF (0.167 g, 0.0011 mol) is then degassed for 10 minutes. Then 2-tributylstannylpyrazine (0.406 g, 0.0011 mol) is added and then added and the reaction mixture is heated for 16 h. The reaction is then filtered through a pad of silica gel and concentrated. The crude product is purified by preparative TLC to provide the desired product. MS (ES) m / e 385 [M + H] +.

EXAMPLE 100 Preparation of 6-methyl-2-r2- (methoxyl) phen-3- (2-phenylethyl) -5- (2-thienyl) -4 (3H) -pyrimidinone To a solution of 5-chloro-6-methyl-2- [2- (methyloxy) phenyl] -3- (2-phenylethyl) -4 (3H) -pyrimidinone (0.32 g, 0.903 mmol) from Example 26 in low dioxane Argon atmosphere is added Pd (tBu3P) 2 (0.028 g, 0.054 mmol) and CsF (0.3 g, 1.98 mmol) then degassed for 10 minutes. Later add 2-tributylstannylthiophene (0.32 ml, 0.99 mmol) and the reaction is heated for 16 h. The reaction is then filtered through a pad of silica gel and concentrated. The crude product is purified by flash chromatography using 20% EtOAc / hexanes to give the product (0.2 g) in 54% yield. MS (ES) m / e 403 [M + H] +.

EXAMPLE 101 Preparation of 2- (2-hydroxyphenyl) -6-methyl-5-phenyl-3- (2-phenylethyl-4 (3H.- pyrimidinone The title compound is prepared following the general procedure briefly described in example 99 substituting tributylphenyl tin for 2-tributylstannylthiophene. MS (ES) m / e 383 [M + H] +.

EXAMPLE 102 Preparation of 5- (4-fluorophenyl) -2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone The title compound is prepared following the general procedure briefly described in Example 99 except substituting 5-chloro-2- (2-methoxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone by 5-chloro-2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone and 4-fluoro- (tributylstannyl) -benzene by 2-tributylstanilpyrazine. Subsequent deprotection using BBr3 as previously detailed produces the final product. MS (ES) m / z 401 [M + H] P EXAMPLE 103 Preparation of 2- (2-hydroxyphenyl) -6-methyl-5- (3-methylphenyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone The title compound is prepared following the procedure general described briefly in example 99 except substituting 5-chloro-2- (2-methoxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone for 5-chloro-2- (2-hydroxyphenyl) ) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone and 3-methyl- (tributylstannyl) -benzene by 2-tributylstanilpyrazine. Subsequent deprotection using BBr3 as previously detailed produces the final product. MS (ES) m / z 396 [M + H] +.

EXAMPLE 104 Preparation of 2- (3-fluoro-2-hydroxyphenyl) -6-methyl-5- (1-methyl-1 H -indol-5-yl) -3- (2-phenylethyl (3H) -pyrimidinone The title compound is prepared following the general procedure briefly described in Example 13 except substituting N-methylindol-5-boronic acid for quinolin-6-boronic acid. MS (ES) m / e 454 [M + H] +.

EXAMPLE 105 Preparation of 2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5-f4-r (trifluoromethyl) oxylphenylM (3H) -pyrimidinone The title compound is prepared following the general procedure briefly described in Example 13 except substituting 4- (trifluoromethoxy) benzene acid for quinolin-6-boronic acid. MS (ES) m / e 485 [M + H] + EXAMPLE 106 Preparation of 2- (3-fluoro-2-hydroxyphenyl) -6-methyl-5-. { 4 - [(1-methylethyl) oxphenyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone The title compound is prepared following the general procedure briefly described in example 13 except substituting 4- isopropoxyphenyl by quinolin-6-boronic acid. MS (ES) m / e 459 [M + H] +.

EXAMPLE 107 Preparation of 2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- (6-quinoline) -4 (3H) -pyrimidinone The title compound is prepared following the general procedure briefly described in Example 13 except substituting 5-bromo-6-methyl-3- (2-phenylethyl) -2-. { 2 - [(phenylmethyl) oxy] phenyl} -4 (3H) -pyrimidinone of example 20 by 5-bromo-2-. { 3-fluoro-2 - [(phenylmethyl) oxy] phenyl} -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone. Subsequent deprotection using BBr3 as detailed previously produces the final compound. MS (ES) m / e 434 [M + H] P EXAMPLE 108 Preparation of 5- (2,3-dihydro-1,4-benzodioxin-6-yl) -2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone The title compound is prepared following the general procedure briefly described in Example 13 except substituting 5-bromo-6-methyl-3- (2-phenylethyl) -2-. { 2 - [(phenylmethyl) oxy] phenyl} -4 (3H) -pyrimidinone of Example 20 by 5-bromo-2-. { 3-fluoro-2 - [(phenylmethyl) oxy] phenyl} -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone and 1,4-benzodioxane-6-boronic acid by quinoline-6-boronic acid. Subsequent deprotection using catalytic hydrogenolysis as detailed previously produces the final compound. MS (ES) m / e 441 [M + Hf.

EXAMPLE 109 Preparation of 5- [5-chloro-3-methyl-1-benzothien-2-yn-2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 ( 3H) -pyrimidinone to. 5- (5-chloro-3-methyl-1-benzothien-2-yl) -2- (3-fluoro-2 - [(phenylmethyl) oxylfenyl) -6-methyl-3- (2-phenylethyl) L) -4 (3H) -pyrimidinone A solution of 5-bromo-2-. { 3-fluoro-2 - [(phenylmethyl) oxy] phenyl} -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone (0.3 g, 0.61 mmol) from Example 11, 2-bromo-5-chloro-3-methyl-1-benzothiophene (0.16 g, 0.61 mmol), hexamethyldistan (0.13 ml, 0.61 mmol), Pd (PPh3) 4 (0.070 g, 0.061 mmol) in 10 ml of dioxane is degassed for 10 minutes and then heated at 90 ° C for 16 h. The reaction mixture is concentrated, diluted with dichloromethane, filtered through Celite, and concentrated. The crude product is purified by flash silica gel column and eluted with hexane / EtOAc (7: 3) to give the product (0.2 g) in 55% yield. MS (ES) m / e 594 [M + Hf. b. 5- (5-chloro-3-methyl-1-benzothien-2-yl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone 5- (5-chloro-3-methyl-1-benzothien-2-yl) -2-. { 3-fluoro-2 - [(phenylmethyl) oxy] phenyl} -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone (0.1 g, 0.168 mmol) is taken in glacial acetic acid. To this is added Pd / C at 10% (0.02 g). This mixture is placed under a hydrogen atmosphere at 3.27 atm and is stirred for 16 h. The reaction mixture is filtered through a pad of Celite and concentrated. The crude residue is taken up in dichloromethane and washed with NaHCO3 and brine. The organic layer is dried over Na2SO, filtered and concentrated. The crude residue is purified by chromatography on silica gel (ethyl acetate / hexane 15%) to yield the desired product (0.030 g). MS (ES) m / e 505 [M + Hf.

EXAMPLE 110 Preparation of 2- (3-fluoro-2-hydroxyphenyl) -6-methyl-5- [5- (1, 3-oxazol-5-yl) -2-thienyl-3- (2-phenylethyl) -4 (3H) -pyrimidnone to. 4- [5- (trimethylstannanyl) -2-thienyl-1,3-oxazole 5- (5-bromo-2-thienyl) -1,3-oxazole (0.53g, 2.30 mmol), hexamethyldistan (3.0 g, 9.2 mmol ), Pd (PPh3) 4 (0.40 g, 0.35 mmol) in 20 ml of toluene is degassed for 10 minutes and then heated at 90 ° C for 16 h. The reaction mixture is concentrated, diluted with dichloromethane, the solid material is filtered and reconcentrated. The crude product is purified on a flash silica gel column and eluted with hexane / EtOAc (7: 3) to provide 0.2 g (28%) of the title compound. MS (ES) m / e 314 [M + Hf. b. 2- (3-fluoro-2-hydroxyphenyl) -6-methyl-5- [5- (1,3-oxazol-5-yl) -2-thienyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone One 5-bromo-2- solution. { 3-fluoro-2 - [(phenylmethyl) oxy] phenyl} -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone from example 11f (0.315 g, 0.64 mmol), 5- [5- (trimethylstannanyl) -2-thienyl] -1,3-oxazole ( 0.2 g, 0.64 mmol), Pd (tBu3P) 2 (0.020 g, 0.038 mmol), CsF 0.21 g (1.41 mmol) in 20 ml of dioxan is degassed for 10 minutes and heated at 90 ° C for 48 hours. The reaction mixture is concentrated in vacuo, it is diluted with dichloromethane, filtered, washed with 10% KF solution, dried (MgSO4) and purified on a flash silica gel column to provide 0.12 g, 33% yield of 2-. { 3-fluoro-2 - [(phenylmethyl) oxy] phenyl} 6-methyl-5- [5- (1, 3-oxazol-5-yl) -2-thienyl] -3- (2-phenylethyl) -4 (3H) -pyrimidinone. MS (ES) m / e 564 [M + Hf. The subsequent catalytic hydrogenolysis provides the title compound. MS (ES) m / e 474 [M + Hf.

EXAMPLE 111 Preparation of 5-f1uoro-2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone The title compound is prepared according to the procedure of Example 26 except substituting ethyl 2-fluoro-3-oxobutanoate for ethyl 2-chloro-3-oxobutanoate and subsequently deprotecting using the method of BBr3. MS (ES) m / e 325 [M + Hf.

EXAMPLE 112 Preparation of 2- (2-hydroxyphenyl) -6-methyl-5- (2-methylpropyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone The title compound is prepared according to the procedure of Example 26 except substituting ethyl 2-acetyl-4-methylpentanoate for ethyl 2-chloro-3-oxobutanoate and subsequent deprotection using the method of BBr3. MS (ES) m / e 363 [M + Hf.

EXAMPLE 113 Preparation of 2- (2-hydroxyphenyl) -6-methyl-5- (2-methyl-2-propen-1 -yl) -3- (2-phenylethyl) -4 (3H) -pyridmidinone to. Methyl 2-acetyl-4-methyl-4-pentanoate 3-bromo-2-methyl-1-propane (6.75 g, 0.05 mol) and potassium carbonate (4.84 g, 0.035 mol) is added to a stirred solution of acetoacetate of methyl in ACN (500 ml). The resulting heterogeneous mixture is stirred for 4 days and the solid is removed by filtration. Et2O is added and washed with H2O and brine. The organic layer is dried (Na2SO), filtered and concentrated. The crude residue is purified by flash chromatography (10% EtOAc / hexanes) to yield the product (4.29 g). b. 2- (2-hydroxyphenyl) -6-methyl-5- (2-methyl-2-propen-1-yl) -3- (2-phenylethyl-4 (3H) -pyrimidinone The title compound is prepared from according to the procedure of example 26 except substituting 2-acetyl-4-methyl-4- ethyl pentanoate by ethyl 2-chloro-3-oxobutanoate and subsequent deprotection using the BBr3 method. MS (ES) m / e 361 [M + Hf.

EXAMPLE 114 Preparation of 5- (cyclobutylmethyl) -6-methyl-2-f2- (methyloxy) phenan-3- (2-phenylethyl) -4 (3H) -pyrimidinine The title compound is prepared according to the procedure of Example 26 except substituting 2-cyclobutylmethyl-3-oxo-butyric acid ethyl ester for ethyl 2-chloro-3-oxobutanoate. MS (ES) m / e 389 [M + Hf.

EXAMPLE 115 Preparation of 5- (cyclobutylmethyl) -2-r2-hydroxyphenyl] -6-methyl-3- (2-phenylethyl) -4 (3H) -pyridiminone The title compound is prepared in deprotection of Example 114 using BBr3 as previously described. MS (ES) m / e 375 [M + Hf.

EXAMPLE 116 Preparation of 2- (2-hydroxyphenyl) -6,6-dimethyl-3- (2-phenylethyl) -4a, 5.6.7, 8.8a- hexahydro-4 (3H) -quinazolinone The title compound is prepared according to the procedure of Example 26 except substituting methyl 5,5-dimethyl-2-oxocyclohexanecarboxylate (synthesized in accordance with procedure reported in Can. J. Chem. 66 (9) 2345-2347, 1988) by ethyl 2-chloro-3-oxobutanoate and subsequent deprotection using the BBr3 method. MS (ES) m / e 375 [M + Hf.

EXAMPLE 117 Preparation of 5- (cyclopropylmethyl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone 3-fluoro-2-hydroxyl benzamide? you (iPr?))., reflux to. Ethyl 2- (cyclopropylmethyl) -3-oxobutanoate Ethyl 3-oxobutanoate (4.0 g, 31 mmol) is added to a suspension of NaOEt (4.9 g, 36.2 mmol) in 40 mL of absolute EtOAc. The reaction temperature is rinsed at 50 ° C and stirred for 15 minutes wherein bromomethylcyclopropane (4.9 g, 36.2 mmol) is added at 90 ° C in 2 portions in 0.5 h and is heated at reflux for 12 hours. The reaction is concentrated in vacuo and the residue is treated with saturated NH 4 Cl solution and extracted with ether. The combined organic layers are dried (MgSO) filter and concentrate to give ethyl 2- (cyclopropylmethyl) -3-oxobutanoate (4.8 g) in 84% yield. b. 2- (cyclopropylmethyl) -3-oxo-N- (2-phenylethyl) butanamide A solution of DME (5 ml) of phenylmethyl 2-cyclopropyl-3-oxobutanoate (4.8 g, 0.026 mol), phenethylamine (3.1 ml, 0.024) mol) and ethanol (0.5 ml) is subjected to irradiation in microwaves at 180 ° C for 1200 seconds. The reaction mixture is purified by flash column chromatography (30% ethyl acetate / hexanes) to provide the desired product as a white solid in 30% yield (2.0 g) c. 5- (Cyclopropylmethyl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrin-β-idinone The title compound is prepared following the procedure briefly described in example 11, step d, except substituting 2- (cyclopropylmethyl) -3-oxo-N- (2-phenylethyl) butanamide for 3-oxo-N- (2-phenylethyl) butanamide. MS (ES) m / e 379 [M + Hf.

EXAMPLE 118 Preparation of 5-cyclopropyl-2- (3-f1uoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone to. Phenylmethyl cyclopropylacetate To a solution of cyclopropylacetic acid (5.0 g, 0.05 mol) in DMF (100 ml) is added K2CO3 (6.9 g, 0.05 mol) and benzyl bromide (5.95 ml, 0.05 mol). The reaction is stirred at room temperature overnight. The reaction mixture is diluted with EtOAc and washed with dilute HCl and brine. Dry over Na2SO, filter and concentrate. The crude residue is purified by chromatography on silica gel (Biotage) using EtOAc / hexane (0-60%) to give the product (8.4 g) in 89% yield. b. Phenylmethyl 2-cyclopropyl-3-oxobutanoate To a solution of phenylmethyl cyclopropylacetate (0.6 g, 3.15 mmol) in THF at -78 ° C is added 1 M solution of LiHMDSA (3.75 mL, 3.78 mmol). The reaction is stirred for 10 minutes then acetyl chloride (0.27 ml, 3.78 mmol) is added and stirring is continued for an additional 1 h. The The reaction is quenched with saturated NH CI and diethyl ether is added. This mixture is poured into H O followed by the separation of the organic layer. The organic layer is dried over Na2SO4, filtered and concentrated. The crude residue is purified by flash column chromatography purification system using EtOAc / hexane (0-60%) to provide the product (0.4 g) in 55% yield. c. 2-cyclopropyl-3-oxo-N- (2-phenylethyl) butanamide A solution of DME (10 ml) of phenylmethyl 2-cyclopropyl-3-oxobutanoate (1.6 g, 6.88 mmol), phenethylamine (0.8 g, 6.54 mmol) and ethanol (0.5 ml) is subjected to microwave irradiation at 180 ° C for 1200 seconds. The reaction mixture is purified by flash column chromatography (30% ethyl acetate / hexanes) to provide the desired product as a white solid in 38% yield (0.64 g). MS (m / z): 246 (M + H). d. 5-cyclopropyl-2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone The title compound is prepared following the procedure briefly described in example 11, step d, except substituting 2-cyclopropyl-3-oxo-N- (2-phenylethyl) butanamide for 3-oxo-N- (2-phenylethyl) butanamide. MS (ES) m / e 365 [M + H] +.

EXAMPLE 119 Preparation of 2- (3-f1uoro-2-hydroxyphenyl) -6-methyl-5- (3-methylbutyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone na to. Ethyl 2-acetyl-5-methylhexanoate To the suspension of NaOEt (2.5 g, 0.037 mol) in 40 ml of dry EtOH is added ethyl 3-oxobutanoate (4.0 g, 0.031 mol) from a syringe and stirred for 15 minutes . The reaction is then refluxed gently and 1-bromo-3-methyl butane (4.4 ml, 0.037 mol) is added in portions over 2 hours. The reflux is continued for 16 hours. In cooling, it is concentrated and diluted with a mixture of Et20 and ammonium chloride. The aqueous layer is re-extracted with EtOAc, dried (Na2SO4), filtered and concentrated. The crude residue is purified by 10% EtOAc in hexanes to provide the clean product (4.18 g) in 67% yield. b. 2-Acetyl-5-methylhexanoic acid A round bottom flask is charged with ethyl 2-acetyl-5-methylhexanoate (4.18 g, 0.021 mol). To this is added a cold solution of 41.5 ml of 0.5N NaOH. The reaction mixture is stirred at this temperature until the starting material is completely consumed. The reaction mixture is extracted with diethyl ether and the aqueous layer is acidified by 5% HCl and extracted with dichloromethane (x3). The combined organic layers are dried (Na2SO), filtered and concentrated and taken directly in the next step. c. 2-Acetyl-N- [2- (3-fluorophenyl) etyl-5-methylhexanamide To a solution of 2-acetyl-5-methylhexanoic acid (2.4 g, 0.014 mol) in DMF is added 3-fluorophenethylamine (1.64 ml, 0.0126 mol), HBTU (5.49 g, 0.0145 mol) and TEA (2 ml, 1.15 mol) is added subsequently and the reaction is stirred at room temperature. The reaction mixture is concentrated, diluted with H2O and extracted with dichloromethane. The extracts are washed with 1 N HCl, followed by 5% NaHCO3 solution and brine. The combined organic layers are dried (Na2SO4), filtered and concentrated and purified by flash column chromatography (MeOH / 5% dichloromethane) to give 0.73 g of the product. d. (2Z) -3-amino-N-f2- (3-fluorophenyl) etl-2- (3-methylbutyl) -2-butenamide A solution of 2-acetyl-N- [2- (3-fluorophenyl) ethyl ] -5-methylhexanamide (0.73 g, 0.00249 mol) in dry diethyl ether (100 ml) and THF (10 ml) at 0 ° C is saturated with ammonia gas for 3 h. ACI3 (0.5 g) is added, and the mixture is allowed to warm to room temperature while stirring overnight. The resulting suspension is filtered, and the filtrate is concentrated to provide the product (0.35 g). and. 3-fluoro-N - [(1Z) -2 - (([2- (3-fluorophenyl) ethylamino) carbonyl) -1,5-dimethyl-1-hexen-1-in-2-hydroxybenzamide To an acid solution 3-fluoro-2-hydroxybenzoic acid (0.21 g, 1.32 mmol) and (2Z) -3-amino-N- [2- (3-fluorophenyl) ethyl] -2- (3-methylbutyl) -2-butenamide (0.35 g , 1.2 mmol) in dry THF is added EDC (0.25 g, 1.32 mmol), HOBt (0.178 g, 1.32 mmol) and TEA (0.20 mL, 1.32 mmol) consecutively. The reaction is stirred at room temperature for 18 h. The reaction is diluted with EtOAc and washed with dilute HCl, 5% NaHC 3 3 and brine. The organic layer is separated, dried over Na 2 SO 4, filtered and concentrated. The crude product is purified by flash column chromatography (5% MeOH / DCM) to yield the desired product (0.08 g). MS (ES) m / e 431 [M + Hf.

F. 2- (3-fluoro-2-hydroxyphenyl) -6-methyl-5- (3-methylbutyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone 3-fluoro-N - [(1Z) -2 - ( { [2- (3-fluorophenyl) ethyl] amino.} Carbonyl) -1,5-dimethyl-1-hexen-1-yl] -2-hydroxybenzamide (0.08 g) is taken in ethanol (5. ml) and 5 ml of 25% NaOH is added and the reaction is heated to reflux overnight. After the reaction is cooled to room temperature the pH is adjusted to ~1 with 3N HCl and extracted with dichloromethane. The combined organic layers are dried over Na2SO, filtered and concentrated. The crude product is purified by flash column chromatography (MeOH / 5% DCM) followed by preparative TLC (50% EtOAc / hexanes) to produce the desired product. MS (ES) m / e 413 [M + Hf.

EXAMPLE 120 Preparation of 5- (2-cyclohexylethyl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone The preparation of the title compound follows the methods described in Example 119 except substituting 1-bromo-3-methyl butane for bromoethyl cyclohexane and 3-fluorophenethylamine for 2-fluorophenethylamine.

MS (ES) m / e 453 [M + H] +.

EXAMPLE 121 Preparation of 5- (cyclohexylmethyl) -2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone The title compound is prepared following the general procedures of example 119 except substituting 2- (2-cyclohexylethyl) -3-oxobutanoic acid for 2-acetyl-5-methylhexanoic acid and phenethylamine for 3-fluorophenethylamine in step 119c and salicylic acid for 3-fluoro-2-hydroxybenzoic acid in step 119d. MS (ES) m / e 403 [M + Hf.

EXAMPLE 122 Preparation of 2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- (phenylmethyl) -4 (3H) -pyrimidinone The title compound is prepared following the general procedures of Example 119 except substituting benzyl bromide for 1-bromo-3-methyl butanone. MS (SE) m / e 433 [M + Hf.

EXAMPLE 123 Preparation of 5-amino-2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone % Pd / C EtOH, H, 10% Pd / C EtOH, H, a, 5-r (diphenylmethylidene) aminol-6-methyl-3- (2-phenylethyl) -2- (2-f (phenylmethyl) oxylphenyl) -4 (3H) -pyrimidinone To a solution of 5-bromo-6- methyl-3- (2-phenylethyl) -2-. { 2 - [(phenylmethyl) oxy] phenyl} -4 (3H) -pyrimidinone (2.74 g, 5.76 mmol) and 1,1-diphenylmethanoimine (1.25 g, 6.92 mmol) in 45 ml of toluene is degassed for 5 minutes; then add Pd2 (dba) 3 (0.264, 0.283 mmol), and BINAP (0.538 g, 0.864 mmol) and degas again for 10 minutes followed by NaOtBu (0.775 g, 0.864 mmol) and heat for 12 hours at 80 ° C. The reaction mixture is concentrated in vacuo and the column chromatography on flash silica gel and elute with hexane / EtOAc to provide 3.2 g of the title compound (79%). MS (ES) m / e 576 [M + Hf. b. 5-amino-6-methyl-3- (2-phenylethyl) -2- (2 - ((phenylmethyl) oxy) phenyl) -4 (3H) -pyrimidinone It is treated 5 - [(diphenylmethylidene) amino] -6-methyl -3- (2-phenylethyl) -2-. { 2 - [(phenylmethyl) oxy] phenyl} -4 (3H) -pyrimidinone with 3 ml of 3N HCl in 20 ml of THF at room temperature for 12 hours. The reaction is concentrated and triturated with ether. The resulting white solid is filtered, dissolved in water and the pH adjusted to 13. The aqueous solution is extracted with dichloromethane, washed with brine, dried (MgSO4), filtered and concentrated to give 2 g of the title compound. (87%). MS (ES) m / e 412 [M + Hf. p 5-amino-2- (2-hydroxyphenyl) -6-methyl-3- (2-phenyletin-4 (3H) -pyrimidinone The title compound is prepared by catalytic hydrogenolysis of 6-amino-6-methyl- 3- (2-phenylethyl) -2- {2 - [(phenylmethyl) oxy] phenyl} -4- (3H) -pyrimidinone as previously described MS (ES) m / e 322 [M + Hf.

EXAMPLE 124 Preparation of 2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- (1-piperidin) -4 (3H) -pyrimidinone To a solution of 5-amino-6-methyl-3- (2-phenylethyl) -2-. { 2 - [(phenylmethyl) oxy] phenyl} -4 (3H) -pyridinone (0.1 g, 0.24 mmol) of Example 123b in 2. 5 ml of acetonitrile is added 1,5-dibromopentane (0.033 ml, 0.24 mmol) and K2CO3 (0.084 g, 6.1 mmol). The reaction is heated to reflux overnight.

LCMS shows a very small amount of the product. Additional amount of 1,5-dibromopentane (0.066g, 0.48 mmol) is added and the reaction is continued for 48 hours. Upon cooling, the reaction mixture is diluted with EtOAc and washed with 1 N HCl. The organic layer is separated and dried over Na2SO4. It is filtered and concentrated and purified by Biotage (0-50% ethyl acetate / hexane) to yield pure amide (0.05 g) in 43% yield. Subsequent debenzylation provides the title compound. MS (m / z) 390.2 [M + Hf EXAMPLE 125 Preparation of 5- (dimethylamino) -2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone To a solution of 5-amino-6-methyl-3- (2-phenylethyl) -2-. { 2- . { (phenylmethyl) oxy} phenyl } -4 (3H) -pyrimidinone from Example 123 (0.1 g, 0.243 mmol), iodomethane (1 mL) and K2C? 3 (1.0 g) in acetone is stirred at room temperature for 12 h. The reaction mixture is concentrated in vacuo, redissolved in DME, washed with water, dried (MgSO4), filtered and concentrated to provide 0.1 g of the product in 90% yield. MS (ES) m / e 440 [M + Hf Subsequent deprotection via BBr3 is previously described providing the objective. MS (ES) m / e 350 [M + Hf.

EXAMPLE 126 Preparation of N-r2- (2-hydroxyphenyl) -4-methyl-6-oxo-1- (2-phenylethyl) -1,6-dihydro-5-pyrimidinin-2,2-dimethylpropanamide To a solution of 5-amino-6-methyl-3- (2-phenylethyl) -2-. { 2- [(phenylmethyl) oxy] phenyl} -4 (3H) -pyrimidinone from Example 123b (0.2 g, 0.486 mmol) and 2,2-dimethylpropanoyl chloride (0.072 g, 0.584 mmol), TEA (0.14 mL, 0.973 mmol) in dichloromethane at room temperature and stirred for 12 hours.

The reaction mixture is concentrated in vacuo, redissolved in dichloromethane and washed with 1 N HCl, brine, dried (MgSO4), filtered and concentrated to give 2,2-dimethyl-N- (4-methyl) -6-oxo-1 - (2-phenylethyl) -2- [2 - [(phenylmethyl) oxy] phenyl] -1,6-dihydro-5-pyrimidinyl) propanamide as an amber oil (0.2 g) in 83 Performance% MS (ES) m / e 496 [M + Hf. Subsequent deprotection via BBr3 as described previously yields the title compound. MS (ES) m / e 406 [M + Hf.

EXAMPLE 127 Preparation of N-f2- (2-hydroxyphenyl) -4-methyl-6-oxo-1- (2-phenylethyl-1,6-dihydro-5-pyrimidinyl) -2-methylpropanamide The title compound is synthesized according to the procedure of Example 126 except substituting 2-methylpropanoyl chloride for 2,2-dimethylpropanoyl chloride. MS (ES) m / e 392 [M + Hf.

EXAMPLE 128 Preparation of N-r2- (2-hydroxyphenyl) -4-methyl-6-oxo-1- (2-phenylethyl) -1,6-dihydro-5-pyrimidinyl-1-N-2-dimethylpropanamide To a solution of 2,2-dimethyl-N- (4-methyl-6-oxo-1- (2-phenylethyl) -2-. {2- 2- [(phenylmethyl) oxy] phenyl] -1-6. dihydro-5-pyrimidinyl) propanamide from Example 127 (0.2 g, 0.415 mmol), iodomethane (0.12 mL, 1.2 mmol) and 60% NaH (0.031 g, 0.72 mmol) in 10 mL of DMF is stirred at room temperature for 12 hours. hours, it Concentrate in vacuo and dilute with water and extract with DME. The extracts are washed with brine, dried and concentrated. The crude product is subjected to flash column chromatography on silica gel and eluted with hexane / EtOAc (7: 3) to provide 0.11 g in 53% yield. MS (ES) m / e 496 [M + Hf. The final objective is prepared via deprotection of BBr3 as previously described. MS (ES) m / e 406 [M + H] +.

EXAMPLE 129 Preparation of 5- (dipropylamino) -2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone A solution of 5-amino-6-methyl-3- (2-phenylethyl) -2-. { 2 - [(phenylmethyl) oxy] phenyl} -4 (3H) -pyrimidinone (0.15 g, 0.365 mmol), vinyl bromide (0.132 g, 1.09 mmol) and K2CO3 (0.151 g, 1.09 mmol) in acetonitrile is heated under reflux for 18 hours. The reaction mixture is concentrated in vacuo, diluted with water and extracted with dichloromethane; The extracts are washed with brine, dried (MgSO), filtered and concentrated to provide the mixture of mono and dialkylated products. Bis-alkylated product MS (ES) m / e 492 [M + Hf; Monoalkylated product EM (ES) m / e 452. { M + Hf. The above mixture 0.13 g is hydrogenated under atmospheric pressure in 10 ml of EtOH and 10 mg of 10% Pd / C for 18 hours. The crude product is subjected to flash silica gel column chromatography and eluted with hexane / EtOAc (6: 4) to provide 0.023 g of the title compound. MS (ES) m / e 406 [M + H] +.

EXAMPLE 130 Preparation of 5- (diethylamino) -2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone A solution of 5-amino-3- (2-phenylethyl) -2-. { 2 - [(2-phenylmethyl) oxy] phenyl} -4 (3H) -pyrimidinone (0.16 g, 0.389 mmol), ethyl bromide (0.212 g, 1.96 mmol) and CsCO3 (1.9 g, 5.85 mmol) in DMF is stirred at 40 ° C for 18 hours. The reaction mixture is concentrated in vacuo, diluted with water and extracted with dichloromethane; the extracts are washed with brine, Dry (MgSO4), filter and concentrate to provide the mixture of mono and dialkylated products. Bis-alkylated product: MS (ES) m / e 468 [M + H] +; Monoalkylated product EM (ES) m / e 440 [M + Hf. The above mixture is hydrogenated under atmospheric pressure as previously detailed to produce the desired product. MS (ES) m / e 378 [M + Hf.

EXAMPLE 131 Preparation of 5- (ethylamine) -2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone The title compound is produced as a by-product of example 130. MS (ES) m / e 350 [M + Hf.

EXAMPLE 132 Preparation of 2- (2-hydroxyphenyl) -5- (2-methylpropyl) -3- (2-phenylethyl) -6-propyl-4 (3H) -pyrimidinone The title compound is prepared according to the procedures briefly described in Example 45 except substituting 6-methyl-2- (2- {[[methyloxy) methyl] oxy} phenyl) -5- (2-methylpropyl) ) -3- (2-phenylethyl) -4 (3H) -pyrimidinone from example 112 by 5-ethyl-2- (3-fluoro-2-. {[[(Methyloxy) methyl] oxy} phenyl) -3 - [2- (2-fluorophenyl) ethyl] -6-methyl-4 (3H) -pyrimidinone and iodoethane by iodomethane in step 45e. MS (ES) m / e 391 [M + Hf.

EXAMPLE 133 Preparation of 6-ethyl-2- (2-hydroxyphenyl) -5- (2-methylpropyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone The title compound is prepared according to the procedures briefly described in Example 45 except substituting 6-methyl-2- (2- {[[methyloxy) methyl] oxy} phenyl) -5- (2-methylpropyl) ) -3- (2-phenylethyl) -4 (3H) -pyrimidinone from example 112 by 5-ethyl-2- (3-fluoro-2-. {[[(Methyloxy) methyl] oxy} phenyl) -3 - [2- (2-fluorophenyl) ethyl] -6-methyl-4 (3H) -pyrimidinone in step 45e. MS (ES) m / e 377 [M + Hf.

EXAMPLE 134 Preparation of 6-butyl-2- (2-hydroxyphenyl) -5- (2-methylpropyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone The title compound is prepared according to the procedures briefly described in Example 45 except substituting 6-methyl-2- (2. {[[(Methyloxy) methyl] oxy} phenyl) -5- (2-methylpropyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone of example 112 by 5-ethyl-2- (3-fluoro-2-. {[[(methyloxy) methyl] oxy} phenyl) -3- [2- (2-fluorophenyl) ethyl] -8-methyl-4 (3H ) -primidinone and iodopropane by iodomethane in step 45e. MS (ES) m / e 405 [M + Hf.

EXAMPLE 135 Preparation of 2- (2-hydroxyphenyl) -5- (2-methylpropyl) -3- (2-phenylethyl) -6-f2- [(phenylmethyl) oxylethyl (3H) -pyrimidinone The title compound is prepared according to the procedures briefly described in Example 45 except substituting 6-methyl-2-. { [(methyloxy) methyl] oxy} phenyl) -5- (2-methylpropyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone from example 112 by 5-ethyl-2- (3-fluoro-2-. {[[(methyloxy) methyl] ] oxy] phenyl) -3- [2- (2-fluorophenyl) ethyl] -6-methyl-4 (3H) -pyrimidinone and chloromethylphenylmethyl ether by iodine methane in steps 45e. MS (ES) m / e 483 [M + Hf.

EXAMPLE 136 Preparation of 6- (2-hydroxyethyl) -2- (2-hydroxyphenyl) -5- (2-methylpropyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone to. f2- (2-Hydroxyphenyl) -5- (2-methylpropyl) -6-oxo-1- (2-phenylethyl) -1,6-dihydro-4-pyrimidinyl acetate methyl ester The title compound is prepared according to the procedures briefly described in Example 45 except substituting 6-methyl-2- (2- {[[(methyloxy) methyl] oxy} phenyl) -5- (2-methylpropyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone from example 112 by 5-ethyl-2- (3-fluoro-2-. {[[(Methyloxy) methyl] oxy} phenyl) -3- [2- (2-fluorophenyl) ethyl] ] -6-methyl-4 (3H) -pyrimidinone and ethyl chloroformate by iodomethane in steps 45e. MS (ES) m / e 479 [M + Hf. b. 6- (2-hydroxyethyl) -2-r2 - ([(methyloxy) methyloxy) phenyl-5- (2-methylpropyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone Crude product 0.2 g (0.419 mmol) in THF 10 ml and at room temperature is treated with 0.1 g (4.8 mmol) of LiBH4 and stirred for 18 hours. The reaction mixture is concentrated in vacuo, the solid residue is treated with excess 1N HCl solution and extracted with dichloromethane, dried (MgSO), filtered and concentrated to provide 0.2 g of crude product. MS (ES) m / e 437 [M + Hf. c. 6- (2-hydroxyethyl) -2- (2-hydroxyphenyl) -5- (2-methylpropyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone The above crude product is treated with 5 ml of TFA in 10 ml of dichloromethane and stir at room temperature for 16 hours. Concentrate in vacuo and treat with 5% Na 2 C 3 solution and extract with dichloromethane, dry (MgSO), filter and concentrate to give the crude product which is purified on a flash silica gel column and dried. elute with hexane / EtOAc to provide the crude product (0.030 g). MS (ES) m / e 393 [M + Hf.

EXAMPLE 137 Preparation of 6-r2- (methyloxy) ethyl-5- (2-methyl-1-propen-1-yl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone a, 5-bromo-6-I2- (methyloxy) etyl-3- (2-phenylethyl) -2- (2- [(phenylmethyl) oxylphenyl) -4 (3H) -pyrimidinone To a solution at -78 ° C 5-bromo-6-methyl-3- (2-phenylethyl) -2-. { 2 - [(phenylmethyl) oxy] phenyl} -4 (3H) -pyrimidinone (0.475 g, 0.001 mol) in THF is added LDA (0.0015 mol, prepared from n-BuLi and diisopropylamine) in THF and the reaction is stirred for 1 h. MOMCI (0.12 ml, 0.0015 mmol) is added and the reaction is stirred until the starting material is completely consumed. The reaction is quenched by NH4CI, extracted with EtOAc. Then the organic layer is washed with brine, dried over Na2SO, filtered and concentrated. The residue is purified by flash column chromatography (30% EtOAc / hexane) to provide the product (0.2 g) in 39% yield. b. 6- [2- (methoxyl) etill-5- (2-methyl-1-propen-1 -yl) -3- (2-phenylethyl) -2- (2 - [(phenylmethyl) oxphenyl) -4 (3H) -pyrimidinone To a solution of 5-bromo-6- [2- (methyloxy) ethyl] -3- (2-phenylethyl) -2-. { 2 - [(phenylmethyl) oxy] phenyl} -4 (3H) -pyrimidinone (0.2 g, 0.39 mmol) in dioxane (5 ml) is added 2-methyl-1-propen-1-yl-boronic acid (0.077 g) is dissolved in solvent mixture of 0.5 ml of ethanol and 0.5 ml of aqueous sodium carbonate (0.19 g, 0.39 mmol) in a microwave reaction vessel. This mixture is irradiated at 150 ° C for 1000 seconds. The reaction mixture is filtered through a syringe filter (Acrodisc CR25 mm with 0.2 μm PTFE membrane). The filtrate is diluted with EtOAc and washed with brine and the organic layer is separated, dried over sodium sulfate, filtered and concentrated. The residue is purified by chromatography on silica gel (30% ethyl acetate / hexane) to yield the desired product (0.20 g) in 40% yield. Catalytic hydrogenolysis provides the title compound. MS (ES) m / e 405 [M + Hf.

EXAMPLE 138 Preparation of 2- (2-hydroxyphenyl) -6-r2- (methyloxy) etin-5- (2-methylpropyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone The title compound is a by-product of the deprotection step, step 137c in example 137. MS (ES) m / e 407 [M + Hf.

EXAMPLE 139 Preparation of 5- (dimethylamino) -2- (3-fluoro-2-hydroxyphenyl-6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone a, 5-amino-2-. { 3-Fluoro-2 - [(phenylmethyloxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone The title compound is prepared following the methods described by Example 123 except using 5-bromo-2 -. { 3-fluoro-2- [(phenylmethyl) oxy] phenyl} -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone of example 11 in place of 5-bromo-2-. { 2 - [(phenylmethyl) oxy] phenyl} -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone b, 5- (dimethylamino) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone The title compound is prepared following the methods described by example 125 except using 5-amino-2-. { 3-fluoro-2 - [(phenylmethyl) oxy] phenyl} -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone in place of 5-amino-6-methyl-2- (2-phenylethyl) -2-. { 2 - [(phenylmethyl) oxy] phenyl} -4 (3H) -pyrimidinone. MS (ES) m / e 368 [M + Hf.

EXAMPLE 140 Preparation of 5- (dimethylamino) -2-r2-fluoro-3-hydroxyphenyl] -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone a, 2-2 2-fluoro-3- (methyloxy) phenyl-6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone 3-Oxo-N- (2-phenylethyl) butanamide (2.09 g, 0.01 mol) is placed in a 44 ml round bottom flask. To this is added titanium isopropoxide (). Although the reaction is stirred, 2-fluoro-3- (methyloxy) benzamide (2.58 g, 0.015 mol) is added, a condenser is placed and the reaction is heated to reflux (oil bath temperature = 150 ° C). The reaction is run for 36 hours and cooled to room temperature and diluted with dichloromethane. 3N HCl is added slowly until the solid that is initially formed has diluted. The organic layer is separated and the aqueous layer is further extracted with dichloromethane. The combined organic layer is dried over sodium sulfate and filtered and concentrated. The crude solid is triturated with Et2O. The solid is filtered (1.5 g) and taken in the next step without further purification. b. 5-bromo-2-r2-fluoro-3- (methyloxy) phenyl-6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone 2- [2-fluoro-3- (methyloxy) phenyl is taken ] -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone (1.5 g, 4.44 mmol) in glacial acetic acid. To this is added bromine (0.34 ml, 6.66 mmol) dropwise by syringe. The reaction is stirred for 16 hours. Ethyl acetate is added and the acetic acid is washed with saturated sodium bicarbonate. The organic layer is further washed with saturated sodium hydrogen sulfite / sodium metabisulfite solution and sodium sulfate is dried. Sodium sulfate is filtered and the organic layer is concentrated. The crude product is triturated with Et2O to obtain the desired product. c. 5-bromo-2- (2-fluoro-3-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone 5-bromo-2- [2-fluoro-3- ( methyloxy) phenyl] -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone (1.0 g, 0.0024 mol) in DCM (15 ml) and cooled to 0 ° C. To this is added 12 ml of 1 M BBr3 in DCM and stirred overnight while heating to room temperature. The reaction is diluted with DCM and washed with Na2CO3 and the organic layers are dried (Na2SO4), filtered and concentrated to yield the product (0.9 g) in 93% yield. MS (ES) m / e 405 [M + H] +. g \ 5-bromo-2-. { 2-fluoro-3-r (phenylmethyl) oxy-phenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone 5-Bromo-2- is dissolved. { 2-fluoro-3-hydroxyphenyl} -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone (0.9 g, 0.00223 mol) in dry DMF (10 ml). To this is added potassium carbonate (0.463 g, 0.00335 mol) and benzyl bromide (0.4 ml, 0.0035 mol) subsequently. The reaction is heated to 60 ° C and stirred for 16 hours. The reaction mixture is cooled to room temperature, filtered and diluted with EtOAc. This is washed successively with 5% HCl and saturated sodium chloride solution. The organic layer is dried over sodium sulfate and concentrated to provide 1.0 g of desired compound. MS (ES) m / e 493 [M + H] +. and. 5 - [(diphenylmethylidene) amnol-2-. { 2-fluoro-3 - [(phenylmethyl) oxylphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone To a solution of 5-bromo-2-. { 2-fluoro-3 - [(phenylmethyl) oxy] phenyl} -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone (1.0 g, 0.00203 mol) and 1,1-diphenylmethanoimine (0.41 ml, 0.00243 mol) in 10 ml of toluene are degassed for 5 minutes; then Pd2 (dba) 3 (0.093 g, 0.0001 mol) and BINAP (0.189 g, 0.000304 mol) is added and degassed again for 10 minutes followed by NaOtBu (0.273 g, 0.00283 mol) and heated for 12 h at 80 ° C . The reaction mixture is concentrated in vacuo and flash column chromatography on flash silica gel is carried out and eluted with hexane / EtOAc to give 0.3 g of the title compound (25%). MS (ES) m / e 594 [M + Hf.

F. 5-amino-2- (2-fluoro-3 - [(phenylmethyl) oxy-phenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone 5 - [(diphenylmethylidene)] amino] -2-. { 2-fluoro-3 - [(- phenylmethyl) oxy] phenyl} -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone (0.3 g, 0.000506 mol) with 3 ml of 3N HCl in 20 ml of THF at room temperature for 12 h. The reaction is concentrated and triturated with ether. The resulting white solid is filtered, dissolved in water and the pH adjusted to 13. The aqueous solution is extracted with dichloromethane, washed with brine, dried (MgSO4), filtered and concentrated to provide 0.2 g of the Title (92%). q. 5- (dimethylamino) -2- (2-fluoro-3-r (phenylmethyl) oxphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrmidinone The amine (0.2 g, 0.465 mmol) is taken up in dry acetone (5 ml). To this is added potassium carbonate (0.128 g, 0.93 mmol) and methyl iodide (0.2 ml, 0.00233 mol) consecutively. The reaction is stirred overnight and concentrated. The crude mixture is diluted with H2O and extracted with DCM. The combined organic layers are combined, dried (Na2SO) and concentrated. The residue is purified by flash chromatography using 30% EtOAc / hexanes to yield the product (0.1 g) in 47% yield. The catalytic hydrogenolysis as described previously provides the product. MS (ES) m / e 368 [M + Hf.

EXAMPLE 141 Preparation of 6-methyl-2,5-diphenyl-3- (2-phenylethyl) -4 (3H) -pyrimidone to. 6-Methylene-2-phenyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone 3-Oxo-N- (2-phenylethyl) butanamide (2 g, 0.0097 mol) of the example 11 is placed in the 500 ml round bottom flask. To this is added titanium isopropoxide (37 ml, 0.13 mol). Although the reaction is stirred, benzamide (1.8 g, 0.0146 mol) is added, a condenser is placed and the reaction is heated to reflux (oil bath temperature = 150 ° C). The reaction is run for 36 hours and cooled to room temperature and diluted with dichloromethane. 3N HCl is added slowly until the solid that is initially formed has dissolved. The organic layer is separated and the aqueous layer is further extracted with dichloromethane. The combined organic layer is dried over sodium sulfate and filtered and concentrated. The crude solid is triturated with Et2O. The solid (2.1 g, 50%) is filtered and taken in the next step without purification. b. 5-bromo-6-methyl-2-phenyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone 6-methyl-2-phenyl-3- (2-phenylethyl) -4 ( 3H) -pyrimidinone (2.1 g, 0.0074 mol) is taken in glacial acetic acid (29 ml). To this is added bromine (1.2 ml, 0.0074 mol) drop by drop in a syringe. The reaction is stirred for 16 hours. Ethyl acetate is added and the acetic acid is washed with saturated sodium bicarbonate. The organic layer is further washed with saturated sodium hydrogen sulfite / sodium metabisulfite solution and dried over sodium sulfate. Sodium sulfate is filtered and the organic layer is concentrated. The crude product is triturated with Et2O to obtain the desired product (2 g) in 75% yield. c. 6-methyl-2,5-diphenyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone To a solution of 5-bromo-6-methyl-2-phenyl-3- (2-phenylethyl) - 4 (3H) -pyrimidinone (0.25 g, 0.68 mmol) in dioxane (6 ml) is added phenylboronic acid (0.165 g, 0.0014 mol) dissolved in the solvent mixture of 0.5 ml of ethanol and 0.5 ml of aqueous sodium carbonate ( 0.09 g, 0.8 mmol) in a microwave reaction vessel. The mixture is irradiated at 150 ° C for 2400 seconds The reaction mixture is filtered through a syringe filter (Acrodísc CR25 mm with 0.2 μm PTFE membrane). The filtrate is diluted with EtOAc and washed with brine, separated, dried over sodium sulfate, filtered, concentrated in vacuo and the residue was purified by chromatography on silica gel (ethyl acetate / 30% hexane) to produce the desired product (0.07 g). MS (ES) m / e 366 [M + Hf.

EXAMPLE 142 Preparation of 2- (2-fluorophenyl) -6-methyl-5-phenyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone The title compound is prepared according to the procedures of Example 141 except substituting 2-fluorobenzamide for benzamide. MS (ES) m / e 385 [M + H] +.

EXAMPLE 143 Preparation of 3-r2- (2-chlorophenyl) etn-2- (2-hydroxyphenyl) -5,6,7,8-tetrahydro-4 (3H) -quinazolinone to. 2-methoxy-benzamidine At 0 ° C anhydrous ether is introduced into a flask under Ar, LiHMDS (94 ml, 93.9 mmol) and then introduced and stirred for 5 minutes. 2-Methoxy-benzonitrile (5 g, 37.6 mol) is added and the reaction mixture is stirred at room temperature for 2-3 days. At the end of the reaction the solvent is removed and 200 ml of cold 1N HCl is added and stirred. The aqueous layer is extracted with Et2O, then the pH is adjusted by 6N NaOH to 13. Extraction with CH2Cl2, dried over Na2SO4 and filtered. In the concentration, the above benzamidine compound is obtained in 91% yield. b. 2-f2- (methyloxy) phenyl-5,6,7,8-tetrahydro-4 (1H) -quinazolinone 2-methoxy-benzamidine (150 mg, 1.0 mmol) is dissolved in MeOH / dioxane (15 ml / 5 ml) and cooled to 0 ° C. Then NaOCH3 is added to the % in MeOH (0.44 ml) and stirred for 15 minutes. 2-Oxo-cyclohexanecarboxylic acid ethyl ester (260 mg, 1.5 mmol) is introduced and the reaction mixture is refluxed for 1 h. The reaction is concentrated and the residue is taken up in 10 ml of H2O and acetic acid is used to adjust the pH to 7-8. Extract with CH2Cl2 (3x100 ml). The combined organic layers are dried over Na2SO4. Purification by flash column chromatography, (70% ethyl acetate / hexane) yields the product 220 mg in 86% yield. c. 3-r2- (2-chlorophenyl) ethyl1-2- (2-methoxy-phenol) -5,6,7,8-tetrahydro-4 (3H) -quinazoline Dissolve 2-. { 2-methoxy-phenyl} 5,6,7,8-tetrahydro-3H-quinazolin-4-one (150 mg, 0.6 mmol) in dry DMF (3 ml). NaH (2.9 mg, 1.2 mmol) is added and stirred for 10 minutes at room temperature. Then 2-chloro-phenethyl bromide (655 mg, 3.00 mmol) is added and the mixture is stirred at room temperature overnight. The mixture is poured, the reaction mixture on ice and the mixture of 6N HCl. It is extracted with EtOAc and the organic layer is washed with aqueous NaHC 3, brine and dried over Na 2 SO 4. It is filtered and concentrated and purified by flash column chromatography to obtain the desired product in 38% yield (85 mg). d. 3- [2- (2-chlorophenyl) etyl-2- (2-hydroxyphenyl) -5.6.7.8-tetrahydro-4 (3H) -quinazolinone 3- [2- (2-chlorophenyl) ethyl] -2- ( 2-methoxyphenyl) -5,6,7,8-tetrahydro-4 (3H) -quinazolinone (161 mg, 0.41 mol) in 5 ml of CH2Cl2 is cooled to -60 ° C. Then 2.46 ml of BBr3 (1 M in CH2Cl2) are added and the reaction mixture is allowed to warm to room temperature. At the termination the reaction mixture is diluted with CH 2 Cl 2 and aqueous NaHC 3, then added. The organic layer is separated. The aqueous layer is neutralized by 1 N HCl until the pH is 4 and extracted with CH 2 Cl 2. The organic layers are combined and washed with H O and brine. The organic layer is dried over Na2SO4, filtered and concentrated. The crude residue is purified by flash column chromatography (methanol / 3% -5% methylene chloride) to the product in 69% yield (0.11 g). 1 H NMR (400 MHz, CDCl 3) d 8.59 (s, 1 H), 7.28-7.07 (m, 6H), 6.83 (t, 1 H), 6.81 (d, 1 H), 4.33 (t, 2 H), 3.05 (t, 2H), 2.58 (m, 4H), 1.80 (m, 4H). MS (m / z) 381/383 (M + H).

EXAMPLE 144 Preparation of 3- [2- (3-fluorophenyl) ethyl1-2- (2-hydroxyphenyl) -5,5-dimethyl-5,6,7,8-tetrahydro-4 (3H) -quinazolinone The title compound is prepared by replacing 3-fluorophenethyl bromide with 2-chlorophenethyl bromide and 3,3-dimethyl-2-oxo-cyclohexanecarboxylic acid methyl ester (synthesized according to J.

Org. Chem. 59 (23), 1994; 6922-6927) by 2-oxo-cyclohexanecarboxylic acid ethyl ester in Example 143. 1 H NMR (400 MHz, CDCl 3) d 9.58 (br, 1 H), 7.30 (m, 2 H), 7.28 (m, 1 H) , 7.01 (m, 3H), 6.78 (d, 1 H), 6.68 (m, 1 H), 4.35 (t, 2H), 2.97 (t, 2H), 2.59 (t, 2H), 1.80 (m, 2H) ), 1.64 (m, 2H), 1.45 (s, 6H). MS (m / z) 393.4 (M + H).

EXAMPLE 145 Preparation of 3- (2-cyclohexylethyl) -2- (2-hydroxyphenyl) -5,5-dimethyl-5,6,7,8-tetrahydro-4 (3H) -quinazolinone The title compound is prepared by the substitution of 2-cyclohexylethyl bromide for 2-chlorophenethyl bromide and 3,3-dimethyl-2-oxo-cyclohexanecarboxylic acid methyl ester (synthesized according to J. Org.

Chem; 59 (23); 1994; 6922-6927) by 2-oxo-cyclohexanecarboxylic acid ethyl ester in Example 143. 1 H NMR (400 MHz, CDCl 3): d 9.95 (br, 1 H), 7.01 (m, 2 H), 6.70 (t, 1 H ), 6.65 (d, 1 H), 3.90 (m, 2H), 2.58 (t, 2H), 1.80 (m, 2H), 1.54 (m, 2H), 1.50 (3H), 1.47 (s, 6H), 1.38 (m, 4H), 0.99 (m, 4H), 0.64 (m, 2H). MS (m / z): 381.5 (M + H).

EXAMPLE 146 Preparation of 3-r2- (3-f1-orophenyl) etn-2- (2-furanl) -5,6,7,8-tetrahydro-4 (3H) -quinazolinone to. 2 - [(2-furanylcarbonyl) aminol-1-cyclohexane-1-ethylcarboxylate To a stirred solution of ethyl (2Z) -3-amino-2-propyl-2-pentanoate (500 mg, 2.95 mmol) in dichloromethane 2-furancarbonyl chloride (300 μl, 2.95 mmol) is added at 0 ° C and allowed to warm to room temperature. The reaction is then heated to 50 ° C and stirred for 1 h. The reaction mixture is washed with aqueous NaHC03, the organic layer is dried over NaSO and purified on a silica gel column to provide the product (630 mg, 81%). MS (m / z) (M + H) 264.2. b. 2- (furanyl) -5,6,7,8-tetrahydro-4H-3, 1-benzoxazin-4-one To a stirred solution of 2 - [(2-furanylcarbonyl) amino] -1-cyclohexane-1-carboxylate Ethyl (700 mg, 2.95 mmol) in THF: H20 (10 mL) was added LiOH.H2O (280 mg, 7.35 mmol) and refluxed at 50 ° C for 4 hours. The solvent is removed in vacuo and diluted with dichloromethane followed by the addition of 1N HCl. The organic layer is dried over Na2SO4, filtered, concentrated and used directly in the next step (500 mg, 80%). To a stirred solution of 2 - [(2-furanylcarbonyl) amino] -1-cyclohexene-1-carboxylic acid (500 mg, 2.12 mmol) in dichloromethane (10 ml) is added EDC. HCl (410 mg, 2.13 mmol) and HOBT (60 mg, 0.84 mmol) and stirred for 16 h. The reaction mixture is washed with water, followed by brine, and the organic layer is dried over Na2SO4, filtered, concentrated and purified on a column of silica gel to provide (280 mg, 60%) of the product. MS (m / z) 218.2 (M + H). c. 3-r2- (3-fluorophenyl) etn-2- (2-furanyl) -5,6,7,8-tetrahydro-4 (3H) -quinazolinone To a solution of 2- (2-furanyl) -5 , 6,7,8-tetrahydro-4H-3,1-benzoxazin-4-one (40 mg, 0.184 mmol) is dissolved in AcOH (1 ml), 2- (3-fluorophenyl) ethanamine (51 mg, 0.368) is added. mmol) and heated to reflux for 4pm AcOH is quenched with 6N NaOH and the product is extracted into dichloromethane.

The organic layer is separated, dried over Na2SO4, filtered, concentrated and purified by flash chromatography to give the title compound (25 mg, 40%). MS (m / z) 339.4 (M + H).

EXAMPLE 147 Preparation of 3-r2- (3-fluorophenyl) ethyl-2- (2-thienyl) -5,6,7,8-tetrahydro-4 (3H) -quinazolinone to. 2 - [(2-thienylc; arbonyl) aminol-1-cyclohexene-1-ethylcarboxylate To a stirred solution of ethyl (2Z) -3-amino-2-propyl-2-pentenoate (1.0 g, 5.91 mmol) in dichloromethane is added 2-thiophenecarbonyl chloride (0.87 g, 5.93 mmol) at 0 ° C and it is allowed to warm to room temperature. The reaction is then heated to 50 ° C and stirred for 1 hour. The reaction mixture is washed with aqueous NaHCO3, the organic layer is dried over Na2SO4 and purified on a column of silica gel to provide the product (1.25 g, 76%). b. 2- (2-thienyl) -5,6,7,8-tetrahydro-4H-3,1-benzoxazin-4-one To a stirred solution of 2 - [(2-thienylcarbonyl) amino] -1-cyclohexene-1 ethylcarboxylate (1.25 g, 4.48 mmol) in THF: HO (20 ml) is added LiOH.H2O (600 mg, 14.28 mmol) and heated at reflux at 50 ° C for 4 hours. The solvent is removed in vacuo and diluted with dichloromethane followed by the addition of 1N HCl. The organic layer is dried over Na2SO4, filtered and concentrated and used directly in the next step (89 mg, 81%). To a stirred solution of 2 - [(2-thienylcarbonyl) amino] -1-cyclohexene-1-carboxylic acid (200 mg, 0.796 mmol) in dichloromethane (10 ml) is added EDC. HCl (170 mg, 0.582 mmol) and HOBT (22 mg, 0.162 mmol) and stirred for 16 h. The reaction mixture is washed with water, followed by brine, and the organic layer is dried over Na 2 SO 4, filtered, concentrated and purified on a column of silica gel to provide (110 mg, 59%) of the title compound . MS (ESI) 234.2 (M + H). c. 3-r2- (3-fluorophenyl) etyl-2- (2-thienyl) -5,6,7,8-tetrahydro-4 (3H) -quinazolinone A 2- (2-thienyl) -5,6,7, 8-tetrahydro-4H-3,1-benzoxazin-4-one (50 mg, 0.214 mmol) is dissolved in AcOH (1 ml), 2- (3-fluorophenyl) ethylamine (59 mg, 0.428 mmol) is added and heated refluxed for 16 hours. AcOH is quenched with 6N NaOH and the product is extracted into dichloromethane. The organic layer is separated, dried over Na2SO, filtered, concentrated and purified by flash chromatography to give the title product (30 mg, 40%). MS (ESI) 355.2 (M + H).

EXAMPLE 148 Preparation of Ethyl 2- (2-hydroxyphenyl) -4-methyl-6-oxo-1- (2-phenylethyl) -1,6-dihydro-5-pyrimidinocarbonitrile to. (1Z) -N - ((2 - [(phenylmethyl) oxylphenyl) carbonyl) ethyl ethanimidoate Ethyl acetimidate hydrochloride (1.08 g, 8.74 mmol) is dissolved in toluene (24 ml) and placed under argon. Triethylamine (2.75 ml, 19.7 mmol) is added and the reaction is stirred at room temperature for 10 minutes. 2 - [(Phenylmethyl) oxy] benzoyl chloride (2.16 g, 8.76 mmol) in toluene (8 ml) is added dropwise via addition funnel about 15 minutes. The resulting reaction mixture is stirred for 5 days. The precipitated white solid is filtered off in the distance and rinsed with an excess of toluene. The filtrate is concentrated in vacuo and the crude product (2.45 g) is carried out in the next step without purification. b. 4-Methyl-6-oxo-2- [2 - [(phenylmethyl) oxylfenin-1,6-dihydro-5-pyrimidinecarbonitrile A flask is charged with ethanol (27 ml) under argon. Sodium ethoxide (95%, 0.731 g, 10.2 mmol) is added and the reaction is stirred for 3-5 minutes Cyanoacetamide (0.695 g, 8.27 mmol) is added in one portion and the reaction is stirred for 5 minutes. (1Z) -N- (. {2- [(phenylmethyl) oxy] phenyl} carbonyl) ethyl ethanimidoate (2.45 g, 8.24 mmol) in ethanol (6 ml) is added dropwise about 8 minutes. The reaction mixture is stirred at room temperature for 60 h. The reaction is neutralized with concentrated H2SO4 (0.31 ml) and a yellow solid formed. The reaction is then filtered but in washing the solid is filtered with water, the material is dissolved. The resulting filtrate is extracted three times with CH2Cl2. The combined organic layers are dried over Na2SO4, filtered and concentrated. Column chromatography (CH3OH / CH2Cl2 0-1%) yields 4-methyl-6-oxo-2- [2-. { (phenylmethyl) oxy} phenyl] -1,6-dihydro-5-pyrimidinecarbonitrile (1.85 g, 71% yield). 1 H NMR (400 MHz, Chloroform-d) d ppm 8.55 (d, 1 H), 7.63 (m, 1 H), 7.46 (m, 6 H), 7.20 (m, 2 H), 5.38 (s, 2 H), 2.64 (s, 3H); MS (ESI) 318.2 (M + H) +. c 4-methy1-6-oxo-1- (2-phenylethyl) -2-f2-r (phenylmethyl) oxylfenyl-1,6-dihydro-5-pyrimidinecarbonitrile To a solution of 4-methyl-6- oxo-2-. { 2 - [(phenylmethyl) oxy] phenyl} -1,6-dihydro-5-pyrimidinecarbonitrile (0.265 g, 0.836 mmol) in ethanol: H20 (95: 5, 5.6 ml) is added sodium hydroxide (0.193 g, 4.83 mmol). After completing the solution of 4-methyl-6-oxo-2-. { 2 - [(phenylmethyl) oxy] phenyl} -1,6-Dihydro-5-pyrimidinecarbonitrile, 2-iodoethylbenzene (2.5 mL, 17.3 mmol) is added. He The reaction flask is sealed and refluxed for 27 hours. The reaction mixture is cooled to room temperature and poured into cold H O. The resulting aqueous layer is extracted five times with CH2Cl2. The combined organic layers are washed with saturated Na 2 S 2 O 3 and brine, dried over Na 2 SO, filtered and concentrated. Column chromatography (CH 2 OH / CH 2 Cl 2 0-2%) yields 0.117 g (33%) of the title compound. 1 H NMR (400 MHz, chloroform-d) d ppm 7.45 (m, 1 H), 7.30 (m, 3 H), 7.18 (m, 5 H), 7.05 (m, 2 H), 6.95 (m, 1 H), 6.75 (m, 2H), 5.1 (dd, 2H), 4.40 (m, 1 H), 3.72 (m, 1 H), 2.84 (m, 1 H), 2.76 (m, 1 H), 2.58 (s, 3H) ). MS (ESI) 422.2 (M + H) +. d. 2- (2-hydroxyphenyl) -4-methyl-6-oxo-1- (2-phenylethyl) -1,6-dihydro-5-pyrimidinecarbonitrile Pd / C (10%, 0.017 g) is added to a solution purged of 4-methyl-6-oxo-1- (2-phenylethyl) -2- argon. { 2 - [(phenylmethyl) oxy] phenyl} -1,6-dihydro-5-pyrimidinecarbonitrile (0.156 g, 0.370 mmol) in ethanol (4.0 ml). The reaction is then placed under H2 balloon pressure and stirred for 21 hours. The reaction mixture is filtered through a filter frit clogged with Celite, dried with CH 3 OH and CH 2 Cl 2 and concentrated. Column chromatography (4% CH3OH / CH2Cl2) yields the title compound (0.109 g, 89%). 1 H NMR (400 MHz, DMSO-d) d ppm 10.4 (s, 1 H), 7.40 (m, 1 H), 7.15 (m, 3 H), 7.05 (m, 1 H), 6.95 (m, 1 H) , 6.88 (m, 1 H), 6.75 (m, 2H), 3.95 (m, 2H), 3.31 (s, 3H), 2.73 (m, 2H). MS (ESI) 332.2 (M + H) +.

EXAMPLE 149 Preparation of ethyl 2- (2-hydroxyphenyl) -4-methyl-6-oxo-1- (2-phenylethyl) -1,6-dihydro-5-pyrimidinecarboxylate ilbenzene a, 4-methyl-6-oxo-2- (2 - [(phenylmethyl) oxylphenyl) -1,6-dihydro-5-pyrimidinecarboxylate ethyl A flask is charged with ethanol (25 ml) and argon. Sodium ethoxide (95%, 0.827 g, 11.5 mmol) is added and the reaction is stirred for 3-5 minutes. Ethyl malonate monoamide (1.25 g, 9.53 mmol) is added in one portion and the reaction is stirred for 45 minutes. (1Z) -N- (. {2 - [(phenylmethyl) oxy] phenyl} -carbonyl) ethanimidoate ethyl (2.83 g, 9.52 mmol) in ethanol (14 ml) is added dropwise about 7 minutes The reaction mixture is stirred at room temperature for 67 hours. The reaction is neutralized with concentrated H2SO (0.35 ml). The reaction is diluted with H2O and it is extracted three times with CH2Cl2. The combined organic layers are dried over Na2SO4, filtered and concentrated. Column chromatography (0-1% CH3OH / CH2Cl2) yields 4-methyl-6-oxo-2-. { 2-. { (phenylmethyl) oxy} phenyl } Ethyl 1-6-dihydro-5-pyrimidinecarboxylate (1.68 g crude) which is carried out in the next step. MS (ESI) 365.4 (M + H) +. b. 4-methyl-6-oxo-1- (2-phenylethyl) -2- [2 - ((phenylmethyl) oxy) phenyl-1,6-dihydro-5-pyrimidinecarboxylate ethyl To a solution of 4-methyl-6- oxo-2-. { 2 - [(phenylmethyl) oxy] phenyl} Ethyl 1-6-dihydro-5-pyrimidinecarboxylate (1.68 g, 4.61 mmol) in DMF (13 ml) under argon is added lithium hydride (0.95%, 0.063 g, 7.53 mmol) and the reaction is stirred for 5 minutes . 2- (bromoethyl) benzene (2.0 ml, 14.6 mmol) is added and the reaction is stirred for 28 hours. The reaction mixture is quenched with H2O and extracted twice with ethyl acetate. The combined organic layers are washed with brine, dried over MgSO 4, filtered and concentrated. Purification by column chromatography (25-33% ethyl acetate: hexane) yields 0.190 g (4% yield over 2 steps) of 4-methyl-6-oxo-1- (2-phenylethyl) -2- . { 2 - [(phenylmethyl) oxy] phenyl} Ethyl 1-, 6-dihydro-5-pyrimidinecarboxylate. H NMR (400 MHz, Chloroform-d) d ppm 7.46 (m, 1 H), 7.29 (m, 5H), 7.18 (m, 3H), 7.07 (m, 3H), 6.83 (m, 2H), 5.12 ( d, J = 2.73 Hz, 2H), 4.47 (m, 2H), 4.35 (m, 1 H), 3.72 (m, 1 H), 2.95 (m, 1 H), 2.74 (m, 1 H), 2.44 (s, 3H), 1. 46 (t, J = 7.14 Hz, 3H). MS (ESI) 469.3 (M + H) +. c. Ethyl 2- (2-hydroxyphenyl) -4-methyl-6-oxo-1- (2-phenylethyl) -1,6-dihydro-5-pyrimidinecarboxylate Pd / C (10%, 0.010 g) is added to a solution purged with 4-Methyl-6-oxo-1- (2-phenylethyl) -2- ar. { 2 - [(phenylmethyl) oxy] phenyl} -1Ethyl 6-dihydro-5-pyrimidinecarboxylate (0.092 g, 0.196 mmol) in ethanol (2.4 ml). The reaction is then placed under pressure and the mixture is stirred for 24 hours. The reaction mixture is filtered through a filter frit clogged with Celite, rinsed with CH3OH and CH2Cl2, and concentrated. Column chromatography (1-4% CH3OH / CH2Cl2) yields ethyl 2- (2-hydroxyphenyl) -4-methyl-6-oxo-1- (2-phenylethyl) -1,6-dihydro-5-pyrimidinecarboxylate (0.053 g, 72%). 1 H NMR (400 MHz, Chloroform-d) d ppm 7.38 (m, 1 H), 7.21 (m, 4 H), 6.96 (m, 4 H), 4.46 (q, J = 7.13 Hz, 2 H), 4.30 (t, J = 7.69 Hz, 2H), 2.98 (t, J = 7.71 Hz, 2H), 2.43 (s, 3H), 1.44 (t, J = 7.14 Hz, 3H). MS (ESI) 379.4 (M + H) +.

EXAMPLE 150 Preparation of 2- (2-hydroxyphenyl) -6-methyl-5- (1-methylpropyl) -3- [2- (2-thienyl) ethyl] -4 (3H)) - pyrimidinone to. Ethyl 2-acetyl-3-methylpentanoate A solution of THF (170 ml, 0.2 M) of LDA (21 ml, 2M in heptane THF / ethylbenzene) is cooled to -78 ° C in an oven-dried flask under N2. A THF solution (10 ml) of ethyl 3-methylpentanoate (5.0 g, 34.67 mmol) is added dropwise and the resulting solution is stirred at -78 ° C for 1 hour. Pure acetyl chloride (7.4 ml, 104.01 mmol) is added to the cold solution, and the resulting mixture is allowed to warm to room temperature for several hours. The reaction mixture is quenched by the addition of 1N HCl. The layers are separated and the organic phase is washed with 5% NaHCO3 and brine. The combined organic portion is dried over Na2SO4 and concentrated to an orange oil for purification. Purification by flash column chromatography (5-30% ethyl acetate / hexanes) gives the pure product as a slightly yellow volatile oil which is visualized by l2 staining (3.64 g, 56%). 1 H NMR (400 MHz, chloroform-d) d ppm 4.13-4.24 (m, J = 7.12, 7. 12, 7.12, 1.64, 1.52 Hz, 2H), 3.31 (dd, J = 12.76, 9.22 Hz, 1 H), 2.19-2.28 (m, 4H), 1.37-1.48 (m, 1 H), 1.29 (ddd, J = 13.83, 6.76, 4.42 Hz, 3H), 1.18 (ddd, J = 14.08, 6.76, 2.15 Hz, 1 H), 0.87-0.97 (m, 6H). b. 2-acetyl-3-methyl-N- [2-. { 2-thienyl) ethamphenamide A DME solution (3 ml) of ester (1.0 g, 5.37 mmol) of example 150a, thienylethylamine (0.57 ml, 4.89 mmol) and ethanol (0.5 ml) are subjected to microwave irradiation at 180 °. C for 15 minutes. The reaction mixture is purified by flash column chromatography (10-70% ethyl acetate / hexanes) to give the desired product as a white solid in 41% yield (0.54 g). 1 H NMR (400 MHz, chloroform-d) d ppm 7.17 (dd, J = 5.18, 1.14 Hz, 1 H), 6.95 (dd, J = 5.05, 3.54 Hz, 1 H), 6.82 (t, J = 2.40 Hz , 1 H), 6.36 (d, J = 20.72 Hz, 1 H), 3.47-3.58 (m, J = 19.39, 6.63, 6.38, 6.38, 3.92 Hz, 2H), 3.19 (t, J = 10.36 Hz, 1 H), 3.02 (t, J = 6.69 Hz, 2H), 2.23-2.26 (m, 3H), 2.01-2.11 (m, 1 H), 1.35-1.47 (m, 1 H), 1.05-1.16 (m, 1 H), 0.89 (ddd, J = 9.09, 7.07, 2.78 Hz, 5H), 0.86 (s, 1 H). MS (m / z) 268 (M + H). c. 2- (2-hydroxyphenyl) -6-methyl-5- (1-methylpropyl) -3- [2- (2-thienyl) ethyl-4- (3H) -pyrimidinone To a suspension of ketoamide (0.23 g, 0.84 mmol ) of example 150b in m-xylene (2.1 ml, 0.4 M), salicylamide (0.17 g, 1.26 mmol) and some drops of isopropoanol is added titanium (IV) sopropoxide (1.2 ml, 4.21 mmol). The resulting mixture is stirred at reflux for 3 days. The reaction mixture is quenched by the addition of 6N HCl and ethyl acetate and allowed to stir overnight. The layers are separated, and the aqueous phase is extracted with 2 portions of dichloromethane. The combined organic portions are dried over Na2SO and concentrated to a brown oil. Purification by flash column chromatography (5% methanol / dichloromethane) provides the title compound as a white solid (0.03 g, 10%). 1 H NMR (400 MHz, chloroform-d) d ppm 9.84 (br s, 1 H ), 7.35 (ddd, J = 8.53, 7.14, 1.77 Hz, 1 H), 7.10 (dd, J = 5.18, 1.14 Hz, 1 H), 7.02 (dd, J = 8.34, 1.01 Hz, 1 H), 6.93 -6.98 (m, 1 H), 6.86 (dd, J = 5.18, 3.41 Hz, 1 H), 6.62-6.66 (m, 1 H), 4.34-4.42 (m, 2H), 3.23-3.29 (m, 2H) ), 2.81-2.91 (m, 1 H), 2.35 (s, 3H), 1.92-2.04 (m, 1 H), 1.69-1.80 (m, 1 H), 1.31-1.37 (m, 3H), 0.89 ( t, J = 7.45 Hz, 3H). MS (m / z): 369 (M + H).

EXAMPLE 151 Preparation of 2- (2-hydroxyphenyl) -6-methyl-5- (1-methylpropyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone The title compound is prepared following the general procedure previously described in Example 150 except substituting phenethylamine for [2- (2-thienyl) ethyl] amine (0.07 g, 20%). 1 H NMR (400 MHz, chloroform-d) d ppm 7.36 (td, J = 7.20, 1.52 Hz, 2H), 7.17-7.25 (m, 3H), 6.94-7.04 (m, 4H), 4.33-4.41 (m, 2H), 2.94-3.01 (m, 2H), 2.79-2.90 (m, 1 H), 2.33 (s, 3H), 1.98 (ddd, J = 13.52, 8.08, 7.96 Hz, 1 H), 1.75 (dt, J = 13.83, 6.85 Hz, 1 H), 1.35 (d, J = 7.07 Hz, 3H), 0.84-0.92 (t, J = 8.0 Hz, 3H). MS (m / z) 363 (M + H).

EXAMPLE 152 Preparation of 2- (3-fluoro-2-hydroxyphenyl) -6-methyl-5- (1-methylpropyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone to. 2-r3-fluoro-2- (methyloxy) phenyl-6-methyl-5- (1-methylpropyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone The title compound is prepared following the procedure general described briefly in example 150 except substituting 3-fluoro-2-methoxybenzamide for salicylamide (0.03 g, 8% yield) in step c. MS (m / z): 395 (M + H). b. 2- (3-fluoro-2-hydroxyphenyl) -6-methyl-5- (1-methylpropyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone To a solution of dichloromethane at 0 ° C (4 ml) , 0.2 M) of methyl ether from example 3a (0.03 g, 0.076 mmol) is added BBr3 (0.23 ml, 1 M in dichloromethane) dropwise under N. The reaction mixture is allowed to warm to room temperature overnight. The reaction is quenched by the addition of methanol and purified in two steps by flash column chromatography (methanol / 5% dichloromethane then ethyl acetate). ethyl / hexanes at 20-50%) to provide the pure product as a white solid (0.02 g, 74% yield). 1 H NMR (400 MHz, chloroform-d) d ppm 7.18-7.25 (m, 3H), 7.10 (ddd, J = 10.11, 8.21, 1.64 Hz, 1 H), 6.85-6.96 (m, 4H), 4.19 (dt) , J = 10.55, 7.61 Hz, 2H), 2.92 (t, J = 7.58 Hz, 2H), 2.85 (d, J = 7.83 Hz, 1 H), 2.31 (s, 3H), 1.90-2.02 (m, 1 H), 1.78 (ddd, J = 13.77, 7.07, 6.95 Hz, 1 H), 1.37 (d, J = 7.07 Hz, 3H), 0.85-0.94 (m, 3H). MS (m / z): 381 (M + H).

EXAMPLE 153 Preparation of 5-butyl-2- (2-hydroxy-phenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone to. 2- (methoxy) benzenecarboxamide 2-methoxybenzonitrile (5 g, 37.5 mmol) is added to a solution at 0 ° C of LiHMDS (94 ml, 1 M in hexanes) in anhydrous Et2O (75 ml, 0.5M) under N2 After warming to room temperature, the mixture is stirred for three days. The resulting reaction mixture is quenched by the addition of 1N HCl. The layers are separated and the aqueous phase is extracted twice with Et2O. The aqueous layer is cooled in an ice bath, the pH adjusted to 12, and extracted three times with dichloromethane. The organic portions are pooled, dried over Na 2 SO 4, and concentrated to a brown oil which solidifies to a brown solid under vacuum (4.5 g, 80% yield). 1 H NMR (400 MHz, chloroform-d) d ppm 7.57 (dd, J = 58, 1.77 Hz, 1 H), 7.35-7.41 (m, 1 H), 6.94-7.03 (m, 2H), 5.24 (s, 3H), 3.89 (s, 3H). b. 5-Butyl-6-methyl-2- [2- (methyloxy) phenylH-4 (1 H) -pyrimidinone NaOMe (1.14 g, 20.0 mmol) is added to a solution at 0 ° C of 2- (methoxy) ) benzenecarboxamidine (1.0 g, 6.67 mmol) and ethyl 2-acetylhexanoate (1.49 g, 8.0 mmol) in methanol (70 ml) and 1,4-dioxane (20 ml). The resulting mixture is heated in an oil bath at 120 ° C and the tube is sealed for 6 hours. The solvents are removed and the residue is taken up in ethyl acetate and 1 N HCl. The layers are separated and the aqueous layer is extracted with dichloromethane 3 times. The combined organic portions are dried over Na2SO and purified by flash column chromatography (dichloromethane / 20% ethyl acetate) to provide 0.64 g of the product (35% yield). 1 H NMR (400 MHz, chloroform-d) d ppm 10.97 (s, 1 H), 8.41 (dd, J = 7.83, 1.77 Hz, 1 H), 7.49 (ddd, J = 8.53, 7.14, 1.77 Hz, 1 H ), 7.08-7.15 (m, 1 H), 7.04 (d, J = 7.83 Hz, 1 H), 4.04 (s, 3H), 2.53-2.60 (m, 2H), 2.39 (s, 3H), 1. 47-1.55 (m, 2H), 1.39-1.45 (m, 2H), 0.95 (t, J = 7.20 Hz, 3H). MS (m / z): 273 (M + H). c, butyl-6-methyl-2-r2- (methoxy) phenyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone LiH (0.02 g, 2.57 mmol) is added to a solution at 0 ° C. of 5-butyl-6-methyl-2- [2- (methyloxy) phenyl] -4 (1 H) -pyrimidinone (0.20 g, 0.74 mmol) in DMF (5 mL, 0.15 M) and stirred at 0 ° C for 30 minutes. Bromoethyl benzene (0.3 ml, 2.21 mmol) is added and the resulting mixture is stirred at room temperature for 40 hours. The reaction is quenched by the addition of ethyl acetate (15 ml) and water (25 ml). The layers are separated and the organic portion is washed three times with water, dried over NaSO, filtered, and concentrated to a yellow oil. Flash column chromatography (10-100% ethyl acetate / hexanes) gives the pure product as a white solid (0.14 g, 50%) plus the O-alkylated by-product (0.12 g, 43%). Desired N-alkylation product: 1 H NMR (400 MHz, chloroform-d) d ppm 7.44-7.49 (m, 1 H), 7.14-7.21 (m, 3H), 7.07-7.12 (m, 1 H), 7.01- 7.06 (m, 1 H), 6.97 (d, J = 8.34 Hz, 1 H), 6.85 (dd, J = 7.20, 2.15 Hz, 2H), 4.30 (ddd, J = 13.14, 10.48, 4.93 Hz, 1 H ), 3.79 (s, 3H), 3.62 (ddd, J = 13.14, 10.36, 6.32 Hz, 1 H), 2.89 (ddd, J = 12.82, 10.29, 4.93 Hz, 1 H), 2.76 (ddd, J = 12.69) , 10.42, 6.44 Hz, 1 H), 2.55-2.66 (m, 2H), 2.36 (s, 3H), 1.53-1.60 (m, 2H), 1.44-1.52 (m, 2H), 1.00 (t, J = 7.20 Hz, 3H). Undesired O-alkylation by-product: 1 H NMR (400 MHz, chloroform-d) d ppm 7.67 (dd, J = 7.58m, 1.77 Hz, 1 H), 7.38 (td, J = 7.83, 1.77 Hz, 1 H), 7.31 (td, J = 6.25, 1.89 Hz, 4H) , 7.25 (dd, J = 6.19, 2.40 Hz, 1 H), 6.99-7.07 (m, 2H), 4.63 (t, J = 6.69 Hz, 2H), 3.86 (s, 3H), 3.13 (t, J = 6.82 Hz, 2H), 2.54-2.61 (m, 2H), 2.51 (s, 3H), 1.36-1.47 (m, 4H), 0.96 (t, J = 7.07 Hz, 3H). < ± 5-butyl-2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone To a solution of dichloromethane at 0 ° C (1.8 ml, 0.2 M) of butyl -6-methyl-2- [2- (methyloxy) phenyl] -3- (2-phenylethyl) -4 (3H) -pyrimidinone (0.14 g, 0.37 mmol) is added BBr3 (1.1 mL, 1 M in dichloromethane) drop a drop. The resulting solution is allowed to warm to room temperature while stirring overnight. The reaction is quenched by the addition of saturated Na 2 C 3+ and dichloromethane. The layers are separated and the organic portion is dried over MgSO, filtered and concentrated to a yellow oil which is purified by flash column chromatography (15-100% ethyl acetate / hexanes) to give the title compound as a solid white (0.13 g, 98% yield). 1 H NMR (400 MHz, chloroform-d) d ppm 7.14-7.25 (m, 5H), 6.87-6.93 (m, 3H), 6.82 (d, J = 8.08 Hz, 1 H), 4.12-4.23 (m, 2H ), 2.85-2.94 (m, 2H), 2.51-2.60 (m, 2H), 2.27 (s, 3H), 1.47-1.57 (m, 2H), 1.39 -d.

EXAMPLE 154 Preparation of 2- (2-hydroxyphenyl) -6-methyl-5-pentyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone The title compound is prepared following the general procedure described in Example 153 except substituting ethyl 2-acetyl heptanoate for ethyl 2-acetyl hexanoate (0.13 g, quantitative yield) in step 153 b. 1 H NMR (400 MHz, chloroform-d) d ppm 9.74 (br, s, 1H), 7.24-7.32 (m, 2H), 7.18-7.22 (m, 3H), 6.89-6.98 (m, 4H), 4.24- 4.32 (m, 2H), 2.89-2.98 (m, 2H), 2.52-2.61 (m, 2H), 2.29 (s, 3H), 1.54 (d, J = 7.83 Hz, 2H), 1.41 (ddd, J = 6.82, 3.79, 3.54 Hz, 4H), 0.89-0.98 (m, 3H). MS (m / z) 377 (M + H).

EXAMPLE 155 Preparation of 5-hexyl-2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone The title compound is prepared following the general procedure described in Example 153 except substituting ethyl 2-acetyl octanoate for ethyl 2-acetyl hexanoate (0.083 g, 81% yield) in step 153 b. 1 H NMR (400 MHz, chloroform-d) d ppm 9.61 (s, 1 H), 7.35 (d, J = 7.33 Hz, 2H), 7.17-7.26 (m, 3H), 6.94-7.03 (m, 4H), 4.31-4.39 (m, 2H), 2.96-3.03 (m, 2H), 2.53-2.60 (m, 2H), 2.32 (s, 3H), 1.49-1.60 (m, 2H), 1.33-1.45 (m, 5H) ), 1.27 (t, J = 7.07 Hz, 1 H), 0.87-0.96 (m, 3H). MS (m / z): 391 (M + H).

EXAMPLE 156 Preparation of 5-butyl-2- (2-hydroxyphenyl) -6-methyl-3-r2- (2-thienyl) -etin-4 (3H) -pyrimidinone The title compound is prepared following the general procedure described in Example 153 except substituting 2- (2-bromoethyl) thiophene for bromoethyl benzene (0.081 g, 66% yield) in step 153 b. 1 H NMR (400 MHz, chloroform-d) d ppm 9.78 (br s, 1 H), 7.32 (td, J = 7.83, 1.52 Hz, 1 H), 7.20-7.26 (m, 1 H), 7.10 (dd, J = 5.05, 1.26 Hz, 1 H), 6.95 (td, J = 8.59, 2.02 Hz, 2H), 6.86 (dd, J = 5.05, 3.54 Hz, 1 H), 6.63 (d, J = 2.53 Hz, 1 H), 4.30-4.38 (m, 2H), 3.21-3.28 (m, 2H), 2.53-2.60 (m, 2H), 2.31 (s, 3H), 1. 49-1.55 (m, 2H), 1.43-1.47 (m, 2H), 0.98 (t, J = 7.20 Hz, 3H). MS (m / z): 369 (M + H).

EXAMPLE 157 Preparation of 2- (2-hydroxyphenyl) -6-methyl-5-pentyl-3-r2- (2-thienyl) etn-4 (3H) -pyrimidinone The title compound is prepared following the general procedure described in Example 153 except substituting ethyl 2-acetyl heptanoate for ethyl 2-acetyl hexanoate in step 153b and 2- (2-bromoethyl) thiophene for bromoethyl benzene (0.094 g, 78%) in 153c. 1 H NMR (400 MHz, chloroform-d) d ppm 9.77 (br. S, J = 1.77 Hz, 1 H) 7.29-7.36 (m, 2 H) 7.10 (dd, J = 5.18, 1.14 Hz, 1 H) 6.93 - 7.01 (m, 2 H) 6.86 (dd, J = 5.05, 3.54 Hz, 1 H) 6.63 (d, J = 2.53 Hz, 1 H) 4.31 - 4.40 (m, 2 H) 3.26 (t, J = 7.33 Hz, 2 H) 2.53 - 2.60 (m, 2 H) 2.32 (s, 3 H) 1.50 - 1.61 (m, 2 H) 1.35 - 1.44 (m, 4 H) 0.88 - 0.97 (m, 3 H); MS (m / z): 383 (M + H) EXAMPLE 158 Preparation of 5-hexyl-2- (2-hydroxyphenyl) -6-methyl-3-r2- (2-thienyl) etn-4 (3H) -pyrimidinone The title compound is prepared following the general procedure described in Example 153 except substituting ethyl 2-acetyl octanoate for ethyl 2-acetyl hexanoate in step 153b and 2- (2-bromoethyl) thiophene for bromoethyl benzene (0.056 g, 64%) in step 153c. 1 H NMR (400 MHz, chloroform-d) d ppm 9.75 (br. S., 1 H) 7.31 -7.38 (m, 1 H) 7.11 (dd, J = 5.18, 1.14 Hz, 1 H) 7.01 (d, J = 8.34 Hz, 1 H) 6.93 -6.99 (m, 1 H) 6.87 (dd, J = 5.05, 3.28 Hz, 1 H) 6.65 (d, J = 2.78 Hz, 1 H) 4.34 -4.41 (m, 2H) , 3.27 (t, J = 7.33 Hz, 2 H) 2.53 - 2.60 (m, 2 H) 2.33 (s, 3 H) 1.50 -1.61 (m, 2 H) 1.32 - 1.44 (m, 6 H) 0.86 - 0.96 (m, 3 H); MS (m / z): 397 (M + H) EXAMPLE 159 Preparation of 2- (3-f1uoro-2-hydroxyphenyl) -3-r2- (3-f1-orophenyl) ethyl-1-5-6,7,8-tetrahydro-4 (3H) -quinazolinone to. 1,4-dioxaspiro [4,51-decano-6-carboxylic acid ethyl ester A mixture of commercially available ethyl 2-oxocyclohexanecarboxylate (20 g, 17 mmol), ethylene glycol (8.02 g, 129 mmol), and p-toluenesulfonic acid (1 .0 g) in toluene (200 ml) is heated at 120 ° C for 4 hours under a Dean-Stark apparatus. The reaction mixture is cooled to room temperature, the solvent is removed, and the residue is partitioned between ethyl acetate and saturated NaHCO3. The layers are separated, and the aqueous portion is extracted 3 times with ethyl acetate. The organic portions are combine, dry (MgSO4) and concentrate to provide the product as a colorless oil which is carried out in the next step without further purification. b. 1,4-dioxaespirof4,51decano-6-carboxylic acid To a solution of 1,4-dioxanospiro [4,5] decane-6-carboxylic acid ethyl ester in EtOH (150 ml) is added 85% KOH solution in water ( 15 g / 100 ml), and the mixture is stirred at reflux overnight. The reaction mixture is cooled to room temperature, the solvent is evaporated, and the residue is partitioned between CH2Cl2 and 2N HCl. After separation in layers, the aqueous portion is extracted three times with CH2Cl2. The organic portions are combined, dried (Na2SO4), and concentrated in vacuo to give the acid product as a light yellow oil (14 g, two steps yield 65%). c. N- [2- (3-fluorophenol) etn-1,4-dioxaespiro [4,5-decano-6-carboxamide To a solution at 0 ° C of 1,4-dioxaspiro [4,5] decano- 6-carboxylic acid (7.0 g, 34.65 mmol) in CH 2 Cl 2 (200 ml) is added oxalyl chloride (4.9 ml) in a dropwise manner. After 15 minutes it is stirred at 0 ° C, the mixture is allowed to stir at room temperature for 2 hours. The excess oxalyl chloride and solvent is removed to provide an oil, which is taken up in fresh CH 2 Cl 2 and cooled to 0 ° C. A solution of pyridine (20 ml) of 2- (3-fluorophenyl) ethanamine (7.22 g, 51.98 mmol) is added drop by drop, and the resulting solution is allowed to warm to room temperature while stirring overnight. The reaction mixture is partitioned between CH 2 Cl 2 and 1 N HCl. After separation of the layers, the organic portion is washed with water and aqueous NaHCO 3. The organic portion is combined, dried (Na2SO4), and concentrated in vacuo to provide the product as a white solid (11.0 g, yield = 95%) which is used in the next reaction without further purification. d. N- [2- (3-fluorophenyl) etyl-2-oxycyclohexanecarboxamide To a solution of N- [2- (3-fluorophenyl) ethyl] -1,4-dioxaspiro [4,5] decane-6-carboxamide (11.0 g , 34.1 mol) in acetone and water (200 ml / 100 ml) is added p-toluenesulfonic acid (9.72 g, 51.15 mol). This mixture is stirred and heated at 95 ° C for 8 hours. After cooling to room temperature, the solvent is removed and the residue is partitioned between CH 2 Cl 2 and aqueous Na 2 CO 3. After separation of the layers, the aqueous layer is extracted twice with fresh CH2CI2 and the combined organic portions are dried (Na2SO), filtered and concentrated to provide the crude as a white solid. Purification by column chromatography on silica gel (50% ethyl acetate / hexanes) gives the product as a white solid in 82% yield (7.3 g). and. 2-amino-N- [2- (3-fluorophenyl) ethyl] -1-cyclohexane-1-carboxamide A solution at 0 ° C of N- [2- (3-fluorophenyl) ethyl] -2-oxocyclohexanecarboxamide (2.08 g , 7.91 mmol) in diethyl ether (250 ml) and THF (10 ml) is saturated with aqueous ammonia for 3 hours. ACI3 (2 g) is added, and the mixture is allowed to warm to room temperature while stirring overnight. The resulting suspension is filtered, and the filtrate is concentrated to provide the product as a colorless oil in 97% yield (2.0 g). MS (m / z): 263 (M + H). 2-fluoro-6- (N-f2- ( { r2- (3-fluorophenyl) ethylamino) carbonyl) -1-cyclohexen-1-illglycyl) phenyl acetate To a solution of 2-amino-N- [ 2- (3-fluorophenyl) ethyl] -1-cyclohexene-1-carboxamide (1.0 g, 3.82 mmol) in THF (100 ml) and pyridine (7 ml) is added 2- (chlorocarbonyl) -6-fluorophenyl acetate ( 1.46 g, 6.10 mmol). The mixture is heated to reflux overnight. After cooling to room temperature, diethyl ether (200 ml) is added, and the precipitate salts are removed by filtration. The filtrate is concentrated, diluted with diethyl ether (250 ml), and washed three times with 2N HCl (50 ml portions). The organic layer is washed successively with water and brine, and dried over Na 2 SO 4, filtered and concentrated by purification. Purification by column chromatography on silica gel (30-50% ethyl acetate / hexanes) gives the pure product as a white solid in 33% yield (0.51 g). MS (m / z) 442 (M + H). g, 2- (3-fluoro-2-hydroxyphenyl) -3-f2- (3-fluorophenyl) etyl-5,6,7,8-tetrahydro-4 (3H) -quinazolinone A solution of 2-fluoro- 6- (N- [2- ( { [2- (3-fluorophenyl) ethyl] amino} carbonyl) -1-cyclohexen-1-yl] glycyl) phenyl (0.510 g, 1.15 mmol) in EtOH ( 20 ml) and 85% KOH (20 ml) is heated to reflux overnight. After cooling to room temperature, the pH is adjusted to approximately 1 with 2N HCl and extracted three times with CH 2 Cl 2. The organic portions are combined, dried (Na2SO), filtered and concentrated. Purification by silica gel column chromatography (2-3% CH3OH / CH2Cl2) gives the pure product as a white solid in 59% yield (260 mg). MS (m / z): 383.2 (M + H).

EXAMPLE 160 Preparation of 2- (3-f1uoro-2-hydroxyphenyl) -3-r2- (3-fluorophenyl) ethyl1- 3.5.6.7.8.9-hexahydro-4H-cycloheptard-1-pyrimidin-4-one The title compound is prepared following the general procedure of Example 159 except substituting 2-oxocyclohexanecarboxylate ethyl with ethyl 2-oxocycloheptanecarboxylate. MS (m / z): 397.4 (M + H) EXAMPLE 161 Preparation of ethyl 2- (2-hydroxyphenyl) -4-oxo-3- (2-phenylethyl) -3,5,7,8-tetrahydropyrido [4.3-d] pyrimidine-6 (4H) -carboxylate to. 6-benzyl-2- (2-methoxy-phenyl) -5,6,7,8-tetrahydro-3H-pyrido4.3-dlpyrimidin-4-one To a solution at 0 ° C of 2- (methyloxy) benzenecarboximidamide ( 300 mg, 2.0 mmol) in MeOH / 1,4-dioxane (20 ml / 7 ml) is added NaOCH3 to the % in MeOH (1.39 ml) and then stirred for 15 minutes. 1-benzyl-4-oxo-piperidine-3-carboxylic acid ethyl ester hydrochloride salt is introduced (893 mg, 3.0 mmol) and the reaction mixture is refluxed for 2 hours. hours. The solvent is removed, the residue is diluted with 10 ml of H 2 O, the pH = 7.8 is adjusted by the addition of acetic acid and the aqueous layer is extracted by CH 2 Cl 2 (3 x 100 ml). The organic layers are combined, dried over Na2SO and concentrated. Purification by column chromatography on silica gel (10% ethyl acetate / hexane to 95%, with 1% MeOH) to give the product 1.21 g as a white solid in 87% yield. MS (m / z): 348 (M + H). b. 2-f2- (Methyloxy) phenin-4-oxo-3,5,7,8-tetrahydropyridine-3,4-d-pyrimidine-6 (4H) -ethylcarboxylate To a solution of 6-benzyl-2- (2-methoxy) phenyl) -5,6,7,8-tetrahydro-3H-pyrido [4,3-d] pyrimidin-4-one (300 mg, 0.865 mmol) in dichloromethane (8 ml) is added ethyl chloroformate. The mixture is heated to reflux for 2.5 hours. The reaction mixture is concentrated and purified by column chromatography on silica gel (ethyl acetate / hexane from 30% to 90%) to give the product as a white solid in 89% yield (230 mg). MS (m / z): 330 (M + H). c. 2- [2- (methyloxy) phenyl-1-4-oxo-3- (2-phenylethyl) -3,5,7,8-tetrahydropyrido [4,3-dlpyrimidine-6 (4H) -ethylcarboxylate) To a solution at 0 ° C 2- [2- (methyloxy) phenyl] -4-oxo-3,5,7,8- Ethyl tetrahydropyrido [4,3-d] pyrimidine-6 (4H) -carboxylate (220 mg, 0.699 mmol) in dry DMF is added lithium hydride (10.57 mg, 1.34 mmol) and the mixture is stirred for 5 minutes at this Temperature and 1- (2-bromo-ethyl) -benzene (0.55 ml, 0.01 mmol) is added and stirred at room temperature overnight. The mixture is concentrated and diluted with Et2O, dried over MgSO4, filtered and concentrated. The crude residue is purified by column chromatography on silica gel (ethyl acetate / hexane from 30% to 90%) to provide the desired product in 59% yield (170 mg). MS (m / z): 434 (M + H). a-2- (2-hydroxyphenyl) -4-oxo-3- (2-phenylethyl) -3,7,8,8-tetrahydropyridofof.3,3-d] pyrimidine-6 (4H) -ethylcarboxylate To a solution of 2- [2- (methyloxy) phenyl] -4-oxo-3- (2-phenylethyl) -3,7,8,8-tetrahydropyrido [4,3-d] pyrimidine-6 (4H) - ethyl carboxylate (150 mg, 0.346 mmol) in dichloromethane at -60 ° C is added boron tribromide (1.0 M solution in dichloromethane) (2.0 ml, 2.0 mmol) and stirred at this temperature for 1 h and then stirred at room temperature atmosphere all night. The reaction is quenched by water (15 ml). The aqueous layer is separated, extracted with dichloromethane twice after the pH is adjusted to 7 with 2N NaOH. The organic layers are combined and washed with brine, dried (MgSO), filtered and concentrated. Purification by column chromatography on silica gel (ethyl acetate / hexane 30% -90%) provides the product as a white solid in 93% yield (135 mg). MS (m / z): 420 (M + H). EXAMPLE 162 Preparation of (2-hydroxyphenyl) -6- (3-methylbutanoyl) -3- (2-phenylethyl) -5,6,7,8-tetrahydropyrido [4.3-d] pyrimidin-4 (3H) -one a, 2- [2- (methyloxy) phenyl-3- (2-phenylethyl) -6- (phenylmethyl) -5,6,7,8-tetrahydropyrido [4,3-dlpyrimidin-4 (3H) -one The title compound is prepared from the alkylation of 6-benzyl-2- (2-methoxy-phenyl) -5,6,7,8-tetrahydro-3H-pyrido [4,3-d] pyrimidine- 4-one from example 161 using phenethyl bromide as the alkylating agent as previously outlined. MS (m / z): 452 (M + H). b. 2-r2- (methyloxy) phenyl-3- (2-phenylethyl) -5,6,7,8-tetrahydropyrido [4,3-dlpyrimidin-4 (3H) -one To a solution of 2- [2- (methyloxy ) phenyl] -3- (2-phenylethyl) -6- (phenylmethyl) -5,6,7,8-tetrahydropyrido [4,3-d] pyrimidin-4 (3H) -one (300 mg, 0.665 mmol ) in dichloromethane (5 ml) is added 1-chloroethyl chloridocarbamate (0.29 ml, 2.66 mmol). The mixture is heated to reflux for one hour. The solvent is removed and refilled with methanol (6 ml) and heated to reflux for 1 hour.

After concentrating underneath, the crude is purified by column chromatography on silica gel (10% methanol / dichloromethane) to give the product as a white solid in 90% yield (216 mg). MS (m / z): 362 (M + H). c. 6- (3-methylbutanol) -2- [2- (methyloxy) phenyl-3- (2-phenylethyl) -5,6,7,8-tetrahydropyrido [4,3-dlpyrimidin-4 (3H) -one A a solution of 2- [2- (methyloxy) phenyl] -3- (2-phenylethyl) -5,6,7,8-tetrahydropyrido [4,3-d] pyrimidin-4 (3H) -one (100 mg, 0.277 mmol) in dichloromethane is added 3-methylbutanoic anhydride (0.065 ml, 0.332 mmol). The mixture is stirred at room temperature for 4 hours. The reaction is concentrated and purified by column chromatography on silica gel (ethyl acetate / hexanes of 40-90%) which gives as a solid in 92% yield (113 mg). MS (m / z). 445 (M + H). The subsequent deprotection using BBr3 as outlined previously results in the title compound. MS (m / z): 432 (M + H).

EXAMPLE 163 Preparation of 5-ethyl-2- (2-hydroxyphenyl) -6-methyl-3-r2- (2-thienyl) etn-4 (3H) -pyrimidinone to. 2- (2-methyl- [1, 3-dioxolan-2-yl) -butyric acid A mixture of commercially available 2-ethyl-3-oxo-butyric acid ethyl ester (54 g, 0.34 mol), ethylene glycol (23.3 g, 0.375 mol), and p-toluenesulfonic acid (0.2 g) in toluene (500 ml) is heated at 120 ° C for 4 h under a Dean-Stark apparatus. The reaction mixture is cooled to room temperature, the solvent is removed, and the residue is partitioned between ethyl acetate and saturated NaHCO3. The layers are separated, and the aqueous portion is extracted three times with ethyl acetate. The organic portions are pooled, dried (MgSO4) and concentrated to give the product ethyl 2- (2-methyl-1, 3-dioxolan-2-yl) butanoate as a colorless oil in 91% yield (63 g. ). To a solution of the ester (60 g, 0.297 mol) provided above in EtOH (750 ml) is added 85% KOH solution in water (30 ml), and the mixture is stirred at reflux overnight. The reaction mixture is cooled to room temperature, the solvent is evaporated, and the residue is partitioned between CH2Cl2 and 2N HCl. After separation of the layers, the aqueous portion is extracted three times with CH2Cl2. The portions are pooled, dried (Na2SO4), and concentrated in vacuo to provide the acidic product as a light yellow oil (27 g, 52% yield). b. 2-Ethyl-3-oxo-N- (2-thiophene-2-yl-ethyl) butyramide To a solution at 0 ° C of 2- (2-methyl- [1, 3] dioxolan-2-yl) - butyric (4 g, 0.023 mol) in CH 2 Cl (30 ml) is added oxalyl chloride (7.2 ml) in a dropwise manner. After 15 minutes at 0 ° C, the mixture is allowed to stir at room temperature for 2 hours. The excess oxalyl chloride and solvent are removed to provide an oil, which is taken up in fresh CH 2 Cl 2 and cooled to 0 ° C. A solution of pyridine (4 ml) of 2-thiophen-2-yl ethylamine (5.3 g, 0.041 mol) is added dropwise, and the resulting solution is allowed to warm to room temperature while stirring overnight. The reaction mixture is partitioned between CH 2 Cl 2 and 1 N HCl. After separation of the layers, the organic portion is washed with water and aqueous NaHCO 3. The organic portion is pooled, dried (Na2SO4) and concentrated in vacuo to give the product 2- (2-methyl-1,3-dioxolan-2-yl) -N- [2- (2-thienyl) ethyl] butanamide (4.4 g, 68%) which is used in the next reaction without further purification. To a solution of ketal (4.4 g, 0.016 mol) in acetone and water (50 ml / 1 ml) is added p-toluenesulfonic acid (4.7 g, 0.025 mol). This The mixture is stirred and heated at 95 ° C for 4 hours. After cooling to room temperature, the solvent is removed and the residue is partitioned between CH2Cl2 and aqueous Na2CO3. After separation of the layers, the aqueous layer is extracted twice with fresh CH 2 Cl 2, and the combined organic portions are dried (Na 2 SO 4), filtered and concentrated to provide a white solid. The solid is triturated with hexanes / diethyl ether 1: 1 to provide 3.2 g (88%) of the product. c. (2Z) -3-amino-2-ethyl-N-y2- (2-thienyl) etyl-2-butenamide A 0 ° C solution of 2-ethyl-3-oxo-N- [2- (2 -thienyl) ethyl] butanamide (3.2 g, 11.3 mmol) in diethyl ether (250 ml) and THF (10 ml) is saturated with gaseous ammonia for 3 hours. ACI3 (2 g) is added, and the mixture is allowed to warm to room temperature while stirring overnight. The resulting suspension is filtered, and the filtrate is concentrated to provide the product as a colorless oil (0.8 g, 25%). α-5-ethyl-2- (2-hydroxyphenyl) -6-methyl-3- [2- (2-thienyl) ethyl-4 (3H) -pyrimidinone To a solution of [2- (thiophene-2- il) -ethyl] -amide of (Z) -3-amino-2-ethyl-but-2-enoic acid (1.9 g, 8.15 mmol) in THF (50 ml) and pyridine (3 ml) is added 2-chlorocarbonyl -phenyl ester of acetic acid (2.6 g, 13 mmol). The mixture is heated to reflux overnight. After cooling to room temperature, diethyl ether (200 ml) is added, and the precipitated salts they are removed by filtration. The filtrate is concentrated, diluted with diethyl ether (250 ml), and washed three times with 2N HCl (50 ml portions). The organic layer is washed successively with water and brine, and dried over Na2SO4, filtered and concentrated by purification. Flash column chromatography (0.4 g, 0.1 mmol) in EtOH (40 mL) and 85% KOH (40 mL) is heated to reflux overnight. After cooling to room temperature, the reaction mixture is adjusted to pH 1 with 2N HCl and extracted three times with CH 2 Cl 2. The organic portions are combined, dried (Na2SO4), filtered and concentrated for purification. Flash column chromatography (CH3OH / CH2Cl2 2-3%) gives the pure pyrimidinone product 0.15 g, yield 45%. 1 H NMR (400 MHz, CDCl 3) d 9.66 (br 1 H), 7.14 (m, 2 H), 6.95 (m, 3 H), 6.55 (d, 1 H), 4.28 (t, 2 H), 3.30 (t, 2 H) ), 2.46 (q, 2H), 2.33 (s, 3H), 1.08 (t, 3H). MS (m / z) 341.2 (M + H).

EXAMPLE 164 Preparation of 5-isopropyl-2- (2-hydroxy-phenyl) -6-methyl-3- (2-thiophen-2-yl-ethyl) -3H-pyrimidin-4-one The title compound is prepared by substituting 2-isopropyl-3-oxo-butyric acid ethyl ester for 5-chloro-3-oxobutanoate in Example 26b followed by deprotection leading to the product. 1 H NMR (400 MHz, CDCl 3) d 9.84 (br, 1 H, OH), 7.40-7.26 (m, 2H), 7.10 (d, 1 H), 7.05 (d, 1 H), 6.96 (t, 1 H), 6.87 (t, 1 H), 6.68 (d, 1 H), 4.39 (t, 2H), 3.30 (t, 2H), 3.15 (m, 1 H), 2.38 (s, 3H), 1.40 (d, 6H). MS (m / z): 355.4 (M + H).

EXAMPLE 165 Preparation of 5-isopropyl-2- (2-hydroxy-phenyl) -6-methyl-3- (2-cyclohexyl-ethyl) -3H-pyrimidin-4-one The title compound is prepared by substituting 2-isopropyl-3-oxo-butyric acid ethyl ester for 5-chloro-3-oxobutanoate in 26b and substituting 2-cyclohexylethyl bromide for phenethyl bromide in the example 26c followed by the deprotection leading to the product. 1 H NMR (400 MHz, CDCl 3) d 9.60 (br, 1 H, OH), 7.33-7.27 (m, 2H), 6.97-6.91 (m, 2H), 4.02 (t, 2H), 3.13-3.09 (m, 1 H), 2.32 (s, 3H), 1.61-1.52 (m, 7H), 1.36 (d, 6H), 1.16-1.09 (m, 4H), 0.81-0.78 (m, 2H). MS (m / z): 355.2 (M + H).

EXAMPLE 166 Preparation of 5-ethyl-2- (2-hydroxy-3-fluorophenyl) -6-methyl-3-r2-fluorophenylethyl-3H-pyrimidin-4-one The title compound is a synthetic intermediate in the preparation of Example 45. 1 H NMR (400 MHz, CDCl 3) d 9.41 (br, 1 H, OH), 7.19-7.11 (m, 1 H), 7.16-7.05 (m, 1 H), 6.98-6.90 (m, 2H), 6.88-6.81 (m, 3H), 4.21 (t, 2H), 2.97 (t, 2H), 2.57 (q, 2H) 1 2.26 (s, 3H), 1.14 (t, 3H). MS (m / z): 371.2 (M + H).

EXAMPLE 167 Preparation of 5-propenyl-2- (2-hydroxy-3-fluorophenyl) -6-methyl-3- (3-fluorophenylethyl) -3H-pyrimidin-4-one The title compound is prepared by substituting 2-acetyl-pent-4-enoic acid for 2-ethyl 2-oxocyclohexanecarboxylate in Example 159. 1 H NMR (400 MHz, CDCl 3) d 9.55 (br, 1H1 OH), 7.10-6.99 (m, 2H), 6.90-6.72 (m, 4H), 6.58 (d, 1 H), 6.47 (d, 1 H), 6.21 (d, 1 H), 4.16 (t, 2H), 2.80 (t, 2H), 2.25 (s, 3H), 1.90 (d, 3H). MS (m / z): 383.2 (M + H).

EXAMPLE 168 Preparation of 3- (2-cyclohexylethyl) -2- (2-hydroxyphenyl) -5.6.7.8-tetrahydro-4 (3H) -quinazolinone to. 2-methoxy-benzamidine Anhydrous ether at 0 ° C is introduced into a flask under argon, LiHMDS (94 ml, 93.9 mmol) then introduced and stirred for 5 minutes. HE add 2-methoxy-benzonitrile (5 g, 37.6 mmol) and the mixture is stirred at room temperature for 2-3 days. When all the starting material is consumed, the solvent is removed and 200 ml of crude 1N HCl is added and stirred to make HCl salt. It is extracted with Et2O (3 x 300 ml) and then the pH is adjusted to 13 by 6N NaOH. Extract with CH2Cl2 and dry over Na2SO4. It is filtered and the filtrate is concentrated to obtain the above benzamidine compound in 91% yield. b. 2- [2- (methyloxy) phenyl-5,6,7,8-tetrahydro-4 (1H) -quinazolinone 25% NaOMe in methanol (0.44 ml) is added to a solution of 0 ° C of 2- (methoxy) benzenecarboxamidine (0.15 g, 1.0 mmol) and 2-oxo-cyclohexanecarboxylic acid ethyl ester (0.26 g, 1.5 mmol) in methanol (15 ml) and 1,4-dioxane (5 ml) . The resulting mixture is heated in an oil bath at 120 ° C in a sealed tube for 1 hour. The solvents are removed and the residue is diluted with H2O and the pH is adjusted to 8 with acetic acid. The layers are separated and the aqueous layer is extracted with dichloromethane 3 times. The combined organic portions are dried over Na2SO4 and purified by flash column chromatography (70% ethyl acetate / hexanes) to provide 0.22 g of the product (86% yield). c. 3- (2-cyclohexylethyl) -2-r2- (methoxy) phenin-5,6,7,8-tetrahydro-4 (3H) -quinazolinone NaH (0.029 g, 1.2 mmol) is added to a solution at 0 ° C from 2- [2- (methyloxy) phenyl] -5,6,7,8-tetrahydro-4 (1 H) -quinazolinone (0.15 g, 0.60 mmol) in DMF (3 ml) and stirred at room temperature for 10 minutes. Bromoethyl cyclohexane (0.3 ml, 2.21 mmol) is added and the resulting mixture is stirred at room temperature overnight. The reaction is quenched with cold 6N HCl and extracted with ethyl acetate. The layers are separated and the organic portion is washed 3 times with water, dried over NaSO, filtered and concentrated. The crude product is purified by flash column chromatography to yield the crude product (0.081 mg) in 38% yield. d. 3- (2-cyclohexylethyl) -2- (2-hydroxyphenyl) -5,6,7,8-tetrahydro-4 (3H) -quinazolinone To a solution of dichloromethane at -60 ° C (5 ml) of 3- ( 2-cyclohexyl) -2- [2- (methyloxy) phenyl] -5,6,7,8-tetrahydro-4 (3H) -quinazolinone (0.15 g, 0.41 mmol) is added BBr3 dropwise. The resulting solution is allowed to warm to room temperature while stirring overnight. The reaction is quenched by the addition of saturated NaHCO3 and dichloromethane. The layers are separated and the organic portion is dried over Na 2 SO 4, filtered and concentrated to a yellow oil which is purified by flash column chromatography (3-5% MeOH / DCM) to give the title compound (0.10. g, 69% yield). 1 H NMR (400 MHz, CDCl 3) d 9.97 (br, 1 H), 7.03 (m, 2 H), 6.72 (t, 1 H), 6.68 (d, 1 H), 3.90 (m, 2 H), 2.32 (m , 4H), 1.70 (m, 4H), 1.50 (m, 3H), 1.32 (m, 4H), 0.99 (m, 4H), 0.59 (m, 2H).

MS (m / z): 353.4 (M + H).

EXAMPLE 169 Preparation of 3- (2-thiophen-2-yl-ethyl) -2- (2-hydroxy-phenyl) -5.6.7.8-tetrahydro-3H-quinazolin-4-one The title compound is prepared by substituting 2-thiophene-2-yl-ethyl bromide for (2-bromo-ethyl) -cyclohexane in Example 168. 1 H NMR (400 MHz, CDCl 3) d 62 (br, 1 H), 7.22 (m, 2H), 7.18 (d, 1 H), 7.00 (m, 2H), 6.89 (t, 1 H), 6.63 (d, 1 H), 4.27 (t, 2H), 3.29 ( t, 2H), 2.68 (m, 4H), 1.90 (m, 4H). MS (m / e): 353.4 (M + H).

EXAMPLE 170 Preparation of 3- (2-thiophen-2-yl-etl) -2- (2-hydroxy-3-fluorophenyl) -5, 6.7,8-tetrahydro-3H-quinazolin-4-one The title compound is prepared by substituting 2-thiophene-2-yl-ethyl bromide for (2-bromo-ethyl) -cyclohexane in Example 159 c. 1 H NMR (400 MHz, CDCl 3) d 9.22 (br, 1 H), 7.13 (m, 2 H), 6.92 (m, 3 H), 6.60 (d, 1 H), 4.28 (t, 2 H), 3.20 (t, 2H), 2.70 (m, 4H), 1.84 (m, 4H). MS (m / z): 371.2 (M + H).

EXAMPLE 171 Preparation of 3- (2-thiophen-3-yl-ethyl) -2- (2-hydroxy-phen.p-5.6.7.8-tetrahydro-3H-quinazolin-4-one) The title compound is prepared by substituting 3- (2-bromoethyl) thiophene for (2-bromo-ethyl) -cyclohexane in Example 168. 1 H NMR (400 MHz, CDCl 3) d 59.61 (br, 1 H), 7.34 - 7.13 (m, 4H), 7.11-6.82 (m, 3H), 4.32 (t, 2H), 2.93 (t, 2H), 2.56 (m, 4H), 1.84 (m, 4H). MS (m / z): 353.4 (M + H).

EXAMPLE 172 Preparation of 3- (3-chlorophenethyl) -2- (2-hydroxy-phenyl) -5,6,7,8-tetrahydro-3H-quinazolin-4-one The title compound is prepared by replacing 3-chlorophenethyl bromide with (2-bromo-ethyl) -cyclohexane in Example 168. 1 H NMR (400 MHz, CDCl 3) d 8.59 (s, 1 H), 7.28- 7.07 (m, 6H), 6.83 (t, 1 H), 6.81 (d, 1 H), 4.33 (t, 2H), 3.05 (t, 2H), 2.58 (m, 4H), 1.80 (m, 4H). MS (m / z): 381/383 (M + H).

EXAMPLE 173 Preparation of 3- (2-cyclopentylethyl) -2- (2-hydroxy-phenyl) -5.6.7.8-tetrahydro-3H-quinazolin-4-one The title compound is prepared by replacing 2-cyclopentylethyl bromide with (2-bromo-ethyl) -cyclohexane in Example 168. 1 H NMR (400 MHz, CDCl 3) d 9.94 (br, 1 H), 7.33 (m, 2H), 6.96 (m, 2H), 4.08 (t, 2H), 2.55 (m, 4H), 1.78 (m, 4H), 1.63 (m, 4H), 1.51 (m, 5H), 0.95 (m, 2H). MS (m / z): 339.4 (M + H).

EXAMPLE 174 Preparation of 3- (3-trifluoromethylphenethyl) -2- (2-hydroxy-phenyl) -5.6.7.8-tetrahydro-3H-quinazolin-4-one The title compound is prepared by replacing 3-trifluoromethylphenethyl bromide with (2-bromo-ethyl) -cyclohexane in Example 168. 1 H NMR (400 MHz, CDCl 3) d 9.66 (br, 1 H), 7.44 (d , 1 H), 7.28 (m, 2H), 7.13 (m, 3H), 6.85 (t, 1 H), 6.83 (d, 1 H), 4.31 (t, 2H), 2.96 (t, 2H), 2.57 (m, 4H), 1.79 (m, 4H). MS (m / z): 415.2 (M + H).

EXAMPLE 175 Preparation of 2- (2-hydroxyphenyl) -3- (2-phenylethyl) -5,6,8,9-tetrahydrooxepinor-4,5-d-pyrimidin-4 (3H) -one to. Ethyl 5-oxo-4-oxepanecarboxylate A solution of tetrahydro-4H-pyran-4-one (4.89 g, 0.049 mol) in dry diethyl ether is cooled to -30 ° C. BF3.Et2O (7.36 ml) is added dropwise maintaining the temperature thereof. Ethyl diazoacetate diethyl ether solution (6.08 ml, 0.058 mol) is added slowly over 15 minutes and the reaction is stirred for an additional 3 hours while the reaction is warmed to -15 ° C. The reaction mixture is poured into ice and saturated NaHCO3 and the organic layer is separated, dried over Na2SO4. The crude product is purified in FCC (40% EtOAc / hexane) to yield the desired product (6.5 g) in 72% yield. b. 2- (2-hydroxyphenyl) -3- (2-phenylethyl) -5,6,8,9-tetrahydrooxepinof4,5-dlpyrimidin-4 (3H) -one To a solution of 2- (methyloxy) benzenecarboximidamide (0.81 g, 5.38 mmol) in 54 ml of MeOH / dioxane solvent mixture (1/1) is added NaOMe (0.58 g, 10.8 mmol) and stirred for 15 minutes. Ethyl 5-oxo-4-oxepanecarboxylate (1.0 g, 5.38 mmol) is added and the reaction mixture is refluxed for 16 hours. At the termination, the reaction mixture is concentrated, diluted with dichloromethane and dilute HCl is added. The dichloromethane layer is separated and washed with brine, dried over Na2SO. In filtration and concentration the crude product is purified by FCC (0-10% MeOH / dichloromethane) to give the product (0.36 g) in 25% yield. c. 2- [2- (methoxy) phenyl1-3- (2-phenethyl) -5,6,8,9-tetrahydrooxepinoyl-4,5-dlpyrimidin-4 (3H) -one To a solution of 2- [2-hydroxyphenyl] ] -3- (2-phenylethyl) -5,6,8,9-tetrahydrooxepino [4,5-d] pyrimidin-4 (3H) -one (1.18 g, 4.33 mmol) in dry DMF (43 ml) is added lithium hydride (0.069 g, 8.66 mmol) and lithium bromide (1.13 g, 13.0 mmol) and stirred for 10 minutes at room temperature. Then (2-bromoethyl) benzene (4.01 g, 21.7 mmol) is added and the mixture is stirred overnight. The reaction mixture is quenched by the addition of ice and 6N HCl. This mixture is extracted with EtOAc and the organic layer is washed with aqueous NaHCO3, brine, and dried over Na2S4. The sodium sulfate is filtered and concentrated. The crude product is purified by FCC (30% ethyl acetate / hexane) to give the product (0.86 g) in 53% yield. d. 2- (2-hydroxyphenyl) -3- (2-phenylethyl) -5,6,8,9-tetrahydro-oxepinoyl-4,5-d-pyrimidin-4 (3H) -one 2- [2- (methyloxy) phenyl] -3 is placed - (2-phenylethyl) -5,6,8,9-tetrahydrooxepino [4,5-d] pyrimidin-4 (3H) -one (0.18 g, 0.48 mmol) in a sealed tube. To this is added a large excess (8.3 g) of pyridine hydrochloride salt and the reaction vessel is placed in an oil bath. The reaction is heated at 150 ° C for 16 h. The crude reaction mixture is diluted with dichloromethane and washed with water and brine. In the drying over Na2SO. It is concentrated and purified in the Biotage purification system using EtOAc / hexane mixture (0-60%) to produce the desired product (0.034 g) in 20% yield. MS (m / z): 363.2 [M + Hf.

EXAMPLE 176 Preparation of 3- (2-cyclohexyl-ethyl) -2- (2-hydroxy-phenyl) -3.5.6.7.8.9- hexahydro-cycloheptapyrimidin-4-one The title compound is prepared by replacing 2-oxo-cycloheptanecarboxylic acid ethyl ester with ethyl acid ester 2-oxo-cyclohexanecarboxylic acid in example 168. 1 H NMR (400 MHz, CDCl 3) d 10.05 (s, 1H, OH), 7.40-7.34 (m, 2H), 7.06 (d, 1 H), 6.96 (t, 1 H), 4.13 (t, 2H), 2.88-2.79 (m, 4H), 1.90-1.82 (m, 2H), 1.75-1.51 (m, 11 H) 1 1.25-1.10 (m, 4H), 0.90-0.80 (m, 2H). MS (m / z): 367.2 (M + H).

EXAMPLE 177 Preparation 2- (2-hydroxyphenyl) -3- (2-phenylethyl) -6- (phenylmethyl) -5.6.7.8- tetrahydropyridof4,3-d] pyrimidin-4 (3H) -one to. 6-benzyl-2- (2-methoxy-phenyl) -5,6,7,8-tetrahydro-3H-pyrido [4,3-dlpyrimidin-4-one 2- (methyloxy) benzenecarboximidamide (300 mg, 2.0 mmol) is dissolved in MeOH / dioxane (20 ml / 7 ml) and cooled to 0 ° C. Then 25% NaOCH3 in MeOH (1.39 ml) is added and stirred for 15 minutes. 1-Benzyl-4-oxo-piperidine-3-carboxylic acid ethyl ester hydrochloride salt (893 mg, 3.0 mmol) is introduced and the reaction mixture is refluxed for 2 hours. After removal of the solvent, 10 ml of H2O are added to the residue and acetic acid is used to adjust the pH to 7.8. It is extracted by CH2Cl2 (3 x 100 ml). The organic layer is dried over Na2SO4. Purification by Biotage (ethyl acetate / hexane from 10% to 95%, with 1% MeOH) to give the product 1.21 g as a white solid in 87% yield. 2-f2- (methyloxy) phenyl-3- (2-phenylethyl) -6- (phenylmethyl) -5,6,7,8-tetrahydropyrido [4,3-dlpyrimidin-4 (3H) -one 6-benzyl is dissolved -2- (2-methoxy-phenyl) -5,6,7,8-tetrahydro-3H-pyrido [4,3-d] pyrimidin-4-one (200 mg, 0.58 mmol) in dry DMF at 0 ° C . LiH (5.5 mg, 0.69 mmol) is added and stirred for 5 minutes at this temperature. Then (2-bromoethyl) benzene (0.533 g, 2.88 mol) is added and the mixture is stirred at room temperature overnight. It is diluted with Et2O and dried over MgSO. It is filtered, concentrated and purified by flash column chromatography (ethyl acetate / hexane from 30% to 90%) to maintain the desired product 100 mg (yield 30.8%). c. 2- (2-hydroxyphenyl) -3- (2-phenylethyl-6- (phenylmethyl) -5,6,7,8-tetrahydro-pyrido [4,3-d-pyrimidin-4 (3H) -one is dissolved 2- [ 2- (methyloxy) phenyl] -3- (2-phenylethyl) -6- (phenylmethyl) -5,6,7,8-tetrahydropyrido [4,3-d] pyrimidin-4 (3H) -one (90 mg, 0.20 mmol) in dichloromethane at -60 ° C, BBr3 (2.4 ml, 2.4 mmol) is introduced into the reaction mixture and stirred at this temperature for 1 hour and then stirred at room temperature for 2 days. purify in column (MeOH / 2% dichloromethane) and then biotage (ethyl acetate / hexane 60% to 90%) to give the product as a white solid (55 mg, 63% yield). H NMR (400 MHz, CDCl 3) d 7.33-6.69 (m, 14H), 4.08 (t, 2H), 3.71 (s, 2H), 3.53 (s, 2H), 2.77 (t, 2H), 2.61 (m, 4H). MS (m / z): 438.4 (M + H).

EXAMPLE 178 Preparation of 2- (2-hydroxyphenyl-oxo-3-.2-phenylethyl) -3,5,7,8-tetrahydropyrido 4,3-d-pyrimidine-6 (4H) -carboxylic acid 2-methylpropyl ester The title compound is prepared by replacing isobutyl chloroformate with ethyl chloroformate in Example 181. 1 H NMR (400 MHz, CDCl 3) d 8.60 (br, 1 H), 7.29 (m, 1 H), 7.20 (m , 4H), 6.88 (m, 4H), 4.47 (s, 2H), 4.18 (t, 2H), 4.88 (s, 2H), 3.70 (t, 2H), 2.87 (t, 2H), 2.66 (t, 2H), 1.91 (m, 1 H), 0.96 (d, 6H). MS (m / z): 448.4 (M + H).

EXAMPLE 179 Preparation of 2- (3-fluoro-2-hydroxyphenyl) -6-methyl-5-r5- (2-methyl-1,3-thiazol-4-yl) -2-thienyl-3- (2-phenylethyl) ) -4 (3H) -pyrimidinone to. 2- (3-fluoro-2-r (phenylmethyl) oxy-phenyl) -6-methyl-5- [5- (2-methyl-1,3-thiazol-4-yl) -2-thienyl-3- ( 2-phenylethyl) -4 (3H) -pyrimidinone A solution of 5-bromo-2-. { 3-fluoro-2 - [(phenylmethyl) oxy] phenyl} -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone (0.3 g, 0.61 mmol) from example 11, 4- (5-bromo-2-thienyl) -2-methyl-1, 3- thiazole (0.158 g, 0.61 mmol), hexamethyldistan (0.13 ml, 0.61 mmol), Pd (PPh3) 4 (0.070 g, 0.061 mmol) in 10 ml of dioxane is degassed for 10 minutes and then heated at 90 ° C for 16 minutes. hours. The reaction mixture is concentrated and the crude product is purified on a flash silica gel column (EtOAc / hexanes) to give the product (0.2 g) in 55% yield. MS (ESI) m / e 594 [M + Hf. b. 2- (3-fluoro-2-hydroxyphenyl) -6-methyl-5-r5- (2-methyl-1,3-thiazol-4-yl) -2-thienyl-3- (2-phenylethyl) - 4 (3H) -pyrimidinone 2- is taken. { 3-fluoro-2 - [(phenylmethyl) oxy] phenyl} -6-methyl-5- [5- (2-methyl-1, 3-thiazol-4-yl) -2-thienyl] -3- (2-phenylethyl) -4 (3H) -pyrimidinone (0.1 g, 0.168) mmol) in glacial acetic acid (20 ml). To this is added Pd / C at 10%. This mixture is placed under a hydrogen atmosphere at 3.27 atm and is stirred for 48 hours. The reaction mixture is filtered through a pad of Celite and concentrated. The crude residue is taken up in dichloromethane and washed with NaHCO3 and brine. The organic layer is dried, filtered and concentrated. The crude residue is purified by chromatography on silica gel to produce the desired product (0.003 g) in 3.5% yield. MS (ES) m / e 504 [M + Hf.

EXAMPLE 180 Preparation of 2-.2- (hydroxy) phenyl] -3- (2-phenylethyl) -5,6,7,8-tetrahydropyrido3,2-dlpyridin-4 (3H) -one a, 2- [2- (methyloxy) phenan-4-oxo-4,6,7,8-tetrahydropyrid [3.2-dlpyrimidine-5 (1 H)-1,1-dimethylethylcarboxylate A suspension of 2-methyl-3-oxo-1,2-piperidinecarboxylic acid 1- (1,1-dimethylethyl) (J. Med. Chem. 1989, 32, 2116-2128) (0.78 g, 3.04 mmol) and 2- (methoxy) ) benzenecarboxamidine (0.68 g, 1.5 eq) in dry toluene (10 ml) and stirred at 100 ° C for 3 hours. The reaction mixture is concentrated and the The residue is purified by flash column chromatography on silica gel (hexane / EtOAc 3: 1) to give 0.95 g of the product. b, 2-y2- (methyloxy) phenyl-4-oxo-3- (2-phenylethyl) -4.6.7.8-tetrahydropyrido [3,2-dlpyrimidine-5 (3H) -carboxylic acid 1,1-dimethylethyl ester suspension of 2- [2- (methyloxy) phenyl] -4-oxo-4,6,7,8-tetrahydropyrido [3,2-d] pyrimidine-5 (1 H) -pyrimidinone 1,1-dimethylethylcarboxylate ( 0.95 g, 2.66 mmol), NaH (222 mg, 1.2 eq, 60% suspension in mineral oil) and LiBr (1.14 g, 5 eq) in DMF are stirred at room temperature for 20 minutes. Phenethyl bromide (1.70 ml) is added dropwise, 2 eq) and the resulting mixture is stirred at room temperature overnight. The reaction mixture is diluted with EtOAc, which is washed with H2O and brine. The organic layer is dried (Na2SO4), concentrated, and the residue is purified by flash column chromatography on silica gel (hexane / EtOAc 2: 1) to provide 0.40 g of the O-alkylated product (33%) and 663 mg of the desired N-alkylated product (55%). c. 2-r2- (hydroxy) phenyl-3- (2-phenylethyl) -5.6.7.8-tetrahydropyridof3.2-d1-pyrimidin-4 (3H) -one BBr3 (4.8 ml, 6.0 eq, 1 m / CH2Cl2) to a solution of 2- [2- (methyloxy) phenyl] -4-oxo-3- (2-phenylethyl) -4,6,7,8-tetrahydro-pyrido [3,2-d] pyrimidine-5 (3H) -carboxylic acid 1,1-dimethylethyl ester (0.37 g, 0.80 mmol) in CH 2 Cl 2 (4 mL) at -78 ° C. The yellow precipitate is formed. The reaction is heated to temperature atmosphere and is stirred all night. The reaction mixture is treated with saturated aqueous NaC 3 solution and the organic layer is washed with H 2 O, brine, and dried (Na 2 SO 4). Removal of the solvent and purification of the residue by flash column chromatography on silica gel (hexane / EtOAc 1: 1) yields 150 mg of the white solid (54%). 1 H NMR (400 MHz, CDCl 3) d 9.94 (br, 1 H, OH), 7.22-7.14 (m, 5H), 6.92-6.88 (m, 3H), 6.78 (d, 1 H, J = 8.2Hz), 4.54 (br, 1 H, NH), 4.25 (t, 2H, J = 7.9Hz), 3.50-3.33 (m, 2H), 2.86 (t, 2H, J = 7.9Hz), 2.58 (t, 2H, J = 6.4 Hz), 2.01-1.95 (m, 2H). MS (m / e): 348.2 (M + H).

EXAMPLE 181 Preparation of 2- (2-hydroxyphenyl) -5-methyl-3- (2-phenylethyl) -5,6,7,8-tetrahydropyrido3.2-d1-pyrimidin-4 (3H) -one NaCNBH3 is added to a mixture of 2- [2- (hydroxy) phenyl] -3- (2-phenylethyl) -5,6,7,8-tetrahydropyrido [3,2-d] pyrimidin-4 (3H) -one (41 mg, 0.012 mmol), aqueous HCHO (0.11 ml, 12 eq 37%). The resulting mixture is stirred at room temperature overnight and taken in DCM, which is washed with saturated aqueous solution of NaHCO3, brine, and dried (Na2SO4). Removal of the solvent and purification of the residue by flash column chromatography on silica gel (hexane / EtOAc 1: 1) yield 38.2 mg of yellow solid (88%). 1 H NMR (400 MHz, CDCl 3) d 7.24-7.13 (m, 5H), 7.02-6.82 (m, 4H), 4.22 (t, 2H, J = 7.8Hz), 3.11-3.07 (m, 2H), 3.04 (s, 3H), 2.88 (t, 2H, J = 7.8Hz), 2.58 (t, 2H3 J = 6.4Hz), 1.93-1.86 (m, 2H). MS (m / z): 362.2 (M + H).

EXAMPLE 182 Preparation of 5-ethyl-2-r 2 -hydroxyphenyl-3- (2-phenylethyl) -5,6,7,8-tetrahydropyrido3.2-dlpyrimidin-4 (3H) -one to. 2- [2- (methyloxy) phenin-3- (2-phenylethyl) -5.6.7.8-tetrahydropyridoi3.2-d1-pyrimidin-4 (3H) -one A solution of 2- [2- (methyloxy) phenyl] -4- 3,1-dimethylethyl oxo-3- (2-phenylethyl) -4,6,7,8-tetrahydropyrido [3,2-d] pyrimidine-5 (3H) -carboxylate (0.16 g, 0.35 mmol) from Example 180b and TFA (1 ml) in CH2Cl2 (3 ml) is stirred at room temperature for 4 hours, poured into saturated aqueous solution of Na2CO3 cooled with ice. The resulting mixture is extracted with CH2Cl2 and the combined organic layers are washed with brine, dried (Na2SO4) and concentrated. The residue is purified by flash column chromatography on silica gel (hexane / EtOAc 1: 1) to give 0.11 g of the title compound (88%). b. 5-ethyl-2-f2-hydroxyphenyl-1,3- (2-phenylethyl) -5,6,7,8-tetrahydropyridor3.2-d1-pyrimidin-4 (3H) -one A solution of 2- [2- (methyloxy) phenyl ] -3- (2-phenylethyl) -5,6,7,8-tetrahydropyrido [3,2-d] pyrimidin-4 (3H) -one (90 mg, 0.25 mmol) and CH 3 CHO (70 μl) , 5 eq) in CH2Cl2 (2.5 ml) is stirred at room temperature for 1 hour. NaBH (OAc) 33 (79 mg, 1.5 eq) is added and the resulting mixture is stirred at room temperature overnight. The reaction is quenched with saturated aqueous NaHCO3 solution and the organic layer is separated, dried (Na2SO) and concentrated. The residue is purified by flash column chromatography on silica gel (hexane / EtOAc 1: 1) to provide 77.5 milligrams of product. Subsequent demethylation using the procedure detailed previously produces the product. 1 H NMR (400 MHz, CDCl 3) d 9.80 (br, 1 H, OH), 7.11-7.05 (m, 5H), 6.81-6.77 (m, 3H), 6.68 (d, 1 H1 J = 8.1 Hz), 4.11 -4.07 (m, 2H), 3.31 (q, 2H, J = 7.0Hz), 3.05-3.02 (m, 2H), 2.77 (t, 2H, J = 7.4Hz), 2.48 (t, 2H, J = 6.4 Hz), 1.78-1.28 (m, 2H), 1.13 (t, 3H, J = 7.0Hz). MS (m / z): 376.2 (M + H).

EXAMPLE 183 Preparation of 2- (2-hydroxy-phenyl) -4-oxo-3- (2-phenylethyl) -3.4.5.7-tetrahydro-6H-pyrrolo [3,4-d1-pyrimidine-6-carboxylate of 1,1-dimethylethyl to. 4-oxo-2- [2- ( { [(Phenylmethyl) oxycarbonyl) oxy) phenyl1-1, 4,5,7-tetrahydro-6H-pyrrolof3,4-dlpyrimidine-6-carboxylate of 1,1dimethylethyl The title compound is prepared by following the procedure briefly described in example 180 except substituting ethyl ester 3-ester-4-oxo-pyrrolidine-1,3-dicarboxylic acid-tert-butyl ester (Tetrahedron, Lett 2002, 43 (17) , 3243-3246) by 1- (1,1-dimethylethyl) -2-methyl 2-methyl-3-oxo-1,2-piperidinecarboxylate. b. 2- (2-Hydroxyphenyl) -4-oxo-3- (2-phenylethyl) -3,4,5,7-tetrahydro-6H-pyrrolo [3,4-d-pyrimidine-6-carboxylate of 1, 1-dimethylethyl A suspension of 1,1-dimethylethyl-4-oxo-3- (2-phenylethyl) -2- [2- (. {[[(Phenylmethyl) oxy] carbonyl} oxy) phenyl] -3, 4,5,7-tetrahydro-6H-pyrrolo [3,4-d] pyrimidine-6-carboxylate (78 mg, 0.15 mmol) and Pd / C (10 mg, 10%) in EtOH are stirred under a H2 balloon at room temperature for 3 hours. The mixture of The reaction is filtered through a pad of Celite, which is rinsed with CH2Cl2. The combined filtrates are concentrated and the residue is purified by flash column chromatography on silica gel (hexane / EtOAc 1: 1) to provide 49 mg of the product (76%). 1 H NMR (400 MHz, CDCl 3) d 8.69 (br, 1 H, OH), 7.34-7.30 (m, 1 H), 7.19-7.17 (m, 3H), 7.05-7.03 (m, 1 H), 6.97-6.89 (m, 4H), 4.63-4.52 (m, 4H), 4.20-4.15 (m, 2H), 2.89-2.85 (m, 2H), 1.52, 1.50 (S, 9H, rotamers): MS (m / z): 434.4 (M + H).

EXAMPLE 184 Preparation of 5- (2-methylpropyl-2-yl) -2- (2-hydroxy-phenyl) -6-methyl-3- (2-phenethyl) -3H-pyrimidin-4-one to. Ethyl 2-acetyl-3,3-dimethylbutanoate To the mixture of 3-oxo-butyric acid ethyl ester (19.5 g, 150 mmol) and 2-bromo-2-methylpropane (6.85 g, 50 mmol) in 5 ml of nitromethane under Ar at 0 ° C, silver perchlorate (10.4 g, 50 mmol) is added in 20 ml of nitromethane. The mixture is stirred at 0 ° C for 3 hours. The solid is filtered and the filtrate is concentrated. The crude residue is purified in flash column chromatography (10% EtOAc / hexanes) to provide 3.5 g (38%) of the compound of the title. b. 5- (2-methylpropyl-2-yl) -2- (2-hydroxy-phenyl) -6-methyl-3- (2-phenethyl) -3H-pyrimidin-4-one The title compound is prepared following the procedures of Example 26 except substituting ethyl 2-acetyl-3,3-dimethylbutanoate for ethyl 2-chloro-3-oxobutanoate. 1 H NMR (400 MHz, CDCl 3) d 10.25 (br, 1 H), 2.40-7.35 (m, 2 H), 7.23-7.20 (m, 3 H), 7.03-6.92 (m, 4 H), 4.48 (t, 2 H) , 3.03 (t, 2H), 2.49 (s, 3H), 1.53 (s, 9H). MS (m / z): 363.4 (M + H).

EXAMPLE 185 Preparation of 5-f2- (3-fluorophenyl) etn-6- (2-hydroxyphenyl) -1-methyl-1,5-dihydro-4H-pyrazolo3.4-d] pyrimidin-4-one a, N-f2- (3-fluorophenyl) etn-1-methyl-5-nitro-1 H-pyrazole-4-carboxamide A 1-methyl-5-nitro-1 H-pyrazole-4-carboxylic acid ( 500 mg, 2.9 mmol) is added CH2CI2 50 ml and (COCI) 2 (0.92 ml, 10.5 mmol) and the mixture is heat at reflux for 3 hours. (COCI) 2 in excess and the solvent is removed in a rotary evaporator. The residue is dissolved in 50 ml of CH CI2 and 3-fluorophenethylamine (730 mg, 5.22 mmol) in pyridine (1 ml) is added and stirred at room temperature overnight. The reaction mixture is diluted with CH 2 Cl 2 and washed with H 2 O, 1 N HCl and brine (100 ml, each) and then purified by flash column chromatography (EA / 50% hexane). To provide 500 mg of a white solid. Performance 65%. b. 5-amino-N- [2- (3-fluorophenyl) etyl-1-methyl-1 H -pyrazole-4-carboxamide N- [2- (3-fluorophenyl) ethyl] -1-methyl-5-nitro-1 H-pyrazole-4-carboxamide (300 mg, 1.03 mmol) and zinc powder (2.0 g, 30.8 mmol) is mixed in 2 ml of HOAc and 2 ml of THF. The resulting mixture is stirred at room temperature for 1.5 hours. The mixture is filtered through Celite and evaporated. The residue is diluted in EtOAc and washed with 1 N NaOH and brine. Dry over Na 2 SO 4, filter and concentrate to provide 0.25 g of the title compound. to N-r2- (3-fluorophenyl) etin-1-methyl-5-r 2- [(phenylmethyl) oxy1phenyl) carbonyl) amino1-1 H-pyrazole-4-carboxamide 5-amino-N- [2- (3-fluorophenyl) ethyl] -1-methyl-1 H-pyrazole-4-carboxamide (200 mg, 0.76 mmol) and 2-benzyloxy-benzoyl chloride (226 mg, 0.92 mmol) are mixed in THF 50 ml and 2 ml of pyridine. The mixture is stirred overnight and THF is removed and the residue is diluted in EtOAc and washed with H2O, 1 N HCl, NaHC? 3 saturated and brine. The organic layer is concentrated and purified by flash column chromatography (50% EtOAc / hexane) to give 350 mg of the title compound. d. 5-I2- (3-fluorophenyl) etin-6- (2-hydroxyphenyl) -1-methyl-1, 5-dihydro-4H-pyrazolo [3,4-dlpyrimidin-4-one To the solution of N- [2- (3-fluorophenyl) ethyl] -1-methyl-5 - [(. {2- [(phenylmethyl) oxy] phenyl} carbonyl) amino] -1H-pyrazole-4-carboxamide (50 mg, 0.11 mmol) in toluene is added catalytic amount of pTsOH and heated at reflux for 2 days. The solvent removed and the residue purified in flash column chromatography (30% EtOAc / hexane) to provide 15 mg of the title compound. 1 H NMR (400 MHz, CDCl 3) d 8.13 (s, 1 H), 7.49-7.42 (m, 1 H), 7.26-7.05 (m, 4H), 6.92-6.87 (m, 1 H), 6.65 (d, 1 H), 6.53 (d, 1 H), 4.33 (t, 2H), 3.99 (s, 3H), 2.90-2.86 (t, 2H). MS (m / z): 365.2 (M + H).

EXAMPLE 186 Preparation of 5-ethyl-2- (3-fluoro-2-hydroxyphenyl) -3-r2- (3-fluorophenyl) etn-6-phenyl-4 (3H) -pyrimidinone to. 5-ethyl-2- (3-fluoro-2-hydroxyphenyl) -3-r2- (3-fluorophenyl) etyl-6-phenyl-4 (3H) -pyrimidinone To the solution of 5-ethyl trifluoromethanesulfonate -1- [2- (3-fluorophenyl) ethyl] -6-oxo-2- [2-. { (phenylmethyl) oxy} phenyl] -1,6-dihydro-4-pyrimidinyl from example 27 (81 mg, 0.14 mmol) in 3 ml of toluene was added Pd (PPh3) (16 mg, 0.014 mmol) and phenylboronic acid (35 mg, 0.29 mmol) in 0.5 ml of EtOH followed by aqueous Na2CO3 (215 mg in 0.5 ml of H2O) at room temperature. The mixture is then stirred vigorously for 5 minutes and heated at 90 ° C for 3 hours. After which another portion of reagents (0.1 eq, Pd (PPh3) 4, 2.1 eq of boronic acid and (1.0 eq of Na2C03) is added and the reaction mixture is heated to reflux overnight. residue by flash column chromatography (EtOAc / hexane from 0% to 50%) gives 52 mg of the title compound.The subsequent catalytic hydrogenolysis affords the title compound.1H NMR (400 MHz, CDCl3) d 8.85 (br, 1 H , OH), 7.47-7.43 (m, 4H), 7.20-7.10 (m, 4H), 6.93-6.65 (m, 4H), 4.40 (t, 2H), 3.02 (t, 2H), 2.64 (q, 2H), 1.24 (t, 3H).

EXAMPLE 187 Preparation of 6-r3,4-bis (methyloxy) phenyl-1-ethyl-2- (3-fluoro-2-hydroxyphenyl) -3- f2- (3-fluorophenyl) -etin-4 (3H) -pyrimidinone The title compound is prepared following the general procedures of Example 186 except substituting 3,4-dimethoxyphenyl acid for phenyl boronic acid. 1 H NMR (400 MHz, CDCl 3) d 5 9-10 (br, 1 H, OH), 7.20-6.60 (m, 10H), 4.34 (t, 2H), 3.93 (s, 1 H), 3.92 (s, 1 H), 2.98 (t, 2H), 2.68 (q, 2H), 1.25 (t, 3H). MS (m / z): 493.4 (M + H).

EXAMPLE 188 Preparation of 5-ethyl-2- (3-fluoro-2-hydroxyphenyl) -3-r2-. { 3-fluorophenyl) ethyl 1-6- (3-nitrophenyl) -4 (3H) -pyrimidinone The title compound is prepared following the general procedures of Example 186 except substituting 3-nitrophenyl boronic acid for phenyl boronic acid. H NMR (400 MHz, CDCl 3) d 8.74 (t, 1H), 8.39-8.38 (m, 1 H), 7.85-7.83 (m, 2H), 7.63 (t, 1 H), 7.19-7.17 (m, 2H ), 6.97-6.89 (m, 3H), 6.71 (d, 1 H), 6.59 (d, 1 H), 4.25 (t, 2H), 2.95 (t, 2H), 2.59 (q, 2H), 1.26 ( t, 3H). MS (m / z): 434.4 (M + H).

EXAMPLE 189 Preparation 5-ethyl-3-r2- (3-fluorophenyl) ethyn-2- (2-hydroxyphenyl) -6- (1-pyrrolidinyl) -4 (3H) -pyrimidinone To the solution of trifluoromethanesulfonate of 5-ethyl-1- [2- (3-fluorophenyl) ethyl] -6-oxo-2-. { 2 - [(phenylmethyl) oxy] phenyl} -1,6-dihydro-4-pyrimidinyl from example 28 (30 mg, 0.07 mmol) in dry dioxane is added pyrrolidine (7.7 μl, 0. 08 mmol) and Cs2C? 3 (31 mg, 0.1 mmol) in dry dioxane is added pyrrolidine (7.7 μl, 0.08 mmol) and Cs2CO3 (31 mg, 0.1 mmol). The reaction mixture is heated at 150 ° C overnight. At the completion, the reaction is concentrated and purified on flash column chromatography (EtOAc / hexane from 0 to 50%) to provide 25.5 mg of 5-ethyl-3- [2- (3-fluorophenyl) ethyl] -2- (2- [(phenylmethyl) oxy] phenyl) -6- (1-pyrrolidinyl) -4 (3H ) -pyrimidonone. This compound is deprotected using the procedure BBr3 briefly described previously to provide the title compound. 1 H NMR (400 MHz, CDCl 3) d 9.81 (br, 1 H), 7.22 (m, 2 H), 7.08 (m, 1 H), 6.90 (d, 1 H), 6.78 (m, 2H), 6.67 (d, 1 H), 6.55 (d, 1H), 4.30 (t, 2H), 2.92 (t, 2H), 2.68 (q, 2H), 1.92 (m, 4H), 1.22 (m, 4H), 1.19 (t, 3H). MS (m / z): 408.4 (M + H).

EXAMPLE 190 Preparation of 6- (dimethylamino) -5-ethyl-3-r2- (3-fluorophenyl) eti.l-2- (2-hydroxyphenyl) -4 (3H) -pyrimidinone The title compound is prepared following the general procedures of Example 189 except substituting dimethylamine for pyrrolidine. 1 H NMR (400 MHz, CDCl 3) d 9.68 (br, 1 H), 7.22 (t, 1 H), 7.20 (d, 2H), 7.01 (m, 1 H), 6.91-6.46 (m, 4H), 4.29 (t, 2H), 2.95 (s, 6H), 2.88 (t, 2H), 2.52 (q, 2H), 1.08 ( t, 3H). MS (m / e): 382.4 (M + H).

EXAMPLE 191 Preparation of 5-ethyl-3-r2- (3-fluorophenyl) ethyl-2- (2-hydroxyphenyl) -6- (methylamino) -4 (3H) -pyrimidinone The title compound is prepared following the general procedures of Example 189 except substituting methylamine for pyrrolidine. 1 H NMR (400 MHz, CDCl 3) d 7.31-6.72 (m, 8 H), 4.31 (t, 2 H), 2.99 (s, 3 H), 2.96 (t, 2 H), 2.43 (q, 2 H), 1.09 (t, 3H). MS (m / z): 368.2 (M + H).

EXAMPLE 192 Preparation of 5-cyclopentyl-3-r2- (3-fluorophenyl) ethyl-2- (2-hydroxyphenyl) -6-methyl-4 (3H) -pyrimidinone The title compound is prepared by substituting ethyl 2-cyclopentyl-3-oxobutanoate for ethyl 2-chloro-3-oxobutanoate and 2-fluoro- (2-bromoethyl) benzene for (2-bromoethyl) benzene in Example 26. 1 H NMR (400 MHz, CDCl 3) d 7.31 (m, 1 H), 7.18 (m, 2 H), 6.95 (m, 5 H), 4.34 (t, 2 H), 3.11 (m, 1 H), 2.99 (t, 2H), 2.39 (s, 3H), 2.05-1.60 (m, 8H). MS (m / z): 393.2 (M + H).

EXAMPLE 193 Preparation of 2- (2-hydroxyphenyl) -6-methyl-5- (2-methylpropyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone The title compound is prepared by substituting ethyl ester 2- (2-methyl-propyl) -3-oxo-butyric acid for ethyl 2-chloro-3-oxobutanoate and 2-fluoro- (2-bromoethyl) benzene by (2-bromoethyl) benzene in Example 26. 1 H NMR 9.70 (br, 1 H), 7.06 (m, 2 H), 6.90-6.66 (m, 6 H), 4.07 (t, 2 H), 2.88 (t, 2 H) ), 2.38 (d, 2H), 2.18 (s, 3H), 1.88 (m, 1 H), 0.85 (d, 6H). MS (m / z): 381.2 (M + H).

EXAMPLE 194 Preparation of 2- (2-hydroxyphenyl) -6-methyl-5- (2-methylpropyl) -3-y2- (2-thienyl) etp-4 (3H) -pyrimidinone The title compound is prepared by replacing 2- (2-methyl-propyl) -3-oxo-butyric acid ethyl ester by ethyl 2-chloro-3-oxobutanoate and 2-thiophene-2-yl-ethyl bromide by (2-bromoethyl) benzene in the Example 26. 1 H NMR (400 MHz, CDCl 3) d 7.30 (t, 1 H), 7.02 (d, 1 H), 6.96-6.79 (m, 4 H), 6.66 (t, 1 H), 4.37 (t, 2 H) ), 3.28 (t, 2H), 2.49 (d, 2H), 2.38 (s, 3H), 2.02 (m, 1 H), 0.95 (d, 6H). MS (m / z): 369.0 (M + H).

EXAMPLE 195 Preparation of 5-ethyl-2- (2-hydroxy-phenyl) -5-ethyl-3-phenylethyl-3H-pyrimidin-4-one a, 5-ethyl-6-methyl-2- [2- (methyloxy) phenyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone The title compound is prepared by the substitution of 2-ethyl-3- ethyl oxobutanoate by ethyl 2-chloro-3-oxobutanoate in Example 26. b. 5-ethyl-2- (2-hydroxy-phenyl) -6-etl-3-phenylethyl-3H-pyrimidin-4-one To the solution of 5-ethyl-6-methyl-2- [ 2- (methyloxy) phenyl] -3- (2-phenylethyl) -4 (3H) -pyrimidinone (0.2 g, 0.48 mmol) in THF is cooled to -75 ° C. To this is added LDA 2M (0.27 ml, 0.53 mmol) dropwise. After the agitation by at least one hour of methyl iodide (0.083 g, 0.53 mmol) is added via syringe. The reaction is stirred overnight and quenched by NH 4 Cl, extracted with EtOAc. The EtOAc layer is washed with brine. The aqueous layer is back extracted with EtOAc, the EtOAc layers are combined, dried over Na2SO, filtered and concentrated in vacuo. The residue is purified by flash chromatography (hexane / EtOAc = 4: 1) to yield 5,6-diethyl-2- [2- (methoxy) phenyl] -3- (2-phenylethyl) -4 (3H) - pyrimidinone (0.145 g). This material is converted to the title compound using BBr3 as previously detailed. 1 H NMR 7.22 (m, 2 H), 7.02 (m, 3 H), 6.90 (m, 4 H), 4.35 (t, 2 H), 3. 08 (t, 2H), 1.28 (t, 3H), 1.20 (t, 3H). MS (m / z): 349.4 (M + H).

EXAMPLE 196 Preparation of 5-ethyl-2- (2-hydroxy-phenyl) -6-propyl-3-phenethylethyl-3H-pyrimidin-4-one The title compound is prepared by replacing ethyl iodide with methyl iodide in Example 195. 1 H NMR: 9.90 (br, 1 H), 7.31-7.18 (m, 5H), 6.91 (m, 4H), 4.28 (t, 2H), 2.59 (q, 2H), 2.51 (t, 2H), 1.61 ( q, 2H), 1.12 (1, 3H), 0.99 (t, 3H). MS (m / z): 363.4 (M + H).

EXAMPLE 197 Preparation of 5-ethyl-2- (3-f1uoro-2-hydroxy-phenyl) -6- (2-phenylethyl) -3- (2-f1-uoro-phenylethyl) -3H-pyrimidin-4-one To the solution of 5-ethyl-2- (3-fluoro-2-. {[[(Methyloxy) methyloxy] phenyl] -3- [2-. {2-fluorophenyl} ethyl] -6- methyl-4 (3H) -pyrimidinone (0.3 g, 0.725 mmol) from Example 45 in THF is cooled to -75 ° C. To this is added 2M LDA (0.38 mL, 0.76 mmol) dropwise. At least one hour is added benzyl bromide (0.086 ml, 0.725 mmol) per syringe. At the completion of the reaction, quench by NH 4 Cl, extract with EtOAc. The EtOAc layer is washed with brine. The aqueous layer is back extracted with EtOAc. The EtOAc layers are combined, dried over Na2SO4, filtered and concentrated in vacuo. The residue is purified by flash chromatography (hexanes / 20% EtOAc) to yield 5,6-diethyl-2- [2- (methyloxy) phenyl] -3- (2-phenylethyl) -4 (3H) -pyrimidinone (0.186). g) in 77% yield. This material is converted to the title compound using TFA as previously detailed. 1 H NMR: 7.29-7.16 (m, 7H), 6.99-6.79 (m, 5H), 4.31 (t, 2H), 3.00 (t, 2H), 2.93 (m, 2H), 2.84 (m, 2H), 2.52 (q, 2H), 1.10 (t, 2H). MS (m / z): 461.4 (M + H).

EXAMPLE 198 Preparation of 5-ethyl-2- (3-fluoro-2-hydroxy-phenyl) -6-propyl-3- (2-fluoro-phenylethyl) -3H-pyrimidin-4-one The title compound is prepared by replacing ethyl bromide with benzyl bromide in Example 197. 1 H NMR: 7.21-7.17 (m, 2H), 6.99-6.88 (m, 5H), 4.38 (t, 2H), 3.05 (t, 2H), 2.62 (m, 4H), 1.71 (q, 2H), 1.20 (t, 3H), 1.01 (t, 3H). MS (m / e): 399.4 (M + H).

EXAMPLE 199 Preparation of 5-ethyl-2- (3-fluoro-2-hydroxy-phenyl) -6- (3-phenyl-propyl) -3- (2-fluoro-phenylethyl) -3H-pyrimidin-4-one The title compound is prepared by replacing phenethyl bromide with benzyl bromide in Example 197. 1 H NMR: 7.31-7.20 (m, 7H), 6.99-6.88 (m, 5H), 4.34 (t, 2H), 3.04 (t, 2H), 2.76-2.54 (m, 6H), 2.03 (m, 2H), 1.14 (t, 3H). MS (m / z): 475.5 (M + H).

EXAMPLE 200 Preparation of 5-ethyl-2- (3-fluoro-2-hydroxy-phenyl) -6-butyl-3- (2-fluoro-phenylethyl) -3H-pyrimidin-4-one The title compound is prepared by replacing propyl bromide with benzyl bromide in Example 197. 1 H NMR: 7.13 (m, 2 H), 6.94-6.81 (m, 5 H), 4.31 (t, 2 H), 2.99 ( t, 2H), 2.55 (m, 4H), 1.55 (m, 2H), 1.34 (m, H), 1.13 (t, 3H), 0.88 (t, 3H). MS (m / z): 413.4 (M + H).

EXAMPLE 201 Preparation of 5-Ethyl-2- (3-fluoro-2-hydroxy-phenyl) -6- (2-methyl-propyl) -3- (2-fluoro-phenylethyl) -3H-pyrimidin-4- ona The title compound is prepared by replacing isopropyl bromide with benzyl bromide in Example 197. 1 H NMR: 7.19-7.11 (m, 2H), 7.02-6 84 (m, 5H), 4.44 (t, 2H ), 3 04 (t, 2H), 2.64 (q, 4H), 2.48 (d, 2H), 2.08 (m, 1 H), 1.16 (t, 3H), 0.98 (d, 6H). MS (m / z): 413.2 (M + H).

EXAMPLE 202 Preparation of 5-ethyl-2- (3-fluoro-2-hydroxy-phenyl) -6- (3-methyl-butyl) -3- (2-fluoro-phenylethyl) -3H-pyrimidin-4 -one The title compound is prepared by replacing 3-methylbutyl bromide with benzyl bromide in Example 197. 1 H NMR: 7.16-7.11 (m, 2H), 7.98-6.84 (m, 5H), 4.35 (t, 2H ), 3.02 (t, 2H), 2.61 (m, 4H), 1.62 (m, 1 H), 1.50 (m, 2H), 1.20 (t, 3H), 0.98 (d, 6H). MS (m / z): 427.4 (M + H).

EXAMPLE 203 Preparation of 5-ethyl-2- (3-f1uoro-2-hydroxy-phenyl) -6- (2-cyclobutyl-ethyl) -3- (2-fluoro-phenylethyl) -3H-pyrimidin-4-one The title compound is prepared by replacing cyclobutylmethyl bromide with benzyl bromide in Example 197. 1 H NMR: 7.21-7.11 (m, 2H), 7.98-6.81 (m, 5H), 4.37 (t, 2H), 3.06 (t, 2H), 2.61-2.47 (m, 4H), 2.30 (m, 1 H), 1.96-1.58 (m, 6H), 1.22 (t, 3H). MS (m / z): 439.4 (M + H).

EXAMPLE 204 Preparation of 2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- (3-thienyl) -4 (3H) -pyrimidinone The title compound is prepared by substituting thiophene-3-boronic acid for 6-quinolinylboronic acid in Example 13. MS (m / z) 407.2 [M + Hf. EXAMPLE 205 Preparation of 5-ethyl-2- (4-fluoro-2-hydroxyphenyl) -6-methyl-3-r2-phenylethi.1-4 (3H) -pyrimidinone to. Ethyl 2-ethyl-3-oxo-N- (2-phenylethyl) butanamide 2-ethylacetoacetate (2.0 ml, 12.4 mmol) and phenylamine (0.78 ml, 6.19 mmol) in ethanol (0.2 ml) is heated to 180 ° C in a microwave during 20 minutes. The reaction mixture is purified via 2-6% ethyl acetate / hexane column chromatography) to yield 0.860 g (60%) of the title compound. LCEM (m / z) 234.2 (M + H). b. 5-Ethyl-2- (4-fluoro-2-hydroxyphenyl) -6-methyl-3-I2-phenyletin-4 (3H) -pyrimidinone 4-Fluoro-2-hydroxybenzamide (0.200 g, 1.29 mmol) is added to 2-ethyl-3-oxo-N- (2-phenylethyl) butanamide (0.150 g, 0.644 mmol) in titanium isopropoxide (3.0 mL, 10.2 mmol) and heated at 150 ° C for 4 days. The reaction is diluted with CH2Cl2 and 1 N HCl and stirred at room temperature for 3 hours. The layers are separated and the aqueous layer is extracted twice with CH2CI. The combined organic layers are dried over Na2SO4, filtered and concentrated. Preparative HPLC (CH3CN: 20-95% H2O) affords 0.063 g (28%) of the title compound. LCMS (m / z) 353.2 (M + H).

EXAMPLE 206 Preparation of 2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- (5-phenyl-2-thienyl) -4 (3H) -pyrimidinone The title compound is prepared by substituting 5-phenylthiylboronic acid for 6-quinolinboronic acid in Example 13. MS (m / z): 483.2 [M + Hf.

EXAMPLE 207 Preparation of 2- (2-hydroxyphenyl) -6-methyl-5- (5-methyl-2-thienyl) -3- (2-phenylethiD-4 (3H) -pyrimidinone a, 6-methyl-5- (5-methyl-2-thienyl) -3- (2-phenylethyl) -2- [2- [(phenylmethyl) oxpfenill-4 (3H) -pyrimidinone To a solution of 5-bromo -6-methyl-3- (2-phenylethyl) -2- [2 - [(phenylmethyl) oxy] phenyl] -4 (3H) -pyrimidinone (0.862 g, 1.81 mmol) in toluene (9.0 ml), ethanol (0.1 ml), and H2O (0.1 ml) is added sodium carbonate (0.385 g, 3.63 mmol), 5-methylthiophene boronic acid (0.516 g, 3.63 mmol), and bis (tri-t-butylphosphine) palladium (0.145 g, 0.284). mmol). The resulting reaction mixture It is heated at 110 ° C for 3 hours. The reaction is cooled to room temperature, filtered through a filter frit clogged with Celite, washed with CH3OH and CH2Cl2, and concentrated. Column chromatography (ethyl acetate / hexane 1-35%) gives 0.750 g (84%) of the title compound. LCEM (m / z): 493.2 (M + H). b. 2- (2-hydroxyphenyl) -6-methyl-5- (5-methyl-2-thienyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone The title compound is prepared following the same procedure as the example 206e substituting 6-methyl-5- (2-methyl-1, 3-thiazol-5-yl) -3- (2-phenylethyl) -2- [2 - [(phenylmethyl) oxy] phenyl] -4 (3H ) -pyrimidinone with 6-methyl-5- (5-methyl-2-thienyl) -3- (2-phenylethyl) -2-. { 2 - [(phenylmethyl) oxy] phenyl} -4 (3H) -pyrimidinone. LCMS (m / z): 403.2 (M + H).

EXAMPLE 208 Preparation of 2- (2-hydroxyphenyl) -6-methyl-5- (5-methyl-3-thienyl-3- (2-phenylethyl-4 (3H) -pyrimidinone a, 6-methyl-5- (5-methyl-3-thienyl) -3- (2-phenylethyl) -2- (2- [(phenylmethyl) oxy-phenyl) -4 (3H) -pyrimidinone The title compound is prepared following the same procedure as example 206d substituting 2-methyl-5- (tributylstannanyl) -1,3-thiazole with tributyl (5-methyl-3-thienyl) stannane. LCEM (m / z): 493.2 (M + H). b. 2- (2-hydroxyphenyl) -6-methyl-5- (5-methyl-3-thienyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone The title compound is prepared following the same procedure as the example 206e substituting 6-methyl-5- (2-methyl-1,3-thiazol-5-yl) -3- (2-phenylethyl) -2-. { 2 - [(phenylmethyl) oxy] phenyl} -4 (3H) -pyrimidinone with 6-methyl-5- (5-methyl-3-thienyl) -3- (2-phenylethyl) -2-. { 2 - [(phenylmethyl) oxy] phenyl} -4 (3H) -pyrimidinone. LCMS (m / z): 403.2 (M + H).

EXAMPLE 209 Preparation of 2- (3-fluoro-2-hydroxyphenyl) -6-methyl-5- (5-methyl-3-thienyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone to. 2- (3-fluoro-2-f (phenylmethyl) oxylphenyl) -6-methyl-5- (5-methyl-3-thienyl) -3- (2-phenylethyl) -4 (3H) pyrimidinone The title compound is prepared following the same procedure as example 206d substituting 5-bromo-6-methyl-3- (2-phenylethyl) -2 - [(phenylmethyl) oxy] phenyl} -4 (3H) -pyrimidinone with 2- (3-fluoro-2- [(phenylmethyl) oxy] phenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone and 2-methyl-5 - (tributylstannanyl) -l, 3-thiazole with tributyl (5-methyl-3-thienyl) stannane. LCMS (m / z): 511.2 (M + H). b. 2- (3-fluoro-2-hydroxyphenyl) -6-methyl-5- (5-methyl-3-thienyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone The title compound is prepared following the same procedure as example 206e substituting 6-methyl-5- (2-methyl-1,3-thiazol-5-yl) -3- (2-phenylethyl) -2-. { 2-. { (phenylmethyl) oxy} phenyl } -4 (3H) -pyrimidinone with 2- (3-fluoro-2 - [(phenylmethyl) oxy] phenyl) -6-methyl-5- (5-methyl-3-thienyl) -3- (2 phenylethyl) -4 (3H) -pyrimidinone. LCMS (m / z): 421.2 (M + H).

EXAMPLE 210 Preparation 5- (4,5-Dimethyl-2-thienyl) -2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone a, 5- (4,5-Dimethyl-2-thienyl) -6-methyl-3- (2-phenylethyl) -2- (2 - [(phenylmethyl) oxy-phenyl) -4 (3H) -pyrimidinone The title compound is prepared following the same procedure as example 206d substituting 2-methyl-5- (tributylstannanyl) -1,3-thiazole with tributyl (4,5-dimethyl-2-thienyl) stannane LCEM (m / z): 507.2 (M + H) b. 5- (4,5-dimethyl-2-thienyl) -2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone The title compound is prepared following the same procedure as example 206e substituting 6-methyl-5- (2-methyl-1,3-thiazol-5-yl) -3- (2-phenylethyl) -2-. { 2 - [(phenylmethyl) oxy] phenyl} -4 (3H) -pyrimidinone with 5- (4,5-dimethyl-2-thienyl) -6-methyl-3- (2-phenylethyl) -2- [2 - [(phenylmethyl) oxy] phenyl] -4 (3H) -pyrimidinone. LCEM (m / z). 417.0 (M + H).

EXAMPLE 211 Preparation of 2- (2-hydroxyphenyl) -6-methyl-5-r5- (1, 3-oxazol-5-yl) -2-thienyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone a, 6-methyl-5- [5- (1, 3-oxazol-5-yl) -2-thienyl-3- (2-phenylethyl) -2- (2-f (phenylmethyl) oxphenyl) -4 (3H ) -pyrimidinone A solution of hexamethylditin (0.630 g, 1.92 mmol) in 1,4-dioxane (15 ml) is purged with N2 for 15-20 minutes. 5- (5-Bromo-2-thienyl) -1,3-oxazole (0.450 g, 1.96 mmol) and bis (tri-t-butylphosphine) palladium (0.117 g, 0.229 mmol) are added and the reaction is heated to 100 ° C for 3 h. The reaction is cooled to room temperature for about 30 minutes, 5-bromo-6-methyl-3- (2-phenylethyl) -2- [2-. { (phenylmethyl) oxy} phenyl] -4 (3H) -pyrimidinone (0.908 g, 1.91 mmol) and the reaction is heated at 100 ° C for 48 hours. The reaction is cooled, filtered through filter frit clogged with Celite, washed with CH3Cl2, and concentrated. Column chromatography (ethyl acetate / hexane of 1-50%) yields 0.310 g (30%) of the title compound. LCMS (m / z): 546.2 (M + H). b. 2- (2-hydroxyphenyl) -6-methyl-5- [5- (1, 3-oxazol-5-yl) -2-thienyl-3- (2-phenylethyl) -4 (3H) -pyrmidinone The The title compound is prepared following the same procedure as example 206e substituting 6-methyl-5- (2-methyl-1,3-thiazol-5-yl) -3- (2-phenylethyl) -2-. { 2 - [(phenylmethyl) oxy] phenyl} -4 (3H) -pyrimidinone with 6-methyl-5- [5- (1, 3-oxazol-5-yl) -2-thienyl] -3- (2-phenylethyl) -2- [2-. { (phenylmethyl) oxy} phenyl] -4 (3H) -pyrimidinone. LCMS (m / z): 456.0 (M + H).

EXAMPLE 212 Preparation of 2- (2-hydroxyphenyl) -6-methyl-5- (4-methyl-2-thienyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone a, 6-methyl-5- (4-methyl-2-thienyl) -3- (2-phenylethyl) -2- (2- [(phenylmethyl) oxy-phenyl) -4 (3H) -pyrimidinone The title compound is prepared following the same procedure as example 207a substituting 5-methylthiophene boronic acid with 4-methylthiophene boronic acid. LCEM (m / z): 493.2 (M + H). b. 2- (2-hydroxyphenyl) -6-methyl-5- (4-methylene-2-thienyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone The title compound is prepared following the same procedure as example 206e substituting 6-methyl-5- (2-methyl-1,3-thiazol-5-yl) -3- (2-phenylethyl) -2-. { 2 - [(phenylmethyl) oxy] phenyl} -4 (3H) -pyrimidinone with 6-methyl-5- (4-methyl-2-thienyl) -3- (2-phenylethyl) -2-. { 2 - [(phenylmethyl) oxy] phenyl} -4 (3H) -pyrimidinone. LCMS (m / z): 403.2 (M + H).

EXAMPLE 213 Preparation of 2- (3-fluoro-2-hydroxyphenyl) -6-methyl-5-f2-methyl-1,3-thiazol-5-D-3- (2-phenylethyl) -4 (3H) - pyrimidinone to. 2-methyl-5- (tributylstananyl) -1,3-thiazole To a solution of 2-methyl-1,3-thiazole (5 g, 0.05 mol) in dry diethyl ether (60 ml) at -78 ° C is added n-butyllithium 1.6M (31.51 ml) in hexanes. While stirring for 1 h at -78 ° C, n-tributyltin chloride (16.32 ml, 0.061 mol) is added and the bath on dry ice is removed. The reaction is allowed to warm slowly to room temperature overnight. The reaction mixture is filtered and concentrated and the crude residue is purified by distillation. 1 H NMR (400 MHz, CDCl 3) d ppm 0.92 (t, J = 7.8 Hz, 9H), 1.10- 1. 13 (m, 6H), 1.29-1.38 (m, 6H), 1.52-1.60 (m, 6H), 2.77 (s, 3H), 7.58 (d, J = 6.57 Hz, 1 H). b. 2- (3-fluoro-2-hydroxyphenyl) -6-methyl-5- (2-methyl-1,3-thiazol-5-yl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone To a solution containing 5-bromo-2-. { 3-fluoro-2 - [(phenylmethyl) oxy] phenyl} -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone (0.2 g, 4.10 mmol, example 11) in a sealed tube in deoxygenated dioxane is added Pd (t-Bu3P) 2 (0.021 g, 0.41 mmol), cesium fluoride (0.14 g, 8.90 mmol) and 2-methyl-5- (tributylstannanyl) -1,3-thiazole (0.47 ml, 12.2 mmol) is added consecutively. The reaction is sealed and heated at 100 ° C for 16 hours and concentrated. The crude residue is filtered and concentrated. The crude material is purified by chromatography on silica gel (Biotage, 0.50% ethyl acetate / hexane) to yield the desired product (0.148 g) in 71% yield. c. 2- (3-fluoro-2-hydroxyphenyl) -6-methyl-5- (2-methyl-1,3-thiazol-5-yl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone It is placed 2-. { 3-fluoro-2 - [(phenylmethyl) oxy] phenyl} -6-methyl-5- (2-methyl-1,3-thiazol-5-yl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone (0.148 g, 0.29 mmol) in a flask of Round bottom equipped with a stir bar. To this is added HBr in acetic acid (5 ml) and stir until the starting material is completely consumed. The reaction is quenched with saturated NaHC 3 3 and extracted with dichloromethane. The combined organic layers are dried over Na2SO, filtered and concentrated. The crude residue is purified by HPLC to yield the title compound (0.067 g) in 55% yield. MS (m / z): 422.2 [M + Hf] EXAMPLE 214 Preparation of 2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5-r5- (1 H-tetrazol-5-yl) -2-thienin-4 (3H) - pyrimidinone to. 6-methyl-3- (2-phenylethyl) -2-r2-. { (phenylmethyl) oxi > phenyl-5-I5- (1 H-tetrazol-5-yl) -2-thienyl-1-4 (3H) -pyrimidinone Ammonium chloride (0.024 g, 0.449 mol) and sodium azide (0.029 g, 0.446 mmol) are add to 5- (4-methyl-oxo-6-1- (2-phenylethyl) -2- [2 - [(phenylmethyl) oxy] phenyl] -1,6-dihydro-5-pyrimidinyl) -2-thiophenecarbonitrile ( 0.215 g, 0.427 mmol) in DMF 81.0 ml) and heated at 80 ° C for 4 days. The reaction is cooled to room temperature, diluted with ethyl acetate and washed with 0.5 N HCl and brine. The organic layer is dried over Na2SO, filtered and concentrated to provide 0.210 g (90%) of the title compound. LCEM (m / z: 547.2 (M + H). b. 2- (2-hydroxyphenyl) -8-methylene-3- (2-phenoltyl) -5-f5- (1 H-tetrazol-5-yl) -2-t-enep-4 (3H) -pyrimidinone The title compound is prepared following the same procedure as example 206e substituting 6-methyl-5- (2-methyl-1,3-thiazol-5-yl) -3- (2-phenylethyl) - 2- (2 - [(phenylmethyl) oxy] phenyl) -4 (3H) -pyrimidinone with 6-methyl-3- (2-phenylethyl) -2- [2-. { (phenylmethyl) oxy} phenyl] -5- [5- (1 H -tetrazol-5-yl) -2-thienyl-4 (3H) -pyrimidinone. LCMS (m / z): 457.0 (M + H).

EXAMPLE 215 Preparation of 5-r5- (aminomethyl) -2-thienyl] -2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyridmidone - (4-Methyl-6-oxo-1- (2-phenylethyl) -2- [2 - [(phenylmethyl) oxy] phenyl] -1,6-dihydro-5-pyrimidinyl) -2-thiophenecarbonitrile (0.630 g , 1.25 mmol) of Example 213 in methanol (15 mL) is purged with N2 for 10-15 minutes. 10% Pd / C (0.500 g) is added and the reaction mixture is stirred under H2 (balloon pressure) for 3 days. The reaction is filtered through a filter frit clogged with Celite, washed with CH2OH and CH2Cl2 and concentrated. Column chromatography (CH3OH: CH2Cl2 0-9%) yields 0.123 g (24%) of the compound of the Title. LCMS (m / z): 418.0 (M + H).

EXAMPLE 216 Preparation of 2- (2-hydroxyphenyl) -6-methyl-5-. { 5 - [(methylamino) metin-2-thienyl > - 3- (2-phenylethyl) -4 (3H) -pyrimidinone A solution of 5- [5- (aminomethyl) -2-thienyl] -2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone (0.055 g, 132 mmol) of Example 215 in methanol (1.4 ml) under N2 is cooled to 0 ° C. Formaldehyde (37% aqueous, 0.18 ml, 2.22 mol) and sodium cyanoborohydride (0.032 g, 0.509 mmol) are added. The reaction is stirred at 0 ° C for 5 minutes and then warmed to room temperature for 5 days. The reaction mixture is diluted with H2O and extracted twice with CH2Cl2. The combined organic layers are dried over Na2SO, filtered and concentrated. Column chromatography (CH3OH: CH2CI2 0-8%) gives 0.023 g (40%) of the title compound. LCMS (m / z): 432.2 (M + H).

EXAMPLE 217 Preparation of 5- [5- (hydroxymethyl) -2-thienyl-2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone to. 5- (4-Methyl-6-oxo-1- (2-phenylethyl) -2-f2 - [(phenylmethyl) oxyphenyl-1,6,6-dihydro-5-pyrimidinyl) -2-thiophenecarboxylic acid. sodium (10%, 21 ml) to 5- (4-methyl-6-oxo-1- (2-phenylethyl) -2- {2 - [(phenylmethyl) oxy] phenyl} -1, 6- dihydro-5-pyrimidinyl) -2-thiophenecarbonitrile (0.813 g, 1.62 mmol) in ethanol (25 ml) and the reaction is refluxed for 3.5 hours. The reaction is cooled and acidified to pH -3 with 6N HCl. The aqueous layer is extracted twice with ethyl acetate. The combined organic layers are washed with brine, dried over Na 2 SO 4, filtered and concentrated. The title compound is isolated in 99% yield (0.840 g) and carried out in the next step without further purification. LCMS (m / z): 523.0 (M + H). - [5- (hydroxymethyl) -2-thieni-11-6-methyl-3- (2-phenylethyl) -2- (2- [(phenylmethyl) oxyphenyl) -4 (3H) -pyrimidinone It is added sulfuric acid to 5- (4-methyl-6-oxo-1- (2-phenethyl) -2- [2 - [(phenylmethyl) oxy] phenyl] -1,6-dihydro-5-pyrimidinyl) -2- thiophenecarboxylic acid (0.250 g, 0.479 mmol) in ethanol (23 ml) under N2 and refluxed for 40 hours.

The reaction is concentrated in vacuo under cooling. The residue is diluted with NaHCO3 saturated and extracted twice with CH2Cl2. The combined organic layers are washed with brine, dried over Na2SO, filtered and concentrated. The crude product is then dissolved in CH2Cl2 under N2 and cooled to 0 ° C. DIBAL (1.0M in toluene, 1.9 ml, 1.91 mmol) is added and the reaction is stirred at 0 ° C for 1.5 hours before heating to room temperature for 3 days. Acetone (3 ml), H2O (6 ml), and Rochelle's saline (12 ml) are added and the reaction is stirred for 1 hour. The reaction mixture is extracted four times with CH2Cl2. The combined organic layers are washed with brine, dried over Na2SO, filtered and concentrated. Column chromatography (CH 3 OH: CH 2 Cl 2 0-10%) gives 0.111 g (45% about two steps) of the title compound. LCMS (m / z): 509.2 (M + H). c, 5- [5- (hydroxymethyl) -2-thienyl-2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone The title compound is prepared following the same procedure as example 206e substituting 8-methyl-5- (2-methyl-1,3-thiazole- -yl) -3- (2-phenylethyl) -2-. { 2-. { (phenylmethyl) oxy} phenyl } -4 (3H) -pyrimidinone with 5- [5- (hydroxymethyl) -2-thienyl] -6-methyl-3- (2-phenylethyl) -2-. { 2 - [(phenylmethyl) oxy] phenyl} -4 (3H) -pyrimidinone. LCEM (m / z): 419.2 (M + H).

EXAMPLE 218 Preparation of 2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- ^ 2-phenylethyl) -5- (4,5,6,7-tetrahydro-1-benzothien-2-yl) - 4 (3H) -pyrimidinone to. 2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- (4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl) ) -4 (3H) -pyrimidinone A solution of 2- (3-fluoro-2-. {(Phenylmethyl) oxy} phenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) - pyrimidinone (0.5 g, 1.02 mmol) of Example 11, 2-bromo-4,5,6,7-tetrahydro-1,3-benzothiazole (0.22 g, 1.02 mmol). hexamethyldistan (0.21 ml, 1.02 mmol), Pd (t-Bu3P) 2 (0.052 g, 0.102 mmol) in dioxane is degassed for 10 minutes and then heated to 48 ° C at 90 ° C in a sealed tube. The reaction mixture is filtered through a pad of Celite and concentrated and the crude product is purified on a flash silica gel column (0-40% EtOAc / hexanes) to give the product (0.1 g, MS (ES) m / e 551 [M + Hf together with a secondary product, 2- (3-fluoro-2 - [(phenylmethyl) oxy] phenyl) -6-methyl-3- (2-phenylethyl) -5- (trimethylstannayl) -4 (3H) -pyrimidinone (0.15 g). MS (ES) m / e 578 [M + Hf. b. 2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- (4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl) -4 (3H) -pyrimidinone A solution of 2-. { 3-fluoro-2 - [(phenylmethyl) oxy] phenyl} -6-methyl-3- (2-phenylethyl) -5- (4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl) -4 (3H) -pyrimidinone (0.1 g, 0.181 mmol) in HBr (48% in acetic acid, 0.7 ml, 3.62 mmol) is stirred at room temperature for 3 hours and additional HBr (0.5 ml) is added. After the starting material is completely consumed, the reaction mixture is diluted with DCM and washed with saturated NaHC 3. The organic layers are dried over sodium sulfate, filtered and concentrated and purified by the Biotage purification system to give the title compound as a solid (61 mg) in 73% yield. MS (ES) m / e 462.2 [M + Hf.

EXAMPLE 219 Preparation of 2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- (2-phenyl-1,3-thiazol-5-yl) -4 (3H) -pyrimidinone to. 2- (3-Fluoro-2-f (phenylmethyl) oxy1phenyl) -6-methyl-3- (2-phenylethyl) -5- (2-phenyl-1,3-thiazol-5-yl) -4 ( 3H) -pyrimidinone to a solution containing 2-. { 3-fluoro-2 - [(phenylmethyl) oxy} phenyl] -6-methyl-3- (2-phenylethyl) -5- (trimethylstannanyl) -4 (3H) -pyrimidinone (0.15 g, 0.26 mmol) a by-product of example 218 stage a and 5-bromo-2-phenyl -1, 3-thiazole (0.063 g, 0.26 mmol) in dsydrogenated dioxane is added Pd (t-Bu3P) 2 (0.013 g, 0.026 mol) and cesium fluoride (0.087 g, 0.572 mmol) and heated to reflux overnight. The crude residue is filtered through a pad of Celite and diluted with dichloromethane and washed with saturated aqueous potassium fluoride, water and brine. The organic layer is separated, dried over Na2SO, filtered and concentrated. The crude material is purified by reverse phase HPLC (not TFA) to produce the desired product (0.03 g). Subsequent deprotection using HBr as detailed in Example 1 provides the product (0.013 g) in 52% yield. MS (m / z): 484.2 [M + H] +.

EXAMPLE 220 Preparation of 2- (3-fluoro-2-hydroxyphenyl) -5- (4-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone The title compound is prepared by deprotection of BBr3 of Example 75 as previously detailed. MS (m / z): 417 [M + H].

EXAMPLE 221 Preparation of 2- (3-fluoro-2-hydroxyphenyl) -5- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone The title compound is prepared by deprotection of BBr of Example 94 as detailed previously. MS (m / z) 417 [M + Hf.

EXAMPLE 222 Preparation of 2- (3-fluoro-2-hydroxyphenyl) -5- (3-hydroxy-phenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone The title compound is prepared by deprotection of BBr3 from! example 95 as detailed previously. MS (m / z): 417 [M + Hf.

EXAMPLE 223 Preparation of 2- (2-hydroxyphenyl) -6-methyl-5- (2-methylpropyl) -3-r2- (1-piperidinyl) etn-4 (3H) -pyrimidinone to. 2-Acetyl-4-methyl-N- [2- (1-piperidine-Detillpentanamide To a solution of methyl 2-acetyl-4-methyl-4-pentanoate (2.0 g, 0.012 mol) in dimethoxyethane is added [2- (1 -piperidinyl) ethyl] amine (0.83 ml, 5.81 mmol) This mixture is heated in a microwave at 180 ° C for 20 minutes in a where it is concentrated and purified by flash column chromatography (0-100% EtOAc / hexanes) to provide 1.1 g of the product. b. 2- (3-fluoro-2-hydroxyphenyl) -6-methyl-5- (2-methylpropyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone To a solution of 2-acetyl-4- methyl-N- [2- (1-piperidinyl) ethyl] pentanamide (1.1 g, 4.10 mmol) and salicylamide (1.12 g, 8.2 mmol) and Ti (Oi-Pr) 4 (18 mL, 49.2 mmol). This mixture is heated to reflux for 48 hours where it is cooled to room temperature and concentrated. The mixture is diluted with CH2Cl2 and washed with 6N HCl. The organic layer is concentrated and the residue is purified by flash column chromatography (0-100% EtOAc / hexanes) to provide the title compound (0.193 g). MS (El) 370 (M + H) +.

EXAMPLE 224 Preparation of 5-ethyl-3-r2- (2-fluorophenyl) ethyl-2- (3-hydroxyphenyl) -6-methyl-4 (3H) -pyrimidinone The title compound is prepared following the procedures briefly described in Example 1 except substituting 2-ethyl-N- [2- (2- fluorophenyl) ethyl] -3-oxobutanamide by 2-acetyl-4-methyl-N- (2-phenylethyl) pentanamide and 3-methoxybenzamide by 2-fluoro-3-methoxybenzamide. MS (m / z): 353 [M + Hf.

EXAMPLE 225 Preparation of 2- (2-hydroxyphenyl) -6-methyl-5-r5- (5-methyl-1, 3,4-oxadiazol-2-yl) -2-t-phenyl-3- (2-phenylethyl) ) -4 (3H) -pyrimidinone to. 2-. { 3-fluoro-2 - [(phenylmethyl) oxylphenyl) -6-methyl-5-r5- (2-methyl-1,3-thiazol-4-yl) -2-thienyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone A solution of 5-bromo-6-methyl-3- (2-phenylethyl) -2-. { 2 - [(phenylmethyl) oxy] phenyl} -4 (3H) -pyrimidinone (0.3 g, 0.63 mmol, example 20), 2- (5-bromo-2-thienyl) -5-methyl-1, 3,4-oxadiazole (0.155 g, 0.63 mmol), hexamethyldistan (0.13 ml, 0.63 mmol), Pd (PPh3) (0.073 g, 0.063 mmol) in dioxane is degassed for 10 minutes and then heated at 90 ° C for 16 hours. The reaction mixture is concentrated and the crude product is purified on a flash silica gel column (EtOAc / hexanes) to provide the desired product (0.03 g) in yield. MS (ES) (m / z) 561 [M + Hf. b. 2- (2-Hydroxyphenyl) -6-methyl-5-f5- (5-methyl-1,3,4-oxadiazol-2-yl) -2-thienip-3- (2-phenylethyl) - 4 (3H) -pyrimidinone 2-. { 3-Fluoro-2 - [(phenylmethyl) oxy] phenyl-9-6-methyl-5- [5- (2-methyl-1,3-thiazol-4-yl) -2-thienyl] -3- (2 phenylethyl) -4 (3H) -pyrimidinone (0.03 g, 0.053 mmol) is taken in glacial acetic acid (10 ml). To this is added Pd / C at 10%. This mixture is placed under a hydrogen atmosphere at 2.93 atm and is stirred for 16 hours. The reaction mixture is filtered through a pad of Celite and concentrated. The crude residue is purified by chromatography on silica gel to produce the desired product. MS (ES) m / e 471 [M + Hf.

EXAMPLE 226 Preparation of 5- (2,3-dihydro-1,4-benzodioxin-6-yl) -2- (2-hydroxyphenyl) -6- f (methyloxy) metin-3- (2-phenylethyl) -4 (3H) -pyrimidinone a, 5-bromo-6 - [(methyloxy) methyl-3- (2-phenylethyl) -2-y2 - [(phenylmethyl) oxylfenip-4 (3H) -pyrimidinone 5-bromo-6 - [(methyloxy) methyl] -3- (2-phenylethyl) -2-. { 2 - [(phenylmethyl) oxy] phenyl} -4 (3H) -pyrimidinone (12.0 g, 0.028 mol) from example 38 is taken in glacial acetic acid (200 ml). To this is added bromine (1.4 ml, 0.028 mol) drop to drop by a syringe. The reaction is stirred for 16 hours. Ethyl acetate is added and the acetic acid is washed with saturated sodium carbonate. The organic layer is further washed with brine and dried (MgSO4). The solid is filtered and the organic layer is concentrated. The crude product is triturated with hexanes to obtain the desired product (2.05 g). MS (m / z) 507 [M + Hf. b. 5- (2,3-Dihydro-1,4-benzodioxin-6-yl) -6 - [(methyloxy) methyl-3- (2-phenylethyl) -2-. { 2 - [(phenylmethyl) oxylphenyl) -4 (3H) -pyrimidinone To a solution of 5-bromo-6 - [(methyloxy) methyl] -3- (2-phenylethyl) -2-. { 2- [(phenylmethyl) oxy] phenyl} -4 (3H) -pyrimidinone (0.505 g, 0.001 mol) in dioxane (6 ml) is added 1,4-benzodioxane-6-boronic acid (0.36 g, 0.002 mmol) is dissolved in solvent mixture of 1 ml of ethanol and 0.5 ml aqueous sodium carbonate (0.21 g, 0.002 mol) in a microwave container. Pd (PPh3) (0.17 g, 0.15 mmol) is added thereto and irradiated at 150 ° C for 3000 seconds. The reaction mixture is filtered through a syringe filter (Acrodisc CR25 mm with 0.2 μm PTFE membrane). The filtrate is diluted with EtOAc and washed with brine, separated, dried over sodium sulfate, filtered and concentrated in vacuo and the residue purified by chromatography on silica gel (ethyl acetate / 30% hexane) to produce the desired product (0.3 g). MS (m / z): 563 [M + H] +. Subsequent deprotection with HBr in acetic acid as described Detail previously produces the title compound. MS (m / z): 473 [M + Hf.

EXAMPLE 227 Preparation of 2- (2-hydroxyphenyl) -6-f (methyloxy) methyl-1-5- (4-methyl-2-t-penyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone The title compound is prepared following the procedures briefly described in Example 225 except substituting (4-methyl-2-thienyl) boronic acid for 1,4-benzodioxane-6-boronic acid. MS (m / z) 433 [M + Hf.

EXAMPLE 228 Preparation of 2- (2-hydroxyphenyl) -6-r (methyloxy) metin-5- (5-methyl-2-thienl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone The title compound is prepared following the procedures briefly described in Example 226 except substituting (5-methyl-2-thienyl) boronic acid for 1,4-benzodioxane-6-boronic acid. MS (m / z). 433 [M + Hf.

EXAMPLE 229 Preparation of 5-bromo-6-r (dimethylamino) metin-2- (2-hydroxyphenyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone a, 5-bromo-2- (2-hydroxyphenyl) -6 - [(methyloxy) methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone The title compound is prepared in the deprotection of the example 226a using BBr3 as previously detailed. b. 5-bromo-6- (bromomethyl) -2- (2-hydroxyphenyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone To a cold solution is 5-bromo-2- (2-hydroxyphenyl) -6 - [(methyloxy) methyl] -3- (2-phenylethyl) -4 (3H) -pyrimidinone (1.46 g, 0.0036 mol) and CBr4 (1.52 g, 0.0046 mol) in DCM (30 ml) is added triphenylphosphine (1.43 g) , 0.0054 mol). The reaction is stirred overnight while heating slowly to room temperature. The reaction mixture is concentrated and purified by chromatography on silica gel (30% ethyl acetate / hexane) to yield the desired product (0.9 g) in 55% yield. c. 5-bromo-6-f (dimethylamino) methyl-2- (2-hydroxyphenyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone To a solution of 5-bromo-6- (bromomethyl) -2- (2-hydroxyphenyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone (0.232 g, 0.51 mmol) and N, N-dimethylamine hydrochloride (0.203 g, 0.0025 mol) in 10 ml of DMF is added carbonate of cesium (0.98 g, 0.003 mol) and stirred at room temperature for 16 hours. The reaction is concentrated and diluted with water and extracted with DCM. The organic layer is washed with brine, dried (MgSO4) and concentrated. The crude residue is triturated with hexanes / ether mixtures to give the title compound (0.09 g) in 42% yield. MS (m / z): 428 [M + H] +.

EXAMPLE 230 Preparation of 6 - [(dimethylamino) methyl1-2- (2-hydroxyphenyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone The title compound is prepared in catalytic hydrogenolysis of Example 229. MS (m / z): 350 [M + Hf.

EXAMPLE 231 Preparation of 2- (2-hydroxyphenyl) -3- (2-phenylethyl) -5.6.7.8.9.10-hexahydrocycloocta [d] pyrimidin-4 (3H) -one to. 2- (Methyloxy) benzenecarboximidamide To a cold solution of anhydrous ether is introduced under argon, LiHMDS (150 ml, 150 mmol) and stirred for 5 minutes. After it is added 2-methoxy-benzonitrile (8g, 60 mmol) and the mixture is stirred at room temperature for 3 days. When all the starting material is consumed the The reaction mixture is concentrated and 200 ml of cold 1N HCl is added and stirred for an additional 0.5 hours. The aqueous layer is extracted with diethylether then the pH of the aqueous layer is adjusted to 13 by the addition of 6N NaOH. The free base of 2- (methyloxy) benzenecarboximidamide is extracted with dichloromethane. The combined organic layers are dried over Na2SO4 and concentrated to give the crude product (9.4 g) which is carried out in the next step without purification. b. 2- [2- (methyloxy) phenyl-5,6,7,8,9, 10-hexahydrocycloocta [d-pyrimidin-4 (1 H) -one To a solution of 2- (methyloxy) benzenecarboximidamide (3.78 g, 0.025 mol) In 250 ml of the MeOH / dioxane solvent mixture (1/1), NaOMe (2.72 g) is added and the mixture is stirred for 15 minutes. Ethyl 2-oxo-1-cyclooctanecarboxylate is introduced and the reaction mixture is refluxed for 16 hours. At the termination the reaction mixture is concentrated, diluted with dichloromethane and diluted HCl is added. The dichloromethane layer is separated and washed with brine, dried over Na2SO. In filtration and concentration the crude product is purified by FCC (30% ethyl acetate / hexane) to give the product (3.81 g) in 53% yield. c. 2- [2- (methyloxy) phenyl-3- (2-phenylethyl) -5,6,7,8,9, 10-hexahydrocycloocta [dlpyrimidin-4 (3H) -one To a solution of 2- [2- ( methyloxy) phenyl] -5,6,7,8,9,10-hexahydrocycloocta [d] pyrimidin-4 (1 H) -one (1.95 g, 6.86 mmol) in dry DMF is added LiH (0.11 g, 13.7 mmol) and lithium bromide (1.79 g, 20.6 mmol) and stirred for 10 minutes at room temperature. Then (2-bromoethyl benzene (6.35 g, 34.3 mmol) is added and the mixture is stirred overnight.The reaction mixture is quenched by the addition of ice and 6N HCl, this mixture is extracted with EtOAc and the organic layer is washed with aqueous NaHC03, brine and dried over Na2SO4 The sodium sulfate is filtered and concentrated The crude product is purified by FCC (30% ethyl acetate / hexane) to give the product (1.60 g) in 60% strength. performance. g \ 2- (2-hydroxyphenyl) -3- (2-phenylethyl) -5,6,7,8,9, 10-hexahydrocycloocta [dlpyrimidin-4 (3H) -one 2- [2- (methyloxy) phenyl] -3- (2-phenylethyl) -5,6,7,8,9,10-hexahydrocycloocta [d] pyrimidin-4 (3H) -one (1.60 g, 4.12 mmol) in 10 ml of dichloromethane is cooled to 0 °. C. 1 M dichloromethane solution of BBr3 (21 ml, 20.6 mmol) is then added and the heated reaction mixture is brought to room temperature while the stirring is continued for 12 hours. The reaction mixture is then diluted with dichloromethane and aqueous NaHCO3 and then added. The organic layer is separated and washed with H2O, brine, and dried over Na2SO4. It is filtered, concentrated and purified by chromatography on silica gel (Biotage, 0-20% ethyl acetate / hexane) to yield the pure compound (1.43 g) in 93% yield. MS (m / z): 375.4 [M + H] +.

EXAMPLE 232 Preparation of 5- (4,5-dimethyl-1,3-thiazol-2-yl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone The title compound is prepared according to the procedure of Example 97 except substituting 4,5-dimethyl-2- (tributylstannanyl) -1,3-thiazole for 2- (tributylstannanyl) -1,3-thiazole. MS (m / z): 436.2 [M + Hf.

EXAMPLE 233 Preparation 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-5- (4-methyl-1,3-thiazol-2-yl) -3- (2-phenylethyl) -4 (3H) - pyrimidinone The title compound is prepared according to the procedure of Example 97 except substituting 2- (tributylstannanyl) -1,3-thiazole for 4-methyl-2- (tributylstannanyl) -1,3-thiazole. MS (m / z) 422.0 [M + Hf.

EXAMPLE 234 Preparation of 5- (1,3-benzodioxol-5-yl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone The title compound is prepared according to the procedure of Example 74 except substituting 3,4-acid.

Methylenedioxyphenylboronic acid by 4- (N, N-dimethylamino) phenyl] boronic acid. MS (m / z): 445.0 [M + Hf.

EXAMPLE 235 Preparation of 3- (2,3-dihydro-1 H -inden-2-yl) -2- (2-hydroxyphenyl) -6-methyl-5- (5-methyl-2-thienyl) -4 (3H ) -pyrimidinone to. (2Z) -3 - [((methyl 2 - [(phenylmethyl) oxy-phenyl) carbonyl) amino-1-butenoate To a solution of 2 - [(phenylmethyl) oxy] benzoic acid (11.89 g, 0.052 mol) in 1, 2-DCE is added HATU (20.64 g, 0.054 mol) and TEA (6.66 ml, 0.043 mol). The reaction mixture is stirred for 1 hour. After this time, methyl (2Z) -3-amino-2-butenoate (5.0 g, 0.043 mol) is added followed by another portion of TEA (6.66 ml, 0.043 mol). The reaction is then heated to reflux for 16 hours. The reaction mixture is cooled and diluted with EtOAc and washed successively with 1 N HCl, 5% NaHCO3, and brine. Dry over sodium sulfate, filter and concentrate in vacuo. The residue is purify by Biotage purification system (0-50% ethyl acetate / hexane) to yield the title compound as two geometric isomers in ratio 1: 6.87 (6.63 g, 47%). b, 5-bromo-3- (2,3-dihydro-1 H -inden-2-yl) -6-methyl-2- (2- [(phenylmethyl) oxylphenyl) -4 (3H) -p rimidinone A 2,3-dihydro-1 H-inden-2-amine (6.66 g, 0.05 mol) in toluene is added chlorotriisopropyltitanium (13-03 g, 0.05 mol) and stirred for 30 minutes. Methyl (2E) -3 - [( {2 - [(phenylmethyl) oxy] phenyl} carbonyl) amino] -2-butenoate (3.25 g, 0.01 mol) is added and the reaction is heated to reflux. At the end of the reaction, concentrate in vacuo, then dilute with EtOAc, wash with 1 N HCl, saturated (NH) 2 CO 3, and brine. The EtOAc layer is dried over Na2SO4, filtered and concentrated. The residue is purified by flash chromatography (0-50% EtOAc / hexane) to yield the product (1.27 g) in 31% yield. Subsequent bromination as detailed previously provides the title compound. c. 3- (2,3-dihydro-1 H -inden-2-yl) -2- (2-hydroxyphenyl) -6-methyl-5- (5-methyl-2-thienyl) -4 (3H) -pyrimidinone The The title compound is prepared according to the procedures of Example 74 except substituting 5-bromo-3- (2,3-dihydro-1 H -inden-2-yl) -6-methyl-2-. { 2 - [(phenylmethyl) oxy] phenyl} -4 (3H) -pyrimidinone by 5-bromo-2-. { 3-fluoro-2 - [(phenylmethyl) oxy] phenyl} -6-methyl-3- (2-phenylethyl) -4 (3H) - pyrimidinone and 5-methylthiophene-2-boronic acid by 4- (N, N-dimethylamino) phenylboronic acid. The debenzylation using HBr in acetic acid as previously detailed to produce the product. MS (m / z) 415.2 [M + Hf.

EXAMPLE 236 Preparation of 3-M - (2,3-dihydro-1 H -nden-2-yl) -2- (2-hydroxyphenyl) -4-methyl-6-oxo-1,6-dihydro-5-pyrimidi n-benzonitrile The title compound is prepared according to the procedures of Example 235 except substituting 3-cyanophenylboronic acid for 5-methylthiophene-2-boronic acid. The subsequent catalytic hydrogenolysis provides the title compound. MS (m / z): 420.2 [M + Hf.

EXAMPLE 237 Preparation of 3- (2,3-dihydro-1 H -inden-2-yl) -5- (4,5-dimethyl-1,3-thiazol-2-yD-2- (2-hydroxyphenyl) -6-methyl- 4 (3H) -pyrimidinone To a solution of 5-bromo-2- (3-fluoro-2 - [(phenylmethyl) oxy] phenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone (0.20 g, 0.41 mmol ) of cesium fluoride (0.137 g, 0.89 mmol) is added from Example 234b in dioxane. After 10 minutes of deoxygenation, bis (tri-t-phosphine) palladium ((0.021 g), 0.041 mmol) and 4,5-dimethyl-2- (tributylstananyl) -1,3-thiazole (0.197 g, 0.49 mmol). The mixture in the sealed container is heated to 100 ° C overnight. The reaction mixture is filtered through Celite and diluted with ethyl acetate. The filtrate is washed with 10% w / v potassium fluoride, separated, dried over sodium sulfate, filtered and concentrated in vacuo and the residue purified by column chromatography to produce the desired product (0.152 g, 71% yield). Deprotection produces the title compound (0.039 g). MS (m / z) 430.2 [M + Hf.

EXAMPLE 238 Preparation of 3- (2-cyclohexylethyl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-5-r5-methyl-2-thienin-4 (3H) -pyrimidinone ? to. 3-Fluoro-2 - [(phenylmethyl) oxybenzenecarboximidamide The title compound is prepared following the procedure briefly described in Example 35 except substituting benzyl bromide for methyl iodide. b. 2-. { 3-Fluoro-2 - [(phenylmethyl) oxy-phenyl) -6-methyl-4 (1 H) -pyrimidinone NaOMe (8.52 g, 0.158 mol) is added to a solution at 0 ° C of 3-fluoro-2 - [( phenylmethyl) oxy] benzenecarboximidamide (17.51 g, 0.072 mol) and methylacetoacetate (9.99 g, 0.086 mol) in a mixture of methanol and 1,4-dioxane. The resulting mixture is heated to reflux overnight. The solvents are stir and the residue is diluted with H2O and quenched with NH4CI. The layers are separated and the aqueous layer is extracted with dichloromethane 3 times. The combined organic portions are dried over Na2SO4 and purified by flash column chromatography to provide 19.37 g of the product in 87% yield. c. 3- (2-cyclohexylethyl) -2- (3-fluoro-2 - [(phenylmethyl) oxylphenyl) -6-methyl-4 (3H) -pyrimidinone To a solution of 2-. { 3-fluoro-2 - [(phenylmethyl) oxy] phenyl} -6-methyl-4 (1 H) -pyrimidinone (5.0 g, 16.12 mmol) in DMF is added lithium hydride (0.384 g, 48.30 mmol), lithium bromide (4.20 g, 48.3 mmol), and 2-bromide. cyclohexylethyl (15.4 g, 80.6 mmol). While quenching overnight at room temperature, the reaction is quenched with saturated ammonium chloride, extracted with ethyl acetate. The combined organic layers are washed with brine, dried over sodium sulfate, filtered, concentrated in vacuo and the residue purified by flash chromatography (0-30% ethyl acetate / hexane) to yield the desired product (2.46). g, 36%). d. 5-bromo-3- (2-cyclohexylene-2- (3-fluoro-2-r (phenylmethyl) oxy-phenyl) -6-methyl-4 (3H) -pyrimidinone 3- (2-cyclohexylethyl) -2- { 3-Fluoro-2 - [(phenylmethyl) oxy] phenyl] -6-methyl-4 (3H) -pyrimidinone (2.46 g, 5.85 mmol) is taken in glacial acetic acid (60 ml). (0.40 ml, 7.78 mmol) drop by drop in a syringe.

The reaction is stirred for 16 hours. Ethyl acetate and acetic acid are added and washed with saturated sodium bicarbonate. The organic layer is further washed with saturated sodium hydrogen sulfite / sodium metabisulfite solution and dried over sodium sulfate. Sodium sulfate is filtered and the organic layer is concentrated. The crude product is purified by chromatography on silica gel (Biotage) using mixtures of ethyl acetate and hexane (10-50%) to obtain the desired product (2.72 g) in 93% yield. and. 3- (2-Cyclohexylethyl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-5- (5-methyl-2-thiol) -4 (3H) -pyrimidinone A solution of 5-bromo-3- (2-cyclohexylethyl) -2- (3-fluoro-2 - [(phenylmethyl) oxy] phenyl) -6-methyl-4 (3H) -pyrimidinone (0.462 g, 0.92 mmol ) 5-Methylthiopheneboronic acid (0.263 g, 1.85 mmol) is added in dioxane, dissolved in a solvent mixture of 0.5 ml of ethanol and 0.5 ml of dioxane, and 0.5 ml of aqueous sodium carbonate (0.196 g, 1.85 mmol) in a microwave reaction vessel and irradiated at 150 ° C for 2400 seconds. The reaction mixture is filtered through a syringe filter (Acrodisc CR25 mm with 0.2 μl PTFE membrane). The filtrate is diluted with EtOAc and washed with brine, separated, dried over sodium sulfate, filtered, concentrated in vacuo and the residue purified by chromatography on silica gel (Biotage, ethyl acetate / hexane at 20 ° C). %) to produce the desired product. The subsequent debenzylation using hydrobromic acid in acid acetic acid as detailed previously produces the title compound. MS (m / z): 427.2 [M + Hf.

EXAMPLE 239 Preparation of 3- (2-cyclohexylethyl) -5- (4,5-dimethyl-1,3-thiazol-2-yl) -2- (3-fluoro-2-hydroxy-phenyl) -6- methyl-4 (3H) -pyrimidinone The title compound is prepared according to the procedures of Example 97 except substituting 5-bromo-3- (2-cyclohexylethyl) -2-. { 3-fluoro-2 - [(phenylmethyl) oxy] phenyl} -6-methyl-4 (3H) -pyrmidinone by 5-bromo-2-. { 3-fluoro-2 - [(phenylmethyl) oxy] phenyl} -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone and 4,5-dimethyl-2- (tributylstannanyl) -1,3-thiazole by 2- (tributylstannanyl) -1,3-thiazole. Subsequent debenzylation using hydrobromic acid in acetic acid as detailed previously yields the title compound. MS (m / z): 442.2 [M + Hf.

EXAMPLE 240 Preparation of 3- (2-cyclohexylethyl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-5- (2-methyl-1,3-thiazole-5-yl) -4 (3H) -pir¡m¡dinona The title compound is prepared according to the procedures of Example 97 except substituting 2- (tributylstannanyl) -1,3-thiazole for 2-methyl-5- (tributylstannanyl) -1,3-thiazole. Subsequent debenzylation using hydrobromic acid in acetic acid as previously described yields the title compound. MS (m / z): 428.0 [M + Hf.

EXAMPLE 241 Preparation of 2- (3-fluoro-2-hydroxyphenyl) -6-methyl-5- (5-methyl-2-thienyl) -3-r2- (2-thienyl-ethyl-4 (3H) - pyrimidinone The title compound is prepared according to the procedure of Example 238 except substituting 2- (2-bromoethyl) thiophene for 2- (2-bromoethyl) cyclohexane. The debenzylation occurs during the Suzuki coupling reaction further eliminating the need for the deprotection step. MS (m / z): 427.0 [M + Hf.

EXAMPLE 242 Preparation of 5- (4,5-dimethyl-1,3-thiazol-2-yl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3-r2- (2-thienyl) ) etill-4 (3H) -pyridinone The title compound is prepared according to the procedure of Example 97 except substituting 4,5-dimethyl-2- (tributylstannanyl) -1,3-thiazole for 2- (tributylstannanyl) -1,3-thiazole and 5-bromo-2 -. { 3-fluoro-2 - [(phenylmethyl) oxy] phenyl} -6-methyl-3- [2- (2-thienyl) ethyl] -4 (3H) -pyrimidinone by 5-bromo-2- [3-fluoro-2- [(phenylmethyl) oxy] phenyl] -6-methyl -3- (2-phenylethyl) -4 (3H) -pyrimidinone. Subsequent debenzylation using catalytic hydrogenolysis provides the product. MS (m / z): 442.2 [M + Hf.

EXAMPLE 243 Preparation of 2- (3-fluoro-2-hydroxyphenyl) -6-methyl-5-.5-methyl-2-thienyl) -3-r2- (tetrahydro-2H-pyran-4-yl) ethyl 1-4 (3H) -pyrimidinone The title compound is prepared according to the procedures of Example 238 except substituting 4- (2-bromoethyl) tetrahydro-2H-pyran for 2- (2-bromoethyl) cyclohexane. The debenzylation that occurs during the Suzuki coupling reaction further eliminates the need for the deprotection step. MS (m / z): 429.0 [M + Hf.

EXAMPLE 244 Preparation of 2- (3-fluoro-2-hydroxyphenyl) -3-r2- (2-fluorophenyl) etn-6-methyl-5- (5-methyl-2-thienyl) -4 (3H) - pyrimidinone The title compound is prepared according to the procedures of Example 238 except substituting 1- (2-bromoethyl) -2-fluorobenzene for 2- (2-bromoethyl) cyclohexane. The debenzylation occurring during the Suzuki coupling reaction further eliminates the need for the deprotection step. MS (m / z): 439.2 [M + Hf.

EXAMPLE 245 Preparation of 2- (3-fluoro-2-hydroxyphenyl) -3-r2- (3-fluorophenyl) ethyne-6-methyl-5- (5-methyl-2-thienyl) -4 (3H) -pyrimidinone The title compound is prepared according to the procedures of Example 238 except substituting 1- (2-bromoethyl) -3-fluorobenzene for 2- (2-bromoethyl) cyclohexane. The debenzylation occurring during the Suzuki coupling reaction further eliminates the need for the deprotection step. MS (m / z): 439.2 [M + Hf.

EXAMPLE 246 Preparation of 2- (3-fluoro-2-hydroxyphenyl) -3- [2- (4-fluorophenyl) ethyl-6-methyl-5- (5-methyl-2-thienyl (3H) -pyrimidinone The title compound is prepared according to the procedures of Example 238 except substituting 1- (2-bromoethyl) -4- fluorobenzene for 2- (2-bromoethyl) cyclohexane. The debenzylation occurring during the Suzuki coupling reaction further eliminates the need for the deprotection step. MS (m / z): 439.2 [M + Hf.

EXAMPLE 247 Preparation of 2- (3-fluoro-2-hydroxyphenyl) -6-methyl-5- (3-methyl-2-thienyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone The title compound is prepared according to the procedures of Example 13 except substituting 3-methylthiophene-2-boronic acid for 6-quinolinylboronic acid. The debenzylation using hydrobromic acid in acetic acid yields the title compound. MS (m / z): 421.2 [M + Hf.

EXAMPLE 248 Preparation of 5-f 1 -benzothien-2-yl) -3- (2,3-dihydro-1 H -inden-2-yl) -2- (2-hydroxyphenyl-6-methyl-4 (3H) - pyrimidinone The title compound is prepared according to the procedures of Example 235 except substituting benzothiophene-2-boronic acid for 5-methylthiophene-2-boronic acid. The subsequent catalytic hydrogenolysis provides the title compound. MS (m / z): 451.2 [M + Hf.

EXAMPLE 249 Preparation of 2- (3-fluoro-2-hydroxyphenyl) -6-methyl-5- (2-methylpropyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone to. 2-acetyl-4-methylpentanoate To a suspension of NaOMe (12.78 g, 0.24 mol) in dry methanol (430 ml) is added methyl acetoacetate (25 g, 0.22 mol) and stirred for 15 minutes and heated to gentle reflux. Add 1-bromo-2-methylpropane (29.5 g, 0.22 mol) in portions within two hours and continue heating overnight. The reaction is concentrated and diluted with NH CI and extracted with diethyl ether. The ether layer is dried and concentrated. The residue is purified by flash column chromatography (10% EtOAc / hexanes) to provide 2 g (5%) of the title compound. b. 2-. { 3-fluoro-2-r (phenylmethyl) oxylphenyl) -6-methyl-5- (2-methylpropyl) -4 (1 H) -pyrimidinone to. 2-chloro-6-fluorophenyl-phenylmethyl ether To a solution of sodium methoxide (3.08 g) is added 3-fluoro-2 - [(phenylmethyl) oxy] benzenecarboximidamide (3.95 g, 1.6 mmol). This mixture is kept at room temperature for 15 minutes after which methyl 2-acetyl-4-methylpentanoate (2.23 g, 13 mmol) is added. This mixture is heated to reflux overnight after which it is cooled to room temperature and quenched with NH 4 Cl. 2-Chloro-6-fluoro-phenol (2.0 g, 13.6 mmol) is dissolved in 68 ml of DMF. To this solution is added Cs2CO3 (6.67 g, 20.5 mmol) and benzyl bromide (1.78 ml, 15 mmol) consecutively and stirred for 12 hours. This residual reaction mixture is diluted with EtOAc and washed with brine (3 x 100 ml). The aqueous organic layer is re-extracted with EtOAc and the combined organic layers are dried over Na2SO4, filtered and concentrated. The residue is purified by column chromatography Instantaneous (30% EtOAc / hexanes) to provide 0.9 g (19%) of the title compound to provide 2.97 g of the product in 92% yield. b. 2- (3-Fluoro-2 - [(phenylmethyl) oxy-phenyl) -6-methyl-5- (2-methylpropyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinonebenzonitrile To a solution of 2-. { 3-fluoro-2 - [(phenylmethyl) oxy] phenyl} -6-methyl-5- (2-methylpropyl) -4 (1 H) -pyrimidinone (0.9 g, 2.46 mmol) in DMF (25 mL) is added lithium hydride (0.039 g, 4.91 mmol) and lithium bromide ( 0.64 g, 7.37 mmol). This mixture is stirred at room temperature for 15 minutes after which phenethyl bromide (2.27 g, 12.3 mmol) is added. This mixture is kept at room temperature for 12 hours after which it is diluted with EtOAc, washed with brine (3 x) and concentrated. Column chromatography of the residue (25% EtOAc / hexanes) gives 0.323 g (28%) of the title compound. c. Solution of 1-benzyloxy-2- (3-fluoro-2-hydroxyphenyl) chloro-6-methyl-5- (2-methylpropyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone To one solution of fluoro-benzene (200 mg), at 0 ° C of 2-. { 3-fluoro-2 - [(phenylmethyl) oxy] phenyl} -6-Methyl-5- (2-methylpropyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone (0.323 g, 0.68.42 mmol) in 8 ml of dry DMF is added BBr3 (2.0 ml, DCM 1 M solution, 2.06 mmol). This Zn (CN) 2 (110 mg, 0.93 mmol) and Pd (t-Bu2P) 2 (86 mg, 0.08 mmol) and the mixture is allowed to warm to room temperature overnight after which the methanol is added and the mix concentrate Column chromatography of the residue (0-30% EtOAc / hexanes) gives 0.22 g (85%) of the title compound. MS (El) 381.2 (M + H) + is placed in the microwave reactor (150 ° C, 20 min). The reaction mixture is diluted with EtOAc and washed with brine. The organic layer is dried over Na2SO, filtered and concentrated. The crude product is purified by flash chromatography (EtOAc / hexane from 0 to 20%) yields the desired product (0.8 g) in 83% yield. d. 3-fluoro-2-f (phenylmethyl) oxybenzenecarboximidamide 3-Fluoro-2 - [(phenylmethyl) oxy] benzonitrile (3.88 g) is added., 0.017 mol) was added to a 0o solution of LiHMDS (43 ml, 1 M in hexanes) in anhydrous Et2O (34 ml) under N2. After warming to room temperature, the mixture is stirred for three to four days. The resulting reaction mixture is cooled to 0 ° C and quenched by the addition of 1N HCl. The layers are separated and the aqueous phase is extracted twice with Et2O. The aqueous layer is cooled in an ice bath, the pH adjusted to 12 with 6N NaOH, and extracted 3 times with dichloromethane. The portions are pooled, dried over Na 2 SO 4 and concentrated to a brown oil which solidifies to a brown solid under vacuum (3.95 g, 95% yield). and. 2-acetyl-4-methylpentanoate To a suspension of NaOMe (13.45 g, 0.237 mol) in dry methanol (430 ml) is added methyl acetoacetate (25 g, 0.215 mol) and stirred for 15 minutes and heated to gentle reflux. . 1-Bromo-2-methylpropane (29.5 g, 0.215 mol) is added in portions within two hours and the heating is continued overnight. The reaction is concentrated and diluted with NH CI and extracted with diethyl ether. The ether layer is dried and concentrated. The residue is purified by flash column chromatography (10% EtOAc / hexanes) to provide 2.01 g of the title compound.

F. 2- (3-fluoro-2-r (phenylmethyl) oxylphenyl) -6-methyl-5- (2-methylpropyl) -4 (1 H) -pyrimidinone To a solution of 3-fluoro-2- [(phenylmethyl) oxy] ] benzenecarboximidamide (3.95 g) in solvent mixture methanol and dioxane (108 ml / 22 ml) at 0 ° C is added sodium methoxide (3.08 g). The mixture is stirred for 15 minutes after which methyl 2-acetyl-4-methylpentanoate (2.23 g) is added. This mixture is heated to reflux overnight after which it is cooled to room temperature and quenched with NH 2 Cl. The residue is diluted with EtOAc and washed with brine. The aqueous layer is re-extracted with EtOAc and the combined organic layers are dried, filtered and concentrated. The residue is purified by flash column chromatography (30% EtOAc / hexanes) to provide 0.9 g (19%) of the title compound. q. 2- (3-fluoro-2-r (phenylmethyl) oxylphenyl) -6-methyl-5- (2-methylpropyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone To a solution of 2-. { 3-fluoro-2 - [(phenylmethyl) oxy] phenyl} -6-methyl-5- (2-methylpropyl) -4 (1 H) -pyrimidinone (0.9 g, 2.46 mmol) in DMF (25 mL) is added lithium hydride (0.039 g, 4.91 mmol) and bromide. lithium (0.64 g, 7.37 mmol). The mixture is stirred at room temperature for 15 minutes after which the phenethyl bromide (2.27 g, 12.3 mmol) is added. The mixture is kept at room temperature for 12 hours after which it is diluted with EtOAc, washed with brine (x3), concentrated. Column chromatography of the residue (25% EtOAc / hexanes) gives 0.323 g (28%) of the title compound. h. 2- (3-fluoro-2-hydroxyphenyl) -6-methyl-5- (2-methylpropyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone To a solution at 0 ° C of 2-. { 3-fluoro-2 - [(phenylmethyl) oxy] phenyl} -6-methyl-5- (2-methylpropyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone (0.323 g, 0.68 mmol) is added BBr3 (2.0 ml of 1 M DCM solution, 2.04 mmol) . This mixture is allowed to warm to room temperature overnight, after which the methanol is added and the mixture is concentrated. Column chromatography of the residue (0-30% EtOAc / hexanes) gives 0.22 g (85%) of the title compound. MS (El) 381.2 (M + H) +.

EXAMPLE 250 Preparation of 2- (2-hydroxyphenyl) -5,5-dimethyl-3- (2-phenylethyl) -5.6.7.8-tetrahydro-4 (3H) -quinazolinone a, 2- (2-hydroxyphenyl) -5,5-methyl-5,6,7,8-tetrahydro-4 (1 H) -quinazolinone To a solution of sodium methoxide (38.3 ml of 0.5 M solution in methanol) is added 2- (methyloxy) benzenecarboximidamide (1.29 g, 8.59 mmol). This mixture is kept at room temperature for 15 minutes after which methyl 2,2-dimethyl-6-oxocyclohexanecarboxylate (1.6 g, 8.7 mmol) is added. This mixture is heated to reflux overnight after which it is cooled to room temperature and concentrated. The residue is diluted with CH CI2 and the pH is adjusted to 3. The aqueous layer is extracted with CH2Cl2 and the combined organic layers are dried, filtered and concentrated. The residue is purified by flash column chromatography (0-75% EtOAc / hexanes) to provide 2.2 g (89%) of the title compound. MS (El) 285.2 (M + H) +. b. 5,5-dimethyl-2-r2- (methyloxy) phenyl-3- (2-phenylethyl) -5,6,7,8-tetrahydro-4 (3H) -quinazolinone To a solution of 2- (2-hydroxyphenyl) 5,5-dimethyl-5,6,7,8-tetrahydro-4 (1 H) -quinazolinone (0.4 g, 1.41 mmol) in DMF (14 mL) is added lithium hydride (13.5 mg, 1.7 mmol). This mixture is stirred at room temperature for 15 minutes after which phenethyl bromide (0.23 ml, 0. 17 mmol). This mixture is kept at room temperature for 12 hours after which it is diluted with EtOAc, washed with brine (3x) and concentrated. Column chromatography of the residue (10-50% EtOAc / hexanes) gives 0.21 g (39%) of the title compound. MS (El) 389.2 (M + H) +. c. 2- (2-hydroxy-phenyl) -5,5-dimethyl-3- (2-phenylethyl) -5,6,7,8-tetrahydro-4 (3H) -quinazolinone To a solution at 0 ° C of 5.5- dimethyl-2- [2- (methyloxy) phenyl] -3- (2-phenylethyl) -5,6,7,8-tetrahydro-4 (3H) -quinazolinone (0.20 g, 0.51 mmol) in CH 2 Cl (5 mL) BBr3 is added (2.5 ml of a 0.5 M solution in CH2Cl2). This mixture is allowed to warm to room temperature overnight, after which the methanol is added and the mixture is concentrated. Column chromatography of the residue (0-30% EtOAc / hexanes) gives 0.15 g (76%) of the title compound. MS (El) 375.2 (M + H) +.

EXAMPLE 251 Preparation of 5-chloro-2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone The title compound is prepared following the procedures described in example 1a-c except substituting ethyl 2-chloro-3-oxobutanoate for ethyl 2-acetyl-4-methyl-4-pentanoate from step 1a1e and 2-hydroxybenzenecarboxamidemethoxybenzenecarboxamide by 3-Fluoro-2-hydroxybenzenecarboxamide [(phenylmethyl) oxy] benzenecarboximidamide. MS (El) 341.4 (M + H) P EXAMPLE 252 Preparation of 342 - (3-fluorophenyl) ethyn-2- (2-hydroxyphenyl) -5.6.7.8-tetrahydro-4 (3H) -quinazolinone The title compound is prepared following the procedures described in example 2a-c except substituting ethyl 2-oxocyclohexanecarboxylate for methyl 2,2-dimethyl-6-oxocyclohexanecarboxylate in step 2a and 1- (2-bromoethyl) -3- Fluorobenzene per bromide phenethyl in step 2b. MS (El) 365.2 (M + H) +.

EXAMPLE 253 Preparation of 2- (3-fluoro-2-hydroxyphenyl) -6-methyl-5- (5-methyl-2-thienyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone to. Phenylmethyl 3-fluoro-2-phenyl (phenylmethyl) oxybenzoate 3-Fluoro-2-hydroxybenzoic acid (10 g, 0.064 mol) is dissolved in dry DMF (128 ml). To this is added potassium carbonate (18.5 g, 0.14 mol) and benzyl bromide (16.74 ml, 0.14 mol) consecutively. The reaction is stirred overnight at room temperature. The reaction is filtered and diluted with EtOAc. This is washed consecutively with 5% HCl and saturated sodium chloride solution (x3). The organic layer is dried over sodium sulfate and concentrated to give the product (21.9 g) in quantitative yield. b. 3-Fluoro-2-f (phenylmethyl) oxy-benzoic acid A solution of phenylmethyl 3-fluoro-2 - [(phenylmethyl) oxy] benzoate (20 g, 0.059 mol) in methanol (150 ml) and water (50 ml) was added. treat with NaOH at 50% w / w (9.5 ml) and stir overnight. The ethanol is removed in vacuo and the aqueous layer is diluted with water (10 ml) and then extracted with ether (2 x 100 ml). The aqueous layer is collected and the acidity is adjusted to pH ~ 4 with 3N HCl. The aqueous layer is extracted with EtOAc and the organic layer is washed with brine. The organic layer is dried over sodium sulfate and concentrated to give the product (14.4 g) in 98.6% yield. c. 3-fluoro-2 - [(phenylmethyl) oxy] benzamide A solution of 3-fluoro-2 - [(phenylmethyl) oxy] benzoic acid (11.3 g, 0.046 mol) is taken in dry THF (34 ml), cooled to 0 ° C. To this is added TEA (5.66 ml, 0.046 mol) and ethyl chloroformate (5.03 ml, 0.046 mol) and stirred for 20 minutes. Ammonia solution (30% aqueous NH 4 OH, 28 ml) in THF (15 ml) is then added to the reaction and stirred for 30 minutes and then concentrated. The solid residue is then partitioned with dichloromethane and water. The aqueous ones are then washed again with dichloromethane and the combined organics are washed with saturated sodium hydrogen carbonate solution, brine, dried and concentrated to yield the product (11.2 g) in 99% yield. d. 3-Fluoro-2-hydroxybenzamide 3-fluoro-2 - [(phenylmethyl) oxy] benzamide (1.0 g, 4.07 mmol) is taken up in ethanol. To this is added Pd / C at 10% (0.10 g). This mixture is placed under a hydrogen atmosphere (balloon) and stirred overnight. The mixture of The reaction is filtered through a pad of Celite and concentrated to yield the desired product (0.61 g) in 97% yield. MS (m / z): 156.2 [M + Hf. and. 3-Oxo-N- (2-phenylethyl) butanamide Dice-tene (10.0 g, 0.12 mol) is taken in anhydrous ether (237 ml). To this is added phenylethylamine (14.93 ml, 0.12 mol). After the addition of amine is complete the reaction is heated to reflux for 3 hours. The crude mixture is concentrated and purified by Biotage purification system using EtOAc / hexanes (1: 1) to provide 22.78 grams in 93% yield. 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone 3-Oxo-N- (2-phenylethyl) butanamide (10 g, 0.049 mol) it is placed in a 500 ml round bottom flask. To this is added titanium isopropoxide (214 ml, 0.73 mol). While the reaction is stirred, 3-fluoro-2-hydroxybenzamide (11.42 g, 0.098 mol) is added in portions, a condenser is placed and the reaction is heated to reflux (oil bath temperature = 150 ° C). The 2-hydroxy-3-fluorobenzamide dissolves slowly and provides a brown homogeneous solution at some time at elevated temperatures. The reaction is run for 36 hours and cooled to room temperature and diluted with dichloromethane. 3N HCl is added slowly until the solid that is initially formed has been dissolved. The organic layer is separated, dried over sodium sulfate and filtered and concentrated and purified to break up the mixture EtOAc / hexanes (6.79 g 43%). q. 2- (3-fluoro-2-r (phenylmethyloxy-phenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone 2-. {3-fluoro-2-hydroxyphenyl} is dissolved. 6-Methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone (6.0 g, 0.019 mol) in dry DMF (92 ml) To this is added potassium carbonate (3.83 g, 0.028 mol) and bromide. The reaction is heated to 60 [deg.] C. and stirred overnight, the reaction mixture is cooled to room temperature and washed with H2O and brine (x3). dried over sodium sulfate and concentrated and purified by the Biotage purification system using EtOAc / hexanes (0-50%) to provide the product (7.12 g) in 93% yield. h, 5-bromo-2- (3-fluoro-2 - [(phenylmethyl) oxylphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone 2-. { 3-fluoro-2 - [(phenylmethyl) oxy] phenyl} -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone (6.0 g, 0.0145 mol) is taken in glacial acetic acid (100 ml). To this is added bromine (0.74 ml, 0.0145 mol) dropwise by syringe.

The reaction is stirred for 3 hours. Additional amount of bromine (1 eq) is added and stirred overnight. Ethyl acetate and acetic acid are added wash with saturated sodium bicarbonate. The organic layer is further washed with saturated sodium sulfite / sodium metabisulfite solution and dried over sodium sulfate. Sodium sulfate is filtered and the organic layer is concentrated. The crude product is purified by chromatography on silica gel (Biotage) using ethyl acetate and hexane mixtures (0.50%) to obtain the desired product (7.06 g) in 98% yield. MS (m / z): 495.2 [M + Hf. 2- (3-fluoro-2-hydroxyphenyl) -6-methyl-5- (5-methyl-2-thienyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone To a solution of 5-bromo- 2- (3-fluoro-2-. {(Phenylmethyl) oxy} phenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone (0.20 g, 0.41 mmol) in dioxane ( 5 ml) is added 5-methyl-2-thiopheneboronic acid (0.12 g, 0.81 mmol), 0.5 ml of ethanol, and 0.5 ml of aqueous sodium carbonate (0.086 g, 0.81 mmol) in microwave reaction vessel. After 10 minutes of deoxygenation, tetrakis (triphenyl) phosphine) palladium (0.047 g, 0.041 mmol) is added. The mixture in a sealed container is irradiated at 150 ° C for 2400 seconds. The reaction mixture is filtered through a syringe filter (Acrodisc CR25 mm with 0.2 μl PTFE membrane). The vessel and filter are washed with dichloromethane. The dichloromethane is concentrated and the residue is purified by flash chromatography (0-40% ethyl acetate / hexane) to yield the title compound (0.14 g, 79%). MS (m / z): 421.2 [M + Hf. 1 H NMR (400 MHz, CDCl 3) d ppm 2.50 (s, 3 H), 2.57 (s, 3 H), 3.01 (t, J = 7.4 Hz, 2 H), 4.30 (t, J = 7.4 Hz, 2 H), 6.80 ( s, 1 H), 6.92-7.19 (s, 6H), 7.20 7.28 (m, 3H), 9.00 (brs, 1 H). Analysis calculated for C 24 H 2iFN 2 O 2 S: C, 67.91; H, 4.84; N, 6.62. Found: C, 68.55; H, 5.03; N, 6.66.

Alternative synthetic route to. Phenylmethyl 3-fluoro-2 - [(phenylmethyl) oxobenzoate 3-Fluoro-2-hydroxybenzoic acid (210 g, 1345 mol) is dissolved in dry DMF (2 I) and added to a 3-necked flask of 51. Powdered potassium carbe (390 g, 2.82 mol, 2.1 equiv) is added in portions to control the evolution of the gas, and then benzyl bromide (506 g, 2.96 mol, 2.2 equivalents) is added to this suspension. The reaction is mechanically stirred at room temperature for 16 hours; it is filtered using a sintered glass funnel and then the filtrate is diluted with ethyl acetate (3 I). This solution is washed successively with 5% HCl and saturated sodium chloride solution (3 x 11). The organic layer is dried over sodium sulfate and concentrated to give the product (429.9 g) in 95% yield. b. 3-fluoro-2- acid. { (phenylmethyl) oxy benzoic A solution of 3-fluoro-2-. { (phenylmethyl) oxy} Phenylmethyl benzoate (429 g, 1.275 mol) in methanol (800 ml) and water (300 ml) is treated with 50% (w / w) NaOH solution (150 ml) and stirred at room temperature for 3 hours. The methanol is removed in vacuo and the waxy residue is diluted with water (1.5 L) and then extracted with t-butyl methyl ether (2 x 500 ml). The aqueous layer is collected, cooled in an ice water bath, and the pH is adjusted to pH 3 with concentrated HCl (-200 ml) while stirring. The precipitate is collected by filtration and the aqueous layer is extracted with EtOAc (3 x 500 ml). The combined organic layers are used to dissolve the filtered precipitate, and then this solution is washed with brine. The organic layer is dried over sodium sulfate and concentrated to give 3-fluoro-2 - [(phenylmethyl) oxy] benzoic acid (301 g, 1222 mol) in 95.9% yield. c. (2E, Z) -3 - [(2-benzyloxy) -3-fluorobenzoyl-amino) but-2-enoate methyl A suspension of 3-fluoro-2 - [(phenylmethyl) oxy] benzoic acid (301 g, 1222 mol) in thionyl chloride (713 ml, 9.78 mol, 8 equivalents) is heated at reflux for 1.5 hours. The reaction is cooled, and then excess thionyl chloride is evaporated using a rotary evaporator. The residue is azeotroped with toluene (4x600 ml) and then dichloromethane (1 x 600 ml). The resulting acid chloride is dissolved in dichloromethane (500 ml) and added dropwise to a solution of methyl 3-aminocrote (141 g, 1222 mol) and pyridine (178 ml, 2.2 mol, 1.8 equivalents) in dichloromethane (1.8 I) and then stirred at room temperature for 4.5 hours. The reaction is then quenched with ice-cold aqueous HCl solution and extracted with dichloromethane (3 x 250 mL). The combined organic layers are washed consecutively with water (11), saturated sodium bicarbe solution (1 I). The solvent is removed in vacuo, and the residue is chromatographed on 2.5 kg of silica gel eluted with a gradient of chloroform / hexanes (50:50) to chloroform / hexanes / ethyl acetate (45:45:10). . The fractions corresponding to the product are combined, then concentrated to provide GSK1507280A (320 g, 0.933 mol, 74% yield) as a mixture of isomers (E, Z). d. 2-. { 3-fluoro-2-r (phenylmethyl) oxylphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone A solution of phenylethylamine (142 ml, 1.2 mol, 3 equivalents) in 1, 2- Dichloroethane (1 L) is cooled to 0 ° C. A solution of trimethylaluminum in toluene (565 ml, 1.13 mol, 3 equivalents) is added dropwise. The ice bath is removed and the mixture is stirred mechanically at room temperature for 45 minutes, and then cooled to 0 ° C. A solution of GSK1507280A (129.2 g, 0.377 mol) in 1,2-dichloroethane (350 ml) is added under nitrogen about 45 minutes, and the resulting mixture is stirred at room temperature for 30 minutes, then heated at 65 ° C for 2 hours. The reaction mixture is cooled to room temperature and quenched by addition of the mixture as a portion with stirring of ice water to pH 3 with 3N aqueous HCl solution. The aqueous phase is extracted with dichloromethane (3 x 300 ml). The combined organic layers are washed with ice cold 3N aqueous HCl solution (500 ml), water (500 ml), brine (500 ml) and dried over sodium sulfate. The dried solution is concentrated in vacuo to provide GSK1511986A (126.4 g, 0.305 mol) in 81% yield. e, 5-bromo-2- (3-fluoro-2-f (phenylmethyl) oxylphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone A solution of GSK1511986A (201.7 g, 0.487 mol ) in N, N. dimethylformamide (400 ml) is cooled to 0 ° C and a solution of N- Bromosuccinimide (173.4 g, 0.974 mol, 2 equivalent) in N, N-dimethylformamide (400 ml) is added dropwise. The reaction mixture is warmed to room temperature and stirred at room temperature for 4 hours. The DMF is removed in vacuo, then the crystallized residue forms 2-propanol (600 ml) to provide GSK970293A (177 g, 0.36 mol) in 74% yield after crystallization and column chromatography on silica gel.

F. 2- (3-fluoro-2-r (phenylmethyl) oxylphenyl) -6-methyl-5- (5-methyl-2-thienyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone A suspension of 5 -bromo-2-. { 3-fluoro-2 - [(phenylmethyl) oxy] phenyl} -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone (70 g, 0.142 mol) 5-methyl-thiopheneboronic acid (40 g, 0.282 mol, Frontier Scientific), crushed sodium carbonate (30 g , 0.282 mol), water (7 ml), ethanol (7 ml) in toluene (800 ml) in a 2-liter, 3-necked round bottom flask is degassed for 10 minutes with nitrogen. Add (t-Bu3P) P (10.8 g, 21 mmol) to the suspension. The resulting reaction mixture is placed in a preheated oil bath at 100 ° C under nitrogen. After stirring for 1 hour, the black suspension is filtered through a pad of Celite. The filtrate is concentrated and the residue is azeotroped with 3x toluene to provide the titled GSK125064641 A (70 g) in 95% crude yield. g, 2- (3-fluoro-2-hydroxyphenyl) -6-methyl-5- (5-methyl-2-thienyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone A 2-. { 3-fluoro-2 - [(phenylmethyl) oxy] phenyl} -6-Methyl-5- (5-methyl-2-thienyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone crude (78 g) is added HBr / HOAC 45% (550 ml) . The reaction mixture is stirred at room temperature for 5 hours. The dark mixture is quenched in ice water (3 I) and the pH is carefully adjusted to 4 by the addition of 50% NaOH: the aqueous phase is extracted well with DCM, dried over Na2SO, and filtered. The filtrate is concentrated to provide the desired crude product GSK728817A (78 g). Purification of Biotage silica gel (750 cartridge) using DCM, 2% hexane (60) / EtOAc (30) / MeOH (10) in DCM as the mobile phase provides pure GSK728817A (45 g) in 67% isolated on yield complete in 2 stages. To remove traces of Pd metal, a sample (1 g) was dissolved in EtOH (10 ml) and heated to reflux for 18 hours in the presence of Darco G060 100 mesh (0.5 g). The cooled suspension is filtered and concentrated to dryness to produce GSK728817A (0.8 g). A sample (78 g) is dissolved in MTBE (650 ml) and placed in a 1 l round bottom flask. The MTBE solution is concentrated in the Buchie to approximately 350 ml and heptane (100 ml) is added. The resulting crystalline suspension is sonicated and filtered to yield 61 g of the pure product. Novel intermediates of the present invention involve compounds of formula (VII), (VIII), (IX) and (X): (Vile) (VIII) A novel synthetic step described by the present invention includes the cyclization of an enamide according to the structure (VII) (VII) with phenethylamine and trimethylaluminum, in toluene, to produce a pyrimidinone according to structure (VIII) (VIII).

EXAMPLE 254 Preparation of 2- 3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylmethyl) -5- (2-thienyl) -4 (3H) -pyrimidinone to. 2-. { 3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- (2-thyl) -4 (3H) -pyrimidinone To a solution containing 5-bromo- 2-. { 3-fluoro-2 - [(phenylmethyl) oxy] phenyl} -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone (1.0 g, 2.02 mol) of the example 253 h in deoxygenated dioxane is added Pd (t-Bu3P) 2 (0.10 g, 0. 20 mol), cesium fluoride (0.67 g, 4.5, mol) and tributyl (2-thienyl) ethanone (0.6 ml, 2.22 mol) are added consecutively. The reaction is heated at 90 ° C for 16 hours and concentrated. The crude residue is diluted with dichloromethane and washed with saturated aqueous potassium fluoride, filtered and concentrated. The crude material is purified by chromatography on silica gel dBiotage, 0-50% ethyl acetate / hexane) to yield the desired product (0.81 g) in 81% yield. b. 2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- (2-thienyl) -4 (3H) -pyrimidinone 2- (3-fluoro-2-hydroxyphenyl) -6-Methyl-3- (2-phenylethyl) -5- (2-thienyl) -4 (3H) -pyrimidinone (0.81 g, 1.63 mmol) is placed in a round bottom flask equipped with a stir bar and a condenser . To this is added HBr (45%) in acetic acid (10 ml), water (1.0 ml) and stirred for 5 hours. The reaction is quenched with saturated NaHC 3 3 and extracted with dichloromethane. The combined organic layers are dried over Na2SO, filtered and concentrated. The crude residue is purified by chromatography on silica gel (Biotage, 50% ethyl acetate / hexane) to yield the desired product (0.61 g) in 91% yield. MS (m / z): 407.2 [M + Hf. 1 H NMR (400 MHz, CDCl 3) d ppm 2.51 (s, 3 H), 3.02 (t, J = 7.6 Hz, 2 H), 4.31 (t, J = 7.6 Hz, 2 H), 6.95-6.98 (m, 4 H), 7.06-7.26 (m, 6H), 7.52 (d, J = 1.06 Hz, 1 H), 8.50 (brs, 1 H).

EXAMPLE 255 Preparation of 3-r2- (3-fluoro-2-hydroxyphenyl) -4-methyl-6-oxo-1- (2-phenylethyl) -1,6-dihydro-5-pyrimidinylbenzontrile The title compound is prepared by substituting 3-cyanophenylboronic acid for 5-methyl-2-thiopheneboronic acid in Example 253 (h). MS (m / z): 426.2 [M + Hf. 1 H NMR (400 MHz, CDCl 3) d ppm 2.26 (s, 10 H), 2.98 (t, J = 7.7 Hz, 2 H), 4.26 (t, J = 7.7 Hz, 2 H), 6.94-7.09 (m, 4 H) , 7.22-7.28 (m, 3 H), 7.60-7.72 (m, 5 H), 7.9 (brs, 1 H). Analysis calculated for C 26 H 20 FN 3 O 2: C, 72.43; H, 4.54; N, 9.66. Found: C, 73.40; H, 4.74; N, 9.88.

EXAMPLE 256 Preparation of 5- (2,3-dihydro-1,4-benzodioxin-β-yl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone The title compound is prepared by substituting 2,3-d? H? Dro-benzo [1,4] d? Ox? Na-6-boron? Co acid for 5-met? L-2-thiopheneboronic acid in Example 253 (h) MS (m / z) 459 4 [M + Hf 1 H NMR (400 MHz, CDCl 3) d 2 26 (s, 3 H), 3 00 (t, J = 7 7 Hz, 2 H), 4 28 (t, J = 7 8 Hz, 2H), 4 32 (s, 4H), 6 83-7 25 (m, 10H), 8 7 (brs, 1 H) Analysis Calculated for C27H23FN2O4 C, 69 74, H , 4 95, N, 5 94 Found C, 70 73, H, 5 06, N, 6 11 EXAMPLE 257 Preparation of 5- (3,5-difluorophenyl) -2- (3-f1uoro-2-hydroxyphenyl) -6-methyl-3-r2-phenylethyl] -4 (3H) -pyrimidinone The title compound is prepared by replacing 3,5-difluorophenylboronic acid with 5-methyl-2-thiopheneboronic acid in Example 253 (h). MS (m / z): 437.2 [M + H] +. 1 H NMR (400 MHz, CDCl 3) d 2.15 (s, 3 H), 2.76 (t, J = 7.8 Hz, 2 H), 3.96 (t, J = 7.8 Hz, 2 H), 6.81-7,303 (m, 11 H), 10.7 (brs, 1 H).

EXAMPLE 258 Preparation of 2- (3-fluoro-2-hydroxyphenyl) -6-methyl-5- (4-methyl-2-thienyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone The title compound is prepared by substituting 4-methyl-2-thiopheneboronic acid for 5-methyl-2-thiopheneboronic acid in the example 253 (h). MS (m / z): 421.2 [M + Hf.

EXAMPLE 259 Preparation of 5- (1-benzothien-2-yl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone The title compound is prepared by substituting benzothiophene-2-boronic acid for 5-methyl-2-thiopheneboronic acid in Example 253 (h). MS (m / z): 457.2 [M + H] + Analysis calculated for C27H21FN2O2S: C, 70.69; H, 4.33; N, 6. 20. Found: C, 71.03; H, 4.64; N, 6.14.

EXAMPLE 260 Preparation of 2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- (2-thienyl) -4 (3H) -pyrimidininone to. 2- (3-Fluoro-2 - ((phenylmethyl) oxy) phenyl) -6-methyl-3- (2-phenylethyl) -5- (2-thienyl) -4 (3H) -pyrimidinone A solution containing 5-bromo-2-. { 3-fluoro-2- [(phenylmethyl) oxy] phenyl} -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone (1.0 g, 2.02 mol) of the example 5h in dioxane is added Pd (t-Bu3P) 2 (0.10 g, 0.20 mol), fluoride cesium (0.67 g, 4.5 mol) and tributyl (2-thienyl) stannane (0.6 ml, 2.22 mol) are added consecutively. The reaction is heated at 90 ° C for 16 hours. The reaction mixture is cooled to room temperature and the crude residue is purified by chromatography on silica gel (Biotage, 0-50% ethyl acetate / hexane) to yield the desired product (0.81 g) in 81% yield. b. 2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- (2-thienyl) -4 (3H) -pyrimidinone La 2-. { 3-fluoro-2 - [(phenylmethyl) oxy] phenyl} -6-methyl-3- (2-phenylethyl) -5- (2-thienyl) -4 (3H) -pyrimidinone (0.81 g, 1.63 mmol) is placed in a bottom flask round equipped with a stir bar and a condenser. S this is added HBr (45%) in acetic acid (10 ml), water and stirred for 5 hours. The reaction is quenched with saturated NaHC 3 3 and extracted with dichloromethane. The combined organic layers are dried over Na2SO4, filtered and concentrated. The crude residue is purified by column chromatography on silica gel (Biotage, 0-50% ethyl acetate / hexane) to yield the desired product (0.61 g) in 91% yield. MS (m / z): 407.2 [M + Hf. 1 H NMR (400 MHz, CDCl 3) d ppm 2.51 (s, 3 H), 3.02 (t, J = 7.6 Hz, 2 H), 4.31 (t, J = 7.6 Hz, 2 H), 6.95-6.98 (m, 4 H), 7.06-7.26 (m, 6H), 7.52 (d, J = 1.06 Hz, 1 H), 8.50 (brs, 1 H).

EXAMPLE 261 Preparation of 5- (1,3-benzothiazol-2-yl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl-4 (3H) -pyrimidinone The title compound is prepared by the general procedure briefly described in Example 11 substituting tributyl (2-thienyl) stannane for 2-tributylstannyl benzothiazole. MS (m / z): 458.2 [M + Hf.

EXAMPLE 262 Preparation of 5- (1-benzothien-2-yl) -2- (2-hydroxyphenyl) -6-methyl-3-r2-phenylethyl] -4 (3H) -pyrimidinone to. 5-Bromo-6-methyl-3- (2-phenylethyl) -2- (2 - [(phenylmethyl) oxylphenyl) -4 (3H) -pyrimidinone The title compound is prepared by the general procedure briefly described in example 253f-h except substituting 2- hydroxybenzamide by 3-fluoro-2-hydroxybenzamide in Example 253 (f). MS (m / z): 477.2 [M + Hf. b, 5- (1-benzothien-2-yl) -6-methyl-3- (2-phenylethyl) -2-. { 2 - [(Phenylmethyl) oxy-phenyl) -4 (3H) -pyrimidinone To a solution of 5-bromo-6-methyl-3- (2-phenylethyl) -2-. { 2 - [(phenylmethyl) oxy] phenyl} -4 (3H) -pyrimidinone (0.60 g, 1.26 mmol) in dioxane (3 ml) is added benzothiophene-2-boronic acid (0.45 g, 2.53 mmol) dissolved in 1.0 ml of ethanol and 1.0 ml of dioxane, and 1.0 ml of aqueous sodium carbonate (0.27 g, 2.53 mmol) in microwave reaction vessel. This mixture is irradiated at 150 ° C for 2000 seconds. The reaction mixture is filtered through a syringe filter (Acrodisc CR25 mm with 0.2 μm PTFE membrane). The filtrate is diluted with EtOAc and washed with brine, separated, dried over sodium sulfate. It is filtered, concentrated in vacuo and the residue is purified by chromatography on silica gel (Biotage, 0-40% ethyl acetate / hexane) to yield the desired product (0.53 g) in 79% yield. c. 5- (1-benzothien-2-yl) -2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone 5- (1-benzothien-2-yl) - 6-methyl-3- (2-phenylethyl) -2-. { 2- [(phenylmethyl) oxy] phenyl} -4 (3H) -pyrimidinone (0.53 g, 1.0 mmol) is taken in ethanol. To this is added Pd / c at 10% (0.5 g). This mixture is placed under a hydrogen atmosphere in a parr vessel (3.4 atm) and stirred for 12 hours. Mix The reaction medium is filtered through a pad of Celite and concentrated and purified by chromatography on silica gel (Biotage, 0-40% ethyl acetate / hexane) to yield the desired product (0.31 g) in 71% yield. performance. MS (m / z): 439.2 [M + Hf 1 H NMR (400 MHz, CDCl 3) d ppm 2.51 (s, 3 H), 3.08 (t, J = 7.6 Hz, 2H), 4.43 (t J = 7.6 Hz, 2H), 7.01-7.04 (m, 4H), 7.07- 7.28 (m, 4H), 7.37-7.43 (m, 3H), 7.88-7.94 (s, 2H), 9.41 (s, 1 H).

EXAMPLE 263 Preparation of 2- (2-hydroxyphenyl-6-methyl-5- (2-methyl-1,3-thiazo-5-yl-3-.2-phenylethyl) -4 (3H) -pyrimidinone 6-Methyl-5- (2-methyl-1,3-thiazol-5-yl) -3- (2-phenylethyl) -2- (2-y (phenylmethyl) oxp-phenyl) -4 (3 H) -pyrimidinone To a solution of 5-bromo-6-methyl-3- (2-phenylethyl) -2-. { 2 - [(phenylmethyl) oxy] phenyl} -4 (3H) -pyrimidinone (2.79 g, 5.87 mmol) in example 15a in 1,4-dioxane (42 ml) is added cesium fluoride (1.96 g, 12.9 mmol) and (t-Bu3P) 2Pd (0.451 g) 0.88 mmol) and the reaction is purged with N2 for 10 minutes. 2-Methyl-5- (tributylstannanyl) -1,3-thiazole (15.5 g, 40.1 mmol) is added and the reaction is refluxed for 20 hours. The reaction is cooled and filter through a filter frit clogged with Celite, wash with CH3OH and CH2Cl2, and concentrate. Column chromatography (ethyl acetate / hexane 1-80%) gives the desired product (1.99 g, 69%). MS (m / z): 494.2 [M + Hf. b. 2- (2-hydroxy-phenyl) -6-methyl-5- (2-methyl-1,3-thiazol-5-yl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone A solution of 6 methyl-5- (2-methyl-1,3-thiazol-5-yl) -3- (2-phenylethyl) -2-. { 2 - [(Phenylmethyl) oxy] -phenyl} -4 (3H) -pyrimidinone (1.99 g, 4.03 mmol) in ethanol (36 ml) is purged with N2. Pd / C (10%, 2.5 g) is added and the reaction is stirred under H2 balloon pressure for 3 days. The reaction is filtered through a filter frit clogged with Celite, washed with CH2OH and CH2Cl2 and concentrated.

Column chromatography (5-100% ethyl acetate: hexane) affords the title compound (1.16 g, 71%). MS (m / z): 404.0 [M + Hf.

EXAMPLE 264 Preparation of 5-22- (2-hydroxyphenyl) -4-methyl-6-oxo-1- (2-phenylethyl) -1,6-dihydro-5-pyrimidinyl] -2-thiophenecarbonitrile to. 5- (4-Methyl-6-oxo-1- (2-phenylethyl) -2- (2 - [(phenylmethyl) oxylphenyl) -1,6-dihydro-5-pyrimidinyl) -2-thiophenecarbonitrile A solution of toluene ( 13 ml) of 5-bromo-6-methyl-3- (2-phenylethyl) -2-. { 2 - [(phenylmethyl) oxy] phenyl} -4 (3H) -pyrimidinone (2.0 g, 4.22 mmol) from Example 262 (a) in a sealed tube is added (5-cyano-2-thienyl) boronic acid (1.29 g, 8.44 mmol), potassium phosphate (2.69 g, 12.66 mmol), tri (dibenzylideneacetone) dipalladium (0) (386 mg, 0.422 mmol) and 2-dicyclohexylphosphino-2 ', 6'-dimethoxy-1, 1 '-biphenyl (346 mg, 0.844 mmol) under nitrogen medium. The reaction vessel is covered lightly and heated for 100 ° C overnight. The mixture is filtered through a pad of Celite and concentrated. Column chromatography of the crude material (0-50% EtOAc / hexanes) gives 1.78 g (84%) of the desired compound. MS (El) 504 (M + H) +. b. 5- [2- (2-hydroxyphenyl) -4-methyl-6-oxo-1- (2-phenylethyl) -1,6-dihydro-5-pyrimidinyl-2-thiophenecarbonitrile A solution of 5- (4-methyl- 6-Oxo-1- (2-phenylethyl) -2- [2- [(phenylethyl) oxy] phenyl] -1,6-dihydro-5-pyrimidinyl) -2-thiophenecarbonitrile (800 mg, 1.59 mmol) in HBr (48% in acetic acid, 4 ml, 23.8 mmol) is stirred at room temperature overnight. The reaction mixture is quenched with water and the pH is adjusted to ~7 with 6N NaOH. The aqueous layer is extracted with dichloromethane. The combined organic layers are dried over sodium sulfate, filtered, concentrated and purified by Biotage purification system using 0-90% EtOAc / hexanes to give the title compound as a white solid (540 mg, 82%). . MS (El) 414 (M + H) EXAMPLE 265 Preparation of 3-.2- (2-hydroxypheni-4-methyl-6-oxo-1- (2-phenylethyl) -1,6-dihydro-5-pyrimidiniphenebenitrile The title compound is prepared by replacing 3-cyanophenylboronic acid with benzothiophene-2-boronic acid in the example 262 (b). 13b. MS (ES) m / e 408 [M + H] +.

EXAMPLE 267 Preparation of 2- (3-fluoro-2-hydroxyphenyl) -6-methyl-5-phenyl-3- (2-phenylethyl-4 (3H) -pyrimidinone to. 3-Oxo-2-phenyl-N- (2-phenylethyl) butanamide To a solution of ethyl 3-oxo-2-phenylbutanoate (49 g, 0.238 mol) in DME is added phenylethylamine (24 g, 0.198 mmol) in a microwave reaction vessel. Add a few drops of ethanol to the reaction mixture and irradiate at 180 ° C for 1200 s. The reaction mixture is diluted with EtOAc and washed with 1 N HCl. The organic layer is separated and dried over Na2SO4. It is filtered, concentrated and purified by chromatography on silica gel to produce pure amide (17.26 g). b. Trifluoromethanesulfonate (1Z) -1-methyl-3-oxo-2-phenyl-2 - [(2-phenylethyl) aminol-1-propen-1-yl To a solution of 3-oxo-2-phenyl-N- ( 2-phenylethyl) butanamide (17.26 g, 0.061 mol) in dry dichloromethane is cooled to -78 ° C. To this is added trifluoromethanesulfonic anhydride (12.36 ml, 0.073 mol) and triethyl amine (12.80 ml, 0.092 mol) consecutively and stir while the reaction is warmed to 0 ° C. The reaction is concentrated and purified by chromatography on silica gel (Biotage, 0-40% ethyl acetate / hexane) to yield the triflate (14.3 g) in 56% yield. c. 3-fluoro-N - ((1Z) -1-methyl-3-oxo-2-phenyl-3 - [(2-phenylethyl) aminol-1-propen-1-yl) -2- (methyloxy) benzamide A Trifluoromethanesulfonate solution of (1Z) -1-methyl-3-oxo-2-phenyl-3 - [(2-phenylethyl) amino] -1-propen-1-yl (13.1 g, 32 mmol) and dry deoxygenated dioxane were added. add 3-fluoro-2-hydroxybenzamide (5.49 g, 35 mmol), cesium carbonate (14.7 g, 45 mol), Pd2 (dba) 3 (0.74 g, 0.081 mmol) and xanthophos (1.40 g, 2.4 mmol). The reaction is heated to reflux for 16 hours. The cooled reaction mixture is filtered through a pad of Celite and concentrated. The purification is purified by chromatography on silica gel (Biotage) to provide enamide (7.56 g) in 56% yield. d. 2- (3-Fluoro-2-hydroxyphenyl) -8-methyl-5-phenyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone 3-fluoro-N - ((1Z) -1- methyl-3-oxo-2-phenyl-3 { [2- (2-thienyl) ethyl] amino.} - 1-propen-1-yl) -2- (methyloxy) benzamide (7.56 g, 0.018) mol) is dissolved in ethanol (100 ml). To this is added 20 ml of 25% aqueous potassium hydroxide (v / v) and heated at reflux for 16 h. The crude reaction mixture is acidified 6N HCl to pH ~ 1 and extracted with dichloromethane. The combined organic layers are washed with brine and concentrated. The crude residue is purified by chromatography on silica gel (Biotage) followed by recrystallization from EtOAc to provide the desired product (6.32 g) in 88% yield. MS (m / z): 401.2 [M + Hf. 1 H NMR (400 MHz, CDCl 3) d ppm 2.29 (s, 3 H), 3.01 (t, J = 7.8 Hz, 2 H), 4.28 (t, J = 7.8 Hz, 2 H), 6.94-7.09 (m, 4 H), 7.11-7.39 (m, 4H), 7.41-7.51 (m, 5H).

EXAMPLE 268 Preparation of 2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5-propyl-4 (3H) -pyrimidinone to. 2-Acetyl-N- (2-phenylethyl) pentanamide To a solution of ethyl 2-acetylpentanoate (8.0 g, 0.051 mol) and DME is added phenethylamine (5.17 g, 0.043 mol) in a microwave reaction vessel. A few drops of ethanol are added to the reaction mixture is irradiated at 180 ° C for 1200 s. The reaction mixture is concentrated and purify by Biotage to produce the pure amide (5.1 g) along with some impure material (1.75 g). The catalytic hydrogenolysis of these individually separated batches then then combining the purification results in a total of 6.3 grams of the pure product in 50% of two steps. b. 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5-propyl-4 (3H) -pyrimidinone 3-Oxo-N- (2-phenylethyl) butanamide (6.2 g , 0.025 mol) is placed in the 500 ml round bottom flask and 251 ml of m-xylene is added followed by titanium isopropoxide (74 ml, 0.25 mol). Although the reaction is stirred, 3-fluoro-2-hydroxybenzamide (3.92 g, 0.025 mol) is placed in a condenser and the reaction is heated to reflux (oil bath temperature = 150 ° C). The 2-hydroxy-3-fluorobenzamide dissolves slowly and provides a brown homogeneous solution at some time at elevated temperatures. The reaction is run for 36 hours and cooled to room temperature and diluted with dichloromethane. 3N HCl is added slowly until the solid which is initially formed has dissolved. The organic layer is separated and the aqueous layer is further extracted with dichloromethane. The combined organic layer is dried over sodium sulfate and filtered and concentrated. The crude reaction mixture is purified by EtOAc / hexanes and followed by MeOH in dichloromethane to give the pure product in 46% yield (4-21 g). 1 H NMR (400 MHz, CDCl 3) d ppm 1.04 (t, J = 7.4 Hz, 2H), 1.55- 1. 61 (m, 2H), 2.27 (s, 3H), 2.52-2.56 (m, 2H), 2.88 (t, J = 7.4 Hz, 2H), 4.17 (t, J = 7.4 Hz, 2H), 6.85-6.89 (m, 5H), 7.04-7.19 (m, 3H), 9.98 (brs, 1 H). MS (m / z): 367.2 [M + Hf.

EXAMPLE 269 Preparation of 2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- (1 H -pyrrol-1-yl) -4 (3H) -pyrimidinone to. 2-. { 3-fluoro-2-r (phenylmethyl) oxy-phenyl) -6-methyl-3- (2-phenylethyl) -5- (1 H) -pyrrol-1-yl) -4 (3H) -pyrimidinone To a solution of 5-bromo-2-. { 3-fluoro-2 - [(phenylmethyl) oxy] phenyl} -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone (0.3 g, 0.61 mol) in deoxygenated toluene (3.2 ml) is added xanthophos (0.05 g, 0.091 mmol), Pd2 (dba) 3 (0.028 g, 0.03 mmol) and NaOtBu (0.083 g, 0.85 mmol) in a microwave container. The reaction is stirred for 5 minutes, and pyrrolo (0.051 ml, 0.073 mmol) is added. The reaction vessel is capped and irradiated in Smith's synthesizer at 150 ° C for 1000 s. The reaction mixture is concentrated and purified by chromatography on silica gel (Biotage) using a mixture of EtOAc and hexane (5-30%) to obtain the desired product (0.11 g) in 38% yield. b. 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- (1 H -pyrrol-1-yl) -4 (3 H) -pyrimidinone 2-. { 3-fluoro-2 - [(phenylmethyl) oxy] phenyl} -6-methyl-3- (2-phenylethyl) -5- (1 H -pyrrol-1-yl) -4 (3 H) -pyrimidinone (0.601 g, 0.35 mmol) is taken in ethanol. To this is added Pd / C at 10% (0.10 g). This mixture is placed under a hydrogen atmosphere at atmospheric pressure and is stirred for 12 hours. The reaction mixture is filtered through a pad of Celite, concentrated and purified by chromatography on silica gel (Biotage) using mixtures of EtOAc and hexane (5-30%) to obtain the desired product (0.41 g, 84%). %). MS (m / z): 390.2 (M + H) +.

Parenteral Formulation A pharmaceutical composition for parenteral administration is prepared by dissolving an appropriate amount of a compound of formula (I) in polyethylene glycol with heating. This solution is then diluted with water by injections (to 100 ml). The solution is then rendered sterile by filtration through a 0.22 micron membrane filter and sealed in sterile containers. All publications, including but not limited to patents and patent applications cited in this specification are incorporated herein for reference as if each of the individual publications were specifically and individually indicated to be incorporated for reference as if they were fully disclosed.

Claims (26)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound according to formula (I): where: X is O or S; R1 and R2 are independently selected from the group consisting of H, halogen, CN, C-MO alkyl, C2-6 alkenyl, cycloalkyl, cycloalkyl-C6-6 alkyl, aryl, C6-6 arylalkyl, heterocyclyl , heteroaryl, (CR10R ??) xNR5R6, C (O) OR5, C (0) NR5R6, NR5C (O) R6, (CR? or R ??) OR5 and NC (O) R5, optionally substituted, except for H, halogen and CN, one to three times, independently, by halogen, CN, C1- alkyl, aryl, heteroaryl, C (0) OR? 9, O- (CR? 9R2o) qO, C (O) R19, CF3, OCF3, NO2, C (O) NR19R20, (CR10R ??) zOR19, (CR10R ??) zNR? 9R2o and C (R? 0R ??) xS (O) mR19; or R and R2 together form an optionally substituted 5 to 8 membered ring, optionally containing one to three heteroatoms selected from N, O and S, wherein the optional substituents are selected, independently, at each occurrence, one to three times, from the group consisting of halogen, C- alkyl, (CR? or Rn) zS (O) mR, (CR10R ??) zOR5, (CR? 0R ??) zNR5R6, C (O) R5 and C (O) OR5; or R1 and R2 together form an optionally substituted heteroaryl ring, wherein the optional substituents are independently selected, at each occurrence, one to three times, from the group consisting of halogen, C- alkyl, (CR? or Rn) zS (0) mR5. (CR10Rn) zOR5, (CR10R ??) zNR5R6, C (O) R5 and C (O) OR5; or, when R1 is NR5R6, R5 and Re together can be joined to form a 5- to 7-membered ring, optionally substituted by C ?4 alkyl or halogen; R5 and R6 represent, independently, at each occurrence, H, C1-4alkyl, cycloalkyl, cycloalkylalkyl of C6-6, alkenyl of C2-6, heterocyclyl, heterocyclylalkyl of C6-6, aryl, arylalkyl of C6-6. , heteroaryl, or heteroaryl-C-? -6 alkyl, wherein each portion, except H, is optionally substituted, independently, one to three times, by halogen or C? _4 alkyl. R10 and R11 represent, independently, in each occurrence, H or C ^ alkyl; R19 and R2o represent, independently, in each occurrence, H, C1.4 alkyl, cycloalkyl, cycloalkylC1-6alkyl, C2-6alkenyl, heterocyclyl, C1.4 heterocyclylalkyl, aryl, arylalkyl ? -6, heteroaryl or a heteroaryl-C-? 6 alkyl portion, wherein each portion, except H, can be substituted, independently, one to three times, by halogen or C? _ Alkyl; R3 represents aryl or heteroaryl, optionally substituted, independently, one to three times, by C ?4 alkyl, halogen, CN or CF3; R4 is selected from the group consisting of the group consisting of cycloalkyl-C1-4alkyl, heteroaryl, heterocyclyl, aryl, heteroarylalkyl of C-1-2, heterocyclylalkyl of C? _2, cycloalkyl-alkenyl of C2, aryl-alkenyl of C2, C2 heteroaryl-alkenyl, and C2 heterocyclyl-alkenyl, wherein each portion it is optionally substituted, independently, one to three times, by C 1-4 alkyl, F, CF 3 or Cl; m is 0, 1 or 2; x is 0, 1, 2 or 3; q is 1, 2 or 3; and z is 0, 1, 2, 3 or 4; or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, further characterized in that X is O.

3. The compound according to claim 1, further characterized in that R1 and R2 are independently selected from the group consisting of H, I , Cl, Br, F, CN, methyl, ethyl, isobutyl, propyl, butyl, isopropyl, hexyl, 2-methylbutyl, 3-methylbutyl, 2-hydroxyethyl, 2-methyl-2-propenyl, 2-methyl-1-propenyl , 1-propenyl, cyclopentyl, cyclopropyl, cyclobutylethyl, cyclobutylmethyl, cyclopropylmethyl, phenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 4-fluorophenyl, 2-fluorophenyl, 3-fluorophenyl, 3-methylphenyl, 4-hydroxyphenyl, -cyanophenyl, 4-cyanophenyl, 4-trifluoromethylphenyl, 3-hydroxymethylphenyl, 3-hydroxyphenyl, 4-N, N-dimethylphenyl, 4-ethoxyphenyl, 4-biphenyl, 4-iopropoxyphenyl, 5-methylsulfonylphenyl, 3-ethoxyphenyl, 2- ethoxyphenyl, 3-cyanophenyl, 4-trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl, 3-dimethylaminomethylphenyl, 3-N, N-dimethylbenzamidyl, 4-t-butylphenyl, 4-isopropylphenyl, 3-N, N-dimethylmethylphenyl, 3-nitrophenyl, carboxylic acid, pyrrolidinyl, morpholinyl, azetidinyl, phenpropyl, phenethyl, 3,4-dichlorophenethyl, ethylamino, methylethylisobutylamino, diethylamino, dimethylamino, 2,2-dimethylpropanamide, NH 2, NN-dimethylamino, aniline, N-propyl, methylmethylether, benzylethylether, methylethylether, ethyl ether, isopropyl ether, N, 2-dimethylpropanamide, 2-methylpropanamide, pyrazinyl, 3-pyridyl, 2-furyl, 3-furyl, 2-indanyl, 3-methyl-2- thienyl, 4-methyl-2-thienyl, 5-methyl-2-thienyl, 3-thienyl, 2-thienyl, 5-chloro-2-thienyl, 2-pyrrolyl, 1-methyl-2-pyrrolyl, 5-methyl- 3-thienyl, 5-methylamino-2-thienyl, 5-hydroxymethyl-2-thienyl, 4,5-dimethyl-2-thienyl, 5-cyano-2-thienyl, 5-phenyl-2-thienyl, 2-methyl- 1,3-thiazol-5-yl, 1,3-thiazol-2-yl, 5-acetyl-2-thienyl, 4,5-dimethyl-1,3-thiazol-2-yl, 4-methyl-1, 3-thiazol-2-yl, 5-methyl-1, 3,4-oxadiazol-2-yl, quinolinyl, 1, 2,3,4-tetrahydroquinolinyl, 1, 2,3,4-methyltetrahydroquinolinyl, 2,3- dihydro-1,4-benzodioxinyl, 3-benzothiophenyl, 1,3-benzodioxol-5-yl, 4-benzothienyl, 2-benzofuranyl, 4,5,6,7-tetrahydrobenzothienyl, 1-methylindol-5-yl, 5- (2-phenyl-1,3-thiazol-5-yl), 5-chloro-3-methyl-1-benzothien-2-yl, 2-benzothiophenyl, 1-methylindol-2-yl, and 5- (2- methyl-1,3-thiazol-4-yl) -2-thienyl.

4. The compound according to claim 1, further characterized in that R4 is selected from the group consisting of phenyl-C de _2 alkyl, cyclohexyl-C de.-Alkyl, cyclopentyl-C de? Alquilo-alkyl, thienyl. -alkyl of C? _2, pyranyl-C-? -2 alkyl, indenyl-C1-2-alkyl and piperidinyl-Ci-alkyl. 2, optionally substituted, independently, once or twice, by F, CF3 or CI.

5. The compound according to claim 1, further characterized in that R1 is selected from the group consisting of isobutyl, ethyl, phenyl, furanyl, quinolinyl, halogen, tetrahydroquinolinyl, pyrrolidinyl, thiophenyl, morpholinyl, cyclopentyl, isopropyl, amino, pyrazinyl , indolyl, thiazolyl, piperidinyl, N-acyl, benzothiophenyl and benzothiazolyl moiety, optionally substituted, independently, one to three times, by C 4 alkyl or halogen; and R2 is selected from the group consisting of methyl, methoxymethyl, piperidinyl, ethyl, methoxyethyl, benzyloxyethyl, phenyl, pyrrolidinyl, amino, alkylamino, propyl, phenethyl, phenpropyl, butyl, isobutyl, cyclobutylethyl, 3-methylbutyl, dimethylaminomethyl, piperidinylmethyl, and alkylaminomethyl portion, optionally substituted, independently, one to three times, by C1-4 alkyl or halogen.

6. The compound according to claim 1, further characterized in that R3 represents an optionally substituted heteroaryl portion.

7. The compound according to claim 1, further characterized in that R3 represents an optionally substituted aryl portion.

8 - The compound according to claim 1, further characterized in that it is selected from the group consisting of: 2- (2-Fluoro-3-hydroxyphenyl) -6-methyl-5- (2-methylpropyl) -3- (2 phenylethyl) -4 (3H) -pyrimidinone; 2- (3-Hydroxyphenyl) -6-methyl-5- (2-methylpropyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (2,3-D-Hydroxyphenyl) -6-methyl-5- (2-methylpropyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 6-Methyl-5- (2-methylpropyl) -3- (2-phenylethyl) -2- (1 H -pyrrol-2-yl) -4 (3 H) -pyrimidinone; 6- Methyl-5- (2-methylpropyl) -3- (2-phenylethyl) -2- (2-thienyl) -4 (3H) -pyrimidinone; 6-Methyl-5- (2-methylpropyl) -3- (2-phenylethyl) -2- (2-pyridinyl) -4 (3H) -pyrimidinone; 2- (2-Furanyl) -6-methyl-5- (2-methylpropyl) -3- (2-phenylethyl) -4 (3H-pyrimidinone; 2- (1 H-imidazol-2-yl) -6-methyl-5 - (2-methylpropyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5-Ethyl-2- (2-fluoro-3-hydroxyphenyl) -3- [2- (3-fluorophenyl) ethyl] -6-methyl-4 (3H) -pyrimidinone; 5-Ethyl-3- [2- (3-fluorophenyl) ethyl] -6-methyl-2- (1H-pyrrol-2-yl) -4 (3H) -pyrimidonone; 5-Bromo-2- { 3- fluoro-2 - [(phenylmethyl) oxy] phenyl} -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5-Bromo-2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- (6-quinolinyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- (1, 2,3,4-tetrahydro-6-quinolinyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-5- (1-methyl-1, 2,3,4-tetrahydro-6-quinolinyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -5- (2-furanyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-5-phenyl-3- [2- (2-thienyl) ethyl] -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- (1-pyrrolidinyl) -4 (3H) -pyrimidinone; 5- (5-Chloro-2-thienyl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5-bromo-6-methyl-3- (2-phenylethyl) -2-. { 2 - [(phenylmethyl) oxy] phenyl} -4 (3H) -pyrimidinone; 2- (2-Hydroxy-phenyl) -3- (2-phenylethyl) -6- (1-piperidinylmethyl) -4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -6-. { [methyl (2-methylpropyl) amino] methyl} -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -6-methyl-5 - [(1-methylethyl) oxy] -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- (2-Furanyl) -2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- (2-thienyl) -4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -6-methyl-5- (4-morpholinyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5-Ethyl-2- (3-fluoro-2-hydroxyphenyl) -3- [2- (3-fluorophenyl) ethyl] -6- (1-piperidinyl) -4 (3H) -pyrimidinone; 5-Ethyl-1 - [2- (3-fluorophenyl) ethyl] -2- [2- (methyloxy) phenyl] -6-oxo-1,6-dihydro-4-pyrimidinecarboxylic acid; 5-Ethyl-2- (2-hydroxyphenyl) -6-methyl-3 - [(E) -2-phenylethenyl] -4 (3H) -pyrimidinone; 2- (3,6-Difluoro-2-hydroxy-phenyl) -5-etl-3- [2- (3-fluorophenyl) ethyl] -6-methyl-4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxy-phenyl) -6-methyl-5-propyl-3- [2- (2-thienyl) ethyl] -4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -5,5-dimethyl-3- [2- (2-thyl) ethyl] -5,6,7,8-tetrahydro-4 (3H) -quinazolinone; 3- [2- (2-Fluorophenyl) ethyl] -2- (2-hydroxyphenyl) -5,5-dimethyl-5,6,7,8-tetrahydro-4 (3H) -quinazolinone; 2- (2-Hydroxyphenyl) -3- (2-phenylethyl) -3,5,6,6,8,9-hexahydro-4H-cyclohepta [d] pyrimidin-4-pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -3- (2-phenylethyl) -5,6,7,8-tetrahydro-4 (3H) -quinazolinone; 5-Cyclopentyl-2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- (2,3-Dihydro-1,4-benzodioxin-6-yl) -6-methyl-3- (2-phenylethyl)) - 2- (2-thienyl) -4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -6 - [(methyloxy) methyl] -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -6 - [(methyloxy) methyl] -5- (2-methylpropyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2-. { 3-Fluoro-2 - [(phenylmethyl) oxy] phenyl} -5- (2-hydroxyethyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5-propyl-4 (3H) -pyrimidinationa; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-5-phenyl-3- (2-phenylethyl) -4 (3H) -pyrimidinationa; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-5- (2-methylpropyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinationa; 3- (2,3-Dihydro-1 H-inden-2-i) -2- (2-hydroxyphenyl) -6-methyl-5- (1-methyl-ethyl) -4 (3H) -pyrimidinone; 5,6-Diethyll-2- (3-fluoro-2-hydroxyphenyl) -3- [2- (2-fluorophenyl) ethyl] -4 (3H) -pyrimidinone; 6- (2-Cyclohexylethyl) -5-ethyl-2- (3-fluoro-2-hydroxyphenyl) -3- [2- (2-fluorophenyl) ethyl] -4 (3H) -pyrimidinone; 6- [2- (3,4-Dichlorophenyl) ethyl] -5-ethyl-2- (3-fluoro-2-hydroxyphenyl) -3- [2- (2-fluorophenyl) ethyl] -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -3- [2- (2-fluorophenyl) ethyl] -6methyl-5- (2-methylpropyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-5- (2-methylpropyl) -3- [2- (2-thienyl) ethyl] -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -3- [2- (4-fluorophenyl) ethyl] -6-methyl-5- (2-methylpropyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -3- [2- (3-fluorophenyl) ethyl] -6-methyl-5- (2-methylpropyl) -4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -7-methyl-3- (2-phenylethyl) -3,5,6,7,8,9-hexahydro-4H-pyrimido [4,5-d] azepin-4-one; 7-Acetyl-2- (2-hydroxyphenyl) -3- (2-phenylethyl) -3,5,6,7,8,9-hexahydro-4H-pyrimido [4,5-d] azepin-4-one; 2- (2-Hydroxyphenyl) -7- (methylsulfonyl) -3- (2-phenylethyl) -3,5,6,7,8,9-hexahydro-4H-pyrimido [4,5-d] azepine- 4-one; 5-Bromo-2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -5-iodo-6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5-Chloro-3- (2-cyclohexylethyl) -2- (2-hydroxyphenyl) -6-methyl-4 (3H) -pyrimidinone; 5-Chloro-2- (2-hydroxyphenyl) -6-methyl-3- [2- (2-thienyl) ethyl] -4 (3H) -pyrimidinone; 5-Chloro-2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinationa; 5-Bromo-2- (3-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (3-Hydroxyphenyl) -6-methyl-5-phenyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (2-hydroxyphenyl) -6-methyl-5- (phenylamino) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- (1-Azetidinyl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxypheni)) - 6-methyl-3- (2-phenylethyl) -5- (propylamino) -4 (3H) -pyrimidinone; 2- (2-Fluoro-3-hydroxyphenyl) -6-methyl-5-phenyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- (3-thienyl) -4 (3H) -pyrimidinone; 5- (3-Furanyl) -2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- (4-Biphenylyl) -2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- (1, 3-Benzodioxol-5-yl) -2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- (2-fluorophenyl) -2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5-. { 4- (trifluoromethyl) phenyl] -4 (3H) -pyrimidinone; 5- (3-Fluorophenyl) -2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- (2,4-Difluorophenyl) -2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- [4- (Dimethylamino) phenyl] -2- (3-fluoro-2- hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- [4- (Ethyloxy) phenyl] -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- (1-Benzothien-3-yl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- (1-Benzothien-4-yl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- [2- (3-Fluoro-2-hydroxyphenyl) -4-methyl-6-oxo-1- (2-phenylethyl) -1,6-dihydro-5-pyrimidinyl-benzonitrile; 4- [2- (3-fluoro-2-hydroxyphenyl) -4-methyl-6-oxo-1- (2-phenylethyl) -1,6-dihydro-5-pyrimidinyl] benzonitrile; 5- [2- (Ethyloxy) phenyl] -2- (3-fluoro-2-hydroxyphenyl) -6-methyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- [3- (Ethyloxy) phenyl] -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- (1-Benzofuran-2-yl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- (1 H -pyrrol-2-yl) -4 (3 H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -5- [3- (hydroxymethyl) phenyl] -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-5- [3- (methylsulfonyl) phenyl] -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- [3- (trifluoromethyl) phenyl] -4 (3H) -pyrimidinone; 5- (3,4-Difluorophenyl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- [4- (1, 1-Dimethylethyl) phenyl] -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- (5-Acetyl-2-thienyl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5-. { 3 - [(trifluoromethyl) oxy] phenol} -4 (3H) -pyrimidinone; 5-. { 3- . { (Dimethylamino) methyl] phenyl} -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 3- [2- (3-Fluoro-2-hydroxyphenyl) -4-methyl-6-oxo-1- (2-phenylethyl) -1,6-dihydro-5-pyrimidinyl] -N, N-dimethylbenzamide; 5- (4,5-Dimethyl-2-thienyl) -2- (3- fluoro-2-hydroxy-phenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- [2- (3-Fluoro-2-hydroxyphenyl) -4-methyl-6-oxo-1- (2-phenylethyl) -1,6-dihydro-5-pyrimidinyl] -2-thiophenecarbonitrile; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-5- (1-methyl-1 H -pyrrol-2-yl) -3- (2-phenylethyl) -4 (3 H) -pyrimidinone; 2- (3-fluoro-2-hydroxyphenyl) -6-methyl-5- (1-methyl-1 H -indol-2-yl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- (1,3-thiazol-2-yl) -4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- (3-pyridinyl) -4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- (2-pyrazinyl) -4 (3H) -pyrimidinone; 6-Methyl-2- [2- (methyloxy) phenyl] -3- (2-phenylethyl) -5- (2-thienyl) -4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -6-methyl-5-phenyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- (4-Fluorophenyl) -2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -6-methyl-5- (3-methylphenyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-5- (1-methyl-1 H -indol-5-yl) -3- (2-phenylethyl) -4 (3 H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5-. { 4 - [(trifluoromethy1) oxy] phenyl} -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-5-. { 4 - [(1-methylethyl) oxy] phenyl} -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- (6-quinolinyl) -4 (3H) -pyrimidinone; 5- (2,3-Dihydro-1,4-benzodioxin-6-yl) -2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- (5-Chloro-3-methyl-1-benzothien-2-yl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-5- [5- (1, 3-oxazol-5-yl) -2-thienyl] -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5-Fluoro-2- (2-hydroxyphenii) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -6-methyl-5- (2-methylpropyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -6-methyl-5- (2-methyl-2-propen-1-yl) -3- (2-phenylethyl) - 4 (3H) -pyrimidinone; 5- (Cyclobutylmethyl) -6-methyl-2- [2- (methyloxy) phenyl] -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- (Cyclobutylmethyl) -2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (2-Hydroxy-phenyl) -6,6-dimethyl-3- (2-phenylethyl) -4a, 5,6,7,8,8a-hexahydro-4 (3H) -quinazolinone; 5- (Cyclopropylmethyl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5-Cyclopropyl-2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-5- (3-methylbutyl)) - 3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- (2-Cyclohexylethyl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-prienylethyl) -4 (3H) -pyrimidinone; 5- (Cyclohexylmethyl) -2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-metii-3- (2-phenylethyl) -5- (phenylmethyl) -4 (3H) -pyrimidinone; 5-Amino-2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- (1-piperidinii) -4 (3H) -pyrimidinone; 5- (Dimethylamino) -2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; N- [2- (2-Hydroxyphenyl) -4-methyl-6-oxo-1- (2-phenylethyl) -1,6-dihydro-5-pyrimidinyl] -2,2-dimethylpropanamide; N- [2- (2-Hydroxyphenyl) -4-methyl-6-oxo-1- (2-phenylethyl) -1,6-dihydro-5-pyrimidinyl] -2-methylpropanamide; N- [2- (2-hydroxyphenyl) -4-methyl-6-oxo-1- (2-phenylethyl) -1,6-dihydro-5-pyrimidinyl] -N, 2-dimethylpropanamide; 5- (Dipropylamino) -2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- (Diethylamino) -2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- (Etylamino) -2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -5- (2-methylpropyl) -3- (2-phenylethyl) -6-propyl-4 (3H) -pyrimidinone; 6-Ethyl-2- (2-hydroxyphenyl) -5- (2-methylpropyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 6-Butyl-2- (2-hydroxyphenyl) -5- (2-methylpropyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (2- Hydroxyphenyl) -5- (2-methylpropyl) -3- (2-phenylethyl) -6-. { 2 - [(phenylmethyl) oxy] ethyl} -4 (3H) -pyrimidinone; 6- (2-Hydroxyethyl) -2- (2-hydroxypheni)) - 5- (2-methylpropyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 6- [2- (methyloxy) ethyl] -5- (2-methyl-1-propen-1-yl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (2-hydroxyphenyl) -6- [2- (methyloxy) ethyl] -5- (2-methylpropyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- (dimethylamino) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- (Dimethylamino) -2- (2-fluoro-3-hydroxy-phenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 6-Methyl-2,5-diphenyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (2-Fluorophenyl) -6-methyl-5-phenyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 3- [2- (2-Chlorophenyl) ethyl] -2- (2-hydroxyphenyl) -5,6,7,8-tetrahydro-4 (3H) -quinazolinone; 3- [2- (3-Fluorophenyl) ethyl] -2- (2-hydroxyphenyl) -5,5-dimethyl-5,6,7,8-tetrahydro-4 (3H) -quinazolinone; 3- (2-Cyclohexylethyl) -2- (2-hydroxyphenyl) -5,5-dimethyl-5,6,7,8-tetrahydro-4 (3H) -quinazolinone; 3- [2- (3-Fluorophenyl) ethyl] -2- (2-furanyl) -5,6,7,8-tetrahydro-4 (3H) -quinazolinone; 3- [2- (3-Fluorophenyl) ethyl] -2- (2-thienyl) -5,6,7,8-tetrahydro-4 (3H) -quinazolinone; 2- (2-Hydroxyphenyl) -4-methyl-6-oxo-1- (2-phenylethyl) -1,6-dihydro-5-pyrimidinecarbonitrile of ethyl; 2- (2-Hydroxyphenyl) -4-methyl-6-oxo-1- (2-phenylethyl) -1,6-dihydro-5-pyrimidinecarboxylate ethyl; 2- (2-Hydroxyphenyl) -6-methyl-5- (1-methylpropyl) -3- [2- (2-thienyl) ethyl] -4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -6-methyl-5- (1-methylpropyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-5- (1-methylpropyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5-Butyl-2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -6-methyl-5-pentyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5-Hexyl-2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5-Butyl-2- (2-hydroxyphenyl) -6-methyl-3- [2- (2-thienyl) ethyl] -4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -6-methyl-5-pentyl-3- [2- (2- thienyl) ethyl] -4 (3H) -pyrimidinone; 5-Hexyl-2- (2-hydroxyphenyl) -6-methyl-3- [2- (2-thienyl) ethyl] -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -3- [2- (3-fluorophenyl) ethyl] -5,6,7,8-tetrahydro-4 (3H) -quinazolinone; 2- (3-Fluoro-2-hydroxyphenyl) -3- [2- (3-fluorophenyl) ethyl] -3,5,6,7,8,9-hexahydro-4H-cyclohepta [d] pyrimidin-4-one; 2- (2-Hydroxyphenyl) -4-oxo-3- (2-phenylethyl) -3,5,7,8-tetrahydropyrrho [4,3-d] pyrimidine-6 (4H) -ethylcarboxylate; (2-Hydroxyphenyl) -6- (3-methylbutanoyl) -3- (2-phenylethyl) -5,6,7,8-tetrahydropyrido [4,3-d] pyrimidin-4 (3H) -one; 5-Ethyl-2- (2-hydroxyphenyl) -6-methyl-3- [2- (2-thienyl) ethyl] -4 (3H) -pyrimidinone; 5-lsopropyl-2- (2-hydroxy-phenyl) -6-methyl-3- (2-thiophen-2-yl-etl) -3H-pyrimidin-4-one; 5-lsopropyl-2- (2-hydroxy-phenyl) -6-methyl-3- (2-cyclohexyl-ethyl) -3H-pyrimidin-4-one; 5-Ethyl-2- (2-hydroxy-3-fluorophenyl) -6-methyl-3- (2-fluorophenylethyl) -3H-pyrimidin-4-one; 5-Propenyl-2 (2-hydroxy-3-fluorophenyl) -6-methyl-3- (3-fluorophenylethyl) -3H-pyrimidin-4-one; 3- (2-Cyclohexylethyl) -2- (2-hydroxyphenyl) -5,6,7,8-tetrahydro-4 (3H) -quinazolinone; 3- (2-Thiophene-2-yl-ethyl) -2- (2-hydroxy-phenyl) -5,6,7,8-tetrahydro-3H-quinazolin-4-one; 3- (2-Thiophene-2-yl-ethyl) -2- (2-hydroxy-3-fluorophenyl) -5,6,7,8-tetrahydro-3H-quinazolin-4-one; 3- (2-Thiophene-3-yl-ethyl) -2- (2-hydroxy-phenyl) -5,6,7,8-tetrahydro-3H-quinazolin-4-one; 3- (3-Chloro-phenethyl) -2- (2-hydroxy-phenyl) -5,6,7,8-tetrahydro-3H-quinazolin-4-one; 3- (2-Cyclopentylethyl) -2- (2-hydroxy-phenyl) -5,6,7,8-tetrahydro-3H-quinazolin-4-one; 3- (3-Trifluoromethyl-phenethyl) -2- (2-hydroxy-phenyl) -5,6,7,8-tetrahydro-3H-quinazolin-4-one; 2- (2-Hydroxyphenyl) -3- (2-phenylethyl) -5,6,8,9-tetrahydrooxepino [4,5-d] pyrimidin-4 (3H) -one; 3- (2-Cyclohexyl-ethyl) -2- (2-hydroxy-phenyl) -3,5,6,7,8,9-hexahydro-cycloheptapyrimidin-4-one; 2- (2-Hydroxyphenyl) -3- (2-phenylethyl) -6- (phenylmethyl) -5,6,7,8-tetrahydropyrido [4,3-d] pyrimidin-4 (3H) -one; 2-Methylpropyl-2- (2-hydroxyphenyl) -4-oxo-3- (2-phenylethyl) -3,5,7,8- tetrahydrofoam [4,3-d] p? r? m? d? na-6 (4H) -carboxylate, 2- (3-Fluoro-2-hydrox? phen?) -6-met? L-5- [5- (2-met? L-1, 3-t? Azol-4-? L) -2-t? In? L] -3- (2-phen? Let ?) -4 (3H) -p? r? m? d? none, 2- [2- (H? drox?) phen? l] -3- (2-phen? let? l) -5.6 , 7,8-tetrah? Drop? Pdo [3,2-d] p? Pm? D? N-4 (3H) -one, 2- (2-H? Drox? Phen?) -5-met? l-3- (2-phen? let? l) -5,6,7,8-tetrah? drop? r? do [3,2-djpipmidin-4 (3H) -one, 5-Et? l-2 - [2-h? Drox? Phen?] -3- (2-phen? Let? L) -5,6,7,8-tetrah? Drop? Pdo [3,2-d] p? R? M ? d? n-4 (3H) -one, 2- (2-H? drox? phen? l) -4-oxo-3- (2-phen? let? l) -3,4,5,7- tetrahydro-6H-pyrrolo [3,4-d] p? pm? d? na-6-carboxylate of 1, 1-d? met? lel, 5- (2-Met? lprop ? l-2-? l) -2- (2-h? drox? -fen? l) -6-met? l-3- (2-phenet? l) -3H-p? pm? d? n- 4-one, 5- [2- (3-Fluorophen? L) et? L] 6- (2-h? Drox? Phen? L) -1-met? L-1, 5-d? H? Dro- 4H-p? Razolo [3,4-d] p? R? M? D? N-4-one, 5-Et? L-2- (3-fluoro-2-hydrox? Phen?) - 3- [2- (3-fluorophen? L) et? L] -6-phen? L-4 (3H) -pipmidinone, 6- [3,4-B? S (met? Lox?) Phen? L] -5-et? 2- (3-fluoro-2-h? Drox? Phen?) -3- [2- (3-fluorophen? L) et? L] -4 (3H) -p? R? m? d? none, 5-Et? l-2- (3-fluoro-2-h? drox? phen?) -3- [2- (3-fluorofen ? l) et? l] -6- (3-n? trofen? l) -4 (3H) -p? r? m? d? none, 5-Et? l-3- [2- (3-fluorofen (I) et? l] -2- (2-hydrox? phen?) -6- (1-p? rrol? d? n? l) -4 (3H) -p? pm? d? none , 6- (D? Met? Lam? No) -5-et? L-3- [2- (3-fluorofen? L) et? L] -2- (2-h? Drox? Phen?) - 4 (3H) - pipmidinone, 5-Et? L-3- [2- (3-fluorophen? L) et? L] -2- (2-h? Drox? Phen?) -6- (met? Lam) ? no) -4 (3H) - pipmidinone, 5-C? clopent? l-3- [2- (3-phorophen? l) et? l] -2- (2-hydrox? phen? ) -6-met? L-4 (3H) -p? R? M? D? None, 2- (2-H? Drox? Phen?) -6-met? L-5- (2-met? lprop? l) -3- (2-phen? let? l) -4 (3H) -pipmidinone, 2- (2-H? drox? phen? l) -6-met? l-5- (2-met) ? lprop?) -3- [2- (2-t? in? l) et?)] - 4 (3H) -pipmidinone, 5-Et? l-2- (2-h? drox? -fen? l) -6-et? l-3-phen? let? l-3H-p? r? m? d? n-4-one, 5-Et? l-2- (2-h? drox? -fen ?) -6-prop? l-3-phen? let? l-3H-p? pm? d? n-4-one, 5-Et? l-2- (3-fluoro-2-hydro? ? -fen?) -6- (2-phenol? l) -3- (2-fluoro-phenol? l) -3H-p? r? m? d? n-4-one, 5 -Et? L-2- (3-fluoro-2-hydrox? -fen? L) -6-prop? L-3- (2-fluoro-phen? Le? L) -3H-p? R? m? d? n-4-one, 5-Et? l-2- (3-fluoro-2- hydroxy-phenyl) -6- (3-phenyl-propyl) -3- (2-fluoro-phenylethyl) -3H-pyrimidin-4-one; 5-Ethyl-2- (3-fluoro-2-hydroxy-phenyl) -6-butyl-3- (2-fluoro-phenylethyl) -3H-pyrimidin-4-one; 5-Ethyl-2- (3-fluoro-2-hydroxy-phenyl) -6- (2-methyl-propyl) -3- (2-fluoro-phenylethyl) -3H-pyrimidin-4-one; 5-Ethyl-2- (3-fluoro-2-hydroxy-phenyl) -6- (3-methyl-butyl) -3- (2-fluoro-phenylethyl) -3H-pyrimidin-4-one; 5-Ethyl-2- (3-fluoro-2-hydroxy-phenyl) -6- (2-cyclobutyl-ethyl) -3- (2-fluoro-phenylethyl) -3H-pyrimidin-4-one; 5-Ethyl-2- (3-fluoro-2-hydroxy-phenyl) -6- (3,4-dichlorophenethyl) -3- (2-fluoro-phenylethyl) -3H-pyrimidin-4-one; 5-Ethyl-2- (4-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 6-Methyl-5- (2-methyl-1,3-thiazol-5-yl) -3- (2-phenylethyl) -2-. { 2 - [(phenylmethyl) oxy] phenyl} -4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -6-methyl-5-. { 5-methyl-2-thienyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -6-methyl-5- (5-methyl-3-thienyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-5- (5-methyl-3-thienyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- (4,5-Dimethyl-2-thienyl) -2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -6-methyl-5- [5- (1, 3-oxazol-5-yl) -2-thienyl] -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -6-methyl-5- (4-methyl-2-thienyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- [2- (2-Hydroxyphenyl) -4-methyl-6-oxo-1- (2-phenylethyl) -1,6-dihydro-5-pyrimidinyl] -2-thiophenecarbonitrile; 2- (2-Hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- [5- (1 H-tetrazol-5-yl) -2-thienyl] -4 (3H) -pyrimidinone; 5- [5- (Amomethyl) -2-thienyl] -2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -6-methyl-5-. { 5 - [(methylamino) methyl] -2-thienyl} -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- [5- (Hydroxymethyl) -2-thienyl] -2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- (4,5,6,7-tetrahydro-1-benzothien-2-yl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6- methyl-3- (2-phenylethyl) -5- (2-phenyl-1,3-thiazol-5-yl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -5- (4-hydroxyphenyl) -6-methyl-3 - (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -5- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -5- (3-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (2-Hydroxy-phenyl) -6-methyl-5- (2-methy1propyl) -3- [2- (1-piperidinyl) ethyl] -4 (3H) -pyrimidinone; 5-Ethyl-3- [2- (2-fluorophenyl) ethyl] -2- (3-hydroxyphenyl) -6-methyl-4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -6-methyl-5- [5- (5-methyl-1, 3,4-oxadiazol-2-yl) -2-thienyl] -3- (2-phenylethyl) -4 ( 3H) -pyrimidinone; 5- (2,3-Dhydro-1,4-benzodioxin-6-yl) -2- (2-hydroxyphenyl) -6 - [(methyloxy) methyl] -3- (2-phenylethyl) -4 (3H) - pyrimidinone; 2- (2-Hydroxyphenyl) -6 - [(methyloxy) methyl] -5- (4-methyl-2-thienyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -6 - [(methyloxy) methyl] -5- (5-methyl-2-thienyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5-Bromo-6 - [(dimethylamino) methyl] -2- (2-hydroxyphenyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 6 - [(Dimethylamino) methyl] -2- (2-hydroxyphenyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-5- (5-methyl-3-thienyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- (4,5-Dimethyl-1,3-thiazol-2-yl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimid ninth; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-5- (4-methyl-1,3-thiazol-2-yl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- (1, 3-Benzodioxol-5-yl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 3- (2,3-Dihydro-1 H -inden-2-yl) -2- (2-hydroxyphenyl) -6-methyl-5- (5-methyl-2-thienyl) -4 (3H) -pyrimidinone; 3- [1- (2,3-Dihydro-1 H -inden-2-yl) -2- (2-hydroxyphenyl) -4-methyl-6-oxo-1,6-dihydro-5-pyrimidinyl] benzonitrile; 3- (2,3-Dihydro-1 H -inden-2-yl) -5- (4,5-dimethyl-1,3-triazol-2-yl) -2- (2-hydroxyphenyl) -6-methyl -4 (3H) -pyrimidinone; 3- (2-Cyclohexylethyl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-5- (5-methyl-2-thienyl) -4 (3H) - pyrimidinone; 3- (2-Cyclohexylethyl) -5- (4,5-dimethyl-1,3-thiazol-2-yl) -2- (3-fluoro-2-hydfoxyphenyl) -6-methyl-4 (3H) -pyrimidinone; 3- (2-Cyclohexylethyl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-5- (2-methyl-1,3-thiazol-5-yl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-5- (5-methyl-2-thienyl) -3- [2- (2-thienyl) ethyl] -4 (3H) -pyrimidinone; 5- (4,5-Dimethyl-1, 3-thiazol-2-yl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- [2- (2-thienyl) ethyl] -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxy-phenyl) -6-methyl-5- (5-methyl-2-thienyl) -3- [2- (tetrahydro-2H-pyran-4-yl) ethyl] -4 (3H ) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -3- [2- (2-fluorophenyl) ethyl] -6-methyl-5- (5-methyl) -2-thienyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -3- [2- (3-fluorophenyl) ethyl] -6-methyl-5- (5-methyl-2-thienyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -3- [2- (4-fluorophenyl) ethyl] -6-methyl-5- (5-methyl-2-thienyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-5- (3-methyl-2-thienyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -3- (2-phenylethyl) -5,6,7,8,9,10-hexahydrocycloocta [d] pyrimidin-4 (3H) -one; 5- (1-Benzoten-2-yl) -3- (2,3-dihydro-1 H -inden-2-yl) -2- (2-hydroxyphenyl) -6-methyl-4 (3H ) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-5- (2-methylpropyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -5,5-dimethyl-3- (2-phenylethyl) -5,6,7,8-tetrahydro-4 (3H) -quinazolinone; 5-Chloro-2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 3- [2- (3-Fluorophenyl) ethyl] -2- (2-hydroxyphenyl) -5,6,7,8-tetrahydro-4 (3H) -quinazolinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-5- (5-methyl-2-thienyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 3- [2- (3-Fluoro-2-hydroxyphenyl) -4-methyl-6-oxo-1- (2-phenylethyl) -1,6-dihydro-5-pyrimidinyl] benzonitrile; 5- (2,3-Dihydro-1,4-benzodioxin-6-yl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidonone; 5- (3,5-Difluorophenyl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) - pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-5- (4-methyl-2-thienyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- (1-Benzothien-2-yl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- (3-thienyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- (5-phenyl-2-thienyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- (2-thienyl) -4 (3H) -pyrimidinone; 5- (1, 3-Benzothiazol-2-yl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl)) - 4 (3H) -pyrimidinone; 5- (1-Benzothien-2-yl) -2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -6-methyl-5- (2-methyl-1,3-thiazol-5-yl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- [2- (2-Hydroxyphenyl) -4-methyl-6-oxo-1- (2-phenylethyl) -1,6-dihydro-5-pyrimidinyl] -2-thiophenecarbonitrile; 3- [2- (2-Hydroxyphenyl) -4-methyl-6-oxo-1- (2-phenylethyl) -1,6-dihydro-5-pyrinnidinyl] benzonitrile; 2- (3-Fluoro-2-hydroxy-phenyl) -6-methyl-5-phenyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5-propyl-4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-5- (2-methyl-1,3-thiazol-5-yl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; and 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- (1 H -pyrrol-1-yl) -4 (3 H) -pyrimidinone; or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 1, further characterized in that it is of formula (II): wherein: R1 and R2 are, independently, selected from the group consisting of H, halogen, Ci-β alkyl, aryl, heterocyclyl, and heteroaryl, optionally substituted, except for H, and halogen, one to three times, independently, by halogen, CN, C1-4 alkyl, aryl, heteroaryl, -O- (CH2) nO-, CF3, and OCF3; or R1 and R2 together form a 5- to 8-membered ring, optionally containing one to three heteroatoms selected from N, O and S, optionally substituted, independently, once or twice, by methyl; R 14 represents F or H; R 4 represents aryl-C 2 -alkyl, optionally substituted, independently, one to three times, by F, CF 3 or Cl; and n is 1, 2 or 3; or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 9, further characterized in that R1 is selected from the group consisting of chloro, propyl, isobutyl, 2-thienyl, 5-methyl-2-thienyl, 3-cyano-2-thienyl, -methyl-2-thienyl, 3-cyano-2-thienyl, 2-cyanophenyl, 3-cyanophenyl, 3,5-difluorophenyl, dihydrobenzodioxyl, benzothienyl, benzothiazolyl, 2-methylthiazolyl, N-pyrrolyl and 2-methylthiazolyl.

11. The compound according to claim 9, further characterized in that R1 and R2 form a cyclohexyl ring, optionally substituted, independently, once or twice by methyl.

12. The compound according to claim 9, further characterized in that R2 is methyl.

13. The compound according to claim 9, further characterized in that R4 is 3-fluorophenethyl.

14. The compound according to claim 9, further characterized in that R14 is F.

15. The compound according to claim 9, further characterized in that it is selected from the group consisting of: 2- (3-fluoro-2) -hydroxyphenyl) -6-methyl-5- (2-methylpropyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (2-hydroxyphenyl) -5,5-dimethyl-3- (2-phenylethyl) -5,6,7,8-tetrahydro-4 (3H) -quinazolinone; 5-chloro-2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 3- [2- (3-Fluorophenyl) ethyl] -2- (2-hydroxyphenyl) -5,6,7,8-tetrahydro-4 (3H) -quinazolinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-5- (5-methyl-2-thienyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 3- [2- (3-Fluoro-2-hydroxyphenyl) -4-methyl-6-oxo-1- (2-phenylethyl) -1,6-dihydro-5-pyrimidinyl] benzonitrile; 5- (2,3-dihydro-1,4-benzodioxin-6-yl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- (3,5-Difluorophenyl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (3-fluoro-2-hydroxyphenyl) -6-methyl-5- (4-methyl-2-thienyl) -3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- (1-benzothien-2-yl) -2- (3-fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- (2-thienyl) -4 (3H) -pyrimidinone; 5- (1, 3-Benzothiazol-2-yl) -2- (3-fluoro-2-hydroxyphenyl) - 6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 5- (1-Benzothien-2-yl) -2- (2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (2-Hydroxyphenyl) -6-methyl-5- (2-methyl-1,3-thiazol-5-yl) -3- (2-phenylethyl) -4 (3 H) -pyrimidinone; 5- [2- (2-Hydroxyphenyl) -4-methyl-6-oxo-1- (2-phenylethyl) -1,6-dihydro-5-pyrimidinyl] -2-thiophenecarbonitrile; 3- [2- (2-hydroxyphenyl) -4-methyl-6-oxo-1- (2-phenylethyl) -1,6-dihydro-5-pyrimidinyl-benzonitrile; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-5-phenyl-3- (2-phenylethyl) -4 (3H) -pyrimidinone; 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5-propyl-4 (3H) -pyrimidinone; and 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-3- (2-phenylethyl) -5- (1 H -pyrrol-1-yl) -4 (3 H) -pyrimidinone; or a pharmaceutically acceptable salt thereof.

16. The compound according to claim 9, further characterized in that it is 2- (3-Fluoro-2-hydroxyphenyl) -6-methyl-5- (5-methyl-2-thienyl) -3- (2-phenylethyl) ) -4 (3H) -pyrimidinone.

17 - A pharmaceutical composition comprising a compound according to claim 1 or 9, and a pharmaceutically acceptable carrier or diluent.

18. The use of a compound of claim 1 or 9, for the manufacture of a medicament useful for antagonizing a calcium receptor in a subject in need thereof.

19 - The use of a compound of claim 1 or 9, for the manufacture of a medicament useful for the treatment of a disease or disorder represented by an abnormal bone or mineral homeostasis in a subject in need thereof.

20 - The use as claimed in claim 19, wherein the The disease or disorder of abnormal bone or mineral homeostasis is selected from the group consisting of osteosarcoma, periodontal disease, fracture healing, osteoarthritis, rheumatoid arthritis, Paget's disease, humoral hypercalcemia, malignancy and osteoporosis.

21. The use as claimed in claim 20, wherein the bone or mineral disease or disorder is osteoporosis.

22. The use of a compound of claim 1 or 9, for the manufacture of a medicament useful for increasing serum parathyroid levels in a subject in need thereof.

23. The use as claimed in claim 20, wherein the medicament is adapted to be co-administrable with an anti-resorbing agent.

24. The use as claimed in claim 23, wherein the anti-resorptive agent is selected from the group consisting of estrogen, 1a, 25- (OH) 2D3, 1a- (OH) D3, calcitonin, selective modulators of the Estrogen receptor, vitronectrin receptor antagonists, V-H + -ATPase inhibitors, src SH2 antagonists, bio-phosphonates and cathepsin K inhibitors.

25. - A method for synthesizing a compound according to claim 1 comprising the step of cyclizing an enamide in accordance with structure (III) (III) with R4NH2 and trimethylaluminum to produce a pyrimidinone according to (IV): wherein: R 4 is selected from the group consisting of phenethyl, 3-fluorophenethyl, 4-fluorophenethyl, 2-fluorophenethyl, 2-thienylethyl, phenylethyl, dihydroindenyl, cohexylethyl, 3-chlorophenethyl, 3-trifluoromethylphenethyl, cyclopentylethyl and tetrahydropyranylethyl; And it is a displacement group selected from the group consisting of F, Cl, Br and I; and R18 is a protecting group selected from C -? - 2 alkyl, benzyl and acetyl.

26. - An intermediate according to the formula (III) wherein: R18 is C- | 2 alkyl, benzyl or acetyl; and Y is a displacement group selected from F, Cl, Br and I. 27.- An intermediate according to the formula (IV) wherein: R 4 is selected from the group consisting of phenethyl, 3-fluorophenethyl, 4-fluorophenethyl, 2-fluorophenethyl, 2-thienylethyl, phenylethyl, dihydroindenyl, cohexylethyl, 3-chlorophenethyl, 3-trifluoromethylphenethyl, cyclopentylethyl and tetrahydropyranylethyl; And it is a displacement group selected from F, Cl, Br and I; and R18 is C? alkyl? , benzyl and acetyl. 28.- An intermediate according to the formula (V) wherein: R4 is selected from the group consisting of phenethyl, 3-fluorophenethyl, 4-fluorophenethyl, 2-fluorophenethyl, 2-thienylethyl, phenylethyl, dihydroindenyl, cohexylethyl, 3-chlorophenethyl, 3-trifluoromethylphenethyl, cyclopentylethyl and tetrahydropyranylethyl; And it is a displacement group selected from F, Cl, Br and I; and R18 is C alquilo .2 alkyl, benzyl and acetyl. 29.- An intermediate according to the formula (VI) wherein: R is selected from the group consisting of phenethyl, 3-fluorophenethyl, 4-fluorophenethyl, 2-fluorophenethyl, 2-thienylethyl, phenylethyl, dihydroindenyl, cohexylethyl, 3-chlorophenethyl, 3-trifluoromethylphenethyl, cyclopentylethyl and tetrahydropyranylethyl; And it is a displacement group selected from F, Cl, Br and I; and R18 is C- | 2 alkyl, benzyl and acetyl.