MXPA99008489A

MXPA99008489A - Novel pyridine derivatives and pharmaceutical compositions containing them

Info

Publication number: MXPA99008489A
Application number: MXPA/A/1999/008489A
Authority: MX
Inventors: Cheshire David; Cladingboel David; Hirst Simon; Manners Carol; Stocks Michael
Original assignee: Astra Aktiebolag; Astra Pharmaceuticals Ltd; Cheshire David; Cladingboel David; Hirst Simon; Manners Carol; Stocks Michael
Priority date: 1997-03-25
Filing date: 1999-09-15
Publication date: 2000-01-01

Abstract

A compound of formula (I) wherein:X is O or S;R1 and R2 are independently hydrogen, C1-6 alkyl or C3-6 cycloakyl or R1 and R2 together with the carbon atom to which they are attached form a C3-6 cycloalkyl group;R3 is hydrogen, and R4 is C1-6 alkyl or C3-6 cycloalkyl or R3 and R4 together with the carbon atom to which they are attached form a C3-6 cycloalkyl group. The compounds of the invention are indicated for use in the treatment or prevention of allergic, inflammatory, auto-immune, proliferative and hyper-proliferative diseases.

Description

NOVIDATIVE PIRIDINE DERIVATIVES AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM DESCRIPTION OF THE INVENTION This invention relates to novel pyridyl derivatives, with their use as medicaments, with pharmaceutical formulations that include them and with methods for their preparation. The applications for European Patent EP-A-0 264 114 and EP-A-0 267 439 describe certain phenylalkyl- and phenylalkoxypyridine alkanol derivatives and their use as antagonists of platelet activating factor (PAF). A series of structurally distinct compounds have now been found which are useful for modulation of inflammatory conditions. In a first aspect, the present invention provides, therefore, a compound of formula I: (I) REF .: 31241 where X is 0 or S; R1 and R2 are independently hydrogen, alkyl Cj_6 or cycloalkyl of C3_6, or R1 and R2 together with the carbon atom to which they are attached form a cycloalkyl group of R3 is hydrogen, and R4 is C3_6 alkyl or C3_3 cycloalkyl, or R3 and R4 together with the carbon atom to which they are attached form a cycloalkyl group of C3_6; Ar1 is indanyl, tetrahydronaphthyl, naphthyl, phenyl, C7_9 alkylphenyl or biphenyl, the last four groups which optionally may be substituted by one or more groups selected from halo, nitro, cyano, pyridyl, thiazinyl, C ^^ alkyl. (optionally substituted by one or more fluorine atoms), -Y-OR5, -Y-NR6C (O) NR7R8, -OZC (O) NR7R8, -0-YC (S) NR7R8, -YC (0) NR7R8, - Y-S02NR7R8, -Y-NR7R8, -Y-OC (O) NR7R8, -YC (S) NR7R8, -YC (0) R9, -Y-OC (0) R9, -Y-C02R9, -Y-NR10C (O) NR ?: LZ-R12, SO2NR10C (O) NR7R8, -Y- S02NHNR7R8, -YC (OjNR ^ -Z-R12, -YC (S) NRX1-Z-R12, -YN (R10) S02R1: L -YN (R10) C (O) R?: L or -YN (R10) CO2R11, wherein Y is a bond, C-6 alkylene or alkenylene of C2-6 / * R7 and R8 are independently hydrogen or alkyl CL-S O, together with the nitrogen atom to which they are attached, form an optionally substituted 5- to 7-membered heterocyclic ring, optionally containing an additional heteroatom which is selected from nitrogen, oxygen or sulfur; R5, R5, R9, R10 and R11 are independently hydrogen or CX_1Q alkyl (optionally substituted by one or more fluorine atoms); Z is C1.6 alkylene; and R12 is a group NR10C (O) R11, NR10CO2R11, OR5, NR7R8 or C02R13 wherein R5, R7, R8, R10 and R11 are as defined above and R13 is hydrogen, C1_6 alkyl, C1_6 alkylaryl or optionally substituted aryl by hydroxy, or a salt or solvate thereof. The alkyl, alkylene, alkenyl and alkenylene groups, alone or as part of another group, may be straight or branched chain. Suitably, X is O or S, preferably X is O. Suitably, R1 and R2 are independently hydrogen, C6 alkyl or C3_6 cycloalkyl, or R1 and R2 together with the carbon atom to which they are attached form a cycloalkyl group of C3-6 attached to spiro. Preferably R1 and R2 are hydrogen. Suitably, R3 is hydrogen and R4 is C3_6 cycloalkyl alkyl, or R3 and R4 together with the carbon atom to which they are attached form a cycloalkyl group of C3_6. Preferably R3 is hydrogen and R4 is C1_6 alkyl, in particular methyl, ethyl or isopropyl, or R3 and R4 together with the carbon atom to which they are attached form a cyclopropyl group. Suitably, Ar1 is indanyl, tetrahydronaphyl, naphthyl, phenyl, C7.go.-biphenyl alkylphenyl, the last four groups which may be optionally substituted by one or more groups selected from halo, nitro, cyano, pyridyl, thiazinyl, alkyl of ^^ (optionally substituted by one or more fluorine atoms), -Y-OR5, -Y-NR6C (0) NR7R8, -OZC (O) NR7R8, -OYC (S) NR7R8, -YC (O) NR7R8, -Y-S02NR7R8, -Y-NR7R8, -Y-OC (0) NR7R8, -YC (S) NR7R8, -YC (0) R9, -Y-0C (0) R9, -Y-C02R9, -Y- NR10C (O) NR1: LZ-R12, SO2NR10C (O) NR7R8, -Y-S02NHNR7R8, -YC (0) NR1: LZ-R12, -YC (S) NR ^ -Z-R12, -YN (R10) SOaR11 -YN (Rí0) C (O) Ríl, or -YN (R10) CO2R11; wherein Y is a bond, C ^ .g alkylene or C2.6_6 alkenylene. More than one substituent may be present in the group Ar1 and multiple substituents may be the same or different. Preferably Ar1 is a naphthyl or biphenyl group. Preferred substituents for the Ar1 groups include those groups exemplified herein. More preferably, Ar1 is biphenyl optionally substituted by one or more substituents which are selected from halo, cyano, alkyl or S02NR7R8. More preferably, Ar1 is biphenyl substituted by cyano, halo, methyl or -S02NH2.

Particularly preferred compounds of the invention include those exemplified herein in free base form as well as salts or solvates thereof. The compounds of the invention can form solvates and pharmaceutically acceptable salts. The compounds of formula (I) can form acid addition salts with acids such as conventional pharmaceutically acceptable acids, for example maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, oxalic, mandelic, tartaric acids. and methanesulfonic. The compounds of the invention can also form alkali metal salts such as magnesium, sodium, potassium and calcium salts. Certain compounds of formula (I) are capable of existing in stereoisomeric forms including enantiomers and the invention extends to each of these stereoisomeric forms and mixtures thereof including racemates. The different stereoisomeric forms can be separated from each other by the usual methods, or any given isomer can be obtained by stereospecific or asymmetric synthesis. The invention also extends to any tautomeric form and mixtures thereof. According to the invention, a process for the preparation of compounds of formula I is also provided, which comprises: (a) reduction of a compound of formula (II): (II) wherein R3, R4, X and Ar1 are as defined in formula (I); or (b) reduction of a compound of formula (III): (III) wherein R1, R2, R3, R4, X and Ar1 are as defined in formula (I); or (c) preparation of compounds of formula (I) wherein Ar 1 is a biphenyl group substituted by reaction of a compound of formula (IV): with a compound of formula (V): (V) wherein X, R1, R2, R3 and R4 are as defined in formula (I), R15 is a substituent Ar1 as defined in formula (I), and R16 is a suitable hydroxy protecting group, and one of R17 / R18 is triflate or halo and the other is B (OH) 2 or ZnHal, or and optionally subsequently, in any order: remove any protecting group converting a compound of formula (I) into another compound of formula (I) forming a pharmaceutically acceptable salt or solvate. The reduction of compounds of formula (II) are carried out using conventional procedures, for example by hydrogenation using palladium catalyst in an inert solvent such as ethyl acetate. The reduction of the compounds of formula (III) is carried out using conventional procedures, for example using sodium or zinc borohydride or other reducing agents, in a suitable solvent such as ethanol. Process (c) is carried out under Suzuki reaction conditions (Synthetic Communications 11 (7), 513-519, 1081) for example at about 100 ° C in the presence of a suitable catalyst and a base (for example tetrakis) (triphenylphosphine) palladium (0) and aqueous sodium carbonate) in a suitable solvent (for example ethanol / toluene). The compounds of formula (II) can be prepared by oxidation of a compound of formula (VI): (VI) wherein X, Ar1, R3 and R4 are as defined in formula (I), followed by reaction of the resulting aldehyde with a compound of formula (VII): (VII) wherein M is lithium, sodium, potassium, MgX 'or ZnX1 wherein X' is halogen optionally in the presence of additives such as boron trifluoride. Oxidation of a compound of formula (VI) can be carried out under conventional conditions, for example by oxidation of Swe n. The compounds of formula (VI) can be prepared by reduction of a compound of formula (VIII): (VIII) in which X, Ar1, R3 and R4 are as defined in formula (VI) and R19 is hydrogen, Cx_6 alkyl or benzyl using a suitable reducing agent such as lithium aluminum hydride or diborane. of formula (VIII) can be prepared from compounds of formula (IX): : ??) wherein R19, R3 and R4 are as defined in formula (VIII) and L is a leaving group such as halogen or a group which can be activated to subsequently act as a leaving group, for example hydroxy, with a compound of formula (X) Ar1-OH (X) in which Ar1 is as defined in formula (I).

The reaction is carried out in the presence of a base such as potassium or cesium carbonate in an inert solvent such as dimethylformamide or acetone.

The compounds of formula (VIII) can also be prepared using the chemistry of Mitsonobu using a compound of formula (IX) wherein L is hydroxy. The compounds of formula (IX) are commercially available or can be prepared using standard or conventional methods. For example, when L is hydroxy, the compounds of formula (IX) can be prepared by diazotization of commercially available amino acids. The compounds of formula (IX) wherein R19 is hydrogen or Cx_6 alkyl and one of R3 / R4 is hydrogen and the other is methyl, are available as lactic acid or esters thereof. The compounds of formula (IV) are prepared from a compound of formula (XI): wherein R1, R2, R3, R4 and R16 are as defined above, by reaction with a compound of formula (XII): (XII) wherein R17 is triflate or halogen, The reaction is carried out under the conditions of the Mitsonobu reaction, for example at about 0-25 ° C in the presence of diethyl azodicarboxylate and triphenylphosphine, in an appropriate solvent (for example toluene) . The compounds of formula (XI) can be prepared by reduction of a compound of formula (XIII) using conventional procedures, for example hydrogenation using a palladium catalyst in an inert solvent such as ethyl acetate, followed by debenzylation using conventional methods such as those described in "Protective Groups in Organic Synthesis", 2nd edition, TW Greene & P.G.M. Wuts, Wiley-Interscience (1991).

(XIII) The compounds of the formula (XIII) can be prepared by reaction of the compound (XIV) in which R3 and R4 are as defined in the formula (I) reported by Reetz et al.

Angew. Chem. Suppl. , (1983), 1511.) with a compound of formula (VII): (XIV) in which R .33 and Rt, 44 is as defined in the formula (I) The compounds of formula (I) can be converted to additional compounds of formula (I) using standard procedures. For example, compounds of formula (I) wherein the group Ar 1 is substituted by bromine, can be converted to compounds of formula (I) wherein the group Ar 1 is substituted by -CH = CH-R 20 wherein Y is CH = CH and R20 is a group -NR6C (0) NR7-R8, -C (0) NR7R8, -NR7R8, -C (0) OR9, -NR10C (0) NRX1-Z-R12 or -C (0) NRX1- Z-R12 wherein Rs, R7, R8, R9, R10, R11 and R12 are as defined in formula (I) when reacting with compounds of formula (XV): H2C = CH- R2 (XV) where R20 is as defined above, using Heck chemistry. For example, compounds of formula (I) wherein Ar 1 is naphthyl substituted by bromine or iodine, can be treated with palladium catalyst and a compound of formula (XV) in a suitable solvent at elevated temperature. If desired, the palladium catalyst can be formed in situ. The resulting compounds of formula (I) prepared using the above chemistry can be converted to additional compounds of formula (I) by reduction of the double bond of the group -CH = CH-R20. This can be carried out under standard hydrogenation conditions, for example using palladium on activated carbon. Other methods for transforming compounds of formula (I) into additional compounds of formula (I) will be apparent to those familiar in the art. For example, compounds of formula (I) containing a group -YC (0) OR9 wherein R1 is methyl, can be converted to compounds of formula (I) having a -YC (0) NHMe group by treating them with methylamine in methanol at elevated temperature. Preferably, the reaction is carried out at approximately 100 ° C in a sealed container. The same transformation can be carried out using trimethylaluminium and methylamine hydrochloride in toluene at reduced temperature, for example at about 0 ° C. The compounds of formula (I) which contain a group -Y-C (0) OR 9 can also be converted to the corresponding carboxylic acids by hydrolysis. Preferred conditions include treatment with lithium hydroxide in a suitable solvent system, for example in water / THF at room temperature. The compounds of formula (I) which contain a group -Y-C (0) OH can also be converted to compounds of formula (I) having a group -Y-C (0) NR7R8 by reacting with the appropriate amine. For example, amines of the formula HNR7R8 can be reacted in a suitable solvent such as DMF in the presence of 1-hydroxybenzotriazole and l-ethyl-3- (3'-dimethylaminopropyl) -carbodiimide. Compounds of formula (I) containing a -Y-C (0) R7R8 group can be converted to compounds of formula (I) having a -Y-NR7R8 group by treating them with a borane / tetrahydrofuran complex. An alternative synthesis of compounds of formula (II) is via (a) selective reduction of compounds of formula (XVI): (? V?: wherein R3, R4, X and Ar1 are as defined in formula (I). Suitable reducing agents include sodium borohydride or zinc borohydride (Tetrahedron Lett., (1985), 26, 4463). The triple bond in the compounds of formula (XVI) can also be reduced to form compounds of formula (III) using conventional procedures, for example hydrogenation using a palladium catalyst in an inert solvent such as ethyl acetate. The compounds of formula (XII) can be prepared by reacting a compound of formula (VIII) as defined above with a compound of formula (VII) as defined above. The intermediates described above are prepared as described above, are commercially available, or can be conveniently prepared using known techniques. Certain intermediate compounds are novel and form a further aspect of the invention. It will be appreciated by those familiar with the art that in the process described above, the functional groups of the intermediate compounds do not need to be protected by protecting groups. The functional groups which it is desirable to protect include hydroxy, amino and carboxylic acid. Suitable protecting groups for hydroxy include organosilyl groups (for example tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), benzyl and tetrahydropyranyl. Suitable protecting groups for amino include tert-butoxycarbonyl or benzyloxycarbonyl. Suitable protecting groups for carboxylic acid include alkyl or benzyl esters. The protection and deprotection of functional groups can be carried out before or after a reaction step. The use of protective groups is fully described in "Protective Groups in Organic Chemistry", edited by J. W. F. McOmie, Plenum Press (1973), and "Protective Groups in Organic Synthesis ", 2nd edition, T. W. Greene &P. G.

M. Wutz, Wiley-Interscíence (1991). The compounds of the invention are useful because they possess pharmacological activity and more particularly activity in the modulation of inflammatory and allergic conditions, for example as shown in the test described below. The compounds of the invention inhibit the activation of a range of cell types of the hematopoietic line including pluripotent, neutrophil and eosinophil cells. In a further aspect, the invention therefore provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in therapy. The compounds of the invention are indicated for use in the treatment or prevention of allergic, inflammatory, autoimmune, proliferative and hyperproliferative diseases. The compounds of the invention are also indicated in the treatment and prevention of allergic, inflammatory or autoimmune conditions of the lung, including diseases of reversible obstructive airways which include asthma (for example bronchial, allergic, intrinsic asthma, extrinsic and chronic asthma), and associated manifestations of the disease (late responses, hyperresponsiveness), also farmer's lung diseases and related diseases, fibrosis, idiopathic interstitial pneumonia, chronic obstructive airways disease (COPD), brochiectasis, cystic fibrosis, eosinophilic pneumonias, adult respiratory distress syndrome (ARDS), emphysema and alveolitis, for example cryptogenic fibrosing alveolitis. In addition, the compounds of the invention are indicated in the treatment or prevention of allergic, inflammatory or autoimmune conditions in the nose that include all conditions characterized by inflammation of the nasal mucous membrane such as acute rhinitis, allergic rhinitis, atrophic rhinitis, chronic rhinitis that includes caseosa, hypertrophic rhinitis, purulent rhinitis and dry rhinitis, rhinitis medicamentosa, membranous rhinitis including croup, fibrinous and pseudomembranous rhinitis, scrofulous rhinitis, seasonal rhinitis including rhinitis nervosa (hay fever) and vasomotor rhinitis. Of particular interest are allergic rhinitis and seasonal rhinitis that includes rhinitis nervosa (hay fever). The compounds are also indicated for the treatment of nasal polyps and allergic manifestations of the nasopharynx different from those described above. The compounds of the invention are also indicated in the treatment or prevention of allergic, inflammatory or autoimmune conditions of the eye such as conjunctivitis (allergic, acute, vernal, hay fever, chronic), inflammation disorders of the eyelids, cornea, tract uveal and retina. The compounds of the invention are also indicated in the treatment and prevention of allergic, inflammatory and autoimmune conditions of the gastrointestinal tract such as food allergy and food intolerance, ulcerative colitis, Crohn's disease, irritable bowel disease, gastric ulcers and allergic diseases related to food which have symptomatic manifestations far from the gastrointestinal tract, for example migraine, rhinitis and eczema. The compounds of the invention are indicated for use in the treatment or prevention of allergic, inflammatory or autoimmune conditions of the skin such as psoriasis, atopic dermatitis, contact dermatitis / herpeiform dermatitis, erythema nodosum, urticaria, cutaneous eosinophilia, acne, alopecia areata, eosinophilic fasciitis dermatomyositis, photoallergic sensitivity and periodontal disease. Therefore, the compounds of the invention are indicated for use in the treatment or prevention of allergic, inflammatory or autoimmune conditions of the joints and connective tissue including osteoarthritis, rheumatoid arthritis, systemic lupus erythematosus, vasculitis, Wegener's granulomatosis, polyarthritis nodosa , bursitis, tendonitis, gout, Behcet's syndrome, ankylosing sponditis, Reiter's syndrome and psoriatic arthritis. The compounds of the invention are indicated in the treatment and prevention of allergic, inflammatory and autoimmune conditions of the circulatory system including atheroma, reperfusion damage (for example in angioplasty), myocardial infarction, thrombosis and vascular and tissue damage caused by ischemic disease. or damage. The compounds of the invention are indicated in the treatment and prevention of allergic, anti-inflammatory or autoimmune conditions of the CNS which include Parkinson's disease, Alzheimer's disease or other dementias, attack and subarachnoid hemorrhage. The compounds of the invention are indicated in the treatment and prevention of inflammatory conditions of the liver, for example hepatitis, cirrhosis and glomerulonephritis. The compounds of the invention are indicated in the treatment and prevention of allergic, inflammatory and autoimmune conditions of the bladder and the urogenital tract including cystitis. The compounds of the invention are indicated in the treatment and prevention of tumors and other proliferative diseases. Of particular interest among the above indications is the use of the compounds of the invention in a reversible obstructive airway disease, more particularly asthma, and especially the treatment and prophylaxis of rhinitis asthmaand.

According to a further aspect of the invention there is provided the use of a compound of formula I, as defined above or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment of the above diseases, in Particular reversible obstructive airway disease, especially the treatment and prophylaxis of asthma. The administration of the compounds of the invention can be topical (for example by inhalation to the lung). The compounds of the invention can be inhaled as a dry powder which can be pressurized and non-pressurized. In the non-pressurized powder compositions, the active ingredient is in finely divided form and can be used in admixture with a larger pharmaceutically acceptable inert carrier. The composition can alternatively be pressurized and contain a compressed gas, for example nitrogen, or a liquefied gaseous propellant. In such pressurized compositions, the active ingredient is preferably finely divided. The pressurized composition may also contain a surfactant. The pressurized compositions can be made by conventional methods. The compounds of the invention can be administered systemically (for example by oral administration to the gastrointestinal tract). The active ingredient can be formulated together with known adjuvants, diluents or carriers using conventional techniques to produce tablets or capsules for oral administration to the gastrointestinal tract. Examples of suitable adjuvants, diluents or carriers for oral administration in the form of tablets, capsules and lozenges include microcrystalline cellulose, calcium phosphate, diatomaceous earth, a sugar such as lactose, dextrose or mannitol, talc, stearic acid, starch, bicarbonate. of sodium and / or gelatin. According to a further aspect of the invention, there is provided a pharmaceutical composition which includes a compound of formula I or a salt or solvate thereof as defined above, in association with a pharmaceutically acceptable adjuvant, diluent or carrier. Suitable doses for such oral administration are in the range of 0.3 to 30 mg / kg "1 day" 1, for example 3 mg kg "1 day" 1. According to a further aspect of the present invention, there is provided a method of treatment or prophylaxis of a reversible obstructive airway disease, in particular asthma, which method comprises administering a therapeutically effective amount of a compound of formula I as is defined in the above or a pharmaceutically acceptable derivative thereof to a person suffering from, or who is susceptible to, the disease.

The invention is illustrated by the following examples.

Example 1 (3R, 4R) -4- (biphenyl-4-yloxy) -l-pyridin-3-yl-pentan-3-ol 3 (3S.4R) -4- (biphenyl-4-yloxy) -l-pyridine- 3-ilpentan-3 -ol a) [2R) -2- (biphenyl-4-yloxy) propionic acid ethyl ester Diethylazodicarboxylate (8.66 ml) in dry tetrahydrofuran (25 ml) is added dropwise over 30 minutes to a stirred solution of triphenylphosphine (13.11 g), (S) - (-) -ethyl lactate (5.67 ml) and 4-phenylphenol ( 8.51 g) in dry tetrahydrofuran (100 ml). The resulting solution is stirred at room temperature for 18 hours and then concentrated under reduced pressure. A solution of isohexanorheter (9: 1) (200 ml) is added to the residue and stirred at room temperature for 30 minutes. The solution is filtered and the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography on silica eluting with isohexane: dichloromethane (2; 3) to give the subtitle compound as an oil (11.79 g). ? E NMR (CDC13) 7.55-7.47 (4H, m); 7.43-7.38 (2H, m); 7.32-7.25 (1H, m); 6.97-6.92 (2H, m); 4.78 (1H, c); 4.24 (2H, c); 1.64 (3H, d); 1.26 (3H, t). b) (2R) -2- (biphenyl-4-yloxy) propan-l-ol Lithium aluminum hydride (86.67 ml, 1.0 M solution in tetrahydrofuran) is added dropwise to a stirred solution of (2R) -2- (biphenyl-4-yloxy) propanoic acid ethyl ester (11.79 g, example a) in dry tetrahydrofuran (200 ml) at 0 ° C. The resulting solution is stirred at room temperature under nitrogen for 3 hours. Water (3.3 ml) is added to the solution at 0 ° C, then aqueous sodium hydroxide (50% solution, 3.3 ml) and then water (9.9 ml) with caution.

Diethyl ether (200 ml) and anhydrous magnesium sulfate (20 g) are added and the solution is stirred at room temperature for 20 minutes. The solution is filtered and the filtrate is concentrated under reduced pressure to provide the subtitle compound as a solid (9.43 g). p.f. 76-77.6 ° C EM (El) 228 (M) +? NMR (CDCl 3) 7.56-7.49 (4H, m); 7.39 (2H, t); 7.33-7.28 (1H, m); 7.03-6.98 (2H, m); 4.57-4.52 (1H, m); 3.83-3.69 (2H, m); 2.02 (1H, dd); 1.31 (3H, d). The subtitle compound can also be prepared as follows: A suspension of 4-biphenol (3.4 g), acid (S) - (+) -2-bromopropionic (3.06 g) and potassium carbonate (5.52 g) in acetone (50 ml) is heated at reflux for 3 hours before being cooled and concentrated under reduced pressure. The residue is partitioned between water (100 ml) saturated aqueous sodium carbonate acid solution (50 ml) and ether (100 mi) The organic phase is separated and the aqueous phase is acidified with 2 M hydrochloric acid and extracted with ethyl acetate (3 x 50 mL). The combined organic extracts are dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residual white solid is immediately dissolved in tetrahydrofuran (50 ml) and cooled to 0 ° C.

Then a solution of lithium aluminum hydride (1 M in diethyl ether, 20 ml) is added dropwise. The reaction is allowed to warm to room temperature and stir during 1 hour before cooling down to 0 ° C. Water (0.75 ml) is added with caution followed by the sodium hydroxide solution (50% w / v, 0.75 ml) and a second aliquot of water (2 mi) The resulting mixture is stirred at room temperature for 30 minutes and then dried over anhydrous magnesium sulfate (10 g), filtered and concentrated to give the subtitle compound (1.44 g) as a solid, m.p. 66-69 ° C MS (APCI) 229 (M + H) *? NMR (CDC13) 7.56-7.50 (4H, m); 7.42 (2H, t); 7.31 (1H, t); 7.01 (2H, d); 4.58-4.51 (1H, m); 3.77-3.71 (2H, m); 2.03 (1H, broad); 1.31 (3H, d). c) (2R, 3SR) -4- (biphenyl-4-yloxy) -l-pyridin-3-yl-pent-4-in-3-ol Oxalyl chloride (1.4 ml) is added dropwise to a solution of dimethyl sulfoxide (1.70 ml) in dry dichloromethane (60 ml) at -60 ° C, dropwise. The resulting solution is stirred for 20 minutes and then a solution of (2R) -2- (biphenyl-4-yloxy) -1-propanol (2.88 g, Example Ib) in dry dichloromethane (20 ml) is added dropwise. The mixture is stirred for an additional 30 minutes and then triethylamine (11.2 ml) is added dropwise. The mixture is allowed to reach room temperature with stirring for 1 hour. The mixture is diluted with anhydrous ether (100 ml), filtered and concentrated under reduced pressure. The residue is dissolved in dry tetrahydrofuran (20 ml) and added to a solution of l-lithium-2-pyridin-3-ylacetylene [generated by the addition of n-butyllithium (2.5 M in hexanes, 4.4 ml) to a solution of 3-pyridylacetylene (1.04 g) (J. Amer. Chem. Soc. 1935, 57, 1284) in tetrahydrofuran (40 ml) at -60 ° C with stirring for 20 minutes]. The mixture is stirred for 1 hour at -60 ° C and then allowed to warm to room temperature for 2 hours. The mixture is poured into a saturated solution of ammonium chloride (100 ml) and extracted with ethyl acetate (3 x 100 ml). The combined organic extracts are dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by column chromatography on silica eluting with ethyl acetate: hexane (1: 4) and then ethyl acetate to give the subtitle compound as a solid as a 4: 1 mixture of diastereomers (2.18 g). MS (APCI) 330 (M + H) + XH NMR (CDC13, major diastereomer) 8.72 (1H, dd); 8.55 (1H, dd); 7.76-7.72 (1H, m); 7.55-7.52 (4H, m); 7.44 (2H, t); 7.34-7.26 (2H, m); 7.07-7.04 (2H, m); 4.86-4.83 (1H, m); 4.67-4.64 (1H, m); 2.78 (1H, d); 1.51 (3H, d). d) (2R, 2RS) -2- (biphenyl-4-yloxy) -5-pyridin-3-yl-pentan-3-ol Dissolve (2R, 3RS) -2- (biphenyl-4-yloxy) -5-pyridin-3-yl-pent-4-yn-3-ol (4.86 g, example le) in ethyl acetate (100 ml) and hydrogenated at 5 atmospheres using 10% palladium on activated carbon (0.5 g) as a catalyst. The mixture is filtered through Celite "and the filtrate is concentrated under reduced pressure to provide the title compounds (3.95 g) .The diastereomers are separated by CLAP in the normal phase eluting with isopropanol: dichloromethane (1: 20) to provide the Title compounds The product (3R, 4R) is recrystallized from ethyl acetate: isohexane (1: 4) to provide (3R, 4R) -4- (biphenyl-4-yloxy) -l-pyridin-3. il-pentan-3-ol as a solid (0.25 g) p.f. 98-99.5 ° C MS (APCI) 334 (M + H) + 'H NMR (CDC13) 8.52 (1H, d); 8.46 (1H, dd); 7.57-7.50 (5H, m); 7. 41 (2H, t); 7.33-7.31 (1H, m); 7.24-7.21 (1H, m); 6.97 (2H, d); 4.28 (1H, quintet); 3.68-3.64 (1H, m); 2.96-2.89 (1H, m); 2. 83-2.76 (1H, m); 2.51 (1H, d); 1.90-1.83 (2H, m); 1.29 (3H, d).

Recrystallize (3S, 4R) -4- (biphenyl-4-yloxy) -1-pyridin-3-yl-pentan-3-ol (main diastereomer) from ethyl acetate: isohexane (1: 1) to provide the title compound as a solid (2.23 g). p.f. 121.5-123 ° C MS (APCI) 334 (M + H) +? E NMR (CDC13) 8.51 (1H, d); 8.46 (1H, dd); 7.57-7.49 (5H, m); 7. 42 (2H, t); 7.39-7.33 (1H, m); 7.26-7.22 (1H, m); 6.94 (2H, d); 4.40-4.37 (1H, m); 3.89-3.85 (1H, m); 3.0-2.95 (1H, m); 2. 76-2.71 (1H, m); 2.28 (1H, d); 1.89-1.81 (2H, m); 1.31 (3H, d).

Example 2 (3R74S) -4- (biphenyl-4-yloxy) -l-pyridin-3-yl-pentan-3-yl and (3S, 4S) -4- (biphenyl-4-yloxy) -l-pyridin-3- il-pentan-3-ol 2S) -2- (biphenyl-4-yloxy) propanoic acid ethyl ester Prepared according to the method described in example la) from diethylazodicarboxylate (6.74 ml), triphenylphosphine (13.11 g), lactate (R) - (+) - ethyl (5.67 ml) and 4-phenylphenol (8.51 g) ) in dry tetrahydrofuran (125 ml). The residue which is obtained after the treatment is purified by column chromatography on silica eluting with isohexane: dichloromethane (2: 3) to give the subtitle compound as an oil (11.3 g). EM (El) 270 (M) +? NMR (CDC13) 7.55-7.47 84H, m); 7.43-7.38 (2H, m); 7.32-7.25 (1H, m); 6.97-6.92 (2H, m); 4.78 (1H, c); 4.24 (2H, c); 1.64 (3H, d); 1.26 (3H, t). (2S) -2- (biphenyl-4-yloxy) propan-l-ol is prepared according to the method described in example Ib) from lithium aluminum hydride (41.9 ml, solution 1. OM in ether) and a solution of (2S) -2- (biphenyl-4-yloxy) propanoic acid ethyl ester (11.3 g, example 2a)) in dry tetrahydrofuran (200 ml) at 0 ° C. The subtitle compound obtained after the treatment is used directly without further purification (9.52 g). p.f. 75-78 ° C MS (El) 228 (M) + XH NMR (CDC13) 7.56-7.49 (4H, m); 7.39 (2H, t); 7.33-7.28 (1H, m); 7.03-6.98 (2H, m); 4.57-4.52 (1H, m); 3.83-3.69 (2H, m); 2.04-1.99 (1H, dd); 1.31 (3H, d). c) (3RS, 4S) -4- (biphenyl-4-yloxy) -l-pyridin-3-yl-pent-4-in-3-ol Prepared according to the method described in example le) from (2S) -2- (biphenyl-4-yloxy) -1-propanol (2.88 g, example 2b), oxalyl chloride (1.4 ml), sulfoxide of dimethyl (1.70 ml), triethylamine (11.18 ml), 3-pyridylacetylene (1.04 g) and n-butyl lithium (2.5M in hexanes, 4.4 ml) to provide the subtitle compound as a cream solid and as a 4: 1 mixture. of diastereomers (2.13 g). MS (APCI) 330 (M + H) *? R NMR (CDC13, major diastereomer) 8.72 (1H, dd); 8.55 (1H, dd); 7.76-7.72 (1H, m); 7.55-7.52 (4H, m); 7.44 (2H, t); 7.34- 7.26 (2H, m); 7.07-7.04 (2H, m); 4.86-4.83 (1H, m); 4.67-4.64 (1H, m); 2.78 (1H, d); 1.51 (3H, d). d) (3RS, 4S) -4- (biphenyl--yloxy) -l-pyridin-3-yl-pentan-3-ol.

Prepared according to the method described in Example Id) from (3S, 3RS) -2- (biphenyl-4-yloxy) -5-pyridin-3-yl-pent-4-yn-3-ol ( 4.16 g, example 4c)), 10% palladium on activated carbon (0.5 g) in ethyl acetate (100 ml) to provide the subtitle compound as a white solid and as a 4: 1 mixture of diastereomers (4.13 g). The diastereomers are prepared by CLAP in the normal phase eluting with isopropanol: dichloromethane (1:20) to provide the title compounds. Recrystallize (3S, 4S) -4- (biphenyl-4-yloxy) -1-pyridin-3-yl-pentan-3-ol (minor diastereomer) from ethyl acetate: isohexane (1: 4) to provide the title compound as a solid (0.352 g) p.f. 102.5-103.5 ° C MS (APCI) 334 (M + H) + R NMR (CDC13) 8.52 (1H, d); 8.46 (1H, dd); 7.57-7.50 (5H, m); 7. 41 (2H, t); 7.33-7-31 (1H, m); 7.24-7.21 (1H, m); 6.97 (2H, d); 4.28 (1H, quintet); 3.68-3.64 (1H, m); 2.96-2.89 (1H, m); 2. 83-2.76 (1H, m); 2.52 (1H, d); 1.90-1.83 (2H, m); 1.29 (3H, d).

Recrystallize (3R, 4S) -4-biphenyl-4-yloxy) -1-pyridin-3-yl-pentan-3-ol (main diastereomer) from ethyl acetate: isohexane (1: 1) to provide the compound of the title as a solid (1.76 g). p.f. 123.5-124 ° C MS (APCI) 334 (M + H) + XH NMR (CDCl 3) 8.51 (1H, d); 8.46 (1H, dd); 7.57-7.49 (5H, m); 7.42 (2H, t); 7.39-7.33 (1H, m); 7.26-7.22 (1H, m); 6.94 (2H, d); 4.40-4.37 (1H, m); 3.89-3.85 (1H, m); 3.0-2.95 (1H, m); 2.76-2.71 (1H, m); 2.24 (lH, d); 1.89-1.81 (2H, m); 1.31 (3H, d).

Example 3 (3R, 4S) -4- (biphenyl-4-yloxy) -l-pyridin-3-yl-pentan-3-ol via diastereomeric esters a) Ester 2 - (bifenyl-4-yloxy) -1- (2-pyridin-3-ylethyl) propylic acid (2S) -methoxyphenylacetic acid Solid (S) - (+) -a-methoxyphenylacetic acid (0.25 g), 4-dimethylaminopyridine (0.18 g) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.29 g) are added to a solution of ( 3RS, 4S) -4- (biphenyl-4-yloxy) -1-pyridin-3-yl-pentan-3-ol (0.44 g, example 2c) in dry dichloromethane (30 ml). The reaction is stirred at room temperature for 20 hours and then concentrated under reduced pressure. The residue is purified by chromatography on silica eluting with ethyl acetate: hexane (2: 1) to give the subtitle compound as an oil (0.44 g). MS (APCI) 482 (M + H) +? NMR (CDC13) 8.40 (1H, d); 8.11 (1H, d); 7.56-7.48 (6H, m); 7.48-7.37 (6H, m); 7.15-7.12 (2H, m); 6.92 (2H, d); 5.18-5.02 (1H, m); 4.76 (1H, s); 4.52 (1H, dc); 3.41 (3H, s); 2.22-2.11 (2H, m); 1.97-1.9 (2H, m); 1.30 (3H, d). b) (3R, 4S) -4-biphenyl-4-yloxy) -l-pyridin-3-yl-pentan-3-ol Water (1 mL) and lithium hydroxide (0.063 g) are added to a solution of the (2S, 3R) -4- (biphenyl-4-yloxy-1-pyridin-3-yl-pent-3-yl ester of the acid. (S) -a-methoxyphenylacetic acid (0.44 g) in methanol (5 ml) and the resulting solution is stirred at room temperature for 4 hours.The mixture is concentrated under reduced pressure and the residue is partitioned between ethyl acetate (10 ml) and water (10 mL) The organic layer is separated and the aqueous layer is extracted with ethyl acetate (2 x 10 mL) The combined organic extracts are dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue is recrystallized from ethyl acetate: hexane (1: 3) to provide the title compound as a solid (0.21 g) mp 122-123 ° C MS (APCI) 334 (M + H) + XH NMR (CDC13 ) 8.52 (1H, d), 8.46 (1H, d), 7.57-7.50 (5H, m), 7.43 (2H, t), 7.33 (1H, t), 7.23 (1H, dd), 6.97 (2H, d), ), 4.39 (1H, cd), 3.88-3.86 (1H, m), 2.96-2.92 (1H, m), 2.78-2.72 (1H, m), 2.05 (1H, broad); 1.89-1.83 (2H, m); 1.31 (3H, d).

Example 4 (1S, 2R) -4 • - (2-hydroxy-l-methyl-4-pyridin-3-ylbutoxy) biphenyl-3'-carbonitrile and (1S, 2S) -4 • - (2-hydroxy-1-methyl- 4-pyridin-3-ylbutoxy) biphenyl-3-carbonitrile a) (2S) -2- (4-bromophenoxy) propionic acid ethyl ester Prepared according to the method described in example la) from diethylazodicarboxylate (6.7 ml), triphenylphosphine (13.11 g), lactate of (R) - (+) - ethyl (5.67 ml) and 4-bromophenol (8.65 g) ) in dry tetrahydrofuran (125 ml). The residue which is obtained after the treatment is purified by column chromatography on silica eluting with isohexane: dichloromethane (2: 3) to give the subtitle compound as an oil (12.2 g). XK NMR (CDC13) 7.36 (2H, d); 6.75 (2H, d); 4.69 (1H, c); 4.20 (2H, C); 1.61 (3H, d); 1.25 (3H, t). b) (2S) -2- (4-bromophenoxy) propan-1-ol Sodium borohydride (1.15 g) is added to a solution of (2S) -2- (4-bromophenoxy) propionic acid ethyl ester (7.5 g, example 4a)) in ethanol (20 ml) at 5 ° C. Allow the resulting solution to reach room temperature and stir for 10 hours before concentrating under reduced pressure. The residue is partitioned between ethyl acetate (100 ml) and 2M hydrochloric acid (50 ml). The mixture is extracted into ethyl acetate and the combined extracts are dried over anhydrous magnesium sulfate., they are filtered and concentrated under reduced pressure. The product is used directly in the next step without further purification (6.32 g). MS (El) 230, 232 (M) +? R NMR (CDC13) 7.39 (2H, d); 6.83 (2H, d); 4.50-4.41 (1H, m); 3.77-3.70 (2H, m); 1.93 (1H, broad); 1.26 (3H, d). c) (3RS, 4R) -4- (4-bromophenoxy) -l-pyridin-3-yl-pent-l-in-3-ol Prepared according to the method described in example le) starting from dd (2S) -2- (4-bromophenoxy) propan-l-ol (9.24 g, example 4b)), oxalyl chloride (4.38 ml), sulfoxide of dimethyl (4.4 ml), triethylamine (22.4 ml), 3-pyridylacetylene (6.3 g) and n-butyllithium (2.5 M in hexanes, 24 ml), to provide the subtitle compound as an oil and as a 4.1 mixture of diastereomers (8.31 g). MS (APCI) 332, 334 (M + H) + 1 H NMR (CDC13, major diastereomer) 8.73 (1H, d); 8.53 (1H, dd); 7.74-7.70 (1H, m); 7.39 (2H, d); 7.29-7.24 (1H, m); 8.67 (2H, d); 4.82-4.78 (1H, m); 4.57-4.53 (1H, m); 3.43 (1H, broad); 1.45 (3H, d). d) (3RS, 4R) -4- (4-bromophenoxy) -l-pyridin-3-yl-pentan-3-ol.

Prepared according to the method described in Example Id) from (3RS, 4R) -4- (4-bromophenoxy) -l-pyridin-3-yl-pent-4-yn-3-ol (7.0 g , example 4c)) and 5% rhodium in activated carbon (1.0 g) in ethyl acetate (100 ml) to provide the subtitle compound as an oil and as a 4: 1 mixture of diastereomers (5.6 g). MS (APCI) 336, 338 (M + H) + 2 H NMR (CDC13, major diastereomer) 8.50 (1H, d), -8.45 (1H, dd); 7.54 (1H, dt); 7.37 (2H, d); 7.22 (1H, dd); 6.76 (2H, d); 4.30-4.27 (1H, m); 3.82 (1H, p); 2.94-2.89 (1H, m); 2.77-2.70 (1H, m); 2.18 (1H, broad); 1.86-1.78 (2H, m); 1.26 (3H, d). e) (1R, 2R) -4'- (2-hydroxy-l-methyl-4-pyridin-3-ylbutoxy) biphenyl-3-carbonitrile and (IR, 2S) -4 '- (2-hydroxy-l- methyl-4-pyridin-3-ylbutoxy) biphenyl-3-carbonitrile Refluxing for 3 hours a solution of (3RS, 4R) -4- (4-bromophenoxy) -l-pyridin-3-yl-pentan-3-ol (1.0 g, example 4d)), 3-cyanobenzanboronic acid (0.74 g), an aqueous solution of carbonate sodium 2M (5 ml) and tetrakis (triphenylphosphine) palladium (0) (0.1 g) in toluene (25 ml) and ethanol (5 ml). The reaction mixture is cooled and poured into water (100 ml) and extracted into ethyl acetate. The mixture is extracted into ethyl acetate (3 x 50 mL) and the combined extracts are dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to provide the subtitle compound as an oil and as a 4: 1 mixture. diastereomers (0.86 g). The diastereomers are separated by CLAP in the normal phase eluting with isopropanol: dichloromethane (1:33) to provide the title compounds: (1S, 2S) -4 '- (2-hydroxy-l-methyl-4-pyridin-3-ylbutoxy) biphenyl-3-carbonitrile (minor diastereomer) as an oil (0.22 g). MS (APCI) 359 (M + H) + XH NMR (CDC13) 8.51 (1H, d); 8.47 (1H, d); 7.82 (1H, s); 7.76 (1H, dt); 7.60-7.48 (5H, m); 7.25-7.21 (1H, m); 7.10 (2H, d); 4.30 (1H, p); 3.72-3.64 (1H, m); 2.99-2.90 (1H, m); 2.84-2.74 (1H, m); 2.44 (1H, d); 1.91-1.84 (2H, m); 1.30 (3H, d). (1S, 2R) -4 '- (2-hydroxy-l-methyl-3-pyridin-3-ylbutoxy) biphenyl-3-carbonitrile (main diastereomer) as an oil (0.52 g).

MS (APCI) 359 (M + H) + XH NMR (CDCl 3) 8.51 (1H, d); 8.47 (1H, d); 7.82 (1H, s); 7.76 (1H, dt); 7.60-7.48 (5H, m); 7.25-7.21 (1H, m); 7.10 (2H, d); 4.42-4.39 (1H, m); 3.88-3.82 (1H, m); 3.01-2.90 (1H, m); 2.84-2.74 (1H, m); 2.20 (1H, d); 1.88-1.84 82H, m); 1.32 (3H, d).

Example 5 Amide of (1S, 2R) -4- (2-hydroxy-l-methyl-4-pyridin-3-yl-butoxy) -biphenyl-3-sulfonic acid and (1S, 2S) -4- (2 -hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -biphenyl-3-suphonic a) (3RS, 4S) -3- [4- (4-bromophenoxy) -3- (tert-butyldimethyl-silanyloxy) pentyl] pyridine.

To a solution of (3RS, 4S) -4- (4-bromophenoxy) -1-pyridin-3-yl-pentan-3-ol (2.0 g, example 4d)) in dry dichloromethane (50 ml) is added tert-butyldimethylsilyl (1.17 g) and imidazole (1.08 g) and the resulting solution is stirred for 24 hours, concentrated and the residue purified by chromatography on silica gel eluting with ethyl acetate: hexane (1: 4 to 1.1) to provide the subtitle compound as an oil (2.52 g). MS (APCI) 450.1, 452.1 (M + H) + E NMR (CDCl 3, main diastereomer) 8.45-8.42 (2H, m); 7.4 (1H, dt); 7.35 (2H, d); 7.22-7.18 81H, m); 6.73 (2H, d); 4.23-4.20 (1H, m); 3.82-3.78 (1H, m); 2.84-2.62 (2H, m); 1.96-1.88 (1H, m); 1.82-1.78 (1H, m); 1.27 (3H, d); 0.94 (9H, s); 0.12 (3H, s); 0.09 (3H, s). b) (1S, 2RS) -4- [2- (tert-Butyldimethylsilanyloxy) -1-methyl-4-pyridin-3-ylbutoxy] benzeneboronic acid A solution of tert-butyllithium (2.5 ml, 1.7M in hexanes) is added over a period of 1 hour to a solution of (2S, 3RS) -2- (4-bromophenoxy) -3-tert-butyldimethylsilyloxy-5-pyridine. 3-ylpentane (1.60 g, example 5b)) and triisopropylborate (1.07 ml) in tetrahydrofuran (25 ml) at -78 ° C. The resulting solution is stirred at -78 ° C for 2 hours and then suspended by the addition of a saturated solution of ammonium chloride in water (50 ml). The mixture is poured into water (50 ml) and extracted into ethyl acetate (2 x 50 ml). The combined extracts are dried over anhydrous magnesium sulfate, filtered and concentrated. The residue is purified by chromatography on silica eluting with ethyl acetate and then with ethyl acetate: methanol (4: 1) to give the subtitle compound as a foam (1.2 g). XH NMR (CDC13 major diastereomer) 8.60-8.53 (2H, m); 7.95 (2H, d); 7.6-7.54 (1H, m), 7.26-7.22 (1H, m); 6.86 (2H, d); 4.33-4.27 (1H, m); 3.93-3.86 (1H, m); 2.82-2.62 (2H, m); 1.98-1.75 (2H, m); 1.28 (3H, d); 0.94 (9H, s); 0.08 (6H, s). c) (1S, 2R) -4 '(2-hydroxy-l-methyl-4-pyridin-3-ylbutoxy) biphenyl-3-sulfonic acid amide and (1S, 2S) -4' (2- hydroxy-l-methyl-4-pyridin-3-ylbutoxy) biphenyl-3-sulfonic acid Prepared according to the method described in Example 4e) from (1S, 2RS) -4- [2- (tert-butyldimethyl-silanyloxy) -l-methyl-4-pyridin-3-ylbutoxy] -benzanboronic acid (1.9 g) , example 5b)), 3-bromobenzenesulfonamide (1.62 g), a solution of 2M sodium carbonate (5 ml) and tetrakis (triphenylphosphine) -palladium (0) (0.1 g) in toluene (25 ml) and ethanol (5 ml) ). The reaction is refluxed for 3 hours. The solvent is concentrated in vacuo and the residue is redissolved in methanol (5 ml) and concentrated hydrochloric acid (1 ml) is added.

After 16 hours the mixture is again evaporated and treated as described in example 4e) to provide the subtitle compounds as a mixture of diastereomers (1.62 g); The diastereomers are separated by CLAP in the normal phase eluting with isopropanol: dichloromethane (1:33) to provide the title compounds. (1S, 2R) -4 '- (2-Hydroxy-l-methyl-4-pyridin-3-ylbutoxy) biphenyl-3-sulfonic acid amide (main diastereomer) as an oil (0.70 g) MS (APCI) 413.1 (M + H) + XH NMR (CDC13) 8.49 (1H, d); 8.45 (1H, d); 8.10 (1H, t); 7.87 (1H, dt); 7.75 (1H, dt); 7.58-7.49 (4H, m); 7.49-7.21 (1H, m); 6.95 (2H, d); 5.03 (2H, s); 4.41-4.37 (1H, m); 3.83-3.80 (1H, m); 3.01-2.92 (1H, m); 2.80-2.71 (1H, m); 3.32 (1H, broad); 1.90-1.82 (2H, m); 1.31 (3H, d). (1S, 2S) -4 '- (2-hydroxy-l-methyl-4-pyridin-3-ylbutoxy) biphenyl-3-sulfonic acid amide (minor diastereomer) as an oil (0.31 g) MS (APCI) 413.1 (M + H) + XH NMR (CDC13) 8.50 (1H, d); 8.46 (1H, d); 8.10 (1H, t); 7.87 (1H, dt); 7.75 (1H, dt); 7.58-7.49 (4H, m); 7.49-7.21 (1H, m); 6.99 (2H, d); 4.87 (2H, s); 4.30 (1H, p); 3.73-3.63 (1H, m); 3.01-2.92 (1H, m); 2.80-2.71 (1H, m); 2.46 (1H, broad); 1.90-1.82 (2H, m); 1.30 (3H, d).

Example 6 Salt of (3R, 4S) -3- (3 • -chlorobiphenyl-4-yloxy) -l-pyridin-3-yl-pentan-3-ol-oxalic acid and salt of (3S, 4S) -4- (3 'Chlorobiphenyl-4-yloxy) -l-pyridin-3-yl-pentan-3-ol oxalic Prepared according to the method as described in example 4e) from (3RS, 4R) -4- (4-bromophenoxy) -1-pyridin-3-yl-pentan-3-ol (1.05 g, example 4d), 3-chlorobenzanboronic acid (1.1 g), aqueous 2M sodium carbonate solution (3.6 ml) and tetrakis (triphenylphosphine) palladium (0) (0.36 g), toluene (25 ml) and ethanol (5 ml) to provide the subtitle compound as an oil and as a 4: 1 mixture of diastereomers (1.09 g). The diastereomers are separated by CLAP in normal phase eluting with isopropanol: dichloromethane (1:33) to provide two oils which are converted to the oxalate salts by treatment with oxalic acid (excess) in ether to provide the title compounds: Salt of the acid (3S, 4S9- (3'-chlorobiphenyl-4-yloxy) -l-pyridin-3-yl-pentan-3-ol (minor diastereomer) as a solid (0.11 g). p.f. 71-73 ° C MS (APCI) 368 [(M-oxalic acid) + H) + 2 H NMR (DMSO-D 6) 8.46 (1H, d); 8.40 (1H, dd); 7.68-7.57 (5H, m); 7.45 (1H, t); 7.37-7.30 (2H, m); 7.0 (2H, d); 4.45-4.37 (1H, m); 4.0 (1H, broad s); 3.58-3.53 (1H, m); 2.87-2.78 (1H, m); 2.68-2.58 (1H, m); 1.81-1.69 (2H, m); 1.21 (3H, d).

Oxalic acid salt of (3R, 4S) -4- (3'-chlorobiphenyl-4-yloxy) -1-pyridin-3-ylpentan-3-ol (main diastereomer) as a solid (0.50 g). p.f. 146.5-147.5 ° C MS (APCI) 368 [(M-oxalic acid) + H) * XH NMR (DMSO-D6) 8.47 (1H, d); 8.42 (1H, dd); 7.70-7.56 (5H, m); 7.44 (1H, m); 7.36-7.32 (2H, m); 7.0 (2H, d); 4.36-4.32 (1H, m); 3.58-3.53 (1H, m); 2.86-2.78 (1H, m); 2.71-2.64 (1H, m); 1.89-1.85 (1H, m); 1.68-1.63 (1H, m); 1.24 (3H, d).

Example 7 (3R, 4S) -4- (4 * -fluoro-biphenyl-4-yloxy) -1-pyridin-3-yl-pentan-3-ol and (3S, 4R) -4- (4'-fluoro-biphenyl) 4-yloxy) -l-pyridin-3-yl-pentan-3-ol.

Prepared according to the method as described in example 4e) from (3RS, 4R) -4- (4-bromophenoxy) -1-pyridin-3-yl-pentan-3-ol (1.0 g, 4d), 4-fluorobenzanboronic acid (0.62 g), an aqueous solution of 2M sodium carbonate (2.2 ml) and tetrakis (triphenylphosphine) palladium (0) (0.34 g), toluene (30 ml) and ethanol (10 ml) for provide the title compound as a solid and as a 4: 1 mixture of diastereomers (0.6 g). The diastereomers are separated by CLAP in the normal phase eluting with isopropanol: dichloromethane (1:33) to give two solids which recrystallize from hexane: ethyl acetate (1: 1) to give the title compounds: (3R, 4S) -4- (4'-Fluoro-biphenyl-4-yloxy) -1-pyridin-3-yl-pentan-3-ol (main diastereomer) as a solid (0.26 g). p.f. 121-122 ° C MS (APCI) 352 (M + H) + 1 H NMR (CDC13) 8.50 (1H, d); 8.45 (1H, dd); 7.60-7.55 (1H, m); 7.50-7.40 (4H, m); 7.25-7.20 (1H, m); 7.05-7.15 (2H, m); 7.0-6.95 (2H, m); 4.45-4.35 (1H, m); 3.90-3.80 (1H, m); 3.0-2.90 (1H, m); 2.80-2.65 (1H, m); 2.50 (1H, d); 1.90-1.80 (2H, m); 1.30 (3H, d). (3S, 4S) -4- (4'-Fluoro-biphenyl-4-yloxy) -l-pyridin-3-yl-pentan-3-ol (minor diastereomer) as a solid (0.106 g). p.f. 147-148 ° C MS (APCI) 352 (M + H) +? NMR (CDC13) 8.50 (1H, d); 8.45 (1H, dd); 7.60-7.55 (1H, m); 7. 50-7.40 (4H, m); 7.25-7.20 (1H, m); 7.05-7.15 (2H, m); 7.0-6.95 (2H, m); 4.30-4.20 (1H, m); 3.70-3.60 (1H, m); 3.0-2.90 (1H, m); 2.85-2.70 (1H, m); 2.45 (1H, d); 1.90-1.80 (2H, m); 1. 30 (3H, d).

Example 8 (3R, 4S) -4- (biphenyl-4-yloxy) -5-methyl-1-pyridin-3-yl-exan-3-ol. a) (2S) -2 - (biphenyl-4-yloxy) -3-methylbutyric acid methyl ester Diethyl azodicarboxylate (11.5 ml) in dry tetrahydrofuran (40 ml) is added dropwise over 30 minutes to a stirred solution of triphenylphosphine (22 g), methyl (R) -2-hydroxy-3-methylbutanoate (11.2 g, J. Am. Chem. Soc. (1990), 112, 21, 7659) and 4-phenylphenol (14.5 g) in dry tetrahydrofuran. (120 mi). The resulting solution is stirred at room temperature overnight and then concentrated under reduced pressure. A mixture of isohexane: ether (9: 1) (750 ml) is added to the residue and the mixture is stirred at room temperature for 30 minutes. The solution is filtered and the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography on silica eluting with isohexane: dichloromethane (1: 4) and then (1.1) to provide the subtitle compound as a solid which recrystallizes from hexane to give a crystalline solid (7.9 g) . p.f. 82-85 ° C 'H NMR (CDCl 3) 7.55-7.45 (4H, m); 7.41 (2H, t); 7.35-7.25 (1H, m); 6.94 (2H, dt); 4.42 (1H, d), 3.77 (3H, s); 2.30 (1H, sextet), 1.11 (3H, d); 1.08 (3H, d). b) (2S) -2- (biphenyl-4-yloxy) -3-methylbutan-1-ol.

A solution of lithium aluminum hydride (1.0M) in tetrahydrofuran (16 ml) is added dropwise to (2S) -2-biphenyl-4-yloxy) -3-methylbutyric acid methyl ester (4.0 g, example 8a) ) stirred, in dry tetrahydrofuran (80 ml) at room temperature, and the reaction is allowed to stir overnight. Water (0.6 ml) and then aqueous sodium hydroxide (50%, 0.6 ml) and then water are added cautiously. (2.4 ml) to the solution at 0 ° C. Diethyl ether (200 ml) and anhydrous magnesium sulfate (10 g) are added and the solution is stirred at room temperature for 10 minutes. The solution is filtered and the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography on silica eluting with dichloromethane and then with dichloromethane: ether (49: 1) to give the subtitle compound as an oil which solidifies upon standing (3.43 g). p.f. 45-47 ° C? NMR (CDCl 3) 7.58-7.48 (4H, m); 7.41 (2H, t); 7.35-7.25 (1H, m); 7.04 (2H, d); 4.25-4.15 (1H, m); 3.90-3.75 (2H, m); 2.10 (1H, sextet); 1.77 (1H, dd); 1.1-0.9 (6H, m). c) (3RS, 4S) -4- (biphenyl-4-yloxy) -5-methyl-l-pyridin-3-yl-hex-l-in-3-ol Oxalyl chloride (1.65 ml) is added dropwise to a solution of dimethyl sulfoxide (2.25 ml) in dry dichloromethane (120 ml) at -65 ° C. The resulting solution is stirred for 10 minutes and then a solution of (2S) -2- (biphenyl-4-yloxy) -3-methylbutan-1-ol (3.40 g, example 8b) is added dropwise at -65 ° C. ) in dry dichloromethane (30 ml). The mixture is stirred for an additional 15 minutes and then triethylamine (12 ml) is added dropwise. The mixture is allowed to warm to 10 ° C with stirring. The mixture is then diluted with isohexane (250 ml), stirred for 10 minutes, filtered and concentrated under reduced pressure. The residue is dissolved in dry tetrahydrofuran (20 ml) and added at -20 ° C to a solution of l-lithium-2-pyridin-3-ylacetylene [generated by the addition of n-butyl lithium (2.5M in hexanes, 8.4 ml) to a solution of pyridylacetylene (2.0 g) (J. Amer. Chem. Soc. 1935, 57, 1284) in tetrahydrofuran (80 ml) at -60 ° C with stirring for 20 minutes]. The mixture is allowed to warm to room temperature and, after 30 minutes, it is poured into water (200 ml). The mixture is extracted with ethyl acetate, the combined organic extracts are dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by column chromatography on silica eluting with dichloromethane: ethyl acetate (4: 1) to give the subtitle compound as an oil and as a 3: 1 mixture of diastereomers (4.38 g).

MS (APCI +) 358 (M + H) + XH NMR (CDC13) 8.65 and 8.58 (together 1H, 2xd); 7.52-7.48 (1H, m); 7.65-7.46 (5H, m); 7.42 (2H, m); 7.35-7.10 (4H, m); 4.93-4.83 (1H, m); 4.38-4.30 (1H, m); 2.75-2.65 (1H, m); 2.32 (1H, septet); 1.15-1.05 (6H, m). d) (3RS, 4S) -4- (biphenyl-3-yloxy) -5-methyl-l-pyridin-3-yl-3-hexanol Dissolve (3RS, 4S) -4- (biphenyl-4-yloxy) -5-methyl-1-pyridin-3-ylhex-1-yn-3-ol (4.38 g, example 8c)) in ethyl acetate ( 100 ml) and hydrogenated at 3 atmospheres using 10% palladium on activated carbon (0.6 g) as a catalyst. The mixture is filtered through Celite and the filtrate is concentrated under reduced pressure to provide a mixture of the subtitle compounds as an oil (4.68 g).

The diastereomers are separated by CLAP in the normal phase eluting with isopropanol: dichloromethane (1:20) to provide the subtitle compounds as oils which are converted to their oxalic acid salts by treatment with a saturated ethacrylate solution of oxalic acid.

Oxalic acid salt of (3S, S) -4- (biphenyl-4-yloxy) -5-methyl-1-pyridin-3-yl-3-hexanol (minor diastereomer). p.f. 75 ° C (decomposition) MS (APCI +) 362.2 (M-oxalic acid + H) + XH NMR (DMSO) 8.42-8.32 (2H, m); 7.65-7.50 (5H, m); 7.40 (2H, t); 7.35-7.25 (2H, m); 7.08 (2H, m); 4.1-4.05 (1H, m); 3.7-3.65 (1H, m); 2.85-2.7 (1H, m); 2.68-2.55 (1H, m); 2.08 (1H, sextet); 1.75-1.65 (2H, m); 1.0-0.85 (6H, m).

Oxalic acid salt of (3R, 4S) -4- (biphenyl-4-yloxy) -5-methyl-1-pyridin-3-yl-3-hexanol (main diastereomer). p.f. 100-105 ° C MS (APCI +) 362.2 (M - oxalic acid + H) + H NMR (DMSO) 8.39 (2H, s); 7.65-7.50 (5H, m); 7.42 (2H, t); 7.35-7.25 (2H, m); 7.05 (2H, d); 4.15-4.10 (1H, m); 2.85-2.55 (2H, m); 2.20-2.10 (1H, m); 1.9-1.7 (1H, m); 1.7-1.55 (1H, m); 0.94 (3H, d); 0.89 (3H, d). • Example 9 (±) -1- [1- (biphenyl-4-yloxy) -syclopropyl] -3-pyridin-3-yl-propan-1-ol. a) 4- (1-phenylsulfa-cyclopropoxy) biphenyl.

Butyllithium (2.5M in hexanes, 6.1 ml) is added to a stirred solution of phenylcyclopropyl sulphide (2 g) in dry tetrahydrofuran (45 ml) at 0 ° C, under nitrogen. Stirring is continued for 3 hours at 0 ° C, the solution is then cooled to -78 ° C and iodine (4.05 g) in dry tetrahydrofuran (20 ml) is added over a period of 10 minutes. Stirring is continued at this temperature for 15 minutes, and then a solution of sodium metabisulfite (10% aqueous, 20 ml) is added and the mixture is allowed to warm to room temperature. The iodinated product is extracted into diethyl ether, washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure to provide a light brown oil. The above oil is dissolved in acetonitrile (30 ml), and 4-biphenol (2.7 g) and cesium carbonate (5.2 g) are added. The mixture is heated to reflux for 24 hours. The cooled mixture is filtered and the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography on silica eluting with dichloromethane: hexane (1:19) to give the subtitle compound as an oil (0.95 g). MS (El) 318 (M) + 2 H NMR (DMSO) 7.70-7.60 (4H, m); 7.53-7.27 (8H, m); 7.18 (2H, d); 1.55-1.38 (4H, m). b) (±) -1- [1- (biphenyl-4-yloxy) -cyclopropyl] -3-pyridin-3-yl-propan-1-ol.

Slowly add lithium naphthalenide (0.625M, 7.4 ml, prepared by adding equimolar amounts of naphthalene and lithium metal to tetrahydrofuran, under nitrogen, and stirring at room temperature overnight) to a stirred solution of 4- (1-phenylsulfanil). -cyclopropoxy) biphenyl (0.7 g) in dry tetrahydrofuran at -78 ° C, under nitrogen, and then stirred at this temperature for 15 minutes. To this is added a solution of 3-pyridinepropanal (0.3 g, prepared according to the method of example 3 of the application for international patent number WO-A-92/19593) in dry tetrahydrofuran (15 ml), and the stirring at -78 ° C for 5 minutes, and then allowed to warm to room temperature. The reaction is suspended with a saturated aqueous solution of ammonium chloride and extracted into diethyl ether (3 x 30 mL). The combined extracts are washed with brine, dried over anhydrous magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure to provide a pale yellow gum which is further purified by reverse phase CLAP to give the title compound as a pale yellow gum (0.11 g). MS (APCI) 346 (M + H) + ZH NMR (DMSO) 8.4 (1H, d); 8.35 (1H, dd); 7.65-7.50 (5H, m); 7.43 (2H, t); 7.35-7.2 (2H, m); 7.1 (2H, d); 5.1 (1H, d); 3.9-3.8 (1H, m); 2.9-2.55 (2H, m); 2.05-1.9 (1H, m); 1.75-1.6 (1H, m); 1.15-1.05 (1H, m); 0.95-0.88 (1H, m); 0.82-0-70 (2H, m).

Example 10 (2S / 3R) -4- (6-Bromonaphthalen-2-yloxy) -l-pyridin-3-yl-pentan-3-ol and (2R, 3S) -4- (6-bromonaphthalen-2-yloxy) - 1-pyridin-3-yl-pentan-3-ol a) (2S) -2- (6-Bromonaphthalen-2-yloxy) -propionic acid ethyl ester.

Prepared according to the method described in example la) from 2-hydroxy-6-bromonaphthalene (11.2 g), lactate of R- (+) - ethyl (5.93 g), triphenylphosphine (13.15 g) and diethylazodicarboxylate ( 9.61 g) in dry tetrahydrofuran (120 ml). The untreated product is purified by column chromatography on silica eluting with dichloromethane: hexane (1: 4-2: 3) to give the subtitle compound as a solid (12.45 g). p.f. 72-74 ° C GC / MS 322-324 [M] + E NMR (DMSO) 8.13 (1H, d); 7.85 (1H, d); 7.75 (1H, d); 7.57 (1H, dd); 7.25 (2H, d); 5.12 (1H, c); 4.16 (2H, c); 1.57 (3H, d); 1.17 (3H, t). b) (2S) -2- (6-bromonaphthalen-2-yloxy) -propan-2-ol.

Prepared according to the method described in Example 4b) from (2S) -2- (6-bromonaphthalen-2-yloxy) -propionic acid ethyl ester 12.45 g, example 10a) and sodium borohydride (1.6 g) in ethanol (150 ml). The untreated material is purified by column chromatography on silica eluting with methanol: dichloromethane (1:99) to provide the sub-title compound as a solid 810.5 g) m.p. 71-72 ° C g / C / MS 280-282 [M] + NMR (CDCl 3) 7.92 (1H, dd); 7.59 (1H, d); 7.50 (1H, dd); 7.18 (2H, dd); 4.70-4.61 (1H, m); 3.87-3.74 (2H, m); 2.02 (1H, broad S); 1.35 (3H, d) c) (2S, 3RS) -4- (6-bromo-naphthalen-2-yloxy) -l-pyridin-3-yl-pent-l-yl-in-3-ol Prepared according to the method described in example le) from (2S) -2- (6-bromonaphthalen-2-yloxy) -propan-l-ol (5 g, example 10b)), oxalyl chloride ( 2.9 g), dimethylsulfoxide (2.64 g), triethylamine (11.43 g), n-butyllithium (2.5M in hexanes, 12 ml) and 3-pyridylacetylene (3.15 g) to provide the subtitle compound as a 4: 1 mixture of diastereomers (4.4 g). MS (APCI) 383 (M + H) + E NMR (CDCI3 major diastereomer) 8.75 (1H, d); 8.54 (1H, dd); 7.93 (1H, d); 7.75-7.66 (2H, m); 7.60 (1H, d); 7.51 (1H, dd); 7.49-7.20 (3H, m); 4.88 (1H, broad s); 4.80-4.72 (1H, m); 3.23 (1H, broad s); 1.55 (3H, d). d) (2S, 3RS) -4- (6-bromonaf-alen-2-yloxy) -l-pyridin-3-yl-pentan-3-ol.

Prepared according to the method described in Example Id) from (2S, 3RS) -4- (6-bromonaphthalen-2-yloxy) -1-pyridin-3-yl-pent-l-in-3 ol (2.78 g, example 10c)) and 5% rhodium on carbon (1.5 g) in ethyl acetate (150 ml) at a pressure of two atmospheres to provide the subtitle compound as an oil and as a 4: 1 mixture of diastereomers (2.6 g). The diastereomers are separated by CLAP in a normal phase eluting with isopropanol: dichloromethane (1:20) to give (3R, 2S) -4- (6-bromonaphthalen-2-yloxy) -l-pyridin-3-yl-pentan-3. -il as the second main diastereomer eluting. MS (APCI) 388 (M + H) + H NMR (CDC13) 8.52 (1H, d); 8.46 (1H, dd); 7.91 (1H, d); 7.66 (1H, d); 7.56 (1H, dt); 7.50 (2H, dd); 7.26-7.20 (1H, m); 7.16-7.90 (2H, m); 4.50-4.47 (1H, m); 3.92-3.87 (1H, m); 2.96-2.92 (1H, m); 2.80-2.73 (1H, m); 2.20 (1H, broad s); 92-1.84 (2H, m); 1.35 (3h, d). e.e. 44% (estimated by CLAP using a Chiralpak AD column and eluting with cyclohexane: ethanol (60:40). e) Ester (2R, 3S) -2- [2- (6-bromonaphthalen-2-yloxy) -1- (2-pyridin-3-yl-ethyl) propyl] of the 1-benzyl ester of 5-oxo- pyrrolidin-1, 2-dicarboxylic ester (2S, 3R) -2- [2- (6-bromonaphthalen-2-yloxy) -1- (2-pyridin-3-yl-ethyl) propyl] ester of 1-benzyl ester of 5-oxo-pyrrolidin-1,2-dicarboxylic acid (2S, 3R) -4- (6-Bromonaphthalen-2-yloxy) -l-pyridin-3-yl-pentan-3-ol, (2R, 3S) -4- (6-bromonaphthalen-2-yloxy) - l-pyridin-3-yl-pentan-3-ol (1.5 g, example lOd)), 1-benzyl ester of 5-oxo-pyrrolidin-1,2-dicarboxylic acid (2.05 g), hydrochloride of 1- (3 -dimethylaminopropyl) -3-ethylcarbodiimide (1.5 g) and 4-dimethylaminopyridine (0.95 g) are stirred in dichloromethane (50 ml) at room temperature overnight. The reaction mixture is concentrated under reduced pressure and the residue is purified by column chromatography on silica gel eluting with ethyl acetate: hexane (4: 1) to give an oil (2.3 g). The diastereomers are separated by CLAP in the normal phase with ethyl acetate-hexane (4: 1) to give the subtitle compounds. Ester (2S, 3R) -2- [2- (6-bromonaphthalen-2-yloxy) -1- (2-pyridin-3-yl-ethyl) propyl] of the 5-oxo-pyrrolidinyl 1-benzyl ester 1, 2-dicarboxylic (second major diastereomer eluting, 1.46 g). MS (APCI) 632 (M + H) + 'H NMR (CDC13) 8.46 (1H, dd); 8.42 (1H, d); 7.91 (1H, d); 7.64 (1H, d); 7.55 (2H, d); 7.50 (1H, d); 7.45-7.26 (5H, m); 7.20 (1H, t); 7.08 (1H, d); 7.05 (1H, s); 5.29 (2H, d); 5.18-5.15 (1H, m); 7.45 (1H, dd); 4.63-4.53 (1H, m); 2.69-2.30 (5H, m); 2.05-1.92 (3H, m); 1.31 (3H, d).

Ester (2R, 3S) -2- [2- (6-bromonaphthalen-2-yloxy) -1- (2-pyridin-3-yl-ethyl) propyl] of the 5-oxo-pyrrolidin-1-benzyl ester 1,2-dicarboxylic (first diastereomer minor in elution, 0.37 g). MS (APCI) 632 (M + H) + XH NMR (CDC13) 8.47 (1H, dd); 8.45 (1H, d); 7.91 (1H, s); 7.64 (1H, d); 7.52 (2H, d); 7.48 (1H, d); 7.34-7.26 (5H, m); 7.20 (1H, t); 7.07-7.01 (2H, m); 5.21-5.19 (2H, m); 4.75 (1H, dd); 4. 65-4.55 (1H, m); 2.78-2.25 (5H, m); 2.18-1.92 (3H, m); 1.35 (3H, d). f) Ester (2S, 3R) -2- [2- (6-bromonaphthalen-2-yloxy) -1- (2-pyridin-3-yl-ethyl) propyl ester of the 5-oxo-pyrrolidin 1-benzyl ester -1, 2 -dicarboxylic acid (1.46 g, example lOe) and potassium carbonate (0.96 g) are stirred at room temperature in methanol (24 ml) and water (1 ml) overnight. The reaction mixture is heated under reduced pressure and the residue is partitioned between ethyl acetate and water. The organic phase is separated, washed with brine, dried over anhydrous magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure and the residue is triturated in ether: hexane (1: 1) to give the title compound as a solid (0.7 g) p.f. 117-118 ° C MS (APCI) 388 (M + H) + XH NMR (CDC13) 8.52 (1H, d), 8.46 (1H, dd); 7.91 (1H, d); 7.66 (1H, d); 7.56 (1H, dt); 7.50 (2H, dd); 7.26-7.20 (1H, m); 7.16-7.09 (2H, m); 4.50-4.47 (1H, m); 3.92-3.87 (1H, m); 2.96-2.92 (1H, m); 2.80-2.73 (1H, m); 2.20 (1H, broad s); 1.92-1.84 (2H, m); 1.35 (3H, d). (2R, 3S) -3- (6-Bromonaphthalen-2-yloxy) -l-pyridin-3-yl-pentan-3-ol It is prepared according to the method described in Example 10) from the ester (2R, 3S) -2- [2- (6-bromonaphthalen-2-yloxy) -1- (2-pyridin-3-yl-ethyl) ) -propyl 1-benzyl ester of 5-oxo-pyrrolidin-1, 2-dicarboxylic acid (0.37 g, example lOe) and potassium carbonate (0.24 g) in methanol (14 ml) and water (1 ml) to provide the title compound as a solid (0.15 g). p.f. 116-117 ° C MS (APCI) 388 (M + H) + "H NMR (CDC13) 8.52 (1H, d); 8.46 (1H, dd); 7.91 (1H, d); (1H, d); 7.56 (1H, dt); 7.50 (2H, dd); 7.26-7.20 (1H, m); 7.16-7.09 (2H, m); 4.50-4.47 (1H, m); 3.92-3.87 (1H, m); 2.96-2.92 (1H, m); 2.80-2.73 (1H, m); 2.20 (1H, broad s); 1.92-1.84 (2H, m); 1.35 (3H, d).

Example 11 Acid (1S, 2R) -4- [2- (tert-Butyldimethylsilanyloxy) -l-methyl-4-pyridin-3-ylbutoxy] benzeneboronic acid a) (3S, 4R) -4- (4-bromophenoxy) -l-pyridin-3-yl-pentan-3-ol.

Prepared according to the method described in Example Id) from (3RS, 4R) -4- (4-bromophenoxy) -l-pyridin-3-yl-pent-l-in-3-ol (5.93 g , example 4c)) and 5% rhodium on activated carbon (2.0 g) in ethyl acetate (100 ml) to provide the subtitle compound as an oil and as a 4: 1 mixture of diastereomers (5.6 g). The diastereomers are separated using CLAP in the normal phase eluting with 3% isopropyl alcohol in dichloromethane to give the (2S, 3R) -2- (4-bromophenoxy) -5-pyridin-3-yl-pentan-3-ol as the diastereomer main (3.21 g) and (2S, 3S) -2- (4-bromophenoxy) -5-pyridin-3-yl-pentan-3-ol as the second eluting diastereomer, minor (0.71 g). MS (APCI) 336/338 (M + H) + XH NMR (CDC13, major diastereomer) 8.50 (1H, d); 8.45 (1H, dd); 7.54 (1H, dt); 7.37 (2H, d); 7.22 (1H, dd); 6.76 (2H, d); 4.30-4.27 (1H, m); 3.82 (1H, p); 2.94-2.89 (1H, m); 2.77-2.70 (1H, m); 2.18 (1H, broad); 1.86-1.78 (2H, m); 1.26 (3H, d). b) (3R, 4S) -3- [4- (4-bromophenoxy) -3- (tert-butyldimethylsilanyloxy) pentyl] pyridine.

Prepared according to the method described in example 5a) from (3S, 4R) -4- (4-bromophenoxy) -l-pyridin-3-yl-pentan-3-ol (2.01 g, example 5a) ), tert-butyldimethylsilyl chloride (1.81 g) and imidazole (0.814 g) in dry dichloromethane to give the subtitle compound as an oil (2.52 g) after column chromatography eluting with dichloromethane: diethylether (1: 1) MS ( APCI) 450/452 (M + H) + XH NMR (CDC13) 8.45-8.42 (2H, m); 7.4 (1H, dt); 7.35 (2H, d); 7.22-7.18 (1H, m); 6.73 (2H, d); 4.23-4.20 (1H, m); 3.82-3.78 (1H, m); 2.84-2.62 (2H, m); 1.96-1.88 (1H, m); 1.82-1.78 (1H, m); 1.27 (3H, d); 0.94 (9H, s); 0.12 (3H, s); 0.09 (3H, s). c) (1S, 2R) -4- [2- (tert-Butyldimethylsilanyloxy) -1-methyl-4-pyridin-3-ylbutoxy] benzeneboronic acid It is prepared according to the method described in example 5b) from ter-butyl lithium (3.95 ml, 1.7M in hexanes), (3R, 4S) -3- [4- (4-bromophenoxy) -3- (ter -butyldimethyl-silanyloxy) pentyl] pyridine (2.52 g, example 11b)) and triisopropylborate (1.68 ml) in tetrahydrofuran (20 ml) to give the subtitle compound as a foam (1.22 g) after chromatography on silica eluting with ethyl acetate. ethyl and then with ethyl acetate: methanol (4: 1). MS (APCI) 416 (M + H) + 1K NMR (CDCl 3) 8.60-8.53 (2H, m); 7.95 (2H, d); 7.6-7.54 (1H, m); 7.26-7.22 (1H, m); 6.86 (2H, d); 4.33-4.27 (1H, m); 3.93- 3.86 (1H, m); 2.82-2.62 (2H, m); 1.98-1.75 (2H, m); 1.28 (3H, d); 0.94 (9H, s); 0.08 (6H, s).

Example 12 (1S, 2R) -2- [3 '(2-hydroxy-l-methyl-4-pyridin-3-ylbutoxy) biphenyl-3-yl] -N-methylacetamide a) 2- (3-bromophenyl) -N-methyl-acetamide A solution of 3-bromophenylacetic acid (2.15 g), a tetrahydrofuran solution of methylamine (6 ml, 2M); dimethylaminopyridine (1.32 g), and l- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2.06 g) in dichloromethane is stirred at room temperature for 16 h. The organic solution is washed three times with a 2M hydrochloric acid solution, dried over magnesium sulfate, filtered and evaporated to give a solid (1.86 g).

MS (APCI) 228/230 (M + Hd XE NMR (CDCl 3) 7.44 (2H, m); 7.21 (2H, m); 3.59 (1H, broad s); 3.54 (2H, S); 2.79 (3H, d); ). b) (1S, 2R) -2- [4 '(2-hydroxy-1-methyl t-1-4-pyridin-3-ylbutoxy) biphenyl-3-yl] -N-methylacetamide A solution of (1S, 2R) -4- [2- (tert-butyldimethylsilanyloxy) -l-methyl-4-pyridin-3-ylbutoxy] benzanboronic acid (0.20 g, example 11), 2- (3-bromophenyl) - N-methyl-acetamide (0.21 g, example 12a)), 2M aqueous sodium carbonate (0.57 ml) and tetrakis (triphenylphosphine) palladium (0) (0.1 g) in toluene (5 ml) and ethanol (2 ml) is heated at 100 ° C for 4 hours. After cooling, the solution is concentrated under reduced pressure. Concentrated hydrochloric acid is added (1 ml) to a solution of the residue in methanol (5 ml). The suspension is stirred at room temperature for 18 hours.

The mixture is concentrated under reduced pressure and the residue is partitioned between ether and water. The aqueous layer is neutralized and extracted with dichloromethane (2 x 50 mL). The combined extracts are dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by CLAP in the normal phase eluting with a gradient of 0-25% ethanol in dichloromethane to give the title compound as an oil (0.15 g).

MS (APCI) 405 (M + H) + X H NMR (CDCl 3) 8.51 (1H, d); 8.46 (1H, dd); 7.57-7.54 (1H, m) / 7.52 (2H, d); 7.47-7.46 (1H, m); 7.43-7.38 (2H, m); 7.24-7.18 (2H, m); 6.95 (2H, d); 5.40 (1H, broad s); 4.40-4.37 (1H, m); 3.88-3.85 (1H, m); 3.63 (2H, s); 2.98-2.91 (1H, m); 2.77 (3H, d); 2.74-2.68 (1H, m); 2.16 81H, d); 89-1.82 (2H, m); 1.31 (3H, d).

Example 13 (3R, 4S) -4- (41-chloro-2 * -fluorobiphenyl-4-yloxy) -l-pyridin-3-yl-pentan-3 -ol It is prepared according to the method described in example 12b) from (1S, 2R) -4 - [2 - (tert-butyldimethylsilanyloxy) -l-methyl-4-pyridin-3-ylbuo] benzeneboronic acid (0.20 g , example 11)), l-bromo-4-chloro-2-f luorobenzene (0.21 g), 2M aqueous sodium carbonate (0.57 ml) and tetrakis (triphenylphosphine) palladium (0) (0.1 g) in toluene (5 ml) ) and ethanol (2 ml). The reaction mixture is heated at 100 ° C for 4 hours. After cooling, the solution is concentrated under reduced pressure. Concentrated hydrochloric acid (10 mL) is added to a solution of residue in methanol (50 mL) and the suspension is stirred at room temperature for 16 hours. After treatment, the residue is purified by CLAP in the normal phase eluting with a gradient of 0-25% ethanol in dichloromethane to provide an oil (0.13 g). MS (APCI) 386 (M + H) + XH NMR (CDC13) 8.51 (1H, d); 8.45 (1H, dd); 7.56-7.54 (1H, m); 7.43 (2H, dd); 7.33 (1H, t); 7.26-7.15 (3H, m); 6.94 (2H, d); 4.41-4.37 (1H, m); 3.87-3.86 (1H, m); 3.0-2.95 (1H, m); 2.80-2.75 (1H, m); 2.15 (1H, d); 1.87-1.84 (2H, m); 1.31 (3H, d).

Example 14 (3R, 4S) -4- (41-chlorobiphenyl-4-yloxy) -l-pyridin-3-yl-pentan-3-ol It is prepared according to the method described in example 12b) from (1S, 2R) -4- [2- (tert-butyldimethylsilanyloxy) -1-metyl-4-pyridin-3-ylbutoxy] - bencenboronic acid (0.20 g, example 11)), 4-chloro-iodobenzene (0.24 g), 2M aqueous sodium carbonate (0.5 ml) and tetrakis (triphenylphosphine) palladium (0) (0.1 g) in toluene (4 ml) and ethanol (1 mi) The reaction mixture is heated at 100 ° C for 4 hours. After cooling, the solution is concentrated under reduced pressure. Concentrated hydrochloric acid (1 mL) is added to a solution of the residue in methanol (5 mL) and the suspension is stirred at room temperature for 3 hours. After the treatment, the residue is purified by normal phase CLAP eluting with a gradient of 0-25% ethanol in dichloromethane to provide a gum, from which the oxalate salt (0.11 g) is made. p.f. 133-135 ° C MS (APCI) 368 (M + H) + X H NMR (DMSO) 8.44 (1H, s); 8.38 (1H, d); 7.63-7.62 (3H, m); 7.56 (2H, d); 7.46 (2H, d); 7.3 (1H, c); 7.00 (2H, d); 5.00 (1H, d); 4.37-4.3 (1H, m); 3.6-3.5 (1H, m); 2.87-2.75 (1H, m); 2.7-2.6 (1H, m); 1.93-1.8 (1H, m); 1.7-1.6 (1H, m); 1.24 (3H, d).

Example 15 (3R, 4S) -4- (5'-methoxy-2'-methylbiphenyl-4-yloxy) -l-pyridin-3-yl-pentan-3-ol It is prepared according to the method described in example 12b) from (1S, 2R) -4- [2- (tert-butyldimethylsilanyloxy) -1-methyl-4-pyridin-3-ylbutoxy] -benzeneboronic acid (0.20 g, example 11)), 4-chloro-bromo-3-methylanisole (0.2 g), 2M aqueous sodium carbonate (0.5 ml) and tetrakis (triphenylphosphine) palladium (0) (0.1 g) in toluene (4 ml) and ethanol (1 ml). The reaction mixture is heated at 100 ° C for 4 hours. After cooling, the solution is concentrated under reduced pressure. Concentrated hydrochloric acid is added (1 mL) to a solution of the residue in methanol (5 mL) and the suspension is stirred at room temperature for 6 hours.

After the treatment, the residue is purified by CLAP in the normal phase eluting with a gradient of 0-25% ethanol in dichloromethane to give a gum, from which the oxalate salt (0.11 g) is prepared. p.f. 86-88 ° C MS (APCI) 377 (M + H) + (free base) XR NMR (DMSO) 8.47 (1H, s); 8.41 (1H, d); 7.68 (1H, d); 7.34 (1H, c); 7.16 (2H, d); 7.07 (1H, d); 6.92 (2H, d); 6.85-6.75 (2H, m); 4.29 (1H, t); 3.75 (3H, s); 3.6-3.5 (1H, m); 2.9-2.7 (2H, m); 2.2 (3H, s); 1.95-1.8 (1H, m); 1.72-1.6 (1H, m); 1.24 (3H, d).

Example 16 Oxalic acid salt of (3R, 4S) -4- (3 •, 4'-dichlorobiphenyl-4-yloxy) -l-pyridin-3-ylpentan-3-ol It is prepared according to the method described in example 12b) from (1S, 2R) -4- [2- (tert-butyldimethylsilanyloxy) -1-methyl-4-pyridin-3-ylbutoxy] -benzanboronic acid ( 0.20 g, example 11)), 3,4-dichloroiodobenzene (0.273 g), 2M aqueous sodium carbonate (0.5 ml) and tetrakis (triphenylphosphine) palladium (0) (0.025 g) in toluene (5 ml) and ethanol (1 my) . The reaction mixture is heated at 100 ° C for 4 hours. After cooling, the solution is concentrated under reduced pressure. Concentrated hydrochloric acid (1 mL) is added to a solution of the residue in methanol: water (4: 1) (5 mL) and the suspension is stirred at room temperature for 3 hours. After the treatment, the residue is purified by normal phase CLAP eluting with a gradient of 0-25% ethanol in dichloromethane to give a gum, from which the oxalate salt (0.23 g) is made. p.f. 86.4-88.4 ° C MS (APCI) 402/404 (M + H) + (free base) X H NMR (DMSO) 8.51 (1H, d); 8.46 (1H, dd); 7.62 (1H, d); 7.55 (1H, dt); 7.48-7.45 (3H, m); 7.36 (1H, dd); 7.23 (1H, dd); 6.93 (2H, d); 4.39 (1H, dc); 3.87-3.85 (1H, m); 2.95-2.9 (1H, m); 2.76-2.77 (1H, m); 2.21 (1H, broad S); 1.89-1.84 (2H, m); 1.30 (3H, d).

Example 17 (1S, 2R) -4 '- (2-hydroxy-l-methyl-4-pyridin-3-yl-butoxy) biphenyl-3-sulfonic acid (2-morpholin-4-ylethyl) amide a) 3-Bromo-N- (2-morpholin-4-yl-ethyl) benzenesulfonamide hydrochloride.

Add, deplete, 4- (2-aminoethyl) morpholine (2.54 g) to a stirred solution of 3-bromobenzenesulfonyl chloride (5.0 g) in ether (50 ml) at 5 ° C. The resulting suspension is stirred for 30 minutes and filtered to give the subtitle compound as a solid (4.45 g). p.f. 82.4-84.0 ° C MS (APCI) 349/351 (M + H) + (free base) H NMR (DMSO) 7.96 (1H, t); 7.88-7.80 (3H, m); 7.56 (1H, t); 3.59 (2H, t); 3.50 (2H, t); 2.92 (2H, t); 2.39 (2H, t); 2.35-2.20 (2H, broad). b) (1S, 2R) -4 '- (2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) biphenyl-3-sulfonic acid (2-morpholino-4-ylethyl) is prepared from according to the method described in example 12b) from (1S, 2R) -4- [2- (tert-butyldimethylsilanyloxy) -1-methyl-4-pyridin-3-ylbutoxy] -benzeneboronic acid (0. .20 g, example 11)), 3-bromo-n- (2-morpholin-4-yl-ethyl) -benzenesulfonamide hydrochloride (0.385 g, example 17a)), 2M aqueous sodium carbonate (0.5 ml) and tetrakis (triphenylphosphine) palladium (0) (0.025 g) in toluene (5 ml) and ethanol (1 ml). The reaction mixture is heated at 100 ° C for 4 hours. After cooling, the solution is concentrated under reduced pressure. Concentrated hydrochloric acid (1 mL) is added to a solution of the residue in methanol: water 4: 1 (5 mL) and the suspension is stirred at room temperature for 3 hours. After treatment, the residue is purified by normal phase CLAP eluting with a gradient of 0-25% ethanol in dichloromethane to provide a gum, from which the oxalate salt is worked up as a gum (0.295 g). MS (APCI) 526 (M + H) + (free base) X H NMR (DMSO) 8.46 (1H, d); 8.41 (1H, dd); 7.99 (1H, d); 7.90 (2H, dt); 7.74 (1H, dd); 7.69-7.64 (4H, m); 7.33 (1H, dd); 7.05 (2H, d); 4.36 (1H, p); 3.69-3.66 (4H, m); 3.58-3.54 (1H, m); 3.10-3.04 (2H, broad); 2.90-2.81 (7H, broad m); 2.75-2.61 (2H, m); 1.94-1.80 (2H, m); 1.76-1.62 (2H, m); 1.25 (3H, d).

Example 18 (3R, 4S) -4- (2 ', 4 * -dichlorobiphenyl-4-yloxy) -1-pyridin-3-yl-pentan-3-ol.

It is prepared according to the method described in example 12b) from (1S, 2R) -4- [2- (tert-butyldimethylsilanyloxy) -1-metyl-4-pyridin-3-ylbutoxy] -benzeneboronic acid ( 0.20 g, example 11)), l-bromo-2,4-dichlorobenzene (0.218 g), 2M aqueous sodium carbonate (0.5 ml) and tetrakis (triphenylphosphine) palladium (0) (0.020 g) in toluene (5 ml) and ethanol (2 ml). The reaction mixture is heated to 100 ° C under nitrogen for 4 hours. After cooling, the solution is concentrated under reduced pressure. Concentrated hydrochloric acid (1 mL) is added to a solution of the residue in methanol (5 mL) and the suspension is stirred at room temperature for 5 hours. The mixture is concentrated under reduced pressure and the residue is partitioned between diethyl ether and water. The aqueous layer is neutralized with a solution of sodium hydrogen carbonate (in water) and the aqueous solution is extracted with ethyl acetate. The combined organic phases are dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by CLAP in the normal phase eluting with a gradient of 0-25% ethanol in dichloromethane to provide a solid (0.064 g) from which the oxalate salt (0.54 g) is made. p.f. 98-100 ° C MS (APCI) 402.1, 404.1, 405.1 (M + H) + 2 H NMR (DMSO) 8.44 (2H, m); 7.69 (2H, broad s); 7.49-7.32 (5H, m); 7.00 (2H, d); 4.34 (1H, m); 3.38 (1H, m); 2.83 (1H, m); 2.70 (1H, m); 1.86 (1H, m); 1.66 (1H, m); 1.25 (3H, d).

Example 19 (1S, 2R) -4'- (2-Hydroxy-l-methyl-4-pyridin-3'-yl-butoxy) biphenyl-3-sulfonic acid methylamide a) 3-bromo-N-methyl-benzenesulfonamide Methylamine is bubbled through a solution of 3-bromobenzenesulfonyl chloride (5.0 g) in tetrahydrofuran (50 ml) at 0 ° C. The resulting suspension is stirred for 3 hours, filtered and concentrated under reduced pressure. The residue is triturated with hexane and filtered to provide the subtitle compound as a solid (4.52 g). mp88-89 ° C MS (APCI) 250 (M + H) + (free base) X H NMR (DMSO) 8.02 (1H, m); 7.80 (1H, m); 7.72 (1H, m); 7.42 (1H, t); 4.44 (1H, broad m); 2.70 (3H, d). b) (1S, 2R) -4 '- (2-hydroxy-l-methyl-4-pyridin-3-yl-butoxy) biphenyl-3-sulfonic acid methylamide It is prepared according to the method described in example 12b) from (1S, 2R) -4- [2- (tert-butyldimethylsilanyloxy) -1-methyl-4-pyridin-3-ylbutoxy] -benzeneboronic acid (0.20 g, example 11)), 3-bromo-N-methylbenzenesulfonamide (0.240 g, example 19a)), 2M aqueous sodium carbonate (0.55 ml) and tetrakis (triphenylphosphine) palladium (0) (0.020 g) in toluene (5 ml) and ethanol (2 ml). The reaction mixture is heated at 100 ° C for 4 hours. After cooling, the solution is concentrated under reduced pressure. Concentrated hydrochloric acid (1 mL) is added to a solution of the residue in methanol (4 mL) and the suspension is stirred at room temperature for 1.5 hours. The mixture is concentrated under reduced pressure and the residue is partitioned between diethyl ether and water. The aqueous layer is made basic with a 10% sodium hydrogen carbonate solution and the aqueous solution is extracted with ethyl acetate. The combined organic phases are dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by normal phase CLAP eluting with a gradient of 0-25% ethanol in dichloromethane to provide a foam (0.0495 g). MS (APCI) 427.1 (M + H) + XE NMR (DMSO) 8.44 (1H, m); 8.39 (1H, dt); 7.95 (1H, d); 7.89 (1H, dt); 7.72-7.60 (4H, m); 7.47 (1H, c); 7.30 (1H, dd); 7.05 (2H, d); 5.01 (1H, d); 4.36 (1H, m); 3.56 (1H, m); 2.82 (1H, m); 2.67 (1H, m); 2.43 (3H, d); 1.87 (1H, m); 1.65 (1H, m); 1.25 (3H, d).

Example 20 (1S, 2R) -4 '- (2-hydroxy-l-methyl-4-pyridin-3-yl-butoxy) biphenyl-3-sulfonic acid (2-pyrrolidin-1-ylethyl) -amide a) 3-Bromo-N- (2-pyrrolidin-1-yl-ethyl) benzenesulfonamide hydrochloride.

N- (2-aminoethyl) pyrrolidine (1.61 g) is added dropwise to a solution of 3-bromobenzenesulfonyl chloride (3.61 g) in diethyl ether (100 ml) at room temperature. The resulting suspension is stirred for 30 minutes and filtered to give the subtitle compound as a solid (4.48 g). p.f. 144-146 ° C MS (APCI) 333/335 [M-HC1] + E NMR (DMSO) 8.28 (1H, broad s); 7.99 (1H, m); 7.93-7.84 (2H, m); 7.60 (1H, t) 3.3-2.9 (8H, broad m); 1.88 (4H, broad s). b) (1S, 2R) -4 '- (2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) biphenyl-3-sulfonic acid (2-pyrrolidin-1-ylethyl) is prepared from according to the method described in Example 12b) from (1S, 2R) -4- [2- (tert-butyldimethylsilanyloxy) -l-methyl-4-pyridin-3-ylbutoxy] -benzeneboronic acid (0.20 g, 11)), 3-bromo-N- (2-pyrrolidin-1-yl-ethyl) benzenesulfonamide hydrochloride (0.355 g, example 20a)), 2M aqueous sodium carbonate (0.55 ml) and tetrakis (triphenylphosphine) palladium (0) ) (0.020 g) in toluene (5 ml) and ethanol (1 ml). The reaction mixture is heated at 100 ° C for 4 hours. After cooling, the solution is concentrated under reduced pressure. Concentrated hydrochloric acid (1 mL) is added to a solution of the residue in methanol (4 mL) and the suspension is stirred at room temperature for 0.75 hours. The mixture is concentrated under reduced pressure and the residue is partitioned between diethyl ether and water. The aqueous layer is made basic with a sodium hydrogen carbonate solution and the aqueous solution is extracted with ethyl acetate. The combined organic extracts are dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by CLAP in the normal phase eluting with a gradient of 0-25% ethanol in dichloromethane to provide a foam (0.113 g). MS (APCI) 510.1 (M + H) + X H NMR (DMSO) 8.44 (1H, m); 8.39 (1H, m); 8.00 (1H, m); 7.86 (1H, dt); 7.72 (1H, m); 7.63 (4H, m); 7.30 (1H, dd); 7.05 (2H, d); 5.01 (1H, d); 4.36 (1H, quintet); 3.57 (1H, m); 2.92 (2H, t); 2.86 (1H, m); 2.67 (1H, m); 2.40 (2H, t); 2.31 (4H, m); 1.87 (1H, m); 1.63 (1H, m); 1.58 (4H, m); 1.25 (3H, d).

Example 21 (1S, 2R) -4 '- (2-hydroxy-l-methyl-4-pyridin-3-yl-butoxy) -2-methyl-biphenyl-4-carbonitrile It is prepared according to the method described in example 12b) from (1S, 2R) -4- [2- (tert-butyldimethylsilanyloxy) -1-met-4-pyridin-3-ylbutoxy] -benzeneboronic acid ( 0.20 g, example 11)), 4-bromo-3-methylbenzonitrile (0.20 g), a 2M sodium carbonate aqueous solution (0.5 ml) and tetrakis (triphenylphosphine) palladium (0) (0.02 g) in toluene (5 ml) and ethanol (2 ml). The reaction mixture is heated at 100 ° C under nitrogen for 4 hours.

After cooling, the solution is concentrated under reduced pressure. Concentrated hydrochloric acid (1 mL) is added to a solution of the residue in methanol (50 mL) and the suspension is stirred at room temperature for 2 hours. The mixture is concentrated under reduced pressure and the residue is partitioned between diethyl ether and water. The aqueous layer is neutralized with a saturated sodium bicarbonate solution and extracted with dichloromethane. The organic fractions are dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by CLAP in the normal phase eluting with a gradient of 0-25% ethanol in dichloromethane to provide an oil (0.15 g). MS (APCI) 373 (M + H) + ZE NMR (CDC13) 8.52 (1H, d); 8.46 (1H, dd); 7.53 (3H, m); 7.25 (4H, M); 6.94 (2H, d); 4.40 (1H, m); 3.87 (1H, m); 2.96 (1H, m); 2.75 (1H, m); 2.30 (3H, s); 2.17 (1H, broad s); 1.88 (2H, m); 1.33 (3H, d).

EXAMPLE 22 Oxalic acid salt of (1S, 2R) -N- [2-chloro-4 '- (2-hydroxy-l-methyl-4-pyridin-3-yl-butoxy) -biphenyl-4-yl] -acetamide Oxalic acid salt of (3R, 4S) -4- (4'-amino-2'-chloro-biphenyl-4-yloxy) -l-pyridin-3-yl-pentan-3-ol It is prepared according to the method described in example 12b) from (1S, 2R) -4- [2- (tert-butyldimethylsilanyloxy) -1-met-4-pyridin-3-ylbutoxy] -benzeneboronic acid ( 0.20 g, example 11)), 4-bromo-3-chloroacetanilide (0.20 g), a 2M sodium carbonate aqueous solution (0.5 ml) and tetrakis (triphenylphosphine) palladium (0) (0.02 g) in toluene (5 ml) and ethanol (2 ml). The reaction mixture is heated at 100 ° C under nitrogen for 4 hours. After cooling, the solution is concentrated under reduced pressure. Concentrated hydrochloric acid (1 mL) is added to a solution of the residue in methanol (5 mL) and the suspension is stirred at room temperature for 16 hours. The mixture is concentrated under reduced pressure and the residue is partitioned between diethyl ether and water. The aqueous layer is neutralized with a saturated solution of sodium bicarbonate in water and extracted with dichloromethane. The combined organic extracts are dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by CLAP in the normal phase eluting with a gradient of 0-25% ethanol in dichloromethane to provide two products, the first being the title compound (0.05 g) as an oil from which the salt is prepared. oxalate as a foam (0.05 g); MS (APCI) 425 (M + H) + X H NMR (DMSO) 10.16 (1H, s); 8.47 (1H, s); 8.41 (1H, d); 7.88 (1H, d); 7.68 (1H, d); 7.49 (1H, dd); 7.35-7.29 (3H, m); 6.96 (2H, d); 6.68 (1H, dd); 4.32 (1H, m); 3.56 (1H, m); 2.82 (1H, m); 2.66 (1H, m); 2.07 (3H, s); 1.86 (1H, m); 1.66 (1H, m); 1.25 (3H, d).

In an additional elution, a second compound (3R, 4S) -4- (4'-amino-2'-chloro-biphenyl-4-yloxy) -1-pyridin-3-yl-pentan-3-ol ( 0.10 g), as an oil from which the solid oxalate salt (0.10 g) is also prepared. p.f. 142-145 ° C MS (APCI) 383 (M + H) X H NMR (DMSO) 8.47 (1H, d); 8.42 (1H, dd); 7.70 (1H, d); 7.35 (1H, m); 7.22 (2H, d); 7.00 (1H, d); 6.91 (2H, d); 6.68 (1H, d); 6.55 (1H, dd), 4.28 (1H, m); 3.54 (1H, m); 2.80 (1H, m); 2. 69 (1H, m); 1.87 (1H, m); 1.64 (1H, m); 1.24 (3H, d).

Example 23 (1S, 2R) -4 • - (2-hydroxy-l-methyl-4-pyridin-3-yl-butoxy) biphenyl-3-sulfonic acid (2-dimethylaminoethyl) amide a) 3-Bromo-N- (2-dimethylamino-ethyl) benzenesulfonamide hydrochloride N, N-dimethylethylenediamine (1.76 g) is added dropwise to a solution of 3-bromobenzenesulfonyl chloride (5.11 g) in diethyl ether (100 ml) at room temperature. The resulting suspension is stirred for 30 minutes and filtered to provide the subtitle compound as a solid (4.31 g). p.f. 154-156 ° C MS (APCI) 305/307 (M-HC1 + 1) + E NMR (DMSO) 8.32 (1H, broad s); 8.00 (1H, m); 7.95-7.85 (2H, m); 7.60 (1H, t) 3.15 (4H, s); 2.75 (6H, s). b) (1S, 2R) -4 '- (2-hydroxy-l-methyl-4-pyridin-3-yl-butoxy) biphenyl-3-sulfonic acid (2-dimethylaminoethyl) amide It is prepared according to the method described in example 12b) from (1S, 2R) -4- [2- (tert-butyldimethylsilanyloxy) -1-metyl-4-pyridin-3-ylbutoxy] -benzeneboronic acid ( 0.20 g, example 11)), 3-bromo-N- (2-dimethylamino-ethyl) benzenesulfonamide hydrochloride (0.331 g, example 23a)), 2M aqueous sodium carbonate (0.723 ml) and tetrakis (triphenylphosphine) palladium (0). ) (0.1 g) in toluene (5 ml) and ethanol (2 ml). The reaction is heated at 110 ° C for 6 hours. After cooling, the solution is concentrated under reduced pressure, the residue is dissolved in methanol (10 ml), concentrated hydrochloric acid (1 ml) is added and the solution is stirred at room temperature for 18 hours. The mixture is concentrated under reduced pressure and neutralized using saturated sodium hydrogen carbonate and extracted with ethyl acetate. The combined extracts are dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by normal phase CLAP eluting with a gradient of 0-10% ethanol in dichloromethane to give the title compound as a colorless oil (0.087 g). MS (APCI) 484 (M + H) + E NMR (CDC13) 8.51 (1H, s); 8.45 (1H, d); 8.05 (1H, dd); 7.75 (1H, dd); 7.60-7.5 (4H, m); 7.3-7.2 (1H, m); 7.0 (2H, d); 4.45-4.35 (1H, m); 3.95-3.80 (1H, m); 3.05-2.80 (3H, m); 2.80-2.70 (1H, m); 2.40-2.30 (2H, m); 2.1 (6H, s); 1.90-1.80 (4H, m); 1.30 (3H, d).

Example 24 (1S, 2R) -2- [4'-Hydroxy-l-methyl-4-pyridin-3-ylbutoxy) biphenyl-4-yl] -N-methylacetamide a) 2- (3-bromophenyl) -N-methyl-acetamide Add 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (8.88 g), 4-dimethylaminopyridine (5.67 g) and a 2M solution of methylamine in tetrahydrofuran (23 ml) to a solution of 4-bromophenylacetic acid ( 5.0 g) in dichloromethane (100 ml). The mixture is stirred overnight at room temperature. The reaction mixture is washed with 2M hydrochloric acid (3 x 100 mL), the organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated. The subtitle compound is obtained as a solid (4.74 g) after recrystallization from 1% hexane in ethyl acetate, m.p. 117-118 ° C MS (APCI) 228/230 (M + H +) X H NMR (CDC13) 7.96 (1H, s); 7.48 (2H, d); 7.20 (2H, d); 3.40 (2H, s); 2.60 (3H, d). b) (1S, 2R) -2- [4l- (2-Hydroxy-1-methyl-4-pyridin-3-ylbutoxy) biphenyl-4-yl] -N-methylacetamide It is prepared according to the method described in example 12b) from (1S, 2R) -4- [2- (tert-butyldimethylsilanyloxy) -1-met-4-pyridin-3-ylbutoxy] -benzeneboronic acid (0.20 g, example 11)), 2- (3-bromophenyl) -N-methyl-acetamide (0.244 g, example 24a)), 2M aqueous sodium carbonate (0.265 ml) and tetrakis (triphenylphosphine) palladium (0) ( 0.1 g) in toluene (5 ml) and ethanol (2 ml). The reaction is heated at 110 ° C for 6 hours. After cooling, the solution is concentrated under reduced pressure, the residue is dissolved in methanol (10 ml), concentrated hydrochloric acid (1 ml) is added and the solution is stirred at room temperature for 18 hours. The mixture is concentrated under reduced pressure, the residue is neutralized using saturated sodium hydrogen carbonate and extracted with ethyl acetate. The combined extracts are dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by normal phase CLAP eluting with a gradient of 0-10% ethanol in dichloromethane to provide the title compound as an oil which is converted to the oxalic acid salt by treatment with an ethereal solution saturated with acid. oxalic to afford the title compound as a gum (0.123 g). MS (APCI) 405 (M + H) -oxalate] + XH NMR (DMSO) 8.45 (1H, s); 8.40 (1H, d); 7.95 (1H, d); 7.70 (1H, d); 7.50 (4H, dt); 7.35 (1H, dd); 7.30 (2H, d); 4.35-4.30 (1H, m); 3.55-3.50 (1H, m); 3.45-3.40 (2H, m); 2.85-2.75 (1H, m); 2.70-2.60 (1H, m); 2.55 (3H, d); 1.85-1.80 (1H, m); 1.70- 1.55 (1H, m); 1.25 (3H, d).

Example 25 (1S, 2R) -2- [4"(2-hydroxy-l-methyl-4-pyridin-3-ylbutoxy) biphenyl-3-yl] -N, N-dimethylacetamide a) 2- (3-bromo-phenyl) -N, N-dimethyl-acetamide Prepared according to the method described in example 24a) from l- (3-dimethylaminopropyl) -3-ethylcarbodiimide-hydrochloride (2.15 g), 4-dimethylaminopyridine (3.82 g), a 2M solution of dimethylamine in tetrahydrofuran. (10 ml) and a solution of 3-bromophenylacetic acid (2.15 g) in dichloromethane (100 ml). The mixture is stirred overnight at room temperature. The reaction mixture is washed with 2M hydrochloric acid (3 x 100 mL), the organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated. The subtitle compound is obtained as an oil (2.89 g).

MS (APCI) 242/244 (M + H +) 'H NMR (CDCl 3) 7.45-7.35 (2H, m); 7.20-7.15 (2H, m); 3.65 (2H, s); 3.05 (3H, s); 2.95 (3H, s). b) (1S, 2R) -2- [4 '- (2-Hydroxy-1-methyl-4-pyridin-3-ylbutoxy) biphenyl-3-yl] -N, N-dimethylacetamide It is prepared according to the method described in Example 12b) from (1S, 2R) -4- [2- (tert-butyldimethylsilanyloxy) -1-metyl-4-pyridin-3-ylbutoxy] -benzeneboronic acid ( 0.20 g, example 11)), 2- (3-bromo-phenyl) -N, N-dimethylacetamide (0.234 g, example 25a)), 2M aqueous sodium carbonate (0.241 ml) and tetrakis (triphenylphosphine) palladium (0) (0.1 g) in toluene (5 ml) and ethanol. (2 mi) The reaction is heated at 110 ° C for 6 hours. After cooling, the solution is concentrated under reduced pressure, the residue is dissolved in methanol (10 ml), concentrated hydrochloric acid (1 ml) is added and the solution is stirred at room temperature for 18 hours. The mixture is concentrated under reduced pressure, the residue is neutralized using saturated sodium hydrogen carbonate and extracted with ethyl acetate. The combined extracts are dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by CLAP in the normal phase eluting with a gradient of 0-10% ethanol in dichloromethane to give the title compound as an oil (0.144 g). MS (APCI) 419 (M + H +) E NMR (CDC13) 8.50 (1H, d); 8.45 (1H, d); 7.55 (1H, d); 7.50 (2H, d); 7.45 (2H, d); 7.35 (1H, t); 7.25-7.15 (2H, m); 6.95 (2H, d); 4.45-4.35 (1H, m); 3.90-3.80 (1H, m); 3.75 (2H, s); 3. 00 (3H, s); 2.95 (3H, s); 2.95-2.90 (1H, m); 2.80-2.65 (1H, m); 2.20 (1H, d); 1.90-1.80 (2H, m); 1.25 (3H, d).

Example 26 (4S, 3R) -4- (4'-methanesulfonyl-biphenyl-4-yloxy) -l-pyridin-3-yl-pentan-3-ol Prepared according to the method described in example 12b) from (1S, 2R) -4 - [2 - (tert-butyldimethyl-silanyloxy) -1-met-4-pyridin-3-ylbutoxy] - bencenboronic acid (0.25 g, example 11c)), 4-bromophenylmethanesulfone (0.19 g), 2M aqueous sodium carbonate (0.64 ml) and tetrakis (triphenylphosphine) palladium (0) (0.16 g) in ethanol (3 ml) with heating to 90 ° C for 4 hours. After cooling, the solution is concentrated under reduced pressure. The residue is divided between water and ethyl acetate. The organic layer is concentrated under reduced pressure. The residue is purified by column chromatography on silica gel eluting with ethyl acetate to provide an oil. Concentrated hydrochloric acid (1 mL) is added to a solution of the oil in methanol (5 mL). The solution is stirred at room temperature for 18 hours. The mixture is concentrated under reduced pressure. The residue is neutralized using a saturated solution of sodium bicarbonate and extracted with ethyl acetate. The combined extracts are dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give a solid (0.17 g). MS (APCI) 412 (M + H) + "• H NMR (CDC13) 8.44 (1H, d), 8.39 (1H, dd), 7.95 (2H, d), 7.88 (2H, d), 7.69-7.61 ( 3H, m), 7.32-7.29 (1H, m), 7.04 (2H, d), 5.01 (1H, d), 4.38-4.35 (1H, m), 3.57-3.55 (1H, m), 3.24 (3H, s), 2.81-2.67 (2H, m), 1.94-1.79 (1H, m), 1.72-1.57 (1H, m), 1.25 (3H, d).

Example 27 (3R, 4S) -4- [3 '- (2-dimethylaminoethyl) biphenyl-4-yloxy] -l-pyridin-3-yl-pentan-3 -ol a) [2- (3-Bromophenyl) ethyl] dimethylamine hydrochloride.

Borane in tetrahydrofuran (1.0M, 24. 7 ml) to a solution of tetrahydrofuran of 2- (3-bromophenyl) -N, N-dimethyl acetamide (1.5 g, example 25a)) at 0 ° C. Once the addition is complete, the solution is refluxed at 90 ° C for 20 hours. The solution is cooled to room temperature, acidified with hydrochloric acid (6M, 10 ml) and refluxed for an additional 1 hour. The solution is cooled to room temperature and extracted with diethyl ether. The aqueous layer is made basic with 10% aqueous sodium hydroxide and extracted with ethyl acetate. The extracts are dried over anhydrous magnesium sulfate, filtered and concentrated. The residue is converted to the hydrochloride salt by treatment with a 4M hydrogen chloride solution in dioxane to give the subtitle compound as a hygroscopic gum (0.949 g). MS (APCI) 228/230 [(M-HC1) + H] + XH NMR (DMSO) 7.63 (1H, s); 7.55-7.45 (1H, m); 7.35-7.25 (2H, m); 3.28-3.24 (2H, m); 3.05-3.00 (2H, m); 2.84 (6H, s). b) (3R, 4S) -4- [3 '- (2-dimethylaminoethyl) biphenyl-4-yloxy] -1-pyridin-3-yl-pentan-3-ol.

Prepared according to the method described in example 12b) from (1S, 2R) -4- [2- (tert-butyldimethylsilanyloxy) -1-methyl-4-pyridin-3-ylbutoxy] -benzanboronic acid (0.2 g, example 11), [2- (3-bromophenyl) ethyl] dimethylamine hydrochloride (0.21 g, example 27a))), aqueous sodium carbonate (2M, 0. 82 ml) and tetrakis (triphenylphosphine) palladium (0) (0.1 g) in toluene (5 ml) and methanol (2 ml). The reaction is heated at 100 ° C for 4 hours. After cooling, the solution is concentrated under reduced pressure. Concentrated hydrochloric acid is added (1 mL) to a solution of the residue in methanol (5 mL) and stirred at room temperature for 2 hours. After the treatment, the residue is purified by CLAP in the normal phase eluting with a gradient of 0-25% ethanol in dichloromethane to provide the title compound as an oil (0.07 g). MS (APCI) 405 (M + H) + XH NMR (CDC13) 8.51 (1H, d); 8.46 (1H, dd); 7.57-7.54 (1H, m); 7.5 (2H, d); 7.39-7.31 (3H, m); 7.24-7.17 (2H, m); 6.95 (2H, d); 4.40-4.37 (1H, m); 3.95-3.85 (1H, m); 2.95-2.90 (1H, m); 2.88-2.85 (2H, m); 2.76-2.71 (1H, m); 2.67-2.61 (2H, m); 2.36 (6H, s); 2.10 (1H, broad s), 1.89-1.81 (2H, m); 1.31 (3H, d).

Example 28 Oxalic acid salt of (1S, 2R) -2- [4 '(2-hydroxy-l-methyl-4-pyridin-3-ylbutoxy) biphenyl-3-yl] -1-morpholin-4-yl-ethanone a) 3-bromo-phenyl-1-morpholin-4-yl-ethanone Prepared according to the method described in example 24a) from 4-hydroxy-3- (dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.764 g), 4-dimethylaminopyridine (0.488 g), morpholine (0.35 ml) and a solution of 3-bromophenylacetic acid (0.43 g) in dichloromethane (10 ml). The mixture is stirred overnight at room temperature. The reaction mixture is washed with 2M hydrochloric acid (3 x 100 mL), the organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated. The subtitle compound is obtained as a solid (0.550 g). MS (APCI) 242/244 (M + H +) E NMR (CDC13) 7.40 (2H, m); 7.17 (2H, m); 3.70 (2H, s); 3.65 (4H, s); 3.53 (2H, m); 3.45 (2H, m). b) Oxalic acid salt of (1S, 2R) -2- [4 '- (2-hydroxy-l-methyl-4-pyridin-3-ylbutoxy) biphenyl -3-yl] -1-morpholin- -yl- Etanone Prepared according to the method described in example 12b) from (1S, 2R) -4- [2- (tert-butyldimethylsilanyloxy) -1-met-4-pyridin-3-ylbutoxy] -benzeneboronic acid (0.20 g, example 11)), 3-bromophenyl-1-morpholin-4-yl-ethanone (0.234 g, example 28a)), 2M aqueous sodium carbonate (0.241 ml) and tetrakis (triphenylphosphine) palladium (0) ( 0.1 g) in toluene (5 ml) and ethanol (2 ml). The reaction is heated at 110 ° C for 6 hours. After cooling, the solution is concentrated under reduced pressureThe residue is dissolved in methanol (10 ml), concentrated hydrochloric acid (1 ml) is added and the solution is stirred at room temperature for 18 hours. The mixture is concentrated under reduced pressure, the residue is neutralized using saturated sodium hydrogen carbonate and extracted with ethyl acetate. The combined extracts are dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by CLAP in the normal phase eluting with a gradient of 0-10% ethanol in dichloromethane to give the title compound as an oil (0.144 g). MS (APCI) 419 (M + H +) XE NMR (CDC13) 8.50 (1H, d); 8.45 (1H, d); 7.55 (1H, d); 7.50 (2H, d); 7.45 (2H, d); 7.35 (1H, t); 7.25-7.15 (2H, m); 6.95 (2H, d); 4.45-4.35 (1H, m); 3.90-3.80 (1H, m); 3.75 (2H, s); 3.00 (3H, s); 2.95 (3H, s); 2.95-2.90 (1H, m); 2.80-2.65 (1H, m); 2.20 (1H, d); 1.90-1.80 (2H, m); 1.25 (3H, d).

Example 29 (3S74S) -4- [4- (3-Methylaminoethyl) biphenyl-4-yloxy) -1-pyridin-3-yl-pentan-3-ol a) [2- (3-Bromophenyl) ethyl] methylamine hydrochloride Borane in tetrahydrofuran (1.0M, 26.3 ml) is added dropwise to a tetrahydrofuran solution of 2- (3-bromophenyl) -N-methyl-acetamide (1.5 g, Example 12a)) at 0 ° C. Once the addition is complete, the solution is refluxed at 90 ° C for 20 hours. The solution is cooled to room temperature, acidified with 6M hydrochloric acid (10 ml) and refluxed for an additional 1 hour. The solution is cooled to room temperature and extracted with diethyl ether. The aqueous layer is made basic with 10% sodium hydroxide and extracted with ethyl acetate. The extracts are dried over anhydrous magnesium sulfate, filtered and concentrated. The residue is converted to the hydrochloride salt by treatment with a solution of 4M hydrochloric acid in dioxane to give the subtitle compound as a solid (0.727 g) • m.p. 135-136 ° C MS (APCI) 214/216 [(M-HCl) + H] + 2 H NMR (DMSO) 9.00 (1H, s); 7.51 (1H, s); 7.50-7.45 (1H, m); 7.35-7.25 (2H, m); 3.20-3.05 (2H, m); 3.00-2.90 (2H, m); 2.55 (3H, s). b) (3R, 4S) -4- [4- (3 • - (methylaminoethyl) biphenyl-4-yloxy] -1-pyridin-3-yl-pentan-3-ol.

It is prepared according to the method described in example 12b) from (1S, 2R) -4- [2- (tert-butyldimethylsilanyloxy) -1-metyl-4-pyridin-3-ylbutoxy] -benzeneboronic acid ( 0.20 g, example 11)), [2- (3-bromophenyl) ethyl] methylamine hydrochloride (0.241 g, example 29a)), 2M aqueous sodium carbonate (0.72 ml) and tetrakis (triphenylphosphine) palladium (0) (0.1 g) in toluene (5 ml) and ethanol (2 ml). The reaction is heated at 110 ° C for 6 hours. After cooling, the solution is concentrated under reduced pressure, the residue is dissolved in methanol (10 ml), concentrated hydrochloric acid (1 ml) is added and the solution is stirred at room temperature for 18 hours. The mixture is concentrated under reduced pressure, the residue is neutralized using saturated sodium hydrogen carbonate and extracted with ethyl acetate. The combined extracts are dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by normal phase CLAP eluting with a gradient of 0-10% ethanol in 1% triethylamine in dichloromethane to give the title compound as an oil (0.14 g). MS (APCI) 391 (M + H +) E NMR (CDC13) 8.50 (1H, d); 8.45 (1H, dd); 7.55 (1H, dd); 7.50 (2H, dd); 7.40-7.30 (3H, m); 7.25-7.15 (2H, m); 6.95 (2H, d); 4.45-4.30 (1H, m); 3.90-3.80 (1H, m); 3.00 (4H, s); 2.95-2.90 (1H, m); 2.80-2.65 (1H, m); 2.50 (3H, s); 1.90-1.80 (2H, m); 1.30 (3H, d).

Example 30 (3R, 4S) -4- [4 '- (2-methylaminoethyl) biphenyl-4-yloxy] -l-pyridin-3-yl-pentan-3-ol H a) [2- (4-Bromophenyl) ethyl] -N-methylamine hydrochloride Prepared according to the method described in example 29a) from borane (solution 1. OM in tetrahydrofuran, 35 ml), acid methylamide 4-bromophenylacetic acid (2.0 g, example 24a)) in dry tetrahydrofuran (60 ml) to give the subtitle compound as a solid (0.45 g). p.f. 198-200 ° C MS (APCI) 214 (M + H) + XH NMR (CDC13) 7.43 (2H, d); 7.12 (2H, d); 3.25-3.09 (4H, m); 2.72 (3H, s). b) (3R, 4S) -4- [4 '- (2-methylaminoethyl) biphenyl-4-yloxy] -1-pyridin-3-yl-pentan-3-ol.

Prepared according to the method described in Example 12b) from [2- (4-bromophenyl) ethyl] methylamine hydrochloride (0.214, example 30a)), ethanol (1 mL), toluene (4 mL), 2M aqueous sodium carbonate (0.5 mL), (1S, 2R) -4- [2- (tert-butyldimethylsilanyloxy) -l-methyl-4-? Iridin-3 acid. ilbutoxy] benzeneboronic acid (0.2 g, example 11)), and tetrakis (triphenylphosphine) palladium (0) (0.02 g) with heating at 120 ° C for 4 hours. After treatment, the residue is purified by normal phase CLAP eluting with a gradient of 0-25% ethanol in dichloromethane to provide the title compound as a pale yellow solid (0.081 g). p.f. 113-114 ° C MS (APCI) 391 (M + H) + X NMR (DMSO) 8.44 (1H, d); 8.38 (1H, d); 7.62 (1H, d), 7.51 (4H, t); 7.32-7.23 (3H, m); 6.97 (2H, d); 4.98 (1H, d); 4.31 (1H, c); 3.54 (1H, broad d); 2.89-2.73 (1H, m); 2.71 (4H, s); 2. 69-2.53 (1H, m); 2.30 (3H, s); 1.91-1.79 (1H, m); 1.72-1.59 (1H, m); 1.23 (3H, d).

Example 31 (1S, 2R) -4"- (2-Hydroxy-1-methyl-4-pyridin-3-ylbutoxy) biphenyl-3-yl-urea Prepared according to the method described in example 12b) from 3-bromo-phenylurea (0.215 g), ethanol (1 ml), toluene (4 ml), 2M aqueous sodium carbonate. (0.5 ml), (1S, 2R) -4- [2- (tert-butyldimethylsilanyloxy) -1-methyl-4-pyridin-3-ylbutoxy] benzeneboronic acid (0.2 g, example 11)) and tetrakis (triphenylphosphine) palladium (0) (0.02 g) with heating at 120 ° C for 4 hours. After the treatment, the residue is purified by CLAP in the normal phase eluting with a gradient of 0-25% ethanol in dichloromethane to give the title compound as a solid (0.116 g). p.f. 75-76 ° C MS (APCI) 392 (M + H) + X H NMR (DMSO) 8.58 (1H, s); 8.43 (2H, d); 7.64 (2H, d); 7.48 (2H, d); 7.32-7.23 (3H, m); 7.11 (1H, d); 6.98 (2H, d); 5.87 (2H, d); 5.00 (1H, d); 3.56 (1H, d); 3.49-3.34 (1H, m); 2.87-2.76 (1H, m); 2.71-2.60 (1H, m); 1.92-1.82 (1H, m); 1.72-1.63 (1H, m); 1.24 (3H, d).

Example 32 Acid salt (3R, 4S) -4- (3 •, 4'-dichlorobiphenyl-4-yloxy) -1-pyridin-3-yl-pentan-3-ol Prepared according to the method described in example 12b) from 3,4-dichloroiodobenzene (0.273 g), ethanol (2 ml), toluene (5 ml), 2M aqueous sodium carbonate. (0.5 ml), (1S, 2R) -4- [2- (tert-butyldimethylsilanyloxy) -1-methyl-4-pyridin-3-ylbutoxy] benzeneboronic acid (0.2 g, example 11)) and tetrakis (triphenylphosphine) palladium (0) (0.025 g) with heating at 120 ° C for 4 hours. After the treatment, the residue is purified by normal phase CLAP eluting with a gradient of 0-25% ethanol in dichloromethane to provide the title compound which is converted to the oxalic acid salt by treatment with a saturated ethereal solution of oxalic acid to provide the title compound as a solid (0.229 g). p.f. 86-88 ° C MS (APCI) 402, 404 (M + H) + XH NMR (DMSO) 8.46 (1H, d); 8.44 (1H, d); 7.87 (1H, d); 7.70 (1H, dt); 7.65-7.58 (4H, m); 7.35 (1H, dd); 7.0 (2H, d); 4.35 (1H, dc); 3.60-3.52 (1H, m); 2.88-2.78 (1H, m); 2.72-2.61 (1H, m); 1.95-1.82 (1H, m); 1.70-1.59 (1H, m); 1.25 (3H, d) Example 33 (1S, 2R) -4- (2-Hydroxy-l-methyl-4-pyridin-3-ylbutoxy) benzeneboronic acid A solution of (1S, 2R) -4- [2- (tert-butyldimethylsilanyloxy) -l-methyl-4-pyridin-3-ylbutoxy] benzanboronic acid (10 g, example 11) in methanol (150 ml) is stirred for 16 hours at room temperature and 2M hydrochloric acid (25 ml) The solution is concentrated to give an acidic aqueous residue which is washed with diethyl ether, the aqueous layer is made basic with saturated sodium bicarbonate, the product is extracted ethyl, dried over anhydrous magnesium sulfate, filtered and concentrated to give the title compound as a foam (6.97 g) .MS (APCI) 302 (M + H) + 'H NMR (DMS? / D20) 8.42 (1H, s), 8.39 (1H, s), 7.70-7.64 (3H, m), 7.33 (1H, dd), 6.85 (2H, d), 4.32 (1H, m), 3.53 (1H, m); 2.79 (1H, m), 2.66 (1H, m), 1.84 (1H, m), 1.65 (1H, m), 1.21 (3H, d).

Example 34 (1S, 2R) -4 '- (2-Hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -3-methyl-biphenyl-4-carbonitrile Prepared according to the method described in Example 12b) from (1S, 2R) -4- (2-hydroxy-l-methyl-4-pyridin-3-ylbutoxy) benzanboronic acid (0.150 g, example 33) , 4-bromo-2-methylbenzonitrile (0.301 g), 2M aqueous sodium carbonate (0.50 ml) and tetrakis (triphenylphosphine) palladium (0) (0.025 g) in ethanol (3 ml). The reaction mixture is heated at 90 ° C for 4 hours. After cooling, the solution is concentrated under reduced pressure, taken up in ethanol and concentrated again (twice). The residue is triturated with acetone and then filtered through silica gel. The filtrate is concentrated under reduced pressure, it is dissolved in dichloromethane, filtered and purified by CLAP in a normal phase eluting with a gradient of 0-25% ethanol in dichloromethane to provide an oil which crystallizes under high vacuum for 24 hours. Trituration with diethyl ether results in isolation of the title compound as a solid (0.11 g). p.f. 93.5-94.5 ° C MS (APCI) 373.2 (M + H) + E NMR (DMSO) 8.44 (1H, m); 8.38 (1H, m); 7.79 (1H, d); 7.34 (1H, s); 7.68-7.60 (4H, m); 7.31 (1H, m), 7.02 (2H, d), 5.01 (1H, d), 4.36 (1H, m); 3.55 (1H, m), 2.80 (1H, m), 2.65 (1H, m), 2.53 (3H, s), 1.86 (1H, m), 1.64 (1H, m), 1.24 (3H, d).

Example 35 Amide of (1S, 2R) -4-Fluoro-4 '- (2-hydroxy-l-methyl-4-pyridin-3-yl-butoxy) biphenyl-3-sulfoniso acid and (1S, 2S) -amide 4-f luoro -4 * - (2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy) biphenyl-3-sulfonic acid a) 5-Bromo-2-fluorophenylsulfonic acid amide A mixture of 5-bromo-2-fluoronitrobenzene (11 g), iron (20 g) and ammonium chloride (20 g) is refluxed in ethanol (200 ml) and water (150 ml) for 1 hour. The reaction is cooled, filtered and concentrated (200 ml). The filtrate is extracted with ether, dried over anhydrous magnesium sulfate and concentrated. The residue is added to concentrated hydrochloric acid (20 ml) and cooled to -5 ° C. A saturated solution of sodium nitrite (388 g) in water (6 ml) is added dropwise at a rate such that the temperature below 0 ° C is maintained. Magnesium chloride (8 g) is added (caution: exotherm) and the resulting mixture is added with stirring to a saturated solution of sulfur dioxide in acetic acid (40 ml) and toluene (20 ml), which contains cupric chloride (2.75). g) at room temperature. The mixture is stirred for 60 minutes, poured into water and extracted into toluene. The combined toluene extracts are washed with water, dilute sodium hydrogen carbonate, dried over anhydrous magnesium sulfate and concentrated. The residue is dissolved in tetrahydrofuran (50 ml) and ammonia (0.880, 10 ml) is added. The resulting mixture is stirred for 30 minutes and concentrated to give an aqueous residue which is divided between ethyl acetate (30 ml) and water (30 ml). The aqueous residue is extracted with ethyl acetate (3 x 30 mL) and the combined extracts are dried over anhydrous magnesium sulfate and concentrated. The residue is triturated with ether: 1: 4 exano and filtered to give the subtitle compound as a solid (6.37 g). p.f. 153-154 ° C MS (APCI) 254 (M-H) "JH NMR (CDC13) 8.05 (1H, dd); 7.71-7.66 (1H, m); 7.13 (1H, dd); 5.11 (2H, s); . b) (1S, 2R) -4-Fluoro-4 '- (2-hydroxy-l-methyl-4-pyridin-3-yl-butoxy) biphenyl-3-sulfonic acid amide and (1S, 2S) amide ) -4-fluoro- '- (2-hydroxy-l-methyl-4-pyridin-3-ylbutoxy) biphenyl-3-sulfonic acid It is prepared according to the method described in example 12b (from the amide of 5-bromo-2-fluorophenylsulphonic acid (0.191 g, example 34a)), ethanol (2 ml), toluene (5 ml), carbonate aqueous sodium 2M (0.5 ml), acid (1S, 2R) -4- [2- (tert-butyldimethylsilanyloxy) -l-methyl-4-pyridin-3-ylbutoxy] benzanboronic acid (0.2 g, example 11)), and tetrakis (triphenylphosphine) palladium (0) (0.025 g) with heating at 80 ° C for 2 hours. After the treatment, the residue is purified by normal phase CLAP eluting with a gradient of 0-25% ethanol in dichloromethane to provide the minor diastereomer, (1S, 2S) -4-fluoro-4 '- (2 -hydroxy-l-methyl-4-pyridin-3-yl-butoxy) biphenyl-3-sulfonic acid as a foam and with further elution of the main product, (1S, 2R) -4-fluoro-4 '- ( 2-hydroxy-l-methyl-4-pyridin-3-yl-butoxy) biphenyl-3-sulfonic acid (0.15 g).

Amide of (1S, 2S) -4-fluoro-4 '- (2-hydroxy-l-methyl-4-pyridin-3-yl-butoxy) ifenyl-3-sulfonic acid MS (APCI) 431 (M + H) + NMR (DMSO) 8.43 (1H, d); 8.37 (1H, dd); 7.94 (1H, dd); 7.89-7.85 (1H, m); 7.71 (2H, s); 7.64-7.61 (1H, m); 7.56 (2H, d); 7.50-7.44 (1H, m); 7.30-7.26 (1H, m); 7.04 (2H, d); 4.97 (1H, d); 4.43-4.40 (1H, m); 3.60-3.50 (1H, m), 2.85-2.58 (2H, m); 1.82-1.60 (2H, m); 1.21 (3H, d).

Amide of acid (1S # 2R) -4-fluoro-4 '- (2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) biphenyl-3-sulfonic acid MS (APCI) 431 (M + H) + XH NMR (CDC13) 8.46 (1H, d); 8.43 (1H, d); 8.04 (1H, dd); 7.71-7.68 (1H, m); 7.54 (1H, dt); 7.55 (2H, d); 7.28-7.21 (2H, m); 6.95 (2H, d); 5.32 (2H, s); 4.40-4.30 (1H, m); 3.87-3.83 (1H, m); 2.98-2.93 (1H, m); 2.79-2.70 (1H, m); 2.34 (1H, broad); 1.92-1.80 (2H, m); 1.31 (3H, d).

Example 36 (1S, 2S) -4-fluoro-4 • - (2-hydroxy-l-methyl-4-pyridin-3-yl-butoxy) biphenyl-3-carbonitrile.

OH It is prepared according to the method described in Example 12 from (1S, 2R) -4- (2-hydroxy-l-methyl-4-pyridin-3-ylbutoxy) benzanboronic acid (0.4 g, example 33), 3-cyano-4-fluorobromobenzene (0.399 g), ethanol (10 ml), 2M aqueous sodium carbonate (1.66 ml) and tetrakis (triphenylphosphine) palladium (0) (0.3 g) with heating at 80 ° C for 3 hours. After the treatment, the residue is purified by CLAP in the normal phase by eluting a gradient of 0-10% ethanol in dichloromethane to give the title compound as a solid (0.24 g). p.f. 108-109 ° C MS (APCI) 377 (M + H) + E NMR (CDCl 3) 8.55 (1H, s); 8.45 (1H, d); 7.75-7.70 (2H, m); 7.60-7.50 (1H, m); 7.45-7.40 (2H, m); 7.25-7.20 (2H, m); 6.95 (2H, d); 4.45-4.35 (1H, m); 3.90-3.80 (1H, m); 3.00-2.90 (1H, m); 2.80-2.70 (1H, m); 2.15 (1H, d); 1.90-1.80 (2H, m); 1.30 (3H, d).

Example 37 (1S, 2R) -4-Difluoro-4 '- (2-hydroxy-l-methyl-4-pyridin-3-yl-butoxy) biphenyl-4-sulfonic acid amide.

OH a) 4-bromo-2, 5-difluorobenzenesulfonamide.

Ammonium hydroxide (5 ml) is added to a solution of 2,5-difluoro-4-bromo-phenylsulfonyl chloride (4.3 g) in tetrahydrofuran (20 ml) at room temperature (CAUTION: exotherm) and stirred for 10 min. The reaction mixture is poured into water and extracted with ethyl acetate. The ethyl acetate is dried over anhydrous magnesium sulfate and filtered. The filtrate is evaporated and the residue triturated with 20% diethyl ether in isohexane to give the subtitle compound as a solid (4.3 g). p.f. 161-163 ° C MS (El) 271/273 (M +) 4 1 NMR (CDC13) 7.69 (1H, dd); 5.17 (2H, s); b) (1S, 2R) -2,5-difluoro-4 '- (2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) biphenyl-4-sulfonic acid amide.

Prepared according to the method described in example 12) from (1S, 2R) -4- (2-hydroxy-l-methyl-4-pyridin-3-ylbutoxy) benzanboronic acid (0.2 g, example 33), 4-bromo-2, 5-difluorobenzenesulfonamide (0.19 g, example 37a)), ethanol (3 ml), 2M aqueous sodium carbonate (0.7 ml) and tetrakis (triphenylphosphine) palladium (0) (0.03 g) with heating to 80 ° C for 3 hours. After treatment, the residue is purified by CLAP in the normal phase eluting with a gradient of 0-25% ethanol in dichloromethane to give the title compound as a foam (0.11 g). MS (APCI) 449 (M + H) + NMR (CDCl 3) 8.51 (1H, d); 8.46 (1H, d); 7.69 (1H, dd); 7.54 (1H, dd); 7.48 (2H, dd); 7.31-7.02 (2H, m); 6.97 (2H, dd); 5.16 (2H s); 4.44-4.39 (1H, m); 3.88-3.85 (1H, m); 2. 99-2.92 (1H, m); 2.80-2.74 (1H, m); 2.12 (1H, d); 1.92-1.80 (2H, m); 1.32 (3H, d).

Example 38 (1S, 2R) -3-chloro-4 '- (2-hydroxy-l-methyl-4-pyridin-3-ylbutoxy) biphenyl-4-carbonitrile.

OH Prepared according to the method described in example 12b) from (1S, 2R) -4- (2-hydroxy-l-methyl-4-pyridin-3-ylbutoxy) benzeneboronic acid (0.20 g, example 33), 4-bromo-2-chlorobenzonitrile (0.288 g), 2M aqueous sodium carbonate (0.76 ml) and tetrakis (triphenylphosphine) palladium (0) (0.075 g) in ethanol (5 ml) with heating at 90 ° C for 4 hours. After the treatment, the residue is purified by CLAP in the normal phase eluting with a gradient of 0-10% ethanol in dichloromethane to give the title compound as an oil (0.18 g). MS (APCI) 393 (M + H) + XH NMR (CDC13) 8.51 (1H, d); 8.46 (1H, dd); 7.69-7.67 (2H, m); 7.56-7.54 (1H, m); 7.54-7.52 (1H, m); 7.51 (2H, D); 7.49-7.22 (1H, m); 6.98 (2H, d); 4.41-4.39 (1H, m); 3.86-3.85 (1H, m); 2.95-2.94 (1H, m); 2.76-2.73 (1H, m); 2.25-2.24 (1H, m); 1.89-1.84 (2H, m); 1.32 (3H, d).

Example 40 (1S, 2R) -3- [6- (2-Hydroxy-l-methyl-4-pyridin-3-ylbutoxy) naphthalen-2-yl] -N, N-dimethylacrylamide.

OH a) (1S, 2R) -3- [6- (2-hydroxy-l-methyl-4-pyridin-3-ylbutoxy) naphthalen-2-yl] -N, N-dimethylacrylamide. (2S, 3R) -4- (6-Bromonaphthalen-2-yloxy) -1-pyridin-3-yl-pentan-3-ol (0.25 g, example 10), N, N-dimethylacrylamide (0.64 g) are added. , tri-o-tolylphosphine (0.04 g), triethylamine (2 ml) and palladium acetate (0.01 g), to acetonitrile (10 ml) and the mixture is heated at 70 ° C in a sealed tube for 16 hours. Allow the reaction mixture to cool to room temperature and then concentrate under reduced pressure. The residue is purified by flash column chromatography on silica gel eluting with 20% acetone in isohexane followed by 50% acetone in isohexane and finally 5% methanol in dichloromethane, to give the subtitle compound as an oil (0.27 g). MS (APCI) 405 (M + H) + NMR (CDC13) 8.52 (1H, s).; 8.46 (1H, d); 7.84 (1H, s); 7.80 (1H, d); 7.75 (1H, s); 7.66 (2H, d); 7.56 (1H, d); 7. 25-7.20 (1H, m); 7.14 (2H, d); 6.96 (1H, d); 4.55-4.47 (1H, m); 3.94-3.88 (1H, m); 3.21 (3H, s); 3.09 (3H, s); 3.02-2.92 (1H, m); 2.80-2.70 (1H, m); 1.93-1.85 (2H, m); 1.36 (3H, d). b) (2S, 3R) -3- [6- (3-hydroxy) -5-pyridin-3-ylpent-2-yloxy) naphth-2-yl] propionic acid dimethylamide.

A suspension of 10% palladium on carbon (0.1 g) in ethanol (20 ml) is added to (2S, 3R) -3- [6- (3-Hydroxy) -5-pyridin-3-ylpent-2-yloxy acid. ) aft-2-yl] propionic, dimethylamide (0.27 g, example 40a) in ethanol (30 ml) and the mixture is hydrogenated at a pressure of 1.5 atmospheres for 2 hours. The reaction mixture is filtered through Celite '* to remove the catalyst and the filter cake is washed with ethanol (2 x 50 mi). The combined filtrate and washings are concentrated under reduced pressure and the residue is purified by normal phase CLAP eluting with a gradient of 0.25% ethanol in dichloromethane to give the title compound as an oil (0.11 g). MS (APCI) 407 (M + H) + NMR (CDC13) 8.52 (1H, s); 8.46 (1H, d); 7.69 (1H, d); 7.63 (1H, d); 7.59-7.55 (2H, m); 7.33 (1H, dd); 7.24-7.22 (1H, m); 7.11-7.09 (2H, m); 4.52-4.45 (1H, m); 3.97-3.90 (1H, m); 3.10 (1H, t); 2.94 (6H, d); 2.76-2.66 (4H, m); 2.35-2.15 (2H, m); 1.95-1.85 (2H, m); 1.34 (3H, d).

Example 41 (1S, 2R) -4 '- (2-hydroxy-l-methyl-4-pyridin-3-yl-butoxy) ifenyl-3-N-sulfonamido-N' -isopropyl-urea. a) N - [(Methylamino) carbonyl] -3-bromobenzenesulfonamide.

Isopropyl isocyanate (0.6 ml) is added to a solution of 3-bromobenzenesulfonamide (1.18 g), and copper (I) chloride (0.025 g) in anhydrous dimethylformamide (3 ml). The resulting solution is stirred for 20 hours and poured into a 2N hydrochloric acid solution (50 ml) and the resulting precipitate is filtered. The resulting solid is dissolved in dichloromethane (40 ml) and dried over anhydrous magnesium sulfate, filtered and concentrated. The residue is triturated with hexane and filtered to give the subtitle compound as a solid (1.34 g). p.f. 136.5-137 ° C MS (APCI) 321, 323 (M + H) + XH NMR (CDCl 3) 8.18 (1H, broad); 8.04 (1H, t); 7.82 (1H, dt); 7.76 (1H, dt); 7.42 (1H, t); 6.38 (1H, d); 4.01-3.88 (1H, m); 1.18 (6H, d). b) (1S, 2R) -4'- (2-hydroxy-l-methyl-4-pyridin-3-yl-butoxy) biphenyl-3-N-sulfonamido-N '-isopropyl-urea.

Prepared according to the method described in Example 4e) from (1S, 2R) -4- [2- (tert-Butyldimethylsilanyloxy) -l-methyl-4-pyridin-3-ylbutoxy) benzeneboronic acid (0.20 g, example 11), N- [(methylamino) -carbonyl] -3-bromobenzenesulfonamide (0.28 g), 2M aqueous sodium carbonate (0.5 ml) and tetrakis (triphenylphosphine) palladium (0) (0.05 g) in toluene (5 ml) and ethanol (2 ml). The reaction is heated at 120 ° C for 4 hours. After cooling, 2M hydrochloric acid (10 ml) and methanol are added. The mixture is stirred for 30 minutes and then extracted with ether (30 ml). The residual aqueous phase is adjusted to pH 7 and extracted with ethyl acetate. The combined organic extracts are dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue is dissolved in tetrahydrofuran (20 mL) and a solution of tetrabutylammonium fluoride in tetrahydrofuran (1M, 10 mL) is added. The solution is stirred for 18 hours and then concentrated under reduced pressure. The residue is divided between pH 7 buffer and ethyl acetate. The combined organic extracts are dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by CLAP in the normal phase eluting with a gradient of 0-25% ethanol in dichloromethane to give a gum (0.07 g). This is triturated with isohexane: ether (9: 1) to give a solid. MS (APCI) 498 (M + H) + ^ - H NMR (DMSO) 8.45 (1H, s); 8.39 (1H, d); 8.07 (1H, s); 7.87 (1H, d); 7.79 (1H, d); 7.7-7.5 (4H, m); 7.35-7.25 (1H, m); 7.05 (2H, d); 6.33 (1H, broad s); 5.05-4.95 (1H, m); 4.4-4.3 (1H, m); 3.7-3.5 (2H, m); 2.9-2.55 (3H, m); 1.95- 1.8 (1H, m); 1.8-1.55 (1H, m); 1.25 (3H, d); 0.98 (6H, d).

Example 42 Oxalic acid salt of (1S, 2R) -3- [6- (2-hydroxy-l-methyl-4-pyridin-3-yl-butoxy) naph alen-2-yl] -1-morpholin-4- il-? ropan-1-one.

OH a) l-morpholin-4-yl-propenone.

Acrylonol chloride (8 g), morpholine (7.7 g) and triethylamine (8.94 g) are added to tetrahydrofuran (100 ml) at -30 ° C. The reaction mixture is stirred and allowed to slowly reach room temperature overnight. The triethylamine hydrochloride is removed by filtration and the concentrate is concentrated under reduced pressure. The residue obtained in this way is stirred in a 1: 1 mixture of isohexane: diethylether (500 ml) to precipitate more triethylamine hydrochloride. The salt is removed by filtration and the filtrate is concentrated under reduced pressure to provide the subtitle compound as an oil (11 g). GC / MS 141 (M) + NMR (CDC13 6.55 (1H, dd); 6.32 (1H, dd); 5.72 (1H, dd); 3.70 (8H, broad s). b) (1S, 2R) -3- [6- (2-hydroxy-l-methyl-4-pyridin-3-yl-butoxy) -naphthalen-2-yl] -l-morpholin-4-yl-propenyone.

Prepared according to the method described in example 40a) from (2S, 3R) -4- (6-bromonaphthalen-2-yloxy) -l-pyridin-3-yl-pentan-3-ol (0.60 g) , example 10), 1-morpholin-4-ylpropenone (1.09 g, example 42a)), palladium acetate (0.03 g), tri-o-tolylphosphine (0.09 g) and triethylamine (2 ml) in acetonitrile (10 ml) . After treatment, the untreated material is purified by flash column chromatography on silica eluting with 20% acetone in isohexane, followed by 50% acetone in isohexane and finally 5% methanol in dichloromethane to provide the subtitle compound as a foam (0.52). g). MS (APCI) 447 (M + H) + NMR (CDC13 8.52 (1H, d); 8.46 (1H, dd); 7.85 (1H, d); 7.79 (1H, d); 7.72 (1H, d); (1H, s), 7.64 (1H, dd), 7.56 (1H, dd), 7.26-7.20 (1H, m), 7.15 (1H, dd), 7.12 (1H, dd), 6.91 (1H, d); 4.53-4.49 (1H, m), 3.91 (1H, broad), 3.74 (8H, broad), 2.99-2.92 (1H, m), 2.80-2.73 (1H, m), 2.30 (1H, broad); 1.93-1.85 (2H, m); 1.36 (3H, d). c) Oxalic acid salt of (1S, 2R) -3- [6- (2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) naphthalen-2-yl] -l-morpholin-4- il-propan-1-one.

Prepared according to the method described in Example 40b) from (1S, 2R) -3- [6- (2-hydroxy-l-methyl-4-pyridin-3-yl-butoxy) -naphthalene-2 -yl] -1-morpholin-4-yl-propenone (0.52 g, example 42b)), 10% palladium on carbon (0.2 g) and ethanol (50 ml). After treatment, the untreated material is purified by flash column chromatography on silica eluting with 5% ethanol in dichloromethane to provide an oil (0.5 g). A portion of this (0.15 g) is treated with ethereal oxalic acid to provide the title compound as a solid (0.14 g). p.f. 156-159 ° C MS (APCI) 449 (M + H) + NMR (DMSO) 8.47 (1H, d); 8.41 (1H, dd); 7.72-7.67 (3H, m); 7.62 (1H, s); 7.36-7.32 (2H, m); 7.24 (1H, d); 7.11 (1H, dd); 4.45-4.39 (1H, m); 3.62-3.56 (1H, m); 3.50-3.37 (8H, m); 2.93 (2H, t); 2.83-2.79 (1H, m); 2.73-2.69 (3H, m); 1.92-1.88 (1H, m); 1.71-1.66 (1H, m); 1.28 (3H, d).

Example 43 Oxalic acid salt of (3R, 4S) -4- [6- (3-morpholin-4-yl-propyl) naphlene-2-yloxy] -l-pyridin-3-yl-pentan-3-ol.

OH It is cooled to 0 ° C diborane (10 ml, 1.0 M solution in tetrahydrofuran) and stirred under a nitrogen atmosphere. To this is added, dropwise, oxalic acid salt of (1S, 2R) -3- [6- (2-hydroxy-l-methyl-4-pyridin-3-yl-butoxy) -naphthalen-2-yl] -l-morpholin-4-yl-propan-l-one (0.35 g, example 42c)) in tetrahydrofuran (10 ml), for a period of 15 minutes. The resulting colorless solution is subjected to reflux temperature and heated under reflux for 1 hour. The reaction is allowed to cool to room temperature and acidified with 6M hydrochloric acid (2 mL) and then heated at reflux temperature for 0.5 hour. The solution is cooled and divided between ether and water. The aqueous layer is made basic with 2M sodium hydroxide and extracted with ethyl acetate. The ethyl acetate is washed with brine and dried over anhydrous magnesium sulfate. After filtration, the solvent is removed by evaporation under reduced pressure and the residue is purified by flash column chromatography on silica eluting with dichloromethane containing 2% triethylamine and 1% ethanol to give the free base of the title compound as an oil (0.25 g). . This is treated with ethereal oxalic acid to provide the title compound as a solid (0.15 g). MS (APCI) 435 (M + H) + NMR (DMSO) 8.44 (1H, d); 8.38 (1H, dd); 7.73 (2H, dd); 7.64 (2H, dd); 7.35-7.26 (3H, m); 7.12 (1H, dd); 4.43-4.39 (1H, m); 3.78 (4H, broad s); 3.60-3.58 (1H, m); 3.42- 3.35 (2H, m); 3.13 (4H, broad s); 3.02 (1H, t); 2.82-2.66 (3H, m); 2.09-1.95 (2H, m); 1.95-1.82 (1H, m), 1.76-1.62 (1H, m); 1.28 (3H, d).

Example 44 Oxalic acid salt of (3R, 4S) -4- [6- (3-methylaminopropyl) naph talen-2-yloxy] -l-pyridin-3-yl-pentan-3-ol.

OH It is prepared according to the method described in example 43 from (1S, 2R) -3- [6- (2-hydroxy-l-methyl-4-pyridin-3-yl-butoxy) naphthalen-2-yl. ] -N-methylpropionamide (0.12 g, example 85c)) and diborane (10 ml, 1.0M solution in tetrahydrofuran) in tetrahydrofuran (30 ml). After working-up the solvent is removed by evaporation under reduced pressure and the residue is treated with ethereal oxalic acid to give the title compound as a hygroscopic solid (0.017 g). MS (APCI) 379 (M + H) + NMR (DMSO) 8.67 (1H, broad s); 8.44 (1H, d); 8.38 (1H, dd); 7.73 (2H, dd); 7.63 (2H, m); 7.33-7.26 (3H, m); 7. 12 (1H, dd); 4.43-4.40 (1H, m); 3.62-3.57 (1H, m); 2.95-2.60 (6H, m); 2.54 (3H, s); 2.00-1.85 (3H, m); 1.72-1.63 (1H, m); 1. 28 (3H, d).

Example 45 (1S, 2R) -4 '- (2-hydroxy-l-isopropyl-4-pyridin-3-yl-butoxy) biphenyl-3-carbonitrile.

OH It is prepared according to the method described in example 12b) from 3-cyanobenzeneboronic acid (0.40 g), (3S, 4R) -3- (4-bromophenyloxy) -2-methyl-6- (3-pyridyl) hexan-4-ol (0.90 g, example 61d)), 2M aqueous sodium carbonate (2.72 ml) and tetrakis (triphenylphosphine) palladium (O) (0.160 g) in ethanol (4 mi) The reaction mixture is heated at 90 ° C for 4 hours. After cooling, the solution is poured into water, and extracted with ethyl acetate. The combined extracts are washed with brine, dried over magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure, dissolved in dichloromethane, filtered and purified by CLAP in the normal phase eluting with a gradient of ethanol in dichloromethane 0-25% to give the title compound as a gum (0.54 g). MS (APCI) 387 (M + H) + X H NMR (DMSO) 8.35 (2H, s); 8.07 (1H, s); 7.95 (1H, d); 7.75 (1H, d); 7.69-7.5 (4H, m); 7.25 (1H, t); 7.1 (2H, d); 5.0 (1H, d); 4.2-4.12 (1H, m); 3.7-3.6 (1H, m); 2.85-2.72 (1H, m); 2.7.2.65 (1H, m); 2.2-2.05 (1H, m); 1.85-1.55 (2H, m); 0.9 (6H, dd).

Example 46 (3R, 4S) -l-pyridin-3-yl-4- [4 '- (2-pyrrolidin-1-yl-ethoxy) biphenyl-4-yloxy] pen an-3-ol.

OH Prepared according to the method described in example 12b) from (1S, 2R) -4- (2-hydroxy-l-methyl-4-pyridin-3-ylbutoxy) benzenesulfonic acid (0.190 g, example 33) , 1- [2- (4-bromophenoxy) ethyl] pyrrolidine (0.27 g), 2M aqueous sodium carbonate (0.75 ml) and tetrakis (triphenylphosphine) palladium (0) (0.025 g) in ethanol (2 ml). The reaction mixture is heated at 90 ° C for 4 hours. After cooling, the solution is concentrated under reduced pressure, taken up in ethanol and concentrated again (twice). The residue is triturated with acetone and then filtered through silica gel. The filtrate is concentrated under reduced pressure, dissolved in dichloromethane, filtered and purified by CLAP in the normal phase eluting with a gradient of ethanol in dichloromethane 0-25% to provide an oil which crystallizes under high vacuum for 24 hours. Trituration with diethyl ether results in isolation of the title compound as a foam (0.194 g) MS (APCI) 447.2 (M + H) + XH NMR (CDC13) 8.51 (1H, d); 8.46 (1H, dd); 7.55 (1H, dt); 7.46 (4H, d); 7.22 (1H, dd); 6.98 (2H, d); 6.92 (2H, d); 4.37 (1H, dt); 4.15 (2H, t); 3.88-3.85 (1H, m); 2.83 (3H, t); 2.78-2.67 (1H, m); 2.73-2.63 (4H, m); 2.2 (1H, broad); 1.89 (6H, m); 1.30 (3H, d).

Example 47 (1S, 2R) -4 '- (2-hydroxy-l-methyl-4-pyridin-3-ylbutoxy) -4- (2-morphsin-4-yl-ethoxy) biphenyl-3-carbonitrile.

OH a) 5-bromo-2 - (2-morph ol in 4-i l-e t i lamino) -benzonitrile.

-Bromo-2-fluorobenzonitrile (1.0 g) and 4- (2-aminoethyl) morpholine (0.65 g) in acetonitrile (5 ml) are mixed together at 70 ° C for 4 hours, cooled and poured into an aqueous solution. of sodium hydrogen carbonate and extracted in ethyl acetate, dried over anhydrous magnesium sulfate and concentrated. The residue is purified by chromatography on silica gel eluting with methanol in 2.5% dichloromethane containing 1% triethylamine to give the subtitle compound as an oil (0.77 g). EM (APCI) 310, 312 (M + H) + b) (1S, 2R) -4 * - (2-hydroxy-l-methyl-4-pyridin-3-ylbutoxy) -4- (2-morpholin-4-yl-ethoxy) biphenyl-3-carbonitrile.

Prepared according to the method described in example 12b) from (1S, 2R) -4- (2-hydroxy-l-methyl-4-pyridin-3-ylbutoxy) benzeneboronic acid (0.190 g, example 33) , 5-bromo-2- (2-morpholin-4-yl-ethylamino) enzonitrile (0.31 g, example 47a)), 2M aqueous sodium carbonate (0.75 ml) and tetrakis (triphenylphosphine) palladium (0) (0.025 g) in ethanol (2 ml). The reaction mixture is heated at 90 ° C for 4 hours. After cooling, the solution is concentrated under reduced pressure, taken up in ethanol and concentrated again (2 times). The residue is triturated with acetone and then filtered through silica gel. The filtrate is concentrated under reduced pressure, dissolved in dichloromethane, filtered and purified by CLAP in the normal phase eluting with a gradient of 0-25% ethanol in dichloroethane to provide an oil which crystallizes under high vacuum for 24 hours. Trituration with diatyl ether results in the isolation of the title compound as a foam (0.19 g). MS (APCI) 487.2 (M + H) + XE NMR (CDC13) 8.50 (1H, d); 8.45 (1H, dd); 7.60-7.54 (3H, m); 7.40 (2H, dd); 7.24-7.22 (1H, dd); 6.93 (2H, dd); 6.70 (1H, d); 5.40 (1H, t); 4.38-4.35 (1H, m); 3.87-3.83 (1H, m); 3.76 (4H, dd); 3.27 (2H, c); 2.95-2.90 (1H, m); 2.80-2.75 (1H, m); 2.70 (2H, t); 2.54-2.49 (4H, m); 2.20 (1H, d); 1.89-1.80 (2H, m); 1.30 (3H, d).

Example 48 (3R, 4S) -4- (3'-methanesulfonylbiphenyl-4-yloxy) -1-pyridin-3-yl-pentan-3-yl-pentan-ol. a) l-bromo-3-methanesulfonylbenzene Dissolve 3-bromothioanizol in methanol (20 mL) and cool to 0 ° C (ice / water bath). A solution of Oxone'® (9.22 g) in water (30 ml) is added thereto, and the resulting cloudy suspension is stirred at room temperature for 3 hours. The reaction mixture is diluted with water and the product is extracted with dichloromethane. The combined dichloromethane fractions are washed with brine and dried over anhydrous magnesium sulfate. After filtration, the solvent is removed by evaporation under reduced pressure to provide the subtitle compound as a solid (1.02 g). p.f. 63-64 ° C GC / MS 236/238 (M) + XH NMR (CDC13) 8.10 (1H, s); 7.89 (1H, dd); 7.80 (1H, dd); 7.47 (1H, t); 3.08 (3H, s). b) (2S, 3R) -2- [4- (3'-methylsulf onyl) bifyloxy] -5- (pyridin-3-yl) pentan-3-ol.

Prepared according to the method described in example 12b) from (1S, 2R) -4- [2- (tert-butyldimethylsilanyloxy) -l-methyl-4-pyridin-3-ylbutoxy] benzanboronic acid (0.2 g) , example _ 11), l-bromo-3-methanesulfonylbenzene (0.23 g, example 48a)), ethanol (2 ml), toluene (5 ml) and 2M aqueous sodium carbonate (0.5 ml) and tetrakis (triphenylphosphine) palladium ( O) (0.03 g) with heating at reflux temperature for 4 hours. After cooling, the solution is concentrated under reduced pressure. Concentrated hydrochloric acid (1 mL) is added to a solution of the residue in methanol (5 mL) and the suspension is stirred at room temperature for 1 hour. After the treatment, the residue is purified by CLAP in the normal phase, eluting with a gradient of 0-25% ethanol in dichloromethane to give the title compound as an oil (0.17 g). MS (APCI) 412 (M + H) + XH NMR (CDC13) 8.52 (broad 1H s); 8.47 (1H, broad s); 8.11 (1H, t); 7.89-7.80 (2H, m); 7.63 (1H, d); 7.59-7.52 (3H, m); 7.26-7.21 (1H, m); 6.98 (2H, dd); 4.43-4.39 (1H, m); 3.92-3.83 (1H, m); 3.09 (3H, s); 2.96 (1H, m); 2.77-2.70 (1H, m); 2.25 (1H, broad s); 1.90-1.82 (2H, m); 1.32 (3H, d).

Example 49 (1S, 2R) -4 '- (2-Hydroxy-l-methyl-4-pyridin-3-yl-butoxy) biphenyl-3-carboxylic acid amide.

Prepared according to the method described in example 12b) from (1S, 2R) -4- (2-hydroxy-l-methyl-4-pyridin-3-ylbutoxy) benzanboronic acid (0.150 g, example 33) , 3-bromo-2-benzamide (0.20 g), 2M aqueous sodium carbonate (0.50 ml) and tetrakis (triphenylphosphine) palladium (O) (0.020 g) in ethanol (3 ml) with heating at 90 ° C for 2 hours . After the treatment, the residue is purified by normal phase CLAP eluting with a gradient of 0-25% ethanol in dichloromethane to give the title compound as a solid (0.107 g). p.f. 74-76 ° C MS (APCI) 377 (M + H) + XE NMR (DMSO) 8.45 (1H, s); 8.40 (1H, d); 8.11 (2H, s); 7.80 (1H, d); 7.75 (1H, d); 7.64 (3H, d); 7.50 (1H, t); 7.42 (1H, S); 7.30 (1H, t); 7.02 (2H, d); 5.31 (1H, d); 5.02 (1H, t); 3.57 (1H, broad s); 2.85-2.79 (1H, m); 2.70-2.62 (1H, m); 1.89-1.85 (1H, m); 1.70-1.65 (1H, m); 1.25 (3H, d).

Example 50 (1S, 2R) -2- [4 '- (2-hydroxy-l-methyl-4-pyridin-3-yl-butoxy) -biphenyl-3-yloxy] -acetamide.

OH a) 2- (3-bromophenoxy) -acetamide.

A mixture of 2-chloroacetamide (5.6 g), 3-bromophenol (10 g), potassium carbonate (8.3 g) and potassium iodide (1 g) in acetonitrile is stirred at room temperature for 72 hours. The resulting mixture is filtered and the solids are washed with ethyl acetate and then with water. The dry solids are recrystallized from boiling ethanol: water (8: 2) to provide the sub-title compound as a solid (13.8 g) - m.p. 96-98 ° C MS (APCI) 228 (M + H) + X H NMR (DMSO) 7.55 (1 H, broad s); 7.4 (1H, broad s), 7.25 (1H, t); 7.13-7.18 (2H, m); 6 96 (1H, dd); 4.45 (2H, s). b) (2S, 3R) -3- acid amide. { 4- [3-hydroxy-5- (3-pyridyl) pentan-2-yloxy] phenyloxyacetic acid.

Prepared according to the method described in example 12b) from (1S, 2R) -4- (2-hydroxy-l-methyl-4-pyridin-3-ylbutoxy) benzanboronic acid (0.150 g, example 33) , 2- (3-bromophenoxy) acetamide (0.230 g), 2M aqueous sodium carbonate (0.50 ml) and tetrakis (triphenylphosphine) palladium (O) (0.025 g) in ethanol (3 ml). The reaction mixture is heated at 90 ° C for 4 hours. After cooling, the solution is concentrated under reduced pressure, dried in ethanol and concentrated again (2 times). The residue is triturated with acetone and then filtered through silica gel. The filtrate is concentrated under reduced pressure, dissolved in dichloromethane, filtered and purified by CLAP in a normal phase eluting with a gradient of 0-25% ethanol in dichloromethane to give a colorless solid, which recrystallizes from ethyl acetate : isohexane (1: 1) in boiling to give the title compound as a solid (0.138 g). p.f. 120-122 ° C MS (APCI) 407 (M + H) + X H NMR (DMSO) 8.15 (1H, s); 8.46 (1H, d); 7.56 (1H, d); 7.49 (2H, d); 7.37 (1H, t); 7.3-7.19 (2H, m); 7.1 (1H, s); 6.95 (2H, d); 6.86 (1H, dd); 6.58 (1H, broad s); 5.69 (1H, broad s); 4.56 (2H, s); 4.45-4.35 (1H, m); 3.9-3.85 (1H, m); 3.0-2.9 (1H, m); 2.8-2.7 (1H, m); 2.26 (1H, broad s); 1.9-1.8 (2H, m); 1.31 (3H, d).

Example 51 (2S, 3R) -l-pyridin-3-yl-4- (2'-trifluorome-oxybiphenyl-4-yloxy) -pentan-3-ol.

OH Prepared according to the method described in example 12b) from (1S, 2R) -4- (2-hydroxy-l-methyl-4-pyridin-3-ylbutoxy) encenboronic acid (0.150 g), example 33 ), 2-bromo (trifluoromethyloxy) benzene (0.26 g), 2M aqueous sodium carbonate (0.50 ml) and tetrakis (triphenylphosphine) palladium (O) (0.025 g) in ethanol (3 ml). The reaction mixture is heated in a sealed bottle at 80 ° C for 2 hours. After cooling, the solution is concentrated under reduced pressure and taken up in acetone and filtered through a small plug of silica. The filtrate is concentrated under reduced pressure, dissolved in dichloromethane, filtered and purified by CLAP in the normal phase eluting with a gradient of 0-25% ethanol in dichloromethane to provide an oil (0.145 g). MS (APCI) 418 (M + H) +? NMR (CDC13) 8.52 (1H, d); 8.46 (1H, dd); 7.56 (1H, dd); 7.43-7.30 (6H, m); 7.25-7.20 (1H, m); 6.93 (2H, d); 4.45-4.35 (1H, m); 3.93-3.85 (1H, m); 3.0-2.9 (1H, m); 2.8-2.7 (1H, m); 2.20 (1H, broad s); 1.95-1.8 (2H, m); 1.32 (3H, d).

Example 52 (1S, 2R) -4 '- (2-hydroxy-l-methyl-4-pyridin-3-yl-butoxy) -6-methoxybiphenyl-3-carbonitrile.

OH Prepared according to the method described in example 12b) from (1S, 2R) -4- (2-hydroxy-l-methyl-4-pyridin-3-ylbutoxy) benzeneboronic acid (0.20 g, example 33) , 3-bromo-4-methoxybenzonitrile (0.20 g), 2 M aqueous sodium carbonate (0.5 ml) and tetrakis (triphenylphosphine) palladium (O) (0.03 g) in toluene (5 ml) and ethanol (2 ml), with heating at 90 ° C for 4 hours. After the treatment, the residue is purified by CLAP in the normal phase eluting with a gradient of 0-10% ethanol in dichloroethane to give the title compound as an oil (0.17 g). MS (APCI) 389/390 (M + H) + XH NMR (CDC13); 8.52 (1H, s); 8.46 (1H, d); 7.60 (1H, d); 7.56 (2H, m); 7.40 (2H, d); 7.23 (1H, dd); 7.00 (1H, d); 6.93 (2H, d); 4.39 (1H, m); 3.87 (4H, m); 2.95 (1H, m); 2. 74 (1H, m); 2.29 (1H, broad s); 1.86 (2H, m); 1.32 (3H, d).

Example 53 (3R, 4S) -4- (4'-Chloro-2'-methoxy-5 '-methylbiphenyl-4-yloxy) -l-pyridin-3-yl-pentan-3-ol.

OH Prepared according to the method described in example 12b) from (1S, 2R) -4- (2-hydroxy-l-methyl-4-pyridin-3-ylbutoxy) benzeneboronic acid (0.15 g, example 33) , 5-bromo-2-chloro-4-methoxytoluene (0.12 g), 2M aqueous sodium carbonate (0.57 ml) and tetrakis (triphenylphosphine) palladium (O) (0.014 g) in ethanol (5 ml) with 90 ° heating C for 4 hours. After treatment, the residue is purified by CLAP 'in the normal phase eluting with a gradient of 0-10% ethanol in dichloromethane to give the title compound as an oil (0.13 g). MS (APCI) 412 (M + H) + E NMR (CDC13) 8.51 (1H, d); 8.45 (1H, dd); 7.57- 7.54 (1H, m); 7.46 (2H, d); 7.24-7.21 (1H, m); 7.12 (1H, s); 6. 95 (1H, s); 6.90 (2H, d); 4.38-4.36 (1H, m); 3.87-3.85 (1H, m); 3.78 (3H, s); 2.98-2.91 (1H, m); 2.77-2.69 (1H, m); 2.33 (3H, s); 2.19 (1H, m); 1.87-1.81 (2H, m); 1.31 (3H, d).

Example 54 (1S, 2R) -4 '- (2-Hydroxy-l-methyl-4-pyridin-3-yl-butoxy) -biphenyl-3-carboxylic acid methylamide.

Prepared according to the method described in example 12b) from (1S, 2R) -4- (2-hydroxy-l-methyl-4-pyridin-3-ylbutoxy) benzanboronic acid (0.150 g, example 33) , 3-bromo-N-methylbenzamide (J. of Org. Chem.; 1963, 28, 3147-3149) (0.214 g), 2M aqueous sodium carbonate (0.25 ml) and tetrakis (triphenylphosphine) palladium (O) ( 0.05 g) in ethanol (3 ml). The reaction mixture is heated at 80 ° C for 3 hours. After cooling, the solution is concentrated under reduced pressure. The residue is triturated with acetone and then filtered through silica gel. The filtrate is concentrated under reduced pressure, dissolved in dichloromethane, filtered and purified by CLAP in the normal phase eluting with a gradient of 0-10% ethanol in dichloromethane. The product is further purified by flash column chromatography eluting with ethyl acetate to give the title compound as a solid (0.12 g). p.f. 54-55 ° C MS (APCI) 391 (M + H) + XE NMR (CDC13) 8.50 (1H, d); 8.45 (1H, dd); 7.96-7.95 (1H, m); 7.65 (2H, dd); 7.57-7.51 (3H, m); 7.46 (1H, t); 7.24-7.21 (1H, m); 6.95 (2H, dd); 6.26 (1H, broad s); 4.40-4.38 (1H, m); 3.88-3.85 (1H, m); 3.05 (3H, d); 2.95-2.92 (1H, m); 2.78-2.72 (1H, m); 2.32 (1H, d); 1.89-1.83 (2H, m); 1.32 (3H, d).

Example 55 (1S, 2R) - [41 - (2-Hydroxy-l-methyl-4-pyridin-3-yl-butoxy) -biphenyl-4-yl] -acetic acid.

OH Prepared according to the method described in example 12b) from (1S, 2R) -4- (2-hydroxy-l-methyl-4-pyridin-3-ylbutoxy) benzeneboronic acid (0.6 g, example 33) , 4-bromophenylacetic acid (0.624 g), 2M aqueous sodium carbonate (2.5 ml) and tetrakis (triphenylphosphine) palladium (O) (0.5 g) in ethanol (15 ml). The reaction mixture is heated at 100 ° C for 3 hours. After cooling the solution is concentrated under reduced pressure. Water is added to the residue and then washed with diethyl ether. The aqueous layer is acidified with 2M hydrochloric acid and washed with diethyl ether. The aqueous layer is neutralized to pH 7.11 and the solid is filtered off by washing with diether to give the title compound as a solid (0.431 g). p.f. 196-197 ° C MS (APCI) 392 (M + H) + 'H NMR (DMSO) 8.45 (1H, d); 8.40 (1H, d); 7.63 (1H, dt); 7.55-7.52 (4H, m); 7.31-7.28 (3H, m); 6.99 (2H, dd); 5.0 (1H, broad s); 4.33-4.30 (1H, m); 3.58-3.37 (3H, m); 2.80-2.77 (1H, m); 2.67-2.63 (1H, m); 1.88-1.85 (1H, m); 1.66-1.62 (1H, m); 1.24 (3H, d).

Example 56 (1S, 2R) -N- [4 '- (2-hydroxy-l-methyl-4-pyridin-3-yl-butoxy) -5-trifluoromethyl-biphenyl-2-yl] acetamide.

Prepared according to the method described in example 12b) from (1S, 2R) -4- (2-hydroxy-l-methyl-4-pyridin-3-ylbutoxy) benzeneboronic acid (0.15 g, example 33) , 2-bromo-4-trifluoromethyl) acetanilide (0.28 g), 2M aqueous sodium carbonate (0.57 ml), and tetrakis (triphenylphosphine) palladium (0) (0.014 g) in ethanol (5 ml) with heating under reflux for 2 hours. hours. After treatment, the residue is purified by CLAP in the normal phase eluting with a gradient of 0-5% ethanol in dichloromethane to give the title compound as a solid (0.16 g). p.f. 44-47 ° C MS (APCI) 459 (M + H) + XH NMR (CDC13) 8.47 (1H, d); 8.44 (1H, dd); 7.60-7.56 (2H, m); 7.45-7.41 (2H, m); 7.29-7.21 (3H, m); 6.99 (2H, d); 4.40-4.39 (1H, m); 3.90-3.86 (1H, m), 2.98-2.81 (1H, m); 2.78-2.71 (1H, m); 2.64 (1H, broad s); 2.06 (3H, s); 1.89-1.87 (3H, m); 1.35 (3H, d).

Example 57 (1S, 2R) -2- [4 '- (2-hydroxy-l-methyl-4-pyridin-3-yl-butoxy) -biphenyl-2-yl] -N-methylacetamide. a) 2- (2-bromo-phenyl) -N-methylacetamide.

To a solution of 2-bromo-phenylacetic acid (2.15 g) in dichloromethane (100 ml) is added methylamine (2M solution in tetrahydrofuran, 6 ml), 4-dimethylaminopyridine (1.32 g) and 1- (3-dimethylaminopropyl) -3 hydrochloride. ethylcarbodiimide (2.055 g). The mixture is allowed to stir at room temperature for 16 hours, after which the organic portion is washed with 2M aqueous hydrogen chloride, dried over magnesium sulfate and filtered. The filtrate is concentrated to provide a solid (2.04 g). MS (APCI) 228/230 (M + H) + XH NMR (CDC13) 7.60 (1H, d); 7.33 (2H, m); 7.17 (1H, t); 5.40 (1H, s); 3.72 (2H, s); 2.79 (3H, d). b) (2S, 3R) -5- (3-pyridyl) -2- [4- (2- (2-N-methyletanamide) phenyl) phenoxy] pentan-3-ol.

Prepared according to the method described in example 12b) from (1S, 2R) -4- (2-hydroxy-l-methyl-4-pyridin-3-ylbutoxy) benzanboronic acid (0.150 g, example 33) , 2- (2-bromophenyl) -N-methylacetamide (0.228 g), 2M aqueous sodium carbonate (0.5 ml), and tetrakis (triphenylphosphine) palladium (O) (0.025 g) is dissolved in ethanol (3 ml) and heat at 90 ° C for 90 minutes. After cooling, the solution is concentrated and azeotropically distilled with ethanol 2 more times. The residue is triturated with acetone and filtered through silica gel. The filtrate is concentrated, dissolved in dichloromethane and purified by CLAP in a normal phase, eluting with a gradient of 0-25% ethanol in dichloromethane to give a solid (0.055 g). p.f. 85-86 ° C MS (APCI) 405 (M + H) + XH NMR (CDC13) 8.45 (2H, d); 7.58 (1H, d); 7.34-7.15 (7H, m); 6.92 (2H, d); 5.37 (1H, s); 4.35 (1H, t); 3.84 (1H, t); 3.54 (2H, s); 2.93 (1H, m); 2.76 (4H, m); 1.87 (3H, m); 1.33 (3H, d).

Example 58 (1S, 2R) -N- [4 '- (2-hydroxy-l-methyl-4-pyridin-3-yl-butoxy) -2-methylbiphenyl-4-yl] acetamide.

OH It is prepared according to the method described in example 12b) from (1S, 2R) -4- (2-hydroxy-l-methyl-4-pyridin-3-ylbutoxy) benzanboronic acid (0.150 g, example 33). ), 4-bromo-3-methylacetanilide (0.228 g), 2M aqueous sodium carbonate (0.50 ml) and tetrakis (triphenylphosphine) palladium (0) (0.020 g) in ethanol (3 ml) with heating at 90 ° C for 2 hours. hours. After treatment, the residue is purified by CLAP in the normal phase eluting with a gradient of 0-25% ethanol in dichloromethane, and then by reverse phase CLAP eluting with a gradient of 25-100% acetonitrile in 0.1 p / v. of an aqueous solution of ammonium acetate to provide the title compound as an oil (0.041 g). MS (APCI) 405 (M + H) + XE NMR (DMSO) 9.9 (1H, s); 8.45 (1H, broad s); 8.39 (1H, broad s); 7.64 (1H, d); 7.46-7.43 (2H, m); 7.32-7.29 (1H, t); 7.19 (2H, d); 7.08 (1H, d); 6.94 (2H, d); 5.01 (1H, d); 4.30 (1H, t); 3.60-3.52 (1H, m); 2.85-2.79 (1H, m); 2.71-2.63 (1H, m); 2.20 (3H, s); 2.05 (3H, s); 1.89-1.85 (1H, m); 1.71-1.66 (1H, m); 1.24 (3H, d).

Example 59 (1S, 2R) -N- [4 • - (2-hydroxy-l-methyl-4-pyridin-3-yl-butoxy) biphenyl-3-yl] -methanesulfonamide.

OH a) 3-bromomethanesulfonanilide Triethylamine (0.6 ml) is added to a stirred solution of 3-bromoaniline (0.5 ml) in dichloromethane (10 ml). The resulting mixture is stirred at room temperature for 15 minutes and then methanesulfonyl chloride (0.36 ml) in dichloromethane (5 ml) is added dropwise. The reaction mixture is stirred for 3 hours at room temperature. Water is added and the product is extracted with dichloromethane. The combined extracts are dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel eluting with dichloromethane, then with methanol to give the subtitle compound as a solid (0.662 g). p.f. 109 ° C 2 H NMR (DMSO) 9.99 (1H, broad s); 7.37 (1H, s); 7.31-7.26 (2H, m); 7.24-7.15 (1H, m); 3.04 (3H, s). b) (1S, 2R) -N- [4 '- (2-hydroxy-l-methyl-4-pyridin-3-yl-butoxy) biphenyl-3-yl] methanesulfonamide.

Prepared according to the method described in example 12b) from (1S, 2R) -4- (2-hydroxy-l-methyl-4-pyridin-3-ylbutoxy) benzanboronic acid (0.150 g, example 33) , 3-bromomethanesulfonanilide (0.250 g), 2M aqueous sodium carbonate (0.50 ml) and tetrakis (triphenylphosphine) palladium (O) (0.020 g) in ethanol (3 ml) with heating at 90 ° C for 2 hours. After treatment, the residue is purified by CLAP in the normal phase eluting with a gradient of 0-25% ethanol in dichloromethane, and then by reverse phase CLAP eluting with a gradient of 25-100% acetonitrile in a 0.1 p solution. / v aqueous ammonium acetate to provide the title compound as an oil (0.60 g). MS (APCI) 427 (M + H) + 1 H NMR (DMSO) 9.82 (1H, broad s); 8.45 (1H, s); 8.40 (1H, d); 7.64 (1H, d); 7.50 (2H, d); 7.41-7.31 (4H, m); 7.14 (1H, d); 7.01 (2H, d); 5.01 (1H, d); 4.37-4.31 (1H, m); 3. 61-3.52 (1H, m); 3.02 (3H, s); 2.87-2.78 (1H, m); 2.70-2.62 (1H, m); 1.91-1.82 (1H, m); 1.71-1.62 (1H, m); 1.24 (3H, d).

Example 60 (1S, 2R) -4 '- (2-Hydroxy-l-methyl-4-pyridin-3-yl-butoxy) biphenyl-4-sulfonic acid amide.

OH Prepared according to the method described in example 12b) from (1S, 2R) -4- (2-hydroxy-l-methyl-4-pyridin-3-ylbutoxy) benzeneboronic acid (0.30 g, example 33) , 4-bromophenylsulphonic acid amide (0.26 g), ethanol (6 ml), 2M aqueous sodium carbonate (1.0 ml) and tetrakis (triphenylphosphine) palladium (O) (0.03 g) with heating at 90 ° C for 6 hours. After workup, the residue is purified by column chromatography on silica gel eluting with methanol: 5:95 ethyl acetate to provide the title compound as a solid (0.04 g). p.f. 222-223 ° C MS (APCI) 413/414 (M-H) "NMR (DMSO) 8.44 (1H, s); 8.39 (1H, d); 7.81 (4H, c); 7.64 (2H, d); 7.36 (2H, broad s), 7.30 (1H, dd), 7.04 (2H, d), 5.01 (1H, d), 4.36 (1H, m), 3.55 (1H, m), 2.82 (1H, m); 2.65 (1H, m), 1.88 (1H, m), 1.66 (1H, m), 1.24 (3H, d).

Example 61 (1S, 2R) -4 '- (2-Hydroxy-l-isopropyl-4-pyridin-3-yl-butoxy) biphenyl-3-sulfonic acid amide. a) (2S) -2- (4-Bromophenoxy) -3-methylbutanoic acid methyl ester.

Diethyl diethylazodicarboxylate is added dropwise (17.5 ml) in dry toluene (60 ml) for 30 minutes to a stirred and cooled solution of triphenylphosphine (34 g), methyl (R) -2-hydroxy-3-methylbutanoate (17 g, J. Am. Chem. Soc., (1990), 112, 21, 7659) and 4-bromofeμol (24 g) in dry toluene (180 mi). The resulting solution is stirred at room temperature for 30 minutes and then concentrated under reduced pressure to about half the original volume. A mixture of isohexane (700 ml) is added and the mixture is stirred at room temperature for 20 minutes. The solution is filtered to remove the triphenylphosphine oxide and the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography on silica eluting with isohexane: dichloromethane (1: 4) and then (2: 3) to give the subtitle compound as an oil (28 g). H NMR (CDC13) 7.36 (2H, d); 6.76 (2H, d); 4.33 (1H, d); 3.74 (3H, s); 2.35-2.2 (1H, m); 1.06 (6H, t). b) (2S) -2- (4-bromo-phenoxy) -3-methyl-1-butanol Solid sodium borohydride (11.8 g) is added with cooling, in three portions, for three days to a stirred solution of (2S) -2- (4-bromophenoxy) -3-methylbutanoic acid methyl ester (27.7 g) in ethanol (400 mi). The reaction is concentrated under reduced pressure and the residue is partitioned between 2M hydrochloric acid (400 ml) and ether. The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel eluting with dichloromethane: isohexane (1: 1) to give the subtitle compound as an oil (13.7 g). XE NMR (CDC13) 7.37 (2H, d); 6.86 (2H, d); 4.15-4.05 (1H, m); 3.85-3.75 (2H, m); 2.15-2.0 (1H, m); 0.99 (3H, d); 0.96 (3H, d). c) (3RS, 4S) -4- (4-bromophenoxy) -5- (methyl) -1- (pyridin-3-yl) -hex-l-in-3-ol.

Oxalyl chloride (6.0 ml) is added dropwise to a solution of dimethyl sulfoxide (7.5 ml) in dry dichloromethane (300 ml) at -70 ° C. The resulting solution is stirred for 15 minutes and then a solution of (2S) -2- (4-bromophenoxy) -3-methyl-1-butanol (13 g) in dry dichloromethane (100 g) is added dropwise at -70 ° C. my) . The mixture is stirred for an additional 15 minutes and then triethylamine (45 ml) is added.

The mixture is allowed to warm to 10 ° C with stirring. The mixture is then diluted with isohexane (600 ml), stirred for 10 minutes, filtered and concentrated under reduced pressure. The residue is dissolved in isohexane (500 ml) and ether (50 ml) and then filtered and concentrated under reduced pressure. The residue is dissolved in dry tetrahydrofuran (100 ml) and added at -78 ° C to a solution of l-lithium-2-pyridin-3-ylacetylene [generated by the addition of n-butyllithium (2.5M in hexanes, mi) to a solution of pyridin-3-ylacetylene (8.0 g) ("Amer. Chem. Soc. 1935, 57, 1284) in tetrahydrofuran (150 ml) at -78 ° C with stirring for 15 minutes]. it is left at room temperature for 30 minutes and poured into saturated aqueous ammonium chloride (200 ml) The layers are separated and the organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. 20 g) is purified by column chromatography on silica eluting with dichloromethane with dichloromethane: ethyl acetate (4: 1) to give the subtitle compound as an oil as a 3: 1 mixture of diastereomers (15.9 g). ) 360, 362 (M + H) + d) (3RS, 4S) -4- (4-bromophenoxy) -5- (methyl) -1-pyridin-3-yl-3-hexanol.

Dissolve (3RS, 4S) -4- (4-bromophenoxy) -5- (methyl) -1-pyridin-3-yl-hex-l-in-3-ol (13.6 g) in ethyl acetate (350 ml). ) and hydrogenated at 3 atmosphere for 6 days using 10% rhodium in activated carbon (2.1 g) as a catalyst. The catalyst and the solvent are replaced 5 times during this period. The mixture is filtered through Celite "11 and the filtrate is concentrated under reduced pressure to provide a The mixture is purified by CLAP eluting with dichloromethane: 2-propanol (97: 3) to provide a mixed fraction containing reduced and no reduced (6.0 g), (3S, 4S) -4- (4-bromophenoxy) -5- (methyl) -l-pyridin-3-yl-3-hexanol pure (1.73 g), and (3R, 4S) - 4- (4-Bromophenoxy) -5- (methyl) -l-pyridin-3-yl-3-hexanol (2.73 g). (3S, 4S) -4- (4-Bromophenoxy) -5-methyl-1-pyridin-3-yl-3-hexanol.

NMR (CDC13) 8.46-8.43 (2H, m); 7.48 (1H, dt); 7. 35 (2H, d); 7.20 (1H, dd); 6.84 (2H, d); 3.93 (1H, dd); 3.85-3.75 (1H, m); 2.95-2.83 (1H, m); 2.78-2.65 (1H, m); 2.15- 2.05 (2H, m); 1.9-1.65 (2H, m); 0.95 (3H, d); 0.92 (3H, d). (3R, 4S) -4- (4-bromophenoxy) -5-methyl-1-pyridin-3-yl-3-hexanol. 2 H NMR (CDCl 3) 8.48-8.43 (2H, m); 7.50 (1H, dt); 7. 35 (2H, d); 7.21 (1H, dd); 6.86 (2H, d); 4.06 (1H, dd); 3. 9-3.75 (1H, m); 2.95-2.85 (1H, m); 2.75-2.63 (1H, m); 2.1- 1.95 (1H, m); 1.95-1.75 (2H, m); 1.71 (1H, d); 0.97 (3H, d); 0.89 (3H, d). e) 3 - [4 - (4-Bromophenoxy) -3-tert-butyldimethylsilanyloxy) -5-methylhexyl] pyridine.

Solid tert-butyldimethylsilyl chloride (0.46 g) is added to a solution of (3R, 4S) -4- (4-bromophenoxy) -5-methyl-1-pyridin-3-yl-3-hexanol (0.93 g) and imidazole ( 0.26 g) in dry dimethylformamide (12 ml) and the resulting solution is stirred at room temperature for 3 days. Water is added (100 ml) and ether (100 ml). The organic phase is separated, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel eluting with dichloromethane and then with dichloromethane: hexane (1: 1) to give the subtitle compound as an oil (0.70 g). X H NMR (CDC13) 8.43-8.40 (1H, m); 8.33 (1H, d); 7.34 (2H, d); 7.32-7.28 (1H, m); 7.16 (1H, dd); 6.86 (2H, d); 4.03 (1H, t); 4.0-3.9 (1H, m); 2.7-2.55 (2H, m); 2.15-2.05 (1H, m); 1.95-1.75 (2H, m); 1.01 (3H, d); 0.99 (3H, d); 0.89 (9H, s); 0.08 (3H, s); 0.09 (3H, s). f) (1S, 2R) -4 '- (2-hydroxy-l-isopropyl-4-pyridin-3-yl-butoxy) -biphenyl-3-sulfonic acid amide.

A solution of tert-butyl lithium is added dropwise (1.7M in pentane, 1.7 ml) for 5 minutes to a solution of 3- [4- (4-Bromophenoxy) -3- (tert-butyldimethylsilanyloxy) -5-methylhexyl] pyridine (0.7 g, Example 61e)) and triisopropyl borate (0.75 mL) in tetrahydrofuran (20 mL) a - 78 ° C.

The solution is stirred for 30 minutes and then tert-butyllithium (0.5 ml) is added. The solution is stirred for an additional 30 minutes and then tert-butyllithium (0.5 ml) is added. After stirring for 30 minutes, a saturated solution of aqueous ammonium chloride (50 ml) is added, followed by ethyl acetate (50 ml). The layers are separated, the organic layer is separated, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel eluting with ether to give the recovered starting material (0.29 g) and then with ethyl acetate: methane. (4: 1) to provide (1S, 2R) -4 '-] 2-tert-butyldimethylsilanyloxy) -l-isopropyl-4-pyridin-3-ylbutoxy] -benzeneboronic acid. This is dissolved in toluene (5 ml) and ethanol (3.5 ml) and 3-bromobenzenesulfonamide (0.37 g), 2M aqueous sodium carbonate (2 ml) and tetrakis (triphenylphosphine) palladium (O) are added. The mixture is heated at 100 ° C for 2 hours and then allowed to stir at room temperature overnight. The reaction mixture is concentrated under reduced pressure and methanol (10 ml) and concentrated hydrochloric acid (2 ml) are added to the residue. After stirring at room temperature for 2 hours, the reaction mixture is concentrated under reduced pressure. To the residue water (50 ml) is added and neutralized by the addition of solid sodium acid carbonate. The aqueous phase is extracted with ethyl acetate, the combined extracts are dried over anhydrous magnesium sulfate, dried and concentrated under reduced pressure. The residue (0.60 g) is purified by column chromatography on silica gel eluting with dichloromethane and then with ethyl acetate to give an oil (0.34 g). This is further purified by column chromatography on silica eluting with dichloromethane: ethanol (19: 1). This material is then purified twice by reverse phase CLAP eluting with a gradient of 25-100% acetonitrile in an aqueous solution of ammonium acetate 0.1 w / v. The material recovered from this purification is triturated with isohexane to give a solid (0.20 g). MS (APCI) 441 (M + H) + X H NMR 8.37 (2H, s); 8.04 (1H, t); 7.83 (1H, d) 7. 73 (1H, d); 7.65-7.5 (4H, m); 7.37 (2H, s); 7.26 (1H, dd) 7.12 (2H, d); 5.02 (1H, d); 4.17 (1H, dd); 3.7-3.55 (1H, m) 2.85-2.7 (1H, m); 2.7-2.55 (1H, m); 2.25-2.05 (1H, m); 1.9-1.7 (1H, m); 1.7-1.5 (1H, m); 0.95 (3H, d); 0.89 (3H, d).

Example 62 (1S, 2R) - [4 '- (2-hydroxy-l-methyl-4-pyridin-3-yl-butoxy) biphenyl-4-yl] urea.

OH It is prepared according to the method described in example 12b) from (1S, 2R) -4- (2-hydroxy-l-methyl-4-pyridin-3-ylbutoxy) benzeneboronic acid (0.15 g, example 33) , 4-bromophenylurea (0.16 g), 2M aqueous sodium carbonate (0.25 ml) and tetrakis (triphenylphosphine) palladium (0) (0.1 g) in ethanol (3 ml). The reaction mixture is heated at 100 ° C for 3 hours. After cooling, the solution is concentrated under reduced pressure. The residue is triturated with acetone and then filtered through silica gel. The filtrate is concentrated under reduced pressure and purified by flash column chromatography eluting with 10% methanol in dichloromethane giving the title compound as a solid (0.046 g). p.f. 181-182 ° C MS (APCI) 392 (M + H) + 'H NMR (DMSO) 8.53 (1H, s); 8.44 (1H, s); 8.38 (1H, d); 7.63 (1H, d); 7.49-7.42 (6H, m); 7.31-7.27 (1H, m); 6.95 (2H, d); 5.84 (2H, s); 5.0 (1H, s); 4.31-4.27 (1H, m); 3.55-3.53 (1H, m); 2.86-2.59 (2H, m); 1.90-1.80 (1H, m); 1.67-1.57 (1H, m); 1.23) 3H, d).

Example 63 (1S, 2R) -4 '- (2-hydroxy-l-methyl-4-pyridin-3-yl-butoxy) -2-methyl-biphenyl-4-pyrrolidinyl-yl-ethyl) amide carboxylic OH a) 4-bromo-3-methyl-N- (2-pyrrolidin-1-yl-ethyl) -benzamide.

Add l-ethyl-3- (3'-dimethylamino-propyl) carbodiimide hydrochloride (2.68 g) to a solution of 4-bromo-3-methylbenzoic acid (3.0 g), 1- (2-aminoethyl) pyrrolidine (1.78 g). mi) and 1-hydroxybenzotriazole hydrate (1.89 g) in dry N, N-dimethylformamide (30 ml). The reaction is stirred at room temperature for 24 hours. The solution is concentrated under reduced pressure. The residue is dissolved in ethyl acetate and washed with brine. The organic layer is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel eluting with dichloromethane: methanol (9: 1) to give the subtitle compound as an oil (3.55 g). MS (APCI) 313/315 (M + H) +? NMR (CDC13) 8.51 (1H, broad s); 7.73 (1H, dd); 7.44 (1H, d); 7.30-7.22 (1H, m); 3.86 (2H, c); 3.29 (2H, t); 3.27-3.23 (4H, m); 2.30 (3H, s); 2.05-1.98 (4H, m). b) (1S, 2R) -4 '- (2-hydroxy-l-methyl-4-pyridin-3-yl-butoxy) -2-methyl-biphenyl- (2-pyrrolidinyl-yl-ethyl) amide 4-carboxylic acid.

Prepared according to the method described in example 12b) from (1S, 2R) -4- (2-hydroxy-l-methyl-4-pyridin-3-ylbutoxy) benzeneboronic acid (0.15 g, example 33) , 4-bromo-3-methyl-N- (2-pyrrolidin-1-yl-ethyl) benzamide (0.31 g, example 63a)), 2M aqueous sodium carbonate (0.57 ml) and tetrakis (triphenylphosphine) palladium (0) (0.012 g) in ethanol (5 ml) with heating under reflux for 4 hours. After the treatment, the residue is purified by normal phase CLAP eluting with a gradient of 0-10% ethanol in dichloromethane to give the title compound as an oil (0.14 g) - MS (APCI) 488 (M + H) + 2 H NMR (CDC13) 8.82 (1H, broad t); 8.51 (1H, d); 8.45 (1H, dd); 8.0 (1H, s); 7.92 (1H, d); 7.56 (1H, d); 7.27 (1H, s); 7.25-7.22 (1H, m); 7.21 (2H, d); 6.92 (2H, d); 4.42-4.39 (1H, m); 3.93 (2H, c); 3.91-3.87 (1H, m); 3.60 (4H, m); 3.41 (2H, t); 3.01-2.93 (1H, m); 2.78-2.70 (1H, m); 2.50 (1H, broad s); 2.27 (3H, s); 2.16 (4H, broad s); 1.91-1.83 (2H, m); 1.32 (3H, d).

Example 64 (1S, 2R) -4 '- (2-hydroxy-l-methyl-4-pyridin-3-yl-butoxy) i-enyl-3-sulfonic acid (2, 2, 2-trifluoroethyl) amide.

OH a) Amide of (N-2, 2, 2-trifluoroethyl) -3-bromobenzenesulfonic acid. 3-Bromobenzenesulfonyl chloride (1.27 g) is added to a stirred solution of 2,2,2-trifluoroethylamine hydrochloride (0.8 g) and triethylamine (1.7 ml) in tetrahydrofuran (30 ml) and the resulting mixture is stirred for 20 hours. at room temperature. The reaction mixture is concentrated and the residue is partitioned between ether (20 ml) and 2M hydrochloric acid (30 ml). The mixture is separated and the aqueous layer is extracted with ether and the combined extracts are dried over anhydrous magnesium sulfate and concentrated. The residue is recrystallized from hexane to give the subtitle compound as a solid (0.60 g). p.f. 98-99 ° C MS (GC) 317, 319 (M) + XH NMR (CDCl 3) 8.02 (1H, t); 7.81 (1H, ddd); 7.74 (1H, ddd); 7.42 (1H, t); 4.95 (1H, t); 3.71 (2H, m). b) (1S, 2R) -4 '- (2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) biphenyl-3-sulfonic acid (2,2,2-trifluoroethyl) amide.

It is prepared according to the method described in example 12b) from (1S, 2R) -4- (2-hydroxy-l-methyl-4-pyridin-3-ylbutoxy) benzeneboronic acid (0.15 g, example 33) , (N-2, 2, 2-trifluoroethyl) -3-bromobenzenesulfonic acid amide (0.25 g, example 64a)), 2M aqueous sodium carbonate (0.57 ml) and tetrakis (triphenylphosphine) palladium (O) (0.014 g) in ethanol (5 ml) with stirring at 90 ° C for 2 hours. After the treatment, the residue is purified by normal phase CLAP eluting with a gradient of 0-10% ethanol in dichloromethane to give the title compound as a solid (0.17 g). p.f. 47-48 ° C MS (APCI) 495 (M + H) +? NMR (CDCl 3) 8.46 (1H, d); 8.42 (1H, dd); 8.01 (1H, s); 7.78-7.70 (2H, m); 7.58-7.49 (2H, m); 7.45 (2H, d); 7.26-7.22 (1H, m); 6.93 (2H, d), 4.41-4.29 (1H, m); 3.86-3.80 (1H, m); 3.70 (2H, c); 2.97-2.91 (1H, m); 2.77-2.67 (1H, m); 1.88-1.81 (2H, m); 1.30 (3H, d).

Example 65 (1 S, 2 R) -1- [4 '- (2-hydroxy-l-methyl-4-pyridin-3-yl-butoxy) -biphenyl-4-yl] -3-methylurea.

OH a) N- (4-bromo-phenyl) -N '-methylurea.

A solution of methylamine in tetrahydrofuran (2M, 4 ml) is added to a solution of phenylisocyanate (1.06 g). A precipitate of product forms immediately. The reaction mixture is diluted with hexane (100 ml) and then filtered to give the subtitle compound as a foam (0.90 g). MS (APCI) 229 (M-H) "X H NMR (DMSO) 8.63 (1H, s); 7.37 (4H, s); 6.03 (1H, c); 2.62 (3H, d). b) (1S, 2R) -1- [4 '- (2-hydroxy-l-methyl-4-pyridin-3-yl-butoxy) -biphenyl-4-yl] -3-methylurea.

Prepared according to the method described in Example 12b) from (1S, 2R) -4- (2-hydroxy-l-methyl-4-pyridin-3-ylbutoxy) benzeneboronic acid (0.419 g, example 33) , N- (4-bromophenyl) -N '-methylurea (0.225 g), 2M aqueous sodium carbonate (1.0 ml) and tetrakis (triphenylphosphine) palladium (O) (0.028 g) in ethanol (3 ml). The reaction mixture is heated in a sealed flask at 100 ° C for 2 hours. After cooling, the solution is concentrated under reduced pressure. The residue is purified by chromatography on silica eluting with tetrahydrofuran: hexane (1: 1). The residue is further purified by chromatography on silica gel eluting with dichloromethane: ethanol (9: 1). The residue is then further purified by reverse phase CLAP eluting with a gradient of 25-100% acetonitrile in an aqueous solution of ammonium acetate 0.1 w / v. The CLAP fractions are concentrated under reduced pressure, the residue is dissolved in ethanol, filtered and concentrated under reduced pressure to provide the title compound as a solid (0.050 g). p.f. 139-141 ° C MS (APCI) 406 (M + H) +! H NMR (DMSO) 8.54 (1H, s); 8.44 (1H, s); 8.39 (1H, d); 7.63 (1H, d); 7.49 (2H, d); 7.45 (4H, s); 7.30 (1H, t); 6. 95 (2H, d); 6.01 (1H, d); 4.98 (1H, d); 4.29 (1H, quintet); 3.6-3.5 (1H, m); 2.85-2.75 (1H, m); 2.7-2.6 (4H, m); 1.9-1.8 (1H, m); 1.7-1.6 (1H, m); 1.24 (3H, s).

Example 66 (1S, 2R) -2- [4 '- (2-hydroxy-l-methyl-4-pyridin-3-yl-butoxy) -biphenyl-4-yl] -N-isopropylacetamide.

OH Acid (1S, 2R) - [4 '- (2-hydroxy-l-methyl-4-pyridin-3-yl-butoxy) -biphenyl-4-yl] -acetic acid (example 55, 0.07 g), isopropylamine is dissolved. (0.012 g), l- (3-dimethylaminopropyl) -3-ethylcarboiimide hydrochloride (0.038 g) and 1-hydroxybenzotriazole (0.027 g) in dimethylformamide (2 ml) and stir for 16 hours at room temperature. The dimethylformamide is removed by distillation in vacuo, the residue is dissolved in dichloromethane, filtered and purified by CLAP in the normal phase eluting with a gradient of 0-10% ethanol in dichloromethane to give the title compound as a solid (0.061). g). p.f. 103-104 ° C MS (APCI) 433 (M + H) + XE NMR (CDC13) 8.51 (1H, d); 8.47 (1H, dd); 7.58-7.49 (5H, m); 7.30-7.26 (2H, m); 7.25-7.20 (1H, m); 6.95 (2H, dd); 5.2 (1H, broad s); 4.40-4.37 (1H, m); 4.12-4.05 (1H, m); 3.89-3.85 (1H, m); 3.56 (2H, s); 2.96-2.91 (1H, m); 2.76-2.71 (1H, m); 2.13 (1H, d); 1.90-1.81 (2H, m); 1.30 (3H, d); 1.10 (6H, d).

Example 67 (1S, 2R) -N-cyclopropyl-2- [4 * - (2-hydroxy-l-methyl-4-pyridin-3-yl-butoxy) -biphenyl-4-yl] -acetamide.

OH It is prepared according to the method described in example 66. Acid (1S, 2R) - [4 '- (2-hydroxy-l-methyl-4-pyridin-3-yl-butoxy) -biphenyl-4-yl] acetic acid (example 55, 0. 07 g), cyclopropylamine (0.011 g), l- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.038 g) and 1-hydroxybenzotriazole (0.027 g) in dimethylformamide (2 ml) and stir for 16 hours at room temperature . The dimethylformamide is removed by vacuum distillation, the residue is dissolved in dichloromethane, filtered and purified by CLAP in the normal phase eluting with a gradient of 0-10% ethanol in dichloromethane to give the title compound as a solid (0.063 g). ). p.f. 117-118 ° C MS (APCI) 431 (M + H) + XH NMR (CDC13) 8.51 (1H, d); 8.47 (1H, dd); 7.55-7.48 (5H, m); 7.29-7.26 (1H, m); 7.25-7.20 (2H, m); 6.96 (2H, dd); 5.50 (1H, broad s); 4.41-4.37 (1H, m); 3.90-3.80 (1H, m); 3.57 (2H, s); 3.05-2.90 (1H, m); 2.80-2.65 (2H, m); 2.18 (1H, d); 1.90-1.80 (2H, m); 1.30 (3H, d); 0.75-0.70 (2H, m); 0.45-0.40 (2H, m).

Example 68 (1 S, 2 R) -2- [4 '- (2-hydroxy-l-methyl-4-pyridin-3-yl-butoxy) bi enyl-4-yl] -1-pyrrolidin-1-yletanone.

OH It is prepared according to the method described in example 66. (1S, 2R) - [4 '- (2-hydroxy-l-methyl-4-pyridin-3-yl-butoxy) -biphenyl-4-acid is dissolved. il) acetic acid (example 55, 0.07 g), pyrrolidine (0.014 g), l- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.038 g) and 1-hydroxybenzotriazole (0.027 g) in dimethylformamide (2 ml) and Stir for 16 hours at room temperature. The dimethylformamide is removed by vacuum distillation, the residue is dissolved in dichloromethane, filtered and purified by CLAP in the normal phase eluting with a gradient of 0-10% ethanol in dichloromethane to give the title compound as a glass (0.068 g. ). MS (APCI) 435 (M + H) + XH NMR (CDC13) 8.51 (1H, d); 8.46 (1H, dd); 7.55 (1H, dt); 7.50-7.47 (4H, m); 7.32 (2H, d); 7.24-7.22 (1H, m); 6. 95-6.92 (2H, m); 4.40-4.36 (1H, m); 3.87-3.86 (1H, m); 3.68 (2H, s); 3.53-3.44 (4H, m); 3.0-2.90 (1H, m); 2.80-2.65 (1H, m); 2.15 (1H, d); 2.0-1.80 (6H, m); 1.30 (3H, d).

Example 69 (1S, 2R) -2-Methyl-4 '- (2-hydroxy-l-methyl-4-pyridin-3-yl-butoxy) biphenyl-5-sulfonic acid amide.

OH a) 3-Bromo-4-methylphenylsulfonic acid amide.

A solution of 3-bromo-4-methylaniline (3.0 g) in concentrated hydrochloric acid (15 ml) is cooled to below 5 ° C. A solution of sodium nitrite (1.17 g) in water (4 ml) is added dropwise while maintaining the internal temperature below 5 ° C. After the addition is complete, anhydrous magnesium chloride (2.0 g) is added (CAUTION: exotherm). A saturated solution of sulfur dioxide in glacial acetic acid (40 ml) is prepared at 0 ° C and copper (II) chloride (0.22 g) is added. To this solution of acetic acid at room temperature, the diazonium salt solution is added, and the mixture is heated to 30 ° C. After 1 h the mixture is poured into saturated brine and extracted with ethyl acetate. The combined extracts are washed with water and brine, dried over magnesium sulfate, filtered and evaporated. The residual oil is dissolved in tetrahydrofuran (50 ml) and ammonium hydroxide (50 ml) is added. After 2 hours, the mixture is diluted with water and extracted with ethyl acetate. The combined extracts are dried over magnesium sulfate, filtered and evaporated. The untreated material is purified by column chromatography on silica gel eluting with ethyl acetate: isohexane 1: 1, to give the subtitle compound as a solid (0.49 g). MS (APCI-ve) 249/251 (M + H) +? NMR (CDC13) 8.09 (1H, s); 7.76 (1H, d); 7.38 (1H, d); 4.85 (2H, broad s); 2.48 (3H, s). b) (1S, 2R) -2-Methyl-4 '- (2-hydroxy-l-methyl-4-pyridin-3-yl-butoxy) biphenyl-5-sulfonic acid amide.

It is prepared according to the method described in example 12b) from (1S, 2R) -4- (2-hydroxy-l-methyl-4-pyridin-3-ylbutoxy) benzeneboronic acid (0.15 g, example 33) , 3-bromo-4-methylphenylsulfonic acid amide (0.25 g, example 69a)), ethanol (3 ml), 2M aqueous sodium carbonate (0.5 ml) and tetrakis (triphenylphosphine) palladium (O) (0.03 g) with heating at 90 ° C for 3 hours. After workup, the residue is purified by normal phase CLAP eluting with a gradient of 0-25% ethanol in dichloromethane to provide the title compound as a foam (0.19 g). MS (APCI) 427 (M + H) * XR NMR (CDC13) 8.48 (1H, s); 8.44 (1H, d); 7.78 (1H, s); 7.77 (1H, d); 7.57 (1H, d); 7.39 (1H, d); 7.25 (1H, d); 7.21 (2H, d); 6.93 (2H, d); 5.00 (2H, broad s); 4.40 (1H, m); 3.87 (1H, m); 2.95 (1H, m); 2.75 (1H, m); 2.33 (3H, s); 1.85 (2H, m); 1.33 (3H, d).

Example 70 (1S, 2R) -2, 2, 2-trifluoro-N- [4 '- (2-hydroxy-l-methyl-4-pyridin-3-yl-butoxy) -biphenyl-3-yl] -N-methylacetamide a) N- (3-bromo-f eni 1) - 2, 2, 2 - t r i f luoro-N 'methylacetamide N- (3-bromophenyl) -2 is added dropwise, 2,2-trifluoroacetamide (J. Chem. Soc., 1952, 4014) in tetrahydrofuran (3 ml) to sodium hydride (0.16 g) in tetrahydrofuran (5 ml). The reaction mixture is stirred for 30 minutes at room temperature. Iodomethane (0.25 ml) is added dropwise to the reaction mixture and stirred overnight at room temperature. Water is added and the product is extracted with ethyl acetate. The combined extracts are dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel eluting with isohexane: dichloromethane (1: 1) to give the subtitle compound as an oil (0.385 g). 'H NMR (CDC13) 7.57 (1H, d); 7.43 (1H, s); 7.32 (1H, t); 7.21 (1H, d); 3.35 (3H, s). b) (1S, 2R) -2, 2, 2-trifluoro-n- [4 • - (2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) biphenyl-3-yl] -N- methylacetamide.

According to the method described in Example 12b) from (1S, 2R) -4- (2-hydroxy-l-methyl-4-pyridin-3-ylbutoxy) benzanboronic acid (0.150 g, Example 33), N - (3-bromo-phenyl) -2, 2, 2-trifluoro-N-methylacetamide (0.282 g), 2 M aqueous sodium carbonate (0.50 ml) and tetrakis (triphenylphosphine) palladium (0) (0.020 g) in ethanol (3 ml) with heating at 90 ° C for 2 hours. After the treatment, the residue is purified by CLAP in the normal phase eluting with a gradient of 0-25% ethanol in dichloromethane.

The product obtained is dissolved in dichloromethane (3 ml) and cooled to 0 ° C. Trifluoroacetic anhydride is added dropwise (0.09 ml), the reaction mixture is stirred for 1 hour at room temperature, before concentrating under reduced pressure. Methanol (10 ml) and water (10 ml) are added and the resulting mixture is stirred for 30 minutes at room temperature. The product is extracted with ethyl acetate and the combined extracts are dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound as an oil (0.148 g). MS (APCI) 459 (M + H) +. X H NMR (CDC13) 8.82 (1H, s); 8.65 (1H, d); 8.18 (1H, d); 7.74 (1H, t); 7.57 (1H, d); 7.52-7.45 (3H, m); 7.40 (1H, s); 7.18 (1H, d); 6.97 (2H, d); 5.10 (1H, broad s); 4.42-4.36 (1H, m); 3.84-3.79 (1H, m); 3.40 (3H, s); 3.18-3.10 (1H, m); 3.02-2.94 (1H, m); 1.96-1.90 (2H, m); 1.31 (3H, d).

Example 71 (1S, 2R) -4 '- (2-hydroxy-l-methyl-4-pyridin-3-ylbutoxy) biphenyl-3,4-dicarbonitrile.

It is prepared according to the method described in Example 12b) from (1S, 2R) -4- (2-hydroxy-l-methyl-4-pyridin-3-ylbutoxy) benzeneboronic acid (0.197 g, Example 33), 4-iodo-1,2-dicyanobenzene (0.421 g, Can J. Chem., 1985, 63, 3057), 2M aqueous sodium carbonate (0.50 ml) and te trakis (triphenylphosphine) palladium (0) (0.054 g) in ethanol (3 ml). The reaction mixture is heated in a sealed bottle at 90 ° C for 4 hours. After cooling, the solution is concentrated under reduced pressure and the residue is purified by chromatography on silica eluting with ethyl acetate. The residue is further purified by chromatography on silica gel eluting with dichloromethane: 2-propanol (19: 1). The residue is further purified by reverse phase CLAP eluting with a gradient of 25-100% acetonitrile in an aqueous solution of ammonium acetate 0.1 w / v. The CLAP fractions are concentrated under reduced pressure, the residue is dissolved in dichloromethane, filtered and concentrated under reduced pressure. The residue is triturated with ether to give the title compound as a solid (0.060 g). p.f. 135.5-137 ° C MS (APCI) 384 (M + H) + XH NMR (CDC13) 8.47-8.43 (2H, m); 8.38 (1H, dd); 8.25-8.12 (2H, m); 7.79 (2H, d), 7.63 (1H, dt); 7.30 (1H, dd); 7.06 (2H, d); 5.03 (1H, d); 4.41 (1H, quintet); 3.63-3.5 (1H, m); 2. 9-2.75 (1H, m); 2.75-2.6 (1H, m); 1.95-1.8 (1H, m); 1.75-1.55 (1H, m); 1.24 (3H, d).

Example 72 (3R, 4S) -l-pyridin-3-yl-4- [3 '- (pyrrolidin-1-sulf onyl) biphenyl-4-yloxy] pen an-3-ol. a) Pi r ol i dini 1 ami da of bromobenzenesulphonic acid.

A solution of pyrrolidine (0.33 ml) and triethylamine (0.6 ml) in dichloromethane (10 ml) is added dropwise to a stirred solution of 3-bromobenzenesulfonyl chloride (1 g) in dichloromethane (20 ml), and the mixture is stirred at room temperature for 18 hours. The reaction is poured into water, and the aqueous mixture is extracted with dichloromethane. The combined organic extracts are washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to provide an oil. This is purified by column chromatography on silica gel, eluting with ethyl acetate: isohexane (1: 4) to give the subtitle compound as a solid (1.10 g). p.f. 82-84 ° C MS (APCI) 290 (M + H) + 41 NMR (DMSO) 7.95-7.9 (2H, m); 7.85-7.8 (1H, m); 7.60 (1H, t); 3.2-3.13 (4H, m); 1.75-1.6 (4H; m). b) (3R, 4S) -1-pyridin-3-yl-4- [3 '- (pyrrolidin-1-sulfonyl) biphenyl-4-yloxy] pentan-3-ol.

Prepared according to the method described in Example 12b) from (1S, 2R) -4- (2-hydroxy-l-methyl-4-pyridin-3-ylbutoxy) benzanboronic acid (0.150 g, Example 33) , acid 3 - . 3-bromobenzenesulfonic acid, pyrrolidinylamide (0.290 g), aqueous or 2M aqueous carbonate (0.5 ml) and tetrakis (triphenylphosphine) palladium (0) (0.025 g) in ethanol (3 ml). The reaction mixture is heated at 90 ° C for 4 hours.

After cooling, the solution is concentrated under reduced pressure, and is taken up in ethanol and concentrated again (twice) . The residue is triturated with acetone and then filtered through silica gel. The filtrate is concentrated under reduced pressure, dissolved in dichloromethane, filtered and purified by CLAP in the normal phase eluting with a gradient of 0.25% ethanol in dichloromethane to provide a gum, which is further purified by reverse phase CLAP to provide the title compound as a foam (0.137 g). MS (APCI) 467 (M + H) +. XR NMR (DMSO) 8.44 (1H, s); 8.38 (1H, d); 7.95-7.88 (2H, m); 7.75-7.6 (5H, m); 7.30 (1H, c); 7.4 (2H, d); 5.01 (1H, d); 4.4-4.3 (1H, m); 3.6-3.5 (1H, m); 3.18 (4H, t); 2.9-2.6 (2H, broad m); 1.92-1.8 (1H, m); 1.7-1.6 (5H, m); 1.25 (3H, d).

Example 73 (1S, 2R) -6-fluoro-4 '- (2-hydroxy-l-methyl-4-pyridin-3-yl-butoxy) biphenyl-3-carbonitrile Prepared according to the method described in Example 12b) from (1S, 2R) -4- [2- (tert-Butyldimethylsilanyloxy) -l-methyl-4-pyridin-3-ylbutoxy] benzeneboronic acid (0.20 g) , Example 33), 3-bromo-4-fluorobenzonitrile (0.27 g), 2M aqueous sodium carbonate (0.76 ml) and tetrakis (triphenylphosphine) palladium (0) (0.019 g) in ethanol (5 ml) with 90 ° heating C for 4 hours. After the treatment, the residue is purified by normal phase CLAP eluting with a gradient of 0-10% ethanol in dichloromethane to give the title compound as an oil (0.22 g). MS (APCI) 377 (M + H) +.

Example 74 (1S, 2R) -4 '- (2-hydroxy-l-methyl-4-pyridin-3-yl-butoxy) -5- rifluoromethyl-biphenyl-3-sulfonic acid amide a) 3-bromo-5-trifluoromethylbenzenesulfonamide 3-Amino-5-bromobenzotrifluoride is added to concentrated hydrochloric acid (20 ml) and cooled to -5 ° C. A saturated solution of sodium nitrite (3.88 g) in water (4 ml) is added dropwise at a rate such that the temperature is maintained below 0 ° C. Magnesium chloride (8 g) is added (CAUTION: exotherm) and the resulting mixture is added with stirring to a saturated solution of sulfur dioxide in acetic acid (37.5 ml) and toluene (20 ml), which contains cupric chloride (2.75). g) at room temperature. The mixture is stirred for 16 hours, poured into water and filtered in toluene. The combined toluene extracts are washed with water, dilute sodium acid carbonate, dried over anhydrous magnesium sulfate and concentrated. The residue is dissolved in tetrahydrofuran (200 ml) and 880 ammonia (50 ml) is added to the solution. The mixture is stirred at room temperature for 4 hours and then concentrated under reduced pressure. The residue is divided between water and ethyl acetate. The combined ethyl acetate extracts are dried over anhydrous magnesium sulfate and concentrated to give the subtitle compound as a solid (4.2 g). p.f. 174-175 ° C MS (APCI) 302/304 (M-H) + XH NMR (CDCl 3) 8.31 (1H, s); 8.27 (1H, s); 8.11 (1H, s); 7.72 (2H, s). b) (1S, 2R) -4 '- (2-hydroxy-l-methyl-4-pyridin-3-yl-butoxy) -5-trifluoromethyl-biphenyl-3-sulfonic acid amide Prepared according to the method described in Example 12b) from (1S, 2R) -4- (2-hydroxy-l-methyl-4-pyridin-3-ylbutoxy) benzanboronic acid (0.20 g, Example 33) , 3-bromo-5-trifluoromethylbenzosulfonamide (0.40 g, Example 74), 2M aqueous sodium carbonate (0.76 ml) and. tetrakis (triphenylphosphine) palladium (0) (0.019 g) in ethanol (5 ml) with heating at 90 ° C for 4 hours. After the treatment, the residue is purified by CLAP in the normal phase eluting with a gradient of 0-10% ethanol in dichloromethane to give the compound as a solid (0.24 g). p.f. 57-59 ° C MS (APCI) 481 (M + H) + 41 NMR (CDCl 3) 8.49 (1H, d); 8.45 (1H, dd); 8.26 (1H, s); 8.09 (1H, s); 7.95 (1H, s); 7.59-7.56 (1H, m); 7.54 (2H, d); 7.26-7.22 (1H, m); 6.98 (2H, d); 5.18 (2H, broad s); 4.42-4.39 (1H, m); 3.87-3.84 (1H, m); 2.95-2.93 (1H, m); 2.77-2.73 (1H, m); 1.90-1.82 (2H, m); 1.32 (3H, d).

Example 76 (1S, 2R) -N- [3-fluoro-4 '- (2-hydroxy-l-methyl-4-pyridin-3-yl-butoxy) -biphenyl-4-yl] -acetamide. a) 2-fluoro-4-iodo-acetanilide 2-Fluoro-4-iodoaniline (5.0 g) in acetic anhydride (50 ml) is heated to reflux. The reaction is suspended by pouring it into water and the product is extracted into ethyl acetate. The organic layers are combined, dried over anhydrous magnesium sulfate and filtered before evaporation. The product is purified by flash chromatography on silica gel eluting with 4: 1 isohexane: ethyl acetate to give the subtitle compound as a solid (0.390 g). p.f. 155-156 ° C MS (GCMS) 279 (M) + XH NMR (CDC13) 9.78 (1H, broad s); 7.73 (1H, t), 7.65 (1H, m); 7.50 (1H, broad d); 2.08 (3H, s). b) (1S, 2R) -N- [3-fluoro-4 '- (2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -biphenyl-4-yl] -acetamide.

Prepared according to the method described in Example 12b) from (1S, 2R) -4- (2-hydroxy-l-methyl-4-pyridin-3-ylbutoxy) benzeneboronic acid (0.200 g, Example 33) , 2-fluoro-4-iodo-acetanilide (0.279 g, Example 76 a)), ethanol (3 ml), 2M aqueous sodium carbonate (0.67 ml) and tetrakis (triphenylphosphine) palladium (0) (0.030 g), heat at 90 ° C for 4 hours, after treatment the residue is purified by CLAP in normal phase, eluting with a gradient of 0-10% ethanol in dichloromethane to give the title compound as a foam (0.107 g). MS APCI 409 (M + H) * 4 * NMR (CDC13) 8.51 (1H, m); 8.45 (1H, m); 8.32 (1H, t); 7.56 (2H, m); 7.45 (2H, m); 7.20-7.32 (3H, m); 6.93 (2H, d); 4.38 (1H, m); 3.86 (1H, broad m); 2.95 (1H, m); 2.73 (1H, m); 2.35 (1H, s, broad); 2.39 (3H, s); 1.85 (2H, m); 1.31 (3H, d).

Example 77 (1S, 2R) -4 '- (2-Hydroxy-l-methyl-4-pyridin-3-yl-butoxy) -6-methyl-biphenyl-3-carboxylic acid methylamide a) 3-Bromo-4-methylbenzoic acid methylamide. Oxalyl chloride (1.45 ml) is added dropwise to a stirred solution of 3-bromo-4-methylbenzoic acid (3.5 g) in dichloromethane (25 ml) and dimethylformamide (1 drop). The mixture is stirred at room temperature for 2 hours. The solvents are removed under reduced pressure and the residue is dissolved in tetrahydrofuran (10 ml). A portion of this solution (5 ml) is added dropwise to a stirred solution of methylamine in tetrahydrofuran (2M, 10 ml) and stirred at room temperature for 3 days. The mixture is poured into water, and the organic phase is separated. The organic phase is extracted into dichloromethane, the combined organic phases are washed with brine, dried over magnesium sulfate, filtered and the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography on silica eluting with ethyl acetate: isohexane (3: 1) to give the subtitle compound as a solid (1.33 g). p.f. 114-116 ° C. MS (APCI) 228/230 (M + H) + 4 * NMR (CDC13) 8.5 (1H, broad d); 8.03 (1H, d); 7.74 (1H, dd); 7.44 (1H, d); 2.77 (3H, d); 2.52-2.48 (3H, m). b) (1S, 2R) -4 '- (2-Hydroxy-l-methyl-4-pyridin-3-yl-butoxy) -6-methylbiphenyl-3-carboxylic acid methylamide.

It is prepared according to the method described in Example 12b) from (1S, 2R) -4- [2-hydroxy-l-methyl-4-pyridin-3-ylbutoxy] benzanboronic acid (0.20 g, Example 33 (0.290 g), 3-bromo-4-methylbenzoic acid, methylamide (0.30 g), 2M aqueous sodium carbonate (0.66 ml) and tetrakis (triphenylphosphine) palladium (0) (0.038 g) in ethanol (3 ml). The reaction mixture is heated at 90 ° C for 4 hours. After cooling, the solution is concentrated under reduced pressure, taken up in ethanol and concentrated again (twice) . The residue is triturated with acetone and then filtered through silica gel, the filtrate is concentrated under reduced pressure, dissolved in dichloromethane, filtered and purified by normal phase CLAP eluting with a gradient of 0-25% ethanol. in dichloromethane to provide an oil, which is further purified by column chromatography on silica gel eluting with ethyl acetate: ethanol (9: 1) to provide the title compound as a foam (0.20 g). MS (APCI) 405 (M + H) + 4 * NMR (DMSO) 8.40 (3H, m); 7.73-7.6 (3H, m); 7.39-7.25 (4H, m); 6.98 (2H, d); 5.00 (1H, d); 4.33 (1H, t); 3.56 (1H, d); 2.87-2.6 (5H, m); 2.27 (3H, s); 1.95-1.82 (1H, m); 1.7-1.6 (1H, m); 1.25 (3H, d).

Example 78 (1S, 2R) -4-Methyl-4 '- (2-hydroxy-l-methyl-4-pyridin-3-yl-butoxy) biphenyl-3-sulfonic acid amide a) 5-bromo-2-methylaniline A suspension of 5-bromo-2-methylnitrobenzene (3.00 g), iron powder (3.11 g) and ammonium chloride (2.97 g) in ethanol: water 3: 1 (50 ml) is heated at reflux temperature for 1 hour. The mixture is poured into 10% aqueous sodium hydroxide and filtered through Celite "1 * .The filtrate is then extracted with ethyl acetate, the extracts are washed with brine, dried over magnesium sulfate, filtered and evaporated. to provide the subtitle compound as an oil (2.64 g), HRMN (CDC13) 6.89 (1H, d), 6.79 (2H, m), 3.64 (2H, broad s), 2.10 (3H, s). b) 5-Bromo-2-methylbenzenesulfonic acid amide.

Prepare by the method of Example 69a) using 5-bromo-2-methylaniline (2.60 g, Example 78a)), sodium nitrite (1.05 g), concentrated hydrochloric acid (20 ml), anhydrous magnesium chloride (2.6 g) , acetic acid saturated with sulfur dioxide (50 ml) and containing copper (II) chloride (0.37 g). Normal treatment and subsequent treatment with ammonium hydroxide (50 ml) followed by the same treatment affords the subtitle compound as a solid. (0.42 g).

MS (APCI) 248/250 (M-H) * XR NMR (CDCl3) 8.15 (1H, s); 7.58 (1H, d); 7.20 (1H, d); 4.86 (2H, broad s); 2.63 (3H, s). c) (1S, 2R) -4-Methyl-4 '- (2-hydroxy-l-methyl-4-pyridin-3-yl-butoxy) biphenyl-3-sulfonic acid amide.

Prepared according to the method described in Example 12b) from (1S, 2R) -4- (2-hydroxy-l-methyl-4-pyridin-3-ylbutoxy) benzeneboronic acid (0.2 g, Example 33) , 5-bromo-2-methylbenzenesulfonic acid amide (1.7 g, Example 78a), ethanol (3 ml), 2M aqueous sodium carbonate (0.7 ml) and tetraJis (triphenylphosphine) palladium (0) (0.03 g) with heating 80 ° C for 3 hours. After treatment, the residue is purified by normal phase CLAP with a gradient of 0-25% ethanol in dichloromethane to provide the title compound as a foam (0.10 g). MS (APCI) 427 (M + H) + 4 * NMR (CDC13) 8.50 (1H, s); 8.45 (1H, d); 8.20 (1H, s); 7.63 (1H, d); 7.56 (1H, d); 7.50 (2H, d); 7.37 (1H, d); 7.24-7.21 (1H, m); 6.95 (2H, d); 4.95 (2H, s); 4.42-4.38 (1H, m); 3.87 (1H, broad s); 2.98-2.91 (1H, m); 2.77-2.71 (4H, m); 2.26 (1H, broad s); 1.94-1.79 (2H, m); 1.31 (3H, d).

Example 79 (1S, 2R) -3-methyl-4 '- (2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -biphenyl-4-sulfonic acid a) 4-Bromo-2-methylbenzenesulfonic acid amide Prepared by the method of Example 69a) using 3-bromo-4-methylaniline (2.60 g, Example 78a)), sodium nitrite (1.05 g), concentrated hydrochloric acid (20 ml), anhydrous magnesium chloride (2.6 g) , acetic acid saturated with sulfur dioxide (50 ml) and copper (II) chloride (0.37 g). Normal treatment and subsequent treatment with ammonium hydroxide (50 ml) followed by the same treatment gives the subtitle compound as a solid (1.51 g). p.f. 179-180 ° C MS (APCI) 250/251 (M-H) + 4. NMR (CDCl 3) 7.76 (1H, d); 7.64 (1H, s); 7.59 (1H, d); 7.49 (2H, broad s); 2.57 (3H, s). b) (1S, 2R) -3-methyl-4 '- (2-hydroxy-l-methyl-4-pyridin-3-yl-butoxy) biphenyl-4-sulfonic acid amide Prepared according to the method described in Example 12b) from (1S, 2R) -4- (2-hydroxy-l-methyl-4-pyridin-3-ylbutoxy) benzanboronic acid (0.2 g, Example 33) , 4-bromo-2-methylbenzenesulfonic acid amide (1.7 g, Example 79a), ethanol (3 ml), 2M aqueous sodium carbonate (0.7 ml) and tetrakis (triphenylphosphine) palladium (0) (0.03 g) with heating 80 ° C for 3 hours. After treatment, the residue is purified by normal phase CLAP eluting with a gradient of 0-25% ethanol in dichloromethane to provide the title compound as a foam (0.13 g). MS (APCI) 427 (M + H) +! H NMR (CDCl 3) 8.52 (1H, s); 8.46 (1H, d); 8.05 (1H, d); 7.57-7.46 (5H, m); 7.26-7.21 (1H, m); 6.97 (2H, d); 4.83 (2H, s); 4.42-4.39 (1H, m); 3.92-3.83 (1H, m); 3.01-2.91 (1H, m); 2.79-2.69 (4H, m); 2.17-2.14 (1H, m); 1.90-1.82 (2H, m); 1.32 (3H, d).

Example 80 (1S, 2R) -3-Fluoro-4 '- (2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) biphenyl-4-sulfonic acid amide b) (1S, 2R) -3-Fluoro-4 '- (2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) biphenyl-4-sulfonic acid amide It is prepared according to the method described in Example 12b) from 4- [(2S, 3R) -5- (pyridin-3-yl) -3-hydroxypent-2-yloxy] benzeneboronic acid (0.20 g, Example 33), 4-bromo-4-amide 2-fluorophenylsulphonic (0.20 g), ethanol (3 ml), 2M aqueous sodium carbonate (1.0 ml) and tetrakis (triphenylphosphine) palladium (0) (0.03 g) with heating at 90 ° C for 3 hours. After treatment, the residue is purified by normal phase CLAP eluting with a gradient of 0-25% ethanol in dichloromethane, followed by recrystallization from aqueous ethanol to give the title compound as a solid (0.11 g). p.f. 178.5-179.5 ° C MS (APCI) 431 (M + H) + 2 H NMR (CDC13) 8.44 (1H, s); 8.39 (1H, d); 7.80 (1H, dd); 7.65 (7H, m); 7.30 (1H, dd); 7.03 (2H, d); 5.01 (1H, d); 4.37 (1H, m); 3.55 (1H, m); 2.80 (1H, m); 2.65 (1H, m); 1.84 (1H, m); 1. 64 (1H, m); 1.24 (3H, d).

Example 81 (1S, 2R) -3-Fluoro-4 '- (2-hydroxy-l-methyl-4-pyridin-3-yl-butoxy) -biphenyl-4-carbonitrile Prepared according to the method described in Example 12b) from (1S, 2R) -4- (2-hydroxy-l-methyl-4-pyridin-3-ylbutoxy) benzeneboronic acid (0.20 g, Example 33) , 4-bromo-2-fluorobenzonitrile (0.16 g), 2M aqueous sodium carbonate (0.76 ml) and tetrakis (triphenylphosphine) palladium (0) (0.03 g) in ethanol (3 ml) with heating at 90 ° C for 4 hours . After treatment, the residue is purified by normal phase CLAP eluting with a gradient of 0-25% ethanol in dichloromethane to provide the title compound as a gum (0.14 g). MS (APCI) 377/378 (M + H) + 'H NMR (CDC13) 8.51 (1H, s); 8.46 (1H, d); 7.64 (1H, dd); 7.24 (1H, dd); 7.52 (3H, m); 7.43 (1H, dd); 7.37 (1H, dd); 6.98 (2H, d); 4.41 (1H, m); 3.85 (1H, m); 2.96 (1H, m); 2.75 (1H, m); 2.25 (1H, broad s); 1.87 (2H, m); 1.32 (3H, d).

Example 82 Hydrochloride salt of (1S, 2R) -4-fluoro-4 '- (2-hydroxy-l-methyl-4-pyridin-3-yl-butoxy) -biphenyl-3-carboxylic acid amide a) 2-fluoro-5-bromobenzamide.

-Bromo-2-fluorobenzonitrile (0.370 g) is heated at 110 ° C for 1 hour in concentrated sulfuric acid (10 ml). After cooling, the reaction is diluted with ice water and the suspension is extracted into ethyl acetate, dried over anhydrous magnesium sulfate, filtered and evaporated to give the sub-title compound as a solid (0.328 g). 4 L NMR (CDC13) 8.26 (1H, m); 7.61 (1H, m); 7.05 (1H, m); 6.64 (1H, broad s); 5.89 (1H, broad s). b) (2S, 3R) -2- (4'-Fluoro-3 • -carboxamide-4-biphenyloxy) -5- (pyridin-3-yl) -pentan-3-ol hydrochloride salt.

Prepared according to the method described in Example 12b) from (1S, 2R) -4- [2- (tert-Butyldimethylsilanyloxy) -l-methyl-4-pyridin-3-ylbutoxy] benzeneboronic acid (0.200 g) , Example 11), 5-bromo-2-fluorobenzamide (0.158 g, Example 82a), ethanol (3 ml), 2M aqueous sodium carbonate (0.48 ml) and tetrakis (triphenylphosphine) palladium (0) (0.030 g), heating at 60 ° C for 8 hours. After cooling, the reaction mixture is evaporated and subjected to azeotropic distillation with ethanol. The residue is taken up in acetone, filtered through a pad of silica gel and evaporated to give an oil which is stirred 1 hour at room temperature in a mixture of methanol (4 ml) and concentrated hydrochloric acid (1 ml. ). The reaction is cooled with an ice bath, diluted with water and made basic at pH 9 by careful addition of a sodium bicarbonate solution. The product is extracted into ethyl acetate, the organic phases are combined, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue is purified by normal phase CLAP eluting with a gradient of 0-10% ethanol in dichloromethane to provide the title compound as a foam (0.040 g). MS (APCI) 395 (M + H) + 4l NMR (CDC13) 8.51 (1H, s); 8.46 (1H, m); 8.30 (1H, m); 7.66 (1H, m); 7.56 (1H, m); 7.50 (2H, d); 7.20 (2H, m); 6.97 (2H, d); 6.74 (1H m broad); 5.98 (1H, broad s); 4.39 (1H, m); 3.87 (1H, m); 2.96 (1H, m); 2.74 (1H, m); 2.44 (1H, broad s); 2.17 (1H, s); 1.84 (2H, m); 1.31 (3H, d).

Example 85 (1S, 2R) -3- [6- (2-Hydroxy-l-methyl-4-pyridin-3-yl-butoxy) na talen-2-yl] -N-me-il-propionamide. a) (2S, 3R) -3- [6- (3-Hydroxy) -5- (pyridin-3-yl) pent-2-yloxy) naphth-2-yl] propenoic acid methyl ester Prepared according to the method described in Example 40a) from (2S, 3R) -4- (6-bromonaphthalen-2-yloxy) -1-pyridin-3-yl-pentan-3-ol (0.68 g) , Example 10), methyl acrylate (0.76 g), palladium acetate (0.04 g), tri-o-tolylphosphine (0.11 g) and triethylamine (2 ml) in acetonitrile (10 ml). After workup, the crude material is purified by flash column chromatography on silica eluting with 20% acetone in isohexane, followed by 50% acetone in isohexane to provide the subtitle compound as an oil (0.73 g). MS (APCI) 392 (M + H) + 4 * NMR (CDC13) 8.52 (1H, d); 8.46 (1H, dd); 7.85 (1H, s); 7.79 (1H, d); 7.73 (1H, d); 7.64 (1H, dd); 7.61 (1H, dd); 7.56 (1H, d); 7.24-7.20 (1H, m); 7.16 (1H, dd); 7.12 (1H, dd); 6.52 (1H, d); 4.53-4.50 (1H, m); 3.94-3.88 (1H, m); 3.83 (3H, s); 2.99-2.92 (1H, m); 2.81-2.73 (1H, m); 2.18 (1H, broad s); 1.92-1.85 (2H, m); 1.36 (3H, d). b) (2S, 3R) -3- [6- (3-hydroxy) -5- (pyridin-3-yl) pent-2-yloxy) naphth-2-yl] propanoic acid methyl ester It is prepared according to the method described in Example 40b) from (2S, 3R) -3- [6 - (3-hydroxy) -5- (pyridin-3-yl) pent-2-methyl ester. iloxy) naf t-2-yl] propenoic acid (0.73 g, Example 84b)), 10% palladium on carbon (0.2 g) and ethanol (50 ml). After workup, the crude material is purified by flash column chromatography on silica eluting with 5% ethanol in dichloromethane to provide an oil (0.57 g). MS (APCI) 394 (M + H) + 41 NMR (CDC13) 8.52 (1H, s); 8.46 (1H, d); 7.69 (1H, d); 7.63 (1H, d); 7.56 (2H, dd); 7.30 (1H, d); 7.24-7.21 (1H, m); 7.10 (2H, d); 4.49-4.48 (1H, m); 3.98-3.87 (1H, m); 3.67 (3H, s); 3.08 (2H, t); 3.09-3.06 (1H, m); 2.72-2.69 (3H, m); 1.80 (1H s broad); 1.89-1.85 (2H, m); 1.35 (3H, d). c) (1S, 2R) -3- [6- (2-hydroxy-l-methyl-4-pyridin-3-yl-butoxy) naphthalen-2-yl] -N-methyl-propionamide Trimethylaluminium is added with caution ( 2.9 ml, 2.0 M solution in toluene) to a suspension of methylamine hydrochloride (0.39 g) in toluene (6 ml) at 0 ° C, with stirring, under nitrogen. During the addition, the reaction temperature is maintained between 0 ° C and 5 ° C. The reaction mixture is then allowed to reach room temperature for about 1 hour. This aluminum / amide reagent is added to a solution of the (2S, 3R) -3- [6- (3-hydroxy) -5- (pyridin-3-yl) pent-2-yloxy) naphthyl methyl ester. 2-yl] clothingnoic (0.57 g, Example 84b) in toluene (20 ml) and heating at reflux temperature, under nitrogen, for 16 hours. After cooling, the reaction mixture is acidified with 2M hydrochloric acid and stirred for 1 hour. The aqueous layer is separated and made basic by the addition of a saturated solution of sodium bicarbonate and then extracted with ethyl acetate (3 x 100 ml). The ethyl acetate fractions are combined, washed with brine and dried over anhydrous magnesium sulfate. After filtration, the solvent is removed by evaporation under reduced pressure and the residue is purified by flash column chromatography on silica eluting with 5% ethanol in dichloromethane to give the title compound as a solid (0.2 g). p.f. 68-70 ° C MS (APCI) 393 (M + H) + 4i NMR (CDCl 3) 8.51 (1H, s); 8.46 (1H, d); 7.68 (1H, d); 7.63 (1H, d); 7.55 (2H, d); 7.30 (1H, dd); 7.24-7.20 (1H, m); 7.12- 7.08 (2H, m); 5.32 (1H, broad s); 4.50-4.47 (1H, m); 3.91-3.88 (1H, m); 3.10 (2H, t); 3.01-2.90 (1H, m); 2.85-2.70 (4H, m); 2.53 (2H, t); 2.21 (1H, d); 1.90-1.84 (2H, m); 1.34 (3H, d).

Example 86 3-cyano-4-fluorobenzanboronic acid A solution of n-butyllithium (5.6 ml, 2.5 M in hexanes) is added over a period of 20 minutes to a solution of 5-bromo-2-fluorobenzonitrile and triisopropylborate (3.46 ml) in tetrahydrofuran (10 ml) at -78 ° C. The resulting solution is stirred at -78 ° C for 30 minutes and then suspended by the addition of 2M hydrochloric acid (20 ml) and extracted into ethyl acetate. The combined extracts are dried over anhydrous magnesium sulfate, filtered and concentrated.

The residue is purified by trituration using diethyl ether: hexane 1: 2 to give the subtitle compound as a solid (1.24 g). p.f. > 250 ° C MS (APCI-ve) 164 (M-H) "1 H NMR (DMSO / D 20) 8.20 (1H, dd); 8.16-8.12 (1H, m); 7.53-7.49 (1H, m).

Example 87 (1S, 2R) -4-Fluoro-4 '- (1-yl-2-hydroxy-4-pyridin-3-ylbutoxy) biphenyl-3-carbonitrile. a) Methyl ester of (2S) -2- (4-bromophenoxy) butanoic acid.

Prepared according to the method described in Example la) from diethylazodicarboxylate (7.8 g), 4-bromophenol (7.8 g), triphenylphosphine (11.8 g) and methyl ester of R-2-hydroxybutanoic acid (5.31 g, Tetrahedron , 35, 1601) in anhydrous tetrahydrofuran. After treatment of the crude material it is purified by flash column chromatography on silica eluting with 30% dichloromethane in isohexane to give the subtitle compound as an oil (7.53 g).

EMI NMR (CDCl3) 7.37 (2H, dt); 6.76 (2H, dt); 4.52 (1H, t); 3.75 (3H, s); 2.03-1.94 (2H, m); 1.07 (3H, t). b) (2S) -2- (4-bromophenoxy) -1-butanol Prepared according to the method described in Example 4b) from (2S) -2- (4-bromophenoxy) butanoic acid methyl ester (7.53 g, Example 87a)) and sodium borohydride (1.09 g) in ethanol (100 ml). After working-up, the crude material is purified by flash column chromatography on silica eluting with dichloromethane to give the subtitle compound as an oil (5.24 g). 4) NMR (CDCl 3) 7.37 (2H, dt); 6.83 (2H, dt); 4.28-4.21 (1H, m); 3.85-3.70 (2H, m); 1.85-1.81 (1H, m); 1.77-1.57 (2H, m); 0.96 (3H, t). c) (3RS, 4S) -4- (4-bromophenoxy) -l-pyridin-3-yl-hex-l-in-3-ol Freshly activated powdered molecular sieves (oven dried at 300 ° C) (20 g, 3A, &5 microns) are added to (2S) -2- (4-bromophenoxy) -1-butanol (5.24 g, Example 87b)) and pyridinium dichromate (12.07 g) in anhydrous dichloromethane (200 ml). This mixture is treated with anhydrous acetic acid (2 drops) and stirred under nitrogen for 2 hours. Celite® (10 g) is added to the reaction mixture which is stirred for 20 minutes. Isohexane (100 ml) is added thereto and the mixture is filtered. The filtrate is concentrated under reduced pressure and the residue obtained is triturated in diethyl ether. This is filtered through anhydrous magnesium sulfate and the filtrate is concentrated under reduced pressure. The resulting residue is assumed to be (2S) -2- (4-bromophenoxy) -1-butanal and dissolved in anhydrous tetrahydrofuran (40 ml). N-Butyllithium (5.88 ml, 2.5 M solution in hexanes) is added dropwise to a solution of pyridin-3-ylacetylene (1.6 g, J. Amer. Chem. Soc. 1935, 57, 1284) in anhydrous tetrahydrofuran (80 ml. ) at -70 ° C, under nitrogen. After stirring for 20 minutes, the solution of (2S) -2- (4-bromophenoxy) -1-butanal in tetrahydrofuran is added dropwise, maintaining the reaction temperature at -70 ° C. The reaction mixture is then allowed to warm slowly to 0 ° C and poured into brine (200 ml). The organic layer is separated and the aqueous layer is extracted with ethyl acetate. The organic fractions are combined and dried over anhydrous magnesium sulfate. After filtration, the filtrate is concentrated under reduced pressure to provide an oil which is purified by flash column chromatography on silica eluting with isohexane: ethyl acetate (2: 1) This gives the subtitle compound as an oil (3.42 g).

MS (APCI) 348 (M + H) + 4i NMR (CDCl 3) 8.70 (1H, dd); 8.51 (1H, dd); 7.69-7.65 (1H, m); 7.40-7.36 (2H, m); 7.27-7.23 (1H, m); 6.93-6.88 (2H, m); 4.81 (1H, t); 4.37-4.33 (1H, m); 3.24 (1H, d); 1.94-1.89 (2H, m); 1.08-1.01 (3H, m). d) (3R, 4S) -4- (4-bromophenoxy) -l-pyridin-3-yl-hexan-3-ol It is prepared according to the method described in Example Id) from (3RS, 4S) -4- (4-bromophenoxy) -l-pyridin-3-yl-in-3-ol (3.42 g, Example 87c)) and 5% rhodium on carbon (0.5 g) ) in ethyl acetate (100 ml). After workup, the crude material is purified by flash column chromatography on silica eluting with ethyl acetate to provide a mixture of diastereomers. The mixture is separated by normal phase CLAP eluting with 2% propan-2-ol in dichloromethane to provide the title compound as the second major diastereomer eluting (2 g). MS (APCI) 350 (M + H) + 4_ NMR (CDC13) 8.48 (1H, s); 8.45 (1H, d); 7.52 (1H, dt); 7.38-7.34 (2H, m); 7.23-7.20 (1H, m); 6.82-6.77 (2H, m); 4.15-4.10 (1H, m); 3.83 (1H, s ampliio); 2.96-2.89 (1H, m); 2.73-2.66 (1H, m); 2.08 (1H, broad s); 1.89-1.61 (4H, m); 0.95 (3H, t). e) (1S, 2R) -4-fluoro-4 '- (1-ethyl-2-hydroxy-4-pyridin-3-ylbutoxy) biphenyl-3-carbonitrile.

Prepared according to the method described in Example 12b) from (3R, 4S) -4- (4-bromophenoxy) -l-pyridin-3-yl-hexan-3-ol (0.3 g, Example 87d) ), 3-cyano-4-fluorobenzeneboronic acid (0.17 g, Example 86), ethanol (3.0 ml), 2M aqueous sodium carbonate (0.5 ml) and tetrakis (triphenylphosphine) palladium (0) (0.03 g) with heating at 100 ° C for 4 hours. After treatment, the residue is purified by flash column chromatography on silica eluting with isohexane: acetone (2: 1) to give the title compound as an oil (0.17 g). MS (APCI) 391 (M + H) + 4? NMR (CDC13) 8.50 (1H, s); 8.46 (1H, d); 7.75-7.70 (2H, m); 7.57 (1H, d); 7.42 (2H, d); 7.28-7.21 (2H, m); 7.00 (2H, d); 4.27-4.23 (1H, m); 3.89-3.85 (1H, m); 2.98-2.91 (1H, m); 2.76-2.68 (1H, m); 2.05 (1H, broad s); 1.91-1.67 (4H, m); 0.99 (3H, t).

Example 88 (1S, 2R) -4 '- [l-Ethyl-2-hydroxy-4-pyridin-3-yl-butoxy] -4-fluorobiphenyl-3-sulfonic acid amide a) (3R, 4S) -3- [4- (4-bromophenoxy) -3- (t-butyldimethylsilanyloxy) hexyl] pyridine.

To a solution of (3R, 4S) -4- (4-bromophenoxy)) -1-pyridin-3-yl-hexan-3-ol (1.34 g, Example 87d)) in dry N, N-dimethylformamide (30 ml ) add tert-butyldimethylsilyl chloride (0.80 g) and imidazole (0.77 g) and the resulting solution is heated at 50 ° C for 20 hours. The solution is concentrated in vacuo. The residue is made basic by the addition of a saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The combined extracts are dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by column chromatography on silica eluting with ethyl acetate: isohexane (1: 1) to give the subtitle compound as an oil (0.71 g). MS (APCI) 466 (M + H) + 4 * NMR (CDCl 3) 8.43 (1H, dd); 8.40 (1H, d); 7.41-7.33 (1H, m); 7.34 (2H, d); 7.20-7.16 (1H, m); 6.76 (2H, d); 4.11-4.08 (1H, m); 3.92-3.90 (1H, m); 2.88-2.78 (2H, m); 1.98-1.71 (4H, m); 0.96 (3H, t); 0.91 (9H, s); 0.06 (6H, d). b) (1S, 2R) -4- [2- (t-Butyldimethylsilanyloxy) -1-ethyl-4-pyridin-3-yl-butoxy] benzeneboronic acid Prepared according to the method as described in Example 5b) from (3R, 4S) -3- [4- (4-bromophenoxy) -3- (t-butyldimethylsilanyloxy) hexyl] pyridine (0.71 g, Example 88a)), terbutyllithium (1.80 ml, 1.7M in hexanes) and triisopropylborates (0.74 ml) in dry tetrahydrofuran (25 ml).

After treatment, the residue is purified by column chromatography eluting with a gradient of 0-25% ethanol in ethyl acetate to provide the subtitle compound as a foam (0.41 g). MS (APCI) 430 (M + H) +! H NMR (CDC13) 8.53-8.51 (2H, m); 7.95 (2H, d); 7.45-7.42 (1H, m); 7.22-7.18 (1H, m); 6.89 (2H, d); 4.20-4.16 (1H, m); 3.98-3.93 (1H, m); 3.76-3.69 (1H, m); 2.74-2.61 (2H, m); 1.98-1.91 (1H, m); 1.82-1.73 (3H, m); 1.60 (1H, broad s); 0.98 (3H, t); 0. 92 (9H, s); 0.02 (6H, d). c) (1S, 2R) -4 '- [l-Ethyl-2-hydroxy-4-pyridin-3-yl-butoxy] -4-fluorobiphenyl-3-sulfonic acid amide Prepared according to the method described in Example 12b) from (3R, 4S) -3- [4- (4-bromophenoxy) -3- (t-butyldimethylsilanyloxy) hexyl] pyridine (0.20 g, Example 88b) ), 2-fluoro-5-bromophenylsulfonamide (0.177 g, Example 35a)), 2M aqueous sodium carbonate (0.54 ml) and tetrakis (triphenylphosphine) palladium (0) (0.014 g) in ethanol (3 ml) with heating to 90 ° C for 4 hours. The residue is purified by column chromatography on silica eluting with ethyl acetate to give the title compound as a foam (0.14 g). MS (APCI) 445 (M + H) + 4 * NMR (CDC13) 8.49 (1H, d); 8.45 (1H, dd); 8.05 (1H, dt); 7.74- 7.68 (1H, m); 7.55-7.52 (1H, m); 7.46 (2H, d); 7.30-7.21 (2H, m); 6.98 (2H, d); 5.08 (2H, s); 4.23-4.21 (1H, m); 3.96-3.85 (1H, m); 2.95-2.86 (1H, m); 2.74-2.64 (1H, m); 1.96 (1H, d); 1. 91-1.83 (4H, m); 0.98 (3H, t).

Example 89 (1S, 2R) -3-chloro-4 '- (1-ethyl-2-hydroxy-4-pyridin-3-ylbutoxy) biphenyl-4-carbonitrile It is prepared according to the method described in Example 12b) from (1S, 2R) -4- [2- (erbutyldimethylsilanyloxy) -l-ethyl-4-pyridin-3-ylbutoxy] benzanboronic acid (0.18 g, Example 88b)), 4-bromo-2- chlorobenzonitrile (0.18 g), 2M aqueous sodium carbonate (0.48 ml) and tetrakis (triphenylphosphine) palladium (0) (0.012 g) in ethanol (3 ml) with heating at 90 ° C for 4 hours. The residue is purified by column chromatography eluting with a gradient of 50-100% ethyl acetate in isohexane to give the title compound as a solid (0.125 g). p.f. 99-100 ° C MS (APCI) 407 (M + H) + 4 * NMR (CDC13) 8.48 (1H, d); 8.45 (1H, dd); 7.70-7.56 (2H, m); 7.56-7.48 (2H, m); 7.51 (2H, d); 7.24-7.20 (1H, m); 7.0 (2H, d); 4.27-4.25 (1H, m); 3.86-3.80 (1H, m); 2.94-2.92 (1H, m); 2. 74-2.69 (1H, m); 2.12 (1H, d); 1.92-1.73 (4H, m); 0.98 (3H, t).

Pharmacological activity The pharmacological activity of the compounds of the invention can be tested by the methods of E. Wells et al, 'Characterization of primate bronchoalveolar mast cells: II-inhibition of histamine, LTC4 and PGD2 from primate bronchoalveolar mast cells and a comparison with peritoneal rat mast cells', ". Immunol., vol 137, 3941, 1986. The compounds of Examples 1 to 89 were tested and found to inhibit the release of histamine at a concentration of less than 10 5 M (IC 50). It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects or products to which it refers.

Claims

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. A compound of formula I: (I) characterized in that: X is O or S; R1 and R2 are independently hydrogen, C ^ g alkyl or C3_6 cycloalkyl, or R1 and R2 together with the carbon atom to which they are attached form a cycloalkyl group of C3.6; R3 is hydrogen, and R4 is C6 alkyl or C3_6 cycloalkyl, or R3 and R4 together with the carbon atom to which they are attached form a cycloalkyl group of C3_6; Ar1 is indanyl, tetrahydronaphthyl, naphthyl, phenyl, C7_9 alkylphenyl or biphenyl, the last four groups which optionally may be substituted by one or more groups selected from halo, nitro, cyano, pyridyl, thiazinyl, C1.10 alkyl (optionally substituted by one or more fluorine atoms), -Y-OR5, -Y-NR6C (0) NR7R8, -OZC (0) NR7R8, -0-YC (S) NR7R8, -YC (0) NR7R8, - Y-S02NR7R8, -Y-NR7R8, -Y-OC (0) NR7R8, -YC (S) NR7R8, -YC (0) R9, -Y-0C (0) R9, -Y-C02R9, -Y-NR10C (0) NRX1-Z-R12, SO2NR10C (0) NR7R8, - Y- S02NHNR7R8, -YC (0) NR11-Z-R12, -YC (S) NR11-Z-R12, - YN (R10) S02Ra? , -Y-N (R10) C (O) R11 or -Y-N (R10) CO2R1: L; wherein Y is a bond, C 1-6 alkylene or alkenylene of R7 and R8 are independently hydrogen or C1-6alkyl or, together with the nitrogen atom to which they are attached, form an optionally substituted 5- to 7-membered heterocyclic ring, optionally containing an additional heteroatom which is selected from nitrogen, oxygen or sulfur; R5, R6, R9, R10 and R11 are independently hydrogen or C1_10 alkyl (optionally substituted by one or more fluorine atoms); Z is alkylene of C? _6; and R12 is a group NR10C (O) R11, NR10CO2R?: L, OR5, NR7R8 or COzR13 wherein R5, R7, R8, R10 and R11 are as defined above and R13 is hydrogen, C1_6 alkyl, C-alkylaryl L_6 or aryl optionally substituted by hydroxy, or a salt or solvate thereof.

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

3. The compound according to claim 1 or 2, characterized in that R1 and R2 are both hydrogen.

4. The compound according to any of claims 1 to 3, characterized in that R3 is hydrogen and R4 is C. Β alkyl or R3 together with R4 forms a cyclopropyl group.

5. The compound according to any of claims 1 to 4, characterized in that Ar1 is naphthyl or biphenyl.

6. The compound according to any of claims 1 to 4, characterized in that Ar1 is biphenyl optionally substituted by one or more substituents that are selected from halo, cyano, ethyl or S02NR7R8.

7. The compound according to claim 1, characterized in that it is: (3R, 4R) -4- (biphenyl-4-yloxy) -l-pyridin-3-yl-pentan-3 -ol, (3S, 4R) -4- (biphenyl-4-yloxy) -l-pyridin- 3-yl-pentan-3-ol, (3R, 4S) -4- (biphenyl-4-yloxy) -l-pyridin-3-yl-pentan-3-ol, (3S, 4S) -4- (biphenyl) 4-yloxy) -l-pyridin-3-yl-pentan-3-ol, (1S, 2R) -4 '- (2-hydroxy-l-methyl-4-pyridin-3-ylbutoxy) biphenyl-3 - carbonitrile, (lS, 2S) -4 '- (2-Hydroxy-l-methyl-4-pyridin-3-ylbutoxy) biphenyl-3-carbonitrile, (1S, 2R) -4' - (2-Hydroxy) amide -l-methyl-4-pyridin-3-yl-butoxy) -ylphenyl-3-sulfonic acid, (1S, 2S) -4 '- (2-Hydroxy-1-ethyl-4-pyridin-3-yl) amide -butoxy) -biphenyl-3-sulfonic acid, (3R, 4S) -4- (3'-chlorobiphenyl-4-yloxy) -l-pyridin-3-yl-pentan-3-ol, (3S, 4S) -4 - (3'-Chlorobiphenyl-4-yloxy) -l-pyridin-3-yl-pentan-3-ol, (3R, 4S) -4- (4'-Fluoro-biphenyl-4-yloxy) -l-pyridin -3-yl-pentan-3-ol, (3S, 4R) -4- (4 '-Fluoro-biphenyl-4-yloxy) -l-pyridin-3-yl-pentan-3-ol, (3R, 4S ) -4- (Biphenyl-4-yloxy) -5-methyl-l-pyridin-3-yl-hexan-3-ol, (+) 1- [1- (Biphenyl-4-yloxy) -cyclopropyl] -3 -pi Ridin-3-yl-propan-1-ol, (2S, 3R) -4- (6-Bromonaphthalen-2-yloxy) -I-pyridin-3-yl-pentan-3-ol, (2R, 3S) - 4- (6-Bromonaphthalen-2-yloxy) -l-pyridin-3-yl-pentan-3-ol, (1S, 2R) -2- [4 l (2-Hydroxy-1-methyl-4-pyridin - 3-ylbutoxy) bifenyl-3-yl] -N-methylacetamide, (3R, 4S) -4- (4'-Chloro-2'-fluorobiphenyl-4-yloxy) -1-pyridin-3-yl-pentan-3-yl, (3R, 4S) -4- (4 '- Chloro-biphenyl-4-yloxy) -l-pyridin-3-yl-pentan-3-ol, (3R, 4S) -4- (5'-methoxy-2'-methyl-biphenyl-4-yloxy) -1-pyridin-3 il-pentan-3-ol, (3R, 4S) -4- (3 ', 4'-Dichlorobiphenyl-4-yloxy) -l-pyridin-3-yl-pentan-3-ol, (2-morpholin-4) (1S, 2R) -4 '- (2-hydroxy-1-methyl-4-pyridin-3-yl-butoxy) biphenyl-3-sulfonic acid, (3S, 2S) -4- ( ', 4' -Dichloro biphenyl-4-yloxy) -l-pyridin-3-yl-pentan-3-ol, (1S, 2R) -4 '- (2-Hydroxy-l-methyl-4-pyridin) methylamide -3-yl-butoxy) biphenyl-3-sulfonic acid; (1S, 2R) -4 '- (2-Hydroxy-1-methyl-4-pyridin-3-yl-butoxy) biphenyl-3-sulfonic acid (2S) 2-pyrrolidin-1-ylide (1S, 2R) ) -4 '- (2-Hydroxy-l-methyl-4-pyridin-3-yl-butoxy) -2-methyl-biphenyl-4-carbonitrile, (1S, 2R) -N- [2-Chloro-4' - (2-hydroxy-l-methyl-4-pyridin-3-yl-butoxy) -biphenyl-4-yl] acetamide, (3R, 4S) -4- (4 '-Amino-2'-chloro-biphenyl- (1S, 2R) -4 '- (2-Hydroxy-l-methyl-4-pyridin-3-yl) -3-pyridin-3-yl-pentan-3-ol, (2-dimethylaminoethyl) amide il-butoxy) biphenyl-3-sulfonic (1S, 2R) -2- [4 '(2-Hydroxy-l-methyl-4-pyridin-3-ylbutoxy) biphenyl-4-yl] -N-methylacetamide, (lS , 2R) -2- [4 '(2-Hydroxy-1-methyl-4-pyridin-3-ylbutoxy) biphenyl-3-yl] -N, N-dimethylacetamide, (3R, 4S) -4- [3' - (2-Dimethylaminoethyl) biphenyl-4-yloxy] -1-pyridin-3-yl-pentan-3-ol, (1S, 2R) -2- [41 (2-Hydroxy-l-methyl-4-pyridine -3-ylbutoxy) biphenyl-3-yl] -l-morpholin-4-ylethanone, (3R, 4S) -4- [4-3- (Methylaminoethyl) biphenyl-4-yloxy] -1-pyridin-3-yl -pentan-3 -ol, (3R, 4S) -4- [41 - (2 -Methylaminoethyl) biphenyl-4-yloxy] -1-pyridin-3-yl-pentan-3-ol, (1S, 2R) -4 '- (2-Hydroxy-l-methyl-4-pyridin-3-ylbutoxy) biphenyl-3-yl-urea, (3R, 4S) -4- (3 ', 4'-Dichlorobiphenyl-4-yloxy) -l-pyridin-3-yl-pentan-3-ol, (1S, 2R) Acid -4- (2-Hydroxy-l-methyl-4-pyridin-3-ylbutoxy] benzeneboronic acid, (1S, 2R) -4 '- (2-Hydroxy-l-methyl-4-pyridin-3-yl-butoxy) -3-methyl-biphenyl-4-carbonitrile, (1S, 2R) -4-Fluoro-4 '- (2-hydroxy-l-methyl-4-pyridin-3-yl-butoxy) -ifenil-3 - acid amide sulphonic, (1S, 2S) -4-Fluoro-4 '- (2-hydroxy-l-methyl-4-pyridin-3-yl-butoxy) ifenyl-3-sulfonic acid amide, (1S, 2R) -4 -Fluoro-4 '- (2-hydroxy-l-methyl-4-pyridin-3-yl-butoxy) biphenyl-3-carbonitrile, (1S, 2R) -2,5-Difluoro-4' - ( 2-hydroxy-l-methyl-4-pyridin-3-yl-butoxy) biphenyl-4-sulfonic acid, (1S, 2R) -3-Chloro- '- (2-hydroxy-l-methyl-4-pyridin-3 -ylbutoxy) biphenyl-4-carbonitrile, (1S, 2R) -3- [6- (2-Hydroxy-l-methyl-4-pyridin-3-ylbutoxy) naphthalen-2-yl] -N, N-dimethylacrylamide. (1S, 2R) -4 * - (2-Hydroxy-1-methyl-4-pyridin-3-ylbutoxy) biphenyl-3-N-sulfonamido-N '-isopropyl-urea, (lS, 2R) -3- [ 6- (2-Hydroxy-1-methyl-4-pyridin-3-ylbutoxy) -naphthalen-2-yl] -l-morpholin-4-yl-propan-l-one, (3R, 4S) -4- [ 6- (3-Morpholin-4-yl-propyl) naphthalen-2-yloxy] -1-pyridin-3-yl-pentan-3-ol, (3R, 4S) -4- [6- (3-Methylaminopropyl) naph talen-2-yloxy] -l-pyridin-3-yl-pentan-3-ol, (1S, 2R) -4 '- (2-Hydroxy-1-isopropyl-4-pyridin-3-ylbutoxy) bif enyl-3-carbonitrile, (3R, 4S) -l-Pyridin-3-yl-4- [4 '- (2-pyrrol idin-1-yl-ethoxy) bifenyl-4-yloxy] pentan-3-ol (1S, 2R) -4 '- (2-Hydroxy-l-methyl-4-pyridin-3-ylbutoxy) -4- (2-morpholin-4-yl-ethoxy) biphenyl-3-carbonitrile, (3R, 4S) -4- (3 '-Metanesulfonylbiphenyl-4-yloxy) -1-pyridin-3-yl-pentan-3 -ol, (1S, 2R) -4' - (2-Hydroxy-1-methyl-) amide 4-pyridin-3-yl-butoxy) biphenyl-3-carboxylic acid, (1S, 2R) -2- [4'- (2-Hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -biphenyl- 3-yloxylacetamide, (2S, 3R) -l-Pyridin-3-yl-4- (2 '- trifluoromethoxybiphenyl-4-yloxy) pentan-3-ol, (1S, 2R) -4 '- (2-Hydroxy-l-methyl-4-pyridin-3-yl-butoxy) -6-methoxybiphenyl-3-carbonitrile, ( 3R, 4S) -4- (4'-Chloro-2'-methoxy-5'-methylbiphenyl-4-yloxy) -1-pyridin-3-yl-pentan-3-ol, (1S, 2R) methylamide -4 '- (2-Hydroxy-l-methyl-4-pyridin-3-yl-butoxy) -biphenyl-3-carboxylic acid, (1S, 2R) - [4'-2-Hydroxy-1-methyl-4] -pyridin-3-yl-butoxy) -biphenyl-4-yl] acetic acid (1S, 2R) -N- [4 '- (2-Hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -5 -trifluoromethyl-biphenyl-2-yl] acetamide, (1S, 2R) -2- [4 '- (2-Hydroxy-1-methyl-4-pyridin-3-ylbutoxy) -biphenyl-2-yl] -N- methylacetamide, (1S, 2R) -N- [4 '- (2-Hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -2-methyl-biphenyl-4-yl] -acetamide, (1S, 2R) -N- [4 »- (2-Hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -biphenyl-3-yl] -methanesulfonamide, (1S, 2R) -4 '- (2-Hydroxy-1-methyl) amide 4-pyridin-3-yl-butoxy) biphenyl-4-suphonic acid, (1S, 2R) -4 '- (2-Hydroxy-1-isopropyl-4-amide) -pyridin-3-yl-butoxy) biphenyl-3-sulfonic acid(lS, 2R) - [4'- (2-Hydroxy-1-methyl-4-pyridin-3-ylbutoxy) biphenyl-4-yl] -urea, (2-pyrrolidin-1-yl-ethyl) -amide of the acid (1S, 2R) -4'- (2-Hydroxy-1-methyl-4-pyridin-3-yl-butoxy) -2-methyl-biphenyl-4-carboxylic acid (2,2,2-trifluoroethyl) -amide (1S, 2R) -4 • - (2-Hydroxy-1-methyl-4-pyridin-3-yl-butoxy) biphenyl-3-sulfonic acid, (lS, 2R) -l- [4'- (2-Hydroxy -1-methyl-4-pyridin-3-ylbutoxy) -biphenyl-4-yl] -3-methylurea, (1S, 2R) -2- [4 '- (2-Hydroxy-1-methyl-4-pyridin- 3-ylbutoxy) -biphenyl-4-yl] -N-isopropylacetamide, (1S, 2R) -N-Cyclopropyl-2- [4 '- (2-hydroxy-l-methyl-4-pyridin-3-yl-butoxy ) -biphenyl-4-yl] acetamide, (1S, 2R) -2- [4 '- (2-Hydroxy-1-methyl-4-pyridin-3-ylbutoxy) biphenyl-4-yl] -1-pyrrolidin- l-Iletanone, (1S, 2R) -2-Methyl-4 '- (2-hydroxy-l-methyl-4-pyridin-3-yl-butoxy) biphenyl-5-sulfonic acid amide, (1S, 2R) -2, 2, 2 -Trifluoro-N- [4 '- (2-hydroxy-l-methyl-4-pyridin-3-butoxy) -biphenyl-3-yl] -N-methylacetamide, (1S, 2R) - 4 »- (2-Hydroxy-l- methyl-4-pyridin-3-ylbutoxy) biphenyl-3,4-dicarbonitrile, (3R, 4S) -l-Pyridin-3-yl-4- [3 '- (pyrrolidin-1-sulfonyl) biphenyl-4-yloxy] pentan-3-ol, (1S, 2R) -6-Fluoro-4 '- (2-hydroxy-l-methyl-4-pyridin-3-yl-butoxy) -biphenyl-3-carbonitrile, (1S) acid amide , 2R) -4 '- (2-Hydroxy-l-methyl-4-pyridin-3-yl-butoxy) -5-trifluoromethyl-biphenyl-3-sulfonic acid, (1S, 2R) -N- [3-Fluoro- 4! - (2-hydroxy-l-methyl-4-pyridin-3-yl-butoxy) -biphenyl-4-yl] -acetamide, (1S, 2R) -4 '- (2-Hydroxy-1-methyl) methylamide -4-pyridin-3-yl-butoxy) -6-methyl-biphenyl-3-carboxylic acid, (1S, 2R) -4-Methyl-4 '- (2-hydroxy-l-methyl-4-pyridin) amide -3-yl-butoxy) biphenyl-3-sulfonic acid (1S, 2R) -3-Methyl-4 '- (2-hydroxy-l-methyl-4-pyridin-3-yl-butoxy) biphenyl-4-amide -sulfonic, (1S, 2R) -3-Fluoro-4 '- (2-hydroxy-l-methyl-4-pyridin-3-yl-butoxy) biphenyl-4-sulfonic acid amide, (1S, 2R) - 3-Fluoro-4 '- (2-hydroxy-l-methyl-4-pyridin-3-yl-butoxy) -biphenyl-4-carbonitrile, (1S, 2R) -4-Fluoro-4' - ( 2-hydroxy-l-methyl-4-pyridin-3-yl-butoxy) -biphenyl-3-carboxylic acid, (1S, 2R) -3- [6- (2-Hydroxy-1-methyl-4-pyridin-3 -ylbutoxy) naph alen-2-yl] -N-methyl-propionamide. (1S, 2R) -4-Fluoro-4 '- (1-ethyl-2-hydroxy-4-pyridin-3-ylbutoxy) biphenyl-3-carbonitrile, (1S, 2R) -4' - [ Ethyl-2-hydroxy-4-pyridin-3-yl-butoxy] -4-fluorobiphenyl-3-sulfonic acid, (1S, 2R) -3-Chloro-4 '- (1-ethyl-2-hydroxy) -4- pyridin-3-ylbutoxy) biphenyl-4-carbonitrile, (4S, 3R) -4- (4'-Methanesulfonyl-biphenyl-4-yloxy) -1-pyridin-3-yl-pentan-3-ol, or salts or solvates of the same.

8. The compound according to any of claims 1 to 7, characterized in that it is used in therapy.

9. The compound according to any of claims 1 to 7, characterized in that it is used in the treatment of prophylaxis of asthma or rhinitis.

10. A pharmaceutical composition characterized in that it comprises a compound of formula I or a salt or solvate thereof according to any of claims 1 to 7 in association with a pharmaceutically acceptable adjuvant, diluent or carrier.

11. A process for the preparation of compounds of formula I, characterized in that it comprises: (a) reduction of a compound of formula (II) (II) wherein R3, R4, X and Ar1 are as defined in formula (I); or (b) reduction of a compound of formula (III): (neither: wherein R1, R2, R3, R4, X and Ar1 are as defined in formula (I); or (c) preparation of compounds of formula (I) wherein Ar 1 is a biphenyl group substituted by reaction of a compound of formula (IV): with a compound of formula (V) (V) wherein X, R1, R2, R3 and R4 are as defined in formula (I), R15 is a substituent Ar1 as defined in formula (I), and Rld is a suitable hydroxy protecting group, and one of R17 / R18 is triflate or halo and the other is B (OH) 2 or ZnHal, or and optionally subsequently, in any order: remove any protecting group converting a compound of formula (I) into another compound of formula (I) a pharmaceutically acceptable salt or solvate.