MX2008010004A - Compounds and methods for modulating fx-receptors - Google Patents

Abstract

Compounds of formula and their pharmaceutical compositions and methods of use are disclosed as useful for treating dyslipidemia and related diseases.

Description

COMPOUNDS AND METHODS TO MODULATE FARNESOID X RECEIVERS (FXR) FIELD OF THE INVENTION The current invention is related to the fields of organic medicinal chemistry, pharmacology, and medicine.

BACKGROUND OF THE INVENTION Dyslipidemia and diseases related to dyslipidemia, for example atherosclerosis, coronary artery disease, stroke, etc., are major causes of death, morbidity, and economic loss. Plasma lipids, especially cholesterol fractions, are recognized to have a significant role in cardiovascular health. Favorable modulation of plasma lipids, such as triglycerides, HDL cholesterol, and LDL cholesterol is desirable. International application WO 03/015771 Al, describes certain isoxazoles for use in the treatment of diseases mediated by the FXR receptor NR1H4. International Application WO 03/37077 describes certain isoxazoles that bind to the farnesoid X receptor (FXR). International application WO 2004/048349 Al, describes compounds useful as farnesoid X receptor agonists. International application WO 98/28269 describes compounds useful as factor Xa inhibitors.

The receptors of the nuclear hormone FXR, regulate the metabolism of plasma cholesterol and HDL. Thus, the compounds which modulate the FXR, could improve the lipid regulation profile, particularly increased levels of HDL. Such compounds are desirable and could be useful for the treatment of disorders characterized by, or resulting from, an undesirable lipid profile including, dyslipidemia, atherosclerosis, diabetes and related diseases. The present invention provides novel selective and potent FXR agonists for beneficial regulation of lipid profiles including high levels of HDL.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides a compound of formula I p is 0 or 1; R1 and R2 are independently selected from the group consisting of hydrogen, -C1-C6 alkyl, -haloalkyl Ci-C6, -alkoxy Ci-C6, -haloalkoxy Ci-C6, halo, -SR11, and -S-haloalkyl C1-C3; each R3 is independently selected from the group consisting of-C1-C6alkyl, -haloalkyl C1-C6, -alkoxy Ci-Ce, -haloalkoxy C1-C6 and halo; R4 is selected from the group consisting of hydrogen, Ci-C6 alkyl, Ci-C6 haloalkyl, C3-C8 cycloalkyl, C-C8 alkylcycloalkyl, Ci-C6 alkoxy and Ci-C6 haloalkoxy; R5 and R5a are independently selected from the group consisting of hydrogen, and-C1-C3 alkyl; R6 is selected from the group consisting of hydrogen, -alkyl i-C &, -haloalkyl C1-C6, and halo; Ar 1 is selected from the group consisting of indolyl, pyridinyl, thienyl, benzothienyl, indazolyl, benzothiazolyl, benzisoxazolyl, benzofuranyl and thiazolyl, each optionally substituted with one or two groups independently selected from the group consisting of hydroxy, Ci-C 6 alkyl, -C3-C8-cycloalkyl, -Ci-C4SC alkyl > 2-C1-C2alkyl, -Ci-C4alkylC1-C2alkyl, -Ci-C4NR10Rnalkyl, phenyl, -Ci-C4alkyl-C1-C4alkyl, and -NHC (0) R10; R7 is selected from the group consisting of CH2COOR10, -COOR10, -CONR11R11, -C (0) NHS02Ci-C4alkylC (O) HS02R12, oxadiazolethione and oxadiazolone; each R10 is independently selected from the group consisting of hydrogen, -C1-C4 alkyl, and phenyl; each R is independently hydrogen, or -alkyl R12 is -Ci-C6 alkyl or phenyl optionally substituted with -C1-C3 alkyl, or a pharmaceutically acceptable salt thereof. The compounds of the invention are modulators of FXR. As such, the compounds of the invention are employed to beneficially alter lipid profiles, including but not limited to, total cholesterol reduction, reduction of LDL cholesterol, reduction of VLDL cholesterol levels, elevation of HDL levels, reduction of levels of triglycerides and beneficially sensitize the effects of insulin. Therefore, the present invention provides a method for treating FXR-mediated conditions such as dyslipidemia and dyslipidemia-related diseases comprising administering a therapeutically effective amount of a compound of the present invention to a patient in need thereof. The present invention also provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier. The present invention also relates to the use of a compound of the invention, for the manufacture of a medicine. The present invention also provides the use of a compound of the invention, for the manufacture of a medicament for treating conditions mediated by FXR described herein.

DETAILED DESCRIPTION OF THE INVENTION The terms "modulation" and "modulator" as used herein, refer to the beneficial modulation of genes and enzymatic processes that result in or of FXR receptor agonism. FXR modulates key genes in multiple metabolic pathways, including cholesterol, triglycerides, bile acid, and glucose metabolism. The term "dyslipidemia" as used herein refers to an abnormality in, or abnormal amounts of lipids and lipoproteins in the blood and the resulting disease states, caused by, exacerbated by, or attached to such an abnormality (see Dorland ' s Illustrated Medical Dictionary, 29th edition, WB Saunders publishing Company, New York, NY). Disease states included within the definition of dyslipidemia as used herein include hyperlipidemia, hypertriglycemia, low plasma HDL, high plasma LDL, high plasma VLDL, liver cholestasis, and hypercholesterolemia. The phrase "diseases related to dyslipidemia" as used herein refers to diseases including but not limited to atherosclerosis, thrombosis, coronary artery disease, stroke, and hypertension. Diseases related to dyslipidemia also include diabetes, insulin resistance, and complications thereof. Complications of diabetes include but are not limited to diabetic retinopathy and obesity. As used herein, the term "patient" includes human and non-human animals, such as companion animals (dogs and cats and the like) and livestock animals. The terms "treatment", "treats" and "treat", include inhibiting, alleviating, hindering, reducing and reversing the progress of, or reducing the severity of, pathological symptoms of dyslipidemia and diseases related to dyslipidemia. As used herein, the term "therapeutically effective amount" means an amount of a compound of the invention that is part of an approved therapeutic regimen, or is determined by a qualified prescriber to be sufficient taken as directed, to treat a condition, or harmful effects thereof described herein. The term "pharmaceutically acceptable" is used herein as an adjective and means substantially non-detrimental to the recipient patient. The term "Ci-C6 alkyl" or the like (e.g., -Ci-C2 alkyl, -C1-C3 alkyl, -C1-C4 alkyl, -C1-C5 alkyl, etc.), represents a straight or branched hydrocarbon portion that has from 1 to 6 (or as indicated), carbon atoms, including but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, and the like. An optionally substituted alkyl group is divalent when connected to the substrate or molecular structure. The term "C3-C8 cycloalkyl", or similar terms, refers to a carbocyclic ring having from 3 to 8 carbon atoms (or as indicated), including but not limited to cyclopropyl, cyclopentyl and cyclohexyl. The term "C4-C8 alkylcycloalkyl", and the like (depending on the indicated number of carbon atoms) as used herein, refers to the combination of an alkyl and a cycloalkyl group, such that the total number of carbon atoms is carbon is 4 to 8, or as indicated and the entire group is attached to the substrate via the alkyl portion. For example, C4-Cs alkylcycloalkyl includes cycloalkyl rings (eg, C3-C cycloalkyl) linked at least to a carbon atom, so that the total number of carbon atoms is any from 4 to 8 as in, for example, -CH2cyclopropyl. The term "halo" means halogens, which include iodine, chlorine, bromine and fluorine. The term "C1-C6 haloalkyl" or the like (eg, C1-C3 haloalkyl), refers to a Ci-C6 alkyl group (or as indicated), substituted with one, two, three or more halogen atoms as indicates, or is chemically appropriate. Examples of C1-C6 haloalkyl include but are not limited to trifluoromethyl, chloroethyl, and 2-chloropropyl. A "C 1 -C 6 alkoxy" or similar group (e.g., C 1 -C 3 alkoxy, C 2 -C 6 alkoxy, etc.), is a C 1 -C 6 alkyl (or as indicated), a portion connected through an oxy-bond. . Examples of alkoxy groups include but are not limited to methoxy (-OMe), ethoxy (-OEt), propoxy (-OPr), isopropoxy (-OiPr), butoxy (-OBu), etc. The term "C 1 -C 6 haloalkoxy" or similar (e.g., C 1 -C 3 haloalkoxy) embraces C 1 -C 6 alkoxy wherein one or more of the hydrogens have been replaced with halogens. Examples of haloalkoxy groups include, difluoromethoxy, trifluoromethoxy, 2-haloethoxy, 2,2,2-trifluoroethoxy, 4,4,4-trifluorobutoxy, up to and including similar groups having the indicated number of carbon atoms. A compound of the invention as illustrated by the invention, can occur as any of one of its isomers which are subject of the invention. Certain compounds of the invention may possess one or more chiral centers, and thus, may exist in their optically active forms. All isomers, as well as mixtures thereof, are within the scope of the present invention. If a particular stereoisomer is desired, it can be prepared by methods well known in the art.

Preferred Modes of the Invention Preferably, p is 0 or 1. More preferably, p is 0. Preferably R1 and R2 are each independently selected from the group consisting of hydrogen, C1-C3 alkyl, -haloalkyl -C1-C3, C1 alkoxy -C3-, C1-C3 haloalkoxy-, -C1-C3 -Saltyl, -ShaloalkylCi-C3, and halo. More preferred R1 and R2 groups are independently selected from the group consisting of hydrogen, chloro, fluoro, trifluoromethyl, thiotrifluoromethyl, and trifluoromethoxy. A preferred R3 group is selected from the group consisting of C1-C4 alkyl, -C1-C3 haloalkyl, C1-C3 alkoxy-, C1-C3 haloalkoxy-, and halo. More preferred is a group R3 selected from the group consisting of chloro, fluoro, trifluoromethoxy, thiotrifluoromethyl, and trifluoromethyl. More preferably, R3 is absent (p is 0). Preferably, R 4 is selected from H, methyl, ethyl, isopropyl, cyclopropyl, and methylcyclopropyl. More preferably R4 is isopropyl or cyclopropyl. Preferably, R5 and R5a are each independently selected from the group consisting of hydrogen, methyl and ethyl. More preferably, R5 and R5a are both hydrogen. A preferred R6 group is selected from the group consisting of hydrogen, halo, and C1-C3 alkyl. More preferably, R6 is hydrogen or methyl. A preferred Ar1 group is selected from the group consisting of optionally substituted indolyl, thienyl, pyridinyl, benzothienyl, indazolyl, benzothiazolyl, benzisoxazolyl, benzofuranyl and thiazolyl, each attached to the chain of the compound of the invention at any available carbon atom. More preferably Ar1 is indolyl, thienyl, benzothienyl, and thiazolyl each optionally substituted with one or two groups independently selected from the group consisting of halo, Ci-C5 alkyl, -Ci-C3S02alkylCi-C3alkyl, -Ci-C3-0alkyl-alkyl C1-C3, -Ci-C3-S alkyl -Ci-C3 alkyl, -Ci-C3NH alkyl (C1-C3 alkyl), -Ci-C3 alkylN (Ci-C3 alkyl) 2, phenyl, and -NHC (O) Ci-C3 alkyl , wherein said substitution may be in carbon and / or nitrogen. More preferably, Ar1 is substituted once at the nitrogen atom of a nitrogen-containing group. A preferred R7 substituent is selected from the group consisting of -COOH, -C (O) NHS02Ci-C3alkyl, C (0) NHS02phenyl, -C (O) HS02phenylCH3, and -COOCH3. A more preferred R7 group is -COOH. Each R 10 is preferably hydrogen, or C 1 -C 6 alkyl.

Each R is preferably C 1 -C 6 alkyl. R12 is preferably phenyl optionally substituted with C1-C3 alkyl. Also preferred is a compound of the invention wherein: p is 0, or 1; R1 and R2 are independently selected from the group consisting of hydrogen, fluoro, chloro, CF3, and -OCF3, R3 is fluoro, chloro, CF3, SCF3, or OCF3; R 4 is H, isopropyl or cyclopropyl; R5 and R5a are each independently selected from H or methyl; Ar1 is indolyl, pyridinyl, thienyl, thiazolyl and benzothienyl each optionally substituted with a group selected from the group consisting of C1-C4 alkyl, CF3, -CH2CH2SCH2, -CH2CH2OCH3, -CH2CH2S02CH3, -CH2CH2N (CH3) 2, and phenyl; R6 is hydrogen, or methyl; R7 is -COOH, -COOalkylCi-C2, -CONHS02alkylCi-C4, -CONHS02phenyl, CONHS02phenylmethyl, oxadiazolone, and thiadiazolone; each R10 is independently hydrogen or alkyl Ci-C6; and each R 11 is independently hydrogen or alkyl C1-C6. More preferred is a compound of the invention wherein each p is 0; R1 and R2 are independently selected from the group consisting of chloro, fluoro, trifluoromethyl, and trifluoromethoxy; R 4 is isopropyl or cyclopropyl; R5 and R5a are both hydrogen; R6 is hydrogen, methyl, ethyl or chloro; Ar 1 is thienyl, benzothienyl, indolyl or thiazolyl, each bonded at any available carbon atom and each optionally substituted with a group selected from methyl, ethyl, propyl, butyl, isopropyl, cyclopropyl, -CH 2 CH 2 SO 2 CH 3, -CH 2 CH 2 N (CH 3) 2 , -CH2CH2SCH2, CH2CH2OCH2, and phenyl; and R7 is -COOH or -COOMe. Especially preferred are compounds of the invention exemplified herein. The compounds of the invention (formula I) can be prepared by a variety of methods known in the art and those described below. The products of each stage in the subsequent reaction schemes can be recovered by conventional methods including extraction, evaporation, precipitation, chromatography, filtration, trituration, crystallization, and the like. In the subsequent reaction scheme all substituents, unless otherwise indicated, are as previously defined and suitable reagents are well known and appreciated in the art.

Reaction scheme 1 Reaction scheme 1 represents the reaction of an appropriate compound of formula (1) with an appropriate compound of formula (2) to produce a compound of formula (I). The reaction in Reaction Scheme 1 can be carried out by at least two variants discussed below. In a first variant, an appropriate compound of formula (1) in which R1, R2, R3, p, R4, R5 and R6, are defined for formula I and Y is -OH and an appropriate compound of formula (2) is one in which R6, R7, and Ar1 are as defined in formula (I) or a group which originates R7 as defined in formula (I), for example, by formation of an ester, amide, sulfonamide, or acid. For example, a compound of formula (1) is reacted with a compound of formula (2) in a Mitsunobu reaction using a suitable diazo reagent, such as DEAD or ADDP, and the like, and a suitable phosphine reagent such as triphenyl phosphine. or tributylphosphine and the like. Such reactions are carried out in a suitable solvent such as toluene, tetrahydrofuran and the like. In general, the reactions are carried out at temperatures from about 0 ° C to 50 ° C. The typical stoichiometry for this reaction, based on the compound of formula (1) is about 1 to 2 equivalents of a compound of formula (2) and about 1 to 2 equivalents each of the phosphine and diazo reagents. In the second variant, a compound of formula (1) appropriate in which R1, R2, R3, p, R4, R5 and R5a, are as defined by formula 1 and Y is a leaving group and an appropriate compound of formula (2) is as defined above, is reacted to form the compound of formula (I) with appropriate protections and / or deprotections or other processing steps known to one of skill in the art or described herein. Suitable leaving groups are well known in the art and include, halides, particularly chlorine, bromine and iodine; and sulfonate esters, such as brosyl, tosyl, methanesulfonyl and trifluoromethanesulfonyl. For example, a compound of the formula (1) is reacted with a compound of the formula (2) in a suitable solvent, such as acetonitrile, dimethylformamide, dimethylsulfoxide, tetrahydrofuran, pyridine, methylethyl ketone and the like. As will be readily appreciated, an excess of a suitable base is usually used in the reaction, which includes sodium hydride, potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, triethylamine, diisopropylethylamine. Such reactions are generally carried out at temperatures from about room temperature to about the reflux temperature of the chosen solvent and typically use from about 1 to 2 equivalents of the compound of formula (2). Additionally, compounds of formula (I) wherein R7 is an ester, can be converted to compounds of formula (I) wherein R7 is an acid via methods well known to one of ordinary skill in the art. For example, the hydrolysis of simple alkyl esters in suitable solvents such as THF, methanol, ethanol, mixtures of water at temperatures from about 25-100 ° C with suitable bases (NaOH, LiOH). In a modification of this hydrolysis method a microwave apparatus can be used as a source of energy / heat, especially when the ester is sterically clogged. For example, a laboratory microwave that uses the lowest energy setting at about 125 ° C for about 20 minutes in solvent mixtures described above is useful. When R7 is a t-butyl ester the corresponding acid can be formed under acidic conditions well known to those skilled in the art. Additionally, compounds of formula (I) wherein R is a carboxylic acid, can be converted to compounds of formula (I) wherein R7 is an amide or sulfonamide by coupling procedures well known in the art. For example, a compound of formula (I) wherein R7 is an acid, is reacted with an amine or sulfonamide compound in the presence of a coupling agent such as dicylohexylcarbodiimide, 1- [3- (dimethylamino) propyl] -3 hydrochloride. -ethylcarbodiimide, and the like, and optionally N, N-dimethylaminopyridine and / or an amine base, such as triethylamine, diisopropylethylamine and the like, in a suitable solvent, such as DMF, THF and the like. Such reactions are generally carried out at a temperature from about room temperature to about 60-80 ° C. In an optional step, a pharmaceutically acceptable salt of a compound of formula (I) is formed. The formation of the pharmaceutically acceptable salts is well known and appreciated in the art. As will be readily appreciated, the compounds of formula (1) and (2) can be readily prepared by methods that are well known and established in the art to include methods and processes similar to those described herein. For example, compounds of formula (1) are prepared by the reaction of benzaldehydes optionally substituted with hydroxylamine, followed by chlorination with a suitable chlorinating agent, such as N-chloro succinimide, to provide chloroximes (See, for example, J. Med. Chem. 2000, 43 (16), 2971-2974). The reaction of the chloroximes and an appropriate β-ketoester under basic conditions with a suitable base, such as triethylamine or sodium methoxide, provides the penultimate isoxazole esters. The isoxazole esters can be reduced to the alcohol compounds of the formula (1) by well-known methods (e.g., DIBAL-H, LAH) and subsequently converted to a leaving group. The compounds of formula (2) are prepared by coupling / carbon-carbon bond formation reactions. Also, it is recognized that the steps required to prepare a compound of formula (1) can be carried out in any order. For example, including the reaction of a partial compound of formula (2) with a compound of formula (1), such that the latter performing the coupling / carbon-carbon bond formation reaction provides a compound of formula 1. More specifically, a compound of formula (3) can be reacted with a compound of formula (1) as described above, to provide compounds of formula (4), which can be converted to compounds of formula (I) via carbon-carbon bond formation with compounds of formula (5) (Reaction Scheme 2).

Reaction scheme 2 Alternatively, the sequence of reactions can be adjusted to prepare compounds of formula (I). For example, as shown in Reaction Scheme 3, the compounds of formula (6) can be reacted with compounds of formula (1) to provide compounds of formula (7) and compounds of formula (8) provide compounds of formula ( I). reaction scheme As will be readily understood, the steps for preparing the compounds of the invention are dependent on the particular compound that is synthesized, the starting compound, and labile capacity of the substituted portions. Several stages of protection and deprotection are also contemplated as may be required or beneficial to perform the above reactions. The selection and use of suitable protecting groups is well known and appreciated in the art (see, for example, Protecting Groups in Organic Synthesis, Theodora Greene (Wiley-Interscience)). Certain compounds of the invention exist as solid crystalline or amorphous forms. A compound of the invention may also exist in multiple crystalline form wherein one or more of the crystalline forms are preferred over others in consideration of having more desirable properties such as, for example, improved solubility, improved bioavailability and / or improved stability. All crystalline forms are within the scope of the present invention. For example, the compound of Example 101 has been found to exist in two forms (forms I and I). The present invention is further illustrated by the examples and preparations described herein. These examples and preparations are illustrative only and are not intended to limit the invention in any way. The terms used in the examples and preparations have their normal meanings unless designated otherwise. All chromatography is performed using silica gel, unless otherwise indicated.

Assay The following results and protocols demonstrate the utility, in vitro efficacy and in vivo compounds and / or methods of the current invention provided for the purpose of illustration and not if it is limited in any way.

Cofactor Recruitment Assay FXR-SRC-1 Compounds are evaluated in concentration-response curves by a Cofactor Recruitment assay FXR-SRC-1 using Alpha Sieve Technology (Amplified Luminescent Proximity Homogeneous Assay) according to the manufacturer's instructions (Perkin Elmer). Briefly, the human FXR ligand binding domain labeled with purified 6-HIS (amino acids 242-472), human SRC-1 nuclear receptor interaction domain labeled with purified GST (amino acids 220-394), Nickel Chelate donor beads (Perkin Elmer Corporation) and Anti-GST antibody acceptor beads (Perkin Elmer Corporation), are mixed together and 12] iL aliquots per well in 384-well plates. Compounds are added in 3 μ? > per cavity for a total assay volume of 15 pL and incubated at room temperature in the dark for 4 hours. After incubation, compounds that bind FXR and induce the interaction between FXR and SRC-1, could put the two types of beads in proximity generating luminescence that is quantified using a Packard Fusion instrument. The EC50 values are calculated for each test compound. It was found that the compounds of the invention are effective in the interaction assay of SRC-1 FXR with EC50S of about 365-3000 nM. For example, the compound of Example 7 exhibited an EC50 of approximately 1300 nM.

LDLR serum lipid modulation - / - LDLR - / - mice are purchased from Jackson Laboratories (Stack Number 002207, Bar Harbor, Maine, USA). Animals are acclimated for a week prior to the start of the study. Mice are housed individually in polycarbonate cages with upper filters, and mice are maintained in a light-dark cycle of 12:12 hours (lights at 6:00 AM) at 21 ° C. Deionized water is provided ad libitum and maintained for two weeks on the 'Western diet' Diet TD 88137 (42% fat), 0.15% cholesterol, Harlan Teklad, Madison, WI, USA) at will. Groups of five mice with ten-week-old male LDLR - / - are optimized based on serum cholesterol and triglyceride levels. The groups are dosed once a day by forced oral feeding with several doses of the test compound for seven days. At the end of the seven-day dosing period, the blood is collected by holding the tail for chemical titration. Triglycerides, glucose and total cholesterol are measured in serum using reagents and standard clinical chemistry instrumentation (Roche Diagnostic, Indianapolis, IN, USA). The mice are smothered in a C02 chamber. Cardiac puncture is performed to collect blood samples for serum FPLC analysis. The combined serum samples are assayed by lipoprotein cholesterol fraction (VLDL, LDL, HDL) by separation on a size exclusion column (Superóse® 6HR, Pharmacia Biotech AB, Uppsala, Sweden), with online determination of cholesterol In this test, the tested compounds of the invention, reduce total cholesterol up to 80% and triglycerides up to 90%, when dosed at 10 mg / kg. More specifically, the compound of Example 7, reduces the total cholesterol 63% and triglycerides 61% when dosed at 10 mg / kg. The specific dose of a compound administered according to this invention, of course, will be determined by the particular circumstances surrounding the case including, for example, the compound administered, the route of administration, the patient's state of life, and the condition pathological that is treated. A typical daily dose will have a non-toxic dosage level from about 0.1 mg to about 500 mg / day of a compound of the present invention. Preferred daily doses in general will be from about 1 mg to about 250 mg / day. The compounds of this invention can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular and intranasal. These compounds are preferably formulated before administration. The selection of the appropriate dose and route of administration will be declined by the specialist who attends. Thus, another aspect of the present invention is a pharmaceutical composition comprising an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient. One skilled in the art can easily select the appropriate form and route of administration, depending on the particular characteristics of the selected compound, the disorder or condition to be treated, the stage of the disorder or condition, and other relevant circumstances. Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Co. (1990)). The pharmaceutical compositions of the present invention can be adapted for these various routes and can be administered to the patient, for example, in the form of tablets, capsules, pillules, papers, dragees, wafers, elixiris, ointments, transdermal patches, aerosols, inhalants, suppositories, solutions and suspensions. The total active ingredients in such compositions comprise from 0.1% to 99.9% by weight of the formulation. The compounds of the invention can be formulated as elixirs or solutions for convenient oral administration or as solutions suitable for parenteral administration, for example, by intramuscular, subcutaneous or intravenous routes. Additionally, the compounds can be formulated as sustained release dosage forms and the like. The formulations can be constituted in such a way that they release the active ingredient only or preferably, in possible physiological location, possibly for a period of time. Coatings, wrappings and protective matrices can be processed, for example, of polymeric substances or waxes.

Preparations and Examples The following preparations and examples further illustrate the invention. The abbreviations used herein are defined in accordance with Aldrichimica Acta, Vol 17, No. 1, 1984. Other abbreviations are defined as follows. "ACN" is acetonitrile; "AcOH" is acetic acid; "MeOH" is methanol; "EtOH" is ethanol; "EtOAc" is ethyl acetate; "ADDP" is 1,1- (azodicarbonyl) dipiperidine; "DEAD" is diethyl azodicarboxylate; "TBME" is t-butyl methyl ether; "(OAC)" is acetate; "dmso-d6" is deuterated dimethylsulfoxide; "PCy3" is tricyclohexyl phosphine, "dba" is dibenzylideneacetone; "NaOEt" is sodium ethoxide. All compounds are named using ChemDraw Ultra 7.0 and 10.0 available from CambridgeSoft Corporation, Cambridge, MA.

Preparation 1 3- (2,6-Dichloro-phenyl) -5-isopropyl-isoxazole-4-carbinol The title compound was prepared essentially as described in J. Med. Chem. 2000, 43 (16), 2971-2974 .

Preparation 2 (5-Cyclopropyl-3- (2,6-dichloro-phenyl) -isoxazol-4-yl) -methanol Step 1: 2,6-Dichloro-benzaldehyde oxime: 2,6-dichloro-benzaldehyde (7.0 g, 40 mmol) to 10 mL of water and 30 mL of methanol. Sodium hydroxide (4.0 g, 100 mmol) was dissolved in 8 mL of water slowly. The sodium hydroxide solution was added to the benzaldehyde solution. The reaction was stirred overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine and dried over solid sodium sulfate. The organic layer was filtered and the solvent was removed under reduced pressure to yield the title compound.

Step 2: 2,6 Dichloro-benzaldehyde chloroxime To a solution of 2,6-dichloro-benzaldehyde (7.6 g, 40 mmol) in DMF (56 mL) was added N-chlorosuccinimide (5.9 g, 44.0 mmol) followed by a catalytic amount of HCl gas. The reaction mixture is stirred overnight. The reaction mixture is divided between ether and water. The layers are separated and the ether layer is washed with brine and dried over sodium sulfate. The ether layer is filtered and the solvent is removed under reduced pressure to provide the crude product. The crude product is chromatographed using a gradient of 10% ethyl acetate in hexanes to 15% ethyl acetate in hexanes to give the title compound. XH-NMR (400MHz, CDC13) d 8.76 (b, lH), 7.38-7.26 (m, 3H).

Step 3 5-Cyclopropyl-3- (2,6-dichloro-phenyl) -isoxazole-4-carboxylic acid methyl ester 3-Cyclopropyl-3-oxo-propionic acid methyl ester (0.55 g, 3.9 mmol) is combined with triethylamine (0.393 g, 3.9 mmol) and stirred for five minutes. 2, 5-Dichlorobenzaldehyde-chloro-oxime (0.88 g, 3.9 mmol) is added and the reaction is stirred overnight. The solvent is removed under reduced pressure and the residue is purified via flash chromatography using a gradient of 1% ethyl acetate in hexanes to 10% ethyl acetate in hexanes to give the title compound (0.80g, 66%). 1 H-NMR (400MHz, CDCl 3) d 7.37 (d, 2H), 7.31 (t, 1H), 3.66 (s, 3H), 2.88 (m, 1H), 1.38 (m, 2H), 1.25 (m, 2H ).

Step 4 (5-Cyclopropyl-3- (2,6-dichloro-phenyl) -isoxazol-4-yl) -methanol To a solution at 0 ° C of 5-cyclopropyl-3- (2, 6-methyl) methyl ester dichloro-phenyl) -isoxazole-4-carboxylic acid (0.80 g, 2.6 mmol) in THF (8 mL), a 1M solution of DIBAL in toluene (5.66 mL) is added. The reaction is stirred one hour. An additional 1M solution of DIBAL in toluene (5.66 mL) is added and the reaction is stirred for an additional hour. The reaction is quenched with methanol and acidified with aqueous HC1 solution (1M). The aqueous solution is extracted with ethyl acetate. The organic layer is washed with brine, dried over sodium sulfate, and filtered. The solvent is removed under reduced pressure to provide the title compound (0.68 g, 93%). ER / MS m / e 284.0 (+ l). The following list of compounds is prepared essentially as described in the synthesis of (5-cyclopropyl-3- (2,6-dichloro-phenyl) -isoxazol-4-yl) -methanol.

Preparation 2Aj [5-Cyclopropyl-3- (2-trifluoromethoxy-phenyl) -isoxazole-4-yl] -methanol (0.2 g, 99%), using 2-trifluoromethoxy-benzaldehyde, 1 H-NMR (400 MHz, CDC13) d 7.56- 7.49 (2H), 7.38 (t, 2H), 4.60 (s, 2H), 2.15 (m, 1H), 1.23 (m, 2H), 1.14 (m, 2H); Preparation 2B: [5-Cyclopropyl-3- (2-fluoro-6-trifluoromethyl-phenyl) -isoxazol-4-yl] -methanol, using 2-fluoro-6-trifluoromethyl-benzaldehyde, 1 H-NMR (400MHz, CDC13 ) d 7.67-7.55 (m, 2H), 7.37 (m, 1H), 4.34 (s, 2H), 2.13 (m, 1H), 1.22 (m, 2H), 1.10 (m, 2H); Preparation 2C: [5-Isopropyl-3- (2-isopropyl-phenyl) -isoxazol-4-yl] -methanol, using 2-isopropyl-benzaldehyde, RE / MS m / e 260.0 (M + 1), 258.0 (Ml ).

Preparation 3 4-Bromomethyl-3- (2,6-dichloro-phenyl) -5-isopropyl-isoxazole To a solution of [3- (2,6-dichloro-phenyl) -5-isopropyl-isoxazol-4-yl] -methanol (1.14 g, 4 mmol) in THF (20 mL) is added PBr3 (0.76 mL, 8 mmol). The reaction mixture is stirred at reflux for 30 minutes. The reaction mixture is diluted with EtOAc and washed with 0.2 N HC1. The organic layer is separated, dried (MgSO 4), filtered, and concentrated to give the title compound as an oil.

Preparation 4 4-Bromomethyl-5-cyclopropyl-3- (2-fluoro-6-trifluoromethyl-phenyl) -isoxazole A solution of 5-cyclopropyl-3- (2-fluoro-6-trifluoromethyl-phenyl) -isoxazole-4-yl) -methanol (0.203 g, 0.674 mmol) and phosphorus tribromide (0.094 g, 1.35 mmol) in dichloromethane (2 mL) is stirred for 40 minutes. The reaction mixture is divided between water and dichloromethane. The layers are separated and the organic layer is dried over sodium sulfate and filtered. The solvent is removed under reduced pressure to provide the title compound.

Preparation 5 4-Bromomethyl-5-cyclopropyl-3- (2,6-dichloro-phenyl) -isoxazole To a solution at 0 ° C of (5-cyclopropyl-3- (2,6-dichloro-phenyl) -isoxazole- 4-yl) -methanol (0.124 g, 0.44 mmol) in dichloromethane (4 mL) is added phosphorus tribromide (0.261 g, 0.963 mmol). The ice bath is removed after 20 minutes and the reaction is allowed to stir for an additional twenty minutes at room temperature. The reaction mixture is quenched with buffer at pH 7 and extracted with dichloromethane several times. The organic layers are combined, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide the title compound (0.124 g, 82%). 1 H-NMR (400 MHz CDC13) d 7.45-7.33 (m, 3H), 4.20 (s, 2H), 2.09 (m, 1H), 1.27 (m, 2H), 1.16 (m, 2H).

Preparation 6 5- (Hydroxy-2-methyl-phenyl) -4-methyl-thiophene-2-carboxylic acid methyl ester Stage 1 To a mixture of 4-methoxy-2-methylphenylboronic acid (912 mg, 6 mmol), 5-bromo-4-methyl-thiophene-2-carboxylic acid methyl ester (1.1 g, 5 mmol) and K2CO3 (1.38 g, 10 mmol) in toluene (30 mL) and water ( 5 mL), N2 was bubbled for 15 minutes followed by the addition of tetrakis (triphenylphosphine) palladium (289 mg, 0.25 mmol). The mixture is stirred at 80 ° C under N2 overnight and filtered through a pad of diatomaceous earth by levigating with EtOAc. The combined filtrate is concentrated. The resulting residue is purified by column chromatography (0-15% EtOAc in hexanes) to give 5- (4-methoxy-2-methyl-phenyl) -4-methyl-thiophene-2-carboxylic acid methyl ester (540 mg , 39%). 1 H-NMR (CDC13): d 7.63 (s, 1H), 7.15 (d, 1H, J = 8.4 Hz), 6.82 (d, 1H, J = 2.8 Hz), 6.78 (dd, 1H, J = 2.8, J = 8.4 Hz), 4.79 (bs, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 2.17 (s, 3H), 2.02 (s, 3H).

Step 2 To a solution of 5- (4-methoxy-2-methyl-phenyl) -4-methyl-thiophene-2-carboxylic acid methyl ester (540 mg, 2 mmol) in dichloromethane (30 mL) at 0 ° C. BBr3 is added in dichloromethane (1N, 5.0 mL). The mixture is stirred at room temperature overnight. The reaction is quenched by the addition of methanol and evaporated. The residue is purified by column chromatography (0-20% EtOAc in hexanes) to give 5- (4-hydroxy-2-methyl-phenyl) -4-methyl-thiophene-2-carboxylic acid methyl ester (420 mg, 82%). 1 H-NMR (CDC13): d 7.62 (s, 1 H), 7.10 (d, 1 H, J = 7.9 Hz), 6.76 (s, 1 H), 6.70 (d, 1 H, J = 7.9 Hz), 4.79 (bs, 1H), 3.88 (s, 3H), 2.15 (s, 3H), 2.02 (s, 3H). The following list of compounds is prepared essentially in accordance with the preparation of 5- (4-hydroxy-2-methyl-phenyl) -4-methyl-thiophene-2-carboxylic acid methyl ester.

Preparation 6A: 5- (4-Hydroxy-phenyl) -thiophene-2-carboxylic acid methyl ester, using 5-bromo-thiophene-2-carboxylic acid methyl ester and 4-methoxyphenylboronic acid, 1 H-NMR (D SO- d6): d 9.87 (s, 1H), 7.74 (d, 1H, J = 4.0 Hz), 7.57 (d, 2H, J = 8.8 Hz), 7.40 (d, 1H, J = 4.0 Hz), 6.83 (d , 2H, J = 8.8 Hz), 3.81 (s, 3H).

Preparation 6B: 5- (4-Hydroxy-2-methyl-phenyl) -thiophene-2-carboxylic acid methyl ester, using 5-bromo-thiophene-2-carboxylic acid methyl ester and 4-methoxy-2-methylphenylboronic acid , 1H-RN (DMSO-d6): d 9.71 (s, 1H), 7.76 (d, 1H, J = 3.5 Hz), 7.26 (d, 1H, J = 8.4 Hz), 7.17 (d, 1H, J = 4.0 Hz), 6.72 (d, 1H, J = 2.6 Hz), 6.67 (dd, 1H, J = 2.6, J = 8.4 Hz), 3.81 (s, 3H), 2.32 (s, 3H).

Preparation 6C: 5- (2-Chloro-4-hydroxy-phenyl) -thiophene-2-carboxylic acid methyl ester, using 4-bromo-3-chloro-phenol and 5-methoxycarbonyl-thiophene-2-boronic acid, 1H -NRM (DMSO-d6): d 10.33 (s, 1H), 7.78 (d, 1H, J = 3.8 Hz), 7.53 (d, 1H, J = 8.6 Hz), 7.37 (d, 1H, J = 3.8 Hz ), 6.96 (s, 1H), 6.84 (d, 1H, J = 8.6 Hz), 3.82 (s, 3H).

Preparation 6D: 5- (2-Chloro-4-hydroxy-phenyl) -4-methyl-thiophene-2-carboxylic acid methyl ester, using 5-bromo-4-methyl-thiophene-2-carboxylic acid methyl ester and 4-methoxy-2-chloro-phenylboronic acid, 1 H-NMR (D SO-d 6): d 10.26 (bs, 1H), 7.68 (s, 1H), 7.25 (d, 1H, J = 8.4 Hz), 6.96 ( d, 1H, J = 2.6 Hz), 6.83 (dd, 1H, J = 2.6, 8.4 Hz), 3.82 (s, 3H), 2.03 (s, 3H).

Preparation 6E: 2- (4-Hydroxy-2-methyl-phenyl) -4-methyl-thiazole-5-carboxylic acid methyl ester, using 2-bromo-4-methyl-thiazole-5-carboxylic acid methyl ester and 4-methoxy-2-methylphenylboronic acid, 1H-NMR (SODE-d6): d 10.0 (s, 1H), 7.74 (d, 1H, J = 8.4 Hz), 6.74 (s, 1H), 6.73 (d, 1H, J = 8.4 Hz), 3.81 (s, 3H), 2.67 (s, 1H), 2.50 (s, 3H).

Preparation 6F: 2- (4-Hydroxy-2-methyl-phenyl) -thiazole-5-carboxylic acid ethyl ester, using 2-bromo-thiazole-5-carboxylic acid ethyl ester and 4-methoxy-2-methylphenyl acid boronic, 1 H-NMR (DMSO-d 6): d 8.44 (s, 1 H), 7.74 (d, 1 H, J = 8.4 Hz), 6.76 (s, 1 H), 6.75 (d, 1 H, J = 8.4 Hz), 4.33 (q, 2H), 2.51 (s, 3H), 1.30 (t, 3H).

Preparation 6G: 6- (4-hydroxy-2-methyl-phenyl) -nicotinic acid methyl ester, using 6-chloro-nicotylic acid methyl ester and 4-methoxy-2-methylphenyl boronic acid, 1H-NMR (DMSO- d6): d 9.65 (s, 1H), 9.10 (s, 1H), 8.27 (dd, 1H, J = 2.2, J = 8.4 Hz), 7.62 (dd, 1H, J = 0.9, J = 8.4 Hz), 7.32 (d, 1H, J = 8.8 Hz), 6.71 (s, 1H), 6.69 (t, 1H), 3.89 (s, 3H), 2.31 (s, 3H).

Preparation 7 2- (Hydroxy-phenyl) -4-methyl-thiazole-5-carboxylic acid ethyl ester Step A A mixture of 4-methoxy-thiobenzamide (5 g, 30 mmol) and 2-chloro-2-ethyl ester 3-Oxo-butyric acid (4.6 mL, 33 mmol) in ethanol is stirred under reflux overnight. The reaction is concentrated and the residue triturated with ether to give 2- (4-methoxy-phenyl) -4-methyl-thiazole-5-carboxylic acid ethyl ester as a yellow solid (5.8 g, 70%). LC-ER / MS m / e 278 (M + 1).

Step BA a solution at -80 ° C of 2- (4-methoxy-phenyl) -4-methyl-thiazole-5-carboxylic acid ethyl ester (550 mg, 2 mmol) in dichloromethane (20 mL) is added BBr3 ( 5 mL, 1M solution in dichloromethane). The reaction is stirred at room temperature overnight. The reaction is quenched by the addition of methanol and concentrated in vacuo. The residue is partitioned between EtOAc and 1N HC1. The organic layer is concentrated and the residue is purified by chromatography (0 to 30% EtOAc in hexanes) to give the title compound as a tan solid (500 mg, 95%). LC-RE / MS m / e 264 (M + 1), XH-NMR (DMSO-d 6) d 10.22 (s, 1 H), 7.82 (d, 2 H), 6.86 (d, 2 H), 4.27 (q, 2 H) ), 2.64 (s, 3H), 1.29 (t, 3H).

Preparation 8 3-Methyl-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenol A mixture of tricyclohexylphosphine (525 mg, 1.87 mmol), bis (dibenzylidene) Palladium acetone (460 mg, 0.801 mmol) and dioxane (200 mL) are stirred at room temperature for a half hour. 4-Bromo-3-methyl-phenol (5.00 g) is added to the reaction mixture., 26.7 mmol), pinacolborane (7.45 g, 40.1 mmol) and potassium acetate (3.93 g, 40.1 mmol). The reaction mixture is heated at 80 ° C for 20 hours. The reaction mixture is cooled and diluted with water. The resulting aqueous mixture is extracted with ether several times. The combined ether fractions are washed with brine, dried (MgSO 4), and concentrated under reduced pressure. The residue is purified via flash chromatography (gradient: 0 to 2%? T ?? / ?? 2012) to provide the title compound (1.6 g, 47%). A second purification of impure fractions is performed to provide an additional 2.76 g of the title compound for a total of 4.36 g (70%). ES / MS m / e 233.3 (M-1).

Preparation 9 (5-Bromo-lH-indol-3-yl) -acetic acid methyl ester To a solution of (5-bromo-lH-indol-3-yl) -acetic acid (683 mg, 2.69 mmol) in methanol (6 mL) is added (trimethylsilyl) diazomethane (2.0 M solution in hexanes, approximately 6 mL) for two minutes at room temperature. The yellow mixture is concentrated. The residue is taken up in methanol and concentrated several times to give the title compound (710 mg, 99%). ES / MS m / e 266.2 (M-2). The following list of compounds is prepared essentially as described in the preparation of (5-bromo-lH-indol-3-yl) -acetic acid methyl ester.

Preparation 9: 6-Bromo-lH-indole-3-carboxylic acid methyl ester, using 6-bromoindol-3-carboxylic acid, ER / MS m / e 256.0 (M + 2); Preparation 9B: 5-Bromo-lH-indole-3-carboxylic acid methyl ester, using 5-bromo-lH-indole-3-carboxylic acid; Preparation 9C: 6-Bromo-lH-indole-2-carboxylic acid methyl ester, using 6-bromo-lH-indole-2-carboxylic acid, RE / MS m / e 270.0 (M + 2); Preparation 9D: 5-Bromo-benzo [b] thiophene-3-carboxylic acid methyl ester, using 5-bromo-benzo [b] thiophene-3-carboxylic acid, ^ -RMN (400 MHz, CDC13) d 8.73 (s) , 1H), 8.36 (s, 1H), 7.70 (d, 1H), 7.49 (d, 1H), 3.93 (s, 3H); Preparation 9E; 6-Bromo-benzo [b] thiophene-2-carboxylic acid methyl ester, using 6-bromo-benzofb] thiophene-2-carboxylic acid, 1 H-NMR (400 MHz, CDC13) d 7.99 (m, 2H), 7.70 (d, 1H), 7.50 (d, 1H), 3.92 (s, 3H).

Preparation 10 6-Bromo-1-methyl-1H-indole-3-carboxylic acid methyl ester A mixture of 5-bromo-1H-indole-3-carboxylic acid methyl ester (200 mg, 0.787 mmol), potassium carbonate (100 mg, 0.394 mmol) and DMF (1 mL) is stirred at room temperature and iodomethane (30 pL, 0.47 mmol) is added. After 5 hours, additional iodomethane (10 μ ??) is added and the reaction is stirred for 30 minutes and diluted with dichloromethane and filtered. The filtrate is concentrated under high vacuum, diluted with ethyl acetate, filtered and concentrated under reduced pressure to provide the title compound (105 mg, 99%). ES / MS m / e 270.0 (M + 2). The following list of compounds is prepared essentially in accordance with the preparation of 6-bromo-1-methyl-1H-indole-3-carboxylic acid methyl ester.

Preparation 10A: 6-Bromo-l-methyl-lH-indole-2-carboxylic acid methyl ester, using 6-bromo-lH-indole-2-carboxylic acid methyl ester, ER / MS m / e 270.0 (M + 2); Preparation 10B: 6-Bromo-l-isopropyl-1H-indole-3-carboxylic acid methyl ester, using 6-bromo-1H-indole-3-carboxylic acid methyl ester and isopropyl bromide, the title compound is prepared . 1 H-NMR (400 MHz, CDCl 3) d 8.02 (d, 1 H), 7.88 (s, 1 H), 7.52 (s, 1 H), 7.33 (d, 1 H), 4.60 (m, 1 H), 3.88 (s) , 3 H), 1.55 (d, 6H); Preparation 10C: 6-Chloro-1,2-dimethyl-1H-indole-3-carboxylic acid methyl ester, using 6-chloro-2-methyl-1H-indole-3-carboxylic acid methyl ester. ES / MS m / e 238.0 (M + 1).

Preparation 11 6-Bromo-1- (2-methoxy-ethyl) -lH-indole-3-carboxylic acid methyl ester Sodium hydride (60% in mineral oil, 87 mg, 2.2 mmol) is added to an ester solution 6-Bromo-lH-indole-3-carboxylic acid methyl ester (500 mg, 1.97 mmol) in DMF (5 mL) at room temperature and the mixture is stirred for 30 minutes. To the reaction mixture is added l-bromo-2-methoxy-ethane (222 [mu], 2.36 mmol). After one hour, sodium hydride (20 mg) is added. Thirty minutes later, l-bromo-2-methoxy-ethane (60 μ ?,) is added. The mixture is heated at 60 ° C for one hour. The cooled mixture is quenched with a small amount of water being concentrated under reduced pressure. The residue is taken up in ethyl acetate and filtered. The filtrate is concentrated under reduced pressure and the resulting residue is purified by column chromatography (gradient: 10 to 60% ethyl acetate / heptane) followed by purification via radial chromatography (gradient: 0 to 1% MeOH / CH2Cl2) to provide the title compound (386 mg, 63%). ES / MS m / e 314.0 (M + 2). The following list of compounds is prepared essentially in accordance with the preparation of 6-bromo-1- (2-methoxy-ethyl) -lH-indole-3-carboxylic acid methyl ester.

Preparation 11A: 6-Bromo-l-butyl-lH-indole-3-carboxylic acid methyl ester, using 6-bromo-lH-indole-3-carboxylic acid methyl ester and 1-bromobutane, ER / MS m / e 311.9 (M + l); Preparation 11B: 6-Bromo-1- (2-methylsulfanyl-ethyl) -lH-indole-3-carboxylic acid methyl ester, using 6-bromo-lH-indole-3-carboxylic acid methyl ester and 1-chloro- 2-methylsulfanyl-ethane, RE / MS m / e 329.9 (M + 1).

Preparation 12 6-Bromo-1-methyl-1H-indol-3-carboxylic acid methyl ester To a mixture at room temperature of 5-bromo-1H-indole-3-carboxylic acid methyl ester (100 mg, 0.394 mmol) , potassium carbonate (163 mg, 1.18 mmol) and DMF, iodomethane (30 μ! _, 0.47 mmol) is added. After 1.5 hours, additional iodomethane (10) iL) is added and the reaction is stirred for 30 minutes. The reaction mixture is diluted with dichloromethane and filtered. The filtrate is concentrated under high vacuum, diluted with ethyl acetate, concentrated to give the title compound (105 mg, 99%). ER / E m / e 270.0 (M + 2).

Preparation 13 6-Bromo-1-methyl-1H-indole-2-carboxylic acid methyl ester The title compound is prepared essentially as described in the preparation of 6-bromo-1-methyl-1H-methyl acid methyl ester indole-3-carboxylic acid using 6-bromo-lH-indole-2-carboxylic acid methyl ester, ER / MS m / e 270.0 (M + 2).

Preparation 14 6-Bromo-1- (2-dimethylamino-ethyl) -lH-indole-3-carboxylic acid methyl ester A mixture of 6-bromo-1H-indole-3-carboxylic acid methyl ester (500 mg, 1.97 mmol), sodium hydride (60% in mineral oil, 748 mg, 31.2 mmol), sodium iodide (295 mg, 1.96 mmol), 2-dimethylaminoethyl hydrochloride (341 mg, 2.37 mmol) and DMF (60 mL) It is heated at 100 ° C for 8 hours. The reaction mixture is cooled, filtered, and the solids are washed with water and air dried. The solids are dissolved in MeOH (200 mL) and added (trimethylsilyl) diazomethane (2.0 M solution in hexanes, 20 mL) for several minutes. The reaction mixture is stirred for one hour, concentrated under reduced pressure. The residue is divided between water and ethyl acetate. The ethyl acetate layer is separated and dried over MgSO4. The crude product is purified via radial chromatography using 2.5% MeOH / CH2Cl2 to give the title compound (195 mg, 30%). ES / MS m / e 327.0 (M + 2).

Preparation 15 [5- (4-Hydroxy-2-methyl-phenyl) -lH-indol-3-yl] -acetic acid methyl ester A mixture of 3-methyl-4- (4,5,5-tetramethyl) [1, 3, 2] dioxaborolan-2-yl) -phenol (287 mg, 1.22 mmol), (5-bromo-lH-indol-3-yl) -acetic acid methyl ester (273 mg, 1.02 mmol), tetrakis (triphenylphosphine) palladium (0) (57 mg, 0.046 mmol), DMF (2.7 mL), ethanol (1.34 mL) and potassium carbonate 2 (1.34 mL) is heated at 100 ° C for 16 hours. The reaction is cooled to room temperature and diluted with water and acidified with 1N HC1. The resulting solution is extracted with ethyl acetate. The combined organic layers are dried over anhydrous magnesium sulfate and concentrated. The residue is dissolved in methanol (6 mL) and trimethylsilyldiazomethane (2.0 M solution in hexanes, approximately 4 mL) is added for about two minutes at room temperature. The yellow mixture is concentrated and the residue is purified via radial chromatography by levigating with a gradient of 20 to 50% ethyl acetate / heptane and crystallized from CH2Cl2 / heptane to give the title compound (180 mg, 60%). ER / MS m / e 296.1 (+ l). The following list of compounds is prepared essentially as described in the preparation of [5- (4-hydroxy-2-methyl-phenyl) -lH-indol-3-yl] -acetic acid methyl ester.

Preparation 15A: 6- (4-hydroxy-2-methyl-phenyl) -lH-indole-3-carboxylic acid methyl ester, using 6-bromo-lH0indol-3-carboxylic acid methyl ester, (134 mg, 63% ); Preparation 15B: 5- (4-hydroxy-2-methyl-phenyl) -lH-indole-3-carboxylic acid methyl ester, using 5-bromo-lH-indole-2-carboxylic acid methyl ester, ER / MS m / e 296.1 (M + l); Preparation 15C: 6- (4-hydroxy-2-methyl-phenyl) -lH-indole-2-carboxylic acid methyl ester, using 6-bromo-lH-indole-2-carboxylic acid methyl ester, ER / EM m / e 296.1 (+ l); Preparation 15D: 6- (4-hydroxy-2-methyl-phenyl) -lH-indole-3-carboxylic acid methyl ester, using 6-bromo-lH-indole-3-carboxylic acid methyl ester, ER / EM / e 282.1 (M + l); Preparation 15E; 6- (4-hydroxy-2-methyl-phenyl) -l-methyl-lH-indole-3-carboxylic acid methyl ester, using 6-bromo-l-methyl-lH-indole-3-carboxylic acid methyl ester , CL-ER / MS m / e 296.0 (M + 1); Preparation 15F: 6- (4-hydroxy-2-methyl-phenyl) -l-methyl-1H-indole-2-carboxylic acid methyl ester, using 6-bromo-1-methyl-1H-indole-6-methyl-methyl ester 2-carboxylic acid and 3-methyl-4- (4, 4, 5, 5-tetramethyl- [1, 3,2] dioxaborolan-2-yl) -phenol, RE / MS m / e 296.1 (M + 1); Preparation 15G: 5- (4-hydroxy-2-methyl-phenyl) -benzo [b] thiophene-3-carboxylic acid methyl ester, using 5-bromo-benzo [b] thiophene-3-carboxylic acid methyl ester, ES / MS m / e 299.1 (M + 1); Preparation 15H: 6- (4-hydroxy-2-methyl-phenyl) -benzo [b] thiophene-2-carboxylic acid methyl ester, using 6-bromo-benzo [b] thiophene-2-carboxylic acid methyl ester, ES / MS m / e 297.3 (Ml); Preparation 151: 6- (4-hydroxy-2-methyl-phenyl) -1- (2-methoxy-ethyl) -lH-indole-3-carboxylic acid methyl ester, using 6-bromo-l- methyl ester (2-methoxy-ethyl) -lH-indole-3-carboxylic acid, ES / MS m / e 340.1 (M + 1); Preparation 15J: 1-Butyl-6- (4-hydroxy-2-methyl-phenyl) -lH-indole-3-carboxylic acid methyl ester using 6-bromo-1-butyl-1H-indol-3 methyl ester -carboxylic, MS m / e 338.1 (M + 1); 15K Preparation: 6- (4-hydroxy-2-methyl-phenyl) -l-isopropyl-1H-indole-3-carboxylic acid methyl ester, using 6-bromo-l-isopropyl-1H-indole-6-methyl-methyl ester 3-carboxylic acid, ES / MS m / e 324.1 (M + 1); Preparation 15L: 6- (4-hydroxy-2-methyl-phenyl) -1- (2-methylsulfanyl-ethyl) -lH-indole-3-carboxylic acid methyl ester, using 6-bromo-l- methyl ester (2-methylsulfanyl-ethyl) -lH-indole-3-carboxylic acid, RE / MS m / e 354.2 (Ml); Preparation 15M: l- (2-Dimethylamino-ethyl) -6- (4-hydroxy-2-methyl-phenyl) -lH-indole-3-carboxylic acid methyl ester, using 6-bromo-l- methyl ester (2-dimethylamino-ethyl) -lH-indole-3-carboxylic acid, ES / MS m / e 353.1 (M + 1); Preparation 15N: 6- (4-hydroxy-2-methyl-phenyl) -benzo [b] thiophene-3-carboxylic acid methyl ester; compound with 6- (4-hydroxy-2-methyl-phenyl) -benzo [b] thiophene-2-carboxylic acid methyl ester, using a 7: 3 mixture of 6-bromo-benzo [b] thiophenic acid methyl ester -3-carboxylic acid and 6-bromo-benzo [b] thiophene-2-carboxylic acid methyl ester, MS m / z: 297.0 (-1).

Preparation 16 2- (4-Hydroxy-2-methyl-phenyl) -4-isopropyl-thiazole-5-carboxylic acid ethyl ester Step 1 2-Amino-4-isopropyl-thiazole-5-carboxylic acid ethyl ester To a solution of 4-methyl-3-oxo-pentanoic acid ethyl ether (10 g, 63.2 mmol) in dichloromethane (150 mL) at 0 ° C is added S02C12 (5.64 mL, 69.5 mmol). The reaction mixture is stirred at room temperature for 1 hour. The reaction mixture is extracted with water (30 mL). To the aqueous layer is added 1,4-dioxane (60 mL) followed by thiourea (8.8 g, 63.2 mmol). The mixture is stirred at 80 ° C overnight and cooled to room temperature. The reaction mixture is adjusted to pH 12 with conc. NH 4 OH. and it filters. The filtered paste is washed with water to provide the title compound (12.4 g, 92%). ^ -RM (DMSO-de) d 7.72 (s, 2H), 4.14 (q, 2H), 3.76 (m, 1H), 1.21 (t, 3H), 1.11 (d, 6H).

Step 2: 2-Bromo-4-isopropyl-thiazole-5-carboxylic acid ethyl ester To a solution of 2-amino-4-isopropyl-thiazole-5-carboxylic acid ethyl ester (4.28 g, 20 mmol) in CH3CN ( 30 mL) is added iso-amylnitrite (4.3 mL, 32 mmol) followed by copper bromide (8.9 g, 40 mmol). The reaction mixture is stirred at 80 ° C for 3 hours and concentrated under reduced pressure. The residue is partitioned between EtOAc and water. The organic phase is filtered through a pad of Celite® and the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography (gradient: 0 to 10% EtOAc in hexanes) to give the title product (5 g, 90%). 1 H-NMR (CDC13) d 4.33 (q, 2H), 3.95 (m, 1H), 1.36 (t, 3H), 1.28 (d, 6H).

Stage 3 2- (4-hydroxy-2-methyl-phenyl) -4-isopropyl-thiazole-5-carboxylic acid ethyl ester To a solution of 2-bromo-4-isopropyl-thiazole-5-carboxylic acid ethyl ester (834 mg, 3 mmol), 3-methyl-4- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -phenol (1.4 g, 6 mmol) and K2C03 ( 828 mg, 6 mmol) in 1,4-dioxane / H20 (30 mL / 5 mL) is bubbled with nitrogen gas for 10 minutes. To this solution is added tetrakistriphenylphosphine palladium (173 mg, 0.15 mmol). The reaction mixture is stirred at 100 ° C overnight. The reaction mixture is concentrated under reduced pressure and the residue is partitioned between EtOAc and 1N HC1. The organic phase is concentrated and purified by column chromatography (gradient: 0 to 15% EtOAc in hexanes) to give the title product (730 mg, 80%). 1 H-NMR (D SO-d 6) d 9.99 (s, 1 H), 7.68 (d, 1 H), 6.68.6.72 (m, 2 H), 4.26 (q, 2 H), 3.88 (m, 1 H), 2.50 (s) , 3H), 1.26 (t, 3H), 1.23 (d, 6H). The following list of compounds is prepared essentially as described in the preparation of 2- (4-hydroxy-2-methyl-phenyl) -4-isopropyl-thiazole-5-carboxylic acid ethyl ester.

Preparation 16A: 2- (4-hydroxy-2-methyl-phenyl) -4-propyl-thiazole-5-carboxylic acid ethyl ester, using 2-amino-4-propyl-thiazole-5-carboxylic acid ethyl ester, XH-NMR (DMSO-d6) d 10.00 (s, 1H), 7.72 (d, 1H), 6.71.6.75 (m, 2H), 4.28 (q, 2H), 3.06 (t, 2H), 2.50 (s, 3H), 1.72 (m, 2H), 1.28 (t, 3H), 0.92 (t, 3H); Preparation 16B: 2- (4-hydroxy-2-methyl-phenyl) -4-trifluoromethyl-thiazole-5-carboxylic acid ethyl ester, using 2-amino-4-trifluoromethyl-thiazole-5-carboxylic acid ethyl ester, CL-ER / MS m / e 332 (M + l), 330 (Ml), Preparation 16C: 2- (4-hydroxy-2-methyl-phenyl) -4-phenyl-thiazole-5-carboxylic acid ethyl ester, using 2-amino-4-phenyl-thiazole-5-carboxylic acid ethyl ester, 1 H-NMR (DMSO-d 6) d 10.06 (s, 1H), 7.76, 7.79 (m, 3H), 7.44, 7.46 (m, 3H), 6.74, 6.77 (m, 2H), 4.23 (q, 2H), 2.56 (s, 3H), 1.21 (t, 3H); Preparation 16D: 2- (4-hydroxy-2-methyl-phenyl) -thiazole-4-carboxylic acid ethyl ester, using 2-bromo-thiazole-4-carboxylic acid ethyl ester, CL-ER / MS m / e 264 (M + 1), 262 (Ml), 100%; Preparation 16E: 2- (4-hydroxy-2-methyl-phenyl) -5-isopropyl-thiazole-4-carboxylic acid ethyl ester, using 2-amino-5-isopropyl-thiazole-4-carboxylic acid ethyl ester, LC-RE / MS m / e 292 (M + 1), 290 (Ml), 95.6%.

Preparation 17 4-Bromo-benzo [b] thiophene Step 1 2-bromo-6-fluoro-benzaldehyde A solution of n-butyllithium (2.5M in hexanes, 2.866 L, 7.17 mol) is added dropwise to a stirred solution of diisopropylamine (745.7 g, 7.37 mol) in tetrahydrofuran (1.630L) such that the temperature is maintained in the range -60 to -78 ° C. The resulting suspension is stirred for 1.5 h at -75 to -78 ° C. A solution of l-bromo-3-fluorobenzene (1.228 Kg, 7.02 mol) in tetrahydrofuran (2.40 L) is slowly added to the reaction mixture for 1.5 h. Stirring is continued for 30 min at -70 to -71 ° C. Dimethylformamide (511.3 g) is added over 1 h. The reaction mixture is allowed to warm to -15 ° C and quenched by the slow addition of acetic acid (1965 L) for 20 min. TBME (5.20 L) and water (6.25 L) are added. The resulting solution is stirred vigorously and the layers are separated. The aqueous layer is extracted with TBME (1965 L) twice and the combined organic layers are washed with 0.2 M hydrochloric acid (2x 5.00 L), saturated aqueous sodium hydrogen carbonate solution (2x 2.50 L) and water (3.50 L) ). The organic layer is dried over magnesium sulfate, filtered and concentrated under reduced pressure to provide the title compound as a yellow crystalline solid (1.367 Kg, 96%). 1 H-NMR (CDC13): d 10.36 (s, 1H), 7.49 (d, 1H, J = 7.8 Hz), 7.45-7.37 (m, 1H), 7.15 (t, 1H, J = 7.9 Hz).

Step 2: 4-Bromo-benzo [b] thiophene-2-carboxylic acid. Potassium hydroxide (415.1 g, 7.40 mol) is added to a stirred solution of 2-bromo-6-fluorobenzaldehyde (1.00 Kg)., 4.93 mol) and mercaptoacetic acid (453.8 g, 4.93 mol) in dimethylformamide (5.0 L). The resulting solution is started and maintained at reflux (136 ° C) for 90 min. The reaction mixture is allowed to cool to room temperature and quenched by the slow addition of hydrochloric acid (2.25, 5.90 L) for 5 min. The mixture is cooled to 10 ° C, stirred for 1 h and the solid material observed is collected by filtration. The filtered paste is washed with water (1.00 L) and hexanes (2.00 L) and dried under vacuum at 40 to 45 ° C to constant weight to provide the title compound (990.0 g, 78.2%). 1 H-NMR (DMSO, d 6): d 13.8 (bs, 1H), 8.10 (d, 1H, J = 8.2 Hz), 7.97 (s, 1H), 7.72 (d, 1H, J = 7.6 Hz), 7.45 ( t, 1H, J = 8.0Hz).

Stage 3 4-Bromo-benzo [b] thiophene Copper powder (49.8 g) is added to a stirred mixture of 4-bromo-benzo [b] thiophene-2-carboxylic acid (995.5 g, 3.87 mol) and quinoline (1.99 g). L) and the resulting mixture is heated and maintained at 185 to 195 ° C for 5 h. The mixture is allowed to cool to room temperature and the reaction is quenched by the addition of a mixture of ice (5.81 Kg) and concentrated hydrochloric acid (2.48 L). TBME (9 L) is added and the mixture is stirred vigorously for 10 min and filtered. The clarified layers are separated and the aqueous layer is extracted with TBME (1.0 L). The combined extracts are washed with hydrochloric acid (1 M, 2x 5.00 L) and water (4.0 L), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the crude product (640 g) as an oil. brown which solidified at rest during the night. The residue is subjected to suspension in methanol (500 mL, 0.5 vol) at -10 to 0 ° C for 1.5 h, the solid material observed is collected by filtration and removed dry in the filter. The methanolic mother liquors are concentrated by rotary evaporation. The residue is combined with the isolated solid material, subjected to suspension in TBME (2.0 L) and the solids collected are washed with TBME (660 L). The combined liquors are combined and washed with hydrochloric acid (1 M, 660 mL), saturated aqueous sodium hydrogen carbonate. (2x 1.0 L) and water (4.0 L), dried over magnesium sulfate, filtered, concentrated by rotary evaporation at 40 ° C to provide the crude product. The residue is subjected to suspension in methanol (1.10 L) at -10 to 0 ° C for 1 h. The solid observed is collected by filtration and dried under vacuum at 20 ° C to provide 4-bromo-benzo [b] thiophene as a whitish solid (315g, 37%). 1 H-NMR (CDC13): d 7.81 (d, 1H, J = 8.0 Hz), 7.57-7.48 (m, 3H), 7.21 (t, 1H, J = 7.7 Hz).

Preparation 18 Benzo [b] thiophene-4-carboxylic acid The title compound (12.4 g, 85%) is prepared according to J. Heterocyclic Chem. 1967, 4 (4), 651-2, using 4-bromo-benzo [b] thiophene, ^ "H-NMR (CDC13): d 8.32-8.25 (m, 2H), 8.14 (d, 1H, J = 8.0 Hz), 7.67 (d, 1H, J = 5.75 Hz), 7.45 ( t, 1H, J = 8.0Hz) The following list of compounds is prepared essentially as described in the preparation of benzo [b] thiophene-4-carboxylic acid.

Preparation 18: Benzo [b] thiophene-6-carboxylic acid (112.2 g, 67%), using 6-bromo-benzo [b] thiophene; Preparation 18B: Benzo [b] thiophene-7-carboxylic acid, (1.05 g, 63%), using 7-Bromo-benzo [b] thiophene 1 H-NMR (CDCl 3): d 8.26 (d, 1 H, J = 6.5 Hz ), 8.10 (dd, 1H, J = 7.3 Hz, 1 Hz), 7.61 (d, 1H, J = 5.6 Hz), 7.51 (t, 1H, J = 7.3 Hz), 7.44 (d, 1H, J = 5.6) Hz).

Preparation 19 4-Carboxy-benzo [b] thiophene-2-boronic acid A solution of n-BuLi (2.5M in hexane, 1.69 mol, 676 mL) is slowly added at -78 ° C to a solution of diisopropylamine (1.69 mol) , 236 mL) in 2 L of anhydrous THF. The mixture is stirred for 30 min. A solution of benzo [b] thiophene-4-carboxylic acid (0.8 mol, 143 g) in 2 L of anhydrous THF is added slowly and the mixture is allowed to reach 0 ° C. The reaction is cooled to -30 ° C and triisopropyl borate (2 mol, 463 mL) is added slowly. The cooling bath is removed and the mixture is allowed to reach room temperature. The reaction is quenched with 1.3 L of concentrated HC1 and 1 L of water. The mixture is stirred overnight. The organic solvent is removed under reduced pressure. The precipitate is collected by filtration, washed with water, and dried under vacuum to provide the title compound (170.5 g, 96%). ES / MS m / e 221 (M-1).

Preparation 20 6-Carboxy-benzo [b] thiophene-2-boronic acid The title compound (120g, 86%) is prepared essentially as described in the preparation of 4-carboxy-benzo [b] thiophen-2-boronic acid using benzo [b] thiophene-6-carboxylic acid, ER / MS m / e 221 Ml).

Preparation 21 4- (4-Bromo-3-methyl-phenoxymethyl) -3- (2,6-dichloro-phenyl) -5-isopropyl-isoxazole To a mixture of 3- (2,6-dichloro-phenyl) -5 -isopropyl-isoxazole-4-carbinol (6.99 mmol; 2.0 g) and 4-bromo-3-methylphenol (8.38 mmol, 1.6 g) in toluene (100 mL) is added with 1,1'- (azodicarbonyl) dipipiperidine (10.48 mmol, 2.7 g) followed by tri-n-butylphosphine ( 10.48 mmol, 2.91 mL) and the mixture is stirred for 4 h. The solid is filtered and washed with dichloromethane. The filtrate is concentrated under reduced pressure. The residue is chromatographed using a gradient of 0% ethyl acetate in hexane at 50% ethyl acetate in hexane to give the title compound (2.95 g, 93%) as a pale yellow solid. ES / MS m / e 454 (M-1).

Preparation 22 Benzo [b] thiophene-5-carboxylic acid ethyl ester A saturated solution of HC1 in ethanol (15 mL) is added to benzothiophene-5-carboxylic acid (1 g, 5.44 mmol) and the reaction mixture is stirred at 80 ° C during the night.

The solvent is removed under reduced pressure and diethyl ether and saturated sodium bicarbonate are added to the residue. The layers are separated. The organic layer is washed with saturated sodium bicarbonate and water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide the title compound (1.0 g, 89%) as a pale brown oil. XH-NMR (CDC13): d 8.54 (s, 1H), 8.01 (d, 1H, J = 8.1 Hz), 7.92 (d, 1H, J = 8.1 Hz), 7.51 (d, 1H, J = 5.4 Hz) , 7.42 (d, 1H, J = 5.4 Hz), 4.42 (c, 2H, J = 6.8 Hz), 1.43 (t, 3H, J = 6.8 Hz).

Preparation 23 Benzo [b] thiophene-7-carboxylic acid methyl ester (14.8 mmol, 1.05 mL) is added to a solution of benzo [b] thiophene-7-carboxylic acid (4.94 mmol, 880 mg) in methanol (20 mL). The reaction mixture is stirred at reflux for 24 h. The solvent is removed under reduced pressure. The residue is taken up in ethyl acetate, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (880 mg, 92%) as a colorless oil. 1 H-NMR (CDC13): d 8.12 (dd, 1H, J = 7.2 Hz, 0.6 Hz), 8.03 (dd, 1H, J = 7.6 Hz, 1.2 Hz), 7.58 (d, 1H, J = 5.6 Hz), 7.46 (t, 1H, J = 7.6 Hz), 7.41 (t, 1H, J = 5.2 Hz), 4.03 (s, 3H).

Preparation 24 2- (Methoxy-2-methyl-phenyl) -benzo [b] thiophene-5-carboxylic acid ethyl ester Cesium carbonate (9.70 mmol, 3.19 g) is dried in a 150 ° C resealable tube under vacuum for 2 h and cooled to room temperature. Copper (I) iodide (9.70 mmol, 1.86 g), Pd (OAc) 2 (0.24 mmol, 55 mg), triphenylphosphine (0.485 mmol, 128.50 mg), 2-bromo-5-methoxytoluene (9.70 mmol, 2.14) are added. mL), benzo [b] thiophene-5-carboxylic acid ethyl ester (4.85 mmol, lg) and anhydrous dimethylformamide (24 mL) under nitrogen atmosphere and the mixture is stirred at 140 ° C. After 24 h, Pd (OAc) 2 (0.24 mmol, 55 mg) and triphenylphosphine (0.485 mmol, 128.50 mg) are added and the mixture is stirred for 24 hours. The mixture is allowed to cool to room temperature followed by the addition of water and ethyl acetate. The suspension is filtered through Celite® and washed with ethyl acetate. The organic layer is separated and the aqueous layer is extracted with ethyl acetate. The organic layers are combined, washed with water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure. The residue is chromatographed using a gradient of 0% ethyl acetate in hexane to 10% ethyl acetate in hexane to give the title compound (960 mg, 61%) as a colorless waxy solid. ES / MS m / e 326 (M +).

Preparation 25 2- (4-Methoxy-2-methyl-phenyl) -benzo [b] thiophene-7-carboxylic acid methyl ester The title compound (130 mg, 12%) is prepared essentially as described in the synthesis of 2- (-methoxy-2-methyl-phenyl) -benzo [b] thiophene-5-carboxylic acid ethyl ester, using benzo [b] thiophene-7-carboxylic acid methyl ester. 1 H-NMR (CDC13): d 8.08 (dd, 1H, J = 7.55 Hz, 1.1 Hz), 7.97 (dd, 1H, J = 7.8 Hz, 1.1 Hz), 7.48-7.42 (m, 2H), 6.87-6.79 (m, 2H), 4.03 (s, 3H), 3.85 (s, 3H), 2.48 (s, 3H).

Preparation 26 2- (4-Hydroxy-2-methyl-phenyl) -benzo [b] thiophene-5-carboxylic acid ethyl ester To a solution at 0 ° C of 2- (4-Methoxy-2-) ethyl ester methyl-phenyl) -benzo [b] thiophene-5-carboxylic acid (1.07 mmol, 350 mg) in anhydrous dichloromethane (4.00 mL) is added a 1 M solution of boron tribromide (1.29 mmol, 1.29 mL) in dichloromethane. The reaction mixture is stirred at room temperature for 4 h. Water and ethyl acetate are added. The aqueous layer is separated and the organic layer is dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is dissolved in ethanol (5 mL) and acetyl chloride (3.48 mmol, 0.25 mL) is added. The mixture is stirred at reflux for 5 h. The solvent is removed under reduced pressure and the residue is chromatographed using a gradient of 5% ethyl acetate in hexane at 20% ethyl acetate in hexane to give the title compound (145 mg, 40%) as a white solid. . ES / MS m / e 313 (M + 1).

Preparation 27 2- (4-Hydroxy-2-methyl-phenyl) -benzo [b] thiophene-7-carboxylic acid methyl ester The title compound (85 mg, 69%) is prepared essentially as described in the synthesis of 2- (4-Hydroxy-2-methyl-phenyl) -benzo [b] thiophene-5-carboxylic acid ethyl ester, using 2- (4-Methoxy-2-methyl-phenyl) -benzoic acid methyl ester [b] ] thiophene-7-carboxylic acid and methanol. ES / MS m / e 297 (M-1).

Preparation 28 Step 1 3-Cyclopropylamino-but-2-enoic acid ethyl ether A mixture of ethyl acetoacetate (5.00 mL, 39.3 mmol) and cyclopropylamine (3.27 mL, 47.1 mmol) is stirred at 40 ° C for 3 h. The mixture is concentrated under high vacuum overnight to give the title compound (6.23 g, 94%) as an oil, which is used without further purification in the next reaction.

Stage 2 l-Cyclopropyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid ethyl ester 3-cyclopropylamino-but-2-enoic acid ethyl ether (5.63 g, 33.2 mmol) is added to a mixture of p-benzoquinone (7.19 g, 66.5 mmol) and acetic acid (120 mL). The mixture is stirred at room temperature for 5 h and a dark solid is precipitated. The solid is washed with acetic acid and water, dried, absorbed on silica gel and purified by flash chromatography by levigating with dichloromethane. The product is triturated in dichloromethane-hexane to give the title compound (440 mg, 21%). ER / MS m / e 260.0 (M + l) Step 3: 6-Bromo-l-cyclopropyl-5-hydroxy-2-methyl-lH-indole-3-carboxylic acid ethyl ester Bromine (277 μl, 5.40 mmol) is added to a suspension of ethyl ester of l-1 Cyclopropyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid (1.40 g, 5.40 mmol) in acetic acid (50 mL). The mixture is stirred for one hour at room temperature. The mixture is diluted with water and the resulting solids are filtered and washed with water. The solids are absorbed on silica gel and purified by flash chromatography by levigating with 30% THF-heptane. The fractions are combined to give the title compound (763 mg, 42%). ES / MS m / e 339.8 (M + l).

Step 4: 6-Bromo-l-cyclopropyl-5-methoxy-2-methyl-lH-indole-3-carboxylic acid ethyl ester Sodium hydride (60% in mineral oil, 71 mg, 1.8 mmol) is added to a solution of 6-bromo-l-cyclopropyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester (200 mg, 0.590 mmol) in DF (4.0 mL). The mixture is stirred for 20 minutes at room temperature. Methyl iodide (110) iL, 1.77 mmol) is added and the mixture is stirred for 1 h at room temperature. The mixture is diluted with water and ether. The layers are separated. The ether layer is washed with water and brine, dried over MgSO4, concentrated under reduced pressure. The residue is triturated in ethyl acetate-hexane to give the title compound as an off white solid (183 mg, 88%). ES / MS m / e 353.8 (M + 1).

Step 5 L-Cyclopropyl-6- (4-hydroxy-2-methyl-phenyl) -5-methoxy-2-methyl-lH-indole-3-carboxylic acid ethyl ester A mixture of 6-bromo-3-methyl-ethyl ester l-cyclopropyl-5-methoxy-2-methyl-lH-indole-3-carboxylic acid (355 mg, 1.01 mmol), 3-methyl-4- (4, 4, 5, 5-tetramethyl- [1, 3, 2] ] dioxaborolan-2-yl) -phenol (472 mg, 2.20 mmol), tetrakis (triphenylphosphene) palladium (87 mg, 0.075 mmol), aqueous sodium carbonate (2 M, 3.0 mL, 6.00 mmol), DMF (5.9 mL) and ethanol (5.9 mL) is heated under nitrogen at 85 ° C for 4 h. The mixture is acidified with 1N HC1 and extracted with ethyl acetate. The ethyl acetate layer is combined and washed with water and brine and dried over MgSO4. The residue is purified via flash chromatography by levigating with THF-heptane (25? 40%) to give the title compound (187 mg, 49%) as a white solid. ER / E m / e 380.0 (+ l).

Preparation 29 6-Chloro-1-isopropyl-2-methyl-1H-indole-3-carboxylic acid methyl ester Stage 1 2- (4-Chloro-2-nitro-phenyl) -3-hydroxy-butyl methyl ester -2-enoic A mixture of sodium hydride (60% in mineral oil, 2.60 g, 65.0 mmol) and DMF (52 mL) is stirred in a cold bath and methylacetoacetate (6.46 mL, 59.9 mmol) is added via a syringe for 10 minutes. The mixture is stirred for an additional 10 minutes and the ice bath is removed. The solution is stirred at room temperature for 30 minutes and transferred via cannula into a flask containing 4-chloro-1-fluoro-2-nitrobenzene (5.00 g, 28.5 mmol) cooled to 0 ° C via a cold bath. The reaction is allowed to warm slowly and is stirred for two days at room temperature. The black mixture is acidified with 2 N HC1, turning yellow. The resulting solution is diluted with water and extracted with ether. The combined ether layers are washed with water and brine and dried over gSC to provide the crude title compound (8.26 g), which contains a small amount of mineral oil. The material is used without purification in the next step.

Step 2 6-Chloro-2-methyl-1H-indole-3-carboxylic acid methyl ester A mixture of iron (5.76 g, 103 mmol), 2- (-chloro-2-nitro-phenyl) methyl ester - 3-hydroxy-but-2-enoic (3.84 g, 17.2 mmol) and glacial acetic acid (16 mL) is heated at 115 ° C for 1 h. The mixture is diluted with water and extracted repeatedly with ethyl acetate. The combined ethyl acetate layers are washed with brine and dried over MgSO4. The residue is absorbed on silica gel and purified via flash chromatography (120 g SiO2) by levigating with a gradient of 70% to 100% CH2Cl2-heptane to give the title compound (1.28). ER / MS m / e 22 .0 (M + l).

Step 3 6-Chloro-1-isopropyl-2-methyl-1H-indole-3-carboxylic acid methyl ester A mixture of 6-chloro-2-methyl-1H-indole-3-carboxylic acid methyl ester (300 mg , 1.34 mmol), 2-bromopropane (1.75 mL, 18.6 mmol), potassium carbonate (743 mg, 5.37 mmol) and DMF (3.5 mL) is heated at 100 ° C for 14 h. The mixture is diluted with water and extracted with ether. The ether layers are washed with water and brine and dried over MgSO4. The residue is purified via flash chromatography by levigating with 80% CH2Cl2-heptane to give the title compound (217 mg, 61%) as a white solid. ES / MS m / e 266.0 (M + 1).

Preparation 30 6- (4-Hydroxy-2-methyl-phenyl) -l-isopropyl-2-methyl-1H-indole-3-carboxylic acid methyl ester A mixture of 6-chloro-1-isopropyl methyl ester 2-methyl-lH-indole-3-carboxylic acid (200 mg, 0.75 mmol), 3-methyl-4- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) - phenol (351 mg, 1.50 mmol), dioxane (2.5 mL), tribasic potassium phosphate, N-hydrate (2.59 g, 1.28 mmol), tris (dibenzylideneacetone) dipalladium (0) (12 mg, 0.013 mmol) and tricyclohexylphosphine (9 mg, 0.03 mmol) is stirred under nitrogen at 120 ° C for 16 h. The mixture is acidified with 1N HC1, diluted with water, and extracted with ether. The combined ether layers are washed with brine and dried over MgSO-i. The crude product is purified via flash chromatography (40 g SÍO 2) by levigating with 30% THF-heptane to give the title compound (223 mg, 88%) as a white solid. ES / MS m / e 338.0 (M + l).

Preparation 31 6- (4-Hydroxy-2-methyl-phenyl) -1,2-dimethyl-lH-indole-3-carboxylic acid methyl ester The title compound is prepared essentially in accordance with the preparation of acid methyl ester 6- (4-hydroxy-2-methyl-phenyl) -l-isopropyl-2-methyl-lH-indole-3-carboxylic acid using 6-Chloro-l, 2-dimethyl-lH-indol-3-methyl ester carboxylic ES / MS m / e 310.3 (M + 1).

Preparation 32 6- (4-Hydroxy-2-methyl-phenyl) -benzo [d] isoxazole-3-carboxylic acid ethyl ester Stage 1 (-Bromo-2-nitro-phenyl) -acetic acid methyl ester A solution of acid (4-bromo-2-nitro-phenyl) -acetic acid (5.00 g, 19.2 mmol) in methanol (100 mL) is treated with HC1 conc. (1.0 mL). The mixture is stirred at 85 ° C for 16 hours and cooled to room temperature. The mixture is neutralized with Na2CC > 3 aqueous and concentrated under reduced pressure. The residue is extracted with ethyl acetate (50 mL x 2), and the combined organic layers are dried over sodium sulfate, concentrated under reduced pressure to provide the title compound (5.27 g, 100%) as a brown solid.

Step 2 6-Bromo-benzo [d] isoxazole-3-carboxylic acid ethyl ester A solution of (4-bromo-2-nitro-phenyl) -acetic acid methyl ester (0.99 g, 3.61 mmol) in ethanol (8 mL) at room temperature is treated with isoamyl nitrite (0.60 mL, 4.47 mmol). A solution of NaOEt in ethanol (1.9 M, 2.0 mL) is added, and the mixture is stirred at 60 ° C for 2 hours and at room temperature for 16 hours. The mixture is neutralized with HC1 (1.0 M, 4.0 mL) concentrated under reduced pressure. The residue is extracted with ethyl acetate (20mL x 2) and the combined organic layers are dried over sodium sulfate, concentrated under reduced pressure. The residue is purified via chromatography on silica gel by levigating with 25% ethyl acetate in hexanes to give the title compound (0.36 g, 37%). ER / MS m / e 269.8; 271.8 (M + l).I.

Step 3 6- (4-Hydroxy-2-methyl-phenyl) -benzo [d] isoxazole-3-carboxylic acid ethyl ester A solution of 3-methyl-4- (4, 4, 5, 5-tetramethyl- [ 1, 3, 2] dioxaborolan-2-yl) -phenol (0.624 g, 2.67 mmol) and 6-bromo-benzo [d] isoxazole-3-carboxylic acid ethyl ester (0.360 g, 1.33 mmol) in 1.4 -dioxane (20 mL) is added to a flask. The flask is emptied and filled with N2 3 times. To this solution, Pd2 (dba) 3 (0.010 g), tricyclohexyl phosphine (10 mg), and aqueous K3P04 (1.5 mL, 1.30) are added. The resulting mixture is heated at 50 ° C for 2 hours under N2. The reaction mixture is cooled to room temperature and filtered through a pad of diatomaceous earth. The filtrate is concentrated under reduced pressure. The residue is purified via chromatography on silica gel by levigating with 25% ethyl acetate in hexanes to give the title compound (0.366 g, 93%). ES / MS m / e 298.0 (M + 1); 296.0 (M-1).

Preparation 33 2-Methyl-6- (4, 4, 5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzofuran-3-carboxylic acid methyl ester Stage 1 6-methoxy-2- methyl-benzofuran A solution of 2-iodo-5-methoxy-phenol (39 g, 156 mmol) in dimethylformamide (300 mL) and?,?,? ',?' - tetramethylguanidine (150 mL) is treated with copper iodide (I) (1.89 g, 9.82 mmol) and bis (triphenylphosphine) palladium (II) chloride (1.9 g, 2.71 mmol, 1900 g). The mixture is cooled to -78 ° C. Propene (100 g, 2.50 moles) is bubbled through the mixture for 1 hour. The reaction mixture is stirred and allowed to warm to room temperature gradually over 6 hours and stirred for 2 days. The reaction mixture is quenched with water (800 mL) and extracted with EtOAc. (500 mL). The organic layers are dried over Na 2 SO 4, filtered, and concentrated under reduced pressure. The crude product is purified via flash chromatography by levigating with 10% EtOAc / Hexanes. The appropriate fractions are concentrated. The material is dried under vacuum to provide the title compound (17.5 g, 69%). 1 H-NMR (400 MHz, CDC13): d 7.31-7.29 (d, 1H), 6.95 (s, 1H), 6.81-6.79 (d, 1H), 6.26 (s, 1H), 3.81 (s, 3H), 2.40 (s, 3H).

Step 2 Ester 2-methyl-benzofuran-6-yl acetic acid A solution of 6-methoxy-2-methyl-benzofuran (17.4 g, 107 mmol) in dichloromethane (200 mL) at 0 ° C is treated with boron tribromide (1.0 M, 107 mL). The mixture is stirred at 0 ° C for 60 minutes and quenched with water (50 mL). The organic layer is dried over Na2SC > 4, filtered, and concentrated under reduced pressure. The crude product is purified by flash chromatography by levigating with 25% EtOAc / Hexanes. The appropriate fractions are concentrated under reduced pressure. The resulting material is dissolved in dichloromethane (150 mL) and triethylamine (17.0 mL, 122 mmol) at 0 ° C and treated with anhydrous acetic acid (7.22 mL, 76.35 mmol). The reaction is stirred for 16 hours and allowed to warm to room temperature. The reaction is quenched with MeOH (10 mL) and concentrated under reduced pressure. The residue is purified by chromatography on silica gel by levigating with 25% EtOAc / Hexanes to give the title compound (9.50 g, 82%). 1 H-NMR (400 MHz, CDCl 3): d 7.40-7.38 (d, 1H), 7.15 (s, 1H), 6.91-6.88 (d, 1H), 6.32 (s, 1H), 2.41 (s, 3H), 2.29 (s, 3H).

Step 3: 6-Hydroxy-2-methyl-benzofuran-3-carboxylic acid To a suspension of aluminum trichloride (20.0 g, 150 mmol) in dichloromethane (200 mL) is added oxalyl chloride (13.0 mL, 150 mmol). The mixture is stirred at 0 ° C for 30 minutes. A solution of 2-methyl-benzofuran-6-yl ester of acetic acid (9.50 g, 49.9 mmol) in dichloromethane (50 mL) is added over 10 minutes. The cold bath is removed and the reaction is stirred at room temperature for 2 hours. The reaction mixture is cooled to 0 ° C and quenched with MeOH (50 mL). The mixture is concentrated to a residue under reduced pressure, dissolved in methanol (250 mL), and treated with potassium carbonate (8.28 g, 59.9 mmol). The mixture is stirred at room temperature for 16 hours, filtered through a pad of diatomaceous earth, concentrated under reduced pressure. The residue is diluted with water (100 mL) and extracted with EtOAc (250 mLx2). The combined organic layers are dried over Na 2 SO 4, filtered, and concentrated under reduced pressure. The crude product is purified by flash chromatography by levigating with 25% EtOAc / Hexanes. The appropriate combined fractions are concentrated under reduced pressure to provide the title compound (9.56 g, 93%). MS: 207.0 (M + 1); 205.0 (M-l).

Step 4 2-Methyl-6-trifluoromethanesulfonyloxy-benzofuran-3-carboxylic acid methyl ester A 0 ° C solution of 6-hydroxy-2-methyl-benzofuran-3-carboxylic acid methyl ester (9.5 g, 46.07 mmol ) in dichloromethane (100 mL) and triethylamine (12.8 mL, 92.14 mmol) is treated with trifluoromethanesulfonic anhydride (8.54 L, 50.68 mmol). The reaction mixture is stirred at 0 ° C for 60 minutes and quenched with MeOH (10 mL). The mixture is concentrated to a residue under reduced pressure. The residue is purified by chromatography on silica gel by levigating with 20% EtOAc / Hexanes to give the title compound (14.1 g, 90%). 1 H-NMR (400 MHz, CDC13): d 7.99-7.96 (d, 1H), 7.37 (s, 1H), 7.21-7.18 (d, 1H), 3.93 (s, 3H), 2.76 (s, 3H).

Step 5 2-Methyl-6- (4, 4, 5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzofuran-3-carboxylic acid methyl ester A solution of 2-methyl-2-methyl ester -methyl-6-trifluoromethanesulfonyloxy-benzofuran-3-carboxylic acid (3.25 g, 9.61 mmol) and bis (pinacolato) diboro (3.05 g, 12.0 mmol) in acetonitrile (50 mL) is added to a flask. The flask is emptied by vacuum and filled with nitrogen gas three times. Tricyclohexylphosphine (108 mg, 0.384 mmol), Pd (OAc) 2 (43 mg, 0.192 mmol), and cesium fluoride (2.92 g, 19.2 mmol) are added and the mixture is heated at 85 ° C for 16 hours. The reaction mixture is cooled to room temperature and filtered through a pad of diatomaceous earth. The filtrate is concentrated to a residue. The residue is purified by chromatography on silica gel by levigating with 15% EtOAc / Hexanes to give the title compound (1.96 g, 65%). ES / MS m / e 317.0 (M + l).

Preparation 34 [6- (, 4,5,5-Tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzo [b] thiophen-3-yl] -acetic acid methyl ester Step 1 4- (3-Methoxy-phenylsulphane) -3-oxo-butyric acid ethyl ester To a 0 ° C solution of 3-methoxy-benzthiol (5.75 g, 41.0 mmol) and potassium carbonate (11.45 g, 82.02 mmol ) in acetonitrile (150 mL) is added butanoic acid, 4-chloro-3-oxo-butanoic acid ethyl ether 6.12 mL, 45.11 mmol). The mixture is stirred at room temperature for 2 hours and filtered through a pad of diatomaceous earth. The filtrate is concentrated under reduced pressure. The residue is purified via chromatography on silica gel by levigating with 25-30% EtOAc / Hexanes to give the title compound (10.9 g, 99%). S: 267.0 (M-l) Step 2 4-Methoxy-benzo [b] thiophene-3-acetic acid ethyl ester 4- (3-Methoxy-phenylsulphane) -3-oxo-butyric acid ethyl ester (10.9 g, 40.62 mmol) is added to methanesulfonic acid (26.6 mL, 406 mmol). The mixture is stirred at room temperature for 30 minutes. The reaction mixture is poured into cold water (300 g) and extracted with EtOAc (100 mL x 2). The combined organic layers are dried over Na 2 SO 4, filtered, and concentrated under reduced pressure. The crude product is purified by flash chromatography by levigating with 20% EtOAc / Hexanes. The appropriate combined fractions are concentrated under reduced pressure to provide the title compound (6.00 g, 59%). ER / E m / e 251.0 (M + l) Step 3 (6-Hydroxy-benzo [b] thiophen-3-yl) -acetic acid ethyl ester To a solution -78 ° C of ethyl ester of acid (6-methoxy-benzo [b] thiophen-3-yl) -acetic acid (3.81 g, 15.22 mmol) in dichloromethane (50 mL) is added boron tribromide (38.1 mL, 38.1 mmol) by dropwise. The mixture is allowed to warm to room temperature and is stirred for 16 hours. The mixture is cooled to 0 ° C and quenched with water (100 mL). The organic layer is separated, and the aqueous layer is extracted with EtOAc (50 mL). The combined organic layers are dried over Na2SC > 4, filter, and concentrate under reduced pressure. The crude product is purified by flash chromatography by levigating with 30-40% EtOAc / Hexanes. The appropriate combined fractions are concentrated under reduced pressure to provide the title compound (3.35 g, 93%). ER / E m / e 237.0 (M + 1); 235.0 (-l).

Step 4 (6-Trifluoromethanesulfonyloxy-benzo [b] thiophen-3-yl) -acetic acid ethyl ester To a -78 ° C solution of (6-hydroxy-benzo [b] thiophen-3-yl) ethyl ester) -acetic (3.31 g, 14.0 mmol) in dichloromethane (50 mL) was added triethylamine (3.90 mL, 28.0 mmol) and trifluoromethanesulfonic anhydride (2.60 mL, 15.4 mmol). The mixture is allowed to warm to room temperature and is stirred and for 30 minutes. The reaction is quenched with MeOH (5.0 mL) concentrated under reduced pressure. The residue is purified via chromatography on silica gel by levigating with 20% EtOAc / Hexanes to give the title compound (5.05 g, 98%). ES / MS m / e 366.8 (M-1).

Step 5 [6- (4, 4, 5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzo [b] thiophen-3-yl] -acetic acid ethyl ester An ester solution Ethyl (6-trifluoromethanesulfonyloxy-benzo [b] thiophen-3-yl) -acetic acid (2.21 g, 6.00 mmol) and bis (pinacolato) diboro (1.90 g, 7.50 mmol) in acetonitrile (25 mL) is drained and refilled with N2 three times.

Pd (0Ac) 2 (27 mg, 0.12 mmol), tricyclohexylphosphine (67 mg, 0.24 mmol), and cesium fluoride (1.82 g, 12.00 mmol) are added. The mixture is stirred at 95 ° C for 1 hour and quenched with water (5 mL). The mixture is filtered through a pad of diatomaceous earth and the filtrate is concentrated under reduced pressure. The residual aqueous solution is extracted with EtOAc (20 mL x 2). The combined organic layers are dried over Na 2 SO, filtered, and concentrated under reduced pressure. The crude product is purified via flash chromatography by levigating with 20% EtOAc / Hexanes. The appropriate fractions are combined and concentrated under reduced pressure to provide the title compound (1.56 g, 75%). ES / MS m / e (M + 18): 364.0; (M + l): 347.0 Preparation 35 (6-Bromo-benzo [b] thiophen-2-yl) -acetic acid methyl ester Stage 1 6-Bromo-benzo [b] thiophene-2-carboxylic acid ethyl ester Sodium hydride (1.41 g) is added , 35.32 mmol) was added to a round bottom flask and washed with hexanes (10 mL) twice. To the flask is added dimethyl sulfoxide (30 mL) and ethyl 2-mercaptoacetate (3.54 g, 29.43 mmol). The mixture is stirred for 10 minutes and 4-bromo-2-fluoro-benzaldehyde (4.78 g, 23.55 mmol) is added. The reaction mixture is stirred for 15 minutes and quenched with cold water (100 g). The mixture is extracted with CH2Cl2 (50 mL x2). The combined organic layers are dried over Na 2 SC), filtered, and concentrated under reduced pressure. The crude product is purified via flash chromatography by levigating with 10% EtOAc / Hexanes. The appropriate combined fractions are concentrated under reduced pressure to provide the title compound (5.75 g, 86%). 1 H-NMR (400 MHz, CDC13): d 8.00 (s, 1 H), 7.99 (s, 1 H), 7.75 (d, 1 H), 7.48 (d, 1 H), 4.38 (q, 2 H), 1.39 ( t, 3H).

Step 2 (6-bromo-benzo [b] thiophen-2-yl) -methanol A solution -78 ° C of 6-bromo-benzo [b] thiophene-2-carboxylic acid ethyl ester (5.75 g, 20.2 mmol) in THF (200 mL) it is treated with diisobutylaluminum hydride (50.4 mL, 1.0 M) by drip. The mixture is stirred at 0 ° C for 10 minutes and quenched with HC1 (1 M, 50 mL). The mixture is extracted with EtOAc (150 mL). The organic layer is dried over Na 2 SO, filtered, and concentrated under reduced pressure. The crude product is purified via flash chromatography by levigating with 25% EtOAc / Hexanes. The appropriate combined fractions are concentrated under reduced pressure to provide the title compound (2.92 g, 60%). X H-NMR (400 MHz, CDCl 3): d 7.95 (s, 1 H), 7.68 (d, 1 H), 7.42 (d, 1 H), 7.18 (s, 1 H), 4.90 (s, 2 H) Step 3 6-bromo-benzo [b] thiophene-2-carbaldehyde To a solution -78 ° C of oxalyl chloride (1.30 mL, 14.9 mmol) in CH 2 Cl 2 (20 mL) is added a solution of dimethyl sulfoxide (2.13 mL). , 29.9 mmol) in CH2C12 (10 mL). The mixture is stirred for 5 minutes and a solution of (6-bromo-benzo [b] thiophen-2-yl) -methanol (2.91 g, 12.0 mmol) in CH2C12 (30 mL) is added. The mixture is stirred at -78 ° C for 30 minutes and triethylamine (8.34 mL, 60.0 mmol) is added. The mixture is stirred for 1 hour while heating to room temperature. The reaction mixture is quenched with water (50 mL). The organic layer is separated and concentrated under reduced pressure to a residue. The residue is purified via chromatography on silica gel by levigating with 20% EtOAc / Hexanes to give the title compound (2.58 g, 89%). 1 H NMR (400 MHz, CDCl 3): d 10.4 (s, 1 H), 8.02 (s, 1 H), 7.98 (s, 1 H), 7.79 (d, 1 H), 7.52 (d, 1 H).

Step 4 (6-bromo-benzo [b] thiophen-2-yl) -acetaldehyde To a 0 ° C solution of potassium tert-butoxide (2.50 g, 21.4 mmol) in tetrahydrofuran (100 mL) is added (methoxymethyl chloride). ) triphenylphosphonium (7.49 g, 21.4 mmol). The reaction mixture is stirred for 20 minutes. 6-Bromo-benzo [b] thiophene-2-carbaldehyde (2.58 g) is added; 10.7 mmol) and the cold bath is removed. The mixture is stirred at room temperature for 16 hours. The reaction mixture is quenched with AcOH (5 mL). The mixture is treated with water (50 mL) and concentrated to a residue under reduced pressure. The residual aqueous solution is extracted with EtOAc (50 mL x2). The combined organic layers are dried over Na2SC > 4, filter, and concentrate under reduced pressure. The crude product is purified via flash chromatography by levigating with 10% EtOAc / Hexanes. The appropriate combined fractions are concentrated under reduced pressure to a residue. The residue is dissolved in THF (50 mL) and treated with HC1 (5 N, 5 mL). The mixture is stirred at 70 ° C for 60 minutes and neutralized with NaOH (5 N, 5 mL). The mixture is concentrated to a residue under reduced pressure. The residual aqueous mixture is extracted with EtOAc (50 mL x2). The combined organic layers are dried over Na 2 SO 4, filtered, and concentrated under reduced pressure. The crude product is purified via chromatography on silica gel by levigating with 25% EtOAc / Hexanes to give the title compound (2.25 g, 82%). ER / E m / e 254.8, 252.8 (M-l).

Step 5 (6-Bromo-benzo [b] thiophen-2-yl) -acetic acid methyl ester To a 0 ° C solution of (6-bromo-benzo [b] thiophen-2-yl) -acetaldehyde (2.21 g) 8.66 mmol) in t-butyl alcohol (50 mL, 526.36 mmol, 50.00 mL, 39.015 g) and 2-methyl-2-butene (20 mL, 188 mmol) is added a solution of sodium chloride (6.27 g; mmol) in water (20 mL) and a solution of sodium phosphate monobasic (4.20 g, 34.6 mmol) in water (10 mL). The reaction mixture is stirred at 0 ° C for 12 hours while heating to room temperature. The mixture is extracted with EtOAc (50 mL x2). The combined organic layers are dried over Na 2 SO 4, filtered, and concentrated under reduced pressure. The crude product is dissolved in methanol (30 mL). Sulfuric acid (1.0 mL, 18.8 mmol) is added and the mixture is stirred at 95 ° C for 4 hours. The mixture is neutralized with aqueous NaHCO 3 and concentrated under reduced pressure. The residual aqueous mixture is extracted with EtOAc (50 mL x2). The combined organic layers are dried over Na 2 SO 4, filtered, and concentrated under reduced pressure. The crude product is purified via flash chromatography by levigating with 20% EtOAc / Hexanes. The appropriate combined fractions are concentrated under reduced pressure to provide the title compound (1.51 g, 61%). ES / MS m / e (+18): 303.8; (Ml): 284.7 Preparation 36 (l-Methyl-6-trifluoromethanesulfonyloxy-lH-indol-3-yl) -acetic acid methyl ester Stage 1 (6-benzyloxy-lH-indol-3-yl) - methyl ester oxo-acetic A 0 ° C solution of 6-benzyloxyindole (2.10 g, 9.41 mmol) in diethyl ether (20 mL) is treated with oxalyl chloride (1.02 mL, 11.8 mmol). The mixture is stirred for 2 hours while heating to room temperature. The mixture is cooled to -78 ° C and sodium methoxide is added (5.41 mL, 4.35 M). The mixture is warmed to room temperature for 20 minutes and the reaction is quenched with water (10 mL). The resulting mixture is filtered to obtain the title compound (2.75 g, 95%) as a yellow solid. ES / MS m / e 310.0 (M + 1), 308.0 (M-1).

Stage 2 (6-Benzyloxy-1-methyl-1H-indol-3-yl) -oxo-acetic acid methyl ester A 0 ° C suspension of (6-benzyloxy-1H-indol-3-yl) methyl ester -oxo-acetic acid (2.70 g, 8.73 mmol) in dimethylformamide (25 mL) is treated with sodium hydride (437 mg, 10.9 mmol). The mixture is stirred at 0 ° C for 20 minutes. Methyl iodide (1.00 mL, 16.1 mmol) is added. The reaction mixture is stirred at 0 ° C for 30 minutes and quenched with water (100 mL). The mixture is extracted with EtOAc (50 mL x2). The combined organic layers are dried over Na 2 SO 4, filtered, and concentrated under reduced pressure. The crude product is purified by flash chromatography by levigating with 60% EtOAc / Hexanes. The appropriate combined fractions are concentrated under reduced pressure to provide the title compound (0.68 g, 24%). ER.E m / e 324.0 (M + l).

Step 3 (6-Hydroxy-1-methyl-1H-indol-3-yl) -acetic acid methyl ester To a solution of (6-benzyloxy-1-methyl-1H-indol-3-yl) methyl ester -oxo-acetic (0.68 g, 2.10 mmol) in 1,4-dioxane (12 mL) is added a suspension of Pd / C (10%, 0.25 g). The flask is emptied and filled with N2 three times. The mixture is heated to 100 ° C and a solution of sodium hypophosphite, hydrated (5.0 g, 47 mmol) in water (5 mL) is added dropwise. The mixture is stirred at 100 ° C for 16 hours and cooled to room temperature. The mixture is filtered through a pad of diatomaceous earth and the filtrate is concentrated under reduced pressure. The residue is purified via chromatography on silica gel by levigating with 25-50% EtOAc / Hexanes to give the title compound (0.24 g, 52%). ES / MS m / e 220.0 (M + 1), 218.0 (M-1).

Step 4 (1-Methyl-6-trifluoromethanesulfonyloxy-1H-indol-3-yl) -acetic acid methyl ester A -40 ° C solution of (6-hydroxy-1-methyl-1H-indol-3) methyl ester -yl) -acetic (0.231 g, 1.05 mmol) in dichloromethane (20 mL) and triethylamine (0.294 mL, 2.11 mmol) is treated with trifluoromethanesulfonic anhydride (0.266 mL, 1.58 mmol). The mixture is stirred at -40 ° C for 2 hours and quenched with MeOH (1.0 mL). The mixture is concentrated to a residue which is purified by chromatography on silica gel by levigating with 25-30% EtOAc / Hexanes to give the title compound (0.26 g, 71%). ES / MS m / e 351.8 (M + l), 368.8 (+18).

Preparation 37 6-Trifluoromethanesulfonyloxy-benzofuran-3-carboxylic acid ethyl ester Step 1 6-Methoxy-benzofuran-3-yl ester of phyllic acid Trifluoro-methansulphonate A solution -70 ° C of 6-methoxy-benzofuran-3-one ( 5.12 g, 31.2 mmol) in CH2C12 (100 mL) and diisopropylethylamine (6.53 mL, 37.4 mmol) is treated with trifluoromethanesulfonic anhydride (6.31 mL, 37.4 mmol). The mixture is stirred while heating at 0 ° C for 2 hours. The mixture is quenched with water (20 mL). The organic layer is separated, dried over Na2SC > 4, concentrated under reduced pressure. The residue is purified via chromatography on silica gel by levigating with 10% EtOAc / Hexanes to give the title compound (9.10 g, 98%). 1 H-NMR (400 MHz, CDC13): d 7.70 (s, 1 H), 7.43 (d, 1 H), 6.99 (s, 1 H), 6.96 (d, 1 H), 3.82 (s, 3 H) .

Step 2 6-Methoxy-benzofuran-3-carboxylic acid ethyl ester In a high-pressure steel reaction vessel, a solution of 6-methoxy-benzofuran-3-yl ester of trifluoromethanesulfonic acid (9.10 g, 30.7 mmol ) in dimethylformamide (120 mL) is bubbled with carbon monoxide gas for 10 minutes. Ethanol (60 mL), triethylamine (9.25 mL), Pd (OAc) 2 (0.20 g), bis- (1, 3-diphenylphosphino) propane (0.38 g) are added to the reaction mixture. The mixing vessel is sealed, charged with carbon monoxide (10 g, 30 psi), and heated at 80 ° C for 4.5 hours. The mixture is concentrated under reduced pressure and diluted with water (300 mL), and extracted with EtOAc (150 mL x 2). The combined organic layers are dried over Na 2 SO 4, filtered, and concentrated under reduced pressure. The crude product is purified by flash chromatography by levigating with 15% EtOAc / Hexanes. The appropriate combined fractions are concentrated under reduced pressure to provide the title compound (5.50 g, 81%). 1 H-NMR (400 MHz, CDC13): d 8.16 (s, 1 H), 7.88 (d, 1 H), 7.01 (s, 1 H), 6.96 (d, 1 H), 4.38 (q, 2 H) , 3.81 (s, 3 H), 1.40 (t, 3 H).

Step 3 6-Hydroxy-benzofuran-3-carboxylic acid ethyl ester A solution -78 ° C of 6-methoxy-benzofuran-3-carboxylic acid ethyl ester (1.50 g, 6.81 mmol) in dichloromethane (20 mL) is treated with boron tribromide (20 mL) by drip. The mixture is stirred at 0 ° C for 60 minutes. The reaction is quenched by adding MeOH (10 mL) by dripping for 10 minutes. The mixture is concentrated. The residue is purified via flash chromatography by levigating with 25% EtOAc / hexanes to give the title compound (0.95 g, 68%). ES / MS m / e 207.0 (M + 1), 205.0 (M-1).

Stage 4 6-Trifluoromethanesulfonyloxy-benzofuran-3-carboxylic acid ethyl ester A solution -70 ° C of 6-hydroxy-benzofuran-3-carboxylic acid ethyl ester (0.95 g) in dichloromethane (30 mL) is added triethylamine (1.28 mL, 9.21 mmol) and trifluoromethanesulfonic anhydride (0.97 mL, 5.76 mmol). The resulting mixture is stirred and heated at 0 ° C for 60 minutes. The reaction is quenched with MeOH (5.0 mL) and the mixture is concentrated to a residue, which is purified by chromatography on silica gel by levigating with 15% EtOAc / Hexanes to give the title compound (1.43 g, 92%). 1 H-NMR (400 MHz, CDC13): d 8.33 (s, 1 H), 8.12 (d, 1 H), 7.48 (s, 1 H), 7.29 (d, 1 H), 4.40 (q, 2 H) , 1.40 (t, 3 H).

Preparation 38 6- Trifluoromethanesulfonyloxy-benzofuran-2-carboxylic acid tert-butyl ester Step 1 4-Benzyloxy-2-hydroxy-benzaldehyde A solution of 2,4-dihydroxy-benzaldehyde (101 g, 0.731 mol) in acetonitrile (700 mL ) is treated with KI (12.1 g, 73.1 mmol) and NaHCO3 (70.0 g, 0.834 mol). The mixture is stirred while heating at 60 ° C. Benzyl chloride (120 g, 0.950 mol) is added and the mixture is refluxed at 82 ° C for 16 hours and cooled to room temperature. The solvent is evaporated and the reaction is quenched with water (250 mL) and HC1 (5.0 N, 30 mL). The mixture is extracted with EtOAc (300 mL x2), and the organic layers are dried over a2SO4, filtered, and concentrated to an approximate volume of 200 mL. 400 mL hexanes are added and the resulting solution is heated to 60 ° C until dissolved. The solution is cooled to room temperature and crystallized for 16 hours. The solid is filtered and dried to obtain the title compound (130 g, 78%). CL-ER / MS m / e 227.0 (M-l).

Step 2: 6-Benzyloxy-benzofuran-2-carboxylic acid tert-butyl ester To a solution of 4-benzyloxy-2-hydroxy-benzaldehyde (5.56 g, 24.4 mmol) in DMF (20 mL) is added K2CO3 (6.73 g, 48.8 mmol), bromo-acetic acid tert-butyl ester (4.75 g, 24.4 mmol), and DBU (1.0 mL). The mixture is heated at 140 ° C for 2 hours and cooled to room temperature. The mixture is quenched with water (200 mL) and extracted with EtOAc (100 mL). The organic layer is dried over Na 2 SO 4, filtered, and concentrated under reduced pressure. The residue is purified by chromatography on silica gel by levigating with 15% EtOAc / Hexanes to give the title compound (5.68 g, 72%). CL-ER / EM m / e 269.0 (acid, M + l) Step 3 6-Hydroxy-benzofuran-2-carboxylic acid tert-butyl ester A solution of 6-benzyloxy-benzofuran-2-carboxylic acid tert-butyl ester (5.68 g, 17.5 mmol) in THF (50 mL) and MeOH (20 mL) is added to Pd / C (5%, 200 mg). The mixture is stirred under a hydrogen balloon for 16 hours at room temperature. The mixture is filtered through a pad of diatomaceous earth and the filtrate is concentrated under reduced pressure. The residue is purified by chromatography on silica gel by levigating with 25% EtOAc / Hexanes to give the title compound (3.99 g, 97%). CL-ER / MS m / e 233.0 (M-1).

Step 4: 6-Trifluoromethanesulfonyloxy-benzofuran-2-carboxylic acid tert-butyl ester To a 0 ° C solution of 6-hydroxy-benzofuran-2-carboxylic acid tert-butyl ester (0.51 g, 2.18 mmol) in dichloromethane (20 ml). mL) and triethylamine (2.0 mL) was added trifluoromethanesulfonic anhydride (0.46 mL, 2.74 mmol). The mixture is stirred for 2 hours and quenched with MeOH (2.0 mL). The mixture is concentrated and the residue is purified by chromatography on silica gel by levigating with 15% EtOAc / Hexanes to provide (475 mg, 59%). 1 H-NMR (400 MHz, CDC13): d 7.70 (d, 1 H), 7.52 (s, 1 H), 7.41 (s, 1 H), 7.23 (s, 1 H), 1.60 (s, 9 H) .

Preparation 39 6-Bromo-benzo [d] isothiazole-3-carboxylic acid The title compound is prepared essentially as described in process 3 of WO2005 / 092890? 2 using 3-bromo-benzothiol. ER / MS m / e 255.0 (M-l).

Preparation 40 6-Bromo-l-isopropyl-lH-indazole-3-carboxylic acid methyl ester Step 1: 6-Bromo-lH-indazole-3-carboxylic acid methyl ester The title compound is prepared essentially as described in procedure 4 of O2005092890 using 6-bromo-lH-indole-2,3-dione. ES / MS m / e 254.0 (M + 1).

Step 2: 6-Bromo-l-isopropyl-lH-indazole-3-carboxylic acid methyl ester The title compound is prepared essentially as described in method Id of WO2005 / 080389 using 6-bromo-lH- methyl ester indazole-3-carboxylic acid and methyl iodide. ES / MS m / e 268.0 (M + l).

Preparation 41 6-Bromo-lmethyl-lH-indazole-3-carboxylic acid methyl ester The title compound is prepared essentially as described in procedure Id WO2005 / 080389 using 6-bromo-lH-indazol-3 methyl ester -carboxylic ES / MS m / e 296.0 (M + l).

Preparation 42 5- (4-Hydroxy-2-methyl-phenyl) -benzofuran-2-carboxylic acid ethyl ester A solution of 5-bromo-benzofuran-2-carboxylic acid ethyl ester (275 mg, 1.02 mmol) and 2 -methyl-4- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -phenol (239 mg, 1.11 mmol) in toluene (5.0 mL) and THF (5.0 mL) It is added to a flask. The flask is emptied and filled with N2 three times. Pd (OAc) 2 (5 mg, 0.022 mmol) and 2-dicyclohexylphosphino-2,6-dimethoxy-1, 1-biphenyl (20 mg, 0.049) and potassium phosphate, tribasic, N-hydrate (432 mg) are added. , 2.04 mmol) and the mixture is heated at 85 ° C for 8 hours. The reaction mixture is cooled to room temperature and filtered through a pad of diatomaceous earth. The filtrate is concentrated to a residue which is purified by chromatography on silica gel by levigating with 20-30% EtOAc / Hexanes to give the title compound (179 mg, 56%). ESRIM m / e 297.0 (M + 1), 295.0 (M-1). The following list of compounds is prepared essentially as described in the preparation of 5- (4-hydroxy-2-methyl-phenyl) -benzofuran-2-carboxylic acid ethyl ester.

Preparation 42A; 6- (4-hydroxy-2-methyl-phenyl) -benzo [d] isoxazole-3-carboxylic acid ethyl ester (0.065 g, 47%) using 2-methyl-6-trifluoromethanesulfonyloxy-benzofuran-3-methyl ester -carboxylic with stirring at 100 ° C for 16 hours. ES / MS m / e 297.0 (M + 1), 295.0 (M-1).

Preparation 42B: [6- (4-hydroxy-2-methyl-phenyl) -benzo [b] thiophen-2-yl] -acetic acid methyl ester (40 mg, 14%) using (6-bromine) methyl ester -benzo [b] thiophen-2-yl) -acetic acid (255 mg, 0.894 mmol) with stirring at 110 ° C for 16 hours. ER / MS m / e 313.0 (M + 18), 311.0 (M-l) Preparation 42C: [6- (4-hydroxy-2-methyl-phenyl) -l-methyl-lH-indol-3-yl] -acetic acid methyl ester (40 mg, %) using (l-methyl-6-trifluoromethanesulfonyloxy-lH-indol-3-yl) -acetic acid methyl ester with stirring at 100 ° C for 16 hours. ER / MS m / e 310.0 (M + l), 308.0 (M-l) Preparation 42D; 6- (4-hydroxy-2-methyl-phenyl) -benzofuran-3-carboxylic acid ethyl ester (160 mg, 58%) using 6-trifluoromethanesulfonyloxy-benzofuran-3-carboxylic acid ethyl ester (325 mg, 0.960 mmol ) with stirring at 100 ° C for 16 hours. ES / MS m / e 295.0 (M-l).

Preparation 42E: 6- (4-hydroxy-2-methyl-phenyl) -benzofuran-3-carboxylic acid tert-butyl ester (98 mg, 50%) using 6-trifluoromethanesulfonyloxy-benzofuran-2-tert-butyl ester carboxylic with stirring at 100 ° C for 16 hours. ES / MS m / e 323.0 (M-1).

Preparation 42F: 6- (4-hydroxy-2-methyl-phenyl) -benzo [d] isothiazole-3-carboxylic acid methyl ester (0.12 g, 26%) using 6-bromo-benzo [d] isothiazole-3 acid -carboxylic with stirring at 80 ° C for 18 h. ES / MS m / e 300.0 (M + 1).

Preparation 42G: 6- (4-hydroxy-2-methyl-phenyl) -l-methyl-lH-indazole-3-carboxylic acid methyl ester (0.53 g, 75%) using 6-bromo-l- methyl ester isopropyl-lH-indazole-3-carboxylic acid with stirring at 90 ° C for 18 h. ES / MS m / e 297.0 (M + l).

Preparation 42H: 6- (4-hydroxy-2-methyl-phenyl) -l-isopropyl-lH-indazole-3-carboxylic acid methyl ester (2.28g, 80%) using 6-bromo-methylmethyl methylester lH-indazole-3-carboxylic acid with stirring at 90 ° C for 18 h. ES / MS m / e 325.0 (M + 1).

Preparation 43 5-Cyclopropyl-4- [3-methyl-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-y1) -oxymethyl] -3- (2-trifluoromethoxy- phenyl) -isoxazole Step 1 4-Bromomethyl-5-cyclopropyl-3- (2-trifluoromethoxy-phenyl) -isoxazole Triphenylphosphine (1.1 equiv., 51.5 mmol, 13.5 g) is added in small portions to a 0 ° C solution of [ 5-Cyclopropyl-3- (2-trifluoromethoxy-phenyl) -isoxazol-4-yl] -methanol and carbon tetrabromide (1.1 equiv, 51.5 mmol, 17.1 g) in dichloromethane (187.1 mL). The reaction mixture is stirred at room temperature for 15 h and concentrated under reduced pressure. The crude residue is purified via chromatography on silica gel by levigating with 5: 1 hexanes / ethyl acetate) to give the title compound (15g, 88%) as a white powder. 1 H-NMR (DMS0-d 6, 500MHz): d.7.7-7.5 (m, 4H), 4.55 (s, 2H), 2.41 (m, 1H), 1.17 (m, 2H), 1.11 (m, 2H) Step 2 5-Cyclopropyl-4- [3-methyl-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenoxymethyl] -3- (2-trifluoromethoxy-) phenyl) -isoxazole To a 3-neck 5-L round bottom flask with a mechanical stirrer, thermocouple, reflux condenser, and drying tube is added 4-bromomethyl-5-cyclopropyl-3- (2-trifluoromethoxy). phenyl) -isoxazole (221.7 g, 0.612 mol, 1.05 eq), acetonitrile (2 L), 3-Methyl-4- (4, 4, 5, 5-tetramethyl- [1, 3, 2] dioxaborolan-2-il ) -phenol (136.5 g, 0.583 mol, 1 eq) and potassium carbonate (241.8 g, 1.749 mol, 3 eq). The reaction mixture is heated to reflux and stirred at this temperature for 1 hour. At the end of the reaction, as is evident by thin layer chromatography, the reaction mixture is cooled to 0-20 ° C. The reaction mixture is filtered and the filtered pulp is washed with acetonitrile (2 x 100 mL). The reaction mixture is concentrated under reduced pressure to a solid, which is co-evaporated with 1,4-dioxane (500 mL). The title compound is used without further purification. 1 H-NMR (DMSO-d 6, 300 MHz): d.7.7-7.5 (m, 5H), 6.61 (m, 2H), 4.90 (s, 2H), 2.39 (m, 1H), 2.36 (s, 3H) , 1.24 (s, 12H), 1.10 (m, 4H).

Preparation 44 6-Bromo-benzo [b] thiophene-3-carboxylic acid The title compound is prepared essentially as described in J. ed. Chem. 2003, 46, 2446-2455.

Preparation 45 6-Bromo-benzo [b] thiophene-2-carboxylic acid A stirred solution of 2-bromo-6-fluorobenzaldehyde (2.3 Kg, 11.33 mole) acid and mercaptoacetic acid (1.04 Kg, 11.33 mole) is added to a solution of KOH (951 g, 16.99 mol) in dimethylformamide (11.0 L) at room temperature. The reaction mixture is stirred for 1.5 h at 136 to 140 ° C. At the end of the reaction, the reaction mixture is cooled to 10 ° C and quenched with concentrated HC1 (2.5 L). The mixture is stirred for 1 h at 10 ° C and the resulting solid is filtered. The filter cake is washed with water (2 X 3 L) and dried under vacuum to give the title compound (2.2 Kg, 76%) as a yellow solid.

Preparation 46 6-Bromo-benzo [b] thiophene Copper powder (100 g, 1.57 mol) is added to a solution of 6-bromo-benzo [b] -thiophene-2-carboxylic acid (1.04 Kg, 4.04 mol) in quinoline (2.5 L) at room temperature. The reaction mixture is heated to reflux (195 ° C) for 10 h. The reaction mixture is cooled to room temperature and poured into ice (2.5 Kg). Concentrated HC1 (2.5 L) is added while stirring the resulting mass per lh. The reaction mixture is extracted with hexane (4 x 3 L) and washed with dilute HC1 (1 x 2 L), aqueous bicarbonate (1 x 5 L), and brine solution (1 x 5 L). The layers are separated and the organic layer is dried over sodium sulfate, concentrated to give the title compound (0.54 Kg, 62%) as a light yellow solid.

Preparation 47 6-Bromo-benzo [b] thiophene-3-carboxylic acid ethyl ester Procedure 1 A solution of 6-Bromo-benzo [b] thiophene-3-carboxylic acid (65 g, 252.8 mmol) and sulfuric acid (0.10) Equiv; 25.3 mmol, 1.35 mL, 2.48 g) in ethanol (1.0 L) is heated at 65 ° C for 3 days. The solution is cooled to room temperature. The resulting light brown precipitate is filtered. The filter cake is washed with methanol to provide the title compound (32 g, 44%).

Procedure 2 Oxalyl chloride (717.2 g, 5.65 mol, 3.5 eq) is added to a 0-5 ° C suspension of dichloromethane (3.44 L) and aluminum chloride (753.4 g, 5.65 mol, 3.5 eq). The resulting suspension is stirred for 30-60 minutes at 0-5 ° C and cooled -20 to -25 ° C. A solution of 6-bromobenzo [b] thiophene (344 g, 1614 mol, 1 eq) in dichloromethane (1.72 L) is added for 1 h while maintaining the temperature at -20 to -25 ° C. The reaction mixture is stirred for 30 minutes at -20 to -25 ° C and heated to 18 to 20 ° C using a hot water bath. The reaction mixture is stirred for 1.5 h at this temperature. The reaction mixture is filtered and the filtered pulp is washed with dichloromethane (3 x 300 mL). The combined filtrate is concentrated to provide a thick black oil in the flask (600 g). This residue is dissolved in dichloromethane (1 L) and added to ethanol (3.5 L) at -10 to 0 ° C in portions at such a rate to maintain the temperature at 10 to 20 ° C. Once the addition is complete, the reaction mixture is partially concentrated to remove dichloromethane only and then the vacuum is released. The reaction mixture is heated to 60-70 ° C and stirred at this temperature for 1 h. At the end of the reaction, the solution is decanted from the resulting tar. The tar is discarded. The ethanol solution is evaporated to a residue. The residue is diluted with EtOAc (2 L). At this point, the current reaction mixture is combined with another reaction mixture by additional raising (starting with 330 g of 6-Bromobenzo [b] thiophene, 1549 mol). The combined reaction mixture is poured into a stirred mixture of EtOAc (1 L) and brine solution (10 L). The layers are separated and the organic layer is washed with brine solution (2 L). The combined aqueous layer is extracted with EtOAc (4 L). The organic layer is washed with brine solution (1 L). The combined organic layers are dried over magnesium sulfate and charcoal, filter, and concentrate under reduced pressure. The resulting oil is further concentrated in a vacuum oven for 15 h at room temperature to provide waxy solids after drying (750 g). The solids are suspended in heptane (5 L) with stirring and the suspension is heated to 70 ° C. Magnesium sulfate (300 g) is added and the resulting suspension is stirred for 10 minutes at 70 ° C. The suspension is filtered. The solids are suspended in heptane (5 L) and heated to 70 ° C. The suspension is stirred for 10-20 minutes at this temperature and filtered. The filtered pulp is washed with heptane (1 L). The heptane filtrates are collected and concentrated under reduced pressure to give light brown solids (550 g). The solids are dissolved in heptane (4 L) at 60 ° C. The resulting solution is cooled to 35 to 50 ° C. The solution is loaded uniformly on silica gel plugs (1.5 kg each) by levigating with 0.5% EtOAc in heptane. The pure process fractions are combined and concentrated under reduced pressure. The impure product fractions are combined, concentrated, and purified as described above. The total purified product is isolated (500 g) and crystallized from heptane (1.2 L). The solids are collected by filtration, washed with cold heptane (200 mL, -20 ° C), and dried in a vacuum oven at room temperature for 15 h to provide the title compound (460 g, 51%). Analysis GC 98.8%; 1 H-NMR (DMSO-d 6, 500 MHz): d .8.65 (s, 1H), 8.36 (d, 1H, J = 1.5), 8.33 (d, 1H, J = 8.5), 7.63 (dd, 1H, J = 2, 8.5), 4.33 (q, 2H, J = 7), 1.33 (t, 3H, J = 6.5).

EXAMPLES Example 1 Acid 6-. { 4- [3- (2,6-Dichloro-phenyl) -5-isopropyl-isoxazol-4-ylmethoxy] -2-methyl-phenyl} -lH-indole-3-carboxylic acid Stage 1 6- methyl acid ester. { 4- [3- (2,6-Dichloro-phenyl) -5-isopropyl-isoxazol-4-ylmethoxy] -2-methyl-phenyl} -1H-indole-3-carboxylic acid To a mixture of [3- (2,6-dichloro-phenyl) -5-isopropyl-isoxazol-4-yl] -methanol (112 mg, 0.391 mmol) and methyl 6-methyl ester - (4-hydroxy-2-methyl-phenyl) -lH-indole-3-carboxylic acid (100 mg, 0.355 mmol) and toluene (7 mL) is added with 1,1'- (azodicarbonyl) dipipiperidine (99 mg, 0.39 mmol ) followed by tri-n-butylphosphine (105 μL, 0.426 mmol). The mixture is allowed to stir overnight at room temperature. The reaction mixture is concentrated and purified via chromatography by levigating with CH2C12 to give 85 mg (40%) of the title compound. ES / MS m / e 549.0 (M + l).

Stage 2 acid 6-. { 4- [3- (2,6-Dichloro-phenyl) -5-isopropyl-isoxazol-4-ylmethoxy] -2-methyl-phenyl} -lH-indole-3-carboxylic acid A mixture of 6- methyl acid ester. { 4- [3- (2,6-dichloro-phenyl) -5-isopropyl-isoxazol-4-ylmethoxy] -2-methyl-phenyl} -lH-indole-3-carboxylic acid (80 mg, 0.15 mmol), 5 N sodium hydroxide (150 μL, 0.750 mmol), methanol (2 mL) and THF (1 mL) is heated at 85 ° C for five hours. The mixture is cooled and 5 mL of water is added and the volatile solvents are evaporated under reduced pressure. The basic layer is washed with ether and then acidified with 1N HC1 and extracted with ether.

The second ether layers are dried over anhydrous magnesium sulfate, concentrated, and crystallized from ether-hexane to provide 42 mg (54%) of the title compound. LC-MS / MS m / e 535.0 (M + 1), 93.2% purity. The compounds in Table 1 are prepared essentially in accordance with the preparation of 6- acid. { 4- [3- (2,6-dichloro-phenyl) -5-isopropyl-isoxazol-4-ylmethoxy] -2-methyl-phenyl} -lH-indole-3-carboxylic acid.

Table 1 Example 35 - (4- (5-Cyclopropyl-3. {2, 6-dichloro-phenyl) -isoxazol-4-ylmethoxy) -2-methyl-phenyl) -thiophene-2-carboxylic acid Step 1 - (4- (5-Cyclopropyl-3- (2,6-dichloro-phenyl) -isoxazol-4-ylmethoxy) -2-methyl-phenyl) -thiophene-2-carboxylic acid methyl ester To a solution of ( 5-cyclopropyl-3- (2,6-dichloro-phenyl) -isoxazol-4-yl) -methanol (0.188g, 0.66mmol), 5- (4-hydroxy-2-methyl-phenyl) -methyl ester - thiophen-2-carboxylic acid (0.15g, 0.60mmol), and tri-N-butyl-phosphine (0.16g, 0.79mmol) in toluene (2 mL) is added a solution of ADDP (0.2 g, 0.79 mmol) in 1 mL of toluene. The reaction is stirred overnight. The reaction mixture is partitioned between ethyl acetate and water and the layers are separated. The organic layer is washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide a crude oil. The oil is chromatographed using a gradient of 10% ethyl acetate in hexanes to 40% ethyl acetate in hexanes to give the title compound (0.14 g, 41%). ER / MS m / e 514.0 (+ l).

Step 2 5- (4- (5-Cyclopropyl-3- (2,6-dichloro-enyl) -isoxazol-4-ylmethoxy) -2-methyl-phenyl) -thiophene-2-carboxylic acid To a solution of methyl ester 5- (4- (5-Cyclopropyl-3- (2,6-dichloro-phenyl) -isoxazol-4-ylmethoxy) -2-methyl-phenyl) -thiophene-2-carboxylic acid (0.138 g, 0.27 mmol) in 3 mL of methanol and 3 mL of THF a solution of lithium hydroxide (0.06 g, 2.7 mmol) in 3 mL of water is added. The reaction is heated to 55 ° C for 1 hour. The solvent is evaporated to give a white solid. The solid is dissolved in aqueous 1M HC1 and extracted with ethyl acetate. The organic layer is washed with brine and dried over sodium sulfate. The reaction is filtered and concentrated under reduced pressure to provide the title compound. ER / E m / e 500.0; 498.1 (M + l). The compounds in Table 2 are prepared essentially in accordance with the preparation of 5- (4- (5-Cyclopropyl-3- (2,6-dichloro-phenyl) -isoxazol-4-ylmethoxy) -2-methyl-phenyl) -thiophen-2-carboxylic acid.

Table 2 Example 40 2- (4- (5-Cyclopropyl-3- (2-fluoro-6-trifluoromethyl-enyl) -isoxazol-4-ylmethoxy) -2-methyl-phenyl) -4-methyl-thiazole-5-carboxylic acid Step 1 2- (4- (5-Cyclopropyl-3- (2-fluoro-6-trifluoromethyl-phenyl) -isoxazol-4-ylmethoxy) -2-methyl-phenyl) -4-methyl-thiazole-5- methyl ester carboxylic To a solution of 4-bromomethyl-5-cyclopropyl-3- (2-fluoro-6-trifluoromethyl-phenyl) -isoxazole (0.083 g, 0.256 mmol) and 2- (4-hydroxy-2-methyl) methyl ester phenyl) -4-methyl-thiazole-5-carboxylic acid (0.067g, 0.256 mmol) in 1 mL of DMF is added potassium carbonate (0.035g, 0.256). The reaction is stirred for 60 hours. The reaction is partitioned between ethyl acetate and water. The layers are separated and the organic layer is washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue is chromatographed using a gradient of 5% ethyl acetate in hexanes at 40% ethyl acetate in hexanes to give the title compound (0.027 g, 18%). ES / MS m / e 547.0 (M + l).

Step 2 2- (4- (5-Cyclopropyl-3- (2-fluoro-6-trifluoromethyl-phenyl) -isoxazol-4-ylmethoxy) -2-methyl-phenyl) -4-methyl-thiazole-5-carboxylic acid To a solution of 2- (4- (5-Cyclopropyl-3- (2-fluoro-6-trifluoromethyl-phenyl) -isoxazol-4-ylmethoxy) -2-methyl-phenyl) -4-methyl- methyl ester. thiazole-5-carboxylic acid (0.025 g, 0.046 mmol) in 1 mL of methanol and 1 mL of THF is added a solution of LiOH (0.011 g, 0.46 mmol) in water (lmL). The reaction is heated to 55 ° C for 30 minutes. The reaction is cooled, acidified with aqueous 1M HC1, and extracted with ethyl acetate. The organic layer is washed with brine, dried over sodium sulfate, filtered, and evaporated to give the title compound (24 mg, 99%). ES / MS m / e 533.0 (M + l). The compounds in Table 3 are prepared essentially in accordance with the preparation of 2- (4- (5-Cyclopropyl-3- (2-fluoro-6-trifluoromethyl-phenyl) -isoxazol-4-ylmethoxy) -2-methyl- phenyl) -4-methyl-thiazole-5-carboxylic acid.

Table 3 Example 75 N- (5- { 4- [3- (2,6-Dichloro-phenyl) -5-isopropyl-isoxazol-4-ylmethoxy] -2-methyl-phenyl} -thiofen-2-carbonyl) - methanesulfonamide A mixture of 5- acid. { - [3- (2,6-dichloro-phenyl) -5-isopropyl-isoxazol-4-ylmethoxy] -2-methyl-phenyl} -thiophene-2-carboxylic acid (250 mg, 0.5 mmol), l- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (144 mg, 0.75 mmol),?,? ' dimethylamino pyridine (122 mg, 1.0 mmol) and methanesulfonamide (57 mg, 0.6 mmol) in dichloromethane (20 mL) is stirred at room temperature overnight. The reaction mixture is diluted with dichloromethane and washed with 1N HC1. The organic phase is concentrated under reduced pressure and purified by column chromatography (gradient: 0 to 20% EtOAc in hexanes with 0.1% AcOH) to give the title compound (160 mg, 55%). LC-MS / MS m / e 579 (M + 1), 100%. The compounds in Table 4 are prepared essentially in accordance with the preparation of N- (5-. {4- [3- (2,6-dichloro-f-enyl) -5-isopropyl-isoxazol-4-ylmethoxy] -2 -methyl-f-enyl.} -thiofen-2-carbonyl) -methanesulfonamide.

Table 4 Example 83 - (5- { 4- [5-Isopropyl-3- (2-trifluoromethoxy-phenyl) -isoxazol-4-ylmethyl] -2-methyl-phenyl} -4-methyl-thiophen-2- il) -3H- [1,3,4] oxadiazol-2-one Stage 1 Hydrazide of acid 5-. { 4- [5-Isopropyl-3- (2-trifluoromethoxy-phenyl) -isoxazol-4-ylmethoxy] -2-methyl-phenyl} -4-methyl-thiophene-2-carboxylic acid Stage A To a solution of 5- methyl acid ester. { 4- [5-isopropyl-3- (2-trifluoromethoxy-phenyl) -isoxazol-4-ylmethoxy] -2-methyl-phenyl} -4-methyl-thiophene-2-carboxylic acid (980 mg, 1.8 mmol) in EtOH (7 mL) is added hydrazine hydrate (5 mL) and the mixture is stirred at 80 ° C overnight. The reaction mixture is concentrated under reduced pressure. The residue is partitioned between EtOAc and water. The layers are separated and the organic phase is concentrated under reduced pressure to provide 5- hydrazide. { 4- [5-isopropyl-3- (2-trifluoromethoxy-phenyl) -isoxazol-4-ylmethoxy] -2-methyl-phenyl} -4-methyl-thiophene-2-carboxylic acid (890 mg, 90%) as a slightly yellow foam. CL-ER / MS m / e 546 (M + 1), 100%.

Stage B A mixture of 5- hydrazide. { 4- [5-isopropyl-3- (2-trifluoromethoxy-phenyl) -isoxazol-4-ylmethoxy] -2-methyl-phenyl} -4-methyl-thiophene-2-carboxylic acid (382 mg, 0.7 mmol), 1,1 '-carbonyl-diimidazole (170 mg, 1.05 mmol) and Et3N (0.2 mL, 1.4 mmol) in THF (7 mL) is stirred reflux overnight. The reaction mixture is diluted with EtOAc and washed with 1N HC1. The organic phase is concentrated under reduced pressure and purified by column chromatography (gradient: 0 to 20% EtOAc in hexanes with 0.1% AcOH) to give the title compound (340 mg, 85%). LC-MS / MS m / e 572 (M + 1), 100%.

Example 84 - (5- { 4- [5-Isopropyl-3- (2-trifluoromethoxy-phenyl) -isoxazol-4-ylmethoxy] -2-methyl-phenyl} -4-methyl-thiophen-2-yl ) -3H- [1,3,4] oxadiazole-2-thione A mixture of 5- hydrazide. { 4- [5-isopropyl-3- (2-trifluoromethoxy-phenyl) -isoxazol-4-ylmethoxy] -2-methyl-phenyl} -4-methyl-thiophene-2-carboxylic acid (382 mg, 0.7 mmol), carbon disulfide (0.11 mL, 1.75 mmol) and KOH (43.2 mg, 0.77 mmol) in MeOH (10 mL) is stirred at 80 ° C for the night. The reaction mixture is concentrated under reduced pressure and the residue is partitioned between EtOAc and 1N HC1. The layers are separated and the organic phase is concentrated under reduced pressure. The residue is purified by column chromatography (gradient: 0 to 20% EtOAc in hexanes with 0.1% AcOH) to give the title compound (393 mg, 96%). CL-ER / MS m / e 588 (M + 1), 95.4%.

Example 85 Acid 2-. { 4- [3- (2,6-Dichloro-phenyl) -5-isopropyl-isoxazol-4-ylmethoxy] -2-methyl-phenyl} -benzo [b] thiophene-4-carboxylic acid At a 60 ° C suspension of 4- (-Bromo-3-methyl-phenoxymethyl) -3- (2,6-dichloro-phenyl) -5-isopropyl-isoxazole (0.90 mmol 410 mg) in a solution of 2M sodium carbonate (7.20 mmol, 3.6 mL) and 1.5 mL of deoxygenated dioxane under a nitrogen atmosphere is slowly added a solution of 4-carboxy-benzo [b] thiophen-2-boronic acid (1.08 mmol, 240 mg) in 3.5 mL of deoxygenated dioxane for 1 h via an addition pump. The mixture is stirred for 1 h. The organic solvent is removed under reduced pressure and the residue is acidified with 1N HC1 to pH 4. The resulting solution is extracted with dichloromethane. The organic layers are combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue is chromatographed using a gradient of 100% dichloromethane to 100% ethyl acetate to obtain a solid which is washed with acetonitrile to give the title compound (135 mg, 27%) as a white solid.

Example 86: Acid 2-. { 4- [3- (2,6-Dichloro-phenyl) -5-isopropyl-isoxazol-4-ylmethoxy] -2-methyl-phenyl} -benzo [b] thiophene-6-carboxylic acid The title compound is prepared essentially in accordance with the preparation of 2- acid. { 4- [3- (2,6-dichloro-phenyl) -5-isopropyl-isoxazol-4-ylmethoxy] -2-methyl-phenyl} - benzo [b] thiophene-4-carboxylic acid using 6-carboxybenzo [b] thiophen-2-boronic acid. ES / MS m / e 550 (M-1).

Example 87 Acid 6-. { - [3- (2,6-Dichloro-phenyl) -5-isopropyl-isoxazol-4-ylmethoxy] -2-methyl-phenyl} -1- (2-methanesulfonyl-ethyl) -lH-indole-3-carboxylic Step 1 Acid methyl ester 6-. { 4- [3- (2,6-Dichloro-phenyl) -5-isopropyl-isoxazol-4-ylmethoxy] -2-methyl-phenyl} -1- (2- Methanesulfonyl-ethyl) -lH-indole-3-carboxylic solid 4-methylmorpholine N-oxide (151 mg, 1.29 mmol) is added to a mixture of 6- (4-hydroxy) methyl ester. 2-methyl-phenyl) -1- (2-methylsulfanyl-ethyl) -lH-indole-3-carboxylic acid (268 mg, 0.429 mmol) in acetone (4.9 mL) and water (1.7 mL), followed by dropwise addition of osmium tetroxide (21 μ ?, of a 2.5% by weight solution in 2-methyl-2-propanol, 15 mol%). The mixture is stirred overnight at room temperature and quenched with saturated aqueous sodium bisulfite solution (10 mL). The mixture is extracted repeatedly with CH2Cl2. The combined CH2Cl2 layers are washed with brine and dried (MgSO4). The residue is purified using flash chromatography (gradient: 20 to 50% ethyl acetate / heptane) to give the title compound (240 mg, 85%). ES / MS m / e 657.0 (M + 2).

Stage 2 Acid 6-. { 4- [3- (2,6-Dieloro-phenyl) -5-isopropyl-isoxazol-4-ylmethoxy] -2-methyl-phenyl} -1- (2-methanesulfonyl-ethyl) -lH-indole-3-carboxylic acid A mixture of 6- methyl acid ester. { 4- [3- (2,6-dichloro-phenyl) -5-isopropyl-isoxazol-4-ylmethoxy] -2-methyl-phenyl} -1- (2-methanesulfonyl-ethyl) -lH-indole-3-carboxylic acid (235 mg, 0.358 mmol), methanol (17 mL), THF (8 mL), and 5 N sodium hydroxide (1.29 mL) is heated reflux for two days. The mixture is allowed to cool and concentrated under reduced pressure to near dryness. Approximately 10 mL of water are added and the mixture is stirred for two hours. The mixture is filtered and the solid is washed with water and dried to provide the title compound (187 mg, 81%). LCMS (ES +): (641.0).

Example 88 Acid 6-. { 4- [5-Cyclopropyl-3- (2-trifluoromethoxy-phenyl) -isoxazol-4-ylmethoxy] -2-methyl-phenyl} -2-methyl-benzo [b] thiophene-3-carboxylic acid A solution of diisopropylamine (120 L, 0.849 mmol) and THF (4 mL) is cooled to -78 ° C. A solution of n-butyl lithium (1.6 M in hexanes, 487 μL, 0.779 mmol) is added dropwise and the reaction is stirred for 40 minutes at -78 ° C. A solution of 6- acid. { 4- [5-cyclopropyl-3- (2-trifluoromethoxy-phenyl) -isoxazol-4-ylmethoxy] -2-methyl-phenyl} -benzo [b] thiophene-3-carboxylic acid (200 mg, 0.354 mmol) in THF (2 mL) is added dropwise and the resulting yellow solution is stirred at -78 ° C for one hour. Methyl iodide (221 yiL, 3.54 mmol) is added dropwise and the reaction is allowed to warm gradually to room temperature overnight. The flask is cooled in a cold bath and saturated aqueous ammonium chloride (5 mL) is added. The mixture is diluted with water and ethyl acetate. The ethyl acetate layer is washed with brine, dried over MgSC > 4, concentrated under reduced pressure. The residue is purified via radial chromatography by levigating with 2% MeOH-CH2Cl2. The purification is repeated for the impure fractions contained in the product. The title compound (44 mg, 21%) is obtained as a gray solid.

Example 89 Acid 6-. { 4- [3- (2,6-Dichloro-phenyl) -5-isopropyl-isoxazol-4-ylmethoxy] -2-methyl-phenyl} -l-isopropyl-2-methyl-lH-indole-3-carboxylic acid Stage 1 Ethyl ester of 6- acid. { 4- [3- (2,6-Dichloro-phenyl) -5-isopropyl-isoxazol-4-ylmethoxy] -2-methyl-phenyl} - 1-isopropyl-2-methyl-lH-indole-3-carboxylic acid [3- (2,6-dichloro-phenyl) -5-isopropyl-isoxazol-4-yl] -methanol (0.2 g, 0.71 mmol), ester 1-isopropyl-6- (-hydroxy-2-methyl-phenyl) -2-methyl-1H-indole-3-carboxylic acid methyl ester (0.2 g, 0.59 mmol), tri-n-butylphosphine (0.14 g, 0.71 mmol) ) and azodicarboxylic acid dipiperidine (0.18 g, 0.71 mmol) are stirred in dry toluene (9 mL) for 2 days at room temperature. The reaction is diluted with hexane (9 mL), stirred for 30 minutes, and filtered. The filtrate is concentrated and the residue purified via flash chromatography (40 g SiO2) by levigating with 30% THF in heptane to give the title compound (124 mg, 34.6%). ER / MS m / e 606.8 (M + 1) · Stage 2 Acid 6-. { 4- [3- (2,6-Dichloro-phenyl) -5-isopropyl-isoxazol-4-ylmethoxy] -2-methyl-phenyl} -l-isopropyl-2-methyl-lH-indole-3-carboxylic acid A mixture of 6- methyl acid ester. { - [3- (2,6-dichloro-phenyl) -5-isopropyl-isoxazol-4-ylmethoxy] -2-methyl-phenyl} -l-isopropyl-2-methyl-lH-indole-3-carboxylic acid (239 mg, 0.390 mmol), sodium hydroxide (5 M, 0.5 mL) and methanol (1 mL) is heated in a microwave reactor using the adjustment of lower energy at 125 ° C for 20 minutes. The mixture is acidified with 1N HC1 and extracted with ether. The ether layer is washed with brine, dried over MgSO 4, concentrated under reduced pressure. The residue is purified via radial chromatography (2 mm plate, 3% MeOH-CH 2 Cl 2) to give the title compound (59 mg, 25%) as a white solid. ES / MS m / e 592.8 (M + l) The compounds in Table 5 are prepared essentially in accordance with the preparation of 6- acid. { 4- [3- (2,6-Dichloro-phenyl) -5-isopropyl-isoxazol-4-ylmethoxy] -2-methyl-f-enyl} -l-isopropyl-2-methyl-lH-indole-3-carboxylic acid.

Table 5 Example 94 Acid 6-. { 4- [3- (2,6-Dichloro-phenyl) -5-cyclopropyl-isoxazol-4-ylmethoxy] -2-methyl-phenyl} -2-methyl-benzofuran-3-carboxylic acid Stage 1 4- (bromo-3-methyl-phenoxymethyl) -5-cyclopropyl-3- (2,6-dichloro-phenyl) -isoxazole A solution of 4-bromo-3 -methyl-phenol (143 mg, 0.764 mmol) and 4-bromomethyl-5-cyclopropyl-3- (2,6-dichloro-phenyl) -isoxazole (221 mg, 0.636 mmol) in dimethylformamide (1 mL) is treated with carbonate of potassium (89 mg, 0.637 mmol). The reaction mixture is heated to 80 ° C for 60 minutes and cooled to room temperature. The mixture is loaded directly onto a column of silica gel and purified by flash chromatography by levigating with 15% EtOAc / Hexanes. The fractions are combined to give the title compound (0.26 g, 92%). CL-MS: (+ l); Stage 2 - Acid methyl ester 6-. { - [5-Cyclopropyl-3- (2 and 6-dichloro-phenyl) -isoxazol-4-ylmethoxy] -2-methyl-phenyl} -2-methyl-benzofuran-3-carboxylic acid A solution of 2-methyl-6- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzofuran- methyl ester 3-carboxylic acid (0.145 g, 0.459 mmol) and 4- (4-bromo-3-methyl-phenoxymethyl) -5-cyclopropyl-3- (2,6-dichloro-phenyl) -isoxazole (229 mg, 0.504 mmol) in toluene (5 mL) is drained and filled with N2 three times. Pd (OAc) 2 (10 mg), 2-dicyclohexylphosphino-2,6-dimethoxy-1, 1-biphenyl (38 mg) and potassium phosphate, tribasic, N-hydrate (195 mg) in water (0.5 mL) Add to. The resulting mixture is drained and refilled with N2 three times and stirred at 110 ° C for 16 hours. The mixture is cooled to room temperature and filtered through a pad of diatomaceous earth. The filtrate is concentrated to a residue. The residue is purified via chromatography on silica gel by levigating with 25% EtOAc / Hexanes to give the title compound (0.14 g, 55%). 1 H-NMR (400 MHz, CDC13): 7.90 (d, 1H), 7.39 (d, 1H), 7.37 (s, 1H), 7.31-7.29 (m, 2H), 7.18 (d, 1H), 7.10 (d , 1H), 6.70-6.66 (m, 2H), 4.80 (s, 2H), 3.94 (s, 3H), 2.76 (s, 3H), 2.18 (s, 3H), 2.17 (m, 1H), 1.29- 1.25 (m, 2H), 1.15-1.11 (m, 2H).

Stage 3 Acid 6-. { - [3- (2,6-Dieloro-enyl) -5-cyclopropyl-isoxazol-4-ylmethoxy] -2-methyl-phenyl} -2-methyl-benzofuran-3-carboxylic acid A solution of 6- methyl acid ester. { 4- [5-cyclopropyl-3- (2,6-dichloro-phenyl) -isoxazol-4-ylmethoxy] -2-methyl-phenyl} -2-methyl-benzofuran-3-carboxylic acid (0.142 g, 0.252 mmol) in tetrahydrofuran (1 mL) and methanol (1 mL) is treated with sodium hydroxide (1 mL). The reaction mixture is stirred at 100 ° C for 4 hours and cooled to room temperature. The mixture is neutralized with HC1 (1.0N, 1.0 mL) concentrated to a residue. The aqueous residue is extracted with EtOAc (10 mL x2). The combined organic layers are dried over Na2SC > 4, filter, and concentrate. The crude product is purified by flash chromatography by levigating with 25% -50% EtOAc / Hexanes. The appropriate combined fractions are concentrated under reduced pressure to provide the title compound. CL-ER / MS m / e 546.0 (M-l) The compounds in Table 6 are prepared essentially in accordance with the preparation of 6- acid. { 4- [3- (2,6-Dichloro-phenyl) -5-cyclopropyl-isoxazol-4-ylmethoxy] -2-methyl-phenyl} -2-methyl-benzofuran-3-carboxylic acid.

Table 6 Example 100 Acid 6-. { - [3- (2,6-Dichloro-phenyl) -5-isopropyl-isoxazol-4-ylmethoxy] -2-methyl-phenyl} -benzofuran-2-carboxylic acid Stage 1: Ter-butyl ester of 6- acid. { 4- [3- (2,6-dichloro-phenyl) -5-isopropyl-isoxazol-4-ylmethoxy] -2-methyl-phenyl} -benzofuran-2-carboxylic acid A solution of 6- (4-hydroxy-2-methyl-phenyl) -benzofuran-3-carboxylic acid tert-butyl ester (85 mg, 0.26 mmol) and 4-bromomethyl-3- (2) , 6-dichloro-phenyl) -5-isopropyl-isoxazole (110 mg, 0.31 mmol) in DF (1.0 mL) is treated with potassium carbonate (72 mg, 0.52 mmol). The reaction mixture is stirred at 90 ° C for 60 minutes and cooled to room temperature. The mixture is loaded onto a column of silica gel and rinsed with 20% EtOAc / Hexanes to provide the title compound (124 mg, 80%). CL-ER / MS m / e 593.7 (M + 1); Stage 2 Acid 6-. { 4- [3- (2,6-Dichloro-phenyl) -5-isopropyl-isoxazol-4-ylmethoxy] -2-methyl-phenyl} -benzofuran-2-carboxylic acid To a solution of 6- tert-butyl ester. { 4- [3- (2,6-dichloro-phen l) -5-isopropyl-isoxazol-4-ylmethoxy] -2-methyl-phenyl} -benzofuran-2-carboxylic acid (65 mg, 0.011 mmol) in dichloromethane (1.0 mL) is added TFA (1.0 mL). The mixture is stirred at room temperature for 60 minutes, concentrated under reduced pressure. The residue is purified by chromatography on silica gel by levigating with EtOAc to give the title compound (32 mg, 54%). CL-ER / MS m / e 537.8 (M + l).

Example 101 Acid 6-. { 4- [5-Cyclopropyl-3- (2-trifluoromethoxy-phenyl) -isoxazol-4-ylmethoxy] -2-methyl-phenyl} -benzo [b] thiophene-3-carboxylic acid Acid 6-. { 4- [5-Cyclopropyl-3- (2-trifluoromethoxy-phenyl) -isoxazol-4-ylmethoxy] -2-methyl-phenyl} -benzo [b] thiophene-3-carboxylic acid Stage 1 Ethyl ester of 6- acid. { 4- [5-Cyclopropyl-3- (2-trifluoromethoxy-phenyl) -isoxazol-4-ylmethoxy] -2-methyl-phenyl} - benzo [b] thiophene-3-carboxylic acid A solution of water (850 mL), potassium carbonate (212.08 g, 1.5345 mol, 3 eq), dioxane (500 mL), ethyl ester of 6-bromo-benzo [b] ] thiophene-3-carboxylic acid (175 g, 0.6138 mol, 1.2 eq) and tetrakis (triphenylphosphine) palladium (35.47 g, 0.03 mol, 0.06 eq) is heated to reflux (87-90 ° C). A solution of 5-cyclopropyl-4- [3-methyl-4- (4, 4, 5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenoxymethyl] -3- (2-trifluoromethoxy) phenyl) -isoxazole crude (0.5115 mol, 1 eq) in dioxane (1 L) is added over a period of 1 hour. The reaction mixture is stirred for 2 h at reflux. At the end of the reaction, the reaction mixture is cooled to room temperature. The combined reaction mixture is poured into a mixture of brine (5 L) and EtOAc (3 L) with stirring. The organic layer is separated and washed with brine (3 L). The combined aqueous layers are extracted with EtOAc (2 L). The organic layer is separated and washed again with brine (2 L). The organic layers are combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is dried under vacuum to provide a yellow oil (737 g). The oil (737 g) is dissolved in EtOAc (500 mL). Heptane is added until the solution becomes cloudy and the oil is separated (~ 3 L). The resulting cloudy solution is stirred for 1 h. The suspension is filtered and the filtered pulp is washed with heptane (200 mL). The combined filtrate is purified via column chromatography on a column of silica gel (2 X 1.5 Kg) by levigating with EtOAc (5 to 20%) in heptane. The appropriate combined fractions are concentrated under reduced pressure to provide a pale yellow oil (401 g). The impure fractions of the product are concentrated (~ 200 g of oil) and the purification is repeated on silica gel using 2 Kg of silica gel. The combined appropriate fractions are concentrated to give the title compound as a thick pale yellow oil (496 g, 99%). 1 H NMR (DMSO-d 6, 300 MHz): d.8.66 (s, 1H), 7.67-7.60 (m, 2H), 7.54-7.48 (m, 2H), 7.42 (dd, 1H, J = 3, 8.4 ), 7.12 (d, 1H, J = 8.4), 6.8-6.7 (m, 2H), 4.93 (s, 2H), 4.35 (q, 2H, J = 7.2), 2.39 (m, 1H), 2.17 (s) , 3H), 1.34 (t, 3H, J = 7.3), 1.2-1.08 (m, 4H).

Stage 2 Acid 6-. { 4- [5-Cyclopropyl-3- (2-trifluoromethoxy-phenyl) -isoxazol-4-ylmethoxy] -2-methyl-phenyl} -benzo [b] thiophene-3-carboxylic acid Solution A: A solution of 6- ethyl ester. { 4- [5-cyclopropyl-3- (2-trifluoromethoxy-phenyl) -isoxazol-4-ylmethoxy] -2-methyl-phenyl} -benzo [b] thiophene-3-carboxylic acid (470 g) in EtOH (1.8 L) is heated at 40 ° C. Solution B: 50% NaOH (158.6 g, 1.9825 mol, 2.5 eq) in water (125 mL) and EtOH (600 mL) are added to a separate flask. Solution B is added via addition funnel to Solution A at 40-50 ° C at such a ratio to prevent the formation of significant amounts of solids. At the end of the addition, the reaction mixture is heated to 65-75 ° C and stirred at this temperature for 1 h. After finishing the reaction, the reaction mixture is cooled to room temperature. The reaction mixture is diluted with water (3 L), EtOAc (2.5 L), and 10% aqueous citric acid solution (3 L). The layers are separated and the aqueous layer is extracted with EtOAc (2 L). The combined organic layer is washed with brine (3 L), dried over magnesium sulfate, filtered, and concentrated to give a pale yellow oil (480 g). The oil is co-evaporated with EtOH (1 L) and dissolved (510 g) in MeOH (1.2 L).

A solution of the crude title compound in MeOH is added dropwise for 3 h to water (8 L) with stirring. The resulting suspension is stirred for an additional 2 h at room temperature. The solids are collected by filtration, washed with water (2 L), and dried in a vacuum oven at 40 ° C. The wet title compound (530 g) is added in portions to MeOH (1.2 L) at 50-60 ° C. The resulting suspension is heated to reflux (64 ° C) and stirred at this temperature for 1 h. The suspension is cooled to 0-5 ° C and stirred at this temperature for 1 h. The solids are collected by filtration and washed with cold MeOH (200 mL, -20 ° C). The product is dried in a vacuum oven at 40 ° C to provide the title compound as a white powder (354 g, 78.9%). HPLC: 99.5% area. Elemental analysis for C30H22 F3NO5S: Theoretical: 63.71% C, 3.92% H, 2.48% N. Found: 63.10% C, 3.83% H, 2.51% N. This procedure provides crystalline Form II: start of fusion 151.22 ° C. XH-NMR (DMSO-d6, 300 MHz): d.12.93 (s, 1H), 8.61 (s, 1H), 8.49 (d, 1H, J = 8.4), 7.97 (m, 1H), 7.7-7.6 ( m, 2H), 7.58-7.49 (m, 2H), 7.40 (dd, 1H, J = 1.8, 8.4), 7.13 (d, 1H, J = 8.4), 6.82-6.72 (m, 2H), 4.93 (s) , 2H), 2.40 (m, 1H), 2.18 (s, 3H), 1.2-1.18 (m, 4H).

XRD patterns are collected from 4 to 40 degrees in 2-teta using a CuK source (? = 1.54056 Angstroms)) and a power source of 40kV and 50 mA.

XRD Form II Angle 2-Theta ° value d (Angstrom) Intensity 6.914 12.77 29.1 8.305 10.64 19.6 9.901 8.93 11.2 10.778 8.20 8.8 12.067 7.33 35.9 12.233 7.23 39.7 13.845 6.39 14.6 14.104 6.27 100.0 16.521 5.36 50.0 16.848 5.26 19.0 17.065 5.19 33.1 17.976 4.93 33.2 18,514 4.79 31.7 18.920 4.69 17.8 19.307 4.59 28.9 19.838 4.47 11.2 20.113 4.41 41.2 20.807 4.27 96.4 21.775 4.08 21.0 22.769 3.90 13.6 23.169 3.84 61.5 23.694 3.75 9.2 24.311 3.66 9.6 25.025 3.56 7.9 26.038 3.42 29.3 28.358 3.14 18.1 30.490 2.93 17.7 30.818 2.90 8.3 Procedure Form I. The title compound (400 mg) is mixed with MeOH (15 mL) and heated to about 64 ° C. Water (4-5 mL) is added by direct dripping up to the point where a solution may not be achieved with further heating. The solution is allowed to cool to room temperature with slow stirring. The solids are filtered, washed with water, and dried by suction to give the title compound (365 mg, 91%) as a crystalline Form I: start of fusion 124.54 ° C.

XRD Form I Angle 2 -Teta ° value d (Angstrom) Intensity (%) 8.759 10.09 56.0 10.087 8.76 11.1 10.343 8.55 36.4 10.476 8.44 100.0 12. 837 6.89 24.5 13. 246 6.68 56.7 13. 588 6.51 99.5 14,091 6.28 75.1 14. 449 6.13 74.1 . 559 5.69 73.5 . 848 5.59 22.7 16. 324 5.43 43.5 17.579 5.04 19.9 18. 490 4.79 19.4 18. 899 4.69 26.6 19. 169 4.63 60.9 19. 323 4.59 44.3 19,969 4.44 25.8 . 767 4.27 13.9 21. 040 4.22 40.5 21. 444 4.14 12.3 22. 989 3.87 25.8 23.410 3.80 81.9 23. 998 3.71 29.0 . 416 3.50 27.2 . 552 3.48 55.4 27. 373 3.26 24.5 28.411 3.14 19.5

Claims (17)

1. A compound of formula characterized in that p is 0 or 1; R1 and R2 are independently selected from the group consisting of hydrogen, -Ci-C4alkyl, C1-C6haloalkyl, -C1-C6alkoxy, -C1-C6haloalkoxy, halo, -SR11, and -S-haloalkyl C1- C3; each R3 is independently selected from the group consisting of-Ci-C6 alkyl, -haloCalkyl Ci-C6, -alkoxy Ci-C6-haloalkoxy C1-C6 and halo; R 4 is selected from the group consisting of hydrogen, Ci-C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, C 4 -C 8 alkylcycloalkyl, C 1 -C 6 alkoxy and C 1 -C 6 haloalkoxy; R5 and R5a are independently selected from the group consisting of hydrogen, and C1-C3 alkyl; R6 is selected from the group consisting of hydrogen, C1-C6 alkyl, Ci-C6 haloalkyl and halo; Ar is selected from the group consisting of indolyl, pyridinyl, thienyl, benzothienyl, indazolyl, benzothiazolyl, benzoisoxazolyl, benzofuranyl and thiazolyl, each optionally substituted with one or two groups independently selected from the group consisting of hydroxy, Ci-C6 alkyl, -C3-C8-cycloalkyl, -Ci-C4S02alkyl Ci-C2alkyl, Ci-C4alkyl Ci-C2alkyl, CX-C4NR10Rn alkyl, phenyl, Ci-C4-0alkyl Ci-C4 alkyl, and -NHC (0) R10; R7 is selected from the group consisting of CH2COOR10, -COOR10, -CONR11R11, -C (O) NHS02Ci-C4alkyl, C (O) NHS02R12, oxadiazolethione and oxadiazolone; each R10 is independently selected from the group consisting of hydrogen, Ci-C4 alkyl, and phenyl; each R11 is independently hydrogen, or Ci-C6 alkyl; R12 is -C1-C6 alkyl or phenyl optionally substituted with -C1-C3 alkyl, or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1, characterized in that p is 0, or 1; R1 and R2 are independently selected from the group consisting of hydrogen, fluoro, chloro, CF3 / and -OCF3, R3 is fluoro, chloro, CF3, SCF3, or OCF3; R 4 is H, isopropyl or cyclopropyl; R5 and R5a are each independently selected from H or methyl; Ar 1 is indolyl, pyridinyl, thienyl, thiazolyl and benzothienyl each optionally substituted with a group selected from the group consisting of C 1 -C 4 alkyl, CF 3, -CH 2 CH 2 SCH 2, -CH 2 CH 2 OCH 3, -CH 2 CH 2 SO 2 CH 3, -CH 2 CH 2 N (CH 3) 2, and phenyl; R6 is hydrogen, or methyl; R7 is -COOH, -COOalkylCi-C2, -CONHS02alkylCi-C4, -CONHS02phenyl, CONHS02phenylmethyl, oxadiazolone, and thiadiazolone; each R10 is independently hydrogen or alkyl Ci-C6; each R11 is independently hydrogen or alkyl Ci-C6; and R12 is phenyl, or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 1, characterized in that each p is 0; R1 and R2 are independently selected from the group consisting of chloro, fluoro, trifluoromethyl, and trifluoromethoxy; R 4 is isopropyl or cyclopropyl; R5 and Ra are both hydrogen; R6 is hydrogen, methyl, ethyl or chloro; Ar1 is thienyl, benzothienyl, indolyl or thiazolyl, each optionally substituted with a group selected from methyl, ethyl, propyl, butyl, isopropyl, cyclopropyl, -CH2CH2SO2CH3, CH2CH2N (CH3) 2, -CH2CH2SCH2, CH2CH2OCH2, and phenyl; and R7 is COOH, or a pharmaceutically acceptable salt thereof.

4. A compound characterized in that it is selected from the group consisting of: 6- acid. { 4- [5-Isopropyl-3- (2-trifluoromethoxy-phenyl) -isoxazol-4-ylmethoxy] -2-methyl-phenyl} -1-methyl-lH-indole-3-carboxylic acid 6-. { 4- [5-Cyclopropyl-3- (2-trifluorornetoxy-phenyl) -isoxazol-4-ylmethoxy] -2-methyl-phenyl} -1-methyl-lH-indole-3-carboxylic acid, 6-. { 4- [5-Cyclopropyl-3- (2,6-dichloro-phenyl) -isoxazol-4-ylmethoxy] -2-methyl-phenyl} -benzo [b] thiophene-3-carboxylic acid, 6-. { 4- [5-Cyclopropyl-3- (2-trifluoromethoxy-phenyl) -isoxazol-4-ylmethoxy] -2-methyl-phenyl} -benzo [b] thiophene-3-carboxylic acid, 6-. { 4- [5-Isopropyl-3- (2-trifluoromethoxy-phenyl) -isoxazol-4-ylmethoxy] -2-methyl-phenyl} -benzo [b] thiophene-3-carboxylic acid, 6-. { 4- [3- (2, 6-dichloro-phenyl) -5-isopropyl-isoxazol-4-ylmethoxy] -2-methyl-phenyl} -l-methyl-lH-indole-3-carboxylic acid, 6-. { 4- [3- (2,6-Dichloro-phenyl) -5-isopropyl-isoxazol-4-ylmethoxy] -phenyl} -l-isopropyl-lH-indole-3-carboxylic acid, 6-. { 4- [3- (2,6-Dichloro-phenyl) -5-isopropyl-isoxazol-4-ylmethoxy] -2-methyl-phenyl} -benzo [b] thiophene-3-carboxylic acid, 6-. { 4- [5-Cyclopropyl-3- (2,6-dichloro-phenyl) -isoxazol-4-ylmethoxy] -2-methyl-phenyl} -benzo [b] thiophene-3-carboxylic acid, 6-. { 4- [5-Cyclopropyl-3- (2-trifluoromethoxy-phenyl) -isoxazol-4-ylmethoxy] -2-methyl-phenyl} -benzo [b] thiophene-3-carboxylic acid, 6-. { 4- [5-Isopropyl-3- (2-trifluoromethoxy-phenyl) -isoxazol-4-ylmethoxy] -2-methyl-phenyl} -benzo [b] thiophene-3-carboxylic acid, 6-. { 4- [5-Cyclopropyl-3- (2-trifluoromethoxy-phenyl) -isoxazol-4-ylmethoxy] -2-methyl-phenyl} -1-isopropyl-lH-indole-3-carboxylic acid, 6-. { - [3- (2,6-Dichloro-phenyl) -5-isopropyl-isoxazol-4-ylmethoxy] -2-methyl-phenyl} -1, 2-dimethyl-lH-indole-3-carboxylic acid, 6-. { 4- [5-Cyclopropyl-3- (2-trifluoromethoxy-phenyl) -isoxazol-4-ylmethoxy] -2-methyl-phenyl} -1, 2-dimethyl-lH-indole-3-carboxylic acid, 6-. { 4- [5-Cyclopropyl-3- (2,6-dichloro-phenyl) -isoxazol-4-ylmethoxy] -2-methyl-phenyl} -l-methyl-lH-indole-3-carboxylic acid, 6-. { 4- [3- (2,6-Dichloro-phenyl) -5-isopropyl-isoxazol-4-ylmethoxy] -phenyl} -benzo [d] isothiazole-3-carboxylic acid, 6-. { 4- [5-Cyclopropyl-3- (2,6-dichloro-phenyl) -isoxazol-4-ylmethoxy] -phenyl} -benzo [d] isothiazole-3-carboxylic acid, 6-. { 4- [5-Cyclopropyl-3- (2-trifluoromethoxy phenyl) -isoxazol-4-ylmethoxy] -phenyl} -benzo [d] isothiazole-3-carboxylic acid, 6-. { 4- [3- (2,6-Dichloro-phenyl) -5-isopropyl isoxazol-4-ylmethoxy] -phenyl} -1-methyl-lH-indazole-3-carboxylic acid 6-. { 4- [5-Cyclopropyl-3- (2-trifluoromethoxy phenyl) -isoxazol-4-ylmethoxy] -phenyl} -l-methyl-lH-indazole-3-carboxylic acid, 6-. { 4- [3- (2,6-Dichloro-phenyl) -5-isopropyl isoxazol-4-ylmethoxy] -phenyl} -l-isopropyl-lH-indazole-3-carboxylic acid, 6-. { 4- [3- (2,6-Dichloro-phenyl) -5-isopropyl isoxazol-4-ylmethoxy] -phenyl} -l-isopropyl-lH-indazole-3-carboxylic acid, 5- (4- (5-Cyclopropyl-3- (2,6-dichloro-phenyl) -isoxazol-4-ylmethoxy) -2-methyl-phenyl) -thiophen -2-carboxylic acid, 5- (4- (5-Cyclopropyl-3- (2-trifluoromethoxy phenyl) -isoxazole-4-ylmethoxy) -2-methyl-phenyl) -thiophene-2-carboxylic acid, 2- (4- ( 5-Cyclopropyl-3- (2-fluoro-6-trifluoromethyl-phenyl) -isoxazol-4-ylmethoxy) -2-methyl-phenyl) -4-methyl-thiazole-5-carboxylic acid, 2- (4-cyclopropyl) -3- (2,6-dichloro-phenyl) -isoxazol-ylmethoxy) -2-methyl-phenyl) -4-methyl-thiazole-5-carboxylic acid, 5- acid. { 4- [3- (2,6-Dichloro-phenyl) -5-isopropyl isoxazol-4-ylmethoxy] -2-methyl-phenyl} -4-methyl-thiophene-2-carboxylic acid, 2-. { 4- [5-Isopropyl-3- (2-trifluoromethoxy phenyl) -isoxazol-4-ylmethoxy] -2-methyl-phenyl} -4-methyl-thiazole-5-carboxylic acid, 2- acid. { 4- [5-Isopropyl-3- (2-trifluoromethoxy phenyl) -isoxazol-4-ylmethoxy] -2-methyl-phenyl} -thiazole-5-carboxylic acid, 5- (4- (5-Cyclopropyl-3- (2,6-dichloro-phenyl) -isoxazol-ylmethoxy) -2-methyl-phenyl) -4-methyl-thiophene-2-carboxylic acid , acid 2-. { 4- [5-Cyclopropyl-3- (2,6-dichloro-phenyl) -isoxazol-4-ylmethoxy] -2-methyl-phenyl} -4-isopropyl-thiazole-5-carboxylic acid, 6-. { 4- [3- (2,6-Dichloro-phenyl) -5-isopropyl isoxazol-4-ylmethoxy] -2-methyl-phenyl} -2-methyl-benzofuran-3-carboxylic acid, 6-. { - [5-Cyclopropyl-3- (2,6-dichloro-phenyl) -isoxazol-4-ylmethoxy] -2-methyl-phenyl} -benzo [d] isoxazole-3-carboxylic acid, 6-. { 4- [5-Cyclopropyl-3- (2-trifluoromethoxy phenyl) -isoxazol-4-ylmethoxy] -2-methyl-phenyl} -2-methyl-benzo [b] thiophene-3-carboxylic acid, 6-. { 4- [3- (2,6-Dieloro-phenyl) -5-isopropyl-isoxazol-4-ylmethoxy] -2-methyl-phenyl} -l-isopropyl-2-methyl-lH-indole-3-carboxylic acid, and 6- acid. { - [5-Cyclopropyl-3- (2-trifluorornetoxy-phenyl) -isoxazol-4-ylmethoxy] -2-methyl-phenyl} -2-methyl-benzofuran-3-carboxylic acid, or a pharmaceutically acceptable salt thereof.

5. The compound, characterized in that it is acid 6-. { 4- [5-Cyclopropyl-3- (2-trifluoromethoxy-phenyl) -isoxazol-4-ylmethoxy] -2-methyl-phenyl} -benzo [b] thiophene-3-carboxylic acid or a pharmaceutically acceptable salt thereof.

6. The compound, characterized in that it is, acid 6-. { 4- [5-Cyclopropyl-3- (2-trifluoromethoxy-phenyl) -isoxazol-4-ylmethoxy] -phenyl} -benzo [d] isothiazole-3-carboxylic acid or a pharmaceutically acceptable salt thereof.

7. The compound, characterized in that it is acidic. { 4- [5-Cyclopropyl-3- (2-trifluoromethoxy-phenyl) -isoxazol-4-ylmethoxy] -phenyl} -l-methyl-lH-indazole-3-carboxylic acid or a pharmaceutically acceptable salt thereof.

8. The compound, characterized because it is 6- acid. { 4- [3- (2,6-Dihloro-phenyl) -5-isopropyl-isoxazol-4-ylmethoxy] -phenyl} -l-isopropyl-lH-indole-3-carboxylic acid or a pharmaceutically acceptable salt thereof.

9. A method for treating dyslipidemia characterized in that it comprises administering a therapeutically effective amount of a compound according to any of claims 1-10 or a pharmaceutically acceptable salt thereof to a patient in need thereof.

10. A method for raising plasma HDL levels, characterized in that it comprises administering a therapeutically effective amount of a compound according to any of claims 1-10 or a pharmaceutically acceptable salt thereof to a patient in need thereof.

11. A method for reducing LDL cholesterol levels, characterized in that it comprises administering a therapeutically effective amount of a compound according to any of claims 1-10 or a pharmaceutically acceptable salt thereof to a patient in need thereof.

12. A method for reducing plasma triglycerides, characterized in that it comprises administering a therapeutically effective amount of a compound according to any of claims 1-10 or a pharmaceutically acceptable salt thereof to a patient in need thereof.

13. A method for treating atherosclerosis characterized in that it comprises administering a therapeutically effective amount of a compound according to any of claims 1-10 or a pharmaceutically acceptable salt thereof to a patient in need thereof. A method for treating diabetes and complications thereof, characterized in that it comprises administering a therapeutically effective amount of a compound according to any of claims 1-10 or a pharmaceutically acceptable salt thereof to a patient in need thereof. 15. A pharmaceutical composition, characterized in that it comprises a compound according to any of claims 1-10 or a pharmaceutically acceptable salt thereof, and a carrier, diluent, or excipient. 16. A compound, characterized in that it is as claimed according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof for use in the preparation of a medicament. 17. Use of a compound as claimed in any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof in the treatment of conditions mediated by FXR.