PT2029547E - Fxr agonists - Google Patents

Description

ΡΕ2029547 1 DESCRIPTION " FXR AGONISTS "

Field of the Invention The current invention relates to the fields of medical organic chemistry, pharmacology and medicine. Specifically, the invention relates to novel compounds useful for the treatment of diseases related to dyslipidemia.

Background of the Invention Dyslipidemia and diseases related to dyslipidemia, e.g. g. atherosclerosis, coronary artery disease, stroke, etc. are major causes of death, morbidity and economic losses. 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.

Numerous efforts are underway to provide safe and effective molecular entities for the treatment of diseases related to dyslipidemia. For example, International Application WO 2004/0483449 A1 discloses 2 ΡΕ2029547 compounds useful as farnesid receptor agonists X (FXR).

FXR agonists are ligands for a nuclear receptor that regulates the transcription of genes that control the metabolism of triglycerides, cholesterol and carbohydrates. Notwithstanding the above and other efforts there remains a need to discover and develop compounds believed to be potent, (2) efficient (based on in vivo) and / or (3) FXR (1) agonists. Such compounds should 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 compounds believed to be potent, (2) effective (based on in vivo models) and / or (3) FXR (1) agonists.

Summary of the Invention The present invention provides a compound of formula

0 or 1 or 2; 3 ΡΕ2029547

X 1 is C or N and X 2 is C or N; with the proviso that both X 1 and X 2 are not N; R 1 and R 2 are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, halo, -S-C 1 -C 6 alkyl and -S-C 1 -C 3 haloalkyl; each R is independently selected from the group consisting of hydrogen, C1-C6 alkyl, halo

C1 -C6 alkyl, C1 -C6 alkoxy, C1 -C6 haloalkoxy and halo; R 4a is selected from the group consisting of hydrogen, C 1 -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; R 4b is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, C 4 -C 8 alkylcycloalkyl, C 1 -C 8 alkoxy and C 1 -C 6 haloalkoxy; R 5 and R 5a are independently selected from the group consisting of hydrogen and C 1 -C 3 alkyl; R 6 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halo, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, NO 2, C 3 -C 8 cycloalkyl and C 4 -C 8 alkylcycloalkyl;

Li is selected from the group consisting of a bond, C1 -C6 alkyl, CRa = CRb, ethynyl, C1 -C5 alkylene, C1 -C5 alkylS-, C1 -C5 alkyl-O-, N (Rc) C 1 -C 5 alkyl and - (C 1 -C 5 alkyl) -N (R 6) -, wherein Ra and R 5 are independently selected from the group consisting of hydrogen and C 1 -C 3 alkyl; and Rc is independently selected from the group consisting of H, C1 -C5 alkyl, C1 -C3 alkylphenyl and alkylcycloalkyl 04-08; 4 ΡΕ2029547

Ar1 is selected from the group consisting of indolyl, thienyl, benzothienyl, naphthyl, phenyl, pyridinyl, pyrazolyl, oxazolyl, benzoisoxazolyl, benzofuranyl, pyrrolyl, thiazolyl, benzoisothiazolyl, indazolyl, and furanyl, each optionally substituted by or two groups independently selected from the group consisting of hydroxy, C1 -C6 alkyl, C1 -C6 haloalkyl, halo, C2 -C6 alkenyl, C2 -C6 alkynyl, C1 -C6 alkoxy, -O- (C1 -C2 alkyl) phenyl , N (Rc) SO2 -C1 -C6 alkyl, -C (O) R10 and NHC (O) R10; R7 is selected from the group consisting of COOH, (C1 -C5 alkyl) COOH, -O-C1 -C5 alkyl-COOH, C2 -C4 alkenyl-COOH, C3 -C8 cycloalkyl-COOH and CONRnRn; each R 10 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl and phenyl; each R 11 is independently hydrogen or

C1 -Cs; or a pharmaceutically acceptable salt thereof.

The compounds of the present invention are FXR agonists. The compounds of the present invention are useful for beneficially altering lipid profiles, including lowering total cholesterol, lowering LDL cholesterol, lowering VLDL cholesterol, increasing HDL levels and lowering triglyceride levels. Accordingly, the present invention provides a method for the treatment of FXR mediated conditions such as dyslipidemia and diseases related to dyslipidemia comprising administering a therapeutically effective amount of a compound of the present invention to a patient in need thereof. The present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier. The present invention relates to the use of a compound according to the invention for lowering total cholesterol, lowering LDL cholesterol, lowering VLDL cholesterol, increasing HDL levels and / or lowering triglyceride levels comprising administering a the therapeutically effective amount of a compound of the present invention to a patient in need thereof. The present invention relates to the use of a compound according to the invention for the treatment of FXR mediated conditions such as dyslipidemia and diseases related to dyslipidemia comprising administering a therapeutically effective amount of a compound of the present invention to a patient in need his. The present invention also relates to the use of a compound of the present invention for the manufacture of a medicament.

Detailed Description of the Invention The term " dyslipidemia " as used herein refers to an abnormality in or abnormal amounts of 6 ΡΕ2029547 lipids and lipoproteins in blood and resulting disease states caused by, exacerbated by or attached to such abnormality (see Dorland's Illustrated Medical Dictionary, 29th edition, WB Saunders Publishing Company, New York, NY). Disease states encompassed by the definition of dyslipidemia as used herein include hyperlipidemia, hypertriglyceremia, low blood HDL, high plasma LDL, high plasma VLDL, liver cholestasis and hypercholesterolemia. The phrase " dyslipidemia-related diseases " 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 metabolic diseases such as obesity, diabetes, insulin resistance and its complications. Complications of diabetes include for example diabetic retinopathy.

As used herein, the term " patient " refers to humans, companion animals (e.g., dogs and cats and the like), and livestock.

The terms " treatment " " treat " and " treating " include amelioration, arrest, restriction, slowing down, and reversal of the progression or reduction of the severity of the pathological symptoms of dyslipidemia and diseases related to dyslipidemia. 7 ΡΕ2029547

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 prescriber approved to be deemed sufficient taken as indicated, for the treatment of a condition, or its detrimental effects described herein. The term " pharmaceutically acceptable " is used herein as an adjective and means substantially non-deleterious to the recipient patient. The term " C 1 -C 6 alkyl " represents a straight or branched hydrocarbon moiety having from 1 to 6 carbon atoms, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl , t-butyl and the like. Similarly, the term " C 1 -C 5 alkyl " represents a straight or branched hydrocarbon moiety having from 1 to 5 carbon atoms, including, but not limited to, methyl, ethyl, n-propyl and isopropyl. It is understood by one skilled in the art that a " C 1 -C 6 alkyl " or the like is synonymous with " C 1 -C 6 alkylene " or the like, a diradical when the " C 1 -C 6 alkyl " is sandwiched between two groups such that it becomes a diradical. The term " C 1 -C 3 alkyl " represents a straight or branched hydrocarbon moiety having from 1 to 3 carbon atoms, including methyl, ethyl, n-propyl and isopropyl. It is understood by one skilled in the art that a " C 1 -C 3 alkyl " is synonymous with " C 1 -C 6 alkylene " a diradical when the " C1-C3 alkyl " is sandwiched between two groups such that it becomes a diradical. The term " C 2 -C 6 alkenyl " represents a straight or branched hydrocarbon moiety having at least one double bond and having from 2 to 6 carbon atoms. Examples include but are not limited to vinyl, propenyl and 2-butenyl. In a similar way. the term " C 2 -C 4 alkenyl " represents a straight or branched hydrocarbon moiety having at least one double bond and having from 2 to 4 carbon atoms. The term " C 2 -C 6 alkynyl " or the like represents a straight or branched hydrocarbon moiety having at least one triple bond and having from 2 to 6 carbon atoms. Examples include but are not limited to ethynyl, propynyl, 2-butynyl, and the like. Similarly, the term " C2-C4 alkynyl " or the like represents a straight or branched hydrocarbon moiety having at least one triple bond and having from 2 to 4 carbon atoms. The term " C 3 -C 8 cycloalkyl " refers to a saturated carbocyclic ring having from 3 to 8 carbon atoms including, but not limited to, cyclopropyl, cyclopentyl and cyclohexyl. Similarly, the term " C3-C6 cycloalkyl " refers to a saturated carbocyclic ring having from 3 to 6 carbon atoms including cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term " C 4 -C 8 alkylcycloalkyl " as used herein refers to the combination of an alkyl group and a cycloalkyl such that the total number of carbon atoms is 4 to 8 or as indicated. For example, C 4 -C 8 -alkylcycloalkyl includes cycloalkyl rings attached to at least one carbon atom such that the total number of carbon atoms is any of from 4 to 8. Similarly, the term " C 4 -C 5 alkylcycloalkyl " as used herein refers to the combination of an alkyl group and a cycloalkyl such that the total number of carbon atoms is 4 to 5. For example, C4-C5-alkylcycloalkyl includes -CPb-cyclopropyl, i.e. methylenecyclopropyl which is C4-alkylcycloalkyl. The term " haloalkyl χ-εε " refers to a χ2 -alkyl group substituted with one, two, three or more halogen atoms as indicated or chemically appropriate. Examples of C1 -C6 haloalkyl include, but are not limited to, trifluoromethyl, chloroethyl and 2-chloropentyl. Similarly, the term " CX-C3 haloalkyl " refers to a C 1 -C 3 alkyl group substituted with one, two, three or more halogen atoms as indicated or chemically appropriate. Examples of CX-C3 haloalkyl include, but are not limited to, trifluoromethyl, chloroethyl and 2-chloropropyl. 10 ΡΕ2029547

A " C 1 -C 6 alkoxy " is a C 1 -C 6 alkyl moiety connected via an oxy chain. Examples of alkoxy groups include, but are not limited to, methoxy (-OMe), ethoxy (-OEt), propoxy (-OPr), isopropoxy (-OiPr) and butoxy (-OBu). Similarly, the term " C 1 -C 3 alkoxy " is a C 1 -C 3 alkyl moiety connected via an oxy chain. C1-C3 alkoxy groups include methoxy (-OMe (OCH3)), ethoxy (-OEt (-OCH2CH2)), propoxy (-OPr (-OCH2CH2CH2)) and isopropoxy (-OiPr (-OCHCH3CH3)). The term " (C1 -C6 alkyl) -O- " referred to as C 1 -C 5 alkyloxy represents an alkyl group (C 1 -C 5 alkyl or as indicated) terminating on an oxygen atom as distinguished from alkoxy (-O-C 1 -C 5 alkyl) by reading from left to right. For example, radicals or groups such as -CH 2 -, -CH 2 CH 2 O- and -CH (CH 3) 0- are herein also referred to as alkyloxy groups. Similarly, the term " (C 1 -C 3 alkyl) -O- " referred to as C 1 -C 3 alkyloxy represents a C 1 -C 3 alkyl group terminating on an oxygen atom as distinguished from alkoxy (-O-C 1 -C 3 alkyl) by reading from left to right. For example, radicals or groups such as -CH 2 O-, -CH 2 CH 2 O- and -CH (CH 3) O- are herein also referred to as alkyloxy groups. The term " C 1 -C 6 haloalkoxy " or the like comprises alkoxy groups in which one or more of the hydrogen atoms in the alkyl moiety has been replaced by halogens. Examples of haloalkoxy groups include difluoromethoxy, trifluoromethoxy, 2-haloethoxy, 2,2,2-trifluoroethoxy, 4,4,4,11,20,20,95 -trifluorobutoxy, up to and including similar groups having the indicated number of carbon atoms. Similarly, the term " C 1 -C 3 haloalkoxy " refers to a C1 -C3 alkoxy wherein one or more of the hydrogen atoms in the alkyl moiety have been replaced by halogens. Examples of C1-C3 haloalkoxy groups include difluoromethoxy, trifluoromethoxy, 2-haloethoxy, 2,2,2-trifluoroethoxy, up to and including similar groups having the indicated number of carbon atoms. The term " S- (C 1 -C 6 alkyl) " represents a straight or branched alkyl or thioalkyl or S-alkyl moiety having from 1 to 6 carbon atoms including, but not limited to, S-methyl, S-ethyl, S-propyl, S-isopropyl, S-butyl, S-isobutyl and S- similar. Similarly, the term " S- (C 1 -C 3 alkyl) " represents a straight or branched C 1 -C 3 -alkyl or S-alkyl moiety comprising S-methyl, S-ethyl, S-n-propyl and S-isopropyl. The term " thio-haloalkyl " or " -S- (halo-alkyl " encompasses -S-alkyl groups in which one or more of the hydrogen atoms have been replaced by halogens. Examples of thiohaloC1-6alkyl groups include thiodifluoromethyl, thiotrifluoromethyl, 2-hothioethyl, 2,2,2-trifluorothioethyl, 4,4,4-trifluorobutyl, up to and including similar groups having the indicated number of carbon atoms. Similarly, the term " thio-C 1 -C 3 haloalkyl " refers to an S-C 1 -C 3 alkyl wherein one or more of the hydrogen atoms have been replaced by halogens. Examples of C1-C3 thiohaloalkyl groups include difluorothiomethyl, trifluoromethyl, 2-hothioethyl, 2,2,2-trifluorothioethyl, up to and including similar groups having the indicated number of carbon atoms. The term " -O- (C1 -C2 alkyl) phenyl " refers to a C1-C2 alkoxy group attached to or substituted on a phenyl group. It is understood that R 6 may be a substituent on X 1 or X 2 when X 1 or X 2 is carbon but not when X 1 or X 2 is nitrogen. The term " halo " means halogens including iodine, chlorine, bromine and fluoro. It is understood that when Ar1 is bicyclic, the attachment of Ar1 to the ring containing R6 may occur at any suitable carbon or nitrogen (chemically) atom of the bicyclic ring unless otherwise indicated.

A compound of the invention may occur in the form of any of its isomers, all of which are objects of the invention. Certain compounds of the invention may possess one or more chiral centers and, therefore, may exist in optically active forms. Likewise, the compounds of the invention may have alkenyl groups and, therefore, 13 ΡΕ 2029547 may exist in the form of geometric isomers. All such isomers as well as mixtures thereof are within the scope and scope of the present invention. If a particular stereoisomer is desired, it may be prepared by methods well known in the art.

One skilled in the art is aware that where amino groups are present in the compounds of the invention (e.g., when L 1 is N (R 6) CH 2 CH 2 -) an acid addition salt of the compound may result in the tetravalent ammonium salt of the compound. For example, reacting an acid such as trifluoroacetic acid with a compound of the invention wherein L 1 is an amino group may result in the tetravalent ammonium salt of the compound. All such salts are contemplated and within the scope of the present invention.

Preferred Embodiments of the Invention

Preferably X 1 and X 2 are both C. Also preferred is a compound of the invention wherein X 1 is N.

Preferably p is 0 or 1. More preferably, p is 0.

Preferably the groups R1 and R2 are each independently selected from the group consisting of hydrogen, C1 -C3 alkyl, C1 -C3 haloalkyl, C1 -C3 alkoxy, C1 -C3 haloalkoxy, -S-C1 -C3 alkyl, S-C1-C3 haloalkyl and halo. More preferably, R1 and R2 the groups are independently selected from the group consisting of hydrogen, chloro, fluoro, CF3, OCF3 and SCF3.

Preferably, the group R 3 is absent or is selected from the group consisting of hydrogen, C 1 -C 3 alkyl, C 3 -C 3 haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy and halo. More preferred is a group R 3 selected from the group consisting of hydrogen, chloro, fluoro, CF 3, OCF 3 and SCF 3. More preferably, R 3 is absent.

Preferably, R 4a is independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, CF 3 and methylcyclopropyl. Most preferably, R 4a is hydrogen.

Preferably, R 4b is independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, CF 3 and methylcyclopropyl. More preferably, R 4b is CF 3, isopropyl or cyclopropyl.

Preferably, R 5 and R 5a are each independently selected from the group consisting of hydrogen, methyl and ethyl. More preferably, R 5 and R 5a are both hydrogen.

A preferred R6 group is selected from the group consisting of hydrogen, halo, C3 -C3 alkyl, C2 -C3 alkenyl, hydroxy, -NO2 and -O-C1 -C2 alkyl. More preferably, R 6 is selected from the group consisting of hydrogen, halo, methyl and methoxy. More preferred is R6 being hydrogen, chloro, or methyl.

Li is preferably selected from the group consisting of a bond, CH = CH, ethynyl, -CH 2 S-, -C (CH 3) 2 -S-, -CH (CH 2 CH 3) s -, -CH (CH 3) CH3) ch2-s-, -ch (ch3) ch2o-, -c (ch3) 2o-, -ch (ch3) o-, -ch (CH2CH3) o-, -N (Rc) (CH2) m- and - (CH 2) m N (R c) - wherein R c is hydrogen or C 1 -C 3 alkyl, m is 1, 2 or 3. More preferably, L 3 is a bond, CH = CH, -N (CH 3) CH 2, -N CH 3) CH 2 CH 2 or -N (CH 3) CH 2 CH 2 CH 2 -. More particularly preferred for Li is a bond, -N (CH 3) CH 2 or -N (CH 3) CH 2. Most preferred is

Li is -N (CH 3) CH 2 or -N (CH 3) CH 2 CH 2.

A preferred Ar 1 group is selected from the group consisting of optionally substituted indolyl, indazolyl, thienyl, benzo-thienyl, benzisothiazolyl, phenyl, pyridinyl, pyrrolyl, thiazolyl and furanyl. More preferably, Ar 1 is selected from the group consisting of optionally substituted benzothienyl, indolyl, indazolyl, benzoisothiazolyl and phenyl. A particularly preferred Ar 1 is phenyl, indolyl, benzothienyl or benzoisothiazolyl. Preferably Ar 1 is optionally substituted with one or two groups independently selected from the group consisting of halo, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy and C 1 -C 3 haloalkyl.

A preferred R7 substituent is COOH or CONHR11. 16 ΡΕ2029547

More preferably, R 7 is COOH or CONH 2, -CONHCH 3 or CONHC 2 H 5. Most preferably R7 is COOH.

Also preferred is a compound of the invention wherein it is 0 or 1 or 2;

X 1 is C or N and X 2 is C or N; with the proviso that both X 1 and X 2 are not N; R 1 and R 2 are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 3 thiohaloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy and halo; R 3 is absent or is independently selected from the group consisting of C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy and halo; R 4a is selected from the group consisting of hydrogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 3 -C 6 cycloalkyl and C 4 -C 5 alkylcycloalkyl; R 4b is selected from the group consisting of hydrogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 3 -C 6 cycloalkyl and C 4 -C 5 alkylcycloalkyl; R 5 and R 5a are independently selected from the group consisting of hydrogen and C 1 -C 3 alkyl; R 6 is selected from the group consisting of hydrogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, halo and -NO 2;

Li is selected from the group consisting of a bond, CRa = CRb, ethynyl, (C1 -C3 alkyl) -S-, C1 -C3 alkyl- O-, N (Rc) -C1 -C3 alkyl and C1 -C3) -N (R6) -, wherein Ra and Rb are independently selected from the group consisting of hydrogen and C1-C3 alkyl; and R 6 is independently selected from the group consisting of H, C 1 -C 5 alkyl, C 1 -C 3 alkyl phenyl and C 4 -C 5 alkylcycloalkyl;

Ar1 is selected from the group consisting of indolyl, benzothienyl, benzoisothiazolyl, indazolyl, naphthyl, phenyl, pyridinyl, pyrazolyl, pyrrolyl, thienyl, thiazolyl and furanyl, each optionally substituted by one or two groups independently selected from the group consisting of hydroxy, C1 -C3 haloalkyl, halo, C2 -C4 alkenyl, C2 -C4 alkynyl, C1 -C4 alkoxy, -O (C1 -C2 alkyl) phenyl, -NHC (O) R10; R 7 is selected from the group consisting of -CONH, - (C 1 -C 3) alkylCONH, -O- (C 1 -C 3) alkylCONH and -CONR 3 R 11; each R 10 is independently selected from the group consisting of hydrogen, C 1 -C 3 alkyl and phenyl; each R 11 is independently hydrogen or C 1 -C 5 alkyl; or a pharmaceutically acceptable salt thereof.

Also preferred is a compound of the invention wherein: 0 or 1;

X 1 and X 2 are both C, or X 1 is N and X 2 is C; R1 and R2 are independently selected from the group consisting of hydrogen, fluoro, chloro, CF3, SCF3, CF3; R 3 is fluoro, chloro C 1 -C 3 alkyl, CF 3, SCF 3 or OCF 3; R4a is hydrogen, methyl, ethyl or isopropyl; R 4b is H, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 haloalkoxy or C 3 -C 4 cycloalkyl; R5 and RSa are each independently selected from 18 ΡΕ2029547 between H or C1 -C3 alkyl; the Ar 1 group is phenyl, indolyl, pyridinyl, pyrrolyl, thienyl, naphthyl, thiazolyl, furanyl, pyrazolyl, indazolyl, benzoisothiazolyl and benzothienyl each optionally substituted with one to two groups independently selected from C 1 -C 5 alkyl, C 1 -C 4 alkoxy, C 1 -C 2 haloalkoxy and C 1 -C 3 haloalkyl; R6 is hydrogen, methyl, ethyl or chloro;

Li is a bond, ethenyl, -O 11 (O) -S-, C (CH 3) 2 -S-, -CH 2 -, -CH 2 CH 2 -, -CH (CH 3) -O-, -CH (CH 3) -, -CH (CH 2 CH 3) - O-, -CH 2 NH-, -CH 2 CH 2 NH-, -N (Rc) CH 2 -, N (Rc) CH 2 CH 2 - or N (Rc) CH 2 CH 2 CH 2 -; wherein Rc is hydrogen, C1 -C2 alkyl or benzyl; R7 is C00H, -CH2C00H, -CH (CH3) C00H, -C (CH3) 2C00H, CO2 NH2, C (O) NHCH3 or C (O) NHCH2 CH3; R 10 is hydrogen or C 1 -C 20 alkyl; and R 11 is hydrogen or C 1 -C 20 alkyl; or a pharmaceutically acceptable salt thereof.

Also preferred is a compound of the invention wherein X 1 and X 2 are both C; p is 0; R1 and R2 are independently selected from the group consisting of hydrogen, chloro, fluoro, trifluoromethyl, thiotrifluoromethyl and trifluoromethoxy; R4a is hydrogen; R 4b is trifluoromethyl, isopropyl or cyclopropyl; R5 and R5a are both hydrogen; Li is ethenyl, ethynyl, -N (CH 3) CH 2 - or -N (CH 3) CH 2 CH 2 -; R6 is hydrogen, methyl, chlorine or bromine; Ar1 is phenyl, indolyl, indazolyl, benzothienyl or benzoisothiazolyl, each optionally substituted with a group selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, isopropoxy and cyclopropoxy; and R7 is COOH.

Also preferred is a compound of the invention wherein X 1 and X 2 are both C; p is 0; R1 and R2 are independently selected from the group consisting of hydrogen, chloro, fluoro, trifluoromethyl, thiotrifluoromethyl and trifluoromethoxy; R4a is hydrogen; R 4b is trifluoromethyl, isopropyl or cyclopropyl; Li is -N (CH 3) CH 2 -, or -N (CH 3) CH 2 CH 2 -; R5 and R5a are both hydrogen; R6 is hydrogen, methyl, ethyl or chloro; Ar1 is phenyl, benzoisothiazolyl, indazolyl, indolyl or benzothienyl, each optionally substituted with a group selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, isopropoxy and cyclopropoxy; and R7 is COOH.

Also preferred is a compound of the invention wherein X 1 and X 2 are both C; p is 1; R1 and R2 are independently selected from the group consisting of hydrogen, chloro, fluoro, trifluoromethyl, thiotrifluoromethyl and trifluoromethoxy; R 3 is hydrogen; R4a is hydrogen; R 4b is trifluoromethyl, isopropyl or cyclopropyl; Li is -N (CH 3) CH 2 - or -N (CH 3) CH 2 CH 2 -; R5 and R5a are both hydrogen; R6 is hydrogen, methyl, ethyl or chloro; Ar 1 is phenyl, optionally substituted with a group selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, isopropoxy and cyclopropoxy; and R7 is COOH.

Also preferred is a compound of the invention wherein 20 ΡΕ 2029547

X1 and Χ2 are both C; p is 0; R1 and R2 are independently selected from the group consisting of hydrogen, chloro, fluoro, trifluoromethyl, thiotrifluoromethyl and trifluoromethoxy; R4a is hydrogen; R 4b is trifluoromethyl, isopropyl or cyclopropyl; Li is a bond, -N (CH 3) CH 2 -, or -N (CH 3) CH 2 CH 2 -; R5 and R5a are both hydrogen; R6 is hydrogen, methyl, ethyl or chloro; Ar1 is phenyl, benzoisothiazolyl, indazolyl, indolyl or benzothienyl, each optionally substituted with a group selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, isopropoxy and cyclopropoxy; and R7 is COOH.

Also preferred is a compound of the invention wherein X 1 and X 2 are both C; p is 0; R1 and R2 are independently selected from the group consisting of hydrogen, chloro, fluoro, trifluoromethyl, thiotrifluoromethyl and trifluoromethoxy; R4a is hydrogen; R 4b is trifluoromethyl, isopropyl or cyclopropyl; Li is ethenyl, -N (CH 3) CH 2 - or -N (CH 3) CH 2 CH 2 -; R5 and R5a are both hydrogen; R6 is hydrogen, methyl, ethyl or chloro; Ar1 is phenyl, thienyl, pyrrolyl, furanyl or thiazolyl, each optionally substituted with a group selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, isopropoxy and cyclopropoxy; and R7 is COOH.

Also preferred is a compound of the invention wherein X 1 and X 2 are both C; p is 0; R1 and R2 are independently selected from the group consisting of hydrogen, chlorine, fluoro, trifluoromethyl, thiotrifluoromethyl, and trifluoromethoxy; R4a is hydrogen; R 4b is trifluoromethyl, isopropyl or cyclopropyl; Li is a bond, -CH (CH 3) O, -CH (CH 3) CH 2 O, -CH (CH 3) S, -C (CH 3) 2 S, -CH 2 -NH- and -CH 2 N (CH 3) -; R5 and R5a are both hydrogen; R6 is hydrogen, methyl, ethyl or chloro; Ar1 is phenyl, benzoisothiazolyl, indazolyl, indolyl or benzothienyl, each optionally substituted with a group selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, isopropoxy and cyclopropoxy; and R7 is COOH.

Also preferred is a compound of the invention wherein X 1 and X 2 are both C; p is 0; R1 and R2 are independently selected from the group consisting of chloro, fluoro, trifluoromethyl, thiotrifluoromethyl and trifluoromethoxy; R4a is hydrogen; R 4b is trifluoromethyl, isopropyl or cyclopropyl; Li is ethenyl, -CH (CH 3) O, -CH (CH 3) CH 2, -CH (CH 3) S, -C (CH 3) 2 S, -CH 2 -NH- and -CH 2 N (CH 3) -; R5 and R5a are both hydrogen; R5 and R5a are both hydrogen; R6 is hydrogen, methyl, ethyl or chloro; Ar1 is phenyl, thienyl, pyrrolyl, furanyl or thiazolyl, each optionally substituted with a group selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, isopropoxy and cyclopropoxy; and R7 is COOH.

Also preferred is a compound of the invention wherein X 1 and X 2 are both C; p is 0; R 1 and R 2 are independently selected from the group consisting of hydrogen, chloro, fluoro, trifluoromethyl, thiotrifluoromethyl and trifluoromethyl; R4a is hydrogen; R 4b is trifluoromethyl, isopropyl or cyclopropyl; Li is -N (CH 3) CH 2 - or -N (CH 3) CH 2 CH 2 -; R5 and R5a are both hydrogen; R6 is hydrogen, methyl, ethyl or chloro; Ar1 is benzoisothiazolyl, indazolyl, indolyl or benzothienyl, each optionally substituted with a group selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, isopropoxy and cyclopropoxy; and R7 is COOH.

Also preferred is a compound of the invention wherein X 1 and X 2 are both C; p is 0; R1 and R2 are independently selected from the group consisting of hydrogen, chloro, fluoro, trifluoromethyl, thiotrifluoromethyl, and trifluoromethoxy; R4a is hydrogen; R 4b is trifluoromethyl, isopropyl or cyclopropyl; Li is a bond; R5 and R5a are both hydrogen; R6 is hydrogen, methyl, ethyl or chloro; Ar1 is phenyl, benzoisothiazolyl, indazolyl, indolyl or benzothienyl, each optionally substituted with a group selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, isopropoxy and cyclopropoxy; and R7 is COOH. both are

Also preferred is a compound of the invention wherein X 1 and X 2 are both C; p is 0; R1 and R2 are independently selected from the group consisting of hydrogen, chloro, fluoro, trifluoromethyl, thiotrifluoromethyl, and trifluoromethoxy; R4a is hydrogen; R 4b is trifluoromethyl, isopropyl or cyclopropyl; Li is a bond; R5 and R5a 23 ΡΕ2029547 hydrogen; R6 is hydrogen, methyl, ethyl or chloro; Ar 1 is phenyl optionally substituted with a group selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, isopropoxy and cyclopropoxy; and R7 is COOH.

Also preferred is a compound of the invention wherein X 1 and X 2 are both C; p is 0; R1 and R2 are independently selected from the group consisting of chloro, fluoro, trifluoromethyl, thiotrifluoromethyl and trifluoromethoxy; R4a is hydrogen; R 4b is trifluoromethyl, isopropyl or cyclopropyl; Li is ethenyl; R5 and R5a are both hydrogen; R6 is hydrogen, methyl, ethyl or chloro; Ar1 is phenyl, thienyl, pyrrolyl, furanyl, or thiazolyl, each optionally substituted with a group selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, isopropoxy and cyclopropoxy; and R7 is COOH. propyl

Also preferred is a compound of the invention wherein X 1 and X 2 are both C; p is 0; R1 and R2 are independently selected from the group consisting of chloro, fluoro, trifluoromethyl, thiotrifluoromethyl and trifluoromethoxy; R4a is hydrogen; R 4b is trifluoromethyl, isopropyl or cyclopropyl; Li is ethenyl, -N (CH 3) CH 2 - or -N (CH 3) CH 2 CH 2 -; R5 and R5a are both hydrogen; R6 is hydrogen, methyl, ethyl or chloro; Ar1 is phenyl, thienyl, pyrrolyl, furanyl, or thiazolyl, each optionally substituted with a group selected from methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy, isopropoxy and cyclopropoxy; and R7 is COOH.

Also preferred is a compound of the invention wherein X 1 and X 2 are both C; p is 0; R1 and R2 are independently selected from the group consisting of chloro, fluoro, trifluoromethyl, thiotrifluoromethyl and trifluoromethoxy; R4a is hydrogen; R 4b is trifluoromethyl, isopropyl or cyclopropyl; L 1 is -N (CH 3) CH 2 - or -N (CH 3) CH 2 CH 2 -; R5 and R5a are both hydrogen; R6 is hydrogen, methyl, ethyl or chloro; Ar1 is phenyl, thienyl, pyrrolyl, furanyl or thiazolyl, each optionally substituted with a group selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, isopropoxy and cyclopropoxy; and R7 is COOH.

The compounds of the present invention (i.e., compound of formula I) may be prepared by a variety of procedures known in the art and those described below. The products of each step in the Scheme below can be recovered by conventional methods including extraction, evaporation, precipitation, chromatography, filtration, trituration, crystallization and the like. In the scheme below all substituents, unless otherwise indicated, are as previously defined and suitable reagents are well known and appreciated in the art. 25 ΡΕ2029547

Scheme 1

Scheme 1 delineates the reaction of an appropriate compound of formula (1) with an appropriate compound of formula (2) to give a compound of formula (I). The reaction in Scheme 1 may be carried out by at least two variants discussed below.

In the first variant, an appropriate compound of formula (1) is one in which R 1, R 2, R 3, P, R 4a, R 4b, R 5b and R 5a are defined by formula I, and Y is -OH and a compound of formula R 2, X 2, I 1 and Ar 1 are as defined in formula (I) or a group giving R 7 as defined in formula (I), for example, by the 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 triphenylphosphine or tributylphosphine, and similar. Such reactions are carried out in a suitable solvent, such as toluene, tetrahydrofuran and the like. Generally, the 26 ΡΕ2029547 reactions are carried out at temperatures of from about 0øC to 50øC. The typical stoichiometry is for this reaction based on the compound of formula (1), about 1 to 2 equivalents of a compound of formula (2) and about 1 to 2 equivalents of each of the diazo and phosphine reactants.

In a second variant, an appropriate compound of formula (1) is one in which R 1, R 2, R 3, p, R 4a, R 4b, R 5b and R 5a are defined for formula I and Y is a leaving group and a compound of formula ) is as defined above. 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 formula (1) is reacted with a compound of formula (2) in a suitable solvent, such as acetonitrile, dimethylformamide, tetrahydrofuran, pyridine, ethyl and methyl ketone, and the like. As will be readily appreciated, an excess of a suitable base is usually used in the reaction, including 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 solvent chosen and typically use from about 1 to 2 equivalents of the compound of formula (2). 27 ΡΕ2029547

In an optional step, a pharmaceutically acceptable salt of a compound of formula (I) is formed. The formation of such 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 similar to those described herein by procedures which are well known and established in the art. For example, the compounds of formula (1) are prepared by the reaction of optionally substituted phenylhydrazine with a 1,3-diketoester (or an equivalent thereof) followed by reduction and optionally conversion to a leaving group and compounds of formula ) are prepared by carbon-carbon bond formation, reductive amination, coupling reaction, etc. It is also recognized that the steps required to prepare a compound of formula (2) may be carried out in any order, including following the reaction of a partial compound of formula (2) with a compound of formula (1), such that subsequent the carbon-carbon bond formation, reductive amination, coupling reaction, etc., provide a compound of formula I. As will be readily understood, the steps for preparing the compounds of formula I are dependent on the particular compound to be synthesized, compound and the relative lability of the substituted portions. A number of protection and deprotection steps are also contemplated as may be required or beneficial for carrying out 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)). The present invention is further illustrated by the following Examples and Preparations. 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 otherwise designated.

Test

The following protocols and test results demonstrate the utility, in vitro and in vivo efficacy of the compounds and / or methods of the current invention and are provided for the purposes of illustration and are not intended to be limiting in any way.

The following abbreviations used herein are defined as follows. " LDL " is Low Density Lipoprotein; " HDL " is High Density Lipoprotein; " VLDL " is Very Low Density Lipoprotein; " LDLR - / - " is a Low Density Lipoprotein Receptor deficient; " DMEM " is Dulbecco's Modified Eagle's Medium; " GAPDH " is glyceraldehyde-3-phosphate dehydrogenase; " NaCMC " is sodium carboxymethylcellulose; " SLS " is sodium lauryl sulfate; " FPLC " is fast liquid chromatography of proteins; " PBS " is phosphate buffered saline; " VLDL-C " is Lipoprotein 29 ΡΕ2029547

Very Low Density-Cholesterol; " HDL-C " is High Density-Cholesterol Lipoprotein.

Assay bDNA for SHP mRNA FXR is a direct key transcriptional regulator of the Small Heterodimer Partner (SHP) gene, accession number NM_021969, an atypical number of the nuclear receptor family lacking a DNA binding domain. SHP interacts with several conventional and orphan members of the nuclear receptor superfamily, including retinoid receptors and thyroid hormone receptor. SHP inhibits the potential transactivation of members of the superfamily with which it interacts. Both FXR and SHP were found to control genes involved in hepatic cholesterol catabolism, triglyceride synthesis and bile acid transport. Since FXR directly transacts the SHP gene transcription, SHP's branched DNA (bDNA) method quantifies the activation of FXR by ligands. Therefore, increased SHP mRNA expression, as determined by increasing the bDNA signal, means the impairment of FXR by an agonist. Human plateau hepatocarcinoma Huh7 cells grown in DMEM: F12 with 10% fetal bovine serum and in 96 well plate at a density of 1 x 105 / well. After incubation overnight, treat the cells with test compound at various concentrations for 24 hours. 30 ΡΕ2029547

Carry out the bDNA assay according to the manufacturer's protocol (Panomics, Fremont, CA) for the QuantiGene® High Volume Kit. Following challenge of the cells with a compound of the invention, lysing the cells with QuantiGene® lysis buffer containing the oligonucleotides of SHP mRNA described below. Suitable bDNA oligonucleotide reagents (capture extenders (CEs), label extenders (LEs) and blockers (BLs)) can be designed and synthesized for detection of human SHP mRNA by Panomics (Fremont, CA).

Incubate the lysis buffer for 15 minutes at 37 ° C, then transfer 100 μl of the lysate from each well to the corresponding wells of the capture plate. Incubate the capture plate overnight at 53 ° C. Wash the capture plate twice with QuantiGene® Wash Buffer followed by the addition of 100 μl / well of QuantiGene® working reagent. Incubate the plate for 60 minutes at 46 ° C followed by two washes. Label the mRNA to be measured by adding 100 μl of QuantiGene® label probe working buffer and incubate for 60 minutes at 46 ° C. Wash the capture plate twice and add 100 μl / well of QuantiGene® substrate plus QuantiGene® boosting reagent. Incubate the plates at 37 ° C for up to 30 minutes and then read in a luminometer (Packard Fusion Alpha, detection 1 second) to detect the luminescent signal. Calculating EC5 values is an effective response to maximal response. 31 ΡΕ2029547

Exemplified compounds are effective as FXR modulators based on the above assay on an EC 50 of 2 μΜ or less. For example the compound of Example 90 shows SHP gene activation EC50 of about 53 nM.

Modulation of serum lipid LDLR - / -

Acclimate the animals for two weeks prior to the start of the study. House the mice individually in polycarbonate cages with filter caps and keep the mice in a light-dark cycle of 12:12 hours (lights at 6:00 AM) at 21 ° C. Provide deionized water ad libitum and maintain two weeks on the western diet TD 88137 Diet (fat 42%, cholesterol 0.15%, Harlan Teklad) ad libitum. Optimize groups of five - ten week old male LDLR - / - mice based on triglyceride and serum cholesterol levels. Dose groups once daily by probing several doses of the test compound dissolved in 5% EtOH / 5% Solutol in NaCMC (1%), SLS (0.5%), antifoam (0.05%), povidone (0.085%) for seven days. At the end of the seven-day dosing period, collect blood by cardiac puncture after asphyxiation in a CO2 chamber. Measure serum triglycerides, glucose and total cholesterol using standard clinical chemistry instrumentation and reagents [Hitachi 912 instrument with reagent kits (Roche, Indianapolis, IN)]. Test combined serum samples for FPLC analysis for lipoprotein cholesterol (VLDL, LDL, HDL) fractions by separation on a size exclusion column with determination in 32 ΡΕ2029547 cholesterol line. Lipoproteins were separated by fast protein liquid chromatography, and the cholesterol was quantified with an in-line detection system. Briefly, 35æL plasma samples / 50æl combined sample were applied to a Superose 6 HR 10/30 size exclusion column (Amersham Pharmacia Biotech, Piscataway, NJ) and eluted with PBS, pH 7.4 ( diluted 1:10) containing 5 mM EDTA in 0.5 mL / min cholesterol reagent from Roche Diagnostics (Indianapolis, IN) at 0.16 mL / min was mixed with the column effluent through a T-connection; the mixture was then passed through a 15 m x 0.5 mm mesh tubing reactor (Aura Industries, New York, NY) immersed in a 37 ° C water bath. The color product produced in the presence of cholesterol was monitored in the flow stream at 505 nm, and the monitor analog voltage was converted to a digital signal for collection and analysis. The change in voltage corresponding to the change in cholesterol concentration was plotted against time, and the area under the curve corresponding to the elution of VLDL-C and HDL-C was calculated using software Turbochrome (version 4.12F 12) PerkinElmer software (Norwalk, CT).

In this assay, the compounds of the invention tested reduce total cholesterol to 84% and triglycerides to 86% when dosed at 10 mg / kg. More specifically, the compound of Example 199 lowers total cholesterol by 60% and triglycerides by 63% when dosed at 10 mg / kg. The specific dose of a compound administered in accordance with this invention will, of course, be determined by the particular circumstances surrounding the case including, for example, the compound administered, the route of administration, the condition of the patient and the condition to be treated. A typical daily dose will contain a non-toxic dosage level of from about 0.1 mg to about 1000 mg / day of a compound of the present invention.

The compounds of this invention may be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular and intranasal. These compounds are preferably formulated prior to administration, the selection of which will be decided by the attending physician. Thus, a further 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 readily select the particular form and route of administration depending on the particular characteristics of the compound selected, the disorder or condition being treated, the disorder stage or condition, and other relevant circumstances (Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Co. (1990)). The pharmaceutical compositions of the present invention may be adapted for these various routes and may be administered to the patient, for example in the form of tablets, capsules, cachets, papers, lozenges, wafers, elixirs, ointments, transdermal patches, aerosols, inhalants , suppositories, solutions and suspensions.

The compounds of the invention may be formulated as elixirs or solutions for convenient oral administration or in the form of solutions for parenteral administration, for example, by intramuscular, subcutaneous or intravenous routes. In addition, the compounds may be formulated in the form of sustained release dosage forms and the like. The formulations may be formed so that they release the active ingredient only or preferably at a particular physiological location, possibly over a period of time. Coatings, envelopes and protective matrices may be made, for example, from polymeric substances or waxes.

Preparations and Examples

The following Preparations and Examples further illustrate the invention.

The abbreviations used herein are defined according to 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; " Et20 " is diethyl ether ΡΕ2029547; " hex " is hexane; " DCE " is dichloroethane; " DCM " is dichloromethane; " TFA " is trifluoroacetic acid; " TMSCHN2 " is (trimethylsilyl) diazomethane; " ADDP " is 1,1- (azodicarbonyl) -dipiperidine; " DPPB " is 1,4-bis- (diphenylphosphino) butane; " dppf " is diphenylphosphinoferrocene; " dba " is dibenzylidinoacetone; " TBAI " is tetrabutylammonium iodide; " DIAD " is diisopropyl azodicarboxylate: " OAc " is acetate; " NaOEt " is sodium ethoxide; " PCy3 " is tricyclohexylphosphine.

All compounds are named using ChemDraw Ultra 7.0 available from CambridgeSoft Corporation, Cambridge, MA, USA.

To a solution of 4-methyl-2-oxo-pentanoic acid (3.4 g, 26 mmol) in methanol (12 mL) and 2,2-dimethyl- dimethoxypropane (48 mL) is added chlorotrimethylsilane (0.38 mL). The reaction mixture is stirred at room temperature overnight. The reaction mixture is concentrated under reduced pressure to give the title compound as an oil, (3.8 g, quant.). 1 H-NMR (400 MHz, CDCl 3): δ 3.86 (s, 3H), 2.72 (d, 2H), 2.16 (m, 1H), 0.96 (d, 6H).

Preparation 2 2-Methoxyimino-4-oxo-pentanoic acid ethyl ester

A mixture of 2,4-dioxo-pentanoic acid ethyl ester (5.4 mL, 50 mmol), methoxyamine hydrochloride 36 ΡΕ2029547 (4.4 g, 52.5 mmol), molecular sieves (3 Ã ..., 35 g) and sodium sulfate (15 g) in ethanol (50 ml) is stirred at room temperature for 5 hours. The reaction mixture is filtered and washed with ethanol. The combined filtrate is concentrated under reduced pressure and partitioned between diethyl ether and saturated sodium bicarbonate. The organic layer is dried (MgSO4), filtered and concentrated. The residue is purified by column chromatography (0 to 15% EtOAc in hexanes) to give the title compound as a colorless oil (3 g, 32%). 1H NMR (400 MHz, CDCl3): δ 4.33 (q, 2H), 4.06 (s, 3H), 3.70 (s, 3H), 2.20 (s, 3H), 1.34 (t, 3H ).

Preparation 3 3-Acetyl-2-methoxyimino-5-methylhexanoic acid ethyl ester To a solution of 2-methoxyimino-4-oxo-pentanoic acid ethyl ester (2.62 g, 14 mmol) is added potassium carbonate (2.5 g, 18.2 mmol) followed by 1-iodo-2-methylpropane (1.62 mL, 14 mmol) in DMF (30 mL) and the mixture is stirred at room temperature during the night. An additional 1-iodo-2-methylpropane (0.8 mL, 7 mmol) is added and the mixture is stirred at 60 ° C for 1 hour. The reaction mixture is diluted with EtOAc and adjusted to pH 3 with 1N HCl. The organic layer is washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue is purified by column chromatography (0 to 20% EtOAc in hexanes) to give the title compound 37 ΡΕ 2029547 as a colorless oil (1 g, 29%). 1 H-NMR (400 MHz, CDCl 3): δ 4.33 (q, 2H), 4.06 (s, 3H), 4.03 (dd, 1H), 2.07 (s, 3H), 1.88 (m, 1H), 1.58 (m, 1H), 1.43 (m, 1H), 1.37 (t, 3H), 0.89 (d, 6H).

Preparation 4 2-Cyclopropylmethyl- [1,3] dithiane-2-carboxylic acid ethyl ester

To dry flask is added dry toluene (80 mL) and sodium hydride (60%, 33.5 mmol, 1.34 g). The reaction mixture is cooled in an ice bath and a solution of ethyl 1,3-dithianecarboxylate (52 mmol, 10 g)

and bromomethyl cyclopropane (62.4 mmol, 8.42 g) in DMF (24 mL) is added dropwise over 10 min. The ice bath is removed and the reaction mixture is stirred for 18 h. Water (50 mL) is added and the organic layer is separated. The organic layer is washed with brine, dried (Na 2 SO 4) and concentrated to a yellow oil (12 g, 92%). LC-MS: 247.0 (M + 1).

Preparation 5 3-Cyclopropyl-2-oxo-propionic acid ethyl ester To a 0 ° C suspension of NBS (439 mmol, 79 g) in a mixture of acetonitrile (400 mL) and water (100 mL) is added a solution of 2-cyclopropylmethyl- [1,3] dithiane-2-carboxylic acid ethyl ester (73.2 mmol, 18.05 g) in acetonitrile (50 mL) over 15 minutes. The reaction is warmed and is stirred at room temperature. 38 ΡΕ2029547

After 45 minutes, 500 mL of 1: 1 hexane / DCM is added. The layers are separated. The organic layer is washed with saturated Na2 SO3 (2 x 225 mL) and brine (2 x 225 mL), dried with Na2 SO4, filtered and concentrated under reduced pressure to a residue. The residue is diluted to CCl 4 and filtered. The filtrate is concentrated to give the title compound (7 g, 61%). LC-MS: 157.0 (M + 1).

To a suspension of 5 mg per mL Rieke magnesium in THF (37.9 mmol, 40 mL) at room temperature is added bromomethyl cyclobutane (37, 9 mmol, 4.25 mL) dropwise. After addition, the reaction is heated to 60 ° C for 1 h. The mixture is transferred via syringe to a -78øC solution of diethyl oxalate (37.9 mmol, 5.14 g) in THF (20 mL). The reaction is allowed to warm to 0 ° C and is quenched with 1N HCl. Diethyl ether is added (20 mL) and the layers are separated. The organic layer is dried (Na 2 SO 4) and adsorbed onto silica and purified using a gradient to 0-10% EtOAc / hexanes to afford the title compound (2.3 g, 37%). LC-MS: 171.0 (M + 1).

Preparation 7 3-Cyclopropyl-4-dimethylamino-2-oxo-but-3-enoic acid ethyl ester

A mixture of 3-cyclopropyl-2-oxo-propionic acid ethyl ester (6.4 mmol, 1.0 g) and dimethylformamide acetal dimethyl (12.8 mmol, 2.0 mL) are combined and stirred at room temperature for 18 hours. The reaction is concentrated under reduced pressure to afford the title compound (1.38 g, 100%). LC-MS: 212.0 (M + 1).

PREPARATION 8 3-Cyclobutyl-4-dimethylamino-2-oxo-but-3-enoic acid ethyl ester The title compound (0.663, 51%) is prepared essentially as described in the preparation of 3- 4-dimethylamino-2-oxo-but-3-enoic acid ethyl ester using 3-cyclobutyl-2-oxo-propionic acid ethyl ester. LC-ES + MS m / e 226.0 (M + 1)

Preparation 9

To a 0 ° C solution of 2-chloro-6-trifluoromethyl-phenylamine (35.7 mmol, 7.0 g) in THF (100 mL) is added 48% BF 3 OEt (143 mmol, 36 mL) followed by addition of isoamyl nitrite (143 mmol, 19 mL). The reaction is stirred for 1 hour and is filtered to collect the diazonium tetrafluoroborate salt (48.7 mmol, 9.0 g). The salt is dissolved in a conc. HCl mixture (30 mL) and water (10 mL) at 0 ° C. To the resulting mixture is added ascorbic acid (48.7 mmol, 8.5 g). The reaction is warmed to 50 ° C for 3 hours and cooled to room temperature. The solid is filtered and washed with ice-water. The wet solid is dissolved in a conc. H₂O mixture (30 mL) and water (20 mL) and heated to 90 ° C for 2 hours. The reaction mixture is cooled to 0øC and filtered to afford the title compound (5.0 g, 60%). LC-ES + MS m / e 157.0 (M + 1). The following list is of compounds which are prepared essentially as described in the preparation of 2-chloro-6-trifluoromethyl-phenyl) -hydrazine hydrochloride using the appropriate starting material.

Preparation 9A: 3,5-Difluoro-2-trifluoromethyl-phenylhydrazine hydrochloride, (3.0 g, 25%), LC-ES / MS m / e 159.0 (M + 1);

Preparation 9B: 2-Fluoro-6-trifluoromethyl-phenylhydrazine hydrochloride (5.2 g, 63%), LC-ES / MS m / e 195.0 (M + 1);

Preparation 9C: 2-Trifluoromethylsulfanyl-phenylhydrazine hydrochloride, (0.414 g, 68%), ES / MS m / e 209.0 (M + 1).

Preparation 10

2,6-Dichloro-4-fluoro-phenylamine (3.0 g, 16.6 mmol) in 12 M HCl (30 mL) mL) and TFA (20 mL) is added slowly and dropwise NaNC> 2 (20 mmol, 1.37 mL) in water (6 mL). The reaction is stirred at 0 ° C for 1 h. A solution of SnCl 2 (5.74 g, 25.6 mmol) in 12 M HCl (16 mL) is added over 15 minutes. The ice bath is removed and the reaction mixture is stirred for 18 h. The reaction is filtered and the solid is washed with isopropyl alcohol. The solid is dried to afford the title compound (41 g, 20%) as a white solid (3.0 g, 96%). LC-ES + MS m / e 194.0 (M + 1)

Preparation 11

(2-Trifluoromethoxy-phenyl) -hydrazine To a stirred solution of hydrochloric acid (37%, 1.6 L) at 0 ° C is added 2-trifluoromethoxy-phenylamine (200 g, 113 mmol) followed by water (160 mL) and an additional hydrochloric acid (160 mL). The mixture is warmed to room temperature, stirred for 20 minutes, and cooled to -5 ° C. A solution of sodium nitrite (82 g, 1.19 mmol) in water (400 mL) is added dropwise maintaining the internal temperature below 0 ° C. The mixture is cooled to -5øC and a solution of tin (II) chloride dihydrate (1020 g, 4520 mmol) in HCl (37%, 3.2 L) is added dropwise maintaining the internal temperature below 0Â ° C. The mixture is warmed to room temperature, stirred for 3 h, filtered and washed with 6N HCl (3 L) to give a yellow solid which is dried under vacuum overnight The title compound (115.8 g , 54%) is obtained as a pink-brown solid.

Preparation 12

Trifluoromethoxy-phenylhydrazine hydrochloride The title compound (115.8 g, 54%) is prepared essentially according to the preparation of (2-trifluoromethoxy-phenyl) -hydrazine hydrochloride using 2-trifluoromethoxy-phenylamine. 42 ΡΕ2029547

Preparation 13 2- (2,6-Dichloro-phenyl) -4-isobutyl-5-methyl-2H-pyrazole-3-carboxylic acid ethyl ester

A mixture of 3-acetyl-2-methoxyimino-5-methylhexanoic acid ethyl ester (1 g, 4.1 mmol), 2,6-dichlorophenylhydrazine hydrochloride (1.76 g, 8 mmol) , 2 mmol) in glacial acetic acid (10 mL) and 2-methoxy ethanol (5 mL) is stirred at 105 ° C for 3 hours. The reaction is concentrated and the residue is partitioned between EtOAc and 1N HCl. The organic layer is concentrated and purified by column chromatography (0-20% EtOAc in hexanes) to give the title product as an oil, 1 , 1 g (76%). 1H NMR (400 MHz, CDCl3): δ 7.41 (d, 2H), 7.31 (dd, 1H), 4.16 (q, 2H), 2.65 (d, 2H), 2.33 (s, 3H), 1.92 (m, 1H), 1.13 (t, 3H), 0.95 (d, 6H).

Preparation 14 4-Cyclopropyl-2- (2,6-dichloro-phenyl) -2H-pyrazole-3-carboxylic acid ethyl ester To a solution of 3-Cyclopropyl-4-dimethylamino- 2-oxo-but-3-enoic acid (6.5 mmol, 1.4 g) in ethanol (25 mL) is added 2,6-dichloro-phenylhydrazine hydrochloride (7.2 mmol, 1.5 g) followed by concentrated HCl (100 μL). The reaction is stirred for 4 h at room temperature followed by heating at 85 ° C for 18 h. The reaction mixture is adsorbed onto silica gel and purified using a gradient of 20-40% EtOAc / 20% EtOAc / EtOAc to yield the title compound (0.8 g, 34%). LC-ES + MS m / e 325.0 (M + 1). The following list is of compounds which are prepared essentially according to the preparation of 4-cyclopropyl-2- (2,6-dichloro-phenyl) -2H-pyrazole-3-carboxylic acid ethyl ester using the starting material appropriate.

Preparation 14A: 4-Cyclobutyl-2- (2,6-dichloro-phenyl) -2H-pyrazole-3-carboxylic acid ethyl ester (0.56 g, 57%), LC-ES / MS m / e 339.0 (M + 1);

Preparation 14B: 2- (2-Chloro-6-trifluoromethyl-phenyl-4-isopropyl-2H-pyrazole-3-carboxylic acid ethyl ester (0.56 g, 10%), LC- and 293.0 (M + 1);

Preparation 14C: 2- (3,5-Difluoro-2-trifluoromethyl-phenyl) -4-isopropyl-2H-pyrazole-3-carboxylic acid ethyl ester (1.6 g, 60%), LC-ES / MS m / e 295.0 (M + 1);

Preparation 14D: 2- (2,6-Dichloro-phenyl) -4-isobutyl-5-methyl-2H-pyrazole-3-carboxylic acid ethyl ester (1.1 g, 76%), 1 H-NMR (CDCl 3): δ 7.41 (d, 2H), 7.31 (dd, 1H), 4.16 (q, 2H), 2.65 (d, 2H), 2.33 (s, 3H), 1.92 (m, 1H), 1.13 (t, 3H), 0.95 (d, 6H);

Preparation 14E: 2- (2-Fluoro-6-trifluoromethyl-phenyl) -4-isopropyl-2H-pyrazole-3-carboxylic acid methyl ester (0.063 g, 67%), LC- and 277.0 (M + 1);

Preparation 14F: 2- (2,6-Dichloro-4-isopropyl-2H-pyrazole-3-carboxylic acid ethyl ester (0.28 g, 39%), LC- MS m / e 331.0 (M + 1);

Preparation 14G: 4-Isopropyl-2- (2-trifluoromethylsulfanyl-phenyl) -2H-pyrazole-3-carboxylic acid methyl ester (0.25 g, 76%), LC-ES / MS m / e 345, 0 (M + 1);

Preparation 14H: 4-Isopropyl-2- (2-trifluoromethoxy-phenyl) -2H-pyrazole-3-carboxylic acid ethyl ester (82 g, 22%);

Preparation 141: 4-Cyclopropyl-2- (2-trifluoromethoxy-phenyl) -2H-pyrazole-3-carboxylic acid ethyl ester (0.65 g, 19%), ES / MS m / e 341.0 ( M + 1);

Preparation 14 J: 2- (2-Chloro-6-trifluoromethyl-phenyl) -4-cyclopropyl-2H-pyrazole-3-carboxylic acid ethyl ester (0.82 g, 38%), ES / e 359.0 (M + 1).

Preparation 15: 2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazole-3-carboxylic acid methyl ester To a solution of 4-methyl-2-oxo -pentanoic acid (3.8 g, 26 mmol) in N, N-dimethylformamide dimethyl acetal (7 mL, 52 mmol) is added p-toluenesulfonic acid monohydrate (30 mg) and the mixture is stirred at 80 ° C overnight. The reaction mixture is concentrated under reduced pressure to give 3-isopropyl-4-dimethylamino-2-oxo-but-3-enoic acid ethyl ester as an orange oil. To a solution of 3-isopropyl-4-dimethylamino-2-oxo-but-3-enoic acid ethyl ester and 45 ΡΕ2029547 2,6-dichlorophenylhydrazine hydrochloride (2.8 g, 13 mmol) in EtOH ( 40 mL) is added concentrated HCl (0.5 mL). The mixture is stirred at room temperature for 2 h followed by reflux overnight. The reaction mixture is concentrated and the residue is partitioned between EtOAc and 1 N HCl. The organic phase is dried (Na 2 SO 4) and concentrated to a residue. The residue is purified by column chromatography (0-15% EtOAc in hexanes) to give the title compound as an oil (2.2 g, 52%). 1H NMR (CDCl3): δ 7.76 (s, 1H), 7.43 (d, 2H), 7.34 (dd, 1H), 3.75 (s, 3H), 3.48 (m, 1H), 1.32 (d, 6H).

Preparation 16 4-Isopropyl-2- (2-trifluoromethoxy-phenyl) -2H-pyrazole-3-carboxylic acid methyl ester The title compound (82 g, 22%) is prepared essentially according to the preparation of 2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazole-3-carboxylic acid ethyl ester using the appropriate starting material.

Preparation 17 [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-yl] -methanol To a solution of 2- (2,6-dichloro-phenyl) -4-isopropyl-2H-pyrazole-3-carboxylic acid at 0øC (2.2 g, 6.8 mmol) in THF (30 mL) is added DIBAL-H (33.7 mL, 1M in toluene). The reaction mixture is stirred at room temperature overnight. The reaction is quenched with the addition of methanol and concentrated under reduced pressure. The residue is partitioned between 5N NaOH and EtOAc. The layers are separated and the organic layer is filtered through a pad of Diatomaceous Earth. The filtrate is concentrated under reduced pressure to give the title compound as a light yellow solid, (1.6 g, 80%) 1 H-NMR (400 MHz, CDCl 3): δ 7.67 (s, 1H) , 7.44 (d, 2H), 7.34 (dd, 1H), 4.45 (s, 2H), 3.00 (m, 1H), 1.32 (d, 6H). The following list is of compounds which are prepared essentially according to the preparation of [2- (2,6-dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-yl] -methanol using the appropriate starting material .

Preparation 17A: [2- (2,6-Dichloro-phenyl) -4-isobutyl-5-methyl-2H-pyrazol-3-yl] -methanol (920 mg, 95%), 1H NMR (400 MHz, CDCl3 ): δ 7.46 (d, 2H), 7.36 (dd, 1H), 4.40 (s, 2H), 2.39 (d, 2H), 2.30 (s, 3H) 83 (m, 1H), 0.94 (d, 6H);

Preparation 17B: [2- (2,6-dichloro-phenyl) -4,5-dimethyl-2H-pyrazol-3-yl] -methanol, 1H NMR (CDCl3): δ 7.46 (d, 2H ), 7.35 (dd, 1H), 4.40 (s, 2H), 2.29 (s, 3H), 2.11 (s, 3H);

Preparation 17C: [2- (2,6-Dichloro-phenyl) -4-ethyl-5-methyl-2H-pyrazol-3-yl] -methanol, 1H NMR (CDCl3): δ 7.45 (d 2H), 7.35 (dd, 1H), 4.40 (d, 2H), 2.55 (q, 2H), 2.32 (s, 3H), 1.20 (t, 3H);

Preparation 17D: [2- (2,6-Dichloro-phenyl) -5-methyl-4-propyl-2H-pyrazol-3-yl] -methanol, 1H NMR (CDCl3): δ 7.46 (d, 2H), 47.42204747 7.35 (dd, 1H), 4.40 (s, 2H), 2.51 (t, 2H), 2.31 (s, 3H), 1.59 (m, 2H), 0.95 (t, 3H);

Preparation 17E: [2- (2,6-Dichloro-phenyl) -5-methyl-2H-pyrazol-3-yl] -methanol, 1H NMR (CDCl3): δ 7.46 (d, 2H) 36 (dd, 1H), 6.27 (s, 1H), 4.45 (s, 2H), 2.36 (s, 3H);

Preparation 17F: [4-Isopropyl-2- (2-trifluoromethoxy-phenyl) -2H-pyrazol-3-yl] -methanol, 1H NMR (CDCl3): δ 7.41, 7.60 (m, 5H) , 4.51 (s, 2H), 3.02 (m, 1H), 1.30 (d, 6H);

Preparation 17G: [4-Isopropyl-2- (2-trifluoromethyl-phenyl) -2H-pyrazol-3-yl] -methanol, 1H NMR (CDCl3): δ 7.82 (d, 1H, J = (M, 2H), 7.57 (s, 1H), 7.50 (d, 1H, J = 7.5

Hz), 4.45 (s, 2H), 2.99 (m, 1H), 1.30 (d, 6H);

Preparation 17H: [2- (2,6-Difluoro-phenyl) -4-isopropyl-2H-pyrazol-3-yl] -methanol, 1H NMR (CDCl3): δ 7.66 (s, 1H), 7.42, 7.46 (m, 1H), 7.08 (m, 2H), 4.52 (s, 2H), 3.01 (m, 1H), 1.31 (d, 6H);

Preparation 171: [2- (2,6-Dichloro-phenyl) -4-methyl-2H-pyrazol-3-yl] -methanol, 1H NMR (CDCl3): δ 7.61 (s, 1H), 7 , 7.38 (dd, 1H, J = 7.0, J = 8.3Hz), (m, 5H), 4.45 (s, 2H ), 2.20 (s, 3H).

Preparation 18 [4-Cyclopropyl-2- (2,6-dichloro-phenyl) -2H-pyrazol-3-yl] -methanol To a 0 ° C mixture of LAH powder in THF (20 mL) is added a To a solution of 4-cyclopropyl-2- (2,6-dichloro-phenyl) -2H-pyrazole-3-carboxylic acid ethyl ester (2.4 mmol, 0.8 g) in THF mL). The reaction is stirred for 2 h at 0 ° C. The reaction is quenched with a water sequence (0.26 mL), 5 N NaOH (0.26 mL) and water (0.78 mL). The reaction mixture is stirred for 1 h at 0 ° C. The reaction is filtered and the filtrate is adsorbed onto silica gel and purified using a gradient of 30-50% EtOAc / hexanes to yield the title compound (0.36 g, 53%). LC-ES / MS m / e 283.0 (M + 1). The following list is of compounds which are prepared essentially according to the preparation of [4-cyclopropyl-2- (2,6-dichloro-phenyl) -2H-pyrazol-3-yl] -methanol using the appropriate starting material .

Preparation 18A: [4-Cyclobutyl-2- (2,6-dichloro-phenyl) -2H-pyrazol-3-yl] -methanol (0.42 g, 86%), LC-ES / MS m / e 297, 0 (M + 1);

Preparation 18B: [2- (2-Chloro-6-trifluoromethyl-phenyl) -4-isopropyl-2H-pyrazol-3-yl] -methanol (0.51 g, 87%), LC-ES / e 265.0 (M + 1);

Preparation 18C: {2- (3,5-Difluoro-2-trifluoromethyl-phenyl) -4-isopropyl-2H-pyrazol-3-yl} -methanol (0.38 g, 26%), LC- MS m / e 267.0 (M + 1);

Preparation 18D: 2- (2-Fluoro-6-trifluoromethyl-phenyl) -4-isopropyl-2H-pyrazol-3-yl} methanol (0.19 g, 15%), LC-ES / MS m / e 249, 0 (M + 1);

Preparation 18E: [2- (2,6-Dichloro-4-fluorophenyl) -4-isopropyl-4H-pyrazol-3-yl] -methanol (0.10 g, 39%), LC-ES / MS m / e 302.0 (M + 1);

Preparation 18F: 4-Isopropyl-2- (2-trifluoromethylsulfanylphenyl) -2H-pyrazol-3-yl] -methanol (0.081 g, 63%), LC-ES / MS m / e 317.0 (M + 1) );

Preparation 18G: [4-Isopropyl-2- (2-trifluoromethoxy-phenyl) -2H-pyrazol-3-yl] -methanol (31 g, 49%).

Preparation 18H: [4-Cyclopropyl-2- (2-trifluoromethoxy-phenyl) -2H-pyrazol-3-yl] -methanol (0.400, 70%), ES / MS m / e 299.0 (M + 1) ;

Preparation 181: [2- (2-Chloro-6-trifluoromethyl-phenyl) -4-cyclopropyl-2H-pyrazol-3-yl] methanol (0.400, 54%), ES / MS m / e 317.0 (M + l).

Preparation 19 1- (2,6-Dichloro-phenyl) -4-isopropyl-5- {3-methyl-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2 -yl) -phenoxymethyl} -1H-pyrazole

A mixture of tricyclohexylphosphine (10 mg, 0.036 mmol) and bis (dibenzylideneacetone) palladium (8.5 mg, 0.015 mmol) in dioxane (3 mL) is stirred at room temperature for half an hour. To a reaction mixture, 5- (4-bromo-3-methyl-phenoxymethyl) -1- (2,6-dichloro-phenyl) -4-isopropyl-1H-pyrazole (227 mg, 0.500 mmol), pinacolborane (140 mg, 0.550 mmol) and potassium acetate (74 mg, 0.750 mmol) are added and the mixture is heated to 80 ° C for 20 hours. The reaction mixture is cooled, 50 æ TE 2, 9547 diluted with water and extracted with ether. The combined ether fractions were dried (MgSO4) and evaporated. The residue is purified via flash chromatography " (10% CH 2 Cl 2 / heptane to 0% CH 2 Cl 2 / heptane) to give the title compound (119 mg, 47%). ES / MS m / e 501.1 (M +).

Preparation 20 6- [4-Isopropyl-2- (2-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -2-methyl-3-nitro-pyridine To a room temperature solution of [4-iso- propyl-2- (2-trifluoromethoxy-phenyl) -2H-pyrazol-3-yl] -methanol (2.0 g, 6.66 mmol) in degassed toluene (22 mL) is added 6-chloro-2- 3-nitro-pyridine (1.15 g, 6.66 mmol), cesium carbonate (3.25 g, 9.99 mmol), 2- (di-t-butylphosphino) -1,1'-binaphthyl 332 mg, 0.833 mmol, 12.5 mol%) and palladium (II) acetate (150 mg, 0.666 mmol, 10 mol%). The reaction mixture is run at 70 ° C overnight. The reaction mixture is filtered through a pad of Celite, is concentrated under reduced pressure and is chromatographed (0% to 20% EtOAc / Hex) to give the title compound (2.73 g, 94%). 1 H-NMR (400 MHz, CDCl 3) δ 8.22 (d, 1H, J = 8.8 Hz), 7.64 (s, 1H), 7.52 (dd, 1H, J = , 7.49-7.44 (m, 1H), 7.41-7.34 (m, 2H), 6.51 (d, 1H, J = 9.2 Hz), 5.35 (s, 2H), 3.05 (sept, 1H, J = 7.0 Hz), 2.72 (s, 3H), 1.29 (d, 6H, J = 7.0 Hz).

Preparation 21 6- [4-Isopropyl-2- (2-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -2-methyl-pyridin-3-ylamine To a room temperature solution of 6- [ 4-isopropyl-2- (2-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -2-methyl-3-nitro-pyridine (2.73 g, 6.25 mmol) in EtOH / THF (100/100 mL) is added platinum (II) oxide (142 mg, 0.625 mmol, 10 mol%). The reaction is placed under an atmosphere of hydrogen gas. After 3 h, the reaction is filtered through diatomaceous earth, concentrated and chromatographed (0% to 30% EtOAc / Hex) to afford the title compound (2.15%) 1 H-NMR (400 MHz, CDCl 3) δ 7.60 (s, 1H), 7.53 (dd, 1H, J = 7.9, 1.8 Hz), 7.46-7.41 (m, 1H), 7.39-7.31 (d, 1H, J = 8.4 Hz), 5.17 (s, 2H), 3.06 (sept) , 1 H, J = 7.0 Hz), 2.32 (s, 3H), 1.27 (d, 6H, J = 7.0 Hz).

Preparation 22 4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-benzaldehyde To a -78 ° C solution of 5- (4- bromo-3-methyl-phenoxymethyl) -1- (2,6-dichloro-phenyl) -4-isopropyl-1H-pyrazole (906 mg, 2.0 mmol) in anhydrous THF is added n- 6 M (1.35 mL). After 30 minutes, N, N-dimethylformamide (0.5 mL, 6.4 mmol) is added. After 30 minutes, saturated aqueous ammonium chloride is added. The mixture is extracted with ethyl acetate (2x). The combined ethyl acetate layers are dried (MgSO4) and concentrated under reduced pressure. The crude residue is purified via flash chromatography " (ethyl acetate / heptane gradient) to give the title compound (110 mg, 14%). LC-ES / MS m / e 403.0 (M + 1). 52 ΡΕ2029547

Preparation 23 4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenylamine To a 0 ° C solution of [2- (2,4- Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-yl] -methanol (3.0 g, 10.6 mmol), 4-amino-3-methylphenol (2.0 g, , And tri-n-butyl phosphine (3.2 g, 15.8 mmol) in toluene (30 mL) is added a solution of 1,1 '- (azodicarbonyl) -dipiperidine (4.0 g , 15.8 mmol) in toluene (40 mL). The reaction mixture is allowed to warm to room temperature and is stirred for 3.0 h. The reaction mixture is partitioned between EtOAc (50 mL) and water (60 mL). The organic layer is washed with brine (60 mL), dried (Na2 SO4 > 4), filtered and concentrated under reduced pressure to a residue. The residue is purified by flash chromatography " (EtOAc / hexane) to afford the title compound as a solid (2.3 g, 56%). LC-ES + MS m / e 390.0 (M + 1).

PREPARATION 24 5- (4-Bromo-3-methyl-phenoxymethyl) -1- (2,6-dichloro-phenyl) -4-isopropyl-1H-pyrazole The title compound is prepared essentially according to the preparation of 4- [2- (2,6-dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenylamine using [2- (2,6-dichloro-phenyl) -4- -isopropyl-2H-pyrazol-3-yl] -methanol and 4-bromo-3-methyl-phenol. ES / MS m / e 454.9 (M + 1). 53 ΡΕ2029547

Preparation 25 {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -carbamic acid tert-butyl ester

A solution of di-tert-butyl dicarbonate (1.55 g, 7.1 mmol) in dichloromethane (3.0 mL) is added to a 0 ° C solution of 4- [2- (2,6-dichloro- phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenylamine (2.3 g, 5.9 mmol) and triethylamine (0.72 g, 7.1 mmol) in dichloromethane ( 20 mL). The reaction mixture is stirred at room temperature for 16.0 h. The reaction mixture is partitioned between dichloromethane (50 mL) and water (50 mL). The organic phase is washed with brine (50 mL), dried (Na2 SO4 > 4), filtered and concentrated under reduced pressure to a residue. The residue is purified by flash chromatography " (EtOAc / hexane) to give the title compound as a solid (1.9 g, 66%). LC-ES + MS m / e 490.0 (M + 1).

Preparation 26 {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-carbamic acid tert -butyl ester To a 0 ° C solution of {4- [2- (2,6-dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl (1.9 g, 3.9 mmol) in DMF (15 mL) is added sodium hydride (60% dispersion in mineral oil, 0.19 g, 4.7 mmol) in portions. The mixture is stirred at 0 ° C for 30 minutes. Iodomethane (0.83 g, 54.42029547 5.9 mmol) is added dropwise. The reaction mixture is then stirred at room temperature for 1.0 h. The reaction is quenched with the addition of saturated ammonium chloride (20 mL) at 0 ° C. The reaction mixture is partitioned between EtOAc (30 mL) and water (20 mL). The organic phase is washed with brine (30 mL), dried (Na2 SO4), filtered and concentrated under reduced pressure to give the title compound (1.85 g, 95%) as a foam oil. LC-ES + MS m / e 526.0 (M + 23).

Preparation 27 {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amine

A solution of 4.0 M HCl in 1,4-dioxane (2.8 mL, 11.0 mmol) is added to a solution of {4- [2- (2,6- dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-carbamic acid benzyl ester (1.85 g, 3.7 mmol) in dichloromethane (25.0 mL) at 0 The reaction mixture is then stirred at room temperature for 2.0 h. The solvents are removed by evaporation under reduced pressure. The residue is partitioned between EtOAc (50 mL) and 5% aqueous sodium bicarbonate (30 mL). The organic layer is washed with brine (40 mL), dried (Na 2 SO 4), filtered and concentrated under reduced pressure to a residue. The residue is purified by flash chromatography " (EtOAc / hexane) to give the title compound as a foamy solid (1.25 g, 84%). LC-ES + MS m / e 404.0 (M + 1). 55 ΡΕ2029547

Preparation 28 (2-Bromo-ethyl) - {4- [2- (2,6-dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amine To a solution of {4- [2- (2, β-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl- , 12 g, 2.77 mmol) in 1,2-

-dibromoethane (5 mL) is added triethylamine (1.54 mL, 11.08 mmol). The reaction is heated to 90 ° C overnight. EtOAc is added to the reaction mixture. The resulting mixture is washed with brine, dried (MgSO4) and chromatographed (EtOAc / 0% to 20% Hex) to give the title compound (520 mg, 37%). 1 H-NMR (400 MHz, CDCl 3): δ 7.70 (s, 1H), 7.43-7.40 (m, 2H), 7.31 (dd, 1H, J = 1Hz), 6.93 (d, 1H, J = 7.3Hz), 6.61-6.54 (m, 2H), 4.77 (s, 2H), 3.34 (t, 2H J = 7.0 Hz), 2.65 (s, 3H), 2.65 (s, 3H), 2.65 (s, 26 (s, 3H), 1.30 (d, 6H, J = 7.0 Hz).

Preparation 29 1- {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -ethanone To a 0 ° C suspension of 4'-hydroxy-2'-methyl-acetophenone (716 mg, 4.77 mmol), [2- (2,6-dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-yl] -methanol (1.36 g, 4.77 mmol), tri-n-butylphosphine (1.78 mL, 7.15 mmol) in toluene (20 mL) is added ADDP (1.80 g, 7.15 mmol). The reaction is warmed to room temperature and stirred for 56 ΡΕ2029547

night. The reaction is concentrated under reduced pressure and the residue is chromatographed (0% to 30% EtOAc / Hex) to give the title compound (857 mg, 64%). 1 H-NMR (400 MHz, CDCl 3): δ 7.70 (s, 1H), 7.65 (d, 1H, J = 8.8 Hz), 7.42-7.38 (m, 2H), 7 , 6.27 (m, 1H), 6.64-6.58 (m, 2H), 4.85 (s, 2H), 2.99 (sept, 1H, J = 7.0 Hz), 2.50 (s, 3H), 2.49 (s, 3H), 1.30 (d, 6H, J = 7.0 Hz).

Preparation 30 2- {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -propan-1-ol

To a 0 ° C solution of 2- {4- [2- (2,6-dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -propionaldehyde (753 mg , 1.74 mmol) in THF (17 mL) and MeOH (3 mL) is added sodium borohydride (198 mg, 5.23 mmol) portionwise. The reaction mixture is warmed to room temperature. After 2 h, the reaction is concentrated under reduced pressure and the residue is partitioned between Et 2 O (100 mL) and 1 N HCl (30 mL). The aqueous layer is extracted with Et 2 (100 mL) and the combined organic layers are washed with brine, dried (MgSO 4), filtered, concentrated and chromatographed (0% to 30% EtOAc / Hex) to yield the title compound (715 mg, 95%). 1 H-NMR (400 MHz, CDCl 3): δ 7.71 (s, 1H), 7.43-7.40 (m, 2H), 7.33-7.28 (m, 1H), 7.04 ( d, 1H, J = 8.4Hz), 6.64-6.58 (m, 2H), 4.79 (s, 2H), 3.68-3.63 (m, 2H), 3.14 1H), 2.99 (sept, 1H, J = 7.0Hz), 2.28 (s, 3H), 1.30 (d, 3H, J = 7.0Hz) , 1.21 (d, 6H, J = 7.0 Hz). The following list is of compounds which are prepared essentially according to the preparation of 2- {4- [2- (2,6-dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] ] -2-methyl-phenyl} -propan-1-ol using the appropriate starting material.

Preparation 30A: 1- {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -ethanol, 1H NMR (400 MHz , CDCl3): δ 7.70 (s, 1H), 7.41 (d, 2H, J = 7.9 Hz), 7.36-7.27 (m, 2H), 6.64 (dd, 1H, J = 8.8, 2.6 Hz), 6.55 (d, 1H, J = 2.6 Hz), 5.2. J = 7.0 Hz), 4.80 (s, 2H), 3.00 (sept, 1H, J = 7.0 Hz), 2.28 (s, 3H), 1.57 (d, 1H, J = 3.5 Hz), 1.42 (d, 3H, J = 6.6 Hz), 1.30 (d, 6H, J = 7.0 H 2 :);

Preparation 30B: {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methanol (322 mg, 97%), 1 H-NMR (400 MHz, CDCl 3): δ 7.71 (s, 1H), 7.43-7.39 (m, 2H), 7.33-7.28 (m, 1H), 7.16 ( d, 1H, J = 7.9Hz), 6.62-6.56 (m, 2H), 4.81 (s, 2H), 4.60 (s, 2H), 3.00 (sept, 1H , J = 7.0Hz), 2.31 (s, 3H), 1.31 (d, 6H, J = 7.0Hz);

Preparation 30C: 2- {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -ethanol (260 mg, 87%) , 1H NMR (400 MHz, CDCl3): δ 7.71 (s, 1H), 7.43-7.40 (m, 2H), 7.31 (dd, 1H, J = 8.8, 7.5 Hz J = 7.9Hz), 6.60-6.54 (m, 2H), 4.79 (s, 2H), 3.77 (t, 2H, J = J = 6.6 Hz), 2.80 (t, 2H, J = 6.8 Hz), 2.25 (s, 3H), 1.30 (d, 6H, J = 6.6 Hz). 58 ΡΕ2029547

Preparation 31 1- (2,6-Dichloro-phenyl) -4-isopropyl-5- [4- (2-methoxy-1-methyl-vinyl) -3-methyl-phenoxymethyl] -1H-pyrazole To a suspension (1.36 g, 12.12 mmol) in THF (30 mL) is added (methoxymethyl) triphenylphosphonium chloride (4.14 g, 12.12 mmol). The reaction mixture is stirred at room temperature for 20 minutes. 1- {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -ethanone (843 mg, 2.02 mmol ) is added and the reaction is stirred at room temperature overnight. The reaction is quenched with saturated aqueous NH4 Cl and is concentrated under reduced pressure. The residue is partitioned between Et2 0 and water. The aqueous layer is extracted with Et 2 O and the combined organic layers are washed with brine, dried (MgSO 4), filtered, concentrated under reduced pressure and chromatographed (0% to 30% EtOAc / Hex) to yield the title compound (836 mg, mg, 93%) as a mixture of E / Z isomers. (Major isomer) 1 H-NMR (400 MHz, CDCl 3) δ 7.70 (s, 1H), 7.41 (d, 2H, J = 7.9

Hz), 7.33-7.28 (m, 1H), 6.93 (d, 1H, J = 8.4 Hz), 6.64-6.52 (m, 2H), 5.83 (S, 2H), 3.63 (s, 3H), 3.00 (sept, 1H, J = 7.0Hz), 2.22 (s, , 3H), 1.83 (d, 3H, J = 1.3 Hz), 1.30 (d, 6H, J = 7.0 Hz).

Preparation 32 4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-benzaldehyde The title compound (1.51 g, 75% %) is prepared essentially according to the preparation of 1- (2,6-dichloro-phenyl) -4-isopropyl-5- [4- (2-methoxy-1-methyl-viyl) -3-methyl -phenoxymethyl] -pyrazole using 5- (4-bromo-3-methyl-phenoxymethyl) -1- (2,6-dichlorophenyl) -4-isopropyl-1H-pyrazole. 1 H-NMR (400 MHz, CDCl 3): δ 10.09 (s, 1H), 7.73 (s, 1H), 7.68 (d, 1H, J = 8.8 Hz), 7.44-7 J = 8.6, 7.3 Hz), 6.71 (dd, 1H, J = 8.6, 2.4 Hz), 6.40 (m, 2H) J = 6.6 Hz), 2.60 (s, 3H), 1.61 (d, 1H, J = 32 (d, 6H, J = 6.6 Hz)

Preparation 33 To a 0 ° C solution of 1- (2,6-dichloro-phenyl) -4-isopropyl-5- [4- (2-methoxy-1-methyl-vinyl) -3-methyl-phenoxymethyl- yl] -1 H -pyrazole (825 mg, 1.85 mmol) in THF (20 mL) is added concentrated HCl (3 mL) dropwise. After 2 h, the reaction is diluted with water and the pH adjusted to 7. The aqueous layer is extracted with Et 2 O (2 x 200 mL). The combined organic layers are washed with brine, dried (MgSO4), filtered and concentrated to afford the title compound (764 mg, 96%). 1 H-NMR (400 MHz, CDCl 3) δ 9.58 (d, 1H, J = 1.3 Hz), 7.70 (s, 1H), 7.43-7.40 (m, 2H) 33 - 7.28 (m, 1H), 6.88 (d, 1H, J = 8.4

Hz), 6.66-6.61 (m, 2H), 4.80 (s, 2H), 3.73 (dq, 1H, J = 7.0, 1.3 Hz), 2.99 J = 7.0Hz), 2.27 (s, 3H), 1.35 (d, 3H, J = 7.0Hz), 1.30 (d, 6H, J = 7.0 Hz) ). 60 ΡΕ2029547

Preparation 34 {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -acetaldehyde

The title compound (292 mg, quantitative yield) is prepared essentially according to the preparation of 2- {4- [2- (2,6-dichloro-phenyl) -4-isopropyl-2H-pyrazol-3- ylmethoxy] -2-methyl-phenyl} -propionaldehyde using 1- (2,6-dichloro-phenyl) -4-isopropyl-5- [4- (2-methoxy-vinyl) -3-methyl-phenoxymethyl] Pyrazole. NMR (400 MHz, CDCl 3): δ 9.65 (t, 1H, CM CM II • " D Hz), 7.70 (s, 1H), 7.41 (d, 2H, J = 4 Hz), 7.31 (dd, 1H, J = 8.8, 7.4 Hz), 6.98 (d, 1H, J = 7.9 Hz), 6.65-6.58 , 2H), 4.80 (m, 2H), 3.60 (d, 2H, J = 2.2 Hz), 3.00 (sept, 1H, J = 7.0 Hz), 2.18 (s, 3H), 1.31 (d, 6H, J = 7.0 Hz) and

Preparation 35 4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-benzonitrile To a room temperature solution of [2- (2,6- 4-isopropyl-2H-pyrazol-3-yl] -methanol (2.50 g, 8.76 mmol) in DMF (15 mL) is added 4-fluoro-2-methyl-benzonitrile (1.18 g, 8.76 mmol) and cesium carbonate (5.71 g, 17.53 mmol). The reaction mixture is heated to 80 ° C overnight. The reaction mixture is concentrated and the residue is partitioned between Et2 0 and water. The aqueous layer is extracted with Et 2 < 0, and the combined organic layers are washed with brine, dried (MgSO 4), filtered, concentrated, and chromatographed (EtOAc / Hex 0% at 61 ° F 2029547 20%) to yield the title compound ( 2.13 g, 61%). 1 H NMR (400 MHz, CDCl 3): δ 7.72 (s, 1H), 7.46-7.40 (m, 3H), 7.32 (dd, 1H, J = 9.0, 7.3 2H), 4.85 (s, 2H), 2.99 (sept, 1H, J = 7.0Hz), 2.46 (s, 3H), 6.68-6.62 (m, 2H). 1.31 (d, 6H, J = 7.0 Hz).

Preparation 36 1- (2,6-Dichloro-phenyl) -4-isopropyl-5- [4- (2-methoxy-vinyl) -3-methyl-phenoxymethyl] -1H-pyrazole To a room temperature suspension of tert- (668 mg, 5.96 mmol) in THF (20 mL) is added (methoxymethyl) triphenylphosphonium chloride (2.04 g, 5.96 mmol) and stirred at room temperature for 20 min. 4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-benzaldehyde (400 mg, 0.992 mmol) is added and the reaction is stirred at the temperature atmosphere at night. The reaction is quenched with saturated aqueous NH 4 Cl and concentrated. The residue is partitioned between Et2 0 and water. The aqueous layer is extracted with Et 2 O and the combined organic layers are washed with brine, dried (MgSO 4), filtered, concentrated and chromatographed (SiO 2, 120 g, 0% to 30% EtOAc / Hex) to give the title compound ( 302 mg, 73%) as a mixture of E / Z isomers. 1 H-NMR (400 MHz, CDCl 3) (major isomer): δ 7.70 (s, 1H), 7.43-7.38 (m, 2H), 7.33-7.26 (m, 1H), 7.08 (d, 1H, J = 8.4 Hz), 6.72 (d, 1H, J = 12.8 Hz), 6.60-6.52 (m, 2H), 5.82 J = 12.8Hz), 4.78 (s, 2H), 3.66 (s, 3H), 3.00 (sept, 1H, J = 7.0Hz), 2.22 (s, , 3H), 1.30 (d, 6H, J = 7.0 Hz). 62 ΡΕ2029547

Preparation 37 1- (4-Methoxy-phenyl) -butane-1,3-dione To a 0 ° C suspension of sodium hydride (853 mg, 21.8 mmol, 60% dispersion in oil) in THF mL) is added ethyl acetate (2.03 mL, 20.8 mmol). The reaction is stirred at room temperature for 1 h. A solution of 4-methoxyacetophenone (1.56 g, 10.4 mmol), dibenzo-18-crown-6 (62 mg, 0.016 mmol) and ethanol (2 drops) in THF (13 mL) is added dropwise and the mixture

The reaction mixture is heated to reflux. After 3 h, the reaction is cooled to room temperature, quenched with saturated aqueous NH 4 Cl and concentrated under reduced pressure. O

The residue is partitioned between EtOAc (200 mL) and water (50 mL). The aqueous layer is extracted with EtOAc (200 mL) and the combined organic layers are washed with brine, dried (MgSO4), filtered and concentrated. The residue is purified via chromatography (0-20% EtOAc / hexanes) to provide the title compound (1.62 g, 81%). GC-ES / MS m / e 192

Preparation 38 3-Methyl-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenol

A mixture of tricyclohexylphosphine (525 mg, 1.87 mmol), palladium bis (dibenzylideneacetone (460 mg, 0.801 mmol) and dioxane (200 mL) is stirred at ambient temperature for half an hour. 3-methylphenol (5.00 g, 26.7 mmol), pinacolborane (7.45 g, 40.1 mmol) and potassium acetate (3.93 g, 40.1 mmol) The combined ether fractions are washed with brine, dried (MgSO 4) and evaporated. The combined ether fractions are washed with brine, dried (MgSO 4), and evaporated. The residue is purified using flash chromatography (0-2% MeOH / CH 2 Cl 2) to give the title compound (1.6 g, 47%). A second purification of the crude fractions provided an additional 2.76 g of the title compound for a total of 4.36 g (70%) ES / MS m / e 233.3 (M +).

Preparation 39 6-Bromo-1H-indole-3-carboxylic acid methyl ester To a solution of 6-bromoindole-3-carboxylic acid (960 mg, 4.00 mmol) in methanol (9.5 mL) (trimethylsilyl) diazomethane (2.0 M solution in hexanes, approximately 9 mL) was added over two minutes at room temperature. The yellow mixture is concentrated under reduced pressure. The residue is redissolved in methanol and concentrated under reduced pressure several times to give the title compound as a solid (100%). ES / MS m / e 256.0 (M + 2). The following list is of compounds which are prepared essentially according to the preparation of 64 ΡΕ2029547 6-bromo-1H-indole-3-carboxylic acid ethyl ester using the appropriate starting material.

Preparation 39A: (5-Bromo-1H-indol-3-yl) -acetic acid methyl ester (710 mg, 99%), ES / MS m / e 266.2 (M-2);

Preparation 39B: 5-Bromo-1H-indole-3-carboxylic acid methyl ester, ES / MS m / e 255.9 (M + 2).

Preparation 40 6- (4-Hydroxy-2-methyl-phenyl) -1H-indole-3-carboxylic acid methyl ester

A mixture of 3-methyl-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenol (213 mg, 0.910 mmol), 3-carboxylic acid (193 mg, 0.759 mmol), tetrakis (triphenylphosphine) palladium (0) (57 mg, 0.046 mmol), DMF (2.7 mL), ethanol (1.34 mL) and 2M aqueous potassium carbonate (1.34 mL) is heated to 100 ° C for 60 hours. The reaction mixture is cooled to room temperature, diluted with water and acidified with 1N HCl. The resulting solution is extracted with ethyl acetate. The combined organic layers are dried over anhydrous magnesium sulfate and concentrated. The residue is purified by flash chromatography " eluting with 25-40% ethyl acetate / heptane to give the title compound (134 mg, 63%). ES / MS m / e 280.3 (M-1). The following list is of compounds which are prepared essentially according to the preparation of 6- (4-hydroxy-2-methyl-phenyl) -1H-indole-3-carboxylic acid ethyl ester using the starting materials appropriate.

Preparation 40A: 6- (4-Hydroxy-2-methyl-phenyl) -1H-indole-2-carboxylic acid ethyl ester, ES / MS m / e 296.1 (M + 1);

Preparation 40B: 5- (4-Hydroxy-2-methyl-phenyl) -1H-indole-3-carboxylic acid methyl ester, ES / MS m / e 252.1 (M-2);

Preparation 40C: [5- (4-Hydroxy-2-methyl-phenyl) -1H-indol-3-yl] -acetic acid methyl ester, (180 mg, 60%), ES / MS m / e 296.1 (M + 1);

Preparation 40D: 6- (4-Hydroxy-2-methyl-phenyl) -benzo [b] thiophene-2-carboxylic acid methyl ester, ES / MS m / e 297.3 (M-1);

Preparation 40E: (4'-Hydroxy-2'-methyl-biphenyl-4-yl) -acetic acid methyl ester (247 mg, 56%), ES / MS m / e 257.0 (M + 1) );

Preparation 40F: 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, ES / MS m / e 297.0 (M-1);

Preparation 40G: 6-Bromo-benzo [b] -thiophene-2-carboxylic acid methyl ester, 1H NMR (400 MHz, CDCl3): δ 7.99 (m, 2H), 7.70 (d, 1H ), 7.50 (d, 1H), 3.92 (s, 3H).

Preparation 41 6-Bromo-1-methyl-1H-indole-3-carboxylic acid methyl ester 66 ΡΕ2029547

A mixture of 5-bromo-1H-indole-3-carboxylic acid ethyl ester (100 mg, 0.394 mmol), potassium carbonate (163 mg, 1.18 mmol) and DMF is stirred at room temperature and iodomethane ( 30 Âμl, 0.47 mmol) is added. After 1.5 hours an additional iodomethane (10æl) is added and the reaction mixture is stirred for 30 minutes, diluted with dichloromethane and filtered. The filtrate is concentrated under high vacuum, diluted with ethyl acetate and concentrated to give the title compound (105 mg, 99%). ES / MS m / e 270.0 (M + 2).

To a solution of 6-bromobenzothiophene (20 g, 93.8 mmol) and acetyl chloride (8.84 g, 112.6 mmol) in 120 mL of 1,2-dichloroethane dichloroethane is added dropwise at room temperature tin tetrachloride (1M in dichloromethane, 112.6 mmol, 112.6 mL) under nitrogen. After the addition is complete, the reaction mixture is stirred at room temperature overnight. The mixture is poured into an ice / water bath and extracted with dichloromethane. The organic phase is washed with sat. NaHCO3, water and brine, dried over MgSO4 and evaporated. The crude residue is purified by flash chromatography using 6: 1 hexane / EtOAc as eluent mixture. The title compound (12 g, 50%) is obtained from a 7: 3 mixture of the two isomers: 3-acetyl-6-bromobenzothiophene and 2-acetyl-6-bromobenzothiophene. ES / MS m / e 256 (M + 2). 67 ΡΕ2029547

Preparation 6 6-Bromobenzothiophene-3-carboxylic acid and 6-bromobenzothiophene-2-carboxylic acid To a 0 ° C solution of sodium hydroxide (13.64 g, 341 mmol) in water (94 mL, 5.22 mmol) is slowly added bromine (21.92 g, 137.18 mmol). The reaction mixture is stirred at 0 ° C for 15 min. To a mixture is added dropwise a solution of 2- and 3-acetyl-6-bromobenzothiophene (10.00 g, 39.19 mmol) in dioxane (75 mL). The reaction mixture is stirred at room temperature for 2 hours followed by the addition of 50 mL of a solution of NaHSO 3 (40%) and then 10 mL of HCl. A solid orange is displayed. The solid is separated by filtration and washed with water and hexanes to give the title compound (7 g, 70%) as a mixture of 6-bromobenzothiophene-3-carboxylic acid and 6-bromobenzothiophene-2 carboxylic acid in ratio 7: 3, ES / MS m / e 258 (M + 2).

Preparation 44 6-Bromobenzothiophene-3-carboxylic acid ethyl ester and 6-bromobenzothiophene-2-carboxylic acid ethyl ester in a ratio

A solution of a mixture of 6-bromobenzothiophene-3-carboxylic acid and 6-bromobenzothiophene-2-carboxylic acid (6.5 g, 25.28 mmol) and sulfuric acid (4.65 g, 47.43 mmol ) in MeOH (100 mL) is heated to 65øC for 68 æ 20 20 957 overnight. A light brown solid is displayed. The solution is cooled to room temperature. The solid is separated by filtration and washed with MeOH to give the title compound (5.6 g, 83%) as a mixture of 6-bromobenzothiophene-3-carboxylic acid ethyl ester and ethyl ester of 6-bromobenzothiophene-2-carboxylic acid in a ratio 7: 3, ES / MS m / e 272 (M + 2).

Preparation 45 3- (4'-Hydroxy-2'-methyl-biphenyl-4-yl) -acrylic acid methyl ester

A mixture of 4-bromo-3-methylphenol (460 mg, 2.01 mmol), [4- (E-3-methoxy-3-oxo-1-propen-1-yl) phenyl] boronic acid 2.32 mmol), tetrakis (triphenylphosphine) palladium (0) (232 mg, 0.201 mmol), cesium carbonate (1.31 g, 4.02 mmol) and DMF (4.8 mL) to 80 ° C for 4.5 hours. The reaction mixture is cooled to room temperature, diluted with water and acidified with 1N HCl. The resulting solution is extracted with ether. The combined organic layers are dried over anhydrous magnesium sulfate and are purified via flash chromatography " eluting with 15% ethyl acetate / heptane to give the title compound (108 mg, 20%). ES / MS m / e 267.3 (M-1). The following list is of compounds which are prepared essentially according to the preparation of 3- (4'-hydroxy-2'-methyl-biphenyl-4-yl) -acrylic acid methyl ester using the appropriate starting material. 69 ΡΕ2029547

Preparation 45A: 6- (4-Hydroxy-2-methyl-phenyl) -1-methyl-1H-indole-3-carboxylic acid methyl ester, LC-ES / MS m / e 296.0 (M + 1) );

Preparation 45B: 3- (4'-Hydroxy-2'-methyl-biphenyl-4-yl) -propionic acid ethyl ester (457 mg, 78%), ES / MS m / e 283.3 (M + ;

Preparation 45C: 3- (4'-Hydroxy-2'-methyl-biphenyl-3-yl) -propionic acid methyl ester, ES / MS m / e 269.2 (M + 1);

Preparation 45D: (4'-Hydroxy-2'-methyl-biphenyl-3-yl) -acetic acid methyl ester, ES / MS m / e 255.2 (M-1);

Preparation 45E: 3- (4'-Hydroxy-2'-methyl-biphenyl-3-yl) -acrylic acid methyl ester, ES / MS m / e 269.2 (M + 1);

Preparation 45F: 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 starting from a 7: 3 mixture of 6-bromo-benzoic acid ethyl ester [b] thiophene-3-carboxylic acid and 6-bromo-benzo [b] thiophene-2-carboxylic acid methyl ester, MS m / z: 297.0 (M +).

Preparation 46

To an ethyl 3-iodobenzoate (2.5 g, 1 equiv) in ethylene glycol dimethyl ether (20 mL) is added 2 M solution of 4'-benzyloxy-biphenyl-3-carboxylic acid sodium carbonate (40 mL), 70 ΡΕ 2029547

4-benzyloxybenzene boronic acid (2.5 g, 1.2 equiv) and tetrakistriphenylphosphine palladium (0) (1.05 g, 0.1 equiv). The reaction mixture is heated at reflux for 2 h. The reaction mixture is allowed to cool to room temperature and is diluted with 300 mL 50% sodium bicarbonate solution. The product is extracted three times with methylene chloride. The combined organic layers are dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified via flash chromatography " eluting with ethyl acetate / hexanes (2:98 to 8:92) to give the desired product (2.3 g, 76%) as a white solid.

Step B 4'-Hydroxy-biphenyl-3-carboxylic acid ethyl ester To a solution of 4'-benzyloxy-biphenyl-3-carboxylic acid ethyl ester (2.3 g) in ethanol / ethyl acetate (3: 1) (200 mL) is added 5% palladium on carbon (300 mg). The reaction mixture is placed under an atmosphere of hydrogen (55 psi) and stirred in a Parr apparatus for 2 h. Concentrated hydrochloric acid (0.3 mL) is added to the reaction mixture. The reaction mixture is allowed to proceed for a further 10 h. Trifluoroacetic acid (1 mL) and 20% palladium hydroxide on carbon (300 mg) are added to the reaction mixture and the reaction is allowed to stir under an atmosphere of hydrogen (60 psi). After an additional 80 h, the reaction mixture is degassed with nitrogen and a plug of silica gel is filtered through a plug of EtOAc, and eluted with 500 mL of ethyl acetate and 500 mL of ethanol. The filtrate is concentrated under reduced pressure and the residue is diluted with 400 mL of saturated sodium bicarbonate solution. The product is extracted three times with methylene chloride. The combined organic layers are dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford the title compound (1.6 g, 95%) as a white solid.

Preparation 47

Step A 4'-Methoxy-2'-nitro-biphenyl-4-carboxylic acid ethyl ester (4.00 g) ) suspended in ethanol (150 mL) and ethyl acetate (150 mL) is added 5% palladium on carbon (0.300 g). The reaction mixture is placed under an atmosphere of hydrogen (50 psi) and stirred in a Parr apparatus. After 18 h, the reaction mixture is degassed with nitrogen and is filtered through a plug of silica gel, eluting with 700 mL of ethyl acetate and 600 mL of methylene chloride. The filtrate is evaporated to afford the title compound (3.52 g, > 99%) as a white solid.

Step B 2'-Bromo-4'-methoxy-biphenyl-4-carboxylic acid methyl ester To a solution of sodium nitrite (1.40 g) in 72 ΡΕ 202 9547 dimethylsulfoxide (50 mL) is added ethyl ester of 2'-amino-4'-methoxy-biphenyl-4-carboxylic acid (2.61 g). After 5 minutes, the reaction mixture is treated with a solution of 4.7 mL of hydrobromic acid (48%) in dimethylsulfoxide (50 mL). The reaction is allowed to stir at room temperature for 2 h. The reaction mixture is diluted with a solution of 20.0 g of potassium carbonate dissolved in 400 ml of water. The product is extracted five times with methylene chloride. The combined organic layers are dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified via flash chromatography " eluting with hexanes / ethyl acetate (99: 1 to 86: 14) to give the title compound (1.00 g, 31%) as a white solid.

Step C 2'-Bromo-4'-hydroxy-biphenyl-4-carboxylic acid methyl ester To a 0 ° C solution of 2'-bromo-4'-methoxy-biphenyl-4 (0.200 g) in methylene chloride (5 mL) is added boron tribromide (0.176 mL). The reaction mixture is maintained at 0 ° C for 2 h. The reaction mixture is slowly quenched with 50 mL of methanol, diluted with 150 mL of 2N hydrochloric acid, and extracted three times with methylene chloride. The combined organic layers are dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (0.180 g, 94%). 73 ΡΕ2029547

To a solution of 4-bromo-3-methyl-phenol (0.300 g, 1 equiv) in DMF (5 mL) are stirred for 2 hours at reflux temperature for 4 hours. phenylboronic acid methyl 4-ester (0.58 g, 2 equiv), dppf (0.27 g, 0.3 equiv), palladium acetate (0.036 g, 0.1 equiv), and cesium carbonate (1 , 4 g, 2 equiv). The reaction mixture is heated to 75 ° C for 1 h. The reaction mixture is cooled to room temperature and is diluted with water. The resulting solution is extracted with ethyl acetate. The combined organic layers are combined, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue is purified via flash chromatography " eluting with 3% ethyl acetate in toluene to afford the desired product (0.224 g, 58%). ES / MS m / e 241.3 (M-1)

Preparation 49 2- (4-Methoxy-phenyl) -4-methyl-thiazole-5-carboxylic acid ethyl ester

A mixture of 4-methoxy-thiobenzamide (5 g, 30 mmol) and 2-chloro-3-oxo-butyric acid ethyl ester (4.6 mL, 33 mmol) in ethanol is stirred under reflux overnight. The reaction mixture is concentrated and the residue is triturated with ether to give the title compound as a yellow solid (5.8 g, 70%). LC-ES / MS m / e 278 (M + 1) - 74 - ΡΕ2029547

PREPARATION 50 2- (4-Hydroxy-phenyl) -4-methyl-thiazole-5-carboxylic acid ethyl ester To a solution of 2- (4-methoxy-phenyl) -4-methyl 5-carboxylic acid (550 mg, 2 mmol) in dichloromethane (20 mL) at -80 ° C is added BBr 3 (5 mL, 1 M solution in dichloromethane). The reaction is stirred at room temperature overnight. The reaction is quenched by the addition of methanol and is concentrated under pressure

reduced. The residue is partitioned between EtOAc and 1N HCl. 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 solid

brownish (500 mg, 95%). 1 H-NMR (400 MHz, DMSO-d 6) δ 10.22 (s, 1H), 7.82 (d, 2H), 6.86 (d, , 2H), 4.27 (q, 2H), 2.64 (s, 3H), 1.29 (t, 3H).

PREPARATION 51 2- (4-Hydroxy-phenyl) -benzo [b] thiophene-6-carboxylic acid methyl ester The title compound (57 mg, 12%) is prepared essentially according to the 2- (4-hydroxy-phenyl) -4-methyl-thiazole-5-carboxylic acid methyl ester using 2- (4-methoxy-phenyl) -benzo [b] thiophene-6-carboxylic acid methyl ester. LC-ES + MS m / e 283 (M-1). 75 ΡΕ2029547

Preparation 52 Trifluoro-methanesulfonic acid 2- (4-methoxy-phenyl) -benzo [b] thiophen-6-yl ester To a solution of 2- (4-methoxy-phenyl) -benzo [b] thio- 6-ol (512 mg, 2 mmol) in dichloromethane (20 mL) at 0 ° C is added triethylamine (0.58 mL, 5 mmol) and trifluoromethanesulfonic anhydride (0.67 mL, 4 mmol). The reaction is stirred at room temperature overnight. The reaction mixture is concentrated and the residue is redissolved in EtOAc, washed with 1 N NaOH followed by 1N HCl. The organic layer is concentrated to give the title compound as a tan solid (800 mg, quant.).

Preparation 53 2- (4-Methoxy-phenyl) -benzo [b] -thiophene-6-carboxylic acid methyl ester

A mixture of trifluoro-methanesulfonic acid 2- (4-methoxy-phenyl) -benzo [b] thiophen-6-yl ester (750 mg), palladium acetate (43 mg), 1,4- butanone (97 mg), triethylamine (1.4 mL) in MeOH (8 mL) and DMSO (12 mL) is stirred under an atmosphere of carbon monoxide (100 psi) at 80 ° C for 4 h. The reaction mixture is filtered through a pad of Celite and the filtrate is concentrated. The residue is purified by column chromatography (0 to 20% EtOAc in hexanes) to give the title compound as a tan solid, (500 mg, 87%). LC-ES + MS m / e 321 (M + Na). 76 ΡΕ2029547

PREPARATION 54 5- (4-Hydroxy-2-methyl-phenyl) -4-methyl-thiophene-2-carboxylic acid methyl ester

Step A

To a mixture of 4-methoxy-2-methylphenylboronic acid (912 mg, 6 mmol), 5-bromo-4-methyl-thiophene-2-carboxylic acid ethyl ester (1.1 g, 5 mmol) and K 2 CO 3 (1.38 g, 10 mmol) in toluene (30 mL) and water (5 mL) is bubbled N 2 for 15 minutes followed by the addition of tetrakis (triphenylphosphine) palladium (289 mg, 0.25 mmol). The mixture is stirred at 80 ° C under N 2 overnight. The reaction mixture is filtered through a pad of Celite eluting with EtOAc. The combined filtrate is concentrated under reduced pressure and the 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 (540 mg, 39%). 1 H-NMR (CDCl 3): δ 7.63 (s, 1H), 7.15 (d, 1H, J = 8.4 Hz), 6.82 (d, 1H, J = 2.8

(S, 3H), 3.83 (s, 3H), 4.79 (bs, 1H), 3.88 (dd, 1H, J = ), 2.17 (s, 3H), 2.02 (s, 3H).

A solution of 5- (4-methoxy-2-methyl-phenyl) -4-methyl-thiophene-2-carboxylic acid ethyl ester (540 mg, 2 mmol) in dichloromethane (30 mL) at 0 ° C is added BBr 3 in dichloromethane (1N, 5.0 mL) and the mixture is stirred at room temperature overnight. The reaction is quenched by the addition of methanol and is evaporated. The residue 77 ΡΕ2029547 is purified by column chromatography (0-20% EtOAc in hexanes) to give 5- (4-hydroxy-2-methyl-phenyl) -4-methyl-thiophene-2-carboxylic acid ethyl ester (420 mg, 82%). 1H NMR (CDCl3): δ 7.62 (s, 1H), 7.10 (d, 1H, J = 7.9 Hz), 6.76 (s, 1H), 6.70 (d, 1H, J = 7.9 Hz), 4.79 (bs, 1H), 3.88 (s, 3H), 2.15 (s, 3H), 2.02 (s, 3H). The following list is of compounds which are prepared essentially according to the preparation of 5- (4-hydroxy-2-methyl-phenyl) -4-methyl-thiophene-2-carboxylic acid ethyl ester using the starting material appropriate.

Preparation 54A: 5- (4-Hydroxy-phenyl) -thiophene-2-carboxylic acid methyl ester, 1H NMR (DMSO-d6): δ 9.87 (s, 1H), 7.74 (d, 1H, J = 4.0 Hz), 6.83 (d, 2H, J = 8.8 Hz), 7.40 (d, 1H, J = 8.8Hz), 3.81 (s, 3H);

Preparation 54B: 5- (4-Hydroxy-2-methyl-phenyl) -thiophene-2-carboxylic acid methyl ester, 1H NMR (DMSO-d6): δ 9.71 (s, 1H) (D, 1H, J = 4.0 Hz), 6.77 (d, 1H, J = 3.5 Hz), 7.26 (d, 1H, d, 1H, J = 2.6Hz), 6.67 (dd, 1H, co-d), d (s, 3H), 2.32 (s, 3H);

Preparation 54C: Hydroxy-phenyl) -thiophene-2-carboxylic acid methyl ester, 10.33 (s, 1H), 7.78 (d, 1H, J = 3.8 Hz), 7.37 (d ,  € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒ6.66 (s, 1H), 3.82 (s, 3H); 1 H-NMR, 7.53 (1H), 5- (2-chloro-4- (DMSO-d6): δ (d, 1H, J = 8.66,

Preparation 54D: 5- (2-Chloro-4-hydroxy-phenyl) -4-methyl-thiophene-2-carboxylic acid methyl ester, 1 H-NMR (DMSO-d6): δ 10.26 (bs, 1H ), 7.68 (s, 1H), 7.25 (d, 1H, N ≥ 006), Î'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 54E: 2- (4-Hydroxy-2-methyl-phenyl) -4-methyl-thiazole-5-carboxylic acid methyl ester, 1H NMR (DMSO-d6): δ 10.0 (s, 1H) , 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 54F: 2- (4-Hydroxy-2-methyl-phenyl) -thiazole-5-carboxylic acid ethyl ester, 1H NMR (DMSO-d6): δ 8.44 (s, 1H) (D, 1H, J = 8.4 Hz), 6.76 (s, 1H), 6.75 (d, 1H, J = 8.4 Hz), 4.33 , 51 (s, 3H), 1.30 (t, 3H);

Preparation 54G: 6- (4-Hydroxy-2-methyl-phenyl) -nicotinic acid methyl ester, 1H NMR (DMSO-d6): δ 9.65 (s, 1H), 9.10 (s, (Dd, 1H, J = 2.2, J = 8.4 Hz), 7.62 (dd, 1H, J = .9, (S, 3H), 2.31 (s, 1H), 6.62 (d, 1H, J = 8.8Hz), 6.71 (s, );

Preparation 54H: 4'-Hydroxy-2,2'-dimethyl-biphenyl-4-carboxylic acid methyl ester, (700 mg, 82%), 1 H-NMR (CDCl 3): δ 7.94 (d, 1H , J = 1.7 Hz), 7.87 (dd, 1H, J = 1.7, J = 7.9 Hz), 7.16 (d, J = 7.9 Hz), 6.94 (d, 1H, J 2 = 1 Hz), 6.77 (d, 1H, J = 2.6 Hz), 6.71 (dd, Hz), 5.0 (bs, 1H), 3.93 (s, 3H), 2.10 (s, 3H), 1.99 (s, 3H). 79 ΡΕ2029547

Preparation 55 2- (4-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-3-oxo-butyric acid ethyl ester (4.6 mL, 33 mmol) in ethanol is stirred under reflux overnight. The reaction mixture 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-MS: 278 (M + 1)

A solution of 2- (4-methoxy-phenyl) -4-methyl-thiazole-5-carboxylic acid ethyl ester (550 mg, 2 mmol) in dichloromethane (20 mL) at -80 ° C is added BBr3 (5 mL, 1M solution in dichloromethane). The reaction mixture is stirred at room temperature overnight. The reaction is quenched by the addition of methanol and is concentrated. The residue is partitioned between EtOAc and 1N HCl. The organic layer is concentrated and purified by chromatography (0 to 30% EtOAc in hexanes) to give the title compound as a tan solid, (500 mg, 95%). . LC-MS: 264 (M + 1); 1 H-NMR (DMSO-d 6) δ 10.22 (s, 1H), 7.82 (d, 2H), 6.86 (d, 2H), 4.27 (q, 2H), 2.64 s, 3H), 1.29 (t, 3H). 80 ΡΕ2029547

Preparation 56 4 - {[(4-Hydroxy-2-methyl-phenyl) -methyl-amino] -methyl] -benzoic acid methyl ester To a room temperature solution of 4-amino-3-methyl- 1.0 g, 8.12 mmol) in MeOH (77 mL) is added 4-formyl-benzoic acid methyl ester

(1.47 g, 8.93 mmol) and decaborane (329 mg, 2.68 mmol). The reaction is stirred at room temperature. After 2 h, formaldehyde (1.23 mL, 16.93 mmol, 37% in water) and decaborane (329 mg, 2.68 mmol) are added and the reaction is stirred overnight. The reaction is concentrated under reduced pressure and the residue is purified via chromatography to afford the title compound (2.07 g, 90%). LC-ES + MS m / e 286.2 (M + 1)

PREPARATION 57 3 - {[(4-Hydroxy-2-methyl-phenyl) -methyl-amino] -methyl] -benzoic acid methyl ester The title compound is prepared essentially as described in the preparation of 4 - {[(4-hydroxy-2-methyl-phenyl) -methyl-amino] -methyl] -benzoic acid methyl ester using 3-formyl-benzoic acid methyl ester (74% yield). LC-ES + MS m / e 286.2 (M + 1)

Preparation 58 3- [2- (2-Chloro-4-hydroxy-phenyl) -vinyl] -benzoic acid methyl ester 81 To a solution of 3-vinylbenzoic acid methyl ester (0.300 g) in dimethylformamide (3 mL) is added 4-bromo-3-methyl-phenol (0.35 g), tri (ortho-luyl) phosphine (0.06 g), Pd (dba) 2 (0.032 g) and triethylamine 26 mL). The reaction is heated to 100 ° C overnight. Upon cooling to room temperature, the solvent is evaporated under reduced pressure. The residue is dissolved in ethyl acetate. The organic layer is washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue is purified via filtration chromatography eluting with 300 mL of toluene followed by 250 mL of 10% ethyl acetate in toluene to give the title compound (0.12 g). 1 H-NMR (400 MHz, CDCl 3) δ 8.20 (s, 1H), 7.95-7.93 (d, 1H), 7.71-7.69 (d, 1H), 7.53-7.51 (d, 1H), 7 1H), 7.38-7.34 (d, 1H), 6.96-6.92 (d, 1H), 6.77-6.72 (m, 2H) , 5.26 (broad s, 1H), 3.99 (s, 3H), 2.43 (s, 3H).

Preparation 59 2-Allyl-4-methyl-benzoic acid methyl ester To a solution of 2-bromo-4-methyl-benzoic acid methyl ester (1.330 g, 5.81 mmol) in 5 mL of DMF and 50 mL of acetonitrile are added allyl-tri-n-butyltin (2.12 g, 6.39 mmol), PdCl 2 (PPh 3) 2 (0.123 g, 0.29 mmol) and lithium chloride (0.493 g , 11.6 mmol). The resulting mixture is heated to 120 ° C for 8 hours. The reaction mixture is cooled to ambient temperature and concentrated under reduced pressure. The residue is dissolved in dichloromethane and purified via chromatography eluting with 10% ethyl acetate in hexanes to give 0.980 g (89%) of the desired product. 1 H-NMR (400 MHz, CDCl 3): δ 7.79-7.76 (d, 1H), 7.05 (s, 1H), 7.05-7.03 (d, 1H), 6-03- 5.92 (dd, 1H), 3.92 (dd, 1H), 3.84 (s, 3H), 3.72 , 70 (dd, 1H), 2.33 (s, 3H).

Preparation 60 4-Methyl-2- (2-oxo-ethyl) -benzoic acid methyl ester To a solution of 2-allyl-4-methylbenzoic acid methyl ester (0.980 g, 5.15 mmol) in acetone (20 mL) and water (2.0 mL) are added N-methylmorpholine oxide (0.89 g, 7.57 mmol) and Cs.4 (1 mg). The resulting reaction mixture is stirred at room temperature for three hours. The reaction mixture is diluted with ethyl acetate (50 mL) and is washed with Na2 S2 C> 3 (1.0 M, 20 mL). The organic layer is concentrated and the residue is dissolved in THF (25 mL) and water (15 mL). To the solution, NaIC > 4 (3.24 g, 15.2 mmol) is added and the mixture is stirred at room temperature for two hours. The mixture is filtered and the filtrate is concentrated, diluted with ethyl acetate (60 mL) and washed with Na2S203 (1.0 M, 20 mL). The organic layer is dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue is purified via flash chromatography " eluting with 30-40% ethyl acetate in hexane to give the title compound (0.260 g, 26%). 1 H-NMR (400 MHz, CDCl 3): δ 9.74 (s, 83 ΡΕ 2029547 1,), 7.94-7.92 (d, 1H), 7.15-7.13 (d, 1H) (S, 1H), 3.99 (s, 2H), 3.81 (s, 3H), 2.35 (s, 3H). The following list is of compounds which are prepared essentially according to the preparation of 4-methyl-2- (2-oxo-ethyl) -benzoic acid methyl ester using the appropriate starting material.

Preparation 60A: 5-Methoxy-2- (2-oxo-ethyl) -benzoic acid methyl ester (29%), 1 H-NMR (400 MHz, CDCl 3): δ 9.72 (s, 1H), 7 (D, 1H), 7.14-7.00 (dd, 1H), 3.95 (s, 2H), 3.84 (s, 3H) ), 3.81 (s, 3H).

Preparation 60B: 5-Methyl-2- (2-oxo-ethyl) -benzoic acid methyl ester (29%), 1 H-NMR (400 MHz, CDCl 3): δ 9.74 (s, 1H), 7 , 3.85 (d, 1H), 7.31-7.29 (dd, 1H), 7.10 (d, 1H), 3.99 (s, 2H), 3.84 (s, 3H) 36 (s, 3H).

Preparation 60C: 4-fluoro-2- (2-oxo-ethyl) -benzoic acid methyl ester (67%), 1 H-NMR (400 MHz, CDCl 3): δ 9.75 (s, 1H), 8 , 08-8.04 (dd, 1H), 7.05-7.01 (m, 1H), 6.93-6.90 (dd, 1H), 4.05 (s, 2H), 3.83 (s, 3H).

Preparation 60D: 4-Methyl-3- (2-oxoethyl) benzoic acid methyl ester (21%), 1 H-NMR (400 MHz, CDCl 3): δ 9.71 (s 1H) 1H), 7.83 (s, 1H), 7.27-7.25 (d, 1H), 3.88 (s, 3H), 3.74 (s, 2H), Preparation 60E: 4-Fluoro-3- (2-oxo-ethyl) -benzoic acid methyl ester (44%), 1 H-NMR (400 MHz, CDCl 3): δ 9.2, (S, 1H), 7.97-7.93 (m, 1H), 7.98-7.86 (d, 1H), 7.12-7.08 (dd, 1H), 3.85 (s, 3H), 3.75 (s, 2H).

Preparation 60F: 2-Fluoro-5- (2-oxo-ethyl) -benzoic acid methyl ester (30%), 1H NMR (400 MHz, CDCl3): δ 9.74 (t, 1H), 7 , 7.77-7.08 (dd, 1H), 3.90 (s, 3H), 3.70 (m, 1H) (s, 2H).

Preparation 61

2-Butoxy-5- (2-oxo-ethyl) -benzoic acid methyl ester Step A A solution of 5-bromo-2-hydroxy-benzoic acid methyl ester (1.100 g, 4.76 mmol) in 5 mL DMF are added 1-iodobutane (1.31 g, 7.14 mmol) and potassium carbonate (1.31 g, 9.52 mmol). The resulting mixture is agitated to 80 ° C for 12 hours. The reaction mixture is cooled to room temperature and quenched with water (30 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic layers are dried over sodium sulfate and concentrated under reduced pressure. The residue is purified via chromatography eluting with 15% ethyl acetate in hexanes to give 1.35 g (99%) of the desired intermediate 5-bromo-2-butoxy-benzoic acid methyl ester. 1 H-NMR (400 MHz, CDCl 3): δ 7.85 (d 1H), 7.50-7.47 (dd, 1H), 6.82-6.80 (d, 1H), 4.00-3 , 96 (t 2H), 3.84 (s, 3H), 1.79-1.73 (m, 2H), 1.57-1.46 (m, 2H) 0.96-0.93 (t , 3H). 85 ΡΕ2029547

Step B

The title compound (30%) is prepared essentially according to the preparation of 4-methyl-2- (2-oxo-ethyl) -benzoic acid methyl ester using 5-bromo-2- butoxy-benzoic acid. 1 H-NMR (400 MHz, CDCl 3): δ 9.70 (s, 1H), 7.61 (t, 1H); 1 Csl 7.23 (dd, 1H), 6.94-6.92 (d, 1H), 4.02-3.99 (t, 2H), 3.85 (s, 3H), 3.62 d, 2H), 1.80-1.76 (m, 2H), 1.52-1.47 (m, 2H), 0.96-0.90 (t, 3H).

PREPARATION 62 4-Butoxy-3- (2-oxo-ethyl) -benzoic acid methyl ester The title compound is prepared essentially according to the preparation of 2-butoxy-5- (2- oxo-ethyl) -benzoic acid methyl ester (52%) using 3-bromo-4-hydroxy-benzoic acid methyl ester. 1 H-NMR (400 MHz, CDCl 3): δ 9.67 (d, 1H), 7.98-7.95 (d, 1H), 7.83 (s, 1H), 6.98-6.87 d, 1H), 4.03-4.01 (t, 2H), 3.86 (s, 3H), 3.65 (d, 2H), 1.76-1.73 (m, , 46-1.41 (m, 2H), 0.96-0.90 (t, 3H).

Preparation 63 2-Allyl-5-methoxy-benzoic acid methyl ester To a room temperature solution of 2-bromo-5-methoxy-benzoic acid methyl ester (750 mg, 3.02 mmol) in benzene (2 mL) is added allyl-n-butyltin (1.16 mL, 3.73 mmol) and tetrakis (triphenylphosphine) -86 ΡΕ2029547 palladium (0) (174 mg, 0.157 mmol, 5 mol%). The reaction mixture is heated in a sealed tube at 100 ° C. After 3 h, the reaction is concentrated under reduced pressure and the residue is chromatographed (0% to 10% EtOAc / Hex) to give the title compound (451 mg, 73%). 1 H-NMR (400 MHz, CDCl 3): δ 7.40 (d, 1H, J = 2.6 Hz), 7.18 (d, 1H, J = 8.6, 2,9Hz), 6.04-5.93 (m, 1H), 5.03-4.94 (m, 2H), 3.88 (s, 3H), 3.82 (s, 3H), 3.70-3.65 (m, 2H).

Preparation 64 5-Methoxy-2-propyl-benzoic acid methyl ester To a room temperature suspension of 10% palladium on carbon (245 mg) in MeOH (5 mL) is added a solution of 2- allyl-5-methoxy-benzoic acid (440 mg, 2.13 mmol) in MeOH (5 mL) in one portion. The reaction is placed under an atmosphere of hydrogen gas and stirred overnight. The reaction mixture is filtered through Celite and concentrated to give the title compound (361 mg, 81%). 1 H NMR (400 MHz, CDCl 3): δ 7.38 (d, 1H, J = 3.1 Hz), 7.15 (d, 1H, J = 8.4 Hz) 6.97 (dd, 1H, J = 8.6, 2.9Hz), 3.89 (s, 3H), 3.82 (s, 3H) 2.88-2.82 (m, 2H), 1.65-1.53 ( m, 2H), 0.95 (t, 3H, J = 7,

Hz).

Preparation 65 5-Hydroxy-2-propyl-benzoic acid methyl ester To a -78 ° C solution of methyl ester of 87 ΡΕ2029547 5-methoxy-2-propyl benzoic acid (350 mg, 1.68 mmol) in DCM (18 mL) is added boron tribromide (840 æl, 8.40 mmol, 1.0 M in DCM) dropwise. The reaction mixture is warmed to room temperature overnight. The reaction mixture is quenched by the dropwise addition of MeOH and is stirred at room temperature for 30 min. The reaction is concentrated and the residue is partitioned between EtOAc and water. The aqueous layer is extracted with EtOAc and the combined organic layers are washed with brine, dried (MgSO4), filtered, concentrated, and chromatographed (0% to 20% EtOAc / Hex) to give the title compound (274 mg, 84%). %). 1H NMR (400 MHz, CDCl3): δ 7.34 (d, 1H, J = 2.6 Hz), 7.11 (d, 1H, J = 8.4 Hz), 6.92 (dd, 1H , J = 8.4, 3.1 Hz), 6.92 (dd, 1H, J = 8.4, 3.1 Hz), 3.88 (s, 3H), 2.87-2.81 ( m, 2H), 1.63-1.52 (m, 2H), 0.94 (t, 3H, J = 7.3 Hz).

PREPARATION 66 4-Hydroxy-2-methyl-benzoic acid methyl ester The title compound (77%) is prepared essentially according to the preparation of 5-hydroxy-2-propyl-benzoic acid methyl ester using of 4-methoxy-2-methyl-benzoic acid. 1 H-NMR (400 MHz, CDCl 3): δ 7.91-7.86 (m, 1H), 6.72-6.67 (m, 2H), 3.86 (s, 3H), 2.57 (m, s, 3H).

PREPARATION 67 4-Methoxy-2-methyl-benzoic acid methyl ester To a suspension at ambient temperature of εΕ 2029547

4-methoxy-2-methyl-benzoic acid (1.0 g, 6.02 mmol) in MeOH (10 mL) is added thionyl chloride (1.10 mL, 15.04 mmol) dropwise. The reaction mixture is heated to reflux. After 3 h, the reaction is concentrated and the residue is partitioned between EtOAc and NaHCO 3. The aqueous layer is extracted with EtOAc and the combined organic layers are washed with brine, dried (MgSO4), filtered and concentrated to afford the title compound (877 mg, 81%). 1 H-NMR (400 MHz, CDCl 3): δ 7.95-7.91 (m, 1H), 6.77-6.72 (m, 2H), 3.86 (s, 3H), 3.84 ( s, 3H). The following list is of compounds which are prepared essentially according to the preparation of 4-methoxy-2-methyl-benzoic acid methyl ester using the appropriate starting material.

Preparation 67A: 1-p-tolyl-cyclopropanecarboxylic acid ethyl ester (98%), 1 H-NMR (400 MHz, CDCl 3): δ 7.24 (d, 2H, J = 7.9 Hz), 7 , 13 (d, 2H, J = 8.4 Hz), 3.62 (s, 3H), 2.34 (s, 3H), 1.60-1.57 (m, 2H) 1.15 (m, 2H).

Preparation 67B: 2-methyl-2-p-tolyl-propionic acid methyl ester (84%), 1 H-NMR (400 MHz, CDCl 3): δ 7.23 (d, 2H, J = 8.4 Hz) , 7.14 (d, 2H, J = 8.4 Hz), 3.65 (s, 3H), 2.33 (s, 3H), 1.57 (s, 6H).

Preparation 67C: 2-Bromo-4-methylbenzoic acid methyl ester, (quantitative), 1 H-NMR (400 MHz, CDCl 3) δ 7.73 (d, 1H, J = 7.9 Hz), 7 J = 7.6, 1.7 Hz), 3.91 (s, 3H), 2.36 (s, 3H). 89 ΡΕ2029547

PREPARATION 68 2- (4-Bromomethyl-phenyl) -2-methyl-propionic acid methyl ester To a refluxing solution of 2-methyl-2-p-tolyl-propionic acid methyl ester (892 mg, (826 mg, 4.64 mmol) in CCl 4 (120 mL) is added 2,2'-azobisisobutyronitrile (12 mg, 0.073 mmol). After 5 h, the reaction is concentrated and the residue is chromatographed (SiO 2, 120 g, 5% to 20% EtOAc / Hex) to give the title compound (906 mg, 72%) 1 H-NMR (400 MHz, CDCl 3: ): δ 7.38-7.28 (m, 4H), 4.48 (s, 2H), 3.65 (s, 3H), 1.57 (s, 6H). The following list is of compounds which are prepared essentially according to the preparation of 2- (4-bromomethyl-phenyl) -2-methyl-propionic acid methyl ester using the appropriate starting material.

Preparation 68A: 1- (4-Bromomethyl-phenyl) -cyclopropanecarboxylic acid ethyl ester (91%), 1 H-NMR (400 MHz, CDCl 3): δ 7.36-7.30 (m, 4H), 4 , 49 (s, 2H), 3.62 (s, 3H), 1.63-1.59 (m, 2H), 1.20-1.16 (m, 2H).

Preparation 68B: 2-Bromo-4-bromomethylbenzoic acid methyl ester (74%), 1 H-NMR (400 MHz, CDCl 3): δ 7.78 (d, 1H, J = 8.4 Hz) , 7.69 (d, 1H, J = 1.3Hz), 7.38 (dd, 1H, J = 8.4, 1.8Hz), 4.42 (s, 2H), 3.93 s, 3H). 90 ΡΕ2029547

PREPARATION 69 2- (4-Formyl-phenyl) -2-methyl-propionic acid methyl ester To a room temperature solution of (2- (4-bromomethyl-phenyl) -2-methylpropionic acid methyl ester 275 mg, 1.01 mmol) in DMSO (8 mL) is added sodium bicarbonate (127 mg, 1.52 mmol). The reaction mixture is warmed to 120øC. After 3 h, the reaction is concentrated and the residue is partitioned between EtOAc and NaHCO 3. The aqueous layer is extracted with EtOAc and the combined organic layers are washed with brine, dried (MgSO 4), dried filtered, concentrated, and chromatographed (EtOAc / Hex 0% to 20%) to give the title compound (179 mg, 86%) 1 H-NMR (400 MHz, CDCl 3) δ 10.00 (s, (D, 2H, J = 8.4 Hz), 3.67 (s, 3H), 1.61 (s, 6H). The following are compounds which are prepared essentially according to the preparation of 2- (4-formyl-phenyl) -2-methyl-propionic acid methyl ester using the appropriate starting material.

Preparation 69A: 1- (4-Formyl-phenyl) -cyclopropanecarboxylic acid ethyl ester (89%), 1 H-NMR (400 MHz, CDCl 3): δ 10.00 (s, 1H), 7.83 (d , 2H, J = 8.4Hz), 7.51 (d, 2H, J = 8.4

Hz), 3.64 (s, 3H), 1.70-1.65 (m, 2H), 1.25-1.21 (m, 2H).

Preparation 69B: 2-Bromo-4-formyl-benzoic acid methyl ester (52%), 1 H-NMR (400 MHz, CDCl 3): δ 10.02 (s, 1H), 91 ΡΕ2029547 8.14 (d J = 7.9 Hz), 7.86 (dd, 1H, J = 6.9, 1.0 Hz), 3.97 (d, 1H, (s, 3H).

Preparation 70 4- (2-Methoxy-Vinyl) -benzoic Acid Methyl Ester To a room temperature suspension of potassium tert-butoxide (2.05 g, 18.27 mmol) in THF (60 mL) is added (methoxymethyl) triphenylphosphonium chloride (6.26 g, 18.27 mmol). The reaction mixture is stirred at room temperature for 20 min. Solid 4-formylbenzoate (1.0 g, 6.09 mmol) is added and the reaction is stirred at room temperature overnight. The reaction mixture is quenched with saturated aq NH4 Cl and concentrated. The residue is partitioned between Et2 0 and water. The aqueous layer is extracted with Et 2 O and the combined organic layers are washed with brine, dried (MgSO 4), filtered, concentrated and chromatographed (0% to 30% EtOAc / Hex) to yield the title compound (939 mg, 80%). %) as a mixture of E / Z isomers. 1 H-NMR (4 C 10 MHz, δ O 3 O): δ 8.04 (d, 1H, J = 7.9 Hz), 7.89 (d, 1H, J = 7.9 Hz), 7.82 (dd, 1H, J = 7.9, 1.3 Hz), 8.04 (dd, 1H, J = 7.9, 0.9 Hz), 7.41-7.39 (m, 2H), 7.23-7.17 (m, 1H), 6.99 (d, 1H, J = 12.8 Hz), 6.74 (d, 1H, J = 12.8 Hz (D, 1H, J = 7.0 Hz), 3.89 (s, 6H), 3.76 (s, 3H) ), 3.73 (s, 3H). The following list is of compounds which are prepared essentially according to the preparation of 92 ΡΕ2029547 4- (2-methoxy-vinyl) -benzoic acid methyl ester using the appropriate starting material.

Preparation 70A: 3- (2-Methoxy-vinyl) -benzoic acid methyl ester (73%), 1 H-NMR (400 MHz, CDCl 3): δ 8.14 (s, 1H), 7.88 (s 1H), 7.80-7.74 (m, 3H), 7.40-7.27 (m, 3H), 7.09 (d, 2H, J = 13.1Hz), 6.17 ( d, 1H, J = 7.1Hz), 5.81 (d, 1H, J = 12.7Hz), 5.23 (d, 1H, J = 7.0Hz), 3.89 (s, 6H), 3.78 (s, 3H), 3.68 (s, 3H).

Preparation 70B: 3- (2-Methoxy-vinyl) -benzoic acid methyl ester (60%), 1 H-NMR (400 MHz, CDCl 3): δ 8.04 (d, 1H, J = 7.9 Hz) J = 7.9 Hz), 7.82 (dd, 1H, J = 7.9, 1.3 Hz), 8.04 (dd, 1H, J = 9, 0.9 Hz), 7.41-7.39 (m, 2H), 7.23-7.17 (m, 1H), 6.99 (d, 1H, J = 12.8 Hz) , 6.74 (d, 1H, J = 12.8 Hz), 6.22 (d, 1H, J = 7.0 Hz), 6.06 (d, 1H, J = 3.89 (s, 6H), 3.76 (s, 3H), 3.73 (s, 3H).

Preparation 71 4- (2-Oxo-ethyl) -benzoic acid methyl ester To a 0 ° C solution of 4- (2-methoxy-vinyl) -benzoic acid methyl ester (930 mg, 4.84 mmol ) in THF (50 mL) is added conc. HCI (7 mL) dropwise. After 2 h, the reaction is diluted with water and the pH is adjusted to 7. The aqueous layer is extracted with Et 2 O (2 x 200 mL). The combined organic layers are washed with brine, dried (MgSO4), filtered, concentrated and chromatographed (0% to 30% EtOAc / Hex) to give the title compound (613 mg, 71%). 1 H NMR (400 MHz, CDCl 3) δ 9.77 (t, 93 ΡΕ 2029547 1 Η, J = 2.2 Hz), 8.04 (d, 2H, J = 8.4 Hz), 7.30 (d, 2H, J = 8.8

Hz), 3.92 (s, 3H), 3.77 (d, 2H, J = 2.2 Hz). The following list is of compounds which are prepared essentially according to the preparation of 4- (2-oxo-ethyl) -benzoic acid methyl ester using the appropriate starting material.

Preparation 71A: 3- (2-Oxo-ethyl) -benzoic acid methyl ester (59%), -NMR (400 MHz, CDCl3): δ 9.78 (t, 1H, J = 2.2 Hz) , 7.98 (d, 1H, J = 7.5Hz), 7.91 (s, 1H), 7.48-7.39 (m, 2H), 7.48-7.39 (m, 2H ), 3.92 (s, 3H), 3.77 (d, 2H, J = 2.2 Hz).

Preparation 71B: 2- (2-Oxo-ethyl) -benzoic acid methyl ester (62%), 1 H-NMR (400 MHz, CDCl 3) δ 9.79 (t, 1H, J = 1.3 Hz) , 8.13-8.05 (m, 2H), 7.58-7.49 (m, 1H), 7.42-7.37 (m, 1H), 7.31-7.23 (m, 1H), 4.07 (d, 2H, J = 1.3Hz), 3.88 (s, 3H).

Preparation 72 (4-Mercapto-phenyl) -acetic acid methyl ester To a room temperature solution of 4-mercaptophenylacetic acid (5.0 g, 29.72 mmol) in MeOH (250 mL) is added sulfuric acid ( 1.25 mL). The reaction mixture is stirred at room temperature overnight. The reaction is concentrated and the residue is partitioned between Et2 0 and water. The aqueous layer is extracted with Et 2 O and the combined organic layers are washed with brine, dried (MgSO 4), filtered, concentrated, and dried.

(EtOAc 0% to 30% / Hex) to yield the title compound (3.69 g, 68%). 1H NMR (400 MHz, CDCl3): δ 7.21 (d, 2H, J = 7.9 Hz), 7.12 (d, 2H, J = 8.4 Hz), 3.66 (s, 3H ), 3.54 (s, 2H).

Preparation 73 1- (4-Benzyloxy-2-methyl-phenyl) -ethanone To a solution of hydroxy-2'-methylacetophenone (5.508 g, 0.037 mol) in DMF (10 mL) is added cesium carbonate (23.8 g , 0.073 mol). The reaction is stirred at room temperature for 10 minutes. Benzyl bromide (4.36 mL, 0.037 mol) is added and after 1 hour at room temperature, the reaction is concentrated under reduced pressure. The residue is dissolved in ethyl acetate and water. The layers are separated and the organic phase is washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound. ES / MS m / e 241.0 (M + 1).

PREPARATION 74 (E / Z) -3- (4-Benzyloxy-2-methyl-phenyl) -but-2-enoic acid ethyl ester To a solution of triethyl phosphonoacetate (1.25 mL, 0.006 mol) in DMF (5 mL) is added sodium hydride (0.25 g, 0.006 mol). After 30 minutes, 1- (4-benzyl-xy-2-methyl-phenyl) -ethanone (0.5 g, 0.002 mol) is added and the reaction is heated to 80 ° C overnight. In cooling, water is added followed by 1 N HCl. The aqueous layer is extracted twice with ethyl acetate and the organic layers are combined, washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound as a white solid. to give the title compound. 1 H-NMR (CDCl 3): δ 1.27 (t, 3H), 2.25 (s, 3H), 2.4 (s, 3H), 4.17 (q, 2H), 5.0 (s, 2H), 5.72 (s, 1H), 6.75 (dd, 1H), 6.8 (s, 1H), 6.98 (d, 1H), 7.27-7.45 (m, 5H ).

PREPARATION 75 (+/-) - 3- (4-Hydroxy-2-methyl-phenyl) -butyric acid ethyl ester To a solution of (E / Z) -3- (4- benzyloxy-2-methyl-phenyl) -but-2-enoic acid in ethyl alcohol is added 10% palladium on carbon. The reaction is placed under 40 psi of hydrogen gas for 6 hours. The catalyst is filtered over diatomaceous earth and the filtrate is concentrated under reduced pressure to give the title compound. ES / MS m / e 221.0 (M-1)

Preparation 76 (+/-) - 3- {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl } -butyric acid ethyl ester To a solution of (+/-) - 3- (4-hydroxy-2-methyl-phenyl) -butyric acid ethyl ester (0.366 g, 0.748 mmol) in DMF (4 mL) of cesium (1.1 g, 1.5 mmol). After 5 minutes at room temperature, methyl 5-chloro-1- (2,6-dichloro-phenyl) -4-isopropyl-1H-pyrazole (0.50 g, 0.748 mmol) is added and the reaction is warmed to 50 ° C overnight. Upon cooling, water is added followed by 1N HCl. The resulting mixture is extracted twice with ethyl acetate and the organic layers are combined and washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified via flash chromatography " eluting with 3-5% ethyl acetate / toluene to give the title compound. 1 H-NMR (CDCl 3): δ 1.113-1.163 (m, 6H), 1.26 (d, 6H), 2.399-2.532 (m, 2H), 2.952 (m, 1H), 3.388 (m, 1H) , 4.024 (q, 2H), 4.741 (s, 2H), 6.513 (d, 1H), 6.54 (dd, 1H), 6.970 (d, 1H), 7.264 (t, 1H), 7.372 , 2H), 7.661 (s, 1H)

Preparation 77 (+/-) 3- {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -butan-1 (+/-) - 3- {4- [2- (2,6-dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl- -phenyl} -butyric acid methyl ester (0.581 g, 1.19 mmol) is dissolved in THF (15 mL) and methyl alcohol (3 mL). Sodium tetrahydride is added portionwise until excess is added. After stirring at room temperature for 3 days, the reaction is quenched with water followed by 1N HCl. The resulting mixture is extracted twice with ethyl acetate. The organic layers are combined, washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified via flash chromatography " eluting with 5-10% ethyl acetate: toluene to give the title compound. 1 H-NMR (CDCl 3): δ 1.134 (d, 3H), 1.262 (d, 6H), 1.456 (s, 2H), 1.764 (m, CM 2.223 (s, 3H), 2.939-3.039 (m, 2H (D, 1H), 6.99 (dd, 1H), 6.99 (d, 1H), 7.263 (t, 1H), 7.37 (m, 1H). d, 2H), 7.663 (s, 1H).

PREPARATION 78 (+/-) - 2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} ) -3-nitro-benzenesulfonic acid To a solution of (+/-) - 3- {4- [2- (2,6-dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2- (0.245 g, 0.548 mmol) in dichloromethane (10 mL) is added triethylamine (0.15 mL, 1.09 mmol). After 10 minutes, m-nitrobenzenesulfonyl chloride (0.243 g, 1.09 mmol) is added. The reaction is stirred at room temperature for 4 hours and the reaction mixture is concentrated under reduced pressure. The residue is dissolved in ethyl acetate and washed with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound. 1 H-NMR (CDCl 3): δ1.1 (d, 3H),. 1.28 (d, 6H), 1.62 (s, 2H), 1.85-1.95 (m, 2H), 2.17 (s, 3H), 2.91-3.009 (m, 2H), 3.85-3.95 (m, 1H), 4.04-4.12 (m, 2H), 4.74 (s, 2H), 6.45 (d, 1H), 6.51 (d, 1H), 6.86 (d, 1H), 7.26 (t, 1H), 98 ΡΕ2029547 7.38 (d, 2H), 7.65 (t, 3H), 8.1 (d, 1H), 8.39 (d, 1H), 8.63 (s, 1H).

Preparation 79 3- {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -butyl ester (+/-) - 4-sulfonic acid The title compound is prepared essentially according to the preparation of 2,6-dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl- phenyl} -butyl ester using 3-nitro-benzenesulfonic acid using the appropriate starting material. 1 H-NMR (CDCl 3): δ 1.057 (d, 3H), 1.264 (d, 6H), 1.86 (q, (d, 1H), 6.94 (d, 1H), 6.97 (d, 1H), 6.94 (m, 1H) 864 (d, 1H), 7.26 (t, 3H), 7.373 (d, 2H), 7.682 (d, 3H).

Preparation 80 4- [1- (4-Hydroxy-2-methyl-phenyl) -ethylamino] -benzoic acid methyl ester

A mixture of methyl 4-aminobenzoate (260 mg, 1.72 mmol) and 4'-hydroxy-2'-methyl-acetophenone in glacial acetic acid (8 mL) is heated to 50 ° C for 50 minutes. The mixture is cooled to room temperature and sodium triacetoxyborohydride (750 mg, 3.54 mmol) is added. After 20 hours, more sodium triacetoxyborohydride (750 mg, 3.54 mmol) is added. Again after 24 hours, more sodium triacetoxyborohydride (750 mg, 99 ΡΕ2029547 3.54 mmol) is added. After seven hours the mixture is concentrated and the residue is partitioned between ethyl acetate and saturated sodium bicarbonate. The layers are separated and the aqueous layer is extracted with ethyl acetate (2x). The combined ethyl acetate layers are dried (MgSO4) and concentrated under reduced pressure. The residue is purified by flash chromatography " to provide the title compound (84 mg, 17%). 1 H-NMR (DMSO-d 6, 400 MHz): δ 9.06 (s, 1H), 7.55 (d, J = 9.2 Hz, 2H), 7.02 (d, 8.4 Hz, 1H ), 6.87 (d, 6.8 Hz, 1H), 6.51-6.39 (m, 4H), 4.53 (m, 1H), 3.66 (s, 3H), 2.25 (s, 3H), 1.31 (d, 6.4 Hz, 3H).

PREPARATION 81 3- (4-Hydroxy-2-methyl-benzylamino) -benzoic acid ethyl ester

Step A

A mixture of 2-methyl-4-benzyloxy benzaldehyde (1.22 g, 5.39 mmol) and ethyl 3-aminobenzoate (912 mg, 5.52 mmol) in glacial acetic acid (40 mL) is stirred for 30 minutes . To the mixture is added sodium triacetoxyborohydride (1.25 g, 5.90 mmol). After 20 hours the mixture is concentrated and the residue is partitioned between ethyl acetate and saturated sodium bicarbonate. The layers are separated and the aqueous layer is extracted with ethyl acetate (2x). The combined ethyl acetate layers are dried (MgSO4) and concentrated. The residue is purified by flash chromatography " to afford the benzyl intermediate (1.6 g, 80%). 100 ΡΕ2029547

Step B To a solution of the benzyl intermediate of Step A (471 mg, 1.25 mmol) in ethyl acetate (20 mL) under nitrogen is added 10% palladium on carbon (80 mg). The mixture is evacuated and is stirred under hydrogen overnight. The mixture is filtered over Celite and concentrated under reduced pressure to provide the title product as a solid (300 mg, 84%). ES / MS m / e 284.3 (M-1).

PREPARATION 82 4- (4-Hydroxy-2-methyl-benzylamino) -benzoic acid methyl ester The title compound (546 mg, 91%) is prepared essentially according to the procedure for 3- - (4-hydroxy-2-methyl-benzylamino) -benzoic acid methyl ester using 2-methyl-4-benzyloxy benzaldehyde and methyl 4-amino benzoate. ES / MS m / e 270.3 (M-1)

To a room temperature solution of 2-bromo-4-formyl-benzoic acid methyl ester (500 mg, 2.05 mmol) in dichloromethane is added triethylamine (2.0 mL, 14.35 mmol), dichlorobis (triphenylphosphine) palladium (II) (144 mg, 0.205 mmol, 10 mol%), 101 ΡΕ 202 9547 iodide

copper (I) (20 mg, 0.103 mmol, 5 mol%) and 1-pentyne (406 μl, 4.10 mmol). The reaction mixture is heated to 80 ° C in a sealed tube. After 2 h, the reaction is concentrated and the residue is chromatographed (0% to 10% EtOAc / Hex) to give the title compound (279 mg, 59%). 1 H-NMR (400 MHz, CDCl 3): δ 10.03 (s, 1H), 8.02-7.98 (m, 2H), δ (dd, 1H, J = 7.9, 1.8 Hz ), 3.95 (s, 3H), 2.48 (t, 2H, II <10

Hz), 1.73-1.63 (m, 2H), 1.09 (t, 3H, J = 7.5 Hz).

Preparation 84 4-Formyl-2-methyl-benzoic acid methyl ester

Under a N 2 atmosphere, a 1 L Parr autoclave is charged with palladium (II) acetate (2.19 g, 0.0097 mol) and butyl-1-diadamantylphosphine (10.42 g, 0.291 mol) in toluene ( 100ml). To this mixture is added (4-bromo-2-methyl-benzoic acid methyl ester (222 g, 0.969 mol) and tetramethylethylenediamine (97.1 mL, 0.63 equiv) in toluene (325 mL) is sealed and removed from the N 2 atmosphere.A constant pressure of SynGas (equal mixture in CO / H2, 75psi) is applied to the autoclave.The reaction is stirred for 18 hours at 85Â ° C. The crude mixture is filtered through a Celite pad and is washed with CH 2 Cl 2 until clarified.The solvent is removed under reduced pressure to give an oil

red (86%) that will crystallize at rest. 1 H-NMR (400 MHz, CDCl 3): δ 2.6 (3H, s), 3.85 (3H, s), 7.65-8.0 (3H, m), 10.0 (1H, s) . 102 ΡΕ2029547 The following list is of compounds which are prepared essentially according to the preparation of 4-formyl-2-methyl-benzoic acid methyl ester using the appropriate starting material.

Preparation 84A: Methyl 2-benzyloxy-4-formyl-benzoic ester (384 mg, 86%), LC-ES / MS m / e 293.0 (M + 23).

Preparation 84B: 4-Formyl-2-trifluoromethyl-benzoic acid methyl ester (1.29 g, 92%), LC-ES / MS m / e 233.3 (M + 1).

Preparation 84C: 3-Formyl-5-trifluoromethyl-benzoic acid methyl ester (0.5 g, 78%), 1 HNMR (CDCl3) (ppm): 3.95 (3H, s), 8.25 ( 1H, s), 8.5 (1H, s), 8.7 (1H, s), 10.1 (1H, s).

To a solution of 4-iodo-3-methyl-benzoic acid (5.2 g, 20 mmol) in THF (30 mL) was added triethylamine (4-Iodo-3-methylphenyl) -methanol (EtOAc / hexane gradient) ) is added 2.0M borane dimethylsulfide complex in THF (40.0 mL, 80 mmol) dropwise. The mixture is stirred overnight. The reaction mixture is quenched carefully at 0 ° C with methanol (20 mL) and the mixture is evaporated to dryness under reduced pressure. The residue is partitioned between EtOAc (80 mL) and water (60 mL). The organic phase is washed with brine (60 mL), dried (Na 2 SO 4), filtered and concentrated under reduced pressure to a residue. The residue is purified by flash chromatography &quot; The title compound was obtained as a white solid (4.7 g, 95%). 1 H-NMR (CDCl3) (ppm): 2.4 (3H, s), 4.55 (2H, s), 6.8-7.75 (3H, m). The following list is of compounds which are prepared essentially according to the preparation of (4-iodo-3-methyl-phenyl) -methanol using the appropriate starting material.

Preparation 85A: (4-Iodo-3-trifluoromethyl-phenyl) -methanol (2.1 g, 92%), 1 H NMR (CDCl3) (ppm): 2.18 (1H, s), 4.8 (2H, s), 7.4-8.0 (3H, m).

Preparation 85B: (3-Iodo-5-trifluoromethyl-phenyl) -methanol (2.1 g, 92%), 1 HNMR (CDCl3) (ppm): 2.7 (1H, s), 4.65 , s), 7.5-7.85 (3H, m).

Preparation 86 4-Hydroxymethyl-2-methyl-benzoic acid methyl ester To a 50 mL Parr alloy pressure reactor is added palladium acetate (0.161 g, 0.7 mmol, 1,4 bis- (diphenylphosphino) butane (DPPB) (0.363 g, 0.85 mmol), (4-iodo-3-methyl-phenyl) -methanol (1.80 g, 7.25 mmol), dry methanol (10.0 mL), dry triethylamine (5.25 mL, 37.7 mmol) and dry acetonitrile (15.0 mL).

is evacuated and filled with nitrogen (4x). The reaction vessel is then evacuated and filled with carbon monoxide (4x). The reaction vessel is pressurized with carbon monoxide (100 psig, 690 KPa), sealed and stirred at 100 ° C 104 ΡΕ 2029547 for 4 hours while the carbon monoxide pressure is maintained at 100 psig. The reaction mixture is cooled to room temperature and the carbon monoxide is vented from the reaction vessel. After filtration, the filtrate is concentrated to a residue. The residue is partitioned between EtOAc (50 mL) and water (50 mL). The organic phase is washed with brine (50 mL), dried (Na 2 SO 4), filtered and concentrated under reduced pressure to a residue. The residue is purified by flash chromatography &quot; to give the title compound as a syrup (1.18 g, 90%). LC-ES + MS m / e 181.3 (M + 1). The following list is of compounds which are prepared essentially according to the preparation of 4-hydroxymethyl-2-methyl-benzoic acid methyl ester using the appropriate starting material.

Preparation 86A: 2-Benzyloxy-4-hydroxymethyl-benzoic acid methyl ester (450 mg, 40%), LC-ES / MS m / e 273.0 (M + 1).

Preparation 86B: 4-Methyl-naphthalene-1-carboxylic acid ethyl ester (3.85 g, 85%), LC-ES / MS m / e 201.0 (M + 1).

Preparation 86C: 4-Hydroxymethyl-2-trifluoromethyl-benzoic acid methyl ester (1.42 g, 87%), LC-ES / MS m / e 235.0 (M + 1).

Preparation 86D: 3-Hydroxymethyl-5-trifluoromethyl-benzoic acid methyl ester (0.65 g, 24%), 1 HNMR (CDCl3) (ppm): 3.05 (1H, br s), 3.9 (3H , s), 4.7 (2H, s), 7.75 (1H, s), 8.1 (2H, s). 105 ΡΕ2029547

Preparation 86E: 2-Benzoyl-4-methyl-benzoic acid methyl ester (67 g, 49%), LC-ES / MS m / e 255.3 (M + 1).

Preparation 87 4-Formyl-2-methyl-benzoic acid methyl ester To a 0 ° C solution of 4-hydroxymethyl-2-methyl-benzoic acid methyl ester (0.49 g, 2.7 mmole) in (8.0 mL) is added sodium bicarbonate (0.46 g, 5.4 mmol) and Dess-Martin periodinane (0.14 g, 3.3 mmol) sequentially. The mixture is stirred at room temperature for 1.0 h and quenched with water (2.0 mL). The mixture is partitioned between CH 2 Cl 2 (30 mL) and water (30 mL). The organic phase is washed with brine (30 mL), dried (Na 2 SO 4), filtered and concentrated under reduced pressure to a residue. The residue is purified by flash chromatography &quot; to give the title compound as a syrup (0.35 g, 72%). 1 HNMR (CDCl 3) (ppm): 2.6 (3H, s), 3.85 (3H, s), 7.65-8.0 (3H, m), 10.0 (1H, s). The following list is of compounds which are prepared essentially according to the preparation of 4-formyl-2-methyl-benzoic acid methyl ester using the appropriate starting material.

Preparation 87A: 2-Bromo-4-formyl-benzoic acid methyl ester (440 mg, 61%), LC-ES / MS m / e 261.0 (M + 18).

Preparation 87B: 2-Butoxy-4-oxo-2-methyl-benzoic acid methyl ester (240 mg, 90%), LC-ES / MS m / e 237.3 (M + 1).

Preparation 87C: 2-Butyrylamino-4-formyl-benzoic acid methyl ester (550 mg, 87%), LC-ES / MS m / e 250.3 (M + 1), 248.3 (M-1).

Preparation 87D: 4-Formyl-2- (propane-1-sulfonylamino) -benzoic acid methyl ester (447 mg, 82%), LC-ES / MS m / e 303.3 (M + 18), 284 , 3 (M1).

Preparation 88 3-Benzyloxy-4-iodo-benzoic acid methyl ester The mixture of 3-hydroxy-4-iodo-benzoic acid methyl ester (1.2 g, 4.3 mmol), potassium carbonate 1.78 g, 13 mmol), acetone (15.0 mL), benzyl bromide

(1.5 g, 8.6 mmol), and TBAI (0.05 g) is heated to 50 ° C overnight. The solvent is removed under reduced pressure. The residue is partitioned between EtOAc (30 mL) and water (30 mL). The organic phase is washed with brine (20 mL), dried (Na2 SO4 &gt; 4), filtered and concentrated under reduced pressure to a residue. The residue is purified by flash chromatography &quot; to give the title compound as a white solid (1.58 g, 99%). LC-ES + MS m / e 386.0 (M + 18).

Preparation 89 3-Benzyloxy-4-iodo-phenyl) -methanol The mixture of 3-benzyloxy-4-iodo-benzoic acid methyl ester (1.58 g, 4.3 mmol), lithium hydroxide 107 ΡΕ2029547 (10 mL), and water (10 mL) is stirred at room temperature for 2.0 h and is acidified with 1.0 M HCl. The mixture is partitioned between EtOAc (30 mL) and water (30 mL). The organic phase is washed with brine (20 mL), dried (Na 2 SO 4), filtered and concentrated under reduced pressure to give the intermediate product. The intermediate product is dissolved in THF (20 mL), and treated with borane complex 2.0 M dimethyl sulphide in THF (10 mL, 20 mmol) overnight. The reaction mixture is quenched carefully at 0 ° C with methanol (10 mL) and evaporated to dryness under reduced pressure. The residue is partitioned between EtOAc (30 mL) and water (30 mL). The organic phase is washed with brine (30 mL), dried (Na 2 SO 4), filtered and concentrated under reduced pressure to a residue. The residue is purified by flash chromatography &quot; to give the title compound as a white solid (1.32 g, 90%). LC-ES + MS m / e 358.0 (M + 18).

Preparation 90 2-Isopropoxy-4-methyl-benzoic acid methyl ester To a mixture of 2-hydroxy-4-methyl-benzoic acid methyl ester (1.0 g, 6.0 mmol), triphenylphosphine (1.9 g, 7.2 mmol), and isopropanol (0.72 g, 12.0 mmol) in THF (10.0 mL) is added DIAD (1.45 g, 7.2 mmol) dropwise at 0 ° C. The mixture is stirred at room temperature overnight. The mixture is evaporated to dryness under reduced pressure. The residue is partitioned between EtOAc 108 ΡΕ2029547 (50 mL) and water (50 mL). The organic phase is washed with brine (50 mL), dried (Na 2 SO 4), filtered and concentrated under reduced pressure to a residue. The residue is purified by flash chromatography &quot; to give the title compound as a white solid (1.4 g, 96%). LC-ES + MS m / e 209.0 (M + 1). The following list is of compounds which are prepared essentially according to the preparation of 2-isopropoxy-4-methyl-benzoic acid methyl ester using the appropriate starting material.

Preparation 90A: 2-Butoxy-4-methyl-benzoic acid methyl ester (1.0 g, 74%), LC-ES / MS m / e 223.3 (M + 1).

Preparation 90B: 2-Butoxy-5-methyl-benzoic acid methyl ester (0.85 g, 64%), LC-ES / MS m / e 223.3 (M + 1).

Preparation 90C: 5-Butoxyiso-phthalic acid dimethyl ester (2.1 g, 83%), LC-ES / MS m / e 284.0 (M + 1).

Preparation 91 4-Bromomethyl-2-isopropoxy-benzoic acid methyl ester The mixture of 2-isopropoxy-4-methyl-benzoic acid methyl ester (1.0 g, 4.8 mmol), dibenzoyl peroxide (100 mg) and NBS (0.85 g, 4.8 mmol) in CCl 4 (20 mL) is heated at 70 ° C overnight. The solid is filtered off and the filtrate is concentrated to a residue. The residue is purified by flash chromatography &quot; 109 ΡΕ2029547 to afford the title compound as a white solid (0.7 g, 51%). LC-ES / MS m / e 287.0 (M + 1). The following list is of compounds which are prepared essentially according to the preparation of 4-bromomethyl-2-isopropoxy-benzoic acid methyl ester using the appropriate starting material.

Preparation 91A: 4-Bromomethyl-2-butoxy-benzoic acid methyl ester (0.6 g, 52%), LC-ES / MS m / e 301.0 (M + 1).

Preparation 91B: 5-Bromomethyl-2-butoxy-benzoic acid methyl ester (0.44 g, 65%), LC-ES / MS m / e 301.0 (M + 1).

Preparation 91C: 3-Bromomethyl-5-methyl-benzoic acid methyl ester (2.73 g, 62%), LC-ES / MS m / e 260.0 (M + 18).

Preparation 91D: 6-Bromomethyl-nicotinic acid methyl ester (575 mg, 43%), LC-ES / MS m / e 230.0 (M + 1).

Preparation 91E: 4-Bromomethyl-2,3-difluoro-benzoic acid methyl ester (1.95 g, 76%), LC-ES / MS m / e 282.0 (M + 18).

Preparation 91F: 4-Bromomethyl-3-trifluoromethyl-benzoic acid methyl ester (0.7 g, 89%), 1 H NMR (CDCl3) (ppm): 3.85 (3H, s), 4.6 ( 2H, s), 7.4-8.3 (3H, m).

Preparation 91G: 2-Bromo-4-methyl-benzoic acid (4.3 g, 63%), LC-ES / MS m / e 292.7 (M-1).

Preparation 91H: 4-Bromomethyl-2-butyrylamino benzoic acid methyl ester (2.9 g, 98%). LC-ES + MS m / e 314.0 (M + 1). 110 ΡΕ2029547

Preparation 911: 4-Bromomethyl-naphthalene-1-carboxylic acid ethyl ester (1.44 g, 86%), LC-ES / MS m / e 281.0 (M + 1).

Preparation 91J: 2-Benzoyl-4-bromomethyl-benzoic acid methyl ester (450 mg, 51%), LC-ES / MS m / e 333.0 (M + 1).

Preparation 91K: 4-Bromomethyl-2- (propane-1-sulfonylamino) -benzoic acid methyl ester (3.75 g, 91%), LC-ES / MS m / e 350.0 (M + 1) , 367.0 (M + 18).

Preparation 92 2,3-Difluoro-4-methyl-benzoic acid methyl ester To a solution of 2,3-difluoro-4-methylbenzoic acid (5.0 g, 29 mmol) in CH2 Cl2 (20 mL) and MeOH (20 mL) is added 2.0M TMSCHN2 in hexane (17.5 mL, 34.9 mmol) at 0 ° C. The reaction mixture is stirred for 1.0 h. The reaction mixture is concentrated to a residue and the residue is purified by flash chromatography &quot; to give the title compound as an oil (5.7 g, 100%). LC-ES + MS m / e 208.3 (M + 23).

PREPARATION 93 4-Methyl-3-trifluoromethyl-benzoic acid methyl ester The title compound (580 mg, 95%) is prepared essentially according to the preparation of 2,3-difluoro-4- methyl-benzoic acid using 4-methyl-3-trifluoromethyl acid. LC-ES + MS m / e 236.3 (M + 18). 111 ΡΕ2029547

Preparation 94 2-Bromo-4-hydroxymethyl-benzoic acid methyl ester The mixture of 2-bromo-4-methyl-benzoic acid (9.5 g, 32.3 mmol), THF (30.0 mL), and 5.0 M NaOH (26 mL, 129 mmol) is stirred at room temperature overnight. The mixture is acidified with 5.0 M HCl and extracted with EtOAc (80 mL). The organic phase is washed with brine (60 mL) and is dried (Na2 SO4 &gt; 4). After filtration, the filtrate is concentrated under reduced pressure to a residue. The residue is dissolved in CH2 Cl2 (50 mL) and MeOH (50 mL) and treated with 2.0 M TMSCHN2 in hexane (30 mL, 60 mmol) at 0 ° C for 1.0 h. The reaction mixture is concentrated to a residue and the residue is purified by flash chromatography &quot; to give the title compound as a solid (2.3 g, 29%). LC-ES + MS m / e 247.0 (M + 1). The following list is of compounds which are prepared essentially according to the preparation 2-bromo-4-hydroxymethyl-benzoic acid methyl ester using the appropriate starting material.

Preparation 94A: 2-Butoxy-4-hydroxy-methyl-benzoic acid methyl ester (270 mg, 68%), LC-ES / MS m / e 239.3 (M + 1).

Preparation 94B: 4-Hydroxymethyl-2- (propane-1-sulfonylamino) -benzoic acid methyl ester (580 mg, 19%), LC-ES / MS m / e 305.0 (M + 18), 286 , 3 (M1).

Preparation 94C: 2-Butyrylamino-4-hydroxymethyl-benzoic acid methyl ester (640 mg, 28%), LC-MS: 252.3 (M + 1). 112 ΡΕ2029547

Preparation 95 2-Bromo-4- [1,3] dioxin-2-yl-benzoic acid methyl ester The mixture of 2-bromo-4-formyl-benzoic acid methyl ester (440 mg, 1.8 mmol), ethylene glycol (1.1 g, 18 mmol) and p-toluenesulfonic acid (30 mg) in THF (10 mL) is stirred at ambient temperature overnight. The reaction mixture is partitioned between EtOAc (30 mL) and water (30 mL). The organic phase is washed with brine (30 mL), dried (Na 2 SO 4), filtered and concentrated under reduced pressure to a residue. The residue is purified by flash chromatography &quot; to give the title compound as a syrup (380 mg, 73%). LC-ES / MS m / e 287.0 (M + 1).

Preparation 96 4- [1,3] Dioxin-2-yl-2-pentyl-benzoic acid methyl ester To a degassed solution of 2-bromo-4- [1,3] dioxin-2 (380 mg, 1.3 mmol) in THF (10 mL) is added PdCl2 (dppf) 2 (108 mg, 0.13 mmol) and n-pentylzinc bromide (0.5 M in THF, , 0 mL, 4.0 mmol). The mixture is heated to 50 ° C overnight. After cooling to room temperature, the mixture is partitioned between EtOAc (30 mL) and water (30 mL). The organic phase is washed with brine (30 mL), dried (Na 2 SO 4), filtered and concentrated under reduced pressure to a residue. The residue is purified by flash chromatography &quot; to give the title compound 113 ΡΕ2029547 in the form of a syrup (360 mg, 98%). LC-ES + MS m / e 279.3 (M + 1).

Preparation 97 4-Formyl-2-pentyl-benzoic acid methyl ester To a solution of 4- [1,3] dioxin-2-yl-2-pentyl-benzoic acid methyl ester (360 mg, 3 mmol) in THF (5.0 mL) is added concentrated HCl (0.55 mL, 6.5 mmol). The reaction is stirred for 2.0 h. The reaction mixture is partitioned between EtOAc (20 mL) and water (20 mL). The organic phase is washed with brine (20 mL), dried (Na2 SO4 &gt; 4), filtered and concentrated under reduced pressure to a residue. The residue is purified by flash chromatography &quot; to give the title compound as a syrup (236 mg, 98%). LC-ES + MS m / e 235.3 (M + 1).

Preparation 98 To a 0 ° C solution of 2-amino-4-methyl-benzoic acid methyl ester (1.5 g, 9.0 mmol) and 2-butyrylamino-4-methyl-benzoic acid methyl ester triethylamine (1.4 g, 13.5 mmol) in methylene chloride (30.0 mL) is added butyryl chloride (1.2 g, 10.8 mmol) dropwise. The mixture is stirred at 0 ° C for 30 min and quenched with saturated sodium bicarbonate (10 mL). The organic phase is washed with brine (20 mL), dried (Na 2 SO 4), filtered and concentrated under reduced pressure to a residue. The residue is purified by flash chromatography &quot; to 114 ΡΕ2029547 to produce the title compound as a syrup (2.2 g, 100%). LC-ES + MS m / e 236.3 (M + 1). The following compound is prepared essentially according to the preparation of 2-butyrylamino-4-methyl-benzoic acid methyl ester using the appropriate starting material.

Preparation 98A: 4-Methyl-2- (propane-1-sulfonylamino) -benzoic acid methyl ester (3.2 g, 93%), LC-ES / MS m / e 272.3 (M + 1) , 289.2 (M + 18).

To a 0 ° C suspension of 4-amino-3-trifluoromethyl benzoic acid (1.8 g, 8.8 mmol) in conc. HCl (30.0 g) in dichloromethane mL) is added a solution of sodium nitrite (0.76 g, 11.0 mmol) in water (15 mL) dropwise. The mixture is stirred at 0-10 ° C for 30 min. A solution of potassium iodide (14.6 g, 88 mmol) in water (25 mL) is added dropwise. The mixture is stirred at room temperature for 1.0 h. The reaction mixture is extracted with EtOAc (80 mL), washed with brine (80 mL), dried (Na2 SO4 &gt; 4), filtered and concentrated under reduced pressure to a residue. The residue is purified by flash chromatography &quot; to give the title compound as a solid (2.4 g, 86%). LC-ES / MS: 339.3 (M + 23), 315.0 (M-1). 115 ΡΕ2029547

Preparation 100 3-Iodo-5-trifluoromethyl-benzoic acid The title compound (3.86 g, 78%) is prepared essentially according to the procedure of 4-iodo-3-trifluoromethyl-benzoic acid using the starting material appropriate. LC-ES / MS m / e 315.0 (M-1).

Preparation 101 5-Butoxy-isophthalic acid monomethyl ester

A suspension of 5-butoxy-isophthalic acid dimethyl ester (2.0 g, 7.5 mmol) in THF / MeOH / water (5.0 mL each) is treated with lithium hydroxide (0.22 9.0 mmol) at room temperature for 1.0 h. The reaction mixture is acidified with 1.0 M HCl and the product is extracted with EtOAc (30 mL), washed with brine (30 mL), dried (Na 2 SO 4), filtered and concentrated under reduced pressure to a residue. The residue is purified by flash chromatography &quot; to yield the title compound as a solid (1.0 g, 53%). LC-ES / MS m / e 270.3 (M + 18), 251.3 (M-1).

Preparation 102 (3-Butoxy-5-hydroxymethyl-phenyl) -methanol

A solution of 5-butoxy-isophthalic acid monomethyl ester (1.0 g, 4.0 mmol) in THF (20 mL) is treated with 2.0 M borane complex dimethylsulfide in hexane (10 mL, 20 mmol). The mixture is stirred at room temperature for 48 h. The mixture is quenched carefully with methanol (10 mL) and concentrated to dryness. The residue is purified by flash chromatography &quot; to yield the title compound as a solid (0.78 g, 88%). LC-ES + MS m / e 211.3 (M + 1).

Preparation 103 3-Butoxy-5-formyl-benzoic acid

Step A (3-Butoxy-5-hydroxymethyl-phenyl) -methanol (780 mg, 3.7 mmol) is oxidized to the aldehyde (740 mg, 97%) by the procedure essentially as described in the synthesis of 4-methyl -formyl-2-methyl-benzoic acid. LC-ES + MS m / e 206.1 (M + 1).

Step B The intermediate aldehyde of Step A (740 mg, 3.6 mmol) is dissolved in DMF (5.0 mL) and treated with Oxone (2.2 g, 3.6 mmol) at room temperature for 2.0 h . The reaction is quenched with 10% sodium bisulfite (10 mL) and the product is extracted with EtOAc (40 mL), washed with brine (30 mL), dried (Na 2 SO 4), filtered and concentrated under reduced pressure to a residue. The residue is purified by flash chromatography &quot; to give the title compound as a white solid which is contaminated with the overproduced bis-acid secondary product (800 mg, 100%). LC-ES + MS m / e 221.3 (M-1). 117 ΡΕ2029547

Preparation 104 4-Amino-3-methyl-phenol (10.8 g, 88 mmol) in THF (80 mL) and sodium bicarbonate (50 mL) is added benzyl chloroformate (18.0 g, 105 mmol) dropwise. The reaction mixture is stirred for 1.0 h. The two phases are separated and the organic phase is concentrated to a residue. The residue is partitioned between EtOAc (100 mL) and 5% HCl (50 mL). The organic phase is washed with brine (100 mL), dried (Na 2 SO 4), filtered and concentrated under reduced pressure to a residue. The residue is purified by flash chromatography &quot; to yield the title compound as a brown solid (21.0 g, 93%). LC-ES / MS m / e 258.3 (M + 1), 256.0 (M-1).

Preparation 105 [4- (tert-Butyl-dimethyl-silanyloxy) -2-methyl-phenyl] -carbamic acid benzyl ester To a solution of (4-hydroxy-2-methyl) -carbamic acid benzyl ester (21.0 g, 81.7 mmol) and imidazole (6.7 g, 98 mmol) in DMF (100 mL) is added a solution of tert-butyldimethylsilyl chloride (14.8 g, 98 mmol) in DMF ( 20 mL) at 0 ° C. After addition, the mixture is stirred at room temperature for 30 min. The solvent is removed under reduced pressure to give a residue, which is partitioned between EtOAc (100 mL) and 5% HCl (50 mL). The organic phase 118 E2029547 is washed with brine (100 mL), dried (Na2 SO4), filtered and concentrated under reduced pressure to a residue. The residue is purified by flash chromatography &quot; to give the title compound as a yellowish solid (28.8 g, 95%). LC-ES + MS m / e 372.3 (M + 1).

Preparation 106 [4- (tert-Butyl-dimethyl-silanyloxy) -2-methyl-phenyl] -methyl-carbamic acid benzyl ester To a solution of [4- (tert-butyl-dimethyl (18 g, 48.5 mmol) in DMF (100 mL) is added sodium hydride (60% dispersion in oil, 2.3 g, 58 mmol) in portions at 0 ° C. The mixture is stirred at room temperature for 30 min, followed by the addition of iodomethane (8.2 g, 58 mmol). The mixture is stirred at room temperature overnight. The solvent is removed under reduced pressure to give a residue, which is partitioned between EtOAc (100 mL) and water (100 mL). The organic phase is washed with brine (100 mL), dried (Na 2 SO 4), filtered and concentrated under reduced pressure to a residue. The residue is purified by flash chromatography &quot; to yield the title compound as an oil (14.0 g, 75%). LC-ES + MS m / e 386.0 (M + 1).

Preparation 107 [4- (tert-Butyl-dimethyl-silanyloxy) -2-methyl-phenyl] -methylamine 119 ΡΕ2029547

The mixture of [4- (tert-butyl-dimethyl-silanyloxy) -2-methyl-phenyl] -methyl-carbamic acid benzyl ester (14.0 g, 36.0 mmol) and palladium on carbon (10% m / m, 0.5 g) in methanol (100.0 mL) is stirred under an atmosphere of hydrogen at room temperature overnight. The reaction mixture is filtered and the filtrate is concentrated under reduced pressure to a residue. The residue is purified by flash chromatography &quot; to give the title compound as an oil (7.4 g, 81%). LC-ES + MS m / e 252.3 (M + 1).

Preparation 108 4 - ({[4- (tert-Butyl-dimethyl-silanyloxy) -2-methyl-phenyl] -methyl-amino} -methyl) -2-methyl-benzoic acid methyl ester

A mixture of [4- (tert-butyl-dimethyl-silanyloxy) -2-methyl-phenyl] -methyl-amine (643 mg, 2.6 mmol, 1.2 eq) and 4- formyl-2-methylbenzoic acid (380 mg, 2.1 mmol), acetic acid (252 mg, 4.2 mmol, 2.0 eq), sodium triacetoxyborohydride (890 mg, 4.2 mmol, 0 eq) in 1,2-dichloroethane is stirred at room temperature overnight. The mixture is concentrated under reduced pressure and the resulting residue is partitioned between EtOAc (50 mL) and 5% NaHCO3 (40 mL). The organic phase is washed with brine (50 mL), dried (Na2 SO4 &gt; 4), filtered and concentrated under reduced pressure to a residue. The residue is purified by flash chromatography &quot; eluting with a EtOAc / hexane gradient to give the title compound as a syrup (1.0 g, 95%). LC-ES + MS m / e 414.3 (M + 1). 120 ΡΕ2029547

Preparation 109 2-Butoxy-4 - ({[4- (tert-butyl-dimethyl-silanyloxy) -2-methyl-phenyl] -methyl-amino} -methyl) -benzoic acid methyl ester The compound mentioned in The title compound is prepared essentially according to the preparation of 4 - ({[4- (tert-butyl-dimethyl-silanyloxy) -2-methyl-phenyl] -methyl-amino} -methyl) -2- methyl-benzoic acid methyl ester starting from [4- (tert-butyl-dimethyl-silanyloxy) -2-methyl-phenyl] -methyl-amine and 2-butoxy-4-formyl-benzoic acid methyl ester. The title compound is obtained as a syrup after handling and is used without further purification. LC-ES / MS m / e 472.3 (M + 1).

PREPARATION 110 4 - {[(4-Hydroxy-2-methyl-phenyl) -methyl-amino] -methyl} -2-methyl-benzoic acid methyl ester To a solution of 4 - ({ [4- (tert-Butyl-dimethyl-silanyloxy) -2-methyl-phenyl] -methyl-amino} -methyl) -2-methyl-benzoic acid (1.0 g, 2.1 mmol) in THF (20 mL, 0 mL) is added M TBAF 1.0 / THF (3.2 mL, 3.2 mmol) at ambient temperature. The reaction mixture is stirred for 1.0 h. The mixture is partitioned between EtOAc (30 mL) and water (30 mL). The organic phase is washed with brine (30 mL), dried (Na2 SO4 &gt; 4), filtered and concentrated under reduced pressure to a residue. The residue is purified by flash chromatography &quot; flash &quot; to give the title compound as an oil (0.45 g, 62%). LC-ES / MS m / e 300.3 (M + 1), 298.3 (M-1).

Preparation 111 2-Butoxy-4 - {[(4-hydroxy-2-methyl-phenyl) -methyl-amino] -methyl] -benzoic acid methyl ester The title compound (200 mg, 55%) is prepared essentially according to the preparation of 4 - {[(4-hydroxy-2-methyl-phenyl) -methyl-amino] -methyl} -2-methyl-benzoic acid methyl ester using the appropriate starting material. LC-ES + MS m / e 358.3 (M + 1).

Preparation 112 6-Bromo-benzo [d] isothiazol-3-carboxylic acid The title compound is prepared essentially according to WO 2005/092890 Procedure 3 using the appropriate starting material. ES / MS m / e 255.0 (M-1).

Preparation 113

To a degassed solution of 6-bromo-benzo [d] isothiazol-3-carboxylic acid (0.42 gm) in dichloromethane , 1.54 mmol), 3-methyl-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl-phenol 122 ΡΕ2029547 (0.54, 2.31 mmol ), 2-dicyclohexylphosphino-2 ', 6'-dimethoxy-1,1'-biphenyl (0.064 g, 0.154 mmol), and potassium phosphate (0.71 g, 3.1 mmol) in dioxane (8 mL) and water (4 mL) is added Pd (OAc) 2 (6.5 mg, 0.03 mmol) .The reaction is again degassed and heated to 80 degrees for 18 h. The reaction mixture is cooled to room temperature The crude material is diluted with 20 mL of MeOH and 2 mL of H 2 SO 4 and heated at reflux for 2 h. The reaction mixture is diluted with EtOAc and 1 N HCl. concentrated on silica and purified by flash chromatography (20-50% EtOAc 20-50% in hexanes) to provide the title compound (0.12 g, 26%). The following compound is prepared essentially according to the preparation of 6- (4-hydroxy-2-methyl-phenyl) -benzo [d] isothiazole-3-carboxylic acid using the appropriate departure.

Preparation 113A: 6- (4-Hydroxy-2-methyl-phenyl) -1-methyl-1H-indazole-3-carboxylic acid (0.53 g, 75%), ES / MS m / e 297.0 (M + 1).

Preparation 114 6-Bromo-1H-indazole-3-carboxylic acid methyl ester The title compound is prepared in substantial accordance with WO 2005/092890 Procedure 4 123 ΡΕ 2029547 using the appropriate starting material. ES / MS m / e 254.0 (M + 1).

Preparation 115 6-Bromo-1-methyl-1H-indazole-3-carboxylic acid methyl ester The title compound is prepared essentially according to WO 2005/080389 Procedure 1d using the appropriate starting material. ES / MS m / e 268.0 (M + 1).

Preparation 116 Benzo [b] thiophene-5-carboxylic acid ethyl ester

A saturated solution of HCl in ethanol (15 mL) is added to benzothiophene-5-carboxylic acid (1 g, 5.44 mmol) and stirred at 80 ° C overnight. The solvent is removed under reduced pressure. Diethyl ether and saturated sodium bicarbonate are added. The aqueous layer is discarded. The organic layer is washed with saturated sodium bicarbonate and water, dried (Na 2 SO 4), filtered and concentrated under reduced pressure to afford the title compound as a pale brown oil (1.0 g, 89%). 1 H-NMR (CDCl 3): δ 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), 4.42 (q, 2H, J = 6.8 Hz), 1.43 (t, 3H, J = 6.8 Hz). 124 ΡΕ2029547

Preparation 117 2- (4-Methoxy-2-methyl-phenyl) -benzo [b] thiophene-5-carboxylic acid ethyl ester

Cisium carbonate (9.70 mmol, 3.19 g) is dried in a reusable tube at 150 ° C under vacuum for 2 h and cooled to room temperature. Copper Iodide (I) (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 mL), benzo [b] thiophene-5-carboxylic acid ethyl ester (4.85 mmol, 1 g) and anhydrous DMF (24 mL) a 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 a further 24 hours. The mixture is allowed to reach room temperature and water and ethyl acetate are added. 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 (Na 2 SO 4), filtered and concentrated under reduced pressure. The residue is chromatographed (0-10% EtOAc in hexanes) to give the title compound (960 mg, 61%) as a colorless waxy solid. LC-ES / MS m / e 326 (M).

Preparation 118 2- (4-Hydroxy-2-methyl-phenyl) -benzo [b] thiophene-5-carboxylic acid ethyl ester 125 ΡΕ2029547

A 0 ° C solution of boron tribromide (1M in dichloromethane, 1.29 mmol, 1.29 mL) is added under a nitrogen atmosphere to a solution of 2- (4-methoxy- -2-methyl-phenyl) -benzo [b] thiophene-5-carboxylic acid (1.07 mmol, 350 mg) in anhydrous dichloromethane (4.00 mL) and the 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 (Na2 SO4), 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 and the residue is chromatographed (5-20% EtOAc in hexanes) to give the title compound (145 mg, 40%) as a white solid. LC-ES + MS m / e 313 (M + 1).

Preparation 119 Benzo [b] thiophene-7-carboxylic acid

A solution of 7-bromobenzothiophene (9.38 mmol, 2 g) in 10 mL of anhydrous THF is added slowly to a suspension of activated magnesium (14.08 mmol, 345.6 mg) in 2 mL of anhydrous THF at 65ø C and stirred for 1 h under an atmosphere of nitrogen. The mixture is allowed to reach room temperature and a stream of carbon dioxide is bubbled into the mixture for 5 minutes. After 1 h, 1N HCl is added until the mixture reaches pH 1. The aqueous layer is extracted with ethyl acetate. The organic layers are combined, dried (Na 2 SO 4), filtered and concentrated under reduced pressure. Petroleum ether is added and the resulting solid is collected by filtration to provide the title compound (1.05 g, 63%) as a white solid. 1 H-NMR (CDCl 3): δ 8.26 (d, 1H, J = 6.5Hz), 8.10 (dd, 1H, J = 7.3Hz, 1Hz), 7.61 (d, 1H , J = 5.6Hz), 7.51 (t, 1H, J = 7.3Hz), 7.44 (d, 1H, J = 5.6Hz).

Preparation 120 Benzo [b] thiophene-7-carboxylic acid ethyl ester

Acetyl chloride (14.8 mmol, 1.05 mL) is added to a solution of benzo [b] thiophene-7-carboxylic acid (4.94 mmol, 880 mg) in ethanol (20 mL) and the mixture is stirred at reflux for 24 h. The solvent is removed. Ethyl acetate is added to the residue and the resulting solution is washed with water, dried (Na 2 SO 4), filtered and concentrated to give the title compound (880 mg, 92%) as a colorless oil. 1 H-NMR (CDCl 3): δ 8.12 (dd, 1H, J = 7.2 Hz, 0.6 Hz), 8.03 (dd, 1H, J = 7.6 Hz, J = 7.6 Hz), 7.46 (t, 1H, J = 7.6 Hz), 7.41 (t, 1H, J = 5.2 Hz), 4.50 (c, 2H, J = 7.3 Hz), 1.47 (t 3H, J = 7.3 Hz).

Preparation 121 2- (4,4,5,5-Tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzo [b] thiophene-7-carboxylic acid ethyl ester

Bis (pinacolato) -diboron (433, 17 andmol; 110.00 mg), di-mu-chlorobis ((1,2,5,6-eta) -1,5-cyclooctadiene) dihydride ( 6.50 æmol, 4.41 mg), 127 ΡΕ2029547

4,4'-di-tert-butyl-2,2'-dipyridyl (13.00 pmol, 3.49 mg). The tube is purged with nitrogen followed by anhydrous octane (2.60 mL). Benzo [b] thiophene-7-carboxylic acid ethyl ester (1.73 mmol, 357.39 mg) is added. The mixture is stirred at 90 ° C for 16 h. Diethyl ether is added to the mixture and it is washed with HCl (1M) and water. The organic layer is dried (Na2 SO4 &gt; 4), filtered and concentrated. Hexane is added. The resulting solid is filtered off and the solvent is removed to give 470 mg of a 1: 1 mixture of the starting material and desired compound. The mixture is used in the next step without further purification. LC-ES + MS m / e 333 (M + 1).

Preparation 122 2- (4-Hydroxy-2-methyl-phenyl) -benzo [b] thiophene-7-carboxylic acid ethyl ester

A solution of 2- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzo [b] thiophene-7-carboxylic acid ethyl ester (1.04 345.00 mg) in anhydrous DMF (2.5 mL) is added, under a nitrogen atmosphere, via syringe pump (3 mL / 2 h) to a suspension at 80 ° C of 4-bromo-3- methylphenol (1.04 mmol, 194.23 mg), cesium carbonate (2.08 mmol, 683.53 mg), Pd (OAc) 2 (103.84 mmol, 23.55 mg), 1,1'- bis (diphenylphosphino) ferrocene (311 mmol, 176 mg) in anhydrous DMF (1.6 mL). The mixture is stirred at 80 ° C for a period of time allowed to reach room temperature. The reaction is poured into a mixture of ethyl acetate and HCl (1M), filtered through Celite and washed with ethyl acetate. The organic layer is separated and the aqueous layer is extracted with ethyl acetate (2 x 20 mL). The organic layers are combined, washed with water, dried (Na 2 SO 4), filtered and concentrated. The residue is chromatographed (10-40% EtOAc in hexanes) to give the title compound (143 mg, 44%) as a white solid. LC-ES / MS m / e 311 (M-1).

PREPARATION 123 3-Fluoro-4'-hydroxy-2'-methyl-biphenyl-4-carboxylic acid methyl ester

A solution of 3-methyl-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenol (0.241 g, 1.03 mmol) and 4-Bromo-2-fluoro-benzoic acid (0.240 g, 1.03 mmol) in 1,4-dioxane (20 mL) is evacuated and refilled with N2 3 times. To this solution, Pd (PPh 3) 4 (0.010 g) and aqueous Na 2 CO 3 (1.0 mL, 2.0 M) are added. The resulting mixture is heated at 90 ° C for 24 hours under N2. The reaction mixture is cooled to room temperature and neutralized with HCl (1.0 M, 3.0 mL) and concentrated. The residue is extracted with ethyl acetate (30 mL x 2), and the combined organic layers are dried over sodium sulfate and concentrated. The residue is purified via silica gel chromatography eluting with residue is extracted into hexanes to give the title compound (0.211 g, 79%). 1 H-NMR (400 MHz, CDCl 3): δ 7.95-7.91 (t, 1H), 7.10-7.04 (m, 3H), 6.74-6.69 (m, 2H), 3.93 (s, 3H), 2.21 (s, 3H). The following list is of compounds which are prepared essentially as described in the preparation of 3-fluoro-4'-hydroxy-2'-methyl-biphenyl-4-carboxylic acid ethyl ester using the appropriate starting material.

Preparation 123A: 3,5-Difluoro-4'-hydroxy-2'-methyl-biphenyl-4-carboxylic acid ethyl ester (0.230 g, 77%), 1 H-NMR (400 MHz, CDCl 3): δ 7 1H), 6.86 (s, 1H), 6.86 (s, 1H), 6.71-6.68 (dd, 1H) , 3.95 (s, 3H), 2.22 (s, 3H).

Preparation 124 3-Methyl-4'-hydroxy-2'-methyl-biphenyl-4-carboxylic acid methyl ester

Step A

A solution of 4-bromo-2-methyl-benzoic acid (1.08 g, 5.02 mmol) in methanol (20 mL) is treated with H2 SO4 (0.20 mL). The mixture is stirred at 80 ° C for 16 hours and cooled to room temperature. The mixture is neutralized with aqueous Na 2 CO 3 and concentrated, the residue is extracted with ethyl acetate (30 mL x 2) and the combined organic layers are dried over sodium sulfate and concentrated to provide 4-bromo-2 (1.25 g, 97%). 1H NMR (400 MHz, CDCl3): δ 7.78 (d, 1H), 7.40 (s, 1H), 7.35 (d, 1H), 3.82 (s, 3H), 2.57 (s, 3H). 130 ΡΕ2029547

Step B

A solution of 3-methyl-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenol (0.241 g, 1.03 mmol) and 4-Bromo-2-methyl-benzoic acid (0.236 g, 1.03 mmol) in 1,4-dioxane (20 mL) is evacuated and refilled with N2 3 times. To this solution, Pd (PPh 3) 4 (0.010 g) and aqueous Na 2 CC> 3 (1.0 mL, 2.0 Μ) are added. The resulting mixture is heated at 90 ° C for 24 hours under N2. The reaction mixture is cooled to room temperature, neutralized with HCl (1.0 M, 3.0 mL), and concentrated. The residue is extracted with ethyl acetate (30 mL x 2) and the combined organic layers are dried over sodium sulfate and concentrated. The residue is purified by chromatography on silica gel eluting with 25-30% ethyl acetate in hexanes to give the title compound (0.199 g, 75%). 1H NMR (400 MHz, CDCl3): δ 7.95-7.91 (d, 1H), 7.18 (s, 1H), 7.18 (d, 1H), 7.08 (d, (S, 3H), 2.61 (s, 3H) The following list is from compounds which are prepared essentially as described in the preparation of 3-methyl-4'-hydroxy-2'-methyl-biphenyl-4-carboxylic acid ethyl ester using the appropriate starting material.

Preparation 124A: 3-Chloro-4'-hydroxy-2'-methyl-biphenyl-4-carboxylic acid ethyl ester (0.089 g, 63%), 1 H-NMR 131: 20209547 (400 MHz, CDCl3): δ 7 (D, 1H), 6.96 (d, 1H), 7.93 (d, 1H) 74 (s, 1H), 6.72-6.70 (d, 1H), 3.94 (s, 3H), 2.20 (s, 3H).

Preparation 125

3-Butoxy-4'-hydroxy-2'-methyl-biphenyl-4-carbaldehyde Step A

A solution of 4-bromo-2-hydroxy-benzonitrile (0.89 g, 4.45 mmol) in THF (50 mL) and 1-butanol (2.0 mL) is

slowly added to NaH (0.356 g, 8.90 mmol). The mixture is stirred at room temperature for one hour and quenched with water (10 mL). The mixture is concentrated and the residue is extracted with ethyl acetate (20 mL x 2). The combined organic layers are dried over sodium sulfate and concentrated to afford 4-bromo-2-butoxy-benzonitrile (0.65 g, 57%). 1 H-NMR (400 MHz, CDCl 3): δ 7.37-7.34 (d, 1H), 7.11-7.08 (d, 1H), 7.08 (s, 1H), 4.04 4.01 (t, 2H), 1.80 (tt, 2H), 1.50 (tt, 2H), 0.95 (t, 3H).

To a solution of 4-bromo-2-butoxy-benzonitrile (0.58 g, 2.28 mmol) in toluene (20 mL) at -78 ° C was added DIBAH (1.0 M, 4.56 mL) . The mixture is stirred overnight and allowed to warm to room temperature. The reaction is quenched with MeOH (5 mL) and the mixture is poured into NH 4 Cl (aq, 30 mL). The mixture is stirred for 5 minutes, treated with H2 SO4 (10%, 10 mL) and stirred for 10 minutes. The mixture is extracted with ethyl acetate (30 mL x 2) and the combined organic layers are dried over sodium sulfate and concentrated to give 4-bromo-2-butoxy-benzaldehyde (0.41 g, 70%). ES / MS m / e 257.0; 259.0 (M + 1).

Step C

A solution of 3-methyl-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenol (0.210 g, 0.898 mmol) and 4-bromo- (0.210 g, 0.817 mmol) in 1,4-dioxane (20 mL) is evacuated and refilled with N2 3 times. To this solution, Pd (PPh 3) 4 (0.010 g) and aqueous Na 2 CC> 3 (1.0 mL, 2.0 M) are added. The resulting mixture is heated at 90 ° C for 24 hours under N2. The reaction mixture is cooled to room temperature, neutralized with HCl (1.0 M, 3.0 mL) and concentrated. The residue is extracted with ethyl acetate (30 mL x 2) and the combined organic layers are dried over sodium sulfate and concentrated. The residue is purified by chromatography on silica gel eluting with 25-30% ethyl acetate in hexanes to give the title compound (0.198 g, 85%). ES / MS m / e 283.0 (M-1).

Preparation 126 6- (4-Hydroxy-2-methyl-phenyl) -benzo [d] isoxazole-3-carboxylic acid ethyl ester

Step A

A solution of (4-bromo-2-nitro-phenyl) -acetic acid (5.00 g, 19.2 mmol) in methanol (100 mL) is treated with ΡΕ 2029547 with conc. HCl (1.0 mL). The mixture is stirred at 85 ° C for 16 hours and cooled to room temperature. The mixture is neutralized with aqueous Na2CO3 and concentrated. The residue is extracted with ethyl acetate (50 mL x 2), and the combined organic layers are dried over sodium sulfate and concentrated to provide (4-bromo-2-nitro-phenyl) -acetic acid methyl ester in the form of a brown solid (5.27 g, 100%).

Step B

A solution of (4-bromo-2-nitro-phenyl) -acetic acid methyl ester (0.99 g, 3.61 mmol) in ethanol (8 mL) at ambient temperature is treated with isoamyl nitrite , 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 HCl (1.0 M, 4.0 mL) and concentrated. The residue is extracted with ethyl acetate (20 mL x 2) and the combined organic layers are dried over sodium sulfate and concentrated. The residue is purified by chromatography on silica gel eluting with 25% ethyl acetate in hexanes to give 6-bromo-benzo [d] isoxazole-3-carboxylic acid ethyl ester (0.36 g, 37%). ES / MS m / e 269.8; 271.8 (M + 1).

Step C

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 134 ΡΕ2029547 ethyl ester of 6-bromo-benzo [d] isoxazole-3-carboxylic acid (0.360 g, 1.33 mmol) in 1,4-dioxane (20 mL) is evacuated and refilled with N2 3 times. To this solution, Pd 2 (dba) 3 (0.010 g), tricyclohexylphosphine (PCy 3, 10 mg) and aqueous K 3 PO 4 (1.5 mL, 1.30 M) 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 Celite. The filtrate is concentrated and the residue is purified via silica gel chromatography eluting 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 127 2-Methyl-6- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzofuran-3-carboxylic acid methyl ester

Step A

A solution of 2-iodo-5-methoxyphenol (39 g, 156 mmol) in dimethylformamide (300 mL) and N, N, N ', N'-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, 1.900 g). The mixture is cooled to -78 ° C, and propyne (100 g, 2.50 mol) is bubbled through the mixture for 1 hour. The reaction mixture is stirred and allowed to warm to room temperature gradually over 6 hours. After stirring for 2 days, the reaction mixture is quenched with water (800 mL) and extracted with EtOAc (500 mL). The organic layer is dried over Na2SO4, filtered and concentrated. The crude product is purified by flash chromatography &quot; (eluting with 10% EtOAc / hexanes) and the appropriate fractions are concentrated. The material is dried in vacuo to afford 6-methoxy-2-methylbenzofuran (17.5 g, 69%). 1 H-NMR (400 MHz, CDCl 3): δ 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 B

A solution of 6-methoxy-2-methylbenzofuran (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 Na2SO4, filtered and concentrated. The crude product is purified by flash chromatography &quot; eluting with 25% EtOAc / hexanes, and the appropriate fractions are concentrated. The material is dissolved in dichloromethane (150 mL) and triethylamine (17.0 mL, 122 mmol) at 0 ° C is treated with acetic anhydride (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. The residue is purified by silica gel chromatography with 25% EtOAc / hexanes to afford 2-methyl-benzofuran-6-yl ester of acetic acid (9.50 g, 82%). 1 H-NMR (400 MHz, CDCl 3): δ 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). 136 ΡΕ2029547

Step C To a slurry of aluminum trichloride (20.0 g, 150 mmol) in dichloromethane (200 mL) is oxalyl chloride (13.0 mL, 150 mmol) added and the mixture is stirred at 0 ° C for 30 minutes. A solution of acetic acid 2-methyl benzofuran-6-yl ester (9.50 g, 49.9 mmol) in dichloromethane (50 mL) is added over 10 minutes. The ice 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, 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 Celite and concentrated. The residue is diluted with water (100 mL) and extracted with EtOAc (250 mL.times.2). The combined organic layers are dried over Na2 SO4, filtered, and concentrated. The crude product is purified by flash chromatography &quot; (eluting with 25% EtOAc / hexanes), and the appropriate fractions are concentrated. The material is dried under vacuum to give 6-hydroxy-2-methyl-benzofuran-3-carboxylic acid (9.56 g, 93%). ES / MS m / e 207.0 (M + 1); 205.0 (M-1).

Step D

A solution of 6-hydroxy-2-methyl-benzofuran-3-carboxylic acid ethyl ester (9.5 g, 46.07 mmol) in dichloromethane (100 mL) and triethylamine (12.8 mL, 92.14 mmol) 137/20209547 at 0 ° C 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, which is purified by chromatography on silica gel with 20% EtOAc / hexanes to provide 2-methyl-6-trifluoromethanesulfonyloxy-benzofuran-3-carboxylic acid ethyl ester (14.1 g g, 90%). 1 H-NMR (400 MHz, CDCl 3): δ 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 E

A solution of 2-methyl-6-trifluoromethanesulfonyloxy-benzofuran-3-carboxylic acid ethyl ester (3.25 g, 9.61 mmol) and bis (pinacolato) diboron (3.05 g, 12.0 mmol) in acetonitrile (50 mL) is degassed by vacuum / nitrogen reflux three times. (43 mg, 0.192 mmol) and cesium fluoride (2.92 g, 19.2 mmol) are added, and the mixture is heated to 85øC for 16 hours. The reaction mixture is cooled to room temperature and filtered through a pad of Celite. The filtrate is concentrated to a residue, which is purified by chromatography on silica gel with 15% EtOAc / hexanes to provide 2-methyl-6- (4,4,5,5-tetramethyl- [ 1,3,2] dioxaborolan-2-yl) -benzofuran-3-carboxylic acid (1.96 g, 65%). ES / MS m / e 317.0 (M + 1). 138 ΡΕ2029547

Preparation 128 [6- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzo [b] thiophen-3-yl] -acetic acid methyl ester

To a solution of 3-methoxybenzenethiol (5.75 g, 41.0 mmol) and potassium carbonate (11.45 g, 82.02 mmol) in acetonitrile (150 mL) is added 4-ethyl 3-oxo-butanoic acid (6.12 mL, 45.11 mmol) at 0 ° C. The mixture is stirred at room temperature for 2 hours and filtered through a pad of Celite. The filtrate is concentrated and purified by silica gel chromatography with 25-30% EtOAc / hexanes to provide 4- (3-methoxy-phenylsulfanyl) -3-oxo-butyric acid ethyl ester (10.9 g, %) ES / MS m / e 267.0 (M +).

Step B 4- (3-Methoxy-phenylsulfanyl) -3-oxo-butyric acid ethyl ester (10.9 g, 40.62 mmol) is added to methanesulfonic acid (26.6 mL, 406 mmol), and The mixture is stirred at room temperature for 30 minutes. The mixture is poured into ice-water (300 g) and extracted with EtOAc (100 mL x 2). The combined organic layers are dried over Na2SO4, filtered and concentrated. The crude product is purified by flash chromatography &quot; (eluting with 20% EtOAc / hexanes), and the appropriate fractions are concentrated. The material is dried in vacuo to give 4-methoxy-benzo [b] thiophen-3-yl) -acetic acid ethyl ester (6.00 g, 59%). ES / MS m / e 251.0 (M + 1). 139 ΡΕ2029547

Step C

A solution of (6-methoxy-benzo [b] thiophen-3-yl) -acetic acid ethyl ester (3.81 g, 15.22 mmol) in dichloromethane (50 mL) at -78 ° C is added boron tribromide (38.1 mL, 38.1 mmol) dropwise. The mixture is stirred and allowed to warm to room temperature overnight. The mixture is cooled to 0øC 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 Na2SO4, filtered and concentrated. The crude product is purified by flash chromatography &quot; eluting with 30-40% EtOAc / hexanes. The appropriate fractions are combined and concentrated under reduced pressure. The material is dried under vacuum to give (β-hydroxy-benzo [b] thiophen-3-yl) -acetic acid ethyl ester (3.35 g, 93%). ES / MS m / e 237.0 (M + 1); 235.0 (M-1).

Step A A solution of (6-hydroxy-benzo [b] thiophen-3-yl) -acetic acid ethyl ester (3.31 g, 14.0 mmol) in dichloromethane (50 mL) at -78 ° C is added triethylamine (3.90 mL, 28.0 mmol) and trifluoromethanesulfonic anhydride (2.60 mL, 15.4 mmol). The mixture is stirred and allowed to warm to room temperature over 30 minutes. The reaction is quenched with MeOH (5.0 mL) and concentrated under reduced pressure. The residue is purified by chromatography on silica gel with 20% EtOAc / hexanes to provide (Î ± -2H) -2- (4-trifluoromethanesulfonyloxy-benzo [b] thiophen-3-yl) -acetic acid ethyl ester (5.05 g, 98%). ES / MS m / e 366.8 (M-1).

Step E

A solution of (6-trifluoromethanesulfonyloxy-benzo [b] thiophen-3-yl) -acetic acid ethyl ester (2.21 g, 6.00 mmol) and bis (pinacolato) diboron (1.90 g, , 50 mmol) in acetonitrile (25 mL) is evacuated and refilled with N2 three times. Pd (OAc) 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 Celite, and the filtrate is concentrated under reduced pressure. The residue is extracted with EtOAc (20 mL x 2). The combined organic layers are dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product is purified by flash chromatography &quot; eluting with 20% EtOAc / hexanes. The appropriate fractions are combined and concentrated under reduced pressure. The material is dried under vacuum to give {6- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzo [b] thiophen-3 -yl} -acetic acid ethyl ester (1.56 g, 75%). ES / MS m / e (M + 18): 364.0; (M + 1): 347.0.

Preparation 129 Trifluoro-methanesulfonic acid 2-benzoyl-4-methyl-phenyl ester 141 ΡΕ2029547

Triethylamine (3.56 g, 35 mmol) is added to a solution of (2-hydroxy-5-methyl-phenyl) -phenyl-methanone (5.0 g, 23.5 mmol) in dichloromethane (40 mL). The mixture is cooled to 0 ° C and trifluoromethanesulfonic anhydride (7.97 g, 28.2 mmol) is added dropwise. The mixture is stirred at 0 ° C for 1.0 h, quenched with satd NaHCO 3 (20 mL), diluted with dichloromethane (30 mL). The layers are separated and the organic layer is washed with water (30 mL) and brine (30 mL), dried (Na2 SO4) and concentrated in vacuo. The residue is purified via column chromatography (SiO2, EtOAc / Hex gradient) to give the title compound (8.18 g, 100%) as an oil. LC-ES / MS: 345.0 (M + 1), 362.0 (M + 18).

Preparation 130 (3-Fluoro-4-nitro-phenoxy) -triisopropyl-silane

A mixture of 3-fluoro-4-nitrophenol (4.94 g, 31.4 mmol), triisopropylsilyl chloride (6.40 mL, 29.9 mmol) and imidazole (4.85 g, 70.7 mmol ) in 70 mL of dichloromethane is stirred for 1.5 hours. Dichloromethane (100 mL) is added and the mixture is washed with water and brine, dried (MgSO4) and concentrated under reduced pressure. The residue is purified on silica gel (120 g) eluting with a gradient of ethyl acetate in heptane (0 to 80%) to provide the title compound (8.55 g, 87%) as an oil. ES / MS m / e 314.3.0 (M + 1). 142 ΡΕ2029547

Preparation 131 2-Fluoro-4-triisopropylsilanyloxy-phenylamine

A flask with a mixture of (3-fluoro-4-nitro-phenoxy) -triisopropylsilane (6.74 g, 21.5 mmol) in ethyl acetate (200 mL) is evacuated and filled with nitrogen three times. 10% palladium on carbon weight basis (550 mg) is added. The flask is evacuated and filled with nitrogen three times and then it is evacuated and filled with hydrogen from a flask. The mixture is stirred under a hydrogen atmosphere (balloon) overnight. The mixture is filtered over diatomaceous earth and concentrated to provide the title compound (6.2 g, 100%) as an oil. LC-ES / MS m / e 284.2 (M + 1). The following compound is prepared essentially according to the preparation of 2-fluoro-4-triisopropylsilanyl-xy-phenylamine using the appropriate starting material.

Preparation 131A: 4-Amino-3-fluoro-phenol (1.7 g, 96%), 1 H-NMR (400 MHz, DMF-d 7) δ 8.75 (s, 1H), 6.78 (m, 1H ), 6.40 (m, 1H), 6.50 (m, 1H), 4.38 (s, 2H).

Preparation 132 (2-Fluoro-4-triisopropylsilanyloxy-phenyl) -carbamic acid tert-butyl ester

A mixture of 2-fluoro-4-triisopropylsilanyloxyphenylamine (6.2 g, 21.9 mmol) and di-t-butyl dicarbonate (4.65 g, 20.7 mmol) in THF (100 mL) is stirred during 143 ΡΕ 202 9547 overnight at 75 ° C. The mixture is concentrated under reduced pressure and purified on silica (120 g) eluting with 100% dichloromethane to provide 6.5 g of oil. The oil is purified on silica (120 g) eluting with a gradient of dichloromethane in heptane (10% to 70%) to provide the title compound (6.1 g, 73%) as a colorless oil. MS (ES) m / z 383.3,0 (M-1).

Preparation 133 To a solution of (2-fluoro-4-triisopropylsilanyloxy-phenyl) -carbamic acid tert -butyl ester (5.64 g) in dichloromethane g, 14.7 mmol) in tetrahydrofuran (100 mL) at -78 ° C is added tert-butyl lithium (17.5 mL, 29.8 mmol). After one hour, methyl iodide (1.83 mL, 29.4 mmol) is added. An additional tert-butyl lithium (17.5 mL, 29.8 mmol) is added followed by additional methyl iodide (1.83 mL, 29.4 mmol). The mixture is then allowed to slowly warm to room temperature overnight. Saturated aqueous ammonium chloride is added and the layers are separated. The organic layer is dried (MgSO4) and concentrated to a mixture of an oil and solids. The crude product is partitioned between dichloromethane and water. The aqueous layer is extracted with dichloromethane (3x). The combined dichloromethane layers are dried (MgSO4) and concentrated. The resulting residue is purified on silica gel with 100% dichloromethane to provide 3.8 g of oil. The oil is treated with cold 4 M HCl in dioxane solution. After one hour the mixture is concentrated and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous layer is extracted with ethyl acetate (2x). The combined ethyl acetate layers are dried (MgSO4) and concentrated. The residue is purified on silica (120 g) with 10% ethyl acetate in heptane (3x) to provide 350 mg (7.6%) of the title compound as an oil. LC-ES / MS m / e 312.2 (M + 1).

Preparation 134 4 - {[(2-Fluoro-6-methyl-4-triisopropylsilanyloxy-phenyl) -methyl-amino] -methyl} -2-methyl-benzoic acid methyl ester

A mixture of (2-fluoro-6-methyl-4-triisopropylsilanyloxy-phenyl) -methyl-amine (326 mg, 1.05 mmol) and 4-formyl-2-methyl-benzoic acid methyl ester (320 mg, 1.80 mmol) in 4 mL of acetic acid is stirred for 2.5 hours at room temperature. Sodium triacetoxyborohydride (773 mg, 3.65 mmol) is added and stirred. Upon completion of the reaction, the mixture is concentrated and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous layer is extracted with ethyl acetate (3x). The combined ethyl acetate layers are dried (MgSO 4) and concentrated. The residue is purified on 40 g of silica with ethyl acetate in heptane gradient 145 ΡΕ 2029547 (10% to 20%) to provide 457 mg (92%) of the title compound as an oil. MS (ES) m / z 475.3 (M + 1). The following list is of compounds which are prepared essentially according to the Preparation of 4 - {[(2-fluoro-6-methyl-4-triisopropylsiloxy-phenyl) -methyl-amino] -methyl} -2-methyl-benzoic acid using the appropriate starting materials.

Preparation 134A: 4 - [(2-Fluoro-4-hydroxy-phenylamino) -methyl] -2-methyl-benzoic acid methyl ester (1.9 g, 93%), starting from 4-amino- fluoro-phenol (900 mg, 7.08 mmol) and 4-formyl-2-methyl-benzoic acid methyl ester (1.23 g, 6.90 mmol), MS (ES) m / z 290.0 ( M + 1).

Preparation 134B: 4 - [(4-Hydroxy-phenylamino) -methyl] -2-methyl-benzoic acid methyl ester (2.10 g, 80%) starting from 4-amino-phenol (1.06 g , 9.71 mmol) and 4-formyl-2-methyl-benzoic acid methyl ester (1.92 g, 10.8 mmol), LC-ES / MS m / e 272.2 (M + 1).

Preparation 134C: 4 - [(2-Chloro-4-hydroxy-phenylamino) -methyl] -2-methyl-benzoic acid methyl ester (420 mg, 41%), starting from 4-amino-3- chloro-phenol (665 mg, 3.69 mmol) and 4-formyl-2-methyl-benzoic acid methyl ester (595 mg, 3.34 mmol) to provide the title compound as a solid. LC-ES + MS m / e 306.2 (M + 1). 146 ΡΕ2029547

Preparation 135 4 - {[(2-Fluoro-4-hydroxy-6-methyl-phenyl) -methyl-amino] -methyl} -2-methyl-benzoic acid methyl ester

A mixture of 4 - {[(2-fluoro-6-methyl-4-triisopropylsilanyloxy-phenyl) -methyl-amino] -methyl} -2-methyl-benzoic acid methyl ester (457 mg, 0.965 mmol ) and tetrabutylammonium fluoride (2.0 mL of 1M in THF, 2.0 mmol) in THF (10 mL) is stirred at 0 ° C for 20 minutes and then 2.0 mL of 1 M HCl are added and the mixture is concentrated. The residue is partitioned between ethyl acetate and brine. The layers are separated and the salt water layer is extracted with ethyl acetate. The combined ethyl acetate layers are dried (MgSO4) and concentrated. The residue is purified on 40 g of silica with ethyl acetate in heptane gradient (10% to 70%) to provide 233 mg (76%) of the title compound as a glass. LC-ES + MS m / e 318.2 (M + 1).

Preparation 136 4 - {[(2-Fluoro-4-hydroxy-phenyl) -methyl-amino] -methyl} -2-methyl-benzoic acid methyl ester

A mixture of 4 - [(2-fluoro-4-hydroxy-phenylamino) -methyl] -2-methyl-benzoic acid methyl ester (1.89 g, 6.53 mmol) and 2.0 mL formaldehyde 37% in 20 mL of acetic acid is stirred for 40 minutes. Sodium triacetoxyborohydride (2.80 g, 13.2 mmol) is added. Upon completion, the mixture is concentrated and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous layer is extracted with ethyl acetate (3x). The combined ethyl acetate layers are dried (MgSO4) and concentrated. The residue is purified on silica (120 g) with heptane gradient (10% to 60%) to provide 1.0 g (51%) of the title compound as a white solid. LC-ES / MS m / e 304.0 (M + 1). The following list is of compounds which are prepared essentially according to Preparation of 4 - {[(2-fluoro-4-hydroxy-phenyl) -methyl-amino] -methyl} -2-methyl- benzoic acid using the appropriate starting material.

Preparation 136A: 4 - {[(4-Hydroxy-phenyl) -methyl-amino] -methyl} -2-methyl-benzoic acid methyl ester (120 mg, 52%), starting from 4- - (4-hydroxy-phenylamino) -methyl] -2-methyl-benzoic acid methyl ester (220 mg, 0.855 mmol), 4-formyl-2-methyl-benzoic acid methyl ester (1.92 g, 10.8 mmol) and 0.5 mL of 37% formaldehyde, LC-ES / MS m / e 272.2 (M + 1);

Preparation 136B: 4 - {[(2-Chloro-4-hydroxy-phenyl) -methyl-amino] -methyl} -2-methyl-benzoic acid methyl ester (250 mg, 61%), starting from of 4 - [(2-chloro-4-hydroxy-phenylamino) -methyl] -2-methyl-benzoic acid methyl ester (390 mg, 1.28 mmol) and 0.5 mL of 37% formaldehyde, LC-ES / MS m / e 320.2 (M + 1). 148 ΡΕ2029547

PREPARATION 137 6-Bromo-benzo [d] isothiazol-3-carboxylic acid The title compound is prepared essentially according to Procedure 3 in WO 2005/092890, ES / MS m / e 255.0 (M-1).

Preparation 138 6- (4-Hydroxy-2-methyl-phenyl) -benzo [d] isothiazol-3-carboxylic acid To a degassed solution of 6-bromo-benzo [d] isothiazol- 42 g, 1.54 mmol), 3-methyl-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl-phenol (0.54, 2.31 mmol ), 2-dicyclohexylphosphino-2 ', 6'-dimethoxy-1,1'-biphenyl (0.064 g, 0.154 mmol), potassium phosphate

(0.71 g, 3.1 mmol) in dioxane (8 mL) and water (4 mL) is added Pd (OAc) 2 (6.5 mg, 0.03 mmol). The reaction is degassed again and heated to 80 ° C for 18 h. The reaction mixture is cooled to room temperature and concentrated under reduced pressure. The material is diluted with EtOAc and 1N HCl. The layers are separated and concentrated under reduced pressure. The crude material is diluted with 20 mL of MeOH and 2 mL of H2 SO4 and heated at reflux for 2 h. The reaction is concentrated on silica and purified using a gradient of 20 to 50% EtOAc in hexanes to give the title compound (0.12 g, 26% yield). ES / MS m / e 300.0 (M + 1). 149 ΡΕ2029547

Preparation 139 6-Bromo-1-methyl-1H-indole-3-carboxylic acid methyl ester

A mixture of 5-bromo-1H-indole-3-carboxylic acid ethyl ester (100 mg, 0.394 mmol), potassium carbonate (163 mg, 1.18 mmol) and DMF is stirred at room temperature. Iodomethane (30 æL, 0.47 mmol) is added. After 1.5 hours an additional iodomethane (10 æl) is added and the reaction mixture is stirred for 30 minutes and diluted with dichloromethane and filtered. The filtrate is concentrated under high vacuum, diluted with ethyl acetate and concentrated to give 105 mg (99%) of the title compound. MS m / z: 270.0 (M + 2). The following compound is prepared essentially according to the preparation of 6-bromo-1-methyl-1H-indole-3-carboxylic acid ethyl ester using the appropriate starting material.

Preparation 139A: 6-Bromo-1-isopropyl-1H-indole-3-carboxylic acid methyl ester starting from 6-bromo-1H-indole-3-carboxylic acid ethyl ester and isopropyl bromide , 1H NMR (400 MHz, CDCl3) δ 8.02 (d, 1H), 7.88 (s, 1H), 7.52 (s, 1H), 7.33 (d, 1H), 4.60 (m, 1H), 3.88 (s, 3H), 1.55 (d, 6H).

Preparation 140 6- (4-Hydroxy-2-methyl-phenyl) -1-methyl-1H-indole-3-carboxylic acid methyl ester 150 ΡΕ2029547

A mixture of 3-methyl-4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenol (2.36 g, 10.1 mmol), 6-bromo-1H-indole-3-carboxylic acid (1.8 g, 6.71 mmol), tetrakis (triphenylphosphine) palladium (0) (300 mg, 0.26 mmol), DMF (27 mL), ethanol (13.5 mL) and 2M aqueous potassium carbonate (13.5 mL) is heated to 85 ° C for 4 hours. The reaction mixture is cooled to room temperature and diluted with water and acidified with 1N HCl. The resulting solution is extracted with ethyl acetate. The combined organic layers are washed with brine and dried over anhydrous magnesium sulfate and concentrated. The residue is purified by flash chromatography &quot; eluting with 25-40% ethyl acetate / heptane to give 1.73 mg (87%) of the title compound. The following compound is prepared essentially according to the preparation of 6- (4-hydroxy-2-methyl-phenyl) -1-methyl-1H-indole-3-carboxylic acid ethyl ester using the appropriate starting material.

Preparation 140A: 6- (4-Hydroxyphenyl) -1-isopropyl-1H-indole-3-carboxylic acid methyl ester starting from 6-bromo-1-isopropyl-1H-indole methyl ester -3-carboxylic acid, ES / MS m / e 324.1 (M + 1).

Preparation 141 2- (4-Chloro-2-nitro-phenyl) -3-hydroxy-but-2-enoic acid methyl ester 151 ΡΕ2029547

A mixture of sodium hydride (60% in mineral oil, 2.6 g, 65 mmol) and DMF (52 mL) is stirred in an ice bath and methyl acetoacetate (6.46 mL, 60 mmol) is added over ten minutes via the syringe. The mixture is stirred in an ice bath for 10 minutes, stirred at room temperature for 20 minutes and finally cannulated over five minutes in cold pure 2-chloro-5-fluoro-nitrobenzene (5.00 g, 28.5 mmol) (ice bath). The ice bath is removed after 40 minutes and the mixture is allowed to stir overnight at room temperature. The mixture is acidified with 2M HCl and diluted with water and ether. The ether layer is dried over MgSO4 and concentrated to afford 6.52 g (84%) of the title compound. MS m / e 270.0 (M-1).

Preparation 142 6-Chloro-2-methyl-1H-indole-3-carboxylic acid methyl ester

A mixture of 2- (4-chloro-2-nitro-phenyl) -3-hydroxy-but-2-enoic acid methyl ester (4.66 g, 17.2 mmol), iron (5.76 g , 103 mmol) and glacial acetic acid (16 mL) is heated at 115 ° C for allowing it to cool. The reaction mixture is diluted with water and ethyl acetate. The ethyl acetate layer is washed with brine and dried over MgSO4. The mixture of the title compound and a small amount of impurity is used in the next reaction without further purification. ES / MS m / e 224.0 (M + 1). 152 ΡΕ2029547

Preparation 143 6-Chloro-1,2-dimethyl-1H-indole-3-carboxylic acid methyl ester

A mixture of 6-chloro-2-methyl-1H-indole-3-carboxylic acid ethyl ester (2.76 g, 12.3 mmol), potassium carbonate (6.80 g, 49.2 mmol) , iodomethane (1.07 mL, 17.2 mmol) and DMF (36 mL) is stirred overnight at room temperature. The mixture is diluted with ethyl acetate, washed twice with water, washed with brine and dried (MgSO4) and concentrated. The residue is triturated in 25 mL of 1: 3 ethyl acetate-heptane and filtered to provide 1.63 g (55%) of the pure title product. An additional material can be obtained by additional grinding of the mother liquor. ES / MS m / e 238.0 (M + 1).

Preparation 144 6- (4-Hydroxy-2-methyl-phenyl) -1,2-dimethyl-1H-indole-3-carboxylic acid methyl ester

A flask containing a mixture of 6-chloro-1,2-dimethyl-1H-indole-3-carboxylic acid ethyl ester (1.60 g, 6.73 mmol), 3-methyl-4- , 5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenol (3.15 g, 13.5 mmol), aqueous tribasic potassium phosphate (1.27 M, 9.0 mL (53 mg, 0.180 mmol) and tris (dibenzylideneacetone) dipalladium (0) (73 mg, 0.080 mmol) and dioxane (22 mL) is evacuated and filled with nitrogen several times. 153 ΡΕ2029547 The reaction mixture is heated to 100 ° C for 18 h. The mixture is allowed to cool and is filtered through Celite, washing with ethyl acetate. The filtrate is concentrated and partitioned between 1N HCl and ethyl acetate. The ethyl acetate layer is washed with brine, dried over MgSO 4 and concentrated. The residue is triturated in THF-heptane to provide 1.83 g (88%) of the title compound as a white solid. MS m / e 310.0 (M + 1).

To a solution of 6-bromobenzothiophene (20 g, 93.8 mmol) and acetyl chloride (8.84 g, 112.6 mmol) in 1,2-dichloroethane ( 120 mL) is added dropwise, at room temperature, tin tetrachloride (1M in dichloromethane, 112.6 mmol, 112.6 mL) under nitrogen. After the addition is complete, the reaction mixture is stirred at room temperature overnight. The mixture is poured into an ice / water bath and extracted with dichloromethane. The organic phase is washed with sat. NaHCO 3, water and brine, dried over MgSO 4 and evaporated. The crude residue is purified by &quot; flash chromatography &quot; on silica gel eluting with 6: 1 hexane / EtOAc as eluent mixture. The title compound (12 g, 50%) is obtained as a 7: 3 mixture of the two isomers: 3-acetyl-6-bromobenzothiophene and 2-acetyl-6-bromobenzothiophene. ES / MS m / e 256 (M + 2). 154 ΡΕ2029547

Preparation 6 6-Bromobenzothiophene-3-carboxylic acid and 6-bromobenzothiophene-2-carboxylic acid To a 0 ° C solution of sodium hydroxide (13.64 g, 341 mmol) in water (94 mL) is slowly added bromine 21.92 g, 137.18 mmol). The reaction mixture is stirred at 0 ° C for 15 minutes. To the reaction mixture is added dropwise a solution of the mixture of 3-acetyl-6-bromobenzothiophene and 2-acetyl-6-bromobenzothiophene (10.00 g, 39.19 mmol) in dioxane (75 mL). The reaction mixture is stirred at room temperature for 2 hours. After 2 h, 50 mL of a solution of NaHSCl (40%) are added followed by 10 mL of HCl to give an orange solid. The solid is separated by filtration and washed with water followed by hexanes to give 7 g (70%) of a mixture of both 6-bromobenzothiophene-3-carboxylic acid and 6-bromobenzothiophene-2-carboxylic acid in a ratio of 7: 3, ES / MS m / e 258 (M + 2).

Preparation 147 6-Bromobenzothiophene-3-carboxylic acid ethyl ester and 6-Bromobenzothiophene-2-carboxylic acid methyl ester

A solution of the mixture of 6-bromobenzothiophene-3-carboxylic acid and 6-bromobenzothiophene-2-carboxylic acid (6.5 g, 25.28 mmol) and sulfuric acid (4.65 g, 47.43 mmol ) in MeOH (100 mL) is heated to 65 ° C overnight. A light brown solid is visualized. The solution is cooled to room temperature and the solid formed 155æ20209547 is separated by filtration and washed with MeOH to give 5.6g (83%) of a mixture of: 6-bromobenzothiophene-3-carboxylic acid ethyl ester and 6-bromobenzothiophene-2-carboxylic acid ethyl ester in a ratio 7: 3, ES / MS m / e 272 (M + 2).

Preparation 148 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 The title compound is prepared essentially according to the preparation of 6- (4-hydroxy-2-methyl-phenyl) -1-methyl-1H-indole-3-carboxylic acid, using a 7: 3 mixture of 6-bromo-benzo [b] thiophene-3 carboxylic acid and 6-bromo-benzo [b] thiophene-2-carboxylic acid methyl ester. ES / MS m / e 297.0 (M-1).

Preparation 149 2-Isopropoxy-4-methyl-benzoic acid methyl ester

Diisopropyl azodicarboxylate (8.7 mL, 44 mmol) is added to a stirred solution of methyl 2-hydroxy-4-methylbenzoate (4.85 g, 29.2 mmol), isopropanol (3.3 mL, 44 mmol) , triphenylphosphene (11.5 g, 43.8 mmol) and THF (50 mL) at room temperature. The exothermic reaction is cooled in an ice bath and is allowed to stir overnight at room temperature. The mixture is extracted with ethyl acetate and water, and the organic phase is washed with brine and dried over MgSO 4. The crude residue is purified by flash chromatography &quot; (20 to 40% EtOAc / heptane) to give the title compound (4.95 g, 81%) as an oil. ES / MS m / e 209.3 (M + 1).

Preparation 150 4-Bromomethyl-2-isopropoxy-benzoic acid methyl ester

A mixture of 2-isopropoxy-4-methyl-benzoic acid methyl ester (1.00 g, 4.8 mmol), N-bromosuccinimide (0.940 g, 5.28 mmol), 2,2 ' (50 mg, 0.30 mmol) and carbon tetrachloride (20 mL) is stirred under a bright lamp for 3 h. The mixture is concentrated and the residue is purified via flash chromatography &quot; (0 to 50% EtOAc-heptane) to provide the title compound (0.85 g, 62%) as an orange oil. ES / MS m / e 288.7 (M + 1). The following compound is prepared essentially according to the preparation of 4-bromomethyl-2-isopropoxy-benzoic acid methyl ester using the appropriate starting material.

Preparation 150: 4-Bromomethyl-2-methoxy-benzoic acid methyl ester starting from 2-iso-propoxy-4-methyl-benzoic acid methyl ester and methanol, MS m / z: 261.0 ( M + 2). 157 ΡΕ2029547

Preparation 151 (4-Hydroxy-2-methyl-phenyl) -carbamic acid tert-butyl ester

Di-tert-butyl dicarbonate (21.3 g, 97.4 mmol) is added to a solution of 4-amino-m-cresol (10.0 g, 81.2 mmol), triethylamine (13.6 mL, 97.4 mmol) and methylene chloride (150 mL) at room temperature and the contents are stirred for 2 h. The mixture is washed with saturated aqueous citric acid and brine, and is dried over aqueous sodium sulfate. The crude product is purified by flash chromatography &quot; (20-40% EtOAc / heptane) to give the title compound (5.9 g, 33%) as a white solid. ES / MS m / e 222.0 (M-1).

Preparation 152 {4- [4-Cyclopropyl-2- (2-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -carbamic acid tert-

Tri-n-butylphosphine (1.9 mL, 7.5 mmol) and azodicarboxylic acid dipiperidine (1.90 g, 7.54 mmol) are added to a mixture of [4-cyclopropyl-2- (2-trifluoromethoxy-phenyl) ) -H-pyrazol-3-yl] -methanol (1.50 g, 5.03 mmol), (4-hydroxy-2-methyl-phenyl) -carbamic acid tert -butyl ester (1.35 g , 6.03 mmol) and toluene at room temperature. After 1 h, an additional tri-n-butylphosphine (0.6 mL) is added and the mixture is stirred for 2 h. The mixture is concentrated and the residue is purified by flash chromatography &quot; (20-50% EtOAc / heptane) to give the title compound (1.92 g, 76%) as a white powder. LC-ES / MS m / e 504.2 (M + 1).

Preparation 153 {4- [4-Cyclopropyl-2- (2-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-carbamic acid tert -butyl ester

Sodium hydride (60% in mineral oil, 183 mg, 4.58 mmol) is added to a solution of tert-

{4- [4-cyclopropyl-2- (2-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -carbamic acid (1.92 g, 3.81 mmol ) and DMF (15 mL) in an ice bath. The mixture is stirred for 30 minutes and iodomethane (0.36 mL, 5.7 mmol) is added. The bath is removed and the mixture is stirred for the remainder with a mixture of ice and ammonium chloride. The mixture is diluted with ethyl acetate and water. The organic layer is washed with brine and dried over MgSO4 to provide 1.94 g (98%) of the title compound as an oil. LC-ES / MS m / e 518.2 (M + 1).

Preparation 154 {4- [4-Cyclopropyl-2- (2-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amine HCl / dioxane (4 N, 3.7 ml) is added to a solution of {4- [4-cyclopropyl-2- (2-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -2- (cis) -2,2-dichloro-2- phenyl} -methyl-carbamic acid tert-butyl ester (1.92 g, 3.71 mmol) in methylene chloride (40 mL) at room temperature. After 2 h of stirring, the mixture is concentrated and handled with ethyl acetate and saturated aqueous sodium bicarbonate. The organic layers are washed with brine and dried over sodium sulfate to provide 1.50 g (97%) of the title compound as an oil. MS m / e 418.0 (M + 1).

Preparation 155 Methyl formyl-3-formylaminobenzoic acid methyl ester 6-carboxylate (1.0 g, 5.7 mmol) is dissolved in methanol (50 mL) and cooled to -78 ° C Ozone is bubbled through until the starting material is completely consumed. Dimethyl sulfide (4.0 mL) and chloroform (25 mL) are added and the reaction mixture is stirred overnight at room temperature. The solvents are removed in vacuo and the crude product is recrystallized from chloroform to give the pure product (0.57 g, 48%). EXAMPLES Example 1

160 ΡΕ2029547

Step A 3- (2- {4- [4-Isopropyl-2- (2-trifluoromethyl-phenyl) -2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -vinyl) -benzoic acid methyl ester To a suspension of 3- [2- (4-hydroxy-2-methyl-phenyl) -vinyl] -benzoic acid methyl ester (107 mg, 0.4 mmol) and potassium carbonate (138 mg, 1 mmol) in CH 3 CN (4 mL) is added 5-bromomethyl-4-isopropyl-1- (2-trifluoromethyl-phenyl) -1H-pyrazole in CH 3 CN (4 mL, approximately 0.1 mmol / mL). The reaction mixture is stirred at 80 ° C for 5 hours and filtered through a pad of Celite eluting with EtOAc. The combined filtrate is concentrated and purified by column chromatography (0 to 20% EtOAc in hexanes) to afford the desired product, 136 mg (64%). LC-ES + MS m / e 535 (M + 1).

Step B 3- (2- {4- [4-Isopropyl-2- (2-trifluoromethyl-phenyl) -2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -vinyl) -benzoic acid To a solution of 3- (2- {4- [4-isopropyl-2- (2-trifluoromethyl-phenyl) -2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -vinyl) - (136 mg, 0.25 mmol) in 1,4-dioxane (7 mL) is added 2 N LiOH / H 2 O (3 mL). The reaction mixture is stirred at 50 ° C overnight. The solvent is evaporated and the residue is partitioned between EtOAc and 1N HCl. The layers are separated and the organic phase is washed with water and concentrated to give the title compound (129 mg, 97%). LC-ES-MS m / e 521 (M + 1), 100%. 161 ΡΕ2029547

The compounds listed in Table 1 are prepared essentially according to the preparation of 3- (2- {4- [4-Isopropyl-2- (2-trifluoromethyl-phenyl) -2H-pyrazol-3- ylmethoxy] -2-methyl-phenyl} -vinyl) -benzoic acid using the appropriate starting material.

Table 1

2 - [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2,2'-dimethyl-biphenyl-4-carboxylic acid LC- MS: 509 (M + 1), 3 5- {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -4- LCMS: 515 (M + 1), 4 5- {4- [2- (2,6-dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] ] -2-methyl-phenyl} -thiophene-2-carboxylic acid LC-MS: 501 (M + 1), 5- {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H LC-MS: 516 (M + 1), 6 5- {4- [4-Isopropyl-2- (3-methoxy- 2-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -thiophene-2-carboxylic acid LC-MS: 517 (M + 1), 2- {4- [4- -2- (2-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -4-methyl-thiazole-5-carboxylic acid LC-MS: 532 (M + 1) 5- {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -phenyl} -thiophene-2-carboxylic acid LC-MS: 487 (M + 1), 9 2- {4- [2- (2,6-dichloro-phenyl) -4- isopropyl-2H-pyrazol-3-ylmethoxy] -phenyl} -4-methyl-thiazole-5-carboxylic acid LC-MS: 502 (M + 1), 4 '- [4-Isopropyl-2- (2-trifluoromethyl) 3-ylmethoxy] -2'-methyl-biphenyl-4-carboxylic acid LC-MS: 495 (M + 1), 4 '- [2- (2,6-Dichloro-phenyl) ) -5-methyl-4-propyl-2H-pyrazol-3-ylmethoxy] -2'-methylbiphenyl-4-carboxylic acid LC / MS (ES +): 509, Dichloro-phenyl) -4,5-dimethyl-2H-pyrazol-3-ylmethoxy] -2'-methyl-biphenyl-4-carboxylic acid LC / MS (ES +): 481.0 13 '- [2- (2,6-dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -3-fluoro-2'-methyl-biphenyl-4-carboxylic acid LC-ES / MS m / e 514.8 (M + 1), 512.8 (M +) 162 ΡΕ2029547

Example 18

(4-Isopropyl-2 H -pyrazol-3-yl) -ethyl] -carbamic acid 2-oxazolidin-4-yl} 3-methyl-2'-methyl-biphenyl-4-carboxylic acid (M + 1), 509.0 (M +) 15 4 '- [2- (2,6-dichloro-phenyl) -4-isopropyl- pyrimidine-4-carboxylic acid (M + 1) 16 ', 4' - [2- (2,4-Difluoro-2'-methyl-biphenyl- Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-yl) 1- {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-LC-ES / MS m / e 3-ylmethoxy] -2-methyl-phenyl} -benzo [ d] isoxazole-3-carboxylic acid; 538.0 (M + 1) carboxylic acid

Step A: 3- {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2'-methyl-biphenyl-4-yl} - -acrylic acid methyl ester To a mixture of 3- (4'-hydroxy-2'-methyl-biphenyl-4-yl) -acrylic acid methyl ester (108 mg, 0.403 mmol), [2- (2,6- dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-yl] -methanol (126 mg, 0.443 mmol) and toluene (2.1 mL) is added 1,1 '- (azodicarbonyl) dipiperidine (112 mg, mmol) followed by tri-n-butylphosphine (109 μl, 0.443 mmol). The reaction is kept overnight at room temperature. The reaction mixture is diluted with hexane and the solid is filtered. The concentrated filtrate is purified via flash chromatography &quot; 163 ΡΕ2029547 eluting with 15% ethyl acetate / heptane) to give 183 mg (85%) of the ester.

Step B 3- {4 '- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2'-methyl-biphenyl-4-yl} -acrylic acid

A mixture of 3- {4 '- [2 - (2,6-dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2'-methyl-biphenyl-4 (510 mg, 0.928 mmol), 5 N sodium hydroxide (928 æl, 4.64 mmol), methanol (15 mL) and THF (12 mL) is stirred overnight at ambient temperature. The reaction mixture is diluted with water and most of the THF and methanol is evaporated. The remaining aqueous portion is washed with ether and the ether layer is discarded. The aqueous layer is acidified with 1N HCl and extracted with ether. The combined ether layers are washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue is purified using flash chromatography &quot; with 5% MeOH / CH 2 Cl 2 and triturated in ether-hexane to give 146 mg (30%) of the title compound. ES / MS m / e (35C1) 521.3 (M + 1)

The compounds listed in Table 2 are prepared essentially according to Preparation of 3- {4- [2- (2,6-dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2'-methyl-biphenyl-4-yl} -acrylic acid using the appropriate starting material. 164 ΡΕ2029547

Table 2

Example 4 4 '- [2- (2,6-Dichloro-phenyl) -4-isobutyl-5-methyl-2H-pyrazol-3-ylmethoxy] -2'-methyl-biphenyl-4-carboxylic acid 4 '- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2'-methyl- biphenyl-3-carboxylic acid LC-MS: 493.3 (M +) 21 6- {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2- methyl-phenyl} nicotinic acid LCMS: 496 (M + 1) 22 4 '- [2- (2,6-dichloro-phenyl) -4-methyl-2H-pyrazol-3-ylmethoxy] -2'- methyl-biphenyl-4-carboxylic acid 4 '- [2- (2,6-difluoro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2' 4-carboxylic acid 4 '- [2- (2,6-dichloro-phenyl) -4-ethyl-5-methyl-2H-pyrazol-3- 1-ylmethoxy] -2'-methyl-biphenyl-4-carboxylic acid LC / MS (ES +): 495,025 3 - [({4- [2- (2,6-dichloro-phenyl) -4-isobutyl-5- 3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) -methyl] -benzoic acid methyl ester 4 - [({ 4- [4-isopropyl-2- (2-trifluoromethoxy-phenyl) -2H-pyrazol-3- methoxy] -2-methyl-phenyl} -methyl-amino) -methyl] -benzoic acid LCMS: 552.0 (M +) 27 4 - [({4- [2- (2,6-Dichloro-phenyl) ) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) -methyl] -benzoic acid LCMS: 538 (M + [2- (2,6-dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) -methyl] -benzoic acid LCMS: 538 (M + 1) 3 - [({4- [2- (2,6-Dichloro-phenyl) -4-methyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) -methyl ] -benzoic acid LC-MS: 510 (M + 1) 30 4 - [({4- [2- (2,6-dichloro-phenyl) -4-methyl-2H-pyrazol-3-ylmethoxy] -2- methyl-phenyl} -methyl-amino) -methyl] -benzoic acid 3 - [({4- [4-isopropyl-2- (2-trifluoromethyl-phenyl) -2H- pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) -methyl] -benzoic acid LC-MS: 538 (M + 1) ΡΕ2029547 (continued)

Example 4: 4 - [({4- [4-isopropyl-2- (2-trifluoromethyl-phenyl) -2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) - methyl] benzoic acid LC-MS: 538 (M + 1) 33 3 - [({4- [4-isopropyl-2- (2-trifluoromethoxyphenyl) -2H-pyrazol-3-ylmethoxy] -2- methyl-phenyl} -methyl-benzoic acid LC-MS: 554 (M + 1) 34 3 - [({4- [2- (2,6-Difluoro-phenyl) -4-isopropyl- Yl) ethoxy] -2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) -methyl] -benzoic acid LC / MS (ES +): 506.235 4 - [({4- [2- , 6-difluoro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) -methyl] -benzoic acid LC / MS (ES +): - [({4- [2- (2,6-dichloro-phenyl) -4-isobutyl-5-methyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) -methyl ] -benzoic acid LC / MS (ES +): 566.037 4 - [({4- [2- (2,6-dichloro-phenyl) -4-isobutyl-5-methyl-2H-pyrazol-3-ylmethoxy ] -2-methyl-phenyl} -methyl-amino) -methyl] -benzoic acid 3 - [({4- [2- (2,4- Dichloro-phenyl) -4-ethyl-5-methyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl (M + 1) 39 4 - [({4- [2- (2,6-Dichloro-phenyl) -piperazin-1-yl] 4-ethyl-5-methyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) -methyl] -benzoic acid MS m / e 538.0 (M + 1) 3 - [({4- [2- (2,6-Dichloro-phenyl) -5-methyl-4-propyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) (M + 1) 41 4 - [({4- [2- (2,6-dichloro-phenyl) -5-methyl-4-methyl-benzoic acid LC- propyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) -methyl] -benzoic acid LCMS / MS m / e 552.0 (M + 1) - {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -vinyl) -benzoic acid LC-ES / MS m / e 521 3- (2- {4- [4-Isopropyl-2- (2-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -vinyl) -benzoic acid LC-ES / MS m / e 537 (M + 1) ΡΕ2029547 166 (continuation)

Chemical Name Physical Data 44 3- (2- {4- [2- (2,6-Dichloro-phenyl) -4-ethyl-5-methyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl (M + 1) 45 3- (2- {4- [2- (2,6-dichloro-phenyl) -4-methyl-2H-pyrazole -3-ylmethoxy] -2-methyl-phenyl} -vinyl) -benzoic acid Methyl 3- (2- {4- [2- (2,6-dichloro- 3-ylmethoxy] -2-methyl-phenyl} -vinyl) -benzoic acid LCMS / MS m / e 493 (M + 1) 47 3- (2- { 4- [2- (2,6-difluoro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -vinyl) -benzoic acid LC-ES / MS m / e 489.0 3- (2- {4- [2- (2,6-Dichloro-phenyl) -4-isobutyl-5-methyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl } -vinyl) -benzoic acid LC-ES / MS m / e 549.0 (M + 1) 49 3- (2- {4- [2- (2,6-dichloro-phenyl) -5-methyl-4- 3-ylmethoxy] -2-methyl-phenyl} -vinyl) -benzoic acid LC-ES / MS m / e 535.0 (M + 1) 50 3- (2- {4- [ 2- (2,6-dichloro-phenyl) -4,5-dimethyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -vinyl) -benzoic acid LC-ES / MS m / e 507.0 ( M + 1) 51 3 - [({4- [2- (2,6-dichloro-4-fluorophenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -phenyl} -methyl-amino} -methyl} -benzoic acid LC-ES / MS m / e 554.0 (M + ) 3 - [({4- [4-isopropyl-2- (2-trifluoromethylsulfanyl-phenyl) -2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) -methyl] benzoic acid LC (4 '- [2- (2,6-dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2'- methyl-biphenyl-3-yl} -propionic acid LCMS (ES +): 523.3 54 {4 '- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] - 2-methyl-biphenyl-4-yl} -acetic acid LCMS (ES +): 509.0 (4 '- [2- (2,6-dichloro-phenyl) -4-isopropyl-2H-pyrazol- ylmethoxy] -2'-methyl-biphenyl-3-yl} -acetic acid LCMS (ES +): 509.0 56 3- {4 '- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H 3-ylmethoxy] -2'-methyl-biphenyl-3-yl} -acrylic acid LCMS (ES +): 521.3 57 6- {4- [2- (2,6-Dichloro-phenyl) -4- 3-ylmethoxy] -2-methyl-phenyl} -1H-indole-3-carboxylic acid LCMS (ES +): 534.0 58 6- {4- [2- (2,6- -phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2- (ES +): 536.0 59 5- {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3 -ylmethoxy] -2-methyl-phenyl} -1H-indole-3-carboxylic acid LCMS (ES +): 534.3 ΡΕ2029547 167 (continued)

Ex. Chemical Name Physical Data 60 6- {4- [4-Isopropyl-2- (2-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -1-methyl-1H-indole -3-carboxylic acid LCMS (ES +): 564.361 (5- {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl 3-yl) -acetic acid LCMS (ES +): 548.0 62 6- {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol- 3-ylmethoxy] -2-methyl-phenyl} -benzo [b] thiophene-3-carboxylic acid LCMS (ES +): 548.0 63 6- {4- [2- (2,6-Dichloro-phenyl) -4- 3-ylmethoxy] -2-methyl-phenyl} -benzo [b] thiophene-2-carboxylic acid LCMS (ES +): 551.0 64 6- {4- [4-Isopropyl- (2-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -benzo [b] thiophene-3-carboxylic acid LCMS (ES +): 567.0 6- {4- [ 4-isopropyl-2- (2-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -benzo [b] thiophene-2-carboxylic acid LCMS (ES +): 567.0 66 4 '- [4-isopropyl-2- (2-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -2'-methyl-biphenyl-4-carboxylic acid LC-MS: 509.0 3 - [({4- [4-cyclopropyl-2- (2,6-dichloro-phenyl) -2H-pyrazol-3-ylmethoxy] -phenyl} -methyl-amino) -methyl] -benzoic acid LC 3 - [({4- [4-cyclobutyl-2- (2,6-dichloro-phenyl) -2H-pyrazol-3-ylmethoxy] -phenyl} methyl-amino) -methyl] -benzoic acid LC-ES / MS m / e 548.0 (M +) 69 3 - [({4- [2- (2-chloro-6-trifluoromethyl-phenyl) -4-isopropyl 3 - [({4- [2- (3,5-Bis-trifluoromethyl-phenyl) -methyl-benzoic acid, 2-trifluoromethyl-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -phenyl} -methyl-amino) -methyl} -benzoic acid LC-ES / MS m / e 518.0 (M + 3 - [({4- [2- (2-fluoro-6-trifluoromethyl-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -phenyl} -methyl-amino) -methyl] -benzoic acid LC 4- {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl- benzylamino} -benzoic acid LC-MS: 522.2 (M +) 73 4- (1- {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] - 2-methyl-phenyl} -ethylamino) -benzoic acid LC-MS: 536.3 (M + ) ΡΕ2029547 168 (cont'd)

Ex-Chemical Name Physical Data 74 3- {4 '- [2- (2,6-dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2'-methyl-biphenyl- -propionic acid LCMS (ES +): 523.3 75 4 - [({4- [2-cyclopropyl-2- (2,6-dichloro-phenyl) -2H-pyrazol-3-ylmethoxy} -2-methyl-phenyl methyl-2-methyl-benzoic acid LCMS / MS m / e 550.0 (M + 1) 76 3 - [({4- [2- (chloro-6-trifluoromethyl 4-cyclopropyl-2H-pyrazol-3-ylmethoxy] -2-methoxy] -2-methyl-phenyl} -methyl-amino) -methyl] -benzoic acid LC-ES / MS m / e 570.0 ( M + 1) 77 6- {4- [4-cyclopropyl-2- (2,6-dichloro-phenyl) -2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -benzo [d] isothiazol-3- cyclopropyl-2- (2-trifluoromethoxy-phenyl) -2H-pyrazol-2-ylmethoxy] -propionic acid LC-ES / MS m / e 550.0 (M + 1) 2-methyl-phenyl} -benzo [d] isothiazole-3-carboxylic acid LC-ES / MS m / e 566.0 (M + 1) 79 6- {4- [4-cyclopropyl- Dichloro-phenyl) -2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -1-methyl-1H-indazole-3-carboxylic acid LC-ES / MS m / e 547.0 (M + 1) ) 4 - [({4- [4-isopropyl-2- (2-trifluoromethoxy-f enyl) -2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) -methyl] -benzoic acid methyl ester 4 - [({4- - [2- (2,6-dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) -methyl] -benzoic acid LC / MS / and Methyl 4 - [({4- [4-cyclopropyl-2- (2-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl- ) -methyl] -benzoic acid LC-ES / MS m / e 552 (M + 1) 83 6- {4- [4-Isopropyl-2- (2-trifluoromethoxyphenyl) -2H-pyrazol-3-ylmethoxy ] -2-methyl-phenyl} -1-methyl-1H-indole-3-carboxylic acid 6- {4- [4-cyclopropyl-2- (2,6-dichloro-phenyl) -2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -1-methyl-1H-indole-3-carboxylic acid LC-ES / MS m / e 546.0 ( M + 1) 6- {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl] -benzo [b] thiophene- 3-carboxylic acid LC-ES / MS m / e 548.0 (M + 1) 169 ΡΕ2029547

Example 88

(continuation)

Ex-Chemical Name Physical Data 6- {4- [4-cyclopropyl-2- (2,6-dichloro-phenyl) -2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -benzo [b] thiophene -3-carboxylic acid 4 - [({4- [4-isopropyl-2- (2-trifluoromethoxy-phenyl) -2H-pyrazol-3 2-methyl-benzoic acid LC-ES-MS m / e 568.3 (M + 1) 566.3 (ñ -1) 2-Amino- - [2 - ({4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy]] - 2-methyl-phenyl} -methyl-amino) -ethyl] -5-methylbenzoic acid

To a solution of {4- [2- (2,6-dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amine (168 mg, 0.416 mmol) in 10 mL of 1,2-dichloroethane is added 4-methyl-2- (2-oxo-ethyl) -benzoic acid methyl ester (80 mg, 0.416 mmol) and AcOH (10 mg). The reaction mixture is allowed to stir at room temperature for 15 min and is treated with sodium triacetoxyborohydride (176 mg, 0.832 mmol). The reaction mixture is allowed to stir at room temperature for 2 h and is quenched with water (5 mL). The mixture is concentrated and extracted twice with ethyl acetate 170 ΡΕ 2029547 (30 mL). The combined organic layers are dried over sodium sulfate, concentrated under reduced pressure and purified by flash chromatography &quot; eluting with hexanes / ethyl acetate (60:40) to afford the intermediate methyl ester (0.125 g, 52%).

Step B To a solution of the intermediate methyl ester of Step A (122 mg, 0.210 mmol) in 2.0 mL THF and 1.0 mL MeOH is added sodium hydroxide (2.0 mL, 2.0 M in water). The reaction mixture is allowed to stir at 60 ° C for 2 h. The reaction mixture is neutralized with HCl (2.0 mL, 2.0 M in water) and the organic solvent is removed under reduced pressure. The resulting residue is extracted twice with ethyl acetate (10 mL). The combined organic layers are dried over sodium sulfate and concentrated under reduced pressure to give the title compound (0.110 g, 92%). ES / MS m / e (35C1) 566.3 (M + 1).

Example 89

4 - {({4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) -methyl} - 2-methyl-benzoic acid The title compound is prepared essentially as in Preparation of 2- {2 - ({4- [2- (2,6-dichloro-phenyl) -4-isopropyl- 2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) -ethyl} -5-methyl-benzoic acid using the appropriate starting material. LC-ES / MS m / e 552.0 (M + 1), 550.0 (M-1).

The compounds listed in Table 3 are prepared essentially according to Preparation of 2- {2 - ({4- [2- (2,6-dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-yl methoxy] -2-m-ethyl-phenyl} -methyl-amino) -ethyl} -5-methyl-benzoic acid using the appropriate starting material.

Table 3

3 - [({4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -ethylamino) - methyl] benzoic acid LC / MS (ES +): 552.0 91 3 - [({4- [2- (2,6-dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2- (ES +): 566.0 92 3 - [({4- [2- (2,6-Dichloro-phenyl) -4-isopropyl] -ethyl] -2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -isobutylamino) -methyl] -benzoic acid LC / MS (ES +): 580.3 93 2- {4 - [({4- [2- - (2,6-dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) -methyl] -phenyl} -2-methyl-propionic acid LC / MS (ES +): 580.3 94 1- {4 - [({4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2- phenyl} -methyl-amino) -methyl] -phenyl} -cyclopropanecarboxylic acid LC / MS (ES +): 578.3 95 2- [2 - ({4- [2- (2,6-Dichloro-phenyl) 4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) -ethyl] -benzoic acid LC / MS (ES +): 552.0 ΡΕ2029547 172

Chemical Name Physical Data 96 3- [2 - ({4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl -amino) -ethyl] -benzoic acid LC / MS (ES +): 552.0 97 4- [2 - ({4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol- 3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) -ethyl] -benzoic acid LC / MS (ES +): 552.0 2- [2 - ({4- [2- (2,6- dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) -ethyl] -4-fluoro-benzoic acid LC-MS: 570.3 (M + 1) ) 2- [2 - ({4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) - ethyl] -5-methoxybenzoic acid LC-MS: 582.5 (M + 1) 100 4-Chloro-2- [2 - ({4- [2- (2,6-dichloro-phenyl) -4- -isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) -ethyl] -benzoic acid LC-MS: 588.3 (M + 1) 101 2- [2 - ({4- - [2- (2,6-dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) -ethyl] -4-methyl-benzoic acid LC- MS: 566.5 (M + 1) 102 3- [2 - ({4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2- ethyl-4-methyl-benzoic acid LC-MS: 566.0 (M + 1) 2-Butoxy-5- [2 - ({4- [2- 3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) -ethyl] -benzoic acid LC-MS: 624.3 (M + 1) 4-Butoxy-3- [2 - ({4- [2- (2,6-dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} amino) -ethyl] -benzoic acid LC-MS: 624.3 (M + 1) 105 3- [2 - ((4- [2- (2,6-dichloro-phenyl) -4-isopropyl-2H-pyrazole -3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) -ethyl] -4-fluoro-benzoic acid LCMS: 570.0 (M + 1) 106 5- [2 - ((4- [2- (2,6-dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) -ethyl] -2-fluoro-benzoic acid LC-MS : 570.0 (M + 1) ΡΕ2029547 173 (cont'd)

Chemical Name Physical Data 107 4 - [({4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amino ) -methyl] -3-formylaminobenzoic acid LC-MS: 581.0 (M + 1) 2 2-Benzyloxy-4 - [({4- [2- (2,6-dichloro-phenyl) -4- isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) -methyl] -benzoic acid LC-MS: 644.0 (M + 1), 642.0 (M) [({4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) -methyl] -2- 2-butyrylamino-4 - [({4- [2- (2,6-dichloro-phenyl) -4-isopropyl-benzoic acid LC-MS: 608.3 (M + 1) 3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) -methyl] -benzoic acid LC-MS: 623.0 (M + 1), 621.0 (M +) 111 4 - [({ 4- [2- (2,6-dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) -methyl] -2-trifluoromethyl-benzoic acid methyl ester LC-MS: 606.0 (M + 1), 604.0 (M +) 112 3 - [({4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3 -ylmethoxy] -2-methyl-phenyl} -methyl-amino) -methyl] -5-trifluoromethyl-benzoic acid methyl ester LC-MS: 606.0 (M + 1), 604.0 (M +) 113 5 - [({4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3 2-fluoro-benzoic acid LC-MS: 556.0 (M + 1), 554.0 (M +) 114 3 - [({ 4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) -methyl] -4-methoxy-benzoic acid LC- 5 - [({4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -5- ] -2-methyl-phenyl} -methyl-amino) -methyl] -1H-pyrrole-2-carboxylic acid LC-MS: 527.0 (M + 1), 525.0 (M +) 116 2 - [({ 4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) -methyl] -furan- MS: 528.0 (M + 1), 526.0 (M +) 117 3- {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] - 2-methyl-benzylamino} -4-methyl-benzoic acid LC-MS: 536.0 (M +) ΡΕ2029547 174 (continued)

3-Butoxy-5 - [({4- [2- (2,6-dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} (M + 1), 608.3 (M +). 5 - [({4- [2- (2,6-Dichloro-phenyl) -methyl- -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) -methyl] -thiophene-2-carboxylic acid LC-MS: 544.0 (M + 1), 542, 2 - [({4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) (M +), 527.0 (M +). 2-Benzoyl-4 - [({4- [2- (2,6-dichlorophenyl) dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) -methyl] -benzoic acid LCMS MS m / e 642.0 (M + 1), 640 , 0 (M1)

Example 122

Step A 3 - [({6- [4-Isopropyl-2- (2-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -2-methyl-pyridin-3-yl} To a solution of 6- [4-isopropyl-2- (2-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -2-methyl- 3-ylamine (100 mg, 0.246 mmol) in MeOH (3 mL) is added 3-formylic acid methyl ester. The reaction mixture is -benzoic (40 mg, 0.246 mmol). 175 ΡΕ2029547 stirred at room temperature for 10 min. Decaborane (12 mg, 0.0738 mmol) is added and the reaction mixture is stirred at room temperature. After 2 h, formaldehyde (2.0 mL, 37% w / w in water) is added and the reaction mixture is stirred at room temperature for 10 min. Decaborane (12 mg, 0.0738 mmol) is added and the reaction is stirred at room temperature. After 2 h, the reaction mixture is concentrated and the residue is chromatographed (SiO2, 40 g, EtOAc / 20% Hex) to give the title compound (97 mg, 69%). 1 H-NMR (400 MHz, DMSO): δ 7.91-7.88 (m, 1H), 7.81 (dt, 1H, J = 4.6, 2.5 Hz), 7.63 (s, 1H), 7.59-7.50 (m, 4H), 7.48-7.41 (m, 3H), 6.39 (d, 1H, J = 7.9 Hz), 5.13 ( 2H), 3.82 (s, 3H), 3.03 (sept, 1H, J = 6.6Hz), 2.46 (s, 3H) 32 (s, 3H), 1.18 (d, 6H, J = 6.6 Hz).

Step B 3 - {({6- [4-Isopropyl-2- (2-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -2-methyl-pyridin-3-yl} -methyl-amino) -methyl} -benzoic acid methyl ester To a room temperature solution of 3 - {({6- [4-isopropyl-2- (2-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] - 2-methyl-pyridin-3-yl} -methyl-amino) -methyl} -benzoic acid (106 mg, 0.186 mmol) in dioxane (2 mL) is added a solution of lithium hydroxide (279 æl, 0.558 mmol, 2 , 0 N in water). The reaction mixture is heated to 50 ° C. The reaction is concentrated under reduced pressure and the residue is partitioned between Et2 0 and water. The pH of the aqueous layer is adjusted to approximately 7 and extracted with a second portion of Et 2 O. The combined organic layers are washed with water, dried (MgSO4), filtered and concentrated to afford the title compound (99 mg, 96%). ES / MS m / e 555.3 (M + 1).

The compounds listed in Table 4 are prepared essentially according to Preparation of 3 - {[6- (4-isopropyl-2- (2-trifluoromethoxy-phenyl) -2H-pyrazol-3-yl-methoxy] - 2-methyl-pyridin-3-yl} -methyl-amino) -methyl} -benzoic acid using the appropriate starting material.

Table 4

Ex 4 - [({6- [4-isopropyl-2- (2-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -2-methyl-pyridin-3-yl} -methyl ester -amino) -methyl] -benzoic acid LC / MS (ES +): 555.3 124 5 - [({6- [4-Isopropyl-2- (2-trifluoromethoxyphenyl) -2H-pyrazol-3-ylmethoxy ] -2-methyl-pyridin-3-yl} -methyl-amino) -methyl] -2-methoxy-benzoic acid LC / MS (ES +): 585.3 125 4 - [({6- [4-Isopropyl (2-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -2-methyl-pyridin-3-yl} -methyl-amino) -methyl] -2-pentyl-benzoic acid LC / MS (ES + ): 625.3 4 - [({6- [4-Isopropyl-2- (2-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -2-methyl-pyridin-3-yl} -methyl (4-isopropyl-2- (2-trifluoromethoxy-phenyl) -2H-pyrazole) -3-ylmethoxy] -2-methyl-pyridin-3-yl} -methyl-amino) -methyl] -2-pent-1-ynylbenzoic acid LC-ES / MS m / e 621.0 (M + 1) ), 100% 177 ΡΕ2029547

Example 128

Step A 3- (1- {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -ethylsulfanyl) To a solution of 1- {4- [2- (2,6-dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -ethanol (299 mg, 1.78 mmol) and tri-N-butylphosphine (668 æL, 2.68 mmol) were added in toluene (20 mL) ). The reaction mixture is cooled to 0 ° C. 1,1 '- (Azocarbonyl) -dipiperidine (676 mg, 2.68 mmol) is added and the reaction mixture is warmed to room temperature overnight. The reaction mixture is concentrated and the residue is chromatographed (40 g SiC> 2, 0% to 30% EtOAc / hexanes) to provide the title compound (541 mg, 54%). 1H NMR (400 MHz, CDCl3):? δ 8.00-7.98 (m, 1H), 7.99 (t, 1H, J = 1.8 Hz), 7.87 (dt, 1H, J = 4.6, 2.5 Hz), 7.70 (s, 1H), 7.43-7.39 (m, 3H), 7.32-7.22 (m, 3H), 6.61-6.54 (m, 2H) (S, 2H), 4.53 (q, 1H, J = 7.0Hz), 3.90 (s, 3H), 2.99 (sept, 1H, J = 32 (s, 3H), 1.56 (d, 3H, J = 6.9 Hz), 1.30 (d, 6H, J = 6.6 Hz). 178

Step B 4- (1- {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -ethylsulfanyl) -benzoic acid A a solution of 3- (1- {4- [2- (2,6-dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl- phenyl} -ethylsulfanyl) benzoic acid (10 mg, 0.0176 mmol) in dioxane (2 mL) is added a solution of lithium hydroxide (26 æl, 0.052 mmol, 2.0 N in water). The reaction mixture is heated to 50 ° C. The reaction mixture is concentrated and the residue is partitioned between Et2 0 and water. The pH of the aqueous layer is adjusted to approximately 4 and extracted with a second portion of Et 2 O. The combined organic layers are washed with water, dried (MgSO 4), filtered and concentrated to give the title compound (10 mg, quant.). ES / MS m / e (35C1) 556.3 (M + 1).

Example 129

2- (2- {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -propoxy) -benzoic acid The mentioned compound The title compound is prepared essentially according to the preparation of 4- (1- {4-1- (cis-2β) -20,29-47- [2- (2,6-dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] - 2-methyl-phenyl} -ethylsulfanyl) -benzoic acid using the appropriate starting material. Racemate LC / MS (ES +): 553.0; Isomer 1 LC / MS (ES +): 553.0; Isomer 2 LC / MS (ES +): 553.0.

The compounds listed in Table 5 are prepared essentially according to Preparation of 4- (1- {4- [2- (2, β-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -ethylsulfanyl) -benzoic acid using the appropriate starting material.

Table 5

Ex-Chemical Name Physical Data 130 2- (2- {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -ethoxy) -6-methylbenzoic acid LC / MS (ES +): 553.0. 3- (2- {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -ethoxy) -naphthalene-2- LC / MS (ES +): 589.0. 5-Chloro-2- (2- {4- [2- (2,6-dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -ethoxy) - benzoic acid LC / MS (ES +): 573.0. 2- (2- {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -ethoxy) -5-methoxy- benzoic acid LC / MS (ES +): 569.0. 2- (2- {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -ethoxy) -5- benzoic acid LC / MS (ES +): 553.0. 4- (2- {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -ethoxy) -benzoic acid LC / MS (ES +): 539.0. 3- (2- {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -ethoxy) -benzoic acid LC / MS (ES +): 539.0. 180 ΡΕ2029547 (cont'd)

Ex-Chemical Name Physical Data 137 2- (2- {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -ethoxy) -benzoic acid ethyl ester LC / MS (ES +): 539.0. 138 2- (2- {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -propoxy) -6- benzoic acid LC / MS (ES +): 567.0. 2- (2- {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -propoxy) -5- benzoic acid LC / MS (ES +): 567.0. 2- (2- {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -propoxy) -4- benzoic acid LC / MS (ES +): 567.0. 141 2- (2- {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -propoxy) -3- benzoic acid LC / MS (ES +): 567.0. 3- (2- {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -propoxy) -benzoic acid Racemic LC / MS (ES +): 553.0. Isomer 1 IC / MS (ES +): 553.0. Isomer 2 IC / MS (ES +): 553.0. 4- (2- {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -propoxy) -benzoic acid Racemic LC / MS (ES +): 553.0. Isomer 1 LC / MS (ES +): 553.0. Isomer 2 LC / MS (ES +): 553.0. 3- (1- {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -ethylsulfanyl) -benzoic acid Racemate LC / MS (ES +): 555.0. Isomer 1 LC / MS (ES +): 555.0. Isomer 2 IC / MS (ES +): 555.0. ΡΕ2029547 181 (cont'd)

Chemical Name Physical Data 145 4- (1- {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -ethylsulfanyl) -benzoic acid Racemate LC / MS (ES +): 555.0. Isomer 1 LC / MS (ES +): 555.0. Isomer 2 LC / MS (ES +): 555.0. 146 3- (1- {4- [4-Isopropyl-2- (2-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -ethylsulfanyl) -benzoic acid Racemate LC / MS (ES +): 571.0. Isomer 1 LC / MS (ES +): 571.0. Isomer 2 LC / MS (ES +): 571.0. 3- (1- {6- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -pyridin-3-yl} -ethylsulfanyl) -benzoic acid Racemate LC / MS (ES +): 542.0. Isomer 1 LC / MS (ES +): 542.0. Isomer 2 LC / MS (ES +): 542.0. 4- (1- {6- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -pyridin-3-yl} -ethylsulfanyl) -benzoic acid Racemate LC / MS (ES +): 542.0. Isomer 1 LC / MS (ES +): 542.0. Isomer 2 LC / MS (ES +): 542.0 149 3- (1- {6- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -pyridine -3-yl} -ethylsulfanyl) -benzoic acid Racemic LC / MS (ES +): 542.0. Isomer 1 LC / MS (ES +): 542.0. Isomer 2 IC / MS (ES +): 542.0. 3- (1- {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -phenyl} -ethylsulfanyl) -benzoic acid LC / MS (ES +): 541 , 0. 4- (1- {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -phenyl} -ethylsulfanyl) -benzoic acid LC / MS (ES +): 541 , 0. ΡΕ2029547 182 (cont'd)

Chemical name Physical Data 152 3- {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-benzyloxy} -benzoic acid LC / MS ES +): 525.0. 4- {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-benzyloxy} -benzoic acid LC / MS (ES +): 525, 0. (3- {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-benzyloxy} -phenyl) -acetic acid LC / MS (ES + ): 539.0. (4- {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-benzyloxy} -phenyl) -acetic acid LC / MS (ES + ): 539.0. 4- {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-benzyloxy} -2-propyl-benzoic acid LC / MS (ES + ): 567.0. 5- {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-benzyloxy} -2-propyl-benzoic acid LC / MS (ES + ): 567.0. 4- {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-benzyloxy} -2-methyl-benzoic acid LC / MS (ES + ): 539.0. 159 3- (1- {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -ethoxy) -benzoic acid Racemic LC / MS (ES +): 539.0. Isomer 1 IC / MS (ES +): 539.0. Isomer 2 IC / MS (ES +): 539.0. 4- (1- {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -ethoxy) -benzoic acid Racemate LC / MS (ES +): 537.0. Isomer 1 IC / MS (ES +): 537.0. Isomer 2 IC / MS (ES +): 537.0. 161 3- (1- {6- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -pyridin-3-yl} -ethoxy) -benzoic acid Racemate LC / MS (ES +): 526.0. Isomer 1 IC / MS (ES +): 526.0. Isomer 2 LC / MS (ES +): 526.0. ΡΕ2029547 183 (cont'd)

Ex 4-6- (2- (2,6-dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -pyridin-3-yl} -ethoxy) -benzoic acid Racemate LC / MS (ES +): 526.0. Isomer 1 LC / MS (ES +): 526.0. Isomer 2 LC / MS (ES +): 526.0. 3- (1- {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -phenyl} -ethoxy) -benzoic acid LC / MS (ES +): 525 , 0. 4- (1- {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -phenyl} -ethoxy) -benzoic acid LC / MS (ES +): 525 , 0. 4 - [({4- [2-Cyclopropyl-2- (trifluoromethoxy-phenyl-2H-pyrazol-3-ylmethoxy) -2-methyl-phenyl] -methyl-amino) -methyl] -2- methyl-benzoic acid LC-ES-MS m / e 580.0 (M + 1) 1-ylmethoxy] -2-methyl-phenyl} -benzo [b] thiophene-5-carboxylic acid 4 - [({2-chloro-4- [4- -2-methyl-benzoic acid LC-ES / MS m / e 588.2 (M +). + 1) 4 - [({2-chloro-4- [4-cyclopropyl-2- (2,6-dichloro-phenyl) -2H-pyrazol-3-ylmethoxy] -phenyl} -methyl-amino) - methyl-2-methyl-benzoic acid LC-ES-MS m / e 570.0 (M + 1) 4 - [({2-Chloro-4- [2- (2,6-dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -phenyl} -methyl-amino) -methyl] -2-methyl-benzoic acid LC-ES / MS m / e 574.0 (M + 1) - [({4- [4-cyclopropyl-2- (2,6-dichloro-phenyl) -2H-pyrazol-3-ylmethoxy] -2-fluoro-phenyl} -methylamino) -methyl] -2- benzoic acid LC-ES / MS m / e 554.0 (M + 1). 4 - [({4- [2- (2,6- pyrazol-3-ylmethoxy] -2-fluoro-phenyl) -methyl-amino] -methyl] -2-methyl-benzoic acid LC-ES / MS m / e 556.0 (M + + l). 4 - [({4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -phenyl} -methylamino) -methyl] -2- benzoic acid LC-ES / MS m / e 538.2 (M + 1). ΡΕ2029547 184 (cont'd)

Chemical Name Physical Data 173 4 '- [4-cyclopropyl-2- (2,6-dichloro-phenyl) -2H-pyrazol-3-ylmethoxy] -2'-methyl-biphenyl-4-carboxylic acid / e 493.0 (M + 1). 174 6- {4- [4-cyclopropyl-2- (2-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -benzo [d] -isothiazole-3- MS m / e 566.0 (M + 1). 6- {4- [4-Cyclopropyl-2- (2-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -1-methyl-1H-indole-3-carboxylic acid ES / MS m / e 562.0 (M + 1). 176 6- {4- [4-Cyclopropyl-2- (2-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -1-isopropyl-1H-indole-3-carboxylic acid, ES / MS m / e 590.0 (M + 1). 6- {4- [4-Cyclopropyl-2- (2-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -1,2-dimethyl-1H-indole-3- carboxylic acid ES / MS m / e 576.0 (M + 1). 6- {4- [4-Cyclopropyl-2- (2-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -benzo [b] thiophene-3-carboxylic acid ES / MS m / e 565.0 (M + 1). 4 - [({4- [4-cyclopropyl-2- (2-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) -methyl] -benzoic acid ES / MS m / e 552.2 (M + 1). 2- {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -benzo [b] thiophene-7-carboxylic acid LC-ES + MS m / e 551 (M + 1). When present, the individual enantiomers are isolated from the racemic mixture via chiral chromatography. Isomer 1 elutes from the first column and Isomer 2 elutes from the second column.

Example 181

185 ΡΕ2029547

[2- (6-Carboxyindol-1-yl) ethyl] - {4- [2- (2,6-dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -piperazine- 2-methyl-phenyl} -methyl-ammonium chloride

Step A To a 0 ° C suspension of sodium hydride (10 mg, 0.235 mmol, 60% dispersion in oil) in DMF (2 mL) is added a solution of 1 H-

2-carboxylic acid (34 mg, 0.195 mmol) in DMF (2 mL) was added dropwise. The reaction is warmed to ambient temperature over 30 min. The reaction mixture is cooled to 0 ° C and a solution of (2-bromoethyl) - {4- [2- (2,6-dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amine (80 mg, 0.156 mmol) in DMF (2 mL) is added dropwise. The reaction is warmed to room temperature and is stirred overnight. The reaction mixture is quenched with saturated aqueous ammonium chloride and concentrated under reduced pressure. The residue is partitioned between Et2 0 and water. The aqueous layer is extracted with Et 2 O and the combined organic layers are washed with brine, dried (MgSO 4), filtered and concentrated under reduced pressure to afford a mixture of ester and carboxylic acid products (83 mg, 88%).

Step B

To a room temperature solution of the methyl ester of Step A (83 mg, 0.137 mmol) in MeOH / water (1/1 mL) is added potassium hydroxide (231 mg, 4.11 mmol). The reaction mixture is heated to 80 ° C overnight. The reaction mixture is concentrated and the residue is partitioned between Et2 0 and water. The pH of the aqueous layer is adjusted to 6-7. The aqueous layer is extracted with Et 2 O and the combined organic layers are washed with water, dried (MgSO 4), filtered and concentrated under reduced pressure. The residue is purified via reverse phase HPLC (C18 OBD 19x100 mm, ACN 30 to 70% / water (0.1% TFA) at 20 mL / min) to afford the title compound (64 mg, 66%). . ES / MS m / e (37 Cl) 593.0 (M + 1).

The compounds listed in Table 6 are prepared essentially according to the preparation of [2- (6-carboxy-indol-1-yl) -ethyl] - {4- [2- (2,6- chloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-ammonium bromide using the appropriate starting material.

Table 6

Ex-Chemical Name Physical Data 182 [2- (4-Carboxy-indol-1-yl) -ethyl] - {4- [2- (2,6-dichloro-phenyl) -4-isopropyl- pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-ammonium chloride LC / MS (ES +): 593.0. [2- (2-Carboxy-indol-1-yl) -ethyl] - {4- [2- (2,6-dichloro-phenyl) -4-isopropyl-2H-pyrazol-3- ylmethoxy] -2-methyl-phenyl} -methyl-ammonium chloride LC / MS (ES +): 593.0. [2- (3-Carboxy-indol-1-yl) -ethyl] - {4- [2- (2,6-dichloro-phenyl) -4-isopropyl-2H-pyrazol-3- ylmethoxy] -2-methyl-phenyl} -methyl-ammonium chloride LC / MS (ES +): 593.0. [2- (5-Carboxy-indol-1-yl) -ethyl] - {4- [2- (2,6-dichloro-phenyl) -4-isopropyl-2H-pyrazol-3- ylmethoxy] -2-methyl-phenyl} -methyl-ammonium chloride LC / MS (ES +): 593.0. 187 ΡΕ2029547

Example 188

(continuation)

[2- (6-Carboxy-indol-1-yl) -ethyl] - {4- [2- (2,6-dichloro-phenyl) -4-isopropyl-2H- pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-ammonium chloride LC / MS (ES +): 593.0. [2- (7-Carboxy-indol-1-yl) -ethyl] - {4- [2- (2,6-dichloro-phenyl) -4-isopropyl-2H-pyrazol-3- ylmethoxy] -2-methyl-phenyl} -methyl-ammonium chloride LC / MS (ES +): 591.0.

Step A {4 - [({4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl amino) -methyl] -phenyl} -acetic acid methyl ester To a room temperature solution of {4- [2- (2,6-dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2- (4-bromomethyl-phenyl) -acetic acid methyl ester (52 mg, 0.214 mmol) in acetonitrile (3 mL) was added methyl ester (82 mg, 0.204 mmol) in acetonitrile cesium carbonate (133 mg, 0.408 mmol). The reaction mixture is run at 80 ° C overnight. The reaction mixture is concentrated under reduced pressure. The residue is chromatographed (SiO2 40 g, 0% to 20% EtOAc / Hex). HPLC to remove phase inversion (C18 OBD 19x100 mm, ACN 30 to 70% / water (0.1% TFA) at 20 mL / min) is employed for approximately ΡΕ2029547 approximately 10% of the starting amine present to give the mentioned compound in title (78 mg, 68%). LC-ES / MS m / e 566.3 (M + 1), 95%

Step B: {4 - [({4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) - methyl] -phenyl} -acetic acid methyl ester To a solution of {4 - {({4- [2- (2,6-dichloro-phenyl) -4-isopropyl-2H-pyrazol- 3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) -methyl} -phenyl} -acetic acid methyl ester (81 mg, 0.143 mmol) in dioxane (2 mL) is added a solution of lithium hydroxide (215 μL, 0.429 mmol, 2.0 N in water). The reaction mixture is heated to 50 ° C. The reaction is concentrated and the residue is partitioned between Et2 0 and water. The pH of the aqueous layer is adjusted to approximately 7 and the aqueous layer is extracted with a second portion of Et 2 O. The combined organic layers are washed with water, dried (MgSO4), filtered and concentrated to afford the title compound (75 mg, 95%). ES / MS m / e (35C1) 552.0 (M + 1).

Example 189

189 ΡΕ2029547

4 - {({4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) -methyl} - 2-methoxybenzoic acid The title compound is prepared essentially according to the preparation of {4 - {({4- [2- (2,6-dichloro-phenyl) -4-isopropyl-2H-pyrazole -3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) -methyl} -phenyl} -acetic acid using the appropriate starting material. LC-ES / MS m / e 568.0 (M + 1), 566.0 (M-1).

Example 190

4 - {({4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) -methyl} -naphthalene carboxylic acid The title compound is prepared essentially according to the preparation of {4 - {({4- [2- (2,6-dichloro-phenyl) -4-isopropyl-2H-pyrazol- 3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) -methyl} -phenyl} -acetic acid using the appropriate starting material. LC-ES / MS m / e 588.3 (M + 1), 586.0 (M-1).

The compounds listed in Table 7 are prepared essentially according to Preparation of {4 - {(4- {2- [2,6-dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] 190 ΡΕ2029547 -2-methyl-phenyl} -methyl-amino) -methyl} -phenyl} -acetic acid using the appropriate starting material.

Table 7

Chemical Name Physical Data 191 2- {4 - [({4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} - methyl-amino) -methyl] -phenyl} -propionic acid LC / MS (ES +): 566.3 192 4 - [({4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H -pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) -methyl] -3-methoxy-benzoic acid LC-MS: 568.0 (M + 1), 566.0 (M +) 193 - [({4- [2- (2,6-dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) -methyl] -3-fluoro (M +) 194 4 - [({4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazole -3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) -methyl] -2-methoxy-benzoic acid LC-MS: 568.0 (M + 1), 566.0 (M +) 195 3-Bromo acid -4 - [({4- [2- (2,6-dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) -methyl] - benzoic acid LC-MS: 618.0 (M + 1) 196 4 - [({4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2- methyl-phenyl} -methyl-amino) -methyl] -2-isopropoxy-benzoic acid LC-MS: 596.0 (M + 1), 594.0 (M +) 1 2-Butoxy-4 - [({4- [2- (2,6-dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) -methyl] -benzoic acid LC-MS: 610.0 (M + 1), 608.0 (M +) 198 4 - [({4- [2- (2,6-Dichloro-phenyl) -4-isopropyl- 2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl] -methyl-amino) -methyl] -naphthalene-1-benzoic acid LC-MS: 588.3 (M + 1), 586.0 (M +) 199 3 - [({4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl] -methyl-amino) -methyl] -5- (M +) 200 4 - [({4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H] -acetic acid LCMS: -pyrazol-3-ylmethoxy] -2-methyl-phenyl] -methyl-amino) -methyl] -2,3-difluoro-benzoic acid LC-MS: 574.0 (M + 1), 572.3 (M +) 191 ΡΕ2029547 (cont'd)

Chemical Name Physical Data 201 4 - [({4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amino ) -methyl] -3-trifluoromethyl-benzoic acid LC-MS: 606.0 (M + 1), 604.3 (M +) 202 6 - [({4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) -methyl] -nicotinic acid LC-MS: 539.3 (M + 1), 537.3 (M + 4 - [({4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) -methyl] - 3-hydroxy-benzoic acid LC-MS: 554.0 (M + 1), 552.0 (M +) 204 3 - [({4- [2- (2,6-Dichloro-phenyl) -4-isopropyl- 2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) -methyl] -4-fluoro-benzoic acid LC-MS: 556.0 (M + 1), 554.0 (M +) 205 2-butoxy-5 - [({4- [2- (2,6-dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methylamino) (M +) 206: 5 - [({4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazole -3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) -methyl] -furan-2-carboxylic acid LC-MS: 528.0 (M + 4-yl) ethoxy] -2-methyl-phenyl} -4,5,6,7-tetrahydroisoquinoline-4-carboxylic acid 4 - [({4- [2- (2,6-dichloro-phenyl) -4-isopropyl- (M + 1), 657.0 (M +), 1 H-NMR (DMSO-d 6)

Example 208

Step A

3- (1- {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -1-methyl- To a solution of 2- {4- [2- (2, β-dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl- methyl-phenyl} -propan-2-ol (100 mg, 0.230 mmol) in DCE (1 mL) is added zinc iodide (37 mg, 0.115 mmol). The reaction is stirred at room temperature for 10 min. A solution of methyl 4-mercaptobenzoate (38 mg, 0.225 mmol) in DCE (1 mL) is added and the reaction is stirred overnight at ambient temperature. The reaction is concentrated under reduced pressure and the residue is chromatographed (SiO 2, 40 g, 0% to 30% EtOAc / Hex) to give the title compound (84 mg, 63%). 1H NMR (400 MHz, CDCl3): δ 7.74 (d, 2H, J = 7.5 Hz), 7.71 (s, 1H), 7.44 (d, 2H, J = 7.9 Hz ), 7.37-7.30 (m, 1H), 7.03 (d, 2H, J = 7.5 Hz), 6.89 (d, 1H, J = 8.8 Hz), 6.61 (s, 1H), 6.41 (d, 1H, J = 8.5Hz), 4.81 (s, 2H), 3.89 (s, 3H), 3.02 (sept, 1H, J = 6.63 Hz), 2.73 (s, 3H), 1.70 (s, 6H), 1.32 (d, 6H, J = 6.6 Hz).

Step B 3- (1- {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -1-methyl-ethylsulfanyl ) -benzoic acid methyl ester To a solution of 3- (1- {4- [2- (2,6-dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -1-methyl-ethylsulfanyl) -benzoic acid (91 mg, 0.156 mmol) in dioxane (2 mL) is added a solution of lithium hydroxide (234 æL, 0.468 mmol, 2.0 N in water). The reaction mixture is heated to 50 ° C. The reaction mixture is concentrated and the residue is partitioned between Et2 0 and water. The pH of the aqueous layer is adjusted to approximately 4 and extracted with a second portion of Et 2 O. The combined organic layers are washed with water, dried (MgSO4), filtered and concentrated to give the title compound (84 mg, 95%). ES / MS m / e (35C1) 569.0 (M + 1).

The compounds listed in Table 8 are prepared essentially according to Preparation of 3- (1- {4- [2- (2,6-dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -1-methyl-ethylsulfanyl) -benzoic acid using the appropriate starting material.

Table 8

Chemical Name Physical Data 209 3- (1- {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -1- methyl-ethylsulfanyl) -benzoic acid LC / MS (ES +): 569.0. 4- (1- {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -1-methyl-ethylsulfanyl) - benzoic acid LC / MS (ES +): 569.0. [4- (1- (4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -1-methyl-ethylsulfanyl- ) -phenyl] -acetic acid LC / MS (ES +): 583.0 212 [3- (1- (4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3 1-methyl-ethylsulfanyl) -phenyl] -acetic acid LC / MS (ES +): 583.0 213 3- (1- (4- [4-Isopropyl-2- (2-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -1-methyl-ethylsulfanyl) -benzoic acid LC / MS (ES +): 585.0 194 ΡΕ2029547

Example 217

(continuation)

Ex-Chemical Name Physical Data 214 4- (1- {4- [4-Isopropyl-2- (2-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} ethylsulfanyl) -benzoic acid LC / MS (ES +): 585.0. [4- (1- {4- [4-Isopropyl-2- (2-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -1-methyl-ethylsulfanyl) -phenyl ] -acetic acid LC / MS (ES +): 599, 216 [3- (1- {4- [4-Isopropyl-2- (2-trifluoromethoxy-phenyl) -2H-pyrazol- methyl-phenyl} -1-methyl-ethylsulfanyl) -phenyl] -acetic acid LC / MS (ES +): 599.0.

3 - ({4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenylamino} -methyl) -benzoic acid To a solution of (4-chloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-propionic acid methyl ester -phenyl} -amino) -methyl} -benzoic acid (797 mg, 1.24 mmol) in dioxane (10 mL) is added hydrochloric acid (3.12 mL, 12.40 mmol, 4 M in dioxane) dropwise . The reaction is warmed to room temperature and is stirred overnight. The reaction mixture is concentrated under reduced pressure and the residue is partitioned between EtOAc and saturated aqueous NaHCO3. 195 ΡΕ2029547 The aqueous layer is extracted with EtOAc and the combined organic layers are washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue is chromatographed (SiO 2, 120 g, 0% to 30% EtOAc / Hex) to give the title compound (603 mg, 90%). ES / MS m / e (35C1) 524.0 (M + 1).

Example 218

4 '- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2'-methyl-biphenyl-4-carboxylic acid The title compound is prepared essentially as described in the preparation of 3 - ({4- [2- (2,6-dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenylamino} -methyl) - benzoic acid using the appropriate starting material. LC-MS: 495 (M + 1).

Example 219

196 ΡΕ2029547 (+/-) 1- (3- {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} - butyl) -1H-pyrrole-2-carboxylic acid

To a solution of methyl pyrrole-2-carboxylate in dimethylformamide (3 mL) is added cesium carbonate (0.119 g, 0.366 mmol) followed by 3- {4- [2- (2,6-dichloro- phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -butyl ester (0.116 g, 0.183 mmol). The reaction mixture is run at 75 ° C overnight. The reaction is quenched with water followed by 1N HCl. The resulting solution is extracted twice with ethyl acetate. The organic layers are combined, washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified via flash chromatography &quot; eluting with 0-3% ethyl acetate: toluene to give the methyl ester.

Step B To a solution of the methyl ester from Step A (12 mg, 1 equiv) in methanol is added 1N NaOH (0.11 mL, 5 equiv). The reaction is heated at reflux for 3 hours. The reaction is concentrated under reduced pressure and the residue is dissolved in water. 1 N HCl is added and the precipitated product is isolated via filtration (7 mg, 58%). ES / MS m / e: 539.8 (M + 0), 541.8 (M + 2). 197 ΡΕ2029547

Example 220

3-Butoxy-4 '- [2- (2,6-dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2'-methyl-biphenyl-4-carboxylic acid

Step A

A solution of 3-butoxy-4'-hydroxy-2'-methylbiphenyl-4-carbaldehyde (0.198 g, 0.666 mmol) and 5-bromomethyl-4-isopropyl-1- (2,6- phenyl) -1H-pyrazole (0.242 g, 0.696 mmol) in DMF (2.0 mL) is treated with K 2 CO 3 (0.192 g, 1.39 mmol). The mixture is stirred at 70 ° C for 2 hours. The mixture is cooled to room temperature and quenched with water (10 mL). The mixture is extracted with ethyl acetate (20 mL x 2) and the combined organic layers are dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by silica gel chromatography eluting with 20% ethyl acetate in hexanes to give 3-butoxy-4 '- [2- (2,6-dichloro-phenyl) -4-isopropyl-2H-pyrazol- 3-ylmethoxy] -2'-methyl-biphenyl-4-carbaldehyde (0.125 g, 33%). ES / MS m / e 551.0; 553.0 (M + 1).

Step B

A solution of 3-butoxy-4 '- [2- (2,6-dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2'-methyl-biphenyl-4-carbaldehyde (0.125 g (2.0 mL) and t-BuOH (2.0 mL) and 2-methanesulfonyl-2-butene (1.0 mL) at 0 ° C is treated with a solution of NaClC> 2 (205 mg, 27 mmol) and NaH 2 PO 4 -H 2 O (313 mg, 2.27 mmol) in water (2.0 mL). The mixture is stirred at 0 ° C for 60 minutes. The organic layer is separated, dried over sodium sulfate and concentrated under reduced pressure. The residue is purified using silica gel chromatography eluting with 50% -100% ethyl acetate in hexanes to give the title compound (0.120 g, 93%). ES / MS m / e 566.8; 568.7 (M + 1).

Example 221

6- {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -2-methyl-benzofuran-3-carboxylic acid

Step A

A solution of 4-bromo-3-methyl-phenol (135 mg, 0.723 mmol) and 5-bromomethyl-1- (2,6-dichloro-phenyl) -4-isopropyl-1H-pyrazole (210 mg, 0.603 mmol) in dimethylformamide (1.0 mL) is treated with potassium carbonate (84 mg, 0.603 mmol). The reaction mixture is heated at 80 ° C for 60 minutes and cooled to room temperature. The mixture is loaded directly onto a silica gel column and purified with 25% EtOAc / hexanes to provide 5- (4-bromo-3-methyl-phenoxymethyl) -1- (2,6-dichloro-phenyl) -4- Î ±] 20,29547 -isopropyl-1H-pyrazole (0.258 g, 94%). ES / MS m / e (M + 1) 454.8.

Step B

A solution of 2-methyl-6- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzofuran-3-carboxylic acid ethyl ester (162 mg, (4-bromo-3-methyl-phenoxymethyl) -1- (2,6-dichloro-phenyl) -4-isopropyl-1H-pyrazole (256 mg, 0.563 mmol) in toluene (5 mL) ) is evacuated and refilled with N2 three times. Pd (OAc) 2 (11.5 mg, 0.051 mmol), 2-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl (42 mg, 0.102 mmol), and potassium phosphate (tribasic, N-hydrate, 218 mg, 1.02 mmol) in 0.5 mL of water are added. The resulting mixture is evacuated and refilled with N2 three times. The mixture is stirred at 110 ° C for 16 hours and cooled to room temperature. The mixture is filtered through a pad of Celite, and the filtrate is concentrated. The residue is purified by silica gel chromatography with 25% EtOAc / hexanes to afford the product 6- {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H- pyrazol-3-ylmethoxy] -2-methyl-phenyl} -2-methyl-benzofuran-3-carboxylic acid (89 mg, 31%). ES / MS m / e 564.8 (M + 1).

Step CO compound of the title compound is prepared by hydrolysis from the ester according to the preparation of 3- (2- {4- [4-isopropyl-2- (2-trifluoromethyl-phenyl) -2H-2β] -20,205,47-pyrazole -3-ylmethoxy] -2-methyl-phenyl} -vinyl) -benzoic acid methyl ester (Example 1) using the appropriate starting material. LC-MS: 550.8; 548.8 (M + 1).

Example 222

(6- {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -benzo [b] thiophen-3-yl) -acetic

Step A

A solution of {6- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -benzo [b] thio-phenyl-3-yl} -acetic acid ethyl ester (267 mg, 0.770 mmol) and 5- (4-bromo-3-methyl-phenoxymethyl) -1- (2, β-dichloro-phenyl) -4-isopropyl-1H-pyrazole (280 mg, 0.616 mmol) in toluene (10 mL) is evacuated and refilled with N2 three times. Pd (OAc) 2 (5.5 mg, 0.024 mmol), 2-dicyclohexylphosphino-2,6-dimethoxy-1,1'-biphenyl (20 mg, 0.049 mmol), and potassium phosphate, tribasic, N- (262 mg, 1.23 mmol) are added. The mixture is stirred at 100 ° C for 15 hours. The reaction mixture is cooled to room temperature and filtered through a pad of Celite. The filtrate is concentrated and the residue is purified by flash chromatography &quot; (eluting with 25% EtOAc / hexanes) and the appropriate fractions are concentrated. The material is dried in vacuo to give ethyl ester of 6- (4- {2- [2,6-dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl -phenyl} -benzo [b] thiophen-3-yl) -acetic acid (43 mg, yield 12%). ES / MS m / e 592.8; 594.8 (M + 1).

Step B

A solution of (6- {4- [2- (2, β-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -benzo [ b] thiophen-3-yl) acetic acid (43 mg, 0.072 mmol) in tetrahydrofuran (1.0 mL) and methanol (1.0 mL) is treated with sodium hydroxide (1.0 mL, 1.0 N). The mixture is stirred at room temperature for 2 hours and quenched with HCl (1.0 mL, 1.0 M). The mixture is extracted with EtOAc (10 mL x 2). The combined organic layers are dried over Na2 SO4, filtered, and concentrated. The crude product is purified by flash chromatography &quot; (eluting with 30-100% EtOAc / hexanes) and the appropriate fractions are concentrated. The material is dried under vacuum to give the title compound (28 mg, 68%). ES / MS m / e 564.8; 566.8 (M + 1); 562.8; 564.8 (M-1).

Example 223

4- (4-Cyclopropyl-2- (2-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) -methyl} -2- -methoxy-benzoic acid 202 ΡΕ2029547

Step A

To a solution of {4- [4-cyclopropyl-2- (2-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] ] -2-methyl-phenyl} -methyl-amine (0.31 g, 0.75 mmol) and 4-bromomethyl-2-methoxy-benzoic acid methyl ester (0.320 g, 1.23 mmol) in DMF (3 mL) at room temperature. The reaction is heated to 40 ° C for 2 h. The mixture is diluted with water and extracted with ethyl acetate. The combined organic layers are washed with brine and dried over MgSO4. The crude residue is purified via radial chromatography (2 mm plate, THF 20 to 40-heptane) to give 4 - {(4- {4-cyclopropyl-2- (2-trifluoromethoxy- phenyl) -2H-pyrazol-3-ylmethoxy} -2-methyl-phenyl} -methyl-amino) -methyl} -2-methoxy-benzoic acid (303 mg, 68%). ES / MS m / e 596.0 (M + 1).

Step B

A mixture of 4 - {[4- (4-cyclopropyl-2- (2-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl- amino) -methyl} -2-methoxy-benzoic acid (0.30 g, 0.51 mmol), sodium hydroxide (5 N, 0.5 mL), THF (3 mL) and methanol (3 mL) reflux for 1 h. The reaction mixture is cooled and acidified with 5N HCl, then diluted with water and extracted with ethyl acetate. The combined organic layers are washed with brine and dried over MgSO4 to give the title compound (285 mg, 97%) as an off-white foam. LC-ES + MS m / e 582.0 (M + 1). 203 ΡΕ2029547

Example 224

4- (4-Cyclopropyl-2- (2-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) -methyl} -2- -isopropoxy-benzoic acid

Step A

In a manner similar to the preparation of 4 - {({4- [4-cyclopropyl-2- (2-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} Using {4- [4-cyclopropyl-2- (2-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -2-methyl-benzoic acid phenyl} -methyl-amine and 4-bromomethyl-2-isopropoxy-benzoic acid methyl ester, 4 - {({4- [4-cyclopropyl-2- (2-trifluoromethoxy- phenyl) -2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) -methyl} -2-isopropoxy-benzoic acid. ES / MS m / e 624.0 (M + 1).

Step B

In a manner similar to the preparation of 4 - [(4- {4-cyclopropyl-2- (2-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amino ) -methyl} -2-methoxy-benzoic acid methyl ester using methyl ester of 204 ΡΕ2029547 4 - {({4- [4-cyclopropyl-2- (2-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy ] -2-methyl-phenyl} -methyl-amino) -methyl} -2-isopropoxy-benzoic acid, the title compound is prepared. LC-ES / MS m / e 610.2 (M + 1).

Lisbon, June 7, 2009

Claims (9)

A compound of formula P is 0 or 1 or 2; X1 is C or N and X2 is C or N; with the proviso that both and X2 are not N; R 1 and R 2 are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, halo, - (C 1 -C 6) alkyl and -S (C 1 -C 3) haloalkyl; each R 3 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy and halo; R 4a is selected from the group consisting of hydrogen, C 1 -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; R 4b is selected from the group consisting of hydrogen, C 1 -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; 2 ΡΕ 2029547 R 5 and R 5a are independently selected from the group consisting of hydrogen and C 1 -C 3 alkyl; R 6 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, halo, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, NO 2, C 3 -C 8 cycloalkyl and C 4 -C 8 alkylcycloalkyl; Li is selected from the group consisting of a bond, C 1 -C 6 alkyl, CR a = CR b, ethynyl, C 1 -C 5 alkylene, (C 1 -C 5 alkyl) -S-, (C 1 -C 5) alkyl-O-, N (R c) C 1 -C 5 alkyl and - (C 1 -C 5 alkyl) -N (R c) -, wherein Ra and R 5 are independently selected from the group consisting of hydrogen and C 1 -C 3 alkyl; and Rc is independently selected from the group consisting of H, C1 -C5 alkyl, C1 -C3 alkylphenyl and C4 -C8 alkylcycloalkyl; Ar1 is selected from the group consisting of indolyl, thienyl, benzothienyl, naphthyl, phenyl, pyridinyl, pyrazolyl, oxazolyl, benzoisoxazolyl, benzofuranyl, pyrrolyl, thiazolyl, benzoisothiazolyl, indazolyl, and furanyl, each optionally substituted by one or two groups independently selected from group consisting of hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, halo, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -O- (C1-C2 alkyl) phenyl, N (Rc) SO2-alkyl C1 -C6, -C (O) R10 and NHC (O) R10; R7 is selected from the group consisting of COOH, (C1 -C5) alkylC00H, -O-C1-C5-alkyl-COOH, C2-C4-alkoxy-COOH, C3-C8-cycloalkyl-COOH and COOR11R11; each R 10 is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl and phenyl; Each R 11 is independently hydrogen or C 1 -C 6 alkyl; or a pharmaceutically acceptable salt thereof. A compound according to Claim 1 wherein is 0 or 1 or 2; X 1 is C or N and X 2 is C or N; with the proviso that both X 1 and X 2 are not N; R 1 and R 2 are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 3 thiohaloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy and halo; R 3 is absent or is independently selected from the group consisting of C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy and halo; R 4a is selected from the group consisting of hydrogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 3 -C 6 cycloalkyl and C 4 -C 5 alkylcycloalkyl; R 4b is selected from the group consisting of hydrogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 3 -C 6 cycloalkyl and C 4 -C 5 alkylcycloalkyl; R 5 and R 5a are independently selected from the group consisting of hydrogen and C 1 -C 3 alkyl; R 6 is selected from the group consisting of hydrogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, halo and -NO 2; Li is selected from the group consisting of a bond, CRa = CRb, ethynyl, (C1 -C3 alkyl) -S-, C1 -C3 alkyl-, N (R °) -C1 -C3 alkyl, and C1 -C3) -N (Rc) -, wherein Ra and 4 ΡΕ2029547 Rb are independently selected from the group consisting of hydrogen and C1 -C3 alkyl; and Rc is independently selected from the group consisting of H, C1 -C5 alkyl, C1 -C3 alkylphenyl and C4 -C5 alkylcycloalkyl; Ar1 is selected from the group consisting of indolyl, benzothienyl, benzoisothiazolyl, indazolyl, naphthyl, phenyl, pyridinyl, pyrazolyl, pyrrolyl, thienyl, thiazolyl and furanyl, each optionally substituted by one or two groups independently selected from the group consisting of hydroxy, C1 -C3 haloalkyl, halo, C2 -C4 alkenyl, C2 -C4 alkynyl, C1 -C4 alkoxy, -O (C1 -C2 alkyl) phenyl, -NHC (O) R10; R 23 is selected from the group consisting of -CONH, - (C 1 -C 3) alkylCONH, -O- (C 1 -C 3) alkylCONH and -CONR 3 R 4; each R 5 is independently selected from the group consisting of hydrogen, C 1 -C 3 alkyl and phenyl; each R 4 is independently hydrogen or C 1 -C 5 alkyl; or a pharmaceutically acceptable salt thereof. R1 and R2 are independently selected from the group consisting of hydrogen, fluoro, chloro, CF3, SCF3, CF3; R6 is fluorine, chlorine C1-C3 alkyl, CF3, SCF3 or OCF3; 4-cyclopropyl; R 4a is hydrogen, methyl, ethyl or isopropyl; A compound according to claim 17 wherein 0 is 0 or 1; X 1 and X 2 are both C, or X 1 is N and X 2 is C; 5 ΡΕ2029547 R4b is H, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 haloalkoxy or C3-C4 cycloalkyl; R 2 and R 5a are each independently selected from H or C 1 -C 3 alkyl; the Ar 1 group is phenyl, indolyl, pyridinyl, pyrrolyl, thienyl, naphthyl, thiazolyl, furanyl, pyrazolyl, indazolyl, benzoisothiazolyl and benzothienyl each optionally substituted with one to two groups independently selected from C 1 -C 5 alkyl, C 1 -C 4 alkoxy, C 1 -C 2 haloalkoxy and C 1 -C 3 haloalkyl; R 3 is hydrogen, methyl, ethyl or chloro; Li is a bond, ethenyl, -CH (CH 3) -S-, C (CH 3) 2 -S-, -CH 2 -, -CH 2 CH 2 -, -CH (CH 3) -O-, -CH (CH 3) -, -CH (CH 2 CH 3) - O-, -CH 2 NH-, -CH 2 CH 2 NH-, -N (Rc) CH 2 -, N (Rc) CH 2 CH 2 - or N (R °) CH 2 CH 2 CH 2 -; wherein R 6 is hydrogen, C 1 -C 2 alkyl or benzyl, or -CH 2 CH 2 -O-CH 2 -;  € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒâ € ƒR4 5 6 is C00H, -CH2C00H, -CH (CH3) C00H, -cyclopropyl-COOH, -C (CH3) 2C00H, CO2 NH2, C (O) NHCH3 or C (O) NHCH2 CH3; R 7 is hydrogen or C 1 -C 20 alkyl; and R 8 is hydrogen or C 1 -C 20 alkyl. A compound according to Claim 1 or 2, wherein χ and X2 are both C; p is 0; R1 and R2 are independently selected from the group consisting of 4-chloro, fluoro, trifluoromethyl, thiotrifluoromethyl and 5-trifluoromethoxy; R4a is hydrogen; R4b is trifluoromethyl, 6-isopropyl or cyclopropyl; Lx is ethenyl, ethynyl, -N (CH 3) CH 2 - or -N (CH 3) CH 2 CH 2 -; R2 and R5a are both hydrogen; R 3 is hydrogen, methyl, chlorine or bromine; Ar1 is phenyl, Î ± 20209547 indolyl, indazolyl, benzothienyl or benzoisothiazolyl, each optionally substituted with a group selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, isopropoxy and cyclopropoxy; and R7 is COOH. A compound selected from the group consisting of: 4 - [({4- [2- (2,6-dichlorophenyl) -4-isopropyl-2 H -pyrazol-3-ylmethoxy] -2- methyl-2-methyl-2-methoxy-benzoic acid, 4 - [({4- [2- (2,6- 3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) -methyl] -2-methyl-benzoic acid, 4 - [({4- [2- (2,6-dichloro-phenyl) 3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) -methyl] -2-isopropoxy-benzoic acid, 2-butoxy-4 - [({4- - [2- (2,6-dichloro-phenyl) -4-isopropyl-2 H -pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) -methyl] -benzoic acid, 2-benzyloxy -4 - [({4- [2- (2,6-dichloro-phenyl) -4-isopropyl-2 H -pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) -methyl ] -benzoic acid, 4 - [({4- [2- (2,6-dichloro-phenyl) -4-isopropyl-2 H -pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amino ) -methyl] -naphthalene-1-carboxylic acid, 4 - [({4- [2- (2,6-dichloro-phenyl) -4-isopropyl-2 H -pyrazol-3-ylmethoxy] -2- methyl-fe nyl} -methyl-amino) -methyl] -2-penyl-benzoic acid, 7α-2-Amino-2-methyl-3 - [({4- [2- (2,6-dichloro-phenyl) -4-isopropyl- 3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) -methyl] -5-methyl-benzoic acid, 2-butyrylamino-4 - [({4- [2- (2,6- dichloro-phenyl) -4-isopropyl-2-yl-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) -methyl] -benzoic acid, 4 - [({4- [2- 6-dichloro-phenyl) -4-isopropyl-2 H -pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) -methyl] -2-trifluoromethyl-benzoic acid, 3 - [( {4- [2- (2,6-Dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) -methyl] -5- fluoromethyl benzoic acid, 4 - [({4- [2- (2,6-dichloro-phenyl) -4-isopropyl-2 H -pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amino ) -methyl] -3-hydroxybenzoic acid, 5 - [({4- [2- (2,6-dichloro-phenyl) -4-isopropyl-2 H -pyrazol-3-ylmethoxy] -2- -methyl-phenyl} -methyl-amino) -methyl] -2-fluoro-benzoic acid, 3 - [({4- [2- (2,6-dichloro-phenyl) -4-isopropyl- 3-ylmethoxy] -2-m ethyl-phenyl} -methyl-amino) -methyl] -4-fluoro-benzoic acid, 3 - [({4- [2- (2,6-dichloro-phenyl) -4-isopropyl- 3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) -methyl] -4-methoxy-benzoic acid, 2-butoxy-5 - [({4- [2- (2,6- dichloro-phenyl) -4-isopropyl-2 H -pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) -methyl] -benzoic acid, 3-butoxy-5 - [({4- [ 2- (2,6-dichloro-phenyl) -4-isopropyl-2 H -pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) -methyl] -benzoic acid, {4- [4-cyclopropyl-2- (2, β-dichloro-phenyl) -2H-pyrazol-3-ylmethoxy] -phenyl} -methyl-amino) -methyl] -benzoic acid, 4 - [({4- [4- 4 - [({4- [2- (2-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -2-methyl- 3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) -methyl] -benzoic acid, 3 - [({4- [2- (4-chlorophenyl) -4-isopropyl- [2- (2-β-chloro-phenyl) -4-isopropyl-2 H -pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) -methyl] -benzoic acid, 3 - [({4- [4-isopropyl-2- (2-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) -methyl] -benzoic acid, 4 - [({6- [4-isopropyl-2- (2-trifluoromethoxy-phenyl) -2 H -pyrazol-3-ylmethoxy] -2-methyl-pyridin-3-yl} -methyl-amino) -methyl] - benzoic acid 3 - [({6- [4-isopropyl-2- (2-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -2-methyl-pyridin-3-yl} -methyl-amino) - methyl] benzoic acid, 5 - [({6- [4-isopropyl-2- (2-trifluoromethoxyphenyl) -2H-pyrazol-3-ylmethoxy] -2-methyl-pyridin-3-yl} 4-Isopropyl-2- (2-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -2-methyl-pyridin- 3-yl} -methyl-amino) -methyl] -2-pentyl-benzoic acid, 4 - [({6- [4-isopropyl-2- (2-trifluoromethoxyphenyl) -2H-pyrazol- -2-methyl-pyridin-3-yl} -methyl-amino) -methyl] -2-methyl-benzoic acid, 9-A2029547 6- {4- [4-Isopropyl-2- (2-trifluoromethoxy-phenyl) 2 H -pyrazol-3-ylmethoxy] -2-methyl-phenyl} -1-methyl-1H-indole-3-carboxylic acid 6- [4- (4-Isopropyl-2- (2-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -benzo [b] thiophene-3-carboxylic acid , 5- {4- [2- (2,6-dichloro-phenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -thiophene-2-carboxylic acid, 5- - {4- [4-Isopropyl-2- (2-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -thiophene-2-carboxylic acid, 2- {4- 4-isopropyl-2- (2-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -4-methyl-thiazole-5-carboxylic acid, 6 - [({4- - [2- (2,6-dichloro-phenyl) -4-isopropyl-2 H -pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) -methyl] -nicotinic acid, 4- - [({4- [4-isopropyl-2- (2-trifluoromethoxy-phenyl) -2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amino) -methyl] -2-methyl 3-ylmethoxy] -2-methyl-phenyl} -ethylamino) -3- [({4- [2- (2,6-dichloro-phenyl) -4-isopropyl-2 H -pyrazol- -methyl] -benzoic acid, and a pharmaceutically acceptable salt, solvate, enantiomer or diastereomer thereof ceptionally acceptable. The compound 2- [2 - ({4- [2- (2,6-dichlorophenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl amino) -ethyl] -5-methyl-benzoic acid. 10 ΡΕ2029547 The compound 3 - [({4- [2- (2,6-dichlorophenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -methyl-amino ) -methyl] -5-methyl-benzoic acid. The compound 3 - [({4- [2- (2,6-dichlorophenyl) -4-isopropyl-2H-pyrazol-3-ylmethoxy] -2-methyl-phenyl} -ethylamino ) -methyl] -benzoic acid. A pharmaceutical composition comprising a compound according to any one of Claims 1-8 and a carrier, diluent or excipient. A compound according to any one of Claims 1-8 for use in therapy. A compound according to any one of Claims 1-8 for use in the treatment of dyslipidaemia. A compound according to any one of Claims 1-8 for use in the treatment of atherosclerosis. REFERENCES ISSUED IN THIS DESCRIPTION This list of references cited by the applicant is for the reader's convenience only. It is not part of the European patent document. While due care has been taken in compiling references, errors or omissions may not be excluded and the IEP declines any liability in this regard. Patent References cited in Description * WO 2004048349 A1 * WO 2005080388 A * WO 2005-092330 Non-Patent Literature cited in the Description * Doiteds ffcsfsi fi ces Jdktaw? W.B Ssub- * ders pOJiisOyx! Cwspasw; Ssabbipg Ga. 1990 * TtoDder · Groen »Prateai SfOips fei Oeganic * Syntfcesis. SVtfev iníersesenoet