| Title of Invention | SUBSTITUTED CARBOXYLIC ACID COMPOUNDS |
|---|---|
| Abstract | Abstract Substituted biphenyl carboxylic acids and derivatives thereof The present invention relates to compounds having the general Formula (I) with the definitions of X, Y, R1,R2, R3. R4 R9, and R10 given below, and/or a salt or ester thereof. Furthermore the invention relates to the use of said compounds for the treatment of Alzheimer's disease and their use for the modulation of 7-secretase activity. |
| Full Text | Substituted biphenyl carboxylic acids and derivatives thereof The present invention relates to compounds having the general formula (I) with the definitions of A, X, Ri -R4 given below, and/or a salt or ester thereof. Furthermore, the invention relates to the use of said compounds for the treatment of Alzheimer's disease and their use for the modulation of y-secrelase activity. Alzheimer's Disease (AD) is a progressive neurodegenerative disorder marked by loss of memory, cognition, and behavioral stability. AD afflicts 6-10% of the population over age 65 and up to 50% over age 85. It is the leading cause of dementia and the third leading cause of death after cardiovascular disease and cancer. There is currently no effective treatment for AD. The total net cost related to AD in the U.S. exceeds $100 billion annually. AD does not have a simple etiology, however, it has been associated with certain risk factors including (1) age, (2) family history (3) and head trauma; other factors include environmental toxins and low level of education. Specific neuropathological lesions in the limbic and cerebral cortices include intracellular neurofibrillary tangles consisting of hyperphosphorylated tau protein and the extracellular deposition of fibrillar aggregates of amyloid beta peptides (amyloid plaques). The major component of amyloid plaques are the amyloid beta (A-beta, Abeta or AB) peptides of various lengths. A variant thereof, which is the ABl-42-peptide (Abeta-42). is believed to be the major causative agent for amyloid formation. Another variant is the ABl-40-peptide (Abeta-40). Amyloid beta is the proteolytic product of a precursor protein, beta amyloid precursor protein (beta-APP or APP). Familial, early onset autosomal dominant forms of AD have been linked to missense mutations in the P-amyloid precursor protein (p-APP or APP) and in the presenilin proteins 1 and 2. In some patients, late onset forms of AD have been correlated with a specific allele of the apolipoprotein E (ApoE) gene, and, more recently, the finding of a mutation in alpha2-macroglobulin, which may be linked to at least 30% of the AD population. Despite this heterogeneity, all forms of AD exhibit similar pathological findings. Genetic analysis has provided the best clues for a logical therapeutic approach to AD. All muiations. found lo date, affect the quantitative or qualitative production of the aniyloidogenic peptides known as Abeta-peptides (Ap), specifically Ap42, and have given strong support to the "amyloid cascade hypothesis" of AD (Tanzi and Bertram. 2005, Cell 120. 545). The likely link between Ap peptide generation and AD pathology emphasizes the need for a better understanding of the mechanisms of Ap production and strongly warrants a therapeutic approach at modulating Ap levels. The release of Ap peptides is modulated by at least two proteolytic activities referred to as p- and y- secretase cleaving at the N-terminus (Met-Asp bond) and the C-terminus (residues 37-42) of the Ap peptide, respectively. In the secretory pathway, there is evidence that p-secretase cleaves first, leading to the secretion of s-APPp (sp) and the retention of a I ( kDa membrane-bound carboxy terminal fragment (CTF). The latter is believed to give rise to Ap peptides following cleavage by y-secretase. The amount of the longer isoform, AM2, is selectively increased in patients carrying certain mutations in a particular protein (presenilJn), and these muiations have been correlated with early-onset familial Alzheimer's disease. Therefore, Ali42 is believed by many researchers to be the main culprit of the pathogenesis of Alzheimer's disease. It has now become clear that the y-secretase activity cannot be ascribed to a single particular protein, but is in fact associated with an assembly of different proteins. The gamma-secretase activity resides within a multiprotein complex containing at least four components: the presenilin (PS) heterodjmer, nicastrin, aph-1 and pen-2. The PS heterodimer consists of the amino- and carboxyterminal PS fragments generated by endoproteolysis of the precursor protein. The two aspartates of the catalytic site are at the interface of this heterodimer. It has recently been suggested that nicastrin serves as a gamma-secreiase-substrate receptor. The functions of the other members of gamma-secretase are unknown, but they are all required for activity (Steiner, 2004. Curr. Alzheimer Research 1(3): 175-181). Thus, although the molecular mechanism of the second cleavage-step has remained elusive until present, the y-secretase-complex has become one of the prime targets in the search for compounds for the treatment of Alzheimer's disease. Various strategies have been proposed for targeting gamma-secretase in Alzheimer's disease, ranging from targeting the catalytic site directly, developing substrate-specific inhibitors and modulators of gamma-secretase activity (Marjaux et a!., 2004. Drug Discovery Today: Therapeutic Strategies. Volume I, !-6). Accordingly, a variety of compounds were described that have secretases as targets {Lamer, 2004. Secretases as therapeutics targets in Alzheimer's disease; patents 2000 - 2004. Expert Opin. Ther. Patents 14, 1403-1420.) Indeed, this finding was recently supported by biochemical studies in which an effect of certain NSAIDs on y-secrelase was shown (Weggen et al (2001) Nature 414, 6860, 212 and WO 01/7872! and US 2002/0128319; Morihara et al (2002) J. Neurochem. 83, 1009; Eriksen (2003) .1. Clin. Invest. 112 , 440). Potential limitations for the use of NSAIDs to prevent or treat AD are their inhibition activity of Cox enzymes, which can lead to unwanted side effects, and their low CNS penetration (Peretto et al., 2005, J, Med. Chem. 48, 5705-5720). Thus, there is a strong need for novel compounds which modulate y-secretase activity thereby opening new avenues for the treatment of Alzheimer's disease. The object of the present invention is to provide such compounds. The object is achieved by a compound having the general Formula (i) A isO. SorNH. X is a bond or a group -CRsR wherein R5 and R6 are independently, selected from the group consisting of H, alkyl selected from the group CHj, C;Hs. i-CH?, n-CsH?, i-C4Hq. n-C4H9, sec-C4H9, tert-C4H; alkeny] selected from C2H5, i-CsHs, n-CjHs, n-Ciii, i-C4H7, sec-C4H7; wherein in any of the alkyl or alkenyl groups one or more H atoms optionally can be substituted with one or more substituents independently selected from the group consisting of OH, F, CI. Br. 1 and CF5; or R5, Rg may jointly form together with the carbon atom to which they are attached a ring, either saturated or unsaturated, substituted or unsubstituted, having 3 to 6 C-atoms. and which may contain in the ring one or more heteroatoms from the group N, S or O, and which heteroatom may be identical or different if more than one heteroatom is present; Ri, R2, R3 and R4 are independently selected from the group consisting of H; F; CI; Br; 1 CN; OH; C(0)N(R7R8); S{0)2R7; S02N(R7R8); S(0)N(R7Rfi},- N(R7)S(0)2R8 N(Rs)S(0)R8; S(0)2R7; N(R7)S(0)2N(RgRBa); SR7; NCRTRS); N(R7)C(0)R8 N(R7)C(0)>J(RsR8a); N(R7)C(0)0R8; 0C(0)N(R7R8); C(0)R7; substituted and unsubstituted Ci-C4-alkyl and substituted and unsubstituted Ci-Ci-alkoxy, and wherein the substituents of both groups Ci-C4-alkyl and Ci-C4-alkoxy are selected from F, CI, Br, 1, CF3; R7, Rs, Rga are independently selected from the group consisting of H; Ci-C4-alkyi; heterocyclyl; and C3.7 cycloalkyl, wherein C!-C4-alkyl; heterocyclyl: and C3-7 cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of F, CI, Br, I and CF3; Y is a carboxy group -C(0)OH or a substituted or unsubstituted tetrazole group Rgand Rio are independently selected from the group consisting of: H, F, and CF3; and solvates, hydrates, esters, and pharmaceutical ly acceptable salts thereof. The term "substituted" as used herein includes both part and full substitution. Substituents can be either saturated or unsaturated. In case R5 and Re are part of a ring, the ring can be substituted by Ci-C4-alkyl or OH. F, CI, Br, 1 and CF3 Esters are those according to formula (I) in wiiich H of the carboxy group is replaced by an organic residue R7a- Suitable organic residues are known to a person skilled in the art. Preferred R7a include the following:an unsubstituted or at least monosubstituted alkyh preferably a Cj-Cjo alkyl, an alkenyl, preferably C2-CiD-aikenyl, an alkynyl, preferably Cj-Cio-alkynyl, and an unsubstituted or at least monosubstituted, saturated or unsaturated, non-aromatic or aromatic ring having 3 to 6 C-aioms, and which may contain in the ring one or more heteroatoms from the group N, S or O, and which heteroatom may be identical or different if more than one heteroatom is present. Said substiluents being selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, N, S, O, carboxy, sulphonyl, and the like and which can be further substituted. Examples for current aromatic groups include aryl groups, for example phenyl groups, and heleroaryl groups, which ary) and heteroaryl groups may be substituted, preferably by the substituents given above. In another embodiment of the invention: A is O or NH; X is -CR5R6 wherein Rj and R are independently selected from the group consisting of H, CH3, C2H5, i-CsH:, H-CSHT, i-CjHg, n-C4H9, sec-C4H9, and tert-C4Hc Ri, R2, R3 and R4 are independently selected from the group consisting of H, OH, C(i_ 4)alkyl, CiMjalkoxy, -N(CH3)2, -SO3CH5, CN, OCF5, -C(0)CH5, OCH3, CF3, F, and CI; wherein said C(i)alkyl and C(M)alkoxy are optionally independetly substituted with one, two, or three substituents selected from the group consisting of I, Br, F, and CI; Y is CO3H; Rijand Rio are independently selected from the group consisting of: H, F. and CF3; and solvates, hydrates, esters, and pharmaceutical!y acceptable salts thereof.. In another embodiment of the invention: AisOorNH; X is -CRjR wherein R5 and R are H, CH, C2H5, i-CH?, n-CiHj, (-C4H9, n-QH, sec-C4H9, or tert-C4H9; R], R2, R3 and R4 are independently selected from the group consisting of H, OH. C(i_ 4)atkyl, C,M)alkoxy, -NCCHj):, -SO2CH3, CN. OCF3, -C(0)CH3, OCH3, CF3, F, and CI; wherein said C(i)alkyl and C(M)alkoxy are optionally independetly substituted with one, two, or three substituents selected from the group consisting of 1, Br, F, and CI; Y is C02H; R9and Ro are independently selected from the group consisting of: H, F, and CF3; and solvates, hydrates, esters, and pharmaceutically acceptable salts thereof. In another embodiment of the invention: AisOorNH; X is -CR5R6 wherein R5 and Rf, are H. CH.,, C2HS, i-C3H7, n-C3H7, i-CH, n-C4H9, sec-C4Hc Y is CO>H; R,, and R2 are independently selected from the group consisting of CF3, H, F, CI, OCH3, C(i.4)alkyl, andCN. R3 and R4 are independently selected from the group consisting of H, CF3, F, and O; R9 is H or F; Rio is H; and solvates, hydrates, esters, and pharmaceutical!y acceptable salts thereof. In another embodiment of the invention, the object is achieved by a compound having the general Formula (I*) X is a bond or a group -CRsRe wherein R5 and R are, independently of each other, selected from the group consisting of H; alkyl selected from the group CH5, CjHs. i-C3H7. n-QHv. i-CHq, n-C4H9. sec-CjHQ. tert-CjHo; aikenyl selected from C2H:,, i-C3H5, n-CjHj, n-C4H7, i-C4H7, sec-C4H7; vi/herein in any of the alky! or aikenyl groups one or more H atoms optionally can be substituted with one or more substituents independently selected from the group consisting of OH, F, CI, Br, I and CF3; or R5 and R6 being part of a ring, either saturated or unsaturated, substituted or unsubstituted, having 3 to 6 C-atoms, and which may contain in the ring one or more heteroatoms from the group N, S or O, and which heteroatom may be identical or different if more than one heteroatom is present; Ri, R2> R3 and R4 are independently selected from the group consisting of H; F; CI; Br; 1; CM; OH; CCONCRvRg); S(0)2R7; S02N(R7R8); S{0)N(R7R8); N(R7)S(0)2R8; N{Rs)S(0)R8; S(0)3R7; N(R7)S(0)2N(RsR8a); SR7; N(R7R8); N(R7)C(0)Rg; N(R7)C(O)N(RgR80; N(R7)C(0)0Rg; 0C(0)N(R7Rg); C(0)R7; substituted and unsubstituted C]-C4-alkyl and substituted and unsubstituted Ci-C4-alkoxy, and wherein the substituents of both groups C ~ ■■ ■ ■ - - .. re selected from F, CI, Br, ICF3: R7, Rg, Rfia are independently selected from the group consisting of H; Ci-C4-alky!: heterocyclyl; and C-,.i cycloalkyi, wherein C|-C4-aikyl: heterocyclyl; and C?.? cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of F, C), Br, ] and CF3; Visa carboxy group -C(0)OH or a substituted or unsubstituted tetrazole group and/or a salt or ester thereof. The term "substituted" as used herein includes both part and full substitution. Substituents can be either saturated or unsaturated. In case R5 and R6 are part of a ring, the ring can be substituted by C|-C4-alkyl or OH, F, CI, Br, / and CF3 Esters are those according to formula (I) in which H of the carboxy group is replaced by an organic residue R7a. Suitable organic residues are known to a person skilled in the art. Preferred R7a include the following: an unsubstituted or at least monosubstituted ajkyl, preferably a Cj-Cio alkyl, an alkenyl, preferably Ci-Cio-alkenyl, an alkynyl, preferably C3-Cio-aIkynyI. and an unsubstituted or at least monosubstituted, saturated or unsaturated, non-aromatic or aromatic ring having 3 to 6 C-atoms, and which may contain in the ring one or more heteroatoms from the group N, S or O, and which heteroalom may be identical or different if more than one heteroatom is present. Said substituents being selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, N, S, O, carboxy, sulphonyl, and the like and which can be further substituted. Examples for current aromatic groups include aryl groups, for example phenyl groups, and heteroaryl groups, which aryl and heteroaryl groups may be substituted, preferably by the substituents given above. The term "C|-C4-alkyl" refers to methyl, ethyl, n-propy!, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert.-butyi. "C3-7 cycloalkyi" or "C3_7 cycloalky) ring" rneans a cyclic ail In preferred embodiments, the invention relates to a compound having the general formula (J) wherein A, X; Y; Ri and R2: and R3, R4, R5 and Rg independently of each other have the following meanings: A is O; and/or X is a group -CR5R6 wherein R5 and Re are, independently of each other, selected from the group consisting of H; alkyl selected from the group CH3, C2H5, i-CsHv, n-CH?, i-C4H9, n-CaHg, sec-C4H9, tert-C4H9; wherein in any of the alky! groups one or more H atoms optionally can be substituted with one or more substituents independently selected from the group consisting of OH, F, CI, Br and 1; and/or Ri, R:, R3 and R4 are independently selected from the group consisting of H; OH; CrC4-alkyl or C1 -C4-alkoxy, substituted partly or fully by F. C!, Br, 1; and/or Ri and R being H; or R5 being H and R6 being CH3. C2H5, C3H7 or C4H9 or isomers thereof; or R\ and R2 being CH3 or R|, R: jointly form together with the carbon atom to which they are attached a cyclopropyl ring; and/or Y is a carboxy group and/or a salt or ester thereof. Within this group of embodiments, it is even more preferred if all the groups A; X; Y; Ri, R2, R3, R4. R5 and R have the meanings defined beforehand. It is even more preferred if A; X; Y; R| and R; and R5, R4, R5 and R independently of each other have the following meanings: A is O; X is a group -CRiR with R5 and R being H; or R5 being H and Rt being CH3, C2H5, C3H7 or C4H9or isomers thereof; or R5 and Rs being CHj or R5, Rt jointly form together with the carbon atom to which they are attached a cyclopropyl ring; and/or R], R2, R3 and R4 are independently selected from the group consisting of H; OH; C1-C4-alkyl or C]-C4-alkoxy, substituted partly or fully by F. C!, Br, I; and/or and/or Y is a carboxy group and/or a salt or ester thereof. Within this group of embodiments, ii is even more preferred if all the groups A; X; Y; R.1, R2, R3, R4, R5 and Re have the meanings defined beforehand. It is still more preferred if A; X; Y; Ri and R2; and Rj, R4, R5 and Re independently of each other have the following meanings: AisO; X is a group -CRsRs , with R5 and Re being H; or R5 being H and R& being CH3, C2H5, CjH? or C4H9or isomers thereof; Y is a carboxy group R|. R2, Rr, and R4 are independently selected from the group consisting of H. OH. CH3. OCH3, CF3, F, and CI: and/or and/or a salt or ester thereof. Within this group of embodiments, it is even more preferred if all the groups A; X: Y; Ri and R2; and R?, R4, R5 and R have the meanings defined beforehand. In another embodiment, the invention relates to compounds selected from the group consisting of 2-(5-(4-fluorophenoxy)-4'-trifluoromethyl-biphenyl-3-yl)-pentanoic acid (I) 2-{5-(phenoxy)-4'-trifluoromethyl-biphenyl-3-yl)-pentanoic acid (II) and solvates, hydrates, esters, and phannaceutically acceptable salts thereof. The term "pharmaceutically acceptable' means approved by a regulatory agency such as the EMEA (Europe) and/or the FDA (US) and/or any other national regulatory agency for use in animals, preferably in humans. Compounds according to the invention which contain several basic groups can simultaneously form different salts. If a compound according to the invention simultaneously contains acidic and basic groups in the molecule, the invention also includes, in addition to the salt forms mentioned, inner salts or belaines. The respective salts of the compounds according to the invention can be obtained by customary methods which are knovifn to the person skilled in the art, for example by contacting these with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange with other salts. Furthermore, the invention includes all salts of the compounds according to the invention which, owing to low physiological compatibility, are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts or which might be suitable for studying y-secretase modulating activity of a compound according of the invention in any suitable manner, such as any suitable in vitro assay. The present invention furthermore includes all solvates of the compounds according to the invention. The present invention furthermore includes derivatives/prodrugs (including the salts thereof) of the compounds according to the invention which contain physiologically tolerable and cleavable groups and which are metabolized in animals, preferably mammals, most preferably humans into a compound according to the invention. The present invention furthermore includes the metabolites of the compounds according to the invention. The term "metabolites" refers to all molecules derived from any of the compounds according to the invention in a ce)] or organism, preferably mammal. Preferably the term "metabolites" relates to molecules which differ from any molecule which is present in any such cell or organism under physiological conditions. The structure of the metabolites of the compounds according to the invention will be obvious to any person skilled in the art, using the various appropriate methods. The compounds according to general formula (I) can be prepared according to methods published in the literature or by analogous methods. Depending on the circumstances of the individual case, in order to avoid side reactions during the synthesis of a compound of the general formula (I), it can be necessary or advantageous to temporarily block functional groups by introducing protective groups and to deprotect them in a later stage of the synthesis, or to introduce functional groups in the form of precursor groups and at a later stage to convert them into the desired functional groups. Suitable synthetic strategies, protective groups and precursor groups are known to the person skilled in tlie art. If desired, the compounds of the formula (1) can be purified by customary purification procedures, for example by recrystallization or chromatography. The starting materials for the preparation of the compounds of the formula (I) are commercially available or can be prepared according to or analogously to literature procedures. These can serve as a basis for the preparation of the other compounds according to the invention by several methods well known to the person skilled in the art. The invention also relates to a compound of the invention for use as a medicament. The compounds are as defined above, furthermore with respect to the medicament the embodiments as desn'bed below with respect to the use of the invention, e.g. formulation, application and combination, also apply to this aspect of the invention. In particular the compounds according to the invention are suitable for the treatment of Alzheimer's disease. Details relating to said use are further disclosed below. The compounds can be used for modulation of y-secretase activity. As used herein, the term "modulation of y-secretase activity" refers to an effect on the processing of APP by the y-secretase-comp!ex. Preferably it refers to an effect in which the overall rate of processing of APP remains essentially as without the application of said compounds, but in which the relative quantities of the processed products are changed, more preferably in such a way that the amount of the AB42-peplide produced is reduced. For example a different Abeta species can be produced (e.g. Abeta-38 or other Abeta peptide species of shorter amino acid sequence instead of Abeta-42) or the relative quantities of the products are different (e.g. the ratio of Abeta-40 to Abeta-42 is changed, preferably increased). Gamma secretase activity can e.g. be measured by determining APP processing, e.g. by determining the levels of Abeta petide species produced, most importantly levels of It has been previously shown that the y-secretase complex is also involved in the processing of the Notch-protein. Notch is a signaling protein which plays a crucial role in developmental processes (e.g. reviewed in SchweisguthF (2004) Curr. Biol. 14, RI29). With respect to the use of said compounds for the modulation of y-secretase activity in therapy, it seems particularly advantageous not to interfere with the Notch-processing activity of the y-secretase activity in order to avoid putative undesired side-effects. Thus, compounds are preferred u'hich do not show an effect on the Notch-processing activity of the y-secretase-comp!ex. Within the meaning of the invention, "eifeci on the Notch processing activity" includes both an inhibition or an activation of the Notch-processing activity by a certain factor. A compound is defined as not having an effect on the Notch processing activity, if said factor is smaller than 20, preferably smaller than 10, more preferably smaller than 5, most preferably smaller than 2 in the respective assay as described in Shimizu et al (2000) Mol. Cell. Biol, 20: 6913 at a concentration of 30 |iM. Such a y-secretase modulation can be carried out, e.g. in animals such as mammals. Exemplary mammals are mice, rats, guinea pigs, monkeys, dogs, cats. The modulation can also be carried out in humans. In a particular embodiment of the invention, said modulation is performed in vitro or in cell culture. As known to the person skilled in the art, several in vitro and cell culture assays are available. Exemplary assays useful for measuring the prodction of C-terminal APP fragments in cell lines or transgenic animals by Western blot analysis include but are not limited to those described in Yan et al., 1999, Nature 402, 533-537. An example of an in vitro y-secretase assay is described in WO-03/008635. In this assay a suitable peptide substrate is contacted with a y-secrelase preparation and the ability to cleave the substrate is measured. Concentrations of the various products of the y-secretase cleavage (the A6-peptides) can be determined by various methods known to a person skilled in the art. Examples for such inethods include determination of the peptides by mass-spectrometry or detection by antibodies. Exemplary assays useful for the characterization of the profile of soluble Abeta peptides in cultured cell media and biological fluids include but are not limited to those described by Wang et al., 1996, J. Biol. Chem. 271, 31894-31902. In this assay a combination of immunoprecipitation of Abeta-peptides with specific antibodies and detection and quantification of the peptide species with matrix-assisted laser desorption ionization time-of-fiight mass spectrometr>' is used. Exemplary assays usefUl for measuring the production of .Abeta-40 and Abeta-42 peptides by ELISA include but are not limited to those described in Vassar et al, 1999, Science 286, 735-741. Further information is disclosed for example in N. Ida et al. (1996) J. Biol. Chem. 271, 22908, and M. Jensen et al. (2000) Mol. Med. 6, 291. Suitable antibodies are available for example from The Genetics Company, Inc., Switzerland. Antibody-based kits are also available from Innogenetics, Belgium. Cells which can be employed in such assays include cells which endogenously express the y-secretase complex and transfected cells which transiently or stably express some or all interactors of the y-secretase complex. Numerous available cell lines suitable for such assays are known to the skilled person. Cells and cell lines of neuronal or glial origin are particularly suitable. Furthermore, cells and tissues of the brain as well as iiomogenates and membrane preparations thereof may be used (Xia et al.. 1998, Biochemistry 37. 16465-16471). Such assays might be carried out for example to study Che effect of the compounds according to the invention in different experimental conditions and configurations. Furthermore, such assays might be carried out as part of functional studies on the y-secretase complex. For example, either one or more interactors (either in their wild-type form or carrying certain mutations and/or modifications) of the y-secretase complex of an animal, preferably a mammal, more preferably humans, might be expressed in certain cell lines and the effect of the compounds according to the invention might be studied. Mutated forms of the interactor(s) used can either be mutated forms which have been described in certain animals, preferably mammals, more preferably humans or mutated forms which have not previously been described in said animals. Modifications of the interactors of the y-secretase complex include both any physiological modification of said interactors and other modifications which have been described as modifications of proteins in a biological system. Examples of such modifications include, but are noi limited to, glycosyJation. phosphorylation, prenylation, myristylation and famesylation. Furthermore, the compounds according to the invention can be used for the preparation of a medicament for the modulation of y-secretase activity. The invention further relates to the use of said compounds for the preparation of a medicament for the modulation of y-secretase activity. The activity of the y-secretase can be modulated in different ways, i.e. resulting in different profiles of the various AB-peptides. Uses of a compound for the modulation of 7-secretase activity resulting in a decrease in the relative amount of AB42-peptides produced are preferred. Respective dosages, routes of administration, formulations etc are disclosed further below. The invention further relates to the use of the compounds according to the invention for the treatment of a disease associated with an elevated level of AM2-production. The disease with elevated levels of Abeta peptide production and deposition in the brain is typically Alzheimer's disease (AD), cerebral amyloid angiopathy, multi-infarct dementia, dementia pugilistica or Down syndrome, preferably AD. As used herein, the term "treatment" is intended to refer to all processes, wherein there may be a slowing, interrupting, arresting, or stopping of the progression of a disease, but does not necessarily indicate a total elimination of all symptoms. As used herein, the term "elevated level of A642-production" refers to a condition in which the rate of production of AB42-peptide is increased due to an overall increase in the processing of APP or, preferably, it refers to a condition in which the production of the AB42 peptide is increased due to a modification of the APP-processing profile in comparison to the wild-type APP and non-pathological situation. As outlined above, such an elevated A642-]evel is a haJimark of patients developing or suffering from Alzheimer's disease. One advantage of the compounds or a part of the compounds of the present invention may lie in their enhanced CNS-penetration. Furthermore the invention relates to a pharmaceutical composition comprising a compound according to the invention in a mixture with an inert carrier. In a preferred embodiment, the invention relates to a pharmaceutical composition comprising a compound according to the invention in a mixture with an inert carrier, where said inert carrier is a pharmaceutical carrier. The term "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which the compound is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, including but not limited to peanut oil, soybean oil. mineral oil. sesame oil and the Hke. Water is a preferred carrier when the pharmaceutical composition is administered orally. Saline and aqueous dextrose are preferred carriers when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions are preferably employed as liquid carriers for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel. sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. The composition, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. These compositions can take the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained-release formulations and the like. The composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides. Oral formuiation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate. sodium saccharine, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E.W, Manin. Such compositions will contain a therapeutically effective amount of the compound, preferably in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the patient. The formulation should suit the mode of administration. Furthermore, the invention relates to methods for the preparation of a compound according to the invention. In one embodiment for the preparation of 9 compound according to the present invention, a dibromofluorobenzene can be treated with a benzyl alcohol in the presence of an alkali metal hydride, typically sodium hydride, in a suitable aprotic solvent such as tetrahydrofuran. The product can be treated with a suitable malonic acid derivative, such as malonic acid ten-butyl ester ethyl ester in the presence of an alkali metal hydride, typically sodium hydride and a metal haiide, typically a copper halide, preferably copper bromide. Further treatment in an acidic solvent such as acetic acid at elevated temperature provides a benzyloxy-bromophenylacetic acid ester. This can be coupled to a boronic acid under the variety of conditions known to those skilled in the art for such Suzuki coupling, typically using solvents such as 1.2-dimethoxyethane and water, an alkali metal carbonate such as potassium carbonate, and a palladium compound such as tetrak i s(triphenyl phosph in e)pal 1 ad i um (0). If required the compound can be alkylated by treatment in a suitable aptotic solvent such as tetrahydrofuran with a suitable base such as a metal dialkylamide, typically LDA, and the appropriate halide at a suitable temperature, typically -7S°C Removal of the benzyl protecting group can be achieved under the variety of conditions known to those skilled in the art for such deprotections, typically using a palladium catalyst such as 10% palladium on charcoal in a suitable solvent, such as ethanol, and under an atmosphere of hydrogen. The phenol can be converted to a biphenyl ether by a variety of methods known to those skilled in the art eg DA Evans et al Tetrahedron Lett. (1998), 39, 2937, Hosseinzadeh R et al Synlett (2005), 7, 1101. Typically the phenol is treated with a tertiary amine, such as tri ethyl amine, a metal acetate, such as copper acetate, an aryl boronic acid and a suitable solvent such as dichloromethane in the presence of an agent such as 4A molecular sieves. Conversion of the ester to the acid can be done using a base such as an alkali metal hydroxide, typically potassium hydroxide in the presence of water and other suitable solvents such as methanol. In another embodiment, compounds where A is S can be prepared by the treatment of a dibromofluorobenzene with an aryl thiol in the presence of a suitable base such as potassium carbonate, in a suitable aprotic solvent such as N,N,dimethyl form amide. The product can be treated with a suitable malonic acid derivative, such as malonic acid tsrt-butyl ester ethyl ester in the presence of an alkali metal hydride, typically sodium hydride and a metal halide, typically a copper halide, preferably copper bromide. Further treatment in an acidic solvent such as acetic acid at elevated temperature provides an arylthio-bromophenylacetic acid ester. This can be coupled to a boronic acid under the variet>' of conditions known to those skilled in the art for such Suzuki coupling, typically using solvents such as 1,2-dimethoxyethane and water, an alkali metal carbonate such as potassium carbonate, and a palladium compound such as ietrakis(triphenylphosphine)palladium (0). If required the compound can be alkylated by treatment in a suitable aprotic solvent such as tetrahydrofuran with a suitable base such as a metal dialkylamide, typically LDA, and the appropriate halide at a suitable temperature, typically -78 "C Conversion of the ester to the acid can be done using a base such as an alkali metal hydroxide, typically potassium hydroxide in the presence of water and other suitable solvents such as methanol. In another embodiment for the preparation of a compound according to the present invention where A is NH, a dibromofluorobenzene can be treated with a benzyl alcohol in the presence of an alkali metal hydride, typically sodium hydride, in a suitable aprotic solvent such as tetrahydrofuran. The product can be treated with a suitable malonic acid derivative, such as malonic acid tert-butyl ester "ethyl ester in the presence of an alkali metal hydride, typically sodium hydride and a metal halide, typically a copper halide, preferably copper bromide. Further treatment in an acidic solvent such as acetic acid at elevated temperature provides a benzyloxy-bromophenylacetic acid ester. This can be coupled to an aniline under the variety of conditions known to those skilled in the art for such Hartwig-Buchwald coupling, typically such as described by Hartwig JF in Modem Arene Chemistry, (2002) ppl07-]68. Removal of the benzyl etherprotecting group can be achieved under the variety of conditions known to those skilled in the art for such deprotections, typically using a palladium catalyst such as 10% palladium on charcoal in a suitable solvent, such as ethanol, and under an atmosphere of hydrogen. The resultant hydroxycompound can be converted to a triflate using eg trifluoromethanesulphonic anhydride, an organic base such as pyridine and in a suitable solvent such as dichloromethane. This triflate can then be coupled to a boronic acid under the variety of conditions known to those skilled in the art for such Suzuki coupling, typically using solvents such as 1,2-dimethoxyethane and water, an alkali metal carbonate such as potassium carbonate, and a palladium compound such as bis(tri-tert-butylphosphine)palladium (0). If required the product can be alkylated by treatment in a suitable aprotic solvent such as tetrahydrofuran with a suitable base such as a metal alkylamide, typically LDA, and the appropriate halide at a suitable temperature, typically -78 °C Conversion of the ester to the acid can be done using a base such as an alkali metal hydroxide, typically sodium hydroxide in the presence of water and other suitable solvents such as ethanol. When compounds of the invention are produced as racemates, these can be separated into their enantiomers by methods known to those skilled in the art, typically by using a chiral HPLC column. Furthermore, the invention relates to a method for the preparation of a medicament comprising the steps of: a) preparing a compound according to the invention b) formulation of a medicament containing said compound. The compounds according to the invention and their pharmaceutically acceptable salts, optionally in combination with other phannaceutically active compounds are suitable to treat or prevent Alzheimer's disease or the symptons thereof. Such additional compounds include cognition-enhancing drugs such as acetylcholinesterase inhibitors (e.g. Donepezil, Tacrine, Galantamine, Rivastigmin), NMDA antagonists (e.g. Memantine) PDE4 inhibitors (e.g. Ariflo) or any other drug known to a person skilled in the art suitable to treat or prevent Alzheimer's disease. Such compounds also include cholesterol-lowering drugs such as statins (e.g. simvastatin). These compounds can be administered to animals, preferably to mammals, and in particular humans, as pharmaceuticals by themselves, in mixtures with one anther or in the form of pharmaceutical preparations. Various delivery systems are known and can be used to administer a compound of the invention for the treatment of Alzheimer's disease or for the modulation of the y-secretase activity, e.g. encapsulation in liposomes, microparticles, and microcapsules: If not delivered directly to the central nervous system, preferably the brain, it is advantageous to select and/or modify' methods of administration in such a way as to allow the pharmaceutical compound to cross the blood-brain barrier. Methods of introduction include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The compounds may be administered by any convenient route, for example by infusion, by bolus injection, by absorption through epithelial or mucocutaneous linings and may be administered together with other biologically active agents. Administration can be systemic or local. In addition, it may be desirable to introduce the pharmaceutical compositions of the invention into the central nervous system by any suitable route, including intraventricular and intrathecal injection; intraventricular injection may be facilitated by an intraventricular catheter, for example, attached to a reservoir, such as an Ommaya reservoir. Pulmonary administration can also be employed, e.g. by use of an inhaler or nebulizer, and formulation with an aerosolizing agent. In another embodiment, the compound can be delivered in a vesicle, in particular a liposome {Langer (1990) Science 249, 1527. In yet another embodiment, the compound can be delivered via a controlled release system. In one embodiment, a pump may be used (Sefton (1987) CRC Crit. Ref. Biomed. Eng. 14, 201; Buchwald et al. (1980) Surgery 88, 507; Saudek et al. (1989) N. Engl. J. Med. 321, 574). In another embodiment, polymeric materials can be used (Ranger and Peppas (1983) Macromol. Sci. Rev. Macromol. Chem. 23, 61; Levy et al. (1985) Science 228, 190; During et al. (1989) Ann. Neurol. 25, 351; Howard et al, (1989) J.Neurosurg. 71, 858). In yet another embodiment, a controlled release system can be placed in proximity of the therapeutic target, i.e., the brain, thus requiring only a fraction of the systemic dose (e.g. Goodson, 1984, In: Medical Applications of Controlled Release, supra. Vol, 2, 115). Other controlled release systems are discussed in the review by Langer (1990, Science 249, 1527). In order to select an appropriate way of administration, tlie person sl Furthermore, the skilled person in the art will take into account the available data with respect to routes of administration of members of the NSAID-family in clinical trials and other studies investigating their effect on Alzheimer's disease. In order to select the appropriate dosage, the person skilled in the art will choose a dosage which has been shown to be not toxic in preclinical and/or clinical studies and which can be in accordance with the values given beforehand, or which may deviate from these. The precise dose to be employed in the formulation will also depend on the route of administration, and the seriousness of the disease or disorder, and should be decided according to the judgment of the practitioner and each patient's circumstances. However, suitable dosage ranges for intravenous administration are generally about 20-500 micrograms of active compound per kilogram body weight. Suitable dosage ranges for intranasal administration are generally about 0.01 mg/kg body weight to 1 mg/kg body weight. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems. An exemplary animal model is the transgenic mouse strain "Tg2576" containing an APP695-form with the double mutation KM670/671NL. For reference see e.g. patent US5877399 and Hsiao et al. (1996) Science 274, 99 and also Kawarabayahsi T (2001) J, Neurosci. 21, 372; Frautschy et al. (1998) Am. J, Pathol. 152, 307; Irizarry et al. (1997) J. Neuropathol, Exp. Neurol. 56, 965; Lehman et al. (2003) Neurobiol. Aging 24, 645. Substantial data from several studies are available to the skilled person in the art, which are instructive to the skilled person to select the appropriate dosage for the chosen therapeutic regimen. The term "therapeutically effective amount'" as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated. Wherein the present invention is directed to co-therapy or combination therapy, comprising administration of one or more compound(s) 'therapeutically effective amount" shall mean that amount of the combination of agents taken together so that the combined effect elicits the desired biological or medicinal response. Further, it will be recognized by one skilled in the art that in the case of co-therapy the amount of each component of the combination if used by itself may or may not be a therapeutically effective amount. Numerous studies have been published in which the effects of molecules on the y-secretase activity are described. Exemplary studies are Lim et al. (2001) Neurobiol. Aging 22, 983; Lim et al. (2000) J Neurosci. 20, 5709; Weggen et al. (2001) Nature 414, 212; Eriksen et al. (2003) J Clin Invest. 112. 440; Yan et al. (2003) J Neurosci. 23. 7504. As used herein, unless otherwise noted, the term "'isolated form'" shall mean that the compound is present in a form which is separate from any solid mixture with another compound(s), solvent system or biological environment. As used herein, unless otherwise noted, the term "substantially pure base' shall mean that the mole percent of impurities in the isolated base is less than about 5 mole percent, preferably less than about 2 mole percent, more preferably, less than about 0.5 mole percent, most preferably, less than about 0.1 mole percent As used herein, unless otherwise noted, the term "substantially free of a corresponding saltform(s)" when used to described the compound of formula (1) shall mean that mole percent of the corresponding salt form(s) in the isolated base of formula (I) is less than about 5 mole percent, preferably less than about 2 mole percent, more preferably, less than about 0.5 mole percent, most preferably less than about 0.! mole percent. The term "pharmaceutically acceptable" means a non-loxic material that does not interfere with the effectiveness of the biological activity of the active ingredients. Such preparations may routinely contain pharmaceutically acceptable concentrations of salts, buffering agents, preservatives, compatible carriers and optionally other therapeutic agents. General Synthesis Description The following general description is for illustrative purposes only and is in no way meant to limit the invention. The compound of Formula I wherein A, X, R', R, R, R', R, and R'° are defined as in Formula 1, and Y is CO2H, may be obtained by hydrolysis of ester II under stnadard acidic or basic hydrolysis conditions, including reaction with NaOH, at room temperature, for several hours, in an appropriate solvent mixture, such as water, tetrahydrofuran (THF), and methanol. For illustrative purposes, ester II is shown with X as CHR, but those skilled in the art will recognize that ester hydrolysis will work for all X as defined in Formula 1. (range from 80-180 degrees C) or the reaction may be preformeed with a microwave reactor. Compound lib, where A is O, may be obtained from coupling phenol lllc with an aryl boronic acid in dicholoromethane (DCM) in the presence of a base, (such as dimethyl am inopyridine (DMAP), or triethylamine), molecular sieves and Cu(0Ac)2 at room temperature, in a similar condition as described In D. Evans, etal.Tetrahedron Lettters (1980, 39(19), 2937-2940. Alternatively compounds lib and lie, where A is O, and S respectively, may be prepared from coupling reaction of Ilia or Illb with aryl phenols or thiophenots. Compound lib may also be prepared from lllc by reacting with methanesulfonyl anhydride in DCM in the presence of triethylamine and then the resulting methane sulfonates can be condensed with phenols or thiophenols in the aprotic solvent in the presence bases, e.g. diisopropylethyl amine. Varous reaction conditons for diaryl ether synthesis see the reviw article by Rok Frian and Danljel Kikkelj (Synthesis 2006, No 14, pp 2271-2285). Compound lib may also be prepared from lllc by reacting with methanesulfonyl anhydride in DCM in the presence of irielhylamine and then the resulting methane sulfonates can be condensed with phenols or thiophenols in the aprotic solvent in the presence bases, e.g. diisopropylethyl amine. Compound Ilia may be obtained from the reaction of phenol lllc with trifluoromethanesulfonic anhydride in DCM in the presence of an amine such as pyridine, or triethylamine at 0 °C. Intermediate Illb can be obtained from reactions of phenol lllc with concentrated HCl, or HBr, or HI at elevated temperature (ranges from 25 to i20°C). Aitematively, compound Illb can be obtained under mild conditions by treatment of the corresponding triflale IIIc with pinacoborane in dioxane in the presence of triethylamine catalyzed with PdCb to give an arj'i pinacol boronate ester which is then treated with copper (II) halide in methanol- water procedure described by Nesmejanow et al. (Chem Ber. 1960, 2729). The aforementioned pinacol boronate ester could also be reacted with Nal in aqueous THF in the presence of chloramines-T to give aryl iodide described by J. W. Hufftnan et. al.( Synthesis , 2005, 547). Compound IV may be prepared from alkylation of compound V with either an alkyl or alkenyl halide. Treatment of compound V in THF or another aprotic solvent with a base, e.g. lithium bis(tnsmethylsiiyi) amide, sodium bis{trismethy(silyi} amide, or lithium diisopropylamide at -78 °C, followed by the addition of an electrophile, e.g. an alky! or alkenyl halide, yields alkylated compound IV. the conditions described above and then can be coupled with aryl bromides or aryl chlorides to give compound V. Intermediate VIII can be easily prepared from reaction of 3,5-dihydroxyphenyl acetic acid methyl ester {commercially available) with benzyl bromide and potassium carbonate in DMF at room temperature. Compound I has a chiral center a to the carboxylic group, and can exist as one of two enantiomers {or a mixture threof, wherein an enantiomeric excess may or may not be present). The enantiomers la (R enantiomer) and lb (S enantiomer) are shown. The pure enantiomers la and lb may be obtained by chiral separation using a chiral column. The enantiomers la and lb may also be separated by resolutions through forming chiral amine salts by fractional recrystallizations. The enantiomers la and lb also may be obtained from kinectic resolution of the racemate of corresponding esters using lipase enzymes, e.g. AmanoAk, Amano lipase PS, Amano lipaseA, Amano lipase M, Amano lipase F-15 Amano lipase G (from Biocatalytics Inc) in aqueous organic solvents, e.g. aqueous DMF, DMSO, t-butyl-ethyl ether or triton X-100 aqueous solutions. Both enantiomers of compound I may be prepared from chiral syntheses. Compounds la and lb may be obtained fi-om the removal of the chiral auxiliary groups from compounds iXa and IXb respectively with litiiium hydroxide in aqueous THF in the presence of Compounds IXa and IXb, where A is NH, may be obtained by coupling compounds Xa and Xb respectively with aryl amines under typical Buckwald or Hartwig conditions, e.g. in toluene, dioxane, or THF in the presence of potassium t-butoxide and catalytic Pd(0Ac)2 or Pd (dba)2. Compounds IXa and IXb, where Ais O, may be obtained from reaction of compounds XIa and Xlb respectively with aryl boronic acids in DCM and DMAP in presence of Pd(0Ac)2 and molecular sieves. Compounds IXa and IXb, where A is O or S, also may be obtained from Xa and Xb respectively with phenols or thiophenols in DCM and DMAP in presence of Pd(0Ac)2 and molecular sieves. Compounds Xa and Xb may be obtained from reaction of phenols XIa and Xlb with Compounds Xllla and Xlllb may be prepared from the common intermediate KIV by coupling with either R-isomer of 4-benzyl-oxazolidin-one XVa or S-lsomer of 4-lenzyl -oxazolidin-one XVb by Evans's procedures. Intermediate XIV may be reacted A'ith pivaloyi cholride, oxalyl chloride or isopropyl chloroformate in THF in the presence )f a base, e.g. triethylamine or N-methylmorpholine, to mixed anhydrides or acid ;hlorides which then were reacted with the lithium salt of XVa or XVb in THF. Synthetic Procedures All reactions were carried out under inert atmosphere unless otherwise stated. NMR spectra were obtained on a Bruker dpx400. LCMS was carried out on an Agilent 1100 using a ZORBAX SB-C18, 4.6 x 75 mm, 3.5 micron column for method A. Column flow was Iml/min and solvents used were water and acetonitrile (0.1%TFA) with an injection volume of lOul, Wavelengths were 254 and 2tOnm. Methods are described below: EXAMPLES: Example (H: Preparation of 2-f5-)4-fluorophenoxv)-4'-trifluQrQtnethvl-biphenvl-3-vD-pentanoic acid Preparation of l-Benzvloxv-3.5-dibromoben2ene Benzylaicohol (9.7 mLl, 94 mmol) was added dropwise to a suspension of NaH (4.0 g of a 60 % suspension in mineral oil, lOOmmol) in THF (150 mL) at room temperature and the mixture was stirred at room temperature for 1 hour before 1,3-dibromo-5-fluorobenzene (15.9 g, 62.5 mmol) was added. The reaction was stirred at room temperature for 12 hours. Water was added carefully and the THF was evaporated under reduced pressure. The residue was extracted with iso-hexane (x3) and the combined organic extracts were washed with NaOH solution (1 M aq.), water, brine, dried (MgS04), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (EtO.Ac : petroleum ether) to give l-benzyloxy-3,5-dibromobenzene (14.7 g, 65 mmol) as a colourless liquid in 69 % yield. 'H NMR (CDCb) 5 7.45-7.33 (m, 5H), 7.30-7.28 (m, IH), 7.10-7.08 (m, 2H), 5.02 (s, 2H). Preparation of (3-Benzvloxy-5-bromo-phenvl)-acetic acid ethvl ester Malonic acid ierl-buX}'\ ester ethyl ester (10.2 mL, 53.8 mmol) was added dropwise to a suspension of NaH (2.2 g of a 60 % suspension in mineral oil, 53.8 mmol) in dioxane (200 mL) at room temperature and the mixture was stirred at this temperature for 1 hour before CuBr (7.7g, 53.8 mmoj) and ]-benzyloxy-3,5-dibromobenzene (9.2g, 26.9 mmol) were added. The reaction mixture was heated to reflux for 5h. HCl solution (IM aq, 100 mL) was carefully added and the mixture was extracted with iso-hexane (x3). The combined organic extracts were washed with HCl solution (1 M aq), water, brine, dried (MgS04), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (EtOAc : petroleum ether) to give, in order of elution, recovered l-benzyloxy-3,5-d!bromobenzene (3.2g, 9.4 mmol) in 35 % yield and 2-(3- benzyloxy-5-bromo-phenyl)-malonic acid (erf-butyl ester ethyl ester (7.2 g, contains 1.4 equivalent malonic acid leri-buty] ester elhyJ ester, 10 mmoi) as a coJourJess liquid in 37 % yield. 2-(3-Benzyloxy-5-broniophenyl)malonic acid tett-butyl esier ethyl ester (7.2g, contains 1.4 equivalent malonic acid tert-huty\ ester ethyl ester, lOmmol) was dissolved in glacial AcOH (50 mLI) and heated to reflux for 12 hours. The AcOH was removed under reduced pressure. The residue was poured into NaiCOa solution (sat. aq.) and the mixture was extracted with EtOAc (x3). The combined organic extracts were washed with water, brine, dried (MgS04), filtered and concentrated under reduced pressure to give (3-benzyloxy-5-bromo-phenyl-)acetic acid ethyl ester (6.8 g, 9.7 mmol) as a yellow liquid in 97 % yield. 'H NMR (CDCI3) 8 7.44-7.30 (m, 5H), 7.07-7.03 (m, 2H), 6.87-6.84 (m, IH), 5.03 (s, 2H), 4.15 (q, 2H), 3.54 (s, 2H}, 1.26 (t, 3H). Preparation of (5-Benzvloxv-4'-trif1uoromethvl-biphenvl-3-vn-acetic acid ethvi ester (3-Benzyloxy-5-bromo-pheny!)-acetic acid ethyl ester (2.50 g, 7.2 mmol) was added to a solution of 4-(trifluoromethyl)phenyl boronic acid (1.5 g, 8.0 mmol) and K3CO3 (14.4 mmol, 2 M aq. ) in DME (25 mL). Nitrogen was bubbled through the reaction mixture for 10 minutes before addition of tetrakis(triphenylphosphine)palladium(0) (1 0 % wt) and the resultant mixture was heated to 80 °C for 4 hours under inert atmosphere. The reaction mixture was diluted with water and extracted with EtOAc (x3). The combined organic extracts were washed with sat. NaiCOj. brine, dried (■MgS04), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (EtOAc : petroleum ether) to give (5-benzylox>'-4'trifIuoromethy'l-biphenyl-3-yJ)-acetic acid ethyl ester (2.2g) as a colourless gum in 74% yield, 'H NMR (CDCI3) 5 7.59-7.54 (m, 2H), 7.48-7.30 (m, 8H), 7.13-7.11 (m, 2H), 6.94-6.91 (m, IH), 5,12 (s, 2H), 4.16 (q, 2H), 3.64 (s, 2H), 1.27 (t,3H). Preparation of 2-f5-Benzvloxv-4'-trif1uoromethyl-biphenvl-3-vl>-pentanoic acid ethvl ester A solution of LDA (4.5 mL of 1.8 M in THF. 8 mmol) was added dropwise to a stirred solution of (5-Benzyioxy-4'-trifIuoromethy(-biphenyl-3-y|}-acetic acid ethyl ester (3 g, 7.3 mmol) in THF (50 mL) at -78 °C. The reaction mixture was stirred for 30 minutes at -78 °C before iodopropane (0.85 mL, 8.7 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature overnight. A saturated aqueous sofution of ammonium chloride (JO mL) was carefully added and the residue was partitionned between EtOAc and water. The aqueous layers were extracted with EtOAc (x3). The combined organic layers were washed with water, brine, dried (MgS04), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (EtOAc : petroleum ether) to give 2-(5-Benzyloxy-4'-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (2.2 g) as an oil in 66 % yield. Preparation of 2-(5-(4-fluorophenoxv)-4'-trifluoromethvl-biphenvl-3-vl)-pentanoic acid 2-(5-Benzyloxy-4'-trifluoromethyl-biphenyI-3-yl)-pentanoic acid ethyl ester (1.1 g, 2.4mmo!) was dissolved in EtOH (10 mL) and stirred with 10% Pd/C (116 mg) under an atmosphere of hydrogen. After 19h. the mixture was filtered through Celite and concsntrated in vacuo to afford 2-(5-hydroxy-4'-trifluorometh)'l-biphenyl-3-y])-penlanoic acid ethyl ester (0.85 g) as a colourless oil. Triethylamine (100 iL, 0.72 mmol) was added to a stirred mixture of 2-(5-hydroxy-4'-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (90 mg, 0.25 mmol), Cu(0Ac)2 (68 mg, 0.38 mmol), 4-fluorophenyJboronic acid (70 mg, 0.57 mmol), 4A molecular sieves (25 mg, powdered) and DCM (2 mL) at room temperature open to the air. After 24 h, the reaction mixture was loaded onto silica and purified (0-10% ethyl acetate in petrol) to give 2-(5-(4-fluorophenoxy)-4'-trifluoromethyl-biphenyl-3-y!)-penlanoic acid ethyl ester (67 mg) as a colourless oil. The ester was dissolved in THF (1.2 mL) and treated with a IM solution of K.OH in 6:1 MeOH/water (0.3 mL, 2 eq). After 65 h, the mixture was diluted with water (5 mL} then acidified with IM HCl(aq). The mixture was extracted with ethyl acetate (2x5 mL), then the combined organic layer was washed with brine; dried (MgS04) and concentrated in vacuo to afford 2-(5-(4-fluorophenoxy)-4'-trifliioromethyl-biphenyl-3-yl)-pentanoic acid (57 mg, 90%) as a pale yellow gum. LCMS Method A - 3.65 min. Example nn 2-r5-fphenoxv)-4'-trifluorQinethvl-biphenvl-3-vn-pentanoicacid In an analogous fashion to Example 1 using phenylboronic acid in place of 4-fluorophenylboronic acid was prepared 2-(5-(phenoxy)-4'-trifluoromethyl-biphenyl-3-y!)-pentanoic acid LCMS Method A - 3.69 min. A mixture of (3,5-dihydroxy-phenyl)-acetic acid methyl ester (from Aldrich, 70g, 0.385 mole), benzytbromide (137mL, 1.16mole), potassium carbonate (160g, i.l6mole) and DMF (1.5L) under N; was mechanically stirred at room temperature overnight. The resuhing reaction mixture was poured into a mixture of 1.5L of ice-water with stirring. The precipitate was obtained by filtration and washed with heptane successively to remove benzyl bromide to give the title compounds (123.7g) as a brown solid which was air dried for the next reaction.'H-NMR( CDCI3): 5 3.60 ( s, 2H), 3.71( sJH), 5.05 (s, 4H), 6.60 (s, 3H), 7.35-7.50 (m, t OH); Calcd for C23H2204 (M+H) 363.15. Found 363. A solution of 50 grams (1.38moles)of 3,5-Bis-benzyIoxy-phenyl)-acetic acid methyl ester and NaOH (6,6 g, 1.65 moles) in 1 L of EtOH in the presence of 10 % of Pd-C was iiyJrogenated in a Parr shaker until one equivalent of hydrogen was consumed. The mixture was acidified with con HCl and then the catalyst and solvent were removed to give an oil residue. The crude product was purified by ISCO silica gel column chromatography (iSCO) using EtO.AC-heptane as eluents (gradient from 10% to 75% of EtOAc) to give 25 grams (65% yield) the title compound ( lb). 'H-NMR( CDCI3): 5 1.15-1.20 (t,3H),3.4-(s,2H), 4.05-4.1 {q, 2H),4.9(s, 2H), 5.5(s, IH), 6.4(s, 2H), 6.5(s, 1H), 7.207.35(m, 5H); Calcd for C17H1804 (M+H) 287.3, Found 287. To a solution of 3-(benxyloxy-5-hydroxy-phenyi)-acetic acid ethyl ester (74.4 g, 0.26 mol) in dichloromethane (700 mL) was added pyridine (62.5 mL, 0.78 mol). The mixture was cooled to 0 °C. To this cold solution was added trifluoromethanesulfonic anhydride (65.6 mL, 0.39 mol), over 1.5 h, maintaining the internal temperature below 5 °C and stirred for further 0.5 h at 0 °C. This reaction mixture was poured to a mixture of 1 N HCl (420 mL), and wet-ice (105 g) and stirred for 0,5 h. The aqueous layer was extracted with dichloromethane (2 x 100 mL). Combined fractions were washed with water (2 x 100 mL), saturated aqueous NaHC03 solution (2 x 100 mL), and brine (2 x 100 mL). The organics were dried (MgSOa) and concentrated in vacuo to receive a reddish liquid (108 g) which was carried on to the next step without further purification. Calcd for CI 8H] 7F306S (M+H) 419.07. Found 41 9.1. A mixture of (3-benzyloxy-5-trifluoromethanesulfonyloxy-phenyl)-acetic acid ethyl ester (108 g, 0.26 mol), 4-(trifluoromethyl)phenylboronic acid (55.6 g. 0.29 mol), 1,2-dimethoxyethane (1.1 L) and aqueous Na2C03 (2 M, 129 mL , 0.26 mol) was mechanically stirred while purging N2 at room temperature for 10 min. To this system was added Pd(Ph3)4 (480 mg, 0.42 mmol) and heated to reflux (95 °C) for 2.5 h. The red-brown mixture was diluted with EtOAc (0.5 L) and washed with saturated aqueous NaHCOj solution (3 x 200 mL) and brine (2 x 200 mL). The organic fraction was dried (NaSOa) and concentrated in vacuo. The crude mixture was purified by ISCO column chromatography to obtain (5-benzyloxy-4'-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester (107 g, 100%). 'H-NMR (CDCI3): 8 1.26 (t, 3H), 3.66 (s, 2H), 4.! 7 (q, 2H), 5.12 (s, 2H), 6.99 (s, IH), 7.12 (s, 2H), 7.34-7.49 (m, 5H), 7.67 (s, 4H); Calcd forC24H21F303 (M+H) 415.14, Found 415.2. e) 2-{5-Ben2yloxy-4'-trifluoromethyl-biphenyl-3-yl)-4-methyl-pent-4-eDoicacid To a solution of compound Id {4.9g, 11 .Smmole) in THF (50 mL) al -78 °C was added Li[N(SiMe3)2] (IN in THF, 14.2mL, ]4.2mtnol) dropwise. Tlie reaction mixture was stirred for 1 h at-78 °C and then 3-bromo-2-metliyl-propene (1.25mL, 12.4mmole) was added dropwise. The solution was slowly warmed up to -35 °C and stirred at -35 °C for 0.5 h. The reaction was quenched with NH4CI saturated solution and extracted with EtOAc. The organic extracts was dried (Na2S04), concentrated and purified by column chromatography give compound le (5.]g, 92%) as a clear oil; IH NMR (400 MH2., CHLOROFORM-D) S ppm t.!9 - 1.29 (m. 3 H), 1.74 (s, 3 H). 2.47 (m. 1 HI. 2.85 (m. ! H),3.83(m, 1 H),4.]] (m, 2 H), 4.72 (s, 1 H), 4.77 (s, ! H), 5.12 (s, 2 H), 7.03 (s, ! H), 7.10 (s, 1 H), 7.15(3, 1 H),7.35-7.48(m, 5H), 7.67(s,4H);CalcdforC28H27F303 (M+H) 469.19, Found 469. f) 2-(5-Hydroxy-4'-trifluoromethyi-biphenyl-3-yl)-4-methyl-pentanoicacid ethyl ester A mixture of compound le(5.1g, ]0.9minole). 10% Pd/C (500mg) in EtOH (50mL) was hydrogenaled under H2 (40psi) in par-shaker for 20h. The resulting reaction mixture was filtered through celite and the fihrale was concentrated to give compound If (4.2g, ! 00%) as a clear oil; IH NMR (300 MHz, CHLOROFORM-D) 6 ppm 0.92 (d, J=6,6 Hz, 6 H), 1.25 (m, 3 H), 1.49 - 1.61 (m, 1 H), 1.65 - 1.70 (m, 1 H), 1.95 - 2.05 (m, 1 H), 3.67 (t, J=7.7Hz, 1 H),4.10-4.29tm,2H),6.91 (s. I H), 6.97 (t,y-2.0 Hz, 1 H), 7.08 (s, 1 H), 7.65 (s, 4 H); Calcd for C21H23F303 (M+H) 381.16, Found 381. (trifluoromethanesulfonimide) (3.16g, 8.83mmol) in THF (30mL) under N; was added EtjN (2.05mL, 14.7mmol). The reaction mixture was heated refluxing over night. After cooling to rooin temperature, the solution was concentrated and purified by column chromatography to give compound !g (3.7g, 98%) as a colorless thick oil; IHNMR (400 MHz, CHLOROFORM-D) 5 ppm 0.94 (dd, J-6.60, 1.47 Hz, 6 H), 1.22 - ) .28 (m, 3 H), 1.46- 1.52 (m, 1 H), 1.69 (ddd, 13.82, 7.09,6.97 Hz, 1 H), 1.98 - 2.06 (m, 1 H), 3.75 (t,J=7.83Hz, 1 H), 4.10-4.21 (m,2H),7.31 (s, 1 H), 7.38 (s, 1 H), 7.57 (s, I H), 7.65-7.75 (m, 4 H): Calcd forC22H22F605S (M+H) 513.11, Found 513. h) 2-[5-(3,5-Difluoro-phenylamino)-4'-trifluoromethyl-biphenyl-3-yl]-4-methyl-pentanoic acid A mixture of compound Ig (50mg, 0.098mmoi), 3, 5-difluoro-aniline (20mg, 0.156mmol), Pd(0Ac)2 (6.6mg, 0.029mmol), racemic-2-{di-t-butylphosphino)-l,r- binaphthyl (35mg, 0.088nimo!) and sodium /er/-butoxide (NaOt-Bu) (11.3mg, O.I2mmoi)in toluene (1.5mL) was heated at 85 °C for 17h. After cooling to room temperature, the solution was partitioned between EtOAc and H2O. The organic layer was dried (Na2S04), concentrated and purified by column chromatography to give an ethyl ester intermediate. A mixture of the above intermediate and NaOH (2N in H2O, 0.147mL, 0.294mmol) in THF-MeOH (0.6mL-0.6mL) was stirred fori 8h and concentrated. CHjCI; and water were added, and the mixture was acidified with IN HCI. The organic phase was separated and the aqueous phase was extracted with CHiCb- The combined organic layers were dried, concentrated, and purified by column chromatography to give 38mg (84%, 2 steps) of the title compound as a white solid; IH NMR (400 MHz, CHLOROFORM-D) 5 ppm 0.91 -1.00 (m, 6 H), 1.51 - ].62(m, t H), !.70- 1.80 (m, 1 H), 1.99 (dd,J=7.83, 5.87 Hz, ] H), 3.71 (t,J7.70H2, I H),6.0I (brs, 1 H), 6.30-6.40 (m, 1 H), 6.50 - 6.60 (m, 2 H), 7.13 (d, J=\.7] Hz, 1 H), 7.18 - 7.29 (m, 2 H), 7.62 - 7.72 (m, 4 H); Calcd for C25H22F5N02 (M+H) 464.16, Found 464. under the condition described in Example 1; 1H NMR {400 MHz, CHLOROFORM-D) 5 ppm 0.88 - 0.99 (m, 6 H), 1.56 (dt, J=13.39, 6.63 Hz, 1 H), 1.72 (ddd, >13.69, 7.21, 6.97 Hz, I H), 1.94 - 2.06 (m, I H), 3.69 (t, J=7.70 Hz, I H), 5.70 (brs, 1 H), 6.78 - 6.85 (m, 1 H), 6.90 (ddd,y-10.94, 8.38, 2.93 Hz, 1 H), 7.00 (s, I H), 7.04 - 7.14 (m, 2 H), 7.24 - 7.33(m, 1 HX7.64(q.y=8.3] Hz, 4 H); Calcd for C25H22F502 (M+H) 464.16, Found 464. The title compound was prepared from 3,4-bis-trifluoromethyl-aniline and compound Ig under the condition described in Example 1; 1H NMR (400 MHz, CHLOROFORM-D) 5 ppmO.88- 1.00 (m, 6 H), 1.56 (ddd,y=13.33, 6.85, 6.72 Hz, I H), 1.71-1.81 (m, 1 H), 1.95-2.06 {m. 1 H), 3.70 - 3.79 (m, 1 H).6.14(s, 1 H), 7.21 fs, 2 H), 7.25 (d, J=4.89 Hz, 1 H), 7.36 (s, 1 H), 7.43 (s, 2 H), 7.62 - 7.72 (m. 4 H); Calcd for C27H22F9N02 (MH) 564.15, Found 564. condition described in Example 1; i H NMR (400 MHz, CHLOROFORM-D) 6 ppm 0.87 -0.98{m,6H), 1.20-1.31 (m, 6 H), 1.52- ! .63 (m. 1 H). 1.72 (ddd, =13.69, 7.21. 6.97 Hz, ] H), 1.94 - 2.05 (m, 1 H), 2.88 (dt, J=I 3.69, 6.85 Hz. 1 H), 3.67 (t, J=7.70 Hz, 1 H). 6.99 - 7.10 (m, 4 H), 7.! I - 7.20 (m, 3 H), 7.59 - 7.69 (m, 4 H); Calcd for C28H30F3NO2 (M+H) 470.22, Found 470. described in Example 1; IH NMR (400 MHz. CHLOROFORM-D) 5 ppm 0.89 - 0.98 (m, 6 H), 1.56 (ddd, J=] 3.33, 6.85, 6.72 Hz, 1 H). 1.72 {ddd,J=13,69, 7.21, 6.97 Hz, I H), 1.94 - 2.06 (m, 1 H), 3.68 (t, 7.70 Hz, 1 H), 6.98 - 7.06 (m, 3 H), 7.09 (s, 1 H), 7.14 (s, i H), 7.20 - 7.3 i (m, 2 H), 7.64 (q, J=8.56 Hz. 4 H); Calcd for C25H23CIF3N02 (M+H) 462.14, Found 462. Example 6 2-[5-(4-Fluoro-phenylamino)-4'-trifluoromethyl-biphenyl-3-yll--4-iiiethyl-pentanoic acid described in Example 1; IH NMR (400 MHz, CHLOROFORM-D) 5 ppm 0.93 (dd, J=6.60, t .22 Hz, 6 H), 1.51 - 1.62 (m, 1 H), 1.71 {ddd, J= 13.82, 7.09, 6.97 Hz, I H), 1.97 (ddd,y=13.57, 7.70, 7.58 Hz, 1 H), 3.67 (t, J=7.70 Hz, 1 H), 6.95 - 6.97 (m, I H), 6.99-7.09 (m, 6 H), 7.63 (q, 8.56 Hz, 4 H); Calcd for C25H23F4N02 (M+H) 446.17, Found 446. condition described in Example 1; IH NMR (400 MHz, CHLOROFORM-D) 5 ppm 0.90 -1.00(m,6H), 1.55 (ddd, 7=13.33,6.85,6.72 Hz, I H), 1.71 -1.81 (m, 1 H), 1.93-2.05 (m, 1 H),3.71 (t, 7=7.70 Hz, 1 H),5.90(brs, 1 H), 6.87 - 6.96 (m, 3 H), 7.13 (d, J=1.47 Hz, ) H), 7.(9 (d,y=l.7J Hz, 2 H), 7.62 - 7.73 (m, 4 H).; Calcd for C25H22C12F3N02 (M+H) 496.10, Found 496. Ig under the condition described in Example 1; IH NMR (400 MHz, CHLOROFORM-D)6ppm0.90-1.00(m,6H), 1.57 (dt,>l 3.27, 6.69 Hz, 1 H), 1.71 (ddd,y=13.69, 7.21, 6.97 Hz, 1 H), 1.95-2.06 (m, 1 H), 3.69 (1,7=7.83 Hz, 1 H), 5.94(s, 1 H), 7.02 (d, J=l.71 Hz, 1 H), 7.10 - 7.19 (m, 3 H), 7.33 (dd,8.68, 3.06 Hz, 1 H), 7.36 (dd, J=9.05, 4.89 Hz, 1 H), 7.65 (q, J=8.40 Hz, 4 H); Calcd for C26H22F7N02 (M+H) 514.15, Found 514. under the condition described in Example 1; IH NMR (400 MHz, CHLOROFORM-D) S ppm 0.95 (d, J-6.36 Hz, 6 H), 1.57 (dt. J=13.27. 6.69 Hz, 1 H), 1,74 (ddd, 13.69, 7.21, 6.97 Hz, I H), 1.96 - 2.05 (m,l H), 3.66 - 3.76 (m, 1 H), 7.07 - 7.12 (m, 2 II), 7.14 - 7.20 (m, 2 H), 7.25 - 7.29 (m, I H) 7.50 (d, J=8.56 Hz, 2 H) 7.62 - 7.72 (m, 4 H); Calcd for C26H23F6N02 (M+H) 496.16, Found 496. Ig under the condition described in Example 1; 1H NMR (400 MHz, MeOD) 5 ppm 0.88 -0.98(m.6H), 1.55 (ddd, 13.33, 6.85, 6.72 Hz, 1 H), 1.67- 1.75 (m. 1 H). 1.92-2.01 (m, 1 H),3.71 (t,y=7.70Hz, 1 H), 7.19 (d, 7=1.71 Hz, 1 H),7.2!(s, 1 H), 7.26 - 7.34 (m, 2 H), 7.35 - 7.45 (m, 2 H), 7.71 - 7.80 (m. 4 H); Caicd for C26H22C1F6N02 (M-H) 530.12, Found 530. O.OSSmmol) and NaOt-Bu (11.3mg, 0.12mmol) in toluene (l.SmL) was microwaved (300w) at 140 "C for 1 Omin. After cooling to room temperature, the solution was partitioned between EtOAc and H2O. The organic layer was dried (Na2S04), concentrated and purified by column chromatography to give an ethyl ester intermediate. To a mixture of the above intermediate in THF (!mL) was added KOt-Bu (IM in THF. 0.098mL, 0.098mmol). After stirring for 30min, Mel (42mg, 0.295mmol) was added. The reaction mixture was stirred at room temperature for 15h, concentrated and purified by preparative TLC to give a methylated ester intermediate. The title compound was prepared from the above intermediate under the same saponification condition described in Example 1; H NMR (400 MHz, MeOD) 5 ppm 0,89 (d, J=6.85 Hz, 3 H), 1.00 (d, J=6.60 Hz, 3 H), 1.73 (m, 1 H), 2.23 (d, J=5.87 Hz, ! H), 2.28 - 2.33 (m, 1 H), 3.45 (s, 3 H), 6.89 - 6.92 (m, 2 H), 7.44 (t, J=] .71 Hz, 1 H), 7.50 - 7.55 {m, 3 H), 7.71 (t,J=1.59Hz, 1 H), 7.77 - 7.85 (m, 4 H); Calcd for C27H25F3N202 (M+H) 467.19, Found 467. Example 15 2-[5-(3-Isopropyl-phenoxy)-4'-trifluoromethyi-biphenyl-3-yl]-4-methyl-pentanoic acid (3,5-dihydroxy-phenyl)-acetic acid methyl ester (5 g, 27,4 mmol) in anhydrous DMF (20 mL) was treated with K2CO3 (11.4 g, 82.5 mmol) and benzyl bromide (6.5 mL, 55 mmol). The resultant mixture was stirred overnight at room temperature. Water was added to the reaction mixture and the aqueous layer extracted with EtOAc (3 x 50 mL). The organic layers were combined, washed with brine, dried over MgS04, filtered and concentrated to give the title compound as a brown solid (9.82 g, 99%). b) 2-(3,5-Bis-benzyloxy-pbenyI>-4-inethyl-pent-4-eDoic acid methyl ester A 2M solution of LDA in THF-heptane-ethylbenzene (21.5 mL, 43.0 mmol) was added dropwise over 12 min to a stirred solution of (3,5-i/5-benzyloxyphenyl)acetic acid methyl ester (13.0 g, 35.9 mmol) in THF (80 mL) at -78 °C under a nitrogen atmosphere. The temperature was maintained below -70 °C for a further 50 min then 3-bromo-2-methylpropene (4.0 mL, 39.7 mmol) was added in one portion and the reaction mixture was warmed to 0 °C. After 2 h the mixture was concentrated in vacuo, diluted with sat. aq. NH4CI (100 mL) and extracted with EtOAc (100 mL). The organic layer was washed with brine (100 mL), dried (MgS04), concentrated in vacuo and purified by flash chromatography (silica, 0-10% EtOAc in petroleum ether) to afford the title product as a yellow oil (14,1 g, 94%). 'H-NMR (400 MHz, CDay. 5 7.42-7.25 (m, J OH), 6.58 (s, 2H), 6.52 (s, IH), 5.02 (s, 4H), 4.74 (s, IH), 4.66 (s, IH), 3.74 (t, IH), 3.64 (s, 3H), 2.79 (dd, IH), 2.38 (dd, IH), 1.70 (s,3H. ] 0% Pd/C (A)drich cal no 205699. 0.55g) was added to a stirred solution of2'(3.5-b!s-ben2yloxyphenyl)-4-methyl-pent-4-enoic acid methyl ester(]4.1 g, 33.8 mmol) and NaOH (1.50 g, 37.5 mmol) in MeOH (180 mL) at room temperature. Stirring was continued for 1 h under H2 (1 atm.) then the mixture was filtered through Celite, coTicentrated in vacuo, suspended in water (100 mL) and adjusted to pH 2 with 1M HCl. The mixture was extracted with EtOAc ( 2 x 180 mL); the combined organic layer was washed with brine (50 mL), dried (MgS04), concentrated in vacuo and purified by flash chromatography (silica, 0-30% EtOAc in petroleum ether) to give the title product as a yellow oil (7.40 g, 67 %). 'H-NMR (400 MHz. CDCb): 5 7.41-7.25 (m, 5H), 6.54 (s, IH), 6,43 (s, IH), 6.38 (s, IH), 5.01 (s, 3H), 4.74 (s, IH), 4.67 (s, IH), 3.70 (t, IH), 3.65 (s, 3H), 2.78 (dd, IH), 2.38 (dd, IH), 1.71 (s, 3H); RT = 3.14 min. Mass spectrum (ESi, m/z)325(M-l) Trifluoromethanesulfonic anhydride (3.3 mL. lO.i mmol) was added dropwise to a stirred solution of 2-(3-benzyloxy-5-hydroxyphenyl)-4-methyl-pent-4-enoic acid methyl ester (4.5 g, 13.8 mmol) and pyridine (3.0 mL, 38.7 mmol) in DCM (80 mL) at 0 °C then warmed to room temperature. After 1 h, the mixture was washed with 1M HCl (50 mL), dried (MgS04) and concentrated in vacuo to afford the title product as an orange oil (6.10 g. 96 %). 'H-NMR (400 MHz, CDCI3): 6 7,42-7.30 (m, 5H), 6.97 (s, IH), 6.85 (s, IH), 6.78 (s, IH), 5.05 (s. 3H), 4,75 (s, IH), 4.64 (s, IH), 3.77 (t, IH), 3.66 (s, 3H), 2.77 (dd, ]H),2.40(dd, JH), 1.69 (s,3H). A mixture of 2-(3-benzyloxy-5-trifluoromethanesulfonyloxy-phenyl)-4-methyl-pent-4-enoic acid methyl ester (4.3g, 9.4 mmol). 4-trifluoromethylphenylboronic acid (2.6g, 13.7 mmol), K2CO3 solution (2M, 9.4 mL) and DME (50 mL) was purged witli N2 three times before adding Pd{PPh3)4 (400 mg, 0.3 mmol). The mixture was heated at 95 °C for 5 h (followed by HPLC). The reaction was diluted with EtOAc {200 mL) and then was washed successively with NaHCOj solution and brine. The organic layer was dried (Mg2S04), filtered and concentrated in vacuo to give the title compound as an oil. The residue was used crude in the next step. iO% Pd/C (Aldrich cat no 205699, 0.30 g) was added to a stirred solution of 2-(5-benzyloxy-4'-trifluoromethyl-biphenyl-3-yI)-4-methyl-pent-4-enoic acid methyl ester (2.71 g, 5.96 mmol) in MeOH {75 niL) at room temperature. Stirring was continued for 2 days under H; (1 atm). Then the mixture was filtered through Celite. concentrated in vacuo to give the compound (] .83 g, 84%) as a yellow oil. 'H-NMR (400 MHz, CD3CI): & 7.70-7.60 (m. 4H), 7.08 (t, IH), 7.00-6.95 {m, IH), 6.90-6.87 (m, IH), 5.56{br. s, IH), 3.73-3.65 min (m, 4H), 2.04-1.92 (m, IH), 1.76-1.64 (m, IH), 1.56-1.42 (m, IH), 0.92 (d, 6H. Mass spectrum (ESI, m/z): 365 (M-H); A mixture of 2-(5-hydroxy-4'-trifluoromethyl-bipheny!-3-y])-4-methy]-penlanoJc acid methyl ester (50 mg, 0.14 mmol), 3-isopropylphenyl boronic acid (45 mg, 0.27 mmol), copper acetate (26 mg, 0.) 4 mmol), triethylamine (57 L, 0.4 mmol) and powdered 4 A molecular sieves in DCM (1 mL) were stirred at room temperature for 2 days. The reaction mixture was concentrated in vacuo. Purification b>' flash chromatography (EtOAc: petroleum ether) give the title compound (32 mg, 48%). . h) 2-[5-(3-IsDpropyl-phenoxy)-4'-trifluoromethyl-biphenyl-3-yI]-4-methyl-pentanorc acid A mixture of2-[5-(3-isopropyl-phenoxy)-4'-trifluoromethyl-biphenyl-3-yl]-4-methy!- pentanoic acid methyl ester (33 iiig. 0.07 mmol). THF (0.6 mL). 10% aq. LiOH (0.2 niL) and MeOH (0.6 mL) was stirred at 30 "C for 3 h. The solution was concentrated and the residue was diluted with HO (1 mL) and then acidified with cone HCI. The aqueous solution was extracted with DCM (3x 1 mL) and the organic layers were filtered through PTFE filter. The solution was concentrated in vacuo to give a solid residue. The solid was purified using reverse phase preparative HPLC (MeCN, HiO) to afford the title compound (2! .6 mg, 67%). 'H-NMR (CD3CI; 400 MHz): 5 7.64 (dd, 4H), 7.29-7.23 (m, 2H), 7.11 (br. s, IH), 7.05 (br. s), 7.00 (dd, IH), 6.96-6.93 (m, IH), 6.84 (d, IH), 3.80-3.65 (m, iH), 2.95-2.85 (m, 1H),2.02-L90(m, IH), h80-}.65(m, IH), 1.60-1.45 (m, IH), 1.23 (d, 6H), 0.92 (d, 6H}. The title compound was prepared in 70 % yield from 2-(3-benzyloxy-5-trifluoromethanesulfonyloxy-phenyl)-4-methyl-pent-4-enoic acid methyl ester (prepared in Example 15, step (d)) under the conditions described in Example 15 step (e-f) using 4-cJi]oro-5-triflLioromethylphenyJboronic acid in step (e). 'H-NMR (400 MHz, CDCI3): 5 7.84 (s, !H),7.65(d, IH), 7.55(d, lH),7.04(s, ]H),6.92(m, !H), 6.86(m, 1H), 4.98 (br s, 1H), 3.68 (m, 4H), 1.97 (m, 1H), 1.68 (m, 1H), 1.49 (m, 1H), 0.92 (d, 6H);. Mass Spectrum (m/z, ESI) 399 (M-H) Example B The title compound was prepared in 73% yield from 2-(3-benzyloxy-5-trifluoromethanesulfony]oxy-phenyl)-4-methyl-pent-4-enoic acid methyl ester (prepared in Example 15, step (d)) under the conditions described in Example 15 , step (e-f) using 3-fluoro-5-trifluoromethylphenyiboronic acid in step (e), 'H-NMR (400 MHz, CDCh): 6 7.59 (s, IH), 7.44 (dm,lH, J= 9.3Hz), 7.30 (dm, IH, J=8.3Hz), 7.06(m, IH), 6.94(m, IH), 6,89(m, IH), 4.97(s, IH). 3.68(m. IH). 3.68(s, 3H), 1.99 (m, 1H), 1.70 (m, 1H), ! .49 (m, 1H), 0.92 (d, 6H, J=6.6Hz). trifluoromethanesulfonyloxy-phenyl}-4-methyl-pent-4-enoic acid methyl ester (prepared in Example 15, step (d)) under the conditions described in Example 15, step (e-f) using 3,5-iw-trifluoromethylphenylboronic acid in step (e). 'H-NMR (400 MHz, CD3CI): 6 7.96 (s, 2H), 7.85 (s, IH), 7.07 (t, IH), 6.97 (t,lH), 6.93 (t, m),3.7l (t, IH),3.70(s,3H),2.04-1.97(mJH), 1.74-1.67 (m, IH), 1.55-1.48 (m, IH), 0.93 (d, 6H);. Mass spectrum (ESI, m/z): 433 (M-H); The titie compound was prepared in 43 % yield from 2-(5-ii yd roxy-4'-trifl uorom ethyl-bipheny]-3-yl)-4-methyl-pentaiioic acid methyl ester and 4-trifluoromethyi phenyl boron ic acid under the conditions described in Example 15, step (g). b) 4-Methyl-2-[4'-trifluoroinethyl-5-(4-trifluoroniethyl-phenoxy)-biphenyl-3-yl]-penttinoic acid The title compound was prepared in 15 % yield from 4-methyl-2-[4'-trifluoromethyl-5-(4-trifl uorom ethyl-phenoxy)-biphenyl-3-y I ]-pentanoic acid methyl ester under the conditions described in Example 15, step (h). 'H-NMR (400 MHz, CDjCi): S 7.75-7.55 (m, 6H), 7.37 (s, IH), 7.16(s, IH), 7.14-7.06 (m,3H), 3.85-3.65 (m, IH), 2.10-1.90 (m, I H), 1.80-1.65 (m, IH), 1.62-1.45 (m, IH), 0.93 (d, 6H). The title compound was prepared in 30 % yield from 2-(5-hydroxy-4'-trifluoromethyi-biphenyl-3-y!)-4-methyl-pentanoic acid methyl ester and 3,4,5-trifluoroplienylboronic acid under the conditions described in ExamplelS, step (g). b) 4-Methyl-2-[4'-trifluoromethyl-5-(3-trifluoromethyl-phenoxy)-biphenyl-3-yl]-pentanoic acid The title compound was prepared in 60 % yield from 4-methyl-2-[4'-trifluoromethyl-5-(3,4,5-trifluoro-phenoxy)-biphenyl-3-yl]-pentanoic acid methyl ester under the conditions described in Example IS, step (h). 'H-NMR (400 MHz, CD3CI); 5 7.66 (dd, 4H), 7.37 (s, IH), 7.13 (s, IH), 7.06 (m, 3H), 6.61 (m, 2H), 3.77 (tJH), 2.0 (m, IH), 1.72 (m JH), 1.54 (m, IH), 0.93 (d, 6H). Example 18 2-[5-(4-Fluoro-3-methoxy-phenoxy)-4'-trifluoromethyl-biphenyI-3-yl]-4-methyl-pentanoic acid The title compound was prepared in 30 % yield from 2-(5-hydroxy-4'-trifluoromethy]-bipheny]-3-yl)-4-methyl-pentanoic acid methyl ester and 4-fluoro-3-methoxyphenylboronic acid under the conditions described in Example 15 ,step (g). b) 4-Methyl-2-[4'-trifluoromethyl-5-(3-trifluoromethyl-phenoxy)-biphenyl-3- yl]-pentanoic acid The title compound was prepared in 60 % yield from 2-[5-(4-fluoro-3-methoxy-phenoxy)-4'-trifluoromethyl-biphenyl-3-yl]-4-methyl-pentanoic acid methyl ester under the conditions described in Example 15, step (h). 'H-NMR (400 MHz. CD3CI): 5 7.64 (dd. 4H). 7.27 (s. IH). 7.07 (s, IH), 7.04 (m, 3H), 7.02 (m, lH),6.72{dd, lH),6.55,(m, IH). 3.84 (s, 3H), 3,72 (t, lH),2.0{m, IH), ].72 (m, IH), ! .54 (m, 1H), 0.93 (d, 6H). trifluorom ethyl phenyl boron ic acid under the conditions described in ExamplelS, step (g). b) 2-[5-{4-Methoxy-3-trifluoromethyl-phenoxy)-4'-trifluoromethyl-biphenyl-3-yl|-4-methyl-pentanoic acid The title compound was prepared in 60 % yield from 2-[5-(4-methoxy-3-trifluoromethyl-phenoxy)-4'-trifluoromethyl-bipheny 1-3-yl]-4-m ethyl-pen tanoic acid methyl ester under the conditions described in Example 15, step (h). 'H-NMR (400 MHZ, CD3CI): S 7.66 (dd, 4H), 7.31 (s, IH), 7.27 (s, IH), 7.20 (m, 3H), 7.04 (m, IH), 7.02 (dd, iH), 7.00 (m, tH), 3.92 (s, 3H), 3.73 (t, IH), 2.0 (m. !H), i.72 (m, IH), 1.54 (m, IH), 0.93 (d, 6H). The title compound was prepared in 25 % yield from 2-(5-hydroxy-4'-trifluoromethyI-biphenyl-3-yl)-4-methyl-pentanoic acid methyl ester and 3-trifluoromethylphenylboranic acid under the conditions described in ExamplelS, step (g). b) 4-Methyl-2-I4'-trifluoromethy!-5-(3-trifluoromethyl-phenoxy)-biphenyl-3-yl]-pentanoic acid The title compound was prepared in 60 % yield from 4-methyl-2-[4'-trifluoromethyl-5-(3-trifluDromethyl-phenoxy)-biphenyl-3-yl]-pentanoic acid under the conditions described in Example 15, step (h). 'H-NMR (400 MHz, CD3CI): 5 7.61 (d, 2H), 7.56 (d, 2H), 7.27 {m, IH), 7.23 (m, IH). 7.04 (d, 1H),6.77 (m, 2H), 6.69 (m, lH),3.62(t, IH), 1.87 (m, IH), 1.65(m, IH), 1.44 (m, ]HX0.83(dd, 6H). Example 21 4-Methyl-2-|4'-chloro-3'-trifluoromethyl-5-(3-fluoro-5-trifluoromethylphenoxy)-biphenyl-3-yl]-pentanoic acid The title compound was prepared in 50 % yield from 2-(5-hydroxy-4'-chloro-3'-trifluoroniethyI-biphenyl-3-yl)-4-methyl-pentanoic acid methyl ester (prepared in Example A) and 3-fluoro-5-trifluoromethylphenylboronic acid under the conditions described in Example 15, step (g). b) 4-Methyl-2-[4'-chloro-3'-trifluoromethyl-5-(3-fluora-5-trinuorometliylphenoxy)-biphenyl-3-yl]-pentanoicacid The title compound was prepared in 90 % yield from 4-methyl-2-[4'-chioro-3'-trif1uoromethyl-5-(3-fluoro-5-trifluoromethylphenoxy)-biphenyl-3-yl]-pentanoicacid > methyl ester under the conditions described in Example 15, step (h). 'H-NMR (400 MHz, CDCI3): 5 7.79 (d, IH), 7.55 (d, IH), 7.50 (d, IH), 7.28 (d, IH), 7.05 (m, 4H), 6.82 (d, IH), 3.59 (t, 1H), 1.84 (m, 1H), 1.64 (m, 1H), ! .41 (m, IH), 0.83 The title compound was prepared in 71 % yield from 2-(5-hydroxy-4'-chloro-3'-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid methyl ester (prepared in Example A) and 3-trifluoromethylphenyIboronic acid under the conditions described in Example IS, step (g). b) 4-Methyl-2-[4'-chloro-3'-trifluoromethyI-5-(3-trifluoromethyIphenoxy)-biphenyl-3-yl]-pentanoic acid The title compound was prepared in 100 %yieid from 4-methyl-2-[4'-chloro-3'- trifluoromethyl-5-(3-trifliJOromethylpheiioxy)-biphenyl-3-yl]-pentaiioic acid methyl ester under the conditions described in Example 15, step (h). H-NMR (400 MHz, CDCI3): 6 7.77 (d, 1H). 7.54 (dd, 1H). 7.47 (d. 1H), 7.40 (t. 1H), 7.32 (d, IH), 7.23 (m, 1H), 7.19 (m, lH),7.]3(m, ]H).7.01 (m, 2H), 3.56 (t, IH), 1.80(m, IH), 1.63 (m, IH). 1.39(m, IH),0.8] (d,6H). b) 4-Methyl-2-[4'-chloro-3'-trifluoromethyl-5-(3,5-difluorophenoxy)-biphenyl-3-yl]-pentanoic acid The title compound was prepared in 100 % yield from 4-methyl-2-[4'-chloro-3'- trifluoromethy!-5-(3,5-diftuorophenoxy)-biphenyl-3-yl]-pentaroic acid methyl ester under the conditions described in Example 15, step (h). 'H-NMR(400MHZ, CDCb):5 7.78(d, lH),7.54(dd, lH),7.49(d, lH),7.25(t, IH), 7.03(s,2H), 7.46 {m,3H), 3.55 (t, IH), 1.81 (m, IH), 1.62 (m,lH), 1.39 (m, iH), 0.81 (d, 6H2).. The title compound was prepared in 21 % yield from 2-(5-hydroxy-4'-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid methyl ester (prepared in Example 15, step (f)) and henzeneboronic acid under the conditions described in Example 15 step (g). b) 4-MethyI-2-(5-pheDoxy-4'-frinuoroniethyl-biphenyl-3-yl)-pentanoicacid The title compound was prepared in 83 %yield from 4-methyl-2-(5-phenoxy-4'-trifluoroethyl-biphenyl-3-yl)-pentanoic acid methyl ester under the conditions described in Example 15 step (h). 'H-MMR (400 MHz, CDCI3): 6 7.64 (d, 2H, 8.6Hz). 7.60 (d, 2H, J=8.4Hz), 7.34 (dd. 2H. J= 7.6, 0.76Hz}, 7.27 (s, IH), 7.12(t, IH, J=7.3Hz), 7.05 (m, 4H), 3.68 (t, IH, J=7.7Hz), 1.95 (m, 1H), 1.70 (m, 1H), 1.50 (m, 1H), 0.90 (dd, 6H, J=6.6, 2.5Hz). Example 25 2-[5-(4-Fluoro-phenoxy)-4'-trifluoromethyl-biphenyl-3-yl]-4-methyl-pentanoicacid The title compound was prepared in 43 % yield from 2-t 5-hydroxy-4'-tr ifluorom ethyl-biphenyi-3-yI)-4-methyi-pentanoic acid methyl ester (prepared in Example 15, step (f)) and 4-fluorobenzeneboronic acid under the conditions described in Example 15, step (g). b) 2-[5-(4-Fluoro-phenoxy)-4'-trinuoromethyl-biphenyl-3-yll-4-methyl-pentanoic acid The title compound was prepared in 100 % yield from 2-[5-(4-fluoro-phenoxy)-4'-trifluoromethyl-biphenyl-3-yl]-4-methyl-pentanoic acid methyl ester under the conditions described in Example 15, step (h). 'H-NMR (400 MHz. CDCI3): 6 7.61 (d. 2H, J=83Hz), 7.55 (d. 2H, J-8.3HzX 7.24 (s. IH), 6.98 (m,6H), 3.62 (m,lH), 1.88 (m. IH), 1.65 (mJH), 1.54 (m, IH), 0.85 (dd. 6H, J=6.3, 3.3Hz). The title compound was prepared in 26 % yield from 2-(5-hydrox>'-4'-trifluoromethyl-biphenyl-3-yl)-4-methy]-pentanoic acid methyl ester (prepared in Example 15, step (f)) and 3-fluorobenzeneboronic acid under the conditions described in Example 15, step (g). b) 2-f5-(3-Fli]oro-pheiioxy)-4'-trifluoromethyl-biphenyl-3-yl]-4-methyl- pentanoic acid The title compound was prepared in 100 % yield from 2-[5-(3-fluoro-phenoxy)-4'-trifluoromethyl-bipheny!-3-yl]-4-methyl-pentanoic acid methyl ester under the conditions described in Example 15, step (h). 'H-NMR (400 MHz, CDCI3): S 7.61 (d, 2H, J-8.3Hz), 7.57 (d, 2H, J=8.3HzX 7.27 (m, IH),7.24(m, lH),7.06(s, lH),7.04(s, lH),6.78(m, lH),6.68(dt, IH, J=10.], 2.3Hz), 3.62 (br.S, IHX 1.87 (m, IH), 1.65{m, IH), 1.44 (m, IH), 0.84 (dd, 6H, J=6.4, 3.4Hz).. b) 2-[5-{3,5-Difluoro-phenoxy)-4'-trifluoroinethyl-biphenyl-3-yl]-4-methyl-pentanoic acid The title compound was prepared in 100 % yield from 2-[5-(3,5-difluoro-phenoxy)-4'-trifluoromethyl-biphenyl-3-yl]-4-methyl-pentanoic acid methyl ester under the conditions described in Example 15, step (h). 'H-NMR (400 MHz, CDCI3): S 7.66 (d, 2H, J=8.3Hz), 7.61 (d, 2H, J=8.3Hz), 7.35 (m, IH), 7.13 (dd, IH, J=2.3, 0.51HZX 7.07 (m, IH), 6.50 (m, 3H), 3.69 (L !H, J=7.8Hz), ] .94 (m, 1H), ! .69 (m, 1H), 1.49 (m, 1H), 0.89 (dd, 6H. J=6.6, 2.5Hz). Example 28 2-[5-(4-Mefhoxy-phenoxy)-4'-trinuoromethyl-biphenyl-3-yl]-4-methyl-pentanoic acid The title compound was prepared in 17 % yield from 2-(5-h ydroxy-4'-tri flu orom ethyl-biphenyl-3-yl)-4-methyl-pentanoic acid methyl ester (prepared in Example 15, step (f)) and 4-methoxybenzene boronic acid under the conditions described in Example 15, step (g)- b) 2-[5-(4-Methoxy-pheno3£y)-4'-trifluoromethyl-biphenyl-3-yl]-4-methyl-pentanoic acid The title compound was prepared in 100 % yield from 2-[5-(4-methoxy-phenoxy)-4'-trifluoromethyl-biphenyl-3-yl]-4-methyl-pentanoic acid methyl ester under the conditions described in Example 15, step (h). 'H-NMR {400 MHz, CDCI3): 5 7,64 (d, 2H, J=8.3Hz), 7.59 (d, 2H, J=8.1Hz), 7.22 (s, IHX7.0] (m,4H), 6.89 (d,2H,J=9.iHz), 3.80 (s,3H), 3.68 (br.S, IH), 1.96(tn, IH), 1.70 (m, IH), 1.52(m, IH), 0.91 (dd, 6H, J-6.6, 2.0Hz). biphenyl-3-yl)-4-methyl-pentanoic acid methyl ester (prepared in Example 15, step (0) and 4-chIorobenzene boronic acid under the conditions described in Example 15, step (g)- b) 2-|5-(4-Chloro-phenoxy)-4'-trinuoroniethy!-biplieDyl-3-yl|-4-methyl-pentanoic acid The title compound was prepared in 83 % yield from 2-[5-(4-chloro-phenoxy)-4'-trifluoromethyl-biphenyl-3-yl]-4-methyl-pentanoic acid methyl ester under the conditions described in Example 15 step (h). 'H-NMR (400 MHz, CDCb): 6 7.62 (d, 2H, J=83Hz}, 7.57 (d, 2H, J=8.]Hz), 7.27 (m, 3H), 7.02 (d, 2H, J=1.5Hz), 6.93 (d, 2H, J=8.8 Hz), 3.62 (t, IH, J=7.7Hz), 1.88 (m, IH), 1.66 (m, 1H), 1.45 (m, 1H), 0.86 (dd, 6H, J=6.6, 4.0Hz). The title compound was prepared in 10 % yield from 2-(5-liydroxy-4'-trifluoromelhyl-biphenyl-3-yl)-4-methyi-pentanoic acid methyl ester (prepared in Example IS, step (1)) and 3-fluoro,5-trifluoromethylbenzene boronic acid under tiie conditions described in Example 15, step (g). b) 2-[5-(4-Chloro-phenoxy)-4'-trifluoromethyi-biphenyl-3-yll-4-niethyl- pentanoic acid The title compound was prepared in 44 %yi6ld from 2-[ 5-(3-fluoro-5-trifluorom ethyl-phenoxy)-4'-trifluoromethyl-biphenyl-3-yl]-4-methyl-pentanoic acid methyl ester under the conditions described in Example 15, step (h), 'H-NMR (400 MHz, CDCh): 5 7.68 (d. 2H, J=8.3Hz), 7.63 (d, 2H, J=8.] Hz), 7.37 (m, 1H), 7.16 (m, 1H), 7.08 (m, 1H), 7.06 (m, 2H), 6,87 (dt, 2H, J=9.6, 2.3 Hz), 3.7i (t, iH, J=7.8Hz), 1.95 (m, IH), 1.71 (m, IB), 1.50 (m, IH), 0.90 (dd, 6H, J=6.6, 2.3Hz). Example 31 2-[3'-Fluoro-5'-trifluoromethyl-5-(3-trlfluoromethyl-phenoxy)-biplienyl-3-ylJ-4- methyl-pentanoic acid The title compound was prepared in 34 % yield from 2-(3'-fluoro-5-hydroxy-5'-trifluoromethyl-biphenyt-3-yl)-4-meihyl-pentanoic acid methyl ester (prepared in Example B) and 3-trifluoromethylbenzene boronic acid under the conditions described in Example 15, step (g). b) 4-Methyl-2-[4'-trifluoromethyl-5-(3-trifluoromethyl-phenoxy)-biphenyl-3-yI]-pentanoic acid The title compound was prepared in 99 % yield from 2-[3'-fluoro-5'-trifluoromethyl-5-(3-trifluoromethy!-phenoxy)-biphenyl-3-yl]-4-methyl-pentanoic acid methyl ester under the conditions described in Example 15, step (h). 'H-NMR (400 MHz, CDCI3}: 8 7.57 (m, IH). 7.47 (t, !H, J=8.0Hz), 737-7.43 (m. 2H), 7.32 (m, 2H}, 7.27 (m, IH), 7.20 (dd, IH, J=8.]. 2.0Hz), 7.14 (t, IH, J= 2.3, 1.77Hz), 7.10 {t, ]H,J-2.0, 1.77HzX3.74(l. ]H, J=7.8Hz). 2.00 (m, IH), 1.73 (mJHX 1.54, (m, 1H), 0.93 (dd, 6H, J=6.6, 1.8Hz). trifluoromethyl-biphenyi-3-yl)-4-methyl-penlanoic acid methyl esler (prepared in Example B) and 3-fluoro-5- trifluorom ethyl benzene boronic acid under the conditions described in Example 15, step (g). b) 2-[3'-Fluoro-5-(3-fluoro-5-trifluoromethyl-phenoxy)-5'-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoicacid The title compound was prepared in 26 % yield from 2-[3'-fluoro-5-(3-fluoro-5- trifluoromethyl-phenoxy)-5'-trifluoromethyl-biphenyl-3-yl]-4-melhyl-:pentanoic acid methyl ester under the conditions described in Example 15, step (h). 'H-NMR (400 MHz, CDCI3): 5 7.58 (br. s. 1H), 7.43 (br. d, 1H, J=9.6Hz), 7.35 (m, 2H), 7.16 (br. s. IH), 7.12, (br. s, IH), 7,06, (m, 2H), 6.88 (d, IH, J= 9.4Hz), 3,83 (br. s, IH), 2.00 (br, s, IH), 1.78 (br. s, IH), 1.52 (br, s, IH), 0.92 (br. s, 6H). The title compound was prepared in 83 % yield from 2-(3'-fluoro-5-hydroxy-5'-trifludromethyl-biphenyi-3-yl)-4-methyl-pentanoic acid methyl ester (prepared in Example B) and 3,5-difluorobenzene boronic acid under the conditions described in Example 15, step (g). b) 4-Methyl-2-[4'-trifluoromethyl-5-(3-trifluorometliyl-phenoxy)-biphenyl-3- yl]-pentaDoic acid The title compound was prepared in 40 %yield from 2-[5-(3,5-difluoro-phenoxy)-3'-fluoro-5'-trifluoromethyl-biphenyl-3-yl]-4-m ethyl-pen tan oic acid methyl ester under the conditions described in Example 15, step (h). 'H-NMR (400 MHz, CDCI3): 5 7.57 (br. s, IH), 7.42 (d, !R J=9. IHz), 7,33 (m, 2H), 7.i5(br.s, lH),7.!2(br.s,lH), 6.59-6.5! (m. 3HX 3.77 (br. s. IH), 2.00 (br. s, IH). 1.75 (br. s, 1H), 1.54 (br. s, 1H), 0.94 (d, 6H., J=5.3Hz). Example 34 2-[5-(3-Fluoro-5-trifluoromethyl-ph6noxy)-3',5'-bis-trifluoromethyl-biphenyl-3-yl]-4- methyl-pentanoic acid The title compound was prepared in 35 % yield from 2-(5-hydroxy-3\5'-bis-trifluoromethyl-biphenyl-3-yl}-4-methyl-pentanoic acid methyl ester (prepared in Example C) and 3-fluoro-5-trifluoromethylpheny!-boronic acid under the conditions described In Example 15, step (g). b) 2-[5-(3-Fiuoro-5-trifluoromethyl-phenoxy)-3',5'-bis-trinuoromethyI-bipheny i-3-y I] -4-methyl-penta noic acid The title compound was prepared in 61 % yield from 2-[ 5-(3-fluoro-5-trifluorom ethyl-phenoxy}-3',5'-bis-trifluoromethyl-biphenyl-3-ytl-4-methyl-penianoic acid methyl ester under the conditions described in Example 15, step (h). 'H-NMR (400 MHz, CD3CI): 8 7.96 (s, 2H), 7.89 (s, IH), 7.38 (s, IH), 7.18 (d, 2H), 7.08 (d. 2HX 6.89 (d, IH), 2.66 (s,2H), 2.03-2.00 (m. IH), 1.79-1.73 (m. IH). 1.57-1.53 (m, lH),0.94{d,6H). Example 35 2-|3',5'-Bis-trifluoromethyl-5-(3-trifluoromethyl-phenoxy)-biphenyI-3-y]]-4-methyl- The title compound was prepared in 60 % yield from 2-(5-liydroxy-3',5'-iii--trifluoromethyl-biphenyl-3-yl)-4-methy!-pentanoic acid metliyl ester (prepared in Example C) and 3-trifluoromethylphenylboronic acid under the conditions described in Example 15, step (g). b) 2-|3',5'-fiK-trifluoromethyl-5-(3-trifluoromethyl-phenoxy)-biphenyI-3-yl]-4-methyl-pentanoic acid The title compound was prepared in 62 % yield from 2-[3',5'-6w-trifluoromethyl-5-(3-trifluovomethyl-phenoxy)-biphenyl-3-y[]-4-niethy!-pentanoic acid methyl ester under the conditions described in Example 15, step (h). 'H-NMR (400 MHz, CD3CI): 5 7.95 (s, 2H), 7.87 (s, IH), 7.48 (t, IH), 7.39 (d, 2H), 7.33 (t, IH), 7.27(s, IH), 7.21 (d, IH), 7.1 7 (t, IH), 7.12(t, ]H),3.76(t, IH), 2.02-1.99 {m, IH), 1.76-1.69 (m, IH), 1.58-1.51 (m, IH), 0,94 (d, 6H). The title compound was prepared in 15% yield from 2-[3',5'-6y-trifluoromethyI-5-(3-trifluoromethyl-phenoxy)-biphenyl-3-y]]-4-methy!-pentanoic acid methyl ester (prepared in Example C) and 3,5-difluoro-phenylboronic acid under the conditions described in Example 15, step (g). b) 2-[5-(3,5-I>inuoro-phenoxy)-3',5'-bis-trinuoromethyl-biphenyl-3-jfl]-4-methyl-pentanoic acid The title compound was prepared in 45% yield from 2-[5-(3,5-difluoro-phenoxy)-3',5'- 6/5-trifluoromethyl-biphenyl-3-yl]-4-methyl-pentanoic acid methyl ester under the conditions described in Example 15, step (h). 'H-NMR (400 MHz, CD3CI): 5 7.95 (s, 2H), 7.88 (s, IH), 7.36 (s, IH), 7.17 (d. 2H), 6.59-6.51 (m, 3H), 2.64 (s,2H) 2.07-1.98 (mJH) J.78'1.71 (m, !H). 1.59-1.53 (m, !H),0.95(d,6H). Example 37 2-[5-(3,5-Bis-trinuoromethyl-phenylamino)-4'-chloro-3'-trinuoromethyI-biphenyl-3- yl]-4-methyl>pentanoic acid Trifluoromethanesulphonic anhydride (93 L, 0.57 mmol) was added dropwise to a stirred solution of 2-(4'-chloro-5-hydroxy-3'-trif]uoromethyl-biphenyl-3-yI)-4-methyI-pentanoic acid methyl ester (prepared in Example A)(] 50 mg, 0.38 mmo]) and pyridine (88 fiL, ]. 1 mmol) in DCM (3 mL) ai 0 °C. The reaction was warmed to room temperature and stirred for 1 h, then 1M hydrochloric acid was added. The organic layer was filtered through a polytetrafluoroethylene (PTFE) frit and concentrated in vacuo to give the title compound (205 mg, 100%) as an orange oil. b) 2-[5-(3,5-Bis-trifluoromethyl-phenylamino)-4'-chloro-3'-trifluoromethyl-biphenyl-3-yl]-4-methyl-pentanoic acid methyl ester. A mixture of 2-(4'-chloro-5-trifluoromethanesulfonyloxy-3'-trifluoromethyl-biphenyl-3-yl)-4-methyI-pentanoic acid methyl ester (48 mg, 0.10 mmol), 3,5-i/5-(trifluoromethyl)-aniline{18 L, 0.12 mmol), sodium/er;-buloxide (9.8 mg, 0.10 mmol), Pd(0Ac)2 (2.5 mg, 0.01 mmol), 2-(di-?ert-butylphoshino-l,r-binaphthyl (3.5 mg, 0.0] mmol) and toluene (I mL) was stirred under microwave irradiation at 130 °C for 3x10 min. The mixture was diluted with toluene (9 mL), washed with IM HCl (2x10 mL) and brine (10 mL), dried (MgS04), concentrated in vacuo and purified by flash column chromatography (diethylether-petroleum ether) to afford the title product as a colourless powder (28 mg, 44%) , Mass spectrum (ESI, m/z): 610, 612 (M-H). c) 2-[5-(3,5-Bis-trinuoroinethyl-phenylamino)-4'-ehloro-3'-trifluoromethy l-bipheny!-3-yl]-4-methyl-pentanoicacid: A mixture of 2-[5-(3,5-i/5-trifluoromethy!-pbenylamino)-4'-chloro-3'-trifluoromethyl-biphenyl-3-yl]-4-methyl-pentanoic acid methyl ester (10 mg, 0.02 mmol), THF (0.6 mL), 10% aq. LiOH (0.2 mL) and MeOH (0.6 mL) was stirred at 30 "C for 3 h. The solution was concentrated and the residue was diluted with H2O (! mL) and then acidified with concentrated (cone) HCl. The aqueous solution was extracted with DCM (3x 1 mL) and the organic layers were filtered through PTFE filter. The solution was concentrated in vacuo to give a solid residue, The solid was purified using reverse phase preparative HPLC (MeCN, H2O) to afford the title compound (3 mg, 30%). Mass spectrum (ni/z, ESI) 598, 600 (M+H). The title compound was prepared in 28 % yield from 2-(4'-ch!oro-5-trifluoromethanesulfonyloxy-S'-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid methyl ester and 3-fiuoro-5-(trifluoromethyl)aniline under the conditions described in Example 37, step (b). Mass spectrum (ES-, m/z): 560, 562 (M-H); b) 4-Methyl-2-{4'-trifluoromethyl-5-(4-trifluoromethyl-phenoxy)-bipheny|-3-yl]-pentanoic acid The title compound was prepared in 73 % yield from 2-[4'-chioro-5-(3-fluoro-5-trifluoromethyl-phenylamino)-3'-trif]uoromethyl-biphenyl-3-yl]-4-methyl-pentanoic acid methyl ester under the conditions described in Example 37, step (c). 'H-NMR (400 MHz, CDCI3): 5 7.80 (br, s. 1H), 7.60 (m, 1H), 7.52 (m, 1H), 7.33 (m. 2H), 7.2-7.i (m, 3H),5.93(br. s, ]H), 3,65 (br. s, IH), 1.97 (m, IH), 1.72 (m, ] H), 1.53 (m, iH), 0.90 (br. s, 6H). Mass spectrum (ES+, m/z): 548, 550 (M+H) b) 2-[4'-Chloro-5-(2,5-bis-trifluoromethyl-phenylainino)-3'-trifluoromethyl- biphenyl-3-yl]-4-methyl-peiitanoicacid The title compound was prepared in 86 % yield from 2-[4'-chloro-5-(2,5-bis- trifluoromethyl-phenylamino)-3'-trifluoromethyl-biphenyl-3-yl]-4-methyl-pentanoicacid methyl ester under the conditions described in Example 37, step (c). 'H-NMR (400 MHz, CDCIj): 5 7.83 (br.§, I H), 7.69 (d, IH), 7.63 {d, IH), 7.57 (m, 2H), 7.19 (m,3H), 6.31 (br s, IH), 3.75 (br. s, IH), 1.98 (m. IH), 1.76 (m, IH), 1.54 (m, IH), 0.93 (br, s, 6H). Mass spectrum (ESI+, m/z): 598, 600 (M+H) trifluoromethyl-biphenyl-3-y!)'4-methyl-pentanoic acid methy! ester (prepared in Example B) under the conditions described in Example 37, step (a). 'H-NMR (400 MHz, CDCI): 6 7.58; (s, IH). 7.53 (m, 1H), 7.44 (dm, IH, J= 9.1 Hz), 7.39 (m, IH), 7.36, (m, IH), 7.33(m, IH), 3.78 (mJH), 3.70 (s, 3H), 2.03 (m, IH), 1.71 (m, 1H), 1.49 (m, 1H), 0.94 (d, 6H, J= 6.8Hz). The title compound was prepared in 100 % yield from 2-(5'-fluoro-5-trifluoromethanesulfony]oxy-3'-trifluoromethyl-biphenyI-3-yI)-4-methy)-pentanoic acid methyl ester and 2,5-6/5-(trifluoromethyl)aniline under the conditions described in Example 37, step (b). c) 2-[5'-Flu oro-5-(2,5-bis-trifluoro methy l-pheny lamino)-3'-tri fluoromethyl- biphenyl-3-yl]-4-methyl-pentanoicacid The title coinpound was prepared in 42 % yield from 2-[5'-fluoro-5-(2,5-6;i'- trifluoromethyl-phenylamino)-3'-trifluoromethyl-biphenyl-3-yl]-4-methyl-pentanoicacid methyl ester under the conditions described in Example 37, step (c). 'H-NMR (400 MHz, CDCI3): 5 7.70 (d, IH), 7.58 (m, 2H), 7.42 (d, IH), 7.32 (d, IH), 7.20 (m,3H), 6.31 (br s, IH), 3.75(m, IH), 1.98 (m,lH), 1.75 (m, IH), 1.55 (m, IH), 0.93 (m, 6H); Mass spectrum (ESi, m/z): 582 (M+H) Example 41 The title compound was prepared in 100 % yield from 2-(5'-fluoro-5-trifluoromethanesulfonyloxy-3'-trifluoromethy]-biphenyl-3-yl)-4-methyl-pentanoic acid methyl ester (prepared in Example 40, step (a)) and 4-fluoro-2-(lrifluoromethyl)aniline under the conditions described in Example 37, step (b). b) 2-[5'-Fluoro-5-(4-nuoro-2-trifluoromethyl-phenylamino)-3'-trinuoromethyl-biphenyl-3-yI] -4-methyl-pentanoic acid The title compound was prepared in 82 %yield from 2-[5'-fluoro-5-(4-fluoro-2- trifluoromethyl-phenylamino)-3'-trifluoromethyl-biphenyl-3-yl]-4-methyl-pentanoicacid methyl ester under the conditions described in Example 37, step (c). 'H-NMR (400 MHz, CDCI3): 5 7.54 (br s, IH), 7.41-7.29 (m, 4H), 7.18-7.02 (m, 4H), 5.94 (brs, ]H),3.75(1H), 1.99 (IH), 1.73 (IH), 1.56 (IH), 0.93 (6H); Mass spectrum (ESI, m/z): 532 (M+H) The title compound was prepared in 97 % yield from 2-(5'-fluoro-5-trifluoromethanesulfonyIoxy-3'-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid methyl ester (prepared in Example 40, step (a)))and 3,5-bis-(trifluoromethyl)aniline under the conditions described in Example 37, step (b). b) 2-[5'-Fluoro-5-(3,5-bis-trifluoromethyl-phenylamino)-3'-trifluoroniethyl- biphenyl-3-y1j-4-inethyI-pentanoicacid The title compound was prepared in 46 % yield from 2-[5'-fiuoro-5-(3.5-A«- trifluoromethyl-phenylamino)-3'-triflLioromethyl-bipheny!-3-yl]-4-methyl-pentanoic acid methyl ester under the conditions described in Example 37, step (c). 'H-NMR (400 MHz, CDCI3): 6 7.56 (1H), 7.44-7.35 (m, 4HX 7.32 (d, i H), 6.12 (] H), 3.78(1H), l.%(m), L78(1H), 1.53 (IH), 0.92 (IH); Mass spectrum (ESI, m/z): 582 (M+H) Example C) under the conditions described in Example 37, step (a)). 'H-NMR (400 MHz, CDCis): S'H-NMR (400 MHz, CD3CI): S 7.96 (s, 2H), 7.94 (s, IH), 7.55 (m, IH), 7.38 (m,2H), 3.80 (t IH), 3.71 (s, 3H),2.01 (m, IH), 1.71 (m, IH). 1.49 (m, lH),0.94(d,6H). b) 2-[5-{3,5-Bis-trifluoromethyl-phenylaniino)-3',5'-bis-trifluoromethyl- biphenyi-3-yll-4-niethyl-pentanoic acid methyl ester The title compound was prepared in 47% yield from 4-methyI-2-(5-trifluoromethanesulfonyloxy-3',5'-Ayj'-trifluoromethyl-biphenyi-3-yi)'pentanoic acid methyl ester and 3,5-bis-trifluoromethyl-aniline under the conditions described in c) 2-[5-(3,5-Bis-trifluoromethyl-phenylamino)-3',5'-bis-trifluororoethyl- biphenyI-3-yI]-4-methyI-pentanoicacid The title compound was prepared in 66% yield from 2-[5-(3,5-6j.y-trifluoromethyI-phenylamino)-3\5'-Ji5-trifluoromethy]-biphenyl-3-yl]-4-methyl-penlanoJc acid methyl ester under the conditions described in Example 37, step (c). 'H-NMR (400 MHz, CD3CI): 5 7.95 (s, 2H), 7.88 (s, IH), 7.44 (s, 2H), 7.39 (s, IH), 7.25 (d, IH), 7.23-7.22 (m,2H), 6.17 (s, lH),3.76(t, IH), 2.05-1,98 (m, IH), 1.79-1.72 (m, ] H), 1.62-1.52 (m, 1H), 0.95 (d, 6H). Example 44 2-[5-(2,5-Bls-trlfluoromethyl-phenylamino)-3',5'-bis-trifluDromethyl-biphenyl-3-yl]-4-methyl-pentanoic acid The title compound was prepared in 39% yield from 4-methy]-2-(5-trifluoromettianesu!fonyloxy-3',5'-bis-trifluoromethyl-biphenyl-3-yl)-pentanoicacid methyl ester (prepared in Example 43, step (a))and 2,5-A/s-trifluoromethy)-aniline under the conditions described in Example 37, step (b). b) 2-[5-(2,5-Bis-trifluoromethyl-phenylamino)-3',5'-bis-trifluoromethyl- biphenyl-3-yl]-4-inethyl-pentanoic acid The title compound was prepared in 40% yield from 2-[5-(2,5-bis-trifluoromethyl-phenylamino)-3',5'-bis-trinuoromethyl-bipheny!-3-yl]-4-methyl-pentanoicacid methyl ester under the conditions described in Example 37, step (c). 'H-NMR(400MHZ,CD3C1):5 7.96(S,2H), 7.88 (sJH), 7.71 (d, !H). 7.61 (s, IH). 7.25 (s,3H}, 7.2] (d, lH),6.35(s, IH), 3.76(t, IH), 2.04-2.00 (m, IH), 1.78-1.71 (m, IH), 1.61-1.54 (m, IH), 0.95(d,6H). Example 45 2-[5-(4-Fluoro-2-trifluoromethyl-phenylammo)-3',5'-bis-trinuoromethyl-biphenyl-3-yl]-4-niethyl-pentanoic acid The title compound was prepared in 46% yield from 4-methyl-2-(5-trifluoromethanesulfonyloxy-3',5'-6w-trifluoromethyl-biphenyl-3-yl)-pentanoic acid methyl ester (prepared in Example 43, step (a))and 4-fluoro-2-trifluoromethy I-aniline under the conditions described in Example 37, step (b). b) 2-(5-(4-Fluoro-2-trifluoromethyl-phenylamino)-3',5'-bis-trifluoromethyl-biphenyl-3-yl]-4-methyl-pentanoic acid The title compound was prepared in 83% yield from 2-[5-(4'fluoro-2-trif]uoromethyl- phenylamino)-3',5'-6;s-trifluoromethy!-biphenyl-3-yn-4-methyl-petitanoicacidmethy! ester under the conditions described in Example 37, step (c). 'H-NMR (400 MHz, CD3CI): 6 7.92 (s, 2H), 7.86 (s, IH), 7.37-7.33 (m, 2H), 7.16-7.06 (m,4H), 5.96(s, 1H),3.71 (t, IH), 2.05-1.96 (m, IH), 1,74-1.67 (m, IH), 1.61-1.53(m, lH),0.94(d,6H). To a solution of (5-ben2yioxy-4'-trifluoromethy!-biphenyl-3-yl)-acetic acid ethyi ester (120 g, 0.29 mol) in THF (1.2 L) was added water (240 mL), LiOH.H20 (16 g, 0.32 mol) and the result!ngmixture was stirred at room temperature for 16 h. The solution was filtered and concentrated in vacuo to remove THF. The resulting thick liquid was acidified to pH 2 by adding 2N aqueous HCl solution and the white suspension was mechanically stirred for Ih at room temperature. The wet white product was recovered after filtration and dissolved in EtOAc (500 mL). The organic layer was separated from water, dried (MgS04) and concentrated in vacuo to obtain (5-benzyloxy-4'-trifluorom ethyl-hi phenyi-3-yl)-aceiic acid (105 g, 94%). 'H-NMR (ds-DMSO): 5 3.64 (s, 2H), 5.18 (s, 2H), 7.02 (s, IH), 7.24 (d, 2H), 7.34-7.50 (m, 5H), 7.81 (d, 2H), 7.89 (d, 2H), 12.25 (bs, 0.6H); Calcd for C22H17F303 (M+H) 387.11, Found 387.1. To a mechanically stirred solution of (5-benzyloxy-4'-trIfluoromethyl-biphenyl-3-yI)-acetic acid (20 g, 52 mmoi) in THF (104 mL) at -78 °C was added N-nethyl morpholine (NMM) (6.3 mL, 57 mmol) and trimethylacetyl chloride (7.0 mL, 57 mmol) maintaining the internal temperature below -70 °C. This mixture was stirred at -78 °C for 15 minute and 0 °C at Ih. The white solid was filtered off to receive the anhydride in the filtrate which was cooled back to -78 "C. In a separate flask, to a solution of (R)-(+)-4-benzyl-2-oxazolidinone (9.6 g, 54.4 mmol) in THF (109 mL) at -78 "C was added nBuLi (1.6M in hexanes, 34 mL, 54.4 mol), drop-wise, maintaining the internal temperature below -70 °C and stirred at -78 °C for 45 min. This metalated chiral auxiliary was cannulated to the anhydride at -78 °C and warmed to 0 °C over 1.5h. The resulting mixture was stirred further at 0 °C for 30 minute and quenched by adding excess saturated aqueous NH4CI solution. The solution was diluted witii EtOAc (200 niL) and tlie organic phase was washed with saturated aqueous NaHCO? solution (3 x 100 mL) and brine (2 x 100 mL). The solution was dried over MgS04 and the solvent was removed in vacuo. The crude materia] was purified by ISCO silica gel column chromatography to yield 20.3 g (72%) of4-benzyi-3-[2-(5-benzyloxy-4'-trifluoromethyl-biphenyl-3-yl)-acetyl]-oxazolidin-2-one as a white solid. 'H-NMR (CDCI3): S 2.76 (dd, IH), 3.26 (dd, IH), 4.19 (m, 2H), 4.35 (q, 2H), 4.69 (m, IH), 5.13 (s, 2H), 7.04-7.46 (m, 13H), 7.67 (s, 4H); Calcd for C32H26F3N04 (M+H) 546.18, Found 546.3. To a colorless solution of 4-benzyl-3-[2-(5-benzyloxy-4'-trifluoromethyl-biphenyl-3-yl)-acetyl]-oxazoUdin-2-one (6.0 g, 11.00 mmol) in dry THF (22 mL) at -78 °C was added sodium hexamethyi disilazide (NaHMDS) (1 M in THF solution, 12.11 mL, 12.11 mmol), drop-wise, maintaining the internal temperature below -75 °C. The resulting red solution was stirred at -78 °C for 30 minutes. To this was added 3-bromo-2-methyl propene (4.44 mL, 44 mmol) maintaining the temperature heiow -75 °C. When the addition was at near completion, the system turned to green. At this point the dry-ice bath was quickly removed and replaced with wet-ice bath and completed the addition. The reaction mixture was stirred further at 0 °C for 30 min and quenched with saturated aqueous NH4CI solution. The system was diluted with EtOAC (100 mL) and the organic phase was washed with saturated aqueous NaHCO solution (3 x 50 mL) and dried (MgS04). SoWem was removed in vacuo and the crude mixture was purified by ISCO silica gel column to yield 4-benzyl-3-f2-(5-benzyioxy-4'-trinuoromethyl-biphenyl-3-yl)-4-methyl-pent-4-enoyl)-oxazolidin-2-one ( 6,3 g, 95 %). 'H-NMR (CDCI3): 6 1.80 (s, 3H), 2.46 (dd, IH), 2.75 (dd, 1H), 3.05 (dd, IH), 3.32 (dd, IH), 4.08 (m, 2H), 4.59 {m, IH), 4.80 (d, 2H), 5.13 (s, 2H), 5,48 (dd, IH), 7.11 (d, 2H), 7.21-7.49 (m, 1 IH), 7.67 (s, 4H); Calcd for C36H32F3N04 (M+H) 600.23, Found 600.3. To a solution of 4-benzyl-3-[2-(5-benzyloxy-4'-trifluoromethyl-biphenyl-3-yl)-4-methyl-pent-4-enoyl]-oxazolidin-2-one (6.7 g, 31.2mmoI) in MeOH (150 mL) was added 10% Pd7C (670 mg, 10 w %). The black suspension was bydrogenated at 45-45 psi overnight. The mixture was filtered through celite and the solvent was remived in vacuo to obtain relatively pure 4-benz>'l-3-[2-(5-hydroxy-4'-trifiuoromethyl-biphenyl-3-yl)-4-methyl-pentanoyl]-oxazoiidin-2-one (5.4 g, 93 %). 'H-NMR (CDCI3): 6 0.94 (d, 3H), 0.98 (d, 3H), 1.54 (m, IH), 1.74 (m, IH), 2.12 (m, IH),2.79(dd, lH),3.36(dd, 1H),4.11 (m, 2H), 4.62 (m, lH),5.25(t, IH), 6.97 (m, 2H), 7.21-7.37 (m, 6H), 7.67 (s, 4H); Calcd for C29H28F3N04 (M+H) 512.20, Found 512.3. e) Trifiuoro-metbanesulfonic acid 5-[l-(4-benzyl-2-oxo-oxazolidine-3-carbonyl)-3-methyl-butyll-4'-trifluoromethyl-biphenyl-3-yl ester To a solution of 4-benzyl-3-[2-(5-hydroxy-4'-trif]uoromethyl-biphenyl-3-yl)-4-inethyl-pentanoyl]-oxazoiidin-2-one (32 g, 62.6 mmol) in dichloromethane (170 mL) was added pyridine (15.0 mL). The system was cooled to 0 °C. To this cold solution was added trifluoromethanesulfonic anhydride (16 mL, 94 mmol) maintaining the internal temperature below 5 °C and stirred for further 0.5 h at 0 "C. This reaction mixture was poured to a mixture of 1 N HCl (100 mL), and wet-ice (25 g) and stirred for 0.5 h. The aqueous layer was extracted with dicWoromethane (2 x 100 mL). Combined fractions were washed with water (2 x 100 mL), saturated aqueous NaHCOs solution (2 x 100 mL), and brine (2 x 100 mL). The organics were dried (MgS04) and concentrated in vacuo to receive a reddish liquid which was purified by ISCO column chromatography to receive trifluoro-methanesulfonicacid 5-[l-(4-benzyl-2-oxo-oxazolidine-3-carbonyl)-3-methyl-butyl]-4'-trifluoromethyl-biphenyl-3-yl ester (34 g, 84%). 'H-NMR(CDCl3):6 0.96(d,3H), 0.98(d, 3H), 1.52 (m, IH), 1.77 (m, lH),2.13(m, IH), 2.79 (dd, IH), 3.37 (dd, IH), 4.14 (m, 2H), 4.67 (m, IH), 5.33 (t, IH), 7.20-7.38 (m, 7H), 7.70 (m, 5H); Calcd for C30H27F6NO6S (M+H) 644.15, Found 644.2. f) 4-Benzy l-3-{2- [5-{2,5-bis-trifl uoromethyl-phenylamino)-4'-trifluoromethy I- bipheny l-3-y 1] -4-niethyl-pentanoy 1} -oxazol idin-2-one To a solution of trifluoro-methanesulfonic acid 5-[l-(4-benzyl-2-oxo-oxazoiidine-3-carbonyl)-3-melh>'l-butyl]-4'-trifluoromethyl-bipheny]-3-yl ester (4.84 g, 7.53 mmol) in toluene (38 mL) in a sealed tube was added 2,5-bis-trifluoromethyl-phenylamine (1.42 mL, 9.04 mmol), [l,l']binaphthalenyl-2-yl-di-/er/-butyl-phosphane (300 mg, 0.75 mmol), PdCOAc). (169 mg, 0.75 mmol) and KOtBu (7.53 . mL of 1.0 M solution in THF, 7.53 mmol). The reaction mixture was heated to 120 "C for 1 h. To this was added another portion each of [l,]binaphthalenyl-2-ydi-rer-buty phosphaT1e (300 mg, 0.75 mmol), Pd(OAc)2 (169 mg, 0.75 mmol) and KOtBu (3.77 mL of 1.0 M solution in THF, 3.77 mmol) and heated for further Ih. The system was cooled to room temperature and quenched by slow addition of water. The mixture was extracted with EtOAc (3 x 50 mL). The organic phase was washed with saturated NaHCOj solution and brine. The organic fraction was dried (Na2S04) and concentrated in vacuo. The crude mixture was purified by ISCO column chromatography to obtain. 4-benzyl-3-{2-[5-(2,5-bis-trifluoromethyl-phenyl am ino)-4'-trifluoromethyl-bi phenyl-3-yl]-4-methyl-pentanoyl}-oxazolidin-2-one (2.32 g, 43%). 'H-NMR (CDCb): B 0.97 (d, 3H), 0.99 (d, 3H), 1.56 (m, IH), 1.76 (m, IH), 2.10 (m, lH),2.78(dd, IH), 3.37 (dd,lH), 4.14 (m,2H), 4.65 (m, lH),5.28(t, lH),6.32(s, IH), 7.17-7.40 (m, 9H), 7.59 (s, IH), 7.69 (m, 5H); Calcd for C37H31F9N203 (M+H) 723.22, Found 723.3. g) (R)-2-[5-(2,5-Bis-trinuDrDinethyl-phenylamino)-4'-trifluoromethyl-biphenyl-3-yll-4-niethyI-pentanoicacid To a solution of 4-benzy!-3-{2-[5-(2,5-bis-trifluoromethyl-phenylamino)-4'-trifluoromelhyl-biphenyl-3-yl]-4-methyl-pentanoyl}-oxazolidin-2-one (2.55 g, 3.53 mmol) in THF (15 mL) was added water (5 mL). The system was cooled to 0 °C. To this cold solution was added LiOH-HiOfMS mg, 3.53 mmol) and 30% H2O2(1.20 mL, 10.59 mmoi,) and stirred at 0 °C for 15 min. The excess H2O2 was quenched by adding i .5 M aqueous Na2S03 solution (7.06 mL, 10.59 mmol) and stirred at room temperature for 10 min. The organic solvent was removed in vacuo. The resulting liquid was acidified to pH = 2 by adding 1 N aqueous HCl solution. The aqueous layer was extracted with EtOAc (3 X 50 mL) and dried (MgS04). The mixture was concentrated in vacuo to receive a crude mixture which was purified by ISCO silica gel column chromatography to yield ( R ) 2-[5-(2,5-Bis-trifluorom ethyl-phenyl am ino)-4'-trifluGrom ethyl-biphenyl-3-yl]-4-m ethyl-pentanoic acid (1.15 g, 58 %). 'H-NMR(CDCl3):5 0.94 (d, 6H), 1.56 (m, IH), 1.76 (m, IH),2.00{m, IH), 3.74(t, IH), 6.32 (s,tH), 7.17-7.29 (m, 4H), 7.60 (s, IH), 7.67 (m, 5H); Calcd for C27H22F9N02 (M+H) 564.15, Found 564.3. Determination of the effect of the compounds according to the invention on cvclooxvgenase-1 and cvclooxvgenase -2 (Cox-1. Cox-2) Inhibition of Cox-l and Cox-2 was determined using the Colorimetric Cox inhibitor screening assay provided by Cayman Chemical Company, Ann Arbor, ML USA. (Cat. No. 760111) according to manufacturer's instructions. Compounds of the invention will show Screening of the compounds of the invention for Y-secretase-modulating activity Screening was carried out using SKNBE2 cells carrying the APP 695 - wild type, grown in DMEM/NUT-mix F12 (HAM) provided by Gibco (cat no. 31330-38) containing 5% Serum/Fe supplemented with i% non-essential amino acids. Cells were grown to near confluency. The screening was performed using the assay as described in Citron et al (1997) Nature Medicine 3: 67. Ap42 lowering agents of the invention can be used to treat AD in mammals such as humans or alternatively in a validated animal model such as the mouse, rat, or guinea pig. The mammal may not be diagnosed with AD, or may not have a genetic predisposition for AD, but may be transgenic such that it overproduces and eventually deposits Ap in a manner similar to that seen in humans afflicted with AD.. Ap42 lowering agents can be administered in any standard form using any standard method. For example, but not limited to, Ap42 lowering agents can be in the form of liquid, tablets or capsules that are taken orally or by injection. A|342 lowering agents can be administered at any dose that is sufficient to significantly reduce levels of Ap42 in the blood, blood plasma, serum, cerebrospinal fluid (CSF), or brain. To determine whether acute administration of an Ap42 lowering agent would reduce AP42 levels in vivo, non-transgenic rodents, e.g. mice or rats can be used. Alternatively, two to three month old Tg2576 mice expressing APP695 containing the "Swedish" variant can be used or a transgenic mouse mode! developed by Dr. Fred Van Leuven (K..U.Leuven, Belgium) and co-workers, with neuron-specific expression of a clinical mutant of the human amyloid precursor protein [V717I] (Moechars et ah, 1999 J. Biol. Chem. 274, 6483). The single transgenic mouse displays spontaneous, progressive accumulation of p-amyloid (Ap) in the brain, eventually resulting in amyloid plaques within subicuium, hippocampus and cortex. Animals of this age have high levels of AP in the brain but no detectable Ap deposition. Mice treated with the Ap42 lowering agent will be examined and compared to those untreated or treated with vehicle and brain levels of soluble Ap42 and total Ap would be quantitated by standard techniques, for example, using ELISA. Treatment periods may vary from hours to days and will be adjusted based on the results of the Ap42 lowering once a time course of onset of effect can be established. A typical protocol for measuring Ap42 lowering in vivo is shown but il is only one of many variations that could be used to optimize the levels of detectable Ap. For example, aliquots of compounds can be dissolved in DMSO (volume equal to 1/10th of the final formulation volume), vortexed and further diluted (!.)0) with a 10 % (w/v) hydroxypropyl p cyclodextrin (HBC. Aldrich, Ref N° 33,260-7) solution in PBS, where after they are sonicated for 20 seconds. AP42 lowering agents may be administered as a single oral dose given three to four hours before sacrifice and analysis or allematively could be given over a course of days and the animals sacrificed three to four hours after the final dose is given. Blood is collected at sacrifice. The blood collection is performed via a heart puncture during anesthesia with a mixture of Ketaiar (Ketamin), Rompun (Xylazin 2%) and Atropin (2:1:1) and collected in EDTA treated collection tubes. Blood is centrifuged at 4000 g for 5 minutes at 4°C and the plasma recovered for analysis. The mice are anaesthetized with a mixture of Ketalar (Ketamin), Rompun (Xylazin 2%) and AtFopin (2:1:1) and flushed trans-cardialiy with physiological serum at 4°C. The brain is removed from the cranium and hindbrain and forebrain are separated with a cut in the coronal/frontal plane. The cerebellum is removed. The forebrain is divided evenly into left and right hemisphere by using a midline sagitai cut. One hemisphere is immediately immersed in liquid nitrogen and stored at -70°C until homogenization for biochemical assays. Brains are homogenized using a Potter, a glass tube (detergent free 2 cm ) and a mechanical homogenizer (650 rpm). A volume of 6,5 x '/s brain weight of freshly prepared 20 mM Tris/HCI buffer (pH 8,5) with Proteinase Inhibitors (I tablet per 50 ml Tris/HCI buffer, CompleteTM, Roche, Mannheim, Germany) is used as homogenization buffer. Samples are transferred from -70°C into a sample holder with liquid nitrogen and each individual sample is pre-warmed by incubation on the bench for a few seconds prior to homogenization. The homogenates are collected in Beckman centrifuge tubes TLX and collected on ice prior to centrifugation. Between two samples, the Potter and the glass tube are rinsed carefully with distilled water without determents and dried with absorption paper. Samples are centrifuged in a pre-cooied ultracentrifuge (Beckman, Mannheim, Germany) for 1 hour and 20 minutes at 48000 rpm (135.000 x g) at 4°C, The supernatant (soluble fraction containing secreted APP and amyloid peptides) is separated from the pellet (membrane fraction containing membrane-bound APP-fragments and plaque-associated amyloid peptides in case of aged mice). Small reversed phase columns (CI8-Sep-Paclc Vac 3cc cartridges. Waters, Massachusetts, MA) are mounted on a vacuum system and washed with 80% acetonitrile in 0,1% Trifluoroacetic acid (A-TFA) followed with 0,1% TFA twice. Then the samples are applied and the columns are washed successively with 5% and 25% A-TFA. Amyloid peptides are eluted with 75% A-TFA and the eluates are collected in 2 ml tubes on ice. Eluates are freeze-dried in a speedvac concentrator (Savant, Farmlngdale, NY) overnight and resolved in 240 ji! of the sample diluent furnished with the ELISA kits. To quantify the amount of human A|3-42 in the soluble fraction of the brain homogenaies. commercially available Enzyme-Linked-lmmunosorbent-Assay (ELISA) kits are used (h Amyloid |342 ELISA high sensitive. The Genetics Company, Zurich, Switzerland). The ELISA is performed according to the manufacturer's protocol. Briefly, the standard (a dilution of synthetic A|31-42) and samples are prepared in a 96-well polypropylene plate without protein binding capacity (Greiner bio-one, Frickenhausen, Germany). The standard dilutions with final concentrations of 1000, 500, 250, 125, 62.5, 31.3 and 15.6 pg/ml and the samples are prepared in the sample diluent, furnished with the ELISA kit, to a final volume of 60 \x\. Samples, standards and blancs (50 fil) are added to the anti-Ap-coated polystyro! plate (capture antibody selectively recognizes the C-terminal end of the antigen) in addition with a selective anti-AP-antibody conjugate (biotinylated detection antibody) and incubated overnight at 4°C in order to allow formation of the antibody-Amyloid-antibody-complex. The following day, a Streptavidine-Peroxidase-Conjugale is added, followed 30 minutes later by an addition of TMB/peroxide mixture, resulting in the conversion of the substrate into a colored product. This reaction is stopped by the addition of sulfuric acid (IM) and the color intensity is measured by means of photometry with an ELISA-reader with a 450 nm filter. Quantification of the Abeta content of the samples is obtained by comparing absorbance to a standard curve made with synthetic Api-42. In such a model at least 20% A642 lowering compared to untreated animals would be advantageous. While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all of the usual variations, adaptations and/or modifications as come within the scope of the following claims and their equivalents. All publications disclosed in the above specification are hereby incorporated by reference in fill!. Claims 1. A compound having the general Formula (I) they are attached a ring, either saturated or unsaturated, substituted or unsubstituted, having 3 to 6 C-atoms, and which may contain in the ring one or more heteroatoms from the group N, S or O, and which heteroatom may be identical or different if more than one heteroatom is present; R1, R2, R3 and R4 are independently selected from the group consisting of H; F; CI; Br; 1; CN; OH; C(0)N(R7R8); S(0)2R7; SOiNCRiRg); S{0)N(R7R8); N(R7)S(0),Rg; N(Rs)S(0)Rg; SCO^RT; N(R7)S(0)2N(R8R8a); SR7; N(R7Rg); N(R7)C(0)R8; N(R7)C{0)N(R8Rsa); N(R7)C(0)OR8; 0C(0)N(R7Rs); C(0)R7; substituted and unsubstituted C1-C4-alkyl and substituted and unsubstituted C1-C4-aikoxy, and wherein tlie substituents of both groups C1-C4-alkyl and C1-C4.alkoxy are selected from F, CI, Br, 1, CF3; R7, Rs, Rsa are independently selected from the group consisting of H; C1-C4-aikyl; heterocyclyl; and C3.7 cycloalkyl, wherein C1-C4-alkyl; heterocyclyl; and C3-7 cycloalkyl are optionally substituted with one or more substituents independently selected from the group consisting of F, CI, Br, i and CF3; Visa carboxy group -C(0)OH or a subslututed or unsubstituted tetrazole group; R9, and Rio are independently H, F, or CF3; and solvates, hydrates, esters, and pharmaceutical ly acceptable salts thereof. 2. A compound according to claim 1, wherein: AisOorNH; X is -CR5R6 wherein R5 and Re are independently selected from the group consisting of H, CH3, C2H5, i-C^Hy, n-C^Hv, i-C4H9, n-C4Hci, sec-C4Hi), and tert-C4H9; wherein in any of the alky! groups one or more H atoms optionally can be substituted with one or more substituents independemly selected from the group consisting of OH, F, CI, Br and !; or R5, R^ jointly form together with the carbon atom to which they are attached a cyclopropyl ring; Ri, R2, R3 and R4 are independently selected from the group consisting of H, OH, C(,^,alkyl, C(M)a!koxy, -NCCHj);, -SO2CH3, CN, OCF3, -C{0)CH3, OCH3, CF3, F, and CI; wherein said C(M)alkyl and C(M|alkoxy are optionally independetly substituted with one, two, or three substituents selected from the group consisting ofI,Br,F,andCl; Y is CO2H; and solvates, hydrates, esters, and pharmaceutical ly acceptable salts thereof. 3. A compound according to claim 2, wherein: X is -CR5R6 wherein R5 and R6 are H, CH3, C2H5, i-C^H,, n-CsH,, i-C4H9, n-C4H9, sec-C4H9, ortert-C4H9; and solvates, hydrates, esters, and pharmaceutically acceptable salts thereof. 4. A compound according to claim 3, wherein: Ri, and R2 are independently selected from the group consisting of CF3, H, F, CI, OCH3, C(M,alkyl, and CN. R3 and R4 are independently selected from the group consisting of H, CF3, F, and CI; R9 is H or F; Rio is H; and solvates, hydrates, esters, and pharmaceutical ly acceptable salts thereof. 5. A compound selected from the group consisting of 2-(5-(4-fluorophenoxy)-4'-trifluoromethyl-biphenyl-3-yl)-pentanoic acid; 2-(5-{phenoxy)-4'-tr!fluoromethyi-biphenyl-3-yl)-pentanoic acid and solvates, hydrates, esters, and pharmaceutically acceptable salts thereof.. 11. A pharmaceutical composition comprising a compound according to any of claims 1 to 6 in admixture with an inert carrier. 12. A process forthe preparation of acompound accordingto any of claims 1 to 6 with A being 0, comprising the following steps: a) treating a dihalidefluorobenzene compound, preferably dibromofluorobenzene, with a benzyl alcohol in the presence of an alkali metal hydride; b) treating the product with a suitable malonic ester derivative in the presence of an alkali metal hydride and a metal halide: c) treatment in an acidic solvent; d) coupling to a boronic acid derivative; e) removal of the benzyl ether piotecting group; f) converting the resulting hydroxycompound to a triflate and coupling to a boronic acid: g) optionally alkylating the resulting compound; h) removal of the benzyl protecting group; i) converting the phenol to a biphenyl ether: j) conversion of the ester to the acid. k) optional resolution of racemic mixture into enantiomers. 13. A process forthe preparation of acompound accordingto any of claims 1 to6with A being S, comprising the steps as laid out in claim 12, with the exception that the alkali metal hydride is replaced by a suitable base and the benzyl alcohol is replaced by an aryl thiol. 14. A process forthe preparation of acompoundaccordingtoany of claims I to6with A being NH, comprising the following steps: a) treating a dihalidefluorobenzene compound, preferably dibromofluorobenzene, with a benzyl alcohol in the presence of an alkali metal hydride; b) treating the product with a suitable malonic ester derivative in the presence of an alkali metal hydride and a metal halide; c) treatment in an acidic solvent; d) coupling to an aniline e) removal of the benzyl ether protecting group; f) converting the resulting hydroxycompound to a inflate and coupling to a boron ic acid; g) optionally alkylating the resulting product; h) conversion of the ester to the acid. i) optional resolution of racemic mixture into enantiomers. 15. Method for the preparation of a medicament comprising the steps of: a) preparing a compound according to any of claims 1 to 6; and b) formulation of a medicament containing said compound. 16. A method of treating a mammal for the modulation of y-secretase, which method comprises administering to said mammal a therapeutically effective amount of a compound according to any of claims 1 to 6. 17. A method of treating in a mammal a disease associated with an elevated level of AM2-production, which method comprises administering to said mammal a therapeutically effective amount of a compound according to any of claims 1 to 6. 18. A method of treating Alzheimer's disease in a mammal, which method comprises administering to said mammal a therapeutically effective amount of a compound according to any of claims 1 to 6. 19. A compound according to claim I as a substantially pure base. 20. A compound according to claim 1 in isolated form. |
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| Patent Number | 277899 | ||||||||||||||||||||||||||||||||||||||||||||||||
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| Indian Patent Application Number | 5661/CHENP/2008 | ||||||||||||||||||||||||||||||||||||||||||||||||
| PG Journal Number | 51/2016 | ||||||||||||||||||||||||||||||||||||||||||||||||
| Publication Date | 09-Dec-2016 | ||||||||||||||||||||||||||||||||||||||||||||||||
| Grant Date | 05-Dec-2016 | ||||||||||||||||||||||||||||||||||||||||||||||||
| Date of Filing | 21-Oct-2008 | ||||||||||||||||||||||||||||||||||||||||||||||||
| Name of Patentee | Janssen Pharmaceuticals, Inc | ||||||||||||||||||||||||||||||||||||||||||||||||
| Applicant Address | 1125 Trenton-Harbourton Road, Titusville NJ 08560 | ||||||||||||||||||||||||||||||||||||||||||||||||
Inventors:
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| PCT International Classification Number | C07C59/68 | ||||||||||||||||||||||||||||||||||||||||||||||||
| PCT International Application Number | PCT/US07/67039 | ||||||||||||||||||||||||||||||||||||||||||||||||
| PCT International Filing date | 2007-04-20 | ||||||||||||||||||||||||||||||||||||||||||||||||
PCT Conventions:
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