Indian Patents
Title of Invention

2-PHENOXY PROPIONIC ACID COMPOUNDS AS PPAR AGONISTS
Abstract This invention is concerned with 2-phenoxy propionic acid compounds as PPAR agonists of the formula wherein one of R5, R6 and R7 is and X1, X2, Y1 to Y4, R1 to R13 and m and n are as defined in the description, and to all enantiomers and pharmaceutically acceptable salts and/or esters thereof. The invention further relates to pharmaceutical compositions containing such compounds, to a process for their preparation and to their use for the treatment and/or prevention of diseases which are modulated by PPAR8 and/or PPARa agonists.
Full Text The present invention is concerned with novel 2-phenoxy propionic acid compounds of the formula
(Formula Removed)
and enantiomers and pharmaceutically acceptable salts and esters thereof, wherein X1 is O;
R1 is hydrogen or C1-7-alkyl; R2 is methyl; R3 is methyl; R4 and R8 independently from each other are hydrogen, C1-7-alkyl,
C3-7-cycloalkyl, halogen, C1-7-alkoxy- C1-7-alkyl, C2-7-alkenyl, C2-7-alkinyl,
fluoro-C1-7-alkyl, cyano-C1-7-alkyl or cyano; R5, R6 and R7 independently from each other are hydrogen, C1-7-alkyl,
C3-7-cycloalkyl, halogen, C1-7-alkoxy- C1-7-alkyl, C2-7-alkenyl, C2-7-alkinyl,
fluoro-C1-7-alkyl, cyano-C1-7-alkyl or cyano; and one of R5, R6 and R7 is
(Formula Removed)
wherein
X2 is (CH2)PNR9CO, or (CH2)PCONR9;
R9 is hydrogen, C1-7-alkyl, C3-7-cycloalkyl, fluoro-C1-7-alkyl, hydroxy-C2-7-alkyl, or C1-7-alkoxy-C2-7-alkyl;
Y1, Y2, Y3 and Y4 are N or C-R12 and 1 or 2 of Y1, Y2, Y3 and Y4 are N and the
other ones are C-R12; R10 is C1-7-alkyl, C3-7-cycloalkyl, fluoro-C1-7-alkyl, or C1-7-alkoxy-C1-7-alkyl; R11 is hydrogen, C1-7-alkyl, C1-7-alkoxy-C1-7-alkyl;
R12 independently from each other in each occurance is selected from hydrogen, C1-7-alkyl, C3-7-cycloalkyl, fluoro-C1-7-alkyl, C1-7-alkoxy-C1-7-alkyl, hydroxy-C1-7-alkyl, C1.7- alkylthio-C1-7-alkyl, carboxy-C1-7-alkoxy-C1-7-alkyl, carboxy, carboxy-C1-7-alkyl, mono- or di-C1-7-alkyl-amino-C1-7-alkyl, C1-7-alkanoyl-C1-7-alkyl, C2-7-alkenyl, and C2-7-alkinyl; R13 is unsubstituted phenyl or phenyl substituted with one to three groups selected from C1-7-alkyl, C1-7-alkoxy, halogen, fluoro-C1-7-alkyl, fluoro-C1-7-alkoxy and cyano; m is 0 or1, n is 0,1,2 or 3, and p is 0,1 or 2, and the sum of m, n and p is 1,2, 3 or
4; Compounds such as {5-methoxy-2-methyl-4-[6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethyl-sulfanyl]-phenoxy}-acetic acid have been described in PCT patent application WO 03/084916.
Compounds of formula I are useful as lipid modulators and insulin sensitizers. In particular, compounds of formula I are PPAR activators.
Peroxisome Proliferator Activated Receptors (PPARs) are members of the nuclear hormone receptor superfamily. The PPARs are ligand-activated transcription factors that regulate gene expression and control multiple metabolic pathways. Three subtypes have
pathways. Three subtypes have

been described which are PPARa, PPAR8 (also known as PPAR|3), and PPARy. PPAR6 is ubiquitously expressed. PPARa is predominantly expressed in the liver, kidney and heart. There are at least two major isoforms of PPARy. PPARyl is expressed in most tissues, and the longer isoform, PPARy2 is almost exclusively expressed in adipose tissue. The PPARs modulate a variety of physiological responses including regulation of glucose- and lipid- homeostasis and metabolism, energy balance, cell differentiation, inllammation and cardiovascular events.
Approximately half of all patients with coronary artery disease have low concentrations of plasma HDL cholesterol. The atheroprotective function of HDL was llrst highlighted almost 25 years ago and stimulated exploration of the genetic and environmental factors that influence HDL levels. The protective function of HDL comes from its role in a process termed reverse cholesterol transport. HDL mediates the removal of cholesterol from cells in peripheral tissues including those in the atherosclerotic lesions of the arterial wall. HDL then delivers its cholesterol to the liver and sterol-mctaboli/ing organs for conversion to bile and elimination. Data from the I ramingham study showed that HDL-C levels are predictive of coronary artery disease risk independently of LDL-C levels. The estimated age-adjusted prevalence among Americans age 20 and older who have HDL-C of less than 35 mg/dl is 16% (males) and 5.7% (females). A substantial increase of HDL-C is currently achieved by treatment with niacin in various formulations. However, the substantial side-effects limit the therapeutic potential of this approach.
As many as 90% of the 14 million diagnosed type 2 diabetic patients in the US are overweight or obese, and a high proportion of type 2 diabetic patients have abnormal concentrations of lipoproteins. The prevalence of total cholesterol > 240 mg/dl is 37% in diabetic men and 44% in women. The respective rates for LDL-C > 160 mg/dl are 31% and 44%, respectively, and for HDL-C
associated with multiple comorbidities including insulin resistance, dyslipidemia, hypertension, cndothelial dysfunction and inflammatory atherosclerosis.
First line treatment for dyslipidemia and diabetes generally involves a low-fat and low-glucose diet, exercise and weight loss. However, compliance can be moderate, and as the disease progresses, treatment of the various metabolic deficiencies becomes necessary with e.g. lipid-modulating agents such as statins and fibrates for dyslipidemia and hypoglycemic drugs, e.g. sulfonylureas or metformin for insulin resistance. A promising new class of drugs has recently been introduced that resensitizes patients to their own insulin (insulin sensitizers), thereby restoring blood glucose and triglyceride levels to normal, and in many cases, obviating or reducing the requirement for exogenous insulin. Pioglitazone (ActosIM) and rosiglitazone (AvandiaIM) belong to the thia/olidincdionc (T/D) class of PPARy-agonists and were the first in their class to be approved for NIDDM in several countries. These compounds, however, suffer from side effects, including rare but severe liver toxicily (as seen with troglitazone). They also increase body weight in patients. Therefore, new, more efficacious drugs with greater safely and lower side effects are urgently needed. Recent studies provide evidence that agonism of PPAR8 would result in compounds with enhanced therapeutic potential, i. c. such compounds should improve the lipid profile, with a superior effect on HDL-C raising compared to current treatments and with additional positive effects on normali/ation of insulin-levels (Oliver et al; Proc Nat Acad Sci USA 2001; 98: 5306-11). Recent observations also suggest that there is a independent PPARa mediated effect on insulin-sensit/ation in addition to its well known role in reducing triglycerides (Guerre-Millo el al; .1 Biol Chem 2000; 275: 16638-16642). Thus selective PPAR8 agonists or PPAR8 agonists with additional PPARa activity may show superior therapeutic efficacy without the side-effects such as the weight gain seen with PPARy agonists.
The novel compounds of the present invention exceed the compounds known in the art. inasmuch as they bind to and selectively activate PPAR8 or coactivate PPAR8 and PPARa simultaneously and very efficiently, and with much improved pharmacokinetic properties. Therefore, these compounds combine the anti-dyslipidemic and anti-glycemic effects of PPAR8 and PPARa activation with no effect on PPARy. Consequently, HDL cholesterol is increased, triglycerides lowered (= improved lipid profile) and plasma glucose and insulin arc reduced (= insulin sensitization). In addition, such compounds may also lower IT)L cholesterol, decrease blood pressure and counteract inflammatory atherosclerosis. Furthermore, such compounds may also be useful for treating inflammatory diseases such as rheumatoid arthritis, osteoarthritis, and psoriasis. Since

multiple facets of combined dyslipidemia and the T2D disease syndrome are addressed by PPAR5 selective agonists and PPAR8 and oc coagonists, they are expected to have an enhanced therapeutic potential compared to the compounds already known in the art.
Object of the present invention therefore is to provide compounds which must have the criteria mentioned above. Furthermore, the compounds of the present invention exhibit improved pharmacological properties compared to known compounds.
Unless otherwise indicated the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein.
The term "alkyl", alone or in combination with other groups, refers to a branched or straight-chain monovalent saturated aliphatic hydrocarbon radical of one to twenty carbon atoms, preferably one to sixteen carbon atoms, more preferably one to ten carbon atoms.
The term "lower alkyl" or "C|.7-alkyl", alone or in combination with other groups, refers to a branched or straight-chain monovalent alkyl radical of one to seven carbon atoms, preferably one to four carbon atoms. This term is further exemplified by such radicals as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl and the groups specifically exemplified herein.
The term "halogen" refers to fluorine, chlorine, bromine and iodine.
The term "fluoro-lower alkyl" or "fluoro-Ci.y-alkyl" refers to to lower alkyl groups which are mono- or multiply substituted with fluorine. Examples of fluoro-lower alkyl groups are e.g. -CE.i, -CHiCF}, -CH(CF3)2 and the groups specifically exemplified herein.
The term "alkoxy" refers to the group R'-O-, wherein R' is alkyl. The term "lower-alkoxy" or "C'i 7-alkoxy" refers to the group R'-O-, wherein R' is lower-alkyl. Examples of lower-alkoxy groups are e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy and hexyloxy. Preferred are the lower-alkoxy groups specifically exemplified herein.
The term "alkylthio" refers to the group R'-S-, wherein R' is alkyl. The term "lovver-alkyithio" or "C^y-alkylthio" refers to the group R'-S-, wherein R' is lowcr-alkyl. Examples of C,.7-alkylthio groups are e.g. methylthio or ethylthio. Preferred are the lower-alkylthio groups specifically exemplified herein.

The term "mono- or di-C|.7-alkyl-amino" refers to an amino group, which is mono-or disubstituted with C|_7-alkyl. A mono-Ci.y-alkyl-amino group includes for example methylamino or ethylamino. The term "di-C|.7-aIkyl-amino" includes for example dimcthylamino, diethylamino or ethylmethylamino. Preferred are the mono- or di-C|.7-alkylamino groups specifically exemplified herein.
The term "carboxy-lower alky!" or "carboxy-C|-7-alkyl" refers to to lower alkyl groups which arc mono- or multiply substituted with a carboxy group (-COOH). Examples of carboxy-lower alkyl groups are e.g. -CH2-COOH (carboxymethyl), -(CH2)2-CX)OI I (carboxyclhyl) and the groups specifically exemplified herein.
The term "alkanoyl" refers to the group R'-CO-, wherein R' is alkyl. The term "lowcr-alkanoyl" or "Ci-7-alkanoyl" refers to the group R'-O-, wherein R' is lower-alkyl. Examples of lower-alkanoyl groups are e.g. ethanoyl (acetyl) or propionyl. Preferred are the lowcr-alkoxy groups specifically exemplified herein.
The term "lower alkenyl" or "C2-7-alkenyl", alone or in combination, signifies a straight-chain or branched hydrocarbon residue comprising an olefinic bond and up to 7, preferably up to 6, particularly preferred up to 4 carbon atoms. Examples of alkenyl groups are ethenyl, l-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl and isobutcnyl. A preferred example is 2-propenyl.
The term "lower alkinyl" or "C2-7-alkinyl", alone or in combination, signifies a straight-chain or branched hydrocarbon residue comprising a triple bond and up to 7, preferably up to 6. particularly preferred up to 4 carbon atoms. Examples of alkinyl groups arc ethinyl, I -propinyl, or 2-propinyl.
The term "cycloalkyl" or "C3.7-cycloalkyr denotes a saturated carbocyclic group containing from 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
The term "aryl" relates to the phenyl or naphthyl group, preferably the phenyl group, which can optionally be mono- or multiply-substituted, particularly mono- or disubstituted by halogen, hydroxy, CM, CF3, NO2, NH2, N(H, lower-alkyl), N(lower-alkyl)2, carboxy, aminocarbonyl, lower-alkyl, lower fluoroalkyl, lower-alkoxy, lower fluoroalkoxy, aryl and/or aryloxy. Preferred substituents are halogen, CI;3, lower-alkyl, and/or lower-alkoxy. Preferred are the specifically exemplified aryl groups.
The term "hetcroaryl" refers to an aromatic 5- or 6-membered ring which can

comprise I, 2 or 3 atoms selected from nitrogen, oxygen and/or sulphur such as furyl, pyridyl, 1,2-, 1,3- and 1,4-diazinyl, thienyl, isoxazolyl, oxazolyl, imidazolyl, or pyrrolyl. The term "heteroaryl" further refers to bicyclic aromatic groups comprising two 5- or 6-mcmbercd rings, in which one or both rings can contain 1, 2 or 3 atoms selected from nitrogen, oxygen or sulphur such as e.g. indole or quinoline, or partially hydrogenated bicyclic aromatic groups such as e.g. indolinyl. A heteroaryl group may have a substitution pattern as described earlier in connection with the term "aryl". Preferred heteroaryl groups are e.g. thienyl and furyl which can optionally be substituted as described above, preferably with halogen, CF;3, lower-alkyl and/or lower-alkoxy.
The term "protecting group" refers to groups such as e.g. acyl, alkoxycarbonyl,
aryloxycarbonyl, ben/yl, silyl, or imine-derivatives, which are used to temporarily block
the reactivity of functional groups. Well known protecting groups are e.g. t-
butyloxycarbonyl, ben/yloxycarbonyl, fluorenylmethyloxycarbonyl or
diphenylmethylcnc which can be used for the protection of amino groups, or lower-alkyl-. (.i-trimcthylsilylethyl- and p-trichloroethyl-esters, which can be used for the protection of carboxy groups. Protecting groups which can be used for the protection of hydroxy groups arc e.g. ben/yl, trimethylsilyl or /er/-butyldimethylsilyl.
"Isomcrs" are compounds that have identical molecular formulae but that differ in the nature or the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomcrs that differ in the arrangement of their atoms in space are termed •"stereoisomers". Stereoisomers that are not mirror images of one another are termed "diastereoisomcrs", and stereoisomers that are non-superimposable mirror images arc termed "enantiomcrs", or sometimes optical isomers. A carbon atom bonded to four nonidcntical substiluents is termed a "chiral center".
The term "pharmaceutically acceptable salts" embraces salts of the compounds of formula (I) with pharmaceutically acceptable bases such as alkali salts, e.g. Na- and K-salts, alkaline earth salts, e.g. Ca- and Mg-salts, and ammonium or substituted ammonium salts, such as e.g. trimethylammonium salts. The term "pharmaceutically acceptable salts" also relates to such salts.
The compounds of formula (I) can also be solvated, e.g. hydrated. The solvation can be effected in the course of the manufacturing process or can take place e.g. as a consequence of hygroscopic properties of an initially anhydrous compound of formula (I) (hydration). The term pharmaceutically acceptable salts also includes pharmaceutically acceptable solvates.

The term "pliannaeeutically acceptable esters" embraces derivatives of the compounds of formula (I), in which a carboxy group has been converted to an ester. Lower-alkyl. hydroxy-lower-alkyl, lower-alkoxy-lower-alkyl, amino-lower-alkyl, mono-or di-lower-alkyl-amino-lower-alkyl, morpholino-lower-alkyl, pyrrolidino-lower-alkyl, piperidino-lowcr-alkyl, pipera/ino-lower-alkyl, lower-alkyl-piperazino-lower-alkyl and aralkyl esters are examples of suitable esters. The methyl, ethyl, propyl, butyl and benzyl esters arc preferred esters. The methyl and ethyl esters are especially preferred. The term "pharmacculically acceptable esters" furthermore embraces compounds of formula (I) in which hydroxy groups have been converted to the corresponding esters with inorganic or organic acids such as, nitric acid, sulphuric acid, phosphoric acid, citric acid, formic acid, inaleic acid, acetic acid, succinic acid, tartaric acid, methanesulphonic acid, p-tolucnesulphonic acid and the like, which are non toxic to living organisms.
In detail, the present invention relates to compounds of formula I
(Figure Remove)
and enanliomers and pharmaceutically acceptable salts and esters thereof, wherein X1 isO, S, (11: R1 is hydrogen or C|.7-alkyl;
or, if X1 is CM2, R2 is hydrogen, C|.7-alkyl or C|.7-alkoxy;
R' is hydrogen or CV7-alkyl;
R1 and R* independently from each other are hydrogen, Ci-7-alkyl, Cjy-cycloalkyl, halogen, C|.7-alkoxy- Ci.7-alkyl, C2-7-alkenyl, C2-7-alkinyl, lluoro-('|.7-alkyl, cyano-C|.7-alkyl orcyano;

R\ R6 and R' independently from each other are hydrogen, C|.7-alkyl, (.\7-cycloalkyl, halogen, C|.7-alkoxy- Ci.7-alkyl, C2_7-alkenyl, C2-7-alkinyl, nuoro-('i.7-alkyl, cyano-Ci .7-alkyl orcyano;
wherein
X" is S, O, NR", (CH2)pNR9CO, or (CH2),.CONR9,
Rg is hydrogen, C|_7-alkyl, Cvrcycloalkyl, fluoro-C|.7-alkyl, hydroxy-C2.7-alkyl, or C| 7-alkoxy-C2.7-alkyl;
Y1, Y2, Y' and Y4 are N or C-R12 and 1 or 2 of Y1, Y2, Y3 and Y4 are N and the other ones are C-R12;
Rlu is C| 7-alkyl. C.j.7-cycloalkyl, fluoro-C|.7-alkyl, or Ci_7-alkoxy-C|.7-alkyl; R" is hydrogen, Ci-7-alkyl, C|.7-alkoxy-C|.7-alkyl;
R12 independently from each other in each occurance is selected from hydrogen, Ci-7-alkyl, C.3-7-cycloalkyl, fluoro-Ci-7-alkyl, Ci-7-alkoxy-Ci-7-alkyl, hydroxy-Ci 7-alkyl, C|.7- alkylthio-Ci_7-alkyl, carboxy-Ci-7-alkoxy-C|.7-alkyl, carboxy, carboxy-C|.7-alkyl, mono- or di-C|.7-alkyl-amino-C|.7-alkyl, C'i-7-alkanoyl-C|.7-alkyl, C2_7-alkenyl, and C2-7-alkinyl;
Rl! is aryl or heteroaryl;
m is 0 orl, n is 0, 1,2 or 3, and p is 0, 1 or 2, and the sum of m, n and p is I, 2, 3 or
4;
provided that compounds of formula 1 are excluded, wherein X1 is (), R2 and RJ arc hydrogen, R6 is equal to

Preferred compounds of formula I of the present invention are compounds, wherein X' is NR9, (CI I2)|>NR4CO or (CH2)PCONR1),
R1' is hydrogen, C|.7-alkyl, Cvy-cycloalkyl, fluoro-C|_7-alkyl, hydroxy-C2-7-alkyl, or C|.7-alkoxy-C2-7-alkyl; and p is 0, I or 2.
Especially preferred are those compounds of formula I in accordance with the present invention, wherein X' is NR , and R9 is hydrogen, Ci-7-alkyl, C3.7-cycloalkyl, fluoro-C|_7-alkyl, hydroxy-C2-7-alkyl, or C|.7-alkoxy-C2-7-alkyl.
Also preferred arc compounds of formula I, wherein X2 is (CH2)pNRyCO, or (CI b)i>CONR', R' is hydrogen, Ci-7-alkyl, C3_7-cycloalkyl, fluoro-C|-7-alkyl, hydroxy-C^-/-alkyl, or Ci-7-alkoxy-C2^-alkyl, and p is 0, I or 2.
Preferred examples of such compounds include the following:
2-methyl-2-(3-{mcthyl-|2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethyl]-
carbamoyl}-phenoxy)-propionic acid,
2-|3-({2-|4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-acetyl} -methyl-
amino)-phenoxy|-2-mcthyl-propionic acid,
2-inethyl-2-|3-(melhyl-{2-|2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetyl}-
amino)-5-tritlLioromethyl-phenoxy|-propionic acid,
2-|4-({|4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbonyl]-amino}-
methyl)-phenoxy|-2-mcthyl-propionic acid, and
2-methyl-2-(4-{|2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylcarbamoyl]-methyl}-phcnoxy)-propionic acid.
Further preferred examples of such compounds are the following:
2-|3-chloro-4-({|4-lrinuoromethyl-2-(4-trittuoromethyl-phenyl)-pyrimidine-5-carbonyr|-
amino}-methyl)-phenoxy|-2-methyl-propionic acid,
2-mcthyl-2-|4-({|4-trinuorornethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-
earbonyl|-amino| -methyl)-phenoxy]-propionic acid; and

2-(4-{|4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylcarbamoyr]-methyl}-phcnoxy)-2-mcthyl-propionic acid.
Compounds of formula I, wherein X2 is NR9, (CH2)pNR9CO or (CH2)i>CONR9 and R is C|.7-alkyl, are more preferred.
Examples of especially preferred compounds, wherein X is NR , (CH2)pNR CO or (CII2)pCONR9, are the following:
(2-(3-inethoxy-propyl)-4-{methyl-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-
ylinethyl|-amino}-phenoxy)-acetic acid,
|rac|-|2-methyl-4-(inethyl-{ l-|2-methyl-6-(3-trifluoromethyl-phenyl)-pyridin-3-yl|-
rnilylj-amino)-phenoxy (-acetic acid,
(4-{|6-(4-chloro-phenyl)-pyridin-3-ylmethyl]-methyl-amino}-2-methyl-phenoxy)-acetic acid,
2-methyl-2-(3-(mcthyl-{2-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl|-acetyl}-
amino)-phcnoxy|-propionic acid, and
(4-{|4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethyl]-methyl-amino}-2-mcthyl-phcnoxy)-acctic acid.
l;urthcrmore. compounds of formula I in accordance with the present invention arc preferred, wherein X1 and X2 are O and R' is C|.7-alkyl, with those compounds of formula I, wherein R2 and R3 are C|_7-alkyl, being especially preferred.
I Examples of such compounds are the following:
2-mcthyl-2-{2-melhyl-4-(2-methyl-6-(3-trifluoromethyl-phenyl)-pyridin-3-yliTiethoxy|-
phcnoxy}-propionic acid,
2-methyl-2-{2-methyl-4-|6-(4-trifluoromethoxy-phenyl)-pyridin-3-ylmethoxy|-
phcnoxyj-propionic acid, and
2-{4-|4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxyJ-2-methyl-phenoxy}-2-mcthyl-propionic acid.
Further preferred examples of such kind of compounds include
2-methyl-2-{2-methyl-4-|2-methyl-6-(4-trifluoromethoxy-phenyl)-pyridin-3-
vlmethoxy|-phenoxy}-propionic acid,
2-{4-|4-cyclopropyl-2-(3-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-2-methyl-
phenoxy}-2-mcthyl-propionic acid, and

2-{4-|4-(2-metho\y-cthyl)-6-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yimclhoxy|-2-mcthyl-phenoxy}-2-methyl-propionicacid.
Furthermore, the following compounds are examples therof:
2-{4-|2-cyclopropyl-6-(4-trifluoromethoxy-phenyl)-pyridin-3-ylmethoxy]-2-methyl-
phcnoxy}-2-mcthyl-propionic acid,
2-(4-|4-methoxymethyl-6-methyl-2-(3-trifluoromethyl-phenyl)-pyrimidin-5-yImethoxyJ-
2-niethy l-phcnoxy} -2-methy l-propionic acid,
2-{4-|2-cyclopropyl-6-(4-trinuoromethoxy-phenyl)-4-trifluoromethyl-pyridin-3-
ylmcthoxy|-2-methyl-phenoxy}-2-methyl-propionic acid,
2-{4-|4-mcthoxymethyl-2-(4-trifluoromethoxy-phenyl)-pyrimidin-5-ylmethoxy]-2-
mcthyl-phenoxy}-2-methyl-propionic acid,
2-{4-|2-cyclopropyl-6-(4-trinuoromethoxy-phenyl)-4-trifluoromethyl-pyridin-3-
ylmethoxy|-2-methyl-phenoxy}-2-methyl-propionic acid, and
2-{4-|4-methoxymethyl-2-(4-trifiuoromethoxy-phenyl)-pyrimidin-5-ylmethoxyl-2-mcthyl-phenoxy}-2-mcthyl-propionic acid.
Further preferred compounds of formula I of the present invention are those, wherein X1 and X~ are O and m is I.
The following compounds, wherein X1 and X2 are O and m is I, are especially preferred:
|rac|-(4-{l-|4-(:yclopropyl-2-(4-tri(luoromethyl-phenyl)-pyrimidin-5-yl]-ethoxy}-2-
methyl-phenoxy)-acetic acid, and
|rac|-(4-{l-|4-Cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-butoxy}-2-methyl-phenoxy)-acelic acid.
Also preferred are compounds of formula I according the present invention, wherein X1 is S.
Examples of such compounds are the following:
|rac|-(2-methyl-4-| l-|2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl|-ethoxy}-
phcnylsulfanyl)-acetic acid, and
| rac |-(2-methy 1-4- j I -| 2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yI]-butoxy} -phcnylsulfanyl)-acetic acid.
l;urther preferred compounds of formula I according to the present invention are those, wherein X1 is O, X* is S and m is 1.

The following compounds, wherein X1 is O, X2 is S and m is 1, arc especially preferred:
|rac|-(2-methyl-4-{ l-|2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-
ethylsullanyl}-phcnoxy)-acctic acid, and
|rac|-(4-{l-[4-Cyclopropyl-2-(4-trinuoromethyl-phenyl)-pyriiTiidin-5-ylJ-ethylsulfanyl}-2-methyl-phcnoxy)-acetic acid.
Compounds of formula I, wherein R13 is aryl, are preferred. More preferred arc those compounds of formula I, wherein R13 is unsubstituted phenyl or phenyl substituted with one to three groups selected from Ci.y-alkyl, C|.7-alkoxy, halogen, fluoro-Ci-7-alkyl, lluoro-C|_7-alkoxy and cyano, with those compounds, wherein R13 is C^-alkyl, C|-?-alkoxy, halogen, fluoro-C|_7-alkyl or cyano, being more preferred, and with those compounds, wherein R13 is phenyl substituted with halogen or fluoro-C|_7-alkyl, being particularly preferred. Especially preferred are those compounds, wherein R13 is 4-trifluoromethylphenyl. Also preferred are those compounds, wherein R13 is 4-trifluoromcthoxy phenyl.
Especially preferred are furthermore compounds of formula 1, wherein R1 is hydrogen.
Preferred compounds of formula I of the present invention are those, wherein R6 is
These compounds have the formula 1-A:



(Figure Remove)
I lowcver, compounds of formula I-A, wherein X1 is O, R2 and R3 are hydrogen, X2 is () or S and m is 0, arc excluded.

Furthermore, compounds of formula I are preferred, wherein R5or R7 is
These compounds have the formula I-B or I-C:

(Figure Remove)
The integer m is 0 or 1, the integer n is 0, 1, 2 or 3 and the integer p is 0, I or 2, provided that the sum of m, n and p is 1, 2, 3 or 4. Especially preferred are compounds of formula I, wherein the sum of m, n and p is 1.
Y1, Y2, Y3 and Y'1 signify N or C-R12, provided that 1 or 2 of Y1, Y2, Y3 and Y4 arc N and the other ones are C-R12. R12 independently from each other in each occurance is selected from hydrogen, C|.7-alkyl, C3_7-cycloalkyl, fluoro-Ci.7-alkyl, Ci.7-alkoxy-Ci-7-alkyl, hydroxy-C i 7-alkyl, C|_7- alkylthio-C|.7-alkyl, carboxy-Ci.7-alkoxy-Ci-7-alkyl, carhoxy, carhoxy-C'i-7-alkyl, mono- or di-Ci.7-alkyl-amino-Ci-7-alkyl, Ci_7-alkanoyl-C|_7-alkyl. (Y7-alkcnyl, and C2-7-alkinyl. Preferably, R12 independently from each other in each occurancc is selected from hydrogen, C|.7-alkyl, C3-7-cycloalkyl, fluoro-Ci-7-alkyl, Ci7-alkoxy-("i 7-alkyl, hydroxy-C|.7-alkyl, and C|.7- alkylthio-Ci_7-alkyl. More preferably, R1" is selected from hydrogen, C|.7-alkyl, and C3.7-cycloalkyl.
Preferred compounds of the present invention are for example those, wherein I of Y , Y", Y and Y is N and the other ones are C-R12, thus meaning compounds containing a pyridyl group.
Especially preferred are those compounds of formula I, wherein Y1 is N and Y2, YJ and Y1 are C-R12, c. g. compounds of formula I containing the group

(Figure Remove)


Further preferred compounds of the present invention are those, wherein 2 of Y1, Y\ Yi and Y4 arc N and the other ones are C-R12, thus meaning compounds containing a pyra/inyl group or a pyrimidinyl group or a pyridazinyl group.
Especially preferred are compounds of formula I, wherein Y1 and Y4 are N and Y2 1 are C-R12, c. g. compounds of formula I containing the pyrimidinyl group
and Y
Also preferred arc compounds of formula I, wherein Y1 and Y3 are N and Y2 and Y4 arc C-R12. e. g. compounds of formula 1 containing the pyrazinyl group
(Figure Remove)
R12 is preferably hydrogen, C|.7-alkyl, or C3.7-cycloalkyl.
Examples of preferred compounds of formula 1 are the following:
(2-(3-mcthoxy-propyl)-4-{methyl-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-
ylmethyl|-aminoj-phenoxy)-acetic acid,
(2-(3-methoxy-propyl)-4-{methyl-|2-methyl-6-(3-trifluoromethyl-phenyl)-pyridin-3-
ylmcthyl|-aminoj-phenoxy)-acetic acid,
|rac|-|2-(3-methoxy-propyl)-4-(methyl-{l-[2-methyl-6-(3-trifluoromethyl-phenyl)-
pyridin-3-yl |-ethyl} -amino)-phenoxy]-acetic acid,
|rac|-|2-(3-methoxy-propyl)-4-(methyl-{l-[2-methyl-6-(3-trifluoromethyl-phenyl)-
pyridin-3-yl|-butyl!-amino)-phenoxy]-acetic acid,
|rac|-|2-methyl-4-(methyl-{l-|2-methyl-6-(3-trifluoromethyl-phenyl)-pyridin-3-yl]-
hutyl}-amino)-phcnoxy]-acetic acid,
|rac|-(4-{mcthyl-|2-methyl-6-(4-trinuoromethyl-phenyl)-pyridin-3-ylmethyl|-amino}-2-
triiluoromcthyl-phenoxy)-acetic acid,
(2,6-dimcthyl-4-!mcthyl-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethyr|-
amino(-phenoxy)-acctic acid,
2-mcthyl-2-{2-mcthyl-4-|2-methyl-6-(3-tritluoromethyl-phenyl)-pyridin-3-ylmethoxy|-
phenoxyj-propionic acid,
2-mcthyl-2-{2-methy l-4-| 6-(4-trifluoroinethyl-phenyl)-pyridin-3-y!methoxy]-phcnoxy}-
propionic acid,
2-mcthyl-2-[2-mcthyl-4-[6-(4-trifluoromethoxy-phenyl)-pyridin-3-ylmethoxy]-
phcnoxyj-propionic acid,
|rac|-|2-methyl-4-(mcthyl-{I-|2-methyl-6-(3-trifluoromethyl-phenyl)-pyridin-3-yl]-
propyl}-amino)-phcnoxy|-acetic acid,
(4-{|6-(4-chloro-phcnyl)-pyridin-3-ylmethyl]-methyl-amino}-2-methyl-phenoxy)-acetic acid,
(2-methyl-4-{mcthyl-|6-(4-trifluoromethoxy-phenyl)-pyridin-3-ylmethyI]-amino}-
phcnoxy)-acctic acid,
(2-(3-mcthoxy-propyl)-4-{methyl-f6-(4-trifluoromethoxy-phenyl)-pyridin-3-ylmethyl|-
amino}-phcnoxy)-acetic acid,
(2-mclhyl-4-{mcthyl-[6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethyl]-amino}-
phcnoxy)-acctic acid,
(2-(3-mcthoxy-propyl)-4-{methyl-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yImethyl|-
amino}-phenoxy)-acctic acid,
| rac |-(2-mcthyl-4- {1 -[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl |-
ethylsulfanyl}-phcnoxy)-acetic acid,
|rac|-(2-methyl-4-{ l-|2-mcthyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-
propylsulfanyl }-phcnoxy)-acetic acid,
|rac|-(2-methyl-4-{ l-|2-methyl-6-(3-trifluoromethyl-phenyl)-pyridin-3-yl]-
cthylsulfanyl}-phcnoxy)-acetic acid,
|rac|-(2-mcthyl-4-| l-|2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethoxy}-
phcnylsulfanyl)-acctic acid.

|rac|-(2-methyl-4-{ l-['2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-butoxy}-
phcnylsulfanyl)-acetic acid,
|rac|-(2-methyl-4-{ l-|2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylJ-
butylsulfanyl}-phenoxy)-acetic acid,
|rac|-(4-{cyclopcntyl-(2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-
mcthylsulfanyl}-2-mcthy l-phenoxy)-acetic acid,
2-{4-|6-(4-fluoro-3-trinuoromethyl-phenyl)-2-methyl-pyridin-3-ylmethoxy]-2-methyl-
phcnoxy} -2-mcthy l-propionic acid,
|rac|-2-mcthyl-2-(2-methyl-4-{l-[2-methyl-6-(3-trifluoromethyI-phenyl)-pyridin-3-yl]-
cthoxy}-phcnoxy)-propionic acid,
2-mcthy 1-2-j 3-(mclhy I- {2-|2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-y I ]-acetyl}-
amino)-phenoxy (-propionic acid,
(4-{|4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethyl]-methyl-amino}-
2-melhyl-phenoxy)-acctic acid,
|rac|-(4-{ l-|4-Cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-ethylsuIfanyl}-
2-mcthyl-phcnoxy)-acclic acid,
|rac|-(4-{ l-|4-Cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yI]-ethoxy}-2-
mcthyl-phenoxy)-acciic acid,
|rac|-(4-{ l-|4-Cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-butylsulfanyl}-
2-mcthyl-phenoxy)-acctic acid,
|rac|-(4-{ l-|4-Cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-butoxy}-2-
mcthyl-phcnoxy)-acctic acid,
2-{4-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-2-methyl-
phcnoxy} -2-mcthy l-propionic acid, and
(2-mcthy 1-4- {methyl-| 5-(4-trifluoromethyl-phenyl)-pyrazin-2-ylmethyl]-amino}-phcnoxyj-acctic acid.
l-'urther examples of preferred compounds include the following:
2-mcthyl-2-{2-methyl-4-|2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethoxyJ-
phenoxyj-propionic acid,
[rac|-2-methyl-2-(2-methyl-4-{l-l2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yrj-
butoxy}-phcnoxy)-propionic acid,
| rac |-2-methy l-2-(2-methyl-4-{ 1 -[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-
propoxy} -phenoxy )-propionic acid,
|rac|-2-methyl-2-(2-mcthyl-4-{l-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl|-
ethoxy}-phenoxy)-propionic acid,
2-{4-|6-(3-nuoro-4-trifluoromethyl-phenyl)-2-methyl-pyridin-3-ylmethoxyJ-2-methyl-

phenoxy}-2-methyl-propionic acid,
2-mcthyl-2-{2-mclhyl-4-|2-methyl-6-(4-trif]uoromethoxy-phenyl)-pyridin-3-
ylmcthoxy|-phcnoxy}-propionic acid,
2-{4-|2-cyclopropyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-y!methoxyj-2-methyl-
phenoxy}-2-mcthyl-propionic acid,
|rac|-2-mcthyl-2-(2-methyl-4-{ l-|2-methyl-6-(3-trifluoromethyl-phenyl)-pyridin-3-yl|-
butoxy}-phenoxy)-propionic acid,
2-[4-[4-cycIopropyl-2-(3-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-2-methyl-
phcnoxy}-2-mcthyl-propionic acid,
2-methyl-2-(2-mcthyl-4-{2-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl|-
cthoxy j -phcnoxy )-propionic acid,
2-mcthyl-2-{2-mcthyl-4-|6-(4-trifluoromethyl-phenyl)-pyridazin-3-ylmethoxy]-
phenoxyj-propionic acid,
2-(4-|2-methoxymethyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethoxy]-2-mcthyl-
phcnoxy}-2-methyl-propionic acid,
|rac|-(2-methyl-4-{ I-| 2-methy l-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-butoxy}-
phcnoxy)-acctic acid,
|rac|-(2-methyl-4-{ l-|2-methyl-6-(3-trifluoromethyl-phenyl)-pyridin-3-yl]-ethoxy}-
phenoxy)-acctic acid,
|rac|-(2-mcthyl-4-{ l-|2-methyl-6-(3-trifluoromethyl-phenyl)-pyridin-3-yl]-butoxy}-
phenoxy)-acctic acid,
|rac|-(2-mcthyl-4-| 1-| 2-methy l-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-propoxy}-
phcnoxy)-acctic acid,
|rac|-(2-mcthyl-4-| l-|2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-cthoxy}-
phcnoxy)-acctic acid,
2-{4-|2-dimcthylaminomcthyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethoxy|-2-
mcthyl-phcnoxyj-2-mcthyl-propionic acid,
2-mcthyl-2-{ 3-[(methyl-{2-| 2-methyl-6-(4-trinuoromethyl-phenyl)-pyridin-3-yl|-
acctyl J -amino)-mcthyl |-phenoxy}-propionic acid,
2-| 3-( {14-cyclopropy l-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbony l]-methy I-
amino}-methyl)-phenoxy|-2-iTiethyl-propionic acid,
2-mcthyl-2-[ 3-( {methyl-| 2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine-3-carbonyl |-
amino}-mclhyl)-phcnoxy|-propionic acid,
2-incthyl-2-| 3-(2- {2-| 2-methy l-6-(4-trifluoromethyl-phenyl)-pyridin-3-y l]-acetylamino} -
cthyl)-phcnoxy|-propionic acid,
2-methy l-2-| 3-(2- {12-mcthyl-6-(4-tri fluoromethyl-phenyl)-pyridine-3-carbony I |-amino} -
cthyl)-phcnoxy|-propionic acid.

2-|3-(2-[|4-cycl()propyl-2-(4-triiluoromethyl-phenyl)-pyrimidine-5-carbonyl]-amino}-
elhyl)-phenoxy|-2-mcthyl-propionic acid,
2-|3-(j2-|4-hutyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-acetyl}-methyl-amino)-
phcnoxy ]-2-methyl-propionic acid,
2-mcthyl-2-(3-{methyl-[2-methyl-6-(4-trifIuoromethyl-phenyl)-pyridin-3-ylmethyl]-
carbamoyl} -phcnoxy )-propionic acid,
3-{4-|4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-2-methyl-
phcnylj-propionic acid,
3-{4-|4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-3-ethoxy-
phcnyl}-propionic acid,
3-!3-cthoxy-4-|2-mcthyl-6-(4-trinuoromethyl-phenyl)-pyridin-3-ylmethoxy]-phcnyl}-
propionic acid,
3-!2-methyl-4-|5-(4-trifluoromethyl-phenyl)-pyrimidin-2-ylmethoxy]-phenyl}-propionic acid,
2-|3-({2-|4-cyclopropyi-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-acetyl}-methyl-
ainino)-phenoxy|-2-methyl-propionic acid,
2-|3-(2-{2-|4-cyclopropyl-2-(4-trifIuoromethyl-phenyl)-pyrimidin-5-yl]-acetylamino}-
cthyl)-phenoxy|-2-mcthyl-propionic acid,
2-[3-({|4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbonyl]-amino}-
mcthyl)-phcnoxy|-2-mcthyl-propionic acid,
2-mclhyl-2-f3-({2-|2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetylamino}-
mcthyl)-phcnoxy|-propionic acid,
2-|3-({2-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-acetylamino}-
mcthyl)-phenoxy]-2-methyl-propionic acid,
2-mcthyl-2-|3-({|2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine-3-carbonyrj-amino}-
mcthyl)-phcnoxy|-propionic acid,
2-mcthyl-2-(2-mcthyl-5-{2-[2-methyl-6-(4-trifIuoromethyl-phenyI)-pyridin-3-yl|-
cthoxy} -phcnoxy )-propionic acid,
2-methy 1-2- {2-mcthy l-5-| 2-methyl-6-(4-trif1uoromethyl-phenyl)-pyridin-3-ylmethoxy|-
phcnoxy}-propionic acid,
|rac|-3-(2-methyl-4-{I-|2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethoxy}-
phcnyl)-propionic acid,
3- {3-methyl-4-| 2-methy l-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethoxy]-phenyl}-
propionic acid,
|rac|-3-(3-methyl-4-{I-|2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethoxy}-
phenyl)-propionic acid,
2-|3-({2-|4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-acetyl} -methyl-

amino)-5-trinuoromethyl-phenoxyj-2-methyl-propionic acid,
2-melhyl-2-[3-(methyl-{2-[2-rnethyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl|-acetyl}-
amino)-5-trinuoromcthyl-phenoxy|-propionic acid,
2-|4-(j2-|4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yI]-acetylamino}-
mcthyI)-phenoxy|-2-rnethyl-propionic acid,
2-mcthyl-2-|4-({2-i2-mcthyl-6-(4-trifluoromethyI-phenyl)-pyridin-3-yl]-acetylamino}-
mcthyl)-phenoxy|-propionic acid,
2-|4-({|4-cyclopropyl-2-(4-trinuoromethyl-phenyl)-pyrimidine-5-carbonylJ-amino}-
mcthyl)-phcnoxy|-2-mcthyl-propionic acid,
2-mcthyl-2-|4-({|2-mcthyl-6-(4-trifluoromethyl-phenyl)-pyridine-3-carbonyl|-amino}-
methyl)-phenoxy|-propionic acid,
2-mcthyl-2-(3-{mcthyl-|4-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethyl]-
carbamoy I} -phenoxy )-propionic acid,
2-(3-{|4-(2-methoxy-cthyl)-6-methyl-2-(4-trinuoromethyl-phenyl)-pyrimidin-5-
ylmcthyl|-melhyl-carbamoyl}-phenoxy)-2-methyl-propionic acid,
2-mclhyl-2-{4-[(mclhyl-{2-|2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylj-
acclyl}-amino)-mcthyl|-phcnoxy}-propionic acid,
2-methyl-2-|4-(2-{|2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine-3-carbonyl]-amino}-
cthyl)-phenoxy |-propionic acid,
2-|4-(2-{|4-cyclopropyl-2-(4-trifluoromethyI-phenyl)-pyrimidine-5-carbonyl]-amino}-
cthyl)-phcnoxy |-2-mcthyl-propionic acid,
2-mcthyl-2-|4-(2-{2-|2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetylamino}-
cthyl)-phcnoxy|-propionic acid,
2-|4-(2-{2-|4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl|-acetylamino}-
cthyl)-phcnoxy|-2-mcthyl-propionic acid.
2-methyl-2-{4-|2-(mcthyl-{2-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl|-
acctyl}-amino)-cthyl|-phenoxy}-propionic acid,
2-mcthyl-2-|4-(2-{mcthyl-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine-3-carbonyl|-
amino}-cthyl)-phcnoxy|-propionic acid,
2-{2-mcthoxy-4-i2-mcthyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethoxy|-
phcnoxy j -2-methyl-propionic acid,
|rac|-2-(2-mcthoxy-4-{l-[2-methyl-6-(4-trifluoromethyI-phenyl)-pyridin-3-yl|-ethoxy}-
phcnoxy)-2-mcthyl-propionic acid,
3-{2-melhoxy-4-|2-methyl-6-(4-triiluoromethyl-phenyl)-pyridin-3-ylmethoxy|-phenyl}-
propionic acid,
2-|3-mcthoxy-5-(2-{[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine-3-carbonyl]-
amino}-cthyl)-phcnoxy|-2-methyl-propionic acid,

2-|3-(2-{|4-cycl()propyl-2-(4-trifIuoromethyl-phenyl)-pyrimidine-5-carbonyl|-amino}-
ethyl)-5-methoxy-phenoxy|-2-methyl-propionic acid,
2-|3-(2-{2-|4-cyclopropyl-2-(4-trifIuoromethyl-phenyl)-pyrimidin-5-yl]-acetylamino}-
ethyl)-5-mcthoxy-phenoxy)-2-methyl-propionic acid,
2-| 3-mcthoxy-5-(2- {2-| 2-methy l-6-(4-trifluoromethyl-phenyl)-pyridin-3-y 1]-
acctylamino}-cthyl)-phenoxy]-2-methyl-propionic acid,
2-mcthyl-2-|2-mcthyl-4-({[2-methyl-6-(4-triiluoromethyl-phenyl)-pyridine-3-carbonyl|-
amino}-methyl)-phcnoxy]-propionic acid,
2-|4-({|4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbonyl]-amino}-
methyl)-2-methyl-phenoxy|-2-methyl-propionic acid,
2-|4-({|4-methoxymethyl-2-(4-trinuoromethyl-phenyl)-pyrimidine-5-carbonyl|-amino}-
methyl)-2-methyl-phcnoxy]-2-methyl-propionic acid,
2-|4-( !|4-(2-mcthoxy-ethyl)-2-(4-trifIuoromethyl-phenyl)-pyrimidine-5-carbonyl]-
amino}-methyl)-2-methyl-phenoxy]-2-methyl-propionic acid,
2-{4-|4-(2-cthoxy-cthyl)-2-(6-trifluoromethyl-pyridin-3-yl)-pyrimidin-5-ylmethoxy]-2-
mcthyl-phcnoxy}-2-methyl-propionic acid,
2-{4-|4-(2-methoxy-elhyl)-2-(6-trinuoromethyl-pyridin-3-yl)-pyrimidin-5-ylmethoxy|-2-
mcthyl-phcnoxy) -2-methyl-propionic acid,
2-{4-|4-(2-hydroxy-cthyl)-2-(6-trifluoromethyl-pyridin-3-yl)-pyrimidin-5-ylmethoxy]-2-
incthyl-phenoxyj -2-methyl-propionic acid,
2-|4-|4-incthoxymcthyl-2-(4-tritluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-2-methyl-
phcnoxy}-2-mclhyl-propionic acid,
2- J4-|4-cyclopropyl-2-(6-tritluoromethyl-pyridin-3-yl)-pyrimidin-5-ylmethoxy]-2-
mcthyl-phcnoxy}-2-methyI-propionic acid,
2-(4-|4-cyclopropyl-2-(4-trinuoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-2,3-dimethyl-
phcnoxy} -2-methyl-propionic acid,
2-methy 1-2-{2-mcthyl-4-|4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-
ylmethoxy|-phenoxy}-propionic acid,
2-inethyl-2-{2-mcthyl-4-|4-trifluoromethyI-6-(4-trifluoromethyl-phenyl)-pyridin-3-
ylmethoxy|-phenoxy}-propionic acid,
2-{4-|4-chloro-6-(4-trifluoromethoxy-phenyl)-pyridin-3-ylmethoxy]-2-methyl-
phenoxy} -2-methyl-propionic acid,
2-{4-|4-(2-hydroxy-ethyl)-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy|-2-
mcthyl-phcnoxyj -2-methyl-propionic acid,
2-methy 1-2-{2-methy l-4-| 2-(4-trifluoromethoxy-phenyl)-4-trifluoromethyl-pyrimidin-5-
ylmethoxy|-phenoxy[-propionic acid,
2-methy 1-2- {2-methy l-4-| 2-methyl-6-(4-trifluoromethoxy-phenyl)-4-trifluoromethyl-

pyridin-3-ylmcthoxy|-phenoxy}-propionic acid,
2-{4-|4-cyclopropyl-6-methoxymethyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-
ylmcthoxy|-2-mcthyl-phenoxy}-2-methyl-propionic acid,
2-{4-|4-cyclopropyl-6-methoxymethyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-
ylmcthoxyj-phenoxy}-2-methyl-propionic acid,
2-{4-|4-butyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-2-methyl-phenoxy}-
2-mcthyl-propionic acid,
2-{4-|4-butyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-phenoxy}-2-methyl-
propionic acid,
2-{4-|4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-phenoxy}-2-
mcthyl-propionic acid,
2-(4-|4-(2-mcthoxy-cthyl)-6-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-
ylmcthoxy|-2-mcthyl-phenoxy}-2-methyl-propionic acid,
2-{4-|4-(2-cthoxy-cthyl)-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-2-
mcthyl-phenoxy}-2-mcthyl-propionic acid and 2-{4-[4-(2-methoxy-ethyI)-2-(4-
trilluoroincthyl-phenyl)-pyrimidin-5-ylmethoxy]-2-methyl-phenoxy}-2-methyl-
propionic acid (3:2),
|rac]-3-(2-mcthyl-4-{3-mcthyl-l-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl|-
butoxy}-phenyl)-propionic acid,
2-|4-({[4-mcthoxymcthyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbonyl]-amino}-
mcthyl)-phenoxy)-2-methyl-propionic acid,
2-[4-({|4-(2-methoxy-ethyI)-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbonyl|-
arnino}-mcthyl)-phenoxy|-2-methyl-propionic acid,
2-(3-mcthoxy-5-{methyl-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethyl|-
carbamoy I} -phcnoxy)-2-methyI-propionic acid,
2-mcthyl-2-|4-({|2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethyl|-
carbamoyl}-methyl)-phenoxyj-propionic acid,
2-mcthyl-2-(4-{|2-methyI-6-(4-trinuoromethyl-phenyl)-pyridin-3-ylcarbamoyl|-
mcthyl}-phcnoxy)-propionic acid,
2-|3-chloro-4-({|2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine-3-carbonyl]-amino}-
mcthyl)-phenoxy|-2-methyl-propionic acid,
2-|3-chloro-4-({|4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbonyl|-
aminoj-mcthyl)-phcnoxy|-2-methyl-propionic acid,
2-|3-chloro-4-({|4-mcthoxymethyl-2-(4-trifluoromethyl-phenyl)-pyriiTiidine-5-
carbonyl|-amino}-methyl)-phenoxy|-2-methyl-propionic acid, and
2-|3-chloro-4-({|4-(2-methoxy-ethyl)-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbonyl|-amino}-mcthyl)-phenoxy]-2-methyl-propionic acid.

l-urther examples of preferred compounds are the following:
2-(3-{|4-cyclopropyl-2-(4-trinuoromethyl-phenyl)-pyrimidin-5-ylmethyl|-methyl-
carbamoyl!-5-rnclhoxy-phcnoxy)-2-methyl-propionic acid,
2-methy l-2-| 4-({ methyl-[2-methyl-6-(4-trinuoromethyl-phenyl)-pyridin-3-yl ]-
carbamoyl}-methyl)-phenoxy|-propionic acid,
2-|3-chloro-4-({|4-trinuoromethyl-6-(4-trifluoromethyl-phenyl)-pyridine-3-carbonyl|-
amino}-methyl)-phenoxyJ-2-methyl-propionic acid,
2-|3-chloro-4-({[4-lrinuoromethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbonyl|-
amino}-methyl)-phenoxy|-2-methyl-propionic acid,
2-methy l-2-| 4-( {(4-tritluoromethyl-6-(4-trinuoromethyl-phenyl)-pyridine-3-carbonylJ-
amino(-mctliyl)-phenoxy|-propionic acid,
2-melhyl-2-|4-({|4-trinuoromethyl-2-(4-trifluoromethyl-phenyI)-pyrimidine-5-
carbonyl |-amino! -methyl)-phenoxy]-propionic acid,
2-(4-{|4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylcarbamoyl|-methyl}-
phenoxy)-2-methyl-propionic acid,
2-(3-{|4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylcarbamoyl|-methyl}-
phenoxy)-2-methyl-propionic acid,
2-mcthyl-2-(3-{ 12-methy l-6-(4-trinuoromethyl-phenyl)-pyridin-3-ylcarbamoyl]-
melhyl}-phenoxy)-propionic acid,
2-methy l-2-(4-{ 14-trinuoromethyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylcarbamoyl|-
methyl }-phenoxy)-propionic acid,
2-j4-|4-(2-methoxy-ethyl)-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxyJ-2-
methyl-phenoxy}-2-methyI-propionic acid,
2-J4-|4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-3-fluoro-
plienoxy}-2-methyl-propionic acid,
2-[4-|4-cyclopropyl-2-(4-trifluoromethoxy-phenyl)-pyrimidin-5-ylmethylsulfanyl|-2-
methy l-phenoxy j -2-methyl-propionic acid,
2- j4-|2-cyclopropyl-6-(4-trifluoromethoxy-phenyl)-pyridin-3-ylmethylsulfanyl]-2-
methy l-phenoxy! -2-methyl-propionic acid,
2-j4-|4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethylsulfanyl]-2-
methy l-phenoxy}-2-methyl-propionic acid,
2-!4-|2-eyclopropyl-6-(4-tritluoromethoxy-phenyl)-pyridin-3-ylmethoxy]-2-methyl-
phcnoxy}-2-melhyl-propionic acid,
!2-methyl-4-|2-mcthyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethoxy]-
phenylsulfanyl}-acetic acid,
2-{4-|4-methoxymethyl-6-methyl-2-(4-trinuoromethyl-phenyl)-pyrimidin-5-ylmethoxy|-
2-methyl-phenoxy I -2-methyl-propionic acid,

2-{4-|4-methoxymelhyi-6-methyl-2-(3-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-
2-mcthyl-phcnoxy}-2-methyi-propionic acid,
2-{4-|4-mcthoxymcthyl-6-methyl-2-(4-trifluoromethoxy-phenyl)-pyrimidin-5-
ylmethoxy|-2-melhyl-phenoxy}-2-methyl-propionic acid,
2-{4-|4-cyclopropyl-2-(4-trifluoromethoxy-phenyl)-pyrimidin-5-ylmethoxy|-2-methyl-
phenoxy}-2-methyl-propionic acid,
2-methyl-2-{2-methyl-4-[6-(4-trifluoromethoxy-phenyl)-4-trifluoromethyl-pyridin-3-
ylmethoxy|-phenoxy}-propionic acid,
2-{4-[2-cyclopropylmethyl-6-(4-trifluoromethoxy-phenyl)-4-tritluoromethyl-pyridin-3-
ylmethoxy|-2-methyl-phenoxy}-2-methyl-propionic acid,
2-{4-|2-cyclopropyl-6-(4-trifluoromcthoxy-phenyl)-4-trifluoromethyl-pyridin-3-
ylmethoxy|-2-mclhyl-phenoxy}-2-methyl-propionic acid,
2-methyl-2-{2-mcthy l-4-| 6-(4-trifluoromethoxy-phenyl)-2-trifluoromethyl-pyridin-3-
ylmcthoxy|-phcnoxy}-propionic acid, and
2-{4-[4-methoxymcthyl-2-(4-trifluoromethoxy-phenyl)-pyrimidin-5-ylmethoxy]-2-mcthyl-phenoxy}-2-methyl-propionic acid.
Particularly preferred compounds of formula I of the present invention are the following:
2-methyl-2-{2-methyl-4-[2-methyl-6-(3-trifluoromethyl-phenyl)-pyridin-3-ylmethoxy|-
phenoxyj-propionie acid,
2-methyl-2-{2-methyl-4-|6-(4-trifluoromethoxy-phenyl)-pyridin-3-yImethoxy]-
phenoxy}-propionic acid,
|rac|-(2-methyl-4-{ l-|2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethoxy}-
phcnylsulfanyl)-acctic acid,
2-mcthyl-2-|3-(methyl-{2-f2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetyl}-
amino)-phenoxyj-propionic acid,
(4-{[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethyl]-methyl-amino}-
2-inethyl-phenoxy)-acetic acid,
|rac|-(4-{ l-|4-Cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-ethylsulfanyl}-
2-methyl-phcnoxy)-aeetic acid,
|rac|-(4-{ I-|4-Cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-ethoxy}-2-
methyl-phenoxy)-acetic acid,
2-{4-|4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-2-methyl-
phcnoxy} -2-methy l-propionic acid,
2-methyl-2-{2-mclhyl-4-|2-methyl-6-(4-trifluoromethoxy-phenyl)-pyridin-3-
ylmethoxy|-phenoxy}-propionic acid,

2-j4-|4-cyclopropyl-2-(3-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-2-methyl-
phenoxy}-2-methyl-propionic acid,
2-j4-|4-(2-mcthoxy-ethyl)-6-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-
ylir)cthoxy]-2-rnetriyl-phenoxy}-2-methyl-propionic acid,
2-mcthyl-2-(3-{mcthyl-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethyll-
carhamoyl}-phenoxy)-propionic acid,
2-|3-({2-|4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-acetyl}-methyl-
ami no)-phenoxy|-2-methyl-propionic acid,
2-mcthyl-2-|3-(methyl-{2-|2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetyl}-
amino)-5-trinuoromcthyl-phenoxy|-propionic acid,
2-|4-({|4-cyclopropyl-2-(4-trifluoromcthyl-phenyl)-pyrimidine-5-carbonyl]-amino}-
methyl)-phenoxy|-2-methyl-propionic acid,
2-mcthyl-2-(4-{[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylcarbamoyl]-
mcthyl}-phenoxy)-propionic acid,
2-|3-chloro-4-({|4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbonyl|-
amino}-mcthyl)-phenoxy|-2-methyl-propionic acid,
2-methy l-2-| 4-( {[ 4-tri nuoromethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-
carbonyl|-amino!-methyl)-phenoxy]-propionic acid,
2-(4-{|4-cyclopropyl-2-(4-tritluoromethyl-phenyl)-pyrimidin-5-ylcarbamoyl|-methyl}-
phcnoxy)-2-mcthyl-propionic acid,
-{4-|2-cyclopropyl-6-(4-trifluoromethoxy-phenyl)-pyridin-3-ylmethoxy]-2-mcthyl-
phenoxy}-2-mcthyl-propionic acid,
2-!4-|4-mcthoxymcthyl-6-methyI-2-(3-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy|-
2-methy l-phcnoxy} -2-methyl-propionic acid,
2-{4-|2-cyclopropyl-6-(4-trifluoromethoxy-phenyl)-4-trifluoromethyl-pyridin-3-
yhncthoxy|-2-mcthyl-phenoxy}-2-methyl-propionic acid,
2-j4-|4-methoxymethyl-2-(4-trinuoromethoxy-phenyl)-pyrimidin-5-ylmethoxy]-2-
mclhyl-phenoxy}-2-inethyl-propionic acid,
2-j4-|2-cyclopropyl-6-(4-trifluoromethoxy-phenyl)-4-trifluoromethyl-pyridin-3-
ylmethoxy|-2-methyl-phenoxy}-2-methyl-propionic acid, and
2-{4-|4-methoxymcthyl-2-(4-trifluoromethoxy-phenyl)-pyrimidin-5-ylmethoxyJ-2-
mcthyl-phenoxy}-2-mcthyl-propionic acid.
Furthermore, the pharmaceutically acceptable salts of the compounds of formula I and the pharmaccutically acceptable esters of the compounds of formula I individually constitute preferred embodiments of the present invention.

Compounds of formula I can have one or more asymmetric carbon atoms and can exist in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers, mixtures of diastereoisomcrs, diastcrcoisomcric racemates or mixtures of diastereoisomeric racemates. The optically active forms can be obtained for example by resolution of the racemates, by asymmetric synthesis or asymmetric chromatography (chromatography with a chiral adsorbens or eluanl). The invention embraces all of these forms.
It will be appreciated, that the compounds of general formula 1 in this invention may be derivatised at functional groups to provide derivatives which are capable of conversion back to the parent compound in vivo. Physiologically acceptable and metabolically labile derivatives, which are capable of producing the parent compounds of general formula 1 in vivo are also within the scope of this invention.
A further aspect of the present invention is the process for the manufacture of compounds of formula I as defined above, which process comprises
a) reacting a compound of formula
(Figure Remove)

as defined above,
wherein R1 is C|.-/-alkyl, R2 to R8 are as defined above and one of R5, R6or R7 is selected from -OH, -SH or -NHR9, wherein R with a compound of formula

wherein Y1 to Y\ R10, R", R13, m and n are as defined above and R14 is -OH, -Cl, -Br, -I or another leaving group, to obtain a compound of formula

(Figure Remove)
and wherein X2 is O, S or NR9, R1 is C|.7-alkyl and X1, Y1 to Y4, R2 to R13 and m and n

and optionally hydrolysing the ester group to obtain a compound of formula I, wherein R1 is hydrogen;
or, alternatively,
b) reacting a compound of formula

(Figure Remove)
wherein R1 is (V/-alkyl, R2 to R8 are as defined above and one of R\ R6or R7 is (CH2)p-NHRg, wherein R9 and p are as defined above, with a compound of formula


wherein Y1 to Y\ R , R , R , m and n are as defined above,

to obtain a compound of formula

(Figure Remove)
and wherein X2 is -(CII2)P-NR9CO-, R1 is C,.7-alkyl and X1, Y1 to Y4, R2 to R13 and m, n

and optionally hydrolysing the ester group to obtain a compound of formula I, wherein R1 is hydrogen;
or, alternatively,
c) reacting a compound of formula

(Figure Remove)
wherein R1 is (Y7-alkyl, R2 to R8 are as defined above and one of R\ R6or R7 is

with a compound of formula

wherein Y1 to Y1, R", R1", R", Rn , m and n are as defined above,

to obtain a compound of formula
(Figure Remove)
and wherein X' is -(CH2)P-CONRV, R1 is C,.7-alkyl and X1, Y1 to Y4, R2 to RIJ and m, n
and p are as defined above,
and optionally hydrolysing the ester group to obtain a compound of formula 1, wherein R1 is hydrogen.
As described above, the compounds of formula (1) of the present invention can be used as medicaments for the treatment and/or prevention of diseases which are modulated by PPAR8 and/or PPARa agonists. Examples of such diseases are diabetes, particularly non-insulin dependent diabetes mellitus, increased lipid and cholesterol levels, particularly low HDL-cholesterol, high LDL-cholesterol, or high triglyceride levels, atherosclerotic diseases, metabolic syndrome (syndrome X), obesity, elevated blood pressure, endothelial dysfunction, procoagulant state, dyslipidemia, polycystic ovary syndrome, inflammatory diseases (such as e.g. Crohn's disease, inflammatory bowel disease, colitis, pancreatitis, cholestasis/fibrosis of the liver, rheumatoid arthritis, ostcoarthritis, psoriasis and other skin disorders, and diseases that have an inflammatory component such as e.g. Al/heimer's disease or impaired/improvable cognitive function) and proliferative diseases (cancers such as e.g. liposarcoma, colon cancer, prostate cancer, pancreatic cancer and breast cancer). The use as medicament for the treatment of low HDL cholesterol levels, high LDL cholesterol levels, high triglyceride levels, and the metabolic syndrome (syndrome X) is preferred.
The invention therefore also relates to pharmaceutical compositions comprising a

compound as defined above and a pharmaceutically acceptable carrier and/or adjuvant.
l;urther, the invention relates to compounds as defined above for use as therapeutically active substances, particularly as therapeutic active substances for the treatment and/or prevention of diseases which are modulated by PPAR8 and/or PPARa agonists. Examples of such diseases are diabetes, particularly non-insulin dependent diabetes mellitus. increased lipid and cholesterol levels, particularly low HDL-cholesterol, high LDL-cholesterol, or high triglyceride levels, atherosclerotic diseases, metabolic syndrome (syndrome X), obesity, elevated blood pressure, endothelial dysfunction, procoagulant state, dyslipidemia, polycystic ovary syndrome, inflammatory diseases such as rheumatoid arthritis, osteoarthritis, psoriasis and other skin disorder, and prolifcrative diseases.
In another embodiment, the invention relates to a method for the treatment and/or prevention of diseases which are modulated by PPAR8 and/or PPARa agonists, which method comprises administering a compound of formula (I) to a human or animal. Preferred examples of such diseases are diabetes, particularly non-insulin dependent diabetes mellitus, increased lipid and cholesterol levels, particularly low HDL-cholcsterol, high I.DL-cholesterol, or high triglyceride levels, atherosclerotic diseases, metabolic syndrome (syndrome X), obesity, elevated blood pressure, endothelial dysfunction, procoagulant state, dyslipidemia, polycystic ovary syndrome, inflammatory diseases such as rheumatoid arthritis, osteoarthritis, psoriasis and other skin disorder, and proliferativc diseases.
The invention further relates to the use of compounds as defined above for the treatment and/or prevention of diseases which are modulated by PPAR5 and/or PPARa agonists. Preferred examples of such diseases are diabetes, particularly non-insulin dependent diabetes mellitus, increased lipid and cholesterol levels, particularly low HDL-cholcsterol, high LDL-cholesterol, or high triglyceride levels, atherosclerotic diseases, metabolic syndrome (syndrome X), obesity, elevated blood pressure, endothelial dysfunction, procoagulant state, dyslipidemia, polycystic ovary syndrome, inflammatory diseases such as rheumatoid arthritis, osteoarthritis, psoriasis and other skin disorder, and proliferative diseases.
In addition, the invention relates to the use of compounds as defined above for the preparation of medicaments for the treatment and/or prevention of diseases which are modulated by PPAR8 and/or PPARa agonists. Preferred examples of such diseases are diabetes, particularly non-insulin dependent diabetes mellitus, increased lipid and

cholesterol levels, particularly low HDL-cholesterol, high LDL-cholesterol, or high triglyccride levels, atherosclerotic diseases, metabolic syndrome (syndrome X), obesity, elevated blood pressure, endothelial dysfunction, procoagulant state, dyslipidemia, polycystic ovary syndrome, inflammatory diseases such as rheumatoid arthritis, osteoarthritis, psoriasis and other skin disorder, and proliferative diseases. Such medicaments comprise a compound as defined above.
The compounds of formula I can be manufactured by the methods given below, by the methods given in the examples or by analogous methods. Appropriate reaction conditions for the individual reaction steps are known to a person skilled in the art. Starting materials are either commercially available or can be prepared by methods analogous to the methods given below, by methods described in references cited in the text or in the examples, or by methods known in the art.
The synthesis of compounds with the general structure I, particularly compounds according to formula la to Iq, are described in scheme 1 to scheme 7. Scheme 8 to scheme 11 describe the synthesis of heterocycles 5 (scheme 1), identical to 11 (scheme 3), 8 (scheme 5) and 8 (scheme 6); 5 (scheme 4) identical to 8 (scheme 7) and 6 (scheme 4) identical to 9 (scheme 7).
The synthesis of compounds with the general structure I, particularly compounds according to formula la with X1 and X2 equal to oxygen can be accomplished according to scheme 1.

(Figure Remove)
I lydroxy aldehydes or hydroxy aryl alkyl ketones 1 are known or can be prepared by methods known in the art. Reaction of phenols 1 with alpha halo esters of formula 2 in the presence of a base like potassium or cesium carbonate in solvents like acetone, methyl-ethyl ketone, acetonitrile or N,N-dimethylformamide in a temperature range between room temperature and 140 °C leads to the corresponding ether compounds 3 (steps a). Baeyer Villiger oxidation e. g. with meta chloro perbenzoic acid in a solvent like dichloromethane, leads to compounds 4 (step b). Heterocycles 5 (prepared as outlined in schemes 8 to 11) are condensed with phenols 4 according to well known

procedures (step c): if R ' represents a hydroxy group e. g. via Mitsunobu-reactlon, with triphenylphosphine and di-tert-butyl-, diisopropyl- or diethyl-azodicarboxylate as reagents; this transformation is preferably carried out in a solvent like toluene, dichloromethanc or tetrahydrofuran at ambient temperature. Alternatively, if R14 represents a halide, mesylate, tosylate or triflate moiety, the heterocycles 5 can be reacted with phenols 4 in solvents like N,N-dimethylformamide, dimethylsulfoxide, acetonitrile, acetone or methyl-ethyl ketone in the presence of a weak base like cesium or potassium carbonate at a temperature ranging from room temperature to 140 °C, preferably around 50 °C to yield ether compounds la (step c). Those can optionally be hydrolyzed according to standard procedures, e. g. by treatment with an alkali hydroxide like LiOI I or NaOlI in a polar solvent mixture like tetrahydrofuran/ethanol/water leading to carboxylic acids la.
An analogous reaction scheme with the same reaction sequences applies for the isomeric compound series leading to compounds of general formula I, particularly compounds according to formula Ib:
(Figure Remove)




The synthesis of compounds with the general structure I, particularly compounds according to formula Ic, with X1 equal to O and X2 equal to nitrogen can be accomplished according to schemes 2 and 3.
(Figure Remove)

0

Nitro-phcnols 2 of scheme 2 are commercial available, or known or can be synlhesi/cd from anisols 3 by demethylation with aqueous 62% HBr in acetic acid between RT and 120 °C (step b). Alternatively, phenols 1 can be nitrated in para-position according to well established methods, e. g. with a solution of NaNCh in water/concentrated hydrochloric acid in a solvent like Et^O, followed by the addition of acetic acid anhydride at RT [following a procedure of P. Keller, Bull. Soc. Fr. 1994, 131, 27-29] leading to phenols 2 (step a). Nitro-phenols 2 are then hydrogenated in an alcohol like KtOH or MeOH with hydrogen in the presence of Pd/C and optionally an acid like MCI or AeOll at RT to give anilines 4 (step c). Intermediates 4 are then alkylated at oxygen with an activated ester compound 5, e.g. a bromo-acetate 5, in the presence of KnCOi or CsjCO; in a solvent like acetonitrile or acetone between 10 °C and RT to give intermediates 6 of scheme 2 (step d). Activated esters 5 are commercial available or can be synthesi/ed by methods known in the art. Triflates 5 can be prepared from the corresponding alcohols. Anilines 6 can alternatively be synthesized from compounds 5 and nitrophenols 2 in a two step procedure: first by O-alkylation as described above.

followed by hydrogenation with Pd/C in an alcohol like MeOH or EtOH optionally in the presence of AcOl I or HC1 (step e). BOC-protection with di-tert-butyl dicarbonate in tetrahydrofuran at RT to reflux yields compound 7 (step f). Compound 7 can also be synthesi/ed directly from activated esters 5 and BOC-protected aniline 8 with K2CO3 or Cs2C(>? as described for the synthesis of compounds 6 (step g).
Intermediates 7 of scheme 3 can optionally be alkylated at nitrogen using sodium hydride and a reactive alkyl halogenide/mesylate or triflate to give compounds 9 (step h, scheme 3). Standard BOC-deprotection (TFA/CH2C12, or HC1 in dioxane) at 0 °C to RT affords anilines 10 of (step i, scheme 3). Reaction with activated heterocycles ll(Ri4 being a halide or a methanesulfonate) using sodium hydride or sodium, potassium or cesium carbonate in N,N-dimethylformamide, dimethylsulfoxide, dimethylacetamide or tetrahydrofuran, at 0 °C to RT, leads to compounds Ic (step k). Alternatively, heterocycles 11 with RI4=OH can be transformed in situ to the coresponding triflate by treatment with trifluoromethanesulfonic anhydride/2,6-di-tert-butylpyridine in CH2CI2 at 0 °C. This triflate is then reacted with anilines 10 in the presence of 2,6-di-tert-butylpyridinc as base in nitromethane between RT and 60 °C to yield compounds Ic (following a procedure of Belostotskii, Anatoly M., Hassner, A., Tetrahedron Lett. 1994, 35(28), 5075-6| (step k). Secondary aniline compounds Ic (R9=H) can be reductively methylated with an aqueous solution of NaH2PO3 and formaldehyde between RT and 65 °C (Loibner, II., Pruckner, A., Stuetz, A., Tetrahedron Lett. 1984, 25, 2535-2536J to give compounds Ic with R9=Me. Ensuing hydrolysis with aqueous LiOH, NaOH or KOH in tctrahyrofuran/EtOI I or another suitable solvent produces compounds Ic of scheme 3 in the form of the free acid.

(Figure Remove)
An analogous reaction scheme with the same reaction sequences applies for the isomcric compound series leading to compounds of general formula I, particularly compounds according to formula Id:

(Figure Remove)

As alternative to the sequences described in scheme 2, the nitrogen containing intermediates can be prepared from suitable intermediates carrying a phenolic hydroxyl moiety. In such intermediates, optionally carrying one or more protective functions, the phenolic OH group can be replaced by the corresponding aromatic NH2 function by methods known in the art. For example by a three step sequence as described in Tetrahedron Letters 43(42), 7617-7619(2002): i) transformation of the phenol moiety into its trifluoromethanesulfonate (triflic anhydride, 2,6-lutidine, 4-dimethylamino-pyridine, dichloromethane, 0 °C to room temperature; ii) treatment of the triflate with benxophenone imine, di-palladium-tris(dibenzylideneacetone) complex, S-(-)-2,2'-bis(diphcnylphosphino)-l,l'-binaphthyl, cesium carbonate, toluene, in a Schlenk tube at temperatures around 120 °C; iii) treatment with catalytic amounts of hydrochloric acid in wet tctrahydrofuran preferably at room temperature to liberate the aromatic NH2 moiety.
The synthesis of compounds with the general structure I, particularly compounds according to formula le and If, with X1 equal to O and X2 equal to (CH2)PNR9CO, or (Cl b)|iCONR9 can be accomplished according to schemes 4.

(Figure Remove)
Nitriles 1 and aldehydes 2 can be prepared from the corresponding cyano- or formyl-phenols (which are known, commercially available or can be prepared by methods known in the art) by reaction with activated esters compounds (compounds 5 in scheme 2) in the presence of a base like potassium or cesium carbonate in solvents like acetone, methyl-ethyl ketone, acetonitrile or N,N-dimethylformamide in a temperature range between room temperature and 140 °C. Hydrogenation of nitrile compounds 1, e.

g. with palladium on charcoal in a mixture of acetic acid and ethanol, or, alternatively, transformation of aldehydes 2 into the corresponding oximes followed by reduction with /inc in acetic acid preferably around 65 °C gives compounds 3 with p = 1 (steps a, c). The preparation of compounds 3 with p=0 has been described in scheme 2 and 3 (compounds 6, scheme 2, and compounds 10, scheme 3). Compounds 3 with p = 2 can be prepared from compounds 2 in a two step procedure: i) treatment with nitro-methane and ammonium acetate in acetic acid at a temperature around 110 °C to form the corresponding nitro styrenc compounds; ii) hydrogenation with palladium on charcoal in the presence of a strong acid like sulfuric acid or hydrogen chloride in solvents like ethanol or acetic acid and in a temperature range between room temperature and 100 °C. In order to introduce an R9 substituent into compounds 3, BOC-protection followed by alkylation and subsequent removal of the BOC group can be performed similarly as described in schemes 2 and 3. Compounds 4 with p = 0 can be prepared from compounds 2 by standard procedures of oxidation of an aromatic aldehyde to an aromatic acid (e. g. with sodium chlorite, sodium dihydrogen-phosphate in a mixture of tert butanol and water and in the presence of 3-methyl-2-butene at temperatures around room temperature). Compounds 4 with p = 1 can be prepared from compounds 2 by a Wittig reaction using (methoxymethyl)-triphenylphosphonium chloride as reagent, treatment of the Wittig product with acid and oxidation of the aldehyde formed to the corresponding acid. Compounds 4 with p = 2 can be prepared from compounds 2 by a Horner-Emmons reaction with c. g. dimethyl(benzyloxycarbonyl)methl phosphonate, followed by concomitant reduction of the double bond and liberation of the ester function by e. g. hydrogenation with palladium on charcoal. Condensation of amines 3 or acids 4 with acids 5 or amines 6 can be performed using well known procedures for amid formation, such as use of N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide-hydrochloride and 4-dimethylamino-pyridine in dichloromethane at temperatures between 0 °C and room temperature yielding compounds le (step e) or If (step d).Those can optionally be hydroly/,ed according to standard procedures, e. g. by treatment with an alkali hydroxide like LiOll or NaOl I in a polar solvent mixture like tetrahydrofuran/ethanol/water, giving carboxylic acids le or If.
An analogous reaction scheme with the same reaction sequences applies for the isomeric compound series leading to compounds of general formula I, particularly compounds according to formula Ig and Ih:

(Figure Remove)

according to formula li, with X1 equal to CH2 and X2 equal to oxygen can be
The synthesis of compounds with the general structure I, particularly compounds •ding to formula li, with X1 e accomplished according to schemes 5.
(Figure Remove)
Aldehydes 1 arc known, commercially available or can be prepared by methods known in the art. Aldehydes 1 can be reacted with a Wittig salt 2 such as (1,2-diethoxy-2-oxocthyl)triphcnyl phosphonium chloride or (l,2-dimethoxy-2-oxoethyl)triphenyl phosphonium bromide in solvents like isopropanol, dichloromethane or tetrahydrofuran or mixtures thereof in the presence of a base like potassium carbonate, 1,8-dia/abicyclo|5.4.0|undec-7-ene (DBU), 1,1,3,3-tetramethyl-guanidine or sodium tert butylatc, preferably between 0 °C and the reflux temperature of the solvents, giving acrylic esters 3 as i: and/or Z isomers (step a). Alternatively, a Horner-Emmons reaction can be used for the transformation of compounds 1 into unsaturated esters 3, e. g. using dimethyl(methoxycarbonyl)methl phosphonate, optionally substituted at the methylene group, a base like sodium hydride in a solvent like tetrahydrofuran. Hydrogenation of acrylic esters 3 using palladium on charcoal as catalyst, preferably at room temperature and I atm. pressure of hydrogen, in solvents like methanol, ethanol, tetrahydrofuran, acetic acid, dichloromethane and mixtures thereof, affords esters 7, provided that the protecting group can be cleaved reductively (step e).
Alternatively, aldehydes 1 are reacted with the enolate of an acetic acid esters 4 (preferably the lithium-enolate, prepared at -78 °C by treatment of 4 with a strong, non-nucleophilic base like lithium diisopropylamide in an inert solvent like tetrahydrofuran), preferably at temperatures around -78 °C, in solvents like tetrahydrofuran giving the aldol product 5 as a mixture of diasteromers (step b). Removal of the benzylic hydroxy group in compounds 5 can be performed with a reducing agent like e. g. triethylsilane in Ihc presence of a Lewis acid, like boron-trifluoride, or a protic acid, like trifluoroacetic acid, in a suitable solvent like trifluoroacetic acid itself or dichloromethane between 0 °C and 60 °C to yield protected phenol compounds 6 (step d). Subsequent removal of the protecting group, e. g. a benzyl group, by standard technology, e. g. catalytic hydrogenation using hydrogen and a catalyst like palladium or by using dimethyl sulfide and boron tri fluoride diethyl etherate in a solvent like dichloromethane between room temperature and the reflux temperature of the solvent gives phenolic compounds 7 (step g). Catalytic hydrogenation can be used to transform unsaturated esters 3 into compounds 6 (step f)- 'n case the protective group in compounds 3 is a benzyl group, then a one step hydrogenation procedure directly gives phenolic compounds 7. Catalytic hydrogenation can also be used for the simultaneous removal of the benzylic hydroxy function and a benzyl protecting group, preferably using palladium on charcoal as catalyst in the presence of an acid like oxalic acid in solvents like alcohols at temperatures around room temperature and a hydrogen pressure up to 100 bar, thus giving the transformation of compounds 5 into compounds 7 in one step (step d and g).
As an alternative method, compounds 5 can be treated with catalytic amounts of an acid like para toluene sulfonic acid in a solvent like benzene or toluene, preferably under conditions allowing the removal of the water formed (e. g. with a Dean Stark trap or in the presence of molecular sieves) at temperatures between room temperature and the reflux temperature of the solvents to yield acrylic esters 3 (step c). The condensation of phenols 7 with heterocycles 8 to form compounds li can be performed as outlined in scheme 1 .
An analogous reaction scheme with the same reaction sequences applies for the isomeric compound series leading to compounds of general formula I, particularly compounds according to formula Ik:
(Figure Remove)
The synthesis of compounds with the general structure I, particularly compounds •ding to formula II, with X1 e
(Figure Remove)
Nitro-phcnyl compounds 3 and 5 are prepared from nitro aldehydes 1, which are known, commercially available or can be prepared by methods known in the art, by Wittig/l lorner-Kmmons or aldol reactions analogous to the reactions described for the synthesis of compounds 3 and 5 in scheme 5 (steps a and b). Catalytic hydrogenation can be used for the simultaneous removal of the benzylic hydroxy function (compounds 5) or the reduction of the double bond (compounds 3) and the reduction of the nitro group, preferably using palladium on charcoal as catalyst optionally in the presence of an acid like oxalic acid in solvents like alcohols at temperatures around room temperature and a hydrogen pressure up to 100 bar (step c). Compounds 1 with R9 substituents different from hydrogen are obtained by first introduction of a BOC group, alkylation and removal of the BOC protective function as described in schemes 2 and 3. The condensation of anilines 1 with hcterocycles 8 to form compounds II can be performed as outlined in scheme 3.
An analogous reaction scheme with the same reaction sequences applies for the isomeric compound series leading to compounds of general formula I, particularly compounds according to formula Im:


(Figure Remove)
As alternative to the sequences described in scheme 6, the nitrogen containing intermediates can be prepared from suitable intermediates carrying a phenolic hydroxyl function. In such intermediates, optionally carrying one or more protective functions, the phenolic OH group can be replaced by the corresponding aromatic NHh function by methods known in the art. For example by a three step sequence as described in Tetrahedron Letters 43(42), 7617-7619 (2002) and discussed in the context of schemes 2 and 3.
The synthesis of compounds compounds with the general structure I, particularly compounds according to formula In and lo, with X1 equal to CH2 and X2 equal to (CTI2)PNR9CO, or (Cll2)pCONR9 can be accomplished according to schemes 7.

(Figure Remove)


Formyl-nitrilcs la or aldehydes Ib, carrying a protected aldehyde function, are known, commercially available or can be prepared by methods known in the art. Compounds 3 and 5 are prepared from aldehydes 1 by Wittig/Horner-Emmons or aldol reactions analogous to the reactions described for the synthesis of compounds 3 and 5 in scheme 5 followed by removal of the aldehyde acetal protective function (if applicable) (steps a and b). Compounds 5 can be transformed into compounds 3 by treatement with catalytic amounts of an acid like para toluene sulfonic acid in a solvent like benzene or toluene, preferably under conditions allowing the removal of the water formed (e. g. with

a Dean Stark trap or in the presence of molecular sieves) at temperatures between room temperature and the reflux temperature of the solvents to yield acrylic esters 3 (step c). Acrylic esters 3 carrying an aldehyde or a nitrile function can be further transformed into compounds of the general formula 6 or 7 using selective transformations as outlined for the transformation of nitrile 1 (scheme 4) and aldehyde 2 (scheme 4). Subsequent amide formation with hcterocycles 5 and 6 can also be performed as outlined in scheme 4 thus yielding compound of the general formula In and lo as esters or acids.
An analogous reaction scheme with the same reaction sequences applies for the isomeric compound series leading to compounds of general formula I, particularly compounds according to formula Ip and Iq:
(Figure Remove)
The synthesis of compounds with the general structure I, particularly compounds with X1 and / or X! equal to S can be accomplished in close analogy to the synthesis of the corresponding analogues with X1 and / or X2 equal to oxygen. Suitable sulfur containing intermediates are known, can be prepared by methods known in the art or are prepared from phenolic intermediates as described by W Zhi-Liang and AP Kozikowski (J. Org. Chem. 2003, web publication release Oct. 10, 2003): treatment of a phenolic intermediate with sodium thiocyanate, sodium bromide and bromine in a solvent like methanol preferably between 0 °C and room temperature gives the corresponding 4-thiocyanato-phenols; subsequent reduction with lithiumaluminium hydride in a solvent like telrahydrofuran at temperatures around 0 °C then liberates the corresponding 4-mcrcaplo-phenol. Alternatively, intermediates carrying an aromatic SH moiety can be
prepared from suitable intermediates carrying a phenolic hydroxyl function. In such intermediates, optionally carrying one or more protective functions, the phenolic OH group can be replaced by the corresponding aromatic SH function by methods known in the art. For example by a three step sequence as described in J. Labelled Compounds & Radiopharmaceuticals 43(7), 683-691, (2000): i) transformation of the phenol moiety into its trifluoromcthanesulfonate (triflic anhydride, triethylamine, dichloromethane, at low temperature, preferably around -30 °C); ii) treatment of the triflate with triisopropylsilanethiolate, tetrakis(triphenylphosphine)-palladium(0) in solvent mixtures like toluene and telrahydrofuran in a temperature range between 60 °C and 150 °C; iii) treatment of the silyl sulfide with hydrogen chloride in methanol preferably around 0 °C to liberate the phenolic SH moiety.
Compounds of the general formula I may be obtained in the form of racemates. Racemic compounds can be separated into their antipodes by methods known in the art, such as separation of the antipodes via diastereomeric salts by crystallization with optically pure amines such as e. g. (R) or (S)-l-phenyl-ethylamine, (R) or (S)-l-naphthalen-1-yl-cthylamine, brucine, quinine or quinidine or by separation of the antipodes by specific chromatographic methods using either a chiral adsorbens or a chiral elucnt.
Schemes 8 to I I describe the synthesis of heterocycles 5 (scheme 1), identical to II (scheme 3), 8 (scheme 5) and 8 (scheme 6); 5 (scheme 4) identical to 8 (scheme 7) and 6 (scheme 4) identical to 9 (scheme 7).
(Figure Remove)
Pyridines 5 and 7 can be synthesized in a three step synthesis from ketones 1 (scheme 8). A mixture of ketones 1 with paraformaldehyde and dimethylamine hydrochloride in a solvent like ethanol in the presence of an acid like 37% HCI is heated to reflux for 2 to 10 hours to give aminoketones 2 (step a). Reaction of compounds 2 with 3-aminocrolonic acid esters 3 in acetic acid at reflux for 2 to 8 hours gives esters 4 (step b), which can be hydrolyzed (alkali hydroxide in solvents like THF, dioxane or DM SO) to give acids 5 (step c). Alternatively, esters 4 can be reduced with diisbutylaluminium hydride-solution (in toluene) at -30 °C to room temperature for 30 min to 3h in solvents like THF to give alcohols 6. Reaction of alcohols 6 with thionyl chloride in dichloromethane at 0 °C to room temperature for 5 min to Ih gives access to chlorides 7. Pyridines 4 can alternatively be synthesized following procedures described in Al-Saleh, Balkis; Abdelkhalik, Mervat Mohammed; Eltoukhy, Afaf Mohammed; Hlnagdi, Mohammed Hilmy (Enaminones in heterocyclic synthesis: A new regioselcctive synthesis of 2,3,6-trisubstituted pyridines, 6-substituted-3-aroylpyridines and 1,3,5-triaroylbenzenes. Journal of Heterocyclic Chemistry (2002), 39(5), 1035-1038). Disubstituted pyridines 4 can be prepared according to procedures described in Kalsuyama, Isamu; Ogawa, Seiya; Yamaguchi, Yoshihiro; Funabiki, Kazumasa; Matsui, Masaki; Muramatsu, Hiroshige; Shibata, Katsuyoshi (A convenient and regioselective synthesis of 4-(trifluoromethyl)pyridines. Synthesis (1997), (11), 1321-1324).
(Figure Remove)
The synthesis of chlormethyl pyrimidines 8 and pyrimidine acids 6 is described in scheme 9. Reaction of 3-oxo-esters 1 with triethyl orthoformate in acetic anhydride at room temperature to reflux for 1 to 8 hours gives an E/Z mixture of the 3-ethoxy-acrylic acid esters 3 (step a). Dikelo-esters 2 are reacted with methyl triflate in the presence of cesium carbonate in acetonitrile to give O-methylated products 3 (step b) [S. W. McCombie et al., Bioorganic & Medicinal Chemistry Letters 13 (2003), 567-571], thus yielding substituted enolethers 3 (R12 not H). Reaction with amidine hydrochlorides 4 in cthanol in the presence of alkali tert-butoxide at room temperature gives access to esters 5 (step c). Kslers 5 can be hydroly/ed (alkali hydroxide in solvents like THF, dioxane or DMSO) to give acids 6 (step d). Alternatively, esters 5 can be reduced with diisbutyl-aluminium hydride-solution (in toluene) at -30 °C to room temperature for 30 min to 3h in solvents like THF to give alcohols 7 (step e). Reaction of alcohols 7 with thionyl chloride in dichloromcthane at 0 °C to room temperature for 5 min to In gives access to chlorides 8 (step I).
(Figure Remove)
A general synthesis for acids 4 and chlorides 6 is depicted in scheme 10. Suzuki-coupling with boronic acides 1 and 6-halo-pyridazine-3-carboxylic acid esters 2, 5-halo-pyra/inc-2-carboxylic acid esters 2, 6-halo-nicotinic acid esters 2, 5-halo-pyridine-2-carboxylic acid esters 2, 2-halo-pyrimidine-5-carboxylic acid esters 2 or 5-halo-pyrimidine-2-carboxylic acid esters 2 with Pd(PhP)4 or PdCl2(dppf) [(U1-bis(diphcnylphosphino)ierrocene)-dichloropalladium(II)xCH2Cl2 (1:1)] in toluene, dimethoxyethanc, cthanol or DMF with cesium carbonate, potassium carbonate or cesium fluoride at room temperature to 90 °C for 2 to 8 h give esters 3 (step a). Esters 2 arc either commercially available or can be prepared by methods known to a person skilled in the art. Ksters 3 can be hydrolyzed (alkali hydroxide in solvents like THF, dioxane or DMSO) to give acids 4 (step b). A Curtius rearrangement can be used to transform acids 4 into the analogous BOC-protected anilines: first, the acid chlorides are synthesi/ed with e.g. oxalyl chloride/DMF in dichloromethane. Then, reaction with sodium a/ide in DMF/ dichloromethane followed by heating to reflux in the presence of 2-methyl-2-propanol gives the BOC protected anilines. Alternatively, such BOC protected anilines can be obtained from acids 4 in a one pot procedure by treatment with diphenylphosphoryl azide in 2-methyl-2-propanol in the presence of triethylamine and anhydrous 4-tolucne sulfonic acid at temperatuares arount 100 °C. Alkylation of these BOC protected anilines with R9-halide in the presence of sodium hydride in solvents like DMF followed by BOC-deprotection with TFA or HC1 in dioxane yields anilines 5 (step c). Alternatively, esters 3 can be reduced with diisbutylaluminium hydride-solution (in toluene) at -30 °C to room temperature for 30 min to 3 h in solvents like THF to give alcohols 6 (step d). Reaction of alcohols 6 with thionyl chloride in dichloromethane at 0 °C to room temperature for 5 min to Ih gives access to chlorides 7 (step e).

(Figure Remove)

Alcohols 1 in scheme 11 comprising a chain length n equal to one or two can be converted into analogues with a chain length of n+1 carbon atoms by methods well known in the art, e. g. by conversion of the primary alcohol into a suitable leaving group, c. g. a halide (2, step a), followed by reaction with cyanide to form nitrites 3 (step b) and saponification to acids 4 (step c). Acids 4 can be further transformed into the primary alcohols 5 (R10 II, R" = H), e. g. by using diborane in tetrahydrofuran (step d). Optionally, such alcohols 5 can be elongated to a chain length of n+1 carbon atoms by repeating the synthesis described for alcohols 1 to 5. In order to introduce substituents R10 and/or R" different from hydrogen, cyano intermediates 3 can be reacted with alkyl Grignard reagents Rl()MgX in solvents like ether or tetrahydrofuran between 0 °C and then reflux temperature of the solvent to form the corresponding R10CO-alkyl ketones 6 (step e) or with diisbutylaluminium hydride the corresponding aldehydes 6 (R1()=ll). Treatment of compounds 6 with an alkyllithium reagent RHLi in solvents like ether or tetrahydrofuran gives alcohols 5 (step f); treatment of compounds 6 with lithium aluminium hydride in solvents like tetrahydrofuran or ether or with sodium borohydride in solvents like cthanol or methanol, preferably at temperatures between -15 °C and 40 °C, gives alcohols 5 with RII=H (step f). The alcohol compounds 5 which contain a chiral center can optionally be separated into optically pure antipodes by methods well

known in the art, e. g. chromatography on a chiral HPLC column, or by derivatization with an optically pure acid to form esters, which can be separated by conventional HPLC chromatography and can then be converted back to the enantiomericaly pure alcohols 5. The reduction of ketones 6 to the corresponding secondary alcohols 5 of scheme 11 can also be carried out in an enantioselective fashion leading to the (R)- or (S)-alcohols 5, e. g. by treatment with borane-dimethylsulfide complex and (S)- or (R)-2-methyl-CBS-oxa/aborolidine as chiral catalyst in tetrahydrofuran, preferably at temperatures between -78 °C and ambient temperature, according to Corey et al. (E. J. Corey, R. K. Bakshi, S. Shibata, ./. Am. Chem. Soc. 1987, 109, 5551-5553), or by treatment with (+)- or (-)-B-chlorodiisopinocamphcyl-borane (DIP-C1), according to Brown et al. (P. V. Ramachandran, B. Gong, A. V. Teodorovic, H. C. Brown, Tetrahedron: Asymmetry 1994, J, 1061-1074). Aldehydes 6 (RIO= H, n = 0) can also be synthesized from primary alcohols 1 by methods known in the art, e. g. by treatment with pyridinium chlorochromate in dichloromethane, preferably at temperatures between room temperature and the reflux temperature of dichloromethane, or by treatment with manganese dioxide in solvents like dichloromethane, preferably at room temperature (step g). These aldehydes 6 can be converted to the corresponding secondary alcohols 5 through reaction with alkyl organometallic compounds, preferably under the conditions discussed above. Finally, the alcohols 5 of scheme 11 can be converted into compounds of formula 7, e. g by treatment with methanesuIfonyl chloride in dichloromethane in the presence of a base like triethylamine preferably in a temperature range between -20 °C and room temperature or thionyl chloride in dichloromethane at 0 °C to room temperature or by reaction with carbon tetrachloride or carbon tetrabromide and triphenylphosphine in solvents like tetrahydrofuran preferably in a temperature range between room temperature and the reflux temperature of the solvents or by treatment with tritlic anhydride, 2,6-lutidine and 4-dimethylaminopyridine in dichloromethane between -30 °C and room temperature; thus yielding compounds of formula 7 as mcthane-sulfonates, Inflates, chlorides or bromides, respectively (step h). Compounds of formula 7 can further be converted (reaction step i) to the amines 8 in solvents like DMA, DMF or dichloromethane at room temperature with an excess of the corresponding amine.
Alpha mono- or di-substituted acids 9 (R10 and/or R" not H) can be synthesized via esters of compounds 4, by treatment with a base like LDA or HMDS in solvents like tetrahydrofuran or 1,2-dimethoxyethane, followed by addition of one or sequentially two different alkyl halides, a reaction preferably performed between -78 °C and room temperature followed by hydrolysis to acid 9 (step k). Compounds 9 can be chiral and

can optionally be separated into optically pure antipodes by methods well known in the art, e. g. chromatography on a chiral HPLC column, or by derivatization with an optically pure acid to form esters, which can be separated by conventional HPLC chromatography and then converted back to the enantiomerically pure alcohol. Additionally, the asymmetric alkylation can be done with chiral amides of 4 which are well known to a person skilled in the art.
The synthesis of compounds with the general structure I, particularly compounds according to formula Ir (scheme 12), with X1 and / or X2 equal to S can be accomplished in close analogy to the synthesis of the corresponding analogues with X1 and / or X2 equal to oxygen and is generally described on pages 41 to 42. In scheme 12, a general synthesis for X1 equal to O and X2 equal to S is shown.

(Figure Remove)
Thiocyanato phenols 1 which are known or can be prepared as discussed before (page 41-42) can be hydrolyzed with NaOH in water at room temperature to reflux temperature and oxidi/ed in DMSO at higher temperature, preferably around 95 °C to the dithiols 2 (step a). Thiophenols 1 described before can be oxidized to the dithiols 2 as well (step a). Reaction of phenols 2 with alpha halo esters or triflates of formula 3 in the presence of a base like potassium or cesium carbonate in solvents like acetone, methyl-ethyl ketone, acetonitrile or N,N-dimethylformamide in a temperature range between room temperature and 100 °C leads to the corresponding ether compounds 4 (step b). Dithiol reduction with (n-Bu3PH)BF4 and Hiinig's base in DMF at room temperature as

described in the literature [Netherton, M. R..; Fu, G. C. Organic Letters 2001, 3(26),
,15
4295-4298] yields thiophenols 5 (R = H) (step c). The reaction can also be carried out with acetic acid anhydride to give the stable compounds 5 (R15 = Ac) (step c).
Heterocycles 6 (prepared as outlined in schemes 8 to 11) are condensed with thiophenols 5 (R1' H) according to well known procedures (step d): if R13 represents a hydroxy group e. g. via Mitsunohu-reaclion, with triphenylphosphine and di-tert-butyl-, diisopropyl- or diethyl-azodicarboxylate as reagents; this transformation is preferably carried out in a solvent like toluene, dichloromethane or tetrahydrofuran at ambient temperature. Alternatively, if R13 represents a halide, mesylate or tosylate, heterocycles 6 can be reacted with S-acetyl protected 5 (R15 = Ac) in solvents like N,N-dimelhylformamide, dimethylsulfoxide, acetonitrile, acetone or methyl-ethyl ketone in the presence of mclhanol and a weak base like cesium or potassium carbonate at a temperature ranging from 0 °C to 140 °C, preferably around room temperature to yield ether compounds Ir (step d). Heterocycles 6 with RI3=OH can also be transformed in .situ to the corcsponding inflates by treatment with trifluoromethanesulfonic anhydride/2,6-di-terl-butylpyridine in Cf^Cb at 0 °C to room temperature. The Inflates are then reacted with thiophenols 5 (R15 = H) in solvents like N,N-dimethylformamide, dimethylsulfoxide, acetonitrile, acetone or methyl-ethyl ketone in the presence of a weak base like cesium or potassium carbonate at a temperature ranging from room temperature to 140 °C, preferably around 50 °C to yield ether compounds Ir (step d). Esters of formula Ir can optionally be hydrolyzed according to standard procedures, e. g. by treatment with an alkali hydroxide like LiOH or NaOH in a polar solvent mixture like tetrahydrofuran/ethanol/water leading to carboxylic acids Ir.
An analogous reaction scheme with the same reaction sequence applies for the isomeric compound series leading to compounds of general formula I, particularly compounds according to formula Is:
(Figure Remove)

Compounds of the general formula I with X1 = S can be prepared from the appropriate thiophenol precursors which themselves can be obtained by converting suitable phenol intermediates into the corresponding thiophenols applying methods described above.
Compounds of the general formula I can contain one or more stereocenters and can optionally be separated into optically pure enantiomers or diastereomers by methods well known in the art, e. g. by HPLC chromatography, chromatography on a chiral HPLC column, chromatography with a chiral eluant or by derivatization with an optically pure alcohol to form esters, which can be separated by conventional HPLC chromatography and then converted back to the enantiomerically pure acids I (R1 = H). In addition, racemic compounds can be separated into their antipodes via diastereomeric salts by crystalli/ation with optically pure amines such as e. g. (R) or (S)-l-phenyl-ethylamine, (R) or (S)-l-naphthalen-l-yl-ethylamine, brucine, quinine or quinidine.
The following tests were carried out in order to determine the activity of the compounds of formula (I).
Background information on the performed assays can be found in: Nichols JS et al. "Development of a scintillation proximity assay for peroxisome proliferator-activated receptor gamma ligand binding domain", (1998) Anal. Biochem. 257: 112-119.
Full-length cl)NA clones for humans PPAR8 and PPARa and mouse PPARy were obtained by RT-PCR from human adipose and mouse liver cRNA, respectively, cloned into plasmid vectors and verified by DNA sequencing. Bacterial and mammalian expression vectors were constructed to produce glutathione-s-transferase (GST) and Gal4 DNA binding domain proteins fused to the ligand binding domains (LBD) of PPAR5 (aa 139 to 442), PPARy (aa 174 to 476) and PPARa (aa 167 to 469). To accomplish this, the portions of the cloned sequences encoding the LBDs were amplified from the full-length clones by PCR and then subcloned into the plasmid vectors. Final clones were verified by DNA sequence analysis.
Induction, expression, and purification of GST-LBD fusion proteins were performed in E. coli strain BL21(pLysS) cells by standard methods (Ref: Current Protocols in Molecular Biology, Wiley Press, edited by Ausubel et al.).

Radjoligand Bindirig Assay
PPAR8 receptor binding was assayed in HNM10 (50mM Hepes, pH 7.4, 10 mM
NaCI, 5mM MgCI;>, 0.15 mg/ml fatty acid-free BSA and 15 mM DTT). For each 96 well
reaction a 500 ng equivalent of GST-PPAR8-LBD fusion protein and radioligand, e.g.
20000 dpm {2-methyl-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl-
ditritiomethylsulfanylj-phenoxyj-acetic acid, was bound to 10 jag SPA beads (PharmaciaAmersham) in a final volume of 50 u.1 by shaking. The resulting slurry was incubated for Ih at RT and centrifuged for 2 min at 1300g. The supernatant containing unbound protein was removed and the semidry pellet containing the receptor-coated beads was resuspended in 50 ul of HNM. Radioligand was added and the reaction incubated at RT for Ih and scintillation proximity counting performed in the presence of test compounds was determined. All binding assays were performed in 96 well plates and the amount of bound ligand was measured on a Packard TopCount using OptiPlates (Packard). Dose response curves were done in triplicates within a range of concentration from IOI()M to 10'1M.
PPARot receptor binding was assayed in TKE50 (50mM Tris-HCI, pH 8, 50 mM KCI, 2mM KDTA. O.I mg/ml fatty acid-free BSA and 10 mM DTT). For each 96 well reaction an 140 ng equivalent of GST-PPARa-LBD fusion protein was bound to 10 u.g SPA beads (PharmaciaAmersham) in a final volume of 50 jal by shaking. The resulting slurry was incubated for Ih at RT and centrifuged for 2 min at 1300g. The supernatant containing unbound protein was removed and the semidry pellet containig the recptor-coated beads was resolved in 50 (il of TKE. For radioligand binding e.g. 10000 dpm of 2(S)-(2-ben/oyl-phenylamino)-3-{4-[l,l-ditritio-2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid or 2,3-ditritio-2(S)-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid in 50 ul were added, the reaction incubated at RT for Ih and scintillation proximity counting performed. All binding assays were performed in 96 well plates and the amount of bound ligand measured on a Packard TopCount using OptiPlates (Packard). Nonspecific binding was determined in the presence of 10"4 M unlabelled compound. Dose response curves were done in triplicates within a range of concentration from 10"'° M to 10"4 M.
PPARy receptor binding was assayed in TKE50 (50mM Tris-HCI, pH 8, 50 mM KCI, 2mM KDTA, 0.1 mg/ml fatty acid-free BSA and 10 mM DTT). For each 96 well reaction an 140 ng equivalent of GST-PPARy-LBD fusion protein was bound to 10 u,g SPA beads (PharmaciaAmersham) in a final volume of 50 ul by shaking. The resulting slurry was incubated for Ih at RT and centrifuged for 2 min at 1300g. The supernatant

containing unbound protein was removed and the semidry pellet containig the recptor-coated beads was resolved in 50 ul of TKE. For radioligand binding e.g. 10000 dpm 2(S)-(2-ben/oyl-phenylamino)-3-{4-[l,l-ditritio-2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy|-phenyl}-propionic acid in 50 uJ were added, the reaction incubated at RT for Ih and scintillation proximity counting performed. All binding assays were performed in 96 well plates and the amount of bound ligand measured on a Packard TopCount using OptiPlates (Packard). Nonspecific binding was determined in the presence of 10"4 M unlabelled compound. Dose response curves were done in triplicates within a range of concentration from 10"'° M to 10"4 M.
IAiciferase Transcriptional Reporter Gene Assays
Baby hamster kidney cells (BHK21 ATCC CCL10) were grown in DMEM medium containing 10% FBS at 37 °C in a 95%O2:5%CO2 atmosphere. Cells were seeded in 6 well plates at a density of 105 Cells/well and then batch-transfected with cither the pFA-PPARS-LBD, pFA-PPARy-LBD or pFA-PPARa-LBD expression plasm ids plus a reporter plasmid. Transfection was accomplished with the Fugene 6 reagent (Roche Molecular Biochemicals) according to the suggested protocol. Six hours following transfection, the cells were harvested by trypsinization and seeded in 96 well plates at a density of 104 cells/well. After 24 hours to allow attachment of cells, the medium was removed and replaced with 100 ul of phenol red-free medium containing the test substances or control ligands (final DMSO concentration: 0.1%). Following incubation of the cells for 24 hours with substances, 50 jil of the supernatant was was discarded and then 50 ^1 of Luciferase Constant-Light Reagent (Roche Molecular Biochemicals) to lyse the cells and initiate the luciferase reaction was added. Luminescence for luciferase was measured in a Packard TopCount. Transcriptional activation in the presence of a test substance was expressed as fold-activation over cells incubated in the absence of the substance. EC50 values were calculated using the XLfit program (ID Business Solutions Ltd. UK).
The free acids of the compounds of the present invention (R1 is hydrogen) exhibit 1C,,, values of 05 nM to 10 uJvl, preferably 1 nM to 100 nM for PPAR8 and IC5 values of 1 nM to 10 (J.M . preferably 10 nM to 5 u,M for PPARa. Compounds, in which R1 is not hydrogen are converted in vivo to compounds in which R1 is hydrogen. The following table shows measured values for some selected compounds of the present invention.

(Table Remove)

The compounds of formula (I) and their pharmaceutically acceptable salts and esters can be used as medicaments, e.g. in the form of pharmaceutical preparations for cnteral, parenteral or topical administration. They can be administered, for example, perorally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions, rectally, e.g. in the form of suppositories, parenterally, e.g. in the form of injection solutions or infusion solutions, or topically, e.g. in the form of ointments, creams or oils.
The production of the pharmaceutical preparations can be effected in a manner which will be familiar to any person skilled in the art by bringing the described compounds of formula (I) and their pharmaceutically acceptable, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.
Suitable carrier materials are not only inorganic carrier materials, but also organic carrier materials. Thus, for example, lactose, corn starch or derivatives thereof, talc, stcaric acid or its salts can be used as carrier materials for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carrier materials for soft gelatine capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (depending on the nature of the active ingredient no carriers are, however, required in the case of soft gelatine capsules). Suitable carrier materials for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar and the like. Suitable carrier materials for injection solutions are, for example, water, alcohols, polyols, glycerol and vegetable oils. Suitable carrier materials for suppositories are, for example, natural or hardened oils, waxes, fats and semi-liquid or liquid polyols. Suitable carrier materials for topical preparations are glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, polyethylene glycols and cellulose derivatives.

Usual slabili/ers, preservatives, wetting and emulsifying agents, consistency-improving agents, flavour-improving agents, salts for varying the osmotic pressure, buffer substances, solubilizers, colorants and masking agents and antioxidants come into consideration as pharmaceutical adjuvants.
The dosage of the compounds of formula (I) can vary within wide limits depending on the disease to be controlled, the age and the individual condition of the patient and the mode of administration, and will, of course, be fitted to the individual requirements in each particular case. l;or adult patients a daily dosage of about 1 mg to about 1000 mg, especially about I mg to about 100 mg, comes into consideration. Depending on the dosage it is convenient to administer the daily dosage in several dosage units.
The pharmaceutical preparations conveniently contain about 0.1-500 mg, preferably 0,5-100 mg, of a compound of formula (I).
The following examples serve to illustrate the present invention in more detail. They are, however, not intended to limit its scope in any manner.

Examples Abbreviations:
AcOKt ethyl acetate, n-BuLi = n-butyllithium, DBU = l,8-diazabicyclo[5.4.0]undec-7-ene, DEAD diethyl azodicarboxylate, DIAD = diisopropyl azodicarboxylate, DIHAL-H solution = diisobutylaluminum hydride solution, DMF = N,N-dimcthyHbrmamidc, DMPU := l,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone, eq. equivalents, h hour(s), DMSO = dimethyl sulfoxide, HPLC = high performance liquid chromatography, i. V. = in vacua, LDA = lithium diisopropylamide, PdCbldppf) -(l,r-bis(diphenylphosphino)fcrrocene)dichloro-palladium(II).CH2Cl2 (1:1), Pd(Ph3P)4 = tctrakis(triphenylphosphine)palladium, POC13 = phosphorous oxychloride, RT = room temperature, TFA = trifluoroacetic acid, TFAA = trifluoroacetic anhydride, THF = tetrahydrofuran.
Example 1
(2-(3-Methoxy-propyI)-4-{methyI-(2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethyl|-amino}-phenoxy)-acetic acid
AJ (2-lodo-phenoxy)-acetic acid ethyl ester
9.10 g (41.4 mmol) of o-iodophenol was dissolved in 102 ml of acetone and treated subsequently at 0 °C with 14.8 g (1.1 eq.) of cesium carbonate and 4.57 ml (1.0 eq.) of ethyl bromoacetale. After vigorous stirring for 1 h at ambient temperature and filtration, the bulk of solvent was evaporated and the residue redissolved in AcOEt. Washing with water, drying over magnesium sulfate, and evaporation of the solvents finally produced 12.66 g of pure title compound as colorless oil.
MS: 306.0 (M)'.
NJ [2K3-Methj)xy-prpp-lj^nyJX-phenoxy]-acetic acid ethyl ester
A three neck reaction flask was successively charged with 12.65 g (41.3 mmol) of the above prepared (2~iodo-phenoxy)-acetic acid ethyl ester, 128 ml of acetonitrile, 5.793 g (2 eq.) of 3-methoxy-l-propyne, 17.28 ml (3 eq.) of NEt3, 1.45 g (0.05 eq.) of (PPhbPdCh, and 0.394 g (0.05 eq.) of Cul. After stirring for 4 h the bulk of the solvent was removed i. V. and the residue distributed between HC1 and AcOEt. Washing of the organic layer with cold water and brine, drying over magnesium sulfate, and evaporation

of the solvents, followed by flash chromatography (SiOa, hexane/AcOEt=8/2), yielded 9.54 g of the title compound as light brown oil.
MS: 248.2 (M)1.
C| 12-(3-Methoxy-propyl)-phenoxy [-acetic acid ethyl ester
9.54 g (38.4 mmol) of the above prepared [2-(3-methoxy-prop-l-ynyl)-phenoxy]-acetic acid ethyl ester was hydrogenated at RT in 130 ml of AcOEt over 2.39 g of Pd/C (10%) under I atm of I {^-pressure. After 2 h at ambient temperature, the reaction mixture was filtrated over ('elite and carefully rinsed with AcOEt. Evaporation of the solvent left finally 9.39 g of the title compound as colorless oil.
MS: 252.2 (M)'.
l)| [2-(3-Methoxy-propyl)-4-nitro-phenoxy]-acetic acid ethyl ester
4.00 g (15.9 mmol) of the above prepared [2-(3-methoxy-propyI)-phenoxyj-acetic acid ethyl ester was dissolved in 5.0 ml of TFAA and added slowly and carefully via dropping funnel to a mixture of 5 ml of TFAA and 4 ml of cone. HNOs (65%) kept at -It) °C; the reaction was then allowed to proceed for additional 30 Min. Careful quenching with ice, twofold extraction with AcOEt, washing with NaHCO3 and brine, drying over magnesium sulfate, and evaporation of the solvents left a crude product which was purified by flash chromatography (SiOj, hexane/AcOEt=75/25) to deliver finally 3.00 g of the title compound as light brown oil, contaminated according to NMR with roughly 35% of the ortho-isomer which was separated after the next step.
MS: 298.3 (M HI)'.
HJ Jj4-Aiiilno-2-(3-mcthoxy-propvl)-phenoxv]-acetic acid ethyl ester
3.00 g (roughly 65%, 6.56 mmol) of the above prepared [2-(3-methoxy-propyl)-4-nitro-phenoxyl-acetic acid ethyl ester was hydrogenated at RT in 50 ml of AcOEt over 0.60 g of Pd/C (10%) under I atm of H2-pressure. After 3 h at ambient temperature, the reaction mixture was filtered over Celite and carefully rinsed with AcOEt. Evaporation of the solvent, followed by flash chromatography (SiO2, hexane/AcOEt=l/l) produced 1.69 g of the title compound as light brown oil; from the more polar fractions, 0.784 g of 8-(3-methoxy-propyl)-4//-ben/o[l,4]oxazin-3-one was isolated (cyclized reduced ortho-amino derivative).

MS: 268.3 (M+lI)'; side product: 221.1 (M)+.
FJ [4-fer/-Butoxycarbonylamino-2-(3-methoxy-propvn-phenoxy]-acetic acid ethyl ester
1.68 g (6.28 mmol) of the above prepared [4-amino-2-(3-methoxy-propyl)-phenoxy]-acetic acid ethyl ester was dissolved in 7 ml of THF, treated with 1.646 g (1.2 eq.) of di-tert-butyl dicarbonate, and refluxed for 1 h. After cooling, the reaction mixture was poured onto crashed ice/AcOEt, the organic layer washed with water and brine, dried over magnesium sulfate, and evaporated to dryness. Flash chromatography (SiO2, hcxanc/AcOEt=75/25) afforded 2.22 g of the title compound as light brown oil.
MS: 387.2 (M)+.
G| |4-(/g^-Butoxycarbonyl-methyl-amino)-2-(3-methoxy-propyl)-phenoxyJ-acetic acid ethyl ester
To 2.21 g (6.01 mmol) of the above prepared [4-/e/-/-butoxycarbonyIamino-2-(3-methoxy-propyl)-phenoxy]-acetic acid ethyl ester, dissolved in 18 ml of abs. DMF, was added at 0 °C 0.313 g of NaH (60% in mineral oil, 1.3 eq.). 5 Min. later, 0.75 ml (2 eq.) of Mel was added and the reaction allowed to proceed for 10 Min. at 0 °C and for 1 h at ambient temperature. Pouring onto crashed ice/KHSO4 solution, twofold extraction with AcOBt. washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt = 8/2), yielded 1.55 g of the title compound as light yellow oil.
HJ [2-(3-Methoxy-propyl)-4-methylamino-phenoxy]-acetic acid ethyl ester
1.55 g (4.06 mmol) of the above prepared [4-(/tr/-butoxycarbonyl-methyl-amino)-2-(3-methoxy-propyl)-phenoxy]-acetic acid ethyl ester was dissolved in 41 ml of CHaCb and treated dropwise with 10 ml of TFA. After additional 30 Min. at RT, the bulk of the solvents was removed i. V. and the residue distributed between cold NaHCOs-solution and AcOEt. Washing with cold water and brine, drying over magnesium sulfate, and evaporation of the solvents left 1.15 g of the title compound as brownish oil which was used as such for the next step.
U .X2j-lld^lh_Qxy-Brogyj)-4-{rnethyl-[2-rnethyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethyl]-amino}-phenoxy)-acetic acid ethyl ester
To 0.102 g (0.36 mmol) of the above prepared [2-(3-methoxy-propyl)-4-methylamino-phenoxy|-acetic acid ethyl ester, dissolved in 1.4 ml of abs. DMF, were added

successively at 0 °C 0.017 g of NaH (60% in mineral oil, 1.2 eq.), 0.054 g (1 eq.) of Nal and 0.100 g (1 eq.) of 3-chloromethyl-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (see below 1 K|). The reaction was allowed to proceed for 5 Min. at 0 °C and for 0.5 h at ambient temperature. Pouring onto crashed ice/KHSO4, twofold extraction with AcOEt, washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=75/25), yielded 0.126 g of the title compound as light yellow oil.
MS: 53I.5(M+II)'.
J| (2-(3-lylethoxy-propvl)-4-lmethvl-r2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethylj-aminot-phenoxy)-acetic acid
0.125 g (0.24 mmol) of the above prepared (2-(3-methoxy-propyl)-4-{methyl-[2-methyl-6-(4-trinuoromethyl-phenyl)-pyridin-3-ylmethyl]-amino}-phenoxy)-acetic acid ethyl ester was dissolved in 1.44 ml of THF/EtOH=l/l, treated with 0.72 ml (3 eq.) of IN NaOl I, and kept at ambient temperature for 0.5 h. The reaction mixture was then poured onto crashed ice/AcOEt/HCl dil., the organic layer washed with water, dried over sodium sulfate, and evaporated to dryness. Crystallization from hexane/AcOEt produced finally 0.102 g of the title compound as off-white crystals of mp. 72-73 °C.
MS: 501.1 (M-H).
The reagent used in 11] was prepared as follows:
K| 3-Dimcthylamino-l-(4-trifluoromethvl-phenyn-propan-l-onehydrochloride
4-(Trifluoromethyt) acetophenone (4.97 g, 26.4 mmol), paraformaldehyde (1.586 g, 2 eq.) and d i methyl am ine hydrochloride (3.231 g, 1.5 eq.) were mixed together in 7 ml of EtOH, treated with 0.08 ml of 37% HC1, and heated to reflux for 5h. Cooling down to ambient temperature, filtration and washing with tiny amounts of cold EtOH delivered 4.59 g of the title compound as white crystals, mp. 128-42 °C (dec.).
MS: 246.3 (M+H)'.
IJ 2-Melhyl-6-(4-trit1uorornethyl-phenyl)-nicotinic acid methyl ester
4.59 g (16.3 mmol) of the above prepared 3-dimethylamino-l-(4-trifluoromethyl-phenyl)-propan-l-one hydrochloride and 1.86 g (1.0 eq.) of 3-aminocrotonic acid methyl ester was dissolved in 50 ml of AcOH and heated to reflux for 4h. After cooling,

the bulk of the solvent was evaporated i. V., the residue dissolved in AcOEt, and washed with water and brine. Drying over sodium sulfate, evaporation of the solvents and flash chromatography (SiCh, hexane/AcOEt=8/2) delivered finally 2.40 g of the title compound as light yellow waxy solid.
MS: 296.1 (MHl)'.
M| [2-Methyl-6-(4-trit1uoromethyl-phenvl)-pyridin-3-vl]-rnethanol
1.00 g (3.39 mmol) of the above synthesized 2-methyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid methyl ester in 7 ml of abs. THF was cooled down to 0 °C and reacted with 7.06 ml of DIBAL-H-solution (1.2 M in toluene, 2.5 eq.) for 1 h. Careful quenching with ice / NIUCI, twofold extraction with AcOEt, washing with brine, drying over sodium sulfate, and evaporation of the solvents left a crude product which was purified by flash chromatography (SiO2, hexane/AcOEt=7/3) to deliver finally 0.875 g of the title compound as off-white solid, mp. 76-78 °C.
MS: 268.1 (M+H)'.
NJ 3-Chloromethyl-2-methvl-6-(4-trifluoromethyl-phenvn-pyridine
0.875 g (3.27 mmol) of the above prepared [2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl|-methanol was dissolved in 16 ml of CHaCb and treated dropwise at 0°C with 0.48 ml (2 eq.) of SOC12. The reaction mixture was kept at 0 °C for 5 Min. and at RT for 30 Min. Pouring onto crashed ice / NaHCOa, twofold extraction with AcOEt, washing with water, drying over sodium sulfate and evaporation of the solvents afforded 0.875 g of pure title compound as light yellow oil.
MS: 285.1, 287.1 (M)'.
Kxamplc 2
(2-(3-Methoxy-propyI)-4-{methyl-[2-methyl-6-(3-trifluoromethyI-phenyl)-pyridin-3-ylmethyl]-amino}-phenoxy)-aceticacid
A j 3 -C h Loromet hy l-2-methyl-6-(3-trifluoromethyl-phenvn-pvridine
was prepared in analogy to example IN], but starting the whole reaction sequence with 3-(trifluoromethyl) acetophenone instead of 4-(trifluoromethyl) acetophenone, as white crystals of mp. 7.3-75 °C.

MS: 285.1,287.1 (M)'.
BJ (2-(3-Methoxv-propyl)-4-{methvl-[2-methvl-6-(3-trifluoromethvl-phenyl)-pyridin-3-ylmcthylj-amino}-phenoxy)-acetic acid
The title compound was prepared in analogy to example 1, but using in step I] 3-chloromethyl-2-methyl-6-(3-trifluoromethyl-phenyl)-pyridine instead of 3-chloromethyl-2-methyl-6-(4-tririuoromethyl-phenyl)-pyridine, as light brown viscous oil.
MS: 501.1 (M-II). Example 3
|rac|-|2-(3-Methoxy-propyl)-4-(methyl-{l-[2-methyl-6-(3-trifluoromethyl-phenyl)-pyridin-3-yl]-ethyl}-amino)-phenoxy]-acetic acid
AJ 2-Methyl-6-(3-trifluoromethyl-phenyl)-pyridine-3-carbaldehvde
3.00 g (11.2 mmol) of |2-methyl-6-(3-trifluoromethyl-phenyl)-pyridin-3-yl]-methanol (synthesi/.ed as described in example IKJ-M], but starting with 3-(trifluoromethyl) acctophenone instead of 4-(trifluoromethyl) acetophenone), was dissolved in 56 ml of ClbCli and treated with 14.6 g (15 eq.) of MnC>2. After vigorous stirring for 2 h at ambient temperature, the reaction mixture was filtered over Celite and carefully rinsed with ClhCk Evaporation of the solvent left 2.659 g of the title compound as white crystals of nip. 61-63 °C.
MS: 266.2 (M+H)1.
BJjracJ- ...l'L2-Mcthyl-6-(3-trifluoromethyl-phcnyl)-pyridin-3-yl]-ethanol
0.500 g (1.89 mmol) of the above prepared 2-methyl-6-(3-trifluoromethyl-phenyl)-pyridine-3-carbaldehyde was dissolved in 9.4 ml of abs. THF and treated at -10 °C with 0.94 ml of 3M methyl magnesium chloride solution (in THF). After 30 Min., the reaction mixture was carefully poured onto crashed ice / NFUCl, extracted twice with AcOHt, washed with water, dried over sodium sulfate, and evaporated to dryness to leave 0.532 g of the title product, pure according to NMR.
MS: 282.1 (MM!)'.
CJJracJ- 3-(l-Chloro-cthyl)-2-methvl-6-(3-trifluoromethyl-phenvl)-pvridine

0.530 g (1.89 mmol) of the above prepared [rac]- l-[2-methyl-6-(3-trifluoromethyl-phenyl)-pyridin-3-yl]-ethanol was dissolved in 9.5 ml of CEbCh and treated dropwise at 0 °C with 0.275 ml (2 eq.) of SOCI2. The reaction mixture was kept at 0 °C for 5 Min. and at RT for 30 Min. Pouring onto crashed ice / NaHCO3, twofold extraction with HlOHt, washing with water, drying over sodium sulfate and evaporation of the solvents yielded 0.586 g of pure title compound as light yellow oil.
D| |rac|-[2-(3-lVlcthoxv-propvn-4-(rnethyl-{l-[2-methvl-6-(3-trifluoromethyl-phenvl)-pyridin-3-ylJ-ethyl}-amino)-phenoxy]-acetic acid ethyl ester
To 0.082 g (0.29 mmol) of the above (example 1H]) prepared [2-(3-methoxy-propyI)-4-methylamino-phenoxyj-acetic acid ethyl ester, dissolved in 1.0 ml of abs. DMF, were added successively at 0 °C 0.014 g of NaH (60% in mineral oil, 1.2 eq.), 0.044 g (1 eq.) of Nal and 0.087 g (I eq.) of the above prepared [rac]-3-(l-chloro-ethyl)-2-methyl-6-(3-trifluoromethyl-phenyl)-pyridine. The reaction was allowed to proceed for 5 Min. at 0 °C and for 0.5 h at ambient temperature. Pouring onto crashed ice/KHSO4, twofold extraction with AcOEt, washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (Si()2, hexanc/AcOEt "8/2), yielded 0.015 g of the title compound as light yellow oil.
MS: 545.5 (MUI)1.
HJ [racH2-(3-Mcthoxy-propyl)-4-(methvl-{l-[2-methyl-6-(3-trifluoromethyl-phenvl)-
pyridin-3-ylJ-ethyl}-aminpj-phenoxy]-acetic acid
0.015 g (0.03 mmol) of the above prepared [rac]-[2-(3-methoxy-propyl)-4-(methyl-{ 1-|2-methyI-6-(3-trilluoromethyl-phenyl)-pyridin-3-yl]-ethyl}-amino)-phenoxy]-acetic acid ethyl ester was dissolved in 0.2 ml of THF/EtOH=l/l, treated with 0.09 ml (3 eq.) of IN NaOIl, and kept at ambient temperature for 0.5 h. The reaction mixture was then poured onto crashed ice/AcOEt/HCl dil., the organic layer washed with water and brine, dried over sodium sulfate, and evaporated to dryness to leave 0.012 g of the title compound as light brown oil.
MS: 515.3 (M-M)'. Example 4
[rac|-|2-(3-Methoxy-propyl)-4-(methyl-{l-[2-methyl-6-(3-trifluoromethyl-phenyl)-pyridin-3-yll-butyl}-amino)-phenoxy]-acctic acid

AJ iracj-1 -|2-Mcthvl-6-(3-trifluoromethyl-phenyl)-pvridin-3-yl]-butan-l-ol
0.600 g (2.26 inmol) of the above prepared 2-methyl-6-(3-trifluoromethyl-phenyl)-pyridine-3-carbaldehyde (example 3 A]) was dissolved in 11.3 ml of abs. THF and treated at -78 °C with 1.2 ml of 2M propyl magnesium chloride solution (in EtOEt, 1.06 eq.). After stirring for 15 Min. at 0 °C, the reaction mixture was carefully poured onto crashed ice / NH.tCI, extracted twice with AcOEt, washed with water, dried over sodium sulfate, and evaporated to dryness. Flash chromatography (SiO2, hexane/AcOEt=8/2) yielded then 0.281 g of the title compound as white crystals of mp. 83-85 °C.
MS: 309.2 (M)+.
BJ [racJ-3-(l-Chloro-butyl)-2-methyl-6-(3-trifluoromethyl-phenyl)-pvridine
0.276 g (0.892 inmol) of the above prepared [rac]-l-[2-methyl-6-(3-trifluoromethyl-phenyl)-pyridin-3-yl|-butan-l-ol was dissolved in 4.3 ml of CF^Cb and treated dropwise at 0 °C with 0.13 ml (2 eq.) of SOCI2. The reaction mixture was kept at 0 °C for 5 Min. and at RT for 30 Min. Pouring onto crashed ice / NaHCOs, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents yielded 0.289 g of pure title compound as light yellow oil.
MS: 327.2, 329.1 (M)1.
CJ |racJ-[2-(3-Mcthoxv-propvl)-4-(methyl-{ l-[2-methyl-6-(3-trifluoromethyl-phenyl)-pyridin-3-ylJ-butyl}-amino)-phenoxy]-acetic acid ethyl ester
To 0.0944 g (0.336 mmol) of the above prepared (example 1H]) [2-(3-methoxy-propyl)-
4-methylamino-phenoxy]-acetic acid ethyl ester and 0.100 g (0.305 mmol) of the above
prepared | rac |-3-( 1 -chloro-butyl)-2-methyl-6-(3-trifluoromethyl-phenyl)-pyridine,
dissolved in 1.9 ml of abs. DMSO, were added successively 0.0505 g of K2CO3 (0.366 mmol) and 0.0503 g (0.336 mmol) of Nal. The reaction was allowed to proceed for 5 h at 50 °C . Pouring onto crashed ice/NF^CI, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromalography (Si()2, hexane/AcOEt=8/2), afforded 0.082 g of the title compound as light yellow oil.
MS: 573.5 (M HI)'.
DJ [racJ-[2-(3-Methoxy-propvn-4-(methvl-{l-[2-methvl-6-(3-trifluoromethvl-phenyl)-pyr id i n-3-y|J-bulyI} -aminoj-phenoxyj-acetic acid

0.082 g (0.143 mmol) of the above prepared [rac]-[2-(3-methoxy-propyl)-4-(methyl-{ I-|2-methyl-6-(3-trinuoromethyl-phenyl)-pyridin-3-yl]-butyl}-amino)-phenoxy]-acetic acid ethyl ester was dissolved in 1.64 ml of THF/EtOH=l/l, treated at 0 °C with 0.43 ml (3 cq.) of IN NaOH, and kept at ambient temperature for 2 h. The reaction mixture was then ncutrali/ed with HC1 dil. to pH 7, extracted with AcOEt, the organic layer was washed with water, dried over sodium sulfate, and evaporated to dryness to leave 0.070 g of the title compound as light brown oil.
MS: 543.3 (M-H)\ Example 5
|rac|-|2-Mcthyl-4-(mcthyI-{l-[2-methyl-6-(3-trifluoromethyl-phenyl)-pyridin-3-yl|-butyl}-amino)-phenoxy]-acetic acid
A | The title compound was prepared in analogy to example 4, but using in step C| (2-methyl-4-methylamino-phenoxy)-acetic acid methyl ester instead of [2-(3-methoxy-propyl)-4-melhylamino-phenoxy]-acetic acid ethyl ester, as yellow foam.
MS: 587.5 (MHI).
The necessary building block was synthesized as follows:
B]..(2-Methy_i-4-nitro j)henoxy)-acetic acid methyl ester
A solution of 15.76 ml (171 mmol) of methyl bromoacetate and 25.0 g (163 mmol) of 2-mcthyl-4-nitrophenol in 300 ml dry acetonitrile was treated with 61.3 g (188 mmol) CsjCOi and stirred at RT for 4h. The mixture was filtered, washed with acetonitrile and evaporated. The residue was suspended in 700 ml ChbCb, filtered and evaporated to give 36.4 g of (2-methyl-4-nitro-phenoxy)-acetic acid methyl ester as yellow crystals.
MS: 225 (M1).
C|X4-Arnin_o-2-iTicthy[-phenoxy)-acetic acid methyl ester
A solution of 36.3 g (161 mmol) of the above prepared (2-methyl-4-nitro-phenoxy)-acetic acid methyl ester in 400 ml MeOH and 11.2 ml (177 mmol) AcOH was hydrogenated in the presence of 3.63 g 10% Pd/C for 7h at atmospheric pressure. After removal of the catalyst the reaction was evaporated, dissolved in toluene and

cvaporaled(5x) to give 32.5g of (4-amino-2-methyl-phenoxy)-acetic acid methyl ester as a brown crystalline residue.
MS: 196(M+H').
D| (4-tert-Butoxycarbonylamino-2-methyl-phenoxy)-acetic acid methyl ester
A solution of 21.1 g (108 mmol) of (4-amino-2-methyl-phenoxy)-acetic acid methyl ester in 210 ml THF was treated with of 24.7 g (111 mmol) di-tert-butyl dicarbonate and heated for 3 h at 80 °C. The solution was evaporated and purified by flash chromatography with a gradient of «-heptane: AcOEt (9:1 to 4:1) to yield 28.1 g of (4-tert-butoxycarbonylamino-2-methyl-phenoxy)-acetic acid methyl ester as a light pink crystalline residue.
MS: 295 (M1).
HJ [4-(tcrt-ButoxycarbQnyl-methyl-amino)-2-methyl-phenoxy]-acetic acid methyl ester
To an ice-cooled and stirred solution of 22.8 g (77 mmol) of the above prepared (4-tert-biitoxycarbonylamino-2-methyl-phenoxy)-acetic acid methyl ester in 230 ml DMF was added within 10 min 3.7 g (55% in oil, 85 mmol) of NaH and, after Ih, 14.5 ml (232 mmol) of Clbl. The reaction was stirred at 0 °C for 2h, neutralized with aqueous 10% KIISO.i, and extracted with aqueous 10% KHSO4/Et2O (3x). The organic phases were washed with aqueous 10% NaCI, dried over sodium sulfate, and evaporated to give 25.8 g of |4-(tert-butoxycarbonyl-methyl-amino)-2-methyl-phenoxy]-acetic acid methyl ester.
MS: 310 (Mill').
I;J (2-Methyl-4-methylamino-phenoxy)-acetic acid methyl ester
A solution of crude 25.8 g (77 mmol) of the above prepared [4-(tert-butoxycarbonyl-methyl-amino)-2-methyl-phenoxy]-acetic acid methyl ester in 600 ml Cr^Cb was treated at 0 °C with 198 ml TFA and stirred at RT for 30 min. The reaction was evaporated and treated with chilled aqueous saturated NaHCO3 solution/Et2O (3x). The organic phases were washed with aqueous 10% NaCI, dried over sodium sulfate, and evaporated to give 16.2 g of crude product. Purification by flash chromatography on SiO2 with a gradient of «-heptane: AcOEt (9:1 to 4:1) yielded 12.7g of (2-methyl-4-mcthylamino-phenoxy)-acetic acid methyl ester as an orange oil.
MS: 210 (M HI1).

Example 6
|rac|-(4-{Methyl-|2-methyl-6-(4-trifluoromethyI-phenyl)-pyridin-3-ylmethyl]-amino}-2-trifluoromethyl-phenoxy)-aceticacid
A J 4-N itro-2-lri lluQromethyJrfihenoJ
A solution of 24.73 g (! 10.7 mmol) 6-methoxy-5-nitrobenzotrifluoride in 260 ml acetic acid and 130 ml of aqueous HBr solution (62%) was heated to reflux for 96 h, cooled down, evaporated and taken up in aqueous saturated NaHCO3 solution/Et2O (3x). The organic phases were washed with aqueous 10% NaCI, dried over sodium sulfate, and evaporated to dryness to yield 19.27 g of the title compound as yellow solid of mp. 103-
MS: 207 (M1).
BJ (4-Mcthylamino-2-trif1uoromethyl-phenoxy)-acetic acid ethyl ester
Analogously to example 5B] to 5F], 4-nitro-2-trifluoromethyl-phenol and ethyl hromoacetate were transformed to (4-methylamino-2-trifluoromethyl-phenoxy)-acetic acid ethyl ester containing some (4-methylamino-2-trifluoromethyl-phenoxy)-acetic acid methyl ester as light yellow waxy solid.
MS: 278 (M+U1) and 264 (M+H+).
CJ_. |ragj- (4-{Methyl-[2-methyl-6-(4-trif1uoromethyl-phenyn-pyridin-3-ylmethyll-am i no } -2 -t rj II u oroincthyl-phenoxy)-acetic acid ethyl ester
To 0.080 g (0.29 mmol) of the above prepared (4-methylamino-2-trifluoromethyl-phenoxy)-acetic acid ethyl ester and 0.124 g (0.43 mmol) of 3-chloromethyl-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (see example IN], dissolved in 1.0 ml of abs. DMSO. were added successively 0.048 g (0.32 mmol) of Nal and 0.066 g (0.43 mmol) ofDBU. The reaction was allowed to proceed for 4 h at ambient temperature, when TLC still indicated some starting amine. Therefore, another 33 mg (0.4 eq.) of 3-chloromethyl-2-inelhyl-6-(4-trifluoromethyl-phenyl)-pyridine was added and stirring continued for 3 h. Pouring onto crashed ice, extraction with AcOEt, filtration over Celite, washing of the organic layer with water, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (SiOj, hexane/AcOEt=8/2), afforded 0.046 g of the title compound as colorless oil.

MS: 527.5 (M+II)'.
DJ ____ [rac]-(4-{IVlethvl-[2-methyl-6-(4-trifluoromethyl-pheny|)-pyridin-3-vlmethyr[-aminoj-2-trifluoromethyl-phenoxy)-acetic acid
0.046 g (0.087 mmol) of the above prepared [rac]- (4-{methyl-[2-methyl-6-(4-trinuoromethyl-phenyl)-pyridin-3-ylmethyl]-amino}-2-trifluoromethyl-phenoxy)-acetic acid ethyl ester was dissolved in 0.52 ml of THF/EtOH=l/l, treated with 0.26 ml (3 eq.) of IN NaOII and kept at ambient temperature for 3.5 h. The reaction mixture was then poured onto crashed ice/AcOEt/HCI dil., the organic layer was washed with water, dried over sodium sulfate, and evaporated to dryness to leave, after recrystallisation from AcOHl/hexane, 0.039 g of the title compound as off-white solid.
MS: 497.0 (M-H) .
Example 7
(2,6-I)imethyl-4-{mcthyl-|2-methyI-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmcthyl|-amino}-phcnoxy)-aceticacid
A | The title compound was prepared in analogy to example 6, but using in step C] (2,6-dimethyl-4-methylamino-phenoxy)-acetic acid ethyl ester (described in US Patent No. 5905068) instead of (4-methylamino-2-trifluoromethyl-phenoxy)-acetic acid ethyl ester, as brownish crystals of mp. 137-138 °C.
MS: 459.6 (M+II)1.
Example 8
2-Methyl-2-{2-mcthyI-4-|2-methyl-6-(3-trinuoromethyl-phenyl)-pyridin-3-ylmethoxy|-phenoxy}-propionicacid
To 0.150 g (0.629 mmol) of 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) and 0.180 g (0.629 mmol) of the above prepared (example 2A|) 3-chloromethyl-2-methyl-6-(3-trifluoromethyl-phenyl)-pyridine, dissolved in 5.4 ml of abs. acetonitrile, was added 0.226 g of Cs2CO3 (0.692 mmol). The reaction was stirred for 3.5 h at ambient temperature. Pouring onto crashed ice, twofold

extraction with AcOlit, washing with water, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (SiC>2, hexane/AcOEt=85/15) yielded 0.248 g of pure title compound as colorless oil.
MS: 488.4 (Mill)".
BJ 2-Mcthyl-2-{2-methyl-4-[2-methvl-6-(3-trifluoromethyl-phenyl)-pvridin-3-
ylmcthoxyj-phenoxyl-propionic acid
0.248 g (0.509 mmol) of the above prepared 2-methyl-2-{2-methyl-4-[2-methyl-6-(3-trif1uoromethyl-phenyl)-pyridin-3-ylmethoxy]-phenoxy}-propionic acid ethyl ester was dissolved in 5.0 ml of THF/EtOH=1/l, treated with 1.50 ml (3 eq.) of IN NaOH and kept at ambient temperature for 20 h. The reaction mixture was then poured onto crashed ice/AcOHt/HCI dil. to bring the pH to 7, the organic layer was washed with water, dried over sodium sulfate, and evaporated to dryness to leave, after recrystallisation from AcOHt/hexane, 0.224 g of the title compound as white crystals of mp. 105-107 °C.
MS: 458.2 (M-H). Example 9
2-Methyl-2-{2-methyl-4-[6-(4-trifluoromethyI-phenyl)-pyridin-3-ylmethoxy]-phenoxy}-propionic acid
A | The title compound was prepared in analogy to example 8, but using in step Aj 5-chloromethyl-2-(4-trilluoromethyl-phenyl)-pyridine instead of 3-chloromethyl-2-methyl-6-(3-trifluoromethyl-phenyl)-pyridine, as white solid of mp. 149-151 °C.
MS: 444.1 (M-H)"-
BJ 5-Chloromethyl-2-(4-trifluoromethyl-phenyl)-pyridine
This reagent, necessary in step A], was prepared in analogy to example IN] from [6-(4-trinuoromcthyl-phenyl)-pyridin-3-yl]-methanol (described in WO 01/060805) as white solid of mp. 73 °C.
MS: 272.1, 274.1 (VHH)*. Example 10

2-Methyl-2-{2-methyl-4-|6-(4-trifluoromethoxy-phenyl)-pyridin-3-ylmethoxy]-phenoxyj-propionic acid
A | The title compound was prepared in analogy to example 8, but using in step A| 5-chloromethyl-2-(4~trifluoromethoxy-phenyl)-pyridine instead of 3-chloromethyl-2-methyl-6-(3-trifluoromethyl-phenyl)-pyridine, as white solid of mp. 146-148 °C.
MS:460.2(M-II).
The reagent, necessary in step A], was prepared as follows:
13J [6-(4-Trinuoromethoxy-phenyl)-pyridin-3-yl]-methanol
2.00 g (7.48 mmol) of commercially available 6-(4-trifluoromethoxy-phenyl)-pyridine-3-carbaldehyde was dissolved in 37 ml of EtOH and treated at 0 °C with 0.283 g (7.48 mmol) of NaBIl.i. After 10 Min. the cooling bath was removed and stirring continued at ambient temperature. Pouring onto crashed ice, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents afforded 2.08 g of pure title compound as off-white solid of mp. 57-58 °C.
MS: 269.1 (M)1.
C J 5 -(" h I prom ethyl -2-(4-trifluoromethoxy-phenyl)-pyridine
0.400 g (1.49 mmol) of the above prepared [6-(4-trifluoromethoxy-phenyl)-pyridin-3-yl|-methanol was dissolved in 7.2 ml of Cl^Cb and treated dropwise at 0 °C with 0.22 ml (2 eq.) of SOCb- The reaction mixture was kept at 0 °C for 5 Min. and at RT for 30 Min. Pouring onto crashed ice / NaHCOs, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents produced 0.419 g of pure title compound as off-white solid of mp. 34-36 °C.
MS: 288.1,290.1 (M+H)(. Example 11
|rac|-|2-Methyl-4-(methyl-{l-|2-methyI-6-(3-trifluoromethyl-phenyl)-pyridin-3-yl|-propyl}-amino)-phcnoxy|-acetic acid
A | The title compound was prepared in analogy to example 5, but using in step C| [rac|-3-( l-chloro-propyl)-2-methyl-6-(3-trifluoromethyl-phenyl)-pyridine instead of [rac|-3-(l-chloro-butyl)-2-methyl-6-(3-trifluoromethyl-phenyl)-pyridine, as yellow solid.

MS: 471.1 (M-Ii).
The necessary intermediate
B| |rac]-3-( 1 -Chloro-propyl)-2-methyl-6-(3-trifluoromethyl-phenyl)-pyridine
Was prepared as described in example 4A]-B], but using ethyl magnesium chloride instead of propyl magnesium chloride, as yellowish oil.
MS:314.ll.316.2(Mt-H)+. Example 12
(4-{|6-(4-Chloro-phenyl)-pyridin-3-ylmethyl]-methyl-amino}-2-methyI-phenoxy)-acetic acid
A| The title compound was prepared in analogy to example 4, but using in step C| (2-methyl-4-methylamino-phenoxy)-acetic acid ethyl ester (prepared in analogy to example 5F|)instead of |2-(3-methoxy-propyl)-phenoxy]-acetic acid ethyl ester and 5-chloromethyl-2-(4-chloro-pheny!)-pyridine instead of [rac]-3-(l-chloro-butyl)-2-methyl-6-(3-trilluoromethyl-phenyl)-pyridine, as off-white crystals of mp. 174-76 °C.
MS: 397.2, 399.4 (M+H)4.
The necessary intermediate
BJ 5-Chi_oromethyl-2-(4-chloro-phenyl)-pyridine
Was prepared in analogy to example IN] from [6-(4-chloro-phenyl)-pyridin-3-yl|-methanol as light brown solid.
MS: 237.1,239.1,241.1 (M)f.
Example 13
(2-Methyl-4-{methyl-(6-(4-trifluoromethoxy-phenyl)-pyridin-3-ylmethylj-ainino}-phcnoxy)-acetic acid
A | The title compound was prepared in analogy to example 12, but using in step C| 5-chloromethyl-2-(4-lrifluoromethoxy-phenyl)-pyridine (example 10C])instead of 5-chloromethyl-2-(4-chloro-phenyl)-pyridin, as off-white solid of mp. 137-138 °C.

MS: 445.2 (M-ll). Example 14
(2-(3-Methoxy-propyI)-4-{methyl-[6-(4-trifluoromethoxy-phenyl)-pyridin-3-ylmcthyl|-amino[-phenoxy)-acetic acid
A) The title compound was prepared in analogy to example 13, but using in step C] [2-(3-methoxy-propyl)-4-methylamino-phenoxy]-acetic acid ethyl ester (example 1H|) instead of (2-methyl-4-methylamino-phenoxy)-acetic acid ethyl ester, as light brown sol id of mp. 73-75 °C.
MS: 505.5 (M HI)'. Example 15
(2-MethyI-4-{methyl-[6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethyl]-amino}-phenoxy)-acetic acid
A | The title compound was prepared in analogy to example 13, but using in step C] 5-chloromethyl-2-(4-trinuoromethyl-phenyl)-pyridine instead of 5-chloromethyl-2-(4-trifluoromethoxy-phenyl)-pyridine, as off-white solid of mp. 199 °C.
MS:431.3(M+liy.
The necessary intermediate
B| 5-Chloromethyl-2-(4-trinuoromethyl-phenyl)-pyridine
was prepared in analogy to example IOC] as white solid of mp. 73 °C.
MS: 272.1,274.1 (Mill)1.
Example 16
(2-(3-Methoxy-propyl)-4-{methyl-|6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethyl|-amino}-phcnoxy)-acetic acid
The title compound was prepared in analogy to example 15, but using in step C] [2-(3-methoxy-propyl)-4-methylamino-phenoxy]-acetic acid ethyl ester instead of (2-methyl-4-mcthylamino-phenoxy)-acetic acid methyl ester, as light brown solid of mp. 72-76 °C.

MS: 487.2 (M-ll)'. Example 17
|rac|-(2-Methyl-4-{l-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-cthylsulfanyl}-phenoxy)-acetic acid
A | (2-Methyl-4-{ I -[2-rnethyl-6-(4-trif1uoromethyl-phenyl)-pvridin-3-yl]-ethylsulfanyl}-phcnoxy)-acetic acid tert-bulyl ester
0.224 g (0.75 mmol) of [rac|-3-(l-chloro-ethyl)-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine and 0.222 g (0.75 mmol) of (4-acetylsulfanyl-2-methyl-phenoxy)-acetic acid /(.'/•/-butyl ester (prepared by standard acetylation of (4-mercapto-2-methyl-phenoxy)-acetic acid lert-buiyl ester, described below in example 28A)-C]) were dissolved in 3.9 ml of acetonitrile and 0.2 ml of MeOH and treated with 0.292 g (1 .2 eq.) of Cs2CO3. The reaction was then allowed to proceed over night. Pouring onto crashed ice, twofold extraction with AcOHt, washing with water, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (SiC>2, hexane/AcOEt=9/l), afforded in the less polar fractions 0.210 g of pure title compound and in the more polar fractions 0. 1 1 2 g of the corresponding methyl ester as waxy solid.
BJ [racJ-(2-Methyl-4-{l-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-
0.322 g (0.62 mmol) of the above prepared (2-methyl-4-{l-[2-methyl-6-(4-trinuoromcthyl-phenyl)-pyridin-3-yl]-ethylsulfanyl}-phenoxy)-acetic acid /e/7-butyl ester, containing some methyl ester, was dissolved in 3.8 ml of THF/EtOH=l/l, treated with 1 .87 ml (3 eq.) of IN NaOH, and kept at ambient temperature for 2 h. The reaction mixture was then poured onto crashed ice/HCI dil., extracted twice with AcOEt, washed with water, dried over sodium sulfate, and evaporated to dryness to leave, after crystalli/ation from AcOEt / hexane, 0.276 g of the title compound as off-white solid of mp. II5-117°C.
MS: 460.3 (M-H)".
T he necessary reagent
Qjj^^3^TiCMjrQ-ethyl)-2-methyl-6-(4-trifluorornethvl-phenyl)-pyridine

Was prepared in analogy to example 3A]-C], but starting the whole reaction sequence with 4-(trifluoromethyl) acetophenone instead of 3-(trifluoromethyl) acetophenone), as colorless oil.
MS: 299.1,301.1 (M)'. Example 18
|rac|-(2-Methyl-4-{l-[2-methyl-6-(4-trifluoromethyI-phenyl)-pyridin-3-yl]-propylsulfanyl}-phenoxy)-acetic acid
A | The title compound was prepared in analogy to example 17, but using [rac]-3-(l-chloro-propyl)-2-mcthyl-6-(4-trifluoromethyl-phenyl)-pyridine instead of [rac|-3-(l-chloro-ethyl)-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine, as off-white solid of mp. 126-128 °C.
MS: 474.1 (M-H).
The necessary reagent
BJ[racJ- 3-(l-Chloro-propyl)-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine
was prepared in analogy to example 17C], but using for the Grignard-reaction ethyl magnesium chloride instead of the methyl derivative, as colorless oil.
MS: 314.2. 316.2 (M+H)f. Example 19
[rac)-(2-Methyl-4-{l-[2-methyl-6-(3-trifluoromethyI-phenyl)-pyridin-3-yl|-ethylsulfanyl}-phenoxy)-acetic acid
A) The title compound was prepared in analogy to example 17, but using [rac]-3-(l-
chloro-ethyl)-2-methyl-6-(3-trifluoromethyl-phenyl)-pyridine (example 3C|) instead of
|rac]-3-( l-chloro-ethyl)-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine, as colorless
loam.
MS: 460.3 (M-H)". Example 20

[rac|-(2-Mcthyl-4-{l-[2-niethyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yI]-ethoxy}-phcnylsult'aiiy l)-acetic acid
A J [rac[-(2-Mcthyl-4-{l-|2-methvl-6-f4-trifluoromethyl-phenvl)-pyridin-3-yl]-ethoxy}-phcnylsulfanyD-acctic acid ter/-butyl ester
To 0.118 g (0.39 mmol) of the above prepared [rac]-3-(l-chloro-ethyl)-2-methyl-6-(4-trifluoromctliyl-phenyl)-pyridine (example I7C]) and 0.100 g (0.39 mmol) of (4-hydroxy-2-melhyl-phenylsulfanyl)-acetic acid ter/-butyl ester (see below example 20C]), dissolved in 2.0 ml of abs. acetone, were added successively 0.065 g (0.39 mmol) of KI and 0.154 g (0.47 mmol) of Cs2CC>3. The reaction was allowed to proceed for 2 h at ambient temperature, when TLC still indicated large amounts of starting material. Therefore, stirring was continued over night at 40 °C. Pouring onto crashed ice, extraction with AcOEt, filtration over Celite, washing of the organic layer with water, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromalography (SiO2, hexane/AcOEt=9/l), produced 0.143 g of the title compound as colorless oil.
MS:5I8.4(M-HI)'.
B| [racJ-(2-Methyl-4-(l-[2-methyl-6-(4-trifluoromethyl-phenyl)-pvridin-3-yl]-ethoxv}-phenylsulfanyj)-acctic ac|d
0.143 g (0.28 mmol) of the above prepared [rac]-(2-methyl-4-{l-[2-methyl-6-(4-trinuoromcthyl-phenyl)-pyridin-3-yl]-ethoxy}-phenylsulfanyl)-acetic acid ter/-butyl ester was dissolved in 2.75 ml of THF/EtOH=l/l, treated with 1.38 ml (3 eq.) of IN NaOH and kept at ambient temperature for 5 h. The reaction mixture was then poured onto crashed ice/AcOBt/HCl dil., the organic layer was washed with water, dried over sodium sulfate, and evaporated to dryness to leave, since recrystallisation from AcOHt/hexanc failed, 0.095 g of the title compound as colorless foam.
MS: 460.1 (M-tl).
The necessary reagent used in 20A] was prepared as follows:
C | (4-1 lydroxy-2-mcthyi-phenylsuIfanyD-acetic acid tert-buty 1 ester
A solution of 10 g (71 mmol) of 4-mercapto-3-methyl-phenol (DE 2101359) and 10.5 ml (I eq., 71 mmol) of bromo-acetic acid tert-butyl ester in 250 ml of THF was treated at room temperature with 12.2 ml (1 eq., 71 mmol) of N-ethyldiisopropylamine. The

suspension was heated at reflux for I h, cooled to ambient temperature, and treated with water. The reaction mixture was then poured onto 0.1 M HCI/AcOEt, the organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated to dryness. Purification by flash chromatography (SiC>2, heptane/toluene/ AcOKt 10/1/1) afforded finally 5.6 g ofthe title product as white solid.
MS: 253 (M-H)". Example 21
| rac|-(2-Mcthyl-4-{ 1 -|2-methyl-6-(4-trifluoromethyl-phenyI)-pyridin-3-yl]-butoxy}-phcnylsuifanyl)~acctic acid
A | The title compound was prepared in analogy to example 20, but using [rac]- 3-(l-chloro-butyl)-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine instead of [racJ-3-(l-chloro-cthyl)-2-methyl-6-(3-trifluoromethyl-phenyl)-pyridine, as colorless foam.
MS: 488.1 (M-H),
The necessary reagent
ill [racj- 3-(l-chloro-butvl)-2-methyl-6-(4-trifluoromethyl-phenyl)-pvridine
Was prepared in analogy to example 17C], but using for the Grignard-rQaclion propyl magnesium chloride instead ofthe methyl derivative, as colorless oil.
MS: 328.2, 330.3 (M+H)4. Example 22
|rac)-(2-Mcthyl-4-{l-[2-methyl-6-(4-trifluoromethyl-phenyI)-pyridin-3-yl]-butylsulfanyl}-phcnoxy)-aceticacid
A | The title compound was prepared in analogy to example 17, but using in step A| |rac|- 3-(l-chloro-butyl)-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (example 2IB]) instead of [rac|-3-(l-chloro-ethyl)-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine, as colorless foam.
MS: 488.0 (M-H). Kxamnlc 23

[rac|-(4-{Cyclopcntyl-[2-methyl-6-(4-trifluoromethyI-phenyl)-pyridin-3-yl]-mcthylsulfanyI}-2-methyl-phenoxy)-acetic acid
A | The title compound was prepared in analogy to example 17, but using in step A] |rac]- 3-(chloro-cyclopentyl-methyl)-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine instead of [rac]-3-(l-chloro-ethyl)-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine, as colorless foam.
MS: 5I4.2(M-I1). Example 24
2-{4-|6-(4-FIuoro-3-trifluoromethyI-phenyl)-2-methyl-pyridin-3-ylinethoxy]-2-methyl-phcnoxy}-2-mcthyl-propionicacid
A] The title compound was prepared in analogy to example 8, but using in step Aj 3-chloromethyl-6-(4-nuoro-3-trifluoromethyl-phenyl)-2-methyl-pyridine instead of 3-chloromcthyl-2-methyl-6-(3-trifluoromethyl-phenyl)-pyridine, as white crystals of mp. 141-143 °C.
MS: 476.1 (M-H)'.
'I he necessary reagent
ill 3-Chjorprnethyl-6-(4-fluoro-3-trifluoromethyl-phenyl)-2-methyl-pyridine
was prepared in analogy to example 1KJ-N], but starting the whole reaction sequence with l-(4-nuoro-3-trifluoromethyl-phenyl)-ethanone instead of 4-(trifluoromethyl) acetophenone, as off-white solid.
MS: 303.1,305.1 (M)\ Example 25
|rac|-2-Mcthyl-2-(2-mcthyl-4-{l-[2-methyl-6-(3-trifluoromethyl-phenyl)-pyridin-3-yl|-ethoxy}-phenoxy)-propionic acid
A| The title compound was prepared in analogy to example 8, but using in step A| [racl-3-(l-chloro-ethyl)-2-methyl-6-(3-trifluoromethyl-phenyl)-pyridine (example 3C]) instead of 3-chloromcthyl-2-methyl-6-(3-trifluoromethyl-phenyl)-pyridine, as white solid.

MS: 472.1 (M-1I). Example 26
2-Mcthyl-2-[3-(mcthyl-{2-|2-inethyl-6-(4-triiluoromethyl-phenyl)-pyridin-3-yl]-acetylj-amino)-phenoxy|-propionic acid
AJ 2-Mcthyl-2-(3-rncthylamino-phenoxy)-propionic acid ethyl ester
In analogy to the procedures described in example 5D], 5E] and 5F], 2-(3-amino-phenoxy)-2-methyl-propionic acid ethyl ester [PCT Int. Appl. WO 2003/063794 A2] was converted into the corresponding tert-butoxycarbonylamino derivative, methylated at N and deprotected again to yield the title compound as light yellow oil.
MS: 238.1 (IVBH)1; 224.1 |(M+H)+ of the corresponding methyl ester present as impurity].
BJ 2-Methvl-2-|3-(methvl-{2-f2-methvl-6-(4-trifluoromethvl-phenvl)-pvridin-3-vll-acetyl}-amino)-phcnoxy]-propionic acid ethyl ester
0.24 g (1.00 mmol) of the above prepared 2-methyl-2-(3-methylamino-phenoxy)-propionic acid ethyl ester and 0.31 g (1.05 mmol) of [2-methyl-6-(4-trifluoromcthyl-phenyl)-pyridin-3-yl|-acetic acid (example 26E]) were dissolved in 15 ml of CH2CI2. This solution was cooled down to 0°C and then 0.24 g (1.20 mmol) of N-(3-dimethylamino-propyl)-N'-ethyl-carbodiimide-hydrochloride and 0.19 g (1.50 mmol) of N,N-dimethylaminopyridine were added and the reaction stirred for 20 hours at ambient temperature. It was subsequently poured into crashed ice / HCI and extracted two fold with ClbCli; the organic layers were washed with water, dried over magnesium sulfate, filtered and evaporated. The crude product was purified by chromatography (SiOs; n-hcplane / AcOHt 95:5 to 4:1) to give 0.50 g of the title compound as a light yellow oil.
MS: 515.3 (M HI)1.
C| 2-Methvl-2-[3-(methvl- acctylj-amino)-phenoxyj-propionic acid
0.50 g (0.97 mmol) of the above prepared 2-methyl-2-[3-(methyl-{2-[2-methyl-6-(4-trinuoromethyl-phenyl)-pyridin-3-yl]-acetyl}-amino)-phenoxy]-propionic acid ethyl ester was dissolved in 15 ml of THF / MeOH = 2:1. To the stirred solution was added 1.16 ml of a LiOH-solution (1 molar in water). After 6 hours, the reaction mixture was

poured into crashed ice / HCI and extracted twice with Cl-^Cb; the organic layers were washed with water, dried over magnesium sulfate, filtered and evaporated to give 0.47 g of pure title compound as colorless foam.
MS: 485.3 (M-H)".
The necessary building block |2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-acctic acid used in procedure 26B] was prepared as follows:
Dj |2-Mcthvl-6-(4-trinuoromethvl-phenyl)-pyridin-3-yl]-acetonitrile
27.2 g (95.2 mmol) of 3-chloromethyl-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (example IN|) was dissolved in 100 ml of dimethyl sulfoxide; 5.9 g of sodium cyanide (120 mmol) was added and the mixture was stirred at room temperature for 18 hours. Then, the reaction mixture was poured into a mixture of ice and water and was subsequently extracted with 3 portions of 400 ml of tert-butyl methyl ether. The combined organic phases were washed with water, then with brine and dried over anhydrous sodium sulfate. After evaporation of the solvent, 25.2 g of the title compound was obtained as a pale yellow solid.
MS: 276.1 (M)f.
1 vj [2-Methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid
A mixture of 25 g (90 mmol) of the above prepared [2-methyl-6-(4-trifluoromethyl-phcnyl)-pyridin-3-yl]-acetonitrile, 20 g of sodium hydroxide (500 mmol), 60 ml of water and 250 ml of propanol was stirred vigorously at 100 °C. Hydrolysis was complete after
2 hours. The reaction mixture was then evaporated to dryness and the residue was
dissolved in 70 ml of water; then, 60 ml of cold 8 N aqueous HCI was added and the
compound was extracted with three portions of 250 ml of ethyl acetate; the combined
organic phases were washed with water and brine, dried over anhydrous sodium sulfate
and evaporated to dryness to yield 25.1 g of the title product as pale yellow solid.
MS: 296.0 (MMI)'.

Example 27
(4-{|4-Cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylinethyl]-methyl-;miino}-2-methyl-phcnoxy)-acetic acid
AJ (4-{|4-Cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethyl]-methyl-ainino)-2-methvl-phcnoxy)-acetic acid methyl ester
To a solution of 400 mg (1.28 mmol) 5-chloromethyl-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 27F]) and 268 mg (1.28 mmol) of (2-methyl-4-methylamino-phenoxy)-acetic acid methyl ester (example 5F]) in 8 ml of DM SO was added 194 mg (1.41 mmol) potasium carbonate and 192mg (1.28 mmol) sodium iodide. The reaction mixture was stirred for 20 min at RT. It was then taken up in ether and washed with aqueous 10% KHSO4-solution (10%) and water. The crude product was purified by chromatography over silica gel with AcOEt/heptane 1:3, to give 403 mg of pure (4-{|4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethylj-mcthyl-amino}-2-methyl-phenoxy)-acetic acid methyl ester.
MS: 486.4 (M-+H)'.
B[ (4-{[4-Cyclopropyl-2-(4-trifluoromethvl-phenyl)-pvrimidin-5-vlmethyl]-methyl-aminoj -2-methyI-phenoxyj^etlc acid
A solution of 351 mg (0.72 mmol) (4-{[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethyl]-methyl-amino}-2-methyI-phenoxy)-acetic acid methyl ester and 1.45 ml IN LiOll in 4 ml of THF was stirred for 3h at RT. The reaction mixture was taken up in ether and washed with IN HCI and water. The crude product was suspended in AcOHt/heptane 1:19 to give 95.64 mg of pure (4-{[4-cycIopropyl-2-(4-trinuoromethyl-phenyl)-pyrimidin-5-ylmethyl]-methyl-amino}-2-methyl-phenoxy)-acetic acid.
MS: 472.3 (M HI)'.
5-Chloromethyl-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine used in 27AJ was synthesi/ed as follows:
CJ (H./)-2-Cyclopropanecarbonyl-3-ethoxv-acrylic acid methyl ester
A solution of 10 g (70.34 mmol) 3-cyclopropyl-3-oxo-propionic acid methyl ester, 23.4 ml (140.68 mmol) of triethyl orthoformate in 100 ml acetic anhydride was refluxed at

150 °C for 5h. The reaction mixture was concentrated at 95 °C under reduced pressure to give 14.35 g of crude (E,Z)-2-cyclopropanecarbonyl-3-ethoxy-acrylic acid methyl ester.
MS: I99.3(M+H)'.
PJ 4-Cyclopropyl-2-(4-trir1uoromethyl-phenyl)-pyrimidine-5-carboxylic acid ethyl ester
To a solution of 4.74 g (18.19 mmol) 4-trifluoromethyl-benzamidine HCI in 50 ml of ethanol was added 1.818 g (18.186 mmol) of sodium tert-butoxide. After 2 min, 3.605 g of crude (B,Z)-2-cyclopropanecarbonyl-3-ethoxy-acrylic acid methyl ester was added and the reaction mixture was then stirred over night at RT. The ethanol was removed under reduced pressure, the residue taken up in ether and washed with IN HCI and water. The ether solution was concentrated under reduced pressure and the crude product purified by chromatography over silica gel with AcOEt/heptane 1:3 to give 4.25 g of pure 4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid ethyl ester.
MS: 337.1 (MH1)'
KJ [4-C'yclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yll-methanol
Within 10 min was dropped 31.6 ml (37.9 mmol) of 1.2 M D1BALH solution in toluene to a dry ice cooled (-50 °C) solution of 4.25 g (12.64 mmol) 4-cyclopropyl-2-(4-trinuoromethyl-phenyl)-pyrimidine-5-carboxylic acid ethyl ester in 50 ml of THF. The reaction mixture was stirred 30 min at -50 °C and after letting rise the temperature to RT, the reaction was stirred for Ih at RT. The reaction mixture was taken up in ether and washed with IN HCL and water. The solvent was removed under reduced pressure to give 3.72 g of pure [4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-methanol.
MS: 295.1 (M+H)1.
FJ 5-Chloromethyl-4-cvclopropyl-2-(4-trifluoromethyl-phenyl)-pvrimidine
A mixture of 1.9 g (6.456 mmol) of [4-cyclopropyl-2-(4-trifiuoromethyl-phenyl)-pyrimidin-5-yl|-methanol and 0.515 ml (7.1 mmol) thionylchloride in 20 ml dichloromethanc was stirred for Ih at RT. The reaction mixture was taken up in ether and washed with sodium bicarbonate solution and water. The ether phase was concentrated under reduced pressure to give 1.97 g of pure 5-chloromethyl-4-cyclopropyl-2-(4-tri1luoromethyl-phenyl)-pyrimidine.

MS: 313.1 (M+H)'.
Example 28
|racj-(4-{l-f4-Cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-ethylsulfanyI}-2-methyl-phenoxy)-acetic acid
AJ 4, 4'-Dithio-bis-(2-methyl-phenol)
To a solution of 5 g (46.23 mmol) o-cresol and 6.15 ml (48.54 mmol) chloro-trimethyl-silane in 50 ml dichloromethane was dropped under ice cooling 6.76 ml (48.55 mmol) triethyl amine within 5 min. The reaction mixture was stirred at RT for 30 min and then it was chilled to -40 °C. At this temperature was dropped 1.86 ml (23.13 mmol) di-sulfur-di-chloride to the mixture, within 10 min. The reaction was allowed to come to RT and was stirred at this temperature for Ih. The lot was taken up in ether and washed with water. The crude product was purified by chromatography over silica gel with AcOEt/ heptane 1:3 providing 4 g pure 4, 4'-dithio-bis-(2-methyl-phenol).
MS: 277.3 (M-NV.
BJ [4-(4-/tjr/-Butoxycarbonylmethoxy-3-methyl-phenyldisulfanvn-2-methyl-phenoxy]-
acetic acid ter/-butyjjjster
To an ice cooled solution of 4.75 g (17.06 mmol) 4, 4'-dithio-bis-(2-methyl-phenol) and 5.55 ml (37.6 mmol) bromo-acetic acid ter/-butyl ester in 50 ml DMF was added 204 mg (85.3 mmol) sodium hydride (55% in oil). The reaction mixture was stirred over night at RT and then it was taken up in ether, washed with IN HCI and water. The crude product was purified by chromatography over silica gel with AcOEt/heptane 1:4 providing 3.4 g pure |4-(4-/er/-butoxycarbonylmethoxy-3-methyl-phenyldisulfanyl)-2-methyl-phenoxy]-acetic acid lerl-bulyl ester.
MS:524(M+NH4)'.
CJ (4-Mcrcapto-2-methyl-phenoxy)-acetic acid tert-butyl ester
To a solution of 3.3 g (6.51 mmol) [4-(4-/er/-butoxycarbonylmethoxy-3-methyl-phenyldisulfanyl)-2-methyl-phenoxy]-acetic acid tert-butyl ester in 30 ml dichloromethane was added under ice cooling 4.26 g (65.1 mmol) zinc powder, 15 ml acetic acid and a few drops of HCI (2*>%V After a few minutes, the reaction completed.

Then the solution filtered, taken up in ether and washed with water. The ether solution was concentrated under reduced pressure, providing 2.86 g of almost pure (4-mercapto-2-mcthyl-phenoxy)-acetic acid ter/-butyl ester.
MS: 225 (Mt II)'.
[racJ-(4-[I-[4-Cvclopropvl-2-(4-trifluoromethvl-phenvl)-pyrimidin-5-yl]-ethylsulfanyl}-2-methyl-phenoxy)-acetic acid tert-butyl ester
To a solution of 180 mg (0.551 mmol) [rac]-5-(l-chloro-ethyI)-4-cyclopropyl-2-(4-lrifluoromethyl-phenyl)-pyrimidine (example 28H]) and 140 mg (0.551 mmol) (4-mercapto-2-methyl-phenoxy)-acetic acid tert-buty\ ester in 3 ml DMF was added 315 mg (0.66 mmol) cesium carbonate. The reaction mixture was stirred for 3 h at RT and then partitioned between ether, IN HC1 and water. The crude product was purified by chromatography over silica gel with AcOEt/Heptan 1:9 to give 150 mg of pure [rac]-(4-{l-|4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-ethylsulfanyl}-2-methyl-phenoxy)-acetic acid ter/-butyl ester.
MS: 544.64 (IVH II)'.
[racJ-(4-[l-[4-Cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-vl]-ethylsulfanyl}-2-methyl-phenoxy)-acetic acid
To asolution of 146 mg (0.268 mmol) [rac]-(4-{l-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylJ-ethyIsulfanyl}-2-methyl-phenoxy)-acetic acid tert-butyl ester in 2 ml dichloromethane was added 0.5 ml trifluoroacetic acid. The reaction mixture was stirred for 4h and then the trifluoroacetic acid was removed under reduced pressure. The crude product was suspended in AcOEt/heptane 1:19. The resulting crystalline product was filtered off to give 1 18mg of pure [rac]-(4-{l-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyriinidin-5-yl|-ethylsulfanyl}-2-methyl-phenoxy)-acetic acid.
MS: 487.2 (M-H).
|rac|-5-( l-Chloro-ethyl)-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine used in 28D| was synthesi/ed as follows:
|-"J 4-Cyclopropyl-2-(4-trifluoromethyl-phenvl)-pyrimidine-5-carbaldehyde
To a dry ice cooled solution of 0.86 ml (12 mmol) DMSO in 10 ml dichloromethane was added 0.68 ml (7.79 mmol) oxalylchloride. After the reaction mixture was stirred for 5

min at -70 °C, 1.8 g (5.99 mmol) of [4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl|-methanol, dissolved in 8 ml dichloromethane, was added by dropping within 5 min. The reaction mixture was then stirred for further ten minutes at -70 °C and alter 4.17 ml (30 mmol) triethylamine was added, the reaction mixture was allowed to come to RT and it was stirred for Ih at RT. The mixture was taken up in ether and washed with IN MCI and water. The ether phase was concentrated under reduced pressure to give 1.75 g of pure 4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbaldehyde.
MS: 264.1 (M-CO)
GJ [racj-1 -[4-Cyclopropyl-2-(4-trifluoromethyl-phenvl)-pyrimidin-5-vl]-ethanol
To a dry ice chilled solution of 0.75 g (2.57 mmol) 4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidinc-5-carbaldehyde in 5 ml THF was dropped a solution of 1.11 ml (3.33 mmol) 3M methylmagnesium bromide in 2.5 ml THF. The reaction mixture was allowed to warm to RT and it was stirred for 15 min at this temperature. The reaction mixture was then taken up in ether and washed with IN HC1 and water. The crude product was purified by chromatography over silica gel with AcOEt/ dichloromethane 1:6, to give 384 mg of pure |rac]-l-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl|-cthanol.
MS: 309.1 (M+ll)1.
11J [racJ-5-(l-Chloro-cthyl)-4-cyclopropyl-2-(4-trifluoromethyl-phenvl)-pyrimidine
A solution of 357 mg (1.16 mmol) [rac]-l-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-ethanol and 0.09 ml (1.22 mmol) thionylchloride in 4 ml dichloromethanc were stirred for Ih at RT. The reaction mixture was concentrated under reduced pressure to provide 390 mg of pure [rac]-5-(l-chloro-ethyl)-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine.
MS: 327,4 (1VH 11) .
Example 29
|rac|-(4-{l-[4-Cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-ethoxy}-2-methyl-phcnoxy)-acctic acid

AJ [raclr(4j:li-14-Cyc.l.Qp.rQpyl-2-(4-trifluoromethyl-phenyl)-pyriniidin-5-yl]-ethoxy}-2-methyl-phenoxv)-acetic acid ethyl ester
180 ing (0.551 mmol) of |rac]-5-(l-chloro-ethyl)-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 28H), 116 mg (0.551 mmol) of (4-hydroxy-2-methyl-phenoxy)-acetic acid ethyl ester (WO02092590) and 31mg (0.71 mmol) sodium hydride (55% in oil) were stirred in 3 ml DMF over night. The reaction mixture was partitioned between ether and water. The crude product was purified by chromatography over silica gel with AcOHt/heptane 1:4 to give 157 mg of pure [rac]- (4-{l-[4-cyclopropyl-2-(4-trinuoromethyl-phenyl)-pyrimidin-5-yl]-ethoxy}-2-methyl-phenoxy)-acetic acid ethyl ester.
MS:501.4(M+H)'.
BJ [racJ-(4-{l-[4-Cvclopropyl-2-(4-trifluoromethyl-phenyl)-pvrimidin-5-yl|-ethoxy}-2-mcthyj-phenoxy)-acetic acid
154 mg (0.307 mmol) of [rac]-(4-{l-[4-cyclopropyl-2-(4-trifluorometriyl-phenyl)-pyrimidin-5-yl]-cthoxy}-2-methyl-phenoxy)-acetic acid ethyl ester and 0.62 ml IN LiOll in 1.6 ml THF were stirred for 2h at RT. The reaction mixture was taken up in ether and washed with IN HCI and water. The crude product was suspended in AcOKt/heptane 1:19 and the resulting crystals were filtered off to give 125 mg of pure |rac|-(4-{ l-|4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-ethoxy}-2-mcthyl-phenoxy)-acetic acid.
MS: 471.1 (M-ll). Example 30
|rac|-(4-{l-[4-Cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yI]-butylsulfanyl}-2-methyl-phenoxy)-aceticacid
_ [racj-(4-{l-[4-Cyclopropyl-2-(4-trifluoromethyl-phenvl)-pyrimidin-5-yl]-
butylsulfanyn-2-inethyl-phenoxy)-acetic acid /gr/-butyl ester
231 ing (0.7 mmol) cesium carbonate was added to a solution of 210 mg (0.59 mmol) |rac|-5-(l-chloro-butyl)-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 30D]) and 151 mg (0.59 mmol) (4-mercapto-2-methyl-phenoxy)-acetic acid /tjr/-butyl ester (example 28C]) in 3 ml DMF. After stirring for 3h at RT, the reaction mixture was taken up in ether and washed with IN HCI and water. The crude product

was purified by chromatography over silica gel with AcOEt/heptane 1: 9 providing 257 mg of pure fracj- (4-{ l-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-butylsulfanyl}-2-methyl-phenoxy)-acetic acid tert-butyl ester.
MS: 573.4 (M+lI)'.
BJ [racJ-(4-{l-[4-Cyclopropyl-2-(4-trifluoromethyl-phenvn-pyrimidin-5-yl]-
butylsulfanyl}-2-methyl-phenoxy)-acetic acid
A solution of 234 mg (0.44 mmol) [rac]-(4-{l-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-butylsulfanyl}-2-methyl-phenoxy)-acetic acid tert-butyl ester and 0.5 ml trifluoroacetic acid in 2.5 ml dichloromethane were stirred at RT for 4h. The solution was concentrated under reduced pressure and the crude product was repeatedly concentrated in vacuo with ether until a foam of 155 mg pure [rac]-(4-{ l-[4-cyclopropyl-2-(4-trinuoro-methyl-phenyl)-pyrimidin-5-yl]-butylsulfanyl}-2-methyl-phenoxy)-acetic acid resulted.
MS: 515.2 (M-H)
| rac|-5-( 1 -Chloro-butyl)-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine used in 30A| was synthesi/ed as follows:
CJ iracJ-l-[4-Cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-vl]-butan-l-ol
The synthesis was accomplished in the same way like 28C] and 28D], with the difference that methylmagncsium bromide was replaced by propylmagnesium bromide. [rac]-l-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-butan-l-ol was received.
MS: 337.0 (M I-H)'. DJJUigJr5j£L^hlQrg-butylj-4-cyclopropyl-2-(4-trifluorom
A solution of 392 mg (1.17 mmol) [rac]-l-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl|-butan-l-ol and 0.09 ml (1.22 mmol) thionylchloride in 4 ml dichloromethane were stirred at RT for Ih. After concentration under reduced pressure 421 mg of pure |rac|-5-(l-chloro-butyl)-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidinc was isolated.
MS: 355.81 (Mill)'.

Example 31
|rac|-(4-{l-[4-CyclopropyI-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl|-butoxy}-2-methyl-phenoxy)-acetic acid
AJ [rac|-(4-| l-[4-Cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-butoxy}-2-methyl-phenoxy)-acetic acid tert-butyl ester
28 mg (0.0.642 mmol) sodium hydride (55% in oil) was added to a solution of 175 mg (0.49 mmol) |racl-5-(l-chloro-butyl)-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 30D|) and 104 mg (0.49 mmol) (4-hydroxy-2-methyl-phenoxy)-acetic acid ethyl ester (WO02/092590) in 3 ml DMF. After stirring for 3h at RT, the reaction mixture was taken up in ether and washed with IN HCI and water. The crude product was purified by chromatography over silica gel with AcOEt/heptane 1: 4 providing 165 mg of pure [rac]-(4-{l-[4-cyclopropyl-2-(4-trifluoromethyI-phenyl)-pyrimidin-5-yl]-butoxy}-2-methyl-phenoxy)-acetic acid / MS: 529.0 (M+I I)1.
BJ [racj-(4-{^l-|4-Cyclopropyl-2-(4-trifluoromethvl-phenyl)-pvrimidin-5-yl]-butoxy}-2-methyl-phcnoxy)-acctic acid
A solution of 150 mg (0.261 mmol) [rac]-(4-{l-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin~5-yl|-butoxy}-2-methyl-phenoxy)-acetic acid fcr/-butyl ester and 0.52 ml IN lithium hydroxide solution in 1.5 ml THF were stirred at RT for 2h. The solution was partitioned between ether, IN HCI and water and the ether layer then concentrated under reduced pressure. The crude product was repeatedly concentrated in with ether until a foam of 121 mg pure [rac]-(4-{l-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylJ-butoxy}-2-methyl-phenoxy)-acetic acid was obtained.
MS: 478.49 (M-ll);
Example 32
2-{4-|4-Cyclopropyl-2-(4-trifluoromethyl-phcnyI)-pyrimidin-5-ylmethoxy]-2-methyl-phenoxy}~2-methyl-propionic acid
MJHM4^Cj/clopropvl-2-(4^ rjhenox-yj-2-iriethyl-propionic acid ethyl ester

In analogy to the procedure described in example 29AJ, 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) was reacted
with 5-chloromethyl-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 27FJ) to give the title compound as colorless solid.
MS:515.3(M+H)'.
lil2-14-|4-Cyclopropvl-2-(4-trifluoromethvl-phenvn-pvrimidin-5-vlmethoxv1-2-methvl-pji enoxy ) -2 -m
In analogy to the procedure described in example 29B], saponification of 2-{4-f4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester yielded the title compound as white crystals of mp. 19I.O-I92.2°C.
MS: 485.5 (M-H)'. Example 33
(2-Methyl-4-{methyI-[5-(4-trifluoromethyI-phenyl)-pyrazin-2-yImethyI]-amino}-phenoxy)-acetic acid
AJ (2-Methyl-4-{methyl-[5-(4-trifluoromethyl-phenyl)-pyrazin-2-ylmethyl]-amino}-phcnoxyj-acetic acid methyl ester
A suspension of 53 mg (0.39 mmol) potasium carbonate and 52 mg (0.35 mmol) sodium iodide and 73 mg (0.35 mmol) (2-methyl-4-methylamino-phenoxy)-acetic acid methyl ester (example 5F) in 2 ml of DMSO was treated with 32 mg (0.12 mmol) of 2-chloromethyl-5-(4-trifluoromethyl-phenyI)-pyrazine (example 33E]). After 1.5h at RT, the second portion of 32 mg (0.12 mmol) of 2-chloromethyl-5-(4-trifluoromethyl-phenyl)-pyra/ine was added. The third part was added after 2h. The reaction mixture was stirred for total 19h at RT. It was then taken up in ether and washed with aqueous 10% KHSO.rsolution and water. The organic phase was washed with NaCI (10%), dried (NaoSO.)) and evaporated. Purification by flash chromatography (SiO^, heptane/AcOHt=9/l) gave 126 mg of pure (2-methyl-4-{methyl-[5-(4-trifluoromethyl-phenyl)-pyra/in-2-ylmethyl]-amino}-phenoxy)-acetic acid methyl ester.
MS: 446.3 (M ( 1 1)'.

Bj (2-Methyl-4-!methyl-[5-(4-trif1uoromethyl-phenyl)-pyrazin-2-ylmethyl]-amino)-phcnoxy)-acetic acid
A solution of 110 mg (0.25 mmol) (2-methyl-4-{methyl-[5-(4-trifluoromethyl-phenyl)-pyrazin-2-ylmethyl]-amino}-phenoxy)-acetic acid methyl ester in 0.75 ml of THF and 0.75 ml cthanol was treated at 0 °C with 0.74 ml IN LiOH and stirred for 45 min at RT. The reaction was extracted with with aqueous 10% KHSO4 /Et2O (3x). The organic phase was washed with aqueous 10% NaCl, dried over Na2SC>4 and evaporated. The product was crystallized from ether to give pure (2-methyl-4-{methyl-[5-(4-trifluoromethyl-phenyl)-pyrazin-2-yImethyl]-amino}-phenoxy)-acetic acid.
MS: 432.4 (MHI)1.
2-Chloromethyl-5-(4-trifluoromethyl-phenyl)-pyrazine used in 33A] was synthesized as follows:
Cj 5-(4-TrifluoroiTicthyl-phenvl)-pvrazine-2-carboxylic acid methyl ester [Following a procedure of Ford, Alan; Sinn, Ekkehard; Woodward, Simon. Exploitation of differential reactivity of the carbon-chlorine bonds in 1,3-dichloroisoquinoline. Routes to new N,N-chelate ligands and 1,3-disubstituted isoquinolines. Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1997), (6), 927-934 1
A solution of 5.18 g (30 mmol) methyl 5-chloropyrazine-2-carboxylate in 150 ml
degassed DMF was treated with 3.47 g (0.1 mmol)
tetrakis(triphenylphosphine)palladium and heated at 80 °C. 6.27 g (33 mmol) of 4-(trifluoromethyl)ben/eneboronic acid and 14 66 g (45 mmol) of cesium carbonate were added and heated far 3.5h. The reaction was cooled to RT and extracted with H2O (0 °C)/Kt2O (3x). The organic phases were washed with aqueous 10% NaCl, dried (NaSO4) and evaporated. Purification by flash-chromatography on silica gel (heptane/AcOEt 95:5 to 2:1) gave 2.3 g (27%) of 5-(4-trifluoromethyl-phenyl)-pyrazine-2-carboxylic acid methyl ester.
MS: 283 (Mill)1.
0.585 g (2.07 mmol) of the above synthesized 5-(4-trifluoromethyl-phenyl)-pyrazine-2-carboxylic acid methyl ester in 10 ml of abs. THF was cooled down to -30 °C and

reacted with 5.18 ml of DIBAL-H-solution (1.2 M in toluene, 3 eq.) for 10 min. The reaction was warmed up during 2.5h to 10 °C and stirred Ih at RT. Careful quenching at 0 °C with saturated NaCI solution, twofold extraction with ether, washing with brine, drying over sodium sulfate, and evaporation of the solvents left a crude product which was purified by Hash chromatography (SiO2, heptane/AcOEt = 4/1) to deliver finally 0.325 g of the title compound as yellow solid.
MS: 254.1 (M)4. ^-J.2-Chioromethyl-5-(.4-trifluorornethyl-phenyl)-pyrazine
0.20 g (0.79 mmol) of the above prepared f5-(4-trifluoromethyl-phenyl)-pyrazin-2-yl|-methanol was dissolved in 8 ml of CH2CI2 and treated dropwise at 0 °C with 0.11 ml (2 eq.) of SOC12. The reaction mixture was kept at 0 °C for Ih, at RT for 18 h and 6 h at 30 °C. Evaporation of the solvents and dissolution in ether and heptane with consecutive evaporation afforded 0.21 g of pure title compound as light brown solid.
MS: 272.1 (M, Id)'. Example 34
2-Methyl-2-{2-methyI-4-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmcthoxy]-phcnoxy}-propionic acid
A| 2-Methyl-2-{2-methyl-4-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-
ylmcthoxyj-phenoxy}-propionic acid ethyl ester
To O.I 19 g (0.499 mmol) of 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) and 0.150 g (0.525 mmol) of the above prepared (example IN]) 3-chloromethyl-2-methyI-6-(4-trifluoromethyl-phenyl)-pyridine, dissolved in 3.3 ml ofabs. acetonitrile, was added 0.179 g of Cs2CO3 (0.549 mmol). The reaction was stirred over night at ambient temperature. Pouring onto crashed ice / NH.,CI-solution, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt^ 8/2) yielded 0.221 g of pure title compound as colorless oil.
MS: 488.4 (MtH)',
BJ 2-Mcthyl-2-{2-methvl-4-(2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-

0.221 g (0.453 mmol) of the above prepared 2-methyl-2-(2-methyl-4-[2-methyl-6-(4-trinuoromethyI-phenyl)-pyridin-3-ylmethoxy]-phenoxy}-propionic acid ethyl ester was dissolved in 2.7 ml of THF/EtOH=l/l, treated with 1.35 ml (3 eq.) of IN NaOH and kept at ambient temperature for 4 h. The reaction mixture was then poured onto crashed ice/AcOHt/HCI dil., the aqueous phase extracted again with AcOEt, the combined organic layers were washed with water, dried over sodium sulfate, and evaporated to dryness. Recrystallisation from AcOEt/hexane afforded finally 0.194 g of the title compound as white solid of mp. 164-165 °C.
MS: 458.2 (M-H)". Example 35
[racJ-2-Methyl-2-(2-mcthyl-4-{l-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-butoxy} -phenoxy)-propionic acid
A | The title compound was prepared in analogy to example 34, via [rac]-2-methyl-2-(2-melhyl-4-{ l-[2-methyl-6-(4-trinuoromethyl-phenyl)-pyridin-3-yl]-butoxy}-phenoxy)-propionie acid elhyl ester, but using in step AJ [rac]- 3-(l-chloro-butyl)-2-methyl-6-(4-trifluoroiTiethyl-phenyl)-pyridine (example 21B]) instead of 3-chloromethyl-2-methyl-6-(4-trinuoromethyl-phenyl)-pyridine, as colorless foam.
MS: 500.2 (M-H)'. Example 36
A ] [racJ-2-Mcthyl-2-(2-rnethyl-4-{l-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylj-propoxy]-phenoxyVpropionic acid
The title compound was prepared in analogy to example 34, via [rac]-2-methyl-2-(2-methyl-4-{ I-|2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-propoxy}-phenoxy)-propionic acid, but using in step A] [rac]-3-(l-chloro-propyl)-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (example 36 B]) instead of 3-chloromethyl-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine, as colorless foam.
MS: 486.3 (M-H)'.
|rac|-3-(l-Chloro-propyl)-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine used in 36A| was synthesized as follows:

BJ [racJ-3-(I -Chloro-propyl)-2-methyl-6-(4-trifluoromethyl-phenyl)-pvridine
Was prepared in analogy to example 17C], but using for the Grignard-reaction ethyl magnesium chloride instead of the methyl derivative, as colorless oil.
MS: 314.2, 316.2 (M HI)'. Example 37
|racJ-2-Methyl-2-(2-methyl-4-{l-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-cthoxy} -phenoxy)-propionic acid
A | The title compound was prepared in analogy to example 34, via [rac]-2-methyl-2-(2-methy!-4-{ l-|2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethoxy}-phenoxy)-propionic acid, but using in step A] [rac]-3-(l-chloro-ethyl)-2-methyl-6-(4-trit1uoromethyl-phenyl)-pyridine (example 17C|) instead of 3-chloromethyl-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine, as off-white foam.
MS: 472.1 (M-H). Example 38
2-{4-|6-(3-Fluoro-4-trifluoromethyI-phenyl)-2-methyl-pyridin-3-ylmethoxy]-2-mcthyl-phenoxy}-2-methyl-propionic acid
AJ 2-{4-[6-(3-Fluoro-4-trifluoromethyl-phenyl)-2-methyl-pvridin-3-ylmethoxy|-2-
mcthyl-phenoxy}-2-methvl-propionic acid ethyl ester
To 0.139 g (0.583 mmol) of 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) and 0.177 g (0.583 mmol) of 3-chloromethyl-6-(3-f1uoro-4-trinuoromethyl-phenyl)-2-methyl-pyridine (example 38C]), dissolved in 3 ml of abs. acetonitrile, was added 0.228 g of Cs2CO3 (0.700 mmol). The reaction mixture was stirred during 3 h at ambient temperature. Pouring onto crashed ice / NFUCl-solution, twofold extraction with AcOEt, washing with water and brine, drying over magnesium sulfatc, and evaporation of the solvents, followed by flash chromatography (SiO2, hcxane/AcOKt ^88/12) yielded 0.219 g of pure title compound as white solid.
MS: 506.4 (MH1)',

BJ 2-{4-[6-(3-Fluoro-4-trifluoromethyl-phenyl)-2-methyl-pyridin-3-ylmethoxyJ-2-
mcthyl-phenoxy}-2-methyl-propionic acid
0.214 g (0.423 mmol) of the above prepared 2-{4-[6-(3-fluoro-4-trifluoromethyl-phcnyl)-2-methyI-pyridin-3-ylmethoxy]-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester was dissolved in 0.85 ml of THF/EtOH=l/l, treated with 1.27 ml (3 eq.) of 1N NaOH and kept at ambient temperature for 2 h. The reaction mixture was then poured onto crashed ice/AcOEt/HCI dil., the aqueous phase extracted again with AcOEt; the combined organic layers were washed with water and brine, dried over magnesium sulfate, and evaporated to dryness. Recrystallisation from AcOEt/hexane yielded finally 0.191 g of the title compound as white crystals of mp. 175-76 °C.
MS: 476.1 (M-H).
3-Chloromethyl-6-(3-nuoro-4-trifluoromethyl-phenyl)-2-methyl-pyridine used in 38A| was synthesized as follows:
(:j.3-ChlQrom_cthyl-6-(3-fluoro-4-trifluoromethyl-phenyl)-2-methyl.-pyridine
was prepared in analogy to example 24B], but starting the whole reaction sequence with
l-(3-fluoro-4-trifluoromethyl-phenyl)-ethanone instead of l-(4-fluoro-3-
irifluoromethyl-phenyl)-ethanone, as off-white solid.
MS: 303.1,305.1 (M)(. Example 39
2-Methyl-2-{2-methyI-4-[2-methyl-6-(4-trifluoromethoxy-phenyl)-pyridin-3-ylmethoxy]-phenoxy}-propionicacid
AJ_2-Methyl-6-(4-trif1uoromethoxy-phenyl)-nicotinic acid methyl ester
was prepared in analogy to example 1L], but starting the whole reaction sequence with 4-(trifluoromethoxy) acetophenone instead of 4-(trifluoromethyl) acetophenone, as beige solid.
MS: 3ll.O(M)f.
BJ [2-Methyl-6-(4-trifluoromethoxy-phenyl)-pyridin-3-yl]-methanol

1.54 g (4.95 mmol) of the above synthesized 2-methyl-6-(4-trifluoromethoxy-phenyl)-nicotinic acid methyl ester in 25 ml of abs. THF was cooled down to -20 °C and reacted with 14.84 ml of DIBAL-H-solution (1.0 M in toluene, 3 eq.) for 0.5 h. Careful quenching with ice / HC1 dil., twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents left a crude product which was purified by flash chromatography (SiO2, hexane/AcOEt=l/l) to deliver finally 0.877 g of the title compound as off-white solid of mp. 68-69 °C.
MS: 283.0 (M)'.
CJ 3-Chloromethyl-2-methyl-6-(4-trifluoromethoxv-phenyl)-pyridine
0.300 g (1.059 mmol) of the above prepared [2-methyl-6-(4-trif!uoromethoxy-phenyl)-pyridin-3-yl]-mcthanol was dissolved in 5.3 ml of Ch^C^ and treated dropwise at 0°C with 0.15 ml (2 eq.) of SOCh. The reaction mixture was kept at 0 °C for 5 Min. and at RT for 30 Min. Pouring onto crashed ice / NaHCCh, twofold extraction with AcOEt, washing with water, drying over sodium sulfate and evaporation of the solvents generated 0.315 g of pure title compound as light yellow oil.
MS: 301.0, 303.0 (M)'.
I)J 2-Mcthyl-2-{2-methyl-4-[2-methyl-6-(4-trifluoromethoxy-phenyl)-pyridin-3-
ylmethoxyj-phcnoxy}-propionic acid ethyl ester
To 0.123 g (0.516 mmol) of 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) and 0.163 g (0.540 mmol) of the above prepared 3-chloromcthyl-2-methyl-6-(4-trifluoromethoxy-phenyl)-pyridine, dissolved in 4.7 ml of abs. acelonitrile, was added 0.184 g of CsaCOa (0.565 mmol). The reaction was stirred over night at ambient temperature. Pouring onto crashed ice / NfUCI-solution, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hcxane/AcOHt=8/2) yielded 0.243 g of pure title compound as colorless oil.
MS: 504.5 (MM 1)'.
EJ 2-Mcthyl-2-{2-methyl-4-[2-methyl-6-(4-trifluoromethoxv-phenyl)-pyridin-3-
ylmcthoxyj-phcnoxy}-propionic acid
0.243 g (0.483 mmol) of the above prepared 2-methy 1-2-{2-methyl-4-[2-methyl-6-(4-trinuoromethoxy-phenyl)-pyridin-3-ylmethoxy]-phenoxy}-propionic acid ethy ester was

dissolved in 2.9 ml olTI-IF/EtOH=l/l, treated with 1.45 ml (3 eq.) of IN NaOH and kept at room temperature for 4 h. The reaction mixture was then poured onto crashed ice/AcOHt/HCI dil., the aqueous phase extracted again with AcOEt; the combined organic layers were washed with water, dried over sodium sulfate, and evaporated to dryness. Recrystallisation from AcOEt/hexane produced finally 0.221 g of the title compound as white solid of mp. 149-151 °C.
MS: 474.1 (M-ll). Example 40
2-{4-[2-CyclopropyI-6-(4-trifluoromethyI-phenyl)-pyridin-3-ylmethoxy]-2-methyl-phenoxy}-2-methyl-propionic acid
A] 3-Amino-3-cyclopropyl-acrylic acid ethyl ester
To 6.54 g of activated (by successively washing with 2N HCI, water, EtOH, and ether) and dried 7,n dust (100 mmol) in 60 ml of abs. EtOH was added 0.4 ml of ethyl bromoacetate and the mixture refluxed under Ar for 20 Min., whereby the color turned greenish. 1.342 g of cyclopropyl cyanide (20 mmol) was then added, followed by the remaining 8.47 ml of ethyl bromoacetate (in total 80 mmol), and refluxing continued for another hour. The reaction mixture was cooled down, poured carefully onto crashed ice / Nal ICOs, and filtrated over Celite. The aqueous phase was extracted once more with AcOKt, the combined organic layers were washed with water and brine, dried over magnesium sulfate, and evaporated to dryness. Flash chromatography (SiC^, hexane/AeOHt==8/2) yielded 3.21 g of material containing according to NMR and GC/MS mainly the desired title compound, besides some 3-cyclopropyl-3-oxo-propionic acid ethyl ester (product of hydrolysis) and 3-oxo-butyric acid ethyl ester (seI (condensation of the reagent); however, it was used as such.
MS: 155 (M)'.
BJ g-Cyclopropyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid ethyl ester
0.657 g (2.33 mmol) of the above prepared (example 1L]) 3-dimethylamino-l-(4-trifluoromethyl-phenyl)-propan-l-one hydrochloride and 0.362 g (1.0 eq., not corrected for impurities) of the above synthesised 3-amino-3-cyclopropyl-acrylic acid ethyl ester was dissolved in 7 ml of AcOH and heated to reflux for 3h. After cooling, the bulk of

the solvent was evaporated i. V. Ensuing flash chromatography (SiO2, hexane/AcOEt==93/7) yielded 0.101 g of the title compound as light yellow solid.
MS: 336.2 (M+H)'.
CJ [2-Cyclopropyl-6-(4-trifluoromethyl-phenvl)-pyridin-3-yl]-methanol
0.193 g (0.576 mmol) of the above prepared 2-cycIopropyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid ethyl ester in 3.0 ml of abs. THF was cooled down to 0 °C and reacted with 1.5 ml of DIBAL-H-solution (1.0 M in toluene, 2.6 eq.) for 1 h. Careful quenching with ice, filtration over Celite, separation of the layers, reextraction of the aqueous phase with AcOEl, washing of the combined organic layers with NfyCl, and drying over magnesium sulfate was followed by evaporation of the solvents. The crude product was finally purified by Hash chromatography (SiOa, hexane/AcOEt=7/3) to deliver 0.128 g of the title compound as white crystals.
MS: 293.1 (M)'.
DJ 3-Chloromethvl-2-cyclopropyl-6-(4-trifluoromethyl-phenyl)-pyridine
0.127 g (0.433 mmol) of the above prepared [2-cyclopropyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl|-methanol was dissolved in 2.0 ml of CF^Cb and treated at 0°C with 0.063 ml (2 eq.) of SOCb. The reaction mixture was kept at 0 °C for 5 Min. and at RT for 60 Min. Pouring onto crashed ice / NaHCCh, twofold extraction with AcOEt, washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents afforded 0.137 g of pure title compound as off-white solid.
MS: 312.1, 314.0 (M+H)*.
HJ 2-[4-|2-Cyclopropyl-6-(4-trifluoromethyl-phenvn-pvridin-3-ylmethoxy]-2-methyl-p henoxy}-2-methy 1-propionic acid ethyl ester
To 0.102 g (0.428 mmol) of 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) and 0.134 g (0.429 mmol) of the above prepared 3-chloromethyl-2-cyclopropyl-6-(4-trifluoromethyl-phenyl)-pyridine, dissolved in 2.5 ml of abs. acetonitrile, was added 0.168 g of CS2CO3 (0.516 mmol). The reaction was stirred over night at ambient temperature. Pouring onto crashed ice / NIUCI-solution, twofold extraction with AcOEt, washing with water and brine, drying over magnesium sulfate. and evaporation of the solvents, followed by flash chromatography i, hexane/AcOKt 88/12) yielded 0.221 g of pure title compound as colorless oil.

MS: 514.5 (M HI)'.
FJ 2-{4-[2-Cyclopropyl-6-(4-trifluoromethvl-phenvl')-pvridin-3-vlmethoxv]-2-methvl-phenoxy}-2-methyl-propionic acid
0.220 g (0.428 mmol) of the above prepared 2-{4-[2-cyclopropyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethoxy]-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester was dissolved in 2.6 ml of THF/EtOH= 1/1, treated with 1.30 ml (3 eq.) of IN NaOH and kept at room temperature for 2 h. The reaction mixture was then poured onto crashed ice/AcOEt/HCl dil., the aqueous phase extracted again with AcOEt; the combined organic layers were washed with water and brine, dried over magnesium sulfate, and evaporated to dryness. Recrystallisation from AcOEt/hexane afforded eventually 0.198 g of the title compound as white crystals of mp. 170-171 °C.
MS: 484.2 (M-H)~. Example 41
|rac]-2-Methyl-2-(2-methyI-4-{l-[2-methyl-6-(3-trifluoromethyl-phenyl)-pyridin-3-yl |-butoxy}-phenoxy)-propionic acid
A | Fhc title compound was prepared in analogy to example 8, via [rac]-2-methyl-2-(2-mcthyl-4-{l-|2-mcthyl-6-(3-trifluoromethyl-phenyl)-pyridin-3-yl]-butoxy}-phenoxy)-propionic acid ethyl ester, but using in step A] [rac]- 3-(l-chloro-butyl)-2-methyl-6-(3-trifluoromethyl-pheny!)-pyridine (example 4B]) instead of 3-chloromethyl-2-methyl-6-(3-trifluoromcthyl-phenyl)-pyridine, as white foam.
MS: 500.2 (M-H)'. Exam pic 42
2-{4-|4-Cyclopropyl-2-(3-trifluoromethyI-phenyl)-pyrimidin-5-ylmethoxy]-2-methyI-phenoxy}-2-methyI-propionic acid
A J 4-Cyclopropyl-2-(3-trifluoromethvl-phenvn-pvrimidine-5-carboxylic acid ethyl ester
To a solution of 0.953 g (4.24 mmol) commercially available 3-trifluoromethyl-ben/amidine hydrochloride in 10 ml of ethanol was added 0.408 g (4.25 mmol) of sodium tert-butoxide. Two Min. later, 0.901 g (4.25 mmol) of crude (E,Z)-2-cyclopropane-carbonyl-3-ethoxy-acrylic acid methyl ester (example 27C], containing

some Kt-ester) was added and the reaction allowed to proceed over night at RT. The mixture was then poured onto crashed ice/AcOEt/HCl dil., the aqueous phase extracted again with AcOEt, the combined organic layers were washed with water, dried over sodium sulfate, and evaporated to dryness. Flash chromatography (SiOj, hexane/AcOEt= 9/1) yielded finally 1.253 g of title compound as white waxy solid (mixture of Me/Et-cster).
MS: 322.1, 336.0 (M)4.
I*J [4-Cyclopropyl-2-(3-trifl.uoromethyl-phenyl)-pyrimidin-S-yl]-methanol
1.250 g (3.717 mmol) of the above prepared 4-cyclopropyl-2-(3-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid ethyl ester in 19ml of abs. THF was cooled down to -15 °C and reacted with I 1.2 ml of DIBAL-H-solution (1.0 M in toluene, 3 eq.) for 1/2 h. Careful quenching with ice / HCI dil., twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents left a crude product which was purified by flash chromatography (SiC>2, hexane/AcOEt=l/l) to yield finally 1.096 g of the title compound as white solid of mp. 108-09 °C.
MS: 294.1 (M)'.
Cj 5-Chloromethyl-4-cyclopropyl-2-(3-trifluoromethyl-phenyl)-pvrimidine
0.300 g (1.019 mmol) of the above prepared [4-cyclopropyl-2-(3-trifluoromethyl-phenyl)-pyrimidin-5-yl|-methanol was dissolved in 5 ml of C^Clj and treated at 0°C with 0.15 ml (2 eq.) of SOC^. The reaction mixture was kept at 0 °C for 5 Min. and at ambient temperature for 30 Min. Pouring onto crashed ice / NaHCO3, twofold extraction with AcOEl, washing with water, drying over sodium sulfate, and evaporation of the solvents gave 0.315 g of pure title compound as white solid of mp. 92-95 °C.
MS: 312.1,314.0 (M)1.
DJ 2-{4-[4-Cyclopropyl-2-(3-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-2-methyl-phcnoxy}-2-methyl-propionic acid ethyl ester
To O.I 14 g (0.478 mmol) of 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid
ethyl ester (described in WO 02/092590) and 0.157 g (0.502 mmol) of the above
prepared 5-chloromethyl-4-cyclopropyl-2-(3-trifluoromethyl-phenyl)-pyrimidine,
dissolved in 4.4 ml of abs. acetonitrile, was added 0.171 g of Cs2CO3 (0.525 mmol). The reaction was stirred over night at ambient temperature. Pouring onto crashed ice / HCI

dil.-solution, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (SiC>2, hexane/AcOEt= 8/2) yielded 0.240 g of pure title compound as white waxy solid.
MS: 515.4 (M+H)'.
HJ 2-{4-[4-Cvclopropyl-2-(3-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxyj-2-methyl-phenoxy}-2-methyl-propionic acid
0.240 g (0.466 mmol) of the above prepared 2-{4-[4-cyclopropyl-2-(3-trifiuoromethyl-phenyl)-pyrimidin-5-ylmethoxyJ-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester was dissolved in 2.8 ml of THI7EtOH=l/l, treated with 1.40 ml (3 eq.) of IN NaOH and kept at ambient temperature for 7 h. The reaction mixture was then poured onto crashed ice/AcOEl/HCl dil., the aqueous phase extracted again with AcOEt; the combined organic layers were washed with water, dried over sodium sulfate, and evaporated to dryness. Recrystallisation from AcOEt/hexane afforded finally 0.196 g of the title compound as white solid of mp. 175-176 °C.
MS:485.2(M-H). Example 43
2-Mcthyl-2-(2-methyl-4-{2-[2-inethyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-cthoxy}-phcnoxy)-propionic acid
AJ|j-Mcthyl-6-(4-trifluoromethyl-phenyn-pvridin-3-vl]-acetonitrile
27.2 g of the above (example IN]) prepared 3-chloromethyl-2-methyl-6-(4-lriniioromethyl-phcnyl)-pyridine (95.2 mmol) was dissolved in 100 ml of dimethyl sulfoxide; 5.9 g of sodium cyanide (120 mmol) was added and the mixture was stirred at room temperature for 18 hours. The reaction mixture was then poured onto a mixture of ice and water and was subsequently extracted with 3 portions of 400 ml of tert-butyl methyl ether. The combined organic layers were washed with water, then with brine, and dried over sodium sulfate. After evaporation of the solvents, 25.2 g of the title compound was obtained as pale yellow solid.
MS: 276.1 (M)'.

Bj |2-Methyl-6-(4-trit1uoromethyl-phenyl)-pyridin-3-vl]-acetic acid
A mixture of 25 g (90 mmol) of the above prepared [2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl|-acetonitrile, 20 g of sodium hydroxide (500 mmol), 60 ml of water, and 250 ml of propanol was stirred vigorously at 100 °C. Hydrolysis was complete after 2 hours. The reaction mixture was then evaporated to dryness and the residue was redissolved in 70 ml of water; 60 ml of cold 8 N aqueous HC1 was then added and the acid extracted with three portions of 250 ml of ethyl acetate; the combined organic phases were washed with water and brine, dried over sodium sulfate, and evaporated to dryness. Thereby, 25.1 g of the title product was obtained as pale yellow solid.
MS: 296.0 (M HI)'.
CJ [2-Methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-vl]-acetic acid methyl ester
A solution of 2.55 g (8.63 mmol) of the above prepared [2-methyl-6-(4-trifluoromethyl-phcnyl)-pyridin-3-yl|-acetic acid in 25 ml of methanol was cooled to -10 °C; 1.88 ml (25.9 mmol) of thionyl chloride was added and the reaction mixture was then stirred at ambient temperature for 2 hours. Subsequently, the solution was poured onto ice water, then extracted with three portions of 50 ml of tert.-butyl methyl ether. The combined organic layers were washed with water, aqueous NaHCC^-solution and brine, and dried over sodium sulfate. After evaporation of the solvents, 2.60 g of the title compound was obtained as light brown solid.
MS:309.I(M)f.
l)| 2-[2-Methvl-6-(4-trif1uoromethyl-phenvl)-pyridin-3-yl]-ethanol
2.60 g (8.40 mmol) of the above prepared [2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl)-acetic acid methyl ester, dissolved in 15 ml of dry tetrahydrofuran, was added under an argon atmosphere within 15 minutes to a stirred suspension of 0.38 g (10 mmol) of lithium aluminum hydride in 5 ml of tetrahydrofuran. The reaction was exothermic. Subsequently, the mixture was stirred at room temperature for 1 hour to complete the reduction. Then, I ml of ethyl acetate was added dropwise to destroy the excess of reagent, followed by water, drop after drop, under argon, with stirring and cooling. The reaction mixture was diluted with 50 ml of ethyl acetate, dried over sodium sulfate, and filtered. The filtrate was evaporated i. V. and the residue was purified by

chromatography on Si(>2 with a mixture of dichloromethane and tert.-butyl methyl ether (4:1) as eluent. Thereby, 1.88 g of the title compound was obtained as white solid.
MS: 281.1 (M)'.
Kj 2-Methyl-2-(2-methyl-4-{2-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-cthoxy|-phcnoxy)-propionic acid ethyl ester
0.181 g (0.642 mmol) of the above prepared 2-[2-methyl-6-(4-trifluorornethyl-phenyl)-pyridin-3-yl]-ethanol and 0.153 g (0.642 mmol) of 2-(4-hydroxy-2-methyl-phenoxy)-2-mcthyl-propionic acid ethyl ester (described in WO 02/092590) were dissolved in 8 ml of abs. THF and treated successively at 0° C with 0.156 g (0.771 mmol) of tributylphosphinc and 0.133 g (0.770 mmol) of N,N,N',N'-lelramethyla/odicarboxamide. The cooling bath was then removed and stirring continued for one night. Filtration over a pad of Celite, evaporation of the solvent, followed by Hash chromatography (SiO2, hexane/AcOEt= 85/15), delivered 0.070 g of the title compound as colorless oil.
MS: 502.4 (Mill)'.
FJ 2-Mcthyl-2-(2-methyl-4-j2-[2-methvl-6-(4-trifluoromethyl-phenvl)-pvridin-3-yH-cthoxyj-phenoxy)-propionic acid
0.070 g (0.140 mmol) of the above prepared 2-methyl-2-(2-methyl-4-{2-[2-methyl-6-(4-trinuoromethyl-phenyl)-pyridin-3-yl]-ethoxy}-phenoxy)-propionic acid ethyl ester was dissolved in 0.84 ml of THF/EtOH=l/l, treated with 0.42 ml (3 eq.) of IN NaOH and kept at ambient temperature for 4 h. The reaction mixture was then poured onto crashed icc/AcOHt/HCI dil., the aqueous phase extracted again with AcOEt; the combined organic layers were washed with water, dried over sodium sulfate, and evaporated to dryncss to yield 0.057 g of the title product as light yellow foam.
MS: 472.1 (M-IIV.

Example 44
2-Methyl-2-{2-methyl-4-[6-(4-trifluoromethyI-phenyl)-pyridazin-3-yImethoxy]-phcnoxy}-propionic acid
A | 6-(4-'['rinuprQir>ethyl-phenyl)-pyridazine-3-carboxylic acid methyl ester
0.400 g (2.32 mmol) of the known 6-chloro-pyridazine-3-carboxylic acid methyl ester was dissolved in 12 ml of abs. DMF and treated with 0.268 g (0.232 mmol) of Pd(Ph3P)4. Alter heating to 80° C, 0.572 g (3.01 mmol) of 4-(trifluoromethyl)benzeneborinic acid and 1.133 g (3.48 mmol) of CS2CO3 was added and the reaction allowed to proceed for 3.5 h at the same temperature. After cooling, the mixture was poured onto crashed ice, extracted twice with AcOEt, washed with brine and water, and dried over sodium sulfate. Evaporation of the solvents i. V., followed by flash chromatography (SiCh, hcxane/AcOEt = 1/1) delivered 0.316 g of a reddish solid which was recrystallised from hcxane/AcOEl to remove remaining impurities. Thereby, 0.230 g of the title compound was isolated.
MS: 282.1 (M)'.
BJ [6-(4Tril1uoromcthyl-phenyl)-pyridazin-3-vl]-methanol
0.582 g (2.062 mmol) of the above prepared 6-(4-trifluoromethyl-phenyl)-pyridazine-3-carboxylic acid methyl ester in 20 ml of abs. THF was cooled down to -15 °C and reacted with 5.16 ml of DIBAL-H-solution (1.0 M in toluene, 2.5 eq.) for 1/2 h. Careful quenching with ice / HCI dil., twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents left a crude product which was purified by Hash chromatography (SiC>2, AcOEt) to yield 0.155 g of the title compound as light brown solid.
MS: 254.1 (M)1.
2-Methyl-2-{2-methyl-4-[6-(4-trifluoromethyl-phenyl)-pyridazin-3-ylmethoxy1-phenoxyj-propionic acid ethyl ester
0.170 g (0.669 mmol) of the above prepared [6-(4-trifluoromethyl-phenyl)-pyridazin-3-yl|-methanol and 0.163 g (0.684 mmol) of 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) were dissolved in 8 ml of abs. THF and treated successively at 0° C with 0.162 g (0.800 mmol) of tributylphosphine and 0.139 g (0.804 mmol) of N,N,N',N'-tetramethylazodicarboxamide. The cooling bath

was then removed and stirring continued for one night. The reaction mixture was then poured onto crashed ice. extracted twice with AcOEt, washed with water, and dried over sodium sulfate. Evaporation of the solvents i. V., followed by flash chromatography (Si()2, hexane/AcOKt = 7/3) yielded, after recrystallisation from hexane/AcOEt, 0.208 g of a colorless solid.
MS: 475.4 (M+H)'.
DJ 2-fV1ethyl-2-{2-methyl-4-[6-(4-trit1uoromethyl-phenyn-pyridazin-3-ylmethoxyJ-
phenoxyl-propjonjc acid
0.183 g (0.386 mmol) of the above prepared 2-methyl-2-{2-methyl-4-[6-(4-triniioromethyl-phenyl)-pyridazin-3-ylmethoxy]-phenoxy}-propionic acid ethyl ester was dissolved in 8 ml of THF/EtOH=l/l, treated with 1.16 ml (3 eq.) of IN NaOH and kept at ambient temperature over night. The reaction mixture was then poured onto crashed ice/AcOEt/MCI dil., the aqueous phase extracted again with AcOEt; the combined organic layers were washed with water, dried over sodium sulfate, and evaporated to dryness to yield, after recrystallisation from hexane/AcOEt, 0.160 g of the title compound as light yellow crystals of mp. 191-192 °C.
MS: 445.1 (M-ll)'. Example 45
2-{4-(2-Mcthoxymcthyl-6-(4-trifluoromethyl-phenyI)-pyridin-3-ylmethoxy]-2-methyl-phenoxy}-2-methyl-propionic acid
AJ 2-Bromomethyl-6-(4-trifluoromethvl-phenvl)-nicotinic acid methyl ester
1.97 g (6.67 mmol) of 2-methyl-6-(4-trifluoromethyl-phenyl)-nicotimc acid methyl ester (example 1L|) was dissolved in 20 ml of CC14 and treated with 1.781 g (10.0 mmol) of N-bromosuccinimide and 0.126 g (0.669 mmol) of dibenzoyl peroxide. The mixture was refluxcd (oilbath temperature 95 °C) and the course of the bromination followed by GC. After 5 h, the reaction mixture was poured onto crashed ice, extracted twice with AcOEt, washed with water and brine, and dried over magnesium sulfate. Evaporation of the solvents i. V., followed by careful flash chromatography (SiO2, hexane/AcOEt= 92/8), afforded 1.39 g of the title compound as white crystals, contaminated with roughly 5 % of the dibromo-analoguc.
MS: 373.9, 375.9 (M)'.

131 2-Mcthoxymethyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid methyl ester
To 0.401 g (1.072 mmol) of the above prepared 2-bromomethyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid methyl ester, dissolved in 4.0 ml of abs. MeOH, was added 0.116 g (2.15 mmol) of sodium methoxide and the mixture stirred for 4 h at ambient temperature, when TLC indicated the complete disappearance of starting material. Pouring onto crashed ice / NH4CI-solution, twofold extraction with AcOEt, washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt= 9/1), produced 0.279 g of pure title compound as white solid.
MS: 326.2 (M+H)f.
CJ [2-Methpxymethyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-methanol
0.364 g (1.119 mmol) of the above prepared 2-methoxymethyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid methyl ester in 6 ml of abs. THF was cooled down to 0 °C and reacted with 2.8 ml of DIBAL-H-solution (1.0 M in toluene, 2.5 eq.) for 1 h. Careful quenching with icewater, filtration over a pad ofCelite, twofold extraction with AcOEt, washing with NILjCI-solution, drying over magnesium sulfate, and evaporation of the solvents left a crude product which was purified by flash chromatography (SiO2, hexanc/AcOEt M/l) to yield finally 0.312 g of the title compound as colorless oil.
MS: 298.1 (M+H)'. DJ3-CM»»""methvl-2-methoxyrnethvl-6-(4-trifluorornethyi-phenvl)-pyridine
0.311 g (1.046 mmol) of the above prepared [2-methoxymethyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-methanol was dissolved in 4 ml of CH2C12 and treated at 0°C with 0.15 ml (2 eq.) of SOCI2. The reaction mixture was kept at 0 °C for 5 Min. and at ambient temperature for 60 Min. Pouring onto crashed ice / NaHCO3, twofold extraction with AcOEt, washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents produced 0.330 g of pure title compound as colorless oil.
MS:3l6.0,3l8.0(M+H)f.
jjj 2J^4j^2-Methoxymethvl-6-(4-trifluoromethvl-phenvl)-Pvridin-3-vlrnethoxv1-2-
meth^J-phenoxvl-2-iTiethyl-propionic acid ethyl ester

To 0.097 g (0.407 mmol) of 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid
ethyl ester (described in WO 02/092590) and 0.145 g (0.459 mmol) of the above
prepared 3-chloromethyl-2-methoxymethyl-6-(4-trifluoromethyl-phenyl)-pyridine,
dissolved in 2.5 ml of abs. acetonitrile, was added 0.180 g of Cs2CC>3 (0.552 mmol). The reaction was stirred for 22 h at ambient temperature. Pouring onto crashed ice / NFUCl-solution, twofold extraction with AcOEt, washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOHt= 88/12), gave 0.214 g of pure title compound as colorless oil.
MS: 518.3 (M HI)'.
FJ 2-{4-[2-Mcthoxymcthyl-6-(4-trifluoromethvl-phenvl)-pyridin-3-vlmethoxvl-2-
nicthyl-phenoxy} -2-methyl-propionic acid
0.213 g (0.412 mmol) of the above prepared 2-{4-[2-methoxymethyl-6-(4-trinuoromethyl-phenyl)-pyridin-3-ylmethoxy|-2-methyl-phenoxy} -2-methyl-propionic acid ethyl ester was dissolved in 2.6 ml of THF/EtOH=l/l, treated with 1.3 ml (3 eq.) of IN NaOII and kept at ambient temperature over night. The reaction mixture was then poured onto crashed ice/AcOEt/HCl dil., the aqueous phase extracted again with AcOEt; the combined organic layers were washed with water, dried over magnesium sulfate, and evaporated to dryness to yield, after recrystallisation from hexane/AcOEt, 0.186 g of the title compound as white crystals of mp. 121-122 °C.
MS: 488.2 (M-H). Example 46
|rac|-(2-Methyl-4-{l-|2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yI]-butoxy}-phenoxy)-acetic acid
A | The title compound was prepared in analogy to example 35, via [rac]-(2-methyl-4-{l-|2-methyl-6-(4-trilluoromethyl-phenyl)-pyridin-3-yl]-butoxy}-phenoxy)-acetic acid ethyl ester, but using in step Aj (4-hydroxy-2-methyl-phenoxy)-acetic acid ethyl ester (WO02092590) instead of 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester, as colorless, viscous oil.
MS: 472.1 (M-II).

Example 47
lrac|-(2-Mcthyl-4-{l-|2-methyl-6-(3-trifluoromethyl-phenyl)-pyridin-3-yl]-ethoxy}-phcnoxy)-acetic acid
A | The title compound was prepared in analogy to example 46, via [rac]-(2-methyl-4-{ 1-12-methy l-6-(3-tri fluoromethyl-phenyl)-pyridin-3-yl]-ethoxy} -phenoxy)-acetic acid ethyl ester, but using in step A] [rac]-3-(l-chloro-ethyl)-2-methyl-6-(3-trifluoromethyl-phenyl)-pyridine (example 3C]) instead of [rac]-3-(l-chloro-butyl)-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine as colorless solid.
MS: 444.1 (M-H)'. Example 48
|rac|-(2-lMethyl-4-{l-[2-methyl-6-(3-trifluoromethyl-phenyl)-pyridin-3-yI]-butoxy}-phcnoxy)-acctic acid
A | The title compound was prepared in analogy to example 47, via [rac]-(2-methyl-4-{ 1 -12-methyl-6-(3-trinuoromethyl-phenyl)-pyridin-3-yl]-butoxy}-phenoxy)-acetic acid ethyl ester, but using in step A] |rac]-3-(l-chloro-butyl)-2-methyl-6-(3-trifluoromethyl-phenyl)-pyridine (example 4B]) instead of [rac]-3-(l-chloro-ethyl)-2-methyl-6-(3-triiluoromethyl-phenyl)-pyridine as light yellow oil.
MS: 472.1 (M-H). Example 49
(rac|-(2-Methyl-4-{l-[2-mcthyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-propoxy}-phcnoxy)-acetic acid
A | The title compound was prepared in analogy to example 48, via [rac]-(2-methyl-4-{l-|2.-methyl-6-(4-trinuoromethyl-phenyl)-pyridin-3-yl]-propoxy}-phenoxy)-acetic acid ethyl ester, but using in step A] [racJ-3-(l-chloro-propyl)-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (example 36B]) instead of [rac]-3-(l-chloro-butyl)-2-methyl-6-(3-trilluoromethyl-phenyl)-pyridine as light yellow foam.
MS: 458.2 (M-H), Example SO

[racj-(2-Methyl-4-{l-[2-methyl-6-(4-trifluoroinethyl-phenyl)-pyridin-3-yl]-ethoxy}-phcnoxy)-acctic acid
A | The title compound was prepared in analogy to example 49, via [rac]-(2-methyl-4-{ 1-|2-methyl-6-(4-trinuoromethyl-phenyl)-pyridin-3-yl]-ethoxy}-phenoxy)-acetic acid ethyl ester, but using in step A] [rac]-3-(l-chloro-ethyl)-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (example 17C]) instead of [rac]-3-(l-chloro-propyl)-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine as off-white foam.
MS: 444.1 (M-H). Example 51
2-{4-[2-Dimcthylaminomethyl-6-(4-trifluoroinethyl-phenyl)-pyridin-3-ylmethoxy]-2-methyl-phenoxy}-2-methyl-propionic acid
A| 2-Dimethylaminomethyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid methyl ester
0.102 g (0.273 mmol) of the above (example 45A]) prepared 2-bromomethyl-6-(4-trifluoromethyl-pheny!)-nicotinic acid methyl ester was dissolved in 1.5 ml of acctonitrile and treated with 0.027 g (0.331 mmol) of dimethylamine hydrochloride and 0.080 ml (2 eq.) of triethylamine. After stirring for 2 h at ambient temperature, the reaction mixture was poured onto crashed ice / KHSCVsolution and extracted twice with AcOKt. Washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (SiOj, AcOEt/MeOH/NEt3= 9/1/0.05), produced 0.047 g of pure title compound as off-white crystals.
MS: 339.2 (M+H)1.
BJ [2-Dimethvlaminomethyl-6-(4-trifluoromethvl-phenyl)-pvridin-3-yl]-methanol
0.046 g (0.136 mmol) of the above prepared 2-dimethylaminomethyl-6-(4-trifluoro-methyl-pheny!)-nicotinic acid methyl ester was dissolved in 1 ml of abs. diethylether and cooled down to -10°. 0.005 g (1 mol-eq.) of LiAlhU was added and stirring continued for 2 h at the same temperature. The reaction mixture was then quenched with 2 drops of cone. NaOIl and, after vigorously stirring for another 3 h, filtered over a pad ofCelite. Careful washing with AcOEt and evaporationof the solvents left finally 0.038 g of the title compound as light yellow solid.
MS: 311.2 (Mill)'.

CJ 2-{4-[2-Dimethylaminomethyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethoxy]-2-mcthyl-phenoxy}-2-methyl-propionic acid ethyl ester
0.170 g (0.548 mmol) of the above prepared [2-dimethylaminomethyl-6-(4-trilluoromethyl-phcnyl)-pyridin-3-yl]-methanol and 0.122 g (0.512 mmol) of 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) were dissolved in 6 ml of abs. THF and treated successively at 0° C with 0.133 g (0.658 mmol) of tributylphosphine and 0.114 g (0.659 mmol) of N,N,N',N'-tetramethylazodicarboxamide. The cooling bath was then removed and stirring continued for additional 6 h. 'The reaction mixture was then poured onto crashed ice, extracted twice with AcOEt. washed with water and brine, and dried over magnesium sulfate. Evaporation of the solvents i. V., followed by flash chromatography (SiCh, hexanc/AcOKt- 25/75) yielded 0.016 g of the title product as yellow oil.
MS: 531.3(M+H)'.
DJ 2-[4-[2-Dimethylaminomethyl-6-(4-trifluoromethvl-phenvl)-pyridin-3-ylmethoxy]-2-iTicthyl-phenoxy}-2-mcthyl-propionic acid
0.015 g (0.028 mmol) of the above prepared 2-{4-[2-dimethylaminomethyl-6-(4-trinuoromcthyl-phcnyl)-pyridin-3-ylmethoxyJ-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester was dissolved in 1.0 ml of THF/EtOH=l/l, treated with 0.5 ml (18 eq.) of IN NaOH and kept at ambient temperature over night. The reaction mixture was then poured onto crashed ice/HCI dil. to adjust the pH to 3, the aqueous phase was extracted twice with AcOEl, the combined organic layers were washed with water and brine, dried over sodium sulfate, and evaporated to dryness to yield 0.014 g of the title compound as off-white amorphous solid.
MS:503.4(M+ll)'.
Example 52
2-Methyl-2-{3-|(mcthyl-{2-[2-methyI-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetylj-amino)-methyl]-phenoxy}-propionic acid
AJ 2-(3-Cyano-phcnoxy)-2-methyl-propionic acid ethyl ester
5.0 g (42.0 mmol) of 3-hydroxybenzonitrile and 16.25 ml = 21.29 g (109 mmol) of ethyl-bromoisobutyrate were dissolved in 70 ml acetonitrile; then, 17.40 g (126 mmol) of potassium carbonate were added and the reaction mixture stirred for 16 hours at 80 °C

(reilux). It was then cooled down to ambient temperature and the solvent was evaporated. The residue was partitioned between water and ether and extracted twice with ether; the organic phases were washed with water, dried (MgSO4) and evaporated. The crude product was purified by flash chromatography (SiC>2, heptane/AcOEt) to finally give 9.10 g of the title compound as colorless oil.
MS: 233.2 (M)'.
B J 2-(3 - A m inomcthyl-phenoxy)-2-rnethyl-propionic acid ethyl ester
8.56 g (36.7 mmol) of 2-(3-cyano-phenoxy)-2-methyl-propionic acid ethyl ester was dissolved in 65 ml ethanol; then, 6.5 ml acetic acid was added, followed by 0.9 g Pd-C (10%) and the reaction mixture was hydrogenated under 1 atm of Fb-pressure during 5 hours. Then, it was filtered (Celite), the filter cake was washed twice with ethanol and the solvents were evaporated. The residue was partitioned between crashed ice / IN NaOll / EtOAc and extracted twice with EtOAc; the organic phases were washed with water, dried (MgSC)4) and evaporated. The crude product was purified by flash chromatography (SiO2, MeCb / MeOH) to give 7.71 g of the title compound as colorless oil.
MS: 238.3 (MilI)'.
Cj 2-Methyl-2-(3-methylaminomethyl-phenoxv)-propionic acid ethyl ester
In analogy to the procedures described in example 5D], 5E] and 5F], 2-(3-aminomethyl-phenoxy)-2-methyl-propionic acid ethyl ester was converted into the corresponding tert-butoxycarbonylamino derivative by treatment with di-tert-butyl dicarbonate and sodium hydrogen carbonate in dioxane/water at r.t., methylated at N and deprotected again to yield the title compound as a yellow oil.
MS: 252.2 (MHI)'.
DJ_ 2-Methvl-2-i3-|(methvl-l2-[2-methvl-6-(4-trifluoromethvl-Dhenvn-pvridin-3-vll-
acetyl}-amino)-mcthyl]-phenoxy}-propionic acid
In analogy to the procedures described in example 26B] and 26C], 2-methyl-2-(3-melhylaminomethyl-phenoxy)-propionic acid ethyl ester was reacted with [2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid (example 26E]) to give 2-methyl-2-{3-|(methyl-{2-|2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetyl}-amino)-

mcthyl|-phenoxy}-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless foam.
MS: 499.1 (M-H)'. Example S3
2-|3-({I4-Cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbonyl]-methyl-amino}-mcthyl)-phcnoxy|-2-methyl-propionic acid
A| In analogy to the procedures described in example 26B] and 26C], 2-methyl-2-(3-methylaminomethyl-phenoxy)-propionic acid ethyl ester (example 52C]) was reacted with 4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid (example 53B|) to give 2-[3-({[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbonyl|-methyl-amino}-methyl)-phenoxy]-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
MS: 512.2 (M-H).
The necessary building block 4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid used in procedure above was prepared as follows:
BJ 4-Cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid
The solutions of 3.6 g (10.7 mmol) of 4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid ethyl ester (example 27D]) in 40 ml of ethanol and of 1.07 g (26.7 mmol) of sodium hydroxide in 5 ml of FbO were mixed and then refluxed for 1 hour. After cooling to ambient temperature, 6.7 ml of 4N aqueous hydrochloric acid was added. The reaction mixture was extracted with three portions of ethyl acetate. The combined organic phases were washed with water and brine and dried over anhydrous sodium sulfate. The 4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid crystalli/cd upon concentrating the solution by evaporation. After cooling in an ice bath, 3.08 g of white crystals were obtained (84 % of theory).
MS: 307.2 (M-H).

Example 54
2-MethyI-2-[3-({mcthyl-[2-methyl-6-(4-trifluoromethyI-phenyl)-pyridine-3-carbonyl]-amino}-methyl)-phenoxy]-propionic acid
In analogy to the procedures described in example 26B] and 26C], 2-methyl-2-(3-methylarninomethyl-phenoxy)-propionic acid ethyl ester (example 52C]) was reacted with 2-methyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid (prepared from 2-methyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid methyl ester (example 1L]) in analogy to the procedure described in example 53B]) to give 2-rnethyl-2-[3-({rnethyl-[2-methyl-6-(4-trinuoromethyl-phcnyl)-pyridine-3-carbonyl]-amino}-methyl)-phenoxy]-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless amorphous solid.
MS: 485.3 (M-H). Example 55
2-Mcthyl-2-[3-(2-{2-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetylamino}-cthyl)-phcnoxy]-propionic acid
AJ 2-(3-l'ormyl-phcnoxy)-2-methyl-propionic acid ethyl ester
In analogy to the procedure described in example 52A], 3-hydroxy-benzaldehyde was reacted with ethyl-bromoisobutyrate to give the title compound in form of a grey viscous
oil.
BJ 2-Methy 1:2-13-((1 :)-2-nitro-vinyl)-phenoxy]-propionic acid ethyl ester
7.8 g (33 mmol) of 2-(3-formyl-phenoxy)-2-methyl-propionic acid ethyl ester was dissolved in 50 ml glacial acetic acid; then, 10.7 ml = 12.09 g (198 mmol) of nilromethane and 7.93 g (106 mmol) of ammonium acetate were added and the reaction mixture heated for 30 min. at reflux temperature. After cooling to ambient temperature, it was poured into crashed ice and extracted twice with ethyl acetate. The combined organic phases were washed with water and brine and dried over anhydrous magnesium sulfate. After evaporation of the solvent, the crude product was purified by flash chromatography (SiO2, heptane / EtOAc) to give 6.56 g of the title compound as yellow oil.
MS: 279.2 (M)'.

CJ 2-[.l-(2-Amino-clhyl)-phenoxy]-2-methyl-propionic acid ethyl ester
7.82 g (28.0 mmol) of 2-methyl-2-[3-((E)-2-nitro-vinyl)-phenoxy]-propionic acid ethyl ester was dissolved in 150 ml ethanol; 6.2 ml (39.7 mmol) hydrochloric acid in ethanol and 1.6 g of Pd-charcoal (10%) were added and the reaction mixture was then hydrogenated under I atm of Hb-pressure during 5 hours. It was subsequently filtered (Celite), the filter cake was washed twice with ethanol and filtrate was evaporated. The residue was then partitioned between crashed ice / Na2CO3-solution / MeC^ and extracted twice with MeCb; the organic phases were washed with water, dried (MgSO4) and evaporated. The crude product was purified by flash chromatography (SiOj, MeC^ / MeOl I) to give 4.36 g of the title compound as yellow oil.
MS: 252.1 (M+ll)s.
DJ 2-Mcthvl-2-[3-(2-(2-[2-iTiethvl-6-(4-trifluoromethvl-phenvl)-pvridin-3-vll-
acetylamino}-ethyl)-phenoxy]-propionic acid
In analogy to the procedures described in example 26B] and 26C], 2-[3-(2-amino-ethyl)-phenoxy|-2-methyl-propionic acid ethyl ester was reacted with [2-methyl-6-(4-trifiuoromethyl-phenyl)-pyridin-3-yl]-acetic acid (example 26E]) to give 2-methyl-2-[3-(2-{2-[2-methyl-6-(4-trifiuoromethyl-phenyl)-pyridin-3-yl]-acetylamino}-ethyl)-phenoxyj-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
MS: 499.1 (M-H). Example 56
2-Mcthyl-2-[3-(2-{[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine-3-carbonyl]-amino}-cthyl)-phcnoxy]-propionic acid
In analogy to the procedures described in example 26B] and 26C], 2-[3-(2-amino-ethyl)-phenoxy|-2-methyl-propionic acid ethyl ester (example 55C]) was reacted with 2-methyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid (prepared from 2-methyl-6-(4-trifiuoromethyl-phenyl)-nicotinic acid methyl ester (example 1L]) in analogy to the procedure described in example 53B]) to give 2-methyl-2-[3-(2-{[2-methyl-6-(4-trinuoromethyl-phenyl)-pyridine-3-carbonyl]-amino}-ethyl)-phenoxy]-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.

MS: 485.3 (M-H) Example 57
2-[3-(2-{[4-Cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbonyl]-amino}-ethyl)-phcnoxy]-2-methyl-propionic acid
In analogy to the procedures described in example 26B] and 26C], 2-[3-(2-amino-ethyl)-phenoxy|-2-methyl-propionic acid ethyl ester (example 55C]) was reacted with 4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid (example 53B]) to give 2-| 3-(2- {14-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbonyl]-amino}-ethyl)-phenoxy]-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
MS: 512.2 (M-H). Example 58
2-[3-({2-(4-Butyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-acetyl}-methyl-amino)-phcnoxy|-2-methyl-propionic acid
In analogy to the procedures described in example 26B] and 26C], 2-methyl-2-(3-methylamino-phenoxy)-propionic acid ethyl ester (example 26 A]) was reacted with [4-butyl-2-(4-trifluorornethyl-phenyl)-pyrimidin-5-yl]-acetic acid (prepared starting from 3-oxo-heptanoic acid ethyl ester in analogy to the sequences described in examples 27C| to 27F| and examples 26D] and 26E]) to give 2-[3-({2-[4-butyl-2-(4-trifluoromethyl-phcnyl)-pyrimidin-5-yl]-acetyl}-methyl-amino)-phenoxy]-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as light yellow amorphous solid.
MS: 528.1 (M-H), Example 59
2-Methyl-2-(3-{methyl-[2-methyl-6-(4-trifluoromethyI-phenyl)-pyridin-3-ylmethyl]-carbamoyl}-phcnoxy)-propionicacid
A] 3-(l-Bthoxycarbonyl-1-methyl-ethoxy)-benzoic acid
3.33 g (14.1 mmol) of 2-(3-formyl-phenoxy)-2-methyl-propionic acid ethyl ester (example 55A])| was dissolved in 60 ml of tert.-butanol; 7.5 ml (70.5 mmol) of 2-

mcthyl-2-butene was added, followed by a solution of 4.14 g (36.6 mmol) of sodium chlorite and 3.30 g (21.1 mmol) of sodium dihydrogen phosphate in 35 ml of water. After 2 hours, the reaction mixture was poured into crashed ice /EtOAc and extracted twice with EtOAc; the organic phases were washed with water, dried (MgSO4) and evaporated. The crude product was purified by recrystallisation from EtOAc/heptane to give 3.19 g of the title compound as colorless solid.
MS:25I.O(M-H)-,
IHJ2-Melhy[:2±(3-methylcarbamoyl-phenoxy)-propionic acid ethyl ester
1.0 g (4.0 mmol) of 3-(l-ethoxycarbonyl-l-methyl-ethoxy)-benzoic acid was dissolved in 50 ml of methylene chloride; then, 1.5 ml (4.0 mmol) of a methylamine-solution in cthanol was added. The reaction mixture was cooled down to 0 °C and 0.91 g (4.8 mmol) of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride and 1.50 g (11.9 mmol) of 4-dimethylaminopyridine were added. After stirring for two hours at ambient temperature, it was poured into crashed ice / HCI (IN) and extracted twice with MeCb. The combined organic phases were washed with water and brine and dried over anhydrous magnesium sulfate. After evaporation of the solvent, the crude product was purified by Hash chromatography (SiCh, MeCh/MeOH) to give 0.97 g of the title compound in form of colorless needles.
MS: 266.3 (M-HI)'.
CJ 2-Methyl-2-(3-(methvl-[2-methyl-6-(4-trifluoromethyl-phenvn-pyridin-3-ylmethvl]-carbamoyl}-phenoxy)-propionic acid ethyl ester
0.28 g (1.05 mmol) of 2-methyl-2-(3-methylcarbamoyl-phenoxy)-propionic acid ethyl ester and 0.36 g (1.05 mmol) of methanesulfonic acid 2-methyl-6-(4-trifluoromethyl-phcnyl)-pyridin-3-ylmethyl ester (example 59E]) were dissolved in 15 ml of DMF. The reaction mixture was cooled down to 0 °C and 0.05 g (1.20 mmol) of sodium hydride (55% in mineral oil) was added. After stirring for sixteen hours at ambient temperature, the reaction mixture was poured into crashed ice and extracted twice with Et2O. The combined organic phases were washed with water and brine and dried over anhydrous magnesium sulfate. After evaporation of the solvent, the crude product was purified by Hash chromatography (SiO2, heptane / EtOAc) to give 0.249 g of the title compound as yellow oil.
MS: 515.4 (MMI)'.

DJ 2-Methyl-2-(3-{mgthyl-[2-methyl-6-(4-trifluoromethyl-phenyn-pyridin-3-ylmethyl]-carbamoylj-phenoxyVpropionic acid
In analogy to the procedure described in example 26C], 2-methyl-2-(3-{methyl-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethyl]-carbamoyl}-phenoxy)-propionic acid ethyl ester was saponified to yield the title compound as a light yellow solid.
MS:485.2(M-II)-.
The methanesulfonic acid 2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethyl ester used in example 59C] was synthesized as follows:
HJ Methanesulfonic acid 2-methyl-6-(4-trif1uoromethyl-phenyl)-pyridin-3-ylmethyl ester
2.60 g (9.7 mmol) of [2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-methanol (example IM|) were dissolved in 50 ml MeCb and cooled down to 0 °C. 2.55 ml = 1.93 g (14.6 mmol) of N-ethyl diisopropylamine was added, followed by 0.85 ml = 1.25 g (10.7 mmol) of methane sulfonylchloride, drop by drop. After stirring for 30 min. at ambient temperature, the reaction mixture was poured into crashed ice and extracted twice with MeCb. The combined organic phases were washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. This gave 3.44 g of crude title compound as yellow solid.
MS: 345.0 (M)'. Example 60
3-{4-[4-Cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy|-2-methyl-phenylj-propionic acid
AJ (H}-3-(4-Beny.yloxy-2-methyl-phenyl)-acrYlic acid ethyl ester
A mixture of 11.2 g (50 mmol) of 4-benzyloxy-2-methyl-benzaldehyde [PCT Int. Appl. (2002), WO 2002/092084/A1] and of 12.33 g (55 mmol) of triethyl phosphonoacetate in 25 ml of absolute ethanol was added to a cooled solution (0 °C) of sodium ethylate (freshly prepared from 1.38 g (60 mmol) of sodium and 25 ml of absolute ethanol). Subsequently, the mixture was stirred at ambient temperature for 2 hours. Then, the solvent was evaporated and the residue was partioned between tert.-butyl methyl ether and water. The organic layer was washed with brine, dried over anhydrous sodium

sulfate and finally evaporated. After crystallization from a mixture of dichloromethane and n-heptane, 12.9 g of (E)-3-(4-benzyloxy-2-methyl-phenyl)-acrylic acid ethyl ester was obtained as beige crystals (87 % of theory).
MS: 296.1 (M)(.
BJ 3-(4-Hydroxy-2-methyl-phenyl)-propionic acid ethyl ester
5 g (16.8 mmol) of the above prepared (E)-3-(4-benzyloxy-2-methyl-phenyl)-acrylic acid ethyl ester was dissolved in 50 ml of tetrahydrofuran and hydrogenated over 0.8 g of 10% of palladium on charcoal as catalyst at ambient temperature and atmospheric pressure. Filtering off the catalyst and evaporating the solvent yielded 3.5 g of the title compound as light yellow oil (100 % of theory).
MS: 208.1 (M)'*.
C) 3-{4-[4-Cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-vlmethoxyJ-2-methyl-phcnylj.-prpjjjonjcacid
In analogy to the procedures described in examples 8A] and 3IB], 3-(4-hydroxy-2-incthyl-phenyl)-propionic acid ethyl ester was reacted with 5-chloromethyl-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 27F]) to give 3-{4-[4-cyclopropyl-2-(4-irinuoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-2-methyl-phenyl}-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
MS: 455.8 (M-H)-. Example 61
3-{4-|4-CycIopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yImethoxy]-3-cthoxy-phcnyl}-propionic acid
In analogy to the procedures described in examples 8A] and 3IB], 3-(3-ethoxy-4-hydroxy-phenyl)-propionic acid ethyl ester [Eur. Pat. Appl. (1996), EP 710659/A1] was reacted with 5-chloromethyl-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidinc (example 27F|) to give 3-{4-|4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-3-ethoxy-phenyl}-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.

MS: 485.3 (M-H)-. Example 62
3-{3-Ethoxy-4-|2-methyl-6-(4-trinuoromethyl-phenyI)-pyridin-3-ylmethoxy]-phcnyl}-propionic acid
In analogy to the procedures described in examples 8A] and 3 IB], 3-(3-ethoxy-4-hydroxy-phenyl)-propionic acid ethyl ester |Eur. Pat. Appl. (1996), EP 710659/A1] was reacted with 3-chloromethyl-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (example IN |) to give 3-{3-ethoxy-4-f2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethoxy|-phenylj-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
MS: 458.4 (M-H)-. Example 63
3-{2-Methyl-4-[5-(4-trifluoromethyI-phenyI)-pyrimidin-2-ylmethoxy]-phenyl}-propionic acid
A J In analogy to the procedures described in examples 8A] and 3 IB], 3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 60B]) was reacted with 2-bromoinethyl-5-(4-trifluoromethyl-phenyl)-pyrimidine (example 63C]) to give 3-{2-methyl-4-|5-(4-trifluoromethyl-phenyI)-pyrimidin-2-ylmethoxy]-phenyl}-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as off-white solid.
MS: 415.2 (M-H).
The necessary building block 2-bromomethyl-5-(4-trifluoromethyl-phenyl)-pyrimidine used in the procedure above was prepared as follows:
A solution of 7.95 g (75 mmol) of sodium carbonate in 15 ml of water was added to a mixture of 2.6 g (15 mmol) of 5-bromo-2-methylpyrimidine [Coll. Czech. Chem. Comm. 14 (1949), 223-235], of 4 g (21 mmol) of 4-(trifluoromethyl)benzeneboronic acid and of 0.52. g (0.45 mmol) of tetrakis(triphenylphosphine)palladium in a mixture of 50 ml of 1,2-dimethoxy-ethane and of 30 ml of ethanol. The reaction mixture was stirred at 80°C

tor 2 hours; afterwards, it was concentrated by distilling off the major part of the organic solvents. Subsequently, the residue was extracted with 3 portions of tert.-butyl methyl ether. The combined organic phases were washed with water and brine, dried over anhydrous sodium sulfate and finally evaporated. The residue was chromatographed on silicagel with a mixture of dichloromethane / tert.-butyl methyl ether (9/1 vol./vol.) as cluent. 3 g of the title compound was obtained as greenish solid.
MS: 239.2 (M HI)'.
C J 2 -IJ romo rncthy I - 5 -(4-trif1uoromethyl-phenyl)-pyrimidine
0.31 g (1.3 mmol) of 2-methyl-5-(4-trifluoromethyl-phenyl)-pyrimidine, 0.255 g (1.43 mmol) of N-bromosuccinimide and 0.15 g (0.91 mmol) of 2,2'-azobis-(2-methyl-propionitril) were dissolved in 5 ml of carbon tetrachloride and the mixture was stirred at 75 °C. Two portions of 0.13 g (0.73 mmol) of N-bromosuccinimide and of 0.075 g (0.046 mmol) of 2,2'-a/obis-(2-methyl-propionitril) were added to the reaction mixture, after 4 and 8 hours, respectively, and heating was continued for additional 16 hours. After cooling to ambient temperature, the mixture was chromatographed on silicagel with dichloromethane as cluent. 0.145 g of the title compound was obtained as pale yellow solid.
MS: 316.0 (M)1, IBr. Example 64
2-|3-({2-|4-Cyclopropyl-2-(4-trifluoromethyl-phenyI)-pyrimidin-5-yl]-acetyl}-mcthyl-amino)-phenoxy]-2-methyl-propionic acid
In analogy to the procedures described in example 26B] and 26C], 2-methyl-2-(3-inethylamino-phenoxy)-propionic acid ethyl ester (example 26 A]) was reacted with [4-cyclopropyl-2-(4-trifiuoromethyl-phenyl)-pyrimidin-5-yl]-acetic acid (prepared from 5-chloromethyl-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 27F]) in analogy to the sequences described in examples 26D] and 26E]) to give 2-[3-({2-[4-cyclopropyl-2-(4-trilluoromethyl-phenyl)-pyrimidin-5-yl]-acetyl}-methyl-am ino)-phenoxy|-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
MS: 512.2 (M-ll)

Example 65
2-|3-(2-{2-|4-CycIopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-acetylamino}-ethyl)-phenoxy]-2-methyl-propionicacid
In analogy to the procedures described in example 26B] and 26C], 2-[3-(2-amino-ethyl)-phenoxy]-2-methyl-propionic acid ethyl ester (example 55C]) was reacted with [4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-acetic acid (prepared from 5-chloromethyl-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 27F]) in analogy to the sequences described in examples 26D] and 26E]) to give 2-f3-(2-{2-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-acetylamino}-ethyl)-phenoxy|-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
MS: 526.1 (M-N) . Example 66
2-[3-({|4-Cyclopropyl-2-(4-trifluoromethyl-phenyI)-pyrimidine-5-carbonyl)-amino}-methyl)-phenoxy |-2-methyl-propionic acid
In analogy to the procedures described in example 26B] and 26C], 2-(3-aminomethyl-phcnoxy)-2-methyl-propionic acid ethyl ester (example 52B]) was reacted with 4-cyclopropyl-2-(4-trilluoromethyl-phenyl)-pyrimidine-5-carboxylic acid (example 53B]) to give 2-| 3-( {14-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbonyl]-aniino}-methyl)-phenoxy|-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless amorphous solid.
MS: 498.1 (M-ll). Example 67
2-Methyl-2-|3-({2-|2-methyl-6-(4-trifluoromethyl-phenyI)-pyridin-3-yl]-acctylamino}-methyl)-phenoxy]-propionic acid
In analogy to the procedures described in example 26B] and 26C], 2-(3-aminomethyl-phenoxy)-2-methyl-propionic acid ethyl ester (example 52B]) was reacted with (2-methyl-6-(4-trinuoromethyl-phenyl)-pyridin-3-yl]-acetic acid (example 26E]) to give 2-methyl-2-|3-({2-|2-mcthyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetylamino}-

inethyl)-phenoxy|-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
MS: 485.3 (M-H)", Example 68
2-[3-({2-[4-CyclopropyI-2-(4-trifluoromethyI-phenyl)-pyriinidin-5-ylj-acetyIamino}-mcthyl)-phcnoxyj~2-mcthyl-propionic acid
In analogy to the procedures described in example 26B] and 26C], 2-(3-aminomethyl-phenoxy)-2-methyl-propionic acid ethyl ester (example 52B]) was reacted with [4-cyclopropyl-2-(4-trinuoromethyl-phenyl)-pyrimidin-5-yl]-acetic acid (prepared from 5-chloromethyl-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 27F]) in analogy to the sequences described in examples 26D] and 26E]) to give 2-[3-({2-[4-cyclopropyl-2-(4-trinuoromethyl-phenyl)-pyrimidin-5-yl]-acetylamino}-methyl)-phcnoxy|-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
MS:5l2.2(M-liy. Example 69
2-Mcthyl-2-|3-({[2-incthyl-6-(4-trifluoromethyl-phenyl)-pyridine-3-carbonyIl-amino}-methyl)-phenoxy|-propionicacid
In analogy to the procedures described in example 26B] and 26C], 2-(3-aminomethyl-phenoxy)-2-methyl-propionic acid ethyl ester (example 52B]) was reacted with 2-methyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid (prepared from 2-methyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid methyl ester (example 1L]) in analogy to the procedure described in example 53B]) to give 2-methyl-2-[3-({[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine-3-carbonyl]-amino}-methyl)-phenoxy]-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as amorphous colorless solid.
MS: 471.1 (M-Iiy.

Example 70
2-Mcthyl-2-(2-methyl-5-{2-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-cthoxy}-phenoxy)~propionic acid
AJ 2-(5-Hydroxy-2-methyl-phenoxy)-2-rnethyl-propionic acid ethyl ester
5.10 g (14.9 mmol) 2-(5-benzyloxy-2-formyl-phenoxy)-2-methyl-propionic acid ethyl ester (prepared from 4-benzyloxy-2-hydroxybenzaldehyde and ethyl-bromoisobutyrate in analogy to the procedure described in example 52A]) was dissolved in 100 ml of ethanol and hydrogenatcd with 1.0 g of Pd-C (5%), 2 bar Hz, 25 °C, for two hours. The reaction mixture was filtered (Celite), the filter cake was washed twice with EtOH and the filtrate was evaporated. The crude product was purified by flash chromatography (SiCh, heptane / KtOAc) to give 3.37 g of the title compound as light yellow oil.
MS: 237.0 (M-H)".
B] 2-lvtcthyl-2-(2-methyl-5-{2-[2-methyl-6-(4-trifluoromethvl-phenyn-pyridin-3-yl]-clhoxy}-phenoxy)-propionic acid ethyl ester
0.24 g (1.0 mmol) of the above prepared 2-(5-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester, 0.31 g (1.10 mmol) of 2-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl|-ethanol (see below example 70E]) and 0.32 g (1.20 mmol) of triphenylphosphine were dissolved in 10 ml of THF. The stirred reaction mixture was cooled down to 0 °C and a solution of 0.27 g (1.15 mmol) of di-tert.-butyl a/odicarboxylate in 5 ml of THF was added drop by drop. Then, the reaction warmed up to ambient temperature. After 20 hours, the solvent was evaporated and the residue purified by chromatography (SiO2, heptane / EtOAc = 95:5 to 9:1) to give 0.23 g of the title compound as colorless oil.
MS: 502.4 (M+lI)'.
C] 2-Mcthvl-2-(2-methyl-5-{2-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-vn-
cthoxy}-phenoxy)-propionic acid
In analogy to the procedure described in example 26C], 2-methyl-2-(2-methyl-5-{2-[2-methyI-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethoxy}-phenoxy)-propionic acid ethyl ester was saponified to yield the title compound as colorless solid.
MS: 472.1 (M-ll).

The necessary building block 2-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yI]-cthanol used in the procedure above was prepared as follows:
D| [2-Methyl-6-(4-trifluoromethyl-phenylVpyridin-3-yl]-acetic acid methyl ester
A solution of 2.55 g (8.63 mmol) of [2-methyl-6-(4-trifluorornethyl-phenyl)-pyridin-3-ylj-acetic acid (example 26E]) in 25 ml of methanol was cooled to -10 °C; 1.88 ml (25.9 mmol) of thionyl chloride was added. The reaction mixture was then stirred at ambient temperature for 2 hours. Subsequently, the solution was stirred with ice water, then extracted with three portions of 50 ml of tert.-butyl methyl ether. The combined organic layers were washed with water, aqueous sodium hydrogen carbonate and brine, and dried over anhydrous sodium sulfate. After evaporation of the solvent, 2.6 g of the title compound was obtained as light brown solid.
MS:309.1(M)+.
BJ 2-[2-Methyl-6-(4-trinuoromethyl-phenyl)-pyridin-3-yl]-ethanol
2.6 g (8.40 mmol) of the above prepared [2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl|-acetic acid methyl ester dissolved in 15 ml of dry tetrahydrofuran was added under an argon atmosphere within 15 minutes to a stirred suspension of 0.38 g (10 mmol) of lithium aluminum hydride in 5 ml of tetrahydrofuran. The reaction was exothermic. Subsequently, the mixture was stirred at room temperature for 1 hour. Then, 1 ml of ethyl acetate was dropped into the reaction mixture, followed by water, drop after drop, under argon, with stirring and cooling until the gas evolution ceased. The reaction mixture was then diluted with 50 ml of ethyl acetate, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated i. V. and the residue was chromatographed on SiO2with a mixture of dichloromethane and tert.-butyl methyl ether (4/1 vol./vol.) as cluent. Thereby, 1.88 g of the title compound was obtained as white solid.
MS: 281.1 (M)'. Example 71
2-Methyl-2-{2-methyl-5-(2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmcthoxy]-phenoxy}-propionicacid
In analogy to the procedures described in examples 70B] and 26C], 2-(5-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (example 70A]) was reacted with

|2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-methanol (example 1M]) in the presence of triphenylphosphine and di-tert.-butyl azodicarboxylate to give 2-methyl-2-j2-methyl-5-l2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethoxy]-phenoxy}-propionic acid ethyl ester which was subsequently saponified to yield the title compound as colorless solid.
MS: 458.2 (M-H)'. Example 72
|rac|-3-(2-Methyl-4-{l-[2-methyI-6-(4-trifluoromethyl-phenyl)-pyridin-3-yI]-cthoxy}-phcnyl)-propionic acid
In analogy to the procedures described in examples 8A] and 3IB], 3-(4-hydroxy-2-mcthyl-phenyl)-propionic acid ethyl ester (example 60B]) was reacted with [rac]-3-(l-chloro-ethyl)-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (example 17C]) to give |rac|-3-(2-methyl-4-{ l-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethoxy}-phenyl)-propionic ac\d ethyl ester, which was subsequently saponified to yield the title compound as light yellow solid.
MS: 442.2 (M-H)-. Example 73
3-{3-Mcthyl-4-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethoxyj-phenylj-propionic acid
AJ 3-(4-Hydroxy-3-methyl-phenyl)-propipnic acid ethyl ester
In analogy to the procedures described in examples 60A] and 60B], 4-benzyloxy-3-mcthyl-ben/aldehydc [Bioorganic & Medicinal Chemistry Letters (2003), 13(3), 399-4031 was reacted with triethyl phosphonoacetate to give (E)-3-(4-benzyloxy-3-methyI-phenyl)-acrylic acid ethyl ester, which was subsequently hydrogenated to yield the title compound in form of a grey solid.
MS: 208.1 (My.
BJ 3-{3-Methyl-4-[2-methyl-6-(4-trifluoromethvl-phenvl)-pvridin-3-ylmethoxvl-
phenyIj-propionic acid

In analogy to the procedures described in examples 8A] and 3IB], 3-(4-hydroxy-3-methyl-phenyl)-propionic acid ethyl ester was reacted with 3-chloromethyl-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (example IN]) to give 3-{3-methyl-4-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethoxy]-phenyl}-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
MS: 428.3 (M-H)-. Example 74
|rac)-3-(3-Methyl-4-{l-|2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yll-cthoxy}-phcnyl)-propionic acid
In analogy to the procedures described in examples 8A] and 3IB], 3-(4-hydroxy-3-methyl-phenyl)-propionic acid ethyl ester (example 73A]) was reacted with [rac]-3-(l-chloro-ethyl)-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (example 17C]) to give |rac|-3-(3-methyl-4-{ l-[2-methyl-6-(4-trifiuoromethyl-phenyl)-pyridin-3-yl]-ethoxy}-phenyl)-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
MS: 442.2 (M-H)-. Example 75
2-|3-({2-[4-CycIopropyl-2-(4-trifluoromethyI-phenyI)-pyrimidin-5-yl]-acetyl}-mcthyl-amino)-5-trifluoromethyl-phenoxy]-2-methyl-propionic acid
A] 2-Methyl-2-(3-nitro-5-trifluoromethyl-phenoxy)-propionic acid ethyl ester
In analogy to the procedure described in example 52A], 3-nitro-5-trifluoromethyl-phenol |PCT Int.Appl. (1994), WO 94/20467AI] was reacted with ethyl bromoisobutyrate to yield the title compound as yellow oil.
MS: 32I.O (M)1.
Bj 2-(3-Amino-5-trinuoromethyj-phenoxy)-2-methyl-propionic acid ethyl ester
13.8 g (43 mmol) of 2-methyl-2-(3-nitro-5-trifluoromethyl-phenoxy)-propionic acid ethyl ester was dissolved in 300 ml of ethanol and hydrogenated with 1.14 g of Pd-C (10%), 1 bar I h, 25 °C, for two hours. The reaction mixture was then filtered (Celite), the filter cake was washed twice with ethanol and the filtrate was evaporated. The crude

product was purified by Hash chromatography (SiC>2, heptane / EtOAc) which gave 11.0 g of the title compound as yellow oil.
MS: 292.2 (Mf-H)1-
CJ 2-Methyl-2-(3-methylamino-5-trifluoromethyl-phenoxy)-propionic acid ethyl ester
In analogy to the procedures described in example 5D], 5E] and 5F], 2-(3-amino-5-trinuoromethyl-phenoxy)-2-methyl-propionic acid ethyl ester was converted into 2-(3-lcrt-butoxycarbonylamino-5-trifluoromethyl-phenoxy)-2-methyl-propionic acid ethyl ester by treatment with di-tert-butyl dicarbonate and sodium hydrogen carbonate in dioxane/water at r.l., methylated at nitrogen to yield 2-[3-(tert-butoxycarbonyl-methyi-amino)-5-trifluoromethyl-phenoxy]-2-methyl-propionic acid ethyl ester and deprotected again to yield the title compound as light yellow oil.
MS: 306.3 (MHI)'.
PJ 2-|_3-({2-[4-Cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-S-yl]-acetyl}-
mcthyl-amino)-5-trinuoromethyl-phenQxy]-2-methyl-propionic acid
In analogy to the procedures described in example 26B] and 26C], 2-methyl-2-(3-methylamino-5-triiluoromethyl-phenoxy)-propionic acid ethyl ester was reacted with [4-cyclopropyl-2-(4-trinuoromethyl-phenyl)-pyrimidin-5-yI]-acetic acid (prepared from 5-chloromethyl-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 27F]) in analogy to the sequences described in examples 26D] and 26E]) to give 2-[3-({2-|4-cyclopropyl-2-(4-trinuoromethyl-phenyl)-pyrimidin-5-yI]-acetyl}-methyl-amino)-5-trinuoromethyl-phenoxy]-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as light yellow oil.
MS: 580,1 (M-1IV. Example 76
2-MethyI-2-[3-(methyl-{2-(2-methyl-6-(4-trifluoroinethyl-phenyI)-pyridin-3-yll-acctyl}-amino)-5-trifluoromethyl-phenoxy]-propionicacid
In analogy to the procedures described in example 26B] and 26C], 2-methyl-2-(3-methylamino-5-trinuoromethyl-phenoxy)-propionic acid ethyl ester (example 75C]) was reacted with [2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid (example 261-;|) to give 2-methyl-2-[3-(methyl-{2-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-

3-yl|-acetyl}-amino)-5-trifluoromethyl-phenoxy]-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as light yellow oil.
MS: 553.1 (M-H). Example 77
2-[4-({2-[4-Cyclopropyl-2-(4-trinuoromethyl-phenyl)-pyrimidin-5-yl]-acetylamino}-mcthyl)-phenoxy|~2-mcthyl-propionicacid
In analogy to the procedures described in example 26B] and 26C], 2-(4-aminomethyl-phenoxy)-2-methyl-propionic acid ethyl ester [PCT lnt.Appl.(2002), WO 2002/096895AI| was reacted with [4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylj-acetic acid (prepared from 5-chloromethyl-4-cyclopropyl-2-(4-trinuoromelhyl-phenyl)-pyrimidine (example 27F]) in analogy to the sequences described in examples 26DJ and 26E|) to give 2-[4-({2-[4-cyclopropyl-2-(4-trinuoroinethyl-phenyl)-pyrimidin-5-yl]-acetylamino}-methyl)-phenoxy]-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
MS: 512.2 (M-H)'-Example 78
2-IMcthyl-2-|4-({2-|2-methyI-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-acctylamino}-methyl)-phenoxy]-propionicacid
In analogy to the procedures described in example 26B] and 26C], 2-(4-aminomethyl-phenoxy)-2-methyl-propionic acid ethyl ester [PCT Int.Appl.(2002), WO 2002/096895AI | was reacted with [2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid (example 26EJ) to give 2-methyl-2-[4-({2-[2-methyl-6-(4-trifluoromethyl-phcnyl)-pyridin-3-yl|-acetylamino}-methyl)-phenoxy]-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless amorphous solid.
MS: 485.2 (M-H)'. Example 79
2-|4-({[4-CyclopropyI-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbonyl]-ainino}-methyl)-phenoxy|-2-methyl-propionic acid

In analogy to the procedures described in example 26B] and 26C], 2-(4-aminomethyl-phenoxy)-2-methyl-propionic acid ethyl ester [PCT Int.Appl.(2002), WO 2002/096895 A 1| was reacted with 4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid (example 53B]) to give 2-[4-({[4-cyclopropyl-2-(4-trinuoromethyl-phenyl)-pyrimidine-5-carbonyl]-amino}-methyl)-phenoxy]-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless oil.
MS: 498.1 (M-H). I'.xamnle 80
2-Methyl-2-[4-({[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine-3-carbonyl]-amino}-mcthyl)-phenoxy]-propionic acid
In analogy to the procedures described in example 26B] and 26C], 2-(4-aminomethyl-phcnoxy)-2-methyl-propionic acid ethyl ester [PCT Int.Appl.(2002), WO 2002/096895A11 was reacted with 2-methyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid (prepared from 2-methyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid methyl ester (example I L|) in analogy to the procedure described in example 53B]) to give 2-methyl-2-|4-({|2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine-3-carbonyl]-amino}-methyl)-phcnoxyj-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless oil.
MS: 471.1 (M-H)'. Example 81
2-Mcthyl-2-(3-{methyl-[4-methyI-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yImethyl |-carbamoyl}-phenoxy)-propionic acid
in analogy to the procedures described in examples 59C] and 26C], 2-methyl-2-(3-
methylcarbarnoyl-phenoxy)-propionic acid ethyl ester (example 59B]) was reacted 5-
chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (prepared from
methylacetoacetate in analogy to the procedures described in examples 27C] to 27F]) to
give 2-methyl-2-(3-{methyl-[4-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-
ylmethyl|-earbamoyl}-phenoxy)-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as light brown oil.
MS: 486.3 (M-H)".

Example 82
2-(3-{|4-(2-Methoxy-cthyI)-6-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmcthyl |-methyl-carbamoyl}-phenoxy)-2-methyl-propionic acid
In analogy to the procedures described in examples 59C] and 26C], 2-methyl-2-(3-melhylcarbamoyl-phenoxy)-propionic acid ethyl ester (example 59B]) was reacted 5-chloromcthyl-4-(2-methoxy-ethyl)-6-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example I18GJ) to give 2-(3-{[4-(2-methoxy-ethyl)-6-methyl-2-(4-trifluoromethyl-phcnyl)-pyrimidin-5-ylmethyl]-methyl-carbamoyl}-phenoxy)-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as light brown solid.
MS: 544.2 (M-ll). Kxample 83
2-Mcthyl-2-{4-[(mcthyl-{2-[2-niethyl-6-(4-trifluoroinethyl-phenyl)-pyridin-3-yl]-acetyl}-amino)-methyl]-phenoxy}-propionic acid
AJ 2-Mcthyl-2-(4-methylaminornethyl-phenoxy)-propionic acid ethyl ester
In analogy to the procedure described in example 52A], (4-hydroxy-benzyl)-carbamic acid tert-butyl ester was reacted with ethyl-bromoisobutyrate to give 2-[4-(tert-butoxycarbony!amino-methyl)-phenoxy]-2-methyl-propionic acid ethyl ester; this compound was then reacted with sodium hydride, methyl iodide in analogy to the procedure described in example 5E| to give 2-{4-[(tert-butoxycarbonyl-methyl-amino)-methyl|-phenoxy}~2-methyl-propionic acid ethyl ester, subsequent deprotection in analogy to the procedure described in example 5F] gave the title compound as light brown oil.
MS: 252.2 (Mill)1.
2-Methyl-2-!4-[(methyl-{2-[2-methyl-6-(4-trifluoromethvl-^ acctyjj -am _ino)-mcthy IJ-phenoxy } -propionic acid
In analogy to the procedures described in example 26B] and 26CJ, 2-methyl-2-(4-methylaminomethyl-phenoxy)-propionic acid ethyl ester was reacted with [2-methyl-6-(4-trinuoromethyl-phenyl)-pyridin-3-yl]-acetic acid (example 26E]) to give 2-methyl-2-{4-|(methyl-{2-|2-mcthyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetyl}-amino)-

methyl |-phenoxy}-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
MS: 499.1 (M-H). Example 84
2-Methyl-2-[4-(2-{|2-methyl-6-(4-trifluoromethyl-phenyI)-pyridine-3-carbonyl]-amino}-cthyl)-phenoxy|-propionic acid
AJ 2-j4_-(2-Amlno-cihyl)-phenoxyJ-2-methyl-propionicacid ethyl ester
In analogy to the procedure described in example 52A], [2-(4-hydroxy-phenyl)-ethyl|-carbamic acid tert-butyl ester was reacted with ethyl-bromoisobutyrate to give 2-[4-(2-tert-butoxycarbonylamino-ethyl)-phenoxy]-2-methyl-propionic acid ethyl ester, .subsequent deprotection in analogy to the procedure described in example 5F] the title compound as yellow oil.
MS: 252.2 (M HI)'.
BJ 2-Mcthyl-2-[4-(2-{[2-methyl-6-(4-trifluoromethvl-phenyl)-pyridine-3-carbonyl|-amino}-cthyl)-phenoxy]-propionicacid
in analogy to the procedures described in example 26B] and 26C], 2-[4-(2-amino-ethyl)-phenoxy|-2-methyl-propionic acid ethyl ester was reacted with 2-methyl-6-(4-trinuoromcthyl-phenyl)-nicotinic acid (prepared from 2-methyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid methyl ester (example 1L]) in analogy to the procedure described in example 53B]) to give 2-methyI-2-[4-(2-{[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine-3-carbonyl|-amino}-ethyl)-phenoxy]-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
MS: 485.2 (M-H)". Example 85
2-|4-(2-{|4-Cyclopropyl-2-(4-trifluoromethyI-phenyI)-pyrimidine-5-carbonyl]-amino}-cthyl)-phenoxy|-2-methyl-propionicacid
In analogy to the procedures described in example 26B] and 26C], 2-[4-(2-amino-ethyl)-phenoxy|-2-methyl-propionic acid ethyl ester (example 84AJ) was reacted with 4-cyclopropyl-2-(4-trinuoromethyI-phenyl)-pyrimidine-5-carboxylic acid (example 53B])

to give 2-|4-(2- {[4-cyclopropyl-2-(4-trittuoromethyl-phenyl)-pyrimidine-5-carbonyl]-amino}-cthyl)-phenoxy|-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
MS: 512.2 (M-H) , Example 86
2-Methyl-2-|4-(2-{2-[2-methyl-6-(4-trifluoroniethyl-phenyl)-pyridin-3-yl|-acetylamino}-ethyl)-phenoxy|-propionic acid
In analogy to the procedures described in example 26B] and 26C], 2-[4-(2-amino-ethyl)-phenoxy|-2-methyl-propionic acid ethyl ester (example 84A]) was reacted with [2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid (example 26E]) to give 2-methyl-2-|4-(2-{2-|2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetylamino}-ethyl)-phcnoxy|-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
MS: 5()I.3(M+H)'. Example 87
2-|4-(2-{2-|4-CyclopropyI-2-(4-trifluoromethyl-phenyI)-pyrimidin-5-yI]-acetylamino}-ethyl)-phenoxy]-2-methyl-propionic acid
In analogy to the procedures described in example 26B] and 26C], 2-[4-(2-amino-ethyl)-phenoxy|-2-methyl-propionic acid ethyl ester (example 84A]) was reacted with [4-cyclopropyl-2-(4-lrilluoroiTiethyl-phenyl)-pyrimidin-5-yl]-acetic acid (prepared from 5-chloromethyl-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 27F|) in analogy to the sequences described in examples 26D] and 26E]) to give 2-[4-(2-{2-[4-cyclopropyl-2-(44rilluoromethyl-phenyl)-pyrimidin-5-yl]-acetylamino}-ethyl)-phenoxy|-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
MS: 528.4 (Mill) .

Example88
2-Mcthyl-2-{4-[2-(nicthyl-{2-[2-methyl-6-(4-trifluoromethyI-phenyl)-pyridin-3-yl]-acctyl}-amino)-cthyl]-phenoxy}-propionic acid
AJ 2-Methyl-2-[4-(2-mcthylamino-ethyl)-phenoxv]-propionic acid ethyl ester
In analogy to the procedure described in example 52A], [2-(4-hydroxy-phenyl)-ethylJ-carbamic acid tcrt-butyl ester was reacted with ethyl-bromoisobutyrate to give 2-[4-(2-tert-butoxycarbonylamino-ethyl)-phenoxy]-2-methyl-propionic acid ethyl ester; this compound was subsequently reacted with sodium hydride, methyl iodide in analogy to the procedure described in example 5E] to give 2-{4-[2-(tert-butoxycarbonyl-methyl-amino)-ethyl|-phenoxy}~2-methyl-propionic acid ethyl ester; subsequent deprotection in analogy to the procedure described in example 5F] gave the title compound as light brown oil.
MS: 266.2 (M+H)1'.
BJ 2-Methyl-> {4-[2-(methyl-l2-[2-methyl-6-(4-trifluoromethyl-phenyn-pyridin-3-yl|-acctyl|-amino)-cthylj-phenoxy}-propionicacid
In analogy to the procedures described in example 26B] and 26C], 2-methyl-2-(4-(2-melhylamino-ethyl)-phenoxy]-propionic acid ethyl ester was reacted with [2-methyl-6-(4-trinuoromethyl-phenyl)-pyridin-3-yl]-acetic acid (example 26E]) to give 2-methyl-2-{4-|2-(methyl-{2-|2-methyl-6-(4-tritluoromethyl-phenyl)-pyridin-3-yl]-acetyl}-amino)-cthyl|-phenoxy}-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
MS:513.3(M-H). Example 89
2-Mcthyl-2-[4-(2-[methyl-[2-methyl-6-(4-trifluoromethyl-phenyI)-pyridine-3-carbonyll-amino}-cthyl)-phenoxy|-propionic acid
In analogy to the procedures described in example 26B] and 26C], 2-methyl-2-[4-(2-mcthylamino-ethyl)-phenoxy]-propionic acid ethyl ester (example 88A]) was reacted with 2-methyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid (prepared from 2-methyl-6-(4-trinuoromethyl-phenyl)-nicotinic acid methyl ester (example 1L]) in analogy to the procedure described in example 53B|) to give 2-methyl-2-[4-(2-{methyl-[2-rnethyl-6-(4-

trilluoromethyl-phenyl)-pyridine-3-carbonyl]-amino}-ethyl)-phenoxy]-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
MS: 501.4 (MfH)'. Example 90
2-{2-Mcthoxy-4-[2-mcthyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yImethoxyj-phenoxy j-2-methyl-propionic acid
A | 2-(4-Hydroxy-2-methoxy-phenoxy)-2-methyl-propionic acid ethyl ester
In analogy to the procedures described in examples 52A] and 60B], 4-benzyloxy-2-methoxy-phenol | Journal of Organic Chemistry (1980), 45(2), 208-12] was reacted with ethyl-bromoisobutyrate to give 2-(4-benzyloxy-2-methoxy-phenoxy)-2-methyl-propionic acid ethyl ester, which was subsequently hydrogenated to yield the title compound in form of a grey viscous oil.
MS: 253.1 (M-H).
Bj 2-{2-Methoxy-4-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethoxvJ-
phcnoxyj -2-mcthyl-propionic acid
In analogy to the procedures described in examples 8A] and 3IB], 2-(4-hydroxy-2-mcthoxy-phenoxy)-2-inethyl-propionic acid ethyl ester was reacted with 3-chloromethyl-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (example IN]) to give 2-{2-methoxy-4-|2-methyl-6-(4-tril1uoromethyl-phenyI)-pyridin-3-ylmethoxy]-phenoxy}-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as light yellow solid.
MS: 474.1 (M-H).
Example 91
|rac|-2-(2-Mcthoxy-4-{l-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yll-ethoxy}-phenoxy)-2-methyI-propionicacid
In analogy to the procedures described in examples 8A] and 3IB], 2-(4-hydroxy-2-methoxy-phcnoxy)-2-melhyl-propionic acid ethyl ester (example 90A]) was reacted with |rac|-3-(l-chloro-ethyl)-2-methyl-6-(4-trifiuoromethyl-phenyl)-pyridine (example 17C|)

to give | rac |-2-(2-methoxy-4-{ 1 -|2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylJ-ethoxyj-phenoxy)-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the litle compound as light yellow solid.
MS: 488. 1 (M-H) . Example 92
3-{2-Methoxy-4-|2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethoxyj-phenyl}-propionic acid
A] 3-(4-Hydroxy-2-mcthoxy-phenvl)-propionic acid ethyl ester
In analogy to the procedures described in examples 60A] and 60B], 4-benzyloxy-2-methoxy-ben/aldehyde was reacted with triethyl phosphonoacetate to give (E)-3-(4-bcn/yloxy-2-methoxy-phenyl)-acrylic acid ethyl ester which was subsequently hydrogenated to yield the title compound in form of a grey solid.
MS: 224.0 (M)BJ _____ 3-{2-Mcthoxy-4-[2-methyl-6-(4-trifluoromethyl-phenvl)-pyridin-3-ylmethoxv|-phenylj-propionic acid
In analogy to the procedures described in examples 8A] and 3 IB], 3-(4-hydroxy-2-inclhoxy-phenyl)-propionic acid ethyl ester was reacted with 3-chloromethyl-2-methyl-6-(4-trifluoromethyl-phenyI)-pyridine (example IN]) to give 3-{2-methoxy-4-|2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethoxy]-phenyl}-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
MS: 444. 1 (M-ll)".
Example 93
2-|3-Mcthoxy-5-(2-l|2-methyI-6-(4-trifluoromethyI-phenyI)-pyridine-3-carbonyl]-amino}-cthyI)-phenoxy|-2-methyl-propionicacid
Aj ?-{3-(:>-Amino-et^^^
In analogy to the procedure described in example 52A], 3-hydroxy-5-methoxy-bcn/aldehyde (Journal of Organic Chemistry (1985), 50(13), 2236-40] was reacted with ethyl-bromoisobutyrate to give 2-(3-formyl-5-methoxy-phenoxy)-2-methyl-propionic

acid ethyl ester; this compound was subsequently transformed in analogy to procedures described in examples 55B] and 55C] into 2-[3-methoxy-5-((E)-2-nitro-vinyl)-phenoxy]-2-mcthyl-propionic acid ethyl ester which was then hydrogenated to give 2-[3-(2-amino-cthyl)-5-methoxy-phenoxyJ-2-methyl-propionic acid ethyl ester as yellow oil.
MS: 282.2 (M HI)1,
Ill 2-|3-Methoxv-5-(2-([2-methvl-6-(4-trifluoromethvl-phenvl)-pvridine-3-carbonyl]-
am i noL-cthyJl-phenoxy]-2-methyl-propi on ic acid
In analogy to the procedures described in example 26B] and 26C], 2-[3-(2-amino-ethyl)-5-methoxy-phenoxy|-2-methyl-propionic acid ethyl ester was reacted with 2-methyl-6-(4-trinuoromethyl-phenyl)-nicotinic acid (prepared from 2-methyl-6-(4-trifluoromethyl-phcnyl)-nicotinic acid methyl ester (example 1L]) in analogy to the procedure described in example 53BJ) to give 2-[3-methoxy-5-(2-{[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine-3-carbonyl|-aniino}-ethyl)-phenoxy]-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
MS: 5I5.2(M-H)\ Example 94
2-|3-(2-{|4-CycIopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbonyl]-amino}-cthyl)-5-methoxy-phenoxy|-2-methyl-propionicacid
In analogy to the procedures described in example 26B] and 26C], 2-[3-(2-amino-ethyl)-5-methoxy-phenoxy|-2-methyl-propionic acid ethyl ester (example 93A]) was reacted with 4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid (example 53BJ) to give 2-[3-(2-{|4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbonyl|-amino}-cthyl)-5-methoxy-phenoxy]-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
MS: 542.2 (M-H)".

Example 95
2-|3-(2-{2-|4-Cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-acetylamino}-cthyl)-5-methoxy-phenoxy|-2-methyl-propionic acid
In analogy to the procedures described in example 26B] and 26C], 2-[3-(2-amino-ethyl)-5-inethoxy-phenoxy|-2-methyl-propionic acid ethyl ester (example 93A]) was reacted with |4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-acetic acid (prepared from 5-chloromethyl-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 27F|) in analogy to the sequences described in examples 26D] and 26E]) to give 2-[3-(2-{2-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-acetylamino}-ethyl)-5-methoxy-phenoxy|-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
MS: 556.1 (MHl)'. Example 96
2-[3-Methoxy-5-(2-{2-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetylamino}-ethyI)-phenoxy]-2-methyl-propionic acid
In analogy to the procedures described in example 26B] and 26C], 2-[3-(2-amino-ethyl)-
5-methoxy-phenoxy]-2-methyl-propionic acid ethyl ester (example 93A]) was reacted
with [2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid (example 26E]) to
give 2-[3-methoxy-5-(2-{2-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-
acetylamino}-ethyl)-phenoxy]-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
MS: 529.2 (M-H)'. Example 97
2-Methyl-2-[2-methyl-4-({[2-methyI-6-(4-trifluoromethyl-phenyI)-pyridinc-3-carbonyl]-amino}-methyl)-phenoxyl-propionicacid
AJ 2-[4-(Z,B-Hydroxyimino-methyl)-2-methyl-phenoxy]-2-rnethyl-propionic acid ethyl ester
19.35 g (77.3 mmol) of 2-(4-formyl-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (prepared from 4-hydroxy-3-methyl-benzaldehyde and ethyl-bromoisobutyrate in

analogy to the procedure described in example 52A]) was dissolved in 200 ml ethanol; while stirring, 8.68 g (123.7 mmol) hydroxylamine hydrochloride were added, followed by a solution of 19.22 g (232.0 mmol) of sodium acetate in 200 ml water. After stirring of the reaction mixture for 18 hours at ambient temperature, the solvent was removed by evaporation at reduced pressure, the residue was then poured into crashed ice and extracted three times with MeCl?. The combined organic phases were washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The crude product was purified by Hash chromatography (SiCh, heptane / EtOAc) to give 20.61 g of the title compound as light yellow oil.
MS: 266.2 (M+H)'.
B| 2-(4-Aminomcthyl-2-methyl-phenoxy)-2-rnethyl-propionic acid ethyl ester
19.9 g (75.0 mmol) of 2-[4-(Z,H-hydroxyimino-methyl)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester was dissolved in 300 ml of glacial acetic acid and heated to 65°C. While stirring, 44.13 g (675 mmol) zinc dust was added in several small portions. Alfter 90 min., the reaction mixture was cooled down to ambient temperature, filtered (('elite) and the filtrate was evaporated. The residue was partitioned between water and ethyl acetate, the pll was adjusted to > 12 with NaOH /H2O, the mixture was filtered again (Celite) and the filtrate extracted twice with ethyl acetate. The combined organic phases were washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The crude product was purified by flash chromatography (SiCh, MeC12 / McOl I) to give 15.72 g of the title compound as light yellow oil.
MS: 252.2 (M+ll)'.
CJ. 2-lvlethyl-2-[2-mcthyl-4-({[2-methyl-6-(4-trif1uoromethyl-phenvl)-pyridine-3-
carbonyl]-amino}-methyl)-phenoxyj-propionic acid
In analogy to the procedures described in example 26B] and 26C], 2-(4-aminomethyl-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester was reacted with 2-methyl-6-(4-trilluoromethyl-phenyl)-nicotinic acid (prepared from 2-methyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid methyl ester (example 1L]) in analogy to the procedure described in example 53li|) to give 2-methyl-2-[2-methyl-4-({[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine-3-carbonyl]-amino}-methyl)-phenoxy]-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as light yellow foam.
MS: 485.3 (M-HV.

F.xample 98
2-|4-({|4-CyclopropyI-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbonyl)-amino}-methyl)-2-mcthyl-phcnoxy|-2-mcthyl-propionic acid
In analogy to the procedures described in example 26B] and 26C], 2-(4-aminomethyl-2-mclhyl-phenoxy)-2-methyl-propionic acid ethyl ester (example 97B]) was reacted with 4-cyclopropyl-2-(4-trinuoromethyl-phenyl)-pyrimidine-5-carboxylic acid (example 53B|) to give 2-[4-({|4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbonyl|-amino}-mcthyI)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as light yellow foam.
MS: 512.2 (M-H). Example 99
2-|4-({|4-Methoxymethyl-2-(4-trifluoromethyI-phenyI)-pyrimidine-5-carbonyI]-amino}-mcthyl)-2-methyl-phenoxy|-2-methyl-propionic acid
In analogy to the procedures described in example 26B] and 26C], 2-(4-aminomethyl-2-mcthyl-phenoxy)-2-methyl-propionic acid ethyl ester (example 97B]) was reacted with 4-methoxymethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid (prepared from 4-methoxy-3-oxo-butyric acid methyl ester, in analogy to the procedures described in examples 27C| and 27D] followed by saponification in analogy to the procedure described in example 53B]) to give 2-[4-({[4-methoxymethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbonyl]-amino}-methyl)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as light yellow foam.
MS: 516.2 (M-H). Example 100
2-[4-({|4-(2-Mcthoxy-ethyl)-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbonyI|-aniinoj-methyI)-2-mcthyl-phcnoxy|-2-methyl-propionic acid
In analogy to the procedures described in example 26B] and 26C], 2-(4-aminomethyl-2-
methyl-phenoxy)-2-methyl-propionic acid ethyl ester (example 97B]) was reacted with
4-(2-methoxy-ethyl)-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid
(prepared from 5-methoxy-3-oxo-pentanoic acid methyl ester, in analogy to the

procedures described in examples 27C] and 27D] followed by saponification in analogy to the procedure described in example 53B]) to give 2-[4-({[4-(2-methoxy-ethyl)-2-(4-trinuoromethyl-phcnyl)-pyrimidine-5-carbonyl]-amino}-methyl)-2-methyl-phenoxy]-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as light yellow oil.
MS: 530.2 (M-H). Example 101
2-{4-[4-(2-Ethoxy-ethyl)-2-(6-trifluoromethyl-pyridin-3-yl)-pyrimidin-5-ylmethoxyl-2-methyl-phenoxy}-2-methyl-propionic acid
AJ 2-j4-|4-(2-Methoxy-ethyl)-2-(6-trifluoromethyl-pyridin-3-yn-pyrimidin-5-
ylmcthoxyJ-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester
To a solution of 133 mg (0.40 mmol) 5-chloromethyl-4-(2-methoxy-ethyl)-2-(6-trifluoromethyl-pyridin-3-yr)-pyrimidine (example 101F]) and 95 mg (0.40 mmol) 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) in 12 ml of acetonitrile was added 143 mg (0.44 mmol) cesium carbonate. The reaction mixture was stirred for 16h at RT. The mixture was filtered, taken up in dichloromethanc dried (Na2SC>4) and evaporated. The crude product was purified by Hash chromatography over silica gel with heptane/AcOEt 9:1, to give 119 mg of the title compound as light yellow viscous oil.
MS: 534.5 (MilI)'.
BJ 2-{4-[4-(2-Ethoxv-ethyl)-2-(6-trifluoromethyl-pyridin-3-yl)-pvrimidin-5-ylmethoxyl-2-rnethyl-phenoxy}-2-methyl-propionic acid
A solution of 110 mg (0.21 mmol) 2-{4-[4-(2-methoxy-ethyl)-2-(6-trifluoromethyl-pyridin-3-yl)-pyrimidin-5-ylmethoxy]-2-methyl-phenoxy}-2-methyl-propionic acid ethyl csterin 1.2 ml of THI-VlitOH (1:1) was cooled (0 °C) treated with 0.62 ml IN LiOH and stirred for 15h at RT. The reaction mixture was taken up in ether and washed with aqueous 10% KHSO4 solution and aqueous 10% NaCl. The organic phase was dried (Na2S()4) and evaporated. The crude product was suspended in ether/petane and filtered to give 87 mg of the title compound as a white powder of mp. 122-124 °C, dec.
MS: 518.2 (M-I1).

5-Chloromcthyl-4-(2-methoxy-ethyl)-2-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine used in I01A| was synthesi/cd as follows:
Cj (H,/)-2-[l-Hthoxy-methylidene]-5-methoxy-3-oxo-pentanoic acid methyl ester
A solution of 21.96 g (116.5 mmol) 5-methoxy-3-oxovaleric acid methyl ester, 35.25 ml (233.1 mmol) of triethyl orthoformate in 240 ml acetic anhydride was refluxed at 150 °C for 2.5h. The reaction mixture was concentrated at 50 °C under reduced pressure to give 29.06 g of crude (E,Z)-2-( l-ethoxy-methylidene]-5-methoxy-3-oxo-pentanoic acid methyl ester.
MS: 217.2 (Mi II)'.
I)J 4-(2-IVIethoxy-cthyl)-2-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine-5-carboxylic acid methyl ester and 4-(2-methoxy-ethyl)-2-(64rifluoromethyl-pyridin-3-yl)-pyrimidine-5-carboxylic add ethyl ester
To a solution of 16.24 g (72.0 mmol) 6-(trifluoromethyl)pyridine-3-benzamidine HCI in 200 ml of cthanol was added 7.61 g (96.1 mmol) of sodium tert-butoxide. After 5 min, 15.57 g (72.0 mmol) of crude (E,Z)-2-[l-ethoxy-methylidene]-5-methoxy-3-oxo-pcntanoic acid methyl ester in 70 ml ethanol was added. The reaction mixture was then stirred over night at 90 °C. The ethanol was removed partially under reduced pressure, (he residue taken up in ether and washed with IN HCI and water. The ether solution was concentrated under reduced pressure and the crude product purified by flash chromatography over silica gel with dichloromethane/ether 99:1 to 95:5 to give 18.36 g of a mixture of 4-(2-rnethoxy-ethyl)-2-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine-5-carboxylic acid methyl ester and 4-(2-methoxy-ethyl)-2-(6-trifluoromethyl-pyridin-3-yl)-pyrimidinc-5-carboxylic acid ethyl ester.
MS: 342.2 and 356,3 (M+H)+. iiil4d.2-Methoxy-othyl)-2-(6-trifluoromethyl-pyridin-3-yl)-pyrimidin-5-yl]-methanol
Within 20 min was dropped 50 ml (60 mmol) of DIBALH (1.2 M solution in toluene) to a dry ice cooled (-30 °C) solution of 6.83 g (20 mmol) 4-(2-methoxy-ethyl)-2-(6-triiluoromethyl-pyridin-3-yl)-pyrimidine-5-carboxylic acid methyl ester and 4-(2-niethoxy-ethyl)-2-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine-5-carboxylic acid ethyl ester in 100 ml of THF. The reaction was warmed up ( 0 °C for Ih) and stirred lh at RT. The reaction was cooled (0 °C) and neutralized with KHSCU solution (10%). The

mixture was extracted with ether (3x), the organic phase was washed with a NaCl solution (10%), dried (NaaSO^ and evaporated. The crude product was crystallized (dichloromethane/ ether, 0 °C) to give 6.72 g of pure [4-(2-methoxy-ethyl)-2-(6-trifluoromethy!-pyridin-3-yl)-pyrimidin-5-yl]-methanol.
MS: 314.2 (M-HI)'.
FJ 5-Chloromethyl-4-(2-methoxy-ethyl)-2-(6-trifluoromethvl-pvridin-3-yn-pyrimidine
A cooled (0 °C) solution of 0.94 g (3 mmol) of [4-(2-methoxy-ethyl)-2-(6-trinuoromethyl-pyridin-3-yl)-pyrimidin-5-yl]-methanol in 30 ml dichloromethane was treated with 0.44 ml (6 mmol) thionylchloride and stirred for 2.5h at RT. The reaction was evaporated, dissolved twice in heptane an evaporated to give 1.0 g of pure 5-chIoromethyl-4-(2-melhoxy-ethyl)-2-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine.
MS: 332.2 (MMI. Id)'. Example 102
2-{4-|4-(2-Methoxy-ethyl)-2-(6-trifluoromethyl-pyridin-3-yI)-pyrimidin-5-ylmcthoxy)-2-mcthyl-phenoxy}-2-methyl-propionic acid
A solution of 133 mg (0.25 mmol) 2-{4-[4-(2-methoxy-ethyl)-2-(6-trifluoromethyl-pyridin-3-yl)-pyrimidin-5-ylmethoxy]-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester (example 101A |) in 1.5 ml of THF/MeOH (1:1) was cooled (0 °C) treated with 0.75 ml IN LiOH and stirred for 15h at RT. The reaction mixture was taken up in ether and washed with aqueous 10% KHSO4 solution and aqueous 10% NaCl. The organic phase was dried (Na2SO,i) and evaporated. The crude product was suspended in ether (RT to 4 °C) and filtered to give 66 mg of the title compound as a white powder of mp. 140.5-141.5 °C,dce.
MS: 504.2 (M-ll).

K sample 103
2-{4-|4-(2-Hydroxy-ethyl)-2-(6-trifluoromethyl-pyridin-3-yl)-pyrimidin-5-ylmethoxy|-2-methyI-phenoxy}-2-methyl-propionic acid
AJ 2-i4-[4-(2-Hydroxy-ethyl)-2-(6-trifluoromethyl-pyridin-3-yn-pyrimidin-5-
ylincthoxyJ-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester
To a solution of 133 mg (0.25 mmol) 2-{4-[4-(2-methoxy-ethyl)-2-(6-trifluoromethyl-pyridin-3-yl)-pyrimidin-5-ylmethoxyj-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester (example 101 AJ) in 1 ml of dichloromethan was treated at -78 °C with 0.31 ml BBn (1M in dichloromethane, 0.3 1 mmol). The reaction was warmed up ( RT for 2.5h) and stirred 30 min at RT. The reaction was treated with saturated NaHCOs-solution. The mixture was extracted with ether (3x), the organic phase was washed with a NaCI solution (10%), dried (Na^SO/i) and evaporated. The crude product was purified by flash chromatography over silica gel with heptane/AcOEt 9:1 to 4:1, to give 21 mg of the title compound as an off-while viscous oil.
MS: 520.5 (MHI) .
BJ 2-|4-[4-(2-Hydroxy-ethyl)-2-(6-trifluoromethyl-pyridin-3-yl)-pyrimidin-5-
ylinethoxyJ-2-mcthyl-phenoxy}-2-inethyl-propionic acid
In analogy to the saponification described in examples 102], 2-{4-[4-(2-hydroxy-ethyl)-2-(6-lrinuoromethyl-pyridin-3-yl)-pyrimidin-5-ylmethoxy|-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester gave the title compound as a white powder of mp. 187-I88°C, dec.
MS: 490.2 (M-H).
Example 104
2-{4-|4-Mcthoxymcthyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylinethoxy|-2-methyl-phenoxy }-2-methyl-propionic acid
In analogy to the procedures described in example 101A], 2-(4-hydroxy-2-methyl-
phcnoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) was reacted
with 5-chloromethyl-4-methoxymethyl-2-(4-trifluoromethyl-phenyI)-pyrimidine
(prepared from methyl 4-methoxyacetoacetate and 6-(trifluoromethyl)pyridine-3-ben/amidine hydrochloride, in analogy to the procedures described in examples IOIC| to

13 J 2- {..4jj4-CycJQprQpyJ-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-2,3-
dimcthyl-phenoxyl-2-methyl-propionic acid
In analogy to the procedures described in example 101 A], 2-(4-hydroxy-2,3-dimethyl-phenoxy)-2-methyl-propionic acid ethyl ester (example 106A]) was reacted with 5-chloromcthyl-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 27FJ) to give 2-{4-|4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yImethoxy]-2,3-dimcthyl-phenoxyj-2-methyl-propionic acid ethyl, which was subsequently saponified in analogy to the procedure described in example 101 B] to yield the title compound as off-white powder of mp. 214-215 °C, dec.
MS: 499. 1 (M-II). Example 107
2-MethyI-2-{2-methyl-4-[4-trifluoromethyl-2-(4-trifluoromethyl-phenyI)-pyrimidin-5-ylmethoxy|-phenoxy}-propionic acid
AJ 2-Mcth^l-2-{2-methyl-4-[44riflu 5-ylmcthoxyJ-phenoxy) -propionic acid
In analogy to the procedures described in example 101 A], 2-(4-hydroxy-2-methyl-
phcnoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) was reacted
with 5-chloromethyl-4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine
(example I071)|) to give 2-methyl-2-{2-methyl-4-[4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-phenoxy}-propionic acid ethyl ester, which was subsequently saponified in analogy to the procedure described in example 101B] to yield the title compound as off-white powder of mp. 149-151 °C, dec.
MS: 513. 1 (M-H)~.
5-Chloromcthyl-4-trinuoromethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine used in I07A| was synthesi/ed as follows:
!iL4£Irjflu^rometh^vl-2-(4-tr acid ethyl
In analogy to the procedures described in example 10 1C] and 101D], ethyl 4,4,4-irifluoroacetoacetate and 4-(trifluoromethyl)benzamidine hydrochloride gave the title compound as a light yellow powder.

MS: 363.9 (M)+.
CJ [4-lrit1uoromethyl-2-(4-trifluoromethvl-phenyl')-pyrimidin-5-vl1-methanol
Within 10 min was dropped 5.5 ml (6.6 mmol) of DIBALH (1.2 M solution in toluene) to a dry ice cooled (-30 °C) solution of 1.09 g (3.0 mmol) 4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid ethyl ester in 15 ml of THF. The reaction was stirred for 2.5h at -30 °C, warmed up (0 °C for 2h) and stirred Ih at 0 °C. The reaction was neutralized with saturated NaHCOs solution. The mixture was extracted with ether (3x), the organic phase was washed with a NaCl solution (10%), dried (Na^SC^) and evaporated. The crude product was purified by flash chromatography over silica gel with heptane/isopropanol 9:1, to give 0.16 g of pure [4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-methanol as a yellow solid.
MS: 322.0 (M)+.
DJ 5-Chloromethyl-4-trifluoromethvl-2-(4-trifluoromethyl-phenvl)-pvrimidinc
A cooled (0 °C) solution of 0.081 g (0.25 mmol) of [4-trifluoromethyl-2-(4-trinuoromethyl-phenyl)-pyrimidin-5-yI]-methanol in 2.5 ml dichloromethane was treated with 0.04 ml (0.50 mmol) thionylchloride and stirred for 14h at RT. The reaction was evaporated, dissolved in ether and twice in heptane and evaporated to give 0.077 g of pure 5-chloromethyl-4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine.
MS: 339.9 (M, ICI)'. Example 108
2-Mcthyl-2-{2-methyl-4-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyI)-pyridin-3-ylmcthoxyl-phcnoxyj-propionic acid
A J 2-Methy [-2- (2-mcthyl-4-[4-trir1uoromethyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethoxyj-phcnoxyt-propionic acid
In analogy to the procedures described in example 101 A], 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) was reacted with 5-chloromethyl-4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-pyridine (example 1081))) to give 2-methyi-2-{2-methyl-4-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethoxy|-phenoxy}-propionic acid ethyl ester, which was subsequently

saponified in analogy to the procedure described in example 101B] to yield the title compound as off-white crystalls of mp. 148-149 °C.
MS: 512.1 (M-II),
5-Chloromethyl-4-trifluoromethyl-2-(4-tritluoromethyl-phenyl)-pyridine used in 108A] was synthcsi/.cd as follows:
BJ 4-Trinuoromcthvl-6-(4-trifluoromethyl-phenyl)-nicotinic acid methyl ester
|Following a procedure of Kaoru Inada and Norio Miyaura, Tetrahedron (2000), 56, 8661-86641
A solution of 0.84 g (1.2 mmol) bis(triphenylphosphine)palladium(Il)chloride, 9.58 g (40 mmol) methyl 6-chloro-4-(trifluoromethyl)nicotinate and 10.08 g (52 mmol) of 4-(trilluoromethyl)ben/eneboronic acid in 200 ml degassed toluene was treated with 40 ml aqueous 2M K^POi and heated at 80 °C for 16h. The reaction was cooled to RT and extracted with IhO (0 °C)/Et2O (3x). The organic phases were washed with aqueous 10% NaCI, dried (NaSO4) and evaporated. Purification by flash-chromatography on silica gel (dichloromethane/heptane 2:1 to 1:1) gave 9.91 g of the title compound as an off-white powder.
MS: 348.9 (M)'. CjJVjJllluorpmethyl-6-(4-trit1uorornethyl-phenyI)-pyridin-3-yl]-rnethanol
Within 15 min was dropped 25 ml (30 mmol) of DIBALH (1.2 M solution in toluene) to a dry ice cooled (-30 °C) solution of 3.49 g (10 mmol) 5-(4-trifluoromethyl-phenyl)-pyra/.ine-2-carboxylic acid methyl ester in 50 ml of THF. The reaction was stirred for 1.25h at -30 °C, and I h at 0 °C. The reaction was neutralized with aqueous 10% Kl 1SO4 solution. The mixture was extracted with ether (3x), the organic phase was washed with a NaCI solution (10%), dried (Na2SO4) and evaporated to give 3.21 g of pure [4-trilluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-methanol as a light yellow powder.
MS:321.()(M)'
l)j 5-Chloromethyl-4-trifluoromethyl-2-(4-trifluoromethyl-phenvl)-pyridine

A] 2- i^-^^-Hydroxy-ethylj^^-trifluoromethyl-phenyD-pyrimidin-S-ylmethoxy]^-mcthyl-phcnoxy}-2-methyl-propionicacid
In analogy to the procedures described in example 101 A], 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) was reacted with 2-|5-chloromethyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-4-yl]-ethanol. (example 1 IOC |) and 5,1 equivalent of cesium carbonate in the presence of catalytic amount of sodium iodide to give 2-{4-[4-(2-hydroxy-ethyl)-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxyJ-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester, which was subsequently saponified in analogy to the procedure described in example 101 B] to yield the title compound as white crysatlls of mp. 155.0-155.5 °C.
MS: 489.1 (M-I1).
2-|5-Chlorornethyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-4-yl]-ethanol used in MOA] was synthcsi/ed as follows:
BJ 5-Chloromethyl-4-^^
In analogy to the procedures described in examples 101CJ to 101F), 5-methoxy-3-oxovaleric acid methyl ester and 4-(trifluoromethyl)benzamidine hydrochloride gave the title compound as a yellow oil.
MS: 329.9 (M. ICI)'.
In analogy to the procedures described in examples 103A], 5-chloromethyl-4-(2-incthoxy-ethyl)-2-(4-trifluoromethyl-phenyl)-pyrimidine and BBr3 (1M in dichloromethane) gave the title compound as a yellow oil, which was used without further purification.
MS: 317.1 (M-t-H.CI)1.
Example 111
2-!Vlethyl-2-{2-methyl-4-[2-(4-trifluoromethoxy-phenyl)-4-trifluoromethyl-pyrimidin-5-ylmethoxy|-phenoxy}-propionicacid
Aj ^-Mcthyl-2-{2-methvl-4-|2-(4-trifluorornethoxv-phenvn-4-trifluoromethvl-

In analogy to the procedures described in example 101 A], 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) was reacted with chlorosulfurous acid 2-(4-trifluoromethoxy-phenyl)-4-trifluoromethyl-pyrimidin-5-ylmethyl ester (example 11 IF]) to give 2-methyl-2-{2-methyl-4-[2-(4-trifluoromethoxy-phenyl)-4-trifluoromethyl-pyrimidin-5-ylmethoxy]-phenoxy}-propionic acid ethyl ester, which was subsequently saponified in analogy to the procedure described in example 10 IB) to yield the title compound as a white powder of mp. 153.5-154.5 °C.
MS: 529.1 (M-H).
Chlorosulfurous acid 2-(4-trifluoromethoxy-phenyl)-4-trifluoromethyl-pyrimidin-5-ylmethyl ester used in MIA] was synthesized as follows:
BJ 2-(4-Trinuoromcthoxy-phenyl)-4-trifluoromethyl-pyrimidine-5-carboxylic acid ethyl ester
In analogy to the procedures described in examples 108B], ethyl 2-chloro-4-(trinuoroinethyl)pyrimidine-5-carboxylate and 4-(trifluoromethoxy)phenylboronic acid gave the title compound as an off-white powder.
MS: 379.9 (M)1.
CJ 2 -|4-' 1 'rjflupromethoxy-phenyl)-4-trifluoromethyl-pyrimidine-5-carboxylic acid
In analogy to the procedures described in examples 101 B], 2-(4-trifluoromethoxy-phenyl)-4-trinuoromethyl-pyrimidine-5-carboxylic acid ethyl ester gave the title compound as a white powder.
MS: 351.1 (M-H)
DJ 2-(4-'rrinuoromethoxy-phenyl)-4-trifluoromethyl-pvrimidine-5-carbonvl chloride
A solution of 0.43 g (1.22 mmol) of 2-(4-trifluoromethoxy-phenyl)-4-trifluoromethyl-pyrimidine-5-carboxylic acid in 8 ml of dichloromethane was treated at RT with 2 drops of DMF. 0.12 ml (1.34 mmol, 1.1 eq) of oxalyl chloride were added within 5 min and stirring was continued for 2h. The solution was evaporated and dried under reduced pressure to give 0.45 g of the title compound.
MS: 370.0 (M, I('!)'.
1 :.\ |_2-(4-Trinuoroinethoxy-phenyl)-4-trifluoromethyl-pyrimidin-5-yr]-methanol

0.45 g (1.21 mmol) 2-(4-Trifiuoromethoxy-phenyl)-4-trifluoromethyl-pyrimidine-5-carbonyl chloride in 4 ml tetrahydrofurane were cooled (-30 °C) and treated during 10 min with 2.23 ml (2.20 mmol) of a DIBALH-solution (1.2 M in toluene). The solution was allowed to come to 0 °C (1.5h). The reaction was then powered to an ice-cooled aqueous 10% KIISO4 solution and extracted with ether. The ether-phase was washed with aqueous 10% NaCl solution, dried (NaSO-O and evaporated. The crude product was purified by flash ehromatography over silica gel with heptane/AcOEt 9:1, to give 0.29 g of the title compound as an off-white solid.
MS: 338.0 (M)'.
F| Chlorosulfurous acid 2-(4-trifluoromethoxy-phenyl)-4-trifluQromethyl-pyrirnidin-5-yimcthyl ester
A cooled (0 °C) solution of 0.40 g (1.20 mmol) of [2-(4-trifluoromethoxy-phenyI)-4-trilluoromethyl-pyrimidin-5-yl]-methanol in 12 ml dichloromethane was treated with 0.10 ml (1.32 mmol) thionylchloride and stirred for 30 min at RT. The reaction was cooled (0 °C), treated with 0.08 ml (1.08 mmol) thionylchloride and stirred for 30 min at RT . The solution was evaporated, dissolved in ether and twice in heptane and evaporated to give 0.44 g of the title compound as an off-white powder.
MS: 338.0 (M-SOC1)', IR: 1227 cm"1. Example 112
2-Methyl-2-{2-mcthyl-4-|2-methyl-6-(4-trifluoromethoxy-phenyl)-4-tritluoromethyl-|>yridm-3-ylmethoxy]-phcnoxy}-propionic acid
AJ 2-Methyl-2-!2-methyl-4-[2-methvl-6-(4-trifluorQmethoxy-phenyl)-4-trinuoromethyl-pyridin-3-ylmethoxyJ-phenoxy}-propionic acid ethyl ester
To an ice cold solution of 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (35 mg, 147 u.mol; described in WO 02/092590), [2-methyl-6-(4-trinuoromethoxy-phenyl)-4-trifluoromethyl-pyridin-3-yl]-methanol (52 mg, 148 urnol, example 112H|) and tributylphosphine (50 u.1, 178 u.mol) in tetrahydrofuran (3,5 ml) was added N,N,N',N'-tctramethyl azodicarboxamide (30 mg, 178 mmol). The cooling bath was removed and stirring continued for!4 h. The mixture was filtered over celite and the solvent removed under reduced pressure to give a yellow oil which was purified by

column chromatography (silica gel, heptane/AcOEt) to give 63 mg (110 u.mol, 75 %) of the title compound as colorless oil.
MS: 572.3 (M+l I)1.
BJ 2-Mcthyl-2-i2-methyl-4-[2-methvl-6-(4-trifluoromethoxv-phenyl)-4-trifluoromethyl-pyridin-3-ylmethoxv]-phenoxyl-propionic acid
In analogy to the procedure described in example 26 C], 2-methyl-2-{2-methyl-4-[2-methyl-6-(4-trinuoromethoxy-phenyl)-4-trifluoromethyl-pyridin-3-ylmethoxy]-phcnoxyj-propionic acid ethyl ester was treated with LiOH to obtain the title compound as colorless solid.
MS: 544.2 (M+lI)1.
[2-mcthyl-6-(4-tril1uoromethoxy-phenyl)-4-trifluoromethyl-pyridin-3-yl]-methanol used in 112A| was synthesi/ed as follows:
CJ (/.)-4,4.4-'rrit1uoro-3-hvdroxy-l-(4-trit1uoromethoxy-phenyl)-but-2-en-l-one
To a toluene (50 ml) suspension of potassium ?-butoxide (3.3 g, 29 mmol) and l-(4-trifluoroinethoxy-phenyl)-ethanone (3.9 ml, 24 mmol) under an argon atmosphere was added dropwise ethyl trifluoroacetate (3.4 ml, 29 mmol) at 10 °C. The suspension was stirred at ambient temperature for 14 h. The pH value of the mixture was adjusted to 6 with 10 % IbSO,), the solution was extracted two times with /-butyl methylether and the combined extracts were washed with brine/ice water 1/1. The organic layer was dried over sodium sulfatc, concentrated under reduced pressure and the residue purified by column chromatography (silica gel, w-heptane/ethyl acetate) to yield 2.9 g (9.7 mmol, 40 %) of the title compound as orange oil.
MS:319.2(M+NH,i)*.
DJ 2-Methyl-6-(4-trifluoromethoxv-phenvl)-4-trifluoromethvl-nicotinic acid ethyl ester
To an acetonitrile (35 ml) solution of (Z)-4,4,4-trifluoro-3-hydroxy-l-(4-trifluoromethoxy-phenyl)-but-2-en-l-one (2.9 g, 10 mmol) was added ethyl-Sam inocrotonate (2.5 g. 19 mmol) under an argon atmosphere. The mixture was heated at reflux for 12 h. The solvent was removed under reduced pressure and the residue purified by column chromatography (silica gel, «-heptane/ethyl acetate) to yield 1.9 g (4.8 mmol, 50 %) of the title compound as yellow oil.

MS: 394.0 (MM I)'.
A solution of 2-mcthyl-6-(4-trifluoromethoxy-phenyl)-4-trifluoromethyI-nicotinic acid ethyl ester (400 mg, I mmol) in diethyl ether (6 ml) was added to a suspension of lithium aluminium hydride (77 mg, 2 mmol) in diethyl ether (12 ml) under an argon atmosphere at ambient temperature within 5 min. The mixture was stirred at reflux for 12 h, cooled to 0 °C and treated cautiously with ice water (12 ml) and 10 % aqueous NaOH (6 ml). The reaction mixture was filtered over celite, r-butyl methylether was added and the layers were separated. The aqueous layer was extracted one more time with /-butyl inethylelher, the combined organic layers were washed with ice water/brine I/ 1 and dried over sodium sulfate. Removal of the solvent under reduced pressure gave an orange oil which was purified by column chromatography (silica gel, heptane/AcOEt) to yield 140 mg (400 mol, 39 %) of the title compound as colorless crystals.
MS: 352.3 (M-H-I)'. Example 113
2-{4-[4-Cyclopropyl-6-methoxymethyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxyJ-2-methyl-phenoxy}-2-methyl-propionicacid
A] 2j-{4-[4-Cyclopropyl-6-methoxymethyl-2-(4-trifluoromethyl-phenvl)-pyrimidin-5-ylrncthoxyJ-2-mcthyl-phenoxy}-2-methyl-propionic acid ethyl ester
A solution of 200 mg (0.56mmol) 5-chloromethyl-4-cyclopropyl-6-methoxymethyl-2-(4-trifiuoromethyl-phenyO-pyrimidine (example 1 13HJ), 134 mg (0.56mmol) 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) and 237 mg (0.73mmol) cesium carbonate in 3 ml DMF was stirred for 3h at RT. The reaction mixture was taken up in ether and washed with IN HCI and water. After purification of the crude product by chromatography over silica gel with AcOHt/ heptane 1:3, 257 mg of pure 2-{4-[4-cyclopropyl-6-methoxymethyl-2-(4-trifluoromethyl-phcnyl)-pyrimidin-5-ylmethoxy]-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester could be isolated.
MS: 559.3 (Mt 1 1)'.
BJ _lri4jJ_4jCyclopropyl-6HTiethoxvmethvl-2-(4-trifluoromethyl-phenyl)-pyrimid ylmethoxyJ-2-mejthyl-pheng^|j:^methyl-prppionicacid

A solution of 215 mg (0.385 mmol) 2-{4-[4-cycloProPyl-6-methoxymethyl-2-(4-trinuoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester and 1.1 ml IN LiOH-solution in 2.5 ml tetrahydrofurane was stirred for 2h at RT. The reaction mixture was taken up in ether and washed with IN HCI and water. The crude residue was suspended in AcOEt/ heptane 1:19. The resulting amorphous crystals were filtered off to provide 164 mg of pure 2-{4-[4-cycIopropyl-6-
methoxymethyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-2-methyl-phenoxy}-2-methyl-propionic acid.
MS: 529.3 (M-H).
5-Chloromelhyl-4-cyclopropyl-6-methoxymethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine used in 113A| was synthesized as follows:
C'j 2-Cyclopropanecarbonyl-4-methoxv-3-oxo-butyric acid methyl ester
To an ice-cooled solution of 10 g (70.35 mmol) 3-cyclopropyl-3-oxo-propionic acid methyl ester and 6.69 g (70.35 mmol) anhydrous magnesium chloride was dropped within 10 min 11.3 2ml (140 7 mmol) pyridine. 15 min later, 12.54 g (77.38 mmol) melhoxyacetic anhydride was added and the reaction mixture was then stirred at RT over night. The reaction mixture was concentrated under reduced pressure and then taken up in ether and washed with water, IN HCI and again with water. The ether-phase was concentrated under reduced pressure providing 13.17 g crude 2-cyclopropanecarbonyl-4-mcthoxy-3-oxo-butyric acid methyl ester.
MS: 215.4 (Mill)'. ilLiJ^l-2zCyclQpropanecarbonyl-3,4-dimethoxv-but-2-enoic acid methyl ester
An ice-cooled solution of 6.43 g (30 mmol) 2-cyclopropanecarbonyl-4-methoxy-3-oxo-butyric acid methyl ester in 60 ml acetonitrile was treated with 9.78 g (30 mmol) cesium carbonate. After the removal of the ice bath 3.39 ml (30 mmol) trifluoro-methanesulfonic acid methyl ester was added. The reaction mixture was stirred over night at RT, concentrated under reduced pressure, taken up in ether and washed with water. The ether-layers were concentrated under reduced pressure to provide 6.48 g crude (E,Z)-2-cyclopropanecarbonyl-3,4-dimethoxy-but-2-enoic acid methyl ester.
MS: 229.3 (M HI)1.

HJ 4-Cycloprgpy|-6-methoxyiTiethyl-2-(4-trifluoromethvl-phenyl)-pyrimidine-5-
carboxylic acid methyl ester and
JlJ 4-Cyclopropyl-6-methoxymethyl-2-(4-trifluoromethyl-phenvl)-pyrimidinc-5-
carboxyI ic acid
A solution of 7.4 g (28.28 mmol) 4-trifluoromethyI-benzamidine HC1 in 40ml ethanol was treated with 2.81 g (28.28 mmol) sodium ter/.-butoxide. After 4 min, 6.48 g (28.28 mmol) of the crude (E,Z)-2-cyclopropanecarbonyl-3,4-dimethoxy-but-2-enoic acid methyl ester, in 30 ml ethanol, was added. The reaction mixture was stirred over night, taken up in ether and washed with IN HC1 and water. The crude product was purified by chromatography over silica gel with AcOEt/ heptane 1:3, providing 2.86 g pure 4-cyclopropyl-6-methoxymethyI-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid methyl ester (example E])
MS: 367.1 (M~iH)'.
And 1.2 g of pure 4-cyclopropyl-6-methoxymethyI-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid (example F]).
MS:35I.4(M-HV.
Ql i4:Cyclopropyi-6^ mcthanol
To a solution of 2.86 g (7.8 mmol) 4-cyclopropyl-6-methoxymethyl-2-(4-trinuoromethyl-phenyl)-pyrimidine-5-carboxylic acid methyl ester in 30 ml tetrahydrofurane was dropped at -78 °C, 20 ml (24 mmol) of a DIBALH-solution ( 1.2 M in toluene). The reaction was stirred for 15 min at -70 °C, then the dry-ice bath was removed, the reaction temperature was allowed to come to RT and the solution was stirred for 2h al RT. To the reaction mixture was then dropped carefully, under ice-cooling, 13 ml of 6N HCI. The reaction mixture was then taken up in ether and was washed with water. The ether-phase was concentrated under reduced pressure providing 1.29 g of pure crystalline [4-cyclopropyl-6-methoxymethyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-methanoI.
MS: 339.1 (M-fH)1.
11| 5-O]jorojiK'thyl-4-cyclopropvl-6-methoxvmethyl-2-(4-trifluoromethyl-phenyD
pyrimidinc

A solution of 1.29 g (3.8 mmol) [4-cyclopropyl-6-methoxymethyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-methanol in 12 ml dichloromethane was treated with 0.29 ml (3.99 mmol) thionylchloride. After 2h stirring at RT, the mixture was partitioned between ether and water. The ether-phase was concentrated under reduced pressure giving 1.35 g pure crystalline 5-chloromethyl-4-cyclopropyl-6-methoxymethyl-2-(4-trifluoromcthyl-phenyl)-pyrimidine.
MS: 357.3 (M+H)f. Example 114
2-{4-|4-Cyclopropyl-6-methoxymethyI-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmcthoxy |-phcn()xy}-2-mcthyl-propionic acid
AJ 2-{4-[4-Cyclopropyl-6-methoxymethvl-2-(4-trifluoromethyl-phenyn-pyrimidin-5-ylmethoxyJ-phenoxy}-2-rnethyl-propionic acid ethyl ester
A solution of 200 mg (0.56mmol) 5-chloromethyl-4-cyclopropyl-6-methoxymethyI-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 113H]), 125 mg (0.56mmol) 2-(4-hydroxy-phenoxy)-2-methyl-propionic acid ethyl ester [Newman, Melvin S.; Cella, James A. Monoalkylation of hydroquinone. Journal of Organic Chemistry (1974), 39(2), p 214-15] and 237 mg (0.73mmol) cesium carbonate in 3 ml DMF was stirred for 3h at RT. The reaction mixture was taken up in ether and washed with IN HCI and water. After purification of the crude product by chromatography over silica gel with AcOHt/ heptane 1:3, 223 mg of pure 2-{4-[4-Cyclopropyl-6-methoxymethyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-phenoxy}-2-methyl-propionic acid ethyl ester was isolated.
MS: 544.58 (MM I)'.
NJ 2-{4-[4-Cyclopropyl-6-methoxymethyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxyJ-phcnoxyl-2-methyl-propionic acid
A solution of 198 mg (0.385 mmol) 2-{4-[4-cyclopropyl-6-methoxymethyl-2-(4-trifiuoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester and 1.1 ml IN LiOH-solution in 2.5 ml tetrahydrofurane was stirred for 2h at RT. The reaction mixture was taken up in ether and washed with IN HCI and water. The crude residue was suspended in Ethylacetate/ heptane 1:19. The resulting crystals were filtered off to provide 170 mg of pure 2-{4-[4-cyclopropyl-6-

In analogy to the procedures described in example example 27F], 3-oxo-heptanoic acid methyl ester and 4-lrifIuoromethyl-benzamidine HCI gave the title compound.
MS: 329.0 (M HI. ICI)'. Example 116
2-{4-|4-Butyl-2-(4-trinuoromethyl-phenyl)-pyrimidin-5-ylniethoxy]-phenoxy}-2-methyl-propionic acid
Aj ______ 2ilM4-l3utyl-2-(4-trifluorornethyl-phenvn-pvrirnidin-5-vlmethoxy]-phenoxy}-2-
ac i.dLe_tiiy]jester
A solution of 367 ing (I.I 1 mmol) 4-butyl-5-chloromethyI-2-(4-trifluoromethyl-phenyl)-pyrimidine (example I I5C]) and 250 mg (I.I 1 mmol) 2-(4-hydroxy-phenoxy)-2-methyl-propionic acid ethyl ester ester [Newman, Melvin S.; Cella, James A. Monoalkylation of hydroquinonc. Journal of Organic Chemistry (1974), 39(2), p 214-15] in 4 ml DMF was was treated with 436 mg ( 1 .34 mmol) cesium carbonate. The reaction mixture was stirred lor 24h at RT and then it was taken up in ether and washed with IN HCI and water. The crude product was purified by chromatography over silica gel with AcOEt/ heptane 1:4 to provide 344 ing pure 2-{4-|4-butyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmcthoxy]-phenoxy}-2-methyl-propionic acid ethyl ester.
MS:5I7.3(M+II)'.
^ methyl-propionic acid
297 mg (0.575 mmol) 2-{4-[4-butyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy|-phenoxy}-2-methyl-propionic acid ethyl ester and 2 ml IN LiOH in 3 ml tcrahydrofurane were stirred over night at RT. The reaction mixture was taken up in ether and washed with IN HCI and water. The crude product was suspended in AcOlit/heptane 1:19. The resulting crystals were filtered off providing 258 mg pure 2-|4.|4.butyl-2-(4-triflLioromethyl-phenyl)-pyrimidin-5-ylmethoxy]-phenoxy}-2-methyl-
propionic acid. MS: 487.2 (M-H)'.

Example 117
2-{4-[4-Cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-phcnoxy$-2-methyl-propionic acid
AJ 2-{4-[4-Cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-vlmethoxv|-
phcnoxyj-2-methyl-propionic acid ethyl ester
A solution of 418 mg (1.34 mmol) 5-chloromethyl-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine and 300 mg (1.34 mmol) 2-(4-hydroxy-phenoxy)-2-methyl-propionic acid ethyl ester (Newman, Melvin S.; Cella, James A. Monoalkylation of hydroquinone. Journal of Organic Chemistry (1974), 39(2), p 214-15] in 5 ml DMF was treated with 523 mg (1.61 mmol) cesium carbonate. The reaction mixture was stirred 4h at RT and then it was taken up in ether and washed with IN HC1 and water. The ether layers were concentrated under reduced pressure and the crude product was purified by chromatography over silica gel with AcOEt/ heptane 1:4 giving 550 mg of pure 2-{4-[4-cyclopropyl-2-(4-trinuoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-phenoxy}-2-methyl-propionic acid ethyl ester.
MS: 501.2 (1VH II)',
BJ 2-{4-[4-Cyclopropyl-2-(4-trifluoromethyl-phenvl)-pyrimidin-5-ylmethoxy|-
phcnoxy}-2-mclhyl-propionic acid
445 mg (0.889 mmol) of 2-{4-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmcthoxy|-phenoxy}-2-methyl-propionic acid ethyl ester and 2.7 ml IN LiOH in 5 ml tctrahydrofurane were stirred at 50 °C over night. The reaction mixture was taken up in ether and washed with IN HC1 and water. The crude product was suspended with AcOHt/ heptane 1:19. The resulting crystals were filtered off providing 393 mg pure 2-{4-|4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-phenoxy}-2-mcthyl-propionic acid.
MS: 471.1 (M-H) .

Example 118
2-{4-|4-(2-Methoxy-ethyl)-6-methyl-2-(4-trifluoromcthyl-phenyl)-pyrimidin-5-ylmethoxy|-2-methyl-phenoxy}-2-methyl-propionic acid
AJ 2-{4-[4-(2-Methoxy-ethyl)-6-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-
ylinethoxyJ-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester
A solution of 350 mg (1 mmol) 5-chloromethyl-4-(2-methoxy-ethyl)-6-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 118G]), 235 mg (1 mmol) 2-(4-hydroxy-2-mcthyl-phenoxy)-2-mcthyl-propionic acid ethyl ester (described in WO 02/092590) and 417 mg (1 mmol) cesium carbonate in 5 ml DMF was stirred for 3h at RT. The reaction mixture was taken up in ether and washed with IN HCI and water. After purification of the crude product hy chromatography over silica gel with AcOEt/ heptane 1:3, 283 mg of pure 2-{4-[4-(2-methoxy-ethyl)-6-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yhr)ethoxy|-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester was isolated.
MS: 547.3 (M+il)1.
B_[ 2-{4-[4-(2-Methoxy-ethyl)-6-methyl-2-(4-trifluoromethvl-phenyl)-pyrimidin-5-
ylmcthoxyJ-2-metri yl-phenoxy} -2-methyl-propionic acid
A solution of 244 mg (0.446 mmol) 2-{4-[4-(2-methoxy-ethyl)-6-methyl-2-(4-trinuoromethyl-phcnyl)-pyrimidin-5-ylmethoxy]-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester and 1.34 ml IN LiOH-solution in 2.5 ml tetrahydrofurane was stirred for 2h at RT. The reaction mixture was taken up in ether and washed with IN HCI and water. The crude residue was suspended in AcOEt/ heptane 1:19. The resulting crystals were filtered off providing 188 mg of pure 2-{4-[4-(2-methoxy-ethyI)-6-methyl-2-(4-trinuoromelhyl-phenyl)-pyrimidin-5-ylmethoxy]-2-methyl-phenoxy}-2-methyl-propionic acid.
MS:5I7.2(M-U).
5-C'hloromethyl-4-(2-methoxy-ethyl)-6-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidine used in I 18A| was synthesized as follows:
CJ 2-Acetyl-5-mcthoxy-3-oxo-pentanoic acid methyl ester
To an ice cooled solution of 5.28 g (32.96 mmol) 5-methoxy-3-oxo-pentanoic acid methyl ester and 3.14 g (32.96 mmol) anhydrous magnesium chloride in 50 ml

dichloromethanc was dropped within 3 min 5.3 ml (65.92 mmol) pyridine. 3.27 ml (34.61 mmol) of acetic anhydride was then added within 3 min. The reaction mixture was stirred over night at RT and after concentration under reduced pressure it was partitioned between ether, IN HCI and water. The ether solution was concentrated under reduced pressure to give 5.87 g pure 2-acetyl-5-methoxy-3-oxo-pentanoic acid methyl ester.
MS: 203.3 (VH II)'.
I)J 5-Mcthoxy-2-[l-methoxy-eth-(E,Z)-ylidene1-3-oxo-pentanoic acid methyl ester
An ice-cooled solution of 5.87 g (29.02 mmol) 2-acetyl-5-methoxy-3-oxo-pentanoic acid methyl ester in 50 ml acetonitrile was treated with 9.46 g (29.02 mmol) cesium carbonate. After the removal of the ice bath 3.28 ml (29.02 mmol) trifluoro-incthanesulfonic acid methyl ester was added. The reaction mixture was stirred for 2h at RT, concentrated under reduced pressure, taken up in ether and washed with water. The ether-layers were concentrated under vacuum to provide 6 g of crude 5-methoxy-2-[ 1-mcthoxy-eth-(K,/)-ylidene]-3-oxo-pentanoic acid methyl ester.
MS: 217.3 (M HI)'.
1 'U 4-(2-Mcthoxy-ethy.l)-6-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid methyl_estcr
A solution of 7.23 g (27.47 mmol) 4-trifluoromethyl-benzamidine HCI in 30ml Ethanol
was treated with 2.67 g (27.47 mmol) Sodium tert.Butoxide. After 4 min, 6 g (27.74
mmol) of the crude 5-methoxy-2-f l-methoxy-eth-(E,Z)-ylidene]-3-oxo-pentanoic acid
methyl ester, in 30 ml Ethanol, was added. The reaction mixture was stirred over night,
then taken up in ether and washed with IN HCI and water. The crude product was
purified by chromatography over silica gel with AcOEt/ heptane 1:3, providing 4.9 g of
pure 4-(2-methoxy-ethyl)-6-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-
carboxylic acid methyl ester.
MS: 355.4 (M HI)'.
>'] [4-(2-Methoxy-ethyl)-6-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylj-
methanpj.
To a dry-ice cooled solution of 4.9 g (13.83 mmol) 4-(2-methoxy-ethyl)-6-methyl-2-(4-trinuoromethyl-phenyl)-pyrimidine-5-carboxylic acid methyl ester in 50 ml

tctrahydroi'uranc was dropped 34.57 ml (41.48 mmol) of DIBALH-solution ( 1.2 M in Toluene). 'I'he reaction mixture was stirred for 15 min at -70 °C and then the dry-ice bath was removed, the reaction temperature was allowed to come to RT and the reaction mixture was stirred for 2h at RT. To the reaction mixture was then dropped carefully, under ice-cooling, 10 ml of 6N HCI. After 4 min was the whole taken up in ether and washed with water. The ether-phase was concentrated under reduced pressure providing 4.67 g pure crystalline |4-(2-methoxy-ethyl)-6-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-mcthanol.
MS: 327.1 (Mill)'.
GJ 5-Chloromethyl-4-(2-methoxy-ethyl)-6-methyl-2-(4-trifluoromethyl-phenyl)-
pyrimidine
A solution of 2.47 g (7.48 mmol) [4-(2-methoxy-ethyl)-6-methyl-2-(4-trifluorornethyl-phcnyl)-pyrimidin-5-yl|-methanol in 25 ml Methylenchloride was treated with 0.57 ml (7.85 mmol) thionylchloride. After 2h stirring at RT, the mixture was partitioned between ether and water. The ether-phase was concentrated under reduced pressure giving 2.42 g pure 5-chloromethyl-4-(2-methoxy-ethyl)-6-methyI-2-(4-trifluoromethyI-phcnyO-pyrimidine.
MS: 345.3 (Mt 11)!. Example U9
2-{4-|4-(2-Kthoxy-ethyl)-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-2-mcthyI-phenoxy}-2-methyl-propionic acid and 2-{4-[4-(2-Methoxy-ethyl)-2-(4-trifluoromethyl-phcnyl)-pyrimidin-5-ylmethoxy]-2-methyI-phenoxy}-2-methyl-propionic acid (3:2)
AJ 2-{4-[4-(2-Methoxy-ethyl)-2-(4-trifluoromethvl-phenyl)-pyrimidin-5-ylmcthoxy|-2-mcthyl-phenoxy! -2-methyl-propionic acid ethyl ester
In analogy to the procedures described in example 101 A], 2-(4-hydroxy-2-methyl-
phcnoxy)-2-methyi-propionic acid ethyl ester (described in WO 02/092590) was reacted
with 5-chloromethyl-4-(2-methoxy-ethyl)-2-(4-trifluoromethyl-phenyl)-pyrimidine
(example 110B|) to give the title compound as light yellow oil.
MS: 533.5 (Mi 11)'.

BJ 2-{4-[4-(2-Hthoxy-ethyl)-2-(4-trifluoromethyl-phenvl)-pyrimidin-5-ylmethoxyJ-2-methyl-phenoxv}-2-methyl-propionic acid and 2-{4-[4-(2-Methoxy-ethyl)-2-(4-trinuoromcthyl-phcnyl)-pyrimidin-5-vlmethoxv1-2-methyl-phenoxv}-2-methyl-propionic acid (3; 2}
2-{4-|4-(2-Methoxy-ethyl)-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-2-mcthyl-phenoxyJ-2-methyl-propionic acid ethyl ester was saponified in THF/EtOH in analogy to the procedure described in example 101B] to yield the title compounds as white crystalls.
MS: 519.5 and 505.4 (M-H)\ Example 120
|rac]-3-(2-lMethyl-4-{3-inethyl-l-[2-inethyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl|-butoxy}-phcnyl)-propionic acid
In analogy to the procedures described in examples 8A] and 3IB], 3-(4-hydroxy-2-methyl-phenyi)-propionic acid ethyl ester (example 60B]) was reacted with [rac]-3-(l-chloro-3-methyl-butyl)-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (prepared from |2-methyl-6-(4-trinuoromethyl-phenyl)-pyridin-3-yl]-methanol (example IM]) by i) oxidation with MnOi in analogy to the procedure described in example 3A] to yield 2-mcthyl-6-(4-trinuoromethyl-phenyl)-pyridine-3-carbaldehyde; ii) treatment with isobutyl magnesium chloride and iii) reaction with SOCb in analogy the procedures described in examples 4A| and 4B|) to give [rac]-3-(2-methyl-4-{3-methyl-l-[2-methyl-6-(4-trifluoromethyl~phcnyl)-pyridin-3-yt]-butoxy}-phenyl)-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as light yellow solid.
MS: 484.3 (M-H)-. Example 121
2-|4-({[4-Mcthoxymcthy|-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbonyl]-amino}-mcthyl)-phcnoxy|-2-mcthyl-propionic acid
In analogy to the procedures described in example 26B] and 26C], 2-(4-aminomethyl-phenoxy)-2-methyl-propionic acid ethyl ester [PCT Int.Appl.(2002), WO 2002/096895A11 was reacted with 4-methoxymetnyl-2-(4-tfifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid (prepared from 4-methoxy-3-oxo-butyric acid methyl ester, in analogy to the procedures described in examples 27C] and 27DJ followed by

The necessary building block methyl-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethyl|-amine used in procedure above was prepared as follows:
BJ 2-[2-Mcthyl-6-(4-trinuoromethyl-phenyl)-pyridin-3-ylmethyl]-isoindole-1.3-dione
0.25 g (0.94 mmol) of |2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-methanol (example 1M|), 0.15 g (1.03 mmol) of phthalimide and 0.32 g (1.20 mmol) of triphenylphosphine were dissolved in 10 ml of THF. The stirred reaction mixture was cooled down lo 0 °C and a solution of 0.27 g (1.15 mmol) of di-tert.-butyl a/odicarboxylale in 2 ml of THF was added drop by drop. Then, the reaction was warmed up to ambient temperature. After 1 hour, the solvent was evaporated and the residue purified by crystallization from MeC^ and n-heptane to give 0.32 g of the title compound as a colorless solid.
MS: 396.0 (M/.
C] [2-N/lcthyl-6-(4-trinuoromethyl-phenyl)-pyridin-3-yl]-methylamine
3.04 ml 3.13 g (62.5 mmol) of hydrazine hydrate was added at the ambient temperature to a slurry of 6.20 g (15.6 mmol) of 2-[2-methyI-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmcthyl|-isoindole-l,3-dione in 130 ml of EtOH. Then, the reaction mixture was stirred at reflux (oil bath ; 110 °C) for I hour. It was subsequently cooled down to ambient temperature, filtered and the filtrate was evaporated. The residue was partitioned between water and MeC^ and the pH was adjusted to > 12 with IMaOH /FhO. The mixture was then extracted twice with MeCb, the combined organic phases were washed with water, dried over anhydrous magnesium sulfate and evaporated. The crude product was purified by Hash chromatography (SiCh, MeC^ / MeOH) to give 4.10 g of the title compound as colorless solid.
MS: 267.2 (M+II)'.
DJ Mcthyl-[2-mcthyl-6-(4-trifluoromethyl-phenyn-pyridin-3-ylmethyl]-aminc
In analogy to the procedures described in example 5D], 5E] and 5FJ, [2-methyl-6-(4-trinuoromethyl-phenyl)-pyridin-3-yl]-methylamine was converted into the corresponding tcrt-butoxycarbonylamino derivative by treatment with di-tert-butyl dicarbonate and sodium hydrogen carbonate in dioxane/water at r.t., methylated at N and deprotected again to yield the title compound as a yellow solid.
MS:28I.2(M+H)'.

Example 124
2-Methyl-2-|4-({|2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yImethyl]-carbamoyl}-mcthyl)-phenoxy]-propionic acid
A] 2-(4-Carboxymethyl-phenoxy)-2-iTiethvl-propionic acid tert-butyl ester
6.27 g (20.3 mmol) of 2-(4-methoxycarbonyImethyl-phenoxy)-2-methyl-propionic acid tcrt-butyl ester (prepared from methyl 4-hydroxyphenylacetate and tert-butyl alpha-bromoisobutyrate, in analogy to the procedure described in example 52A]) was dissolved in 100 ml of dioxane; to the stirred solution, 40.7 ml of IN LiOH solution was added drop by drop. After 30 min., the reaction mixture was poured into crashed ice, the pH was adjusted to MS: 293. 1 (M-ll)'.
BJ 2-Mclhyl^2:i4-(||j^mejhyi-6-(4-trifl
carbampyl}-methyl)-phenoxy]-propionic acid tert-butvl ester
In analogy to the procedure described in example 26B], 2-(4-carboxymethyl-phenoxy)-2-melhyl-propionic acid tert-butyl ester was reacted with [2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl|-methylamine (example I23C]) to give the title compound as colorless oil.
MS: 543.5 (M-t-H)'.
Cj ____ 2jMgthyl-2-[4-({[2-rnethyl-6-(4-trifluoromethyl-phenyl)-pvridin-3-vlmethvl]-carbamoyU-mcthyl)-phenoxy]-propionicacid
0.23 g (0.42 mmol) of 2-methyl-2-|4-({[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethyl]-carbamoyl}-methyl)-phenoxy]-propionic acid tert-butyl ester was dissolved in 10 ml of MeCI2. Then, 0.14 ml = 0.139 g (1.28 mmol) of anisole was added followed by 0.32 ml 0.48 g (4.2 mmol) of trifluoroacetic acid. The reaction mixture was stirred at reflux (oil bath 50 °C) for 16 hours. It was then poured into crashed ice and extracted twice with MeCI2. The combined organic phases were washed with water, dried over anhydrous magnesium sulfate and evaporated. The crude product was purified by flash chromatography (SiO2, MeCI2 / MeOH) to give 0.17 g of the title compound as colorless solid.

MS: 485.3 (M-H). Example 125
2-Mcthyl-2-(4-{|2-mcthyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylcarbamoyl]-methyl}-phenoxy)-propionic acid
A | In analogy to the procedures described in example 26B] and 124C], 2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylamine (example 125C]) was reacted with 2-(4-carboxymethyl-phenoxy)-2-methyl-propionic acid tert-butyl ester (example 124A]) to give 2-methyl-2-(4-{[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylcarbamoyl]-methyl}-phenoxy)-propionic acid tert-butyl ester, which was subsequently cleaved with trifluoroacetic acid to yield the title compound as colorless solid.
MS: 471.1 (M-H).
The necessary building block 2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylamine used in procedure above was prepared as follows:
BJ [2-Methyl-6-(4-trifluoromethyl-phenyn-pyridin-3-yl]-carbamic acid tert-butyl ester
4.30 g (15.3 mmol) of 2-methyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid (prepared from 2-methyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid methyl ester (example IL]) in analogy to the procedure described in example 53B]) was dissolved in 85 ml of 2-methyl-2-propanol and 3.18 ml = 2.32 g (22.9 mmol) of triethylamine was added. After 5 rnin., 4.97 ml 'r-: 6.64 g (22.9 mmol) of diphenylphosphoryl azide (95%) was added. The reaction mixture was then stirred at reflux (oil bath 100 °C). After 10 min., 0.53 g (3.1 mmol) of anhydrous 4-toluene sulfonic acid was added and stirring continued for 1 hour at reflux. The solvent was then completely removed by evaporation at high vacuum; the residue was dissolved in EtzO and washed with H2O, IN HC1, and NaHCCh solution. The combined organic phases were dried over anhydrous magnesium sulfate and evaporated. The crude product was purified by crystallization (EtOAc, n-heptane) to give 4.05 g of the title compound as colorless solid.
MS: 353.3 (M+H)1.
C| 2-Methvl-6-(4-trifluoromethvl-phenvl)-pyridin-3-vlamine

In analog to the procedure described in example 5F], [2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl|-carbamic acid tert-butyl ester was reacted with trifluoroacetic acid to yield the title compound as colorless solid.
MS: 253.1 (M+H)'. Example 126
2-|3-Chloro-4-({|2-methyl-6-(4-trifluoroniethyl-phenyI)-pyridine-3-carbonyl]-amino}-mcthyl)-phcnoxy]-2-methyl-propionic acid
In analogy to the procedures described in example 26B] and 26C], 2-(4-aminomethyl-3-chloro-phenoxy)-2-methyl-propionic acid ethyl ester (prepared from 2-chloro-4-hydroxy-ben/aldehyde by reaction with ethyl-bromoisobutyrate as described in example 52A] followed by oxim formation and reduction as described in examples 97A] and 97B]) was reacted with 2-methyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid (prepared from 2-methyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid methyl ester (example 1L]) in analogy to the procedure described in example 53B]) to give 2-[3-chloro-4-({[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine-3-carbonyl]-amino}-methyl)-phenoxyj-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as light yellow foam.
MS: 505.1 (M-II, ICI). Example 127
2-[3-Chloro-4-({|4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbonyl]-amino}-methyl)-phenoxy]-2-methyl-propionic acid
In analogy to the procedures described in example 26B] and 26C], 2-(4-aminomethyl-3-chloro-phenoxy)-2-methyl-propionic acid ethyl ester (prepared from 2-chloro-4-hydroxy-bcn/aldehyde by reaction with ethyl-bromoisobutyrate as described in example 52A] followed by oxim formation and reduction as described in examples 97A] and 97B]) was reacted with 4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid (example 53B|) to give 2-[3-chloro-4-({[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbonyI]-amino}-methyl)-phenoxy]-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
MS: 532.2 (M-II, ICiy.

Example 128
2-[3-Chloro-4-({|4-mcthoxymethyI-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbonyI|-amino}-methyl)-phenoxy]-2-methyl-propionicacid
In analogy to the procedures described in example 26BJ and 26C], 2-(4-aminomethyl-3-chloro-phenoxy)-2-methyl-propionic acid ethyl ester (prepared from 2-chloro-4-hydroxy-benzaldehyde by reaction with ethyl-bromoisobutyrate as described in example 52A] followed by oxim formation and reduction as described in examples 97A] and 97B]) was reacted with 4-methoxymethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid (prepared from 4-methoxy-3-oxo-butyric acid methyl ester, in analogy to the procedures described in examples 27CJ and 27D] followed by saponification in analogy to the procedure described in example 53B]) to give 2-[3-chloro-4-({[4-methoxymethyl-2-(4-trifluoromethyl-phenyI)-pyrimidine-5-carbonyl]-amino}-methyl)-phenoxy]-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as light yellow foam.
MS: 536.2 (M-H, 1 ('!)". Example 129
2-|3-Chloro-4-({[4-(2-methoxy-ethyl)-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbonyl]-amino}-methyl)-phenoxy]-2-methyl-propionicacid
In analogy to the procedures described in example 26B] and 26C], 2-(4-aminomethyl-3-chloro-phenoxy)-2-methyl-propionic acid ethyl ester (prepared from 2-chloro-4-hydroxy-bcn/aldehyde by reaction with ethyl-bromoisobutyrate as described in example 52A] followed by oxim formation and reduction as described in examples 97A] and 97B]) was reacted with 4-(2-methoxy-ethyl)-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid (prepared from 5-methoxy-3-oxo-pentanoic acid methyl ester, in analogy to the procedures described in examples 27C] and 27D] followed by saponification in analogy to the procedure described in example 53B]) to give 2-[3-chloro-4-({[4-(2-methoxy-cthyl)-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbonyl]-amino}-methyl)-phenoxy]-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as light yellow oil.
MS: 550.1 (M-H, ICI).

Example 130
2-(3-{|4-Cyclopropyl-2-(4-trifluoromethyl-phenyI)-pyrimidin-5-ylmethyI]-methyl-carbamoyI}-5-methoxy-phenoxy)-2-methyl-propionic acid
A| In analogy to the procedures described in example 26B] and 26C], [4-cyclopropyl-2-(4-trinuoromethyl-phenyl)-pyrimidin-5-ylmethyl]-methyl-amine (example 130C]) was reacted with 3-(l-ethoxycarbonyl-l-methyl-ethoxy)-5-methoxy-benzoic acid (prepared from 3-hydroxy-5-methoxy-benzaldehyde [Journal of Organic Chemistry (1985), 50(13), 2236-40], by reaction with ethyl-bromoisobutyrate followed by oxidation with sodium chlorite in analogy to the procedures described in examples 52A] and 59A]) to give 2-(3-{|4-cyclopropyl-2-(4-trinuoromethyl-phenyl)-pyrimidin-5-ylmethyl]-methyl-carbamoyl}-5-methoxy-phenoxy)-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as colorless solid.
MS: 542.2 (M-l I).
The necessary building block [4-cyclopropyI-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylrnethyl|-mcthyl-ainine used in procedure above was prepared as follows:
Bj [4-Cyclopropyl-2-(4-trifluoromethvl-phenvl)-pyrimidin-5-ylmethyl]-methyl-carbamic
acid ethyl ester
1.00 g (3.2 mmol) of 5-chIoromethyl-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 27FJ) was dissolved in 20 ml of DMF. Then, the reaction mixture was cooled down to 0 °C. 0.36 ml = 0.366 g (3.52 mmol) of methyl-carbarnic acid ethyl ester was added to the stirred solution, followed by 0.14 g (3.2 mmol) of sodium hydride (55%). After 18 hours, the reaction mixture was poured into crashed ice, the pH was adjusted to MS: 380.4 (M+l I)1.
C J l4.-CycJop.ropyI-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethyl]-methyl-amine
0.83 g (2.2 mmol) of [4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethyl|-methyl-carbamic acid ethyl ester was dissolved in 15 ml of ethylene glycol. Then, 1.72 g (26.4 mmol) of potassium hydroxide (86%) and 0.44 ml = 0.46 g (9.0

mmol) of hydra/ine hydrate were added and the reaction mixture heated up to 190 °C (oil bath, 210 °C) for 90 minutes. After cooling down below 80 °C, some pieces of ice were added to the reaction mixture followed by EtOAc. It was then extracted twice with KtOAc; the combined organic phases were washed with water, dried over anhydrous magnesium sulfate and evaporated. The crude product was purified by flash chromalography (SiO2, gradient of MeCl2, MeOH) to give 0.59 g of the title compound as yellow solid.
MS: 308.2 (M HI)'. Example 131
2-McthyI-2-|4-({inethyl-|2-methyI-6-(4-trifluoromethyl-phenyI)-pyridin-3-yl]-carbamoyl}-methyl)-phenoxyj-propionic acid
In analogy to the procedures described in example 26B] and 124C], methyl-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylJ-amine (prepared from [2-methyl-6-(4-tri(luoromethyl-phenyl)-pyridin-3-yl]-carbamic acid tert-butyl ester (example 125B| by N-methylation followed by Boc-cleavage in analogy to the procedures described in examples 5E] and 5F|) was reacted with 2-(4-carboxymethyl-phenoxy)-2-methyl-propionic acid tert-butyl ester (example 124A]) to give 2-methyl-2-[4-({methyl-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-carbamoyl}-methyl)-phenoxy]-propionic acid tert-butyl ester, which was subsequently cleaved with trifluoroacetic acid to yield the title compound as colorless solid.
MS: 485.3 (M-l})'. Example 132
2-[3-Chloro-4-({[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridine-3-earbonyl|-amino}-methyI)-phenoxy]-2-methyl-propionicacid
In analogy to the procedures described in example 26B] and 26C], 2-(4-aminomethyl-3-chloro-phenoxy)-2-methyl-propionic acid ethyl ester (prepared from 2-chloro-4-hydroxy-ben/aldehyde by reaction with ethyl-bromoisobutyrate as described in example 52AJ followed by oxim formation and reduction as described in examples 97A] and 97B|) was reacted with 4-tritluoromethyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid (prepared from 4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid methyl ester (example 108B|) by saponification in analogy to example 53B]) to give 2-[3-chloro-4-

(! 14-trinuoromethyl-6-(4-trifluoromethyl-phenyl)-pyridine-3-carbonyl]-amino}-methyl)-phenoxy|-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as amorphous light yellow solid.
MS: 559.2 (M-ll. ICl)". Example 133
2-13-Chloro-4-( {14-trifluoromethyI-2-(4-trifluoromethyl-phenyl)-py rimidine-5-carbonyl|-amino}-methyl)-phenoxy]-2-methyl-propionicacid
In analogy to the procedures described in example 26B] and 26C], 2-(4-aminomethyl-3-chloro-phenoxy)-2-methyl-propionic acid ethyl ester (prepared from 2-chloro-4-hydroxy-ben/aldehyde by reaction with ethyl-bromoisobutyrate as described in example 52A| followed by oxim formation and reduction as described in examples 97A] and 97B]) was reacted with 4-trif1uoromethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid (prepared by saponification from 4-trifluorornethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid ethyl ester (example 107B]) in analogy to example 53B|) to give 2-|3-chloro-4-({[4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbonyl|-amino}-methyl)-phenoxy]-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as amorphous light yellow solid.
MS: 560.2 (M-ll. ICl). Example 134
2-Methyl-2-[4-({|4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridine-3-carbonyl|-amino}-methyl)-phenoxy]-propionic acid
In analogy to ihc procedures described in example 26B] and 26C], 2-(4-aminomethyl-phcnoxy)-2-methyl-propionic acid ethyl ester [PCT Int.Appl.(2002), WO 2002/096895AI | was reacted with 4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid (prepared from 4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid methyl ester (example I08B|) by saponification in analogy to example 53B]) to give 2-mcthyl-2-|4-(||4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridine-3-carbonyl]-amino}-methyl)-phenoxy]-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as amorphous light yellow solid.
MS: 525.1 (M-H) .

trinuoromethyl-phenyl)-pyrimidine-5-carboxylic acid, see example 133], in analogy to the procedures described in examples 125B] and 125C]) was reacted with 2-(3-carboxymethyl-phenoxy)-2-methyl-propionic acid tert-butyl ester (prepared from (3-hydroxy-phenyl)-acetic acid methyl ester and tert-butyl alpha-bromoisobutyrate, in analogy to the procedure described in example 52A], followed by saponification in analogy the procedure described in example 124A]) to give 2-(3-{[4-cyclopropyl-2-(4-trinuoromethyl-phcnyl)-pyrimidin-5-ylcarbamoyl]-methyl}-phenoxy)-2-methyl-propionic acid tert-butyl ester, which was subsequently cleaved with trifluoroacetic acid to yield the title compound as light yellow amorphous solid.
MS: 498.1 (M-H). Example 138
2-Mcthyl-2-(3-{|2-methyI-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylcarbainoyl]-methyl}-phenoxy)-propionic acid
In analogy to the procedures described in example 26B] and 124C], 2-methy!-6-(4-trifluoromethyl-phcnyl)-pyridin-3-ylamine (example 125C]) was reacted with 2-(3-carboxymethyl-phenoxy)-2-methyl-propionic acid tert-butyl ester (prepared from (3-hydroxy-phenyl)-acetic acid methyl ester and tert-butyl alpha-bromoisobutyrate, in analogy to the procedure described in example 52A], followed by saponification in analogy the procedure described in example I24A]) to give 2-methyl-2-(3-{[2-methyl-6-(4-trilluoromethyl-phenyl)-pyridin-3-ylcarbamoyl]-methyl}-phenoxy)-propionic acid tert-butyl ester, which was subsequently cleaved with trifluoroacetic acid to yield the title compound as light yellow amorphous solid.
MS: 471.1 (M-H)\ Example 139
2-Methyl-2-(4-{[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylcarbamoyl|-methyl}-phenoxy)-propionic acid
Aj 2-Methyl-2-(4-{[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-
ylcarbamoylJ-methyl}-phenQxy)-propionic acid tert-butyl ester
0.295 g (1.0 mmol) of 2-(4-carboxymethyl-phenoxy)-2-methyl-propionic acid tert-butyl ester (example 124A|) was dissolved in 10 ml methylenechloride at room temperature; then, one drop of DMF was added followed by addition of 0.09 ml (0.130 g = 1.0 mmol)

of oxalylchloride; after stirring of the reaction for 30 min., the solvent was removed by evaporation at 20 °C. The residue was dissolved in 5 ml of methylenechloride and added to a solution of 0.33 ml -- 0.25 g (2.0 mmol) of N-ethyl-diisopropylamine in 5 ml methylenechloride. A solution of 0.279 g (0.95 mmol) of 4-trifluoromethyl-6-(4-trilluoromethy!-phenyl)-pyridin-3-ylamine (prepared from 4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid (example 132]) and 2-methyl-2-propanol / diphcnylphosphoryi azide followed by Boc cleavage with trifluoroacetic acid in analogy to the procedures described in examples 125 B] and 125C]) in 5ml of methylenechloride was added at room temperature and the reaction mixture was stirred for 16 hours. Then, 0.18 g (1.5 mmol) of N,N?-dimethylaminopyridine was added and the reaction mixture heated at reflux for 8 hours. Subsequently, the solvent was removed by evaporation in vacuo and the residue was purified by chromatography on silica gel with a gradient of MeCljand MeOI I to give 0.39 g of the title compound as colorless oil.
MS: 582.3 (M)'.
BJ 2-Mcthyl-2-(4-{[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-
ylcarbamoyl]-methyl}-phenoxy)-propionic acid
In analogy to the procedure described in example 124C], 2-methyl-2-(4-{[4-trinuoromethyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylcarbamoyl]-methyl}-phenoxy)-propionic acid tert-butyl ester was cleaved with trifluoroacetic acid to yield the title compound as light yellow oil.
MS: 525.1 (M-ll). Example 140
2-{4-|4-(2-Methoxy-ethyl)-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-2-methyl-phenoxyj-2-methyI-propionic acid
In analogy to the procedure described in example 101 A], 2-(4-hydroxy-2-methyl-
phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) was reacted
with 5-chloromethyl-4-(2-methoxy-ethyl)-2-(4-trifluoromethyl-phenyl)-pyrimidine
(example 110B|) in the presence of catalytic amount of sodium iodide to give 2-{4-[4-(2-methoxy-ethyl)-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester, which was subsequently saponified in analogy to the procedure described in example 102] to yield the title compound as white crystals of mp. 119.5-120.0 °C.

MS: 503.2 (M-H)~. Example 141
2-{4-[4-CyclopropyI-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxyl-3-fluoro-phcnoxy }-2-mcthyl-propionic acid
AJ 2-(4-Acetyl-3-fluoro-phenoxy)-2-methyl-propionic acid ethyl ester
A suspension of 12.0 g (77.9 mmol) of 2-fiuoro-4-hydroxyacetophenone, 27.9 g (85.6 mmol) of cesium carbonate and 11.6 ml (77.9 mmol) of ethyl 2-bromo-2-methylpropionate in 200 ml of DMF was heated at 50 °C for 3 days. Twice a day additional 12.7 g (38.9 mmol) of cesium carbonate and 5.8 ml (38.9 mmol) of ethyl 2-bromo-2-methylpropionate were added (total of 2.5 equivalent). The mixture was neutralized with aqueous 10% KHSO4 and extracted with ether (3x). The organic phases were washed with aqueous 10% KHSO4, aqueous 10% NaCl and dried over sodium sulfatc. The crude product was purified by flash chromatography over silica gel with heptane/ AcOEt 9:1 to 6:1, to give 16.7 g of the title compound as colorless oil.
MS: 268,2 (M)'.
B| 2-(4-Acctoxy-3-nuoro-phenoxy)-2-methvl-propionic acid ethyl ester
A solution of 3.0 g (11.2 mmol) of 2-(4-acetyl-3-fluoro-phenoxy)-2-methyl-propionic acid ethyl ester in 30 ml dichloromethane was treated with 4.1 g (70 %, 16.8 mmol) of 3-chloro perben/oic acid. The reaction was stirred at RT. After 1 day additional 1.2 g (70 %, 4.7 mmol), after 2 days 0.8 g (70 %, 3.1 mmol) and after 3 days 0.6 g (70 %, 2.3 mmol) of 3-chloro perbenzoic acid were added. The mixture was poured on ice/aqueous 10% disodium pyroslfite solution and extracted with ether (3x). The organic phases were washed with aqueous 10% NaHCCb, aqueous saturated NFUCI, aqueous 10% NaCl and dried over sodium sulfate to give 3.2 g of the title compound as light yellow oil.
MS: 302.2 (M+NH,,)'.
CJ 2-(3-Fluoro-4-hydroxy-phenoxy)-2-methyl-propionic acid ethyl ester
A solution of 3.10 g (10.9 mmol) of 2-(4-acetoxy-3-fluoro-phenoxy)-2-methyl-propionic acid ethyl ester in 30 ml ethanol was treated at 0 °C with 2.26 g (16.4 mmol) of K2CO3. The mixture was stirred for 1 day at RT, the neutralized with aqueous 10% KHSO4 and extracted with ether (3x). The organic phases were washed with aqueous 10% KHSO4,

aqueous 10% NaCI and dried over sodium sulfate. The crude product was purified by Hash chromatography over silica gel with heptane/AcOEt 97.5:2.5 to 4:1, to give 2.48 g of the title compound as colorless crystalls.
MS: 242.3 (M)'.
D| 2-{4-[4-Cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-3-fluoro-phcnoxy}-2-methyl-propionicacid
In analogy to the procedure described in example 101 A], 2-(3-fluoro-4-hydroxy-phenoxy)-2-methyl-propionic acid ethyl ester was reacted with 5-chloromethyl-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 27F]) in the presence of catalytic amount of sodium iodide to give 2-{4-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxyJ-3-fluoro-phenoxy}-2-methyI-propionic acid ethyl ester, which was subsequently saponified in analogy to the procedure described in example 101H] to yield the title compound as white crystals of mp. 177.5-178.0 °C.
MS: 489.1 (M-II). Example 142
2-{4-|4-Cyclopropyl-2-(4-trifluoromethoxy-phenyl)-pyrimidin-5-yIinethylsulfanyl]-2-mcthyl-phenoxy}-2-methyl-propionic acid
AJ 4,4'-Dithiodi-o-cresol
To a stirred solution of 33.0 g (825.6 mmol) NaOH in 200 ml water was added 44.0 g (266.3 mmol) ol'2-methyl-4-thiocyanato-phenol at 85 °C [Wei, Zhi-Ltang; Kozikowski, Alan P., A Short and Efficient Synthesis of the Pharmacological Research Tool GW501516 for the Peroxisome Proliferator-Activated Receptor delta, Journal of Organic Chemistry (2003), 68(23), 9116-9118]. The temperature was raised to 95 °C and the mixture stirred over night. After cooling (10 °C), ether and 90 ml of aqueous cone. HCT were added. The water phase was extracted with ether (2x). The organic phase was washed with brine, dried (NazSC^) and evaporated. The residue was dissolved in 300 ml of DMSO and heated for 2 h at 95 °C. Subsequently, the solution was poured onto ice water and extracted with three 1 1 portions of TBME. The organic layers were washed with 700 ml of water, dried (NaaSC^) and evaporated to give 42.1 g of the title compound.

BJ 2-[4_-[4-(l-B^ phenoxy)-2-methyl-propionic acid ethyl ester
To a solution of 25.0 g (89.8 mmol) 4,4'-dithiodi-o-cresol and 52.7 ml (360 mmol) ethyl-bromoisobutyrate in 600 ml DMF 117 g (360 mmol) cesium carbonate were slowly added at 45 °C. The reaction mixture was stirred for 5 h at 45 °C, filtered, evaporated and then partitioned between EitOAc and aqueous sat. NUjCl-solution. Twofold extraction with EtOAc, washing with water, drying (Na2SC>4) and evaporation of the solvents followed by Hash chromatography (SiO2, n-hexane/EtOAc 5:1) yielded 21.6 g of pure title compound.
CJ 2-(4-Acetylsulfanyl-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester
A solution of 9.2 g (31.7 mmol) of [(n-Bu)3PH]BF4 [Netherton, Matthew R.; Fu, Gregory C., Air-Stable Trialkylphosphonium Salts: Simple, Practical, and Versatile Replacements for Air-Sensitive Trialkylphosphines. Applications in Stoichiometric and Catalytic Processes, Organic Letters (2001), 3(26), 4295-4298] in 150 ml DMF (degassed with argon) was added to 11.5 g (22.6 mmol) of 2-{4-[4-(l-ethoxycarbonyl-1-methyl-ethoxy)-3-methyl-phenyldisulfanyl]-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester. 5.43 ml (31.7 mmol) N-ethyldiisopropylamine and 0.416 ml (23.1 mmol) of water were added. After 2 h 40 min, 5.14 ml (54.4 mmol) of acetic acid anhydride were added and after 1 h 20 min, the reaction was diluted with isobutyl acetate, washed with O.IN HCI and brine. The organic phase was dried (Na2SO4), concentrated under reduced pressure and purified by chromatography over silica gel with EtOAc/ n-heptane 1:4, to give 12.56 g of the title compound as colorless oil.
MS:319(M+Na)".
DJ 2-{4-[4-Cyclopropyl-2-(4-trifluoromethoxy-phenyl)'pyrimidin-5-ylmethylsulfanyl]-2-mcthyl-phenoxy)-2-methyl-propionic acid ethyl ester
0.399 g (1.2 mmol) of 5-Chlorornethyl-4-cyclopropyl-2-(4-trifluoromethoxy-phenyl)-pyrimidinc (example 150D]) and 0.300 g (1.0 mmol) of 2-(4-acetylsulfanyl-2-methyl-phcnoxy)-2-methyl-propionic acid ethyl ester (example 142C]) were dissolved in 2.0 ml of acetonitrile and 0.08 ml of MeOH and treated with 0.462 g (1.4 mmol) of Cs2CO3. After vigorous stirring for 27h at ambient temperature and filtration, the solvent was evaporated and the residue redissolved in dichloromethane and filtered again and evaporated. Purification by flash chromatography (SiO2, dichloromethane/n-heptane 1:2 to 4:1 and then AcOKt) afforded 0.428 g of the title compound as colorless oil.

MS: 546.3 (M)f.
|^_2-(4-[4-Cyclopropyl-2-(4-tnfluoromethoxy-phenylVpyrimidin-5-ylmethyisulfanvll-2-methyl-phenoxyl-2-methyl-propionic acid
0.386 g (0.7 mmol) of the above prepared 2-{4-[4-cyclopropyl-2-(4-trifluoromethoxy-phenyl)-pyrimidin-5-ylmethylsulfanyl]-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester was dissolved in 12 ml of THF/EtOH (1:1), treated at 0 °C with 2.12 ml (2.1 mmol) of IN LiOtl, and kept at ambient temperature for 23h. The reaction mixture was taken up in ether and washed with aqueous 10% KHSO4 solution and aqueous 10% NaCl solution. The water phases were extracted with ether (2x). The organic phase was dried (NaiSO,}) and evaporated. The crude product was precipitated in ether/pentane (RT to 4 °C) and filtered to give 0.289 g of the title compound as white crystals of mp. 127-128 °C,dec.
MS: 517.3 (M-liy. Example 143
2-{4-[2-Cyclopropyl-6-(4-trifluoromethoxy-phenyl)-pyridin-3-ylmethylsulfanyl]-2-methyl-phenoxy}-2-methyl-propionic acid
A] 2-{4-[2-Cyclopropyl>6-(4-trifluoromethoxy-phenyl)-pyridin-3-ylmethylsulfanyl]-2-mcthyl-phenoxy}-2-methyl-propionic acid ethyl ester
In analogy to the procedure described in example 142D], 2-(4-acetylsulfanyl-2-methyl-phcnoxy)-2-methyl-propionic acid ethyl ester (example 142C]) was reacted with 3-chloromethyl-2-cyclopropyl-6-(4-trifluoromethoxy-phenyl)-pyridine (example 143F]) to give the title compound as colorless oil.
MS: 545.3 (M)1.
BJ 2-{4-[2-Cvclopropyl-6-(4-trifluoromethoxy-phenyl)-pyridin-3-vlmethylsulfanvl]-2-
methyl-phcnoxyl-2-methyl-propionic acid
In analogy to the procedure described in example 142E], saponification of 2-{4-[2-cyclopropyl-6-(4-trifluoromethoxy-phenyl)-pyridin-3-ylmethylsulfanyl]-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester yielded the title compound as colorless oil.
MS: 516.2 (M-H),

3-Chloromethyl-2-cyclopropyl-6-(4-trifluoromethoxy-phenyl)-pyridine used in 143 A] was prepared as follows:
C'J (lQ-3-Dimethy lamino- 1 -(4-trifluoromethoxy-phenyl)-propenone (Following the procedure described in Gammill, R. B. A new and efficient synthesis of 3-halogenated 4H-l-benzopyran-4-ones. Synthesis (1979), (11), 901-3)
A solution of 20.4 g (100.0 mmol) l-(4-trifluoromethoxy-phenyl)-ethanone in 20 ml (150.0 mmol) of dimethylformamide dimethylacetal were heated at 100 °C for 23. 5h. The reaction was evaporated and precipitated from ether/n-pentane to give 23.1 g of the title compound as a yellow solid.
MS: 260. 1 (MfH)'.
DJ 2-Cyclopropyl-6-(4-triflupromethoxy-phenyl)-nicotinic acid methyl ester (Following the procedure described in Al-Saleh, Balkis; Abdelkhalik, Mervat Mohammed; I-lloukhy, Afaf Mohammed; Elnagdi, Mohammed Hilmy. Enaminones in heterocyclic synthesis; A new regioselective synthesis of 2,3,6-trisubstituted pyridines, 6-substituted-3-aroylpyridines and 1,3,5-triaroylbenzenes. Journal of Heterocyclic Chemistry (2002), 39(5), 1035-1038)
A mixture of 2.0 g (7.72 mmol) (E)-3-dimethylamino-l-(4-trifluoromethoxy-phenyl)-propenonc, 1.32 g (9.26 mmol) methyl 3-cycIopropyl-3-oxopropanoate and 0.77 (1 0.0 mmol) ammonium acetate in 8 ml acetic acid were heated under reflux for 1.5h and cooled to room temperature. The reaction was neutralized with aqueous 10% KHSO4 solution. The mixture was extracted with ether (3x); the organic phase was washed with aqueous 10% KHSO4-solution, aqueous saturated NaHCO3, dried (Na2SO4) and evaporated. The side product ((4-trifluoromethoxy-phenyl)-[6-(4-trifluoromethoxy-phenyl)-pyridin-3-yl|-methanone) was precipitated from ether/pentane and the mother liquor purified by flash chromatography (SiO2, n-heptane/AcOEt=97.5/2.5) to give 1.07 g of the title compound as a yellow oil.
MS: 337.1 (M)1.
HJ p.CychpinpyJ-6-(4-i^^
In analogy to the procedure described in example 108C], reduction of 2-cyclopropyl-6-(4-trifluoromethoxy-phenyl)-nicotinic acid methyl ester yielded the title compound as white solid.

MS: 309.2 (M)1.
FJ 5-Chloromethyl-4-trit1uoromethvl-2-(4-trifluoromethyl-phenylVpyridine
In analogy to the procedure described in example 101F], [2-cyclopropyl-6-(4-trifluorornethoxy-phenyl)-pyridin-3-yl]-methanol gave at 0 °C, the title compound as off-white powder.
MS: 327.1 (M, 1CI)'. Example 144
2-{4-j4-Cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethylsulfanyl]-2-mcthyl-phenoxy}-2-methyI-propionic acid
AJ 2-{4-[4-Cyclopropyl-2-(4-trifluoromethyl-phenvn-pyrimidin-5-ylmethylsulfanyl]-2-methyl-phcnoxyi-2-methyl-propionic acid ethyl ester
In analogy to the procedure described in example 142D], 2-(4-acetylsulfanyl-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (example 142C]) was reacted with 5-chloromethyl-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 27F]) to give the title compound as colorless oil.
MS: 531.3 (M-t-ll)'.
BJ 2-{4-|4-Cyclopropyl-2-(4-trifluoromethyl-phenvl)-pyrimidin-5-ylmethylsulfanyl|-2-methyl-phcnoxy}-2-methyl-propionic acid
In analogy to the procedure described in example 142E], saponification of 2-{4-[4-cyclopropyI-2-(4-trinuoromethyl-phenyl)-pyrimidin-5-ylmethylsulfanyl]-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester yielded after precipitation with ether/n-pentane (4 °C) the title compound as white crystals of mp. 129-131 °C.
MS: 501.2 (M-H)".

Example 145
2-{4-[2-CycIopropyl-6-(4-trifluoromethoxy-phenyl)-pyridin-3-ylmethoxy]-2-methyl-phenoxv }-2-methyl-propionic acid
AJ 2-{4-[2-Cyclopropyl-6-(4-trifluoromethoxy-phenyl)-pyridin-3-ylmethoxyj-2-methyl-phcnoxy}-2-methyl-propionic acid ethyl ester
In analogy to the procedure described in example 101 A], 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) was reacted with 5-chloromethyl-4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-pyridine (example 143I'D to give the title compound as light yellow solid.
MS: 530.4 (M+H)'.
BJ 2-{4-[2-Cyclopropvl-6-(4-trit1uoromethoxy-phenyn-pyridin-3-vlmethoxy]-2-methyl-phenoxy} -2-methyl-propionic acid
In analogy to the procedure described in example 101B], saponification of 2-{4-[2-cyck)propyl-6-(4-trinuoromethoxy-phenyl)-pyridin-3-ylmethoxy]-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester yielded the title compound as white crystals of mp. 131-133 °C.
MS: 500.1 (M-H). Kxamnlc 146
{2-Methyl-4-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethoxy]-phenylsulfanyl}-acctic acid
In analogy to the procedure described in example 20A], (4-hydroxy-2-methyl-phenylsulfanyl)-acetic acid ter/-butyl ester (example 20C]), was reacted with 3-chloromethyl-2-methyl-6-(4-trifluoromethyl-phenyI)-pyridine (example IN]) to give {2-methyl-4-|2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethoxy]-phenylsulfanyl}-acctic acid tert-butyl ester, which was subsequently saponified in analogy to the procedure described in example 20B] to yield the title compound as white solid of mp. I68-169°C.
MS: 446.1 (M-M) .

Example 147
2-!4-|4-Methoxymcthyl-6-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxyj-phenoxy}-2-methyl-propionicacid
AJ 2-{4-[4-Methj3xyrnethyl-6-rnethvl-2-(4-trifluoromethyl-phenvn-pyrimidin-5-
yJmgjJioj^J^2-iTiethyl-phenoxy}-2-rnethvl-propionic acid ethyl ester
In analogy to the procedure described in example 113A], 2-(4-hydroxy-2-methyl-
phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) was reacted
with 5-chloromethyl-4-methoxymethyl-6-methyl-2-(4-trifluoromethyl-phenyl)-
pyrimidinc (example 147H|) to give the title compound as light brown oil.
MS: 533.3 (M-HI)'.
BJ 2-[4-[2-Cyclopropyl-6-(4-trifluoromethoxv-phenyn-pvridin-3-ylmethoxy]-2-methyl-phenoxy] -2-mcthy l-propionic acid
In analogy to the procedure described in example 113B], saponification of 2-{4-[4-methoxymethyl-6-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-2-methyl-phcnoxy}-2-methyl-propionic acid ethyl ester yielded the title compound as colorless solid.
MS: 503.1 (M-ll).
5-Chloromethyl-4-methoxymethyl-6-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidine used in 147A] was prepared as follows:
CJ (U./)-3-Metho.xy-2-(2-methoxy-acetyl)-but-2-enoic acid methyl ester
In analogy to the procedures described in example 113C] and 113D], 4-methoxy-3-oxo-butyric acid methyl ester and methoxyacetic anhydride (from methoxyacetyl chloride and methoxyacetic acid with pyridine) gave the title compound as a light brown oil.
MS: 203.1 (M-H1)'.
1)| [4-MethQxymcthyl-6-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-methanol
In analogy to the procedures described in example 113E] and 113G], (E,Z)-3-methoxy-2-(2-methoxy-acetyl)-but-2-enoic acid methyl ester and 4-trifluoromethyl-benzamidine IIC1 gave the title compound as light yellow crystals.

MS: 313.1 (MMI)'.
HJ 5-Chloromcthvl-4-methoxymethyl-6-rnethyl-2-(4-trifluorornethyl-phenyl)-pyrirnidine
In analogy to the procedure described in example 113H], [4-methoxymethyl-6-methyl-2-(4-triniioromethyl-phenyl)-pyrimidin-5-yl]-methanol and thionylchloride gave the title compound as a light red oil.
MS: 331.1 (M+ll, ICI)". Example 148
2-(4-|4-Mcthoxymethyl-6-mcthyl-2-(3-trifluoromethyl-phcnyl)-pyrimidin-5-yImethoxy]-2-methyl-phenoxy}-2-methyl-propionic acid
AJ 2-{4-[4-Methoxymethyl-6-methyl-2-(3-trifluoromethvl-phenyl)-pyrimidin-5-
ylmethoxyJ-2-mclhyl-phenoxy[-2-methyl-propionic acid ethyl ester
In analogy to the procedure described in example 113A], 2-(4-hydroxy-2-methyl-
phcnoxy)-2-methy!-propionic acid ethyl ester (described in WO 02/092590) was reacted
with 5-chloromethyl-4-methoxymethyl-6-methyl-2-(3-trifluoromethyl-phenyl)-
pyrimidine (example I48D]) to give the title compound as light yellow viscous oil.
MS: 533.4 (Mt 11)'.
BJ 2-i4-[4-Mcthoxymethyl-6-methyl-2-(3-trifluoromethyl-phenvl)-pyrimidin-5-
ylmethoxyJ-2-mcthyl-phcnoxy}-2-methyl-propionicacid
In analogy to the procedure described in example 113B], saponification of 2-{4-[4-methoxymethyl-6-methyl-2-(3-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-2-methyl-phenoxyj -2-mcthyl-propionic acid ethyl ester yielded the title compound as light yellow solid.
MS: 503.3 (M-H).
5-Chloromethyl-4-methoxymethyl-6-methyl-2-(3-trifluoromethyl-phenyl)-pyrimidine used in USA] was prepared as follows:
C] [4-Methoxvmethyl-6-methyl-2-(3-trifluoromethyl-ph^nyn-pyrimidin-5-ylJ-methanol

In analogy to the procedures described in example 113E] and 113G], (E,Z)-3-methoxy-2-(2-methoxy-acetyl)-but-2-enoic acid methyl ester (example 147C]) and 3-tri!luoromethyl-bcn/amidine HC1 gave the title compound as light yellow crystals.
MS: 313.1 (Mfll)'.
DJ 5-Chloromcthyl-4-methoxymethvl-6-methyl-2-(3-trifluoromethyl-phenyl)-pyrimidine
In analogy to the procedure described in example 113H], [4-methoxymethyl-6-methyl-2-(3-trinuoromethyl-phenyl)-pyrimidin-5-yl]-methanol and thionylchloride gave the title compound as a brown viscous oil.
MS: 331.1 (Mill, 1CI)'. Example 149
2-{4-[4-MethoxymethyI-6-methyl-2-(4-trifluoromethoxy-phenyl)-pyrimidin-5-ylmcthoxy]-2-methyl-phenoxy}-2-methyl-propionic acid
AJ 2-{4-[4-Methoxymethyl-6-methyl-2-(4-trifluoromethoxy-phenyn-pyrimidin-5-
ylmethoxyJ-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester
In analogy to the procedure described in example 113A], 2-(4-hydroxy-2-methyl-
phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) was reacted
with 5-chloromethyl-4-methoxymethyl-6-methyl-2-(4-trifluoromethoxy-phenyl)-
pyrimidine (example I49D]) to give the title compound as light yellow viscous oil.
MS: 549.3 (M+ll)f.
BJ 2-{4-[4-Methoxymethyl-6-methyl-2-(4-trifluoromethoxy-phenyl)-pyrimidin-5-
ylmcthoxy]-2-methyl-phenoxy}-2-methvl-propionic acid
In analogy to the procedure described in example 113B], saponification of 2-{4-f4-methoxymethyl-6-methyl-2-(4-trittuoromethoxy-phenyl)-pyrimidin-5-ylmethoxy]-2-tnethyl-phenoxyj-2-methyl-propionic acid ethyl ester yielded the title compound as a colorless solid.
MS: 519.5 (M-HV.
5-Chloromcthyl-4-mcthoxymethyl-6-methyl-2-(4-trifluoromethoxy-phenyl)-pyrimidine used in I49A| was prepared as follows:

CJ [4-Methoxymethyl-6-methyl-2-(4-trifluoromethoxv-phenyn-pyrimidin-5-yn-
mcthanol
In analogy to the procedures described in example 113E] and 113G], (E,Z)-3-methoxy-2-(2-methoxy-acetyl)-but-2-enoic acid methyl ester (example 147C]) and 4-triiluoromethoxy-benzamidine HC1 gave the title compound as a light yellow oil.
MS: 329.3 (M+H)'.
DJ 5-Chloromethyl-4-methoxymethyl-6-methyl-2-(4-trifluoromethoxy-phenyl)-
pyrimidinc
In analogy to the procedure described in example 113H], [4-methoxymethyl-6-methyl-2-(4-trinuoromethoxy-phenyl)-pyrimidin-5-yl]-methanol and thionylchloride gave the title compound as a brown oil.
MS: 347.5 (M+H, ICI)'. Example ISO
2-{4-|4-Cyelopropyl-2-(4-trifluoromethoxy-phenyl)-pyrimidin-5-ylmethoxy)-2-mcthyl-phcnoxyj-2-methyl-propionic acid
AJ 2-{4-[4-Cyclopropyl-2-(4-trifluoromethoxy-phenyl)-pyrimidin-S-ylmethoxy]-2-
mcthyl-phcnoxyt-2-methyl-propionic acid ethyl ester
In analogy to the procedure described in example 113A], 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) was reacted with 5-chloromethyl-4-cyclopropyl-2-(4-trifluoromethoxy-phenyl)-pyrimidine (example 150D|) to give the title compound as light yellow viscous oil.
MS: 531.3 (M HI)'.
BJ 2-{4-[4-Cyclopropyl-2-(4-trifluoromethoxy-phenyl)-pyrimidin-5-ylmethoxyJ-2-
mcthyl-phenoxyt-2-methvl-propionic acid
In analogy to the procedure described in example 113B], saponification of 2-{4-[4-cyclopropyl-2-(4-trifluoromethoxy-phenyl)-pyrimidin-5-ylmethoxy]-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester yielded the title compound as a colorless solid.

MS:50I.4(M-H).
5-Chloromethyl-4-cyclopropyl-2-(4-trifluoromethoxy-phenyl)-pyrimidine used in 150AJ was prepared as follows:
CJ L4-CycloprQpyl-2-(4-trifluoromethoxy-phenyl)-pyrimidin-5-yl]-methanol
In analogy to the procedures described in example 27D] and 27E], (E,Z)-2-cyclopropanecarbonyl-3-ethoxy-acrylic acid methyl ester (example 27C]) and 4-trifluoromethoxy-ben/amidine HCI gave the title compound as a colorless solid.
MS:3II.O(M+H)'.
I) J 5-Ch 1 orornethyI-4-cyclopropyl-2-(4-trifluoromethoxy-phenyl)-pyrimidine
In analogy to the procedure described in example 113H], [4-cyclopropyl-2-(4-tritluoromethoxy-phenyl)-pyrimidin-5-yl]-methanol and thionylchloride gave the title compound as a light brown solid.
MS: 329.0 (M+II, IC1)'. Example 151
2-McthyI-2-{2-mcthyl-4-[6-(4-trifluoromethoxy-phenyl)-4-trifluoroinethyI-pyridin-3-ylmcthoxy|-phenoxy}-propionicacid
AJ 6-(4-Tril1uoromethoxy-phenvn-4-trif1uoromethyl-nicotinic acid methyl ester
In analogy to the procedure described in example 108B], 4-(trifluoromethoxy)-phcnylboronic acid was reacted with methyl 6-chloro-4-(trifluoromethyl)nicotinate in the presence of bis(triphenylphosphine)palladium(II)chloride and aqueous 2M K.3PO4 solution to give the title compound as yellow crystals.
MS: 366.0 (M+H)'.
BJ jj)^4^'Jxinuoromethoxy-phenyl)-4-trifluorornethyl-pyridin-3-yl]-rnethanol
In analogy to the procedure described in example 43D], 6-(4-trifluoromethoxy-phenyl)-4-trinuoromethyl-nicotinic acid methyl ester was treated with lithium aluminium hydride in tetrahydrofuran under reflux conditions for 12 h to give the title compound as yellow oil.

MS: 338.0 (M+II)1.
C] 2-Methyl-2-{2-iTiethyl-4-[6-(4-trifluoromethoxy-phenyn-4-trifluoromethvl-pvridin-3-ylmethoxyj-phenoxy}-propionic acid ethyl ester
In analogy to the procedure described in example 43E], 2-(4-hydroxy-2-methyl-phcnoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) was reacted with |6-(4-trifluoromethoxy-phenyl)-4-trifluoromethyl-pyridin-3-yl]-methanol in the presence of N,N,N\N"-tetramethylazodicarboxamide and tributylphosphine to give the title compound as colorless oil.
MS: 557.8 (M+H)'.
DJ 2-Mcthyl-2-{2-methyl-4-[6-(4-trifluoromethoxy-phenyl)-4-trifluoromethyl-pyridin-3-ylmcthoxyj-phenoxyt-propionic acid
In analogy to the procedure described in example 26C], 2-methyl-2-{2-methyl-4-[6-(4-lrifluoromethoxy-phenyl)-4-trifluoromethyl-pyridin-3-ylmethoxy]-phenoxy}-propionic acid ethyl ester was treated with 1 N aqueous LiOH solution to give the title compound as yellow crystals.
MS: 530.0 (M+II)1. Example 152
2-{4-[2-Cyclopropylmethyl-6-(4-trifluoromethoxy-phenyl)-4-trifluoromethyl-pyridin-3-ylmethoxy]-2-methyl-phenoxy}-2-methyl-propionicacid
A | 2-Cyclopropyl-acetimidic acid methyl ester hydrochloride
To a solution of 11.2 ml (120 mmol) cyclopropylacetonitrile in 60 ml diethyl ether, 4.9 ml (120 mmol) methanol were added. The solution was cooled to 4 °C and HC1 gas was bubbled through the solution for 3 h. The mixture was stirred for 14 h at ambient temperature and the solvent removed under reduced pressure. The residue was washed with pentane and diethyl ether to give 10.3 g (69 mmol, 58 %) of the title compound as colorless crystals which were used in the next step without further purification.
BJ 5^(l-Amino-2-cycloprppyl-ethylidene)-2,2-dimethyl-[1.3]dioxane-4.6-dione
I g (7 mmol) 2-Cyclopropyl-acetimidic acid methyl ester hydrochloride, 963 mg (7 mmol) 2,2-dimcthyl-| l,3]dioxane-4,6-dione and 1.07 ml (8 mmol) triethylamine were

heated under reflux in 7 ml chloroform for 14 h. The mixture was diluted with dichloromethane, washed neutral with brine/ice water 1/1 and the organic layer was dried over sodium sulfatc. The solvent was removed under reduced pressure and the residue purified by flash chromatography (silica gel, heptane/AcOEt) to give 128 mg (0.6 mmol, 9 %) of the title compound as yellow crystals.
CJ 3-Amino-4-cvclopropyl-but-2-enoic acid ethyl ester
397 mg (2 mmol) 5-(l-Amino-2-cyclopropyl-ethylidene)-2,2-dimethyl-[l,3]dioxane-4,6-dione were added to a solution of 45 mg (2 mmol) sodium in 3 ml ethanol. The reaction mixture was heated under reflux for 14 h, diluted with dichloromethane and poured onto ice water/brine I/I. The organic layer was dried over sodium sulfate and the solvent removed under reduced pressure to give 231 mg (1.4 mmol, 77 %) of the title compound as orange oil.
MS: 170.3 (M HI)'.
I)J (/)-4,4,4-Tri fliioro-3-hydroxy-1 -(4-trifluoromethoxy-phenyl)-but-2-en-1 -one
25 g (122 mmol) l-(4-Trifluoromethoxy-phenyl)-ethanone were added to a suspension of 16.5 g (147 mmol) potassium-tert-butylate in 250 ml toluene. The suspension was cooled to 2 °C and 17.5 ml (147 mmol) ethyltrifluoroacetate were added within 15 min. The mixture was stirred at ambient temperature for 14 h, cooled to 2 °C and brought to pH 6 with 10 % aqueous HaSO,*. Twofold extraction with tert-butyl methylether was followed by washing of the combined extracts with brine/ice water 1/1 and drying of the organic layer over sodium sulfate. The solvent was removed under reduced pressure and the residue purified by flash chromatography (silica gel, dichloromethane) to give 30.5 g (102 mmol, 83 %) of the title compound as red oil.
MS: 301.9 (MiII)'.
HJ 2-Cyclopropylrnethyl-6-(4-trifluoromethoxy-phenyl)-4-trifluoromethyl-nicotinic acid cthyj_estcr
231 mg (1.4 mmol) 3-Amino-4-cyclopropyl-but-2-enoic acid ethyl ester were added to a solution of 819 mg (2.7 mmol) (Z)-4,4,4-trifluoro-3-hydroxy-l-(4-trifluoromethoxy-phenyl)-but-2-en-l-one in 2.7 ml acetonitrile. The mixture was heated under reflux conditions for 12 h, the solvent was removed under reduced pressure and the residue

purified by Hash chromatography (silica gel, heptane/AcOEt) to give 242 mg (0.56 mmol, 41 %) of the title compound as yellow oil.
MS: 434.3 (M+H)'.
!;j i2-Cyclopropylmcthyl-6-(4-trifluoromethoxy-phenyl)-4-trifluoromethyl-pyridin-3-yl]-mclhanol
In analogy to the procedure described in example 43D], 2-cyclopropylmethyI-6-(4-trinuoromethoxy-phenyl)-4-trifluoromethyl-nicotinic acid ethyl ester was treated with lithium aluminium hydride to give the title compound as colorless crystals.
MS: 392.3 (M+H)'.
GJ 2-{4-[2-Cyclopropylmethyl-6-(4-trifluoromethoxy-phenyn-4-trifluoromethyl-pyridin-3-ylmcthoxyJ-2-mcthyl-phcnoxy)-2-methyl-propionic acid ethyl ester
In analogy to the procedure described in example 43E], 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) was reacted with |2-cyclopropylmethyl-6-(4-trifluoromethoxy-phenyl)-4-trifluoromethyl-pyridin-3-yl|-methanol in the presence of N,N,N',N'-tetramethylazodicarboxamide and tributylphosphine to give the title compound as colorless crystals.
MS: 593.3 (M+H)'.
HJ 2-{4-[2-Cyclopropylrnethyl-6-(4-trifluoromethoxy-phenyl)-4-trifluoromethyl-pvridin-3-ylrnethoxyJ-2-methyl-phenoxy}-2-methyl-propionic acid
In analogy to the procedure described in example 26C], 2-{4-[2-cyclopropylmethyl-6-(4-trinuoromethoxy-phenyl)-4-trifluoromethyl-pyridin-3-ylmethoxy]-2-methyl-phenoxy}-2-mcthyl-propionic acid ethyl ester was treated with 1 N aqueous LiOH solution to give the title compound as off-white crystals.
MS: 584.3 (M+H)'. Example 153
2-{4-|2-Cyclopropyl-6-(4-trifluoromethoxy-phenyI)-4-trifluoromethyI-pyridin-3-ylmethoxy|-2-methyl-phenoxy}-2-methyl-propionic acid

AI 2-Cvclopropvl-6-(4-trinuoromethoxy-phenyn-4-trifluoromethyl-nicotinic acid ethyl ester
In analogy to the procedure described in example 152E], 3-amino-3-cyclopropyl-acrylic acid ethyl ester (J. P. Celerier, E. Deloisy, P. Kapron, G. Lhommet, P. Maitte, Synthesis 1981, 130-133) was reacted with (Z)-4,4,4-trifluoro-3-hydroxy-l-(4-trifluoromethoxy-phcnyl)-but-2-cn-l-onc (example 152DJ) to give the title compound as colorless oil.
MS: 420.3 (M+H)f.
BJ [2-Cyclopropyl-6-(4-trifluoromethoxv-phenvl)-4-trifluoromethyl-pyridin-3-ylj-
mcthanol
In analogy to the procedure described in example 43D], 2-cyclopropyl-6-(4-trinuoromethoxy-phenyl)-4-trifluoromethyl-nicotinic acid ethyl ester was treated with lithium aluminium hydride to give the title compound as colorless crystals.
MS: 378.3 (MtH)'.
CJ 2-{4-[2-('yclopropvl-6-(4-trifluoromethoxy-phenvn-4-trifluoromethyl-pyridin-3-ylmcthoxyJ-2-mcthyl-phenoxy}-2-methyl-propionic acid ethyl ester
In analogy to the procedure described in example 43E], 2-(4-hydroxy-2-methyl-phenoxy)-2-mcthyl-propionic acid ethyl ester (described in WO 02/092590) was reacted with |2-cyclopropyl-6-(4-trifluoromethoxy-phenyl)-4-trifluoromethyl-pyridin-3-yll-mcthanol in the presence of N,N,N',N'-tetramethylazodicarboxamide and tributylphosphine to give the title compound as colorless crystals.
MS: 598.3 (MMI)'.
DJ 2^|4-[2-Cyclopropyl-6-(4-trif1uoromethoxy-phenvl)-4-trifluoromethvl-pvridin-3-
ylmethoxyJ-2-methyl-phenoxy}-2-methyl-propionic acid
In analogy to the procedure described in example 26C], 2-{4-[2-cyclopropyl-6-(4-tril]uoromethoxy-phenyl)-4-trifluoromethyl-pyridin-3-ylmethoxy]-2-methyl-phenoxy}-2-mcthyl-propionic acid ethyl ester was treated with 1 N aqueous LiOH solution to give the title compound as colorless foam.
MS: 570.3 (MMI)'.

Example 154
2-MethyI-2-{2-methyl-4-[6-(4-trifluoromethoxy-phenyI)-2-trifluoromethyl-pyridin-3-ylmethoxy|-phcnoxy}-propionic acid
A| 6-(4-1Yifluoromcthoxy-phenyl)-2-trifluoromethyl-nicotinic acid ethyl ester
In analogy to the procedure described in example 143D], (E)-3-dimethylamino-l-(4-trilluoromcthoxy-phenyl)-propenone (example 143C]) was reacted with 4,4,4-trifluoro-3-oxobulanoic acid ethyl ester in the presence of ammonium acetate and acetic acid to give the title compound as yellow oil.
MS: 380.3 (MMI)'.
BJ [6-(4-rrrinuoroiTiethoxy-phenyl)-2-trifluoromethyl-pyridin-3-vl]-methanol
In analogy to the procedure described in example 43D], 6-(4-trifluoromethoxy-phenyl)-2-trinuoromethyl-nicotinic acid ethyl ester was treated with lithium aluminium hydride to give the title compound as colorless crystals.
MS: 338.0 (MM I)'.
Cj 2-Methyl-2-{2-methvl-4-[6-(4-trifluoromethoxy-phenyl)-2-trifluoromethyl-pyridin-3-ylrnethoxyj-phcnoxyj-propionic acid ethyl ester
In analogy to the procedure described in example 43E], 2-(4-hydroxy-2-methyl-phcnoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) was reacted with |6-(4-trinuoromethoxy-phenyl)-2-trifluoromethyl-pyridin-3-yl]-methanol in the presence of N,N,N',NT-tetramethylazodicarboxamide and tributylphosphine to give the title compound as colorless oil.
MS: 558.3 (MM I)1.
j^l:MgtjTyl-2-{2-iTiethyl-4-[6-(4-trifluorornethoxy-phenyl)-2-trifluorornethyl-pvridin-3-ylincthoxyj-phenoxy|-propionic acid
In analogy to the procedure described in example 26C], 2-methyl-2-{2-methyl-4-[6-(4-trinuoromethoxy-phenyl)-2-trinuoromethyl-pyridin-3-ylmethoxy]-phenoxy}-propionic acid ethyl ester was treated with I N aqueous LiOH solution to give the title compound as colorless oil.

MS: 528.1 (M-H)~, Example 155
2-{4-|4-Methoxymethyl-2-(4-trifluoroniethoxy-phenyI)-pyrimidin-5-ylniethoxy|-2-methyI-phenoxy}-2-methyI~propionic acid
AJ 2-{4-[4-Methoxymethyl-2-(4-trifluoromethoxy-phenvl)-pvrimidin-5-yliTiethoxv|-2-methyl-phcnoxy^-2-methyl-propionic acid ethyl ester
In analogy to the procedure described in example 113A], 2-(4-hydroxy-2-methyl-
phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) was reacted
with 5-chloromethyl-4-methoxymethyl-2-(4-trifluoromethoxy-phenyl)-pyrimidine
(example I55K|) to give the title compound as brown oil.
MS: 535.1 (MMI)1.
BJ 2-{4-[4-Methoxymethyl-2-(4-trifluoromethoxy-phenyl)-pyrimidin-5-ylmethoxv1-2-methyl-phcnoxy)-2-mcthyl-propionic acid
In analogy to the procedure described in example 113B], saponification of 2-{4-|4-inethoxymethyl-2-(4-trifluoromethoxy-phenyl)-pyrimidin-5-ylmethoxy]-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester yielded the title compound as off-white solid.
MS: 505.2 (M-II)'.
5-Chloromethyl-4-inethoxymethyl-2-(4-trifluoromethoxy-phenyl)-pyrimidine used in 155A| was prepared as follows:
{-J (j.v./)-2-Hthoxymcthylcne-4-mcthoxy-3-oxo-butyric acid methyl ester
In analogy to the procedures described in example 27C], methyl 4-methoxyacetoacetate and triethyl orthoformate gave the title compound as orange oil.
MS: 201.9(M)'. DJ|4-Mcthoxymcthyl-2-(4-trifluoromethoxy-phenyl)-pyrimidin-5-yl]-methanol

In analogy to the procedures described in example 27D] and 27B], (E,Z)-2-ethoxymethylene-4-methoxy-3-oxo-butyric acid methyl ester and 4-trifluoromethoxy-bcn/amidine MCI gave the title compound as off-white solid.
MS: 315.1 (M+M)'.
HJ 5-Chloromcthyl-4-methoxymethyl-2-(4-trifluoromethoxv-phenyn-pyrimidine
In analogy to the procedure described in example 113H], [4-methoxymethyl-2-(4-trinuoromethoxy-phenyl)-pyrimidin-5-yI]-methanol and thionylchloride gave the title compound as a brown oil.
MS: 333.1 (MHI. ICI)1.
Example A
Film coated tablets containing the following ingredients can be manufactured in a conventional manner:
ingredients Per tablet
Kernel:
Compound of formula (I) 10.0 mg 200.0 mg
Microcrystalline cellulose 23.5 mg 43.5 mg
Lactose hydrous 60.0 mg 70.0 mg
Povidonc K30 12.5 mg 15.0mg
Sodium starch glycolate 12.5 mg 17.0 mg
Magnesium stearate 1.5 mg 4.5 mg
(Kernel Weight) 120.0 mg 350.0 mg
Film Coat:
I lydroxypropyl methyl cellulose 3.5 mg 7.0 mg
Polyethylene glycol 6000 0.8 mg 1.6 mg
Talc 1.3 mg 2.6 mg
Iron oxydc (yellow) 0.8 mg 1.6 mg
Titan dioxide 0.8 mg 1.6mg
The active ingredient is sieved and mixed with microcristalline cellulose and the mixture is granulated with a solution of polyvinylpyrrolidon in water. The granulate is mixed with sodium starch glycolate and magesiumstearate and compressed to yield
kernels of 120 or 350 mg respectively. The kernels are lacquered with an aqueous
solution / suspension of the above mentioned film coat.
Example B
Capsules containing the following ingredients can be manufactured in a
conventional manner:
Ingredients Per capsuje
Compound of formula (I) 25.0 mg
Lactose 150.0 ing
Maixe starch 20.0 mg
Talc 5.0 mg
The components are sieved and mixed and filled into capsules of size 2.
Example C
Injection solutions can have the following composition:
Compound of formula (I) 3.0 mg
Gelatine ISO.Omg
Phenol 4.7 mg
Sodium carbonate to obtain a final pll of 7
Water for injection solutions ad 1.0 ml

Example 1)
Soft gelatin capsules containing the following ingredients can be manufactured in a conventional manner:
Capsule contents
Compound of formula (1) 5.0 mg
Yellow wax 8.0 mg
I lydrogcnated Soya bean oil 8.0 mg
Partially hydrogenated plant oils 34.0 mg
Soya bean oil llO.Omg
Weight of capsule contents 165.0 mg
Gelatin capsule
Gelatin 75.0 mg
Glycerol 85 % 32.0 mg
Karion 83 8.0 mg (dry matter)
Tilan dioxide 0.4 mg
Iron oxide yellow 1.1 mg
The active ingredient is dissolved in a warm melting of the other ingredients and the mixture is filled into soft gelatin capsules of appropriate size. The filled soft gelatin capsules are treated according to the usual procedures.

Example E
Sachets containing the following ingredients can be manufactured in a
conventional manner:
Compound of formula (I) 50.0 mg
Lactose, line powder 1015.0 mg
Microcristalline cellulose (AVICEL PH 102) 1400.0 mg
Sodium carboxymethyl cellulose 14.0 mg
Polyvinylpyrrolidon K 30 10.0 mg
Magnesiumstearatc lO.Omg
Flavoring additives 1.0 mg
The active ingredient is mixed with lactose, microcristalline cellulose and sodium carboxymethyl cellulose and granulated with a mixture of polyvinylpyrrolidon in water. The granulate is mixed with magnesiumstearate and the flavouring additives and filled into sachets.




We Claim:
1. 2-Phenoxy propionic acid compounds of the formula
(Formula Removed)
and enantiomers and pharmaceutically acceptable salts and esters thereof, wherein
X1 is O;
R1 is hydrogen or C1-7-alkyl;
R2 is methyl;
R3 is methyl;
R4 and R8 independently from each other are hydrogen, C1-7-alkyl,
C3.7-cycloalkyl, halogen, C1-7-alkoxy- C1-7-alkyl, C2-7-alkenyl, C2-7-alkinyl, fluoro-C1-7-alkyl, cyano-C1-7-alkyl or cyano;
R , R and R independently from each other are hydrogen, C1-7-alkyl,
C3_7-cycloalkyl, halogen, C1-7-alkoxy- C1-7-alkyl, C2-7-alkenyl, C2-7-alkinyl, fluoro-C1-7-alkyl, cyano-C1-7-alkyl or cyano;
and one of R5, R6 and R7 is
(Formula Removed)
wherein
X2 is (CH2)PNR9CO, or (CH2)PCONR9;
R9 is hydrogen, C1-7-alkyl, C3.7-cycloalkyl, fluoro-C1-7-alkyl, hydroxy-C2-7-alkyl, or C1-7-alkoxy-C2-7-alkyl;
Y1, Y2, Y3 and Y4 are N or C-R12, and 1 or 2 of Y1, Y2, Y3 and Y4 are N and the
12
other ones are C-R ;
R10 is C1-7-alkyl, C3-7-cycloalkyl, fiuoro-C1-7-alkyl, or C1-7-alkoxy-C1-7-alkyl;
R11 is hydrogen, C1-7-alkyl, C1-7-alkoxy-C1-7-alkyl;
R12 independently from each other in each occurance is selected from hydrogen, C1-7-alkyl, C3_7-cycloalkyl, fluoro-C1-7-alkyl, C1-7-alkoxy-C1-7-alkyl, hydroxy-C1-7-alkyl, C1-7- alkylthio-C1-7-alkyl, carboxy-C1-7-alkoxy-C1-7-alkyl, carboxy, carboxy-C1-7-alkyl, mono- or di-C1-7-alkyl-amino-C1-7-alkyl, C1-7-alkanoyl-C1-7-alkyl, C2-7-alkenyl, and C2-7-alkinyl;
R13 is unsubstituted phenyl or phenyl substituted with one to three groups selected from C1-7-alkyl, C1-7-alkoxy, halogen, fluoro-C1-7-alkyl, fluoro-C1-7-alkoxy and cyano;
m is 0 orl, n is 0,1,2 or 3, and p is 0,1 or 2, and the sum of m, n and p is 1,2, 3 or 4.
2. The compounds of formula I as claimed in claim 1, wherein R9 is C1-7-alkyl.
3. The compound of formula I as claimed in claim 1,
2-methyl-2-[3-(methyl-{2-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetyl}-amino)-phenoxy]-propionic acid.
4. The compounds of formula I as claimed in claim 1, selected from the group
consisting of
2-methyl-2-(3-{methyl-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethyl]-carbamoyl}-phenoxy)-propionic acid,
2-[3-({2-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-acetyl}-methyl-amino)-phenoxy] -2-methyl-propionic acid, 2-methyl-2-[3-(methyl-{2-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetyl}-
amino)-5-trifluoromethyl-phenoxy]-propionicacid,
2-[4-({[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbonyl]-amino}-methyl)-phenoxy]-2-methyl-propionic acid, and
2-methyl-2-(4-{[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylcarbamoyl]-methyl}-phenoxy)-propionic acid.
5. The compounds of formula I as claimed in claim 1, selected from the group
consisting of
2-[3-chloro-4-({[4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbonyl]-amino} -methyl)-phenoxy] -2-methyl-propionic acid,
2-memyl-2-[4-({[4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbonyl]-amino}-methyl)-phenoxy]-propionic acid; and
2-(4-{[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylcarbamoyl]-methyl}-phenoxy)-2-methyl-propionic acid.
6. The compounds of formula I as claimed in to any one of claims 1 to 5, wherein R13 is unsubstituted phenyl or phenyl substituted with one to three groups selected from C1-7-alkyl, C1-7-alkoxy, halogen, fluoro-C1-7alkyl and cyano.
7. The compounds of formula I as claimed in claim 6, wherein R13 is phenyl substituted with halogen or fluoro-C1-7-alkyl.
8. The compounds of formula I as claimed in any one of claims 1 to 5, wherein R13 is phenyl substituted with fluoro-C1-7-alkoxy.
9. The compounds of formula I as claimed in any one of claims 1 to 8, wherein R1 is hydrogen.

10. The compounds of formula I as claimed in claim 1, wherein 2 of Y1, Y2, Y3 and Y4 are N and the other ones are C-R12.
11. A process for the manufacture of compounds as claimed in any one of claims 1 to 10, which process comprises
reacting a compound of formula
(Formula Removed)
wherein R1 is C1-7-alkyl, R2 to R8 are as defined as in claim 1 and one of R5, R6or R7 is -(CH2)P-NHR9, wherein R9 and p are as defined in claim 1, with a compound of formula
(Formula Removed)
wherein Y1 to Y4, R10, R11, R13, m and n are as defined in claim 1, to obtain a compound of formula
(Formula Removed)
wherein one of R5,R6and R7 is
(Formula Removed)
and wherein X2 is -(CH2)p-NR9CO-, R1 is C1-7-alkyl and X1, Y1 to Y4, R2 to R13 and m, n
and p are as defined in claim 1,
and optionally hydrolysing the ester group to obtain a compound of formula I, wherein R1
is hydrogen.
12. A process for the manufacture of compounds as claimed in any one of claims 1 to 10, which process comprises
reacting a compound of formula
(Formula Removed)
wherein R1 is C1-7-alkyl, R2 to R8 are as defined as in claim 1 and one of R5, R6or R7 is -(CH2)p-COOH, and p is defined as in claim 1, with a compound of formula
(Formula Removed)
wherein Y1 to Y4, R9, R10, R11, R13, m and n are as defined in claim 1, to obtain a compound of formula
(Formula Removed)
wherein one of R5, R6 and R7 is
(Formula Removed)
and wherein X2 is -(CH2)p-CONR9, R1 is C1-7-alkyl and X1, Y1 to Y4, R2 to R13 and m, n and p are as defined in claim 1,
and optionally hydrolysing the ester group to obtain a compound of formula I, wherein R1 is hydrogen.

Documents:

2931-delnp-2006-Abstract-(14-05-2012).pdf

2931-delnp-2006-abstract.pdf

2931-delnp-2006-Assignment-(14-05-2012).pdf

2931-delnp-2006-assignments.pdf

2931-delnp-2006-Claims-(14-05-2012).pdf

2931-delnp-2006-claims.pdf

2931-delnp-2006-Correspondence Others-(14-05-2012).pdf

2931-delnp-2006-correspondence-others 1.pdf

2931-delnp-2006-Description (Complete)-(14-05-2012).pdf

2931-delnp-2006-description (complete).pdf

2931-delnp-2006-Form-1-(14-05-2012).pdf

2931-delnp-2006-form-1.pdf

2931-delnp-2006-form-18.pdf

2931-delnp-2006-Form-2-(14-05-2012).pdf

2931-delnp-2006-form-2.pdf

2931-delnp-2006-Form-3-(14-05-2012).pdf

2931-delnp-2006-form-3.pdf

2931-delnp-2006-form-5.pdf

2931-delnp-2006-GPA-(14-05-2012).pdf

2931-delnp-2006-gpa.pdf

2931-delnp-2006-pct-304.pdf

2931-delnp-2006-pct-409.pdf

2931-delnp-2006-pct-search report.pdf


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Patent Number 253605
Indian Patent Application Number 2931/DELNP/2006
PG Journal Number 32/2012
Publication Date 10-Aug-2012
Grant Date 06-Aug-2012
Date of Filing 22-May-2006
Name of Patentee F. HOFFMANN-LA ROCHE AG
Applicant Address GRENZACHERSTRASSE 124 CH-4070 BASEL (SWITZERLAND)
Inventors:
# Inventor's Name Inventor's Address
1 ACKERMANN, JEAN IM GLOEGGLIHOF 16, CH-4125 RIEHEN, SWITZERLAND
2 AEBI, JOHANNES IM KUGELFANG 27, CH-4102 BINNINGEN, SWITZERLAND
3 BINGGELL, ALFRED IM KUGELFANG 50, CH-4102 BINNINGEN, SWITZERLAND
4 GRETHER, UWE KIRCHGASSE 4, D-79588 EFRINGEN-KIRCHEN, GERMANY
5 HIRTH, GEORGES 17 RUE DE LA FECHT,F-68000 COLMAR, FRANCE
6 KUHN, BERND SONNMATTWEG 42, CH-4410 LIESTAL, SWITZERLAND
7 MAERKI, HANS-PETER SELTISBERGERSTRASSE 75, CH-4059 BASEL SWITZERLAND
8 MEYER, MARKUS ERASMUSSTRASSE 23, D-79395 NEUENBURG, GERMANY
9 MOHR, PETER BENKENSTRASSE 26, CH-4054 BASEL, SWITZERLAND
10 WRIGHT, MATTHEW, BLAKE PFEFFINGERSTRASSE 16, CH-4053 BASEL, SWITZERLAND
PCT International Classification Number N/A
PCT International Application Number PCT/EP2004/012217
PCT International Filing date 2004-10-28
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 031040819.9 2003-11-05 EUROPEAN UNION
2 04100759.2 2004-02-26 EUROPEAN UNION