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WO2008117982A1 - Heterocyclic carboxylic acid derivatives and pharmaceutical composition for inhibiting lipid accumulation containing same - Google Patents

Heterocyclic carboxylic acid derivatives and pharmaceutical composition for inhibiting lipid accumulation containing same Download PDF

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Publication number
WO2008117982A1
WO2008117982A1 PCT/KR2008/001682 KR2008001682W WO2008117982A1 WO 2008117982 A1 WO2008117982 A1 WO 2008117982A1 KR 2008001682 W KR2008001682 W KR 2008001682W WO 2008117982 A1 WO2008117982 A1 WO 2008117982A1
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Prior art keywords
methyl
carboxylic acid
benzyl
oxazol
ethoxy
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Ceased
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PCT/KR2008/001682
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French (fr)
Inventor
Joong Myung Cho
Seonggu Ro
Dongkyu Shin
Young-Lan Hyun
Jun Hee Lee
Gyu Hwan Yon
Eun Bok Choi
Hyeon Kyu Lee
Chwang Siek Pak
Hyae Gyeong Cheon
Sang Dal Rhee
Won Hoon Jung
Heui Cheol Yang
So Hee Jo
Eunsil Lee
Jung Hee Im
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Korea Research Institute of Chemical Technology KRICT
CrystalGenomics Inc
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Korea Research Institute of Chemical Technology KRICT
CrystalGenomics Inc
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Publication of WO2008117982A1 publication Critical patent/WO2008117982A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to a novel heterocyclic carboxylic acid derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the same as an active ingredient for inhibiting the lipid accumulation in the body.
  • PPARs peroxisome proliferating-activated receptors
  • PPARs which belong to the family of nuclear receptors are hormones that control the lipid level in the cell.
  • PPARs consist of 2nd zinc finger binding domain and a hydrophobic ligand binding pocket, and are divided into three subtypes, "PPAR ⁇ ,” “PPAR ⁇ ” and “PPAR ⁇ .”
  • PPAR ⁇ which is expressed in the muscle, heart, kidney, and particularly in the liver at a high level, controls the degradation of fatty acids.
  • PPAR ⁇ null mice Studies using PPAR ⁇ null mice have revealed that PPAR ⁇ is involved in the beta oxidation of long chain fatty acids such as palmitic acid present in mitochondria. Also, OEA(oleylethanolamide) which is effective in reducing the weight of normal mice, does not affect the weight of PPAR ⁇ null mice, suggesting that PPAR ⁇ is a target of OEA which controls the appetite and body weight.
  • the activation of PPAR ⁇ lowers the expression of apolipoprotein C-III which is known to inhibit the hydrolysis of TGs(triglycerides) by LDL(low density lipoprotein), leading to the degradation of VLDL(very low density lipoprotein) and lowering of the lipid content in the body.
  • the activation of PPAR ⁇ prevents arteriosclerosis by inhibiting the expression of VCAM(vascular cell adhesion molecule)- 1 to prevent arteriosclerosis, IL-linterleukin-l(interleukin-l)-induced secretion of IL-6(interleukin-6), or the production of prostaglandin in vascular smooth muscles.
  • PPAR ⁇ Compounds which have been previously found to promote the activity of PPAR ⁇ include Wy-14643, clofibrate, fenofibrate, bezafibrate, GW2331, SW9578 and BM17.0744(Willson et al, J. Med. Chem., 43, 527-550, 2000). These agonists of PP ARa bring about increased insulin sensitivity in mouse models by way of reducing the blood levels of TGs as well as suppressing the adiposity and steatosis of the liver or muscle(Chou et al, JBC, 277, 24484-24489, 2002; Kim et al, Diabetes, 52, 1770-1778, 2003; Peters et al, MoI. Cell.
  • ring A is a 4 to 6-membered heterocycle comprising 1 or 2 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur;
  • R 1 is a heterocyclic moiety selected from , ? an( j
  • R 2 and R 3 are each independently H, C r C 4 alkyl, or phenyl substituted with halogen, Ci-C 4 alkyl, or Ci-C 3 alkoxy;
  • X is H or Ci-C 4 alkyl;
  • m is 0, 1 or 2; and
  • n is 1 or 2.
  • a pharmaceutical composition for inhibiting the accumulation of lipids in the body comprising the heterocyclic carboxylic acid derivative, or a pharmaceutically acceptable salt thereof, as an active ingredient.
  • the heterocyclic carboxylic acid derivative of the present invention may also be used in the form of a pharmaceutically acceptable salt thereof.
  • the pharmaceutically acceptable salt may be a salt formed with an inorganic or organic base.
  • said inorganic base include alkali metal and alkaline earth metal hydroxides
  • examples of the organic base include ammonium hydroxide, organic amines such as methylamine, ethylamine and pyridine, guanidine, and arginine.
  • Preferred examples of the compounds of formula (1) according to the present invention are the compounds wherein ring A has a thiazolidine, azetidine, pyrrolidine, piperidine, morpholine or thiomorpholine structure.
  • heterocyclic carboxylic acid derivative of formula (1) of the present invention wherein m is 0; ring A is thiazolidine; and X is H(com ⁇ ound of formula Ia) may be prepared by the procedure shown in Reaction Scheme (I):
  • L is a leaving group such as Cl, Br, I 5 mesyl, or tosyl, or hydroxyl; and R 1 and n have the same meanings as defined in formula (1).
  • an alkyl or alcohol compound of formula 2 is allowed to react with a hydroxybenzaldehyde of formula 3 to obtain an alkoxy benzaldehyde of formula 4.
  • the compound of formula 2, in which L is a leaving group such as Cl, Br, I 5 mesyl, or tosyl, is subjected to an alkylation reaction in the presence of a base in a solvent.
  • the base include an inorganic base such as sodium hydride, potassium t-butoxide, butyl lithium, potassium carbonate, or sodium carbonate, and an organic base such as triethylamine, diisopropylethylamine, N-alkylmorpholine, or N-alkylpyrrolidine.
  • the solvent include dimethylformamide(DMF), tetrahydrofuran(THF), dioxane, or an alcohol such as methanol, ethanol, isopropanol or r-butanol, or a mixture thereof with water.
  • the reaction may be carried out at a temperature ranging from -20 to 100 0 C, and a quaternary amine halogen salt such as (Bu) 4 NI may be added thereto in a catalytic amount to enhance the reaction rate.
  • the compound of formula 4 is allowed to react with cysteine in an alcohol to obtain the inventive heterocyclic carboxylic acid derivative(compound of formula Ia).
  • cycteine is of the form of a hydrochloride salt
  • the reaction may be carried out in the presence of an inorganic base such as lithium hydroxide, potassium hydroxide, sodium hydroxide, potassium carbonate or sodium carbonate, or an organic base such as triethylamine, using a solvent such as methanol, ethanol or tetrahydrofuran.
  • heterocyclic carboxylic acid derivative of formula (1) of the present invention wherein m is 1; ring A is a heterocyclic moiety; and X is H or C 1 -C 4 alkyl(the compound of formula Ic or Ib, respectively) may be respectively prepared by the procedures shown in Reaction Schemes (Ha) to (lie):
  • R 1 , R 2 , R 3 , n, and L have the same meanings as defined above.
  • the compounds of formulae Ib and Ic may be prepared by a process comprising the following steps: An aromatic aldehyde compound of formula 4 is subjected to reductive amination with a heterocyclic carboxylate of formula 5 in the presence of a reducing agent to obtain a carboxylic acid derivative of formula Ib.
  • the reducing agent used in this step may be sodium triacetoxyborohydride or sodium borohydride.
  • the compound of formula 5 is an acid addition salt
  • the above reaction may be conducted in the presence of an organic base such as triethylamine. Also, the reaction may be carried out at a temperature ranging from 0 to 40 "C , using a solvent such as dichloromethane, chloroform or dichloroethane.
  • the compound of formula Ib is then subjected to hydrolysis in the presence of a base to obtain the inventive heterocyclic carboxylic acid derivative of formula Ic.
  • the hydrolysis reaction may be conducted in the presence of an inorganic base such as lithium hydroxide, potassium hydroxide, sodium hydroxide, potassium carbonate or sodium carbonate, or an organic base such as diisopropylethylamine, using a solvent such as water, an alcohol, e.g., methanol and ethanol, an ether, e.g., tetrahydrofuran, and a mixture thereof with water.
  • the compounds of formulae Ib and Ic may be prepared by a process comprising the following steps: An aromatic aldehyde compound of formula 4 is subjected to reductive reaction in the presence of a reducing agent to obtain a benzyl alcohol compound of formula 7.
  • the reducing agent which may be used in this reaction includes metal hydride such as sodium borohydride, lithium aluminium hydride, sodium cyanoborohydride, sodium triacetoxyborohydride, sodium or potassium alkoxyborohydride, DIBAL-H(diisobutylaluminum hydride), diborane, a metal salt thereof, or a mixture thereof.
  • the above reaction may be carried out at a temperature ranging from -20 to 100 ° C, using a solvent such as water, an alcohol, e.g., methanol and ethanol, an ether such as tetrahydrofuran, and a mixture thereof with water.
  • a solvent such as water, an alcohol, e.g., methanol and ethanol, an ether such as tetrahydrofuran, and a mixture thereof with water.
  • the compound of formula 7 thus obtained is then subjected to a reaction to convert the hydroxyl group to a leaving group such as Cl, Br, I, mesyl, or tosyl in a suitable solvent to obtain a substituted aromatic compound of formula 8.
  • the compound of formula 8 in which M is mesyl or tosyl may be prepared by treating the compound of formula 7 with methanesulfonyl chloride or 4-toluenesulfonyl chloride, in the presence of an inorganic base such as potassium carbonate or an organic base such as triethylamine, in benzene or dichloromethane. Subsequently, the compound of formula 8 is allowed to react with a heterocyclic carboxylate of formula 5 in the presence of a base to obtain the inventive heterocyclic carboxylic acid derivative of formula Ib.
  • an inorganic base such as potassium carbonate or an organic base such as triethylamine
  • the base may be an inorganic base such as sodium hydride, sodium methoxide, sodium ethoxide, potassium t-butoxide, butyl lithium, potassium carbonate, and sodium carbonate, or an organic base such as triethyl amine, diisopropyl ethylamine, N-alkyl morpholine, and N-alkyl pyrrolidine.
  • the reaction may be carried out at a temperature ranging from -20 to 100 ° C, in a solvent such as dimethylformamide, tetrahydrofuran, dioxane, an alcohol such as methanol, ethanol, isopropanol, and t-butanol, or a mixure thereof with water.
  • a quaternary amine halide such as (Bu) 4 NI may be added thereto in a catalytic amount to enhance the reaction rate.
  • the compound of formula Ib is hydrolyzed as described in the second step of Reaction Scheme (Ha) to obtain the inventive heterocyclic carboxylic acid derivative of formula Ic.
  • the compounds of formulae Ib and Ic may be prepared by a process comprising the following steps:
  • the hydroxybenzaldehyde of formula 3 is subjected to reductive amination by the procedure described in the first step of Reaction Scheme (Ha) to obtain a heterocyclic carboxylate of formula 9.
  • the procedure in the first step of Reaction Scheme (I) is repeated except for using the compound of formula 9 to obtain a heterocyclic carboxylic acid derivative of formula Ib, which was converted to the inventive heterocyclic carboxylic acid derivative of formula Ic by the procedure described in the second step of Reaction Scheme (Ha).
  • the inventive heterocyclic carboxylic acid derivative of formula (1) wherein m is 1; ring A is thiazolidine; X is H(compound of formula Id) may be preprared by the procedure shown in Reaction Scheme (III):
  • L is Cl, Br, I, mesyl, or tosyl
  • the compound of formula Id may be prepared by a process comprising the following steps: In case L of the compound of formula 2a is a leaving group, the procedure of the first step of Reaction Scheme (I) was repeated except for using hydroxyphenethylalcohol of formula 10 to obtain a phenethyl alcohol compound of formula 11, which is then treated with IBX(I -hydroxy- 1,2-benziodoxo 1-3 (lH)-one l-oxide(2-iodoxybenzoic acid)) in a solvent such as ethyl acetate at the boiling temperature of the solvent in accordance with a conventional method ⁇ ee Marco Frigerio et al, Journal of Organic Chemistry, 64(12), 4537-538(1999)) to obtain an aromatic aldehyde compound of formula 12. Subsequently, the compound of formula 12 is allowed to react with cycteine as in the second step of Reaction Scheme (I) to obtain the inventive heterocyclic carboxylic acid derivative
  • the inventive heterocyclic carboxylic acid derivative of formula (1) wherein m is 2; ring A is a heterocycle; and X is ⁇ or C 1 -C 4 alkyl(compound of formula If or Ie, respectively) may be prepared by repeating the procedure of Reaction Scheme (Ua) except for using an aromatic acetaldehyde compound of formula 12 as a starting material as shown in Reaction Scheme (IV): Reaction Scheme (IV)
  • X is C 1 -C 4 alkyl
  • R 1 , R 2 , R 3 , and n have the same meaning as defined in formula (1).
  • the formulation for administration may be prepared by mixing or diluting the inventive heterocyclic carboxylic acid derivative with a carrier, or sealing in a carrier in the form of a vessel. If the carrier is used as a diluent, it may be a vehicle, adjuvant or medium for active ingredient in the form of a solid, semi-solid, or liquid.
  • the formulation for administration may take various forms such as a tablet, pill, powder, sachet, elixir, suspension, emulsion, solution, syrup, aerosol, soft and hard gelatin capsule, sterilized injection, sterilized powder, or the like, and additionally include conventional additives such as a filler, anti-flocculation agent, lubricant, wetting agent, flavor, emulsifier, preservative, or the like.
  • the pharmaceutical composition of the present invention may also be formulated for fast, continuous or delayed release of an active ingredient after administration using conventional methods.
  • the pharmaceutical composition of the present invention can be administered orally or parenterally as an active ingredient in an effective amount ranging from about 0.1 to 1000 mg/kg body weight per day, preferably from about 1 to 100 mg/kg body weight per day in a single dose or in divided doses in case of mammals including human.
  • Step 2 Preparation of (R)-2- ⁇ 4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenyl ⁇ thiazolidine-4-carboxylic acid
  • Methanesulfonic acid-2-(benzoxazol-2-yl-methylamino)-ethyl ester(246 mg, 0.91 mmol) was dissolved in dimethylformamide(15 ml), and potassium carbonate(190 mg, 1.37 mmol) and 4-hydroxybenzaldehyde(110 mg, 0.91 mmol) were added thereto.
  • the resulting mixture was stirred at a temperature ranging from 90 to 100 ° C for 15 hrs, and then, 30 ml of ethyl acetate and a saturated aqueous NaHCO 3 were added thereto. Then, the resulting mixture was extracted with ethyl acetate(3 x 30 ml).
  • Step 2 Preparation of (R)-2- ⁇ 4-[2-(benzoxazol-2-yl-methylamino)-ethoxy]- phenyl ⁇ -thiazolidine-4-carboxylic acid
  • Step 2 of Example 1 The procedure of Step 2 of Example 1 was repeated except for using the compound obtained in Step 1 of Example 2(0.1 g, 0.34 mmol) and L-cysteine(0.042 g, 0.34 mmol) to obtain the title compound(0.082 g, yield: 61%).
  • Step 1 Preparation of 4-[2-(methylpyridin-2-yl-methylamino)-ethoxy]- benzaldehyde
  • Step 1 of Example 2 The procedure of Step 1 of Example 2 was repeated except for using methanesulfonic acid-2-(methyl-pyridin-2-yl-methylamino)-ethyl ester(209 mg, 0.91 mmol) and 4-hydroxybenzaldehyde(110 mg, 0.91 mmol) to obtain the title compo ⁇ md(185 mg, yield: 79%).
  • Step 2 Preparation of (R)-2- ⁇ 4-[2-(methyl-pyridin-2-yl-methylamino)-ethoxy]- phenyl ⁇ -thiazolidine-4-carboxylic acid
  • Step 2 of Example 1 The procedure of Step 2 of Example 1 was repeated except for using the compound obtained in Step 1 of Example 3(0.087 g, 0.34 mmol) and L-cysteine(0.042 g, 0.34 mmol) to obtain the title compound(0.089 g, yield: 73%).
  • Step 1 Preparation of 4-[2-(5-methyl-2-(4-trifluoromethylphenyl)-oxazol-
  • Step 1 of Example 1 The procedure of Step 1 of Example 1 was repeated except for using 2-(5-methyl-2-(4-trifluoromethyl ⁇ henyl)-phenyloxazol-4-yl)ethanol(0.48 g, 1.76 mmol), 4-hydroxybenzaldehyde(0.215 g, 1.76 mmol), triphenylphosphine(0.46 g,
  • Step 2 Prepration of (R)-2- ⁇ 4-[2-(5-methyl-2-(4-trifluoromethyl ⁇ henyl)-oxazol-
  • Step 2 of Example 1 The procedure of Step 2 of Example 1 was repeated except for using the compound obtained in Step 1 of Example 4(0.1 g, 0.26 mmol) and L-cysteine(0.032 g, 0.26 mmol) to obtain the title compound(0.08 g, yield: 63%).
  • Step 1 Preparation of 4-[2-(5-methyl-2-thiophen-2-yloxazol-4-yl)ethoxy] benzaldehyde
  • Step 2 Preparation of (R)-2- ⁇ 4-[2-(5-methyl-2-thiophen-2-yloxazol-4-yl)ethoxy] phenyl ⁇ thiazolidine-4-carboxylic acid
  • Step 2 of Example 1 The procedure of Step 2 of Example 1 was repeated except for using the compound obtained in Step 1 of Example 5(0.1 g, 0.324 mmol) and L-cysteine(0.04 g, 0.324 mmol) to obtain the title compound(0.077 g, yield: 57%).
  • Step 1 Preparation of 3-[2-(5-methyl-2-/?-tolyloxazol-4-yl)ethoxy]benzaldehyde The procedure of Step 1 of Example 1 was repeated except for using
  • Step 2 of Example 1 The procedure of Step 2 of Example 1 was repeated except for using the compound obtained in Step 1 of Example 6(0.032 g, 0.09 mmol) and L-cysteine(0.012 g 5 0.09 mmol) to obtain the title com ⁇ ound(0.009 g, yield: 21%).
  • Step 2 Preparation of (R)-2- ⁇ 4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenyl ⁇ thiazolidine-4-carboxylic acid
  • Step 2 of Example 1 The procedure of Step 2 of Example 1 was repeated except for using the compound obtained in Step 1 of Example 7(0.09 g, 0.287 mmol) and
  • Step 1 Preparation of 3-[2-(5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl) ethoxy]benzaldehyde
  • Step 2 of Example 1 The procedure of Step 2 of Example 1 was repeated except for using the compound obtained in Step 1 of Example 8(0.06 g, 0.162 mmol) and L-cysteine(0.02 g, 0.162 mmol) to obtain the title com ⁇ ound(0.025 g, yield: 32%).
  • Step 1 Preparation of 3-[2-(5-methyl-2-thiophen-2-yloxazol-4-yl)ethoxy] benzaldehyde
  • Step 2 Preparation of (R)-2- ⁇ 4-[2-(5-methyl-2-thiophen-2-yloxazol-4-yl)ethoxy] phenyl ⁇ thiazolidine-4-carboxylic acid
  • the procedure of Step 2 of Example 1 was repeated except for using the compound obtained in Step 1 of Example 9(0.06 g, 0.19 mmol) and L-cysteine(0.023 g, 0.19 mmol) to obtain the title compound(0.063 g, yield: 77%).
  • Step 2 Preparation of Preparation of (R)-2- ⁇ 3-[2-(5-methyl-2-/?-tolyl-oxazol-4-yl)- ethoxy] -phenyl ⁇ -thiazolidine-4-carboxylic acid
  • Step 2 of Example 1 The procedure of Step 2 of Example 1 was repeated except for using the compound obtained in Step 1 of Example 10(0.06 g, 0.19 mmol) and L-cysteine(0.023 g, 0.19 mmol) to obtain the title compound(8.9 mg, yield: 21%).
  • Step 1 Preparation of 3- ⁇ 2-[5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl]- ethoxy ⁇ -benzaldehyde
  • Step 2 Preparation of (R)-3-(3- ⁇ 2-[5-methyl-2-(4-trifluoromethylphenyl)-oxazol- 4-yl]-ethoxy ⁇ -benzyl)-thiazolidine-4-carboxylic acid methyl ester
  • step 2 of Example 11 The compound obtained in step 2 of Example 11 was dissolved in methanol(7 ml), and lithium hydroxide(l 1 mg, 0.44 mmol) was added thereto. The resulting mixture was heated to reflux for 18 hrs. To the reaction product, water and ethyl acetate were sequentially added. To the resulting mixture, 1 N HCl was added until the reaction solution would become transparent. Then, the organic layer was separated, dried over magnesium sulfate, and distilled under reduced pressure to obtain the title compound(47 mg, yield: 44%).
  • Step 1 Preparation of 4- ⁇ 2-[5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl]- ethoxy ⁇ -benzaldehyde
  • Step 1 of Example 11 The procedure of Step 1 of Example 11 was repeated except for using 4-hydroxybenzaldehyde(730 mg, 6 mmol) and methanesulfonic 2-[5-methyl-2-(4- trifluoromethylphenyl)-oxazol-4-yl]-ethyl ester(1.4 g, 4 mmol) to obtain the title compound(500 mg, yield: 33%).
  • Step 2 of Example 11 was repeated except for using the resulting mixture to obtain the title compound(60 mg, yield: 17%).
  • Step 3 Preparation of 3-(4- ⁇ 2-[5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl]- ethoxy ⁇ -benzyl)-thiazolidine-4-carboxylic acid
  • Step 1 Preparation of 3-(4- ⁇ 2-[5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl]- ethoxy ⁇ -benzyl)-thiazolidine-2-carboxylic acid methyl ester
  • Example 11 was repeated except for using the resulting mixture to obtain the title compound(25 mg, yield: 7%).
  • Step 2 Preparation of 3-(4- ⁇ 2-[5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl]- ethoxy ⁇ -benzyl)-thiazolidine-2-carboxylic acid
  • the compound obtained in Step 1 of Example 13(25 mg, 0.05 mmol) was dissolved in methanol(5 ml).
  • the procedure of Step 3 of Example 11 was repeated except for using the resulting mixture to obtain the title compound(10 mg, yield: 42%).
  • Step 1 Preparation of (R)-3-(3-hydroxy-benzyl)-thiazolidine-4-carboxylic acid methyl ester
  • Step 2 Preparation of (R)-3-[3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzyl]- thiazolidine-4-carboxylic acid methyl ester
  • Step 1 Preparation of (R)-3-[3-(5-methyl-2-jo-tolyl-oxazol-4-ylmethoxy)-benzylj- thiazolidine-4-carboxylic acid methyl ester
  • Step 2 Preparation of (R)-3-[3-(5-methyl-2-/>-tolyl-oxazol-4-ylmethoxy)-benzyl]- thiazolidine-4-carboxylic acid 3-[3-(5-Methyl-2-/?-tolyl-oxazol-4-ylmethoxy)-benzyl]-thiazolidine-4- carboxylic acid methyl ester(30 mg, 0.07 mmol) and lithium hydroxide(3.4 mg, 0.14 mmol) were dissolved in methanol(7 ml). The procedure of Step 3 of Example 11 was repeated except for using the resulting mixture to obtain the title compound(29 mg, yield: 100%).
  • Step 1 Preparation of (R)-3-[3-(2-biphenyl-4-yl-5-methyl-oxazol-4-ylmethoxy)- benzyl]-thiazolidine-4-carboxylic acid methyl ester
  • Step 2 Preparation of (R)-3-[3-(2-biphenyl-4-yl-5-methyl-oxazol-4-ylmethoxy)- benzyl]-thiazolidine-4-carboxylic acid
  • the compound obtained in Step 1 of Example 16(30 mg, 0.06 mmol) and lithium hydroxide(2.9 mg, 0.12 mmol) were dissolved in methanol(7 ml).
  • the procedure of Step 3 of Example 11 was repeated except for using the resulting mixture to obtain the title compound(29 mg, yield: 100%).
  • Step 1 Preparation of (R)-3-[3-(5-methyl-2-thiophen-2-yl-oxazol-4-ylmethoxy)- benzyl]-thiazolidine-4-carboxylic acid methyl ester
  • Step 1 Preparation of (R)-3-[3-(5-methyl-2-(-trifluoromethylphenyl-oxazol-4- ylmethoxy)-benzyl)-thiazolidine-4-carboxylic acid methyl ester
  • Step 2 Preparation of (R)-3- ⁇ 3-[5-methyl-2-(4-trifluoromethylphenyl)-oxazol- 4-ylmethoxy]-benzyl ⁇ -thiazolidine-4-carboxy lie acid
  • Step 2 Preparation of (R)-3- ⁇ 3-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]- benzyl ⁇ -thiazolidine-4-carboxylic acid
  • Step 1 Preparation of 3-(4-hydroxy-benzyl)-thiazolidine-2-carboxylic acid methyl ester Thiazolidine-2-carboxylic acid methyl ester hydrochloride(1.22 g, 0.01 mol),
  • Step 2 Preparation of 3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzyl]- thiazolidine-2-carboxylic acid methyl ester
  • Step 3 Preparation of 3-[4-(5-methyl-2- ⁇ henyl-oxazol-4-ylmethoxy)-benzyl]- thiazolidine-2-carboxylic acid
  • Step 1 Preparation of 3-[4-(5-methyl-2-j ⁇ -tolyl-oxazol-4-ylmethoxy)-benzyl]- thiazolidine-2-carboxylic acid methyl ester
  • Step 2 Preparation of 3-[4-(5-methyl-2-p-tolyl-oxazol-4-ylmethoxy)-benzyl]- thiazolidine-2-carboxylic acid
  • Example 11 was repeated except for using the resulting mixture to obtain the title com ⁇ ound(29 mg 5 100%).
  • Step 1 Preparation of 3-[4-(2-biphenyl-4-yl-5-methyl-oxazol-4-ylmethoxy)-benzyl]- thiazolidine-2-carboxylic acid methyl ester
  • Step 2 Preparation of 3-[4-(2-biphenyl-4-yl-5-methyl-oxazol-4-ylmethoxy)-benzyl]- thiazolidine-2-carboxylic acid
  • Step 1 Preparation of 3-[4-(5-methyl-2-thiophen-2-yl-oxazol-4-ylmethoxy)-benzyl]- thiazolidine-2-carboxylic acid methyl ester
  • Step 1 Preparation of 3-[4-(5-methyl-2-(-trifluoromethyl-phenyl-oxazol-4- ylmethoxy)-benzyl)-thiazolidine-2-carboxylic acid methyl ester
  • Step 2 Preparation of 3-[4-(5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4- ylmethoxy)-benzyl]-thiazolidine-2-carboxylic acid
  • Step 1 Preparation of 3- ⁇ 4-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]- benzyl ⁇ -thiazolidine-2-carboxylic acid methyl ester
  • the procedure of Example 19 was repeated except for using the compound obtained in Step 1 of Example 20(100 mg, 0.4 mmol), 2-(2-biphenyl-4-yl-methyl-oxazol-4-yl)-ethanol(110 mg, 0.4 mmol), triphenylphosphine(126 mg, 0.48 mmol) and diisopropylazodicarboxylate(97 mg, 0.48 mmol) to obtain the title compound(88 mg, yield: 43%).
  • Step 2 Preparation of 3- ⁇ 4-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]- benzyl ⁇ -thiazolidine-2-carboxylic acid
  • Step 1 Preparation of 3- ⁇ 4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]- benzyl ⁇ -thiazolidine-2-carboxylic acid methyl ester
  • Step 1 of Example 19 The procedure of Step 1 of Example 19 was repeated except for using the compound obtained in Step 1 of Example 20(100 mg, 0.4 mmol),
  • Step 2 Preparation of 3- ⁇ 4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]- benzyl ⁇ -thiazolidine-2-carboxylic acid
  • Step 1 Preparation of 3-(3-hydroxy-benzyl)-thiazolidine-4-carboxylic acid methyl ester
  • Step 2 Preparation of 3-[3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzyl]- thiazolidine-2-carboxylic acid methyl ester
  • Step 3 Preparation of 3-[3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzyl]- thiazolidine-2-carboxylic acid
  • Step 1 Preparation of 3-[3-(5-methyl-2-thiophen-2-yl-oxazol-4-ylmethoxy) ⁇ benzyl]-thiazolidine-2-carboxylic acid methyl ester
  • Step 2 Preparation of 3-[3-(5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4- ylmethoxy)-benzyl]-thiazolidine-4-carboxylic acid
  • Step 1 Preparation of 3- ⁇ 3-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzyl ⁇ - thiazolidine-2-carboxylic acid methyl ester
  • Step 1 of Example 19 The procedure of Step 1 of Example 19 was repeated except for using the compound obtained in Step 1 of Example 27(100 mg, 0.4 mmol),
  • Step 2 Preparation of 3- ⁇ 3-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzyl ⁇ - thiazolidine-2-carboxylic acid
  • Step 1 Preparation of 3- ⁇ 3-[2-(2-bi ⁇ henyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]- benzyl ⁇ -thiazolidine-2-carboxylic acid methyl ester
  • the procedure of Step 1 of Example 19 was repeated except for using the compound obtained in Step 1 of Example 27(100 mg, 0.4 mmol),
  • Step 2 Preparation of 3- ⁇ 3-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]- benzyl ⁇ -thiazolidine-2-carboxylic acid
  • Step 1 Preparation of 3-(3- ⁇ 2-[5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl]- ethoxy ⁇ -benzyl)-thiazolidine-2-carboxylic acid methyl ester
  • the procedure of Step 1 of Example 19 was repeated except for using the compound obtained in Step 1 of Example 27(100 mg, 0.4 mmol),
  • Step 2 Preparation of 3-(3- ⁇ 2-[5-methyl-2-(4-trifluoromethyl ⁇ henyl)-oxazol-4-yl]- ethoxy ⁇ -benzyl)-thiazolidine-2-carboxylic acid
  • Step 1 Preparation of (R)-3-(4-hydroxy-benzyl)-thiazolidine-4-carboxylic acid methyl ester (R)-thiazolidine-4-carboxylic acid methyl ester hydrochloride(1.47 g, 8 mmol), 4-hydroxybenzaldehyde(0.97 g, 8 mmol), sodium triacetoxyborohydride(2.54 g, 0.12 mol) and triethylamine(2.02 g, 0.012 mol) were dissolved in l,2-dichloromethane(50 ml). The procedure of Step 2 of Example 11 was repeated except for using the resulting mixture to obtain the title compound(1.15 g, yield: 57%).
  • Step 2 Preparation of (R)-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)- benzyl] -thiazolidine-4-carboxylic acid methyl ester
  • Step 3 Preparation of (R)-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzyl]- thiazolidine-4-carboxylic acid
  • the procedure of Step 3 of Example 11 was repeated except for using the resulting mixture to obtain the title compound(14 mg, yield: 100%).
  • Step 1 Preparation of (R)-3-[4-(5-methyl-2-p-toryl-oxazol-4-ylmethoxy)- benzyl]-thiazolidine-4-carboxylic acid methyl ester
  • Step 2 Preparation of (R)-3-[4-(5-methyl-2-/>-tolyl-oxazol-4-ylmethoxy)- benzyl]-thiazolidine-4-carboxylic acid
  • Step 1 Preparation of (R)-3-[4-(2-biphenyl-4-yl-5-methyl-oxazol-4-ylmethoxy)- benzyl]-thiazolidine-4-carboxylic acid methyl ester
  • Step 2 Preparation of (R)-3-[4-(2-biphenyl-4-yl-5-methyl-oxazol-4-ylmethoxy)- benzyl]-thiazoli dine-4-carboxylic acid
  • the compound obtained in Step 1 of Example 35(30 mg, 0.06 mmol) and lithium hydroxide(2.9 mg, 0.12 mmol) were dissolved in methanol(10 ml).
  • the procedure of Step 3 of Example 11 was repeated except for using the resulting mixture to obtain the title compound(22 mg, yield: 76%).
  • Step 1 Preparation of (R)-3-[4-(5-methyl-2-thiophen-2-yl-oxazol-4-ylmethoxy)- benzyl]-thiazolidine-4-carboxylic acid methyl ester
  • Step 2 Preparation of (R)-3-[4-(5-methyl-2-thio-2-yl-oxazol-4-ylmethoxy)-benzyl]- thiazolidine-4-carboxylic acid
  • Step 1 Preparation of (R)-3-[4-(5-methyl-2-(trifluoromethyl-phenyl-oxazol-4- ylmethoxy)-benzyl)-thiazolidine-4-carboxylic acid methyl ester
  • Step 2 Preparation of (R)-3-[4-(5-methyl-2-(trifluoromethyl-phenyl-oxazol-4- ylmethoxy)-benzyl]-thiazolidine-4-carboxylic acid
  • Step 1 Preparation of (R)-3- ⁇ 4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]- benzyl ⁇ -thiazolidine-4-carboxylic acid methyl ester
  • Step 2 Preparation of (R)-3- ⁇ 4-[2-(5-methyl-2- ⁇ henyl-4-yl-oxazol-4-yl)-ethoxy]- benzyl ⁇ -thiazolidine-4-carboxylic acid
  • Step 1 Preparation of (R)-3- ⁇ 4-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)- ethoxy] -benzyl ⁇ -thiazolidine-4-carboxy lie acid methyl ester
  • Step 1 of Example 19 The procedure of Step 1 of Example 19 was repeated except for using the compound obtained in Step 1 of Example 27(100 mg, 0.4 mmol), 2-(2-biphenyl-4-yl-methyl-oxazol-4-yl)-ethanol(112 mg, 0.4 mmol), triphenylphosphine(126 mg, 0.48 mmol) and diisopropylazodicarboxylate(97 mg, 0.48 mmol) to obtain the title compound(20 mg, yield: 8%).
  • Step 2 Preparation of (R)-3- ⁇ 4-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)- ethoxy]-benzyl ⁇ -thiazolidine-4-carboxylic acid
  • Step 1 Preparation of (R)-3- ⁇ 4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]- benzyl ⁇ -thiazolidine-4-carboxylic acid methyl ester
  • Step 1 of Example 19 The procedure of Step 1 of Example 19 was repeated except for using the compound obtained in Step 1 of Example 27(100 mg, 0.4 mmol), 2-(5-methyl-thiophen-2-yl-oxazol-4-yl)-ethanol(84 mg, 0.4 mmol), triphenylphosphine(126 mg, 0.48 mmol) and diisopropylazodicarboxylate(97 mg, 0.48 mmol) to obtain the title compound(17 mg, yield: 9%).
  • Step 2 Preparation of (R)-3- ⁇ 4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]- benzyl ⁇ -thiazolidine-4-carboxylic acid
  • Step 2 Preparation of (S)-3-[3-(5-methyl-2-/?-tolyl-oxazol-4-ylmethoxy)benzyl] thiazolidine-4-carboxylic acid
  • Step 2 of Example 41 The procedure of Step 2 of Example 41 was repeated except for using the compound obtained in Step 1 of Example 41(64.7 mg, 0.48 mmol), 4-(5-methyl-2-p-toryloxazol-4-ylmethoxy)benzaldehyde(150 mg, 0.48 mmol), triethylamine(122 mg, 1.21 mmol) and sodium triacetoxyborohydride(154 mg, 0.72 mmol) to obtain the title compound(20.2 mg, yield: 9.7%).
  • Step 1 Preparation of (R)-3-[4-(3-j9-tolylisoxazol-5-ylmethoxy)benzyl]thiazolidine- 4-carboxylic acid methyl ester
  • the procedure of Step 1 of Example 19 was repeated except for using the compound obtained in Step 1 of Example 20(0.14 g, 0.56 mmol),(3-;?-torylisoxazol-5-yi)methanol(0.15 g, 0.62 mmol), triphenylphosphine(0.18 g, 0.71 mmol) and diisopropylazodicarboxylate(0.143g,
  • Step 1 Preparation of (R)-3-[4-(3-phenylisoxazol-5-ylmethoxy)benzyl] thiazolidine-4-carboxylic acid methyl ester
  • Step 1 of Example 19 The procedure of Step 1 of Example 19 was repeated except for using the compound obtained in Step 1 of Example 20(0.097 g, 0.385 mmol),(3-phenylisoxazol-5-yl)methanol(0.075 g, 0.427 mmol), triphenylphosphine(0.128 g, 0.49 mmol) and diisopropylazodicarboxylate(0.099 g,
  • Step 2 of Example 43 The procedure of Step 2 of Example 43 was repeated except for using the compound obtained in Step 1 of Example 44(0.093 g, 0.227 mmol) and lithium hydroxide monohydrate(0.0143 g, 0.341 mmol) to obtain the title compound(0.08 g, yield: 88%).
  • Step 1 Preparation of (R)-3- ⁇ 4-[3-(4-chlorophenyl)isoxazol-5-ylmethoxy]benzyl ⁇ thiazolidine-4-carboxylic acid methyl ester
  • Step 1 of Example 19 The procedure of Step 1 of Example 19 was repeated except for using the compound obtained in Step 1 of Example 20(0.163 g, 0.644 mmol),
  • Step 2 Preparation of (R)-3- ⁇ 4-[3-(4-chlorophenyl)isoxazol-5-ylmethoxy]benzyl ⁇ thiazolidine-4-carboxylic acid
  • Step 2 of Example 43 The procedure of Step 2 of Example 43 was repeated except for using the compound obtained in Step 1 of Example 45(0.1 g, 0.225 mmol) and lithium hydroxide monohydrate(0.014 g, 0.337 mmol) to obtain the title com ⁇ ound(0.098 g, yield: 98%).
  • Step 1 Preparation of (R)-3- ⁇ 4-[3-(4-trifluoromethylphenyl)isoxazol-5-ylmethoxy] benzyl ⁇ thiazolidine-4-carboxylic acid methyl ester
  • Step 1 of Example 19 The procedure of Step 1 of Example 19 was repeated except for using the compound obtained in Step 1 of Example 20(0.14 g, 0.555 mmol), [3-(4-trifluoromethylphenyl)isoxazol-5-yl]methanol(0.15 g, 0.617 mmol), triphenylphosphine(0.186 g, 0.71 mmol) and diisopropylazodicarboxylate(0.143 g, 0.71 mmol) to obtain the title compound(0.09 g, yield: 35%).
  • Step 2 Preparation of (R)-3- ⁇ 4-[3-(4-trifluoromethylphenyl)isoxazol-5-ylmethoxy] benzyl ⁇ thiazolidine-4-carboxylic acid
  • Step 2 of Example 43 The procedure of Step 2 of Example 43 was repeated except for using the compound obtained in Step 1 of Example 46(0.081 g, 0.169 mmol) and lithium hydroxide monohydrate(0.011 g, 0.254 mmol) to obtain the title compound(0.046 g, yield: 60%).
  • Step 1 Preparation of (R)-3-[3-(3-j3-tolylisoxazol-5-ylmethoxy)benzyl] thiazolidine-4-carboxylic acid methyl ester
  • Step 1 of Example 19 The procedure of Step 1 of Example 19 was repeated except for using the compound obtained in Step 1 of Example 14(0.2 g, 0.789 mmol), 3-(/?-tolylisoxazol-5-yl)methanol(0.15 g, 0.789 mmol), triphenylphosphine(0.258 g, 0.936 mmol) and diisopropylazodicarboxylate(0.2 g, 0.986 mmol) to obtain the title compound(0.12 g, yield: 36%).
  • Step 2 of Example 43 The procedure of Step 2 of Example 43 was repeated except for using the compound obtained in Step 1 of Example 47(0.077 g, 0.18 mmol) and lithium hydroxide monohydrate(0.0115 g, 0.275 mmol) to obtain the title compound(0.04 g 5 yield: 54%).
  • Step 1 Preparation of (R)-3-[3-(3-phenylisoxazol-5-ylmethoxy)benzyl]thiazolidine- 4-carboxylic acid methyl ester
  • Step 1 of Example 19 The procedure of Step 1 of Example 19 was repeated except for using the compound obtained in Step 1 of Example 14(0.2 g, 0.789 mmol),(3-phenylisoxazol-5-yl)methanol(0.14 g, 0.789 mmol), triphenylphosphine(0.258 g, 0.986 mmol) and diisopropylazodicarboxylate(0.2 g, 0.986 mmol) to obtain the title compound(0.15 g, yield: 47%).
  • Step 2 of Example 43 The procedure of Step 2 of Example 43 was repeated except for using the compound obtained in Step 1 of Example 48(0.06 g, 0.146 mmol) and lithium hydroxide monohydrate(0.092 g 5 0.219 mmol) to obtain the title compound(0.023 g 5 yield: 40%).
  • Step 1 Preparation of (R)-3- ⁇ 3-[3-(4-chlorophenyl)isoxazol-5-ylmethoxy]benzyl ⁇ - thiazolidine-4-carboxylic acid methyl ester
  • Step 1 of Example 19 The procedure of Step 1 of Example 19 was repeated except for using the compound obtained in Step 1 of Example 14(0.2 g, 0.789 mmol),
  • Step 2 Preparation of (R)-3- ⁇ 3-[3-(4-chlorophenyl)isoxazol-5-ylmethoxy]benzyl ⁇ - thiazolidine-4-carboxylic acid
  • the procedure of Step 2 of Example 43 was repeated except for using the compound obtained in Step 1 of Example 49(0.042 g, 0.094 mmol) and lithium hydroxide monohydrate(0.006 g, 0.142 mmol) to obtain the title compound(0.0158 g, yield: 39%).
  • Step 1 Preparation of (R)-3- ⁇ 3-[3-(4-trifluoromethylphenyl)isoxazol-5-ylmethoxy] benzyl ⁇ thiazolidine-4-carboxylic acid methyl ester
  • Step 1 of Example 19 The procedure of Step 1 of Example 19 was repeated except for using the compound obtained in Step 1 of Example 14(0.2 g, 0.789 mmol), [3-(4-trifluoromethylphenyl)isoxazol-5-yl]methanol(0.19 g, 0.789 mmol), triphenylphosphine(0.258 g, 0.986 mmol) and diisopropylazodicarboxylate(0.2 g, 0.986 mmol) to obtain the title com ⁇ ound(0.2 g, yield: 53%).
  • Step 2 Preparation of (R)-3- ⁇ 3-[3-(4-trifluoromethylphenyl)isoxazol-5-ylmethoxy] benzyl ⁇ thiazolidine-4-carboxylic acid
  • Step 2 of Example 43 The procedure of Step 2 of Example 43 was repeated except for using the compound obtained in Step 1 of Example 50(0.2 g, 0.418 mmol) and lithium hydroxide monohydrate(0.026 g, 0.627 mmol) to obtain the title compound(0.14 g, yield: 71%).
  • Step 1 Preparation of (R)-2-isopropylthiazolidine-4-carboxylic acid methyl ester
  • Step 1 of Example 51 The procedure of Step 1 of Example 51 was repeated except for using D-cysteine methyl ester hydrochloride(1.0 g, 5.82 mmol), potassium acetate(0.63 g,
  • Step 2 Preparation of (R)-2-isopropyl-3-[3-(5-methyl-2-p-tolyloxazol-4- ylmethoxy)-benzyl]thiazolidine-4-carboxylic acid
  • the procedure of Step 2 of Example 51 was repeated except for using the compound obtained in Step 1 of Example 52(0.284 g, 1.5 mmol), 4-(3-chloromethylphenoxymethyl)-5-methyl-2-/>-tolyloxazole(0.3 g, 0.92 mmol) and potassium carbonate(0.126 g, 0.915 mmol) to obtain the title compound(0.045 g, yield: 11%).
  • Step 1 of Example 51 The procedure of Step 1 of Example 51 was repeated except for using D-cysteine hydrochloride monohydrate(1.5 g, 8.54 mmol), potassium acetate(0.92 g,
  • Step 2 Preparation of (R)-3-[3-(5-methyl-2- j p-tolyloxazol-4-ylmethoxy)-benzyl]- 2-/>-tolyl-thiazolidine-4-carboxylic acid
  • Step 2 of Example 51 The procedure of Step 2 of Example 51 was repeated except for using the compound obtained in Step 1 of Example 53(0.3 g, 0.92 mmol) and potassium carbonate(0.126 g, 0.915 mmol) to obtain the title compound(0.071 g, yield: 11%).
  • Step 1 Preparation of (R)-2-(4-chlorophenyl)thiazolidine-4-carboxylic acid
  • Step 1 of Example 51 The procedure of Step 1 of Example 51 was repeated except for using D-cysteine hydrochloride monohydrate(2 g, 10.77 mmol), potassium acetate(1.057 g> 10.77 mmol) and 4-chlorobenzaldehyde(1.514 g, 10.77 mmol) to obtain the title compound(1.8 g, yield: 65%).
  • Step 2 Preparation of (R)-2-(4-chlorophenyl)-3-[3-(5-methyl-2-p-tolyloxazol-4- ylmethoxy)-benzyl] -thiazolidine-4-carboxylic acid
  • Step 2 of Example 51 The procedure of Step 2 of Example 51 was repeated except for using the compound obtained in Step 1 of Example 54(0.387 g, 1.5 mmol), 4-(3-chloromethylphenoxymethyl)-5-methyl-2- J p-tolyloxazole(0.3 g, 0.92 mmol) and potassium carbonate(0.126g, 0.915mmol) to obtain the title compound(0.11 g, yield: 23%).
  • Step 1 Preparation of (R)-2-(4-methoxyphenyl)thiazolidine-4-carboxylic acid
  • the procedure of Step 1 of Example 51 was repeated except for using D-cysteine hydrochloride monohydrate(1.4 g, 7.94 mmol), potassium acetate(0.857 g, 8.73 mmol) and 4-methoxybenzaldehyde(1.42 g, 10.45 mmol) to obtain the title compound(1.45 g, yield: 76%).
  • Step 2 Preparation of (R)-2-(4-methoxyphenyl)-3-[3-(5-methyl-2-jo-tolyloxazol-4- ylmethoxy)-benzyl]-thiazolidine-4-carboxylic acid
  • the procedure of Step 2 of Example 51 was repeated except for using the compound obtained in Step 1 of Example 55(0.36 g, 1.5 mmol), 4-(3-chloromethylphenoxymethyl)-5-methyl-2-/>-tolyloxazole(0.3 g, 0.92 mmol) and potassium carbonate(0.126 g, 0.915 mmol) to obtain the title compound(0.07 g, yield: 15%).
  • Step 1 Preparation of 2-[4-(5-methyl-2-j3-tolyloxazol-4-ylmethoxy)phenyl]ethanol 4-Chloromethyl-5-methyl-2-phenyloxazole(3.8 g, 17 mmol) and 4-hydroxyphenethyl alcohol(2 g, 14.5 mmol) were dissolved in acetone(50 ml), and potassium carbonate(3 g, 21.7 mmol) was added thereto. The resulting mixture was heated to reflux for 18 hrs. The reaction product was filtered and the filtrate was distilled under reduced pressure.
  • Step 2 Preparation of [4-(5-methyl-2-jc-tolyloxazol-4-ylmethoxy)phenyl] acetaldehyde
  • the compound obtained in Step 1 of Example 56(0.8 g, 2.4 mmol) was dissolved in ethyl acetate(20 ml), and IBX(o-Iodoxybenzoic acid; 2 g, 7.4 mmol) was added thereto. The resulting mixture was stirred at 80 °C for 4 hrs. After the completion of the reaction, the reactionproduct was filtered. The filtrate was distilled under reduced pressure to obtain the title compound(0.5 g, yield: 63%)
  • Step 3 Preparation of (R)-2-[4-methyl-2-p-tolyloxazol-4-ylmethoxy)benzyl] thiazolidine-4-carboxylic acid
  • Step 1 Preparation of 2-[4-(5-methyl-2-(4-trifluoromethylphenyl)oxazol-4- y lmethoxy)pheny 1] ethanol
  • Step 2 Preparation of [4-(5-methyl-2-(4-trifluoromethylphenyl)oxazol-4- ylmethoxy)phenyl] acetaldehyde
  • Step 2 of Example 56 The procedure of Step 2 of Example 56 was repeated except for using the compound obtained in Step 1 of Example 57(2 g, 5.29 mmol) and IBX(4.45 g, 15.8 mmol) to obtain the title compound(1.56 g, yield: 70%).
  • Step 3 Preparation of (R)-2- ⁇ 4-[5-methyl-2-(4-trifluoromethylphenyl)oxazol-4- ylmethoxy]benzyl ⁇ thiazolidine-4-carboxylic acid
  • Step 3 of Example 56 The procedure of Step 3 of Example 56 was repeated except for using the compound obtained in Step 2 of Example 57(0.285 g, 0.75 mmol) and L-cysteine(0.092 g, 0.75 mmol) to obtain the title compound(0.273 g, yield: 75%).
  • Step 1 Preparation of 2-[4-(5-methyl-2-phenyloxazol-4-ylmethoxy)phenyl]ethanol The procedure of Step 1 of Example 56 was repeated except for using
  • Step 2 Preparation of [4-(5-methyl-2-phenyloxazol-4-ylmethoxy)phenyl] acetaldehyde
  • the procedure of Step 2 of Example 56 was repeated except for using the compound obtained in Step 1 of Example 58(0.71 g, 2.3 mmol) and IBX(1.9 g, 6.87 mmol) to obtain the title compound(0.456 g 5 yield: 65%).
  • Step 3 Preparation of (R)-2-[4-(5-methyl-2-phenyloxazol-4-ylmethoxy)benzyl] thiazolidine-4-carboxylic acid
  • Step 3 of Example 56 The procedure of Step 3 of Example 56 was repeated except for using the compound obtained in Step 2 of Example 58(0.328 g, 1 mmol) and L-cysteine(0.13 g, 1 mmol) to obtain the title compound(0.25 g, yield: 57%).
  • Step 1 Preparation of 2-[4-(5-methyl-2-thiophen-2-yloxazol-4-ylmethoxy)phenyl] ethanol The procedure of Step 1 of Example 56 was repeated except for using
  • Step 2 Preparation of [4-(5-methyl-2-thiophen-2-yloxazol-4-ylmethoxy)phenyl] acetaldehyde
  • the procedure of Step 2 of Example 56 was repeated except for using the compound obtained in Step 1 of Example 59(0.6 g, 1.8 mmol) and IBX(15 g, 5.637 mmol) to obtain the title compound(0.26 g, yield: 44%).
  • Step 3 Preparation of (R)-2-[4-(5-methyl-2-thiophen-2-yloxazol-4-ylmethoxy) benzyl]thiazolidine-4-carboxylic acid
  • Step 3 of Example 56 The procedure of Step 3 of Example 56 was repeated except for using the compound obtained in Step 2 of Example 59(0.297 g, 0.94 mmol) and L-cysteine(0.115 g, 0.94 mmol) to obtain the title compound(0.18 g, yield: 45%).
  • Step 1 Preparation of (R)-3- ⁇ 2-[4-(5-methyl-2-/»-tolyloxazol-4-ylmethoxy)phenyl] ethyl ⁇ thiazolidine-4-carboxylic acid methyl ester
  • the procedure of Step 2 of Example 11 was repeated except for using the compound obtained in Step 2 of Example 56(0.15 g, 0.46 nimol), thiazolidine-4-carboxylic acid methyl ester hydrochloride(0.085 g, 0.46 mmol), triethylamine(0.117 g, 1.16 mmol) and sodium triacetoxyborohydride(0.15 g, 0.7 mmol) to obtain the title compound(0.16 g, yield: 76%).
  • Step 2 Preparation of (R)-3- ⁇ 2-[4-(5-methyl-2- ⁇ -tolyloxazol-4-ylmethoxy) ⁇ henyl] ethyl ⁇ thiazolidine-4-carboxylic acid
  • Step 3 of Example 11 The procedure of Step 3 of Example 11 was repeated except for using the compound obtained in Step 1 of Example 60(0.17 g, 0.37 mmol) and lithium hydroxide monohydrate(0.186 g, 0.44 mmol) to obtain the title compound(0.118 g, yield: 72%).
  • Step 1 Preparation of (R)-3-(2- ⁇ 4-[5-methyl-2-(4-trifluoromethyl ⁇ henyl)oxazol- 4-ylmethoxy]phenyl ⁇ ethyl)thiazolidine-4-carboxylic acid methyl ester
  • the procedure of Step 2 of Example 11 was repeated except for using the compound obtained in Step 2 of Example 58(0.284 g, 0.75 mmol), thiazolidine-4-carboxylic acid methyl ester hydrochloride(0.06 g, 0.32 mmol), triethylamine(0.4 g, 1.89 mmol) and sodium triacetoxyborohydride(0.301 g, 1.13 mmol) to obtain the title compound(0.231 g, yield: 60%).
  • Step 2 Preparation of (R)-3-(2- ⁇ 4-[5-methyl-2-(4-trifluoromethyl ⁇ henyl)oxazol-4- ylmethoxy]phenyl ⁇ ethyl)thiazolidine-4-carboxylic acid
  • Step 3 of Example 11 The procedure of Step 3 of Example 11 was repeated except for using the compound obtained in Step 1 of Example 61(0.117 g, 0.23 mmol) and lithium hydroxide monohydrate(0.01 g, 0.277 mmol) to obtain the title compound(0.08 g, yield: 70%).
  • Step 1 Preparation of (R)-3- ⁇ 2-[4-(5-methyl-2-phenyloxazol-4-ylmethoxy)phenyl] ethyl ⁇ thiazolidine-4-carboxylic acid methyl ester
  • Step 2 of Example 11 The procedure of Step 2 of Example 11 was repeated except for using the compound obtained in Step 2 of Example 57(0.1 g, 0.32 mmol), thiazolidine-4-carboxylic acid methyl ester hydrochloride(0.06 g, 0.32 mmol), triethylamine(0.082 g, 0.81 mmol) and sodium triacetoxyborohydride(0.103 g, 0.488 mmol) to obtain the title compound(0.097 g, yield: 68%).
  • Step 2 Preparation of (R)-3- ⁇ 2-[4-(5-methyl-2-phenyloxazol-4-ylmethoxy)phenyl] ethyl ⁇ thiazolidine-4-carboxylic acid
  • Step 3 of Example 11 The procedure of Step 3 of Example 11 was repeated except for using the compound obtained in Step 1 of Example 62(0.096 g, 0.22 mmol) and lithium hydroxide monohydrate(0.01 g, 0.264 mmol) to obtain the title compound(0.032 g, yield: 34%).
  • Step 1 Preparation of (R)-3- ⁇ 2-[4-(5-methyl-2-thiophen-2-yloxazol-4-ylmethoxy) phenyl]ethyl ⁇ thiazolidine-4-carboxylic acid methyl ester
  • the procedure of Step 2 of Example 11 was repeated except for using the compound obtained in Step 2 of Example 59(0.261 g, 0.83 mmol), thiazolidine-4-carboxylic acid methyl ester hydrochloride(0.06 g, 0.32 mmol), triethylamine(0.21 g, 2.08 mmol) and sodium triacetoxyborohydride(0.265 g, 1.25 mmol) to obtain the title compound(0.254 g, yield: 68%).
  • Step 2 Preparation of (R)-3- ⁇ 2-[4-(5-methyl-2-thiophen-2-yloxazol-4-ylmethoxy) phenyl]ethyl ⁇ thiazolidine-4-carboxylic acid
  • Step 3 of Example 11 The procedure of Step 3 of Example 11 was repeated except for using the compound obtained in Step 1 of Example 63(0.255 g, 0.575 mmol) and lithium hydroxide monohydrate(0.03 g, 0.7 mmol) to obtain the title compound(0.18 g, yield: 73%).
  • Step 1 Preparation of (3S)-4-[4-(5-methyl-2-phenyl-oxazol-4-yl-methoxy) benzyl]-morpholine-3-carboxylic acid methyl ester
  • Step 2 Preparation of (3S)-4-[4-(5-methyl-2-phenyl-oxazol-4-yl-methoxy)benzyl]- morpholine-3-carboxylic acid
  • Step 1 Preparation of (3S)-4-[3-(5-methyl-2-phenyl-oxazol-4-yl-methoxy)benzyl]- morpholine-3-carboxylic acid methyl ester
  • Step 2 Preparation of (3S)-4-[3-(5-methyl-2-phenyl-oxazol-4-yl-methoxy)benzyl]- morpholine-3 -carboxylic acid
  • the procedure of Step 2 of Example 64 was repeated except for using the compound obtained in Step 1 of Example 65(40.8 mg, 0.10 mmol) to obtain the title compound(35 mg, yield: 89%).
  • Step 1 Preparation of (3S)-4-[4-(5-methyl-2-(4-methylphenyl)-oxazol-4-yl- methoxy)benzyl]-morpholine-3-carboxylic acid methyl ester
  • Step 2 Preparation of (3S)-4-[4-(5-methyl-2-(4-methylphenyl)-oxazol-4-yl- methoxy)benzyl]-morpholine-3 -carboxylic acid
  • Step 2 of Example 64 was repeated except for using the compound obtained in Step 1 of Example 66(42 mg, 0.10 mmol) to obtain the title compound(24.6 mg, 60%).
  • Step 1 Preparation of (3S)-4-[3-(5-methyl-2-(4-methylphenyl)-oxazol-4-yl- methoxy)benzyl]-morpholine-3-carboxylic acid methyl ester
  • Step 1 of Example 64 The procedure of Step 1 of Example 64 was repeated except for using 4-(3-chloromethylphenoxymethyl)-5-methyl-2-(4-methylphenyl)-oxazole(34.5 mg, 0.10 mmol) and (3S)-morpholine carboxylic acid methyl ester(15.3 mg, 0.10 mmol) to obtain the title compound(31.3 mg, yield: 70%).
  • Step 2 Preparation of (3S)-4-[3-(5-methyl-2-(4-methyl ⁇ henyl)-oxazol-4-yl- methoxy)benzyl] -morpholine-3 -carboxylic acid
  • Step 2 of Example 64 The procedure of Step 2 of Example 64 was repeated except for using the compound obtained in Step 1 of Example 67(31.3 mg, 0.07 mmol) to obtain the title compound(20 mg, yield: 69%).
  • Step 1 Preparation of (3S)-4-[4-(5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl- methoxy)benzyl] -morpholine-3 -carboxylic acid methyl ester
  • the procedure of Step 1 of Example 64 was repeated except for using
  • Step 2 Preparation of (3S)-4-[4-(5-methyl-2-(4-trifluoromethylphenyl)-oxazol- 4-yl-methoxy)benzyl]-morpholine-3-carboxylic acid
  • the procedure of Step 2 of Example 64 was repeated except for using the compound obtained in Step 1 of Example 68(50 mg, 0.10 mmol) to obtain the title compound(35 mg, yield: 74%).
  • Step 1 Preparation of (3S)-4-[3-(5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl- methoxy)benzyl]-morpholine-3-carboxylic acid methyl ester
  • Step 2 of Example 64 was repeated except for using the compound obtained in Step 1 of Example 69(32.2 mg, 0.07 mmol) to obtain the title compound(25.3 mg, yield: 82%).
  • Step 1 Preparation of (3S)-4-[4-(5-methyl-2-(2-thiophene)-oxazol-4-yl-methoxy) benzylj-morpholine-S-carboxylic acid methyl ester
  • Step 2 Preparation of (3S)-4-[4-(5-methyl-2-(2-thiophene)-oxazol-4-yl-methoxy) benzyl]-morpholine-3-carboxylic acid
  • Step 2 of Example 64 The procedure of Step 2 of Example 64 was repeated except for using the compound obtained in Step 1 of Example 70(50 mg, 0.12 mmol) to obtain the title compound(28 mg, yield: 62%).
  • Step 1 Preparation of (3S)-4-[3-(5-methyl-2-(2-thiophene)-oxazol-4-yl-methoxy) benzyl]-morpholine-3-carboxylic acid methyl ester
  • the procedure of Step 1 of Example 64 was repeated except for using
  • Step 2 Preparation of (3S)-4-[3-(5-methyl-2-(2-thiophene)-oxazol-4-yl-methoxy) benzyl]-morpholine-3-carboxylic acid
  • Step 2 of Example 64 The procedure of Step 2 of Example 64 was repeated except for using the compound obtained in Step 1 of Example 71(22 mg, 0.05 mmol) to obtain the title compound(13 mg, yield: 62%).
  • Step 1 Preparation of 4-[4-(5-methyl-2-phenyl-oxazol-4-yl-methoxy)benzyl]- 3-thiomorpholinecarboxylic acid ethyl ester
  • Step 2 Preparation of 4-[4-(5-methyl-2-phenyl-oxazol-4-yl-methoxy)benzyl]- 3-thiomorpholinecarboxylic acid
  • Step 1 Preparation of 4-[3-(5-methyl-2-phenyl-oxazol-4-yl-methoxy)benzyl]-3- thiomorpholinecarboxylic acid ethyl ester
  • Step 1 of Example 72 The procedure of Step 1 of Example 72 was repeated except for using 4-(3-chloromethylphenoxymethyl)-5-methyl-2-phenyl-oxazole(50 mg, 0.16 mmol) and 3-thiomorpholine carboxylic acid ethyl ester(27.9 mg, 0.16 mmol) to obtain the title compound(43 mg, yield: 60%).
  • Step 2 Preparation of 4-[3-(5-methyl-2-phenyl-oxazol-4-yl-methoxy)benzyl]-3- thiomorpholinecarboxylic acid
  • the procedure of Step 2 of Example 72 was repeated except for using the compound obtained in Step 1 of Example 73(40 mg, 0.09 mmol) to obtain the title compound(34 mg, yield: 89%).
  • Step 1 Preparation of 4-[4-(5-methyl-2-(4-methylphenyl)-oxazol-4-yl-methoxy) benzyl] -3 -thiomorpholinecarboxylic acid ethyl ester
  • Step 1 of Example 72 The procedure of Step 1 of Example 72 was repeated except for using 4-(4-chloromethylphenoxymethyl)-5-methyl-2-(4-methylphenyl)-oxazole(83.4 mg, 0.25 mmol) and 3-thiomorpholine carboxylic acid ethyl ester(44.6 mg, 0.25 mmol) to obtain the title compound(82 mg, yield: 71%).
  • Step 2 Preparation of 4-[4-(5-methyl-2-(4-methylphenyl)-oxazol-4-yl-methoxy) benzyl]-3-thiomorpholinecarboxylic acid
  • Step 2 of Example 72 was repeated except for using the compound obtained in Step 1 of Example 74(42 mg, 0.09 mmol) to obtain the title compound(9 mg, yield: 23%).
  • Step 1 Preparation of 4-[3-(5-methyl-2-(4-methylphenyl)-oxazol-4-yl-methoxy) benzyl]-3-thiomorpholinecarboxylic acid ethyl ester
  • Step 2 Preparation of 4-[3-(5-methyl-2-(4-methylphenyl)-oxazol-4-yl-methoxy) benzyl] -3 -thiomorpholinecarboxylic acid
  • Step 2 of Example 72 was repeated except for using the compound obtained in Step 1 of Example 75(64.5 mg, 0.14 mmol) to obtain the title compound(10 mg, yield: 17%).
  • 1 H NMR(200MHz, CDCl 3 ): ⁇ (ppm) 7.89(d, 2H 5 J 8.2Hz) 3 7.32-7.19(m, 3H), 7.03(s, IH), 7.03-6.88(m, 2H), 4.97(s, 2H), 3.97-3.71(m, IH), 3.60-3.58(m, 2H), 3.32(m, IH), 2.97-2.67(m, 3H), 2.58-2.53(m, 2H), 2.44(s, 3H), 2.39(s, 3H).
  • Step 1 Preparation of 4-[4-(5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl- methoxy)benzyl]-3-thiomorpholinecarboxylic acid ethyl ester
  • the procedure of Step 1 of Example 72 was repeated except for using
  • Step 2 Preparation of 4-[4-(5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl -methoxy)benzyl]-3-thiomorpholinecarboxylic acid
  • Step 2 of Example 72 was repeated except for using the compound obtained in Step 1 of Example 76(27 mg, 0.05 mmol) to obtain the title compound(18.3 mg, yield: 74%).
  • Step 1 Preparation of 4-[3-(5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl- methoxy)benzyl]-3-thiomorpholinecarboxylic acid ethyl ester
  • the procedure of Step 1 of Example 72 was repeated except for using 4-(3-chloromethylphenoxymethyl)-5-methyl-2-(4-trifluoromethylphenyl)-oxazole(7 6.3 mg, 0.20 mmol) and 3-thiomorpholine carboxylic acid ethyl ester(35 mg, 0.20 mmol) to obtain the title compound(31 mg, yield: 30%).
  • Step 2 Preparation of 4-[3-(5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl- methoxy)benzyl]-3-thiornorpholinecarboxylic acid
  • Step 2 of Example 72 was repeated except for using the compound obtained in Step 1 of Example 77(31 mg, 0.059 mmol) to obtain the title compound(17 mg, yield: 58%).
  • Step 1 Preparation of 4-[4-(5-methyl-2-(2-thiophene)-oxazol-4-yl-methoxy) benzyl] -3 -thiomorpholinecarboxylic acid ethyl ester
  • the procedure of Step 1 of Example 72 was repeated except for using
  • Step 2 Preparation of 4-[4-(5-methyl-2-(2-thiophene)-oxazol-4-yl-methoxy)benzyl]- 3 -thiomorpholinecarboxylic acid
  • Step 2 of Example 72 was repeated except for using the compound obtained in Step 1 of Example 78(40 mg, 0.09 mmol) to obtain the title compound(22.6 mg, yield: 60%).
  • Step 1 Preparation of 4-[3-(5-methyl-2-(2-thiophene)-oxazol-4-yl-methoxy) benzyl] -3 -thiomorpholinecarboxy lie acid ethyl ester
  • Step 1 of Example 72 The procedure of Step 1 of Example 72 was repeated except for using 4-(3-chloromethylphenoxymethyl)-5-methyl-2-(2-thiophene)-oxazole(l 11 mg, 0.35 mmol)and 3-thiomorpholine carboxylic acid ethyl ester(61 mg, 0.35 mmol) to obtain the title compound(86 mg, yield: 54%).
  • Step 2 Preparation of 4-[3-(5-methyl-2-(2-thiophene)-oxazol-4-yl-methoxy) benzyl]-3-thiomorpholinecarboxylic acid
  • Step 2 of Example 72 was repeated except for using the compound obtained in Step 1 of Example 79(80 mg, 0.17 mmol) to obtain the title compound(61.2 mg, yield: 82%).
  • Step 1 Preparation of (3S)-4-[4-(5-methyl-2-phenyl-oxazol-4-yl-ethoxy)benzyl]- morpholine-3-carboxylic acid methyl ester
  • Step 2 Preparation of (3S)-4-[4-(5-methyl-2-phenyl-oxazol-4-yl-ethoxy)benzyl]- morpholine-3 -carboxylic acid
  • Step 1 Preparation of (3S)-4-[3-(5-methyl-2-phenyl-oxazol-4-yl-ethoxy)benzyl]- morpholine-3-carboxylic acid methyl ester
  • Step 1 of Example 64 The procedure of Step 1 of Example 64 was repeated except for using 4-(3-chloromethylphenoxyethyl)-5-methyl-2-phenyl-oxazole(35 mg, 0.11 mmol) and (3S)-morpholine carboxylic acid methyl ester(15.5 mg, 0.11 mmol) to obtain the title compound(43 mg, yield: 89%).
  • Step 2 Preparation of (3S)-4-[3-(5-methyl-2-phenyl-oxazol-4-yl-ethoxy)benzyl]- morpholine-3-carboxylic acid
  • Step 2 of Example 64 The procedure of Step 2 of Example 64 was repeated except for using the compound obtained in Step 1 of Example 81(40 mg, 0.09 mmol) to obtain the title compound(34.7 mg, yield: 89%).
  • Step 1 Preparation of (3S)-4-[4-(5-methyl-2-(4-methylphenyl)-oxazol-4-yl-ethoxy) benzyl]-morpholine-3-carboxylic acid methyl ester
  • the procedure of Step 1 of Example 64 was repeated except for using

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Abstract

The present invention relates to a novel heterocyclic carboxylic acid derivative, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising the same as an active ingredient for inhibiting the accumulation of lipids in the body.

Description

HETEROCYCLIC CARBOXYLIC ACID DERIVATIVES AND
PHARMACEUTICAL COMPOSITION FOR INHIBITING LIPID
ACCUMULATION CONTAINING SAME
FIELD OF THE INVENTION
The present invention relates to a novel heterocyclic carboxylic acid derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the same as an active ingredient for inhibiting the lipid accumulation in the body.
BACKGROUND OF THE INVENTION
PPARs(peroxisome proliferating-activated receptors) which belong to the family of nuclear receptors are hormones that control the lipid level in the cell. PPARs consist of 2nd zinc finger binding domain and a hydrophobic ligand binding pocket, and are divided into three subtypes, "PPARα," "PPARγ" and "PPARδ." Among them, PPARα, which is expressed in the muscle, heart, kidney, and particularly in the liver at a high level, controls the degradation of fatty acids.
Studies using PPARα null mice have revealed that PPARα is involved in the beta oxidation of long chain fatty acids such as palmitic acid present in mitochondria. Also, OEA(oleylethanolamide) which is effective in reducing the weight of normal mice, does not affect the weight of PPARα null mice, suggesting that PPARα is a target of OEA which controls the appetite and body weight.
In addition, the activation of PPARα lowers the expression of apolipoprotein C-III which is known to inhibit the hydrolysis of TGs(triglycerides) by LDL(low density lipoprotein), leading to the degradation of VLDL(very low density lipoprotein) and lowering of the lipid content in the body. Moreover, it is known that the activation of PPARα prevents arteriosclerosis by inhibiting the expression of VCAM(vascular cell adhesion molecule)- 1 to prevent arteriosclerosis, IL-linterleukin-l(interleukin-l)-induced secretion of IL-6(interleukin-6), or the production of prostaglandin in vascular smooth muscles.
Compounds which have been previously found to promote the activity of PPARα include Wy-14643, clofibrate, fenofibrate, bezafibrate, GW2331, SW9578 and BM17.0744(Willson et al, J. Med. Chem., 43, 527-550, 2000). These agonists of PP ARa bring about increased insulin sensitivity in mouse models by way of reducing the blood levels of TGs as well as suppressing the adiposity and steatosis of the liver or muscle(Chou et al, JBC, 277, 24484-24489, 2002; Kim et al, Diabetes, 52, 1770-1778, 2003; Peters et al, MoI. Cell. Biol, 20, 5119-5128, 2000). It has been reported the fibrate agonists such as fenofibrate and gemfibrozil reduce the blood levels of TGs and elevates the HDL level in hyperlipidemia patients(Lee et al, Endocrinology, 144, 2201-2207, 2003), but the administration thereof requires a large daily dosage(300 to 1,200 mg/day). Therefore, there exists a need to develop a more effective PPARα agonist having excellent selectivity toward PP ARa.
SUMMARY OF THE INVENTION
Accordingly, it is an object of the present invention to provide a novel heterocyclic carboxylic acid derivative, or a pharmaceutically acceptable salt thereof for inhibiting the accumulation of lipids in the body, and a process for preparing the same.
It is another object of the present invention to provide a pharmaceutical composition for inhibiting the accumulation of lipids in the body comprising the heterocyclic carboxylic acid derivative or a pharmaceutically acceptable salt thereof.
In accordance with one aspect of the present invention, there is provided a heterocyclic carboxylic acid derivative of formula (1):
Figure imgf000003_0001
wherein, ring A is a 4 to 6-membered heterocycle comprising 1 or 2 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur;
R1 is a heterocyclic moiety selected from
Figure imgf000003_0002
, ? an(j
Ra b>et- , in which Ra is phenyl; phenyl substituted with halogen, C1-C4 haloalkyl, or Ci-C3 alkoxy; or thiophenyl; Rb is H or Cχ-C4 alkyl; Het is an oxazole or isoxazole moiety optionally substituted with Ci-C4 alkyl;
R2 and R3 are each independently H, CrC4 alkyl, or phenyl substituted with halogen, Ci-C4 alkyl, or Ci-C3 alkoxy; X is H or Ci-C4 alkyl; m is 0, 1 or 2; and n is 1 or 2.
In accordance with another aspect of the present invention, there is provided a pharmaceutical composition for inhibiting the accumulation of lipids in the body comprising the heterocyclic carboxylic acid derivative, or a pharmaceutically acceptable salt thereof, as an active ingredient.
DETAILED DESCRIPTION OF THE INVENTION
The heterocyclic carboxylic acid derivative of the present invention may contain a chiral carbon, and therefore, it may be in the form of a racemate, or stereoisomers thereof.
The heterocyclic carboxylic acid derivative of the present invention may also be used in the form of a pharmaceutically acceptable salt thereof. The pharmaceutically acceptable salt may be a salt formed with an inorganic or organic base. Examples of said inorganic base include alkali metal and alkaline earth metal hydroxides, and examples of the organic base include ammonium hydroxide, organic amines such as methylamine, ethylamine and pyridine, guanidine, and arginine. Preferred examples of the compounds of formula (1) according to the present invention are the compounds wherein ring A has a thiazolidine, azetidine, pyrrolidine, piperidine, morpholine or thiomorpholine structure.
More preferred examples of the compounds of formula (1) according to the present invention are: (R)-2-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenyl}thiazolidine-4- carboxylic acid;
(R)-2-{4-[2-(benzoxazol-2-yl-methylamino)-ethoxy]-phenyl}-thiazolidine-4- carboxylic acid;
(R)-2- { 4- [2-(methyl-pyridin-2-yl-methylamino)-ethoxy] -phenyl } - thiazolidine-4-carboxylic acid;
(R)-2-{4-[2-(5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl)ethoxy] phenyl}thiazolidine-4-carboxylic acid;
(R)-2-{4-[2-(5-methyl-2-thioρhen-2-yloxazol-4-yl)ethoxy]ρhenyl} thiazolidine-4-carboxylic acid;
(R)-2-{4-[2-(5-methyl-2-p-tolyloxazol-4-yl)ethoxy]phenyl}thiazolidine-4- carboxylic acid;
(R)-2-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenyl}thiazolidine-4- carboxylic acid;
(R)-2-{4-[2-(5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl)ethoxy] phenyl}thiazolidine-4-carboxylic acid;
(R)-2-{4-[2-(5-methyl-2-thiophen-2-yloxazol-4-yl)ethoxy]ρhenyl} thiazolidine-4-carboxylic acid; (R)-2-{3-[2-(5-methyl-2:p-tolyl-oxazol-4-yl)-ethoxy]-phenyl}-thiazolidine-
4-carboxylic acid;
(R)-3-(3-{2-[5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl]-ethoxy}- benzyl)-thiazolidine-4-carboxylic acid;
(R)-3-(4-{2-[5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl]-ethoxy}- benzyl)-thiazolidine-4-carboxylic acid;
3 -(4- {2- [5 -methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl] -ethoxy } - benzyl)-thiazolidine-2-carboxylic acid;
(R)-3-[3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzyl]-thiazolidine-4- carboxylic acid; (R)-3-[3-(5-methyl-2-/?-tolyl-oxazol-4-ylmethoxy)-benzyl]-thiazolidine-4- carboxylic acid;
(R)-3 - [3 -(2-biphenyl-4-yl-5 -methy l-oxazol-4-y lmethoxy)-benzyl] - thiazolidine-4-carboxylic acid;
(R)-3-[3-(5-methyl-2-thiophen-2-yl-oxazol-4-ylmethoxy)-benzyl]- thiazolidine-4-carboxylic acid;
(R)-3 - { 3 - [5-methyl-2-(4-trifluoromethylpheny l)-oxazol-4-ylmethoxy] - benzyl} -thiazolidine-4-carboxylic acid;
(R)-3-{3-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-benzyl}- thiazolidine-4- carboxylic acid; 3 -[4-(5 -Methyl-2-pheny l-oxazol-4-y lmethoxy)-benzyl]-thiazolidine-2- carboxylic acid;
3-[4-(5-Methyl-2-/>-tolyl-oxazol-4-ylmethoxy)-benzyl]-thiazolidine-2- carboxylic acid;
3-[4-(2-Biphenyl-4-yl-5-methyl-oxazol-4-ylmethoxy)-benzyl]-thiazolidine-2- carboxylic acid;
3-[4-(5-Methyl-2-thiophen-2-yl-oxazol-4-ylmethoxy)-benzyl]-thiazolidine-2- carboxylic acid;
3 - [4-(5 -Methyl-2-(4-trifluoromethylpheny l)-oxazol-4-ylmethoxy)-benzyl] - thiazolidine-2-carboxylic acid; 3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-benzyl}- thiazolidine-2-carboxylic acid;
3-{4-[2-(5-Methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]-benzyl}- thiazolidine-2-carboxylic acid;
3-[3-(5-Methyl-2-phenyl-oxazol-4-ylmethoxy)-benzyl]-thiazolidine-2- carboxylic acid;
3-[3-(5-Methyl-2-thiophen-2-yl-oxazol-4-ylmethoxy)-benzyl]-thiazolidine-2- carboxylic acid;
3 - [3 -(5 -Methyl-2-(4-trifluoromethylphenyl)-oxazol-4-ylmethoxy)-benzy 1] - thiazolidine-4-carboxylic acid; 3-{3-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzyl}-thiazolidine-2- carboxylic acid;
3-{3-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-benzyl}- thiazolidine-2-carboxylic acid;
3-(3-{2-[5-Methyl-2-(4-trifluoromethylρhenyl)-oxazol-4-yl]-ethoxy}-benzyl) -thiazolidine-2-carboxylic acid;
(R)-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzyl]-thiazolidine-4- carboxylic acid;
(R)-3-[4-(5-methyl-2-p-tolyl-oxazol-4-ylmethoxy)-benzyl]-thiazolidine-4- carboxylic acid; (R)-3-[4-(2-biphenyl-4-yl-5-methyl-oxazol-4-ylmethoxy)-benzyl]- thiazolidine-4-carboxylic acid;
(R)-3-[4-(5-methyl-2-thiophen-2-yl-oxazol-4-ylmethoxy)-benzyl]- thiazolidine-4-carboxylic acid;
(R)-3-[4-(5-methyl-2-(4-trifluoromethyl-phenyl-oxazol-4-ylmethoxy)- benzyl]-thiazolidine-4-carboxylic acid;
(R)-3-{4-[2-(5-methyl-2-ρhenyl-4-yl-oxazol-4-yl)-ethoxy]-benzyl}- thiazolidine-4-carboxylic acid;
(R)-3-{4-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-benzyl}- thiazolidine-4-carboxylic acid; (R)-3 - { 4- [2-(5-methyl-2-thioρhen-2-yl-oxazol-4-yl)-ethoxy] -benzyl } - thiazolidine-4-carboxylic acid;
(S)-3-[3-(5-methyl-2-/?-tolyl-oxazol-4-ylmethoxy)benzyl]thiazolidine-4- carboxylic acid;
(S)-3-[4-(5-methyl-2-p-tolyl-oxazol-4-ylmethoxy)benzyl]thiazolidine-4- carboxylic acid;
(R)-3-[4-(3-p-tolylisoxazol-5-ylmethoxy)benzyl]thiazolidine-4-carboxylic acid;
(R)-3-[4-(3-phenylisoxazol-5-ylmethoxy)benzyl]thiazolidine-4-carboxylic acid; (R)-3-{4-[3-(4-chlorophenyl)isoxazol-5-ylmethoxy]benzyl}thiazolidine-4- carboxylic acid;
(R)-3 - { 4- [3 -(4-trifluoromethylphenyl)isoxazol-5-ylmethoxy]benzyl } thiazolidine-4-carboxylic acid;
(R)-3-[4-(3-/?-tolylisoxazol-5-ylmethoxy)benzyl]thiazolidine-4-carboxylic acid;
(R)-3-[3-(3-phenylisoxazol-5-ylmethoxy)benzyl]thiazolidine-4-carboxylic acid;
(R)-3 - { 3 - [3 -(4-chlorophenyl)isoxazol- 5-ylmethoxy]benzyl } -thiazolidine-4- carboxylic acid; (R)-3-{3-[3-(4-trifluoromethylphenyl)isoxazol-5-ylmethoxy]benzyl} thiazolidine-4-carboxylic acid;
(R)-2-methyl-3-{3-[5-methyl-2-(4-trifluoromethylρhenyl)oxazol-4- ylmethoxy]-benzyl}-thiazolidine-4-carboxylic acid;
(R)-2-isopropyl-3-[3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)-benzyl] thiazolidine-4-carboxylic acid;
(R)-3-[3-(5-methyl-2-/7-tolyloxazol-4-ylmethoxy)-benzyl]-2-p-tolyl- thiazolidine-4-carboxylic acid;
(R)-2-(4-chlorophenyl)-3-[3-(5-methyl-2-/»-tolyloxazol-4-ylmethoxy)- benzyl]-thiazolidine-4-carboxylic acid; (R)-2-(4-methoxyphenyl)-3-[3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)- benzyl] -thiazolidine-4-carboxylic acid;
(R)-2-[4-methyl-2-p-tolyloxazol-4-ylmethoxy)benzyl]thiazolidine-4- carboxylic acid;
(R)-2-{4-[5-methyl-2-(4-trifluoromethylphenyl)oxazol-4-ylmethoxy]benzyl} thiazolidine-4-carboxylic acid;
(R)-2-[4-(5-methyl-2-phenyloxazol-4-ylmethoxy)benzyl]thiazolidine-4- carboxylic acid;
(R)-2-[4-(5-methyl-2-thiophen-2-yloxazol-4-ylmethoxy)benzyl] thiazolidine-4-carboxylic acid; (R)-3-{2-[4-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)phenyl]ethyl} thiazolidine-4-carboxylic acid;
(R)-3-(2-{4-[5-methyl-2-(4-trifluoromethylphenyl)oxazol-4-ylmethoxy] phenyl} ethyl)thiazolidine-4-carboxylic acid;
(R)-3-{2-[4-(5-methyl-2-phenyloxazol-4-ylmethoxy)phenyl]ethyl} thiazolidine-4-carboxylic acid;
(R)-3-{2-[4-(5-methyl-2-thiophen-2-yloxazol-4-ylmethoxy)phenyl]ethyl} thiazolidine-4-carboxylic acid;
(3S)-4-[4-(5-methyl-2-phenyl-oxazol-4-yl-methoxy)benzyl]-morpholine-3- carboxylic acid; (3S)-4-[3-(5-methyl-2-phenyl-oxazol-4-yl-methoxy)benzyl]-morpholine-3- carboxylic acid;
(3S)-4-[4-(5-methyl-2-(4-methylphenyl)-oxazol-4-yl-methoxy)benzyl]- morpholine-3-carboxylic acid;
(3S)-4-[3-(5-methyl-2-(4-methylphenyl)-oxazol-4-yl-methoxy)benzyl]- morpholine-3 -carboxylic acid;
(3S)-4-[4-(5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl-methoxy) benzyl]-morpholine-3-carboxylic acid;
(3S)-4-[3-(5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl-methoxy) benzyl] -morpholine-3 -carboxylic acid; (3 S)-4-[4-(5-methyl-2-(2-thiophene)-oxazol-4-yl-methoxy)benzyl]- morpholine-3 -carboxylic acid;
(3S)-4-[3-(5-methyl-2-(2-thiophene)-oxazol-4-yl-methoxy)benzyl]- morpholine-3 -carboxylic acid;
4- [4-(5 -Methyl-2-phenyl-oxazol-4-yl-methoxy)benzyl] -morpholine-3 - carboxylic acid;
4-[3-(5-Methyl-2-phenyl-oxazol-4-yl-methoxy)benzyl]-morpholine-3- carboxylic acid;
4-[4-(5-Methyl-2-(4-methylphenyl)-oxazol-4-yl-methoxy)benzyl]- morpholine-3-carboxylic acid; 4-[3-(5-Methyl-2-(4-methylphenyl)-oxazol-4-yl-methoxy)benzyl]- morpholine-3-carboxylic acid;
4-[4-(5-Methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl-methoxy)benzyl]- morpholine-3 -carboxylic acid;
4-[3-(5-Methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl-methoxy)benzyl]- morpholine-3 -carboxylic acid;
4-[4-(5-Methyl-2-(2-thiophene)-oxazol-4-yl-methoxy)benzyl]-morpholine-3- carboxylic acid;
4-[3-(5-Methyl-2-(2-thiophene)-oxazol-4-yl-methoxy)benzyl]-morpholine-3- carboxylic acid; (3S)-4-[4-(5-methyl-2-phenyl-oxazol-4-yl-ethoxy)benzyl]-morpholine-3- carboxylic acid;
(3S)-4-[3-(5-methyl-2-phenyl-oxazol-4-yl-ethoxy)benzyl]-morpholine-3- carboxylic acid;
(3S)-4-[4-(5-methyl-2-(4-methylphenyl)-oxazol-4-yl-ethoxy) benzyl]-morpholine-3-carboxylic acid;
(3S)-4-[3-(5-methyl-2-(4-methylρhenyl)-oxazol-4-yl-ethoxy) benzyl]-morpholine-3-carboxylic acid;
(3S)-4-[4-(5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl-ethoxy) benzyl]-morpholine-3-carboxylic acid; (3S)-4-[3-(5-methyl-2-(4-trifluoromethylρhenyl)-oxazol-4-yl-ethoxy) benzyl]-morpholine-3-carboxylic acid;
(3S)-4-[4-(5-methyl-2-(2-thiophene)-oxazol-4-yl-ethoxy) benzyl]-morpholine-3 -carboxylic acid;
(3S)-4-[3-(5-methyl-2-(2-thiophene)-oxazol-4-yl-ethoxy) benzyl] -morpholine-3 -carboxylic acid;
4-[4-(5-Methyl-2-phenyl-oxazol-4-yl-ethoxy)benzyl]-morpholine-3- carboxylic acid;
4-[3-(5-Methyl-2-phenyl-oxazol-4-yl-ethoxy)benzyl]-morpholine-3- carboxylic acid; 4-[4-(5-Methyl-2-(4-methylphenyl)-oxazol-4-yl-ethoxy)benzyl]- morpholine-3 -carboxylic acid;
4-[3-(5-Methyl-2-(4-methylphenyl)-oxazol-4-yl-ethoxy)benzyl]- morpholine-3 -carboxylic acid;
4-[4-(5-Methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl-ethoxy) benzyl]-morpholine-3-carboxylic acid;
4-[3-(5-Methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl-ethoxy) benzyl]-morpholine-3-carboxylic acid;
4-[4-(5-Methyl-2-(2-thiophene)-oxazol-4-yl-ethoxy)benzyl]-morpholine-3- carboxylic acid; 4-[3-(5-Methyl-2-(2-thiophene)-oxazol-4-yl-ethoxy)benzyl]-morpholine-3- carboxylic acid;
(R)- 1 - [3 - [(5 -methyl-2-p-tolyloxazol-4-yl)methoxy]benzyl] azetidine-2- carboxylic acid;
(R)-l-[3-[[5-methyl-2-(4-trifluoromethylphenyl)oxazol-4-yl]methoxy] benzyl]azetidine-2-carboxylic acid methyl ester;
(R)- 1 - [3 - [2-(5 -methyl-2-/?-tolyloxazol-4-yl)ethoxy]benzyl] azetidine-2- carboxylic acid;
(R)- 1 - [3 - [2- [5-methyl-2-(4-trifluoromethylphenyl)oxazol-4-yl] ethoxy] benzyl] azetidine-2-carboxylic acid; (R)-I- [4- [(5 -methyl-2-pheny loxazol-4-yl)methoxy]benzyl] azetidine-2- carboxylic acid;
(R)-l-[4-[(5-methyl-2-j!7-tolyloxazol-4-yl)methoxy]benzyl]azetidine-2- carboxylic acid methyl ester;
(R)-l-[4-[[5-methyl-2-(4-trifluoromethylphenyl)oxazol-4-yl]methoxy] benzyl] azetidine-2-carboxylic acid methyl ester;
(R)-l-[4-[2-(5-methyl-2-p-tolyloxazol-4-yl)ethoxy]benzyl]azetidine-2- carboxylic acid methyl ester;
(R)-I- [4- [2- [5-methyl-2-(4-trifluoromethylpheny l)oxazol-4-yl] ethoxy] benzyl] azetidine-2-carboxylic acid; (R)- 1 - [3 - [(5 -methyl-2-phenyloxazol-4-yl)methoxy]benzyl]pyrrolidine-2- carboxylic acid;
(R)- 1 - [3 - [(5 -methyl-2-^>-tolyloxazol-4-yl)methoxy]benzyl]pyrrolidine-2- carboxylic acid;
(R)-I- [3 - [[5 -methyl-2-(4-trifluoromethylphenyl)oxazol-4-yl]methoxy] benzyl]pyrrolidine-2-carboxylic acid;
(R)-l-[3-[[5-methyl-2-(thiophen-2-yl)oxazol-4-yl]methoxy]benzyl] pyrrolidine-2-carboxylic acid;
(R)-2-[3-[[4-methyl-2-(4-trifluoromethylphenyl)oxazol-5-yl]methoxy] benzyljpyrrolidin- 1 -carboxylic acid; 2-Methyl- 1 - [3 - [(5 -methyl-2-phenyloxazol-4-yl)methoxy]benzyl]pyrrolidine-
2-carboxylic acid methyl ester;
2-Methyl-l-[3-[(5-methyl-2-p-tolyloxazol-4-yl)methoxy]benzyl]pyrrolidine- 2-carboxylic acid methyl ester;
2-Methyl- 1 - [3 - [ [5-methyl-2-(4-trifluoromethy lphenyl)oxazol-4-yl]methoxy] benzyl]pyrrolidine-2-carboxylic acid methyl ester;
2-Methyl-l-[3-[[5-methyl-2-(thiophen-2-yl)oxazol-4-yl]methoxy]benzyl] pyrrolidine-2-carboxylic acid methyl ester;
2-Ethyl-l-[3-[(5-methyl-2-phenyloxazol-4-yl)methoxy]benzyl]pyrrolidine-2- carboxylic acid methyl ester; 2-Ethyl- 1 - [3 - [(5 -methy l-2-/»-tolyloxazol-4-yl)methoxy]benzyl]ρyrrolidine-2- carboxylic acid methyl ester;
2-Ethyl-l-[3-[[5-methyl-2-(4-trifluoromethylphenyl)oxazol-4-yl]methoxy] benzyl]pyrrolidine-2-carboxylic acid methyl ester;
2-Ethyl-l-[3-[[5-methyl-2-(thioρhen-2-yl)oxazol-4-yl]methoxy]benzyl] pyrrolidine-2-carboxylic acid methyl ester;
(R)-l-[4-[(5-methyl-2:p-tolyloxazol-4-yl)methoxy]benzyl]pyrrolidine-2- carboxylic acid methyl ester;
2-Methyl-l-[4-[(5-methyl-2-phenyloxazol-4-yl)methoxy]benzyl]pyrrolidine- 2-carboxylic acid methyl ester; 2-Methyl- 1 -[4-[(5-methyl-2-/?-tolyloxazol-4-yl)methoxy]benzyl]pyrrolidine-
2-carboxylic acid methyl ester;
2-Methyl-l-[4-[[5-methyl-2-(4-trifluoromethylphenyl)oxazol-4-yl]methoxy] benzyl]pyrrolidine-2-carboxylic acid methyl ester;
2-Methyl-l-[4-[[5-methyl-2-(thiophen-2-yl)oxazol-4-yl]methoxy]benzyl] pyrrolidine-2-carboxylic acid methyl ester;
2-Ethyl-l-[4-[(5-methyl-2-/>-tolyloxazol-4-yl)methoxy]benzyl]pyrrolidine-2- carboxylic acid methyl ester;
2-Ethyl-l-[4-[[5-methyl-2-(4-trifluoromethylphenyl)oxazol-4-yl]methoxy] benzyl]pyrrolidine-2-carboxylic acid methyl ester; 2-Ethyl- 1 -[4-[[5-methyl-2-(thiophen-2-yl)oxazol-4-yl]methoxy]benzyl] pyrrolidine-2-carboxylic acid methyl ester;
2-Methyl-l-[3-[2-(5-methyl-2-jo-tolyloxazol-4-yl)ethoxy]benzyl]pyrrolidine- 2-carboxylic acid methyl ester;
2-Methyl-l-[3-[2-[5-methyl-2-(thiophen-2-yl)oxazol-4-yl]ethoxy]benzyl] pyrrolidine-2-carboxylic acid methyl ester;
2-Ethyl-l-[3-[2-(5-methyl-2-j9-tolyloxazol-4-yl)ethoxy]benzyl]pyrrolidine-2- carboxylic acid methyl ester;
2-Ethyl-l-[3-[2-[5-methyl-2-(thiophen-2-yl)oxazol-4-yl]ethoxy]benzyl] pyrrolidine-2-carboxylic acid methyl ester; 2-Ethyl- 1 -[4-[2-(5-methyl-2-jp-tolyloxazol-4-yl)ethoxy]benzyl]ρyrrolidine-2- carboxylic acid methyl ester;
2-Methyl-l-[4-[2-[5-methyl-2-(thiophen-2-yl)oxazol-4-yl]ethoxy]benzyl] pyrrolidine-2-carboxylic acid methyl ester;
2-Ethyl-l-[4-[2-(5-methyl-2-/?-tolyloxazol-4-yl)ethoxy]benzyl]pyrrolidine-2- carboxylic acid methyl ester;
2-Ethyl- 1 - [4- [2- [5 -methyl-2-(4-trifluoromethylphenyl)oxazol-4-yl] ethoxy] benzyl]pyrrolidine-2-carboxylic acid methyl ester;
2-Ethyl-l-[4-[2-[5-methyl-2-(thiophen-2-yl)oxazol-4-yl]ethoxy]benzyl] pyrrolidine-2-carboxylic acid methyl ester; (R)-l-[3-[(5-methyl-2-phenyloxazol-4-yl)methoxy]benzyl]piperidine-2- carboxylic acid;
(R)-l-[3-[(5-methyl-2-p-tolyloxazol-4-yl)methoxy]benzyl]piperidine-2- carboxylic acid methyl ester methyl ester;
(R)-l-[3-[[5-methyl-2-(4-trifluoromethylphenyl)oxazol-4-yl]methoxy] benzyl]piperidine-2-carboxylic acid;
(R)-l-[3-[[4-methyl-2-(4-trifluoromethylphenyl)oxazol-5-yl]methoxy] benzyl]piperidine-2-carboxylic acid;
(R)-l-[3-[[5-methyl-2-(thiophen-2-yl)oxazol-4-yl]methoxy]benzyl] piperidine-2-carboxylic acid; 2-Methyl- 1 -[3-[[5-methyl-2-(thioρhen-2-yl)oxazol-4-yl]methoxy]benzyl] piperidine-2-carboxylic acid methyl ester;
2-Ethyl-l-[3-[[5-methyl-2-(4-trifluoromethylphenyl)oxazol-4-yl]methoxy] benzyl]piperidine-2-carboxylic acid methyl ester;
(R)-l-[4-[(5-methyl-2-phenyloxazol-4-yl)methoxy]benzyl]piperidine-2- carboxylic acid;
(R)-l-[4-[(5-methyl-2-p-tolyloxazol-4-yl)methoxy]benzyl]piperidine-2- carboxylic acid;
(R)-l-[4-[[5-methyl-2-(4-trifluoromethylphenyl)oxazol-4-yl]methoxy] benzyl]piρeridine-2-carboxylic acid; (R)- 1 -[4-[5-methyl-2-(thiophen-2-yl)oxazol-4-yl]methoxy]benzyl] piperidine-2-carboxylic acid;
2-Methyl-l-[4-[(5-methyl-2-j!?-tolyloxazol-4-yl)methoxy]benzyl]piperidine- 2-carboxylic acid methyl ester;
2-Ethyl-l-[4-[(5-methyl-2-jσ-tolyloxazol-4-yl)methoxy]benzyl]piperidine-2- carboxylic acid methyl ester;
(R)-l-[3-[2-(5-methyl-2-/?-tolyloxazol-4-yl)ethoxy]benzyl]piperidine-2- carboxylic acid;
(R)-l-[3-[2-[5-methyl-2-(4-trifluoromethylρhenyl)oxazol-4-yl]ethoxy] benzyl]piperidine-2-carboxylic acid methyl ester; (R)- 1 -[3-[2-[5-methyl-2-(thiophen-2-yl)oxazol-4-yl]ethoxy]benzyl] piperidine-2-carboxylic acid;
2-Methyl-l-[3-[2-(5-methyl-2-j9-tolyloxazol-4-yl)ethoxy]benzyl]piperidine- 2-carboxylic acid methyl ester;
2-Methyl-l-[3-[2-[5-methyl-2-(thiophen-2-yl)oxazol-4-yl]ethoxy]benzyl] piperidine-2-carboxylic acid methyl ester;
(R)-l-[4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]benzyl]piperidine-2- carboxylic acid;
(R)-l-[4-[2-(5-methyl-2-j9-tolyloxazol-4-yl)methoxy]benzyl]piperidine-2- carboxylic acid; (R)-I- [4- [2- [5-methyl-2-(4-trifluoromethylpheny l)oxazol-4-yl] ethoxy] benzyl]piperidine-2-carboxylic acid;
(R)-l-[4-[2-[5-methyl-2-(thioρhen-2-yl)oxazol-4-yl]ethoxy]benzyl] piperidine-2-carboxylic acid;
2-Methyl-l-[4-[2-(5-methyl-2-/7-tolyloxazol-4-yl)ethoxy]benzyl]piperidine- 2-carboxylic acid methyl ester;
2-Methyl-l-[4-[2-[5-methyl-2-(4-trifluoromethylphenyl)oxazol-4-yl]ethoxy] benzyl]piperidine-2-carboxylic acid methyl ester;
3-Methyl-l-[3-[(5-methyl-2-phenyloxazol-4-yl)methoxy]benzyl]piperidine- 3 -carboxylic acid ethyl ester; 3-Methyl-l-[3-[(5-methyl-2-^-tolyloxazol-4-yl)methoxy]benzyl]piperidine-
3-carboxylic acid ethyl ester;
3-Methyl-l-[3-[[5-methyl-2-(4-trifluoromethylphenyl)oxazol-4-yl]methoxy] benzyl]piperidine-3-carboxylic acid ethyl ester;
3-Methyl-l-[3-[[5-methyl-2-(thiophen-2-yl)oxazol-4-yl]methoxy]benzyl] piperidine-3-carboxylic acid ethyl ester;
3-Ethyl-l-[3-[(5-methyl-2-phenyloxazol-4-yl)methoxy]benzyl]piperidine-3- carboxylic acid ethyl ester;
3 -Ethyl- 1 - [3 - [(5 -methyl-2-p-tolyloxazol-4-yl)methoxy]benzyl]piperidine-3 - carboxylic acid ethyl ester; 3-Ethyl-l-[3-[[5-methyl-2-(4-trifluoromethylphenyl)oxazol-4-yl]methoxy] benzyl]piperidine-3 -carboxylic acid ethyl ester;
3-Ethyl-l-[3-[[5-methyl-2-(thiophen-2-yl)oxazol-4-yl]methoxy]benzyl] piperidine-3-carboxylic acid ethyl ester;
3-Methyl-l-[4-[(5-methyl-2-phenyloxazol-4-yl)methoxy]benzyl]piperidine- 3-carboxylic acid ethyl ester;
3-Methyl-l-[4-[(5-methyl-2-p-tolyloxazol-4-yl)methoxy]benzyl]piperidine- 3-carboxylic acid ethyl ester;
3-Methyl-l-[4-[[5-methyl-2-(4-trifluoromethylphenyl)oxazol-4-yl]methoxy] benzyl]piperidine-3-carboxylic acid ethyl ester; 3-Methyl-l-[4-[[5-methyl-2-(thiophen-2-yl)oxazol-4-yl]methoxy]benzyl] piperidine-3-carboxylic acid ethyl ester;
3 -Ethyl- 1 - [4- [(5-methy l-2-phenyloxazol-4-yl)methoxy]benzyl]piperidine-3 - carboxylic acid ethyl ester;
3-Ethyl-l-[4-[(5-methyl-2-p-tolyloxazol-4-yl)methoxy]benzyl]piperidine-3- carboxylic acid ethyl ester;
3-Ethyl-l-[4-[[5-methyl-2-(4-trifluoromethylphenyl)oxazol-4-yl]methoxy] benzyl]piperidine-3 -carboxylic acid ethyl ester;
3-Ethyl-l-[4-[[5-methyl-2-(thiophen-2-yl)oxazol-4-yl]methoxy]benzyl] piperidine-3-carboxylic acid ethyl ester; 3-Methyl- 1 -[3-[2-(5-methyl-2-p-tolyloxazol-4-yl)ethoxy]benzyl]piperidine-
3 -carboxylic acid ethyl ester;
3-Methyl-l-[3-[2-[5-methyl-2-(4-trifluoromethylρhenyl)oxazol-4-yl]ethoxy] benzyl)piperidine-3 -carboxylic acid ethyl ester;
3 -Methyl- 1 - [3 - [2- [5 -methyl-2-(thiophen-2-yl)oxazol-4-yl] ethoxy]benzy 1] piperidine-3-carboxylic acid ethyl ester;
3-Ethyl-l-[3-[2-(5-methyl-2-jσ-tolyloxazol-4-yl)ethoxy]benzyl]piperidine-3- carboxylic acid ethyl ester;
3-Ethyl-l-[3-[2-[5-methyl-2-(4-trifluoromethylρhenyl)oxazol-4-yl]ethoxy] benzyl]piperidine-3 -carboxylic acid ethyl ester; 3 -Ethyl- 1 - [3 - [2- [5-methyl-2-(thioρhen-2-yl)oxazol-4-yl] ethoxyjbenzyl] piperidine-3-carboxylic acid ethyl ester;
3-Methyl-l-[4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]benzyl]piperidine- 3 -carboxylic acid ethyl ester;
3 -Methyl- 1 - [4- [2- [5 -methyl-2-(4-trifluoromethylphenyl)oxazol-4-yl] ethoxy] benzyl]piperidine-3 -carboxylic acid ethyl ester;
3-Methyl-l-[4-[2-[5-methyl-2-(thiophen-2-yl)oxazol-4-yl]ethoxy]benzyl] piperidine-3-carboxylic acid ethyl ester;
3-Ethyl-l-[4-[2-(5-methyl-2-phenoloxazol-4-yl)ethoxy]benzyl]piperidine-3- carboxylic acid ethyl ester; 3 -Ethyl- 1 - [4- [2- [5 -methoxy-2-(4-trifluoromethylphenyl)oxazol-4-yl] ethoxy] benzyl]piperidine-3-carboxylic acid ethyl ester;
3-Ethyl-l-[4-[2-[5-methyl-2-(thiophen-2-yl)oxazol-4-yl]ethoxy]benzyl] piperidine-3-carboxylic acid ethyl ester;
(R)- 1 - [4-(2-phenyl-oxazol-4-ylmethoxy)-benzy 1] -pyrrolidine-2-carboxylic acid;
(R)- l-[4-(2-p-tolyl-oxazol-4-ylmethoxy)-benzyl] -pyrrolidine-2-carboxylic acid;
(R)- 1 - [4- [2-(4-trifluoromethylphenyl)-oxazol-4-ylmethoxy] -benzyl] - pyrrolidine-2-carboxylic acid; (R)-l-[3-(2-phenyl-oxazol-4-ylmethoxy)-benzyl]-pyrrolidine-2-carboxylic acid;
(R)-l-[3-(2-p-tolyl-oxazol-4-ylmethoxy)-benzyl]-pyrrolidine-2-carboxylic acid;
(R)- 1 - [3 - [2-(4-trifluoromethylphenyl)-oxazol-4-ylmethoxy] -benzyl] - pyrrolidine-2-carboxylic acid;
(R)-l-[4-[2-(2-phenyl-oxazol-4-yl)-ethoxy]-benzyl]-pyrrolidine-2-carboxylic acid;
(R)- 1 - { 4- [2-(2-p-toryl-oxazol-4-yl)-ethoxy]-benzyl } -pyrrolidine-2- carboxylic acid; (R)- 1 -[4-[2-[2-(4-trifluoromethylphenyl)-oxazol-4-yl]-ethoxy]-benzyl]- pyrrolidine-2-carboxylic acid;
(R)-l-[3-[2-(2-phenyl-oxazol-4-yl)-ethoxy]-benzyl]-pyrrolidine-2-carboxylic acid;
(R)-l-[3-[2-(2-/7-tolyl-oxazol-4-yl)-ethoxy]-benzyl]-pyrrolidine-2-carboxylic acid;
(R)-l-[4-[2-[2-(4-trifluoromethylphenyl)-oxazol-4-yl]-ethoxy]-benzyl]- pyrrolidine-2-carboxylic acid;
(R)-l-[4-[2-(5-isopropyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzyl]-pyrrolidine- 2-carboxylic acid; (R)-l-[3-[2-(5-isopropyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzyl]-pyrrolidine-
2-carboxylic acid; l-[4-(2-Phenyl-oxazol-4-ylmethoxy)-benzyl]-piperidine-2-carboxylic acid; l-[4-(2-jp-Tolyl-oxazol-4-ylmethoxy)-benzyl]-piperidine-2-carboxylic acid; l-[4-[2-(4-Trifluoromethylphenyl)-oxazol-4-ylmethoxy]-benzyl]-piperidine- 2-carboxylic acid; l-[3-(2-Phenyl-oxazol-4-ylmethoxy)-benzyl]-piperidine-2-carboxylic acid; l-[3-(2-/?-Tolyl-oxazol-4-ylmethoxy)-benzyl]-piperidine-2-carboxylic acid;
1 - [3 - [2-(4-Trifluoromethylphenyl)-oxazol-4-y lmethoxy] -benzyl] -piperidine- 2-carboxylic acid; l-[4-[2-(2-Phenyl-oxazol-4-yl)-ethoxy]-benzyl]-piperidine-2-carboxylic acid; l-[4-[2-(2-/>-Tolyl-oxazol-4-yl)-ethoxy]-benzyl]-piperidine-2-carboxylic acid; l-[4-[2-[2-(4-Trifluoromethylphenyl)-oxazol-4-yl]-ethoxy]-benzyl]- piperidine-2-carboxylic acid; l-[3-[2-(2-Phenyl-oxazol-4-yl)-ethoxy]-benzyl]-piperidine-2-carboxylic acid; l-[3-[2-(2-/?-Tolyl-oxazol-4-yl)-ethoxy]-benzyl]-piperidine-2-carboxylic acid;
1 - [4- [2- [2-(4-Trifluoromethylphenyl)-oxazol-4-yl] -ethoxy] -benzyl] - piρeridine-2-carboxylic acid; l-[4-(5-Methyl-2-p-tolyl-oxazol-4-ylmethoxy)-benzyl]-pyrrolidine-2-carbox ylic acid t-butyl ester;
(R)- 1 - [4-(2-biphenyl-4-yl- 5 -methyl-oxazol-4-ylmethoxy)-benzyl] - pyrrolidine-2-carboxylic acid;
(R)-l-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzyl]-pyrrolidine-2- carboxylic acid;
(R)-I- [4-(5 -methyl-2-/7-tolyl-oxazol-4-ylmethoxy)-benzyl] -pyrrolidine-2- carboxylic acid;
(R)- 1 - { 4- [5 -methyl-2-(4-trifluoromethy l-phenyl)-oxazol-4-ylmethoxy] - benzyl} -pyrrolidine-2-carboxylic acid; (R)- 1 -[4-(5-methyl-2-thiophen-2-yl-oxazol-4-ylmethoxy)-benzyl]- pyrrolidine-2-carboxylic acid;
(S)-l-{3-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-benzyl}- pyrrolidine-2-carboxylic acid;'
(S)-l-{3-[2-(5-methyl-2rp-tolyl-oxazol-4-yl)-ethoxy-benzyl}-pyrrolidine-2- carboxylic acid;
(S)- 1 -(3 - {2-[5-methyl-2-(4-trifluoromethyl-ρhenyl)-oxazol-4-yl]-ethoxy } - benzyl)-pyrrolidine-2-carboxylic acid;
(S)- 1 - {3 - [2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]-benzyl} - pyrrolidine-2-carboxylic acid; (S)-l-{4-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-benzyl}- pyrrolidine-2-carboxylic acid;
(S)-l-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzyl}-pyrrolidine-2- carboxylic acid;
(S)-l-(4-{2-[5-methyl-2-(4-trifluoromethyl-ρhenyl)-oxazol-4-yl]-ethoxy}- benzyl)-pyrrolidine-2-carboxylic acid;
(S)-l-{4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]-benzyl}- pyrrolidine-2-carboxylic acid; l-[3-(2-Biphenyl-4-yl-5-methyl-oxazol-4-ylmethoxy)-benzyl]-piperidine-2- carboxylic acid; l-[3-(5-Methyl-2:f-tolyl-oxazol-4-ylmethoxy)-benzyl]-ρiρeridine-2- carboxylic acid;
1 - { 3 - [5 -Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy] -benzyl} - piperidine-2-carboxylic acid; l-[3-(5-Methyl-2-thiophen-2-yl-oxazol-4-ylmethoxy)-benzyl]-piperidine-2- carboxylic acid;
1 - { 3 - [2-(5 -Methyl-2-phenyl-oxazol-4-yl)-ethoxy] -benzyl } -ρiperidine-2- carboxylic acid; l-(3-{2-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-ethoxy-benzyl) -piperidine-2-carboxylic acid; 1 - { 3 - [2-(5-Methyl-2-thiophen-2-yl-oxazol-4-y l)-ethoxy] -benzyl } -piperidine-
2-carboxylic acid; l-(4-{2-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-ethoxy}- benzyl)-piperidine-2-carboxylic acid;
(S)-l-[4-(5-methyl-2-p-tolyl-oxazol-4-ylmethoxy)-benzyl]-piperidine-2- carboxylic acid;
(S)-l-{4-[2-(5-methyl-2-/»-tolyl-oxazol-4-yl)-ethoxy]-benzyl}-piperidine-2- carboxylic acid;
(S)- 1 -(3 -((5-methyl-2-phenyloxazol-4-yl)methoxy)benzyl)pyrrolidine-2- carboxylic acid; (S)- 1 -(3-((5-methyl-2-j?-tolyloxazol-4-yl)methoxy)benzyl)pyrrolidine-2- carboxylic acid;
(S)-l-(3-((5-methyl-2-(4-(trifluoromethyl)phenyl)oxazol-4-yl)methoxy) benzyl)pyrrolidine-2-carboxylic acid;
(S)-l-(3-((2-(biphenyl-4-yl)-5-methyloxazol-4-yl)methoxy)benzyl) pyrrolidine-2-carboxylic acid;
(S)-l-(3-((5-methyl-2-(thiophen-2-yl)oxazol-4-yl)methoxy)benzyl) pyrrolidine-2-carboxylic acid;
(S)-l-(4-((5-methyl-2-ρhenyloxazol-4-yl)methoxy)benzyl)pyrrolidine-2- carboxylic acid; (S)- 1 -[4-(5-methyl-2-/»-tolyl-oxazol-4-ylmethoxy)-benzyl]-pyrrolidine-2- carboxylic acid;
(S)-l-{4-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]- benzyl} -pyrrolidine-2-carboxylic acid;
(S)-l-[4-(2-biphenyl-4-yl-5-methyl-oxazol-4-ylmethoxy)-benzyl]- pyrrolidine-2-carboxylic acid;
(S)-l-[4-(5-methyl-2-thiophen-2-yl-oxazol-4-ylmethoxy)-benzyl]- pyrrolidine-2-carboxylic acid;
(S)-l-{4-[2-(5-methyl-2-/?-tolyl-oxazol-4-yl)-ethoxy-benzyl}-pyrrolidine-2- carboxylic acid; 1 -(3 -((5-Methyl-2-phenyloxazol-4-yl)methoxy)benzyl)piperidine-2- carboxylic acid; and l-(3-(2-(5-Methyl-2-p-tolyloxazol-4-yl)ethoxy)benzyl)piperidine-2- carboxylic acid.
The heterocyclic carboxylic acid derivative of formula (1) of the present invention wherein m is 0; ring A is thiazolidine; and X is H(comρound of formula Ia) may be prepared by the procedure shown in Reaction Scheme (I):
Reaction Scheme (I)
CHO
HOT
Figure imgf000017_0001
2 4
Figure imgf000017_0002
1a wherein,
L is a leaving group such as Cl, Br, I5 mesyl, or tosyl, or hydroxyl; and R1 and n have the same meanings as defined in formula (1).
As shown in Reaction Scheme (I), the compound of formula Ia may be prepared by a process comprising the following steps:
First, an alkyl or alcohol compound of formula 2 is allowed to react with a hydroxybenzaldehyde of formula 3 to obtain an alkoxy benzaldehyde of formula 4. The compound of formula 2, in which L is a leaving group such as Cl, Br, I5 mesyl, or tosyl, is subjected to an alkylation reaction in the presence of a base in a solvent. Representative examples of the base include an inorganic base such as sodium hydride, potassium t-butoxide, butyl lithium, potassium carbonate, or sodium carbonate, and an organic base such as triethylamine, diisopropylethylamine, N-alkylmorpholine, or N-alkylpyrrolidine. Representative examples of the solvent include dimethylformamide(DMF), tetrahydrofuran(THF), dioxane, or an alcohol such as methanol, ethanol, isopropanol or r-butanol, or a mixture thereof with water. The reaction may be carried out at a temperature ranging from -20 to 1000C, and a quaternary amine halogen salt such as (Bu)4NI may be added thereto in a catalytic amount to enhance the reaction rate.
Alternatively, when L of the compound of formula 2 is hydroxyl, the compound of formula 2 is subjected to Mitsunobu reaction(^ee Mitsunobu, O., Synthesis, 1, 1981). The Mitsunobu reaction may be conducted in the presence of an agent such as triphenylphosphine(PPh3), diisopropyl azodicarboxylate or diethyl azodicarboxylate(DEAD), using a solvent such as toluene or tetrahydrofuran.
Second, the compound of formula 4 is allowed to react with cysteine in an alcohol to obtain the inventive heterocyclic carboxylic acid derivative(compound of formula Ia). If cycteine is of the form of a hydrochloride salt, the reaction may be carried out in the presence of an inorganic base such as lithium hydroxide, potassium hydroxide, sodium hydroxide, potassium carbonate or sodium carbonate, or an organic base such as triethylamine, using a solvent such as methanol, ethanol or tetrahydrofuran.
The heterocyclic carboxylic acid derivative of formula (1) of the present invention wherein m is 1; ring A is a heterocyclic moiety; and X is H or C1-C4 alkyl(the compound of formula Ic or Ib, respectively) may be respectively prepared by the procedures shown in Reaction Schemes (Ha) to (lie):
Reaction Scheme (Ha)
Figure imgf000018_0001
1C
Reaction Scheme QIb)
Figure imgf000018_0002
Figure imgf000019_0001
Reaction Scheme (lie)
Figure imgf000019_0002
Figure imgf000019_0003
wherein,
M is Cl, Br, I, mesyl, or tosyl;
X is C1-C4 alkyl; and
R1, R2, R3, n, and L have the same meanings as defined above.
The compounds of formulae Ib and Ic may be prepared by a process comprising the following steps: An aromatic aldehyde compound of formula 4 is subjected to reductive amination with a heterocyclic carboxylate of formula 5 in the presence of a reducing agent to obtain a carboxylic acid derivative of formula Ib. The reducing agent used in this step may be sodium triacetoxyborohydride or sodium borohydride. If the compound of formula 5 is an acid addition salt, the above reaction may be conducted in the presence of an organic base such as triethylamine. Also, the reaction may be carried out at a temperature ranging from 0 to 40 "C , using a solvent such as dichloromethane, chloroform or dichloroethane.
The compound of formula Ib is then subjected to hydrolysis in the presence of a base to obtain the inventive heterocyclic carboxylic acid derivative of formula Ic. The hydrolysis reaction may be conducted in the presence of an inorganic base such as lithium hydroxide, potassium hydroxide, sodium hydroxide, potassium carbonate or sodium carbonate, or an organic base such as diisopropylethylamine, using a solvent such as water, an alcohol, e.g., methanol and ethanol, an ether, e.g., tetrahydrofuran, and a mixture thereof with water.
Further, as shown in Reaction Scheme (lib), the compounds of formulae Ib and Ic may be prepared by a process comprising the following steps: An aromatic aldehyde compound of formula 4 is subjected to reductive reaction in the presence of a reducing agent to obtain a benzyl alcohol compound of formula 7. The reducing agent which may be used in this reaction includes metal hydride such as sodium borohydride, lithium aluminium hydride, sodium cyanoborohydride, sodium triacetoxyborohydride, sodium or potassium alkoxyborohydride, DIBAL-H(diisobutylaluminum hydride), diborane, a metal salt thereof, or a mixture thereof. The above reaction may be carried out at a temperature ranging from -20 to 100 °C, using a solvent such as water, an alcohol, e.g., methanol and ethanol, an ether such as tetrahydrofuran, and a mixture thereof with water.
The compound of formula 7 thus obtained is then subjected to a reaction to convert the hydroxyl group to a leaving group such as Cl, Br, I, mesyl, or tosyl in a suitable solvent to obtain a substituted aromatic compound of formula 8.
For example, the compound of formula 8 in which M is Cl may be obtained by treating the compound of formula 7 with thionylchloride in benzene or toluene. Further, the compound of formula 8 in which M is Br may be prepared by subjecting the compound of formula 7 to a reaction with PBr3 in benzene or dichloromethane. The compound of formula 8 in which M is I may be obtained by treating the compound of formula 7 with iodine in petroleum ether. The compound of formula 8 in which M is mesyl or tosyl may be prepared by treating the compound of formula 7 with methanesulfonyl chloride or 4-toluenesulfonyl chloride, in the presence of an inorganic base such as potassium carbonate or an organic base such as triethylamine, in benzene or dichloromethane. Subsequently, the compound of formula 8 is allowed to react with a heterocyclic carboxylate of formula 5 in the presence of a base to obtain the inventive heterocyclic carboxylic acid derivative of formula Ib. The base may be an inorganic base such as sodium hydride, sodium methoxide, sodium ethoxide, potassium t-butoxide, butyl lithium, potassium carbonate, and sodium carbonate, or an organic base such as triethyl amine, diisopropyl ethylamine, N-alkyl morpholine, and N-alkyl pyrrolidine. The reaction may be carried out at a temperature ranging from -20 to 100°C, in a solvent such as dimethylformamide, tetrahydrofuran, dioxane, an alcohol such as methanol, ethanol, isopropanol, and t-butanol, or a mixure thereof with water. A quaternary amine halide such as (Bu)4NI may be added thereto in a catalytic amount to enhance the reaction rate. Finally, the compound of formula Ib is hydrolyzed as described in the second step of Reaction Scheme (Ha) to obtain the inventive heterocyclic carboxylic acid derivative of formula Ic.
Futhermore, as shown in Reaction Scheme (lie), the compounds of formulae Ib and Ic may be prepared by a process comprising the following steps: The hydroxybenzaldehyde of formula 3 is subjected to reductive amination by the procedure described in the first step of Reaction Scheme (Ha) to obtain a heterocyclic carboxylate of formula 9. Subsequently, the procedure in the first step of Reaction Scheme (I) is repeated except for using the compound of formula 9 to obtain a heterocyclic carboxylic acid derivative of formula Ib, which was converted to the inventive heterocyclic carboxylic acid derivative of formula Ic by the procedure described in the second step of Reaction Scheme (Ha).
The inventive heterocyclic carboxylic acid derivative of formula (1) wherein m is 1; ring A is thiazolidine; X is H(compound of formula Id) may be preprared by the procedure shown in Reaction Scheme (III):
Reaction Scheme (IIP
Figure imgf000021_0001
Figure imgf000022_0001
12
Figure imgf000022_0002
1d wherein, L is Cl, Br, I, mesyl, or tosyl; and
R1 and n have the same meanings as defined in formula (1).
As shown in Reaction Scheme (III), the compound of formula Id may be prepared by a process comprising the following steps: In case L of the compound of formula 2a is a leaving group, the procedure of the first step of Reaction Scheme (I) was repeated except for using hydroxyphenethylalcohol of formula 10 to obtain a phenethyl alcohol compound of formula 11, which is then treated with IBX(I -hydroxy- 1,2-benziodoxo 1-3 (lH)-one l-oxide(2-iodoxybenzoic acid)) in a solvent such as ethyl acetate at the boiling temperature of the solvent in accordance with a conventional method^ee Marco Frigerio et al, Journal of Organic Chemistry, 64(12), 4537-538(1999)) to obtain an aromatic aldehyde compound of formula 12. Subsequently, the compound of formula 12 is allowed to react with cycteine as in the second step of Reaction Scheme (I) to obtain the inventive heterocyclic carboxylic acid derivative of formula Id.
The inventive heterocyclic carboxylic acid derivative of formula (1) wherein m is 2; ring A is a heterocycle; and X is Η or C1-C4 alkyl(compound of formula If or Ie, respectively) may be prepared by repeating the procedure of Reaction Scheme (Ua) except for using an aromatic acetaldehyde compound of formula 12 as a starting material as shown in Reaction Scheme (IV): Reaction Scheme (IV)
Figure imgf000023_0001
1f wherein, X is C1-C4 alkyl; and
R1, R2, R3, and n have the same meaning as defined in formula (1).
The inventive heterocyclic carboxylic acid derivative of formula (1) is effective in accelerating the lipid metabolism. Thus, the present invention provides a pharmaceutical composition comprising the compound of formula (1) for inhibiting the lipid accumulation in the body. The inventive pharmaceutical composition is useful for the treatment and prevention of obesity, NIDDM(non-insulin dependent diabetes mellitus), hyperlipidemia, arteriosclerosis, steatosis of the liver or muscle, fatty liver caused by the lipid accumulation. The pharmaceutical composition of the present invention may be formulated for oral or parenteral administration as well as intravenous, intraperitoneal, subcutaneous, rectal and topical administration in accordance with conventional methods. The formulation for administration may be prepared by mixing or diluting the inventive heterocyclic carboxylic acid derivative with a carrier, or sealing in a carrier in the form of a vessel. If the carrier is used as a diluent, it may be a vehicle, adjuvant or medium for active ingredient in the form of a solid, semi-solid, or liquid. Therefore, the formulation for administration may take various forms such as a tablet, pill, powder, sachet, elixir, suspension, emulsion, solution, syrup, aerosol, soft and hard gelatin capsule, sterilized injection, sterilized powder, or the like, and additionally include conventional additives such as a filler, anti-flocculation agent, lubricant, wetting agent, flavor, emulsifier, preservative, or the like. The pharmaceutical composition of the present invention may also be formulated for fast, continuous or delayed release of an active ingredient after administration using conventional methods. The pharmaceutical composition of the present invention can be administered orally or parenterally as an active ingredient in an effective amount ranging from about 0.1 to 1000 mg/kg body weight per day, preferably from about 1 to 100 mg/kg body weight per day in a single dose or in divided doses in case of mammals including human.
The following Examples are intended to further illustrate the present invention without limiting its scope.
Example 1: Preparation of (R)-2-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy] phenyI}thiazolidine-4-carboxylic acid
Step 1: Preparation of 4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]benzaldehyde
2-(5-Methyl-2-ρhenyloxazol-4-yl)ethanol(0.5 g, 2.67 mmol),
4-hydroxybenzaldehyde(0.326 g, 2.67 mmol), triphenylphosphine(0.7 g, 2.67 mmol) and diethylazodicarboxylate(0.42 ml, 2.67 mmol) were mixed together. The resulting mixture was stirred at room temperature for 48 hrs, and distilled water was added thereto. Then, the resultant was extracted with ethyl acetate. The organic layer was separated and dried over anhydrous magnesium sulfate, followed by romoving the solvent under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography(eluent: hexane/ethyl acetate=4/l) to obtain the title compound(0.24 g, yield: 31%).
1H NMR(CDCl3, 200MHz): δ(ppm) 9.91(1H, s), 8.02-8.00(2H, d, J = 4Hz), 7.88-7.84(2H, d, J = 16Hz), 7.47-7.44(3H, m, J = 6Hz), 7.07-7.01(2H, d, J = 12Hz), 4.41-4.33(2H, t, J = 16Hz), 3.09-3.01(2H, t, J = 16Hz), 2.42-2.41(3H, s)
Step 2: Preparation of (R)-2-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenyl} thiazolidine-4-carboxylic acid
The compound obtained in Step 1(0.1 g, 0.34 mmol) and L-cysteine(0.042 g, 0.34 mmol) were dissolved in ethanol and the resulting solution was stirred at room temperature for 3 days. Then, the reaction product was filtered. The residue thus obtained was washed with diethyl ether and dried to obtain the title compound(0.093 g, yield: 66%) as a white solid.
1H NMR(CDCl3, 200MHz): δ(ppm) 7.92-7.90(2H, d, J = 4Hz), 7.51-7.48(3H, d, J = 6Hz), 7.43-7.34(2H, q, J = 18Hz), 6.96-6.88(2H, t, J = 16Hz), 5.59(0.5H, s), 5.44(0.5H, s) 4.24-4.18(2.5H, t, J = 16Hz), 3.87-3.82(0.5H, t, J = 10Hz), 3.16-3.11(2H, m), 3.08-3.02(2H, t, J - 12Hz), 2.36(3H, s)
Example 2: Preparation of (R)-2-{4~[2~(benzoxazol-2-yl-methylamino)-ethoxy]- phenyl}-thiazoIidine-4-carboxylic acid
Figure imgf000025_0001
Step 1: Preparation of 4-[2-(benzoxazol-2-yl-methylamino)-ethoxy]-benzaldehyde
Methanesulfonic acid-2-(benzoxazol-2-yl-methylamino)-ethyl ester(246 mg, 0.91 mmol) was dissolved in dimethylformamide(15 ml), and potassium carbonate(190 mg, 1.37 mmol) and 4-hydroxybenzaldehyde(110 mg, 0.91 mmol) were added thereto. The resulting mixture was stirred at a temperature ranging from 90 to 100 °C for 15 hrs, and then, 30 ml of ethyl acetate and a saturated aqueous NaHCO3 were added thereto. Then, the resulting mixture was extracted with ethyl acetate(3 x 30 ml). The organic layer was separated, dried over sodium sulfate and distilled under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography(eluent: ethyl acetate/hexane=l/2) to obtain the title compound(234.3 mg, yield: 87%). 1H NMR(CDCl3, 200MHz): δ(ppm) 9.88(s, IH), 7.81(d, 2H), 7.35(d, IH), 7.25(d, IH), 7.17(t, IH), 6.99(t and t, 3H), 4.36(t, 2H), 3.99(t, 2H), 3.36(s, 3H)
Step 2: Preparation of (R)-2-{4-[2-(benzoxazol-2-yl-methylamino)-ethoxy]- phenyl}-thiazolidine-4-carboxylic acid
The procedure of Step 2 of Example 1 was repeated except for using the compound obtained in Step 1 of Example 2(0.1 g, 0.34 mmol) and L-cysteine(0.042 g, 0.34 mmol) to obtain the title compound(0.082 g, yield: 61%).
1H NMR(DMSO^6, 200MHz): δ(ppm) 7.38(m, 2H), 7.25(d, 2H), 7.12(t, IH), 6.98(t,
IH), 6.90(d, 2H), 5.38(s, IH), 4.24 and 3.86(two t, 4H), 3.39(br s, IH), 3.28(m, 2H),
3.21(s, 3H), 2.93(t, IH)
Example 3: Preparation of (R)-2~{4-[2-(methyI-pyridin-2-yl-methylamino)- ethoxy]-phenyl}-thiazoIidine-4-carboxylic acid
Figure imgf000025_0002
Step 1 : Preparation of 4-[2-(methylpyridin-2-yl-methylamino)-ethoxy]- benzaldehyde
The procedure of Step 1 of Example 2 was repeated except for using methanesulfonic acid-2-(methyl-pyridin-2-yl-methylamino)-ethyl ester(209 mg, 0.91 mmol) and 4-hydroxybenzaldehyde(110 mg, 0.91 mmol) to obtain the title compoιmd(185 mg, yield: 79%).
Step 2: Preparation of (R)-2-{4-[2-(methyl-pyridin-2-yl-methylamino)-ethoxy]- phenyl} -thiazolidine-4-carboxylic acid
The procedure of Step 2 of Example 1 was repeated except for using the compound obtained in Step 1 of Example 3(0.087 g, 0.34 mmol) and L-cysteine(0.042 g, 0.34 mmol) to obtain the title compound(0.089 g, yield: 73%). 1H NMR(DMSO-d6, 200MHz): δ(ppm) 8.08(m, IH), 7.46(t, IH), 7.36(d, 2H), 6.90(d, 2H), 6.62 and 6.55(m, 2H), 5.38(s, IH), 4.12 and 3.89(two t, 4H), 3.40(br s, IH), 3.26(m, 2H), 3.06(s, 3H), 2.97(m, IH)
Example 4: Preparation of (R)-2-{4-[2-(5-methyl-2-(4-trifluoromethylphenyl)- oxazoI-4-yI)ethoxy]phenyl}thiazolidine-4-carboxyIic acid
Step 1 : Preparation of 4-[2-(5-methyl-2-(4-trifluoromethylphenyl)-oxazol-
4-yl)ethoxy]benzaldehyde
The procedure of Step 1 of Example 1 was repeated except for using 2-(5-methyl-2-(4-trifluoromethylρhenyl)-phenyloxazol-4-yl)ethanol(0.48 g, 1.76 mmol), 4-hydroxybenzaldehyde(0.215 g, 1.76 mmol), triphenylphosphine(0.46 g,
1.76 mmol) and diethylazodicarboxylate(0.31 g, 1.76 mmol) to obtain the title compound(0.2 g, yield: 30%).
1H NMR(CDCl3, 200MHz): δ(ppm) 9.89(1H, s), 8.13-8.08(2H, d, J = lOHz), 7.83-7.81(2H, d, J = 4Hz), 7.72-7.68(2H, d, J = 8Hz), 7.04-7.00(2H, d, J = 16Hz),
4.40-4.33(2H, t, J = 14Hz), 3.08-3.01(2H, t, J = 14Hz), 2.48(3H, s)
Step 2: Prepration of (R)-2-{4-[2-(5-methyl-2-(4-trifluoromethylρhenyl)-oxazol-
4-yl)ethoxy]phenyl}thiazolidine-4-carboxylic acid The procedure of Step 2 of Example 1 was repeated except for using the compound obtained in Step 1 of Example 4(0.1 g, 0.26 mmol) and L-cysteine(0.032 g, 0.26 mmol) to obtain the title compound(0.08 g, yield: 63%).
1H NMR(CDCl3, 200MHz): δ(ppm) 8.27-8.24(2H, d, J = 6Hz), 8.02-8.00(2H, d, J =
4Hz), 7.58-7.48(2H, q, J - 20Hz), 7.09-7.03(2H, t, J = 12Hz), 5.73(0.5H, s), 5.55(0.5H, s), 4.40-4.34(2.5H, q, J = 12Hz), 4.00-3.97(0.5H, t, J = 6Hz),
3.31-3.26(2H, m), 3.23-3.12(2H, t), 2.54(3H, s) Example 5: Preparation of (R)-2-{4-[2-(5-methyI-2-thiophen-2-yloxazol-4-yl) ethoxy] phenyl} thiazoIidine-4-carboxylic acid
Figure imgf000027_0001
Step 1 : Preparation of 4-[2-(5-methyl-2-thiophen-2-yloxazol-4-yl)ethoxy] benzaldehyde
The procedure of Step 1 of Example 1 was repeated except for using 2-(5-methyl-2-thiophen-2-yloxazol-4-yl)ethanol(0.5 g, 2.4 mmol),
4-hydroxybenzaldehyde(0.3 g5 2.4 mmol), triphenylphosphine(0.63 g, 2.4 mmol) and diethylazodicarboxylate(0.42 g, 2.4 mmol) to obtain the title compound(0.25 g, yield: 33.4%).
1H NMR(CDCl3, 200MHz): δ(ppm) 9.89(1H, s), 7.85-7.81(2H3 d, J = 16Hz), 7.61-7.59(1H, d, J = 4Hz), 7.41-7.38(1H, d, J = 6Hz), 7.12-7.1O(1H, t, J = 4Hz), 7.08-6.99(2H, d, J = 18Hz), 4.37-4.30(2H, t, J - 14Hz), 3.04-2.97(2H, t, J = 14Hz), 2.38(3H, s)
Step 2: Preparation of (R)-2-{4-[2-(5-methyl-2-thiophen-2-yloxazol-4-yl)ethoxy] phenyl}thiazolidine-4-carboxylic acid
The procedure of Step 2 of Example 1 was repeated except for using the compound obtained in Step 1 of Example 5(0.1 g, 0.324 mmol) and L-cysteine(0.04 g, 0.324 mmol) to obtain the title compound(0.077 g, yield: 57%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.71-7.7O(1H, d, J = 2Hz), 7.6O-7.59(1H, d, J = 2Hz), 7.43-7.33(2H, q, J = 20Hz), 7.19-7.16(1H, t, J = 6Hz)5 6.94-6.87(2H, t, J = 14Hz), 5.59(0.5H, s), 5.44(0.5H, s), 4.21-4.15(2.5H, m), 3.87-3.82(0.5H, t, J - 8Hz), 3.16-3.05(2H, m), 2.91-2.87(2H, t, J - 8Hz), 2.33(3H, s)
Example 6: Preparation of (R)-2-{4-[2-(5-methyI-2-/?-tolyloxazol-4-yl)ethoxy] phenyl}thiazolidine-4-carboxylic acid
Figure imgf000027_0002
Step 1 : Preparation of 3-[2-(5-methyl-2-/?-tolyloxazol-4-yl)ethoxy]benzaldehyde The procedure of Step 1 of Example 1 was repeated except for using
2-(5-methyl-2-jε>-tolyloxazol-4-yl)ethanol(0.5 g, 2.3 mmol),
3-hydroxybenzaldehyde(0.28 g, 2.3 mmol), triphenylρhosphine(0.6 g, 2.3 mmol) and diethylazodicarboxylate(0.4 g, 2.3 mmol) to obtain the title compound(0.3 g, yield: o ). Step 2: Preparation of (R)-2-{4-[2-(5-methyl-2-^-tolyloxazol-4-yl)ethoxy]ρhenyl} thiazolidine-4-carboxylic acid
The procedure of Step 2 of Example 1 was repeated except for using the compound obtained in Step 1 of Example 6(0.032 g, 0.09 mmol) and L-cysteine(0.012 g5 0.09 mmol) to obtain the title comρound(0.009 g, yield: 21%).
Example 7: Preparation of (R)-2-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy] phenyl}thiazolidine-4-carboxylic acid
Figure imgf000028_0001
Step 1: Preparation of 3-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]aldehyde
The procedure of Step 1 of Example 1 was repeated except for using 2-(5-methyl-2-phenyloxazol-4-yl)ethanol(0.5 g, 2.48 mmol),
3-hydroxybenzaldehyde(0.3 g, 2.48 mmol), triphenylphosphine(0.65 g, 2.48 mmol) and diethylazodicarboxylate(0.43 g, 2.48 mmol) to obtain the title compound(0.2g, yield: 25%).
1H NMR(CDCl3, 200MHz): δ(ppm) 9.96(1H, s), 8.04-8.00(2H, m), 7.48-7.42(6H, m), 7.24-7.16(1H, m), 4.38-4.30(2H, m), 3.08-3.01(2H5 m), 2.42(3H, s)
Step 2: Preparation of (R)-2-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenyl} thiazolidine-4-carboxylic acid
The procedure of Step 2 of Example 1 was repeated except for using the compound obtained in Step 1 of Example 7(0.09 g, 0.287 mmol) and
L-cysteine(0.035 g, 0.287 mmol) to obtain the title compound(0.06 g, yield: 50%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.91-7.90(2H, d), 7.50-7.48(3H5 d, J = 4Hz)5 7.48-7.28(1H5 m), 7.05-6.96(2H5 m), 6.91-6.92(1H5 m), 5.61(0.5H5 s), 5.45(0.5H, s),
4.25-4.19(2.5H5 q, J = 12Hz)5 3.89-3.83(0.5H5 1), 3.15-3.10(2H5 m), 3.09-3.03(2H5 1,
J = 12Hz), 2.36(3H5 s)
Example 8: Preparation of (R)-2-{4-[2-(5-methyI-2-(4-trifluoromethylphenyl)- oxazol-4-yl)ethoxy]phenyl}thiazolidine-4-carboxylic acid
Figure imgf000028_0002
Step 1 : Preparation of 3-[2-(5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl) ethoxy]benzaldehyde
The procedure of Step 1 of Example 1 was repeated except for using
2-(5-methyl-2-(4-trifluoromethylphenyl)-phenyloxazol-4-yl)ethanol(0.5 g, 1.84 mmol), 3-hydroxybenzaldehyde(0.224 g, 1.84 mmol), triphenylphosphine(0.427 g, 1.84 mmol) and diethylazodicarboxylate(0.32 g, 1.84 mmol) to obtain the title compound(0.173 g, yield: 25%).
1H NMR(CDCl3, 200MHz): δ(ppm) 9.96(1H, s), 8.13-8.09(2H, d, J = 8Hz),
7.73-7.68(2H, d, J = 10Hz), 7.48-7.42(3H, m), 7.22-7.16(1H5 m), 4.38-4.31(2H, t),
3.07-3.01(2H, t, J - 12Hz)5 2.43(3H, s)
Step 2: Preparation of (R)-2-{4-[2-(5-methyl-2-(4-trifluoromethylphenyl)-oxazol-
4-yl)ethoxy]phenyl}thiazolidine-4-carboxylic acid
The procedure of Step 2 of Example 1 was repeated except for using the compound obtained in Step 1 of Example 8(0.06 g, 0.162 mmol) and L-cysteine(0.02 g, 0.162 mmol) to obtain the title comρound(0.025 g, yield: 32%).
1H NMR(CDCl3, 200MHz): δ(ppm) 8.12-8.09(2H, d, J = 6Hz), 7.87-7.84(2H, d, J =
6Hz), 7.28-7.22(1H5 m), 7.12-6.99(2H, m), 6.97-6.83(2H, m), 5.61(0.5H, s),
5.45(0.5H5 s), 4.38(2.5H5 q), 3.88-3.83(0.5H, t), 3.24-3.14(2H5 m), 3.11-2.95(2H5 1, J
= 12Hz), 2.34(3H, s)
Example 9: Preparation of (R)-2-{4-[2-(5-methyl-2-thiophen~2-yloxazol-4- yl)ethoxy] phenyl} thiazoIidine-4-carboxylic acid
Figure imgf000029_0001
Step 1 : Preparation of 3-[2-(5-methyl-2-thiophen-2-yloxazol-4-yl)ethoxy] benzaldehyde
The procedure of Step 1 of Example 1 was repeated except for using 2-(5-methyl-2-thioρhen-2-yloxazol-4-yl)ethanol(0.5 g, 2.39 mmol),
3-hydroxybenzaldehyde(0.29 g, 2.39 mmol), triphenylphosphine(0.627 g5 2.39 mmol) and diethylazodicarboxylate(0.416 g, 2.39 mmol) to obtain the title compound(0.17 g, yield: 23%).
1H NMR(CDCl3, 200MHz): δ(ppm) 9.98(1H, s), 7.62-7.60(1H, m), 7.47-7.38(4H, m), 7.22-7.19(1H, m), 7.16-7.10(1H5 m), 4.35-4.29(2H, t, J = 12Hz), 3.04-2.98(2H, t, J = 14Hz), 2.39(3H, s)
Step 2: Preparation of (R)-2-{4-[2-(5-methyl-2-thiophen-2-yloxazol-4-yl)ethoxy] phenyl}thiazolidine-4-carboxylic acid The procedure of Step 2 of Example 1 was repeated except for using the compound obtained in Step 1 of Example 9(0.06 g, 0.19 mmol) and L-cysteine(0.023 g, 0.19 mmol) to obtain the title compound(0.063 g, yield: 77%). 1H NMR(CDCl3, 200MHz): δ(ppm) 7.71-7.70(Is5 d), 7.60-7.59(ls, d), 7.25-7.22(3H5 m), 7.19-6.99(2H5 m), 6.97-6.82(1H5 m), 5.61(0.5H5 s), 5.45(0.5H5 s), 4.25-4.16(2.5H5 m), 3.89-3.84(0.5H5 1), 3.15-3.12(2H5 m), 2.92-2.80(2H5 1), 2.33(2H5 s)
Example 10: Preparation of (R)-2-{3-[2-(5-methyI-2-/?-tolyl-oxazol-4-yl)- ethoxy]-phenyl}-thiazolidine-4-carboxylic acid
Figure imgf000030_0001
Step 1: Preparation of 3-[2-(5-methyl-2-/>-tolyl-oxazol-4-yl)-ethoxy]-benzaldehyde
Methansulfonic acid-2-(5-methyl-2-/?-tolyl-oxazol-4-yl)-ethyl ester(42 mg, 0.14 mmol) was dissolved in 5 ml of acetonitrile, and potassium carbonate(23 mg, 0.16 mmol) and 3-hydroxybenzaldehyde(20.9 mg, 0.17 mmol) were added thereto. The resulting mixture was heated to reflux for 15hrs. Then, The procedure of Step 1 of Example 2 was repeated except for using the reaction mixture thus obtained to obtain the title compound(31.4 mg, yield: 68%).
Step 2: Preparation of Preparation of (R)-2-{3-[2-(5-methyl-2-/?-tolyl-oxazol-4-yl)- ethoxy] -phenyl } -thiazolidine-4-carboxylic acid
The procedure of Step 2 of Example 1 was repeated except for using the compound obtained in Step 1 of Example 10(0.06 g, 0.19 mmol) and L-cysteine(0.023 g, 0.19 mmol) to obtain the title compound(8.9 mg, yield: 21%).
Example 11: Preparation of (R)-3-(3-{2-[5-methyl-2-(4-trifluoromethylphenyl)- oxazol-4-yl]-ethoxy}-benzyl)-thiazolidine-4-carboxyIic acid
Figure imgf000031_0001
Step 1 : Preparation of 3-{2-[5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl]- ethoxy } -benzaldehyde
Sodium hydride(0.24 g, 60%, 6 mmol) was dissolved in dimethylformamide(20 ml) and stirred at 0 °C . To the resulting mixture,
3-hydroxybenzaldehyde(730 nig, 6 mmol) and a solution of methanesulfonic
2-[5-methyl-2-(4-trifluoromethylphenyl)- oxazol-4-yl] -ethyl ester(1.4 g, 4 mmol) in dimethylformamide(10 ml) were added and stirred at room temperature for 2 days.
After the completion of the reaction, ice water was poured to the reaction product. Then, the resulting mixture was extracted with ethyl acetate and dried under reduced pressure. The residue thus obtained was dissolved in a mixture of ethyl acetate and hexane, and the product was recrystallized therefrom. The crystallized product was filtered to obtain the title compound(760 mg, yield: 50%).
1H NMR(CDCl3, 200MHz): δ(ppm) 9.96(1H, s), 8.09(2H, d), 7.68(2H, d), 7.40(3H, m), 7.14(lH,m,Ar-H), 4.32(2H, t), 3.02(2H, t), 2.41(3H, s)
Step 2: Preparation of (R)-3-(3-{2-[5-methyl-2-(4-trifluoromethylphenyl)-oxazol- 4-yl]-ethoxy}-benzyl)-thiazolidine-4-carboxylic acid methyl ester
The compound obtained in Step 1 of Example 11(0.3 g, 0.8 mmol) was dissolved in l,2-dichloroethane(10 ml), and (R)-4-thiazolidine carboxylic acid methyl ester hydrochloride(0.147 g, 0.8 mmol) and triethylamine(0.162 g, 1.6 mmol) were added thereto. While the resulting mixture was stirred, sodium triacetoxyborohydride(0.39 g, 1.6 mmol) was added thereto. The resulting mixture was stirred for 7 days. After the completion of the reaction, ice water was poured to the reaction product. Then, the resulting mixture was acidified with 1 N HCl and extracted with dichloromethane. Then, the organic layer was separated and dried under reduced pressure. The residue thus obtained was subjected to a silica gel chromatography (eluent: hexane/ethyl acetate=4/l) to obtain the title compound(110 mg, yield: 32%). 1H NMR(CDCl3, 200MHz): δ(ppm) 8.08(2H, d), 7.67(2H, d), 7.19(1H, t), 6.96(2H, m), 6.79(lH,m,Ar-H), 4.27(3H, m), 4.00(2H ,m), 3.71(4H, m), 3.57(1H, d), 3.27(1H, m), 3.19(1H, m), 2.99(2H,t,CH2CH2), 2.41(3H, s) Step 3: Preparation of (R)-3-(3-{2-[5-methyl-2-(4-trifluoromethylphenyl)-oxazol- 4-yl]-ethoxy}-benzyl)-thiazolidine-4-carboxy lie acid
The compound obtained in step 2 of Example 11 was dissolved in methanol(7 ml), and lithium hydroxide(l 1 mg, 0.44 mmol) was added thereto. The resulting mixture was heated to reflux for 18 hrs. To the reaction product, water and ethyl acetate were sequentially added. To the resulting mixture, 1 N HCl was added until the reaction solution would become transparent. Then, the organic layer was separated, dried over magnesium sulfate, and distilled under reduced pressure to obtain the title compound(47 mg, yield: 44%). 1H NMR(CDCl3, 200MHz): δ(ppm) 7.98(2H, d), 7.59(2H, d), 7.15(1H, t), 6.85(2H, m), 6.80(1H, m), 4.15(3H5 m), 4.11(2H, m), 3. 71(1H, m), 3.57(1H, d), 3.27(1H, m), 3.19(1H, m), 2.89(2H, t), 2.33(3H, s)
Example 12: Preparation of (R)-3-(4-{2-[5-methyI-2-(4-trifluoromethyIphenyl)- oxazoI-4-yI]-ethoxy}-benzyl)-thiazolidine-4-carboxyIic acid
Figure imgf000032_0001
Step 1 : Preparation of 4-{2-[5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl]- ethoxy } -benzaldehyde
The procedure of Step 1 of Example 11 was repeated except for using 4-hydroxybenzaldehyde(730 mg, 6 mmol) and methanesulfonic 2-[5-methyl-2-(4- trifluoromethylphenyl)-oxazol-4-yl]-ethyl ester(1.4 g, 4 mmol) to obtain the title compound(500 mg, yield: 33%).
1H NMR(CDCl3, 200MHz): δ(ppm) 9.87(1H, s), 8.08(2H, d), 7.81(2Hd), 7.68(2H, d,
Ar-H)5 7.01(2H, d), 4.34(2H, t), 3.02(2H, t), 2.41(3H, s)
Step 2: Preparation of (R)-3-(4-{2-[5-methyl-2-(4-trifluoromethylphenyl)-oxazol-
4-yl]-ethoxy}-benzyl)-thiazolidine-4-carboxylic acid methyl ester
The compound obtained in Step 1 of Example 12(0.25 g, 0.68 mmol),(R)-4-thiazolidine carboxylic acid methyl ester hydrochloride^ 49 mg, 0.81 mmol), sodium triacetoxyborohydride(288 mg, 1.36 mmol), and triethylamine(138 mg, 1.36 mmol) were dissolved in l52-dichloroethane(10 ml). The procedure of
Step 2 of Example 11 was repeated except for using the resulting mixture to obtain the title compound(60 mg, yield: 17%).
1H NMR(CDCl3, 200MHz): δ(ppm) 8.07(2H, d), 7.67(2H, d), 7.27(2H, d), 6.86(2H, d), 4.24(3H, m), 4.02(2H, m), 3.71(3H, s), 3.67(1H5 d), 3.54(1H, d), 3.27(1H, m), 3.17(1H, m), 2.98(2H5 1), 2.40(3H, s)
Step 3: Preparation of 3-(4-{2-[5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl]- ethoxy}-benzyl)-thiazolidine-4-carboxylic acid
The compound obtained in Step 2 of Example 12(60 mg, 0.12 mmol) and lithium hydroxide(6 mg, 0.24 mmol) were dissolved in methanol(5 ml). The procedure of Step 3 of Example 11 was repeated except for using the resulting mixture to obtain the title compound(50 mg, yield: 85%). 1H NMR(CDCl3, 200MHz): δ(ppm) 8.07(2H5 d), 7.67(2H5 d), 7.25(2H, d), 6.88(2H5 d), 5.66(1H, br-s), 4.24(2H, t), 4.13(1H, t), 4.00(2H5 m), 3.80(1H5 d), 3.68(1H5 d), 3.44(1H, m), 3.23(1H, m), 3.00(2H5 1), 2.40(3H, s)
Example 13: Preparation of 3-(4-{2-[5-methyI-2-(4-trifluoromethyIphenyl)- oxazoI-4-yI]-ethoxy}-benzyl)-thiazolidine-2-carboxylic acid
Figure imgf000033_0001
Step 1 : Preparation of 3-(4-{2-[5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl]- ethoxy}-benzyl)-thiazolidine-2-carboxylic acid methyl ester
The compound obtained in Step 1 of Example 12(250 mg, 0.68 mmol), 2-thiazolidine carboxylic acid methyl ester hydrochloride(149 mg, 0.81 mmol), sodium triacetoxyborohydride(288 mg, 1.36 mmol) and triethylamine(138 mg, 1.36 mmol) were dissolved in l,2-dichloroethane(10 ml). The procedure of Step 2 of
Example 11 was repeated except for using the resulting mixture to obtain the title compound(25 mg, yield: 7%). 1H NMR(CDCl3, 200MHz): δ(ppm) 8.08(2H, d), 7.67(2H, d), 7.26(2H, d), 6.85(2H, d), 4.67(1H, s), 4.24(2H, t), 3.66(3H, s), 3.40~3.54(4H, m), 3.00(4H5 m), 2.40(3H5 s)
Step 2: Preparation of 3-(4-{2-[5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl]- ethoxy } -benzyl)-thiazolidine-2-carboxylic acid The compound obtained in Step 1 of Example 13(25 mg, 0.05 mmol) was dissolved in methanol(5 ml). The procedure of Step 3 of Example 11 was repeated except for using the resulting mixture to obtain the title compound(10 mg, yield: 42%). 1H NMR(CDCl3, 200MHz): δ(ppm) 8.08(2H, d), 7.67(2H5 d), 7.26(2H, d), 6.86(2H, d), 5.1O(1H, br-s), 4.24(2H, t), 3.70(2H, m), 3.36(2H, m), 2.97~3.06(4H, m), 2.40(3H, s)
Example 14: Preparation of (R)-3~[3-(5-methyl-2-phenyl-oxazoI-4-ylmethoxy)~ benzyl] -thiazoIidine-4-carboxylic acid
Figure imgf000034_0001
Step 1 : Preparation of (R)-3-(3-hydroxy-benzyl)-thiazolidine-4-carboxylic acid methyl ester
(R)-(-)-thiazolidine-4-carboxylic acid methyl ester(1.84 g, 0.01 mol), 3-hydroxy benzaldehyde(1.22 g, 0.01 mol), sodium triacetoxyborohydride(288 mg,
1.36 mmol) and triethylamine(2.53 g, 0.025 mol) were dissolved in l,2-dichloroethane(100 ml). The procedure of Step 2 of Example 11 was repeated except for using the resulting mixture to obtain the title compound(1.90 g, yield:
75%). 1H NMR(CDCl3, 200MHz): δ(ppm) 7.22(1H, t), 6.93(2H, m), 6.77(2H, d), 4.97(1H, s), 4.27(1H, d), 4.03(2H, m), 3.73(3H, s), 3.69(1H, d), 3.61(1H5 d), 3.31(2H, d),
3.19(2H3 1)
Step 2: Preparation of (R)-3-[3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzyl]- thiazolidine-4-carboxylic acid methyl ester
The compound obtained in Step 1 of Example 14(100 mg, 0.4 mmol), 4-chloromethyl-5-methyl-2-phenyl-4,5-dihydro-oxazole(83 mg, 0.4 mmol) and potassium carbonate(83 mg, 0.6 mmol) were dissolved in dimethylformamide and stirred for 18 hrs. After the completion of the reaction, ice water was poured to the reaction product. Then, the resulting mixture was acidified with 1 N HCl and extracted with dichloromethane. Then, the organic layer was separated and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel chromatography(eluent: hexane/ethyl acetate=4/l) to obtain the title compound(70 mg, yield: 41%). 1H NMR(CDCl3, 200MHz): δ(ppm) 8.02(2H5 m), 7.46(3H, m), 7.28(1H, t), 7.01(1H5 s), 6.95(2H,m,Ar-H), 3.72(3H5 s), 3.59(1H, d), 3.15-3.31(2H, m), 2.44(3H, s)
Step 3: Preparation of (R)-3-[3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzyl]- thiazolidine-4-carboxylic acid The compound obtained in Step 2 of Example 14(30 mg, 0.07 mmol) and lithium hydroxide(3.4 mg, 0.14 mmol) were dissolved in methanol(7 ml). The procedure of Step 3 of Example 11 was repeated except for using the resulting mixture to obtain the title compound(29 mg, yield: 100%). 1H NMR(CDCl3, 200MHz): δ(ppm) 8.02(2H, m), 7.43(3H5 m), 7.31(1H, t), 7.07(1H, s), 6.95(2H,m,Ar-H), 4.88(1H, s), 4.13(1H, d), 4.04(2H, m), 3.84(1H, d), 3.7O(1H, d), 3.45(1H, m), 3.22(1H, m), 2.44(3H, s)
Example 15: Prepration of (R)-3-[3-(5-methyl-2-p-tolyl-oxazol-4- ylmethoxy)-benzyI]-thiazolidine-4-carboxyIic acid
Figure imgf000035_0001
Step 1: Preparation of (R)-3-[3-(5-methyl-2-jo-tolyl-oxazol-4-ylmethoxy)-benzylj- thiazolidine-4-carboxylic acid methyl ester
The compound obtained in Step 1 of Example 14(100 mg, 0.4 mmol), 4-chloromethyl-5-methyl-2-p-tolyl-4,5-dihydro-oxazole(89 mg, 0.4 mmol) and potassium carbonate(83 mg, 0.6 mmol) were dissolved in dimethylformamide(10 ml). The procedure of Step 2 of Example 14 was repeated except for using the resulting mixture to obtain the title compound(100 mg, yield: 57%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.91(2H, m), 7.27(3H, m), 6.99(1H, s), 6.93(2H, m), 4.98(2H, s), 4.29(1H, d), 4.02(2H, m), 3.76(1H, d), 3.71(3H, s), 3.59(1H, d),
3.18-3.30(2H, m), 2.43(3 H, s), 2.38(3 H, s)
Step 2: Preparation of (R)-3-[3-(5-methyl-2-/>-tolyl-oxazol-4-ylmethoxy)-benzyl]- thiazolidine-4-carboxylic acid 3-[3-(5-Methyl-2-/?-tolyl-oxazol-4-ylmethoxy)-benzyl]-thiazolidine-4- carboxylic acid methyl ester(30 mg, 0.07 mmol) and lithium hydroxide(3.4 mg, 0.14 mmol) were dissolved in methanol(7 ml). The procedure of Step 3 of Example 11 was repeated except for using the resulting mixture to obtain the title compound(29 mg, yield: 100%). 1H NMR(CDCl3, 200MHz): δ(ppm) 8.07(2H, d), 7.62~7.68(4H, m), 7.25~7.47(3H, m), 7.11(1H, s), 6.93(2H, m), 5.00(2H, s), 4.3O(1H, d), 4.06(2H, d), 3.85(1H, d),
3.72(1H, d), 3.19~3.45(2H, m), 2.42(3H, s), 2.38(3H, s)
Example 16: Preparation of (R)-3-[3-(2-biphenyI-4-yl-5-methyl-oxazoI-4- ylmethoxy)-benzyl]-thiazolidine-4-carboxylic acid
Figure imgf000036_0001
Step 1 : Preparation of (R)-3-[3-(2-biphenyl-4-yl-5-methyl-oxazol-4-ylmethoxy)- benzyl]-thiazolidine-4-carboxylic acid methyl ester
The compound obtained in Step 1 of Example 14(100 mg, 0.4 mmol), 2-biphenyl-4-chloromethyl-5-methyl-4,5-dihydro-oxazole(110 mg, 0.4 mmol) and potassium carbonate(83 mg, 0.6 mmol) were dissolved in dimethylformamide(10 ml). The procedure of Step 2 of Example 14 was repeated except for using the resulting mixture to obtain the title compound(l 10 mg, yield: 55%). 1H NMR(CDCl3, 200MHz): δ(ppm) 8.09(2H, d), 7.62~7.69(4H, m), 7.31~7.48(5H, m), 6.99(2H,d,Ar-H), 5.00(2H, s), 4.25(1H, d), 4.02(2H, m), 3.72(3H, s), 3.59(1H, d), 3.55(1H, d), 3.31(1H5 d), 3.18(1H, t), 2.45(3H, s)
Step 2: Preparation of (R)-3-[3-(2-biphenyl-4-yl-5-methyl-oxazol-4-ylmethoxy)- benzyl]-thiazolidine-4-carboxylic acid The compound obtained in Step 1 of Example 16(30 mg, 0.06 mmol) and lithium hydroxide(2.9 mg, 0.12 mmol) were dissolved in methanol(7 ml). The procedure of Step 3 of Example 11 was repeated except for using the resulting mixture to obtain the title compound(29 mg, yield: 100%).
1H NMR(CDCl3, 200MHz): δ(ppm) 8.08(2H, d), 7.61-7.69(4H5 m), 7.37~7.48(4H, m), 7.26(lH,s,Ar-H), 6.96(2H, m), 5.07(3H, s), 4.13(1H, d), 4.00(2H5 m), 3.86(1H, d), 3.7O(1H, d), 3.47(lH,m), 3.23(1H5 m), 2.45(3H5 s)
Example 17: Preparation of (R)-3-[3-(5-methyl-2-thiophen-2-yl-oxazol- 4-ylmethoxy)-benzyl] -thiazolidine-4-carboxyIic acid
Figure imgf000036_0002
Step 1 : Preparation of (R)-3-[3-(5-methyl-2-thiophen-2-yl-oxazol-4-ylmethoxy)- benzyl]-thiazolidine-4-carboxylic acid methyl ester
The compound obtained in Step 1 of Example 14(100 mg, 0.4 mmol), 4-chloromethyl-5-memyl-2-thiophen-2-yl-4,5-dihydro-oxazole(85 mg, 0.4 mmol) and potassium carbonate(83 mg, 0.6 mmol) were dissolved in dimethylformamide(10 ml). The procedure of Step 2 of Example 14 was repeated except for using the resulting mixture to obtain the title compound(77 mg, yield: 45%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.64(1H, d), 7.4O(1H, d), 7.25(1H, t), 7.10(2H, m), 6.90~6.99(2H, m), 4.96(2H, s), 4.27(1H, d), 4.02(2H5 m), 3.76(1H, d), 3.72(3H5 S)5 3.59(1H5 d), 3.30(lH,m), 3.17(1H5 m), 2.42(3H5 s)
Step 2: Preparation of (R)-3-[3-(5-methyl-2-thiophen-2-yl-oxazol-4-ylmethoxy)
-benzyl] -thiazolidine-4-carboxy lie acid
The compound obtained in Step 1 of Example 17(26 mg, 0.06 mmol) and lithium hydroxide(2.9 mg, 0.12 mmol) were dissolved in methanol(7 ml). The procedure of Step 3 of Example 11 was repeated except for using the resulting mixture to obtain the title compound(17 mg, yield: 68%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.64(1H, d), 7.40(1H5 d), 7.28(1H5 1), 7.09(2H, m), 6.95(2H,m,Ar-H), 5.12(1H5 s), 4.98(2H, s), 4.13(1H5 d), 4.01(2H5 m), 3.84(1H5 d), 3.71(lH,d), 3.47(1H, m), 3.24(1H, m), 2.42(3H5 s)
Example 18: Preparation of (R)-3-{3-[5-methyl-2-(4-trifluoromethylphenyl)- oxazoI-4-ylmethoxy]-benzyI}-thiazolidine-4-carboxylic acid
Figure imgf000037_0001
Step 1 : Preparation of (R)-3-[3-(5-methyl-2-(-trifluoromethylphenyl-oxazol-4- ylmethoxy)-benzyl)-thiazolidine-4-carboxylic acid methyl ester
The compound obtained in Step 1 of Example 14(100 mg, 0.4 mmol), 4-chloromethyl-5-methyl-2-(4-trifluoromethylphenyl)-4,5-dihydro-oxazole(l 10 mg5 0.4 mmol) and potassium carbonate(83 mg, 0.6 mmol) were dissolved in dimethylformamide(10 ml). The procedure of Step 2 of Example 14 was repeated except for using the resulting mixture to obtain the title compound(80 mg, yield: 41%). 1H NMR(CDCl3, 200MHz): δ(ppm) 8.13(1H, d), 7.70(2H, d), 7.26(1H, t), 7.01(1H, s), 6.95(2H,m,Ar-H), 5.00(2H5 s), 4.29(1H, d), 4.04(2H, m), 3.77(1H, d), 3.72(3H, s), 3.63(1H, d), 3.31(1H, m), 3.18(1H, m), 2.47(3H, s)
Step 2: Preparation of (R)-3-{3-[5-methyl-2-(4-trifluoromethylphenyl)-oxazol- 4-ylmethoxy]-benzyl}-thiazolidine-4-carboxy lie acid
The compound obtained in Step 1 of Example 18(20 mg, 0.04 mmol) and lithium hydroxide(2.4 mg, 0.08 mmol) were dissolved in methanol(7 ml). The procedure of Step 3 of Example 11 was repeated except for using the resulting mixture to obtain the title compound(17 mg, yield: 89%).
1H NMR(CDCl3, 200MHz): δ(ppm) 8.12(1H, d), 7.70(2H, d), 7.26(1H, t), 7.06(1H, s), 6.95(2H, m), 6.2O(1H, s), 5.06(2H5 s), 4.13(1H, d), 4.01(2H, m), 3.87(1H, d), 3.7O(1H, d), 3.45(1H, m), 3.24(1H, m), 2.48(3H, s)
Example 19: Preparation of (R)-3-{3-[2~(2-biphenyI-4-yl-5-methyl-oxazol- 4-yI)-ethoxy] -benzyl} -thiazolidine-4-carboxylic acid
Figure imgf000038_0001
Step 1 : Preparation of (R)-3-{3-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]- benzyl} -thiazolidine-4-carboxylic acid methyl ester The compound obtained in Step 1 of Example 14(100 mg, 0.4 mmol),
[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethanol(110 mg, 0.4 mmol) and triphenylphosphine(126 mg, 0.48 mmol) were dissolved in anhydrous toluene and stirred for 30 mins. To the resulting mixture, diisopropylazodicarboxylate(97 mg, 0.48 mmol) was added and stirred for 3 hrs. After the completion of the reaction, ice water was poured to the reaction product, and the resulting mixture was extracted with ethyl ester. Then, the organic layer was separated and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel chromatography(eluent: hexane/ethyl acetate=4/l) to obtain the title compound(58 mg, yield: 28%). 1H NMR(CDCl3, 200MHz): δ(ppm) 8.05(2H, d), 7.67(4H, m), 7.36~7.47(3H, m), 7.22(1H, t), 6.70~6.97(3H, m), 4.27(3H, m), 4.02(3H, m), 3.74(1H, m), 3.71(3H, s), 3.61(1H, m), 3.27(2H, m), 3.17(1H, m), 2.99(2H, t), 2.40(3H, s)
Step 2: Preparation of (R)-3-{3-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]- benzyl} -thiazolidine-4-carboxylic acid
The compound obtained in Step 1 of Example 19(22 mg, 0.042 mmol) and lithium hydroxide(2 mg, 0.084 mmol) were dissolved in methanol(3 ml). The procedure of Step 3 of Example 11 was repeated except for using the resulting mixture to obtain the title compound(20 mg, yield: 100%). 1H NMR(CDCl3, 200MHz): δ(ppm) 8.04(2H, d), 7.65(4H, m), 7.36~7.47(3H, m), 7.25(1H5 1), 7.05(1H, s), 6.89(2H5 m), 4.6O(1H, br-s), 4.00-4.28(5H5 m), 3.85(1H5 d), 3.74(1H5 d)5 3.43(1H5 d), 3.23(1H, t), 2.99(2H5 1), 2.39(3H5 s)
Example 20: Preparation of 3-[4~(5-methyl-2-phenyl-oxazoI-4-yImethoxy)- benzyl]-thiazolidine-2-carboxyIic acid
Figure imgf000039_0001
Step 1 : Preparation of 3-(4-hydroxy-benzyl)-thiazolidine-2-carboxylic acid methyl ester Thiazolidine-2-carboxylic acid methyl ester hydrochloride(1.22 g, 0.01 mol),
4-hydroxybenzaldehyde(1.84 g, 0.01 mol) and triethylamine(2.53g, 0.025 mol) were dissolved in l,2-dichloromethane(100 ml), and then, sodium triacetoxyborohydride(3.18 g, 0.015 mol) was added thereto. The procedure of Step 1 of Example 11 was repeated except for using the resulting mixture to obtain the title compound( 1.9 g, yield: 75%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.24(2H, d) 6.79(2H, d), 4.94(1H, s), 3.68(3H5 s), 3.54(2H5 d), 3.45(2H5 m), 3.00(2H5 m)
Step 2: Preparation of 3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzyl]- thiazolidine-2-carboxylic acid methyl ester
The compound obtained in Step 1 of Example 20(100 mg, 0.4 mmol), 4-chloromethyl-5-methyl-2-phenyl-455-dihydro-oxazole(83 mg, 0.4 mmol) and potassium carbonate(0.6 mmol) were dissolved in dimethylformamide(10 ml). The procedure of Step 2 of Example 14 was repeated except for using the resulting mixture to obtain the title compound(50 mg, yield: 29%).
1H NMR(CDCl3, 200MHz): δ(ppm) 8.00(2H, m), 7.44(3H, t), 7.30(2H, d), 6.97(2H5 d), 4.99(2H, s), 4.7O(1H, s), 3.68(3H5 s), 3.41~3.56(4H, m), 3.01(2H, m), 2.44(3H, s)
Step 3: Preparation of 3-[4-(5-methyl-2-ρhenyl-oxazol-4-ylmethoxy)-benzyl]- thiazolidine-2-carboxylic acid
The compound obtained in Step 2 of Example 20(30 mg, 0.07 mmol) and lithium hydroxide(3.4 mg, 0.14 mmol) were dissolved in methanol(7 ml). The procedure of Step 3 of Example 11 was repeated except for using the resulting mixture to obtain the title compound(29 mg5 yield: 100%).
1H NMR(CDCl35 200MHz): δ(ppm) 8.01(2H5 m), 7.44(3H, t), 7.41(2H, d), 6.99(2H5 d), 4.99(2H, s), 4.69(1H5 s), 3.68(2H5 s), 3.37(2H5 m), 3.03(2H5 m), 2.43(3H5 s)
Example 21: Preparation of 3-[4-(5-methyI-2-/?-tolyI-oxazol-4-ylmethoxy)- benzyl]-thiazoIidine-2-carboxylic acid
Figure imgf000040_0001
Step 1 : Preparation of 3-[4-(5-methyl-2-j^-tolyl-oxazol-4-ylmethoxy)-benzyl]- thiazolidine-2-carboxylic acid methyl ester
The compound obtained in Step 1 of Example 20(100 mg, 0.4 mmol),
4-chloromethyl-5-methyl-2-/7-tolyl-4,5-dihydro-oxazole(89 mg, 0.4 mmol) and potassium carbonate(83 mg, 0.6 mmol) were dissolved in dimethylformamide(10 ml). The procedure of Step 2 of Example 14 was repeated except for using the resulting mixture to obtain the title compound(l 10 mg, yield: 63%).
1U NMR(CDCl3, 200MHz): δ(ppm) 7.90(2H5 d), 7.28(4H, m), 4.97(2H5 s), 4.7O(1H, s)5 3.68(3H, s), 3.41-3.56(4H5 m), 3.01(2H, m), 2.42(3H5 s), 2.40(3H5 s)
Step 2: Preparation of 3-[4-(5-methyl-2-p-tolyl-oxazol-4-ylmethoxy)-benzyl]- thiazolidine-2-carboxylic acid
3. [4_(5 -Methyl-2-jσ-toly l-oxazol-4-ylmethoxy)-benzyl] -thiazolidine-2- carboxylic acid methyl ester(30 mg, 0.68 mmol) and lithium hydroxide(3.3 mg, 0.136 mmol) were dissolved in methanol(7 ml). The procedure of Step 3 of
Example 11 was repeated except for using the resulting mixture to obtain the title comρound(29 mg5 100%).
1H NMR(CDCl35 200MHz): δ(ppm) 7.89(2H5 d), 7.26(4H, m), 6.90(2H5 d), 6.85(1H, brs), 4.98(2H5 s), 4.69(1H5 s), 3.67(2H5 s), 3.37(2H, m), 3.03(2H5 m), 2.41(3H5 s), 2.38(3H5 s)
Example 22: Preparation of 3-[4-(2-biphenyl-4-yl-5-methyl-oxazol-4- ylmethoxy)-benzyI]-thiazolidine-2-carboxylic acid
Figure imgf000040_0002
Step 1 : Preparation of 3-[4-(2-biphenyl-4-yl-5-methyl-oxazol-4-ylmethoxy)-benzyl]- thiazolidine-2-carboxylic acid methyl ester
The compound obtained in Step 1 of Example 20(100 mg, 0.4 mmol) and
2-biphenyl-4-chloromethyl-5-methyl-4,5-dihydrorθxazole(110 mg, 0.4 mmol) were dissolved in dimethylformamide(10 ml). The procedure of Step 2 of Example 14 was repeated except for using the resulting mixture to obtain the title compound(130 mg, yield: 65%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.89(2H, d), 7.26(4H, m), 6.90(2H, d), 6.85(1H, bra), 4.98(2H, s), 4.69(1H, s), 3.67(2H5 s), 3.37(2H, m), 3.03(2H, m), 2.41(3H, s), 2.38(3H, s)
Step 2: Preparation of 3-[4-(2-biphenyl-4-yl-5-methyl-oxazol-4-ylmethoxy)-benzyl]- thiazolidine-2-carboxylic acid
The compound obtained in Step 1 of Example 22(30 mg, 0.06 mmol) and lithium hydroxide(2.9 mg, 0.12 mmol) were dissolved in methanol(7 ml). The procedure of Step 3 of Example 11 was repeated except for using the resulting mixture to obtain the title compound(28 mg, yield: 100%).
1H NMR(CDCl3, 200MHz): δ(ppm) 8.09(2H, d), 7.64(4H, m), 7.22~7.48(4H, m),
7.00(2H, d), 6.8O(1H, d), 5.00(2H, s), 4.68(1H, s), 3.70(2H, s), 3.35(4H, m), 3.06(2H, m), 2.46(3H5 s)
Example 23: Preparation of 3-[4-(5-methyl-2-thiophen-2-yI-oxazol-4- ylmethoxy)-benzyl]-thiazolidine-2-carboxylic acid
Figure imgf000041_0001
Step 1 : Preparation of 3-[4-(5-methyl-2-thiophen-2-yl-oxazol-4-ylmethoxy)-benzyl]- thiazolidine-2-carboxylic acid methyl ester
The compound obtained in Step 1 of Example 20(100 mg, 0.4 mmol),
4-chloromethyl-5-methyl-2-thiophen-2-yl-4,5-dihydro-oxazole(85 mg, 0.4 mmol) and potassium carbonate(83 mg, 0.6 mmol) were dissolved in dimethylformamide(10 ml). The procedure of Step 2 of Example 14 was repeated except for using the resulting mixture to obtain the title compound(80 mg, yield:
47%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.64(1H, d), 7.38(1H, d), 7.26(2H, d), 7.09(1H, t), 6.90(2H, d), 4.96(2H, s), 4.69(1H5 s), 3.67(3H5 s), 3.60(2H5 s), 3.38~3.48(2H, m), 3.01(2H5 m), 2.41(3H, s) Step 2: Preparation of 3-[4-(5-methyl-2-thiophen-2-yl-oxazol-4-ylmethoxy)-benzyl]- thiazolidine-2-carboxylic acid
The compound obtained in Step 1 of Example 23(20 mg, 0.046 mmol) and lithium hydroxide(2.2 mg, 0.09 mmol) were dissolved in methanol(7 ml). The procedure of Step 3 of Example 11 was repeated except for using the resulting mixture to obtain the title compound(14 mg, yield: 74%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.64(1H, d), 7.4O(1H, d), 7.26(2H, d), 7.1O(1H, t), 6.97(2H, d), 5.30(1H, br-s), 4.96(2H, s), 4.69(1H, s), 3.69(2H, s), 3.35(2H, m), 3.04(2H, m), 2.41(3H, s)
Example 24: Preparation of 3-[4-(5-methyl-2-(4-trifluoromethylphenyI)-oxazol- 4-ylmethoxy)-benzyl]-thiazoIidine-2-carboxylic acid
Figure imgf000042_0001
Step 1: Preparation of 3-[4-(5-methyl-2-(-trifluoromethyl-phenyl-oxazol-4- ylmethoxy)-benzyl)-thiazolidine-2-carboxylic acid methyl ester
The compound obtained in Step 1 of Example 20(100 mg, 0.4 mmol),
4-chloromethyl-5-methyl-2-(4-trifluoromethylphenyl)-4, 5-dihydro-oxazole( 110 mg,
0.4 mmol) and potassium carbonate(83 mg, 0.6 mmol) were dissolved dimethylformamide(10 ml). The procedure of Step 2 of Example 14 was repeated except for using the resulting mixture to obtain the title compound(70 mg, yield:
Oλ O).
1H NMR(CDCl3, 200MHz): δ(ppm) 8.12(2H, d), 7.70(2H, d), 7.29(2H, d), 6.99(2H, d), 4.99(2H, s), 4.69(1H, s), 3.68(3H, s), 3.57(2H, s), 3.40~3.55(2H, m), 3.02(2H, m),
2.47(3H, s)
Step 2: Preparation of 3-[4-(5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4- ylmethoxy)-benzyl]-thiazolidine-2-carboxylic acid
The compound obtained in Step 1 of Example 24(28 mg, 0.056 mmol) and lithium hydroxide(2.6 mg, 0.11 mmol) were dissolved in methanol(7 ml). The procedure of Step 3 of Example 11 was repeated except for using the resulting mixture to obtain the title compound(20 mg, yield: 74%).
1H NMR(CDCl3, 200MHz): δ(ppm) 8.15(2H, d), 7.70(2H, d), 7.26(2H, t), 6.95(2H, d), 5.00(1H, s), 4.69(1H, s), 3.67(2H, s), 3.39~3.48(2H, m), 3.05(2H, m), 2.47(3H, s)
Example 25: Preparation of 3-{4-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)- ethoxy]-ben^I}-thiazoIidine-2-carboxylic acid
Figure imgf000043_0001
Step 1 : Preparation of 3-{4-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]- benzyl}-thiazolidine-2-carboxylic acid methyl ester The procedure of Example 19 was repeated except for using the compound obtained in Step 1 of Example 20(100 mg, 0.4 mmol), 2-(2-biphenyl-4-yl-methyl-oxazol-4-yl)-ethanol(110 mg, 0.4 mmol), triphenylphosphine(126 mg, 0.48 mmol) and diisopropylazodicarboxylate(97 mg, 0.48 mmol) to obtain the title compound(88 mg, yield: 43%). 1H NMR(CDCl3, 200MHz): δ(ppm) 8.04(2H, d), 7.64(4H, m), 7.21~7.28(3H, m), 7.18(2H, d), 6.82(2H, d), 4.69(1H, s), 4.23(2H, t), 3.66(3H, s), 3.50(2H, d), 3.41~3.46(2H, m), 2.98(2H, t), 2.39(3H, s)
Step 2: Preparation of 3-{4-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]- benzyl} -thiazolidine-2-carboxylic acid
3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxyJ-benzyl}-thiazolidine -2-carboxylic acid methyl ester(18 mg, 0.035 mmol) and lithium hydroxide(1.7 mg, 0.07 mmol) were dissolved in methanol(7 ml). The procedure of Step 3 of Example 11 was repeated except for using the resulting mixture to obtain the title compound(14 mg, yield: 82%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.98(2H, d), 7.35~7.47(2H, m), 7.18(2H, d), 6.79(2H, d), 4.69(lH,s), 4.24(2H, t), 3.66(3H, s), 3.46(2H, d), 3.38~3.44(2H, m), 3.00(2H, m), 2.39(3H, s)
Example 26: Preparation of 3-{4-[2~(5-methyl-2-thiophen-2-yI-oxazol-4-yI)- ethoxy]-benzyI}-thiazolidine-2-carboxylic acid
Figure imgf000043_0002
Step 1 : Preparation of 3-{4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]- benzyl }-thiazolidine-2-carboxylic acid methyl ester
The procedure of Step 1 of Example 19 was repeated except for using the compound obtained in Step 1 of Example 20(100 mg, 0.4 mmol),
2-(5-methyl-thiophen-2-yl-oxazol-4-yl)-ethanol(84 mg, 0.4 mmol), triphenylphosphine(126 mg, 0.48 mmol) and diisopropylazodicarboxylate(97 mg,
0.48 mmol) to obtain the title compound(18 mg, yield: 10%).
1H NMR(CDCl3, 200MHZ): δ(ppm) 7.6O(1H, d), 7.37(1H, d), 7.20(2H, d), 7.08(1H, t), 6.82(2H, d), 4.69(1H, s), 4.20(2H, t), 3.66(3H, s), 3.50(2H, d), 3.41-3.46(2H, m),
2.98(2H5 1), 2.35(3H, s)
Step 2: Preparation of 3-{4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]- benzyl} -thiazolidine-2-carboxylic acid
The compound obtained in Step 1 of Example 26(29 mg, 0.065 mmol) and lithium hydroxide(3.1 mg, 0.07 mmol) were dissolved in methanol(7 ml). The procedure of Step 3 of Example 11 was repeated except for using the resulting mixture to obtain the title compound(20 mg, yield: 71%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.6O(1H, d), 7.36(1H, d), 7.23(2H, d), 7.08(1H, t), 6.85(2H, d), 4.66(1H)5 4.22(1H5 s), 3.76(2H, s), 3.64(2H, s), 3.33(2H, d), 3.05(2H, m), 2.98(2H5 1), 2.35(3H, s)
Example 27: Preparation of 3-[3-(5-methyl~2-phenyI-oxazol-4-ylmethoxy)- benzyl] -thiazolidine-2-carboxylic acid
Figure imgf000044_0001
Step 1: Preparation of 3-(3-hydroxy-benzyl)-thiazolidine-4-carboxylic acid methyl ester
Thiazolidine-4-carboxylic acid methyl ester(1.47 g5 0.8 mol), 3-hydroxybenzaldehyde(0.97 g5 0.8 mol) and triethylamine(2.02 g, 0.02 mol) were dissolved in l,2-dichloromethane(100 ml), and then, sodium triacetoxyborohydride(2.54 g, 12 mmol) was added thereto. The procedure of Step 1 of Example 11 was repeated except for using the resulting mixture to obtain the title compound(1.3 g, yield: 64%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.21(1H, t), 6.92(1H5 s), 6.87(1H5 d), 6.77(1H5 d), 5.76(1H5 s), 4.09(3H, s), 3.69(2H, s), 3.44(2H, m), 3.00(2H, m)
Step 2: Preparation of 3-[3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzyl]- thiazolidine-2-carboxylic acid methyl ester
The compound obtained in Step 1 of Example 27(100 mg, 0.4 mmol),
4-chloromethyl-5-methyl-2-phenyl-4,5-dihydro-oxazole(83 mg, 0.4 mmol) and potassium carbonate(83 mg, 0.6 mmol) were dissolved in dimethylformamide(10 ml). The procedure of Step 2 of Example 14 was repeated except for using the resulting mixture to obtain the title compound(69 mg, yield: 41%).
1H NMR(CDCl3, 200MHz): δ(ppm) 8.00(2H, m), 7.42(3H5 m), 7.26(1H, t), 7.08(1H, s), 6.93(2H, t), 4.98(2H, s), 4.7O(1H, s), 3.67(3H, s), 3.59(2H, s), 3.38(2H, m),
3.01(2H, m), 2.44(3H, s)
Step 3: Preparation of 3-[3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzyl]- thiazolidine-2-carboxylic acid
The compound obtained in Step 2 of Example 27(30 mg, 0.07 mmol) and lithium hydroxide(3.4 mg, 0.14 mmol) were dissolved in methanol(7 ml). The procedure of Step 3 of Example 11 was repeated except for using the resulting mixture to obtain the title compound(28 mg, yield: 99%).
1H NMR(CDCl3, 200MHz): δ(ppm) 8.00(2H, m), 7.38(3H, m), 7.26(1H, t), 7.07(1H, s), 6.95(2H, t), 5.01(2H, s), 4.69(1H, s), 3.69(2H, s), 3.37(2H, m), 3.01(2H m),2.43(3H, s)
Example 28: Preparation of 3-[3-(5-methyl-2-thiophen-2-yI-oxazoI-4- ylmethoxy)-benzyl] -thiazolidine-2-carboxylic acid
Figure imgf000045_0001
Step 1: Preparation of 3-[3-(5-methyl-2-thiophen-2-yl-oxazol-4-ylmethoxy)~ benzyl]-thiazolidine-2-carboxylic acid methyl ester
The compound obtained in Step 1 of Example 27(100 mg, 0.4 mmol), 4-chloromethyl-5-methyl-2-thiophen-2-yl-4,5-dihydro-oxazole(85 mg, 0.4 mmol) and potassium carbonate(83 mg, 0.6 mmol) were dissolved in dimethylformamide(10 ml). The procedure of Step 2 of Example 14 was repeated except for using the resulting mixture to obtain the title compound(140 mg, yield: 81%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.64(1H, d), 7.38(1H5 d), 7.24(2H5 1)5 7.09(2H, m), 6.95(2H, m), 4.95(2H, s), 4.69(1H5 s), 3.67(3H, s), 3.66(2H, s), 3.40-3.59(2H5 m), 3.00(2H5 m), 2.41(3H, s) Step 2: Preparation of 3-[3-(5-methyl-2-thiophen-2-yl-oxazol-4-ylmethoxy)-benzyl]- thiazolidine-2-carboxylic acid
The compound obtained in Step 1 of Example 28(30 mg, 0.07 mmol) and lithium hydroxide(3.4 mg, 0.14 mmol) were dissolved in methanol(7 ml). The procedure of Step 3 of Example 11 was repeated except for using the resulting mixture to obtain the title compound(28 mg, yield: 96%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.64(1H, d), 7.39(1H, d), 7.23(2H, t), 7.06(2H5 m), 6.92(2H, m), 6.06(1H, br-s), 4.98(2H, s), 4.69(1H5 s), 3.67(2H, s), 3.40(2H5 m), 3.02(2H5 m), 2.41(3H5 s)
Example 29: Preparation of 3-[3-(5-methyl-2-(4-trifluoromethylphenyI)-oxazol- 4-ylmethoxy)-benzyl]-thiazolidine-4-carboxylic acid
Figure imgf000046_0001
Step 1: Preparation of 3-[2-(5-methyl-2r(-trifluoromethyl-phenyl-oxazol-4- ylmethoxy)-benzyl)-thiazolidine-2-carboxylic acid methyl ester
The compound obtained in Step 1 of Example 27(100 mg, 0.4 mmol),
4-chloromethyl-5-methyl-2-(4-trifluoromethylphenyl)-4, 5-dihydro-oxazole( 104 mg,
0.4 mmol) and potassium carbonate(83 mg, 0.6 mmol) were dissolved in dimethylformamide(10 ml). The procedure of Step 2 of Example 14 was repeated except for using the resulting mixture to obtain the title compound(140 mg, yield:
73%).
1H NMR(CDCl3, 200MHz): δ(ppm) 8.13(2H, d), 7.70(2H, d), 7.09(1H, t), 6.99(1H5 s), 6.92(2H, m), 4.99(2H5 s), 4.70(1H5 s), 3.68(3H, s), 3.60(2H, s), 3.40~3.55(2H, m),
3.02(2H, m), 2.47(3H, s)
Step 2: Preparation of 3-[3-(5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4- ylmethoxy)-benzyl]-thiazolidine-4-carboxylic acid
The compound obtained in Step 1 of Example 29(30 mg, 0.061 mmol) and lithium hydroxide(2.9 mg, 0.12 mmol) were dissolved in methanol(7 ml). The procedure of Step 3 of Example 11 was repeated except for using the resulting mixture to obtain the title compound(29 mg, yield: 100%).
1H NMR(CDCl3, 200MHz): δ(ppm) 8.12(2H, d), 7.70(2H5 d), 7.26(2H, t), 7.07(1H5 s), 6.95(2H, d), 5.08(1H5 s), 5.01(2H, s), 4.7O(.1H, s), 3.69(2H, d), 3.37(2H, m),
3.03(2H, m), 2.45(3H, s) Example 30: Preparation of 3-{3-[2-(5-methyI-2-phenyl-oxazoI-4-yI)-ethoxy]- benzyl}-thiazolidine-2-carboxylic acid
Figure imgf000047_0001
Step 1 : Preparation of 3-{3-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzyl}- thiazolidine-2-carboxylic acid methyl ester
The procedure of Step 1 of Example 19 was repeated except for using the compound obtained in Step 1 of Example 27(100 mg, 0.4 mmol),
2-(5-methyl-2-phenyl-oxazol-4-yl)-ethanol(81 mg, 0.4 mmol), triphenylphosphine(126 mg, 0.48 mmol) and diisopropylazodicarboxylate(97 mg, 0.48 mmol) to obtain the title compound(37 mg, yield: 21 %) .
1H NMR(CDCl3, 200MHz): δ(ppm) 7.98(2H, d), 7.40(3H5 m), 7.21(2H, d), 6.92(2H, d), 6.84(2H, d), 4.67(1H, s), 4.25(2H, t), 3.66(3H5 s), 3.56(2H), 3.39~3.50(2H, m), 2.99(2H3 m), 2.37(3H, s)
Step 2: Preparation of 3-{3-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzyl}- thiazolidine-2-carboxylic acid
The compound obtained in Step 1 of Example 30(29 mg, 0.066 mmol) and lithium hydroxide(3.1 mg, 0.13 mmol) were dissolved in methanol(7 ml). The procedure of Step 3 of Example 11 was repeated except for using the resulting mixture to obtain the title compound(24 mg, yield: 85%).
1H NMR(CDCl3, 200MHz): δ(ppm) 8.04(2H, d), 7.64(4H, m) 7.36~7.45(3H, m), 7.22(1H, m), 7.19(1H, s), 6.88(2H, m), 4.67(1H, s), 4.27(2H, m), 3.70(2H, s), 3.37(2H5 m), 3.06(2H, m), 2.98(2H, t), 2.39(3H5 s)
Example 31: Preparation of 3-{3-[2-(2-biphenyI-4-yl-5-methyl-oxazol-4-yI)- ethoxy]-benzyl}-thiazolidine-2-carboxylic acid
Figure imgf000047_0002
Step 1 : Preparation of 3-{3-[2-(2-biρhenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]- benzyl} -thiazolidine-2-carboxylic acid methyl ester The procedure of Step 1 of Example 19 was repeated except for using the compound obtained in Step 1 of Example 27(100 mg, 0.4 mmol),
2-(2-biphenyl-4-yl-methyl-oxazol-4-yl)-ethanol(110 mg, 0.4 mmol), triphenylphosphine(126 mg, 0.48 mmol) and diisopropylazodicarboxylate(97 mg, 0.48 mmol) to obtain the title compound(95 mg, yield: 46%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.98(2H, d), 7.35~7.47(2H, m), 7.18(2H, d), 6.79(2H, d), 4.69(1H, s), 4.24(2H, t), 3.66(3H, s), 3.46(2H, d), 3.38~3.44(2H, m), 3.00(2H, m), 2.39(3H, s)
Step 2: Preparation of 3-{3-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]- benzyl}-thiazolidine-2-carboxylic acid
The compound obtained in Step 1 of Example 31(30 mg, 0.058 mmol) and lithium hydroxide(2.9 mg, 0.13 mmol) were dissolved in methanol(7 ml). The procedure of Step 3 of Example 11 was repeated except for using the resulting mixture to obtain the title compound(20 mg, yield: 69%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.91(2H, d), 7.26(4H, m), 7.01(2H, d), 5.03(1H, s), 4.99(2H, s), 4.01(3H, m), 3.84(1H, d), 3.7O(1H, d), 3.51(1H, d), 2.38(3H, s), 3.25(1H, t), 2.43(3H, s)
Example 32: Preparation of 3-(3-{2-[5-methyl-2-(4-trifluoromethylphenyI)- oxazol-4-yl]-ethoxy}-benzyl)-thiazolidine-2-carboxylic acid
Figure imgf000048_0001
Step 1 : Preparation of 3-(3-{2-[5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl]- ethoxy}-benzyl)-thiazolidine-2-carboxylic acid methyl ester The procedure of Step 1 of Example 19 was repeated except for using the compound obtained in Step 1 of Example 27(100 mg, 0.4 mmol),
2-[5-methyl-2-(4-trifluoromethylphenyl)-όxazol-4-yl]-ethanol(110 mg, 0.4 mmol), triphenylphosphine(126 mg, 0.48 mmol) and diisopropylazodicarboxylate(97 mg,
0.48 mmol) to obtain the title compound(31 mg, yield: 16%). 1H NMR(CDCl3, 200MHz): δ(ppm) 8.09(2H, d), 7.66(2H, d), 7.22(1H, t), 6.93(2H, m), 6.80(2H, d), 4.68(1H, s), 4.24(2H, t), 3.67(3H, s), 3.57(2H, d), 3.37-3.44(2H, m),
3.01(2H, t), 2.40(3H, s)
Step 2: Preparation of 3-(3-{2-[5-methyl-2-(4-trifluoromethylρhenyl)-oxazol-4-yl]- ethoxy } -benzyl)-thiazolidine-2-carboxylic acid
The compound obtained in Step 1 of Example 32(15 mg, 0.03 mmol) and lithium hydroxide(1.5 mg, 0.06 mmol) were dissolved in methanol(7 ml). The procedure of Step 3 of Example 11 was repeated except for using the resulting mixture to obtain the title compound(13 mg, yield: 92%).
1H NMR(CDCl3, 200MHz): δ(ppm) 8.09(2H, d), 7.68(2H, d), 7.21(1H, t), 6.91(2H, m), 6.83(2H, m). 4.66(1H5 s), 4.26(2H, t), 3.72(2H, s), 3.37(2H, m), 3.10(2H, m), 3.00(2H, t), 2.41(3H, s)
Example 33: Preparation of (R)-3~[4-(5-methyl-2-phenyl-oxazoI-4-yImethoxy)- benzyl] -thiazolidine-4-carboxylic acid
Figure imgf000049_0001
Step 1 : Preparation of (R)-3-(4-hydroxy-benzyl)-thiazolidine-4-carboxylic acid methyl ester (R)-thiazolidine-4-carboxylic acid methyl ester hydrochloride(1.47 g, 8 mmol), 4-hydroxybenzaldehyde(0.97 g, 8 mmol), sodium triacetoxyborohydride(2.54 g, 0.12 mol) and triethylamine(2.02 g, 0.012 mol) were dissolved in l,2-dichloromethane(50 ml). The procedure of Step 2 of Example 11 was repeated except for using the resulting mixture to obtain the title compound(1.15 g, yield: 57%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.22(2H, d), 6.81(2H, d), 5.46(1H, s), 4.27(1H, d), 4.02(2H, m), 3.72(3H, s), 3.69(1H, d), 3.57(1H, d), 3.18(2H, m)
Step 2: Preparation of (R)-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)- benzyl] -thiazolidine-4-carboxylic acid methyl ester
The compound obtained in Step 1 of Example 33(100 mg, 0.4 mmol), 4-chloromethyl-5-methyl-2-phenyl-4,5-dihydro-oxazole(83 mg, 0.4 mmol) and potassium carbonate(83 mg, 0.6 mmol) were dissolved in dimethylformamide(10 ml). The procedure of Step 2 of Example 14 was repeated except for using the resulting mixture to obtain the title compound(47 mg, yield: 28%).
1H NMR(CDCl3, 200MHz): δ(ppm) 8.00(2H, d), 7.44(3H, m), 7.30(2H, d), 6.75(2H, d), 4.98(2H, s), 4.24(1H, d), 4.00(2H, m), 3.71(3H5 s), 3.67(1H5 d), 3.54(1H, d), 3.30(1H, d), 3.17(1H, t), 2.43(3H5 s)
Step 3 : Preparation of (R)-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzyl]- thiazolidine-4-carboxylic acid The compound obtained in Step 2 of Example 33(15 mg, 0.035 mmol) and lithium hydroxide(1.7 mg, 0.06 mmol) were dissolved in methanol(7 ml). The procedure of Step 3 of Example 11 was repeated except for using the resulting mixture to obtain the title compound(14 mg, yield: 100%).
1H NMR(CDCl3, 200MHZ): δ(ppm) 8.02(2H, d), 7.43(3H3 m), 7.40(2H, d), 7.02(2H, d), 5.00(2H, s), 4.04(3H, m,CH2), 3.81(3H, s), 3.68(1H, d), 3.50(1H, d), 3.25(1H, t), 2.42(3H, s)
Example 34: Preparation of (R)-3-[4-(5-methyl-2-/?-toIyl-oxazol-4- yImethoxy)-benzyI]-thiazolidine-4-carboxyIic acid
Figure imgf000050_0001
Step 1 : Preparation of (R)-3-[4-(5-methyl-2-p-toryl-oxazol-4-ylmethoxy)- benzyl]-thiazolidine-4-carboxylic acid methyl ester
The compound obtained in Step 1 of Example 33(100 mg, 0.4 mmol),
4-chloromethyl-5-memyl-2-/?-tolyl-4,5-dihydro-oxazole(89 mg, 0.4 mmol) and potassium carbonate(83 mg, 0.6 mmol) were dissolved in dimethylformamide(10 ml). The procedure of Step 2 of Example 14 was repeated except for using the resulting mixture to obtain the title compound(100 mg, yield: 57%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.91(2H, d), 7.29(2H, d), 7.22(2H, d), 6.97(2H, d), 4.97(2H, s), 4.26(1H, d), 4.02(2H, m), 3.71(3H, s), 3.58(1H, d), 3.54(1H, d), 3.3O(1H, d), 3.18(1H, t), 2.42(3H, s), 2.38(3H, s)
Step 2: Preparation of (R)-3-[4-(5-methyl-2-/>-tolyl-oxazol-4-ylmethoxy)- benzyl]-thiazolidine-4-carboxylic acid
The compound obtained in Step 1 of Example 34(30 mg, 0.068 mmol) and lithium hydroxide(3.4 mg, 0.14 mmol) were dissolved in methanol(10 ml). The procedure of Step 3 of Example 11 was repeated except for using the resulting mixture to obtain the title compound(27 mg, yield: 93%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.91(2H, d), 7.26(4H, m), 7.01(2H, d), 5.03(1H, s), 4.99(2H, s), 4.01(3H, m), 3.84(1H, d), 3.7O(1H, d), 3.51(1H, d), 3.25(1H, t), 2.43(3H, s), 2.38(3 H, s)
Example 35: Preparation of (R)-3-[4-(2-biphenyl-4-yI-5-methyl-oxazol-4- ylmethoxy)-benzyI]-thiazolidine-4-carboxylic acid
Figure imgf000051_0001
Step 1: Preparation of (R)-3-[4-(2-biphenyl-4-yl-5-methyl-oxazol-4-ylmethoxy)- benzyl]-thiazolidine-4-carboxylic acid methyl ester
The compound obtained in Step 1 of Example 33(100 mg, 0.4 mmol), 2-biphenyl-4-chloromethyl-5-methyl-4,5-dihydro-oxazole(110 mg, 0.4 mmol) and potassium carbonate(83 mg, 0.6 mmol) were dissolved in dimethylformamide(10 ml). The procedure of Step 2 of Example 14 was repeated except for using the resulting mixture to obtain the title compound(120 mg, yield: 60%). 1H NMR(CDCl3, 200MHz): δ(ppm) 8.09(2H, d), 7.62~7.69(4H, m), 7.31~7.48(5H, m), 6.99(2H, d), 5.00(2H, s), 4.25(1H, d), 4.02(2H, m), 3.72(3H, s), 3.59(1H, d), 3.55(1H5 d), 3.31(1H, d), 3.18(1H, t), 2.45(3H, s)
Step 2: Preparation of (R)-3-[4-(2-biphenyl-4-yl-5-methyl-oxazol-4-ylmethoxy)- benzyl]-thiazoli dine-4-carboxylic acid The compound obtained in Step 1 of Example 35(30 mg, 0.06 mmol) and lithium hydroxide(2.9 mg, 0.12 mmol) were dissolved in methanol(10 ml). The procedure of Step 3 of Example 11 was repeated except for using the resulting mixture to obtain the title compound(22 mg, yield: 76%).
1H NMR(CDCl3, 200MHz): δ(ppm) 8.09(2H, d), 7.62~7.69(4H, m), 7.27~7.48(5H, m), 7.01(2H, d), 5.01(2H, s), 4.5O(1H, br-s), 3.99-4.13(3H, m), 3.84(1H, d),
3.72(1H, d), 3.48(1H, d), 3.25(1H, t), 2.46(3H, s)
Example 36: Preparation of (R)-3-[4-(5-methyl-2-thiophen-2-yl-oxazol-4- ylmethoxy)-benzyI]-thiazolidine-4-carboxylic acid
Figure imgf000051_0002
Step 1 : Preparation of (R)-3-[4-(5-methyl-2-thiophen-2-yl-oxazol-4-ylmethoxy)- benzyl]-thiazolidine-4-carboxylic acid methyl ester
The compound obtained in Step 1 of Example 33(100 mg, 0.4 mmol), 4-chloromethyl-5-methyl-2-thiophen-2-yl-4,5-dihydro-oxazole(85 mg, 0.4 mmol) and potassium carbonate(83 mg, 0.6 mmol) were dissolved in dimethylformamide(10 ml). The procedure of Step 2 of Example 14 was repeated except for using the resulting mixture to obtain the title compound(70 mg, yield:
%). 1R NMR(CDCl3, 200MHz): δ(ppm) 7.62(1H, d), 7.38(1H5 d), 7.32(2H, m), 7.09(1H, t), 6.95(2H5 d), 4.96(2H5 s), 4.25(1H5 d)5 4.01(2H5 m), 3.72(3H, s), 3.67(1H5 d), 3.56(1H5 d), 3.31(1H5 d)5 3.18(1H5 1)5 2.39(3H5 s)
Step 2: Preparation of (R)-3-[4-(5-methyl-2-thio-2-yl-oxazol-4-ylmethoxy)-benzyl]- thiazolidine-4-carboxylic acid
The compound obtained in Step 1 of Example 36(30 mg, 0.07 mmol) and lithium hydroxide(3.4 mg, 0.14 mmol) were dissolved in methanol(10 ml). The procedure of Step 3 of Example 11 was repeated except for using the resulting mixture to obtain the title compound(28 mg, yield: 96%). 1H NMR(CDCl3, 200MHz): δ(ppm) 7.64(1H5 d), 7.40(1H5 d), 7.29(2H, m), 7.1O(1H, t), 6.98(2H, d), 5.50(IH5 br-s), 4.97(2H5 s), 3.99~4.13(3H, m), 3.80(1H5 d), 3.72(1H5 d), 3.47(1H, d), 3.25(1H, t), 2.42(3H, s)
Example 37: Preparation of (R)-3-[4-(5-methyl-2-(trifluoromethyI-phenyI- oxazoI-4-yImethoxy)-benzyI] -thiazolidine-4-carboxylic acid
Figure imgf000052_0001
Step 1 : Preparation of (R)-3-[4-(5-methyl-2-(trifluoromethyl-phenyl-oxazol-4- ylmethoxy)-benzyl)-thiazolidine-4-carboxylic acid methyl ester
The compound obtained in Step 1 of Example 33(100 mg, 0.4 mmol), 4-chloromethyl-5-methyl-2-(4-trifluoromethylphenyl)-4,5-dihydro-oxazole(l 10 mg, 0.4 mmol) and potassium carbonate(83 mg, 0.6 mmol) were dissolved in dimethylformamide(10 ml). The procedure of Step 2 of Example 14 was repeated except for using the resulting mixture to obtain the title compound(80 mg, yield: 42%). 1H NMR(CDCl3, 200MHz): δ(ppm) 8.12(2H, d), 7.70(2H5 d), 7.30(2H5 d), 6.98(2H, d), 5.00(2H, s), 4.27(1H5 d), 4.01(2H5 m), 3.72(3H5 s), 3.68(1H5 d)5 3.55(1H5 d)5 3.31(1H5 m), 3.18(1H5 m), 2.46(3H5 s)
Step 2: Preparation of (R)-3-[4-(5-methyl-2-(trifluoromethyl-phenyl-oxazol-4- ylmethoxy)-benzyl]-thiazolidine-4-carboxylic acid
The compound obtained in Step 1 of Example 37(30 mg, 0.06 mmol) and lithium hydroxide(2.9 mg, 0.122 mmol) were dissolved in methanol(10 ml). The procedure of Step 3 of Example 11 was repeated except for using the resulting mixture to obtain the title compound(29 mg, yield: 100%).
1H NMR(CDCl3, 200MHz): δ(ppm) 8.12(2H, d), 7.70(2H, d), 7.27(2H, d), 7.00(2H, d), 5.01(2H, s), 4.9O(1H, br-s), 4.0-4.11(3H, m), 3.73(1H, d), 3.7O(1H, d), 3.49(1H, m), 3.24(1H, m), 2.47(3H, s)
Example 38: Preparation of (R)-3-{4-[2-(5-methyl-2-phenyl-4-yI-oxazoI- 4-yl)-ethoxy]-benzyl}-thiazolidine-4-carboxyIic acid
Figure imgf000053_0001
Step 1 : Preparation of (R)-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]- benzyl}-thiazolidine-4-carboxylic acid methyl ester The compound obtained in Step 1 of Example 27(100 mg, 0.4 mmol),
2-(5-methyl-2-phenyl-oxazol-4-yl)-ethanol(81 mg, 0.4 mmol), triphenylphosphine(126 mg, 0.48 mmol) and diisopropylazodicarboxylate(97 mg, 0.48 mmol) were dissolved in methanol(5 ml). The procedure of Step 1 of Example 19 was repeated except for using the resulting mixture to obtain the title compound(20 mg, yield: 11%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.97(2H, d), 7.43(2H, d), 7.38(2H, d), 7.27(1H, t), 6.87(2H, d), 4.26(3H, m), 4.00(2H, m), 3.69(3H, s), 3.67(1H, d), 3.52(1H, d), 3.30(1H, d), 3.18(1H, t), 2.98(2H, t), 2.79(3H, s)
Step 2: Preparation of (R)-3-{4-[2-(5-methyl-2-ρhenyl-4-yl-oxazol-4-yl)-ethoxy]- benzyl}-thiazolidine-4-carboxylic acid
The compound obtained in Step 1 of Example 38(19.7 mg, 0.045 mmol) and lithium hydroxide(2.2 mg, 0.09 mmol) were dissolved in methanol(10 ml). The procedure of Step 3 of Example 11 was repeated except for using the resulting mixture to obtain the title compound(10 mg, yield: 53%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.98(2H, d), 7.40(3H, m), 7.24(2H, d), 6.88(2H, d), 4.27(2H, t), 4.01(3H, m), 3.8O(1H, d), 3.66(1H, d), 3.5O(1H, d), 3.23(1H, t),
2.99(2H, t), 2.38(3H, s)
Example 39: Preparation of (R)-3-{4-[2-(2-biphenyl-4-yl-5-methyl-oxazol- 4-yϊ)-ethoxy]-benzyl}-thiazolidine-4-carboxylic acid
Figure imgf000054_0001
Step 1: Preparation of (R)-3-{4-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)- ethoxy] -benzyl }-thiazolidine-4-carboxy lie acid methyl ester
The procedure of Step 1 of Example 19 was repeated except for using the compound obtained in Step 1 of Example 27(100 mg, 0.4 mmol), 2-(2-biphenyl-4-yl-methyl-oxazol-4-yl)-ethanol(112 mg, 0.4 mmol), triphenylphosphine(126 mg, 0.48 mmol) and diisopropylazodicarboxylate(97 mg, 0.48 mmol) to obtain the title compound(20 mg, yield: 8%).
1H NMR(CDCl3, 200MHz): δ(ppm) 8.00(2H, d), 7.64(4H, m), 7.35~7.64(3H, m), 7.27(2H, d), 6.87(2H5 d), 4.25(3H, m), 4.01(2H, m), 3.70(3H, s), 3.64(1H, d), 3.54(1H, d), 3.29(1H, d), 3.25(1H, t), 3.00(2H, t), 2.39(3H, s)
Step 2: Preparation of (R)-3-{4-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)- ethoxy]-benzyl}-thiazolidine-4-carboxylic acid
The compound obtained in Step 1 of Example 39(20 mg, 0.039 mmol) and lithium hydroxide(1.9 mg, 0.078 mmol) were dissolved in methanol(10 ml). The procedure of Step 3 of Example 11 was repeated except for using the resulting mixture to obtain the title compound(18 mg, yield: 95%).
1H NMR(CDCl3, 200MHz): δ(ppm) 8.02(2H, d), 7.65(4H, m), 7.39~7.48(3H, m), 7.24(2H, d), 6.88(2H, d), 4.28(2H, t), 4.05(3H, m), 3.80(1H. d), 3.65(1H, d), 3.49(1H, d), 3.25(1H, t), 3.00(2H, t), 2.39(3H, s)
Example 40: Preparation of (R)-3-{4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)- ethoxy]-benzyl}-thiazolidine-4-carboxylic acid
Figure imgf000054_0002
Step 1: Preparation of (R)-3-{4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]- benzyl}-thiazolidine-4-carboxylic acid methyl ester
The procedure of Step 1 of Example 19 was repeated except for using the compound obtained in Step 1 of Example 27(100 mg, 0.4 mmol), 2-(5-methyl-thiophen-2-yl-oxazol-4-yl)-ethanol(84 mg, 0.4 mmol), triphenylphosphine(126 mg, 0.48 mmol) and diisopropylazodicarboxylate(97 mg, 0.48 mmol) to obtain the title compound(17 mg, yield: 9%). 1H NMR(CDCl3, 200MHz): δ(ppm) 7.59(1H, d), 7.43(1H, d), 7.36(2H, d), 7.2O(1H, t), 6.83(2H, d), 4.2(3H, m), 4.00(2H, m), 3.67(1H, d), 3.4~3.59(5H, m), 3.1~3.3(2H, m), 2.35(3H, s)
Step 2: Preparation of (R)-3-{4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]- benzyl}-thiazolidine-4-carboxylic acid
The compound obtained in Step 1 of Example 40(17 mg, 0.038 mmol) and lithium hydroxide(1.9 mg, 0.078 mmol) were dissolved in methanol(10 ml). The procedure of Step 3 of Example 11 was repeated except for using the resulting mixture to obtain the title compound(15 mg, yield: 93%). 1U NMR(CDCl3, 200MHz): δ(ppm) 7.69(1H, d), 7.38(1H, d), 7.19(2H, d), 7.09(1H, t), 6.87(2H, d), 4.22(2H, t), 4.03(2H, d), 3.85(1H, m), 3.74(1H5 m), 3.50(1H, d),
3.26(1H, m), 2.96(2H, t), 2.36(3H, s)
Example 41: Preparation of (S)-3-[3-(5-methyl-2-/7-tolyI-oxazoI-4-ylmethoxy) benzyl] thiazolidine-4-carboxylic acid
Figure imgf000055_0001
Step 1 : Preparation of (S)-thiazolidine-4-carboxylic acid
D-Cysteine hydrochloride monohydrate(0.5 g, 2.8 mmol) was dissolved in 15 ml of a mixture of water and ethanol(2:l), and 37% aqueous formaldehyde(0.2 ml, 2.84 mmol) was added thereto. The resulting mixture was stirred at room temperature for 1 hr and at 90 °C for 1 hr, sequentially. After the completion of the reaction, the reaction product was cooled down to room temperature and filtered. The filtrate was distilled under reduced pressure, and the residue thus obtained was recrystallized from hot water to obtain the title compound(0.17 g, yield: 44%). [α]25 D=135.6°(c=l-2, H2O)
Step 2: Preparation of (S)-3-[3-(5-methyl-2-/?-tolyl-oxazol-4-ylmethoxy)benzyl] thiazolidine-4-carboxylic acid
The compound obtained in Step 1 of Example 41(66.3 mg, 0.49 mmol) and 3-(5-methyl-2-/?-tolyl-oxazol-4-ylmethoxy)benzaldehyde(152 mg, 0.49 mmol) were dissolved in dichloromethane(10 ml), and triethylamine(125 mg, 1.24 mmol) was added thereto. To the resulting mixture, sodium triacetoxyborohydride(158 mg, 0.74 mmol) was slowly added and stirred at room temperature for 1 day. The resulting mixture was washed with a saturated aqueous sodium bicarbonate and extracted with dichloromethane. The organic layer was separated, dried and distilled under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography(eluent: hexane/ethyl acetate^l/l) to obtain the title comρound(38.4 mg, yield: 18%).
1H NMR(CDCl3, 200MHz): δ(ppm) 8.07(2H, d), 7.62~7.68(4H, m), 7.25~7.47(3H, m), 7.11(1H, s), 6.93(2H, m), 5.00(2H, s), 4.3O(1H, d), 4.06(2H, d), 3.85(1H, d), 3.72(1H, d), 3.19-3.45(2H5 m), 2.42(3H, s), 2.38(3H, s)
Example 42: Preparation of (S)-3-[4-(5-methyl-2-/>-tolyl-oxazol-4-ylmethoxy) benzyl] thiazolidine-4-carboxylic acid
Figure imgf000056_0001
The procedure of Step 2 of Example 41 was repeated except for using the compound obtained in Step 1 of Example 41(64.7 mg, 0.48 mmol), 4-(5-methyl-2-p-toryloxazol-4-ylmethoxy)benzaldehyde(150 mg, 0.48 mmol), triethylamine(122 mg, 1.21 mmol) and sodium triacetoxyborohydride(154 mg, 0.72 mmol) to obtain the title compound(20.2 mg, yield: 9.7%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.91(2H, d), 7.26(4H, m), 7.01(2H, d), 5.03(1H, s), 4.99(2H, s), 4.01(3H, m), 3.84(1H, d), 3.7O(1H, d), 3.51(1H5 d), 3.25(1H, t), 2.43(3H, s), 2.38(3H, s)
Example 43: Preparation of (R)-3-[4-(3-Jp-tolyIisoxazol-5-yImethoxy)benzyl] thiazolidine-4-carboxylic acid
Figure imgf000056_0002
Step 1 : Preparation of (R)-3-[4-(3-j9-tolylisoxazol-5-ylmethoxy)benzyl]thiazolidine- 4-carboxylic acid methyl ester The procedure of Step 1 of Example 19 was repeated except for using the compound obtained in Step 1 of Example 20(0.14 g, 0.56 mmol),(3-;?-torylisoxazol-5-yi)methanol(0.15 g, 0.62 mmol), triphenylphosphine(0.18 g, 0.71 mmol) and diisopropylazodicarboxylate(0.143g,
OJlmmol) to obtain the title compound(0.09 g, yield: 35%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.69(d, J=8.2Hz, 2H), 7.33(d5 J=8.2Hz, 2H), 7.25(d, J=8.2Hz5 2H), 6.95(d, J=9Hz, 2H), 6.62(s, H), 5.19(s, 2H), 4.25(d, J=9.8Hz,
IH), 4.02(d, J=9.8Hz5 2H), 3.71(s5 3H), 3.54-3.73(m, 2H)5 3.13-3.33(m, 2H), 2.39(s, 3H)
Step 2: Preparation of (R)-3-[4-(3-jo-tolylisoxazol-5-ylmethoxy)benzyl]thiazolidine- 4-carboxylic acid
The compound obtained in Step 1 of Example 43(0.12 g, 0.285 mmol) was dissolved in 10 ml of a mixture of tetrahydrofuran and methanol(3:l), and lithium hydroxide monohydrate(0.018 g, 0.428 mmol) was added thereto. The resulting mixture was stirred at room temperature for 20 hrs. Then, the resultant was acidified with 1 N HCl to pH 2 to 3, and extracted with dichloromethane. The organic layer was separated, dried with anhydrous magnesium sulfate and distilled under reduced pressure. The residue thus obtained was subjected to a silica gel chromatography(eluent: dichloromethane/methanoH20/l) to obtain the title comρound(0.079 g, yield: 68%). 1H NMR(DMSO-d6, 200MHz): δ(ppm) 7.76-7.79(m, 2H)5 7.31-7.35(m, 4H), 7.06-7.15(m, 3H)5 5.3 l(s, 2H)5 3.52-4.18(m5 3H)5 3.02-3.48(m5 4H)5 2.37(s, 3H)
Example 44: Preparation of (R)-3-[4~(3-phenylisoxazoI-5-ylmethoxy)benzyl] thiazolidine-4-carboxylic acid
Figure imgf000057_0001
Step 1 : Preparation of (R)-3-[4-(3-phenylisoxazol-5-ylmethoxy)benzyl] thiazolidine-4-carboxylic acid methyl ester
The procedure of Step 1 of Example 19 was repeated except for using the compound obtained in Step 1 of Example 20(0.097 g, 0.385 mmol),(3-phenylisoxazol-5-yl)methanol(0.075 g, 0.427 mmol), triphenylphosphine(0.128 g, 0.49 mmol) and diisopropylazodicarboxylate(0.099 g,
0.49 mmol) to obtain the title compound(0.093 g, yield: 59%).
1R NMR(CDCl3, 200MHz): δ(ppm) 7.81-7.85(m, 2H), 7.46-7.50(m, 3H)5
7.28-7.39(m, 2H)5 6.68-7.02(m, 2H), 6.67(s5 IH), 5.23(s, 2H)5 4.26(dd5 1^9.8Hz, J2=2.8Hz, IH)5 4.07(dd, Ji=9.8Hz, J2=2.8Hz, 2H)5 3.74(s, 3H)5 3.58-3.75(m, 2H)5
3.16-3.37(m, 2H) Step 2: Preparation of (R)-3-[4-(3-phenylisoxazol-5-ylmethoxy)benzyl]thiazolidine- 4-carboxylic acid
The procedure of Step 2 of Example 43 was repeated except for using the compound obtained in Step 1 of Example 44(0.093 g, 0.227 mmol) and lithium hydroxide monohydrate(0.0143 g, 0.341 mmol) to obtain the title compound(0.08 g, yield: 88%).
1R NMR(DMSO-d6, 200MHz): δ(ppm) 7.86-7.88(m, 2H), 7.50-7.52(m, 3H), 7.30-7.35(m, 2H), 7.19(s, IH)3 7.02-7.05(m, 2H), 5.32(s, 2H), 4.12-4.17(m, IH), 3.88-3.93(m, 3H), 3.01-3.51(m, 3H)
Example 45: Preparation of (R)-3-{4-[3-(4-chlorophenyl)isoxazol-5-ylmethoxy] benzyl}thiazoIidine-4-carboxylic acid
Figure imgf000058_0001
Step 1 : Preparation of (R)-3-{4-[3-(4-chlorophenyl)isoxazol-5-ylmethoxy]benzyl} thiazolidine-4-carboxylic acid methyl ester
The procedure of Step 1 of Example 19 was repeated except for using the compound obtained in Step 1 of Example 20(0.163 g, 0.644 mmol),
[3-(4-chlorophenyl)-isoxazol-5-yl]methanol(0.15 g, 0.715 mmol), triphenylphosphine(0.215 g, 0.822 mmol) and diisopropylazodicarboxylate(0.166 g,
0.822 mmol) to obtain the title compound(0.23 g, yield: 79%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.74(d, J=8.6Hz, 2H)5 .7.42(d, J=8.6Hz, 2H),
7.34(d, J=8.2Hz, 2H), 6.95(d, J=8.2Hz, 2H), 6.63(s, IH), 5.20(s, 2H), 4.25(d,
J=9.8Hz, IH), 4.03 (d, 9.8Hz, 2H), 3.72(s, 3H)5 3.54-3.72(m, 2H), 3.18-3.27(m, 2H)
Step 2: Preparation of (R)-3-{4-[3-(4-chlorophenyl)isoxazol-5-ylmethoxy]benzyl} thiazolidine-4-carboxylic acid
The procedure of Step 2 of Example 43 was repeated except for using the compound obtained in Step 1 of Example 45(0.1 g, 0.225 mmol) and lithium hydroxide monohydrate(0.014 g, 0.337 mmol) to obtain the title comρound(0.098 g, yield: 98%).
1H NMR(DMSO-d6, 200MHz): δ(ppm) 7.70(d, J=8.0Hz, 2H), .7.40(d, J=8.0Hz, 2H),
7.30(d, J=8.2Hz, 2H), 6.90(d, J=8.2Hz, 2H), 6.63(s, IH), 5.20(s, 2H), 4.00-4.20(d,
2H), 3.22-4.00(m, 5H)
Example 46: Preparation of (R)-3-{4-[3-(4-trifluoromethylphenyl)isoxazoI-5- yImethoxy]benzyl}thiazolidine-4-carboxylic acid
Figure imgf000059_0001
Step 1 : Preparation of (R)-3-{4-[3-(4-trifluoromethylphenyl)isoxazol-5-ylmethoxy] benzyl}thiazolidine-4-carboxylic acid methyl ester
The procedure of Step 1 of Example 19 was repeated except for using the compound obtained in Step 1 of Example 20(0.14 g, 0.555 mmol), [3-(4-trifluoromethylphenyl)isoxazol-5-yl]methanol(0.15 g, 0.617 mmol), triphenylphosphine(0.186 g, 0.71 mmol) and diisopropylazodicarboxylate(0.143 g, 0.71 mmol) to obtain the title compound(0.09 g, yield: 35%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.24(d, J=8.2Hz, 2H), 6.82(d, J=8.2Hz, 2H), 4.25-4.30(m, IH), 4.04-4.09(m, 2H), 3.74(s, 3H)5 3.52-3.81(m, 3H), 3.18-3.37(m, 2H)
Step 2: Preparation of (R)-3-{4-[3-(4-trifluoromethylphenyl)isoxazol-5-ylmethoxy] benzyl}thiazolidine-4-carboxylic acid
The procedure of Step 2 of Example 43 was repeated except for using the compound obtained in Step 1 of Example 46(0.081 g, 0.169 mmol) and lithium hydroxide monohydrate(0.011 g, 0.254 mmol) to obtain the title compound(0.046 g, yield: 60%).
1H NMR(DMSO-d6, 200MHz): δ(ppm) 8.12(d, J=8Hz, 2H), 7.88(d, J=8Hz, 2H), 7.32(d, J=8Hz, 2H), 7.04(d, J=8Hz, 2H), 5.35(s, 2H), 4.07-4.1 l(m, 2H), 3.84-3.88(m, 4H), 3.22-3.54(m, IH)
Example 47: Preparation of (R)-3-[3-(3-p-toIylisoxazoI-5-ylmethoxy)benzyl] thiazolidine-4-carboxylic acid
Figure imgf000059_0002
Step 1: Preparation of (R)-3-[3-(3-j3-tolylisoxazol-5-ylmethoxy)benzyl] thiazolidine-4-carboxylic acid methyl ester
The procedure of Step 1 of Example 19 was repeated except for using the compound obtained in Step 1 of Example 14(0.2 g, 0.789 mmol), 3-(/?-tolylisoxazol-5-yl)methanol(0.15 g, 0.789 mmol), triphenylphosphine(0.258 g, 0.936 mmol) and diisopropylazodicarboxylate(0.2 g, 0.986 mmol) to obtain the title compound(0.12 g, yield: 36%).
1B. NMR(CDCl3, 200MHz): δ(ppm) 7.70(d, J=8.2Hz, 2H), 7.24-7.65(m, 3H),
6.90-7.10(m, 3H)5 6.64(s, IH)5 5.21(s, 2H)5 4.(s, 28(d, J=9.8Hz5 IH), 4.03(d5
J=9.8Hz, 2H)5 3.72(s, 3H), 3.60-3.80(m5 2H), 2.40(s5 3H)
Step 2: Preparation of (R)-3-[3-(3-/?-tolylisoxazol-5-ylmethoxy)benzyl]thiazolidine-
4-carboxylic acid
The procedure of Step 2 of Example 43 was repeated except for using the compound obtained in Step 1 of Example 47(0.077 g, 0.18 mmol) and lithium hydroxide monohydrate(0.0115 g, 0.275 mmol) to obtain the title compound(0.04 g5 yield: 54%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.67(d, J=7.6Hz5 2H)5 6.86-7.29(m, 6H), 6.60(s,
IH), 5.13(s5 2H), 4.09-4.16(m, IH)5 3.72-3.94(m, 4H)5 3.37-3.43(m5 IH),
3.10-3.14(m, IH)5 2.38(s5 3H)
Example 48: Preparation of (R)-3-[3-(3-phenylisoxazol-5-ylmethoxy)benzyI] thiazolidine-4-carboxylic acid
Figure imgf000060_0001
Step 1 : Preparation of (R)-3-[3-(3-phenylisoxazol-5-ylmethoxy)benzyl]thiazolidine- 4-carboxylic acid methyl ester
The procedure of Step 1 of Example 19 was repeated except for using the compound obtained in Step 1 of Example 14(0.2 g, 0.789 mmol),(3-phenylisoxazol-5-yl)methanol(0.14 g, 0.789 mmol), triphenylphosphine(0.258 g, 0.986 mmol) and diisopropylazodicarboxylate(0.2 g, 0.986 mmol) to obtain the title compound(0.15 g, yield: 47%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.80-7.86(m, 2H)5 7.46-7.49(m, 3H), 6.69-7.3(m, 4H), 6.69(s, IH)5 5.25(s, 2H), 4.20(d, J=9.8Hz, IH)5 4.05(d, J=9.8Hz, 2H), 3.74(s, 3H), 3.62-3.97(m, 2H)5 3.17-3.37(m5 2H)
Step 2: Preparation of (R)-3-[3-(3-phenylisoxazol-5-ylmethoxy)benzyl]thiazolidine-
4-carboxylic acid
The procedure of Step 2 of Example 43 was repeated except for using the compound obtained in Step 1 of Example 48(0.06 g, 0.146 mmol) and lithium hydroxide monohydrate(0.092 g5 0.219 mmol) to obtain the title compound(0.023 g5 yield: 40%).
1H NMR(DMSO-d65 200MHz): δ(ppm) 7.80-7.86(m5 2H), 7.46-7.49(m, 3H), 6.69-7.3(m, 4H), 6.60(s, IH), 5.20(s, 2H), 3.80-4.38(m, 2H), 3.29-3.8(m, 5H), 2.41(s, 3H)
Example 49: Preparation of (R)-3-{3-[3-(4-chlorophenyl)isoxazoI-5-ylmethoxy] benzyl}-thiazolidine-4-carboxylic acid
Figure imgf000061_0001
Step 1 : Preparation of (R)-3-{3-[3-(4-chlorophenyl)isoxazol-5-ylmethoxy]benzyl}- thiazolidine-4-carboxylic acid methyl ester
The procedure of Step 1 of Example 19 was repeated except for using the compound obtained in Step 1 of Example 14(0.2 g, 0.789 mmol),
[3-(4-chlorophenyl)-isoxazol-5-yl]methanol(0.165 g, 0.789 mmol), triphenylphosphine(0.257 g, 0.986 mmol) and diisopropylazodicarboxylate(0.2 g,
0.986 mmol) to obtain the title compound(0.17 g, yield: 48%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.75(d, J=8.6Hz, 2H), 7.43(d, J=8.2Hz, 2H), 7.24-7.39(m, IH), 6.88-7.10(m, 3H), 6.64(s, IH), 5.21(s, 2H), 4.26(d, J=9.8Hz, IH),
4.02(d, J=9.8Hz, 2H), 3.72(s, 3H), 3.59-3.78(m, 2H), 3.14-3.34(m, 2H)
Step 2: Preparation of (R)-3-{3-[3-(4-chlorophenyl)isoxazol-5-ylmethoxy]benzyl}- thiazolidine-4-carboxylic acid The procedure of Step 2 of Example 43 was repeated except for using the compound obtained in Step 1 of Example 49(0.042 g, 0.094 mmol) and lithium hydroxide monohydrate(0.006 g, 0.142 mmol) to obtain the title compound(0.0158 g, yield: 39%).
1H NMR(DMSO-d6, 200MHz): δ(ppm) 7.40-7.70(m, 4H), 7.24-7.39(m, IH), 6.88-7.10(m, 3H), 6.64(s, IH), 5.21(s, 2H), 3.89-4.3 l(m, 3H), 3.23-3.80(m, 4H)
Example 50: Preparation of (R)-3-{3-[3-(4-trifluoromethylphenyl)isoxazol-5- ylmethoxy]benzyl}thiazolidine-4-carboxylic acid
Figure imgf000061_0002
Step 1 : Preparation of (R)-3-{3-[3-(4-trifluoromethylphenyl)isoxazol-5-ylmethoxy] benzyl}thiazolidine-4-carboxylic acid methyl ester
The procedure of Step 1 of Example 19 was repeated except for using the compound obtained in Step 1 of Example 14(0.2 g, 0.789 mmol), [3-(4-trifluoromethylphenyl)isoxazol-5-yl]methanol(0.19 g, 0.789 mmol), triphenylphosphine(0.258 g, 0.986 mmol) and diisopropylazodicarboxylate(0.2 g, 0.986 mmol) to obtain the title comρound(0.2 g, yield: 53%). 1H NMR(CDCl3, 200MHz): δ(ppm) 7.96(d, J=9.8Hz, 2H), 7.75(d, J=9.8Hz, 2H), 7.27-7.35(m, IH), 6.91-7.13(m, 3H), 6.75(s, IH), 5.26(s, 2H), 4.30(d, J=9.8Hz, IH), 4.05(m, 2H), 3.75(s, 3H), 3.62-3.82(m, 2H), 3.18-3.3 l(m, 2H)
Step 2: Preparation of (R)-3-{3-[3-(4-trifluoromethylphenyl)isoxazol-5-ylmethoxy] benzyl}thiazolidine-4-carboxylic acid
The procedure of Step 2 of Example 43 was repeated except for using the compound obtained in Step 1 of Example 50(0.2 g, 0.418 mmol) and lithium hydroxide monohydrate(0.026 g, 0.627 mmol) to obtain the title compound(0.14 g, yield: 71%). 1H NMR(CDCl3, 200MHz): δ(ppm) 7.94(d, J=8.2Hz, 2H), 7.73(d, J=8.2Hz, 2H), 7.28-7.37(m, IH), 6.93-7.04(m, 3H), 6.73(s, IH), 5.24(s, 2H), 4.00-4.20(m, 3H), 3.88(d, J=13Hz, IH), 3.76(d, J=13Hz, IH), 3.42-3.49(m, IH), 3.21-3.3 l(m, IH)
Example 51: Preparation of (R)-2-methyl-3-{3-[5-methyl-2-(4- trifluoromethylphenyI)oxazol-4-ylmethoxy]-benzyl}-thiazolidine-4-carboxyIic acid
Figure imgf000062_0001
Step 1 : Preparation of (R)-2-methylthiazolidine-4-carboxylic acid
D-Cysteine hydrochloride monohydrate(1.5 g, 8.54 mmol) and potassium acetate(0.92 g, 9.4 mmol) were dissolved in 40 ml of a mixture of water and ethanol(3:2), and acetaldehyde(0.5 g, 11.25 mmol) was slowly added thereto. The resulting mixture was stirred at room temperature for 48 hrs. After the completion of the reaction, the reaction product was filtered. The solids thus obtained were washed with diethyl ether. The organic layer separated, dried and concentrated under reduced pressure to obtain the title compound(0.75 g, yield: 60%) as a white solid.
1H NMR(DMSO-d6, 200MHz): δ(ppm) 4.62(q, J=6.3Hz, IH), 4.45(q, J=6Hz, IH), 4.10(dd, J!=7.2Hz, J2=4.8Hz, 3.68(dd, Ji=9Hz, J2=7Hz, IH), 3.21(dd, 1^9.9Hz, J2=7Hz, IH), 3.14(dd, J1=IO1SHz5 J2=7.2Hz, IH), 2.98(t, J-9.3Hz, IH), 1.46(d, J=6Hz, 3H), 1.37(d, J=6.3Hz, 3H) Step 2: Preparation of (R)-2-methyl-3r{3-[5-methyl-2-(4-trifluoromethylphenyl) oxazol-4-ylmethoxy] -benzyl }-thiazolidine-4-carboxylic acid
The compound obtained in Step 1 of Example 51(0.063 g, 0.43 mmol), 4-(3-chloromethylphenoxymethyl)-5-methyl-2-(4-trifluoromethylphenyl)-oxazole(0. 1 g, 0.262 mmol) and potassium carbonate(0.036 g, 0.262 mmol) were dissolved in 20 ml of a mixture of ethanol and water(l :l), and the resultant was heated to reflux for 9 hrs. After the completion of the reaction, the reaction product was cooled down to room temperature and acidified with 1 N HCl. The resultant was distilled under reduced pressure. The residue thus obtained was extracted with dichloromethane. The organic layer was separated, washed with an aqueous NaCl, dried over anhydrous magnesium sulfate, and distilled under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography (eluent: dichloromethane/methanol=40/l) to obtain the title compound(0.03 g, yield: 23%). 1U NMR(CDCl3, 200MHz): δ(ppm) 8.13(d, J=7.8Hz, 2H)3 7.70(d, J=8.1Hz, 2H), 7.21-7.35(m, 2H), 6.82-7.04(m, 6H), 5.01(s, 4H), 4.62(q, J=6.6Hz, 2H), 4.36(q, J=6.6Hz, 2H), 3.91-4.12(m, 4H), 3.71-3.84(m, 2H), 3.38-3.41(m, 2H), 2.47(s, 6H), 1.59(d, J=6.6Hz, 3H), 1.45(d, J=6.Hz, 3H)
Example 52: Preparation of (R)-2-isopropyl-3-[3-(5-methyl-2-p-toIyloxazoI-4- ylmethoxy)-benzyl]thiazoIidine-4-carboxylic acid
Figure imgf000063_0001
Step 1 : Preparation of (R)-2-isopropylthiazolidine-4-carboxylic acid methyl ester
The procedure of Step 1 of Example 51 was repeated except for using D-cysteine methyl ester hydrochloride(1.0 g, 5.82 mmol), potassium acetate(0.63 g,
6.41 mmol) and isobutyl aldehyde(0.55 g, 7.67 mmol) to obtain the title compound(0.88 g, yield: 80%).
1U NMR(CDCl3, 200MHz): δ(ppm) 4.7(d, J=7.7Hz, IH), 4.5(d, J=7.2Ha, IH), 4.00(t,
J=6.4Hz, IH), 3.75(m, IH), 3.67(s, 3H), 3.65(s, 3H), 3.00-3.25(m, 2H), 2.95(dd, J1=IO-OHz, J2=6.2Hz, IH), 2.65(t, J=9.8Hz, IH), 1.90(°Ct, J=6.7Hz, IH), 1.70(t,
J=6.7Hz, IH), 0.70-1.20(m, 12H)
Step 2: Preparation of (R)-2-isopropyl-3-[3-(5-methyl-2-p-tolyloxazol-4- ylmethoxy)-benzyl]thiazolidine-4-carboxylic acid The procedure of Step 2 of Example 51 was repeated except for using the compound obtained in Step 1 of Example 52(0.284 g, 1.5 mmol), 4-(3-chloromethylphenoxymethyl)-5-methyl-2-/>-tolyloxazole(0.3 g, 0.92 mmol) and potassium carbonate(0.126 g, 0.915 mmol) to obtain the title compound(0.045 g, yield: 11%). 1H NMR(CDCl3, 200MHz): δ(ppm) 7.89(d, J=8.0Hz, 2H), 7.70-7.30(m, 3H), 7.04(s, IH), 6.87-6.97(m, 2H), 5.29(s, 2H), 4.1 l(d, J=8.4Hz IH)5 3.92-3.97(m, 2H), 3.27-3.47(m, 2H), 3.15(q, J-7.2Hz, IH), 2.41(s, 6H), 1.79(t, J=6.7Hz, IH), 0.83-1.01(m, 6H)
Example 53: Preparation of (R)-3-[3-(5-methyl-2-/;-tolyloxazol-4-ylmethoxy)- benzyl]-2-p~tolyl-thiazolidine-4-carboxylic acid
Figure imgf000064_0001
Step 1 : Preparation of (R)-2-(p-tolyl)thiazolidine-4-carboxylic acid
The procedure of Step 1 of Example 51 was repeated except for using D-cysteine hydrochloride monohydrate(1.5 g, 8.54 mmol), potassium acetate(0.92 g,
9.4 mmol) and />-tolualdehyde(1.35 g, 11.25 mmol) to obtain the title compound(1.86 g, yield: 98%).
1H NMR(DMSO-d6, 200MHz): δ(ppm) 7.38(d, J=8.1Hz, 2H), 7.30(d, J=8.1Hz, 2H),
7.16(d, J=7.8Hz, 2H), 7.12(d, J-8.0Hz, 2H)5 5.59(s, IH), 5.44(s, IH), 4.21(dd, J!=6.9Hz, J2=4.2Hz, IH), 3.84(dd, Ji=8.7Hz, J2=7.2Hz, IH), 3.01-3.34(m, 6H)
Step 2: Preparation of (R)-3-[3-(5-methyl-2-jp-tolyloxazol-4-ylmethoxy)-benzyl]- 2-/>-tolyl-thiazolidine-4-carboxylic acid
The procedure of Step 2 of Example 51 was repeated except for using the compound obtained in Step 1 of Example 53(0.3 g, 0.92 mmol) and potassium carbonate(0.126 g, 0.915 mmol) to obtain the title compound(0.071 g, yield: 11%). 1H NMR(CDCl3, 200MHz): δ(ppm) 7.82-8.00(m,4H), 7.42-7.60(m, 3H), 7.02-7.42(m, HH), 6.71-7.00(m, 6H), 5.50(s, IH), 5.12(s, IH), 4.95(s, 4H), 4.00-4.20(m, IH), 3.80-4.00(m, 2H), 3.41-3.80(m, 3H), 3.22-3.37(m, 4H), 2.40(s, 18H)
Example 54: Preparation of (R)-2-(4-chlorophenyl)-3-[3-(5-methyl-2-/?- tolyloxazol-4-ylmethoxy)-benzyl]-thiazolidine-4-carboxylic acid
Figure imgf000065_0001
Step 1 : Preparation of (R)-2-(4-chlorophenyl)thiazolidine-4-carboxylic acid
The procedure of Step 1 of Example 51 was repeated except for using D-cysteine hydrochloride monohydrate(2 g, 10.77 mmol), potassium acetate(1.057 g> 10.77 mmol) and 4-chlorobenzaldehyde(1.514 g, 10.77 mmol) to obtain the title compound(1.8 g, yield: 65%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.27-7.42(m, 8H), 5.75(s, IH), 5.45(s, IH), 4.05-4.21(m, IH), 3.90-4.05(m, IH), 3.79(s, 3H), 3.77(s, 3H), 3.32-3.52(m, 2H), 3.05-3.20(m, IH), 2.90-3.00(m, IH), 2.60-2.90(brs, 2H)
Step 2: Preparation of (R)-2-(4-chlorophenyl)-3-[3-(5-methyl-2-p-tolyloxazol-4- ylmethoxy)-benzyl] -thiazolidine-4-carboxylic acid
The procedure of Step 2 of Example 51 was repeated except for using the compound obtained in Step 1 of Example 54(0.387 g, 1.5 mmol), 4-(3-chloromethylphenoxymethyl)-5-methyl-2-Jp-tolyloxazole(0.3 g, 0.92 mmol) and potassium carbonate(0.126g, 0.915mmol) to obtain the title compound(0.11 g, yield: 23%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.90(d, J=8.1Hz, 2H), 7.46(d, J=8.1Hz, 2H), 7.17-7.35(111, 5H), 6.79-6.94(m, 3H), 5.48(s, IH), 4.98(s, IH), 4.08-4.15(m, IH), 3.76(d, J=13.5Hz, IH), 3.53(d, J=13.5Hz, IH), 3.38(dd, Jj=10.8Hz, J2=7.05Hz, IH), 3.20(dd, J!=2.3Hz, J2=10.6Hz, IH), 2.42(s, 3H), 2.39(s, 3H)
Example 55: Preparation of (R)-2-(4-methoxyphenyI)-3-[3-(5-methyl-2-/7- tolyloxazol-4-ylmethoxy)-benzyl] -thiazolidine-4-carboxylic acid H
Figure imgf000065_0002
Step 1: Preparation of (R)-2-(4-methoxyphenyl)thiazolidine-4-carboxylic acid The procedure of Step 1 of Example 51 was repeated except for using D-cysteine hydrochloride monohydrate(1.4 g, 7.94 mmol), potassium acetate(0.857 g, 8.73 mmol) and 4-methoxybenzaldehyde(1.42 g, 10.45 mmol) to obtain the title compound(1.45 g, yield: 76%). 1H NMR(DMSO-d6, 200MHz): δ(ppm) 7.35-7.46(m, 4H)5 6.87-6.95(m, 4H)5 5.59(s, IH), 5.45(s, IH), 3.82-4.27(m, 2H), 3.75(s5 3H), 3.74(s, 3H), 2.49-3.40(m, 6H)
Step 2: Preparation of (R)-2-(4-methoxyphenyl)-3-[3-(5-methyl-2-jo-tolyloxazol-4- ylmethoxy)-benzyl]-thiazolidine-4-carboxylic acid The procedure of Step 2 of Example 51 was repeated except for using the compound obtained in Step 1 of Example 55(0.36 g, 1.5 mmol), 4-(3-chloromethylphenoxymethyl)-5-methyl-2-/>-tolyloxazole(0.3 g, 0.92 mmol) and potassium carbonate(0.126 g, 0.915 mmol) to obtain the title compound(0.07 g, yield: 15%). 1R NMR(CDCl3, 200MHz): δ(ppm) 7.70-7.90(m, 4H)5 7.43-7.48(m, 4H), 7.18-7.26(m, 8H)5 6.74-6.94(m, 8H), 4.1 l(q, J=4.8Hz, 2H), 3.89-3.97(m, IH), 3.81(s, IH), 3.80(s, IH), 3.74(d, J=8.8Hz, IH), 3.62(d, J=8.6Hz, IH), 3.52(d, J=8.8Hz, IH)5 3.32-3.42(m, 4H), 2.42(s, 6H), 2.39(s, 6H)
Example 56: Preparation of (R)-2-[4-methyl-2-/;-tolyloxazol-4-yImethoxy) benzyl]thiazoIidine-4-carboxylic acid
Figure imgf000066_0001
Step 1 : Preparation of 2-[4-(5-methyl-2-j3-tolyloxazol-4-ylmethoxy)phenyl]ethanol 4-Chloromethyl-5-methyl-2-phenyloxazole(3.8 g, 17 mmol) and 4-hydroxyphenethyl alcohol(2 g, 14.5 mmol) were dissolved in acetone(50 ml), and potassium carbonate(3 g, 21.7 mmol) was added thereto. The resulting mixture was heated to reflux for 18 hrs. The reaction product was filtered and the filtrate was distilled under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography (eluent: hexane/ethyl acetate=l/l) to obtain the title compound(3.5 g, yield: 76%) as a white solid.
1H NMR(CDCl3, 200MHz): δ(ppm) 7.88-7.92(2H, d, J = 8Hz), 7.17-7.26(4H, q), 6.94-6.99(2H, d, J = 8.6Hz), 4.96(2H5 s), 3.78-3.87(2H, q), 2.78-2.84(2H5 t), 2.39-2.41(6H, d, J = 5.4Hz)
Step 2: Preparation of [4-(5-methyl-2-jc-tolyloxazol-4-ylmethoxy)phenyl] acetaldehyde The compound obtained in Step 1 of Example 56(0.8 g, 2.4 mmol) was dissolved in ethyl acetate(20 ml), and IBX(o-Iodoxybenzoic acid; 2 g, 7.4 mmol) was added thereto. The resulting mixture was stirred at 80 °C for 4 hrs. After the completion of the reaction, the reactionproduct was filtered. The filtrate was distilled under reduced pressure to obtain the title compound(0.5 g, yield: 63%)
1H NMR(CDCl3, 200MHz): δ(ppm) 9.73(1H, s), 7.88-7.92(2H, d, J = 8Hz), 7.23-7.26(2H, d, J = 7.8Hz)5 7.12-7.17(2H, d, J - 8.4Hz), 7.00-7.04(2H, d, J = 8.6Hz), 4.98(2H, s), 3.64(2H, s), 2.39-2.42(6H, d, J = 5.4Hz)
Step 3: Preparation of (R)-2-[4-methyl-2-p-tolyloxazol-4-ylmethoxy)benzyl] thiazolidine-4-carboxylic acid
The compound obtained in Step 2 of Example 56(0.243 g, 0.75 mmol) and
L-cysteine(0.092 g, 0.75 mmol) were dissolved in ethanol(10 ml). The resulting solution was stirred at room temperature for 2 days. After the completion of the reaction, the reactionproduct was filtered. The solids thus obtained were washed with diethyl ether and concentrated under reduced pressure to obtain the title compound(0.174 g, yield: 54%) as a white solid.
1H NMR(CDCl3, 200MHz): δ(ppm) 7.60-7.57(2H, d, J = 6Hz), 7.09-7.07(2H, d, J =
4Hz), 6.98-6.93(2H, t, J = 10Hz), 6.73-6.69(2H, d, J = 8Hz), 4.71(1H, s), 4.52(0.5H, t), 4.39-4.35(0.5H, t, J = 8Hz), 3.88-3.86(0.4H, t, J = 4Hz), 3.49-3.46(0.6H, t, J =
6Hz), 2.97-2.85(2H, m), 269-2.63(1H, m), 2.54-2.48(1H, t)
Example 57: Preparation of (R)-2-{4-[5-methyl-2-(4-trifluoromethylphenyl) oxazoI-4-ylmethoxy]benzyl}thiazolidine-4-carboxylic acid
Figure imgf000067_0001
Step 1 : Preparation of 2-[4-(5-methyl-2-(4-trifluoromethylphenyl)oxazol-4- y lmethoxy)pheny 1] ethanol
The procedure of Step 1 of Example 56 was repeated except for using
4-chloromethyl-5-methyl-2-(4-trifluoromethylphenyl)oxazole(4.7 g, 17 mmol), 4-hydroxyphenethyl alcohol(2 g, 14.5 mmol) and potassium carbonate(3 g, 21.7 mmol) to obtain the title compound(4 g, yield: 75%).
1H NMR(CDCl3, 200MHz): δ(ppm) 8.15-8.11(2H, d, J = 7.8Hz), 7.72-7.68(2H, d, J
= 8.2Hz), 7.21-7.15(2H, d, J = 11.8Hz), 7.01-6.95(2H, d, J = 11.4Hz), 5.00(2H, s),
3.85-3.79(2H, q), 2.85-2.82(2H, t, J = 6.4Hz), 2.48-2.46(3H, s)
Step 2: Preparation of [4-(5-methyl-2-(4-trifluoromethylphenyl)oxazol-4- ylmethoxy)phenyl] acetaldehyde
The procedure of Step 2 of Example 56 was repeated except for using the compound obtained in Step 1 of Example 57(2 g, 5.29 mmol) and IBX(4.45 g, 15.8 mmol) to obtain the title compound(1.56 g, yield: 70%).
Step 3: Preparation of (R)-2-{4-[5-methyl-2-(4-trifluoromethylphenyl)oxazol-4- ylmethoxy]benzyl}thiazolidine-4-carboxylic acid
The procedure of Step 3 of Example 56 was repeated except for using the compound obtained in Step 2 of Example 57(0.285 g, 0.75 mmol) and L-cysteine(0.092 g, 0.75 mmol) to obtain the title compound(0.273 g, yield: 75%).
1R NMR(CDCl3, 200MHz): δ(ppm) 8.15-8.13(2H, d, J = 4Hz)5 7.90-7.87(2H, d, J =
6Hz)5 7.23-7.18(2H, d, J = 10Hz)5 6.98-6.94(2H5 d5 J = 8Hz)5 4.99(2H5 s), 4.77(0.5H, t), 4.64-4.59(0.5H5 t, J = 10Hz)5 4.13-4.11(0.4H5 1, J = 4Hz)5 3.72-3.69(0.6H, t, J =
8Hz)5 3.20-3.10(2H5 m), 2.94-2.89(1H5 m), 2.79-2.73(1H5 1, J = 12Hz)5 2.47(3H5 s)
Example 58: Preparation of (R)-2-[4-(5-methyl-2-phenyloxazol-4-ylmethoxy) benzyl] thiazolidine-4-carboxylic acid
Figure imgf000068_0001
Step 1 : Preparation of 2-[4-(5-methyl-2-phenyloxazol-4-ylmethoxy)phenyl]ethanol The procedure of Step 1 of Example 56 was repeated except for using
4-chloromethyl-5-methyl-2-phenyloxazole(3.6 g, 17 mmol), 4-hydroxyphenethyl alcohol(2 g, 14.5 mmol) and potassium carbonate(3 g, 21.7 mmol) to obtain the title compound(3.8 g, yield: 85%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.99-8.06(2H5 m, J = 13.2Hz)5 7.47-7.40(3H5 m, J = 13.8Hz), 7.19-7.12(2H, d, J = 14.2Hz)5 7.01-6.95(2H5 d, J = 11.8Hz)5 4.99(s, 2H)5
3.86-3.80(2H5 q), 2.86-2.78(2H5 1), 2.45-2.43(3H5 s)
Step 2: Preparation of [4-(5-methyl-2-phenyloxazol-4-ylmethoxy)phenyl] acetaldehyde The procedure of Step 2 of Example 56 was repeated except for using the compound obtained in Step 1 of Example 58(0.71 g, 2.3 mmol) and IBX(1.9 g, 6.87 mmol) to obtain the title compound(0.456 g5 yield: 65%).
1H NMR(CDCl3, 200MHz): δ(ppm) 9.77(1H5 s), 8.06-8.01(2H5 m), 7.47-7.44(3H5 m), 7.19-7.15(2H5 d, J = 8Hz)5 7.07-7.03(2H5 d, J = 8Hz)5 5.01(2H5 s), 3.78(2H5 s), 2.46(3H5 s)
Step 3: Preparation of (R)-2-[4-(5-methyl-2-phenyloxazol-4-ylmethoxy)benzyl] thiazolidine-4-carboxylic acid
The procedure of Step 3 of Example 56 was repeated except for using the compound obtained in Step 2 of Example 58(0.328 g, 1 mmol) and L-cysteine(0.13 g, 1 mmol) to obtain the title compound(0.25 g, yield: 57%). 1H NMR(CDCl3, 200MHz): δ(ppm) 7.96-7.92(2H, m), 7.54-7.50(2H, d, J - 8Hz), 7.23-7.12(2H, d), 4.97(2H, s), 4.76(0.5H, t), 4.61-4.59(0.5H, t, J = 4Hz), 4.14-4.10(0.5H, t, J = 8Hz), 3.71-3.68(0.5H, t, J = 6Hz), 3.20-3.11(1H, m), 2.93-2.91(1H, m), 2.79-2.72(1H, t, J = 6Hz), 2.44(s, 3H)
Example 59: Preparation of (R)-2-[4-(5-methyI-2-thiophen-2-yloxazol-4- ylmethoxy)benzyl] thiazolidine-4-carboxylic acid
Figure imgf000069_0001
Step 1 : Preparation of 2-[4-(5-methyl-2-thiophen-2-yloxazol-4-ylmethoxy)phenyl] ethanol The procedure of Step 1 of Example 56 was repeated except for using
4-chloromethyl-5-methyl-2-thiophen-2-yloxazole(3.7 g, 17.3 mmol),
4-hydroxyphenethyl alcohol(2 g, 14.5 mmol) and potassium carbonate(3 g, 21.7 mmol) to obtain the title compound(3.8 g, yield: 85%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.62-7.64(1H, m), 7.38-7.43(2H, d, J = 8.2Hz), 7.07-7.17(3H, m), 6.93-6.99(2H, d, J = 11.8Hz), 4.95(2H, s), 3.78-3.88(2H, q),
2.78-2.85(2H, t, J = 13Hz), 2.40(3H, s)
Step 2: Preparation of [4-(5-methyl-2-thiophen-2-yloxazol-4-ylmethoxy)phenyl] acetaldehyde The procedure of Step 2 of Example 56 was repeated except for using the compound obtained in Step 1 of Example 59(0.6 g, 1.8 mmol) and IBX(15 g, 5.637 mmol) to obtain the title compound(0.26 g, yield: 44%).
1H NMR(CDCl3, 200MHz): δ(ppm) 9.76(1H, s), 7.66-7.64(1H, m). 7.43-7.40(1H, d,
J = 6Hz), 7.19-7.04(m, 3H), 6.99-6.93(1H, d, J = 11.8Hz), 4.98(2H, s), 3.66(2H, s), 2.43(3H, s)
Step 3: Preparation of (R)-2-[4-(5-methyl-2-thiophen-2-yloxazol-4-ylmethoxy) benzyl]thiazolidine-4-carboxylic acid
The procedure of Step 3 of Example 56 was repeated except for using the compound obtained in Step 2 of Example 59(0.297 g, 0.94 mmol) and L-cysteine(0.115 g, 0.94 mmol) to obtain the title compound(0.18 g, yield: 45%). 1H NMR(CDCl3, 200MHz): δ(ppm) 7.65-7.64(1H, d), 7.54-7.52(1H, d), 7.11-7.05(3H5 m), 6.84-6.81(2H5 d, J = 6Hz)5 4.8(1H5 s), 4.65(0.5H5 t), 4.50-4.47(0.5H5 1), 4.03-3.99(0.5H5 1), 3.60-3.57(0.5H, t, J=6Hz), 3.10-2.97(2H5 m), 2.81-2.76(1H5 m), 2.67-2.61(1H, m), 2.29(3H5 s)
Example 60: Preparation of (R)-3-{2-[4-(5-methyl-2-/?-tolyloxazol-4-ylmethoxy) phenyl] ethyl} thiazolidine-4-carboxylic acid
Figure imgf000070_0001
Step 1: Preparation of (R)-3-{2-[4-(5-methyl-2-/»-tolyloxazol-4-ylmethoxy)phenyl] ethyl}thiazolidine-4-carboxylic acid methyl ester The procedure of Step 2 of Example 11 was repeated except for using the compound obtained in Step 2 of Example 56(0.15 g, 0.46 nimol), thiazolidine-4-carboxylic acid methyl ester hydrochloride(0.085 g, 0.46 mmol), triethylamine(0.117 g, 1.16 mmol) and sodium triacetoxyborohydride(0.15 g, 0.7 mmol) to obtain the title compound(0.16 g, yield: 76%). 1H NMR(CDCl3, 200MHz): δ(ppm) 7.94-7.90(2H5 d, J = 8Hz)5 7.28-7.24(2H5 d, J = 8Hz), 7.17-7.13(2H, d, J - 8Hz), 6.98-6.94(2H5 d5 J = 8Hz), 4.98(2H5 s), 4.33-4.29(1H, d, J = 8Hz)5 4.09-4.05(2H5 d, J = 8Hz), 3.82(3H5 s), 3.30-3.09(2H5 m), 2.81(2H5 s), 2.77-2.67(2H5 1), 2.43-2.41(6H5 d, J - 4Hz)
Step 2: Preparation of (R)-3-{2-[4-(5-methyl-2-^-tolyloxazol-4-ylmethoxy)ρhenyl] ethyl}thiazolidine-4-carboxylic acid
The procedure of Step 3 of Example 11 was repeated except for using the compound obtained in Step 1 of Example 60(0.17 g, 0.37 mmol) and lithium hydroxide monohydrate(0.186 g, 0.44 mmol) to obtain the title compound(0.118 g, yield: 72%).
Example 61: Preparation of (R)-3-(2-{4-[5-methyl-2-(4-trifluoromethylphenyl) oxazol-4-ylmethoxy] phenyl}ethyl)thiazolidine-4-carboxylic acid
Figure imgf000070_0002
Step 1 : Preparation of (R)-3-(2-{4-[5-methyl-2-(4-trifluoromethylρhenyl)oxazol- 4-ylmethoxy]phenyl}ethyl)thiazolidine-4-carboxylic acid methyl ester The procedure of Step 2 of Example 11 was repeated except for using the compound obtained in Step 2 of Example 58(0.284 g, 0.75 mmol), thiazolidine-4-carboxylic acid methyl ester hydrochloride(0.06 g, 0.32 mmol), triethylamine(0.4 g, 1.89 mmol) and sodium triacetoxyborohydride(0.301 g, 1.13 mmol) to obtain the title compound(0.231 g, yield: 60%).
Step 2: Preparation of (R)-3-(2-{4-[5-methyl-2-(4-trifluoromethylρhenyl)oxazol-4- ylmethoxy]phenyl} ethyl)thiazolidine-4-carboxylic acid
The procedure of Step 3 of Example 11 was repeated except for using the compound obtained in Step 1 of Example 61(0.117 g, 0.23 mmol) and lithium hydroxide monohydrate(0.01 g, 0.277 mmol) to obtain the title compound(0.08 g, yield: 70%).
Example 62: Preparation of (R)-3-{2-[4-(5-methyl-2-phenyloxazol-4-ylmethoxy) phenyl]ethyl}thiazolidine-4-carboxyϊic acid
Figure imgf000071_0001
Step 1 : Preparation of (R)-3-{2-[4-(5-methyl-2-phenyloxazol-4-ylmethoxy)phenyl] ethyl}thiazolidine-4-carboxylic acid methyl ester
The procedure of Step 2 of Example 11 was repeated except for using the compound obtained in Step 2 of Example 57(0.1 g, 0.32 mmol), thiazolidine-4-carboxylic acid methyl ester hydrochloride(0.06 g, 0.32 mmol), triethylamine(0.082 g, 0.81 mmol) and sodium triacetoxyborohydride(0.103 g, 0.488 mmol) to obtain the title compound(0.097 g, yield: 68%).
1H NMR(CDCl3, 200MHz): δ(ppm) 8.06-8.02(2H, m, J = 8Hz), 7.47-7.43(3H, m, J = 8Hz), 7.17-713(2H, d, J = 8Hz), 6.98-6.94(2H, d, J = 8Hz), 4.98(2H, s),
4.33-4.29(1H, d, J = 8Hz), 4.16-4.04(2H, m), 3.76(3H, s), 3.25-3.15(2H, m),
2.85(2H, s), 2.77-2.73(2H, t, J = 8Hz), 2.44(3H, s)
Step 2: Preparation of (R)-3-{2-[4-(5-methyl-2-phenyloxazol-4-ylmethoxy)phenyl] ethyl}thiazolidine-4-carboxylic acid
The procedure of Step 3 of Example 11 was repeated except for using the compound obtained in Step 1 of Example 62(0.096 g, 0.22 mmol) and lithium hydroxide monohydrate(0.01 g, 0.264 mmol) to obtain the title compound(0.032 g, yield: 34%).
Example 63: Preparation of (R)-3-{2-[4-(5-methyl-2-thiophen-2-yIoxazol-4- ylmethoxy)phenyl] ethyl}thiazolidine-4-carboxyIic acid
Figure imgf000072_0001
Step 1 : Preparation of (R)-3-{2-[4-(5-methyl-2-thiophen-2-yloxazol-4-ylmethoxy) phenyl]ethyl}thiazolidine-4-carboxylic acid methyl ester The procedure of Step 2 of Example 11 was repeated except for using the compound obtained in Step 2 of Example 59(0.261 g, 0.83 mmol), thiazolidine-4-carboxylic acid methyl ester hydrochloride(0.06 g, 0.32 mmol), triethylamine(0.21 g, 2.08 mmol) and sodium triacetoxyborohydride(0.265 g, 1.25 mmol) to obtain the title compound(0.254 g, yield: 68%). 1H NMR(CDCl3, 200MHz): δ(ppm) 7.66-6.92(7H5 m), 4.96(2H5 s), 4.34-4.29(1H, d, J = 10Hz), 4.14-4.01(2H, m), 3.76(3H, s), 3.26-3.15(2H, m), 2.84-2.71(4H, m), 2.42(3H, s)
Step 2: Preparation of (R)-3-{2-[4-(5-methyl-2-thiophen-2-yloxazol-4-ylmethoxy) phenyl]ethyl}thiazolidine-4-carboxylic acid
The procedure of Step 3 of Example 11 was repeated except for using the compound obtained in Step 1 of Example 63(0.255 g, 0.575 mmol) and lithium hydroxide monohydrate(0.03 g, 0.7 mmol) to obtain the title compound(0.18 g, yield: 73%). 1H NMR(CDCl3, 200MHz): δ(ppm) 7.66-6.95(7H, m), 4.97(2H, s), 4.14-3.97(3H, m), 3.42-3.05(2H5 m), 2.84-2.72(4H5 m), 2.42(3H5 s)
Example 64: Preparation of (3S)-4-[4-(5-methyl-2-phenyl-oxazol-4-yl- methoxy)benzyl]-morpholine-3-carboxyIic acid
Figure imgf000072_0002
Step 1 : Preparation of (3S)-4-[4-(5-methyl-2-phenyl-oxazol-4-yl-methoxy) benzyl]-morpholine-3-carboxylic acid methyl ester
4-(4-Chloromethylphenoxymethyl)-5-methyl-2-phenyl-oxazole(48 mg, 0.15 mmol),(3S)-morpholine carboxylic acid methyl ester(22.1 mg, 0.15 mmol) and potassium carbonate(36 mg, 0.26 mmol) were dissolved in acetonitrile(5 ml) and the resultant was heated to reflux for 24 hrs. The reaction product was concentrated under reduced pressure, and an excessive amount of water was added thereto. Then, the resulting mixture was extracted with ethyl acetate. The organic layer was separated and dried with anhydrous magnesium sulfate, followed by removing the solvent to obtain the title compound(41 mg, yield: 60%) as a white liquid. 1H NMR(200MHz, CDCl3): δ(ppm) 8.06-8.00(m, 2H), 7.49-7.42(m, 3H), 7.27(d, 2H, J=7.6Hz), 7.00(d, 2H, J=8.6Hz), 5.00(s, 2H), 3.93-3.82(m, 3H), 3.76(s, 3H), 3.74-3.64(m, 2H), 3.58-3.52(m, IH), 3.30(t, IH, J=4Hz), 3.11-3.00(m, IH), 2.45(s, 3H), 2.42-2.3 l(m, IH).
Step 2: Preparation of (3S)-4-[4-(5-methyl-2-phenyl-oxazol-4-yl-methoxy)benzyl]- morpholine-3-carboxylic acid
The compound obtained in Step 1 of Example 64(41 mg, 0.096 mmol) and an aqueous 1 N lithium hydroxide(0.96 ml, 0.144 mmol) were dissolved in 3 ml of a mixture of methanol and water(3:l). The resultant was stirred at room temperature and concentrated under reduced pressure. The residue thus obtained was extracted with diethyl ether. The organic layer was separated and dried over anhydrous magnesium sulfate, followed by removing the solvent under reduced pressure to obtain the title compound(20 mg, yield: 50%) as a white solid.
1H NMR(200MHz, CDCl3): δ(ppm) 7.94(m, 2H), 7.53(m, 3H), 7.24(m, 2H), 7.03(m,
2H), 4.99(s, 2H), 3.76-3.17(m, 7H), 2.91(m, IH), 2.50(s, 3H), 2.28(m, IH).
Example 65: Preparation of (3S)-4-[3-(5-methyl-2-phenyI-oxazoϊ-4-yl-methoxy) benzyl] -morpholine-3-carboxylic acid
Figure imgf000073_0001
Step 1: Preparation of (3S)-4-[3-(5-methyl-2-phenyl-oxazol-4-yl-methoxy)benzyl]- morpholine-3-carboxylic acid methyl ester
The procedure of Step 1 of Example 64 was repeated except for using
4-(3-chloromethylphenoxymethyl)-5-methyl-2-phenyl-oxazole(48 mg, 0.15 mmol) and (3S)-morpholine carboxylic acid methyl ester(22.1 mg, 0.15 mmol) to obtain the title compound(41 mg, yield: 89%). 1H NMR(200MHz, CDCl3): δ(ppm) 8.07-8.02(m, 2H), 7.49-7.44(m, 2H),
7.30-7.22(m, 2H), 7.05(s, IH), 7.27(d, 2H, J=8Hz), 5.02(s, 2H), 4.01-3.82(m, 3H),
3.77(s, 3H), 3.73-3.58(m, IH), 3.33(t, IH, J=4Hz), 3.09-3.05(m, IH), 2.47(s, 3H),
2.43-2.35(m, IH).
Step 2: Preparation of (3S)-4-[3-(5-methyl-2-phenyl-oxazol-4-yl-methoxy)benzyl]- morpholine-3 -carboxylic acid The procedure of Step 2 of Example 64 was repeated except for using the compound obtained in Step 1 of Example 65(40.8 mg, 0.10 mmol) to obtain the title compound(35 mg, yield: 89%).
1U NMR(200MHz, DMSO-D6): δ(ppm) 8.00(m, 2H), 7.45(m, 2H), 7.26(m, 2H), 6.98(m, 3H), 4.99(s, 2H), 4.15(m, 2H)5 3.74(m, 4H), 3.41(m, IH), 3.15(m, IH), 2.44(m, IH), 2.43(s, 3H).
Example 66: Preparation of (3S)-4-[4-(5-methyl-2-(4-methyIphenyl)-oxazol-4-yI- methoxy)benzyl]-morpholine-3-carboxylic acid
Figure imgf000074_0001
Step 1: Preparation of (3S)-4-[4-(5-methyl-2-(4-methylphenyl)-oxazol-4-yl- methoxy)benzyl]-morpholine-3-carboxylic acid methyl ester
The procedure of Step 1 of Example 64 was repeated except for using
4-(4-chloromethylρhenoxymethyl)-5-methyl-2-(4-methylphenyl)-oxazole(50 mg, 0.15 mmol) and (3S)-morpholine carboxylic acid methyl ester(22.4 mg, 0.15 mmol) to obtain the title compound(42 mg, yield: 64%).
1H NMR(200MHz, CDCl3): δ(ppm) 7.89(d, 2H, J=8.2Hz), 7.26(d, 4H, J=7.8Hz),
6.97(d, 2H, J=8.6Hz), 4.97(s, 2H), 3.85(m, 4H), 3.74(s, 3H), 3.69(m, 2H), 3.28(m,
IH), 3.07(m, IH), 2.42(d, 6H, J=5Hz).
Step 2: Preparation of (3S)-4-[4-(5-methyl-2-(4-methylphenyl)-oxazol-4-yl- methoxy)benzyl]-morpholine-3 -carboxylic acid
The procedure of Step 2 of Example 64 was repeated except for using the compound obtained in Step 1 of Example 66(42 mg, 0.10 mmol) to obtain the title compound(24.6 mg, 60%).
1H NMR(200MHz, DMSO-D6): δ(ppm) 7.89(d, 2H, J=8.2Hz), 7.31-7.22(m, 5H),
6.99(d, 2H, J-8.4Hz), 4.97(s, 2H), 4.01-3.89(m, 3H), 3.73-3.58(m, 4H), 3.38-3.28(m,
IH), 3.12-2.96(m, IH), 2.42(s, 3H), 2.39(s, 3H).
Example 67: Preparation of (3S)-4-[3-(5-methyl-2-(4-methylphenyl)-oxazoI-4-yl- methoxy)benzyI]-morpholine-3-carboxylic acid
Figure imgf000074_0002
Step 1 : Preparation of (3S)-4-[3-(5-methyl-2-(4-methylphenyl)-oxazol-4-yl- methoxy)benzyl]-morpholine-3-carboxylic acid methyl ester
The procedure of Step 1 of Example 64 was repeated except for using 4-(3-chloromethylphenoxymethyl)-5-methyl-2-(4-methylphenyl)-oxazole(34.5 mg, 0.10 mmol) and (3S)-morpholine carboxylic acid methyl ester(15.3 mg, 0.10 mmol) to obtain the title compound(31.3 mg, yield: 70%).
1H NMR(200MHz, CDCl3): δ(ppm) 7.92(d, 2H, JM8.2Hz), 7.28-7.22(m, 3H), 7.05-6.93(m, 3H), 5.00(s, 2H), 3,98-3.79(m, 3H), 3.76(s, 3H), 3.74-3.57(m, 2H), 3.33(t, IH, J=4Hz), 3.15-3.03(m, IH), 2.45(s, 3H), 2.41(s, 3H).
Step 2: Preparation of (3S)-4-[3-(5-methyl-2-(4-methylρhenyl)-oxazol-4-yl- methoxy)benzyl] -morpholine-3 -carboxylic acid
The procedure of Step 2 of Example 64 was repeated except for using the compound obtained in Step 1 of Example 67(31.3 mg, 0.07 mmol) to obtain the title compound(20 mg, yield: 69%).
1H NMR(200MHz, DMSO-D6): δ(ppm) 7.89(d, 2H, J=8.2Hz), 7.21-7.15(m, 4H), 7.02-6.98(m, 2H), 4.98(s, 2H), 4.68-4.40(m, 3H), 4.35-3.83(m, 3H), 3.64-3.56(m, IH), 3.31-3.27(m, IH), 2.74(m, IH), 2.41(s, 3H), 2.38(s, 3H).
Example 68: Preparation of (3S)-4-[4-(5-methyl-2-(4-trifluoromethylphenyl)- oxazol-4-yl-methoxy)benzyl]-morpholine-3-carboxyIic acid
HO^O
Figure imgf000075_0001
Step 1 : Preparation of (3S)-4-[4-(5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl- methoxy)benzyl] -morpholine-3 -carboxylic acid methyl ester The procedure of Step 1 of Example 64 was repeated except for using
4-(4-chloromethylphenoxymethyl)-5-methyl-2-(4-trifluoromethylphenyl)-oxazole(7
6 mg, 0.20 mmol) and (3S)-morpholine carboxylic acid methyl ester(28.9 mg, 0.20 mmol) to obtain the title compound(58 mg, yield: 59%).
1H NMR(200MHz, CDCl3): δ(ppm) 8.13(d, 2H, J=7.8Hz), 7.71(d, 2H, J=8.2Hz), 7.28(m, 2H), 6.98(m, 2H), 4.99(s, 2H), 4.50(m, IH), 3.86(m, 2H), 3.74(s, 3H),
3.74(m, 2H), 3.49(m, 2H), 3.03(m, IH), 2.46(s, 3H), 2.37(m, IH).
Step 2: Preparation of (3S)-4-[4-(5-methyl-2-(4-trifluoromethylphenyl)-oxazol- 4-yl-methoxy)benzyl]-morpholine-3-carboxylic acid The procedure of Step 2 of Example 64 was repeated except for using the compound obtained in Step 1 of Example 68(50 mg, 0.10 mmol) to obtain the title compound(35 mg, yield: 74%).
1H NMR(200MHz, DMSO-D6): δ(ppm) 8.13(d, 2H, J =8.2Hz), 7.71(d5 2H, J=8.6Hz), 7.27-2.22(m, IH), 7.06-6.92(m, 3H), 5.01(s, 2H), 4.00-3.86(m, 3H), 3.72-3.59(m, 3H), 3.48(s, IH), 3.34-3.30(m, IH), 3.10-3.00(m, IH), 2.48(s, 3H).
Example 69: Preparation of (3S)-4-[3-(5-methyl-2-(4-trifluoromethylphenyl)- oxazol-4-yI-methoxy)benzyl]-morpholine-3-carboxylic acid
Figure imgf000076_0001
Step 1 : Preparation of (3S)-4-[3-(5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl- methoxy)benzyl]-morpholine-3-carboxylic acid methyl ester
The procedure of Step 1 of Example 64 was repeated except for using
4-(3-chloromethylphenoxymethyl)-5-methyl-2-(4-trifluoromethylphenyl)-oxazole(5
2.6 mg, 0.14 mmol) and (3 S)-morpholine carboxylic acid methyl ester(20 mg, 0.14 mmol) to obtain the title compound(32.2 mg, yield: 48%). 1H NMR(200MHz, CDCl3): δ(ppm) 8.18(d, 2H, J=8.6Hz), 7.75(d, 2H, J=8.6Hz),
7.31-7.23(m, IH), 7.06(s, IH), 6.99-6.93(m, 2H), 5.02(s, 2H), 4.02-3.79(m, 3H),
3.77(s, 3H), 3.75-3.58(m, 3H), 3.33(t, IH, J=4Hz), 3.15-3.04(m, IH), 2.49(s, 3H),
2.43-2.33(m, IH).
Step 2: Preparation of (3S)-4-[3-(5-methyl-2-(4-trifluoromethylρhenyl)-oxazol-
4-yl-methoxy)benzyl]-morpholine-3 -carboxylic acid
The procedure of Step 2 of Example 64 was repeated except for using the compound obtained in Step 1 of Example 69(32.2 mg, 0.07 mmol) to obtain the title compound(25.3 mg, yield: 82%). 1H NMR(200MHz5 DMSO-D6): δ(ppm) 8.17(d, 2H, J=8.6Hz), 7.74(d, 2H, J=8.6Hz),
7.31-7.23(m, IH), 7.05(s, IH), 6.97-6.91(m, 2H), 5.02(s, 2H), 3.99-3.77(m, 3H),
3.66-3.3 l(m, 4H), 3.15-3.04(m, IH), 2.49(s, 3H), 2.43-2.33(m, IH).
Example 70: Preparation of (3S)-4-[4-(5-methyI-2-(2-thiophene)-oxazol-4-yI- methoxy)benzyl]-morpholine-3-carboxylic acid
HON^O
Figure imgf000076_0002
Step 1: Preparation of (3S)-4-[4-(5-methyl-2-(2-thiophene)-oxazol-4-yl-methoxy) benzylj-morpholine-S-carboxylic acid methyl ester
The procedure of Step 1 of Example 64 was repeated except for using
4-(4-chloromethylphenoxymethyl)-5-methyl-2-(2-thiophene)-oxazole(64 mg, 0.20 mmol) and (3S)-morpholine carboxylic acid methyl ester(29.1 mg, 0.20 mmol) to obtain the title compound(53 mg, yield: 62%).
1H NMR(200MHz, CDCl3): δ(ppm) 7.63(d, IH5 J=2.8Hz), 7.40(d, IH, J=4.8Hz),
7.25-7.22(m, 2H), 7.12-7.02(m, IH), 6.95(d, 2H, J=8.6Hz), 4.96(s, 2H), 3.91-3.79(m,
3H), 3.74(s, 3H), 3.73-3.69(m, IH), 3.56-3.49(m, 2H), 3.30-3.28(m, IH),
3.06-3.04(m, IH), 2.4 l(s, 3H), 2.3 l(m, IH).
Step 2: Preparation of (3S)-4-[4-(5-methyl-2-(2-thiophene)-oxazol-4-yl-methoxy) benzyl]-morpholine-3-carboxylic acid
The procedure of Step 2 of Example 64 was repeated except for using the compound obtained in Step 1 of Example 70(50 mg, 0.12 mmol) to obtain the title compound(28 mg, yield: 62%).
1H NMR(200MHz, DMSO-D6): δ(ppm) 7.63-7.23(m, 3H), 7.12-6.95(m, 4H), 4.95(s,
2H), 3.91-3.79(m, 3H), 3.73-3.49(m, 3H), 3.30-3.03(m, 2H), 2.41(s, 3H), 2.3 l(m,
IH).
Example 71: Preparation of (3S)-4-[3-(5-methyl-2-(2-thiophene)-oxazol-4-yl- methoxy)benzyI]-morpholine-3-carboxylic acid
Figure imgf000077_0001
Step 1 : Preparation of (3S)-4-[3-(5-methyl-2-(2-thiophene)-oxazol-4-yl-methoxy) benzyl]-morpholine-3-carboxylic acid methyl ester The procedure of Step 1 of Example 64 was repeated except for using
4-(3-chloromethylphenoxymethyl)-5-methyl-2-(2-thiophene)-oxazole(64 mg, 0.20 mmol) and (3S)-morpholine carboxylic acid methyl ester(29.5 mg, 0.20 mmol) to obtain the title compound(49 mg, yield: 57%).
1H NMR(200MHz, CDCl3): δ(ppm) 7.63(d, IH, J=3.6Hz), 7.40(d, IH, J=5.4Hz), 7.24-7.19(m, 2H) 7.12-7.07(m, IH), 7.01(s, IH), 6.95-6.88(m, IH), 4.96(s, 2H),
4.17-3.77(m, 4H), 3.74(s, 3H), 3.69-3.55(m, 2H), 3.30(m, IH), 3.12-3.03(m, IH),
2.42(s, 3H), 2.39-2.35(m, IH).
Step 2: Preparation of (3S)-4-[3-(5-methyl-2-(2-thiophene)-oxazol-4-yl-methoxy) benzyl]-morpholine-3-carboxylic acid
The procedure of Step 2 of Example 64 was repeated except for using the compound obtained in Step 1 of Example 71(22 mg, 0.05 mmol) to obtain the title compound(13 mg, yield: 62%).
1H NMR(200MHz, DMSO-D6): δ(ppm) 7.63-7.19(m, 4H), 7.12-7.07(m, IH), 7.01(s, IH)5 6.95-6.88(m, IH), 4.96(s, 2H), 4.16-3.75(m, 4H), 3.69-3.55(m, 2H), 3.30-3.02(m, 2H), 2.42(s, 3H), 2.45-2.34(m, IH).
Example 72: Preparation of 4-[4-(5-methyl-2-phenyl-oxazoI-4-yl-methoxy) benzyl] -3-tliiomorpliolinecarboxylic acid
Figure imgf000078_0001
Step 1 : Preparation of 4-[4-(5-methyl-2-phenyl-oxazol-4-yl-methoxy)benzyl]- 3-thiomorpholinecarboxylic acid ethyl ester
4-(4-Chloromethylphenoxymethyl)-5-methyl-2-phenyl-oxazole(73 mg, 0.23 mmol) and 3-thiomorpholine carboxylic acid ethyl ester(41 mg, 0.23 mmol) and potassium carbonate(54 mg, 0.39 mmol) were dissolved in acetonitrile(6 ml). The resultant was heated to reflux for 24 hrs. The reaction product was concentrated under reduced pressure and an excessive amount of water was poured thereto. Then, the resulting mixture was extracted with ethyl acetate. The organic layer was separated and dried over anhydrous magnesium sulfate, followed by removing solvent under reduced pressure to obtain the title compound(62 mg, yield: 62%) as a white liquid.
1H NMR(200MHz, CDCl3): δ(ppm) 8.06-8.01(m, 2H), 7.48-7.43(m, 3H), 7.25(d, 2H, J-8.6Hz), 6.98(d, 2H, J=8.6Hz), 5.00(s,2H), 4.25(q, 2H, J=7.4Hz), 3.89-3.65(m, IH), 3.63-3.59(m, 2H), 3.38-3.27(m, IH), 2.98-2.93(m, 2H), 2.78-2.49(m, 3H), 2.45(s, 3H), 1.28(t, 3H, J=7.4Hz).
Step 2: Preparation of 4-[4-(5-methyl-2-phenyl-oxazol-4-yl-methoxy)benzyl]- 3-thiomorpholinecarboxylic acid
The compound obtained in Step 1 of Example 72(29 mg, 0.063 mmol) and an aqueous 1 N lithium hydroxide(0.57 ml, 0.57 mmol) were dissolved in 5 ml of a mixture of tetrahydrofuran and water(3:l). The resulting mixture was stirred at 50 °C for 3 days and the reaction product was concentrated under reduced pressure. The residue thus obtained was extracted with diethyl ether. The organic layer was separated and dried over anhydrous magnesium sulfate, followed by removing the solvent to obtain the title compound(8 mg, yield: 30%) as a white solid. 1H NMR(200MHz, CDCl3): δ(ppm) 8.05-7.43(m, 5H), 7.25-7.18(m, 2H), 6.95-6.86(m, 2H), 5.00(s, 2H)3 3.89-3.65(m, IH)5 3.63-3.59(m, 2H), 3.38-3.27(m, IH), 2.98-2.93(m, 2H), 2.78-2.49(m, 3H), 2.45(s, 3H).
Example 73: Preparation of 4-[3-(5-methyl-2-phenyI-oxazoI-4-yI-methoxy) benzylJ-S-thiomorpholinecarboxylic acid
Figure imgf000079_0001
Step 1 : Preparation of 4-[3-(5-methyl-2-phenyl-oxazol-4-yl-methoxy)benzyl]-3- thiomorpholinecarboxylic acid ethyl ester
The procedure of Step 1 of Example 72 was repeated except for using 4-(3-chloromethylphenoxymethyl)-5-methyl-2-phenyl-oxazole(50 mg, 0.16 mmol) and 3-thiomorpholine carboxylic acid ethyl ester(27.9 mg, 0.16 mmol) to obtain the title compound(43 mg, yield: 60%).
1H NMR(200MHz, CDCl3): δ(ppm) 8.00-7.99(m, 2H), 7.45-7.33(m, 2H),
7.28-7.23(m, 2H), 7.04(s, IH), 6.95-6.89(m, 2H), 4.98(s, 2H), 4.25(q, 2H,J =7.4Hz), 3.98-3.71(m, 2H), 3.62-3.60(m, IH), 3.33-3.27(m, IH), 3.00-2.97(m, 2H),
2.81-2.61(m, 3H), 2.45(s, 3H), 1.27(t, 3H, J=7.4Hz).
Step 2: Preparation of 4-[3-(5-methyl-2-phenyl-oxazol-4-yl-methoxy)benzyl]-3- thiomorpholinecarboxylic acid The procedure of Step 2 of Example 72 was repeated except for using the compound obtained in Step 1 of Example 73(40 mg, 0.09 mmol) to obtain the title compound(34 mg, yield: 89%).
1H NMR(200MHz, CDCl3): δ(ppm) 8.00-7.99(m, 2H), 7.45-7.33(m, 2H),
7.28-7.23(m, 2H), 7.04(s, IH), 6.95-6.89(m, 2H), 4.98(s, 2H), 3.98-3.71(m, 2H), 3.62-3.60(m, IH), 3.33-3.27(m, IH), 3.00-2.97(m, 2H), 2.81-2.61(m, 3H), 2.45(s,
3H).
Example 74: Preparation of 4-[4-(5-methyl-2-(4-methylphenyl)-oxazol-4-yl- methoxy)benzyl]-3-thiomorpholinecarboxylic acid
Figure imgf000079_0002
Step 1 : Preparation of 4-[4-(5-methyl-2-(4-methylphenyl)-oxazol-4-yl-methoxy) benzyl] -3 -thiomorpholinecarboxylic acid ethyl ester
The procedure of Step 1 of Example 72 was repeated except for using 4-(4-chloromethylphenoxymethyl)-5-methyl-2-(4-methylphenyl)-oxazole(83.4 mg, 0.25 mmol) and 3-thiomorpholine carboxylic acid ethyl ester(44.6 mg, 0.25 mmol) to obtain the title compound(82 mg, yield: 71%).
1H NMR(200MHz, CDCl3): δ(ppm) 7.92(d, 2H, J=8,2Hz), 7.24-7.23(m, 2H), 6.96(d, 2H, J=8.5Hz), 4.99(s, 2H), 4.23(q, 2H, J=5.6Hz), 3.89-3.59(m, IH)5 3.61(t, 2H5 J=4.2Hz), 3.32-3.27(m, IH), 2.98-2.93(m5 2H)5 2.78-2.46(m, 3H), 2.44(s5 3H)5 2.41(s5 3H), 1.3 l(t, 3H, J=7.2).
Step 2: Preparation of 4-[4-(5-methyl-2-(4-methylphenyl)-oxazol-4-yl-methoxy) benzyl]-3-thiomorpholinecarboxylic acid
The procedure of Step 2 of Example 72 was repeated except for using the compound obtained in Step 1 of Example 74(42 mg, 0.09 mmol) to obtain the title compound(9 mg, yield: 23%).
1H NMR(200MHz, CDCl3): δ(ppm) 7.88(d, 2H, J=8.2Hz), 7.27-7.24(m, 4H), 6.95(d, 2H, J=8.6Hz), 4.96(s, 2H)5 3.95-3.68(m5 2H)5 3.56-3.50(m, IH), 3.39-3.33(m, IH),
2.80-2.61(m5 2H)5 2.59-2.58(m, 3H), 2.43(s, 3H)5 2.40(s, 3H).
Example 75: Preparation of 4-[3-(5-methyl-2-(4-methylphenyl)-oxazol-4-yI- methoxy)benzyl]-3-thiomorpholinecarboxylic acid
Figure imgf000080_0001
Step 1 : Preparation of 4-[3-(5-methyl-2-(4-methylphenyl)-oxazol-4-yl-methoxy) benzyl]-3-thiomorpholinecarboxylic acid ethyl ester
The procedure of Step 1 of Example 72 was repeated except for using
4-(3-chloromethylphenoxymethyl)-5-methyl-2-(4-methylphenyl)-oxazole(147.5 mg, 0.45 mmol) and 3-thiomorpholine carboxylic acid ethyl ester(80 mg, 0.45 mmol) to obtain the title compound(122 mg, yield: 58%).
1H NMR(200MHz, CDCl3): δ(ppm) 7.90(d, 2H5 J=8Hz), 7.25-7.18(m, 3H),
7.02-6.89(m, 3H), 4.97(s, 2H), 4.24-4.17(m5 2H), 3.93-3.68(m, IH), 3.62(t, 2H,
J=4.2Hz)5 3.31-3.26(m, IH), 2.95-2.93(m, 2H)5 2.77-2.68(m5 2H), 2.42(s, 3H)5 2.37(S5 3H), 2.08(s5 IH), 1.28(t, 3H5 J-6.8Hz).
Step 2: Preparation of 4-[3-(5-methyl-2-(4-methylphenyl)-oxazol-4-yl-methoxy) benzyl] -3 -thiomorpholinecarboxylic acid
The procedure of Step 2 of Example 72 was repeated except for using the compound obtained in Step 1 of Example 75(64.5 mg, 0.14 mmol) to obtain the title compound(10 mg, yield: 17%). 1H NMR(200MHz, CDCl3): δ(ppm) 7.89(d, 2H5 J=8.2Hz)3 7.32-7.19(m, 3H), 7.03(s, IH), 7.03-6.88(m, 2H), 4.97(s, 2H), 3.97-3.71(m, IH), 3.60-3.58(m, 2H), 3.32(m, IH), 2.97-2.67(m, 3H), 2.58-2.53(m, 2H), 2.44(s, 3H), 2.39(s, 3H).
Example 76: Preparation of 4-[4-(5-methyl~2-(4-trifluoromethyIphenyl)-oxazol- 4-yl-methoxy)benzyl]-3-thiomorpholinecarboxyϊic acid
Figure imgf000081_0001
Step 1 : Preparation of 4-[4-(5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl- methoxy)benzyl]-3-thiomorpholinecarboxylic acid ethyl ester The procedure of Step 1 of Example 72 was repeated except for using
4-(4-chloromethylphenoxymethyl)-5-methyl-2-(4-trifluoromethylphenyl)-oxazole(9
1.6 mg, 0.24 mmol) and 3-thiomorpholine carboxylic acid ethyl ester(41.8 mg, 0.24 mmol) to obtain the title compound(28 mg, yield: 27%).
1H NMR(200MHz, CDCl3): δ(ppm) 8.17(d, 2H, J=8.2Hz), 7.74(d, 2H, J=8.2Hz), 7.36-7.24(m, 2H), 7.05-6.96(m, 2H), 5.01(s, 2H), 4.23(q, IH3 J=6Hz), 3.90-3.66(m,
IH), 3.62(t, 2H, J=4.0Hz), 3.32-3.27(m, IH), 3.10-2.94(m, 2H) 2.79-2.56(m, 2H),
2.48(s, 3H), 1.32(t, 3H, J=6.8Hz).
Step 2: Preparation of 4-[4-(5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl -methoxy)benzyl]-3-thiomorpholinecarboxylic acid
The procedure of Step 2 of Example 72 was repeated except for using the compound obtained in Step 1 of Example 76(27 mg, 0.05 mmol) to obtain the title compound(18.3 mg, yield: 74%).
1H NMR(200MHz, CDCl3): δ(ppm) 8.08(d, 2H, J=8Hz), 7.65(d, 2H, J=8.2Hz), 7.22-7.20(m, 2H), 6.92(d, 2H3 J=8.4Hz), 4.94(s, 2H), 3.95-3.78(m, 3H), 3.68-3.64(m,
2H), 3.54-3.48(m, IH), 3.24-3.19(m, 2H), 2.42(s,.3H), 2.33-2.27(m, IH).
Example 77: Preparation of 4-[3-(5-methyI-2-(4-trifluoromethylphenyl)-oxazoI- 4-y I-methoxy)benzyI) -3-thiomorpholinecarboxylic acid
Figure imgf000081_0002
Step 1 : Preparation of 4-[3-(5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl- methoxy)benzyl]-3-thiomorpholinecarboxylic acid ethyl ester The procedure of Step 1 of Example 72 was repeated except for using 4-(3-chloromethylphenoxymethyl)-5-methyl-2-(4-trifluoromethylphenyl)-oxazole(7 6.3 mg, 0.20 mmol) and 3-thiomorpholine carboxylic acid ethyl ester(35 mg, 0.20 mmol) to obtain the title compound(31 mg, yield: 30%). 1H NMR(200MHz, CDCl3): δ(ppm) 8.13(d, 2H, J=7.8Hz), 7.70(d, 2H, J=8.1Hz), 7.22(d, IH, J=8. IHz)5 7.02(s, IH), 6.94-6.89(m, 2H), 4.99(s, 2H), 4.27-4.08(m, 2H), 3.92-3.70(m, 2H), 3.63(t, IH5J =4.5Hz), 3.32-3.28(m, IH), 2.97-2.94(m, 2H), 2.77-2.69(m, 2H), 2.5 l(d, IH, J-4.2Hz), 2.47(s, 3H), 1.29(t, 3H5 J=7.2Hz).
Step 2: Preparation of 4-[3-(5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl- methoxy)benzyl]-3-thiornorpholinecarboxylic acid
The procedure of Step 2 of Example 72 was repeated except for using the compound obtained in Step 1 of Example 77(31 mg, 0.059 mmol) to obtain the title compound(17 mg, yield: 58%). 1H NMR(200MHz, CDCl3): δ(ppm) 8.13(d5 2H, J=8.4Hz), 7.70(d, 2H, J=8.6Hz),
7.24-7.20(m, IH), 7.03(s, IH), 6.96-6.90(m, 2H), 5.00(s, 2H), 3.99-3.73(m, 2H),
3.62(t, IH5 J=4.2Hz), 3.33-3.27(m, IH), 2.99-2.73(m, 2H), 2.80-2.63(m, 3H),
1.254(s, 3H).
Example 78: Preparation of 4-[4-(5-methyl~2-(2-thiophene)-oxazol-4-yI- methoxy)benzyl]-3-thiomorpholinecarboxylic acid
Figure imgf000082_0001
Step 1 : Preparation of 4-[4-(5-methyl-2-(2-thiophene)-oxazol-4-yl-methoxy) benzyl] -3 -thiomorpholinecarboxylic acid ethyl ester The procedure of Step 1 of Example 72 was repeated except for using
4-(4-chloromethylphenoxymethyl)-5-methyl-2-(2-thiophene)-oxazole(59.7 mg, 0.19 mmol) and 3-thiomorpholine carboxylic acid ethyl ester(32.7 mg, 0.19 mmol) to obtain the title compound(43 mg, yield: 50%).
1H NMR(200MHz, CDCl3): δ(ppm) 7.66-7.63(m, IH), 7.43-7.40(m, IH), 7.29-7.23(m, 2H), 7.12-7.1 l(m, IH), 6.99-6.94(m, 2H), 4.97(s, 2H), 4.27-4.23(m,
2H), 3.83-3.61(m, 3H), 3.40-3.27(m, IH), 2.94-2.81(m, 2H), 2.74-2.42(m, 3H)5
2.43(s, 3H), 1.32(t, 3H, J=7.4Hz).
Step 2: Preparation of 4-[4-(5-methyl-2-(2-thiophene)-oxazol-4-yl-methoxy)benzyl]- 3 -thiomorpholinecarboxylic acid
The procedure of Step 2 of Example 72 was repeated except for using the compound obtained in Step 1 of Example 78(40 mg, 0.09 mmol) to obtain the title compound(22.6 mg, yield: 60%).
1H NMR(200MHz, CDCl3): δ(ppm) 7.62-7.40(m, 3H), 7.28-7.12(m, IH), 6.99-6.94(m, 3H), 4.97(s, 2H), 3.83-3.61(m, 3H), 3.41-3.27(m, IH), 2.94-2.83(m, 2H), 2.69-2.44(m, 3H), 2.43(s, 3H).
Example 79: Preparation of 4-[3-(5-methyl-2-(2-thiophene)-oxazol-4-yl- methoxy)benzyl]-3-thiomorpholinecarboxylic acid
Figure imgf000083_0001
Step 1: Preparation of 4-[3-(5-methyl-2-(2-thiophene)-oxazol-4-yl-methoxy) benzyl] -3 -thiomorpholinecarboxy lie acid ethyl ester
The procedure of Step 1 of Example 72 was repeated except for using 4-(3-chloromethylphenoxymethyl)-5-methyl-2-(2-thiophene)-oxazole(l 11 mg, 0.35 mmol)and 3-thiomorpholine carboxylic acid ethyl ester(61 mg, 0.35 mmol) to obtain the title compound(86 mg, yield: 54%).
1H NMR(200MHz, CDCl3): δ(ppm) 7.65(d, IH, J=3.6Hz), 7.42(d, IH, J=5.4Hz), 7.31-7.20(m, IH), 7.14-7.00(m, IH), 7.02-6.89(m, 3H), 4.98(s, 2H), 4.29-4.20(m, 2H), 3.89(q, 2H, J=13.8Hz), 3.64(t, IH, J=3.8Hz), 3.33-3.28(m, IH), 2.98-2.96(m, 2H), 2.76-2.69(m, 2H), 2.44(s, 3H), 2.12(s, IH), 1.31(t, 3H, J=7.4Hz).
Step 2: Preparation of 4-[3-(5-methyl-2-(2-thiophene)-oxazol-4-yl-methoxy) benzyl]-3-thiomorpholinecarboxylic acid
The procedure of Step 2 of Example 72 was repeated except for using the compound obtained in Step 1 of Example 79(80 mg, 0.17 mmol) to obtain the title compound(61.2 mg, yield: 82%).
1H NMR(200MHz, CDCl3): δ(ppm) 7.64-7.21(m, 4H), 7.13-6.89(m, 3H), 4.98(s, 2H), 4.29-4.20(m, 2H), 3.78-3.65(m, IH), 3.33-3.28(m, IH), 2.97-2.96(m, 2H), 2.75-2.68(m, 2H), 2.44(s, 3H), 2.12(s, IH).
Example 80: Preparation of (3S)-4-[4-(5-methyl-2-phenyl-oxazol-4-yl-ethoxy) benzyl]-morpholine-3-carboxylic acid
H Ck^O
Figure imgf000083_0002
Step 1 : Preparation of (3S)-4-[4-(5-methyl-2-phenyl-oxazol-4-yl-ethoxy)benzyl]- morpholine-3-carboxylic acid methyl ester
4-(4-Chloromethylphenoxyethyl)-5-methyl-2-phenyl-oxazole(48 mg, 0.15 mmol),(3S)-morpholine carboxylic acid methyl ester(22.1 mg, 0.15 mmol) and potassium carbonate(36 mg, 0.26 mmol) were dissolved in acetonitrile(5 ml). The resultant was heated to reflux for 24 hrs. The reaction product was concentrated under reduced pressure and an excessive amount of water poured thereto. Then, the resulting mixture was extracted with ethyl acetate. The organic layer was separated and dried over anhydrous magnesium sulfate, followed by removing the solvent to obtain the title compound(41 mg, yield: 60%). 1H NMR(200MHz, CDCl3): δ(ppm) 8.06-8.00(m, 2H), 7.49-7.42(m, 3H), 7.27(d, 2H, J=7.6Hz), 7.00(d, 2H, J=8.6Hz), 3.02(t, 2H), 4.24(t, 2H), 3.93-3.82(m, 3H), 3.76(s, 3H), 3.74-3.64(m, 2H), 3.58-3.52(m, IH), 3.30(t, IH, J=4Hz), 3.11-3.00(m, IH), 2.45(s, 3H), 2.42-2.3 l(m, IH).
Step 2: Preparation of (3S)-4-[4-(5-methyl-2-phenyl-oxazol-4-yl-ethoxy)benzyl]- morpholine-3 -carboxylic acid
(3S)-4-[4-(5-methyl-2-phenyl-oxazol-4-yl-ethoxy)benzyl]-morpholine-3- carboxylic acid methyl ester(41 mg, 0.096 mmol) and an aqueous 1 N lithium hydroxide(0.86 ml, 0.86 mmol) were dissolved in 3 ml of a mixture of methanol and water(3 :l). The resulting mixture was stirred for 12 hrs and concentrated under reduced pressure. The residue thus obtained was extracted with diethyl ether.
The organic layer was separated and dried over anhydrous magnesium sulfate, followed by removing the solvent to obtain the title compound(20 mg, yield: 50%) as a white solid. 1H NMR(200MHz, CDCl3): δ(ppm) 7.94(m, 2H), 7.53(m, 3H), 7.24(m, 2H), 7.03(m,
2H), 3.02(t, 2H), 4.24(t, 2H), 3.76-3.17(m, 7H), 2.91(m, IH), 2.50(s, 3H), 2.28(m,
IH).
Example 81: Preparation of (3S)-4-[3-(5-methyl-2-phenyl-oxazol-4-yl-ethoxy) benzyl] -morpholine-3-carboxylic acid
HO^O
Figure imgf000084_0001
Step 1: Preparation of (3S)-4-[3-(5-methyl-2-phenyl-oxazol-4-yl-ethoxy)benzyl]- morpholine-3-carboxylic acid methyl ester
The procedure of Step 1 of Example 64 was repeated except for using 4-(3-chloromethylphenoxyethyl)-5-methyl-2-phenyl-oxazole(35 mg, 0.11 mmol) and (3S)-morpholine carboxylic acid methyl ester(15.5 mg, 0.11 mmol) to obtain the title compound(43 mg, yield: 89%). 1U NMR(200MHz, CDCl3): δ(ppm) 8.07-8.02(m, 2H), 7.49-7.44(m, 2H), 7.30-7.22(m, 2H), 7.05(s, IH), 7.27(d, 2H, J=8Hz), 3.02(t, 2H), 4.24(t, 2H), 4.01-3.82(m, 3H), 3.77(s, 3H)5 3.73-3.58(m, IH), 3.33(t, IH, J=4Hz), 3.09-3.05(m, IH), 2.47(s, 3H), 2.43-2.35(m, IH).
Step 2: Preparation of (3S)-4-[3-(5-methyl-2-phenyl-oxazol-4-yl-ethoxy)benzyl]- morpholine-3-carboxylic acid
The procedure of Step 2 of Example 64 was repeated except for using the compound obtained in Step 1 of Example 81(40 mg, 0.09 mmol) to obtain the title compound(34.7 mg, yield: 89%).
1H NMR(200MHz, DMSO-D6): δ(ppm) 8.00(m, 2H), 7.45(m, 2H), 7.26(m, 2H), 6.98(m, 3H), 3.02(t, 2H), 4.24(t, 2H), 4.15(m, 2H), 3.74(m, 4H), 3.41(m, IH), 3.15(m, IH), 2.44(m, IH), 2.43(s, 3H).
Example 82: Preparation of (3S)-4-[4-(5-methyl-2-(4-methylphenyI)-oxazol-4-yl- ethoxy)benzyl]-morpholine-3-carboxylic acid
Figure imgf000085_0001
Step 1: Preparation of (3S)-4-[4-(5-methyl-2-(4-methylphenyl)-oxazol-4-yl-ethoxy) benzyl]-morpholine-3-carboxylic acid methyl ester The procedure of Step 1 of Example 64 was repeated except for using
4-(4-chloromethylphenoxyethyl)-5-methyl-2-(4-methylphenyl)-oxazole(32 mg, 0.09 mmol) and (3S)-morpholme carboxylic acid methyl ester(13.6 mg, 0.09 mmol) to obtain the title compound(25.5 mg, yield: 64%).
1H NMR(200MHz, CDCl3): δ(ppm) 7.89(d, 2H-, J=8.2Hz), 7.26(d, 4H, J=7.8Hz), 6.97(d, 2H, J=8.6Hz), 3.02(t, 2H), 4.24(t, 2H), 3.85(m, 4H)5 3.74(s, 3H), 3.69(m,
2H), 3.28(m, IH), 3.07(m, IH), 2.42(d, 6H, J=5Hz).
Step 2: Preparation of (3S)-4-[4-(5-methyl-2-(4-methylphenyl)-oxazol-4-yl-ethoxy) benzyl]-morpholine-3-carboxylic acid The procedure of Step 2 of Example 64 was repeated except for using the compound obtained in Step 1 of Example 82(20 mg, 0.04 mmol) to obtain the title compound(11.5 mg, yield: 60%).
1H NMR(200MHz, DMSO-D6): δ(ppm) 7.89(d, 2H5 J=8.2Hz), 7.31-7.22(m, 5H),
6.99(d, 2H, J=8.4Hz), 3.02(t, 2H), 4.24(t, 2H), 4.01-3.89(m, 3H), 3.73-3.58(m, 4H), 3.38-3.28(m, IH), 3.12-2.96(m, IH)5 2.42(s, 3H), 2.39(s, 3H).
Example 83: Preparation of (3S)-4-[3-(5-methyl-2-(4-methylphenyl)-oxazol-4-yl- ethoxy)benzyl]-morpholine-3-carboxylic acid
Figure imgf000086_0001
Step 1 : Preparation of (3S)-4-[3-(5-methyl-2-(4-methylphenyl)-oxazol-4-yl-ethoxy) benzylj-morpholine-S-carboxylic acid methyl ester The procedure of Step 1 of Example 64 was repeated except for using
4-(3-chloromethylphenoxyethyl)-5-methyl-2-(4-methylphenyl)-oxazole(40 mg, 0.12 mmol) and (3S)-morpholine carboxylic acid methyl ester(17 mg, 0.12 mmol) to obtain the title compound(43 mg, yield: 70%).
1H NMR(200MHz, CDCl3): δ(ppm) 7.92(d, 2H, J=8.2Hz), 7.28-7.22(m, 3H), 7.05-6.93(m, 3H), 3.02(t, 2H), 4.24(t, 2H), 3,98-3.79(m, 3H), 3.76(s, 3H), 3.74-3.57(m, 2H), 3.33(t, IH, J=4Hz), 3.15-3.03(m, IH), 2.45(s, 3H), 2.41(s, 3H).
Step 2: Preparation of (3S)-4-[3-(5-methyl-2-(4-methylphenyl)-oxazol-4-yl-ethoxy) benzyl]-morpholine-3-carboxylic acid The procedure of Step 2 of Example 64 was repeated except for using the compound obtained in Step 1 of Example 83(43 mg, 0.09 mmol) to obtain the title compound(29 mg, yield: 69%).
1H NMR(200MHz, DMSO-D6): δ(ppm) 7.89(d, 2H, J=8.2Hz), 7.21-7.15(m, 4H),
7.02-6.98(m, 2H), 3.02(t, 2H), 4.24(t, 2H), 4.68-4.40(m, 3H), 4.35-3.83(m, 3H), 3.64-3.56(m, IH), 3.31-3.27(m, IH), 2.74(m, IH), 2.41(s, 3H), 2.38(s, 3H).
Example 84: Preparation of (3S)-4-[4-(5-methyl-2-(4-trifluoromethylphenyl)- oxazol-4-yl-ethoxy)benzyl]-morpholine-3-carboxylic acid
Figure imgf000086_0002
Step 1: Preparation of (3S)-4-[4-(5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4- yl-ethoxy)benzyl]-morpholine-3 -carboxylic acid methyl ester
The procedure of Step 1 of Example 64 was repeated except for using 4-(4-chloromethylphenoxyethyl)-5-methyl-2-(4-trifluoromethylphenyl)-oxazole(25 mg, 0.06 mmol) and (3S)-morpholine carboxylic acid methyl ester(9.2 mg, 0.06 mmol) to obtain the title compound(27.6 mg, yield: 86%).
1H NMR(200MHz, CDCl3): δ(ppm) 8.13(d, 2H, J=7.8Hz), 7.71(d, 2H, J=8.2Hz), 7.28(m, 2H), 6.98(m, 2H), 3.02(t, 2H), 4.24(t, 2H), 4.50(m, IH)5 3.86(m, 2H), 3.74(s, 3H), 3.74(m, 2H), 3.49(m, 2H), 3.03(m, IH), 2.46(s, 3H), 2.37(m, IH). Step 2: Preparation of (3S)-4-[4-(5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl- ethoxy)benzyl] -morpholine-3 -carboxylic acid
The procedure of Step 2 of Example 64 was repeated except for using the compound obtained in Step 1 of Example 84(26 mg, 0.05 mmol) to obtain the title compound(18.6 mg, yield: 74%).
1H NMR(200MHz, DMSO-D6): δ(ppm) 8.13(d, 2H, J =8.2Hz), 7.71(d, 2H, J=8.6Hz),
7.27-2.22(m, IH), 7.06-6.92(m, 3H), 3.02(t, 2H), 4.24(t5 2H), 4.00-3.86(m, 3H),
3.72-3.59(m, 3H), 3.48(s, IH), 3.34-3.30(m, IH), 3.10-3.00(m, IH), 2.48(s, 3H).
Example 85: Preparation of (3S)-4-[3-(5-methyl-2-(4-trifluoromethylphenyl)- oxazol-4-yl-ethoxy)benzyl] -morpholine-3-carboxylic acid
Figure imgf000087_0001
Step 1: Preparation of (3S)-4-[3-(5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl- ethoxy)benzyl] -morpholine-3 -carboxylic acid methyl ester
The procedure of Step 1 of Example 64 was repeated except for using
4-(3-chloromethylphenoxyethyl)-5-methyl-2-(4-trifluoromethylphenyl)-oxazole(37 mg, 0.09 mmol) and (3S)-morpholine carboxylic acid methyl ester(13.6 mg, 0.09 mmol) to obtain the title compound(22.6 mg, yield: 48%). 1H NMR(200MHz, CDCl3): δ(ppm) 8.18(d, 2H, J=8.6Hz), 7.75(d, 2H, J=8.6Hz),
7.31-7.23(m, IH), 7.06(s, IH), 6.99-6.93(m, 2H), 3.02(t, 2H), 4.24(t, 2H),
4.02-3.79(m, 3H), 3.77(s, 3H), 3.75-3.58(m, 3H), 3.33(t, IH, J=4Hz), 3.15-3.04(m,
IH), 2.49(s, 3H), 2.43-2.33(m, IH).
Step 2: Preparation of (3S)-4-[3-(5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl- ethoxy)benzyl]-morpholine-3-carboxylic acid
The procedure of Step 2 of Example 64 was repeated except for using the compound obtained in Step 1 of Example 85(20 mg, 0.04 mmol) to obtain the title compound(15.9 mg, yield: 82%). 1H NMR(200MHz, DMSO-D6): δ(ppm) 8.17(d, 2H, J=8.6Hz), 7.74(d, 2H, J=8.6Hz),
7.31-7.23(m, IH), 7.05(s, IH), 6.97-6.91(m, 2H), 3.02(t, 2H), 4.24(t, 2H),
3.99-3.77(m, 3H), 3.66-3.31(m, 4H), 3.15-3.04(m, IH), 2.49(s, 3H), 2.43-2.33(m,
IH).
Example 86: Preparation of (3S)-4-[4-(5-methyl-2-(2-thiophene)-oxazol-4-yl- ethoxy)benzyl] -morpholine-3-carboxylic acid
Figure imgf000088_0001
Step 1 : Preparation of (3S)-4-[4-(5-methyl-2-(2-thiophene)-oxazol-4-yl-ethoxy) benzyl]-morpholine-3-carboxylic acid methyl ester The procedure of Step 1 of Example 64 was repeated except for using
4-(4-chloromethylphenoxyethyl)-5-methyl-2-(2-thiophene)-oxazole(30 mg, 0.09 mmol) and (3S)-morpholine carboxylic acid methyl ester(13 mg, 0.09 mmol) to obtain the title compound(24.6 mg, yield: 62%).
1H NMR(200MHz, CDCl3): δ(ppm) 7.63(d, IH, J=2.8Hz), 7.40(d, IH, J=4.8Hz), 7.25-7.22(m, 2H), 7.12-7.02(m5 IH), 6.95(d, 2H, J=8.6Hz), 3.02(t, 2H), 4.24(t, 2H), 3.91-3.79(m, 3H), 3.74(s, 3H), 3.73-3.69(m, IH)5 3.56-3.49(m, 2H), 3.30-3.28(m, IH), 3.06-3.04(m, IH), 2.41(s, 3H)5 2.31(m5 IH).
Step 2: Preparation of (3S)-4-[4-(5-methyl-2-(2-thiophene)-oxazol-4-yl-ethoxy) benzyl]-morpholine-3-carboxylic acid
The procedure of Step 2 of Example 64 was repeated except for using the compound obtained in Step 1 of Example 86(22 mg, 0.05 mmol) to obtain the title compound(13.2 mg, yield: 62%).
1H NMR(200MHz, DMSO-D6): δ(ppm) 7.63-7.23(m, 3H), 7.12-6.95(m, 4H), 3.02(t, 2H), 4.24(t, 2H), 3.91-3.79(m, 3H), 3.73-3.49(m, 3H), 3.30-3.03(m, 2H), 2.41(s, 3H),
2.3 l(m, IH).
Example 87: Preparation of (3S)-4-[3-(5-methyl-2-(2-thiophene)-oxazol-4-yl- ethoxy)benzyl] -morpholine-3-carboxylic acid
Figure imgf000088_0002
Step 1 : Preparation of (3S)-4-[3-(5-methyl-2-(2-thiophene)-oxazol-4-yl-ethoxy) benzyl] -morpholine-3-carboxylic acid methyl ester
The procedure of Step 1 of Example 64 was repeated except for using
4-(3-chloromethylphenoxyethyl)-5-methyl-2-(2-thiophene)-oxazole(32 mg, 0.09 mmol) and (3S)-morpholine carboxylic acid methyl ester(13.9 mg, 0.09 mmol) to obtain the title compound(24.2 mg, yield: 57%).
1H NMR(200MHz, CDCl3): δ(ppm) 7.63(d, IH, J=3.6Hz), 7.40(d, IH, J=5.4Hz),
7.24-7.19(m, 2H) 7.12-7.07(m, IH), 7.01(s, IH), 6.95-6.88(m, IH), 3.02(t, 2H),
4.24(t, 2H), 4.17-3.77(m, 4H)5 3.74(s, 3H), 3.69-3.55(m, 2H), 3.30(m, IH), 3.12-3.03(m, IH), 2.42(s, 3H), 2.39-2.35(m, IH).
Step 2: Preparation of (3S)-4-[3-(5-methyl-2-(2-thioρhene)-oxazol-4-yl-ethoxy) benzylj-morpholine-S-carboxylic acid The procedure of Step 2 of Example 64 was repeated except for using the compound obtained in Step 1 of Example 87(24 mg, 0.05 mmol) to obtain the title compound(14.4 mg, yield: 62%).
1H NMR(200MHz, DMSO-D6): δ(ppm) 7.63-7.19(m, 4H)5 7.12-7.07(m, IH), 7.01(s, IH), 6.95-6.88(m, IH), 3.02(t, 2H), 4.24(t, 2H), 4.16-3.75(m, 4H), 3.69-3.55(m, 2H), 3.30-3.02(m5 2H), 2.42(s, 3H), 2.45-2.34(m, IH).
Example 88: Preparation of 4-[4-(5-methyl-2-phenyl-oxazol-4-yl-ethoxy) benzyl] -3-thiomorpholinecarboxylic acid
Figure imgf000089_0001
Step 1: Preparation of 4-[4-(5-methyl-2-phenyl-oxazol-4-yl-ethoxy)benzyl]- 3-thiomorpholinecarboxylic acid ethyl ester
4-(4-Chloromethylphenoxyethyl)-5-methyl-2-phenyl-oxazole(73 mg, 0.22 mmol), 3-thiomorpholine carboxylic acid ethyl ester(39 mg, 0.22 mmol) and potassium carbonate(54 mg, 0.39 mmol) were dissolved in acetonitrile(6 ml). The resulting mixture was heated to reflux for 24 hrs. The reaction product was concentrated under reduced pressure, and an excessive amount of water was added thereto. Then, the resulting mixture was extracted with ethyl acetate. The organic layer was separated and dried over anhydrous magnesium sulfate, followed by removing the solvent to obtain the title compound(64 mg, yield: 62%) as a white liquid.
1H NMR(200MHz, CDCl3): δ(ppm) 8.06-8.01(m, 2H), 7.48-7.43(m, 3H), 7.25(d, 2H, J=8.6Hz), 6.98(d, 2H, J=8.6Hz), 3.02(t, 2H), 4.24(t, 2H), 4.25(q, 2H, J=7.4Hz), 3.89-3.65(m, IH), 3.63-3.59(m, 2H), 3.38-3.27(m, IH), 2.98-2.93(m, 2H), 2.78-2.49(m, 3H), 2.45(s, 3H)5 1.28(t, 3H, J=7.4Hz).
Step 2: Preparation of 4-[4-(5-methyl-2-phenyl-oxazol-4-yl-ethoxy)benzyl]- 3-thiomorpholinecarboxylic acid
The compound obtained in Step 1 of Example 88(50 mg, 0.10 mmol) and an aqueous 1 N lithium hydroxide(0.90 ml, 0.90 mmol) were dissolved in 5 ml of a mixture of tetrahydrofuran and water(3:l). The resulting mixture was stirred at 50 °C for 3 days and concentrated under reduced pressure. The residue thus obtained was extracted with diethyl ether. The organic layer was separated, dried over anhydrous magnesium sulfate, followed by removing the solvent to obtain the title compound(8 mg, yield: 30%) as a white solid.
1H NMR(200MHz, CDCl3): δ(ppm) 8.05-7.43(m, 5H)5 7.25-7.18(m, 2H), 6.95-6.86(m, 2H)3 3.02(t, 2H), 4.24(t, 2H), 3.89-3.65(m, IH), 3.63-3.59(m, 2H), 3.38-3.27(m, IH), 2.98-2.93(m, 2H), 2.78-2.49(m, 3H), 2.45(s, 3H).
Example 89: Preparation of 4-[3-(5-methyI-2-phenyl-oxazol-4-yl-ethoxy) benzyrj-S-thiomorpholinecarboxylic acid
Figure imgf000090_0001
Step 1 : Preparation of 4-[3-(5-methyl-2-phenyl-oxazol-4-yl-ethoxy)benzyl]-
3-thiomorpholinecarboxylic acid ethyl ester
The procedure of Step 1 of Example 72 was repeated except for using
4-(3-chloromethylphenoxyethyl)-5-methyl-2-phenyl-oxazole(50 mg, 0.15 mmol) and
3-thiomorpholine carboxylic acid ethyl ester(26.7 mg, 0.15 mmol) to obtain the title compound(42.7 mg, yield: 60%).
1H NMR(200MHz, CDCl3): δ(ppm) 8.00-7.99(m, 2H), 7.45-7.33(m, 2H),
7.28-7.23(m, 2H), 7.04(s, IH), 6.95-6.89(m, 2H), 3.02(t, 2H), 4.24(t, 2H), 4.25(q,
2H,J =7.4Hz), 3.98-3.71(m, 2H), 3.62-3.60(m, IH), 3.33-3.27(m, IH), 3.00-2.97(m,
2H), 2.81-2.61(m, 3H), 2.45(s, 3H), 1.27(t, 3H, J=7.4Hz).
Step 2: Preparation of 4-[3-(5-methyl-2-phenyl-oxazol-4-yl-ethoxy)benzyl]-
3-thiomorpholinecarboxylic acid
The procedure of Step 2 of Example 72 was repeated except for using the compound obtained in Step 1 of Example 89(42 mg, 0.09 mmol) to obtain the title compound(35.1 mg, yield: 89%).
1H NMR(200MHz, CDCl3): δ(ppm) 8.00-7.99(m, 2H), 7.45-7.33(m, 2H),
7.28-7.23(m, 2H), 7.04(s, IH), 6.95-6.89(m, 2H), 3.02(t, 2H), 4.24(t, 2H),
3.98-3.71(m, 2H), 3.62-3.60(m, IH), 3.33-3.27(m, IH), 3.00-2.97(m, 2H),
2.81-2.61(m, 3H), 2.45(s, 3H).
Example 90: Preparation of 4-[4-(5-methyI-2-(4-methylphenyl)-oxazol-4-yl- ethoxy)benzyl]-3-thiomorpholinecarboxylic acid
Figure imgf000090_0002
Step 1: Preparation of 4-[4-(5-methyl-2-(4-methylphenyl)-oxazol-4-yl-ethoxy) benzyl] -3 -thiomorpholinecarboxylic acid ethyl ester
The procedure of Step 1 of Example 72 was repeated except for using 4-(4-chloromethylphenoxyethyl)-5-methyl-2-(4-methylphenyl)-oxazole(64 mg, 0.19 mmol) and 3-thiomorpholine carboxylic acid ethyl ester(32.8 mg, 0.19 mmol) to obtain the title compound(63.9 mg, yield: 71%).
1H NMR(200MHz, CDCl3): δ(pρm) 7.92(d, 2H3 J=8,2Hz), 7.24-7.23(m, 2H), 6.96(d, 2H, J=8.5Hz), 3.02(t, 2H), 4.24(t, 2H), 4.23(q, 2H, J=5.6Hz), 3.89-3.59(m, IH)3 3.61(t, 2H, J=4.2Hz), 3.32-3.27(m, IH), 2.98-2.93(m, 2H), 2.78-2.46(m, 3H), 2.44(s, 3H)3 2.41(s, 3H)3 1.3 l(t, 3H, J=7.2).
Step 2: Preparation of 4-[4-(5-methyl-2-(4-methylphenyl)-oxazol-4-yl-ethoxy) benzyl] -3 -thiomorpholinecarboxylic acid
The procedure of Step 2 of Example 72 was repeated except for using the compound obtained in Step 1 of Example 90(60 mg, 0.12 mmol) to obtain the title compound(13 mg, yield: 23%).
1H NMR(200MHz, CDCl3): δ(ppm) 7.88(d, 2H, J=8.2Hz), 7.27-7.24(m, 4H), 6.95(d,
2H3 J=8.6Hz), 3.02(t, 2H), 4.24(t, 2H), 3.95-3.68(m3 2H)3 3.56-3.50(m3 IH)3
3.39-3.33(m, IH), 2.80-2.61(m, 2H), 2.59-2.58(m, 3H)3 2.43(s, 3H), 2.40(s, 3H).
Example 91: Preparation of 4-[3-(5-methyl-2-(4-methylphenyl)-oxazol-4-yl- ethoxy)benzyl]-3-thiomorpholinecarboxylic acid
Figure imgf000091_0001
Step 1 : Preparation of 4-[3-(5-methyl-2-(4-methylphenyl)-oxazol-4-yl-ethoxy) benzyl] -3 -thiomorpholinecarboxylic acid ethyl ester
The procedure of Step 1 of Example 72 was repeated except for using
4-(3-chloromethylphenoxyethyl)-5-methyl-2-(4-methylphenyl)-oxazole(30 mg, 0.09 mmol) and 3-thiomorpholine carboxylic acid ethyl ester(15.3 mg, 0.09 mmol) to obtain the title compound(24.4 mg, yield: 58%). 1H NMR(200MHz, CDCl3): δ(ppm) 7.90(d, 2H3 J=8Hz), 7.25-7.18(m, 3H),
7.02-6.89(m, 3H), 3.02(t, 2H), 4.24(t, 2H)3 4.24-4.17(m, 2H), 3.93-3.68(m, IH),
3.62(t, 2H, J-4.2Hz), 3.31-3.26(m, IH)3 2.95-2.93(m3 2H)3 2.77-2.68(m, 2H)3 2.42(s3
3H)3 2.37(s, 3H), 2.08(s, IH), 1.28(t, 3H, J=6.8Hz).
Step 2: Preparation of 4-[3-(5-methyl-2-(4-methylphenyl)-oxazol-4-yl-ethoxy) benzyl]-3-thiomorpholinecarboxylic acid
The procedure of Step 2 of Example 72 was repeated except for using the compound obtained in Step 1 of Example 91(22 mg, 0.04 mmol) to obtain the title compound(3.5 mg, yield: 17%).
1H NMR(200MHz5 CDCl3): δ(ppm) 7.89(d, 2H, J=8.2Hz), 7.32-7.19(m, 3H), 7.03(s, IH), 7.03-6.88(m, 2H), 3.02(t, 2H), 4.24(t, 2H), 3.97-3.71(m, IH)5 3.60-3.58(m, 2H), 3.32(m, IH), 2.97-2.67(m, 3H), 2.58-2.53(m, 2H), 2.44(s, 3H), 2.39(s, 3H).
Example 92: Preparation of 4-[4-(5-methyl-2-(4-trifluoromethylphenyl)-oxazoI- 4-yl-ethoxy)benzyl]-3-thiomorpholinecarboxyIic acid
Figure imgf000092_0001
Step 1 : Preparation of 4-[4-(5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl- ethoxy)benzyl]-3-thiomorpholinecarboxylic acid ethyl ester
The procedure of Step 1 of Example 72 was repeated except for using
4-(4-chloromethylphenoxyethyl)-5-methyl-2-(4-trifluoromethylphenyl)-oxazole(47 mg, 0.12 mmol) and 3-thiomorpholine carboxylic acid ethyl ester(20.8 mg, 0.12 mmol) to obtain the title compound(17.1 mg, yield: 27%).
1H NMR(200MHz, CDCl3): δ(ppm) 8.17(d, 2H, J=8.2Hz), 7.74(d, 2H, J=8.2Hz),
7.36-7.24(m, 2H), 7.05-6.96(m, 2H), 3.02(t, 2H), 4.24(t, 2H), 4.23(q, IH, J=6Hz),
3.90-3.66(m, IH), 3.62(t, 2H, J=4.0Hz), 3.32-3.27(m, IH), 3.10-2.94(m, 2H)
2.79-2.56(m, 2H), 2.48(s, 3H), 1.32(t, 3H, J=6.8Hz).
Step 2: Preparation of 4-[4-(5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl- ethoxy)benzyl]-3-thiomorpholinecarboxylic acid
The procedure of Step 2 of Example 72 was repeated except for using the compound obtained in Step 1 of Example 92(17 mg, 0.03 mmol) to obtain the title compound(12 mg, yield: 74%).
1H NMR(200MHz, CDCl3): δ(ppm) 8.08(d, 2H, J=8Hz), 7.65(d, 2H, J=8.2Hz),
7.22-7.20(m, 2H), 6.92(d, 2H, J=8.4Hz), 3.02(t, 2H), 4.24(t, 2H), 3.95-3.78(m, 3H),
3.68-3.64(m, 2H), 3.54-3.48(m, IH), 3.24-3.19(m, 2H), 2.42(s, 3H), 2.33-2.27(m,
IH).
Example 93: Preparation of 4-[3-(5-methyl-2-(4-trifluoromethylphenyl)-oxazol-
4-yl-ethoxy)benzyl]-3-thiomorpholinecarboxylic acid
Figure imgf000092_0002
Step 1: Preparation of 4-[3-(5-memyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl- ethoxy)benzyl]-3-thiomorpholinecarboxylic acid ethyl ester
The procedure of Step 1 of Example 72 was repeated except for using 4-(3-chloromethylphenoxyethyl)-5-methyl-2-(4-trifluoromethylphenyl)-oxazole(55 mg, 0.14 mmol) and 3-thiomorpholine carboxylic acid ethyl ester(24.3 mg, 0.14 mmol) to obtain the title compound(22.2 mg, yield: 30%).
1H NMR(200MHz, CDCl3): δ(ppm) 8.13(d, 2H, J=7.8Hz), 7.70(d, 2H5 J=8.1Hz), 7.22(d, IH, J=8.1Hz), 7.02(s, IH), 6.94-6.89(m, 2H), 3.02(t, 2H), 4.24(t, 2H), 4.27-4.08(m, 2H), 3.92-3.70(m, 2H), 3.63(t, IH5J =4.5Hz), 3.32-3.28(m, IH), 2.97-2.94(m, 2H), 2.77-2.69(m, 2H), 2.5 l(d, IH5 J=4.2Hz), 2.47(s, 3H), 1.29(t, 3H, J=7.2Hz).
Step 2: Preparation of 4-[3-(5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl- ethoxy)benzyl] -3 -thiomorpholinecarboxy lie acid The procedure of Step 2 of Example 72 was repeated except for using the compound obtained in Step 1 of Example 93(22 mg, 0.04 mmol) to obtain the title compound(12 mg, yield: 58%).
1H NMR(200MHz, CDCl3): δ(ppm) 8.13(d, 2H5 J=8.4Hz), 7.70(d, 2H, J=8.6Hz),
7.24-7.20(m5 IH), 7.03(s, IH), 6.96-6.90(m, 2H)5 3.02(t, 2H), 4.24(t, 2H)5 3.99-3.73(m, 2H), 3.62(t, IH, J-4.2Hz), 3.33-3.27(m, IH), 2.99-2.73(m, 2H),
2.80-2.63(m, 3H), 1.254(s, 3H).
Example 94: Preparation of 4-[4-(5-methyl-2-(2-thiophene)-oxazol-4-yl-ethoxy) benzyl]-3-thiomorphoIinecarboxylic acid
Figure imgf000093_0001
Step 1 : Preparation of 4-[4-(5-methyl-2-(2-thiophene)-oxazol-4-yl-ethoxy)benzyl]-
3-thiomorpholinecarboxylic acid ethyl ester
The procedure of Step 1 of Example 72 was repeated except for using
4-(4-chloromethylphenoxyethyl)-5-methyl-2-(2-thiophene)-oxazole(45mg, 0.13 mmol) and 3-thiomorpholine carboxylic acid ethyl ester(23.6 mg, 0.13 mmol) to obtain the title compound(31.8 mg, yield: 50%).
1R NMR(200MHz, CDCl3): δ(ppm) 7.66-7.63(m, IH)5 7.43-7.40(m, IH),
7.29-7.23(m5 2H), 7.12-7.1 l(m, IH), 6.99-6.94(m, 2H), 3.02(t, 2H), 4.24(t, 2H)5
4.27-4.23(m, 2H), 3.83-3.61(m, 3H), 3.40-3.27(m, IH)5 2.94-2.81(m, 2H), 2.74-2.42(m, 3H), 2.43(s, 3H), 1.32(t, 3H, J=7.4Hz). Step 2: Preparation of 4-[4-(5-methyl-2-(2-thiophene)-oxazol-4-yl-ethoxy)benzyl]~ 3-thiomorpholinecarboxylic acid
The procedure of Step 2 of Example 72 was repeated except for using the compound obtained in Step 1 of Example 94(31 mg, 0.06 mmol) to obtain the title compound(17.5 mg, yield: 60%).
1H NMR(200MHz, CDCl3): δ(ppm) 7.62-7.40(m, 3H), 7.28-7.12(m, IH)3 6.99-6.94(m, 3H), 3.02(t, 2H), 4.24(t, 2H)5 3.83-3.61(m, 3H), 3.41-3,27(In, IH), 2.94-2.83(m, 2H), 2.69-2.44(m, 3H), 2.43(s, 3H).
Example 95: Preparation of 4-[3-(5-methyl-2-(2-thiophene)-oxazol-4-yl-ethoxy) benzyl] -3-thiomorpholinecarboxylic acid
Figure imgf000094_0001
Step 1 : Preparation of 4-[3-(5-methyl-2-(2-thiophene)-oxazol-4-yl-ethoxy)benzyl]-
3-thiomorpholinecarboxylic acid ethyl ester The procedure of Step 1 of Example 72 was repeated except for using
4-(3-chloromethylphenoxyethyl)-5-methyl-2-(2-thiophene)-oxazole(28 mg, 0.08 mmol) and 3-thiomorpholine carboxylic acid ethyl ester(14.7 mg, 0.08 mmol) to obtain the title compound(21.4 mg, yield: 54%).
1H NMR(200MHz, CDCl3): δ(ppm) 7.65(d, IH, J=3.6Hz), 7.42(d, IH, J=5.4Hz), 7.31-7.20(m, IH), 7.14-7.00(m, IH), 7.02-6.89(m, 3H), 3.02(t, 2H), 4.24(t, 2H),
4.29-4.20(m, 2H), 3.89(q, 2H, J=13.8Hz), 3.64(t, IH, J=3.8Hz), 3.33-3.28(m, IH),
2.98-2.96(m, 2H), 2.76-2.69(m, 2H), 2.44(s, 3H), 2.12(s, IH), 1.31(t, 3H, J=7.4Hz).
Step 2: Preparation of 4-[3-(5-methyl-2-(2-thiophene)-oxazol-4-yl-ethoxy)benzyl]- 3-thiomorpholinecarboxylic acid
The procedure of Step 2 of Example 72 was repeated except for using the compound obtained in Step 1 of Example 95(20 mg, 0.04 mmol) to obtain the title compound(15.4 mg, yield: 82%).
1H NMR^OOMHZ, CDCl3): δ(ppm) 7.64-7.21(m, 4H), 7.13-6.89(m, 3H), 3.02(t, 2H), 4.24(t, 2H), 4.29-4.20(m, 2H), 3.78-3.65(m, IH), 3.33-3.28(m, IH), 2.97-2.96(m,
2H), 2.75-2.68(m, 2H), 2.44(s, 3H), 2.12(s, IH).
Example 96: Preparation of (R)-l-[3-[(5-methyl-2-/7-tolyloxazol-4-yl)methoxy] benzyl] azetidine-2-carboxylic acid
Figure imgf000095_0001
Step 1: Preparation of (R)-l-[3-[(5-methyl-2-p-tolyloxazol-4-yl)methoxy]benzyl] azetidine-2-carboxylic acid methyl ester
4-[[3-(Chloromethyl)phenoxy]methyl]-5-methyl-2-p-tolyloxazole(100 mg, 0.31 mmol), (R)-2-(methoxycarbonyl)azetidinium chloride(0.50 mg, 0.34 mmol) and K2CO3(110 mg, 0.76 mmol) were dissolved in DMF(IO ml). The resulting mixture was stirred at 85 °C for 1 day and cooled down to room temperature. The resultant was extracted with water(30 ml) and dichloromethane(30 ml x 2). The organic layer was separated and dried over anhydrous sodium sulfate, followed by removing the solvent. The residue thus obtained was subjected to a silica gel column chromatography(eluent: hexane/ethyl acetate=2/l) to obtain the title compound(54 mg, yield: 43%).
1H NMR(CDCl3, 200MHz): δ(ppm) 8.15(d, J=8.6Hz, 2H), 7.72(d, J=8.6Hz, 2H), 7.24(d, J=8.6Hz, 2H), 6.97(d, J=8.6Hz, 2H), 5.01(s, 2H), 3.53-3.80(m, 2H), 3.66(s, 3H), 3.27-3.36(m, IH), 2.89-3.01(m, IH), 2.47(s, 3H), 2.15-2.3 l(m, 2H), 1.88(s, IH)
Step 2: Preparation of (R)-l-[3-[(5-methyl-2-/>-tolyloxazol-4-yl)methoxy]benzyl] azetidine-2-carboxylic acid The compound obtained in Step 1 of Example 96(35 mg, 0.085 mmol) was dissolved in a mixture of methanol and water(5:l, 1 ml), and KOH(12 mg, 0.22 mmol) was added thereto. The resulting mixture was stirred at room temperature for 5 days. The reaction product was diluted with ethyl acetate(3 ml) and treated with 1 M HC1(3 ml). Then the resultant was extracted with dichloromethane(3 ml). The organic layer was separated, dried over anhydrous sodium sulfate(2 g) and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography(eluent: methanol/dichloromethane=l/20) to obtain the title compound(20 mg, yield: 60%). 1H NMR(DMSO^6, 200MHz): δ(ppm) 8.1 l(d, J=8.0Hz, 2H), 7.71(d, J=8.0Hz, 2H), 7.23(dd, 1^2.6Hz, J2=8.6Hz, 2H), 6.89(dd, Ji=2.6Hz, J2=8.6Hz, 2H), 4.26(t, J=6.4Hz, 2H), 3.66(s, 3H), 3.52-3.78(m, 2H), 3.27-3.35(m, IH), 3.00(t, J-6.4Hz, 2H), 2.89-3.04(m, IH)5 2.43(s, 3H), 2.19-2.39(m, 2H)
Example 97: Preparation of (R)-l-[3-[[5-methyl-2-(4-trifluoromethylphenyI) oxazol-4-yl]methoxy] benzyl] azetidine-2-carboxylic acid methyl ester
Figure imgf000096_0001
Step 1 : Preparation of (R)-l-[3-[[5-methyl-2-(4-trifluoromethylphenyl)oxazol- 4-yl]methoxy]benzyl]azetidine-2-carboxylic acid methyl ester
The procedure of Step 1 of Example 96 was repeated except for using 4-[[3-(chloromethyl)phenoxy]methyl]-5-methyl-2-(4-trifluoromethylphenyl)oxazole (100 mg, 0.26 mmol) to obtain the title compound(60 mg, yield: 50%). 1H NMR(CDCl3, 200MHz): δ(ppm) 8.10(d, J=8.2Hz, 2H), 7.00(d, J=8.2Hz, 2H), 7.17-7.28(121, IH), 6.79-6.88(m, 3), 4.26(t, J=6.4Hz, 2H), 3.58-3.83(m, 2H), 3.65(s, 3H), 3.29-3.38(m, IH), 3.00(t, J=6.4Hz, 2H), 2.88-3.00(m, IH), 2.42(s, 3H), 2.20-2.38(m, 2H)
Example 98: Preparation of (R)-I- [3- [2-(5-methyI-2-p~tolyloxazol-4-yl)ethoxy] benzyl] azetidine-2-carboxylic acid
Figure imgf000096_0002
Step 1 : Preparation of (R)-l-[3-[2-(5-methyl-2-/?4olyloxazol-4-yl)ethoxy]benzyl] azetidine-2-carboxylic acid methyl ester
The procedure of Step 1 of Example 96 was repeated except for using
4-[2-[3-(chloromethyl)phenoxy]ethyl]-5-methyl-2-p-tolyloxazole(100 mg, 0.29 mmol) to obtain the title compound(55 mg, yield: 45%). 1H NMR(CDCl3, 200MHz): δ(ppm) 7.88(d, =8.0Hz, 2H), 7.17-7.29(m, 3H),
6.78-6.88(m, 3H), 4.25(t, J=6.4Hz, 2H), 3.65(s, 3H), 3.36-3.83(m, 2H), 3.29-3.33(m,
2H), 2.98(t, J=6.4Hz, 2H), 2.88-2.96(m, IH), 2.40(s, 3H), 2.39(s, 3H), 2.17-2.33(m,
IH), 1.78(s, IH)
Step 2: Preparation of (R)-l-[3-[2-(5-methyl-2-jp-tolyloxazol-4-yl)ethoxy]benzyl] azetidine-2-carboxylic acid
The procedure of Step 2 of Example 96 was repeated except for using the compound obtained in Step 1 of Example 98(33 mg, 0.08 mmol) to obtain the title compound(30 mg, yield: 92 %). 1H NMR(DMSO-d6s 200MHz): δ(ppm) 7.81(d, J=8.3HZ, 2H), 7.19-7.33(m, 3H),
6.84-6.92(m, 3H), 4.20(t, J=6.4Hz, 2H), 4.01-4.23(m, IH), 3.51-3.94(m, 4H), 2.92(t,
J=6.4Hz, 2H), 2.35(s, 6H), 2.12-2.24(m, 2H) Example 99: Preparation of (R)-l-[3-[2-[5-methyl-2-(4-trifluoromethylphenyl) oxazol-4-yl]ethoxy] benzyl] azetidine-2-carboxylic acid
Figure imgf000097_0001
Step 1 : Preparation of (R)-l-[3-[2-[5-methyl-2-(4-trifluoromethylphenyl)oxazol- 4-yl]ethoxy]benzyl] azetidine-2-carboxylic acid methyl ester
The procedure of Step 1 of Example 96 was repeated except for using 4-[2-[3-(chloromethyl)phenoxy]ethyl]-5-methyl-2-(4-trifluoromethylphenyl)oxazole (100 mg, 0.25 mmol) to obtain the title compound(48 mg, yield: 40 %). 1H NMR(CDCl3, 200MHz): δ(ppm) 8.10(d, J=8.2Hz, 2H), 7.00(d, J=8.2Hz, 2H), 7.17-7.28(m, IH), 6.79-6.88(m, 3H), 4.26(t, J-6.6Hz, 2H), 3.58-3.83(m, 2H), 3.65(s, 3H) 3.29-3.38(m, IH), 3.00(t, J=6.6Hz, 2H), 2.88-3.00(m, IH), 2.42(s, 3H), 2.20-2.38(m, 2H)
Step 2: Preparation of (R)-l-[3-[2-[5-methyl-2-(4-trifluoromethylphenyl)oxazol-
4-y 1] ethoxyjbenzyl] azetidine-2-carboxylic acid
The procedure of Step 2 of Example 96 was repeated except for using the compound obtained in Step 1 of Example 99(46 mg, 0.097 mmol) to obtain the title compound(25 mg, yield: 56 %). 1H NMR(DMSO-d6, 200MHz): δ(ppm) 8.12(d, J=8.2Hz, 2H), 7.87(d, J=8.2Hz, 2H),
7.20-7.28(m, IH), 6.85-6.95(m, 3H)5 4.23(t, J=6.6Hz, 2H), 4.00(d, J=I 3Hz, IH)5
3.73(d, J=13.4Hz, IH), 3.61-3.80(m, 2H), 3.21-3.50(m, IH)5 2.97(t, J=6.6Hz, 2H)5
2.41(s, 3H)5 2.09-2.40(m5 2H)
Example 100: Preparation of (R)-I- [4- [(5-methyl-2-phenyloxazol-4-yl) methoxy] benzyl] azetidine-2-carboxylic acid
Figure imgf000097_0002
Step 1 : Preparation of (R)-l-[4-[(5-methyl-2-phenyloxazol-4-yl)methoxy] benzyl] azetidine-2-carboxylic acid methyl ester The procedure of Step 1 of Example 96 was repeated except for using
4-[[4-(chloromethyl)phenoxy]methyl]-5-methyl-2-phenyloxazole(100 mg, 0.32 mmol) to obtain the title compound(40 mg, 32 %). 1H NMR(CD3OD-d4, 200MHz): δ(ppm) 8.03-8.05(m, 2H)5 7.45-7.48(m, 3H), 7.26(d, J=8.6Hz, 2H), 6.98(d, J=8.6Hz, 2H)3 5.00(s, 2H) 3.70-3.79(m, 3H), 3.67(s, 3H), 3.29-3.35(m, IH)5 2.90-3.02(m, IH), 2.45(s, 3H)5 2.20-2.38(m, 2H)
Step 2: Preparation of (R)-l-[4-[(5-methyl-2-phenyloxazol-4-yl)methoxy]benzyl] azetidine-2-carboxylic acid
The procedure of Step 2 of Example 96 was repeated except for using the compound obtained in Step 1 of Example 100(36 mg, 0.09 mmol) to obtain the title compound(15 mg, yield: 43 %).
1H NMR(DMSO-d6, 200MHz): δ(ppm) 7.87-7.90(m5 2H), 7.50-7.63(m, 3H), 7.23(d, J=8.6Hz, 2H), 6.95(d, J=8.6Hz, 2H), 4.91(s, 2H), 4.05-4.12(m, 2H), 3.55-4.05(m, IH), 3.21-3.22(m, IH)5 2.34(s5 3H), 2.21-2.34(m, 2H)
Example 101: Preparation of (R)-I- [4- [(5-methyI-2-p-tolyloxazol-4-yl)methoxy] benzyl] azetidine-2-carboxylic acid methyl ester
Figure imgf000098_0001
The procedure of Step 1 of Example 96 was repeated except for using
4-[[4-(chloromethyl)phenoxy]methyl)-5-methyl-2-p-tolyloxazole(100 mg, 0.31 mmol) to obtain the title compound(50 mg, yield: 40%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.92(d, J=8.6Hz, 2H)5 7.19-7.27(m5 4H), 6.96(d5 J=8.6Hz, 2H), 4.98(s, 2H), 3.65(s, 3H), 3.34-3.78(m, 2H), 3.27-3.3 l(m, IH), 2.92-2.97(m, IH), 2.43(s, 3H)5 2.40(s, 3H), 2.20-2.43(m, 2H)
Example 102: Preparation of (R)-l-[4-[[5-methyl-2-(4-trifluoromethylphenyl) oxazol-4-yl]methoxy] benzyl] azetidine-2-carboxylic acid methyl ester
Figure imgf000098_0002
The procedure of Step 1 of Example 96 was repeated except for using
4-[[4-(chloromethyl)phenoxy]methyl]-5-methyl-2-(4-trifluoromethylphenyl)oxazole
(100 mg, 0.26 mmol) to obtain the title compound(51 mg, yield: 43 %).
1H NMR(CDCl35 200MHz): δ(ppm) 8.15(d, J=8.6Hz, 2H)5 7.72(d, J=8.6Hz, 2H), 7.24(d, J=8.6Hz, 2H), 6.97(d5 J=8.6Hz, 2H)5 5.0 l(s, 2H), 3.53-3.80(m5 2H)5 3.66(s,
3H), 3.27-3.36(m, IH) 2.89-3.01(m5 IH), 2.47(s, 3H), 2.15-2.31(m, 2H)5 1.88(s, IH) Example 103: Preparation of (R)-l-[4-[2-(5-methyI-2-jp-tolyloxazol-4- yl)ethoxy] benzyl] azetidine-2-carboxylic acid methyl ester
Figure imgf000099_0001
The procedure of Step 1 of Example 96 was repeated except for using 4-[2-[4-(chloromethyl)phenoxy]ethyl]-5-methyl-2-p-tolyloxazole(100 mg, 0.29 mmol) to obtain the title compound(40 mg, yield: 32%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.88(d, J=8.2Hz, 2H), 7.17-7.30(m, 4H), 6.88(d, J=8.2Hz, 2H), 4.25(t, J=6.4Hz, 2H), 3.65(s, 3H), 3.39-3.77(m, 2H), 2.98(1, J=6.4Hz, 2H), 2.92-3.01(m, IH), 2.38(s, 3H), 2.06-2.27(m, 2H)
Example 104: Preparation of (R)-l-[4-[2-[5-methyl-2-(4-trifluoromethylphenyl) oxazol-4-yl] ethoxy] benzyl] azetidine-2-carboxylic acid
Figure imgf000099_0002
Step 1 : Preparation of (R)-l-[4-[2-[5-methyl-2-(4-trifluoromethylphenyl)oxazol- 4-yl]ethoxy]benzyl] azetidine-2-carboxylic acid methyl ester
The procedure of Step 1 of Example 96 was repeated except for using
4-[2-[4-(chloromethyl)phenoxy]ethyl]-5-methyl-2-(4-trifluoromethylphenyl)oxazole
(100 mg, 0.25 mmol) to obtain the title compound(30 mg, yield: 25 %).
1H NMR(CDCl3, 200MHz): δ(ppm) 8.1 l(d, J=8.0Hz, 2H), 7.71(d, J=8.0Hz, 2H), 7.23(dd, Jr=2.6Hz, J2=8.6Hz, 2H), 6.89(dd, Ji==2.6Hz, J2=8.6Hz, 2H), 4.26(t,
J=6.4Hz, 2H), 3.66(s, 3H), 3.52-3.78(m, 2H), 3.27-3.35(m, IH), 3.00(t, J=6.4Hz,
2H), 2.89-3.04(m, IH), 2.43(s, 3H), 2.19-2.39(m, 2H)
Step 2: Preparation of (R)-l-[4-[2r[5-methyl-2-(4-trifluoromethylphenyl)oxazol- 4-yl]ethoxy]benzyl]azetidine-2-carboxylic acid .
The procedure of Step 2 of Example 96 was repeated except for using the compound obtained in Step 1 of Example 104(30 mg, 0.063 mmol) to obtain the title compound(15 mg, yield: 50 %).
1H NMR(DMSO-d6, 200MHz): δ(ppm) 8.12 d, J=8.0Hz, 2H), 7.88(d, J=8.0Hz, 7.33(d, J=8.2Hz, 2H), 6.96(d, J=8.4Hz, 2H), 3.90-4.46(m, 4H), 3.53-3.90(m, 3H),
3.00(t, J=6.4Hz, 2H), 2.40(s, 3H), 2.00-2.26(m, 2H),
Example 105: Preparation of (R)-l-[3-[(5-methyl-2-phenyloxazol-4-yl)methoxy] benzyl]pyrrolidine-2-carboxylic acid
Figure imgf000100_0001
Step 1 : Preparation of (R)-l-[3-[(5-methyl-2-phenyloxazol-4-yl)methoxy]benzyl] pyrrolidine-2-carboxylic acid methyl ester
4-(Chloromethyl)-5-methyl-2-phenyloxazole(100 mg, 0.48 mmol), (R)-l-(3-hydroxybenzyl)pyrrolidine-2-carboxylic acid methyl ester(94 mg, 0.4 mmol) and K2CO3(66 mg, 0.48 mmol) were dissolved in DMF(20 ml). The resulting mixture was stirred at 80 °C for 1 day and cooled down to room temperature. The resultant was extracted with water and dichloromethane. The organic layer was separated and dried over anhydrous sodium sulfate. The residue thus obtained was subjected to a silica gel column chromatography(eluent: hexane/ethyl acetate=3/l) to obtain the title compound(109 mg, yield: 84%). 1H NMR(CDCl35 200MHz): δ(ppm) 8.01-8.06(m, 2H), 7.43-7.5 l(m, 3H), 7.21-7.5 l(m, IH), 6.91-7.03(m, 3H), 5.02(s, 2H), 3.93(d, J=13Hz, IH), 3.69(s, 3H), 3.56(d, J=13Hz, IH), 3.25-3.29(m, IH), 3.03-3.09(m, IH), 2.46(s, 3H), 2.39-2.46(m, IH), 1.79-2.20(m, 4H)
Step 2: Preparation of (R)-l-[3-[(5-methyl-2-phenyloxazol-4-yl)methoxy]benzyl] pyrrolidine-2-carboxylic acid
The compound obtained in Step 1 of Example 105(99 mg, 0.24 mmol) was dissolved in a mixture of methanol and water(5: l, 1 ml), and lithium hydroxy monohydrate(16 mg, 0.36 mmol) was added thereto. The resulting mixture was stirred at room temperature for 3 days. The reaction product was diluted with ethyl acetate(3 ml) and acidified with 1 M HC1(3 ml). The resultant was extracted with dichloromethane(3 ml). The organic layer was separated, dried over anhydrous sodium sulfate(2 g) and concentrated under reduced pressure. The residue thus obtaine was subjected to a silica gel column chromatography(eluent: methanol/dichloromethane=l/20) to obtain the title compound(87 mg, yield: 91%). 1H NMR(CDCl3, 200MHz) : 7.96-7.80(m, 2H), 7.32-7.44(m, 3H), 7.24-7.30(m, 2H), 7.00-7.12(m, 2H)5 5.0 l(s, 2H), 4.49(s, 2H), 4.01-4.35(m, IH), 3.61-3.71(m, IH), 3.00-3.61(m, IH), 2.43(s, 3H), 2.20-2.60(m, 2H)5 2.01-2.05(m, 2H)
Example 106: Preparation of (R)-I- [3- [(5-methyl-2-p-toIyIoxazol-4-yl)methoxy] benzyl] pyrrolidine-2-carboxylic acid
Figure imgf000101_0001
Step 1: Preparation of (R)-l-[3-[(5-methyl-2-/>-tolyloxazol-4-yl)methoxy]benzyl] pyrrolidine-2-carboxylic acid methyl ester
The procedure of Step 1 of Example 105 was repeated except for using 4-[[3-(chloromethyl)phenoxy]methyl]-5-methyl-2-p-tolyloxazole(100 mg, 0.31 mmol) to obtain the title compound(89 mg, yield: 70%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.89(d, J=8.2Hz, 2H), 7.22(d, J=8.2Hz, 2H), 7.19-7.27(m, IH), 7.04(s, IH), 6.88-6.96(m, 2H)5 4.98(s, 2H), 3.93(d, J-13Hz, IH), 3.67(s, 3H), 3.58(d, 13Hz, IH), 3.30(t, J=7.0Hz, IH), 2.92-3.1 l(m, IH), 2.23-2.86(m, IH), 2.42(s, 3H), 2.38(s, 3H), 1.79-2.13(m, 4H)
Step 2: Preparation of (R)-l-[3-[(5-methyl-2-p-tolyloxazol-4-yl)methoxy]benzyl] pyrrolidine-2-carboxylic acid
The procedure of Step 2 of Example 105 was repeated except for using the compound obtained in Step 1 of Example 106(106 mg, 0.25 mmol) to obtain the title compound(54 mg, yield: 53%).
1H NMR(CDCl3, 200MHz) : 9.53(br, IH), 7.85(d, J=8Hz, 2H), 7.38(s, IH), 7.22(d, J-8Hz, 2H), 7.15-7.28(m, 2H), 6.97-7.01(m, IH), 5.00(s, 2H), 4.53(s, 2H), 4.21-4.40(m, IH), 3.73-3.83(m, IH), 3.61-3.33(m, IH), 2.39(s, 3H), 2.38(s, 3H), 2.33-2.39(m, 2H), 2.03-2.06(m, 2H)
Example 107: Preparation of (R)-l-[3-[[5-methyl-2-(4-trifluoromethylphenyl) oxazol-4-yl] methoxy] benzyl] pyrrolidine-2-carboxylic acid
Figure imgf000101_0002
Step 1 : Preparation of (R)-l-[3-[[5-methyl-2-(4-trifluoromethylphenyl)oxazol- 4-yl]methoxy]benzyl]pyrrolidine-2-carboxylic acid methyl ester
The procedure of Step 1 of Example 105 was repeated except for using 4-[[3-(chloromethyl)phenoxy]methyl]-5-methyl-2-(4-trifluoromethylphenyl)oxazole (100 mg, 0.26 mmol) to obtain the title compound(l 15 mg, yield: 93%). 1H NMR(CDCl3, 200MHz): δ(ppm) 8.15(d, J=8.2Hz, 2H), 7.72(d, J=8.2Hz, 2H), 7.22-7.30(m, IH), 6.92-7.05 m, 3H), 5.03(s, 2H), 3.93(d, J=13Hz, IH), 3.70(s, 3H), 3.56(d, J=13Hz, IH), 3.28(t, J=7Hz, IH)3 3.03-3. l(m, IH)5 2.50(s, 3H), 2.39-2.44(m, IH), 1.77-2.36(m, 4H)
Step 2: Preparation of (R)-l-[3-[[5-methyl-2-(4-trifluoromethylphenyl)oxazol- 4-yl]methoxy]benzyl]pyrrolidine-2-carboxylic acid
The procedure of Step 2 of Example 105 was repeated except for using the compound obtained in Step 1 of Example 107(94 mg, 0.20 mmol) to obtain the title compound(48 mg, yield: 52%).
1R NMR(CDCl3, 200MHz) : 9.79(br, IH), 8.08(d, J=8Hz, 2H), 7.68(d, J=8Hz, 2H), 7.26(d, J=8Hz, 2H), 7.24-7.28(m, IH), 7.12(d, J=7.4Hz, IH), 7.01(d, J=8.2Hz, IH), 5.01(s, 3H), 4.51(s, 2H), 4.21(t, J=7.4Hz, 2H), 3.56-3.76(m, IH), 2.56-3.21(m, IH), 2.44(s, 3H), 2.36-2.49(m, 2H), 2.03-2.18(m, 2H)
Example 108: Preparation of (R)-I- [3- [[5-methyl-2-(thiophen-2-yl)oxazol-4-yI] methoxy] benzyl] pyrrolidine-2-carboxylic acid
Figure imgf000102_0001
Step 1 : Preparation of (R)-l-[3-[[5-methyl-2-(thiophen-2-yl)oxazol-4-yl]methoxy] benzyl]pyrrolidine-2-carboxylic acid methyl ester
The procedure of Step 1 of Example 105 was repeated except for using 4-[[3-(chloromethyl)phenoxy]methyl]-5-methyl-2-(thiophen-2-yl)oxazole(l 50 mg, 0.47 mmol) to obtain the title compound(145 mg, yield: 75%). 1U NMR(CDCl3, 200MHz): δ(ppm) 7.57-7.59(m, IH), 7.34-7.37(m, IH), 7.15-7.29(m, IH), 6.94-7.05(m, 2H), 6.85-6.94(m, 2H), 4.94(s, 2H), 3.96(d, J=13Hz, IH), 3.64(s, 3H), 3.64-3.71(m, IH), 3.12-3.51(m, IH), 3.00-3.21(m, IH), 2.41-2.70(m, IH), 2.37(s, 3H), 1.82-2.14(m, 4H) '
Step 2: Preparation of (R)-l-[3-[[5-methyl-2-(thiophen-2-yl)oxazol-4-yl]methoxy] benzyl]pyrrolidine-2-carboxylic acid
The procedure of Step 2 of Example 105 was repeated except for using the compound obtained in Step 1 of Example 108(146 mg, 0.35 mmol) to obtain the title compound(117 mg, yield: 83%).
1H NMR(CDCl3, 200MHz) : 7.61(d, J=3.6Hz, IH), 7.40(d, J=5.2Hz, IH), 7.12-7.33(m, 2H), 7.08(d, J-3.6Hz, IH), 7.03-7.12(m, 2H), 4.96(s, 2H), 4.25-4.37(m, 2H), 3.90-4.12(m, IH), 3.54-3.71(m, IH), 2.59-3.1 l(m, IH), 2.4 l(s, 3H), 2.29-2.37(m, 2H), 1.95-2.02(m, 2H) Example 109: Preparation of (R)-2-[3-[[4-methyl-2-(4-trifluoromethylphenyI) oxazol-5-yI]methoxy]benzyl]pyrrolidin-l-carboxylic acid
Figure imgf000103_0001
Step 1 : Preparation of (R)-2-[3-[[4-methyl-2-(4-trifluoromethylphenyl)oxazol- 5-yl]methoxy]benzyl]pyrrolidin-l-carboxylic acid methyl ester
The procedure of Step 1 of Example 105 was repeated except for using 5-[[3-(chloromethyl)phenoxy]methyl]-4-methyl-2-(4-trifluoromethylphenyl)oxazole (100 mg, 0.26 mmol) to obtain the title compound(100 mg, yield: 80%). 1H NMR(CDCl3, 200MHz): δ(ppm) 8.14(d, J=8.4Hz, 2H), 7.69(d, J=8.4Hz, 2H)3 7.21-7.29(m, IH), 6.87-7.03(m, 3H), 5.09(s, 2H), 3.92(d, J=13Hz, IH), 3.66(s, 3H)5 3.54(d, J=13.4Hz, IH), 3.24-3.31(m, IH), 3.01-3.10(m, IH), 2.34-2.42(m, IH)5 2.30(s, 3H), 1.76-2.18(m, 3H)
Step 2: Preparation of (R)-2-[3-[[4-methyl-2-(4-trifluoromethylphenyl)oxazol- 5-yl]methoxy]benzyl]pyrrolidin-l-carboxylic acid
The procedure of Step 2 of Example 105 was repeated except for using the compound obtained in Step 1 of Example 109(100 mg, 0.21 mmol) to obtain the title compound(90 mg, yield: 93%).
1H NMR(DMSO-d6, 200MHz) : 8.20(d, J=8.0Hz, 2H), 7.91(d, J=8.0Hz, 2H), 7.21(s, IH), 7.00-7.06(m, 2H), 5.24(s, 2H), 4.05(d, J=13Hz, IH), 3.71(d, J=13Hz, IH),
3.25-3.48(m, 2H), 3.00-3.15(m, IH), .28(s, 3H), 1.65-2.20(m, 5H)
Example 110: Preparation of 2-methyl-l-[3-[(5-methyl-2-phenyloxazol-4-yl) methoxy] benzyl] pyrrolidine-2-carboxylic acid methyl ester
Figure imgf000103_0002
The procedure of Step 1 of Example 96 was repeated except for using 4-[[3-(chloromethyl)phenoxy]methyl]-5-methyl-2-phenyloxazole(100 mg, 0.32 mmol) and 2-(methoxycarbonyl)-2-methylpyrrolidinϊum chloride(103 mg, 0.36 mmol) to obtain the title compound(70 mg, yield: 52%). 1H NMR(CDCl3, 200MHz): δ(ppm) 8.01-8.06(m, 2H), 7.42-7.48(m5 3H), 7.20-7.42(m, IH)5 7.05(s, IH)5 6.99(d, J=7.4Hz, 2H), 5.01(s, 2H)5 3.85(d, J=13.4Hz, IH)5 3.73(s, 3H), 3.49(d, J=13.4Hz, IH), 2.80-2.93(m, IH), 2.49-2.80(m, IH), 2.46(s, 3H), 2.19-2.29(m, IH), 1.77-1.89(m, 3H)5 1.41(s, 3H)
Example 111: Preparation of 2-methyl-l-[3-[(5-methyl-2-/7-tolyloxazol-4-yl) methoxy] benzyl] pyrrolidine-2-carboxylic acid methyl ester
Figure imgf000104_0001
The procedure of Step 1 of Example 110 was repeated except for using 4-[[3-(chloromethyl)phenoxy]methyl]-5-methyl-2-p-tolyloxazole(100 mg, 0.31 mmol) to obtain the title compound(32 mg, yield: 24%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.92(d, J=8.2Hz, 2H), 7.26(d, J=8.2H, 2H), 6.89-7.05(m, 4H), 5.0 l(s, 2H), 3.84(d, J=I 3.4Hz, IH), 3.74(s, 3H), 3.48(d, J=13.4Hz, IH)5 2.97-2.98(m, IH), 2.70-2.86(m, IH), 2.45(s, 3H), 2.42(s, 3H), 2.25-2.29(m, IH), 1.80-2.12(m5 3H)5 1.42(s, 3H)
Example 112: Preparation of 2-methyl-l-[3-[[5-methyl-2-(4-trifluoromethyl- phenyl)oxazol-4-yl]methoxy]benzyl]pyrrolidine-2-carboxylic acid methyl ester
Figure imgf000104_0002
The procedure of Step 1 of Example 110 was repeated except for using 4-[[3-(chloromethyl)phenoxy]methyl]-5-methyl-2-(4-trifluoromethylphenyl)oxazole (100 mg, 0.26 mmol) to obtain the title compound(46 mg, yield: 37%). 1H NMR(CDCl3, 200MHz): δ(ppm) 8.15(d, J=8.6Hz, 2H), 7.72(d, J=8.4Hz. 2H), 7.24(d, J=8.6Hz5 2H), 7.04(s5 IH), 6.80-7.00(m, 2H), 5.02(s, 2H), 3.85(d, J=13.4Hz, IH)5 3.73(s, 3H), 3.5 l(d, -13.4Hz, IH)5 2.80-3.01(m, IH)5 2.52-2.56(m, IH), 2.48(s, 3H), 2.02-2.06(m, IH), 1.71-1.91(m, 3H), 1.41(s, 3H)
Example 113: Preparation of 2-methyl-l-[3-[[5-methyl-2~(thiophen-2-yl)oxazol- 4-yl]methoxy]benzyl]pyrrolidine-2-carboxylic acid methyl ester
Figure imgf000105_0001
The procedure of Step 1 of Example 110 was repeated except for using 4-[[3-(chloromethyl)phenoxy]methyl]-5-methyl-2-(thiophen-2-yl)oxazole(100 mg, 0.31 mmol) to obtain the title compound(37 mg, yield: 30%).
1U NMR(CDCl3, 200MHz): δ(ppm) 7.64-7.66(m, IH), 7.40-7.42(m, IH), 7.22(d, J=7.8Hz, IH), 7.11-7.14(m, IH), 7.03(s, IH), 6.87-6.96(m, 2H), 4.99(s, 2H), 3.83(d, J-13.4Hz, IH), 3.74(s, 3H), 3.47(d, J=13.4Hz, IH), 2.81-2.88(m, IH), 2.64-2.76(m, IH), 2.43(s, 3H), 2.19-2.28(m, IH), 1.77-2.06(m, 3H), 1.41(s, 3H)
Example 114: Preparation of 2-ethyI-l-[3-[(5-methyl-2-phenyloxazol-4-yl) methoxy]benzyI]pyrrolidine-2-carboxylic acid methyl ester
Figure imgf000105_0002
The procedure of Step 1 of Example 96 was repeated except for using 4-[[3-(chloromethyl)phenoxy]methyl]-5-methyl-2-phenyloxazole(100 mg, 0.32 mmol) and 2-ethyl-2-(methoxycarbonyl)pyrrolidmium chloride(74 mg, 0.38 mmol) to obtain the title compound(85 mg, yield: 41%).
1H NMR(CDCl3, 200MHz): δ(ppm) 8.01-8.06(m, 2H), 7.44-7.47(m, 3H), 7.09-7.28(m, IH), 7.03(s, IH), 6.88-6.91(m, 2H), 5.01(s, 2H), 3.98(d, J=13.8Hz, IH), 3.7(s, 3H), 3.30(d, J=13.8Hz, IH), 2.91-2.97(m, IH), 2.45(s, 3H), 2.37-2.46(m, IH), 1.94-2.32(m, IH), 1.47-1.80(m, 3H), 0.96(t, J=7.4Hz, 3H)
Example 115: Preparation of 2-ethyl-l-[3-[(5-methyl-2-p-tolyloxazol-4-yl) methoxy]benzyl]pyrrolidine-2-carboxylic acid methyl ester
Figure imgf000105_0003
The procedure of Step 1 of Example 114 was repeated except for using 4-[[3-(chloromethyl)phenoxy]methyl]-5-methyl-2-p-tolyloxazole(100 mg, 0.31 mmol) to obtain the title compound(60 mg, yield: 43%). 1H NMR(CDCl3, 200MHz): δ(ppm) 7.92(d, J=8.2Hz, 2H), 7.26(d. J=8.2Hz, 2H)5 7.20-7.28(m, lH),7.03(s5 IH), 6.87-6.94(m, 2H), 4.99(s, 2H), 3.96(d, J=13.4Hz, IH), 3.74(s, 3H), 3.30(d, J=13.4Hz, IH), 2.89-2.99(m, IH), 2.41-2.56(m, IH), 2.44(s, 3H), 2.41(s, 3H), 2.11-2.32(m, IH), 2.04(q, J=7.2Hz, IH), 1.70-1.78(m, 3H), 1.54-1.68(m, IH), 0.96(t, J=7.2Hz, 3H)
Example 116: Preparation of 2-ethyl-l-[3-[[5-methyl-2-(4-trifluoromethyl- phenyI)oxazol-4-yl]methoxy]benzyl]pyrrolidine-2-carboxylic acid methyl ester
Figure imgf000106_0001
Step 1: Preparation of 2-ethyl-l-[3-[[5-methyl-2-(4-trifluoromethylphenyl)oxazol- 4-yl]methoxy]benzyl]pyrrolidine-2-carboxylic acid methyl ester
The procedure of Step 1 of Example 114 was repeated except for using 4-[[3-(chloromethyl)phenoxy]methyl]-5-methyl-2-(4-trifluoromethylphenyl)oxazole (100 mg, 0.26 mmol) to obtain the title compound(40 mg, yield: 31%). 1H NMR(CDCl3, 200MHz): δ(ppm) 8.15(d, J=8.2Hz5 2H), 7.72(d, J=8.2Hz, 2H), 7.1507.28(m, IH), 6.88-6.96(m, 3H), 5.02(s, 2H), 3.98(d, -13.4Hz, IH), 3.74(s, 3H), 3.30(d, J=13.4Hz, IH), 2.80-2.97(m, 2H), 2.48(s, 3H), 2.27-2.50(m, IH), 2.12-2.27(m, IH), 2.01(q, J=7.2Hz, IH), 1.66-1.91(m, 3H), 0.96(t, J=7.2Hz, 3H)
Step 2: Preparation of 2-ethyl-l-[3-[[5-methyl-2-(4-trifluoromethylphenyl)oxazol- 4-yl]methoxy]benzyl]pyrrolidine-2-carboxylic acid methyl ester
The procedure of Step 1 of Example 96 was repeated except for using the compound obtained in Step 1 of Example 116(30 mg, 0.06 mmol) to obtain the title compound(12 mg, yield: 49%). 1H NMR(CD3OD, 200MHz) : 8.20(d, J=8.2Hz, 2H), 7.83(d, J=8.2Hz, 2H), 7.37-7.45(m, IH), 7.11-7.26(m, 2H), 6.88-6.98(m, IH), 5.10(s, 2H)3 4.58(d, J=13.4Hz, IH), 4.07(d, J=13.4Hz, IH), 3.19-3.32(m, 2H), 2.51(s, 3H)5 1.58-2.21(m, 6H), 1.19(t, J=7.4Hz, 3H)
Example 117: Preparation of 2-ethyl-l-[3-[[5-methyl-2-(thiophen-2-yl)oxazol- 4-yl]methoxy] benzyl] pyrrolidine-2-carboxylic acid methyl ester
Figure imgf000107_0001
Step 1 : Preparation of 2-ethyl-l-[3-[[5-methyl-2-(thiophen-2-yl)oxazol-4-yl] methoxy]benzyl]pyrrolidine-2-carboxylic acid methyl ester
The procedure of Step 1 of Example 114 was repeated except for using 4-[[3-(chloromethyl)phenoxy]methyl]-5-methyl-2-(thiophen-2-yl)oxazole(100 mg, 0.31 mmol) to obtain the title compound(50 mg, yield: 37%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.66(dd, J1=I .2Hz5 J2=3.8Hz, IH), 7.41(dd, Ji=I.2Hz, J2=3.8Hz, IH), 7.16-7.31(m, IH), 7.11(dd, Ji=3.8Hz, J2=5.4Hz, IH), 7.01(s, IH), 6.85-6.94(m, 2H), 4.98(s, 2H), 3.97(d, J=13.4Hz, IH), 3.74(s, 3H), 3.28(d, J=13.4Hz, IH), 2.90-2.92(m, IH), 2.46-2.56(m, IH), 2.43(s, 3H), 2.22-2.26(m, IH), 2.00(q, J=7.4HZ, IH), 1.72-1.93(m, 3H), 1.54-1.4(m, IH), 0.95(t, J-7.4Hz, 3H)
Step 2: Preparation of 2-ethyl-l-[3-[[5-methyl-2-(thiophen-2-yl)oxazol-4-yl] methoxy]benzyl]pyrrolidine-2-carboxylic acid methyl ester
The procedure of Step 1 of Example 96 was repeated except for using the compound obtained in Step 1 of Example 117(30 mg, 0.07 mmol) to obtain the title compound(10 mg, yield: 3%).
1H NMR(CD3OD, 200MHz): δ(ppm) 7.71(dd, J1=I^Hz, J2=3.8Hz, IH), 7.631(dd, J-1.2Hz, J2=3.8Hz, IH), 7.34(d, J=7.8Hz, 2H), 7.05-7.20(m5 4H), 4.88(s, 2H),
4.33(d, J=13.4Hz, IH), 4.05(d, J=13.4Hz5 IH), 3.08-3.16(m, 2H), 2.45(s, 3H),
2.19-2.47(m, IH), 1.61-2.15(m, 6H), 1.44(t, J=7.4Hz, 3H)
Example 118: Preparation of (R)-l-[4-[(5-methyl-2-/;-tolyIoxazol-4-yl)methoxy] benzyl] pyrrolidine-2-carboxylic acid methyl ester
Figure imgf000107_0002
The procedure of Step 1 of Example 96 was repeated except for using 4-[[4-(chloromethyl)phenoxy]methyl)-5-methyl-2-/>-tolyloxazole(100 mg, 0.31 mmol) and (R)-2-(methoxycarbonyl)pyrrolidinium chloride(61 mg, 0.37 mmol) to obtain the title compound(65 mg, yield: 50%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.90(d, J=8.0Hz, 2H)5 7.20-7.27(m, 4H), 6.92-6.96 d, J=8.0Hz, 2H)5 4.95(s, 2H), 3.80(d, J=12.6Hz, IH), 3.63(s, 3H), 3.51(d, J=12.6Hz, IH), 3.17-3.24(m, IH), 3.00-3.07(m, IH), 2.39(s, 3H), 2.36(s, 3H), 2.30-2.41(m, IH), 1.73-2.30(m, 4H)
Example 119: Preparation of 2-methyl-l-[4-[(5-methyl-2-phenyloxazol-4-yl) methoxy] benzyl] pyrrolidine-2-carboxyIic acid methyl ester
Figure imgf000108_0001
The procedure of Step 1 of Example 110 was repeated except for 4-[[4-(chloromethyl)phenoxy]methyl]-5-methyl-2-phenyloxazole(100 mg, 0.32 mmol) to obtain the title compound(80 mg, yield: 40%).
1H NMR(CDCl3, 200MHz): δ(ppm) 8.01-8.06(m, 2H), 7.41-7.48(m, 3H), 7.26(d, J=8.4Hz, 2H), 6.98(d, J=8.4Hz, 2H), 5.00(s, 2H), 3.76(d, J=13.4Hz, IH), 3.73(s, 3H), 3.45(d, J=13.4Hz, IH), 2.70-2.84(m, 2H), 2.44(s, 3H), 1.81-2.30(m, 3H), 1.42(s, 3H)
Example 120: Preparation of 2-methyI-l-[4-[(5-methyl-2-p-tolyloxazol-4- yl)methoxy] benzyl] pyrroIidine-2-carboxylic acid methyl ester
Figure imgf000108_0002
The procedure of Step 1 of Example 110 was repeated except for using 4-[[4-(chloromethyl)phenoxy]methyl)-5-methyl-2-p-tolyloxazole(100 mg, 0.31 mmol) to obtain the title compound(56 mg, yield: 43%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.91(d, J=8.2Hz, 2H), 7.25(d, J=8.2Hz, 4H), 6.96(d, J=8.2Hz, 2H)5 4.94(s, 2H), 3.76(d, J=13.4Hz, IH), 3.72(s, 3H), 3.42(d, J=13.4Hz, IH), 2.73-2.88(m, 2H), 2.43(s, 3H), 2.40(s, 3H), 2.21-2.29(m, IH), 1.79-1.86(m, 3H), 1.42(s, 3H)
Example 121: Preparation of 2-methyl-l-[4-[[5-methyl-2-(4-trifluoromethyl- phenyl)oxazol-4-yl] methoxy] benzyl] pyrrolidine-2-carboxylic acid methyl ester
Figure imgf000109_0001
The procedure of Step 1 of Example 110 was repeated except for using 4-[[4-(chloromethyl)phenoxy]methyl]-5-methyl-2-(4-trifluoromethylphenyl)oxazole (100 mg, 0.26 mmol) to obtain the title comρound(54 mg, yield: 43%). 1H NMR(CDCl3, 200MHz): δ(ppm) 8.15(d, J=8.6Hz, 2H), 7.71(d, J=8.4Hz, 2H), 7.27(d, J=8.6Hz, 2H), 6.97(d, J=8.6Hz, 2H), 5.01(s, 2H)5 3.77(d, J=13.4Hz, IH), 3.73(s, 3H), 3.43(d, =13.4Hz, IH), 2.65-2.83(m, 2H)5 2.47(s, 3H), 2.20-2.43(m, IH), 1.71-1.90(m, 3H), 1.41(s, 3H)
Example 122: Preparation of 2-methyl-l-[4-[[5~methyl-2-(thiophen-2-yl)oxazol- 4-yl]methoxy]benzyl]pyrrolidine-2-carboxyIic acid methyl ester
Figure imgf000109_0002
The procedure of Step 1 of Example 110 was repeated except for using 4-[[4-(chloromethyl)phenoxy]methyl]-5-methyl-2-(thiophen-2-yl)oxazole(100 mg, 0.31 mmol) to obtain the title compound(53 mg, yield: 3%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.64(d, J=3.8Hz, IH), 7.40(d, J=5.4Hz5 IH), 7.25(d, J=8.2Hz, 2H), 7.08-7.13(m, IH), 6.95(d, J=8.2Hz, 2H), 4.97(s, 2H),4 3.75(d, J=13.4Hz, IH), 3.73(s, 3H), 3.43(d, J=13.4Hz, IH), 2.69-2.90(m, 2H), 2.42(s, 3H), 2.25-2.29(m, IH), 1.77-1.88(m, 3H), .41(s, 3H)
Example 123: Preparation of 2-ethyl-l-[4-[(5-methyl-2-p-tolyloxazoI-4-yl) methoxy] benzyl] pyrrolidine-2-carboxylic acid methyl ester
Figure imgf000109_0003
The procedure of Step 1 of Example 114 was repeated except for using 4-[[4_(chloromethyl)phenoxy]methyl)-5-methyl-2-p-tolyloxazole(100 mg, 0.31 mmol) to obtain the title comρound(60 mg, yield: 43%). 1H NMR(CDCl3, 200MHz): δ(ppm) 7.92(d, J=8.2Hz, 2H), 7.00-7.28(m, 4H), 6.88(d, J=8.2Hz, 2H), 4.98(s, 2H), 3.93(d, J=13.4Hz, IH), 3.82(s, 3H), 3.25(d, J=13.4Hz, IH), 2.80-3.16(m, IH), 2.43(s, 3H), 2.41(s, 3H), 2.34-2.73(m, IH), 1.93-2.27(m, 2H), 1.62-1.79(m, 4H), 0.97(t, J=7.4Hz, 3H)
Example 124: Preparation of 2-ethyl-l-[4-[[5-methyl-2-(4-trifluoromethyl- phenyI)oxazol-4-yl]methoxy]benzyl]pyrrolidine-2-carboxylic acid methyl ester
Figure imgf000110_0001
The procedure of Step 1 of Example 114 was repeated except for using 4-[[4-(chloromethyl)phenoxy]methyl]-5-methyl-2-(4-trifluoromethylphenyl)oxazole (100 mg, 0.26 mmol) to obtain the title compound(35 mg, yield: 27%). 1H NMR(CDCl3, 200MHz): δ(ppm) 8.15(d, J=8.2Hz, 2H), 7.72(d, J=8.2Hz, 2H), 7.25(d, J=9.0Hz, 2H), 6.96(d, J=9.0Hz, 2H), 5.01(s, 2H), 3.92(d, J=13.4Hz, IH), 3.75(s, 3H), 3.25(d, J=13.4Hz, IH), 2.86-2.95(m, IH), 2.47-2.57(m, IH), 2.47(s, 3H), 2.23-2.42(m, IH), 2.10(q, J=6.4Hz, IH), 1.55-1.85(m, 4H), 0.97(t, J=6.4Hz, 3H)
Example 125: Preparation of 2-ethyl-l-4-[[5-methyl-2-(thiophen-2-yl)oxazol- 4-yl]methoxy] benzyl] pyrrolidine-2-carboxylic acid methyl ester
Figure imgf000110_0002
The procedure of Step 1 of Example 114 was repeated except for using
4-[[4-(chloromethyl)phenoxy]methyl]-5-methyl-2-(thiophen-2-yl)oxazole(100 mg, 0.31 mmol) to obtain the title compound(34 mg, yield: 25%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.65(dd, J1=I^Hz, J2=3.8Hz, IH), 7.42(dd, Ji=I.2Hz9 J2=3.8Hz, IH), 7.24(d, J=8.2Hz, 2H), 7.12(dd, Ji=3.8Hz, J2=5.4Hz, IH), 6.98(d, J=8.2Hz, 2H), 4.97(s, 2H), 3.90(d, J=13.4Hz, lH),3.74(s, 3H), 3.25(d, J=13.4Hz, IH), 2.86-2.94(m, IH), 2.48-2.52(m, IH), 2.42(s, 3H), 2.21-2.37(m, IH), 2.02(q, J=7.4Hz, IH), 1.62-1.85(m, 4H), 0.96(t, J=7.4Hz, 3H)
Example 126: Preparation of 2-methyl-l-[3-[2-(5-methyl-2-p-tolyloxazol-4-yl) ethoxy] benzyl] pyrrolidine-2-carboxylic acid methyl ester
Figure imgf000111_0001
The procedure of Step 1 of Example 110 was repeated except for using 4-[2-[3-(chloromethyl)phenoxy]ethyl]-5-methyl-2:p-tolyloxazole(l 00 mg, 0.29 mmol) to obtain the title compound(50 mg, yield: 38%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.91(dd, Ji=I.6Hz, J2=8.2Hz, 2H), 7.17-7.29(m, 3H), 6.90-6.92(m, 2H), 6.77-6.81(m, IH), 4.26(t, J=6.8Hz, 2H), 3.80(d, J=13.4Hz, IH), 3.72(s, 3H), 3.45(d, J=13.4Hz, IH), 2.98(t, J=6.8Hz, 2H), 2.81-2.91(m, IH), 2.64-2.81(m, IH)3 2.40(s, 3H), 2.38(s, 3H), 2.23-2.29(m, IH), 1.70-1.87(m, 3H), 1.41(s, 3H)
Example 127: Preparation of 2-methyl-l-[3-[2-[5-methyl-2-(thiophen-2-yl) oxazol-4-yI]ethoxy] benzyl] pyrroIidine-2-carboxylic acid methyl ester
Figure imgf000111_0002
The procedure of Step 1 of Example 110 was repeated except for using 4- [2- [3 -(chloromethy l)phenoxy] ethyl] -5 -methy l-2-(thiophen-2-yl)oxazole( 100 mg, 0.30 mmol) to obtain the title compound(40 mg, yield: 31%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.59(dd, J1=I^Hz, J2=3.8Hz, IH)3 7.37(dd,
Figure imgf000111_0003
J2-5.4Hz, IH), 6.86-6.93(m, 2H), 6.75-6.80(m, IH), 4.23(t, J=6.4Hz, 2H), 3.80(d, J-13.4Hz, IH), 3.73(s, 3H)3 3.45(d, J=13.4Hz, IH), 2.93(t, J=6.4Hz, 2H), 2.80-2.87(m, IH), 2.68-2.76(m, IH), 2.37(s, 3H), 2.21-2.29(m, IH), 1.71-1.87(m, 3H), 1.41(s, 3H)
Example 128: Preparation of 2-ethyl-l-[3-[2-(5-methyl-2-p-tolyloxazoI-4-yl) ethoxy]benzyl]pyrrolidine-2-carboxylic acid methyl ester
Figure imgf000111_0004
The procedure of Step 1 of Example 114 was repeated except for using 4-[2-[3-(chloromethyl)phenoxy]ethyl]-5-methyl-2-p-tolyloxazole(l 00 mg, 0.29 mmol) to obtain the title compound(37 mg, yield: 28%). 1H NMR(CDCl3, 200MHz): δ(ppm) 7.88(d5 J=8.2Hz, 2H)5 7.15-7.28(m, 3H), 6.76-6.90(m, 3H), 4.24(t, J=6.4Hz, 2H), 3.85(d, J=13.4Hz, IH), 3.74(s5 3H), 3.60-3.74(m, IH), 3.26(d, J=13.4Hz, IH), 2.98(t, J=6.4Hz, 2H), 2.90-2.95(m, IH), 2.40-2.52(m, IH), 2.40(s, 3H), 2.38(s, 3H)5 2.00-2.32(m5 IH), 1.80-1.97(m, IH), 1.61-1.76(m, 3H), 0.92(t, J=6.4Hz, 3H)
Example 129: Preparation of 2-ethyl-l-[3-[2-[5-methyl-2-(thiophen-2-yl)oxazol- 4-yI]ethoxy]benzyl]pyrrolidine-2-carboxylic acid methyl ester
Figure imgf000112_0001
The procedure of Step 1 of Example 114 was repeated except for using
4-[2-[3-(chloromethyl)phenoxy]ethyl]-5-methyl-2-(thioρhen-2-yl)oxazole(100 mg, 0.30 mmol) to obtain the title compound(40 mg, yield: 29%).
1U NMR(CDCl3, 200MHz): δ(ppm) 7.60(dd, Ji=I.2Hz3 J2=3.8Hz, IH), 7.37(dd5
Figure imgf000112_0002
IH), 6.87-6.91(m, 2H), 6.75-6.79(m, IH), 4.23(t, J=6.4Hz, 2H), 3.95(d, J=13.4Hz, IH), 3.74 s, 3H)5 3.27(d5 J=13.4Hz, IH)5 2.96(t5 J=6.4Hz5 2H), 2.50-2.90(m, IH), 2.48-2.50(m, IH), 2.37(s, 3H), 1.61-2.23(m, 6H), 0.96(t, J=7.2Hz5 3H)
Example 130: Preparation of 2-ethyl-l-[4-[2-(5-methyl-2-Jp-tolyloxazol-4-yl) ethoxy]benzyl]pyrrolidine-2-carboxylic acid methyl ester
Figure imgf000112_0003
The procedure of Step 1 of Example 110 was repeated except for using 4-[2-[4-(chloromethyl)phenoxy]ethyl]-5-methyl-2:p-tolyloxazole(l 00 mg, 0.29 mmol) to obtain the title compound(29 mg, yield: 22%). 1H NMR(CDCl3, 200MHz): δ(ppm) 7.88(d, J=8.2Hz, 2H)5 7.15-7.28(m5 4H), 6.85(d, J=8.2Hz, 2H), 4.23(t, J=6.4Hz, 2H), 3.75(d, J=13.4Hz, IH), 3.72(s, 3H), 3.40(d, J=13.4Hz5 IH), 2.98(t, J=6.4Hz, 2H), 2.68-2.82(m, 2H), 2.40(s, 3H), 2.37(s, 3H), 2.21-2.3 l(m, IH), 1.70-2.08(m, 3H), 1.41(s, 3H)
Example 131: Preparation of 2-methyl-l-[4-[2-[5-methyl-2-(thiophen-2-yl) oxazol-4-yl]ethoxy] benzyl] pyrrolidine-2-carboxylic acid methyl ester
Figure imgf000113_0001
The procedure of Step 1 of Example 110 was repeated except for using 4-[2-[4-(chloromethyl)phenoxy]ethyl]-5-methyl-2-(thiophen-2-yl)oxazole(100 mg, 0.30 mmol) to obtain the title compound(45 mg, yield: 35%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.61(dd,
Figure imgf000113_0002
J2=3.8Hz, IH), 7.37(dd,
Figure imgf000113_0003
J2=5.4Hz, IH), 6.84(d, J=8.6Hz, 2H), 4.22(t, J=6.4Hz, 2H), 3.75(d, J=13.4Hz, IH), 3.72(s, 3H), 3.40(d, J=13.4Hz, IH), 2.96(t, J=6.4Hz, 2H), 2.40-2.82(m, 2H), 2.37(s, 3H), 2.08-2.25(m, IH), 1.70-1.89(m, 3H), 1.41(s, 3H)
Example 132: Preparation of 2-ethyl-l-[4-[2-(5-methyl-2-p-tolyIoxazol-4-yl) ethoxy] benzyl] pyrrolidine-2-carboxylic acid methyl ester
Figure imgf000113_0004
The procedure of Step 1 of Example 114 was repeated except for using 4-[2-[4-(chloromethyl)phenoxy]ethyl]-5-methyl-2-p-tolyloxazole( 100 mg, 0.29 mmol) to obtain the title compound(53 mg, yield: 40%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.88(d, J=8.2Hz, 2H), 7.14-7.26(m, 4H), 6.85(d, J=8.2Hz, 2H), 4.23(t, J=6.4Hz, 2H), 3.88(d, J=13.4Hz, IH), 3.73(s, 3H), 3.20(d, J-13.4Hz, IH), 2.98(t, J=6.4Hz, 2H), 2.85-3.01(m, IH), 2.40(s, 3H), 2.38(s, 3H), 2.12-2.5 l(m, 2H), 2.05(q, J=7.4Hz, 2H), 1.27-1.83(m, 3H), 0.96(t, J=7.4Hz, 3H)
Example 133: Preparation of 2-ethyl-l-[4-[2-[5~methyl-2-(4-trifluoromethyl- phenyl)oxazol-4-yl] ethoxy] benzyl] pyrrolidine-2-carboxylic acid methyl ester
Figure imgf000113_0005
The procedure of Step 1 of Example 114 was repeated except for using 4- [2- [4-(chloromethyl)phenoxy] ethyl] -5 -methy l-2-(4-trifluoromethylphenyl)oxazole (100 mg, 0.25 mmol)) to obtain the title compound(30 mg, yield: 23%). 1H NMR(CDCl3, 200MHz): δ(ppm) 8.10(d, J=8.4Hz, 2H), 7.70(d, J=8.6Hz, 2H), 7.20(d, J=8.4Hz, 2H), 6.85(d, J=8.6Hz, 2H), 4.25(t, J=6.4Hz, 2H), 3.88(d, J=13.4Hz, IH), 3.73(s, 3H), 3.20(d, J=13.4Hz, IH), 3.00(t, J=6.4Hz, 2H), 2.84-2.89(m, IH), 2.46-2.5 l(m, IH), 2.41(s, 3H), 2.20-2.26(m, IH), 2.06(q, J=6.4Hz, IH), 1.63-1.79(m, IH)5 0.96(t, J=6.4Hz, 3H)
Example 134: Preparation of 2-ethyl-l-[4-[2-[5-methyI-2-(thiophen-2-yl)oxazol- 4-yl]ethoxy]benzyI]pyrrolidine-2-carboxylic acid methyl ester
Figure imgf000114_0001
The procedure of Step 1 of Example 114 was repeated except for using 4-[2-[4-(chloromethyl)phenoxy]ethyl]-5-methyl-2-(thiophen-2-yl)oxazole(100 mg, 0.30 mmol) to obtain the title compound(25 mg, yield: 19%). 1R NMR(CDCl33 200MHz): δ(ppm) 7.88(d, J=8.2Hz, 2H), 7.14-7.26(m, 4H)5 6.85(d5 J=8.2Hz, 2H)5 4.23(t, J=6.4Hz, 2H)5 3.88(d, J=13.4Hz, IH)5 3.73(s, 3H)5 3.20(d5 J=13.4Hz, IH)5 2.98(t, J=6.4Hz5 2H)5 2.85-3.01(m, IH)5 2.40(s, 3H)5 2.38(s, 3H), 2.12-2.5 l(m, 2H)5 2.05(q5 J=7.4Hz, 2H)5 1.27-1.83(m, 3H)5 0.96(t, J=7.4Hz, 3H)
Example 135: Preparation of (R)-l-[3-[(5-methyl-2-phenyloxazol-4-yl)methoxy] benzyl] piperidine-2-carboxylic acid
Figure imgf000114_0002
Step 1 : Preparation of (R)-l-[3-[(5-methyl-2-phenyloxazol-4-yl)methoxy]benzyl] piperidine-2-carboxylic acid methyl ester The procedure of Step 1 of Example 96 was repeated except for using
4-[[3 -(chloromethyl)phenoxy]methyl]-5-methyl-2-phenyloxazole( 100 mg, 0.30 mmol) and (R)-2-(methoxycarbonyl)piperidinium chloride(60 mg, 0.33 mmol) to obtain the title compound(54 mg, yield: 43 %).
1U NMR(CDCl3, 200MHz): δ(ppm) 8.00-8.06(m, 2H), 7.42-7.49(m, 3H), 7.21-7.30(m, IH)5 7.04-7.06(m5 IH)5 6.92-6.97(m, 2H)5 5.02(s, 2H)5 3.75(s, 3H)5
3.43(d, J=13.6Hz, IH)5 3.18-3.23(m, IH)5 2.85-2.98(m5 IH)5 2.47(s, 3H)5
2.12-2.45(m, IH)5 1.84-1.87(m5 2H)5 1.51-1.65(m, 3H)5 1.24-1.45(m, 2H)
Step 2: Preparation of (R)-l-[3-[(5-methyl-2-phenyloxazol-4-yl)methoxy]benzyl] piperidine-2-carboxylic acid
The procedure of Step 2 of Example 96 was repeated except for using the compound obtained in Step 1 of Example 135(40 mg, 0.095 mmol) and 2 N NaOH(6 mg, 0.143 mmol) to obtain the title compound(25 mg, yield: 65%). 1H NMR(DMSO-(I3): δ(ppm) 7.95-7.97(m, 2H)5 7.31-7.55(m, 3H), 7.23-7.27(m, IH), 6.94-7.04(m, 3H), 5.01(s, 2H), 3.89(d, J=13.4Hz, IH), 3.48(d, J=13.4Hz, IH), 2.52-3.03(m, 2H), 2.47(s, 3H), 1.91-2.19(m5 IH), 1.31-1.77(m, 5H)
Example 136: Preparation of (R)-l-[3-[(5-methyl-2-Jp-tolyIoxazol-4-yl)methoxy] benzyl]piperidine-2-carboxy!ic acid methyl ester
Figure imgf000115_0001
The procedure of Step 1 of Example 135 was repeated except for using 4-[[3-(chloromethyl)phenoxy]methyl]-5-methyl-2-/7-tolyloxazole(100 mg, 0.31 mmol) to obtain the title compound(54 mg, yield: 40%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.92(d, J=8.2Hz, 2H), 7.22(d, J=8.2Hz, 2H), 7.01-7.25(m, IH), 6.90-7.01(m, IH), 5.00(s, 2H), 3.75(s, 3H), 3.43(d, J=13.6Hz, IH), 3.18-3.23(m, IH), 2.93-2.99(m, IH), 2.45(s. 3H), 2.19(s, IH), 1.80-1.87(m, 2H), 1.57-1.68(m, 3H), 1.28-1.45(m, 2H)
Example 137: Preparation of (R)-l-[3~[[5-methyl-2-(4-trifluoromethylphenyl) oxazol-4-yl]methoxy] benzyl] piperidine-2-carboxylic acid
Figure imgf000115_0002
Step 1 : Preparation of (R)-l-[3-[[5-methyl-2-(4-trifluoromethylphenyl)oxazol- 4-yl]methoxy]benzyl]piperidine-2-carboxylic acid methyl ester
The procedure of Step 1 of Example 135 was repeated except for using
4-[[3-(chloromethyl)phenoxy]methyl]-5-methyl-2-(4-trifluoromethylphenyl)oxazole
(98 mg, 0.21 mmol) to obtain the title compound(91 mg, yield: 72%).
1H NMR(CDCl3, 200MHz): δ(ppm) 8.15(d, J=8.6Hz, 2H), 7.72(d, J=8.6Hz, 2H), 7.22-7.28(m, IH), 7.05(s, IH), 6.90-6.97(m, . 2H), 5.03(s, 2H), 3.75(s, 3H),
3.75-3.63(m, IH), 3.42(d, J=13.4Hz, IH), 3.17-3.23(m, IH), 2.92-2.98(m, IH),
2.49(s, 3H), 2.19-2.47(m, IH), 1.82-2.16(m, 2H), 1.46-1.65(m, 3H), 1.35-1.42(m,
IH)
Step 2: Preparation of (R)-l-[3-[[5-methyl-2-(4-trifluoromethylρhenyl)oxazol- 4-yl]methoxy]benzyl]piperidine-2-carboxylic acid The procedure of Step 2 of Example 135 was repeated except for using the compound obtained in Step 1 of Example 137(52 mg, 0.11 mmol) to obtain the title compound(40 mg, yield: 79%).
1H NMR(DMSO-d6, 200MHz): δ(ppm) 8.16(d, J=8.6Hz, 2H)5 7.92(d, J=8.6Hz, 2H), 7.38-7.46(m, IH), 7.27(s, IH), 7.12-7.19(m, 2H), 5.09(s, 2H), 4.45(d, J=13.4Hz, IH), 4.15-4.21(m, IH), 3.90-4.09(m, IH), 3.29-3.34(m, IH), 2.92-3.01(m, IH), 2.51(s, 3H), 1.92-2.16(m, IH), 1.24-1.83(m, 6H)
Example 138: Preparation of (R)-l-[3-[[4-methyl-2-(4-trifluoromethylphenyl) oxazol-5-yl]methoxy] benzyl] piperidine-2-carboxyIic acid
Figure imgf000116_0001
Step 1: Preparation of (R)-l-[3-[[4-methyl-2-(4-trifluoromethylphenyl)oxazol- 5-yl]methoxy]benzyl]piperidine-2-carboxylic acid methyl ester
The procedure of Step 1 of Example 135 was repeated except for using 5-[[3 -(chloromethyl)phenoxy]methyl]-4-methyl-2-(4-trifluoromethylphenyl)oxazole (100 mg, 0.26 mmol) to obtain the title compound(63 mg, yield: 50%). 1H NMR(CDCl3, 200MHz): δ(ppm) 8.17(d, J=8.0Hz, 2H), 7.72(d, J=8.0Hz, 2H), 723-7.29(m, IH), 6.8-7.05(m, 3H), 5.10(s, 2H), 3.74(s, 3H), 3.65-3.77(m, IH), 3.40(d, J-13.4Hz, IH), 3.17-3.23(m, IH), 2.93-3.01(m, IH), 2.32(s, 3H), 2.13-2.21(m, IH), 1.80-2.06(m, 2H), 1.51-1.75(m, 4H)
Step 2: Preparation of (R)-l-[3-[[4-methyl-2-(4-trifluoromethylphenyl)oxazol- 5-yl]methoxy]benzyl]piperidine-2-carboxylic acid
The procedure of Step 2 of Example 135 was repeated except for using the compound obtained in Step 1 of Example 138(55 mg, 0.11 mmol) to obtain the title compound(35 mg, yield: 67%).
1H NMR(DMSO-d6, 200MHz): δ(ppm) 8.18(d, J-8.0Hz, 2H), 7.92(d, J=8.0Hz, 2H), 7.25-7.33(m, IH), 6.97-7.08(m, 3H), 5.24(s, 2H), 3.90(d, J=13.4Hz, IH), 3.52(d, J=13.4Hz, IH), 3.00-3.20(m, IH), 2.86-2.97(m, IH), 2.28(s, 3H), 2.00-2.52(m, IH), 1.33-1.92(m, 6H)
Example 139: Preparation of (R)-l-[3-[[5~methyl-2-(thiophen-2-yl)oxazol-4-yl] methoxy] benzyl] piperidine-2-carboxylic acid
Figure imgf000117_0001
Step 1: Preparation of (R)-l-(3-((5-methyl-2-(thiophen-2-yl)oxazol-4-yl)methoxy) benzyl)piperidine-2-carboxylic acid methyl ester
The procedure of Step 1 of Example 135 was repeated except for using 4-[[3-(chloromethyl)phenoxy]methyl]-5-methyl-2-(thiophen-2-yl)oxazole(150 mg, 0.47 mmol) to obtain the title compound(59 mg, yield: 30%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.66(dd, J=I.2Hz, IH), 7.42(dd, J=I.2Hz, IH), 7.21-7.32(m, IH)5 6.88-7.15(m, 4H)5 4.99(s, 2H), 3.75(s, 3H), 3.43(d, J=13.6Hz, IH), 3.17-3.23(m, IH), 2.92-3.18(m, IH), 2.44(s, 3H), 2.12-2.24(m, IH), 1.75-2.00(m, 2H), 1.51-1.75 m, 3H), 1.28-1.42(m, 2H)
Step 2: Preparation of (R)-l-[3-[[5-methyl-2-(thiophen-2-yl)oxazol-4-yl]methoxy] benzyl]piperidine-2-carboxylic acid
The procedure of Step 2 of Example 135 was repeated except for using the compound obtained in Step 1 of Example 139(55 mg, 0.13 mmol) to obtain the title compound(30 mg, yield: 56%).
1H NMR(CD3OD, 200MHz): δ(ppm) 7.70(d, Ji=0.8Hz, J2=3.6Hz, IH), 7.62(dd, Ji-1.2Hz, J2=5.8Hz, IH), 7.40(d, J=7.4Hz, IH), 7.38-7.40(m, IH), 7.13-7.25(m, 3H), 5.04(s, 2H, 4.58(d, J=12.6Hz, IH), 4.10(d, J=12.6Hz, IH), 3.40-3.55(m, 2H), 2.88-3.32(m, IH), 2.45(s, 3H), 2.00-2.41(m, IH), 1.49-1.94(m, 5H)
Example 140: Preparation of 2-methyl-l-[3-[[5-methyl-2-(thiophen-2-yI)oxazol- 4-yl]methoxy] benzyl] piperidine-2-carboxylic acid methyl ester
Figure imgf000117_0002
The procedure of Step 1 of Example 135 was repeated except for using 4-[[3-(chloromethyl)phenoxy]methyl]-5-methyl-2-(thioρhen-2-yl)oxazole(100 mg, 0.31 mmol) to obtain the title compound(31 mg, yield: 33%).
1R NMR(CDCl3, 200MHz): δ(ppm) 7.64(dd, J1=I .2Hz, J2=3.8Hz, IH), 7.42(dd, Jr=1.2Hz, J2=3.8Hz, IH) 7.21(d, J=7.6Hz, IH), 7.11(dd, J1=S.8Hz, J2=5.4Hz, 2H), 6.98(d, J=7.6Hz, IH), 6.86(m, IH), 4.99(s5 2H), 3.95(d, J=13.4Hz, IH), 3.74(s, 3H), 3.56(d, J=13.4Hz, IH), 2.50-2.66(m, 2H), 2.43(s, 3H), 2.06-2.12(m, IH), 1.44-1.66(m, 5H), 1.40(s, 3H)
Example 141: Preparation of 2-ethyl-l-[3-[[5-methyl-2-(4-trifluoromethyI- phenyl)oxazol-4-yI]methoxy] benzyl] piperidine-2-carboxylic acid methyl ester
Figure imgf000118_0001
The procedure of Step 1 of Example 135 was repeated except for using 4- [[3 -(chloromethyl)phenoxy]methyl] -5 -methy l-2-(4-trifluoromethylphenyl)oxazole (100 mg, 0.26 mmol) to obtain the title compound(40 mg, yield: 42%). 1H NMR(CDCl3, 200MHz): δ(ppm) 8.14(d5 J=8.2Hz, 2H)5 7.72(d, J=8.2Hz, 2H)5 7.21-7.28(m, IH), 6.90-6.97(m, 2H), 5.03(s, 2H)5 3.78(d, J=13.4Hz, IH), 3.75(s, 3H), 3.42(d, J=13.4Hz, IH), 3.14-3.23(m, IH)5 2.92-2.98(m5 IH), 2.49(s5 3H)5 2.12-2.24(m, IH)5 1.79-1.86(m, 2H)5 1.53-1.64(m, 3H), 0.87(t, J=6.4Hz, 3H)
Example 142: Preparation of (R)-l-[4-[(5-methyl-2-phenyloxazol-4-yl)methoxy] benzyl]piperidine-2-carboxylic acid
Figure imgf000118_0002
Step 1 : Preparation of (R)-l-[4-[(5-methyl-2-phenyloxazol-4-yl)methoxy]benzyl] piperidine-2-carboxylic acid methyl ester
The procedure of Step 1 of Example 135 was repeated except for using 4-[[4-(chloromethyl)phenoxy]methyl]-5-methyl-2-phenyloxazole(100 mg, 0.31 mmol) to obtain the title compound(50 mg, yield: 41%).
1H NMR(CDCl3, 200MHz): δ(ppm) 8.02-8.07(m, 2H), 7.44(m, 3H)5 7.26(d, J=8.4Hz, 2H)5 6.98(d5 J=8.4Hz5 2H), 5.00(s5 2H)5 3.76(s, 3H), 3.38(d, J=13.2Hz, IH)5 3.12-3.18(m, IH)5 2.92-2.98(m, IH), 2.45(s, 3H), 2.12-2.17(m, IH), 1.71-1.87(m, 2H), 1.52-1.71(m, 3H), 1.28-1.42(m, 2H)
Step 2: Preparation of (R)-l-[4-[(5-methyl-2-phenyloxazol-4-yl)methoxy] benzyl]piperidine-2-carboxylic acid
The procedure of Step 2 of Example 135 was repeated except for using the compound obtained in Step 1 of Example 142(40 mg, 0.095 mmol) to obtain the title compound(30 mg, yield: 74%). 1H NMR(DMSO-d6, 300MHz): 7.92-7.95(m, 2H), 7.51-7.53(m, 3H)5 7.44(d, J=8.4Hz, 2H), 7.12(d, J=8.4Hz, 2H), 5.04(s, 2H), 4.36(d, J=13Hz, IH), 4.1 l(d, J=13HZ, IH), 3.79-3.82(m, IH), 3.25-3.28(m, IH), 2.88-2.91(m, IH), 2.45(s, 3H), 2.08-2.17(m, IH), 1.23-1.73(m, 6H)
Example 143: Preparation of (R)-I- [4- [(5-methyl~2-p~tolyIoxazol-4-yl)methoxy] benzyl] piperidine-2-carboxylic acid
Figure imgf000119_0001
Step 1: Preparation of (R)-l-[4-[(5-methyl-2-/?-toryloxazol-4-yl)methoxy]benzyl] piperidine-2-carboxylic acid methyl ester The procedure of Step 1 of Example 135 was repeated except for using
4-[[4-(chloromethyl)phenoxy]methyl)-5-methyl-2-j9-tolyloxazole(l 50 mg, 0.46 mmol) to obtain the title compound(123 mg, yield: 62%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.92(d, J=8.2Hz, 2H), 7.25(d, J=8.2Hz, 2H),
6.97(d, J=8.2Hz, 2H), 4.99(s, 2H), 3.76(s, 3H), 3.37(d, J=BHz, IH), 3.11-3.18(m, IH), 2.92-3.00(m, IH), 2.43(s, 3H), 2.41(s, 3H), 2.1-2.20(m, IH), 1.71-1.86(m, 2H),
1.52-1.68(m, 3H), 1.30-1.44(m, 2H)
Step 2: Preparation of (R)-l-[4-[(5-methyl-2-/?-tolyloxazol-4-yl)methoxy]benzyl] piperidine-2-carboxylic acid The procedure of Step 2 of Example 135 was repeated except for using the compound obtained in Step 1 of Example 143(38 mg, 0.087 mmol) to obtain the title compound(20 mg, yield: 55%).
1H NMR(DMSO-d6, 200MHz): δ(ppm) 7.84(d, J=7.8Hz, 2H), 7.46(d, J=8.0Hz, 2H),
7.34(d, J=7.8Hz, 2H), 7.13(d, J=8Hz, 2H), 5.04(s, 2H), 4.40(d, J=13.2Hz, IH), 4.15(d, J=13.2Hz, IH), 3.80-3.83(m, IH), 3.27-3.34(m, IH), 2.75-2.95(m, IH),
2.46(s, 3H), 2.38(s, 3H), 2..15-2.23(m, IH), 1.24-2.00(m, 6H)
Example 144: Preparation of (R)-l-[4-[[5-methyl-2-(4-trifluoromethylphenyl) oxazol-4-yl]methoxy] benzyl] piperidine-2-carboxylic acid
Figure imgf000119_0002
Step 1 : Preparation of (R)-l-4-[[5-methyl-2-(4-trifluoromethylphenyl)oxazol-
4-yl]methoxy]benzyl]piperidine-2-carboxylic acid methyl ester The procedure of Step 1 of Example 135 was repeated except for using 4-[[4-(chloromethyl)phenoxy]methyl]-5-methyl-2-(4-trifluoromethylphenyl)oxazole (100 mg, 0.31 mmol) to obtain the title compound(50 mg, yield: 39%). 1H NMR(CDCl3, 200MHz): δ(ppm) 8.13(d, J=8.2Hz, 2H), 7.70(d, J=8.2Hz, 2H), 7.24(d, J=8.2Hz, 2H), 6.96(d, J=8.0Hz, 2H), 4.99(s, 2H), 3.74(s, 3H), 3.36(d, J=13.2Hz, IH), 3.10-3.16(m, IH), 2.90-2.96(m, IH), 2.45(s, 3H), 2.03-2.16(m, IH), 1.78-2.00(m, 2H), 1.53-1.78(m, 3H), 1.25-1.30(m, 2H)
Step 2: Preparation of (R)-l-[4-[[5-methyl-2-(4-trifluoromethylphenyl)oxazol- 4-yl]methoxy]benzyl]piperidine-2-carboxylic acid
The procedure of Step 2 of Example 135 was repeated except for using the compound obtained in Step 1 of Example 144(30 mg, 0.062 mmol) to obtain the title compound(20 mg, yield: 68%).
1H NMR(DMSO-d6, 200MHz): δ(ppm) 8.15(d, J=8.2Hz, 2H), 7.90(d, J=8.2Hz, 2H), 7.47(d, J=8.2Hz, 2H), 7.14(d, J=8.2Hz, 2H), 5.08(s, 2H), 4.40(d, J=13.2Hz, IH),
4.15(d, J=13.2Hz, IH), 3.80-3.84(m, IH), 3.27-3.14(m, IH), 2.74-2.94(m, IH),
2.51(s, 3H), 2.15-2.37(m, IH), 1.24-2.00(m, 7H
Example 145: Preparation of (R)-l-[4-[5-methyl-2-(thiophen-2-yl)oxazol-4-yl] methoxy] benzyl] piperidine-2-carboxylic acid
Figure imgf000120_0001
Step 1 : Preparation of (R)-l-[4-[[5-methyl-2-(thiophen-2-yl)oxazol-4-yl]methoxy] benzyl]piperidine-2-carboxylic acid methyl ester
The procedure of Step 1 of Example 135 was repeated except for using 4-[[4-(chloromethyl)phenoxy]methyl]-5-methyl-2-(thiophen-2-yl)oxazole(150 mg,
0.47 mmol) to obtain the title compound(100 mg, yield: 50%).
1YL NMR(CDCl3, 200MHz): δ(ppm) 7.63(dd, J1=LOSHz, J2=3.69Hz, IH), 7.39(dd,
Jr=1.05Hz, J2=4.98HZ, IH), 7.22(d, J=8.52Hz, 2H)5 7.07-7.10(m, IH), 6.94(d,
J=8.2Hz, 2H), 4.95(s, 2H), 3.70(d, J=13.4Hz, IH), 3.34(d5 J=13.4Hz, IH)5 3.10-3.14(m, IH), 2.90-2.94(m, IH), 2.40(s, 3H), 2.10-2.14(m, IH)5 1.76-1.83(m,
2H), 1.52-1.58(m5 3H)5 1.25-1.34(m5 2H)
Step 2: Preparation of (R)-l-[4-[5-methyl-2-(thiophen-2-yl)oxazol-4-yl]methoxy] benzyl]piperidine-2-carboxylic acid The procedure of Step 2 of Example 135 was repeated except for using the compound obtained in Step 1 of Example 145(80 mg, 0.188 mmol) to obtain the title compound(40 mg, yield: 52%).
1H NMR(CD3OD, 200MHz): δ(ppm) 7.70(dd, Ji=0.8Hz, J2=3.6Hz, IH), 7.62(dd, Jr=1.2Hz, J2=5.4Hz, IH), 7.49(d, J=8.6Hz, 2H), 7.11-7.20(m, IH), 7.13(d, J=8.6Hz, IH), 5.03(s, 2H), 4.53(d, J=12.6Hz, IH), 4.10(d, J=12.6Hz, IH), 3.32-3.53(m, 2H), 2.88-2.98(m, IH), 2.45(s, 3H), 2.24-2.33(m, IH), 1.55-1.99(m, 5H)
Example 146: Preparation of 2-methyl-l-[4-[(5-methyl-2-p-tolyloxazol-4-yl) methoxy] benzyl] piperidine-2-carboxylic acid methyl ester
Figure imgf000121_0001
The procedure of Step 1 of Example 135 was repeated except for using
4-[[4-(chloromethyl)phenoxy]methyl)-5-methyl-2-p-tolyloxazole(100 mg, 0.31 mmol) to obtain the title compound(56 mg, yield: 57%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.92(d, J=8.2Hz, 2H), 7.24-7.90(m, 4H), 6.97(d, JN8.2Hz, 2H), 4.99(s, 2H), 3.82(d, J=13 7.92(d, J=8.2Hz, 2H), 7.24-7.90(m, 4H), 6.97(d, J=8.2Hz, 2H), 4.99(s, 2H), 3.82(d, J=13.4Hz, IH), 3.75(s, 3H), 3.50(d, J=13.4Hz, IH), 2.50-2.66(m, 2H), 2.44(s, 3H), 2.41(s, 3H), 2.04-2.19(m, IH), 1.47-1.69(m, 5H), 1.42(s, 3H)
Example 147: Preparation of 2-ethyl-l-[4-[(5-methyl-2-p-tolyloxazol-4-yl) methoxy] benzyl] piperidine-2-carboxylic acid methyl ester
Figure imgf000121_0002
The procedure of Step 1 of Example 135 was repeated except for using 4-[[4-(chloromethyl)phenoxy]methyl)-5-methyl-2-j9-tolyloxazole(100 mg, 0.31 mmol) to obtain the title compound(50 mg, yield: 35%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.92(d, J=8.2Hz, 2H), 7.24-7.33(m, 4H), 6.97(d, J=8.4Hz, 2H), 4.99(s, 2H), 4.09(d, J=13.4Hz, IH), 3.75(s, 3H), 3.56(d, J=13.4Hz, lH),2.50-2.67(m, IH), 2.43(s, 3H), 2.41(s, 3H), 1.98-2.03(m, IH), 1.85(q, J=7.2Hz, 2H), 1.60-1.72(m, 3H), 1.37-1.49(m, 3H), 0.97(t, J=7.2Hz, 3H) Example 148: Preparation of (R)-I- [3- [2-(5-methyl-2-/;-toryIoxazol-4-yl)ethoxy] benzyl] piperidine-2-carboxylic acid
Figure imgf000122_0001
Step 1 : Preparation of (R)-l-[3-[2-(5-methyl-2-j9-tolyloxazol-4-yl)ethoxy]benzyl] piperidine-2-carboxylic acid methyl ester
The procedure of Step 1 of Example 135 was repeated except for using 4-[2-[3-(chloromethyl)phenoxy]ethyl]-5-methyl-2-p-tolyloxazole( 100 mg, 0.29 mmol) to obtain the title compound(90 mg, yield: 70%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.89(d, J=8.2Hz, 2H), 7.21-7.30(m5 3H), 6.84-7.17(m, 3H), 4.26(t, J=6.4Hz, 2H), 3.77(d, J=13.4Hz, IH), 3.74(s, 3H), 3.42(d, J=13.4Hz, IH), 3.16-3.72(m, IH), 2.99(d, J=6.4Hz, 2H), 2.96-3.03(m, IH), 2.40(s, 3H, 2.39(s, 3H), 2.06-2.22(m, IH), 1.80-1.86(m, 2H), 1.51-1.67(m, 3H), 1.29-1.45(m, IH)
Step 2: Preparation of (R)-l-[3-[2-(5-methyl-2-jσ-tolyloxazol-4-yl)ethoxy]benzyl] piperidine-2-carboxylic acid
The procedure of Step 2 of Example 135 was repeated except for using the compound obtained in Step 1 of Example 149(80 mg, 0.18 mmol) to obtain the title compound(33 mg, yield: 43%).
1H NMR(DMSO-d6, 200MHz): δ(ppm) 7.81(d, J=7.8Hz, 2H), 7.3 l(d, J=7.8Hz, 2H), 7.20-7.33(m, IH), 6.85-6.95(m, 3H), 4.21(t, J=6.4Hz, 2H), 3.94(d, J=13.4Hz, IH), 3.52(d, J=13.4Hz, IH), 2.95(t, J=6.4Hz, 2H), 2.90-3.08(m, IH), 2.52(s, IH), 2.36(s, 6H)
Example 149: Preparation of (R)-l-[3-[2-[5-methyl-2-(4-trifluoromethylphenyl) oxazol-4-yl]ethoxy] benzyl] piperidine-2-carboxylic acid methyl ester
Figure imgf000122_0002
The procedure of Step 1 of Example 135 was repeated except for using 4-[2-[3-(chloromethyl)phenoxy]ethyl]-5-methyl-2-(4-trifluoromethylphenyl)oxazole (100 mg, 0.25 mmol) to obtain the title compound(40 mg, yield: 32%). 1H NMR(CDCl3, 200MHz): δ(ppm) 8.09(d, J=8.4Hz, 2H), 7.68(d, J=8.4Hz, 2H), 7.17-7.28(m, IH), 6.78-6.95(m, 3H), 4.26(t, J=6.6Hz, 2H), 3.73(s, 3H), 3.40(d, J=13HZ, IH)5 3.15-3.25(m, IH), 3.01(t, J=6.6Hz, 2H), 2.91-3.00(m, IH), 2.41(s, 3H), 2.11-2.20(m, IH)3 1.81-2.05(m, 2H), 1.55-1.57(m, 3H), 1.23-1.40(m, 2H)
Example 150: Preparation of (R)-l-[3-[2-[5-methyl-2-(thiophen-2-yl)oxazol- 4-yl]ethoxy] benzyl] piperidine-2-carboxylic acid
Figure imgf000123_0001
Step 1: Preparation of (R)-l-[3-[2-[5-methyl-2-(thiophen-2-yl)oxazol-4-yl] methoxy]benzyl]piperidine-2-carboxylic acid methyl ester
The procedure of Step 1 of Example 135 was repeated except for using 4-[2-[3-(chloromethyl)phenoxy]ethyl]-5-methyl-2-(thiophen-2-yl)oxazole(l 00 mg,
0.30 mmol) to obtain the title compound(70 mg, yield: 53%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.59-7.61(m, IH), 7.37-7.39(m, IH),
7.17-7.29(m, IH), 7.08-7.12(m, IH), 6.92-7.08(m, 2H), 6.78-6.89(m, IH), 4.24(t,
J=6.4Hz, 2H), 3.78(d, J=13.4Hz, IH), 3.74(s, 3H), 3.40(d, J=13.4Hz, IH), 3.16-3.22(m, IH), 2.97(t, J=6.4Hz, 2H), 2.92-3.01(m, IH), 2.38(s, 3H), 2.13-2.24(m,
IH), 1.68-1.86(m, 2H), 1.52-1.65(m, 3H), 1.31-1.45(m, IH)
Step 2: Preparation of (R)-l-[3-[2-[5-methyl-2-(thiophen-2-yl)oxazol-4-yl]ethoxy] benzyl]piperidine-2-carboxylic acid The procedure of Step 2 of Example 135 was repeated except for using the compound obtained in Step 1 of Example 150(65 mg, 0.15 mmol) to obtain the title compound(46 mg, yield: 72%).
1H NMR(DMSO-d6, 200MHz): δ(ppm) 7.71-7.74(m, IH), 7.59-7.61(m, IH),
7.16-7.27(m, 2H), 6.84-6.94(m, 4H), 4.18(t, J=6.4Hz, 2H), 3.92(d, J=13.4Hz, IH), 3.54(d, J=13.4, IH), 3.04-3.10(m, IH), 2.90(t, J=6.4Hz, 2H), 2.87-2.93(m, IH),
2.51(s, IH), 2.34(s, 3H), 1.23-1.98(s, 8H)
Example 151: Preparation of 2-methyI-l-[3-[2-(5-methyl-2-Jp-tolyloxazol-4-yl) ethoxy] benzyl] piperidine-2-carboxylic acid methyl ester
Figure imgf000123_0002
The procedure of Step 1 of Example 135 was repeated except for using
4-[2-[3-(chloromethyl)ρhenoxy]ethyl]-5-methyl-2-j!7-tolyloxazole(100 mg, 0.29 mmol) to obtain the title compound(56 mg, yield: 42%). 1H NMR(CDCl3, 200MHz): δ(ppm) 7.86(d, J=8.2Hz5 2H), 7.22(d5 J=8.2Hz, 2H), 7.14-7.15(m, IH)5 6.83-7.01(m, 2H), 6.73-6.78(m, 2H), 4.24(t, J=6.4Hz, 2H), 3.90(d, J-13.4Hz, IH), 3.72(s, 3H), 3.52(d, J=13.4Hz, IH)5 2.97(t, J=6.4Hz, 2H), 2.46-2.63(m, 2H)5 2.37(s, 3H)5 2.36(s, 3H), 2.03-2.27(m, IH), 1.42-1.59(m, 5H), 1.38(s, 3H)
Example 152: Preparation of 2-methyl-l-[3-[2-[5-methyl-2-(thiophen-2-yl) oxazol-4-yl]ethoxy] benzyl] piperidine-2-carboxyIic acid methyl ester
Figure imgf000124_0001
The procedure of Step 1 of Example 135 was repeated except for using
4-[2-[3-(chloromethyl)phenoxy]ethyl]-5-methyl-2-(thiophen-2-yl)oxazole(100 mg, 0.30 mmol) to obtain the title compound(37 mg, yield: 38%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.60(dd, J1=I ^Hz, J2=3.8Hz, IH), 7.38(dd, Ji-1.2Hz, J2=3.8Hz, lH),7.18(d, J=7.6Hz, IH), 7.10(dd, J^.δHz, J2=5.4Hz, IH), 6.93-6.97(m, 2H), 6.74-6.78(m,2H), 4.24(t, J=6.4Hz, 2H)5 3.92(d, J=13.4Hz, IH), 3.74(s, 3H)5 3.55(d, J=13.4Hz, IH), 2.98(t, J-6.4Hz, 2H), 2.48-2.62(m, 2H), 2.38(s, 3H), 2.07-2.19(m, IH), 1.46-1.70(m, 5H), 1.40(s, 3H)
Example 153: Preparation of (R)-l-[4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy] benzyl] piperidine-2-carboxylic acid
Figure imgf000124_0002
Step 1: Preparation of (R)-l-[4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]benzyl] piperidine-2-carboxylic acid methyl ester
The procedure of Step 1 of Example 135 was repeated except for using 4-[2-[4-(chloromethyl)phenoxy]ethyl]-5-methyl-2-phenyloxazole(150 mg, 0.46 mmol) to obtain the title compound(62 mg, yield: 31%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.97-8.03(m, 2H), 7.42-7.46(m, 3H), 7.22(d, J=8.4Hz, 2H), 6.86(d, J=8.4Hz, 2H), 4.25(t, J=6.4Hz, 2H), 3.75(s, 3H), 3.35(d, J=13.4Hz, IH), 3.09-3.16(m, IH), 2.99(t, J=6.4Hz, 2H), 2.85-2.99(m, IH), 2.39(s, 3H), 2.07-2.15(m, IH)5 1.70-1.85(m5 2H)5 1.43-1.58(m, 3H), 0.91-1.33(m5 2H)
Step 2: Preparation of (R)-l-[4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]benzyl] piperidine-2-carboxylic acid The procedure of Step 2 of Example 135 was repeated except for using the compound obtained in Step 1 of Example 153(50 mg, 0.11 mmol) to obtain the title compound(20 mg, yield: 40%).
1H NMR(DMSO-d6, 200MHz): δ(ppm) 7.70-7.76(m, 2H)5 7.30-7.32(m, 3H), 7.22(d, J=8.5Hz, 2H), 6.83(d, J=8.5Hz, 2H), 4.17(d, J=12.8Hz, IH)5 4.06(t, J=6.4Hz, 2H), 3.92(d, J=12.8Hz, IH), 3.49-3.60(m, IH), 3.04-3.24(m, IH), 2.78(t, J=6.4Hz, 2H), 2.32(s, 3H), 1.20-1.99(m, 7H)
Example 154: Preparation of (R)-l-[4-[2-(5-methyI-2-/;-toryloxazol-4-yl) methoxy]benzyl]piperidine-2-carboxylic acid
Figure imgf000125_0001
Step 1: Preparation of (R)-I- [4- [2-(5-methyl-2-^-tolyloxazol-4-yl)ethoxy]benzyl] piperidine-2-carboxylic acid methyl ester
The procedure of Step 1 of Example 135 was repeated except for using 4-[2-[4-(chloromethyl)phenoxy]ethyl]-5-methyl-2-j>tolyloxazole(100 mg, 0.29 mmol) to obtain the title compound(71 mg, yield: 55%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.88(d, J=8.2Hz, 2H), 7.19-7.28(m, 4H), 6.86(d, J=8.2Hz, 2H), 4.21-4.28(m, 2H), 3.76(s, 3H)5 3.36(d, J=13.4Hz, IH), 3.12-3.16(m, IH), 2.90-3.09(m, 3H), 2.40(s, 3H), 2.39(s, 3H), 2.09-2.15(m, IH), 1.82-1.85(m, 2H), 1.56-1.69(m, 3H), 0.91-1.29(m, 2H)
Step 2: Preparation of (R)-I- [4- [2-(5-methyl-2-/?-tolyloxazol-4-yl)methoxy]benzyl] piperidine-2-carboxylic acid
The procedure of Step 1 of Example 135 was repeated except for using the compound obtained in Step 1 of Example 154(50 mg, 0.11 mmol) to obtain the title compound(31 mg, yield: 66%).
1H NMR(DMSO-d6, 200MHz): δ(ppm) 7.8 l(d, J=7.8Hz, 2H), 7.42(d, J=7.6Hz, 2H), 7.3 l(d, J=7.6Hz, 2H), 7.03(d, J=7.8Hz, 2H), 4.36-4.43(m, 2H), 4.22(t, J=6.4Hz, 2H), 3.88-4.19(m, 2H), 3.27-3.40(m, IH), 2.94(t, J=6.4Hz, 2H), 2.68-2.94(m, IH), 2.36(s,6H), 2.00-2.23(m, IH), 1.24-2.04(m, 5H)
Example 155: Preparation of (R)-l-[4-[2-[5-methyl-2-(4-trifluoromethylphenyl) oxazol-4-yl] ethoxy] benzyl] piperidine-2-carboxylic acid
Figure imgf000125_0002
Step 1 : Preparation of (R)-l-[4-[2-[5-methyl-2-(4-trifluoromethylphenyl)oxazol- 4-yl]ethoxy]benzyl]piperidine-2-carboxylic acid methyl ester
The procedure of Step 1 of Example 135 was repeated except for using 4-[2-[4-(chloromethyl)phenoxy]ethyl]-5-methyl-2-(4-trifluoromethylphenyl)oxazole
5 (100 mg, 0.25 mmol) to obtain the title compound(60 mg, yield: 48%).
1H NMR(CDCl3, 200MHz): δ(ppm) 8.10(d, J=8.2Hz, 2H), 7.70(d, J=8.2Hz, 2H), 7.22(d, J=8.4Hz, 2H), 6.86(d, J=8.4Hz, 2H), 4.25(t, J=6.4Hz, 2H), 3.75(s, 3H), 3.69-3.75(m, IH), 3.35(d, J=13.4Hz, IH), 3.09-3.15(m, IH), 3.00(t, J=6.4Hz, 2H), 2.92-3.00(m, IH), 2.42(s, 3H), 2.06-2.15(m, IH), 1.72-1.85(m, 2H), 1.52-1.70(m,
[0 3H), 1.30-1.50(m, IH)
Step 2: Preparation of (R)-l-[4-[2-[5-methyl-2-(4-trifluoromethylphenyl)oxazol- 4-yl] ethoxy]benzyl]piρeridine-2-carboxylic acid
The procedure of Step 2 of Example 135 was repeated except for using the
15 compound obtained in Step 1 of Example 155(38 mg, 0.08 mmol) to obtain the title compound(20 mg, yield: 51%).
1H NMR(DMSO-d6, 200MHz): δ(ppm) 8.10(d, JM8.2Hz, 2H), 7.86(d, J=8.2Hz, 2H), 7.25(d, J=8.6Hz, 2H), 6.90(d, J=8.6Hz, 2H), 4.21(t, J=6.4Hz, 2H), 3.90(d, J=13.4Hz, 2H), 3.56(d, J=13.4Hz, IH), 2.95(t, J=6.4Hz, 2H), 2.50-2.98(m, IH), 2.39(s, 3H), 0 1.90-2.28(m, IH), 1.49-1.29(m, 6H)
Example 156: Preparation of (R)-l-[4-[2~[5-methyl~2-(thiophen-2-yl)oxazol- 4-yl]ethoxy] benzyl] piperidine-2-carboxylic acid
Figure imgf000126_0001
5 Step 1 : Preparation of (R)-l-(4-(2-(5-methyl-2-(thiophen-2-yl)oxazol-4-yl)ethoxy) benzyl)piperidine-2-carboxylic acid methyl ester
The procedure of Step 1 of Example 135 was repeated except for using 4-[2-[4-(chloromethyl)phenoxy]ethyl]-5-methyl-2-(thiophen-2-yl)oxazole(100 mg, 0.30 mmol) to obtain the title compound(85 mg, yield: 64%). 0 1R NMR(CDCl3, 200MHz): δ(ppm) 7.59(dd, Ji=I.2Hz, J2=3.7Hz, IH), 7.39(dd, Jr=1.2Hz, J2=3.7Hz, IH), 7.20(d, J=8.4Hz, 2H), 7.10(dd, J1=S-OHz, J2=4.8Hz, IH), 6.85(d, J=8.4Hz, 2H), 4.22(t, J=6.4Hz, 2H), 3.75(s, 3H), 3.73(d, J=13.4Hz, IH), 3.36(d, J=13.4Hz, IH), 3.09-3.15(m, IH), 2.97(t, J=6.4Hz, 2H), 2.90-3.00(m, IH), 2.37(s, 3H), 2.06-2.18(m, IH), 1.78-1.85(m, 2H), 1.50-1.76(m,3H), 1.28-143(m, IH)5
Step 2: Preparation of (R)-l-[4-[2-[5-methyl-2-(thiophen-2-yl)oxazol-4-yl]ethoxy] benzyl]piperidine-2-carboxylic acid
The procedure of Step 2 of Example 135 was repeated except for using the compound obtained in Step 1 of Example 156(36 mg, 0.082 mmol) to obtain the title compound(30 mg, yield: 86%). 1H NMR(DMSO-d6, 200MHz): δ(ppm) 7.72-7.75(m, IH)5 7.60-7.62(m, IH), 7.33(d, J=8.2Hz, 2H), 7.1707.22(m, IH), 6.97(d, J=8.2Hz, 2H), 4.21(t, J=6.4Hz, 2H), 3.80-3.87(m, IH), 3.23-3.44(m, IH), 3.11-3.18(m, IH), 2.92(t, J=6.4Hz, 2H)3 2.45-2.52(m, IH), 2.35(s, 3H), 1.49-2.00(m, 7H) .
Example 157: Preparation of 2-methyl-l-[4-[2-(5-methyl-2~p-tolyloxazol-4-yl) ethoxy] benzyl] piperidine-2-carboxylic acid methyl ester
Figure imgf000127_0001
The procedure of Step 1 of Example 135 was repeated except for 4-[2-[4-(chloromethyl)phenoxy]ethyl]-5-methyl-2-p-tolyloxazole(100 mg, 0.20 mmol) to obtain the title compound(51 mg, yield: 38%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.88(d, J=8.2Hz, 2H), 7.22-7.29(m, 4H), 6.86(d, J=8.4Hz, 2H), 4.24(t, J=6.4Hz, 2H), 3.75(d, J=13.4Hz, IH)5 3.74(s, 3H), 3.48(d, J=13.4Hz, IH), 2.98(t, J=13.4Hz, IH), 2.47-2.59(m, IH), 2.40(s, 3H), 2.38(s, 3H), 2.05-2.15(m, IH), 1.45-1.70(m, 6H), 1.41(s, 3H)
Example 158: Preparation of 2-methyl-l-[4-[2-[5-methyl-2-(4-trifluoromethyl- phenyl)oxazol-4-yl] ethoxy] benzyl] piperidine-2-carboxylic acid methyl ester
Figure imgf000127_0002
The procedure of Step 1 of Example 135 was repeated except for using 4-[2- [4-(chloromethyl)phenoxy] ethyl] - 5 -methyl-2-(4-trifluoromethy lphenyl)oxazole (200 mg, 0.51 mmol) to obtain the title compound(67 mg, yield: 35%). 1H NMR(CDCl3, 200MHz): δ(ppm) 8.10(d, J=8.2Hz, 2H), 7.70(d, J=8.2Hz, 2H), 7.27(d, J=8.4Hz, 2H), 6.85(d, J=8.4Hz, 2H), 4.25(t, J=6.4Hz, 2H), 3.80(d, J=13.4Hz, IH)5 3.74(s5 3H), 3.48(d, J=13.4Hz, IH), 3.00(t, J=6.4Hz, 2H)5 2.47-2.55(m, 2H), 2.42(s, 3H), 1.41(s, 3H), 1.28-1.66(m, 6H)
Example 159: Preparation of 3-methyl-l-[3-[(5-methyl-2-phenyloxazol-4-yl) m ethoxy] benzyl] piperidine-3-carboxylic acid ethyl ester
Figure imgf000128_0001
4- [[3 -(Chloromethyl)phenoxy]methyl] -5 -methy l-2-p-tolyloxazole( 150 mg, 0.48 mmol), 3-(ethoxycarbonyl)-3-methylρiperidinium chloride(200 mg, 0.96 mmol) and diisopropylethylamine(280 mg, 2.15 mmol) were dissolved in N,N-dimethylforøiamide(15 ml). The resulting mixture was stirred at 85 °C for 12 hrs and cooled down to room temperature. The resultant was extracted with water and dichloromethane. The organic layer was separated, dried over anhydrous sodium sulfate and concentrate under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography(eluent: hexane/ethyl acetate =3:1) to obtain the title compound(0.17 g, yield: 78%).
1H NMR(CDCl3, 200MHz): δ(ppm) 8.02-8. 07(m, 2H), 7.43-7.40(m,3H), 7.20-7.28(m, IH), 7.02(s, IH), 6.92-6.95(m, 2H), 5.01(s, 2H), 4.13(q, J-3.2Hz, 2H), 3.53(d, J=13.4Hz, IH), 3.40(ds J=13.4Hz, IH)5 2.90-3.00(m, IH), 2.57-2.69(m, IH), 2.45(s, 3H), 1.93-2.14(m, 3H), 1.59-1.76(m, 2H), 1.24(t, J=7.0Hz, 3H), 1.19-1.3 l(m, IH), 1.14(s, 3H)
Example 160: Preparation of 3-methyl-l-[3-[(5-methyl-2-p-toIyloxazol-4-yl) methoxy] benzyl] piperidine-3-carboxylic acid ethyl ester
Figure imgf000128_0002
The procedure of Step 1 of Example 159 was repeated except for using
4-[[3-(chloromethyl)phenoxy]methyl]-5-methyl-2-/7-tolyloxazole(l 50 mg, 0.46 mmol) to obtain the title compound(150 mg, yield: 70%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.03(d, J=8.2Hz, 2H), 7.20-7.30(m, IH), 7.28(d, J=8.2Hz 2H), 6.88-6.98(m, 2H), 5.00(s, 2H), 4.32(q, J=3.2Hz, 2H), 3.55(d, J=13.4Hz, IH), 3.42(d, J=13.4Hz, IH), 3.01(d, J=I lHz, IH)5 2.55(m, IH), 2.44(s, 3H)5 2.41(s, 3H), 1.91-2.21(m, 3H), 1.51-1.82(m, 2H), 1.23(t, J=7.0Hz, 3H), 1.15(s, 3H), 1.21-1.38(m, IH)
Example 161: Preparation of 3-methyl-l-[3-[[5-methyl-2-(4-trifluoromethyl- phenyl)oxazol-4-yl]methoxy]benzyl]piperidine-3-carboxylic acid ethyl ester
Figure imgf000129_0001
The procedure of Step 1 of Example 159 was repeated except for using 4-[[3-(chloromethyl)phenoxy]methyl]-5-methyl-2-(4-trifluoromethylphenyl)oxazole (150 mg, 0.39 mmol) to obtain the title compound(123 mg, yield: 61%). 1U NMR(CDCl3, 200MHz): δ(ppm) 8.15(d, J=8.2Hz, 2H), 7.72(d, J=8.2Hz, 2H), 7.21-7.25(m, IH), 7.03(s, IH), 6.89-6.96(m, 2H), 5.02(s, 2H), 4.16(q, J=3.2Hz, 2H), 3.54(d, J=13.8Hz, IH), 3.41(d, J=13.4Hz, IH), 3.00(d, J=I lHz, IH)5 2.66-2.71(m, IH), 2.49(s, 3H), 1.93-2.32(m, 2H), 1.56-1.78(m, 3H)5 1.20-1.32(m, IH), 1.23(t, J=7.2Hz, 3H), 1.15(s, 3H)
Example 162: Preparation of 3-methyl-l-[3-[[5-methyl-2-(thiophen-2-yl)oxazol- 4-yl]methoxy] benzyl] piperidine-3-carboxyIic acid ethyl ester
Figure imgf000129_0002
The procedure of Step 1 of Example 159 was repeated except for using 4-[[3-(chloromethyl)phenoxy]methyl]-5-methyl-2-(thiophen-2-yl)oxazole(150 mg, 0.47 mmol) to obtain the title compound(94 mg, yield: 44%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.66(dd, J1=I^Hz5 J2=4.2Hz, IH)5 7.41(dd,
Figure imgf000129_0003
J2=4.2Hz5 IH), 7.19-7.28(m, IH), 7.10-7.12(m, lH),6.86-7.08(m, 3H), 4.98(s, 2H), 4.15(q, J=3.2Hz, 2H), 3.51(d, J=13.4Hz, IH), 3.40(d, J=13.4Hz, IH), 2.95(d, J=I lHz, IH), 2.47-2.50(m, IH), 2.43(s, 3H), 1.93-2.18(m, 2H), 1.62-1.72(m, 3H), 1.26(t, J=7.3Hz, 3H)5 1.19-1.30(m, IH), 1.14(s, 3H)
Example 163: Preparation of 3-ethyl-l-[3-[(5-methyl-2-phenyloxazol-4-yl) methoxy] benzyl] piperidine-3-carboxylic acid ethyl ester
Figure imgf000129_0004
The procedure of Step 1 of Example 159 was repeated except for using 4-[[3-(chloromethyl)phenoxy]methyl]-5-methyl-2-ρhenyloxazole(150 mg, 0.48 mmol) and 3-(ethoxycarbonyl)-3-ethylpiperidinium chloride(210 mg, 0.96 mmol) to obtain the title corapound(165 mg, yield: 74%).
1H NMR(CDCl3, 200MHz): δ(ppm) 8.02-8.07(m, 2H)5 7.44-7.49(m, 3H), 7.01-7.28(m, IH), 6.88-7.01(m, 3H), 5.01(s, 2H), 4.16(q, J=7Hz, 2H), 3.52(d, J=13.4Hz, IH), 3.40(d, J=13.4Hz, IH), 2.98(d, J=IlHz, IH), 2.48-2.60(m, IH), 2.46(s, 3H), 2.06-2.15(m, 2H), 1.98(d, J=I lHz, IH), 1.31-1.74(m, 4H), 1.23(t, J=7.4Hz, 3H), 1.15-1.28(m, IH), 0.79(t, J=7.4Hz, 3H)
Example 164: Preparation of 3-ethyl-l-[3-[(5-methyl-2-p-toIyloxazol-4-yl) methoxy] benzyl] piperidine-3-carboxylic acid ethyl ester
Figure imgf000130_0001
The procedure of Step 1 of Example 163 was repeated except for using 4-[[3-(chloromethyl)phenoxy]methyl]-5-methyl-2-p-tolyloxazole(150 mg, 0.46 mmol) to obtain the title compound(190 mg, yield: 86%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.92(d, J=82Hz, 2H), 7.25(d, J=8.2Hz, 2H), 7.01(s, IH), 6.88-6.95(m, 2H), 5.00(s, 2H), 4.15(q, J=3.2Hz, 2H), 3.52(d, J=13.4Hz, IH), 3.40(d, J=13.4Hz, IH), 2.98(d, J=I lHz, IH), 2.59-2.65(m, IH), 2.44(s, 3H), 2.41(s, 3H), 2.06-2.15(m, 2H), 1.98(d, J=I lHz, IH), 1.42-1.78(m, 4H), 1.20-1.31(m, IH), 1.23(t, J=7.4Hz, 3H), 0.79(t, J=7.2Hz, 3H)
Example 165: Preparation of 3-ethyl-l-[3-[[5-methyl-2-(4-trifluoromethyl- phenyl)oxazol-4-yl]methoxy]benzyl]piperidine-3-carboxylic acid ethyl ester
Figure imgf000130_0002
The procedure of Step 1 of Example 163 was repeated except for using 4-[[3-(chloromethyl)phenoxy]methyl]-5-methyl-2-(4-trifluoromethylphenyl)oxazole (150 mg, 0.39 mmol) to obtain the title compound(154 mg, yield: 74%). 1H NMR(CDCl3, 200MHz): δ(ppm) 8.13(d, J=8.2Hz, 2H), 7.69(d, J=8.2Hz, 2H), 7.22-7.26(m, IH), 6.86-7.00(m, 3H), 5.00(s, 2H), 4.13(q, J=7Hz, 2H), 3.48(d, J=13.4HZ, IH), 3.43(d, J=13.4Hz, IH), 2.95(d, J=I lHz, IH), 2.49-2.60(m, IH), 2.46(s, 3H), 2.04-2.15(m, 2H), 1.94(d, J=I lHz, IH), 1.36-1.75(m, 4H), 1.14-1.28(m, IH), 1.21(t, J=7.4Hz, 3H), 0.77(t, J=7.4Hz, 3H)
Example 166: Preparation of 3-ethyl-l-[3-[[5-methyl-2-(thiophen-2-yl)oxazol- 4-yl]methoxy] benzyl] piperidine-3-carboxyIic acid ethyl ester
Figure imgf000131_0001
The procedure of Step 1 of Example 163 was repeated except for using 4-[[3-(chloromethyl)phenoxy]methyl]-5-methyl-2-(thiophen-2-yl)oxazole(150 mg, 0.47 mmol) to obtain the title compound(66 mg, yield: 31%). 1H NMR(CDCl3, 200MHz): δ(ppm) 7.64(dd, J1=I^Hz, J2=4.2Hz, IH), 7.42(dd, Ji=I.2Hz, J2=4.2Hz, IH)5 7.19-7.28(m, IH), 7.08-7.19(m5 IH), 6.87-6.99(m, 3H), 4.98(s, 2H), 4.16(q, J=3.2Hz, 2H), 3.50(d, J=13.4Hz, IH), 3.40(d, J=13.4Hz, IH), 2.98(d, J=I lHz, IH), 2.59-2.64(m, IH), 2.43(s, 3H), 2.08-2.16(m, 2H), 1.98(d, J=I lHz, IH), 1.42-1.76(m, 4H), 1.23-1.38(m, IH), 1.25(t, J=7.0Hz, 3H), 0.81(t, J=7.2Hz, 3H)
Example 167: Preparation of 3-methyl-l-[4-[(5-methyl-2-phenyloxazol-4-yl) methoxy] benzyl] piperidine-3-carboxylic acid ethyl ester
Figure imgf000131_0002
The procedure of Step 1 of Example 159 was repeated except for using 4-[[4-(chloromethyl)phenoxy]methyl]-5-methyl-2-phenyloxazole(150 mg, 0.48 mmol) to obtain the title compound(154 mg, yield: 72%).
1H NMR(CDCl3, 200MHz): δ(pρm) 8.00-8.04(m, 2H), 7.39-7.46(m,3H), 7.22(d, J=8.2Hz, 2H)9 6.95(d, J=8.2Hz, 2H), 4.98(s, 2H), 4.13(q, J=3.2Hz, 2H), 3.49(d, J=13.4Hz, IH), 3.33(d, J=13.4Hz, IH), 2.90(d, J=I lHz, IH), 2.42(s, 3H), 1.80-2.00(m, 3H), 1.57-1.69(m, 2H), 1.24(t, J=7.0Hz, 3H), l.l(d, J=I lHz, IH), l.l l(s, 3H)
Example 168: Preparation of 3-methyl-l-[4-[(5-methyl-2-/7-tolyloxazol-4-yl) methoxy] benzyl] piperidine-3-carboxylic acid ethyl ester
Figure imgf000132_0001
The procedure of Step 1 of Example 159 was repeated except for using 4-[[4-(chloromethyl)phenoxy]methyl]-5-methyl-2-j!7-tolyloxazole(l 50 mg, 0.46 mmol) to obtain the title compound(152 mg, yield: 70%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.92(d, J=8.2Hz, 2H), 7.21-7.32(m, 4H), 6.98(d, J=8.2Hz, 2H), 5.99(s, 2H), 4.15(q, J=3.2Hz, 2H), 3.50(d, J= 13.4Hz, IH), 3.35(d, J=13.4Hz, IH), 2.98(d, J=I lHz, IH), 2.50-2.63(m, IH), 2.44(s, 3H), 2.41(s, 3H), 1.89-2.37(m, 2H), 1.60-1.89(m, 3H), 1.23(t, J=7.0Hz, 3H), 1.14(s, 3H), 1.21- 1.38(m, IH)
Example 169: Preparation of 3-methyl-l-[4-[[5-methyl-2-(4-trifluoromethyl- phenyI)oxazol-4-yl]methoxy]benzyl]piperidine-3-carboxylic acid ethyl ester
Figure imgf000132_0002
The procedure of Step 1 of Example 159 was repeated except for using 4-[[4-(chloromethyl)phenoxy]methyl]-5-methyl-2-(4-trifluoromethylphenyl)oxazole (150 mg, 0.39 mmol) to obtain the title comρound(94 mg, yield: 48%). 1H NMR(CDCl3, 200MHz): δ(ppm) 8.15(d, J=8.2Hz, 2H), 7.72(d, J=8.2Hz, 2H), 7.25(d, J=8.2Hz, 2H), 6.97(d, J=8.2Hz, 2H), 5.02(s, 2H), 4.16(q, J=3.2Hz, 2H), 3.50(d, J=13.8Hz, IH), 3.35(d, J=13.4Hz, IH), 2.97(d, J=I lHz, IH), 2.58-2.63(m, IH), 2.48(s, 3H), 1.78-2.07(m, 2H), 1.56-1.76(m, 3H), 1.14-1.53(m, IH), 1.24(t, J=7.2Hz, 3H), 1.14(s, 3H)
Example 170: Preparation of 3-methyl-l-[4-[[5-methyl-2-(thiophen-2-yl)oxazol- 4-yl]methoxy]benzyl]piperidine-3-carboxylic acid ethyl ester
Figure imgf000132_0003
The procedure of Step 1 of Example 159 was repeated except for using 4-[[4-(chloromethyl)phenoxy]methyl]-5-methyl-2-(thiophen-2-yl)oxazole(150 mg, 0.47 mmol) to obtain the title compound(98 mg, yield: 46%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.65(dd, J1=LaHz, J2=4.2Hz, IH), 7.42(dd, Ji=L 2Hz, J2=4.2Hz, IH), 7.23(d, J=8.6Hz, 2H), 7.09-7.13(m, IH), 6.95(d, J=8.6Hz, 2H), 4.97(s, 2H), 4.13(q, J=3.2Hz, 2H), 3.50(d5 J=13.4Hz, IH), 3.35(d, J=13.4Hz, IH), 2.96(d, J=I lHz, IH), 2.57-2.63(m, IH), 2.42(s, 3H), 1.88-2.14(m, 2H), 1.57-1.76(m, 3H), 1.22(t, J=7.3Hz, 3H)5 1.19-1.32(m, IH), 1.13(s, 3H)
Example 171: Preparation of 3-ethyl-l-[4-[(5-methyl-2-phenyloxazol~4-yI) methoxy] benzyl] piperidine-3-carboxylic acid ethyl ester
Figure imgf000133_0001
The procedure of Step 1 of Example 163 was repeated except for using 4-[[4-(chloromethyl)phenoxy]methyl]-5-methyl-2-phenyloxazole(150 mg, 0.48 mmol) to obtain the title compound(147 mg, yield: 66%).
1H NMR(CDCl3, 200MHz): δ(ppm) 8.01-8.06(m, 2H), 7.43-7.48(m, 3H), 7.23(d, J=8.2Hz, 2H), 6.94(d, J=8.2Hz, 2H), 5.00(s, 2H), 4.16(q, J=7Hz, 2H), 3.48(d, J=13.4Hz, IH), 3.35(d, J=13.4Hz, IH), 2.96(d, J-I lHz, IH), 2.46-2.63(m, IH), 2.44(s, 3H), 2.04-2.12(m, 2H), 1.93(d, J=I lHz, IH), 1.44-1.74(m, 4H), 1.23(t, J=7.4Hz, 3H), 1.20-1.3 l(m, IH), 0.78(t, J=7.4Hz, 3H)
Example 172: Preparation of 3-ethyl-l-[4-[(5-methyl-2-jp-tolyloxazol-4-yl) methoxy]benzyl]piperidine-3-carboxylic acid ethyl ester
Figure imgf000133_0002
The procedure of Step 1 of Example 163 was repeated except for 4-[[4-(chloromethyl)phenoxy]methyl]-5-methyl-2-/>-tolyloxazole(l 50 mg, 0.46 mmol) to obtain the title compound(175 mg, yield: 80%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.92(d, J=8.2Hz, 2H), 7.21-7.28(m, 4H), 6.95(d, J=8.2Hz, 2H)5 4.99(s, 2H)5 4.15(q, J=3.2Hz, 2H), 3.49(d, J=13.4Hz, IH), 3.35(d, J=13.4Hz, IH), 2.90-2.99(m, IH)5 2.60-2.65(m5 IH), 2.43(s, 3H)5 2.41(s5 3H)5 2.04-2.14(m, 2H), 1.93(d, J=I lHz5 IH), 1.28-1.72(m, 4H)5 1.23 (t, J=7.0Hz, 3H), 1.19-1.28(m, IH), 0.78(t, J=7.2Hz, 3H)
Example 173: Preparation of 3-ethyl-l-[4-[[5-methyl-2-(4-trifluoromethyl- phenyi)oxazol-4~yLJmethoxy]benzyl]piperidine-3-carboxylic acid ethyl ester
Figure imgf000134_0001
The procedure of Step 1 of Example 163 was repeated except for using 4-[[4-(chloromethyl)ρhenoxy]methyl]-5-methyl-2-(4-trifluoromethylphenyl)oxazole (150 mg, 0.39 mmol) to obtain the title compound(192 mg, yield: 93%). 1H NMR(CDCl3, 200MHz): δ(ppm) 8.14(d, J=8.2Hz, 2H), 7.71(d, J=8.2Hz, 2H), 7.24(d, J=8.2Hz, 2H), 6.96(d, J=8.2Hz, 2H)5 5.01(s, 2H), 4.16(q, J=7Hz, 2H), 3.48(d, J=13.4HZ, IH), 3.36(d, J=13.4Hz, IH), 2.96(d, J=I lHz, IH), 2.59-2.65(m, IH), 2.47(s, 3H), 2.02-2.15(m, 2H), 1.94(d, J=I lHz, IH), 1.37-1.78(m, 4H), 1.23(t, J=7.4Hz, 3H), 1.08-1.33(m, IH), 0.78(t, J=7.4Hz, 3H)
Example 174: Preparation of 3-ethyl-l-[4-[[5-methyl-2-(thiophen-2-yl)oxazol- 4-yl]methoxy]benzyl]piperidine-3-carboxylic acid ethyl ester
Figure imgf000134_0002
The procedure of Step 1 of Example 163 was repeated except for using 4-[[4-(chloromethyl)phenoxy]methyl]-5-methyl-2-(thiophen-2-yl)oxazole(150 mg, 0.47 mmol) to obtain the title compound(165 mg, yield: 75%). 1H NMR(CDCl3, 200MHz): δ(ppm) 7.63(dd, J1=I.2Hz, J2=4.2Hz, IH), 7.41(dd, Ji=I .2Hz, J2=4.2Hz, IH), 7.22(d, J=8.2Hz, 2H), 7.10(dd, J1=SHz, J2=3.7Hz, IH), 6.94(d, J=8.2Hz, 2H), 4.92(s, 2H), 4.15(q, J=3.2Hz, 2H), 3.48(d, J=13.4Hz, IH), 3.38(d, J=13.4Hz, IH), 3.12(d, J=I lHz, IH), 2.59-2.65(m, IH), 2.42(s, 3H), 2.02-2.12(m, 2H), 1.93(d, J=I lHz, IH), 1.30-1.75(m, 4H), 1.22(t, J=7.0Hz, 3H), 1.17-1.28(m, IH), 0.77(t, J=7.4Hz, 3H)
Example 175: Preparation of 3-methyl-l-[3-[2-(5-methyl-2-p-toIyloxazol-4-yl) ethoxy] benzyl] piperidine-3-carboxylic acid ethyl ester
Figure imgf000135_0001
The procedure of Step 1 of Example 159 was repeated except for 4-[2-[3-(chloromethyl)phenoxy]ethyl]-5-methyl-2-/7-tolyloxazole(l 50 mg, 0.44 mmol) to obtain the title compound(76 mg, yield: 36%).
1U NMR(CDCl3, 200MHz): δ(ppm) 7.88(d, J=8.2Hz, 2H), 7.25(d J=8.2Hz, 2H), 7.20-7.27(m, IH), 6.78-6.95(m, 3H), 4.25(t, J=6.4Hz, 2H), 4.00-4.25(m, 2H), 3.52(d, J=13.4Hz, IH), 3.28(d, J=13.4Hz, IH), 2.99(t, J=6.4Hz, 2H), 2.89-3.01(m, IH), 2.53-2.65(m, IH), 2.40(, 3H), 2.39(s, 3H), 1.85-2.20(m, 4H), 1.45-1.83(m, 2H), 1.20(1, J=7.2Hz, 3H), 1.14(s, 3H)
Example 176: Preparation of 3-methyl-l-[3-[2-[5-methyl-2-(4-trifluoromethyl- phenyl)oxazol-4-yl]ethoxy]benzyl)piperidine-3-carboxylic acid ethyl ester
Figure imgf000135_0002
The procedure of Step 1 of Example 159 was repeated except for using 4-[2-[3-(chloromethyl)phenoxy]ethyl]-5-methyl-2-(4-trifluoromethylphenyl)oxazole (150 mg, 0.38 mmol) to obtain the title compound(152 mg, yield: 78%). 1U NMR(CDCl3, 200MHz): δ(ppm) 8.10(d, J=8.2Hz, 2H), 7.70(d, J=8.2Hz, 2H), 7.16-7.28(m, IH), 6.76-6.91(m, 3H), 4.26(t, J=6.4Hz, 2H), 4.08-4.15(m, 2H), 3.50(d, J=13.4Hz, IH), 3.37(d5 J=13.4Hz, IH), 3.00(t, J=6.6Hz, 2H), 2.94-3.00(m, IH), 2.56-2.61(m, IH) 2.42(s, 3H), 1.78-2.16(m, 4H), 1.55-1.76(m, 2H), 1.20(t, J=7.2Hz, 3H), 1.14(s, 3H)
Example 177: Preparation of 3-methyl-l-[3-[2-[5-methyl-2-(thiophen-2-yl) oxazol-4-yl]ethoxy] benzyl] piperidine-3-carboxyIic acid ethyl ester
Figure imgf000135_0003
The procedure of Step 1 of Example 159 was repeated except for using 4-[2-[3-(chloromethyl)phenoxy]ethyl]-5-methyl-2-(thiophen-2-yl)oxazole(150 mg, 0.45 mmol) to obtain the title compound(148 mg, yield: 70%). 1U NMR(CDCl3, 200MHz): δ(ppm) 7.58-7.60(m, IH), 7.36-7.38(m, IH), 7.06-7.28(m, 2H), 6.86-6.89(m, 2H)3 6.78(d, J=8.2Hz, 2H)5 4.23(t, J=6.4Hz5 2H), 4.06-4.15(m, 2H)5 3.50(d, J=13.4Hz, IH)5 3.36(d, J=13.4Hz, IH)5 2.97(t, J=6.4Hz5 2H)5 2.93-2.99(m IH)5 2.56-2.61(m, IH), 2.37(s, 3H)5 1.91-2.1 l(m, 3H), 1.57-1.78(m, 2H)5 1.16-1.28(m, IH)5 1.20(t, J=7.2Hz, 3H), 1.14(s, 3H)
Example 178: Preparation of 3-ethyl-l-[3-[2-(5-methyl-2-p-tolyloxazol-4-yl) ethoxy]benzyl]piperidine-3-carboxylic acid ethyl ester
Figure imgf000136_0001
The procedure of Step 1 of Example 163 was repeated except for using 4-[2-[3-(chloromethyl)phenoxy]ethyl]-5-methyl-2-p-tolyloxazole(l 50 mg, 0.44 mmol) to obtain the title compound(196 mg, yield: 91%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.88(d, J=8.2Hz, 2H)5 7.16-7.28(m, 3H)5 6.77-6.89(m5 3H)5 4.25(t, J=6.4Hz, 2H)5 4.07-4.19(m, 2H)5 3.48(d5 J=13.4Hz5 IH)5 3.36(d5 J-13.4Hz, IH)5 2.99(t5 J=6.4Hz, 2H), 2.59-3.02(m, IH), 2.40(s, 3H), 2.38(s, 3H), 1.92-2.15(m, 3H)5 1.31-1.79(m, 4H), 0.87-1.28(m, 5H), 0.78(t, J=7.6Hz, 3H)
Example 179: Preparation of 3-ethyl-l-[3-[2-[5-methyI-2-(4-trifluoromethyl- phenyl)oxazol-4-yl]ethoxy]benzyl]piperidine-3-carboxylic acid ethyl ester
Figure imgf000136_0002
The procedure of Step 1 of Example 163 was repeated except for using
4-[2-[3-(chloromethyl)phenoxy]ethyl]-5-methyl-2-(4-trifluoromethylphenyl)oxazole (150 mg, 0.38 mmol) to obtain the title comρound(178 mg, yield: 86%). 1H NMR(CDCl3, 200MHz): δ(ppm) 8.10(d, J=8.2Hz, 2H)5 7.70(d, J=8.2Hz, 2H), 7.16-7.29(m, IH)5 6.77-7.16(m, 3H)5 4.26(t5 J=6.4Hz, 2H), 4.09-4.18(m, 2H), 3.49(d, J=13.4Hz, IH)5 3.38(d, J=13.4Hz, IH)5 3.00(t, J=6.6Hz5 2H)5 2.80-3.00(m5 IH), 2.59-2.80(m, IH) 2.42(s, 3H)5 1.78-2.15(m, 4H), 1.41-1.72(m, 2H), 1.16-1.31(m, 5H)5 0.78(t, J=7.4 Hz5 3H)
Example 180: Preparation of 3-ethyl-l-[3-[2-[5-methyl-2-(thiophen-2-yl)oxazol- 4-yl]ethoxy]benzyl]piperidine-3-carboxylic acid ethyl ester
Figure imgf000137_0001
The procedure of Step 1 of Example 163 was repeated except for using 4-[2- [3 -(chloromethyl)phenoxy] ethyl] -5 -methyl-2-(thiophen-2-yl)oxazole( 150 mg, 0.45 mmol) to obtain the title compound(158 mg, yield: 73%). 1H NMR(CDCl3, 200MHz): δ(ppm) 7.58-7.61(m, IH), 7.28-7.39(m, IH), 7.06-7.28(m, 2H), 6.75-6.89(m, 3H), 4.23(t, J=6.4Hz, 2H), 4.10-4.20(m, 2H), 3.50(d, J=13.4Hz, IH), 3.35(d5 J=I 3.4Hz, IH)5 2.97(t, J=6.4Hz, 2H), 2.90-2.97(m IH), 2.59-2.90(m, IH), 2.37(s, 3H), 1.92-2.14(m, 3H), 1.44-1.79(m, 3H), 1.08-1.30(m, 5H), 0.78(t, J=7.6Hz, 3H)
Example 181: Preparation of 3-methyI-l-[4-[2-(5-methyl-2-phenyIoxazol-4-yI) ethoxy]benzyl]piperidine-3-carboxyIic acid ethyl ester
Figure imgf000137_0002
The procedure of Step 1 of Example 159 was repeated except for using 4-[2-[4-(chloromethyl)phenoxy]ethyl]-5-methyl-2-p-tolyloxazole(l 50 mg, 0.46 mmol) to obtain the title compound(150 mg, yield: 66%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.97-8.02(m, 2H), 7.42-7.47(m, 3H), 7.20(d, J=8.6Hz, 2H), 6.85(d, J=8.6Hz, 2H), 4.24(t, J=6.4Hz, 2H) 4.07-4.20(m, 2H), 3.48(d, J=13.4Hz, IH)5 3.35(d, J=13.4Hz, IH)5 2.99(t," J=6.4Hz, 2H)5 2.95-3.00(m, IH), 2.58-2.99(m, IH)5 2.39(s, 3H), 1.51-2.13(m, 5H), 1.18-1.27(m, IH)5 1.22(t, J=7.4Hz, 3H)5 1.12(s, 3H)
Example 182: Preparation of 3-methyl-l-[4-[2-[5-methyI-2-(4-trifluoromethyl- phenyl)oxazol-4-yl]ethoxy] benzyl] piperidine-3-carboxylic acid ethyl ester
Figure imgf000137_0003
The procedure of Step 1 of Example 159 was repeated except for using 4-[2-[4-(chloromethyl)phenoxy]ethyl]-5-methyl-2-j3-tolyloxazole(150 mg, 0.38 mmol) to obtain the title compound(171 mg, yield: 85%).
1H NMR(CDCl35 200MHZ): δ(ppm) 8.10(d, J=8.2Hz, 2H), 7.70(d, J=8.2Hz, 2H), 7.20(d, J=8.2Hz, 2H)5 6.85(d, J=8.2Hz, 2H), 4.25(t, J=6.4Hz, 2H), 4.11-4.19(m, 2H), 3.49(d, J=13.4Hz, IH)5 3.35(d, J=13,.4Hz, IH), 3.00(t, J=6.4Hz, 2H), 2.97-3.00(m, IH), 2.56-2.93(m, IH), 2.42(s, 3H), 1.54-2.09(m, 5H), 1.25-1.54(m, IH), 1.23(t, J=7.4Hz, 3H), 1.12(s, 3H)
Example 183: Preparation of 3-methyl-l-[4-[2-[5-methyl-2-(thiophen-2-yl) oxazol-4-yl]ethoxy] benzyl] piperidine-3-carboxylic acid ethyl ester
Figure imgf000138_0001
The procedure of Step 1 of Example 159 was repeated except for using 4-[2-[4-(chloromethyl)phenoxy]ethyl]-5-methyl-2-(thiophen-2-yl)oxazole(150 mg, 0.45 mmol) to obtain the title compound(130 mg, yield: 67%). 1H NMR(CDCl3, 200MHz): δ(ppm) 7.58-7.60(m, IH), 7.28-7.39(m, IH), 7.22(d, J=8.6Hz, 2H), 7.09(dd, Ji=3.6Hz, J2=5.6Hz, IH), 6.84(d, J=8.2Hz, 2H), 4.22(t, J=6.4Hz, 2H), 4.11-4.16(m, 2H), 3.48(d, J=13.4Hz, IH), 3.33(d, J=13.4Hz, IH), 2.96(t, J-6.4Hz, 2H),2.93-3.00(m, IH), 2.56-2.61(m, IH), 2.37(s, 3H), 1.54-2.13(m, 6H), 1.22(t, J=7.0Hz, 3H), 1.12(s, 3H)
Example 184: Preparation of 3-ethyl-l-[4-[2-(5-methyl-2-phenyloxazol-4-yl) ethoxy] benzyl] piperidine-3-carboxylic acid ethyl ester
Figure imgf000138_0002
The procedure of Step 1 of Example 163 was repeated except for using 4-[2-[4-(chloromethyl)phenoxy]ethyl]-5-methyl-2-phenyloxazole(l 50 mg, 0.46 mmol) to obtain the title compound(137 mg, yield: 63%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.97-8.02(m, 2H), 7.28-7.47(m, 3H), 7.20(d, J-8.6Hz, 2H), 6.85(d, J=8.6Hz, 2H), 4.27(t, J=6.4Hz, 2H) 4.15(q, J=7.0Hz, 2H), 3.45(d, J=13.4Hz, IH), 3.34(d, J=13.4Hz, IH), 2.99(t, J=6.4Hz, 2H), 2.93-2.99(m, IH), 2.42-2.64(m, IH), 2.39(s, 3H), 2.06-2.14(m, 2H), 1.89-1.95(m, IH), 1.53-1.71(m, 3H), 1.31-1.47(m, IH), 1.23(t, J=7.0Hz, 3H), 1.12-1.23(m, IH), 0.77(t, J=7.2Hz, 3H)
Example 185: Preparation of 3-ethyl-l-[4-[2-[5-methoxy-2-(4-trifluoromethyl- phenyl)oxazol-4-yl] ethoxy] benzyl] piperidine-3-carboxylic acid ethyl ester
Figure imgf000139_0001
The procedure of Step 1 of Example 163 was repeated except for using 4-[2-[4-(chloromethyl)phenoxy]ethyl]-5-methyl-2-(4-trifluoromethylphenyl)oxazole (150 mg, 0.38 mmol) to obtain the title compound(169 mg, yield: 82%). 1H NMR(CDCl3, 200MHz): δ(ppm) 8.10(d, J=8.2Hz, 2H), 7.70(d, J=8.2Hz, 2H), 7.26(d5 J=8.2Hz, 2H), 6.85(d, J=8.2Hz, 2H), 4.25(t, J=6.4Hz, 2H), 4.07-4.19(m, 2H), 3.46(d, J=13.4Hz, IH), 3.35(d, J=13,.4Hz, IH), 3.00(t, J=6.4Hz, 2H), 2.90-3.00(m, IH), 2.58-2.63(m, IH), 2.42(s, 3H), 1.90-2.1 l(m, 3H), 1.32-1.77(m, 4H), 1.23(t, J=7.2Hz, 3H), 1.12-1.27(m, IH), 0.72(t, J=7.4Hz, 3H)
Example 186: Preparation of 3-ethyl-l-[4-[2-[5-methyI-2-(thiophen-2-yl) oxazol-4-yl]ethoxy] benzyl] piperidine-3-carboxylic acid ethyl ester
Figure imgf000139_0002
The procedure of Step 1 of Example 163 was repeated except for using 4- [2- [4-(chloromethyl)phenoxy] ethyl] -5 -methy l-2-(thiophen-2-yl)oxazole( 150 mg, 0.45 mmol) to obtain the title compound(200 mg, yield: 92%). 1H NMR(CDCl3, 200MHz): δ(ppm) 7.39-7.60(m, IH), 7.36-7.39(m, IH), 7.20(d, J=8.2Hz, 2H), 7.07-7.12(m, IH), 6.84(d, J=8.2Hz, 2H), 4.22(t, J=6.4Hz, 2H), 4.07-4.18(m, 2H), 4.26(d, J=13.4Hz, IH), 3.33(d, J=13.4Hz, IH), 2.97(t, J=6.4Hz, 2H), 2.93-3.00(m, IH), 2.58-2.63(m, IH), 2.37(s, 3H), 1.82-2.1 l(m, 3H), 1.28-1.75(m, 3H), 1.23(t, J=7.2Hz, 3H), 1.13-1.26(m, 2H), 0.77 (t, J=7.2Hz, 3H)
Example 187: Preparation of (R)-I- [4-(2-phenyl-oxazol-4-ylmethoxy)-benzyI]~ pyrrolidine-2-carboxylic acid
Figure imgf000139_0003
Step 1 : Preparation of 4-(2-phenyl-oxazol-4-ylmethoxy)-benzaldehyde
4-Chloromethyl-2-phenyl-oxazole(l g, 5.16 mmol), 4-hydroxy benzaldehyde(0.76 g, 6.19 mmol) and K2CO3(1.07 g, 7.74 mmol) were dissolved in dimethylformamide(30 ml). The resulting mixture was stirred at 90 °C for 3 hrs, and the reaction product was neutralized with an aqueous 1 N HCl. The resultant was extracted with dichloromethane. The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography(eluent: hexane/ethyl acetate^/l) to obtain the title compound(1.05 g, yield: 77%). 1H NMR(CDCl3, 200MHz): δ(ppm) 9.93(1H, s), 8.08(2H, m), 7.89(2H, d, J=8.4Hz), 7.8O(1H, s), 7.50(3H, m), 7.16(2H, d, J=8.4Hz), 5.19(2H, s)
Step 2: Preparation of [4-(2-phenyl-oxazol-4-ylmethoxy)-phenyl]-methanol
The compound obtained in Step 1 of Example 187(1.05 g, 3.76 mmol) and NaBH4(11.28 mmol) were dissolved in methanol(30 ml). The resulting mixture was stirred at room temperature for 1 hr. After the completion of the reaction, 20 ml of water was poured to the reaction product. The resulting mixture was neutralized with an aqueous IN HCl, and the resultant was extracted with dichloromethane. The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography (eluent: hexane/ethyl acetate^θ/l) to obtain the title compound(1.0 g, yield: 80%).
1H NMR(CDCl3, 200MHz): δ(ppm) 8.09(2H, m), 7.76(1H, s), 7.49(3H, m), 7.34(2H, d, J=8.6Hz), 7.3O(1H, s), 7.03(2H, d, J=8.6Hz), 5.11(2H, s), 4.67(2H, d, J=5.6Hz), 1.60(lH, t)
Step 3: Preparation of 4-(4-chloromethyl-phenoxymethyl)~2-phenyl-oxazole
The compound obtained in Step 2 of Example 187(1.0 g, 3.56 mmol), methanesulfonylchloride(0.45 g, 3.91 mmol) and triethylamine(1.08 g, 10.68 mmol) were dissolved in dichloromethane. The resulting mixture was stirred at room temperature for 3 hrs. After the competion of the reaction, 20 ml of water was poured to the reaction product. The resultant was extracted with dichloromethane.
The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue thus obtained was subjected to a a silica gel column chromatography(eluent: hexane/ethyl acetate=5/l) to obtain the title comρound(0.39 g, yield: 37%).
1H NMR(CDCl3, 200MHz): δ(ppm) 8.08(2H, m), 7.77(1H, s), 7.49(3H, m), 7.37(2H, d, J=8.6Hz), 7.02(2H, d, J=8.6Hz), 5.12(2H, s), 4.60(2H, s)
Step 4: Preparation of l-[4-(2-phenyl-oxazol-4-ylmethoxy)-benzyl]-pyrrolidine- 2-carboxylic acid methyl ester
The compound obtained in Step 3 of Example 187(100 mg, 0.33 mmol), D-proline methyl ester • HC1(6O mg, 0.37 mmol) and K2CO3(2.5 eq) were dissolved in dimethylformamide(10 ml). The resulting mixture was stirred at 85 °C for 2 days, and then, the reaction product was neutralized with an aqueous 1 N HCl. The resultant was extracted with dichloromethane. The organic layer was separated, dried and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography(eluent: hexane/ethyl acetate=5/l) to obtain the title compound(49 mg, yield: 38 %). 1H NMR(CDCl3, 200MHz): δ(ppm) 8.10(2H, m), 7.76(1H, s), 7.50(3H, m), 7.30(2H, m), 7.00(2H, m), 5.09(2H5 s), 3.85(1H, m), 3.67(3H5 s), 3.54(1H5 m), 3.30(1H5 m), 3.10(1H5 m), 2.50-1.80(5H5 m)
Step 5: Preparation of l-[4-(2-phenyl-oxazol-4-methoxy)-benzyl]-pyrrolidine- 2-carboxylic acid The compound obtained in Step 4 of Example 187(50 mg, 0.13 mmol) and
LiOH • H2O(1.5 eq) were dissolved in H2O/MeOH(l :55 1 ml). The resulting mixture was stirred at room temperature for 2 days. The reaction product was neutralized with an aqueous 1 N HCl5 and then, the resultant was extracted with dichloromethane. The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue thus obtained was recrystallized from methylene chloride to obtain the title compound(22 mg, yield: 42%).
1H NMR(CDCl3, 200MHz): δ(ppm) 8.08(3H, m), 7.56-7.48(5H, m), 7.16(2H, m), 5.12(2H,s), 4.45(1H, m), 4.2O(1H, m), 4.40-3.80(1H, m), 3.62-3.40(1H5 m), 3.30-3.18(1H, m), 2.60-2.40(1H5 m), 2.20-1.80(3H5 m)
Example 188: Preparation of (R)-I- [4-(2-jp-tolyl-oxazol-4-ylmethoxy)-benzyl]- pyrrolidine-2-carboxylic acid
Figure imgf000141_0001
Step 1: Preparation of 4-(2-p-tolyl-oxazol-4-ylmethoxy)-benzaldehyde
(4-Chloromethyl)-2-p-tolyl-oxazole(l g, 54.81 mmol), 4-hydroxy benzaldehyde(0.65 g, 5.30 mmol) and K2CO3(LOO g) were dissolved in dimethylformamide(30 ml). The resulting mixture was stirred at 90 °C for 3 hrs and the reaction product was neutralized with an aqueous 1 N HCl. Then, the resultant was extracted with dichloromethane. The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography(eluent: hexane/ethyl acetate=5/l) to obtain the title compound(0.81 g, yield: 57%). 1H NMR(CDCl35 200MHz): δ(ppm) 9.93(1H, s), 8.08(2H, m), 7.89(2H, d, J=8.4Hz)5 7.8O(1H, s), 7.50(2H, m), 7.16(2H5 d, J=8.4Hz)5 5.19(2H5 s), 2.43(3H5 s) Step 2: Preparation of [4-(2-p-tolyl-oxazol-4-ylmethoxy)-phenyl]-methanol
The compound obtained in Step 1 of Example 188(0.81 g, 2.76 mmol) and
NaBH4(8.29 mmol) were dissolved in methanol(30 ml). The resulting mixture was stirred at room temperature for 1 hr. After the completion of the reaction, 20 ml of water was poured to the reaction product. The resulting mixture was neutralized with an aqueous 1 N HCl and the resultant was extracted with dichloromethane.
The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography(eluent: hexane/ethyl acetate=5/l) to obtain the title compound(0.56 g, yield: 70%).
1H NMR(CDCl3, 200MHz): δ(ρρm) 8.08(2H, m), 7.77(1H5 s), 7.49(2H, m), 7.37(2H, d, J=8.6Hz), 7.02(2H, d, J=8.6Hz), 5.12(2H, s), 4.60(2H, s), 2.42(3H, s)
Step 3: Preparation of 4-(4-chloromethyl-phenoxymethyl)-2-p-toryl-oxazole The compound obtained in Step 2 of Example 188(0.56 g, 1.09 mmol), methanesulfonylchloride(2.10 mmol) and triethylamine(5.70 mmol) were dissolved in dichloromethane(20 ml). The resulting mixture was stirred at room temperature for 3 hrs. After the completion of the reaction, 20 ml of water was poured to the reaction product. The resultant was extracted with dichloromethane. The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography(eluent: hexane/ethyl acetate=5/l) to obtain the title compound(0.38 g, yield: 64%).
1H NMR(CDCl3, 200MHz): δ(ppm) 8.08(2H, m), 7.77(1H, s), 7.49(3H, m), 7.37(2H, d, J=8.6Hz), 7.02(2H, d, J=8.6Hz), 5.12(2H, s), 4.60(2H, s), 2.36(3H, s)
Step 4: Preparation of l-[4-(2-/>-tolyl-oxazol-4-ylmethoxy)-benzyl]-pyrrolidine- 2-carboxylic acid methyl ester
The compound obtained in Step 3 of Example 188(100 mg, 0.33 mmol), D-proline methyl ester • HC1(6O mmg, 0.37 mmol) and K2CO3(2.5 eq) were dissolved in dimethylformamide(10 ml). The resulting mixture was stirred at 85 °C for 2 days. The reaction product was neutralized with an aqueous 1 N HCl, and the resultant was extracted with dichloromethane. The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography (eluent: hexane/ethyl acetate=5/l) to obtain the title compound(50 mg, yield: 35 %). 1B. NMR(CDCl3, 200MHz): δ(ppm) 7.98(2H, m), 7.94(1H5 s), 7.31-7.26(4H, m), 6.98(2H5 m), 5.08(2H, s), 3.9O-3.75(1H, m), 3.67(3H5 s), 3.60-3.50(1H5 m), 3.25(1H5 m), 3.10(1H5 m), 2.43(3H5 s), 2.20-1.80(5H5 m) Step 5: Preparation of l-[4-(2-p-tolyl-oxazol-4-ylmethoxy)-benzyl]-pyrrolidine- 2-carboxylic acid
The compound obtained in Step 4 of Example 188 (45 mg, 0.32 mmol) and
LiOH-H2O(1.5 eq) were dissolved in H2O/MeOH(l :5(v/v%), 1 ml). The resulting mixture was stirred at room temperature for 2 days. The reaction product was neutralized with an aqueous 1 N HCl, and the resultant was extracted with dichloromethane. The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue thus obtained was recrystallized from methylene chloride to obtain the title compound(20 mg, yield: 47%).
1H NMR(CDCl3, 200MHz): δ(ppm) 8.03(1H, s), 7.93(2H, m), 7.50(2H, m), 7.35(2H, m), 7.15(2H, m), 5.11(2H, s), 4.5O(1H, m), 4.36(1H5 m), 4.1O(1H, m)3.55(lH, m), 3.30(1H5 m), 2.55(1H, m), 2.20-1.80(3H, m)
Example 189: Preparation of (R)-l-[4-[2-(4-trifluoromethylphenyl)-oxazol- 4-ylmethoxy]-benzyl]-pyrrolidine-2-carboxylic acid
Figure imgf000143_0001
Step 1: Preparation of 4-[2-(4-trifluoromethylphenyl)-oxazol-4-ylmethoxy]- benzaldehyde 4-Chloromethyl-2-(4-trifluoromethyl-phenyl)-oxazole(l g, 3.80 mmol),
4-hydroxy benzaldehyde(4.20 mmol) and K2CO3(5.7 mmol) were dissolved in dimethylformamide(30 ml). The resulting mixture was stirred at 90 °C for 3 hrs.
The reaction mixture was neutralized with an aqueous 1 N HCl, and the resultant was extracted with dichloromethane. The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography(eluent: hexane/ethyl acetate=5/l) to obtain the title comρound(0.79 g, yield: 60%).
1H NMR(CDCl3, 200MHz): δ(ppm) 9.94(1H, s) 8.20(2H, d), 7.92-7.75(5H3 m),
7.16(2H, t), 5.20(2H, s)
Step 2: Preparation of [4-[2-(4-trifluoromethylphenyl)-oxazol-4-ylmethoxy]- phenyl] -methanol
The compound obtained in Step 1 of Example 189(0.79 g, 2.31 mmol) and
NaBH4(6.93 mmol) were dissolved in methanol(30 ml). The resulting mixture was stirred at room temperature for 1 hr. After the completion of the reaction, 20 ml of water was poured to the reaction product. The resulting mixture was neutralized with an aqueous 1 N HCl and the resultant was extracted with dichloromethane. The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography(eluent: hexane/ethyl acetate=5/l) to obtain the title compound(0.60 g, yield: 74%).
Step 3: Preparation of 4-(4-chloromethyl-phenoxymethyl)-2-(4- trifluoromethylphenyl)-oxazole
The compound obtained in Step 2 of Example 189(0.60 g, 1.72 mmol), methanesulfonylchloride(1.90 mmol) and triethylamine(5.16 mmol) were dissolved in dichloromethane(2 ml). The resulting mixture was stirred at room temperature for 3 hrs. After the completion of the reaction, 20 ml of water was poured to the reaction product. The resulting mixture was neutralized with an aqueous 1 N HCl and the resultant was extracted with dichloromethane. The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography(eluent: hexane/ethyl acetate^/l) to obtain the title compound(0.21 g, yield: 37%). 1H NMR(CDCl3, 200MHz): δ(ppm) 8.17(2H, d, J=8.14Hz), 7.79(1H, s), 7.73(2H, d, J=8.14Hz), 7.34(2H, d, J=8.55Hz), 7.00(2H, d, J=8.55Hz), 5.10(2H, s), 4.57(2H, s)
Step 4: Preparation of l-[4-[2-(4-trifluoromethylphenyl)-oxazol-4-ylmethoxy]- benzyl]-pyrrolidine-2-carboxylic acid methyl ester
The compound obtained in Step 3 of Example 189(100 mg, 0.33 mmol), D-proline methyl ester • HC1(6O mg, 0.37 mmol) and K2CO3(2.5 eq) were dissolved in dimethylformamide(10 ml). The resulting mixture was stirred at room temperature for 3 hrs. After the completion of the reaction, 20 ml of water was poured to the reaction product. The resulting mixture was neutralized with an aqueous 1 N HCl and the resultant was extracted with dichloromethane. The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography(eluent: hexane/ethyl acetate=5/l) to obtain the title compound(51 mg, yield: 43%). 1H NMR(CDCl3, 200MHz): δ(ppm) 8.10(2H, d, J=8.5Hz), 7.81(1H, s), 7.75(2H, d, J=8.5Hz), 7.30(2H, m), 6.98(2H, m), 5.10(2H, s), 3.86(1H, m), 3.67(3H, s), 3.55(1H, m), 3.24(1H, m), 3.06(1H, m), 2.4O(1H, m), 2.24-1.80(4H, m)
Step 5: Preparation of l-[4-[2-(4-trifluoromethylρhenyl)-oxazol-4-ylmethoxy]- benzyl] -pyrrolidine-2-carboxylic acid The compound obtained in Step 4 of Example 189(51 mg, 0.11 mmol) and LiOH-H2O(1.5 eq) were dissolved in H2OMeOH(1 :5(v/v%), 1 ml). The resulting mixture was stirred at room temperature for 2 days. The resulting mixture was neutralized with an aqueous 1 N HCl and the resultant was extracted with dichloromethane. The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue thus obtained was recrystallized from methylene chloride to obtain the title compound(30 mg, yield: 60%).
1H NMR(CDCl3, 200MHz): δ(ppm) 8.24(2H5 d, J=8.1Hz), 8.15(1H5 s), 7.85(2H, d,
J=8.1Hz), 7.50(2H5 d, J=8.5Hz), 7.15(2H5 d, J=8.5Hz), 5.15(2H5 s), 4.50(1H5 m), 4.25(1H, m), 4.15(1H5 m), 3.58(1H5 m), 3.36(1H5 m), 2.60(1H5 m), 2.25-1.80(3H5 m)
Example 190: Preparation of (R)-l-[3-(2-phenyl-oxazoI-4-ylmethoxy)-benzyl]- pyrroIidine-2-carboxylic acid
Figure imgf000145_0001
Step 1: Preparation of 3-(2-phenyl-oxazol-4-ylmethoxy)-benzaldehyde
4-Chloromethyl-2-phenyl-oxazole(1.00 g, 5.16 mmol), 3-hydroxy benzaldehyde(l.l eq) and K2CO3(2.5 eq) were dissolved in dimethylformamide(30 ml). The resulting mixture was stirred at 90 °C for 3 hrs. The reaction produect was neutralized with an aqueous 1 N HCl and the resultant was extracted with dichloromethane. The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography (eluent: hexane/ethyl acetate=5/l) to obtain the title compound(1.00 g, yield: 70%). 1H NMR(CDCl3, 200MHz): δ(ppm) 10.01(1H, s), 8.07(2H5 m), 7.8O(1H, s), 7.55-7.28(7H, m), 5.16(2H5 s)
Step 2: Preparation of [3-(2-phenyl-oxazol-4-ylmethoxy)-phenyl]-methanol
The compound obtained in Step 1 of Example 190(1.05 g, 3.76 mmol) and NaBH4(3 eq) were dissolved in methanol(30 ml). The resulting mixture was stirred at room temperature for 1 hr. After the completion of the reaction, 20 ml of water was poured to the reaction product. The resulting mixture was neutralized with an aqueous 1 N HCl and the resultant was extracted with dichloromethane. The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography(eluent: hexane/ethyl acetate=5/l) to obtain the title compound(1.00 g, yield: 98%). 1H NMR(CDCl35 200MHz): δ(ppm) 8.10-6.98(1OH, m), 5.09(2H, s), 4.70(2H, d, J=5.2Hz), 2.1O(1H, m)
Step 3: Preparation of 4-(3-chloromethyl-phenoxymethyl)-2-phenyl-oxazole
The compound obtained in Step 2 of Example 190(1.0 g, 3.56 mmol), methanesulfonylchloride(l.l eq) and triethylamine(3 eq) were dissolved in dichloromethane. The resulting mixture was stirred at room temperature for 3 hrs. After the completion of the reaction, 20 ml of water was poured to the reaction product. The resulting mixture was neutralized with an aqueous 1 N HCl and the resultant was extracted with dichloromethane. The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography(eluent: hexane/ethyl acetate=5/l) to obtain the title compound(0.36 g, yield: 34%). 1R NMR(CDCl3, 200MHz): δ(ppm) 8,09(2H, m), 7.77(1H, s), 7.48(3H, m), 7.32-7.02(4H, m), 5.13(2H, s), 4.60(2H, s)
Step 4: Preparation of l-[3-(2~phenyl-oxazol-4-ylmethoxy)-benzyl]-pyrrolidine- 2-carboxylic acid methyl ester
The compound obtained in Step 3 of Example 190(100 mg, 0.33 mmol), D-proline methyl ester • HC1(6O mg, 0.37 mmol) and K2CO3(2.5 eq) were dissolved in dimethylformamide(10 ml). The resulting mixture was stirred at 85 °C for 2 days. The reaction product was neutralized with an aqueous 1 N HCl and the resultant was extracted with dichloromethane. The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography(eluent: hexane/ethyl acetate=5/l) to obtain the title compound(74 mg, yield: 57%).
1H NMR(CDCl3, 200MHz): δ(ppm) 8.05(2H, m), 7.75(1H, s), 7.46(3H, m), 7.22(1H, m), 7.02(1H, s), 6.90(2H, m), 5.09(2H, s), 3.89(1H, d, J=12.9Hz), 3.68(3H, s), 3.55(1H, d, J=12.9Hz), 3.27(1H, m), 3.03(1H, m), 2.4O(1H, m), 2.09(1H, m), 2.05-1.80(4H, m)
Step 5: Preparation of l-[2-(2-phenyl-oxazol-4-methoxy)-benzyl]-pyrrolidine- 2-carboxylic acid
The compound obtained in Step 4 of Example 190(74 mg, 0.20 mmol) and LiOH-H2O(1.5 eq) were dissolved in H2OMeOH(1 :5(v/v%), 1 ml). The resulting mixture was stirred at room temperature for 2 days. The reaction product was neutralized with an aqueous 1 N HCl and the resultant was extracted with dichloromethane. The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue thus obtained was recrystallized from methylene chloride to obtain the title compound(36 mg, yield: 50%). 1H NMR(CDCl3, 200MHz): δ(ppm) 8.04(3H, m), 7.52(3H5 m), 7.27-7.18(2H, m), 7.01-6.95(2H5 m), 5.10(2H,s), 4.14(1H5 d5 J-12.6Hz)5 3.34(1H5 d, J=12.6Hz) 3.05-2.80(2H3 m), 2.30-2.00(2H5 m), 2.00-1.60(3H5 m)
Example 191: Preparation of (R)-I- [3-(2-/;-tolyl-oxazol-4-yImethoxy)-benzyl]- pyrrolidine-2-carboxylic acid
Figure imgf000147_0001
Step 1: Preparation of 3-(2-j9-tolyl-oxazol-4-ylmethoxy)-benzaldehyde
(4-Chloromethyl)-2-p-tolyl-oxazole(l g5 5.16 mmol), 3 -hydroxy benzaldehyde(l.l eq) and K2CO3(2.5 eq) were dissolved in dimethylformamide(30 ml). The resulting mixture was stirred at 90 "C for 3 hrs. The reaction product was neutralized with an aqueous 1 N HCl and the resultant was extracted with dichloromethane. The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography(eluent: hexane/ethyl acetate=5/l) to obtain the title compound(0.82 g5 yield: 58%).
1H NMR(CDCl3, 200MHz): δ(ppm) 9.99(1H, s), 7.94(2H, d5 J=8.3Hz), 7.75(1H5 s), 7.60-7.00(6H5 m), 5.12(2H5 s), 2.41(3H5 s)
Step 2: Preparation of [3 -(2-p-tolyl-oxazol-4-ylmethoxy)-phenyl] -methanol
The compound obtained in Step 1 of Example 191(0.82 g, 2.80 mmol) and NaBH4(3 eq) were dissolved in methanol(30 ml). The resulting mixture was stirred at room temperature for 3 hrs. After the completion of the reaction, 20 ml of water was poured to the reaction product. The resulting mixture was neutralized with an aqueous 1 N HCl and the resultant was extracted with dichloromethane. The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography(eluent: hexane/ethyl acetate=5/l) to obtain the title compound(0.56 g, yield: 70%). 1H NMR(CDCl3, 200MHz): δ(ppm) 7.96(2H, m), 7.74(1H5 s), 7.40-6.80(6H, m), 5.09(2H, s), 4.70((2H5 m), 2.43 (3H, s),
Step 3: Preparation of 4-(3-chloromethyl-phenoxymethyl)-2-/?-tolyl-oxazole
The compound obtained in Step 2 of Example 191(0.56 g, 1.90 mmol), methanesulfonylchloride(0.45 g, 3.91 mmol) and triethylamine(1.08 g, 10.68 mmol) were dissolved in dichloromethane. The resulting mixture was stirred at room temperature for 3 hrs. After the completion of the reaction, 20 ml of water was poured to the reaction product. The resulting mixture was neutralized with an aqueous 1 N HCl and the resultant was extracted with dichloromethane. The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography(eluent: hexane/ethyl acetate=5/l) to obtain the title compound(0.46 g, yield: 77%).
1H NMR(CDCl3, 200MHz): δ(ppm) 8.10-6.95(9H5 m), 5.12(2H5 s), 4.59(2H5 s), 2.44(3H, s)
Step 4: Preparation of l-[3-(2-/?-tolyl-oxazol-4-ylmethoxy)-benzyl]-pyrrolidine- 2-carboxylic acid methyl ester
The compound obtained in Step 3 of Example 191(100 mg, 0.33 mmol), D-proline methyl ester • HCl(60 mg, 0.37 mmol) and K2CO3(2.5 eq) were dissolved in dimethylformamide(10 ml). The resulting mixture was stirred at 85 °C for 2 days. The reaction product was neutralized with an aqueous 1 N HCl and the resultant was extracted with dichloromethane. The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography(eluent: hexane/ethyl acetate=5/l) to obtain the title compound(70 mg, yield: 54%). 1H NMR(CDCl3, 200MHz): δ(ppm) 7.94(2H, m), 7.68(1H, m), 7.20(3H5 m), 6.95(3H5 m), 5.10(2H, m), 3.93(1H5 m), 3.67(3H5 s), 3.54(1H5 m), 3.25(1H, m), 3.03(1H5 m), 2.40(3H, s), 2.35-1.60(5H, m)
Step 5: Preparation of l-[3-(2-p-tolyl-oxazol-4-ylmethoxy)-benzyl]-pyrrolidine- 2-carboxylic acid The compound obtained in Step 4 of Example 191(70 mg, 0.17 mmol) and
LiOH • H2O(1.5 eq)were dissolved in H2OMeOH(1 :5(v/v%), 1 ml). The resulting mixture was stirred at room temperature for 2 days. The reaction product was neutralized with an aqueous 1 N HCl and the resultant was extracted with dichloromethane. The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue thus obtained was recrystallized from methylene chloride to obtain the title compound(21 mg, yield: 30%).
1H NMR(CDCl3, 200MHz): δ(ppm) 8.04(1H, s), 7.93(2H5 d, J=8.2Hz), 7.34(2H5 d5 J=8.2Hz), 7.25-7.18(2H5 m), 7.00-6.89(2H, m), 5.09(2H, s), 4.1O(1H, d, J=12.6Hz), 3.27(1H5 d, J=12.6Hz) 3.10-2.80(2H5 m), 2.43(3H, s), 2.19-2.16(2H, m), 2.00-1.60(3H5 m)
Example 192: Preparation of (R)-l-[3-[2-(4-trifluoromethylphenyl)-oxazol-4- ylmethoxy]-benzyl]-pyrrolidine-2-carboxylic acid
Figure imgf000149_0001
Step 1 : Preparation of 3-[2-(4-trifluoromethylphenyl)-oxazol-4-ylmethoxyl- benzaldehyde
4-Chloromethyl-2-(4-trifluoromethyl-phenyl)-oxazole(l g, 5.16 mmol), 3-hydroxy benzaldehyde(0.76 g, 6.19 mmol) and K2CO3(2.5 eq) were dissolved in dimethylformamide(30 ml). The reaction product was neutralized with an aqueous
1 N HCl and the resultant was extracted with dichloromethane. The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography(eluent: hexane/ethyl acetate=5/l) to obtain the title compound(0.80 g, yield: 60%).
1H NMR(CDCl3, 200MHz): δ(ppm) 9.99(1H, s), 8.16(2H, d, J=8.55Hz), 7.79(1H, s), 7.71(2H, d, J=8.55Hz), 7.33-6.94(4H, m), 5.09(2H, s)
Step 2: Preparation of [3-[2-(4-trifluoromethylphenyl)-oxazol-4-ylmethoxy]- phenyl] -methanol
The compound obtained in Step 1 of Example 192(0.80 g, 2.30 mmol) and NaBH4(3 eq) were dissolved in methanol(30 ml). The resulting mixture was stirred at room temperature for 1 hr. After the completion of the reaction, 20 ml of water was poured to the reaction product. The resulting mixture was neutralized with an aqueous 1 N HCl and the resultant was extracted with dichloromethane. The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography(eluent: hexane/ethyl acetate=5/l) to obtain the title compound(0.56 g, yield: 70%).
1H NMR(CDCl3, 200MHz): δ(ppm) 9.99(1H, s), 8.16(2H, d, J-8.55Hz), 7.79(1H, s), 7.71(2H, d, J=8.55Hz), 7.33-6.94(4H, m), 5.10(2H, s), 4.70((2H, m)
Step 3: Preparation of 4-(3-chloromethyl-phenoxymethyl)-2-(4- trifluoromethylphenyl)-oxazole
The compound obtained in Step 2 of Example 192(0.56 g, 1.60 mmol), methanesulfonylchloride(0.45 g, 3.91 mmol) and triethylamine(1.08 g, 10.68 mmol) were dissolved in dichloromethane. The resulting mixture was stirred at room temperature for 3 hr. After the completion of the reaction, 20 ml of water was poured to the reaction product. The resulting mixture was neutralized with an aqueous 1 N HCl and the resultant was extracted with dichloromethane. The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography (eluent: hexane/ethyl acetate=5/l) to obtain the title compound(0.24 g, yield: 40%). 1H NMR(CDCl3, 200MHz): δ(ppm) 8.16(2H, d, J=8.55Hz), 7.79(1H, s), 7.71(2H, d, J=8.55Hz), 7.33-6.94(4H, m), 5.09(2H, s), 4.56(2H5 s)
Step 4: Preparation of l-[3-[2-(4-trifluoromethylphenyl)-oxazol-4-ylmethoxy]- benzyl]-pyrrolidine-2-carboxylic acid methyl ester The compound obtained in Step 3 of Example 192(100 mg, 0.33 mmol),
D-proline methyl ester • HC1(6O mg, 0.37 mmol) and K2CO3(2.5 eq) were dissolved in dimethylformamide(10 ml). The resulting mixture was stirred at 85 °C for 2 days.
The reaction product was neutralized with an aqueous 1 N HCl and the resultant was extracted with dichloromethane. The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography (eluent: hexane/ethyl acetate=5/l) to obtain the title compound(40 mg, yield: 33%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.94(2H, m), 7.68(1H, m), 7.20(3H, m),
6.95(3H, m), 5.10(2H, m), 3.93(1H5 m), 3.67(3H, s), 3.54(1H, m), 3.25(1H, m), 3.03(1H, m), 2.40(3H, s), 2.35-1.60(5H, m)
Step 5: Preparation of l-[3-[2-(4-trifluoromethylphenyl)-oxazol-4-ylmethoxy]- benzyl]-pyrrolidine-2-carboxylic acid
The compound obtained in Step 4 of Example 192(40 mg, 0.087 mmol) and LiOH-H2O(1.5 eq) were dissolved in H2O/MeOH(l :5(v/v%), 1 ml). The resulting mixture was stirred at room temperature for 3 hr. The reaction product was neutralized with an aqueous 1 N HCl and the resultant was extracted with dichloromethane. The organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue thus obtained was recrystallized from methylene chloride to obtain the title compound(15 mg, yield: 20%).
1H NMR(CDCl3, 200MHz): δ(ppm) 8.24(2H, m), 8.15(1H, s)< 7.85(2H, d), 7.50(3H, m), 7.18(1H, m), 5.16(2H, s), 4.60-4.40(2H, m), 4.1O(1H, m), 3.45(2H, m), 2.95(1H, m), 2.28- 1.80(3H, m)
Example 193: Preparation of (R)-l-[4-[2-(2-phenyl-oxazol-4-yl)-ethoxy]- benzyl] -py rroIidine-2-carboxylic acid
Figure imgf000151_0001
Step 1: Preparation of 4-[2-(2-phenyl-oxazol-4-yl)-ethoxy]-benzaldehyde
Methanesulfonic 2-(2-phenyl-4,5-dihydrooxazol-4-yl)ethyl ester(0.8 g, 2.99 mmol), 4-hydroxybenzaldehyde(0.44 g, 3.59 mmol) and K2CO3(0.62 g, 4.49 mmol) were dissolved in acetonitrile(30 ml) and the resulting mixture was heated to reflux overnight. The procedure of Step 1 of Example 187 was repeated except for using the resultant to obtain the title compound(0.66 g, yield: 75%).
1H NMR(CDCl3, 200MHz): δ(ppm) 9.91(1H5 s), 8.05(2H, m), 7.85(2H, m), 7.61(1H, s), 7.49(2H, m), 7.10(2H, m), 4.41(2H, t), 3.15(2H, t)
Step 2: Preparation of [4-[2-(2-phenyl-oxazol-4-yl)-ethoxy]-phenyl]-methanol
The procedure of Step 2 of Example 187 was repeated except for using the compound obtained in Step 1 of Example 193(0.66 g, 2.24 mmol) and NaBH4(3 eq) to obtain the title compound(0.53 g, yield: 80%). 1H NMR(CDCl3, 200MHz): δ(ppm) 8.03(2H, m), 7.56(1H, s), 7.44(3H5 m), 7.28(2H, d, J=8.5Hz), 6.91(2H, d, J=8.5Hz), 4.61(2H, s), 4.28(2H5 t), 3.08(2H, t), 1.7O(1H, brs)
Step 3: Preparation of 4-[2-(4-chloromethyl-phenoxy)-ethyl]-2-phenyl-oxazole The procedure of Step 3 of Example 187 was repeated except for using the compound obtained in Step 2 of Example 193(0.53 g, 1.79 mmol), methylchloride(l.l eq) and triethylamine(3 eq) to obtain the title compound(0.30 g, yield: 53%).
1H NMR(CDCl3, 200MHz): δ(ppm) 8.05(2H5 m), 7.59(1H5 s), 7.45(3H5 m), 7.33(2H5 m), 6.94(2H, m), 4.59(2H5 s), 4.32(2H5 1, J=6.5Hz)5 3.12(2H, t, J=6.5Hz)
Step 4: Preparation of l-[4-[2-(2-phenyl-oxazol-4-yl)-ethoxy]-benzyl]-pyrrolidine-
2-carboxylic acid methyl ester
The procedure of Step 4 of Example 187 was repeated except for using the compound obtained in Step 3 of Example 193(50 mg, 0.15 mmol), D-prolinemethyl ester • HC1(58 mg, 0.35 mmol) and K2CO3(O-I l g, 0.8 mmol) to obtain the title compound(56 mg, yield: 76%).
1H NMR(CDCl3, 200MHz): δ(ppm) 8.03(2H5 m), 7.57(1H5 s), 7.45(3H5 m),
7.30-7.20(2H, m), 6.87(2H, d, J=8.3Hz)5 4.27(2H5 m), 3.81(1H5 d5 J=12.6Hz), 3.65(3H5 s), 3.51(1H, d, J=12.6Hz), 3.25(1H5 m), 3.00(3H, m), 2.37(1H5 m),
2.20-1.75(4H, m) Step 5: Preparation of l-[4-[2-(2-phenyl-oxazol-4-yl)-ethoxy]-benzyl]-pyrrolidine- 2-carboxylic acid
The procedure of Step 5 of Example 187 was repeated except for using the compound obtained in Step 4 of Example 193(56 mg, 0.138 mmol) and LiOH-H2O(1.5 eq) to obtain the title compound(19 mg, yield: 35%).
1H NMR(CDCl3, 200MHz): δ(ppm) 8.03(2H, m), 7.83(1H, s), 7.51(3H, m), 7.45(2H, d, J=8.6Hz), 7.03(2H, d, J=8.6Hz), 4.4O(1H, d, J=12.8Hz), 4.34(2H, t, J=6.5Hz), 4.2O(1H, d, J=12.8Hz), 3.9O(1H, m), 3.51(1H, m), 3.2O(1H, m), 3.09(2H5 1, J=6.5Hz), 2.5O(1H, m), 2.13-1.95(3H, m)
Example 194: Preparation of (R)-l-{4-[2-(2-p-tolyl-oxazol-4-yl)-ethoxy]- benzyl}~pyrrolidine-2-carboxylic acid
Figure imgf000152_0001
Step 1: Preparation of 4-[2-(2-j!?-tolyl-oxazol-4-yl)-ethoxy]-benzaldehyde Methanesulfonic 2-(2-/?-tolyl-4,5-dihydrooxazol-4-yl)ethyl ester(0.50 g, 1.78 mmol), 4-hydroxybenzaldehyde(l.l eq) and K2CO3(3 eq) were dissolved in acetonitrile(30 ml) and the resulting mixture was heated to reflux overnight. The procedure of Step 1 of Example 187 was repeated except for using the resultant to obtain the title compound(0.50 g, yield: 93%). 1H NMR(CDCl3, 200MHz): δ(ppm) 9.91(1H, s), 7.96-7.84(4H, m), 7.58(1H, s), 7.30(2H, m), 7.05(2H, d, J=8.5Hz), 4.40(2H, t), 3.15(2H, t), 2.15(3H, s)
Step 2: Preparation of [4-[2-(2-p-tolyl-oxazol-4-yl)-ethoxy]-phenyl]-methanol
The procedure of Step 2 of Example 187 was repeated except for using the compound obtained in Step 1 of Example 194(0.50 g, 1.63 mmol) and NaBH4(3 eq) to obtain the title compound(0.44 g, yield: 88%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.90(2H, d, J=8.6Hz), 7.54(1H, s), 7.26(4H, m),
6.91(2H, d, J=8.5Hz), 4.61(2H, d, J=5.6Hz), 4.28(2H, t), 3.08(2H, t), 2.40(3H, s),
1.82(lH, m)
Step 3: Preparation of 4-[2-(4-chloromethyl-phenoxy)-ethyl]-2-Jp-tolyl-oxazole
The procedure of Step 3 of Example 187 was repeated except for using the compound obtained in Step 2 of Example 194(0.44 g, 1.42 mmol), methylchloride(1.5 eq) and triethylamine(3 eq) to obtain the title compound(0.025 g, yield: 53 %).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.94(2H, m), 7.56(1H, s), 7.37-7.26(4H, m),
6.93(2H, m), 4.59(2H, s), 4.31(2H, t), 3.11(2H, t), 2.43(3H, s) Step 4: Preparation of l-[4-[2-(2-p-tolyl-oxazol-4-yl)-ethoxy]-benzyl]-pyrrolidine- 2-carboxylic acid methyl ester
The procedure of Step 4 of Example 187 was repeated except for using the compound obtained in Step 3 of Example 194(50 mg, 0.15 mmol), D-proline methyl ester • HCl(Ll eq) and K2CO3(2.5 eq) to obtain the title compound(52 mg, yield: 81%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.90(2H5 d, J=8. IHz)5 7.53(1H, s), 7.30-7.10(4H, m), 6.93-6.84(2H, m), 4.26(2H, t, J=6.5Hz), 3.80(1H5 d, J=12.8Hz), 3.64(3H5 s), 3.54(1H5 d5 J=12.8Hz), 3.20(1H5 m)5 3.09(2H5 t, J=6.5Hz), 2.39(3H5 s), 2.20-1.70(5H5 m)
Step 5: Preparation of 1- [4- [2-(2-p-tolyl-oxazol-4-yl)-ethoxy] -benzyl] -pyrrolidine-
2-carboxylic acid The procedure of Step 5 of Example 187 was repeated except for using the compound obtained in Step 4 of Example 194(52 mg, 0.128 mmol) and
LiOH-H2O(1.5 eq) to obtain the title compound(52 mg, yield: 40%).
1H NMR(CDCl35 200MHz): δ(ppm) 7.91-7.79(3H, m), 7.45(2H, d, J=12.8Hz),
7.33(2H5 d, J=8.1Hz), 7.05(2H, d, J=8.6Hz), 4.45(1H, d, J=12.8Hz),4.31(2H, m), 4.24(1H5 d, J=12.8Hz), 4.13(1H5 m), 3.53(1H5 m), 3.31(1H, m), 3.10(2H5 m)5
2.45(1H, m), 2.20-2.05(2H, m), 2.05-1.95(3H, m)
Example 195: Preparation of (R)-l-[4-[2-[2-(4-trifluoromethylphenyl)-oxazol-4- yl] -ethoxy] -benzyl] -py rrolidine-2-carboxylic acid
Figure imgf000153_0001
Step 1 : Preparation of 4-[2-[2-(4-trifluoromethylphenyl)-oxazol-4-yl]-ethoxy]- benzaldehyde
2-[2-(4-Trifluoromethylphenyl)-4,5-dihydrooxazol-4-yl]ethyl methane- sulfonate(0.35 g, 1.04 mmol), 4-hydroxybenzaldehyde(l.l eq) and K2CO3(2.5 eq) were dissolved in acetonitrile(30 ml) and the resulting mixture was heated to reflux overnight. The procedure of Step 1 of Example 187 was repeated except for using the resultant to obtain the title compound(0.46 g, yield: 91%).
1H NMR(CDCl35 200MHz): δ(ppm) 9.91(1H, s), 8.15-6.85(9H5 m). 4.41(2H, t),
3.15(2H5 1)
Step 2: Preparation of [4-[2-[2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]- ethoxy] -phenyl] -methanol The procedure of Step 2 of Example 187 was repeated except for using the compound obtained in Step 1 of Example 195(0.35 g, 0.96 mmol) and NaBH4(3 eq) to obtain the title compound(0.28 g, yield: 80%).
1H NMR(CDCl3, 200MHz): δ(ppm) 8.14(2H, d, J=8.1Hz), 7.71(2H, d, J=8.1Hz), 7.62(1H, s), 7.27(2H, d, J=8.5Hz)5 6.92(2H5 d, J=8.5Hz), 4.61(2H5 d, J=5.7Hz)5 4.30(2H5 t), 3.10(2H5 1), 1.57(1H5 m)
Step 3: Preparation of 4-[2-(4-chloromethyl-phenoxy)-ethyl]-2-(4- trifluoromethylphenyl)-oxazole The procedure of Step 3 of Example 187 was repeated except for using the compound obtained in Step 2 of Example 195(0.28 g, 0.77 mmol), methylchloride(1.5 eq) and triethylamine(3 eq) to obtain the title compound(0.17 g, yield: 59%).
1H NMR(CDCl35 200MHz): δ(ppm) 8.16(2H5 d5 J=8.2Hz), 7.74(2H, d, J=8.2Hz), 7.64(1H5 s), 7.32(2H5 m), 6.94(2H5 m), 4.59(2H5 s), 4.33(2H5 1), 3.13(2H, t)
Step 4: Preparation of l-[4-[2-[2-(4-trifluoromethylphenyl)-oxazol-4-yl]-ethoxy]- benzyl]-pyrrolidine-2-carboxylic acid methyl ester
The procedure of Step 4 of Example 187 was repeated except for using the compound obtained in Step 3 of Example 195(50 mg, 0.13 mmol), D-proline methyl ester • HCl(Ll eq) and K2CO3(2.5 eq) to obtain the title compound(20 mg, yield:
32%).
1H NMR(CDCl3, 200MHz): δ(ppm) 8.15(2H, m), 7.80-7.62(3H5 m), 7.50-7.20(2H5 m), 7.10-6.80(2H, m), 4.40-4.20(2H5 m), 3.82(1H, m), 3.65(3H, s), 3.55(1H, m), 3.40-3.00(3H, m), 2.50-2.30(1H, m), 2.30-1.70(5H, m)
Step 5: Preparation of l-[4-[2-[2-(4-trifluoromethylphenyl)-oxazol-4-yl]-ethoxy]- benzyl]-pyrrolidine-2-carboxylic acid
The procedure of Step 5 of Example 187 was repeated except for using the compound obtained in Step 4 of Example 195(20 mg, 0.043 mmol) and
LiOH • H2O(1.5 eq) to obtain the title compound(5 mg, yield: 25%).
1H NMR(CDCl35 200MHz): δ(ppm) 8.24(2H5 d), 7.91(1H5 s), 7.84(2H5 d), 7.50(2H, d), 7.00(2H, m), 4.5O(1H, m), 4.35(3H5 m), 3.90(1H, m), 3.60(1H5 m), 3.18(2H, m),
2.4O(1H, m), 2.15(2H, m), 1.60(2H5 m)
Example 196: Preparation of (R)-I- [3- [2-(2-phenyl-oxazol-4-yl)-ethoxy]- benzyl] -pyrrolidine-2-carboxyIic acid
Figure imgf000155_0001
Step 1: Preparation of 4-[2-(2-phenyl-oxazol-4-yl)-ethoxy]-benzaldehyde
Methansulfonic 2-(2-phenyl-4,5-dihydrooxazol-4-yl)ethyl ester(0.8 g, 2.99 mmol), 4-hydroxybenzaldehyde(l.l eq) and K2CO3(2.5 eq) were dissolved in acetonitrile(30 ml) and the resulting mixture was heated to reflux overnight. The procedure of Step 1 of Example 187 was repeated except for using the resultant to obtain the title compound(0.69 g, yield: 78%).
1H NMR(CDCl3, 200MHz): δ(ppm) 9.91(1H, s), 8.01(2H, m), 7.6O(1H, s),
7.45-7.11(7H, m), 4.33(2H, t), 3.12(2H, t)
Step 2: Preparation of [3- [2-(2-phenyl-oxazol-4-yl)-ethoxy] -phenyl] -methanol
The procedure of Step 2 of Example 187 was repeated except for using the compound obtained in Step 1 of Example 196(0.69 g, 2.36 mmol) and NaBH4(3 eq) to obtain the title compound(0.62g, yield: 88%). 1H NMR(CDCl3, 200MHz): δ(ppm) 8.07(2H, m), 7.6O(1H, s), 7.47(2H, m),
7.33-6.80(5H, m), 4.66(2H, d), 4.29(2H, t, J=6.5Hz), 3.10(2H5 1, J=6.5Hz),
Step 3: Preparation of 3-[2-(4-chloromethyl-phenoxy)-ethyl]-2-phenyl-oxazole
The procedure of Step 3 of Example 187 was repeated except for using the compound obtained in Step 2 of Example 196(0.62 g, 2.10 mmol), methylchloride(l.l eq) and triethylamine(3 eq) to obtain the title compound(0.35 g, yield: 66%).
1H NMR(CDCl3, 200MHz): δ(ppm) 8.05(2H, m), 7.6O(1H, s), 7.46(3H, m),
7.42-7.22(2H, m), 7.05-6.80(2H, m), 4.58(2H, s), 4.33(2H, t, J=8.5Hz), 3.12(2H, t, J=8.1Hz)
Step 4: Preparation of 1- [4- [2-(2-phenyl-oxazol-4-yl)-ethoxy] -benzyl] -pyrrolidine- 2-carboxylic acid methyl ester
The procedure of Step 4 of Example 187 was repeated except for using the compound obtained in Step 3 of Example 196(70 mg, 0.22 mmol), D-proline methyl ester • HC1(58 mg, 0.35 mmol) and K2CO3(CIl g, 0.8 mmol) to obtain the title compound(55 mg, yield: 75%).
Step 5: Preparation of l-[4-[2-(2-phenyl-oxazol-4-yl)-ethoxy]-benzyl]-pyrrolidine- 2-carboxylic acid
The procedure of Step 5 of Example 187 was repeated except for using the compound obtained in Step 4 of Example 196(55 mg, 0.135 mmol) and LiOH • H2O(1.5 eq) to obtain the title compound(0.02 g, yield: 38%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.85(2H, m), 7.38(3H, m), 7.21(1H, m),
7.00-6.73(3H5 m), 4.28(1H, d, J= 12.0Hz), 4.18(2H, d, J=6.0Hz), 3.98(1H, d,
J=12.0Hz), 3.36(1H5 m), 3.10(1H, m), 3.00-2.90(3H5 m), 2.29(1H5 m), 2.10-1.70(3H5 m)5
Example 197: Preparation of (R)-l-[3-[2-(2-/?-tolyl-oxazol-4-yI)-ethoxy]-benzyl]- pyrrolidine-2-carboxylic acid
Figure imgf000156_0001
Step 1 : Preparation of 3 - [2-(2-/>-tolyl-oxazol-4-yl)-ethoxy] -benzaldehyde
Methanesulfonic 2-(2-/?-tolyl-4,5-dihydrooxazol-4-yl)ethyl ester(0.8 g, 2.99 mmol), 4-hydroxybenzaldehyde(l.l eq) and K2CO3(2.5 eq) were dissolved in acetonitrile(30 ml) and the resulting mixture was heated to reflux overnight. The procedure of Step 1 of Example 187 was repeated except for using the resultant to obtain the title compound(0.51 g, yield: 92%).
1H NMR(CDCl3, 200MHz): δ(ppm) 9.95(1H5 s), 7.90(2H5 d), 7.55-7.10(7H5 m), 4.34(2H5 1), 3.10(2H5 1), 2.39(3H5 s)
Step 2: Preparation of [4-[2-(2-p-tolyl-oxazol-4-yl)-ethoxy]-phenyl]-methanol The procedure of Step 2 of Example 187 was repeated except for using the compound obtained in Step 1 of Example 197(0.51 g, 1.98 mmol) and NaBH4(3 eq) to obtain the title compound(0.38 g, yield: 70%).
1H NMR(CDCl35 200MHz): δ(ppm) 7.93(2H5 d5 J=7.7Hz), 7.57(1H5 s), 7.33-6.77(6H5 m), 4.28(2H, d, J=5.3Hz), 4.32(2H5 1, J=6.5Hz), 3.11(2H5 t, J=6.5Hz)5 2.42(3H5 s), 1.68(1H5 1)
Step 3: Preparation of 4-[2-(4-chloromethyl-phenoxy)-ethyl]-2-jc-tolyl-oxazole
The procedure of Step 3 of Example 187 was repeated except for using the compound obtained in Step 2 of Example 197(0.38 g, 1.20 mmol), methylchloride(l.l eq) and triethylamine(3 eq) to obtain the title compound(0.22 g, yield: 55%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.91(2H5 d5 J=I LlHz)5 7.57(1H5 s),
7.40-7.20(3H5 m), 7.00-6.87(3H5 m), 4.55(2H5 s), 4.30(2H5 t, J=6.5Hz)5 3.09(2H5 t5
J=6.5Hz)5 2.40(3H, s)
Step 4: Preparation of 1- [4- [2-(2-p-tolyl-oxazol-4-yl)-ethoxy] -benzyl] -pyrrolidine-
2-carboxylic acid methyl ester The procedure of Step 4 of Example 187 was repeated except for using the compound obtained in Step 3 of Example 197(70 mg, 0.21 mmol), D-proline methyl ester • HCl(I. leq) and K2CO3(2.5eq)to obtain the title compound(0.052 g, yield: 60%). 1H NMR(CDCl3, 200MHz): δ(ppm) 7.90(2H, m), 7.81(1H, s), 7.43-7.32(3H5 m), 7.15-6.96(3H, m), 4.53(1H, d, J=12.7Hz)3 4.38-4.27(4H, m), 3.67(s, 3H)5 3.54(1H, m), 3.36(1H5 m), 3.10(2H, m), 2.6O(1H, m)5 2.42(3H5 s), 2.23-1.8O(3H, m).
Step 5: Preparation of l-[4-[2-(2-p-toIyl-oxazol-4-yl)-ethoxy]-benzyl]-pyrrolidine- 2-carboxylic acid
The procedure of Step 5 of Example 187 was repeated except for using the compound obtained in Step 4 of Example 197(0.052 g, 0.126 mmol) and
LiOH • H2O(1.5 eq) to obtain the title compound(0.056 g, yield: 45%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.90(2H5 m), 7.81(1H, s), 7.43-7.32(3H, m), 7.15-6.96(3H5 m)5 4.53(1H, d, J=12.7Hz), 4.38-4.27(4H5 m), 3.54(1H, m), 3.36(1H5 m), 3.10(2H, m), 2.60(1H5 m), 2.42(3H5 s), 2.23-1.80(3H, m).
Example 198: Preparation of (R)-l-[4-[2-[2-(4-trifluoromethyIphenyl)-oxazoI-4- yl]-ethoxy]-benzyl]-pyrrolidine-2-earboxylic acid
Figure imgf000157_0001
Step 1 : Preparation of 4-[2-[2-(4-trifluoromethylphenyl)-oxazol-4-yl]-ethoxy]- benzaldehyde
2-[2-(4-(Trifluoromethyl)phenyl]-4,5-dihydrooxazol-4-yl)ethyl methane- sulfonate(0.35 g, 1.04 mmol), 4-hydroxybenzaldehyde(l. l eq) and K2CO3(2.5 eq) were dissolved in acetonitrile(30 ml) and the resulting mixture was heated to reflux overnight. The procedure of Step 1 of Example 187 was repeated except for using the resultant to obtain the title compound(0.27 g, yield: 63%).
1H NMR(CDCl3, 200MHz): δ(ppm) 9.97(1H5 s), 8.14(2H, d, J=8.3Hz), 7.71(2H, d,
J=8.3Hz), 7.65(1H5 s), 7.47-7.12(4H5 m), 4.63(2H, t), 3.14(2H, t)
Step 2: Preparation of [4-[2-[2-(4-trifluoromethylphenyl)-oxazol-4-yl]-ethoxy]- phenyl]-methanol
The procedure of Step 2 of Example 187. was repeated except for using the compound obtained in Step 1 of Example 198(0.24 g, 0.66 mmol) and NaBH4(3 eq) to obtain the title comρound(0.14 g, yield: 58%).
1H NMR(CDCl3, 200MHz): δ(ppm) 8.20(2H, m), 7.86-7.66(3H, m), 7.28(1H5 m),
7.02-6.87(3H, m), 4.72(2H5 d, J=5.3Hz), 4.33(2H, t), 3.13(2H, t) Step 3: Preparation of 4-[2-(4-chloromethyl-phenoxy)-ethyl]-2-(4- trifluoromethylρhenyl)-oxazole
The procedure of Step 3 of Example 187 was repeated except for using the compound obtained in Step 2 of Example 198(0.14 g, 0.40 mmol), methylchloride(l.l eq) and triethylamine(3 eq) to obtain the title compound(70 mg, yield: 48%).
1H NMR(CDCl3, 200MHz): δ(ppm) 8.14(2H, d, J=8.1Hz), 7.71(2H, d, J=8.1Hz), 7.63(1H, s), 7.20(1H5 m), 6.99-6.87(3H, m), 4.55(2H, s), 4.31(2H, t, J=6.5Hz), 3.14(2H, t, J=6.5Hz)
Step 4: Preparation of l-[4-[2-[2-(4-trifluoromethylphenyl)-oxazol-4-yl]-ethoxy]- benzyl]-pyrrolidine-2-carboxylic acid methyl ester
The procedure of Step 4 of Example 187 was repeated except for using the compound obtained in Step 3 of Example 198(70 mg, 0.18 mmol), D-proline methyl ester • HCl(Ll eq) and K2CO3(2.5) to obtain the title compound(0.058 g, yield: 68%).
Step 5: Preparation of l-[4-[2-[2-(4-trifluoromethylphenyl)-oxazol-4-yl]-ethoxy]- benzyl] -pyrrolidine-2-carboxylic acid
The procedure of Step 5 of Example 187 was repeated except for using the compound obtained in Step 4 of Example 198(0.058 g, 0.12 mmol) and
LiOH • H2O(1.5 eq) to obtain the title comρound(0.033 g, yield: 60%).
1H NMR(CDCl3, 200MHz): δ(ppm) 8.06(2H, d, J=8.5Hz), 7.78(1H, s), 7.68(2H, d, J=8.5Hz), 7.2O(1H, m), 7.01-6.94(3H, m), 4.39(1H, d, J=12.7Hz), 4.25-4.14(4H, m),
3.4O(1H, m), 3.2O(1H, m), 3.98(2H, m), 2.45(1H, m), 2.09-1.85(3H, m)
Example 199: Preparation of (R)-l-[4-[2-(5-isopropyl-2-phenyl-oxazol-4-yl)- ethoxy] -benzyl] -pyrrolidine-2-carboxylic acid
Figure imgf000158_0001
Step 1: Preparation of 4-[2-(5-isopropyl-2-phenyl-oxazol-4-yl)-ethoxy]- benzaldehyde
The procedure of Step 1 of Example 187 was repeated except for using
2-(5-isopropyl-2-phenyloxazol-4-yl)ethyl methylsulfonate(0.25 g, 0.81 mmol) to obtain the title comρound(0.26 g, yield: 96%).
1H NMR(CDCl3, 200MHz): δ(ρpm) 9.89(1H, s), 8.00(2H, m), 7.83(2H5 d, J=8.5Hz), 7.45(3H, m), 7.00(2H, d, J=8.5Hz), 4.36(2H, d, J=6.5Hz), 3.30-3.05(1H5 m), 3.06(2H, t, J=6.5Hz), 1.37(6H, d, J=6.9Hz)
Step 2: Preparation of [4-[2-(5-isopropyl-2-phenyl-oxazol-4-yl)-ethoxy]- phenyl] -methanol
The procedure of Step 2 of Example 187 was repeated except for using the compound obtained in Step 1 of Example 199(0.26 g, 0.78 mmol) and NaBH4(3 eq) to obtain the title compound(0.21 g, yield: 81%).
1H NMR(CDCl3, 200MHZ): δ(ppm) 8.02(2H, m), 7.45(3H, m), 7.30(2H, d, J=8.5Hz), 6.90(2H, d, J=8.5Hz), 4.63(2H, s), 4.26(2H, t), 3.2O(1H, m), 3.02(2H, t), 1.37(6H, d, J=6.9Hz)
Step 3: Preparation of 4-[2-(5-isopropyl-4-chloromethyl-phenoxy-ethyl]-2-phenyl- oxazole The procedure of Step 3 of Example 187 was repeated except for using the compound obtained in Step 2 of Example 199(0.21 g, 0.60 mmol), methylchloride(l .l eq) and triethylamine(3 eq) to obtain the title compound(0.19 g, yield: 86%).
1H NMR(CDCl3, 200MHz): δ(ppm) 8.30(2H, m), 7.56(3H, m), 7.28(2H, d, J=8.5Hz), 6.87(2H, d, J=8.5Hz), 4.54(2H, s), 4.39(2H, t, J=6.5Hz), 3.32-3.20(1H5 m), 3.28(2H, t J=6.5Hz), 1.41(6H, d, J=6.9Hz)
Step 4: Preparation of l-[4-[2-(5-isopropyl-2-phenyl-oxazol-4-yl)-ethoxy]- benzyl]-pyrrolidine-2-carboxylic acid methyl ester The procedure of Step 4 of Example 187 was repeated except for using the compound obtained in Step 3 of Example 199(100 mg, 0.28 mmol), D-prolinemethyl ester • HCl(Ll eq) and K2CO3(2.5 eq) to obtain the title compound(60 mg, yield:
48%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.97(2H5 m), 7.43(3H, m), 7.26-7.19(2H, m), 6.87-6.82(2H, m), 4.21(2H, t, J=6.6Hz), 3.79(1H, d, J=12.6Hz),3.63(3H, s), 3.50(1H, d, J=12.6Hz), 3.20-3.10(2H, m), 2.99(2H, t, J=6.6Hz), 2.35(1H, m), 2.10(1H, m),
2.00-1.70(2H. m), 1.34(6H, d, J=6.9Hz)
Step 5: Preparation of l-[4-[2-(5-isopropyl-2-phenyl-oxazol-4-yl)-ethoxy]~benzyl]- pyrrolidine-2-carboxylic acid
The procedure of Step 5 of Example 187 was repeated except for using the compound obtained in Step 4 of Example 199(0.06 g, 0.133 mmol) and
LiOH • H2O(1.5 eq) to obtain the title comρound(0.032 g, yield: 56%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.85(2H, m), 7.40(3H, m), 7.15(2H, d, J=9.0Hz), 7.25(1H, dθ, 4.03(2H, t), 4.00(1H5 d), 3.68(1H, m), 3.33(1H, m), 3.11(1H5 m), 2.90(2H5 t, J=6.0Hz), 2.25(6H, d, J=6.0Hz)
Example 200: Preparation of (R)-l-[3-[2-(5-isopropyl-2-phenyl-oxazoI-4-yl)- ethoxy] -benzyl] -pyrrolidine-2-carboxylic acid
Figure imgf000160_0001
Step 1: Preparation of 3-[2-(5-isopropyl-2-phenyl-oxazol-4-yl)-ethoxy]- benzaldehyde
Methanesulfonic 2-(5-isopropyl-2-ρhenyloxazol-4-yl)ethyl ester(0.25g, 0.81 mmol), 4-hydroxybenzaldehyde(l.l eq) and K2CO3(2.5 eq) were dissolved in acetonitrile(30 ml) and the resulting mixture was heated to reflux overnight. The procedure of Step 1 of Example 187 was repeated except for using the resultant to obtain the title compound(0.23 g, yield: 85%).
1H NMR(CDCl3, 200MHZ):9.97(1H, S), 8.01(2H5 m), 7.46-7.39(6H5 m), 7.2O(1H, m),
4.32(2H, d5 J=6.5Hz), 3.30-3.10(1H5 m), 3.06(2H, t, J=6.5Hz), 1.38(6H, d, J=6.9Hz)
Step 2: Preparation of [3-[2-(5-isopropyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl]- methanol
The procedure of Step 2 of Example 187 was repeated except for using the compound obtained in Step 1 of Example 200(0.23 g, 0.69 mmol) and NaBH4(3 eq) to obtain the title compound(0.21 g, yield: 91%).
1H NMR(CDCl3, 200MHz):.00(2H5 m), 7.46(3H5 m), 4.54(2H, t, J=6.5Hz), 3.18(1H5 m), 3.00(2H5 m), 2.97(3H, s), 1.35(6H5 d, J=6.9Hz)
Step 3: Preparation of 3-[2-(5-isopropyl-4-chloromethyl-phenoxy)-ethyl]-2-phenyl- oxazole
The procedure of Step 3 of Example 187 was repeated except for using the compound obtained in Step 2 of Example 200(0.21 g, 0.60 mmol), methylchloride(l.l eq) and triethylamine(3 eq) to obtain the title compound(0.20 g, yield: 90%). 1H NMR(CDCl3, 200MHz): δ(ppm) 8.06(2H5 m), 7.46(3H, m), 7.28(1H5 m),
6.98-6.80(3H5 m), 4.55(2H5 s), 4.30(2H5 1), 3.30-3.10(1H5 m), 3.07(2H5 t), 1.38(6H5 d, J=6.9Hz)
Step 4: Preparation of l-[4-[2-(5-isopropyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzyl]- pyrrolidine-2-carboxylic acid methyl ester
The procedure of Step 4 of Example 187 was repeated except for using the compound obtained in Step 3 of Example 200(100 mg, 0.28 mmol), D-proline methyl ester • HCl(I. leq) and K2CO3(3eq) to obtain the title compound(53 mg, yield: 42%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.99(2H, m), 7.43(3H, m), 7.24-7.16(1H, m), 6.90-6.77(3H, m), 4.24(2H5 t, J=6.7Hz), 3.85(1H5 d, J=12.9Hz), 3.65(3H5 s), 3.53(1H5 d5 J=12.9Hz), 3.25(1H5 m), 3.16(1H5 m), 3.00(2H5 1, J=6.7Hz), 2.40(1H5 m), 2.1O(1H, m), 2.10-1.70(3H. m), 1.34(6H5 d, J-7.0Hz)
Step 5: Preparation of l-[4-[2-(5-isopropyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzyl]- pyrrolidine-2-carboxylic acid
The procedure of Step 5 of Example 187 was repeated except for using the compound obtained in Step 4 of Example 200(0.053 g, 0.12 mmol) and
LiOH • H2O(1.5 eq) to obtain the title comρound(0.036 g, yield: 72%).
1H NMR(CDCl35 200MHz): δ(ppm) 7.85(2H, m), 7.38(3H5 m), 7.21(1H5 m), 7.00-6.73(3H5 m), 4.28(1H5 d, JN12.0Hz), 4.18(2H5 d, J=6.0Hz), 3.98(1H5 d,
J=12.0Hz)5 3.70(1H5 m), 3.36(1H5 m), 3.10(1H5 m), 3.00-2.90(3H, m), 2.29(1H5 m),
2.10-1.70(3H5 m), 1.25(6H5 d5 J=6.0Hz)
Example 201: Preparation of l-[4-(2-phenyl-oxazol-4-yImethoxy)-benzyl]- piperidine-2-carboxylic acid
Figure imgf000161_0001
Step 1: Preparation of l-[4-(2-phenyl-oxazol-4-ylmethoxy)-benzyl]-piperidine-
2-carboxylic acid methyl ester
The compound obtained in Step 3 of Example 187 (100 mg, 0.33 mmol), piperidine 2-carboxylic acid methyl ester(l.l eq) and K2CO3(2.5eq) were dissolved in dimethylformamide(10 ml) and the resulting mixture was stirred at 80 °C for 24 hrs. The procedure of Step 4 of Example 187 was repeated except for using the resultant to obtain the title compound(0.11 g, yield: 95%).
1H NMR(CDCl35 200MHz); 8.10(2H5 m)5 7.74(1H, s), 7.47(3H5 m), 7.25(2H5 d, J=8.5Hz), 6.97(2H, d5 J=8.5Hz), 5.09(2H5 s), 3.75(3H5 s), 3.70(1H5 d), 3.35(1H5 d),
3.18(1H5 m), 2.98(1H5 m), 2.10(1H5 m), 1.90(2H5 k), 1.75-1.50(3H5 m),
1.40-1.20(1H5 m)
Step 2: Preparation of l-[4-(2-phenyl-oxazol-4-methoxy)-benzyl]-piperidine- 2-carboxylic acid
The compound obtained in Step 1 of Example 201(0.11 g, 0.27 mmol) and LiOH • H2O(1.5eq) were dissolved in H2OZMeOH(1 :5(v/v), 1 ml) and the resulting mixture was stirred at room temperature for 2 days. The procedure of Step 5 of Example 187 was repeated except for using the resultant to obtain the title compound(0.05 g, yield: 48%). 1H NMR(CDCl3, 200MHz); 8.05(3H, m), 7.56-7.48(5H5 m), 7.18(2H5 d, J=8.5Hz)5 5.14(2H,s), 4.94(1H, d), 4.20(1H5 m), 4.55(1H, d), 4.25(1H5 m), 3.95(1H, m), 3.48(1H, m), 3.00(1H5 m), 2.32(1H5 m), 1.90-1.50(4H5 m)
Example 202: Preparation of l-[4-(2-/j-tolyI-oxazol-4-ylmethoxy)-benzyl]- piperidine-2-carboxyIic acid
Figure imgf000162_0001
Step 1: Preparation of l-[4-(2-/?-tolyl-oxazol-4-ylmethoxy)-benzyi]-piperidine-
2-carboxylic acid methyl ester
The compound obtained in Step 3 of Example 188(100 mg, 0.32 mmol), piperidine 2-carboxylic acid methyl ester • HCl(Ll eq) and K2CO3(2.5 eq) were dissolved in dimethylformamide(10 ml) and the resulting mixture was stirred. The procedure of Step 4 of Example 187 was repeated except for using the resultant to obtain the title compound(0.11 g, yield: 85%).
1H NMR(CDCl3, 200MHz); 7.96(2H5 d, J=8. IHz)5 7.72(1H5 s), 7.30(4H5 m), 6.97(2H, d, J=8.1Hz), 5.08(2H5 s), 3.93(1H, m), 3.75(3H5 s), 3.73(2H5 d), 3.38(1H, d), 3.18(1H5 m), 2.98(1H, m), 2.43(3H, s), 2.18(1H5 m), 1.85(2H5 m), 1.62-1.50(2H5 m), 1.50-1.20(2H, m)
Step 2: Preparation of l-[4-(2-j9-tolyl-oxazol-4-ylmethoxy)-benzyl]-piperidine- 2-carboxylic acid
The compound obtained in Step 1 of Example 202(0.11 g, 0.26 mmol) and LiOH • H2O(1.5 eq) were dissolved in H2OZMeOH(1 :5(vZv%), 1 ml) and the resulting mixture was stirred at room temperature for 2 days. The procedure of Step 5 of Example 187 was repeated except for using the resultant to obtain the title compound(0.066 g, yield: 63%).
1H NMR(CDCl3, 200MHz); 8.03(1H, s), 7.93(2H5 m), 7.50(2H5 m), 7.35(2H, m), 7.15(2H5 m), 5.11(2H5 s), 4.5O(1H, m), 4.36(1H5 m), 4.1O(1H, m)3.55(lH, m), 3.30(1H5 m), 2.55(1H5 m), 2.20-1.80(3H5 m)
Example 203: Preparation of l-[4-[2-(4-trifluoromethylphenyl)-oxazol-4- ylmethoxy]-benzyl]-piperidine-2-carboxylic acid
Figure imgf000163_0001
Step 1: Preparation of l-{4-[2-(4-trifluoromethylphenyl)-oxazol-4-ylmethoxy]- benzyl}-piρeridine-2-carboxylic acid methyl ester
The compound obtained in Step 3 of Example 189(100 mg, 0.27 mmol), piperidine 2-carboxylic acid methyl ester • HCl(Ll eq) and K2CO3(2.5 eq) were dissolved in dimethylformamide(10 ml) and the resulting mixture was stirred. The procedure of Step 4 of Example 187 was repeated except for using the resultant to obtain the title compound(90 mg, yield: 70%).
Step 2: Preparation of l-[4-[2-(4-trifluoromethylphenyl)-oxazol-4-ylmethoxy]- benzyl]-piperidine-2-carboxylic acid
The compound obtained in Step 1 of Example 203(0.09 g, 0.19 mmol) and LiOH • H2O(1.5eq) were dissolved in H2OZMeOH(1 :5(v/v%), 1 ml) and the resulting mixture was stirred at room temperature for 2 days. The procedure of Step 5 of Example 187 was repeated except for using the resultant to obtain the title compound(0.033 g, yield: 38%).
1H NMR(CDCl3, 200MHz); 8.24(2H5 d, J=8.1Hz), 8.17(1H, s), 7.85(2H, d, J= Hz), 7.46(1H, d, J=8.5Hz), 7.26-7.15(3H, m), 5.18(2H, s), 4.6O(1H, m), 4.15(1H, s), 4.00(1H, m), 3.45(1H, m), 3.05(1H, m), 2.35(1H, m), 1.90-1.65(5H, m)
Example 204: Preparation of l-[3-(2-phenyl-oxazol-4-ylmethoxy)-benzyl]- piperidine-2-carboxylic acid
Figure imgf000163_0002
Step 1 : Preparation of l-[3-(2-phenyl-oxazol-4-ylmethoxy)-benzyl]-piperidine- 2-carboxylic acid methyl ester
The compound obtained in Step 3 of Example 190(100 mg, 0.32 mmol), piperidine 2-carboxylic acid methyl ester ■ HCl(Ll eq) and K2CO3(2.5 eq) were dissolved in dimethylformamide(10 ml) and the resulting mixture was stirred. The procedure of Step 4 of Example 187 was repeated except for using the resultant to obtain the title comρound(0.10 g, yield: 76%).
1H NMR(CDCl3, 200MHz); 8.05(2H, m), 7.75(1H5 s), 7.46(3H5 m), 7.24(1H5 m), 7.04(1H5 m), 6.90(2H5 m), 5.08(2H5 s), 3.76(1H5 d5 J=13.5Hz)5 3.73(3H5 s), 3.4O(1H, d, J=13.5Hz), 3.17(1H, m), 2.16(1H, m), 1.83(2H5 m), 1.61-1.37(3H, m)
Step 2: Preparation of l-[2-(2-phenyl-oxazol-4-methoxy)-benzyl]-piperidine- 2-carboxylic acid The compound obtained in Step 1 of Example 204(0.1 g, 0.246 mmol) and
LiOH • H2O(1.5 eq) were dissolved in H2OMeOH(1 :5(v/v%), 1 ml) and the resulting mixture was stirred at room temperature for 2 days. The procedure of Step 5 of Example 187 was repeated except for using the resultant to obtain the title comρound(0.041 g, yield: 43%). 1H NMR(CDCl3, 200MHz); 8.09(1H5 s), 8.06(2H5 m), 7.55(3H5 m), 7.46(1H5 m), 7.24-7.14(3H5 m), 5.16(2H,s), 4.60(1H5 d), 4.15(1H5 m), 3.90(1H5 m), 3.50(1H5 m), 3.10(1H5 m) 2.35(1H, m), 2.00-1.50(5H5 m)
Example 205: Preparation of l-[3-(2-/;-tolyl-oxazol-4-ylmethoxy)-benzyl]- piperidine-2-carboxylic acid
Figure imgf000164_0001
Step 1: Preparation of l-[3-(2-p-tolyl-oxazol-4-ylmethoxy)-benzyl]-piperidine-
2-carboxylic acid methyl ester
The compound obtained in Step 3 of Example 191(100 mg, 0.31 mmol), piperidine 2-carboxylic acid methyl ester • HCl(Ll eq) and K2CO3(2.5 eq) were dissolved in dimethylformamide(10 ml) and the resulting mixture was stirred at 85 °C for 2 days. The procedure of Step 4 of Example 187 was repeated except for using the resultant to obtain the title compound(0.11 g, yield: 85%).
1H NMR(CDCl3, 200MHz); 7.93(2H5 d, J=8.2Hz), 7.72(1H5 s), 7.26-7.20(3H, m), 6.90(2H, m), 5.07(2H, m), 3.77(1H5 d5 J=I 3.5Hz), 3.72(3H, s), 3.40(1H3 d,
J=13.5Hz), 3.18(1H5 m), 2.93(1H, m), 2.39(3H5 s), 1.82(1H, m), 1.53-1.26(4H5 m)
Step 2: Preparation of 1- [3 -(2-/?-tolyl-oxazol-4-ylmethoxy)-benzyl] -piperidine- 2-carboxylic acid The compound obtained in Step 1 of Example 205(0.11 g, 0.26 mmol) and
LiOH • H2O(1.5eq) were dissolved in H2OZMeOH(1 :5(v/v%), 1 ml)_and the resulting mixture was stirred at room temperature for 2 days. The procedure of Step 5 of Example 187 was repeated except for using the resultant to obtain the title compound(0.029 g, yield: 28%). 1H NMR(CDCl3, 200MHz); 8.05(1H5 s), 7.94(2H5 d5 J=8.3Hz), 7.48(1H5 m), 7.44(2H5 d, J=8.3Hz), 7.23(3H, m), 5.14(2H, s), 4.60(1H5 m), 4.12(1H5 m), 3.97(1H, m), 3.45(1H, m) 3.07(1H5 m), 2.43(3H, s), 2.35(1H, m), 2.00-1.60(5H5 m)
Example 206: Preparation of l-[3-[2-(4-trifluoromethylphenyl)-oxazol-4- ylmethoxy]-benzyl]-piperidine-2-carboxylic acid
Figure imgf000165_0001
Step 1: Preparation of l-[3-[2-(4-trifluoromethylphenyl)-oxazol-4-ylmethoxy]- benzyl]-piperidine-2-carboxylic acid methyl ester
The compound obtained in Step 3 of Example 192(100 mg, 0.33 mmol), piperidine 2-carboxylic acid methyl ester • HCl(Ll eq) and K2CO3(2.5eq) were dissolved in dimethylformamide(10 ml) and the resulting mixture was stirred at 85 "C for 2 days. The procedure of Step 4 of Example 187 was repeated except for using the resultant to obtain the title compound(0.10 g, yield: 80%).
1H NMR(CDCl35 200MHz); 8.17(2H5 d5 J=8.1Hz), 7.81(1H5 s), 7.72(2H5 d, J=8.1Hz),
7.26-7.21(1H5 m), 7.05(1H5 s), 6.95-6.88(2H5 m), 5.09(2H5 s), 3.77(1H5 d, J=13.5Hz)5 3.19(1H5 m), 2.94(1H5 m), 2.18(1H5 m), 1.83(2H5 m), 1.61_1.34(4H, m)
Step 2: Preparation of l-[3-[2-(4-trifluoromethylphenyl)-oxazol-4-ylmethoxy]- benzyl]-piperidine-2-carboxylic acid
The compound obtained in Step 1 of Example 206(0.1 g5 0.21 mmol) and LiOH • H2O(1.5 eq) were dissolved in H2OMeOH(1 :5(v/v%), 1 ml) and the resulting mixture was stirred at room temperature for 2 days. The procedure of
Step 5 of Example 187 was repeated except for using the resultant to obtain the title compound(0.033 g5 yield: 34%).
1H NMR(CDCl3, 200MHz); 8.17(2H5 d, J=8. IHz)5 7.81(1H5 s), 7.72(2H5 d5 J=8.1Hz)5 7.26-7.21(1H5 m), 7.05(1H5 s), 6.95-6.88(2H5 m), 5.09(2H5 s), 3.77(1H5 d5
J=13.5Hz)5 3.19(1H5 m), 2.94(1H5 m), 2.18(1H5 m)5 1.83(2H5 m), 1.61-1.34(4H5 m)
Example 207: Preparation of 1- [4- [2-(2-phenyl-oxazol-4-yl)-ethoxy] -benzyl] - piperidine-2-carboxylic acid
Figure imgf000165_0002
Step 1: Preparation of l-[4-[2-(2-phenyl-oxazol-4-yl)-ethoxy]-benzyl]-piperidine- 2-carboxylic acid methyl ester The compound obtained in Step 3 of Example 193(100 mg, 0.31 mmol), piperidine 2-carboxylic acid methyl ester • HCl(Ll eq) and K2CO3(2.5 eq) were mixed together and stirred at 80 °C for 24 hrs. The procedure of Step 4 of Example
187 was repeated except for using the resultant to obtain the title compound(90 mg, yield: 69%).
1H NMR(CDCl3, 200MHz): δ(ppm) 8.03(2H, m), 7.57(1H, s), 7.45(3H5 m), 7.30-7.20(2H, m), 6.87(2H3 d, J=8.3Hz), 4.27(2H5 m), 3.81(1H5 d, J=12.6Hz)5 3.65(3H, s), 3.51(1H, d, J= 12.6Hz), 3.25(1H, m), 3.00(3H5 m), 2.37(1H5 m), 2.20-1.75(4H, m)
Step 2: Preparation of l-[4-[2-(2-phenyl-oxazol-4-yl)-ethoxy]-benzyl]-piperidine- 2-carboxylic acid
The compound obtained in Step 1 of Example 207(0.09 g, 0.21 mmol) and LiOH • H2O(1.5eq) were dissolved in H2OZMeOH(1 :5(v/v%), 1 ml) and the resulting mixture was stirred at room temperature for 2 days. The procedure of Step 5 of Example 187 was repeated except for using the resultant to obtain the title comρound(0.044 g, yield: 52%).
1H NMR(CDCl3, 200MHz): δ(ppm) 8.03(2H, m), 7.83(1H, s), 7.51(3H5 m), 7.45(2H5 d, J=8.6Hz)5 7.03(2H, d, J=8.6Hz), 4.4O(1H, d, J=12.8Hz), 4.34(2H, t, J=6.5Hz), 4.2O(1H, d, J=12.8Hz), 3.90(1H5 m), 3.51(1H, m), 3.2O(1H, m), 3.09(2H, t, J=6.5Hz), 2.5O(1H, m), 2.13-1.95(3H, m)
Example 208: Preparation of l-[4-[2-(2~/?-tolyl-oxazoI-4-yl)-ethoxy]-benzyl]- piperidine-2-carboxylic acid
Figure imgf000166_0001
Step 1 : Preparation of l-[4-[2-(2-jo-tolyl-oxazol-4-yl)-ethoxy]-benzyl]-piperidine-
2-carboxylic acid methyl ester
The compound obtained in Step 3 of Example 194(100 mg, 0.31 mmol), piperidine 2-carboxylic acid methyl ester • HCl(Ll eq) and K2CO3(2.5 eq) were mixed together and the resulting mixture was stirred at 80 °C for 24 hrs. The procedure of Step 4 of Example 187 was repeated except for using the resultant to obtain the title compound(0.10 g, yield: 77%).
1H NMR(CDCl3, 200MHz):7.90(2H, d, J=8.1Hz), 7.53(1H, s), 7.30-7.10(4H5 m),
6.93-6.84(2H, m), 4.26(2H, t, J=6.5Hz), 3.80(1H5 d, J=12.8Hz), 3.64(3H5 s), 3.54(1H, d, J=12.8Hz), 3.2O(1H, m), 3.09(2H5 t, J=6.5Hz), 2.39(3H, s),
2.20-1.70(5H5 m) Step 2: Preparation of l-[4-[2-(2-j9-tolyl-oxazol-4-yl)-ethoxy]-benzyl]-piperidine- 2-carboxylic acid
The compound obtained in Step 1 of Example 208(0.10 g, 0.23 mmol) and
LiOH • H2O(1.5eq) were dissolved in H2OZMeOH(1 :5(v/v%), 1 ml), and the resulting mixture was stirred at room temperature for 2 days. The procedure of
Step 5 of Example 187 was repeated except for using the resultant to obtain the title comρound(0.062 g, yield: 65%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.90(2H5 d), 7.8O(1H, m), 7.45(2H, d), 7.34(2H, d), 7.10(2H, d), 4.5O(1H, m), 4.30(2H, t), 4.05(1H5 m), 4.65(1H5 m), 3.1O(1H, t), 2.42(3H5 sθ< 2.36(2H, m), 2.10(1H5 m), 1.80-1.60(6H5 m),
Example 209: Preparation of l-[4-[2-[2-(4-trifluoromethylphenyl)-oxazol-4-yI]- ethoxy]-benzyl]-piperidine-2-carboxylic acid
Figure imgf000167_0001
Step 1: Preparation of l-[4-[2-[2-(4-trifluoromethylphenyl)-oxazol-4-yl]-ethoxy]- benzyl]-piperidine-2-carboxylic acid methyl ester
The compound obtained in Step 3 of Example 195(50 mg, 0.32 mmol), piperidine 2-carboxylic acid methyl ester • HCl(Ll eq) and K2CO3(2.5 eq) were mixed together and the resulting mixture was stirred at 80 °C for 24 hrs. The procedure of Step 4 of Example 187 was repeated except for using the resultant to obtain the title compound(0.112 g5 yield: 72%).
1H NMR(CDCl35 200MHz): δ(ppm) 8.15(2H5 m), 7.80-7.62(3H5 m), 7.50-7.20(2H5 m), 7.10-6.80(2H5 m), 4.40-4.20(2H5 m), 3.82(1H5 m)5 3.65(3H, s), 3.55(1H5 m),
3.40-3.00(3H5 m), 2.50-2.30(1H5 m), 2.30-1.70(5H5 m)
Step 2: Preparation of l-[4-[2-[2-(4-trifluoromethylphenyl)-oxazol-4-yl]-ethoxy]- benzyl] -piperidine-2-carboxylic acid
The compound obtained in Step 1 of Example 209(0.112 g, 0.22 mmol) and
LiOH - H2O(1.5 eq) were dissolved in H2OZMeOH(1 :5(vZv%), 1 ml) and the resulting mixture was stirred at room temperature for 2 days. The procedure of
Step 5 of Example 187 was repeated except for using the resultant to obtain the title compound(0.047 g5 yield: 43%).
1H NMR(CDCl3, 200MHz): δ(ppm) 8.24(2H5 d), 7.91(1H, s), 7.84(2H, d), 7.50(2H5 d), 7.00(2H, m), 4.50(1H5 m), 4.35(3H, m), 3.9O(1H, m), 3.6O(1H, m), 3.18(2H, m), 2.40(LH5 m)5 2.15-1.60(5H5 m) Example 210: Preparation of 1- [3- [2-(2-phenyl-oxazol-4-yl)-ethoxy] -benzyl] - piperidine-2-carboxylic acid
Figure imgf000168_0001
Step 1: Preparation of l-[4-[2-(2-phenyl-oxazol-4-yl)-ethoxy]-benzyl]-piperidine- 2-carboxylic acid methyl ester
The compound obtained in Step 3 of Example 196(100 mg, 0.31 mmol), piperidine 2-carboxylic acid methyl ester • HCl(Ll eq) and K2CO3(2.5 eq) were mixed together and the resulting mixture was stirred at 80 °C for 24 hrs. The procedure of Step 4 of Example 187 was repeated except for using the resultant to obtain the title compound(0.068 g, yield: 52%).
Step 2: Preparation of l-[4-[2-(2-phenyl-oxazol-4-yl)-ethoxy]-benzyl]-piperidine-
2-carboxylic acid
The compound obtained in Step 1 of Example 210(0.068 g, 0.16 mmol) and LiOH • H2O(1.5eq) were dissolved in H2OZMeOH(1 :5(v/v%), 1 ml) and the resulting mixture was stirred at room temperature for 2 days. The procedure of
Step 5 of Example 187 was repeated except for using the resultant to obtain the title compound(0.028 g, yield: 44%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.85(2H, m), 7.38(3H, m), 7.21(1H, m), 7.00-6.73(3H5 m), 4.28(1H5 m), 4.18(2H, m), 3.98(1H, m), 3.36(1H5 m), 3.10(1H5 m),
3.00-2.90(3H, m), 2.29(1H, m), 2.10-1.70(5H, m)
Example 211: Preparation of l-[3-[2-(2-j9-tolyl-oxazol-4-yl)-ethoxy]-benzyl]- piperidine-2-carboxylic acid
Step 1 : Preparation of l-[4-[2-(2-/?-tolyl-oxazol-4-yl)-ethoxy]-benzyl]-piperidine-
2-carboxylic acid methyl ester
The compound obtained in Step 3 of Example 197(100mg5 0.31mmol), piperidine 2-carboxylic acid methyl ester • HCl(Ll eq) and K2CO3(2.5eq) were mixed together and the resulting mixture was stirred at 80 °C for 24 hrs. The procedure of Step 4 of Example 187 was repeated except for using the resultant to obtain the title compound(0.056 g, yield: 42%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.90(2H5 d), 7.55(1H5 s), 7.30-6.70(6H5 m).
4.28(2H5 t), 3.80(1H5 m), 3.80(3H5 s), 3.40(1H5 m), 3.08(2H5 t), 2.91(2H, m), 2.40(3H5 s), 2.16(1H5 m), 1.80-1.60(2H5 m)
Step 2: Preparation of l-[4-[2-(2-p-tolyl-oxazol-4-yl)-ethoxy]-benzyl]-piperidine- 2-carboxylic acid
The compound obtained in Step 1 of Example 211(0.056 g, 0.13 mmol) and
LiOH • H2O(1.5eq) were dissolved in H2OZMeOH(1 :5(vZv%), 1 ml) and the resulting mixture was stirred at room temperature for 2 days. The procedure of Step 5 of Example 187 was repeated except for using the resultant to obtain the title compound(0.014 g, yield: 26%).
1H NMR(CDCl3, 200MHz): δ(ppm) 7.90(2H, m), 7.81(1H, s), 7.43-7.32(3H5 m), 7.15-6.96(3H, m), 4.53(1H, d, J=UJHz), 4.38-4.27(4H, m), 3.54(1H, m), 3.36(1H, m), 3.10(2H, m), 2.6O(1H, m), 2.42(3H, s), 2.23-1.80(5H, m)
Example 212: Preparation of l-[4-[2-[2-(4-trifluoromethyIphenyl)-oxazol-4-yl]- ethoxy]-benzyl]-piperidine-2-carboxylic acid
Figure imgf000169_0001
Step 1: Preparation of l-[4-[2-[2-(4-trifluoromethylphenyl)-oxazol-4-yl]-ethoxy]- benzyl]-piperidine-2-carboxylic acid methyl ester
The compound obtained in Step 3 of Example 197 (50 mg, 0.32 mmol), piperidine 2-carboxylic acid methyl ester • HCl(Ll eq) and K2CO3(2.5eq) were mixed together and the resulting mixture was stirred at 80 °C for 24 hrs. The procedure of Step 4 of Example 187 was repeated except for using the resultant to obtain the title compound(0.07 g5 yield: 50%).
Step 2: Preparation of l-[4-[2-[2-(4-trifiuoromethylphenyl)-oxazol-4-yl]-ethoxy]- benzyl]-piperidine-2-carboxylic acid
The compound obtained in Step 1 of Example 212(0.07 g, 0.16 mmol) and LiOH • H2O(1.5eq) were dissolved in H2OZMeOH(1 :5(vZv%), 1 ml) and the resulting mixture was stirred at room temperature for 2 days. The procedure of
Step 5 of Example 187 was repeated except for using the resultant to obtain the title compound(0.023 g, yield: 30 %).
1H NMR(CDCl3, 200MHz): δ(ppm) 8.06(2H, d, J=8.5Hz), 7.78(1H, s), 7.68(2H, d, J=8.5Hz), 7.2O(1H, m), 7.01-6.94(3H, m), 4.39(1H5 d, J=12.7Hz), 4.25-4.14(4H, m),
3.4O(1H, m), 3.2O(1H, m), 3.98(2H5 m), 2.45(1H5 m), 2.09-1.85(5H, m)
Example 213: Preparation of l-[4-(5-methyl-2-Jp-tolyl-oxazol-4-ylmethoxy)- benzyI]-pyrroIidine-2-carboxylic acid ϊ-butyl ester
Figure imgf000170_0001
4-(4-Chloromethyl-phenoxymethyl)-5-methyl-2-/?-tolyl-oxazole(0.24 g, 0.75 mmol), pyrrolidine-2-carboxylic acid f-butyl ester(0.1 g, 0.58 mmol) and K2CO3(0.2 g, 1.45 mmol) were dissolved in DMF (20 ml) and the resulting mixture was stirred at 85 °C for 1 day. The reaction product was cooled down to room temperature and was extracted with water and dichloromethane. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography (eluent: hexane/ethyl acetate^/l) to obtain the title compound(80 mg, yield: 45%). 1H NMR(CDCl3, 200MHz): δ(ppm) 7.92(d, J=8.2Hz, 2H)5 7.24-7.30(m, 4H), 6.96(d, J=8.2Hz, 2H), 4.99(s, 2H), 3.95(d, J=12.6Hz, IH), 3.70-3.86(m, IH), 3.24-3.86(m, 2H), 3.46(d, J=12.6Hz, IH)5 2.43(s, 3H)5 2.41(s, 3H)5 1.76-2.12(m5 4H), 1.47(s, 9H)
Example 214: Preparation of (R)-l-[4-(2-biphenyl-4-yl-5-methyl-oxazol-4- ylmethoxy)-benzyl]-pyrrolidine-2-carboxylic acid
Figure imgf000170_0002
Step 1: Preparation of (R)-l-[4-(2-biphenyl-4-yl-5-methyl-oxazol-4-ylmethoxy)- benzyl]-pyrrolidine-2-carboxylic acid methyl ester
(R)-l-(4-hydroxy-benzyl)-pyrrolidine-2-carboxylic acid methyl ester(0.15 g, 0.64 mmol) and 2-biphenyl-4-yl-4-chloromethyl-5-methyl-oxazole(0.23 g, 0.82 mmol) were dissolved in N,N-dimethylformamide(10 ml), and potassium carbonate(0.08 g, 0.56 mmol) was added thereto. The resulting mixture was stirred at 80 °C for 1 day. After the completion of the reaction, distilled water was poured to the reaction product. The resultant was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography(eluent: hexane/ethyl acetate^θ/l) to obtain the title comρound(0.23 g, 73%). 1H NMR(CDCl3, 300MHz): δ(ppm) 8.08(d, 2H, J=8.4Hz), 7.68(d5 2H5 J=8.4Hz), 7.67-7.62(m, 2H), 7.49-7.33(m5 3H)5 7.25(d, 2H5 J=8.7Hz), 6.96(d, 2H5 J=8.7Hz), 4.99(s, 2H), 3.82(d, IH, J=12.6Hz), 3,65(s, 3H), 3.23(d, IH5 J=12.6Hz)5 3.23-3.19(m, IH)5 3.06-3.01(m, IH), 2.45(s, 3H), 2.44-2.35(m. IH), 2.15-2.09(m, IH), 1.99-1.70(m, 3H)
Step 2: Preparation of (R)-l-[4-(2-biphenyl-4-yl-5-methyl-oxazol-4-ylmethoxy)- benzyl]-pyrrolidine-2-carboxylic acid The compound obtained in Step 1 of Example 214 (0.19 g, 0.41 mmol) was dissolved in a mixture of methanol and water(5:l(v/v%), 1 ml) and lithium hydroxy monohydrate(0.03 g, 0.84 mmol) was added thereto. The resulting mixture was stirred at room temperature for 3 days. The reaction product was diluted with ethyl acetate and acidified with IM HC1(3 ml). The resultant was extracted with dichloromethane(10 ml). The organic layer was separated, dried over anhydrous sodium sulfate(2 g) and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography(eluent: methanol/dichloromethane=l/20) to obtain the title compound(0.18 g, 96%). 1H NMR(DMSO-d6, 300MHz): δ(ppm) 8.02(d, 2H, J=8.1Hz), 7.83(d, 2H, J=8. IHz)5 7.74(d, 2H, J=7.8Hz), 7.53-7.35(m, 3H), 7.37(d, 2H, J=8.0Hz), 7.04(d, 2H5 J=8.0Hz), 5.02(s, 2H)5 4.07(d, IH5 J=12.6Hz), 3.85(d, IH, J=12.6Hz), 3.54-3.38(m, IH)5 3.28-3.06(m, IH)5 2.94-2.62(m, IH), 2.47(s, 3H)5 2.13-2.08(m, IH)5 2.00-1.40(m5 3H)
Example 215: Preparation of (R)-l-[4-(5-methyI-2-phenyl-oxazol-4-ylmethoxy)- benzyl] -py rrolidine-2-carboxyIic acid
Figure imgf000171_0001
Step 1: Preparation of (R)-l-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzyl]- pyrrolidine-2-carboxylic acid methyl ester The procedure of Step 1 of Example 214 was repeated except for using
4-chloromethyl-5-methyl-2-phenyl-oxazole(0.12 g, 0.58 mmol) to obtain the title comρound(0.16 g, 76%).
1H NMR(CDCl3, 300MHz): δ(ppm) 8.03-8.00(m, 2H), 7.50-7.42(m, 3H)5 7.24(d, 2H,
J=8.7Hz), 6.95(d, 2H5 J=8.7Hz)5 4.98(s, 2H), 3.81(d, IH5 J=12.6Hz), 3.65(s, 3H), 3.52(d, IH5 J=12.6), 3.25-3.20(m5 IH), 2.43(s, 3H), 2.42-2.34(m, IH), 2.15-2.09(m,
IH)5 1.98-1.55(m, 3H).
Step 2: Preparation of (R)-l-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzyl]- pyrrolidine-2-carboxylic acid The procedure of Step 2 of Example 214 was repeated except for using the compound obtained in Step 1 of Example 215(0.14 g, 0.33 mmol) to obtain the title compound(0.12 g, 95%).
1H NMR(DMSO-(I6, 300MHz): δ(ppm) 7.87-7.80(m, 2H)5 7.44-7.38(m, 3H), 7.25(d,
2H5 J=8.5Hz)5 6.94(d, 2H5 J=8.5Hz), 4.90(s, 2H)5 3.96(d5 IH5 J=12.8Hz), 3.74(d5 IH5
J=12.8Hz), 3.37-3.29(m5 IH)5 3.15-2.95(m5 IH)5 2.66-2.59(m, IH), 2.10-1.96(m, lH), 1.82-1.59(m, 3H).
Example 216: Preparation of (R)-I- [4-(5-methyl-2-/7-toIyI-oxazol-4-ylmethoxy)- benzyl]-pyrrolidine-2-carboxyIic acid
Figure imgf000172_0001
Step 1 : Preparation of (R)-l-[4-(5-methyl-2-/;-tolyl-oxazol-4-ylmethoxy)-benzyl]- pyrrolidine-2-carboxylic acid methyl ester
The procedure of Step 1 of Example 214 was repeated except for using
4-chloromethyl-5methyl-2-/?-toryl-oxazole(0.16 g, 0.72 mmol) to obtain the title comρound(0.18 g, 67%).
1H NMR(CDCl3, 300MHz): δ(ppm) 7.90(d, 2H5 J=8. IHz)5 7.25(d, 2H5 J=8.4Hz),
7.24(d,2H, J=8.1Hz), 6.94(d5 2H5 J=8.4Hz), 4.97(s, 2H)5 3.81(d, IH5 J=12.6Hz),
3.64(s, 3H)5 3.52(d5 IH5 J=12.6Hz)5 3.25-3.18(m, IH)5 3.05-3.00(m, IH)5 2.42(s5 3H)5
2.40(s, 3H)5 2.39-2.34(m5 IH)5 2.17-2.10(m5 IH)5 1.98-1.25(m, 3H)
Step 2: Preparation of (R)-l-[4-(5-methyl-2-/?-tolyl-oxazol-4-ylmethoxy)-benzyl]- pyrrolidine-2-carboxylic acid
The procedure of Step 2 of Example 214 was repeated except for using the compound obtained in Step 1 of Example 216(0.18 g, 0.42 mmol) to obtain the title compound(0.16 g, 94%).
Example 217: Preparation of (R)-l-{4-[5-methyl-2-(4-trifluoromethyl-phenyl)- oxazol-4-ylmethoxy]-benzyl}-pyrrolidine-2-carboxyIic acid
Figure imgf000172_0002
Step 1 : Preparation of (R)-l-{4-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol- 4-ylmethoxy]-benzyl}-ρyrrolidine-2-carboxylic acid methyl ester
The procedure of Step 1 of Example 214 was repeated except for using 4-chloromethyl-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole(0.21 g, 0.76 mmol) to obtain the title compound(0.25 g, 81%). 1H NMR(CDCl3, 300MHz): δ(ppm) 8.3 l(d, 2H5 J=8.3Hz), 7.20(d, 2H, 8.3Hz),
7.25(d, 2H5 J=8.4Hz), 6.95(d5 2H5 J=8.4Hz) 5.00(s5 2H)5 3.82(d, IH5 J=12.7Hz),
3.65(s, 3H), 3.52(d, IH, J=12.7Hz), 3.23-3.19(m, IH), 3.05-3.01(m5 IH), 2.42(s, 3H),
2.39-2.36(m, IH), 2.15-2.10(m, IH), 1.99-1.75(m, 3H)
Step 2: Preparation of (R)-l-{4-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-
4-ylmethoxy]-benzyl}-pyrrolidine-2-carboxylic acid
The procedure of Step 1 of Example 214 was repeated except for using the compound obtained in Step 1 of Example 217(0.21 g, 0.44 mmol) to obtain the title compound(0.18 g, 91 %).
1H NMR(DMSO-d6, 300MHz): δ(ppm) 8.20(d5 2H5 J=8.3Hz), 7.94(d, 2H5 J=8.3Hz),
7.43(d, 2H, J=8.4Hz), 7.09(d, 2H, J=8.4Hz), 5.08(s, 2H), 4.15(d, IH, J=12.7Hz),
3.95(d, IH, J=12.7Hz), 3.60-3.51(m, IH), 3.28-3.22(m, IH), 2.89-2.80(m, IH)5
2.53(s, 3H), 2.30-2.15(m, IH), 2.03-1.77(m5 3H)
Example 218: Preparation of (R)-l-[4-(5-methyI-2-thiophen-2-yI-oxazol-4- ylmethoxy)-benzyl]-pyrrolidine-2-carboxylic acid
Figure imgf000173_0001
Step 1 : Preparation of (R)-l-[4-(5-methyl-2-thiophen-2-yl-oxazol-4-ylmethoxy)- benzyl]-pyrrolidine-2-carboxylic acid methyl ester
The procedure of Step 1 of Example 214 was repeated except for using
4-chloromethyl-5-methyl-2-thiophen-2-yl-oxazole(0.16 g, 0.75 mmol) to obtain the title comρound(0.20 g, 75%). 1H NMR(CDCl3, 300MHz): δ(ppm) 7.64-7.61(m, IH)5 7.50-7.37(m, IH)5 7.23(d, 2H,
J=8.6Hz), 7.09(d.d.5 IH5 J=4.8Hz, J'=3.8Hz), 6.93(d, 2H5 J=8.6Hz), 4.96(s5 2H),
3.81(d, IH, J=12.6Hz), 3.65(s, 3H), 3.52(d, IH, J=12.6Hz), 3.26-3.17(m, IH),
3.06-3.00(m, IH)5 2.41(s5 3H), 2.40-2.34(m5 IH)5 2.13-2.02(m5 IH)5 1.99-1.58(m,
3H)
Step 2: Preparation of (R)-l-[4-(5-methyl-2-thiophen-2-yl-oxazol-4-ylmethoxy)- benzyl] -pyrrolidine-2-carboxy lie acid
The procedure of Step 2 of Example 214 was repeated except for using the compound obtained in Step 1 of Example 218(0.09 g, 0.21 mmol) to obtain the title compound(0.08 g, 92%).
1H NMR(DMSO-d65 300MHz): δ(ppm) 7.64-7.61(m, IH)5 7.52-7.50(m, IH)5 7.23(d,
2H, J=8.4Hz), 7.16-7.00(m, IH), 6.89(d, 2H, J=8.4Hz), 5.62(s, IH), 4.83(s, 2H)5 3.93(d, IH, J=13.0Hz), 3.72(d, IH5 J=I 3. OHz), 3.50-3.21(m, IH), 3.15-3.00(m, IH), 2.74-2.45(m, IH), 2.28(s, 3H), 2.74-2.45(m, IH), 2.28(s, 3H), 2.14-1.85(m, IH), 1.96-1.34(m, 3H)
Example 219: Preparation of (S)-l-{3-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)- ethoxy]-benzyl}-pyrrolidine-2-carboxylic acid
Figure imgf000174_0001
Step 1 : Preparation of (S)-l-{3-[2-(2-biρhenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]- benzyl}-pyrrolidine-2-carboxylic acid methyl ester 2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethanol(0.27 g, 0.97 mmol),
(S)-l-(3-hydroxy-benzyl)-pyrrolidine-2-carboxylic acid(0.15 g, 0.64 mmol) and triphenylphosphine(0.29 g, 1.10 mmol) were dissolved in anhydrous toluene(10 ml). The resulting mixture was stirred for 30 mins, and diisopropylazodicarboxylate(0.22 g, 1.09 mmol) was added at room temperature. The resulting mixture was stirred for 3 days. After the completion of the reaction, ice water was poured to the reaction product. The resultant was extracted with ethyl acetate. The organic layer was separated and the solvent was removed therefrom. The residue thus obtained was subjected to a silica gel chromatography(eluent: hexane/ethyl acetate=3/l) to obtain the title compound(0.15 g, 48%). 1H NMR(CDCl3, 300MHz): δ(ppm) 8.03(d, 2H, J=8.1Hz), 7.65(d, 2H, J=8.1Hz), 7.63(d, 2H, J=8.2Hz), 7.48-7.33(m, 3H), 7.23-7.16(m, 3H), 6.91-6.88(m, 2H), 6.82-6.78(m, IH), 4.26(t, 2H, J=6.7Hz), 3.85(d, IH, J=12.8Hz), 3.65(s, 3H), 3.53(d, IH, J=12.8Hz), 3.28-3.22(m, IH), 3.05-3.01(m, IH), 2.99(t, 2H, J=6.7Hz), 2.43-2.4 l(m, IH), 2.39(s, 3H), 1.96-1.77(m, 4H).
Step 2: Preparation of (S)-l-{3-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)- ethoxy] -benzyl } -pyrrolidine-2-carboxylic acid
The compound obtained in Step 1 of Example 219(0.14 g, 0.27 mmol) was dissolved in a mixture of methanol and water(5: l, 1 ml) and lithium hydroxy monohydrate(0.017 g, 0.41 mmol) was added thereto. The resulting mixture was stirred at room temperature for 3 days. The reaction product was diluted with ethyl acetate and acidified with IM HC1(3 ml). The resultant was extracted with dichloromethane(3 ml). The organic layer was separated, dried over anhydrous sodium sulfate(2 g) and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography (eluent: methanol/dichloromethane=l/20) to obtain the title compound(0.12 g, 88%). 1H NMR(DMSO-d6, 300MHz): δ(ppm) 7.91(d, 2H5 J=8.1Hz), 7.73 (d, 2H, J=8.1Hz), 7.65(d, 2H, J=8.1Hz), 7.45-7.30(m, 3H), 7.23-7.17(m, IH), 6.98-6.83(m, 3H), 4.16(t, 2H, J=6.4Hz), 4.06(d, IH, J=I 2.8Hz), 3.79(d, IH, J=I 2.8Hz), 3.52-3.46(m, lH),3.15-3.05(m, IH), 2.88(t, 2H, J=6.4Hz), 2.72-2.64(m, IH), 2.31(s, 3H)5 2.11-2.06(m, IH), 1.85-1.65(m, 3H).
Example 220: Preparation of (S)-l-{3-[2-(5-methyl-2-/?-tolyl-oxazol-4-yl)- ethoxy-benzyl}-pyrroIidine-2-carboxylic acid
Figure imgf000175_0001
Step 1 : Preparation of (S)-l-{3-[2-(5-methyl-2-/?-tolyl-oxazol-4-yl)-ethoxy- benzyl}-pyrrolidine-2-carboxylic acid methyl ester
The procedure of Step 1 of Example 219 was repeated except for using 2-(5-methyl-2-p-tolyl-oxazol-4-yl)-ethanol (0.21 g, 0.97 mmol) to obtain the title compound(0.14 g, 52%). 1H NMR(CDCl3, 300MHz): δ(ppm) 7.85(d, 2H, J=8.1Hz), 7.24-7.16(m, 3H), 6.90-6.87(m, 2H), 6.81-6.76(m, IH), 4.23 (t, 2H, J=6.7Hz), 3.85(d, IH, J= 12.8Hz), 3.65(s, 3H), 3.53(d, IH, J=I 2.8Hz), 3.26-3.22(m, IH), 3.07-2.99(m, IH), 2.96(t, 2H, J=6.7Hz), 2.41-2.39(m, IH), 2.38(s, 3H), 2.37(s, 3H), 1.96-1.77(m, 4H).
Step 2: Preparation of (S)-l-{3-[2-(5-methyl-2-p-tolyl-oxazol-4-yl)-ethoxy-benzyl}- pyrrolidine-2-carboxylic acid
The procedure of Step 2 of Example 219 was repeated except for using the compound obtained in Step 1 of Example 220(0.023 g, 0.053 mmol) to obtain the title comρound(0.018 g, 81%). 1H NMR(DMSO-d6, 300MHz): δ(ppm) 7.74(d, 2H, J=8.1Hz), 7.25(d, 2H, J=8.1Hz), 7.24-7.16(m, IH), 6.95-6.70(m, 3H), 4.16(t, 2H, J=6.4 Hz), 4.06(d, IH, J=12.8Hz), 3.79(d, IH, J=12.8Hz), 3.52-3.46(m, IH), 3.15-3.05(m, IH), 2.88(t, 2H, J=6.4Hz), 2.72-2.64(m, IH), 2.3 l(s, 3H), 2.29(s, 3H), 2.11-2.06(m, IH), 1.85-1.65(m, 3H).
Example 221: Preparation of (S)-l-(3-{2-[5-methyI-2-(4-trifluoromethyl- phenyl)-oxazol-4-yl]-ethoxy}-benzyl)-pyrrolidine-2-carboxyIic acid
Figure imgf000176_0001
Step 1: Preparation of (S)-l-(3-{2-[5-methyl-2-(4-trifluoromethyl-ρhenyl)- oxazol-4-yl]-ethoxy}-benzyl)-pyrrolidine-2-carboxylic acid methyl ester
The procedure of Step 1 of Example 219 was repeated except for using 2-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-ethanol(0.26 g, 0.96 mmol) to obtain the title compound(0.21 g, 44%).
1H NMR(CDCl3, 300MHz): δ(ppm) 8.06(d, 2H, J=8.3Hz), 7.67(d, 2H, J=8.3Hz), 7.23-7.16(m, IH), 6.91-6.88(m, 2H), 6.81-6.77(m, IH), 4.25(t, 2H, J=6.7Hz), 3.85(d, IH, J=12.8Hz), 3.65(s, 3H), 3.53(d, IH, J=12.8Hz), 3.26-3.22(m, IH), 3.07-2.99(m, IH), 2.96(t, 2H, J=6.7Hz), 2.41-2.39(m, IH), 2.38(s, 3H), 1.96-1.77(m, 4H).
Step 2: Preparation of (S)-l-(3-{2-[5-methyl-2-(4-trifluoromemyl-phenyl)- oxazol-4-yl]-ethoxy}-benzyl)-pyrrolidine-2-carboxylic acid
The procedure of Step 2 of Example 219 was repeated except for using the compound obtained in Step 1 of Example 221(0.21 g, 0.42 mmol) to obtain the title comρound(0.19 g, 97%).
1H NMR(DMSO-d6, 300MHz): δ(ppm) 7.90(d, 2H, J=8.3Hz), 7.65(d, 2H, J=8.3Hz), 7.07-7.01(m, IH), 6.80-6.65(m, 3H), 4.01(t, 2H, J=6.4Hz), 3.84(d, IH, J=12.8Hz), 3.56(d, IH, J=12.8Hz), 3.21-3.26(m, IH), 2.96-2.84(m, IH), 2.76(t, 2H, J=6.4Hz), 2.48-2.40(m, IH), 2.18(s, 3H), 1.95-1.48(m, 4H)
Example 222: Preparation of (S)-l-{3-[2-(5-methyl-2-thiophen-2-yl-oxazoI-4-yl)- ethoxy]-benzyl}-pyrrolidine-2-carboxyIic acid
Figure imgf000176_0002
Step 1: Preparation of (S)-l-{3-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]- benzyl}-pyrrolidine-2-carboxylic acid methyl ester
The procedure of Step 1 of Example 219 was repeated except for using 2-(5-methyl-2-thioρhen-2-yl-oxazol-4-yl)-ethanol(0.20 g, 0.96 mmol) to obtain the title compound(0.15 g, 55%).
1H NMR(CDCl3, 300MHz): δ(ppm) 7.59-7.57(m, IH)3 7.37-7.34(m, IH), 7.20-7.16(m, IH)5 7.09-7.05(m, IH), 6.90-6.87(m, 2H), 6.80-6.78(m, IH), 4.22(t, 2H, J=6.7Hz), 3.85(d, IH, J=12.8Hz), 3.65(s, 3H), 3.52(d, IH, J=12.8Hz)3 3.27-3.21(m, IH), 3.05-3.00(m, IH), 2.95(t, 2H, J=6.7Hz), 2.40-2.37(m, IH)3 2.36(s, 3H)3 2.10-1.78(m, 4H).
Step 2: Preparation of (S)-l-{3-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)- ethoxy]-benzyl}-pyrrolidine-2-carboxylic acid
The procedure of Step 2 of Example 219 was repeated except for using the compound obtained in Step 1 of Example 222(0.13 g, 0.3 mmol) to obtain the title compound(0.10 g, 80%).
1H NMR(DMSO-d6, 300MHz): δ(ppm) 7.74-7.71(m, IH), 7.62-7.60(m, IH), 7.29-7.24(m, IH), 7.21-7.17(m, IH)5 7.02-6.88(m, 3H), 4.19(t, 2H, J=6.4Hz), 4.09(d,
IH5 J=12.8Hz), 3.82(d, IH5 J=12.8Hz), 3.51-3.46(m, IH), 3.16-3.12(m, IH), 2.92(t3
2H, J=6.4Hz), 2.74-2.67(m, IH), 2.35(s, 3H), 2.17-2.10(m, IH), 1.92-1.74(m, 3H).
Example 223: Preparation of (S)-l-{4-[2-(2-biphenyl-4-yI-5-methyl-oxazoI-4-yI)- ethoxy]-benzyl}-pyrrolidine-2-carboxylic acid
Figure imgf000177_0001
Step 1: Preparation of (S)-l-{4-[2-(2-biphenyl-4-yl-5-memyl-oxazol-4-yl)-ethoxy]- benzyl}-pyrrolidine-2-carboxylic acid methyl ester
The procedure of Step 1 of Example 219 was repeated except for using 2-(2-biρhenyl-4-yl-5-methyl-oxazol-4-yl)-ethanol(0.27 g, 0.96 mmol) and
(S)-l-(4-hydroxy-benzyl)-pyrrolidine-2-carboxylic acid methyl ester(0.15 g, 0.64 mmol) to obtain the title compound(0.17 g, 55%).
1H NMR(CDCl3, 300MHz): δ(ppm) 8.03(d, 2H, J=8.1Hz), 7.66(d, 2H, J=8.1Hz),
7.62(d, 2H, J=8.1Hz), 7.48-7.33(m, 3H)5 7.20(d5 2H, J=8.4Hz), 6.83(d, 2H, J=8.4Hz), 4.23(t, 2H, J=6.7Hz), 3.79(d, IH3 J=12.8Hz),3.65(s, 3H), 3.50(d, IH, J=12.8Hz),
3.23-3.17(m, IH)5 3.03-2.99(m, IH), 2.97(t, 2H5 J=6.7Hz), 2.38(s, 3H), 2.36-2.33(m5
1H), 2.1O-I.77(m, 4H).
Step 2: Preparation of (S)-l-{4-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]- benzyl }-pyrrolidine-2-carboxylic acid
The procedure of Step 2 of Example 219 was repeated except for using the compound obtained in Step 1 of Example 223(0.16 g, 0.32 mmol) to obtain the title compound(0.13 g, 84%).
1H NMR(DMSO-d6, 300MHz): δ(ppm) 7.86(d, 2H, J=8.2Hz), 7.69(d, 2H, J=8.2Hz), 7.60(d, 2H, J=8.3Hz), 7.40~7.28(m, 3H), 7.26(d, 2H, J=8.4 Hz), 6.84(d, 2H, J=8.4Hz), 4.1 l(t, 2H, J=6.5Hz), 4.09(d, IH, J=12.8 Hz), 3.91(d, IH, J= 12.8Hz), 3.70-3.64(m, IH), 3.20-3.12(m, IH), 2.83(1, 2H, J=6.5Hz), 2.81-2.78(m, IH), 2.26(s, 3H), 2.14-2.08(m, IH), 1.80-1.63(m, 3H).
Example 224: Preparation of (S)-l-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)- ethoxy]-benzyl}-pyrroIidine-2-carboxylic acid
Figure imgf000178_0001
Step 1 : Preparation of (S)-l-{4-[2-(5-memyl-2-phenyl-oxazol-4-yl)-ethoxy]- benzyl}-pyrrolidine-2-carboxylic acid methyl ester
The procedure of Step 1 of Example 223 was repeated except for using 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethanol(0.20 g, 0.98 mmol) to obtain the title comρound(0.20 g, 73%).
1H NMR(CDCl3, 300MHz): δ(ppm) 7.99-7.95(m, 2H), 7.46-7.36(m, 3H), 7.20(d, 2H, J=8.4Hz), 6.83(d, 2H, J=8.4Hz), 4.23(t, 2H, J=6.7Hz), 3.79(d, IH, J= 12.8Hz), 3.65(s, 3H), 3.50(d, IH, J=I 2.8Hz), 3.23-3.17(m, IH), 3.03-2.99(m, IH), 2.97(t, 2H, J=6.7Hz), 2.40-2.37(m, IH), 2.36(s, 3H), 2.10-1.78(m, 4H).
Step 2: Preparation of (S)-l-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]- benzyl } -pyrrolidine-2-carboxylic acid
The procedure of Step 2 of Example 223 was repeated except for using the compound obtained in Step 1 of Example 224(0.17 g, 0.41 mmol) to obtain the title compound(0.16 g, 93%).
1H NMR(DMSO-d6, 300MHz): δ(ppm) 7.93-7.89(m, 2H), 7.54-7.44(m, 3H), 7.34(d, 2H, J=8.6Hz), 6.93(d, 2H, J=8.6Hz), 4.22(t, 2H, J=6.5 Hz), 4.08(d, IH, J=12.8Hz), 3.86(d, IH, J=12.8Hz), 3.49-3.42(m, IH), 3.21-3.14(m, IH), 2.93(t, 2H, J=6.5Hz), 2.79-2.72(m, IH), 2.36(s, 3H), 2.18-2.08(m, IH), 1.95-1.65(m, 3H).
Example 225: Preparation of (S)-l-(4-{2-[5-methyl-2-(4-trifluoromethyl~ phenyl)-oxazoI-4-yl]-ethoxy}-benzyl)-pyrrolidine-2-carboxylic acid
Figure imgf000178_0002
Step 1 : Preparation of (S)-l-(4-{2-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol- 4-yl]-ethoxy}-benzyl)-ρyrrolidine-2-carboxylic acid methyl ester
The procedure of Step 1 of Example 223 was repeated except for using 2-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-ethanol(0.26 g, 0.96 mmol) to obtain the title compound(0.12 g, 38%).
1H NMR(CDCl3, 300MHz): δ(ppm) 8.08(d, 2H, J=8.4Hz), 7.68(d, 2H, J=8.4Hz), 7.20(d, 2H, J=8.4Hz), 6.83(d, 2H, J=8.4Hz), 4.23(t, 2H3 J=6.7Hz)3 3.79(d, IH3 J=12.8Hz), 3.65(s, 3H)3 3.50(d3 IH5 J=12.8 Hz)3 3.23-3.17(m, IH), 3.03-2.99(m3 IH), 2.97(t, 2H3 J-6.7Hz), 2.40(s, 3H)3 2.38-2.32(m, IH), 2.10-1.77(m, 4H).
Step 2: Preparation of (S)-l-(4-{2-[5-methyl-2-(4-trifluoromethyl-phenyl)- oxazol-4-yl]-ethoxy } -benzyl)-pyrrolidine-2-carboxylic acid
The procedure of Step 2 of Example 223 was repeated except for using the compound obtained in Step 1 of Example 225(0.10 g, 0.21 mmol) to obtain the title compound(0.08 g, 81%).
1H NMR(DMSO^6, 300 MHz): δ(ppm) 8.10(d, 2H, J=8.3Hz), 7.86(d, 2H, JM8.3 Hz), 7.37(d, 2H, J=8.4 Hz), 6.96(d, 2H, J=8.4 Hz), 4.24(t, 2H3 J=6.5Hz), 4.20(d, IH, J=12.8Hz), 4.02(d, IH, J=12.8Hz), 3.83-3.76(m, IH), 3.29-3.23(m, IH), 2.97(t, 2H3 J=6.5Hz), 2.94-2.88(m, IH), 2.40(s, 3H)3 2.26-2.20(m3 IH), 1.95-1.74(m, 3H).
Example 226: Preparation of (S)-l-{4-[2-(5-methyI-2-thiophen-2-yI-oxazoI- 4-yI)-ethoxy]-benzyl}-pyrrolidine-2-carboxyIic acid
Figure imgf000179_0001
Step 1 : Preparation of (S)-l-{4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)- ethoxy]-benzyl}-pyrrolidine-2-carboxylic acid methyl ester
The procedure of Step 1 of Example 223 was repeated except for using
2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethanol(0.20 g, 0.95 mmol) to obtain the title compound(0.1 g, 36%).
1H NMR(CDCl3, 300MHz): δ(ppm) 7.59-7.57(m, IH)3 7.38-7.35(m, IH), 7.20(d, 2H3 J=8.4Hz), 7.10-7.06(m, IH), 6.83(d, 2H, J=8.4Hz), 4.20(t, 2H, J=6.7Hz), 3.79(d, IH,
J=12.8Hz), 3.65(s, 3H), 3.50(d, IH, J=12.8Hz), 3.23-3.17(m, IH), 3.03-2.99(m, IH),
2.97(t, 2H, J-6.7 Hz), 2.36(s, 3H), 2.35-2.34(m, IH), 2.10-1.77(m, 4H).
Step 2: Preparation of (S)-l-{4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)- ethoxy]-benzyl}-pyrrolidine-2-carboxylic acid
The procedure of Step 2 of Example 223 was repeated except for using the compound obtained in Step 1 of Example 226(0.088 g, 0.21 mmol) to obtain the title compound(0.03 g5 38%).
1H NMR(DMSO-Ci65 300MHz): δ(ppm) 7.56-7.53(m, IH), 7.44-7.41(m5 IH), 7.13(d, 2H, J=8.4Hz), 7.02-6.98(m, IH), 6.74(d, 2H, J=8.4Hz), 4.0 l(t, 2H, J=6.5Hz), 3.86(d, IH, J=12.8Hz), 3.62(d, IH5 J=12.8 Hz), 3.21-3.16(m, IH), 3.04-2.92(m, IH), 2.73(t, 2H5 J=6.5Hz), 2.61-2.45(m, IH), 2.16(s, 3H), 1.97-1.48(m, 4H).
Example 227: Preparation of l-[3-(2-biphenyl-4-yl-5-methyl-oxazol-4- ylmethoxy)-benzyI]-piperidine-2-carboxylic acid
Figure imgf000180_0001
Step 1: Preparation of l-[3-(2-biphenyl-4-yl-5-methyl-oxazol-4-ylmethoxy)- benzyl]-piperidine-2-carboxylic acid methyl ester l-(3-Hydroxy-benzyl)-piperidine-2-carboxylic acid ethyl ester(0.15 g, 0.64 mmol) and 2-biρhenyl-4-yl-4-chloromethyl-5-methyl-oxazole(0.19 g, 0.68 mmol) were dissolved in N,N-dimethylformamide(10 ml) and potassium carbonate(0.08 g, 0.56 mmol) was added thereto. The resulting mixture was stirred at 80 °C for 1 day . After the completion of the reaction, distilled water was poured to the reaction product. The resultant was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography(eluent: hexane/ethyl acetate^/l) to obtain the title compound(0.25 g, 86%).
1H NMR(CDCl3, 300MHz): δ(ppm) 8.08(d, 2H, J=8.4Hz), 7.68(d, 2H, J=8.3Hz), 7.67-7.60(m, 2H), 7.50-7.35(m, 3H), 7.26-7.19(m, IH), 7.04(s, IH), 6.97-6.87(m, 2H)5 5.01(s5 2H), 4.20(q, 2H5 J=7.0Hz), 3.79(d, IH5 J=13.2Hz), 3.40(d, IH, J=13.2Hz), 3.18-3.10(m, IH), 2.97-2.89(m, IH), 2.46(s, 3H), 2.22-2.1 l(m, IH), 1.86-1.79(m, 2H), 1.64-1.50(m, 3H), 1.44-1.33(m, IH)5 1.3 l(t. 3H5 J=7.0Hz)
Step 2: Preparation of l-[3-(2-biphenyl-4-yl-5-methyl-oxazol-4-ylmethoxy)- benzyl]-piperidine-2-carboxylic acid
The compound obtained in Step 1 of Example 227(0.21 g, 0.41 mmol) was dissolved in a mixture of methanol and water(5:l, 1 ml), and potassium hydroxide(0.05 g, 0.82 mmol) was added thereto. The resulting mixture was stirred for room temperature for 3 days. The resulting mixture was diluted with ethyl acetate and acidified with IM HC1(3 ml). The resultant was extracted with dichloromethane(10 ml). The organic layer was separated, dried over anhydrous magnesium sulfate(2 g) and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography(eluent: methanol/dichloromethane^l/^O) to obtain the title compound(0.25 g, 86%). 1H NMR(DMSO-d6, 300MHz): δ(ppm) 8.03(d, 2H, J=7.6Hz), 7.84(d, 2H, J=7.6Hz), 7.75(d, 2H, J=8.0Hz), 7.52(d. 2H, J=8.0Hz), 7.50-7.36(m, 2H)5 7.16(s, IH), 7.15-7.01(m, 2H), 5.05(s, 2H), 4.25(d, IH, J=13.3Hz), 3.94(d, IH, J=13.3Hz), 3.66-3.59(m, IH), 3.17-3.12(m, IH), 2.76-2.70(m, IH), 2.48(s, 3H), 2.10-2.02(m, IH), 1.85-1.45(m, 5H)
Example 228: Preparation of l-[3-(5-methyl-2-/>~toIyl-oxazol-4-ylmethoxy)- benzyl] -piperidine-2-carboxylic acid
Figure imgf000181_0001
Step 1: Preparation of l-[3-(5-methyl-2-/?-tolyl-oxazol-4-ylmethoxy)-benzyl]- piperidine-2-carboxylic acid ethyl ester The procedure of Step 1 of Example 227 was repeated except for using
4-chloromethyl-5-methyl-2-j9-tolyl-oxazole(0.15 g, 0.68 mmol) to obtain the title compound(0.22 g, 86%).
1H NMR(CDCl3, 300MHz): δ(ppm) 7.90(d, 2H5 J=8.4Hz), 7.24(d, 2H, J=8.4Hz),
7.23-7.21(m, IH), 7.05(s, IH), 6.95-6.85(m, 2H), 4.98(s, 2H), 4.20(q, 2H, J=7.1Hz), 3.78(d, IH5 J=I 3.2Hz)5 3.40(d, IH, J-13.2Hz), 3.18-3.10(m5 IH)5 2.95-2.85(m, IH),
2.43(s, 3H), 2.39(s, 3H), 2.19-2.08(m, IH), 1.88-1.78(m, 2H)5 1.63-1.49(m, 3H)5
1.40-1.30(m, IH), 1.29(t. 3H5 J=7.1Hz)
Step 2: Preparation of l-[3-(5-methyl-2-/>-tolyl-oxazol-4-ylmethoxy)-benzyl]- piperidine-2-carboxylic acid
The procedure of Step 2 of Example 227 was repeated except for using the compound obtained in Step 1 of Example 228(0.18 g, 0.40 mmol) to obtain the title comρound(0.12 g, 70%).
1H NMR(DMSO-d6, 300MHz): δ(ppm) 7.63(d, 2H5 J=8. IHz)5 7.13(d, 2H5 J=8.1Hz), 7.11-7.03(m, lH),6.84(s, IH), 6.80-6.71(m, 2H), 4.79(s, 2H), 3.71(d, IH, J=13.3Hz), 3.36(d, IH, J=13.3Hz), 2.97-2.93(m, IH), 2.76-2.68(m, IH), 2.25(s, 3H), 2.17(s, 3H), 2.15-2.07(m, IH), 1.65-1.49(m, 2H)5 1.33-1.14(m, 4H)
Example 229: Preparation of l-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)- oxazol-4-ylmethoxy]-benzyI}-piperidine-2-carboxylic acid
Figure imgf000182_0001
Step 1: Preparation of l-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4- ylmethoxy]-benzyl}-piperidine-2-carboxylic acid ethyl ester
The procedure of Step 1 of Example 227 was repeated except for using 4-chloromethyl-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole(0.19 g, 0.69 mmol) 5 to obtain the title compound(0.22 g, 77%).
1H NMR(CDCl3, 300MHz): δ(ppm) 8.12(d, 2H, J-8.1Hz), 7.69(d, 2H, J=8.1Hz), 7.26-7.19(m, IH)5 7.03(s, IH), 6.93-6.87(m, 2H), 5.01(s5 2H), 4.20(q, 2H, J=6.9Hz), 3.78(d, IH, J=13.2Hz), 3.40(d, IH, J=13.2Hz), 3.18-3.10(m, IH), 2.97-2.89(m, IH), 2.47(s, 3H), 2.19-2.09(m, IH), 1.86-1.79(m, 2H)5 1.61-1.59(m, 3H)5 1.42-1.31(m5 0 IH)5 1.29(t. 3H, J=6.9Hz)
Step 2: Preparation of l-{3-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4- ylmethoxy] -benzyl } -piperidine-2-carboxylic acid
The procedure of Step 2 of Example 227 was repeated except for using the 5 compound obtained in Step 1 of Example 229(0.18 g, 0.36 mmol) to obtain the title compound(0.12 g5 69%).
1H NMR(DMSO-d6, 300MHz): δ(ppm) 7.97(d, 2H, J=8.2Hz), 7.72(d, 2H, J=8.2Hz),
7.18-7.1 l(m, IH)5 6.92(s, IH)5 6.90-6.78(m, 2H), 4.87(s, 2H), 3.90(d, IH, J=13.3Hz),
3.58(d, IH, J=13.3Hz), 3.24-3.15(m, IH), 2.89-2.82(m, IH)5 2.32(s, 3H), (0 2.31-2.24(m5 IH)5 1.80-1.73(m, IH), 1.65-1.52(m, IH)5 1.45-1.16(m, 4H)
Example 230: Preparation of l-[3-(5-methyl-2-thiophen-2-yl-oxazol-4- ylmethoxy)-benzyl]-piperidine-2-carboxylic acid
Figure imgf000183_0001
Step 1: Preparation of l-[3-(5-methyl-2-thiophen-2-yl-oxazol-4-ylmethoxy)- benzyl]-piperidine-2-carboxylic acid ethyl ester
The procedure of Step 1 of Example 227 was repeated except for using 4-chloromethyl-5-methyl-2-thiophen-2-yl-oxazole(0.15 g, 0.70 mol) to obtain the title compound(0.21 g, 84%).
1H NMR(CDCl3, 300MHz): δ(ppm) 7.64-7.61(m, IH), 7.41-7.38(m, IH), 7.27-7.19(m, IH), 7.11-7.07(m, IH), 7.01(s, IH), 6.95-6.87(m, 2H), 4.97(s, 2H), 4.20(q, 2H, J=7.2Hz), 3.78(d, IH, J=13.5Hz), 3.40(d, IH, J=I 3.5Hz), 3.16-3.12(m, IH), 2.96-2.88(m, IH), 2.42(s, 3H), 2.18-2.10(m, IH), 1.84-1.76(m, 2H), 1.66-1.49(m, 3H), 1.35-1.26(m, IH), 1.29(t. 3H, J=7.2Hz)
Step 2: Preparation of l-[3-(5-methyl-2-thiophen-2-yl-oxazol-4-ylmethoxy)- benzyl]-piperidine-2-carboxylic acid The procedure of Step 2 of Example 227 was repeated except for using the compound obtained in Step 1 of Example 230(0.17 g, 0.39 mmol) to obtain the title compound(0.15 g, 92%).
1H NMR(DMSO-d6, 300MHz): δ(ppm) 7.84-7.80(m, IH), 7.72-7.69(m, IH),
7.47-7.39(m, IH), 7.28-7.01(m, 4H), 5.05(s, 2H), 4.37(d, IH, J=13.3Hz), 4.07(d, IH, J=13.3Hz), 3.83-3.76(m, IH), 3.28-3.21(m, IH), 2.90-2.80(m, IH), 2.54(s, 3H)3
2.19-2.05(m, IH), 1.88-1.47(m, 5H)
Example 231: Preparation of l-{3-[2-(5-methyl-2-phenyl-oxazoI-4-yl)~ethoxy]- benzyl}-piperidine-2-carboxylic acid
Figure imgf000183_0002
Step 1 : Preparation of l-{3-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzyl}- piρeridine-2-carboxylic acid ethyl ester
The procedure of Step 1 of Example 227 was repeated except for using l-(3-hydroxy-benzyl)-piperidine-2-carboxylic acid ethyl ester(0.15 g, 0.57 mmol) and 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethanol(0.17 g, 0.86 mmol) to obtain the title compound(0.13 g, 53 %).
1H NMR(CDCl3, 300MHz): δ(ppm) 8.00-7.95(m, 2H), 7.46-7.38(m, 3H), 7.22-7.15(m, IH), 6.91-6.87(m, 2H), 6.81-6.76(m, IH)3 4.24(t, 2H, J=6.7Hz), 4.19(q, 2H, J=7.1Hz), 3.75(d, IH, J=I 3.3Hz), 3.38(d, IH, J=I 3.3Hz), 3.12(dd, IH, J=7.1Hz, J'=4.7Hz), 2.98(t, 2H, J=6.7Hz), 2.94-2.90(m, IH), 2.38(s, 3H), 2.17-2.09(m, IH), 1.84-1.76(m, 2H), 1.57-1.51(m, 3H), 1.41-1.31(m, IH), 1.28(t, 3H, J=7.1Hz)
Step 2: Preparation of l-{3-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzyl}- piperidine-2-carboxylic acid
The procedure of Step 2 of Example 227 was repeated except for using the compound obtained in Step 1 of Example 231(0.12 g, 0.27 mmol) to obtain the title compound(0.06 g, 56%).
1H NMR(DMSO-d6, 300MHz): δ(ppm) 8.15-8.10(m, 2H), 7.72-7.65(m, 3H), 7.46-7.40(m, IH), 7.14-7.04(m, 3H), 4.41(t, 2H, J=6.5Hz), 4.05(d, IH, J=13.3Hz), 3.67(4 IH, J=13.3Hz), 3.28-3.23(m, IH), 3.14(t, 2H5 J=6.5Hz), 3.09-3.05(m, IH), 2.57(s, 3H), 2.45-2.33(m, IH), 2.05-1.84(m, 2H), 1.78-1.50(m, 4H)
Example 232: Preparation of l-(3-{2-[5-methyl-2-(4-trifluoromethyl-phenyl)- oxazol-4-yI]-ethoxy-benzyl)-piperidine-2-carboxyIic acid
Figure imgf000184_0001
Step 1: Preparation of l-(3-{2-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol- 4-yl]-ethoxy-benzyl)-piperidine-2-carboxylic acid ethyl ester
The procedure of Step 1 of Example 231 was repeated except for using 2-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-ethanol(0.23 g, 0.86 mmol) to obtain the title comρound(0.1 g, 33 %) .
1H NMR(CDCl3, 300MHz): δ(ppm) 8.10(4 2H, J=8.1Hz), 7.68(4 2H, J=8.1Hz), 7.22-7.15(m, IH), 6.92-6.87(m, 2H)5 6.81-6.76(m, IH)5 4.24(t, 2H, J=6.7Hz), 4.19(q, 2H, J=7.1Hz), 3.75(4 IH5 J=13.3Hz), 3.37(4 IH5 J=13.3Hz), 3.12(dd, IH, J=7.1Hz5 J'=4.7Hz), 2.98(t5 2H, J=6.7Hz), 2.95-2.91(m, IH)5 2.37(s, 3H), 2.17-2.09(m, IH), 1.84-1.76(m, 2H), 1.57-1.51(m, 3H), 1.41-1.31(m, IH), 1.28(t, 3H, J=7.1Hz)
Step 2: Preparation of l-(3-{2-[5-methyl-2-(4-trifluoromethyl-ρhenyl)- oxazol-4-yl]-ethoxy-benzyl)-piperidine-2-carboxylic acid The procedure of Step 2 of Example 231 was repeated except for using the compound obtained in Step 1 of Example 232(0.08 g, 0.15 mmol) to obtain the title comρound(0.07 g, 93%).
1H NMR(DMSO^6, 300MHz): δ(ppm) 8.16(d, 2H, J=8.2Hz), 7.90(d, 2H, J=8.2Hz), 7.29-7.23(m, IH), 6.98-6.86(m, 3H), 4.26(t, 2H, J=6.5 Hz), 3.89(d, IH, J=13.3Hz), 3.46(d, IH, J=13.3Hz), 3.09-3.02(m, IH), 3.00(t, 2H, J=6.5Hz), 2.92-2.87(m, IH), 2.45(s, 3H), 2.22-2.15(m, IH), 1.87-1.68(m, 2H), 1.64-1.36(m, 4H)
Example 233: Preparation of l-{3-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)- ethoxy]-benzyI}-piperidine-2-carboxylic acid
Figure imgf000185_0001
Step 1: Preparation of l-{3-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]- benzyl}-piperidine-2-carboxylic acid ethyl ester
The procedure of Step 1 of Example 231 was repeated except for using 2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethanol(0.18 g, 0.88 mmol) to obtain the title compound(0.13 g, 51%).
1H NMR(CDCl3, 300MHz): δ(ppm) 7.59-7.57(m, IH), 7.38-7.35(m, IH),
7.21-7.16(m, IH), 7.10-7.05(m, IH), 6.91-6.86(m, 2H), 6.80-6.78(m, IH), 4.24(t, 2H,
J=6.7Hz), 4.19(q, 2H, J=7.1Hz), 3.75(d, IH, J=13.3 Hz)5 3.37(d, IH, J=13.3Hz), 3.12(dd, IH, J=7.1Hz, J'=4.7Hz), 2.98(t, 2H, J=6.7Hz), 2.95-2.9 l(m, IH), 2.37(s,
3H), 2.17-2.09(m, IH), 1.84-1.76(m, 2H), 1.57-1.51(m, 3H), 1.41-1.31(m, IH),
1.28(t, 3H, J=7.1Hz)
Step 2: Preparation of l-{3-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]- benzyl }-piperidine-2-carboxylic acid
The procedure of Step 2 of Example 231 was repeated except for using the compound obtained in Step 1 of Example 233(0.1O g, 0.23 mmol) to obtain the title comρound(0.023 g, 22%). 1H NMR(DMSO-d6, 300MHz): δ(ppm) 7.53-7.50(m, IH), 7.41-7.39(m, IH), 7.04-6.95(m, 2H)5 6.72-6.60(m, 3H), 3.97(t, 2H, J=6.5Hz), 3.65(d, IH, J=13.3Hz), 3.23(d, IH, J=13.3Hz), 2.83-2.78(m5 IH), 2.68(t, 2H5 J=6.5Hz), 2.67-2.63(m, IH), 2.13(s, 3H), 1.98-1.91(m, IH), 1.56-1.44(m, 2H), 1.35-1.06(m, 4H)
Example 234: Preparation of l-(4-{2-[5-methyl-2-(4-trifluoromethyI-phenyl)- oxazol-4-yl]-ethoxy}-benzyl)-piperidine-2-carboxylic acid
Figure imgf000186_0001
Step 1 : Preparation of l-(4-{2-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol- 4-yl]-ethoxy}-benzyl)-piperidine-2-carboxylic acid ethyl ester
The procedure of Step 1 of Example 231 was repeated except for using l-(4-hydroxy-benzyl)-piperidine-2-carboxylic acid ethyl ester(0.15 g, 0.57 mmol) and 2-[5-methyl-2-(trifluoromethyl-phenyl)-oxazol-4-yl]-ethanol(0.17 g, 0.68 mmol) to obtain the title compound(0.15 g, 50%).
1H NMR(DMSO-d6, 300MHz): δ(ppm) 8.08(d, 2H, J=8.4Hz), 7.68(d, 2H, J=8.4Hz), 7.20(d, 2H,J=8.4Hz), 6.84(d, 2H,J=8.4Hz), 4.23(t, 2H, J=6.6Hz), 3.73(s, 3H), 3.70(d, IH5 J=13.2Hz), 3.33(d, IH, J=13.2H), 3.12-3.08(m, IH)5 2.98(t, 2H5 J=6.6Hz), 2.92-2.89(m, IH)5 2.37(s,3H), 2.12-2.08(m, IH)5 1.83-1.76(m, 2H)5 1.57-1.51(m5 3H)5 1.33-1.30(m5 IH)
Step 2: Preparation of l-(4-{2-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol- 4-yl]-ethoxy}-benzyl)-piperidine-2-carboxylic acid
The procedure of Step 2 of Example 231 was repeated except for using the compound obtained in Step 1 of Example 234(0.15 g, 0.29 mmol) to obtain the title compound(0.06 g5 43%).
1H NMR(DMSO-d6, 300MHz): δ(ppm) 8.07(d5 2H5 J=8.10Hz), 7.67(d5 2H, J=8.10Hz), 7.44(m, 2H), 6.90(d, 2H5 J=8.10Hz), 4.39(s, 2H)5 4.21(t, 2H5 J=6.9Hz), 3.71-1.26(m, 9H)5 2.97(t, 2H5 J=6.90Hz), 2.45(s, 3H)
Example 235: Preparation of (S)-l-[4-(5-methyl-2~/;-toryl-oxazol-4-yImethoxy)- benzyl]-piperidine-2-carboxylic acid
Figure imgf000186_0002
Step 1 : Preparation of (S)-l-[4-(5-methyl-2-/»-tolyl-oxazol-4-ylmethoxy)-benzyl]- piperidine-2-carboxylic acid ethyl ester
The procedure of Step 1 of Example 227 was repeated except for using 4-chloromethyl-5-methyl-2-/?-tolyl-oxazole(0.17 g, 0.77 mmol) and (S)-l-(4-hydroxy-benzyl)-piperidine-2-carboxylic acid ethyl ester(0.15 g, 0.64 mraol) to obtain the title compound(0.26 g, 40%).
1H NMR(CDCl3, 300MHz): δ(ppm) 7.90(d, 2H, J=8.10Hz), 7.26-7.21(m, 4H), 6.95(d5 2H5 J=8.10Hz), 5.00(s5 2H)5 3.73(s, 3H)5 3.71(d, IH5 J=I 3.2Hz), 3.35(d, IH5 J=3.2Hz), 3.20-3.15(m, IH)5 2.91-2.80(m, IH)3 2.42(s5 3H), 2.39(s, 3H)5 2.20-2.09(m, IH)5 1.83(m, 2H), 1.63-1.53(m, 4H)
Step 2: Preparation of (S)-l-[4-(5-methyl-2-p-tolyl-oxazol-4-ylmethoxy)-benzyl]- piperidine-2-carboxylic acid
The procedure of Step 2 of Example 231 was repeated except for using the compound obtained in Step 1 of Example 235(0.26 g5 0.58 mmol) to obtain the title compound(0.15 g, 60%).
1H NMR(DMSO-d6, 300MHz): δ(ppm) 7.86(d, 2H5 J=8.10Hz)5 7.49-7.37(m, 2H)5
7.28-7.22(m, 2H)5 6.90(d, 2H5 J=8.10Hz), 4.95(s, 2H)5 4.39(s, 2H)5 3.87-1.79(m, 9H)5
2.45(s, 3H)5 2.41(s, 3H)
Example 236: Preparation of (S)-l-{4-[2-(5-methyl-2~p-tolyl-oxazoI-4-yl)- ethoxy]-benzyl}-piperidine-2-carboxylic acid
Figure imgf000187_0001
Step 1 : Preparation of (S)-l-{4-[2-(5-methyl-2-p-tolyl-oxazol-4-yl)-ethoxy]- benzyl}-piperidine-2-carboxylic acid ethyl ester
The procedure of Step 1 of Example 234 was repeated except for using (S)-l-(4-hydroxy-benzyl)-piperidine-2-carboxylic acid ethyl ester(0.15 g, 0.57 mmol) and 2-(5-methyl-2-/?-tolyl-oxazol-4-yl)-ethanol(0.15 g, 0.68 mmol) to obtain the title compound(0.11 g5 45%).
1H NMR(CDCl3, 300MHz): δ(ppm) 7.86(d, 2H5 J=8.40Hz), 7.26-7.18(m, 4H)5 6.84(d, 2H5 J=4H), 4.22(t, 2H5 J=6.9Hz)5 3.73(s, 3H)5 3.70(d5 IH, J=I 3.2Hz), 3.33(d, IH5 J=13.2Hz)5 3.12-3.08(m, IH)5 2.96(t5 2H5 J=6.90Hz)5 2.92-2.89(m, IH)5 2.38(s, 3H)5 2.36(s, 3H), 2.11-2.01(m, IH)5 1.82-1.78(m, 2H), 1.57-1.51(m, 2H), 1.27-1.26(m, 2H)
Step 2: Preparation of (S)-l-{4-[2-(5-methyl-2-p-tolyl-oxazol-4-yl)-ethoxy]- benzyl }-piperidine-2-carboxy lie acid
The procedure of Step 2 of Example 231 was repeated except for using the compound obtained in Step 1 of Example 236(0.11 g, 0.26 mmol) to obtain the title comρound(0.06 g, 56%).
5 1H NMR(DMSO-d6, 300MHz): δ(ppm) 7.83(d, 2H5 J=8.10Hz), 7.47-7.45(m, 2H), 7.22(d, 2H, J=8.10Hz), 6.87(d, 2H, J=8.10Hz), 4.02(s, 2H), 4.18(m, 2H), 3.69-1.26(m, 9H), 3.01 -2.93 (m, 2H)
Example 237: Preparation of (S)-l-(3-((5-methyl-2-phenyloxazol-4-yl)methoxy) 10 benzyl)pyrrolidine-2-carboxylic acid
Figure imgf000188_0001
Step 1: Preparation of (S)-l-(3-((5-methyl-2-phenyloxazol-4-yl)methoxy)benzyl) pyrrolidine-2-carboxylic acid methyl ester
(S)-l-(3-hydroxy-benzyl)-pyrrolidine-2-carboxylic acid methyl ester(0.15 g, 5 0.68 mmol) and 4-chloromethyl-5-methyl-2-phenyl-oxazole(0.16 g, 0.77 mmol) were dissolved in N,N-dimethylformamide(10 ml) and potassium carbonate(0.11 g,
0.77 mmol) was added thereto. The resulting mixture was stirred at 80 °C for 1 day.
After the completion of the reaction, distilled water was poured to the reaction product. The resultant was extracted with ethyl acetate. The organic layer was 0 separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography(eluent: hexane/ethyl acetate=3/l) to obtain the title compound(0.21 g, 81%).
1H NMR(CDCl3, 300MHz): δ(ppm) 8.04-8.00(m, 2H), 7.49-7.40(m, 3H), 5 7.26-7.20(m, IH), 7.01(s, IH), 6.96-6.88(m, 2H), 5.00(s, 2H), 3.90(d, IH, J=I 2.9Hz),
3.67(s, 3H), 3.54(d, IH, J=12.9Hz), 3.30-3.22(m, IH), 3.06-3.00(m, IH), 2.44(s, 3H),
2.42-2.37(m, IH), 2.19-2.03(m, IH), 2.01-1.69(m, 3H).
Step 2: Preparation of (S)-l-(3-((5-methyl-2-phenyloxazol-4-yl)methoxy)benzyl) 0 pyrrolidine-2-carboxylic acid
The compound obtained in Step 1 of Example 237(0.21 g, 0.52 mmol) was dissolved in a mixture of methanol and water(5: l, 1 ml), and lithium hydroxy monohydrate(0.033 g, 0.78 mmol) was added thereto. The resulting mixture was stirred for room temperature for 3 days. The resulting mixture was diluted with
S 5 ethyl acetate and acidified with IM HC1(3 ml). The resultant was extracted with dichloromethane(10 ml). The organic layer was separated, dried over anhydrous magnesium sulfate(2 g) and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography (eluent: methanol/dichloromethane=l/20) to obtain the title compound(0.13 g, 64%). 1H NMR(DMSO-d6, 300MHz): δ(ppm) 8.19-8.14(m, 2H), 7.80-7.71(m, 3H), 7.55-7.48(m, IH), 7.33(s, IH), 7.25-7.20(m, 2H), 5.23(s, 2H), 4.33(d, IH, J= 13. OHz), 4.04(d, IH, J=13.0Hz), 3.77-3.69(m, IH), 3.37-3.31(m, IH), 2.96-2.89(m, IH), 2.67(s, 3H), 2.48-2.30(m, IH), 2.18-1.90(m, 3H).
Example 238: Preparation of (S)-l-(3-((5-methyI-2-/7-toryloxazol-4-yl)methoxy) benzyI)pyrroIidine-2-carboxylic acid
Figure imgf000189_0001
Step 1: Preparation of (S)-l-(3-((5-methyl-2-p-tolyloxazol-4-yl)methoxy)benzyl) pyrrolidine-2-carboxylic acid methyl ester The procedure of Step 1 of Example 237 was repeated except for using
4-chloromethyl-5-methyl-2-p-tolyl-oxazole(0.17 g, 0.77 mmol) to obtain the title comρound(0.2 g, 75%).
1H NMR(CDCl3, 300MHz): δ(ppm) 7.90(d, 2H, J=8.1Hz), 7.25(4 2H, J=8.1Hz),
7.24-7.19(m, IH), 7.01(s, IH), 6.96-6.87(m, 2H), 4.99(s, 2H), 3.90(4 IH, J=13.0Hz), .3.67(s, 3H), 3.54(d, IH, J=13.0Hz), 3.31-3.22(m, IH)5 3.07-2.97(m, IH), 2.43(s, 3H),
2.39(s, 3H), 2.38-2.35(m, IH), 2.19-2.08(m, IH), 2.05-1.70(m, 3H).
Step 2: Preparation of (S)-l-(3-((5-methyl-2-/»-tolyloxazol-4-yl)methoxy)benzyl) pyrrolidine-2-carboxylic acid The procedure of Step 2 of Example 237 was repeated except for using the compound obtained in Step 1 of Example 238(0.2 g, 0.48 mmol) to obtain the title comρound(0.16 g, 80%).
1H NMR(DMSO-d6, 300MHz): δ(ppm) 7.86(4 2H, J=8.0Hz), 7.58-7.26(m, IH),
7.33(d, 2H, J=8.0Hz),7.11(s, IH), 7.00(d, 2H, J=7.6Hz), 5.01(s, 2H), 4.08(4 IH, J=13.1Hz), 3.78(d, IH, J=13.1Hz), 3.45-3.37(m, IH), 3.13-3.07(m, IH),
2.72-2.68(m, IH), 2.47(s, 3H), 2.39(s, 3H), 2.19-2.08(m, IH), 2.98-2.68(m, 3H).
Example 239: Preparation of (S)-l-(3-((5-methyl-2-(4-(trifluoromethyl)phenyl) oxazol-4-yI)methoxy)benzyl)pyrrolidine-2-carboxylic acid
Figure imgf000190_0001
Step 1: Preparation of (S)-l-(3-((5-methyl-2-(4-(trifluoromethyl)phenyl)oxazol- 4-yl)methoxy)benzyl)pyrrolidine-2-carboxylic acid methyl ester
The procedure of Step 1 of Example 237 was repeated except for using 4-chloromethyl-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole(0.18 g, 0.77 mmol) to obtain the title compound(0.22 g, 72%).
1R NMR(CDCl3, 300MHz): δ(ppm) 8.13(d, 2H, J=8.3Hz), 7.70(d, 2H, J=8.3Hz), 7.27-7.20(m, IH), 7.02(s, IH), 6.96-6.80(m, 2H), 5.00(s, 2H), 3.90(d, IH, J=I 2.9Hz), 3.67(s, 3H), 3.54(d, IH, J=I 2.9Hz), 3.30-3.23(m, IH), 3.09-3.01(m, IH), 2.47(s, 3H), 2.44-2.34(m, IH), 2.19-2.06(m, IH), 2.03-1.73(m, 3H).
Step 2: Preparation of (S)-l-(3-((5-methyl-2-(4-(trifluoromemyl)phenyi)oxazol- 4-yl)methoxy)benzyl)pyrrolidine-2-carboxylic acid
The procedure of Step 2 of Example 237 was repeated except for using the compound obtained in Step 1 of Example 239(0.22 g, 0.46 mmol) to obtain the title compound(0.20 g, 93%).
1H NMR(DMSO^6, 300MHz): δ(ppm) 8.17(d, 2H, J=8.1Hz), 7.91(d, 2H, J=8.1Hz), 7.57-7.27(m, IH), 7.1 l(s, IH), 7.03-6.98(m, 2H), 5.06(s, 2H), 4.08(d, IH, J=I 3. OHz), 3.78(d, IH, J=13.0Hz), 3.44-3.37(m, IH), 3.14-3.07(m, IH), 2.67-2.60(m, IH), 2.53(s, 3H),2.20-2.09(m, IH), 1.98-1.69(m, 3H).
Example 240: Preparation of (S)-l-(3-((2-(biphenyl-4-yl)-5-methyloxazol-4-yl) methoxy)benzyl)pyrrolidine-2-carboxyIic acid
Figure imgf000190_0002
Step 1: Preparation of (S)-l-(3-((2-(biphenyl-4-yl)-5-methyloxazol-4-yl)methoxy) benzyl)pyrrolidine-2-carboxylic acid methyl ester
The procedure of Step 1 of Example 237 was repeated except for using 2-biphenyl-4-yl-4-chloromethyl-5-methyl-oxazole(0.22 g, 0.77 mmol) to obtain the title comρound(0.25 g, 81%). 1H NMR(CDCl3, 300MHz): δ(ppm) 8.03(d, 2H5 J=8.3Hz), 7.68(d, 2H, J=8.3Hz), 7.66-7.61(m, 2H), 7.49-7.35(m, 3H), 7.25-7.20(m5 IH)5 7.02(s5 IH)5 6.96-6.87(m5 2H), 5.01(s, 2H), 3.90(d5 IH5 J=12.9Hz)5 3.67(s, 3H)5 3.55(d, IH5 J=12.9Hz)5 3.30-3.23(m, IH)5 3.06-3.00(m, IH), 2.46(s, 3H)5 2.44-2.37(m, IH), 2.20-2.05(m, lH), 2.03-1.72(m, 3H).
Step 2: Preparation of (S)-l-(3-((2-(biphenyl-4-yl)-5-methyloxazol-4-yl)methoxy) benzyl)pyrrolidine-2-carboxylic acid
The procedure of Step 2 of Example 237 was repeated except for using the compound obtained in Step 1 of Example 240(0.25 g, 0.52 mmol) to obtain the title compound(0.23 g, 93%).
1H NMR(DMSO-d65 300MHz): δ(ppm) 8.07(d, 2H5 J=8.2Hz), 7.88(d, 2H5 J=8.2Hz),
7.79(d5 2H, J=8.0Hz), 7.58-7.42(m, 3H), 7.38-7.30(m, IH)5 7.16(s, IH)5 7.06-7.02(m,
2H), 5.07(s, 2H), 4.13(d, IH, J=13.0Hz), 3.84(d, IH, J=13.0Hz), 3.49-3.43(m, IH)5 3.18-3.12(m, IH), 2.56-2.53(m, IH) 2.52(s, 3H), 2.23-2.10(m, IH), 1.97-1.73(m,
3H).
Example 241: Preparation of (S)-l-(3-((5-methyl-2-(thiophen-2-yl)oxazol-4-yl) methoxy)benzyI)pyrrolidine-2-carboxyIic acid
Figure imgf000191_0001
Step 1: Preparation of (S)-l-(3-((5-methyl-2-(thiophen-2-yl)oxazol-4-yl)methoxy) benzyl)pyrrolidine-2-carboxylic acid methyl ester
The procedure of Step 1 of Example 237 was repeated except for using 4-chloromethyl-5-methyl-2-thiophen-2-yl-oxazole(0.16 g, 0.77 mmol) to obtain the title compound(0.22 g, 83%).
1H NMR(CDCl3, 300MHz): δ(ppm) 7.64-7.62(m, IH), 7.41-7.37(m, IH), 7.25-7.18(m, IH)5 7.11-7.06(M, IH), 6.99(s, IH), 6.97-6.84(m, 2H), 4.97(s, 2H), 3.89(d, IH, J=12.9Hz), 3.67(s, 3H)5 3.54(d, IH, J=12.9Hz), 3.28-3.22(m, IH), 3.05-3.00(m, IH), 2.44(s, 3H), 2.42-2.33(m, IH), 2.22-2.07(m, IH)5 2.05-1.62(m, 3H).
Step 2: Preparation of (S)-l-(3-((5-methyl-2-(thiophen-2-yl)oxazol-4-yl)methoxy) benzyl)pyrrolidine-2-carboxylic acid
The procedure of Step 2 of Example 237 was repeated except for using the compound obtained in Step 1 of Example 241(0.22 g, 0.48 mmol) to obtain the title compound(0.18 g, 83%).
1H NMR(DMSO-d6, 300MHz): δ(ppm) 7.83-7.79(m, IH), 7.72-7.67(m, IH), 7.40-7.33(m, IH), 7.27-7.23(m, IH), 7.07(d. 2H, J=7.7Hz), 5.03(s, 2H), 4.23(d, IH, J=I 3. OHz), 3.96(d, IH, J=I 3. OHz), 3.75-3.68(m, IH), 3.25-3.20(m, IH), 2.91-2.81(m, IH), 2.47(s, 3H), 2.31-2.20(m, IH), 1.99-1.77(m, 3H).
Example 242: Preparation of (S)-l-(4-((5-methyl-2-phenyIoxazol-4-yl)methoxy) benzyl)pyrrolidine-2-carboxylic acid
Figure imgf000192_0001
Step 1 : Preparation of (S)-l-(4-((5-methyl-2-phenyloxazol-4-yl)methoxy)benzyl) pyrrolidine-2-carboxylic acid methyl ester
The procedure of Step 1 of Example 237 was repeated except for using
(S)-l-(4-hydroxy-benzyl)-pyrrolidine-2-carboxylic acid methyl ester(0.15 g, 0.64 mmol) and 4-chloromethyl-5-methyl-2-phenyl-oxazole(0.16 g, 0.77 mmol) to obtain the title compound(0.20 g, 76%).
1H NMR(CDCl3, 300MHz): δ(ppm) 8.03-8.00(m, 2H), 7.50-7.42(m, 3H), 7.24(d, 2H,
J=8.7Hz), 6.95(d, 2H, J=8.7Hz), 4.98(s, 2H), 3.81(d, IH, J=12.6Hz), 3.65(s, 3H),
3.52(d, IH, J=12.6), 3.25-3.20(m, IH), 2.43(s, 3H), 2.42-2.34(m, IH), 2.15-2.09(m,
IH), 1.98-1.55(m, 3H).
Step 2: Preparation of (S)-l-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzyl]- pyrrolidine-2-carboxylic acid
The procedure of Step 2 of Example 237 was repeated except for using the compound obtained in Step 1 of Example 242(0.20 g, 0.49 mmol) to obtain the title comρound(0.18 g, 95%).
1H NMR(DMSO^6, 300MHz): δ(ppm) 7.87-7.80(m, 2H), 7.44-7.38(m, 3H), 7.25(d,
2H, J=8.5Hz), 6.94(d, 2H, J=8.5Hz), 4.90(s, 2H), 3.96(d, IH, J=12.8Hz), 3.74(d, IH,
J=12.8Hz), 3.37-3.29(m, IH), 3.15-2.95(m, IH), 2.66-2.59(m, IH), 2.10-1.96(m,
IH), 1.82-1.59(m, 3H).
Example 243: Preparation of (S)-l-[4-(5-methyl-2-/?-tolyl-oxazol-4-ylmethoxy)- benzyl] -pyrrolidine-2-carboxylic acid
Figure imgf000193_0001
Step 1: Preparation of (S)-l-[4-(5-methyl-2-^-tolyl-oxazol-4-ylmethoxy)-benzyl]- pyrrolidine-2-carboxylic acid methyl ester
The procedure of Step 1 of Example 242 was repeated except for using 4-chloromethyl-5-methyl-2-p-tolyl-oxazole(0.17 g, 0.77 mmol) to obtain the title compound(0.22 g, 67%).
1H NMR(CDCl3, 300MHz): δ(ppm) 7.90(d, 2H, J=8.1Hz), 7.25(d, 2H, J=8.4Hz), 7.24(d,2H, J=8.1Hz), 6.94(d, 2H, J=8.4Hz), 4.97(s, 2H)5 3.81(d, IH, J=12.6Hz), 3.64(s, 3H), 3.52(d, IH, J=12.6Hz), 3.25-3.18(m, IH), 3.05-3.00(m, IH), 2.42(s, 3H), 2.40(s, 3H), 2.39-2.34(m, IH), 2.17-2.10(m, IH), 1.98-1.25(m, 3H)
Step 2: Preparation of (S)-l-[4-(5-methyl-2-p-tolyl-oxazol-4-ylmethoxy)- benzyl]-pyrrolidine-2-carboxylic acid
The procedure of Step 2 of Example 242 was repeated except for using the compound obtained in Step 1 of Example 243(0.22 g, 0.52 mmol) to obtain the title compound(0.20 g, 94%).
1H NMR(DMSO-d6, 300MHz): δ(ppm) 7.78(d, 2H, J=8.1Hz), 7.3 l(d, 2H, J=8.4Hz), 7.28(d, 2H, J=8. IHz)5 6.98(d, 2H, J=8.4Hz), 4.93(s, 2H), 4.01(d, IH, J=12.6Hz), 3.78(d, IH, J=12.6Hz), 3.46-3.27(m, IH), 3.24-3.02(m, IH), 2.79-2.68(m, IH), 2.38(s, 3H), 2.3 l(s, 3H), 2.10-1.95(m, IH), 1.88-1.65(m, 3H)
Example 244: Preparation of (S)-l-{4-[5-methyl-2-(4-trifluoromethyI-phenyl)- oxazol-4-ylmethoxy] -benzyll-pyrrolidine-l-carboxylic acid
Figure imgf000193_0002
Step 1: Preparation of (S)-l-{4-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4- ylmethoxy]-benzyl}-pyrrolidine-2-carboxylic acid methyl ester
The procedure of Step 1 of Example 242 was repeated except for using 4-chloromethyl-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole(0.18 g, 0.77 mmol) to obtain the title compoιmd(0.3 g, 81%).
1H NMR(CDCl3, 300MHz): δ(ppm) 8.3 l(d, 2H5 J=8.3Hz)5 7.20(d, 2H, 8.3Hz), 7.25(d, 2H, J=8.4Hz), 6.95(d, 2H, J=8.4Hz) 5.00(s, 2H), 3.82(d, IH, J=12.7Hz), 3.65(s, 3H), 3.52(d, IH, J= 12.7Hz), 3.23-3.19(m, IH), 3.05-3.01(m, IH), 2.42(s, 3H), 2.39-2.36(m, IH), 2.15-2.10(m, IH), 1.99-1.75(m, 3H)
Step 2: Preparation of (S)-l-{4-[5-methyl-2-(4-trifluoromethyl-ρhenyl)- oxazol-4-ylmethoxy]-benzyl}-pyrrolidine-2-carboxylic acid
The procedure of Step 1 of Example 242 was repeated except for using the compound obtained in Step 1 of Example 244(0.30 g, 0.57 mmol) to obtain the title comρound(0.24 g, 91%).
1H NMR(DMSO-d6, 300MHz): δ(ppm) 8.20(d, 2H, J=8.3Hz), 7.94(d, 2H, J=8.3Hz), 7.43(d, 2H, J=8.4Hz), 7.09(d, 2H, J-8.4Hz), 5.08(s, 2H), 4.15(d, IH, J=12.7Hz), 3.95(d, IH, J=12.7Hz), 3.60-3.51(m, IH), 3.28-3.22(m, IH), 2.89-2.80(m, IH)5 2.53(s, 3H), 2.30-2.15(m, IH), 2.03-1.77(m, 3H)
Example 245: Preparation of (S)-l-[4-(2-biphenyl-4-yI-5-methyl-oxazol-4- ylmethoxy)-benzyl]-pyrrolidine-2-carboxyIic acid
Figure imgf000194_0001
Step 1 : Preparation of (S)-l-[4-(2-biphenyl-4-yl-5-methyl-oxazol-4-ylmethoxy)- benzyl]-pyrrolidine-2-carboxylic acid methyl ester
The procedure of Step 1 of Example 242 was repeated except for using 2-biphenyl-4-yl-4-chloromethyl-5-methyl-oxazole(0.22 g, 0.77 mmol) to obtain the title compound(0.27 g, 73%).
1H NMR(CDCl3, 300MHz): δ(ppm) 8.08(d, 2H, J=8.4Hz), 7.68(d, 2H5 J=8.4Hz)5 7.67-7.62(m, 2H), 7.49-7.33(m, 3H), 7.25(d, 2H5 J=8.7Hz), 6.96(d, 2H, J=8.7Hz), 4.99(s, 2H), 3.82(d, IH5 J=12.6Hz), 3,65(s, 3H)5 3.23(d5 IH5 J=12.6Hz)5 3.23-3.19(m, IH), 3.06-3.01(m, IH), 2.45(s, 3H)5 2.44-2.35(m. IH)5 2.15-2.09(m, IH), 1.99-1.70(m, 3H)
Step 2: Preparation of (S)-l-[4-(2-biphenyl-4-yl-5-methyl-oxazol-4-ylmethoxy)- benzyl]-pyrrolidine-2-carboxylic acid
The procedure of Step 2 of Example 242 was repeated except for using the compound obtained in Step 1 of Example 245(0.27 g, 0.56 mmol) to obtain the title comρound(0.54 g, 96%).
1H NMR(DMSO-d6, 300MHz): δ(ppm) 8.02(d, 2H5 J=8. IHz)5 7.83(d, 2H5 J=8. IHz)5
7.74(d, 2H5 J=7.8Hz), 7.53-7.35(m, 3H)5 7.37(d, 2H5 J=8.0Hz)5 7.04(d, 2H, J=8.0Hz),
5.02(s, 2H)5 4.07(d5 IH, J=12.6Hz), 3.85(d, IH5 J=12.6Hz), 3.54-3.38(m, IH)5
3.28-3.06(m, IH), 2.94-2.62(m, IH), 2.47(s, 3H), 2.13-2.08(m, IH)5 2.00-1.40(m,
3H)
Example 246: Preparation of (S)-l-[4-(5-methyl-2-thiophen-2-yI-oxazol-4- ylmethoxy)-benzyl] -pyrroIidine-2-carboxylic acid
Figure imgf000195_0001
Step 1: Preparation of (S)-l-[4-(5-methyl-2-thiophen-2-yl-oxazol-4-ylmethoxy)- benzyl]-pyrrolidine-2-carboxylic acid methyl ester
The procedure of Step 1 of Example 242 was repeated except for using 4-chloromethyl-5-methyl-2-thiophen-2-yl-oxazole(0.16 g, 0.77 mmol) to obtain the title compound(0.24 g, 75%).
1H NMR(CDCl3, 300MHz): δ(ppm) 7.64-7.61(m, IH), 7.50-7.37(m5 IH), 7.23(d5 2H5 J=8.6Hz), 7.09(d.d.5 IH5 J=4.8Hz, J'=3.8Hz), 6,93(d, 2H5 J=8.6Hz), 4.96(s5 2H), 3.81(d, IH5 J=12.6Hz), 3.65(s, 3H), 3.52(d, IH, J=12.6Hz), 3.26-3.17(m, IH), 3.06-3.00(m, IH)5 2.41(s, 3H), 2.40-2.34(m, IH)5 2.13-2.02(m, IH)5 1.99-1.58(m, 3H)
Step 2: Preparation of (S)-l-[4-(5-methyl-2-thiophen-2-yl-oxazol-4-ylmethoxy)- benzyl] -pyrrolidine-2-carboxylic acid
The procedure of Step 2 of Example 242 was repeated except for using the compound obtained in Step 1 of Example 246(0.24 g, 0.53 mmol) to obtain the title compound(0.20 g, 92%).
1H NMR(DMSO-d6, 300MHz): δ(ppm) 7.64-7.61(m, IH), 7.52-7.50(m, IH)5 7.23(d, 2H, J=8.4Hz)5 7.16-7.00(m, IH), 6.89(d, 2H, J=8.4Hz), 5.62(s5 IH)5 4.83(s, 2H), 3.93(d, IH, J=13.0Hz), 3.72(d, IH, J=13.0Hz), 3.50-3.21(m, IH), 3.15-3.00(m, IH), 2.74-2.45(m, IH), 2.28(s, 3H), 2.74-2.45(m, IH), 2.28(s, 3H)5 2.14-1.85(m5 IH), 1.96-1.34(m, 3H)
Example 247: Preparation of (S)-l-{4-[2-(5-methyl-2-/7-tolyl-oxazoI-4-yI)- ethoxy-benzyl}-pyrroIidine-2-carboxylic acid
Figure imgf000196_0001
Step 1: Preparation of (S)-l-{4-[2-(5-methyl-2-p-tolyl-oxazol-4-yl)-ethoxy-benzyl}- pyrrolidine-2-carboxylic acid methyl ester
2-(5-Methyl-2-p-tolyl-oxazol-4-yl)-ethanol(0.21 g, 0.97 mmol), (S)-l-(4-hydroxy-benzyl)-pyrrolidine-2-carboxylic acid methyl ester(0.15 g, 0.65 mmol) and triphenylphosphine(0.29 g, 1.09 mmol) were dissolved in anhydrous toluene(10 ml). The resulting mixture was stirred for 30 mins and diisopropylazodicarboxylate(0.22 g, 1.09 mmol) was added at room temperature.
The resultant was stirred for 3 days. After the completion of the reaction, ice water was poured to the reaction product. The resulting mixture was extracted with ethyl acetate. The organic layer was separated, and the solvent removed therefrom.
The residue thus obtained was subjected to a silica gel chromatography(eluent: hexane/ethyl acetate=3/l) to obtain the title compound(0.19 g, 69%).
1H NMR(CDCl3, 300MHz): δ(ppm) 7.86(d, 2H, J=8.1Hz), 7.22(d, 2H, J=8.1 Hz), 7.20(d, 2H, J=8.4 Hz), 6.83(d, 2H, J=8.4 Hz), 4.22(t, 2H, J=6.7 Hz), 3.79(d, IH,
J-12.8 Hz), 3.65(s, 3H), 3.50(d, IH, J=12.8 Hz), 3.23-3.17(m, IH), 3.03-2.99(m,
IH), 2.97(t, 2H, J=6.7 Hz), 2.37(s, 3H), 2.36(s, 3H), 2.33-2.29(m, IH), 2.10-1.77(m,
4H).
Step 2: Preparation of (S)-l-{4-[2-(5-methyl-2-/>-tolyl-oxazol-4-yl)-ethoxy-benzyl}- pyrrolidine-2-carboxylic acid
The compound obtained in Step 1 of Example 247(0.19 g, 0.44 mmol) was dissolved in a mixture of methanol and water(5:l, 1 ml), and lithium hydroxy monohydrate(0.02 g, 0.45 mmol) was added thereto. The resulting mixture was stirred for room temperature for 3 days. The resulting mixture was diluted with ethyl acetate and acidified with IM HC1(3 ml). The resultant was extracted with dichloromethane(10 ml). The organic layer was separated, dried over anhydrous magnesium sulfate(2 g) and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography (eluent: methanol/dichloromethane^l/lO) to obtain the title compound(0.17g, 93%).
1H NMR(DMSO-d6, 300MHz): δ(ppm)7.59(d, 2H, J=8.3Hz), 7.14(d, 2H, J=8.3 Hz), 7.10(d, 2H, J=8.4 Hz), 6.74(d, 2H, J=8.4 Hz), 4.01(t, 2H, J=6.5 Hz), 3.91(d, IH, J=12.8 Hz), 3.71(d, IH, J=12.8 Hz), 3.41-3.34(m, IH), 3.03-2.97(m, IH), 2.71(t, 2H, J=6.5 Hz), 2.70-2.57(m, IH), 2.15(s, 3H), 2.13(s, 3H), 2.05-1.90 (m, IH), 1.78-1.55(m, 3H)
Example 248: Preparation of l-(3-((5-methyl-2-phenyloxazol-4-yl)methoxy) benzyl)piperidine-2-carboxyIic acid
Figure imgf000197_0001
Step 1: Preparation of l-(3-((5-methyl-2-phenyloxazol-4-yl)methoxy)benzyl) piperidine-2-carboxylic acid ethyl ester l-(3-Hydroxy-benzyl)-piperidine-2-carboxylic acid ethyl ester(0.15 g, 0.64 mmol) and 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethanol(0.20 g, 0.98 mmol) were dissolved in N,N-dimethylformamide(10 ml), and potassium carbonate(0.08 g, 0.56 mmol) was added thereto. The resulting mixture was stirred at 80 °C for 1 day and distilled water was added therego. The resultant was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography(eluent: hexane/ethyl acetate=3/l) to obtain the title comρound(0.17 g, 68%). 1H NMR(CDCl3, 300MHz): δ(ppm) 8.04-7.99(m, 2H), 7.49-7.40(m, 3H), 7.25-7.18(m, IH), 7.03(s, IH), 6.95-6.87(m, 2H), 5.00(s, 2H), 4.20(q, 2H, =7. IHz) 3.78(d, IH, J=13.4Hz), 3.40(d, IH, J=I 3.4Hz), 3.18-3.10(m, IH), 2.96-2.88(m, IH), 2.45(s, 3H), 2.18-2.1 l(m, IH), 1.85-1.76(m, 2H), 1.62-1.49(m, 3H), 1.40-1.31(m, IH), 1.29(t. 3H, J=7.1Hz)
Step 2: Preparation of l-(3-((5-methyl-2-ρhenyloxazol-4-yl)methoxy)benzyl) piperidine-2-carboxylic acid
The compound obtained in Step 1 of Example 248(0.17 g, 0.40 mmol) was dissolved in a mixture of methanol and water(5:l, 1 ml), and potassium hydroxide(0.05 g, 0.82 mmol) was added thereto. The resulting mixture was stirred for room temperature for 3 days. The resulting mixture was diluted with ethyl acetate and acidified with IM HC1(3 ml). The resultant was extracted with dichloromethane(10 ml). The organic layer was separated, dried over anhydrous magnesium sulfate(2 g) and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography(eluent: methanol/dichloromethane=l/20) to obtain the title compound(0.15 g, 90%).
1H NMR(DMSO-d6, 300MHz): δ(ppm) 7.89-7.82(m, 2H), 7.46-7.40(m, 3H), 7.25-7.16(m, IH), 6.98(s, IH), 6.95-6.84(m, 2H), 4.92(s, 2H), 3.91(d, IH, J=13.3Hz), 3.58(d, IH5 J=13.3Hz), 3.22-3.16(m, IH)5 2.93-2.85(m5 IH)5 2.37(s, 3H)5 2.36-2.29(m, IH)5 1.84-1.76(m, IH)5 1.67-1.60(m, IH), 1.47-1.26(m5 4H)
Example 249: Preparation of l-(3-(2-(5-methyl-2-/;-tolyloxazol-4-yl)ethoxy) benzyI)piperidine-2-carboxylic acid
Figure imgf000198_0001
Step 1: Preparation of l-(3-(2-(5-methyl-2-p-tolyloxazol-4-yl)ethoxy)benzyl) piperidine-2-carboxylic acid ethyl ester
The procedure of Step 1 of Example 247 was repeated except for using 2-(5-methyl-2-p-tolyl-oxazol-4-yl)-ethanol(0.21 g, 0.97 mmol) to obtain the title compound(0.15 g, 58%).
1H NMR(CDCl3, 300MHz): δ(ppm) 7.85(d, 2H5 J-8.1 Hz)5 7.23(d, 2H5 J=8.1 Hz)5 7.21-7.15(m5 IH)5 6.91-6.86(m, 2H)5 6.81-6.76(m, IH), 4.24(t, 2H5 J=6.7 Hz)5 4.19(q, 2H5 J=7.1 Hz)5 3.75(d, IH5 J=13.3 Hz)5 3.37(d5 IH5 J=13.3 Hz), 3.12(dd, IH5 J-7.1 Hz5 J'=4.7 Hz), 2.98(t, 2H5 J=6.7 Hz)5 2.95-2.9 l(m, IH), 2.37(s, 3H), 2.17-2.09(m5 IH)5 1.84-1.76(m, 2H), 1.57-1.51(m, 3H)5 1.41-1.31(m, IH)5 1.28(t, 3H, J=7.1 Hz)
Step 2: Preparation of l-(3-(2-(5-methyl-2-p-tolyloxazol-4-yl)ethoxy)benzyl) piperidine-2-carboxylic acid
The procedure of Step 2 of Example 247 was repeated except for using the compound obtained in Step 1 of Example 249(0.15 g, 0.32 mmol) to obtain the title comρound(0.11 g, 81%).
1H NMR(DMSO-d6, 300MHz): δ(ppm) 7.88(d5 2H5 J-8.1 Hz)5 7.38(d5 2H5 J-8.1 Hz)5 7.31-7.24(m, IH)5 7.01-6.88(m, 3H)5 4.27(t, 2H5 J=6.5 Hz)5 3.94(d5 IH, J=13.3 Hz)5 3.45(d, IH5 J=13.3 Hz)5 3.09-3.02(m5 IH)5 3.00(t, 2H, J-6.5 Hz)5 2.92-2.87(m5 IH), 2.44(s, 3H)5 2.41(s5 3H), 2.20-2.1 l(m, IH), 1.88-1.72(m, 2H)5 1.68-1.39(m, 4H)
Test Example 1 : PP ARa agonist assay
Step 1) Relative luciferase activity: PPARα-GAL4 transactivation assay
Cross-activation assay of the compounds of Examples for human PP ARa was carried out using a DNA construct of PP ARa which included its ligand binding domain and GAL4 DNA binding domain (Sher et al., Biochemistry 32, 5598-5604, 1993) by analyzing whether the binding of each of the compounds of Examples to the ligand binding domain of PP ARa affects the PP ARa activity. When the GAL4 DNA binding domain fused with PP ARa ligand binding domain binds to the UAS (upstream activation sequence) of firefiy-luciferase, the luciferase expression takes place. Therefore, the effect of each compound of Examples on PP ARa activation may be evaluated by analyzing the degree of luciferase activation.
Specifically, 2 x 104 of HepG2 cells(ATCC HB-8065) or HEK293 cells(ATCC CRL- 1573) were aliquotted into each well of a 96-well plate and cultured overnight at 37 "C in a CO2 incubator(culture condition: DMEM, 10% FBS and 1% antibiotics).
The transformation of PP ARa DNA was conducted as follows. First, a mixture containing the following ingredients in specified amounts per well was prepared: Solution A (Promega) containing 50 ng of full length human PP ARa DNA, 50 ng of firefiy-luciferase construct, 5 ng of Renilla-luciferase construct, 1.0 μi of PLUS™ reagent and 8.3 μi of a serum-free medium, without antibiotics; Solution B containing 0.5 μi ofLipofectamine™ reagent and 9.5 μi of serum-free medium, without antibiotics; and Solution C containing 50 μl of serum-free medium. Then, the mixture of solutions A, B and C was kept at room temperature for 15 mins. Single layer of cells on each well of the 96-well plate was washed with serum-free DMEM, and 70 μi of lipofectamine-DNA complex prepared above was added to each well. The plate was incubated at 37 °C in a 5% CO2 incubator for 3 hrs to transform the cells. Then, each compound of Examples was diluted to 50 μM, and 70 μl of the solution was added to each well to a final concentration 25 μM. The plate was incubated at 37 °C in a CO2 incubator for 48 hours. Then, the medium was removed, and 50 μi of passive cell lysis buffer (Promega) was added thereto. The plate was shaken at room temperature for 20 mins to lysis cells. 40 μi of Luciferase Assay reagent of Dual Luciferase Kit (Invitrogen) per 20 μi of cell lysis buffer was added to the plate, followed by allowing the reaction to proceed at 20 °C for 8 seconds. The reaction was terminated by adding 40 μl of Stop & GIo reagent (Promega) as a stop solution. Then, the luminescence intensities of F-luciferase and R-luciferase were measured with MicroLumat Plus (Berthord Technology). The result was analyzed in terms of the ratio of the activity increase observed when treated with 25 μM of each compound of Examples relative to the control as well as the EC50 value, the concentration at which the activity of the test compound increased by 50% over the control.
Step 2) Relative luciferase activity: PPARα/RXRα-mediated transactivation assay
The procedure of Step 1 was repeated except for using a firefly-luciferase
DNA construct containing Renilla-luciferase construct, full length human PP ARa,
RXR (retinoid X receptor) and PPRE (peroxisome proliferator-responsive element) (Sher et al, Biochemistry 32, 5598-5604, 1993; and Fleischhauer et al., Hum Genet
90, 505-510, 1993) to transform HEK293 cells, to conduct endogenous PP ARa agonist assay. Then, the cells were treated with each compound of Examples for 48 hours, and the luciferase activity of the heterodimer generated by the binding of a
R/R (endogenous binding partner of PPAR) to the full length PP ARa bound with the test compound was measured in accordance with the same method as in Step 1.
The measured values are shown in Table 1, wherein "nd" means not treated with any of the inventive compounds and "ia" means that the compound does not activate human PP ARa.
As shown in Table 1, the inventive compounds significantly enhance the PPARα activity.
Table 1
Figure imgf000200_0001
(To be continued)
Figure imgf000201_0001
(To be continued)
Figure imgf000202_0001
(To be continued)
Figure imgf000203_0001
(To be continued)
Figure imgf000204_0001
(To be continued)
Figure imgf000205_0001
(To be continued)
Figure imgf000206_0001
While the invention has been described with respect to the above specific embodiments, it should be recognized that various modifications and changes may be made to the invention by those skilled in the art which also fall within the scope of the invention as defined by the appended claims.

Claims

WHAT IS CLAIMED IS:
1. A heterocyclic carboxylic acid derivative of formula (1), or a pharmaceutically acceptable salt thereof:
Figure imgf000207_0001
wherein, ring A is a 4 to 6-membered heterocycle comprising 1 or 2 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur;
R1 is a heterocyclic moiety selected from
Figure imgf000207_0002
~° " • s an(i
b , in which Ra is phenyl; phenyl substituted with halogen, C1-C4 haloalkyl, or Ci-C3 alkoxy; or thiophenyl; Rb is H or Ci-C4 alkyl; Het is an oxazole or isoxazole moiety optionally substituted with Ci-C4 alkyl;
R2 and R3 are each independently H, CrC4 alkyl, or phenyl substituted with halogen,
CrC4 alkyl, or Q-C3 alkoxy;
X is H or C1-C4 alkyl; m is 0, 1 or 2; and n is 1 or 2.
2. The compound of claim 1, werein the ring A is thiazolidine, azetidine, pyrrolidine, piperidine, morpholine or thiomorpholine.
3. The compound of claim 1, which is selected from the group consisting of: (R)-2-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenyl}thiazolidine-4- carboxylic acid;
(R)-2-{4-[2-(benzoxazol-2-yl-methylamino)-ethoxy]-phenyl}-thiazolidine-4- carboxylic acid;
(R)-2-{4-[2-(methyl-pyridin-2-yl-methylamino)-ethoxy]-phenyl}- thiazolidine-4-carboxylic acid;
(R)-2-{4-[2-(5-methyl-2-(4-trifluoromethylρhenyl)-oxazol-4-yl)ethoxy] phenyl}thiazolidine-4-carboxylic acid;
(R)-2-{4-[2-(5-methyl-2-thiophen-2-yloxazol-4-yl)ethoxy]phenyl) thiazolidine-4-carboxylic acid;
(R)-2- { 4- [2-(5 -methyl-2-/?-toly loxazol-4-yl)ethoxy]phenyl } thiazolidine-4- carboxylic acid;
(R)-2-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenyl}thiazolidine-4- carboxylic acid;
(R)-2-{4-[2-(5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl)ethoxy] phenyl}thiazolidine-4-carboxylic acid;
(R)-2-{4-[2-(5-methyl-2-thiophen-2-yloxazol-4-yl)ethoxy]ρhenyl} thiazolidine-4-carboxylic acid;
(R)-2-{3-[2-(5-methyl-2-jp-tolyl-oxazol-4-yl)-ethoxy]-phenyl}-thiazolidine- 4-carboxylic acid;
(R)-3-(3-{2-[5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl]-ethoxy}- benzyl)-thiazolidine-4-carboxylic acid;
(R)-3-(4-{2-[5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl]-ethoxy}- benzyl)-thiazolidine-4-carboxylic acid;
3-(4-{2-[5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl]-ethoxy}- benzyl)-thiazolidine-2-carboxylic acid;
(R)-3-[3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzyl]-thiazolidine-4- carboxylic acid;
(R)-3-[3-(5-methyl-2-p-tolyl-oxazol-4-ylmethoxy)-benzyl]-thiazolidine-4- carboxylic acid;
(R)-3-[3-(2-biphenyl-4-yl-5~methyl-oxazol-4-ylmethoxy)-benzyl]- thiazolidine-4-carboxylic acid;
(R)-3-[3-(5-methyl-2-thiophen-2-yl-oxazol-4-ylmethoxy)-benzyl]- thiazolidine-4-carboxylic acid;
(R)-3-{3-[5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4-ylmethoxy]- benzyl} -thiazolidine-4-carboxylic acid;
(R)-3-{3-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-benzyl}- thiazolidine-4-carboxylic acid;
3 - [4-(5 -Methyl-2-pheny l-oxazol-4-ylmethoxy)-benzyl] -thiazolidine-2- carboxylic acid;
3-[4-(5-Methyl-2-/>-tolyl-oxazol-4-ylmethoxy)-benzyl]-thiazolidine-2- carboxylic acid;
3-[4-(2-Biphenyl-4-yl-5-methyl-oxazol-4-ylmethoxy)-benzyl]-thiazolidine-2- carboxylic acid;
3-[4-(5-Methyl-2-thiophen-2-yl-oxazol-4-ylmethoxy)-benzyl]-thiazolidine-2- carboxylic acid;
3-[4-(5-Methyl-2-(4-trifluoromethylphenyl)-oxazol-4-ylmethoxy)-benzyl]- thiazolidine-2-carboxylic acid;
3-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-benzyl}- thiazolidine-2-carboxylic acid;
3-{4-[2-(5-Methyl-2-thioρhen-2-yl-oxazol-4-yl)-ethoxy]-benzyl}- thiazolidine-2-carboxylic acid;
3 - [3 -(5 -Methyl-2-phenyl-oxazol-4-ylmethoxy)-benzyl] -thiazolidine-2- carboxylic acid;
3 - [3 -(5-Methyl-2-thiophen-2-yl-oxazol-4-ylmethoxy)-benzyl] -thiazolidine-2- carboxylic acid;
3 - [3 -(5 -Methyl-2-(4-trifluoromethylphenyl)-oxazol-4-ylmethoxy)-benzyl] - thiazolidine-4-carboxylic acid;
3-{3-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzyl}-thiazolidine-2- carboxylic acid;
3 - { 3 - [2-(2-Biρhenyl-4-y 1- 5-methy l-oxazol-4-yl)-ethoxy] -benzy 1 } - thiazolidine-2-carboxylic acid;
3-(3-{2-[5-Methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl]-ethoxy}-benzyl) -thiazolidine-2-carboxylic acid;
(R)-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzyl]-thiazolidine-4- carboxylic acid;
(R)-3-[4-(5-methyl-2-j!?-tolyl-oxazol-4-ylmethoxy)-benzyl]-thiazolidine-4- carboxylic acid;
(R)-3-[4-(2-biphenyl-4-yl-5-methyl-oxazol-4-ylmethoxy)-benzyl]- thiazolidine-4-carboxylic acid;
(R)-3-[4-(5-methyl-2-thiophen-2-yl-oxazol-4-ylmethoxy)-benzyl]- thiazolidine-4-carboxylic acid;
(R)-3-[4-(5-methyl-2-(4-trifluoromethyl-phenyl-oxazol-4-ylmethoxy)- benzyl]-thiazolidine-4-carboxylic acid;
(R)-3-{4-[2-(5-methyl-2-phenyl-4-yl-oxazol-4-yl)-ethoxy]-benzyl}- thiazolidine-4-carboxylic acid;
(R)-3-{4-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-benzyl}- thiazolidine-4-carboxylic acid;
(R)-3-{4-[2-(5-methyl-2-thioρhen-2-yl-oxazol-4-yl)-ethoxy]-benzyl>- thiazolidine-4-carboxylic acid;
(S)-3 - [3 -(5-methyl-2-/?-tolyl-oxazol-4-ylmethoxy)benzyl]thiazolidine-4- carboxylic acid;
(S)-3-[4-(5-methyl-2-/7-tolyl-oxazol-4-ylmethoxy)benzyl]thiazolidine-4- carboxylic acid;
(R)-3-[4-(3-j?-tolylisoxazol-5-ylmethoxy)benzyl]thiazolidine-4-carboxylic acid;
(R)-3-[4-(3-phenylisoxazol-5-ylmethoxy)benzyl]thiazolidine-4-carboxylic acid;
(R)-3-{4-[3-(4-chlorophenyl)isoxazol-5-ylmethoxy]benzyl}thiazolidine-4- carboxylic acid;
(R)-3-{4-[3-(4-trifluoromethylphenyl)isoxazol-5-ylmethoxy]benzyl} thiazolidine-4-carboxylic acid;
(R)-3-[4-(3-p-tolylisoxazol-5-ylmethoxy)benzyl]thiazolidine-4-carboxylic acid;
(R)-3-[3-(3-phenylisoxazol-5-ylmethoxy)benzyl]thiazolidine-4-carboxylic acid;
(R)-3-{3-[3-(4-chlorophenyl)isoxazol-5-ylmethoxy]benzyl}-thiazolidine-4- carboxylic acid;
(R)-3 - { 3 -[3 -(4-trifluoromethylphenyl)isoxazol-5 -ylmethoxy]benzyl } thiazolidine-4-carboxylic acid;
(R)-2-methyl-3-{3-[5-methyl-2-(4-trifluoromethylρhenyl)oxazol-4- ylmethoxy]-benzyl}-thiazolidine-4-carboxylic acid;
(R)-2-isopropyl-3-[3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)-benzyl] thiazolidine-4-carboxylic acid;
(R)-3-[3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)-benzyl]-2-j!?-tolyl- thiazolidine-4-carboxylic acid;
(R)-2-(4-chloroρhenyl)-3-[3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)- benzyl] -thiazolidine-4-carboxylic acid;
(R)-2-(4-methoxyphenyl)-3-[3-(5-methyl-2-j!?-tolyloxazol-4-ylmethoxy)- benzyl]-thiazolidine-4-carboxylic acid;
(R)-2-[4-methyl-2-p-tolyloxazol-4-ylmethoxy)benzyl]thiazolidine-4- carboxylic acid;
(R)-2-{4-[5-methyl-2-(4-trifluoromethylphenyl)oxazol-4-ylmethoxy]benzyl} thiazolidine-4-carboxylic acid;
(R)-2-[4-(5-methyl-2-phenyloxazol-4-ylmethoxy)benzyl]thiazolidine-4- carboxylic acid;
(R)-2-[4-(5-methyl-2-thiophen-2-yloxazol-4-ylmethoxy)benzyl] thiazolidine-4-carboxylic acid;
(R)-3-{2-[4-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)ρhenyl]ethyl} thiazolidine-4-carboxylic acid;
(R)-3-(2-{4-[5-methyl-2-(4-trifluoromethylphenyl)oxazol-4-ylmethoxy] phenyl } ethyl)thiazolidine-4-carboxylic acid;
(R)-3-{2-[4-(5-methyl-2-ρhenyloxazol-4-ylmethoxy)phenyl]ethyl} thiazolidine-4-carboxylic acid;
(R)-3-{2-[4-(5-methyl-2-thioρhen-2-yloxazol-4-ylmethoxy)ρhenyl]ethyl} thiazolidine-4-carboxylic acid;
(3S)-4-[4-(5-methyl-2-phenyl-oxazol-4-yl-methoxy)benzyl]-morpholine-3- carboxylic acid;
(3S)-4-[3-(5-methyl-2-phenyl-oxazol-4-yl-methoxy)benzyl]-morpholine-3- carboxylic acid;
(3S)-4-[4-(5-methyl-2-(4-methylphenyl)-oxazol-4-yl-methoxy)benzyl]- morpholine-3-carboxylic acid;
(3S)-4-[3-(5-methyl-2-(4-memylphenyl)-oxazol-4-yl-methoxy)benzyl]- morpholine-3 -carboxylic acid;
(3S)-4-[4-(5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl-methoxy) benzyl] -morpholine-3 -carboxylic acid;
(3S)-4-[3-(5-rnethyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl-methoxy) benzyl] -morpholine-3 -carboxylic acid;
(3S)-4-[4-(5-methyl-2-(2-thiophene)-oxazol-4-yl-methoxy)benzyl]- morpholine-3 -carboxylic acid;
(3S)-4-[3-(5-methyl-2-(2-thiophene)-oxazol-4-yl-methoxy)benzyl]- morpholine-3-carboxylic acid;
4- [4-(5 -Methyl-2-pheny l-oxazol-4-y l-methoxy)benzyl] -morpholine-3 - carboxylic acid;
4-[3-(5-Methyl-2-phenyl-oxazol-4-yl-methoxy)benzyl]-morpholine-3- carboxylic acid;
4-[4-(5-Methyl-2-(4-methylphenyl)-oxazol-4-yl-methoxy)benzyl]- morpholine-3 -carboxylic acid;
4-[3-(5-Methyl-2-(4-methylphenyl)-oxazol-4-yl-methoxy)benzyl]- morpholine-3 -carboxylic acid;
4- [4-(5 -Methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl-methoxy)benzy 1] - morpholine-3-carboxylic acid;
4-[3-(5-Methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl-methoxy)benzyl]- morpholine-3 -carboxylic acid;
4- [4-(5-Methyl-2-(2-thiophene)-oxazol-4-yl-methoxy)benzyl] -morpholine-3 - carboxylic acid;
4-[3-(5-Methyl-2-(2-thiophene)-oxazol-4-yl-methoxy)benzyl]-morpholine-3- carboxylic acid;
(3S)-4-[4-(5-memyl-2-phenyl-oxazol-4-yl-ethoxy)benzyl]-morpholine-3- carboxylic acid;
(3S)-4-[3-(5-methyl-2-phenyl-oxazol-4-yl-ethoxy)benzyl]-morpholine-3- carboxylic acid;
(3S)-4-[4-(5-methyl-2-(4-methylphenyl)-oxazol-4-yl-ethoxy)benzyl]- morpholine-3 -carboxylic acid;
(3S)-4-[3-(5-methyl-2-(4-methylρhenyl)-oxazol-4-yl-ethoxy)benzyl]- morpholine-3 -carboxylic acid;
(3S)-4-[4-(5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl-ethoxy) benzyl] -morpholine-3 -carboxylic acid;
(3S)-4-[3-(5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl-ethoxy) benzyl]-morpholine-3-carboxylic acid;
(3S)-4-[4-(5-methyl-2-(2-thiophene)-oxazol-4-yl-ethoxy)benzyl]- morpholine-3-carboxylic acid;
(3S)-4-[3-(5-methyl-2-(2-thiophene)-oxazol-4-yl-ethoxy)benzyl]- morpholine-3-carboxylic acid;
4-[4-(5-Methyl-2-phenyl-oxazol-4-yl-ethoxy)benzyl]-morpholine-3- carboxylic acid;
4-[3-(5-Methyl-2-phenyl-oxazol-4-yl-ethoxy)benzyl]-morpholine-3- carboxylic acid;
4-[4-(5-Methyl-2-(4-methylphenyl)-oxazol-4-yl-ethoxy)benzyl]- morpholine-3-carboxylic acid;
4-[3-(5-Methyl-2-(4-methylphenyl)-oxazol-4-yl-ethoxy)benzyl]- morpholine-3-carboxylic acid;
4-[4-(5-Methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl-ethoxy) benzyl]-morpholine-3-carboxylic acid;
4-[3-(5-Methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl-ethoxy) benzyl] -morpholine-3-carboxy lie acid;
4-[4-(5-Methyl-2-(2-thiophene)-oxazol-4-yl-emoxy)benzyl]-morpholine-3- carboxylic acid;
4-[3-(5-Methyl-2-(2-thiophene)-oxazol-4-yl-ethoxy)benzyl]-morpholine-3- carboxylic acid;
(R)-l-[3-[(5-methyl-2-j9-tolyloxazol-4-yl)methoxy]benzyl]azetidine-2- carboxylic acid;
(R)-l-[3-[[5-methyl-2-(4-trifluoromethylphenyl)oxazol-4-yl]methoxy] benzyl] azetidine-2-carboxylic acid methyl ester;
(R)- 1 -[3 -[2-(5-methyl-2-j9-tolyloxazol-4-yl)ethoxy]benzyl]azetidine-2- carboxylic acid;
(R)-l-[3-[2-[5-methyl-2-(4-trifluoromethylphenyl)oxazol-4-yl]ethoxy] benzyl]azetidine-2-carboxylic acid;
(R)-l-[4-[(5-methyl-2-phenyloxazol-4-yl)methoxy]benzyl]azetidine-2- carboxylic acid;
(R)-l-[4-[(5-methyl-2-p-tolyloxazol-4-yl)methoxy]benzyl]azetidine-2- carboxylic acid methyl ester;
(R)-l-[4-[[5-methyl-2-(4-trifluoromethylphenyl)oxazol-4-yl]methoxy] benzyl] azetidine-2-carboxylic acid methyl ester;
(R)-l-[4-[2-(5-methyl-2:/7-tolyloxazol-4-yl)ethoxy]benzyl]azetidine-2- carboxylic acid methyl ester;
(R)-l-[4-[2-[5-methyl-2-(4-trifluoromethylphenyl)oxazol-4-yl]ethoxy] benzyl] azetidine-2-carboxylic acid;
(R)-l-[3-[(5-methyl-2-phenyloxazol-4-yl)methoxy]benzyl]pyrrolidine-2- carboxylic acid;
(R)-l-[3-[(5-methyl-2:p-tolyloxazol-4-yl)methoxy]benzyl]pyrrolidine-2- carboxylic acid;
(R)-l-[3-[[5-methyl-2-(4-trifluoromethylphenyl)oxazol-4-yl]methoxy] benzyl]pyrrolidine-2-carboxylic acid;
(R)-l-[3-[[5-methyl-2-(thiophen-2-yl)oxazol-4-yl]methoxy]benzyl] pyrrolidine-2-carboxylic acid;
(R)-2-[3-[[4-methyl-2-(4-trifluoromethylphenyl)oxazol-5-yl]methoxy] benzyl]pyrrolidin- 1 -carboxylic acid;
2-Methyl-l-[3-[(5-methyl-2-phenyloxazol-4-yl)methoxy]benzyl]pyrrolidine- 2-carboxylic acid methyl ester;
2-Methyl- 1 -[3 -[(5-methyl-2-p-tolyloxazol-4-yl)methoxy3benzyl]pyrrolidine- 2-carboxylic acid methyl ester;
2-Methyl-l-[3-[[5-methyl-2-(4-trifluoromethylphenyl)oxazol-4-yl]methoxy] benzyl]pyrrolidine-2-carboxylic acid methyl ester;
2-Methyl-l-[3-[[5-methyl-2-(thiophen-2-yl)oxazol-4-yl]methoxy]benzyl] pyrrolidine-2-carboxylic acid methyl ester;
2-Ethyl-l-[3-[(5-methyl-2-phenyloxazol-4-yl)methoxy]benzyl]pyrrolidine-2- carboxylic acid methyl ester;
2-Ethyl-l-[3-[(5-methyl-2-p-tolyloxazol-4-yl)methoxy]benzyl]pyrrolidine-2- carboxylic acid methyl ester;
2-Ethyl- 1 -[3 -[ [5 -methyl-2-(4-trifluoromethylphenyl)oxazol-4-y l]methoxy] benzyl]pyrrolidine-2-carboxylic acid methyl ester;
2-Ethyl-l-[3-[[5-methyl-2-(thiophen-2-yl)oxazol-4-yl]methoxy]benzyl] pyrrolidine-2-carboxylic acid methyl ester;
(R)-l-[4-[(5-methyl-2-p-tolyloxazol-4-yl)methoxy]benzyl]pyrrolidine-2- carboxylic acid methyl ester;
2-Methyl- 1 - [4- [(5-methyl-2-phenyloxazol-4-yl)methoxy]benzyl]ρyrrolidine- 2-carboxylic acid methyl ester;
2-Methyl-l-[4-[(5-methyl-2-jc»-tolyloxazol-4-yl)methoxy]benzyl]ρyrrolidine- 2-carboxylic acid methyl ester;
2-Methyl-l-[4-[[5-methyl-2-(4-trifluoromethylphenyl)oxazol-4-yl]methoxy] benzyl]pyrrolidine-2-carboxylic acid methyl ester;
2-Methyl-l-[4-[[5-methyl-2-(thiophen-2-yl)oxazol-4-yl]methoxy]benzyl] pyrrolidine-2-carboxylic acid methyl ester;
2-Ethyl- 1 - [4- [(5 -methy l-2-p-tolyloxazol-4-yl)methoxy]benzyl]pyrrolidine-2- carboxylic acid methyl ester;
2-Ethyl-l-[4-[[5-methyl-2-(4-trifluoromethylphenyl)oxazol-4-yl]methoxy] benzyl]pyrrolidine-2-carboxylic acid methyl ester;
2-Ethyl-l-[4-[[5-methyl-2-(thiophen-2-yl)oxazol-4-yl]methoxy]benzyl] pyrrolidine-2-carboxylic acid methyl ester;
2-Methyl- 1 -[3 -[2-(5-methyl-2-^-tolyloxazol-4-yl)ethoxy]benzyl]pyrrolidine- 2-carboxylic acid methyl ester;
2-Methyl-l-[3-[2-[5-methyl-2-(thioρhen-2-yl)oxazol-4-yl]ethoxy]benzyl] pyrrolidine-2-carboxylic acid methyl ester;
2-Ethyl-l-[3-[2-(5-methyl-2-p-tolyloxazol-4-yl)ethoxy]benzyl]ρyrrolidine-2- carboxylic acid methyl ester;
2-Ethyl-l-[3-[2-[5-methyl-2-(thiophen-2-yl)oxazol-4-yl]ethoxy]benzyl] pyrrolidine-2-carboxylic acid methyl ester;
2-Ethyl-l-[4-[2-(5-methyl-2-/>-tolyloxazol-4-yl)ethoxy]benzyl]pyrrolidine-2- carboxylic acid methyl ester;
2-Methyl-l-[4-[2-[5-methyl-2-(thiophen-2-yl)oxazol-4-yl]ethoxy]benzyl] pyrrolidine-2-carboxylic acid methyl ester;
2-Ethyl-l-[4-[2-(5-methyl-2-jC-tolyloxazol-4-yl)ethoxy]benzyl]pyrrolidine-2- carboxylic acid methyl ester;
2-Ethyl-l-[4-[2-[5-methyl-2-(4-trifluoromethylphenyl)oxazol-4-yl]ethoxy] benzyl]pyrrolidine-2-carboxylic acid methyl ester;
2-Ethyl- 1 - [4- [2- [5-methyl-2-(thiophen-2-yl)oxazol-4-yl] ethoxy]benzyl] pyrrolidine-2-carboxylic acid methyl ester;
(R)-l-[3-[(5-methyl-2-phenyloxazol-4-yl)methoxy]benzyl]piperidine-2- carboxylic acid;
(R)-l-[3-[(5-methyl-2-/?-tolyloxazol-4-yl)methoxy]benzyl]piperidine-2- carboxylic acid methyl ester methyl ester;
(R)-l-[3-[[5-methyl-2-(4-trifluoromethylphenyl)oxazol-4-yl]methoxy] benzyl]piperidine-2-carboxylic acid;
(R)-l-[3-[[4-methyl-2-(4-trifluoromethylphenyl)oxazol-5-yl]methoxy] benzyl]piperidine-2-carboxylic acid;
(R)-l-[3-[[5-methyl-2-(thiophen-2-yl)oxazol-4-yl]methoxy]benzyl] piperidine-2-carboxylic acid;
2-Methyl-l-[3-[[5-methyl-2-(thiophen-2-yl)oxazol-4-yl]methoxy]benzyl] piperidine-2-carboxylic acid methyl ester;
2-Ethyl-l-[3-[[5-methyl-2-(4-trifluoromethylphenyl)oxazol-4-yl]methoxy] benzyl]piperidine-2-carboxylic acid methyl ester;
(R)-l-[4-[(5-methyl-2-phenyloxazol-4-yl)methoxy]benzyl]piperidine-2- carboxylic acid;
(R)-l-[4-[(5-methyl-2-p-tolyloxazol-4-yl)methoxy]benzyl]piperidine-2- carboxylic acid;
(R)-l-[4-[[5-methyl-2-(4-trifluoromethylphenyl)oxazol-4-yl]methoxy] benzyl]piperidine-2-carboxylic acid;
(R)-l-[4-[5-methyl-2-(thiophen-2-yl)oxazol-4-yl]methoxy]benzyl] piperidine-2-carboxylic acid;
2-Methyl-l-[4-[(5-methyl-2-/>-tolyloxazol-4-yl)methoxy]benzyl]piperidine- 2-carboxylic acid methyl ester;
2-Ethyl-l-[4-[(5-methyl-2-f>-tolyloxazol-4-yl)methoxy]benzyl]piperidine-2- carboxylic acid methyl ester;
(R)- 1 -[3 -[2-(5-methyl-2-j3-tolyloxazol-4-yl)ethoxy]benzyl]piperidine-2- carboxylic acid;
(R)-l-[3-[2-[5-methyl-2-(4-trifluoromethylρhenyl)oxazol-4-yl]ethoxy] benzyl]piperidine-2-carboxylic acid methyl ester;
(R)-l-[3-[2-[5-methyl-2-(thiophen-2-yl)oxazol-4-yl]ethoxy]benzyl] piperidine-2-carboxylic acid;
2-Methyl- 1 - [3 - [2-(5 -methyl-2-/>-tolyloxazol-4-yl)ethoxy]benzyl]piperidine- 2-carboxylic acid methyl ester;
2-Methyl-l-[3-[2-[5-methyl-2-(thioρhen-2-yl)oxazol-4-yl]ethoxy]benzyl] piρeridine-2-carboxylic acid methyl ester;
(R)-l-[4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]benzyl]piperidine-2- carboxylic acid;
(R)-l-[4-[2-(5-methyl-2-p-tolyloxazol-4-yl)methoxy]benzyl]piperidine-2- carboxylic acid;
(R)-l-[4-[2-[5-methyl-2-(4-trifluoromethylphenyl)oxazol-4-yl]ethoxy] benzyl]piperidine-2-carboxylic acid;
(R)-l-[4-[2-[5-methyl-2-(thioρhen-2-yl)oxazol-4-yl]ethoxy]benzyl] piperidine-2-carboxylic acid;
2-Methyl-l-[4-[2-(5-methyl-2-j?-tolyloxazol-4-yl)ethoxy]benzyl]piperidine- 2-carboxylic acid methyl ester;
2-Methyl-l-[4-[2-[5-methyl-2-(4-trifluoromethylphenyl)oxazol-4-yl]ethoxy] benzyl]piperidine-2-carboxylic acid methyl ester;
3-Methyl-l-[3-[(5-methyl-2-phenyloxazol-4-yl)methoxy]benzyl]piperidine- 3-carboxylic acid ethyl ester;
3-Methyl-l-[3-[(5-methyl-2-/?-tolyloxazol-4-yl)methoxy]benzyl]piperidine- 3-carboxylic acid ethyl ester;
3-Methyl-l-[3-[[5-methyl-2-(4-trifluoromethylphenyl)oxazol-4-yl]methoxy] benzyl]piperidine-3-carboxylic acid ethyl ester;
3 -Methyl- 1 - [3 - [[5-methyl-2-(thiophen-2-yl)oxazol-4-yl]methoxy]benzyl] piρeridine-3-carboxylic acid ethyl ester;
3-Ethyl-l-[3-[(5-methyl-2-phenyloxazol-4-yl)methoxy]benzyl]piperidine-3- carboxylic acid ethyl ester;
3-Ethyl-l-[3-[(5-methyl-2-p-tolyloxazol-4-yl)methoxy]benzyl]piperidine-3- carboxylic acid ethyl ester;
3 -Ethyl- 1 - [3 - [[5 -methyl-2-(4-trifluoromethylphenyl)oxazol-4-yl]methoxy] benzylJpiperidine-S-carboxylic acid ethyl ester;
3-Ethyl-l-[3-[[5-methyl-2-(thioρhen-2-yl)oxazol-4-yl]methoxy]benzyl] piperidine-3-carboxylic acid ethyl ester;
3-Methyl-l-[4-[(5-methyl-2-phenyloxazol-4-yl)methoxy]benzyl]piperidine- 3-carboxylic acid ethyl ester;
3-Methyl-l-[4-[(5-methyl-2-/)-tolyloxazol-4-yl)methoxy]benzyl]piperidine- 3-carboxylic acid ethyl ester;
3-Methyl-l-[4-[[5-rnethyl-2-(4-trifluoromethylphenyl)oxazol-4-yl]methoxy] benzyljpiperidine-S-carboxylic acid ethyl ester;
3-Methyl-l-[4-[[5-methyl-2-(thioρhen-2-yl)oxazol-4-yl]methoxy]benzyl] piperidine-3-carboxylic acid ethyl ester;
3 -Ethyl- 1 - [4- [(5-methy l-2-phenyloxazol-4-y l)methoxy]benzyl]piperidine-3 - carboxylic acid ethyl ester;
3 -Ethyl- 1 - [4- [(5-methy l-2-/>-tolyloxazol-4-yl)methoxy]benzyl]piperidine-3 - carboxylic acid ethyl ester;
3 -Ethyl- 1 -[4-[[5-methyl-2-(4-trifluoromethylphenyl)oxazol-4-yl]methoxy] benzyl]piperidine-3 -carboxylic acid ethyl ester;
3-Ethyl-l-[4-[[5-methyl-2-(thiophen-2-yl)oxazol-4-yl]methoxy]benzyl] piperidine-3-carboxylic acid ethyl ester;
3-Methyl-l-[3-[2-(5-methyl-2-j!7-tolyloxazol-4-yl)ethoxy]benzyl]piperidine- 3 -carboxylic acid ethyl ester;
3-Methyl-l-[3-[2-[5-methyl-2-(4-trifluoromethylphenyl)oxazol-4-yl]ethoxy] benzyl)piperidine-3 -carboxylic acid ethyl ester;
3-Methyl-l-[3-[2-[5-methyl-2-(thiophen-2-yl)oxazol-4-yl]ethoxy]benzyl] piperidine-3-carboxylic acid ethyl ester;
3-Ethyl-l-[3-[2-(5-methyl-2-/7-tolyloxazol-4-yl)ethoxy]benzyl]piperidine-3- carboxylic acid ethyl ester;
3-Ethyl-l-[3-[2-[5-methyl-2-(4-trifluoromethylρhenyl)oxazol-4-yl]ethoxy] benzyl]piperidine-3-carboxylic acid ethyl ester;
3-Ethyl-l-[3-[2-[5-methyl-2-(thiophen-2-yl)oxazol-4-yl]ethoxy]benzyl] piperidine-3-carboxylic acid ethyl ester;
3-Methyl-l-[4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]benzyl]piρeridine- 3 -carboxylic acid ethyl ester;
3-Methyl-l-[4-[2-[5-methyl-2-(4-trifluoromethylphenyl)oxazol-4-yl]ethoxy] benzyl]piperidine-3 -carboxylic acid ethyl ester;
3-Methyl-l-[4-[2-[5-methyl-2-(thiophen-2-yl)oxazol-4-yl]ethoxy]benzyl] piperidine-3-carboxylic acid ethyl ester;
3-Ethyl-l-[4-[2-(5-methyl-2-phenoloxazol-4-yl)ethoxy]benzyl]piperidine-3- carboxylic acid ethyl ester;
3-Ethyl-l-[4-[2-[5-methoxy-2-(4-trifluoromethylρhenyl)oxazol-4-yl]ethoxy] benzyl]piperidine-3-carboxylic acid ethyl ester;
3-Ethyl-l-[4-[2-[5-methyl-2-(thioρhen-2-yl)oxazol-4-yl]ethoxy]benzyl] piperidine-3-carboxylic acid ethyl ester;
(R)-l-[4-(2-phenyl-oxazol-4-ylmethoxy)-benzyl]-pyrrolidine-2-carboxylic acid;
(R)-l-[4-(2-/?-tolyl-oxazol-4-ylmethoxy)-benzyl]-pyrrolidine-2-carboxylic acid;
(R)-I- [4- [2-(4-trifluoromethylphenyl)-oxazol-4-y lmethoxy] -benzyl] - pyrrolidine-2-carboxylic acid;
(R)- 1 - [3 -(2-phenyl-oxazol-4-ylmethoxy)-benzyl] -pyrrolidine-2-carboxylic acid;
(R)-l-[3-(2-p-tolyl-oxazol-4-ylmethoxy)-benzyl]-pyrrolidine-2-carboxylic acid;
(R)- 1 - [3 - [2-(4-trifluoromethylphenyl)-oxazol-4-y lmethoxy] -benzyl] - pyrrolidine-2-carboxylic acid;
(R)-l-[4-[2-(2-phenyl-oxazol-4-yl)-ethoxy]-benzyl]-pyrrolidine-2-carboxylic acid;
(R)-l-{4-[2-(2-p-tolyl-oxazol-4-yl)-ethoxy]-benzyl}-pyrrolidine-2- carboxylic acid;
(R)-l-[4-[2-[2-(4-trifluoromethylphenyl)-oxazol-4-yl]-ethoxy]-benzyl]- pyrrolidine-2-carboxylic acid;
(R)-l-[3-[2-(2-phenyl-oxazol-4-yl)-ethoxy]-benzyl]-pyrrolidine-2-carboxylic acid;
(R)-l-[3-[2-(2-p-tolyl-oxazol-4-yl)-ethoxy]-benzyl]-pyrrolidine-2-carboxylic acid;
(R)-l-[4-[2-[2-(4-trifluoromethylphenyl)-oxazol-4-yl]-ethoxy]-benzyl]- pyrrolidine-2-carboxylic acid;
(R)-l-[4-[2-(5-isopropyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzyl]-pyrrolidine- 2-carboxylic acid;
(R)-l-[3-[2-(5-isopropyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzyl]-pyrrolidine- 2-carboxylic acid; l-[4-(2-Phenyl-oxazol-4-ylmethoxy)-benzyl]-piperidine-2-carboxylic acid; l-[4-(2-/>-Tolyl-oxazol-4-ylmethoxy)-benzyl]-ρiperidine-2-carboxylic acid; l-[4-[2-(4-Trifluoromethylphenyl)-oxazol-4-ylmethoxy]-benzyl]-piperidine- 2-carboxylic acid; l-[3-(2-Phenyl-oxazol-4-ylmethoxy)-benzyl]-piperidine-2-carboxylic acid; l-[3-(2-/7-Tolyl-oxazol-4-ylmethoxy)-benzyl]-piperidine-2-carboxylic acid; l-[3-[2-(4-Trifluoromethylphenyl)-oxazol-4-ylmethoxy]-benzyl]-piperidine- 2-carboxylic acid; l-[4-[2-(2-Phenyl-oxazol-4-yl)-ethoxy]-benzyl]-piperidine-2-carboxylic acid; l-[4-[2-(2-/?-Tolyl-oxazol-4-yl)-ethoxy]-benzyl]-piperidine-2-carboxylic acid; l-[4-[2-[2-(4-Trifluoromethylphenyl)-oxazol-4-yl]-ethoxy]-benzyl]- piperidine-2-carboxylic acid; l-[3-[2-(2-Phenyl-oxazol-4-yl)-ethoxy]-benzyl]-piperidine-2-carboxylic acid; l-[3-[2-(2-/7-Tolyl-oxazol-4-yl)-ethoxy]-benzyl]-piperidine-2-carboxylic acid; l-[4-[2-[2-(4-Trifluoromethylphenyl)-oxazol-4-yl]-ethoxy]-benzylJ- piperidine-2-carboxylic acid;
1 - [4-(5 -Methyl-2-Jp-tolyl-oxazol-4-ylmethoxy)-benzyl] -pyrrolidine-2-carbox ylic acid ^-butyl ester;
(R)-l-[4-(2-biphenyl-4-yl-5-methyl-oxazol-4-ylmethoxy)-benzyl]- pyrrolidine-2-carboxylic acid;
(R)-l-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzyl]-pyrrolidine-2- carboxylic acid;
(R)-l-[4-(5-methyl-2-p-tolyl-oxazol-4-ylmethoxy)-benzyl]-pyrrolidine-2- carboxylic acid;
(R)-l-{4-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]- benzyl}-pyrrolidine-2-carboxylic acid;
(R)-l-[4-(5-methyl-2-thiophen-2-yl-oxazol-4-ylmethoxy)-benzyl]- pyrrolidine-2-carboxylic acid;
(S)-l-{3-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-benzyl}- pyrrolidine-2-carboxylic acid;
(S)-l-{3-[2-(5-methyl-2-/>-tolyl-oxazol-4-yl)-ethoxy-benzyl}-pyrrolidine-2- carboxylic acid;
(S)-l-(3-{2-[5-methyl-2-(4-trifluoromethyl-ρhenyl)-oxazol-4-yl]-ethoxy}- benzyl)-pyrrolidine-2-carboxylic acid;
(S)-l-{3-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]-benzyl}- pyrrolidine-2-carboxylic acid;
(S)-l-{4-[2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-benzyl}- pyrrolidine-2-carboxylic acid;
(S)-l-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzyl}-pyrrolidine-2- carboxylic acid;
(S)- 1 -(4- {2- [5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-ethoxy } - benzyl)-pyrrolidine-2-carboxylic acid;
(S)-l-{4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]-benzyl}- pyrrolidine-2-carboxylic acid; l-[3-(2-Biphenyl-4-yl-5-methyl-oxazol-4-ylmethoxy)-benzyl]-piperidine-2- carboxylic acid; l-[3-(5-Methyl-2-/>-tolyl-oxazol-4-ylmethoxy)-benzyl]-piperidine-2- carboxylic acid; l-{3-[5-Methyl-2-(4-trifluoromethyl-ρhenyl)-oxazol-4-ylmethoxy]-benzyl}- piperidine-2-carboxylic acid; l-[3-(5-Methyl-2-thiophen-2-yl-oxazol-4-ylmethoxy)-benzyl]-piperidine-2- carboxylic acid; l-{3-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzyl}-piperidine-2- carboxylic acid; l-(3-{2-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-ethoxy-benzyl) -piperidine-2-carboxylic acid; l-{3-[2-(5-Methyl-2-thiophen-2-yl-oxazol-4-yl)-ethoxy]-benzyl}-piperidine- 2-carboxylic acid; l-(4-{2-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-ethoxy}- benzyl)-piperidine-2-carboxylic acid;
(S)-l-[4-(5-methyl-2-jζ?-tolyl-oxazol-4-ylmethoxy)-benzyl]-piperidine-2- carboxylic acid;
(S)-l-{4-[2-(5-methyl-2-/»-tolyl-oxazol-4-yl)-ethoxy]-benzyl}-piperidine-2- carboxylic acid;
(S)- 1 -(3 -((5-methyl-2-phenyloxazol-4-yl)methoxy)benzyl)pyrrolidine-2- carboxylic acid;
(S)-l-(3-((5-methyl-2-p-tolyloxazol-4-yl)methoxy)benzyl)pyrrolidine-2- carboxylic acid;
(S)- 1 -(3 -((5 -methyl-2-(4-(trifluoromethyl)phenyl)oxazol-4-yl)methoxy) benzyl)pyrrolidine-2-carboxylic acid;
(S)-l-(3-((2-(biphenyl-4-yl)-5-methyloxazol-4-yl)methoxy)benzyl) pyrrolidine-2-carboxylic acid;
(S)- 1 -(3 -((5 -methyl-2-(thiophen-2-yl)oxazol-4-yl)methoxy)benzyl) pyrrolidine-2-carboxylic acid;
(S)-l-(4-((5-methyl-2-phenyloxazol-4-yl)methoxy)benzyl)pyrrolidine-2- carboxylic acid;
(S)-l-[4-(5-methyl-2-/?-tolyl-oxazol-4-ylmethoxy)-benzyl]-pyrrolidine-2- carboxylic acid;
(S)-l-{4-[5-methyl-2-(4-trifluoromethyl-ph.enyl)-oxazol-4-ylmethoxy]- benzyl}-pyrrolidine-2-carboxylic acid;
(S)-l-[4-(2-biphenyl-4-yl-5-methyl-oxazol-4-ylmethoxy)-benzyl]- pyrrolidine-2-carboxylic acid;
(S)-l-[4-(5-methyl-2-thiophen-2-yl-oxazol-4-ylmethoxy)-benzyl]- pyrrolidine-2-carboxylic acid;
(S)-l-{4-[2-(5-methyl-2-p>-tolyl-oxazol-4-yl)-ethoxy-benzyl}-pyrrolidine-2- carboxylic acid; l-(3-((5-Methyl-2-phenyloxazol-4-yl)methoxy)benzyl)piperidine-2- carboxylic acid; and l-(3-(2-(5-Methyl-2-/7-tolyloxazol-4-yl)ethoxy)benzyl)piρeridine-2- carboxylic acid.
4. A pharmaceutical composition for inhibiting the accumulation of lipids in the body comprising the heterocyclic carboxylic acid derivative of formula (1) or a pharmaceutically acceptable salt thereof according to claim 1, as an active ingredient.
5. The composition of claim 4 which is used for the treatment or prevention of a disease selected from the group consisting of obesity, NIDDM(non-insulin dependent diabetes mellitus), hyperlipidemia, arteriosclerosis, steatosis of the liver or muscle, fatty liver, and a combination thereof.
PCT/KR2008/001682 2007-03-28 2008-03-26 Heterocyclic carboxylic acid derivatives and pharmaceutical composition for inhibiting lipid accumulation containing same Ceased WO2008117982A1 (en)

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WO2011161030A1 (en) 2010-06-21 2011-12-29 Sanofi Heterocyclic substituted methoxyphenyl derivatives having an oxo group, method for producing same, and use thereof as gpr40 receptor modulators
WO2012010413A1 (en) 2010-07-05 2012-01-26 Sanofi Aryloxy-alkylene substituted hydroxyphenyl hexynoic acids, methods for the production thereof and use of the same as medicament
WO2012004269A1 (en) 2010-07-05 2012-01-12 Sanofi (2-aryloxy-acetylamino)-phenyl-propionic acid derivatives, method for producing same and use thereof as pharmaceuticals
WO2012004270A1 (en) 2010-07-05 2012-01-12 Sanofi Spirocyclically substituted 1,3-propane dioxide derivatives, methods for the production thereof and use of the same as medicament
WO2013037390A1 (en) 2011-09-12 2013-03-21 Sanofi 6-(4-hydroxy-phenyl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors
WO2013045413A1 (en) 2011-09-27 2013-04-04 Sanofi 6-(4-hydroxy-phenyl)-3-alkyl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors
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