WO2002059098A1 - Thiazole and oxazole derivatives as activators of human peroxisome proliferator activated receptors - Google Patents

Thiazole and oxazole derivatives as activators of human peroxisome proliferator activated receptors Download PDF

Info

Publication number
WO2002059098A1
WO2002059098A1 PCT/US2001/051056 US0151056W WO02059098A1 WO 2002059098 A1 WO2002059098 A1 WO 2002059098A1 US 0151056 W US0151056 W US 0151056W WO 02059098 A1 WO02059098 A1 WO 02059098A1
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
phenyl
trifluoromethyl
thiazol
sulfanyl
Prior art date
Application number
PCT/US2001/051056
Other languages
French (fr)
Inventor
Pierette Banker
Rodolfo Cadilla
Millard Hurst Lambert, Iii
Stephen William Rafferty
Daniel David Sternbach
Marcos Luis Sznaidman
Original Assignee
Glaxo Group Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Glaxo Group Limited filed Critical Glaxo Group Limited
Priority to JP2002559400A priority Critical patent/JP4234431B2/en
Priority to DK01994514T priority patent/DK1349843T3/en
Priority to EP01994514A priority patent/EP1349843B1/en
Priority to AT01994514T priority patent/ATE293611T1/en
Priority to DE60110262T priority patent/DE60110262T2/en
Publication of WO2002059098A1 publication Critical patent/WO2002059098A1/en
Priority to US11/550,060 priority patent/US7229998B2/en
Priority to US11/753,848 priority patent/US7449468B2/en

Links

Classifications

    • 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
    • C07D417/06—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 carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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
    • 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
    • A61P3/06—Antihyperlipidemics
    • 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
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/24—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/26—Radicals substituted by sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/28—Radicals substituted by nitrogen atoms
    • 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
    • C07D417/10—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 carbon chain containing aromatic 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

Definitions

  • the present invention relates to certain novel compounds.
  • the present invention relates to compounds that activate human peroxisome proliferator activated receptors ("hPPARs").
  • hPPARs human peroxisome proliferator activated receptors
  • the present invention also relates to methods for preparing the compounds, their use in medicine, pharmaceutical compositions containing them and methods for the prevention or treatment of PPAR mediated diseases or conditions.
  • Syndrome X (including metabolic syndrome) is loosely defined as a collection of abnormalities including hyperinsulinemia, obesity, elevated levels of trigycerides, uric acid, fibrinogen, small dense LDL particles, and plasminogen activator inhibitor 1 (PAI-1), and decreased levels of HDL-c.
  • abnormalities including hyperinsulinemia, obesity, elevated levels of trigycerides, uric acid, fibrinogen, small dense LDL particles, and plasminogen activator inhibitor 1 (PAI-1), and decreased levels of HDL-c.
  • NIDDM is described as insulin resistance which in turn causes anomalous glucose output and a decrea ⁇ e in glucose uptake by skeletal muscle. These factors eventually leaci to impaired glucose tolerance (IGT) and hyperinsulinemia.
  • Peroxisome Proliferator Activated Receptors PPARs are ophan receptors belonging to the steroid/retinoid receptor superfamily of ligand-activated transcription factors. See, for example Willson T.M. and Wahli, W., Curr. Opin. Chem. Biol. (1997) Vol 1 pp 235-241 and Willson T.M. et. al., J. Med. Chem (2000) Vol 43 p527-549.
  • R 1 and R 2 are independently hydrogen or C,. 3 alkyl
  • X 2 is O, S, or CH 2 ;
  • R 3 , R 4 , and R 5 are independently H, C ⁇ alkyl, OCH 3 , CF 3 , OCF 3 , allyl, CN, or halogen;
  • Y is S or O; each R 25 is independently CH 3 , OCH 3 , OCF 3 , CF 3 , or halogen; y is O, 1 , 2, 3, 4 or 5; and
  • the formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.
  • reference herein to treatment extends to prophylaxis as well as the treatment of established diseases or symptoms.
  • the amount of a compound of the invention required for use in treatment will vary with the nature of the condition being treated and the age and the condition of the patient and will be ultimately at the discretion of the attendant physician or veterinarian. In general, however, doses employed for adult human treatment will typically be in the range of 0.02-5000 mg per day, preferably 1-1500 mg per day.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example as two, three, four or more sub-doses per day.
  • the formulations according to the invention may contain between 0.1-99% of the active ingredient, conveniently from 30-95% for tablets and capsules and 3-50% for liquid preparations.
  • Ethyl 4-(hydroxymethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazole-5-carboxylate 42g, 0.127moles, 1eq
  • dry CH 2 Cl 2 300ml
  • reaction mixture was then washed with 0.1 N HCI and the phases were separated, with discarding the aqueous fraction.
  • the organic fraction was washed with 0.1 N HCI, H 2 0, brine and dried over Na 2 S0 4 .
  • the solution was filtered and concentrated in vacuo to yield 119.95g (98%) of pure sulfonyl chloride.
  • Ethyl 2- ⁇ 4-[( ⁇ 4-(2-thienylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl ⁇ methyl)sulfanyl]-2- methylphenoxy ⁇ propanoate From 5-(chloromethyl)-4-(3-furylmethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazole (0.185g, 0.50 mmol), ethyl 2- ⁇ 4-[( ⁇ 4-(2-thienylmethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl ⁇ methyl)sulfanyl]-2-methyIphenoxy ⁇ propanoate (0.21 g, 73%) was obtained as a yellow solid.
  • reaction mixture was cooled to -78°C followed by the dropwise addition of neat ⁇ [tert- Butyl(diphenyl)silyl]oxy ⁇ acetyl chloride (18g, 54mmoles, 1eq) over a period of 15 minutes maintaining the internal reaction temperature below -60°C.
  • Phenylboronic acid (0.143g, 1.2mmoles, 1.5eq) was then added followed by the addition of sodium carbonate (2M aqueous solution, 2.3ml, 4.68mmoles, 6eq).
  • the reaction mixture was heated at 100 degrees centigrade for 13 hours at which point, after cooling to room temperature, the reaction was partitioned between EtOAc and water. After separation of the phases the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated in vacuo to yield after purification by silica gel chromatography (CH 2 CI 2 to 2% MeOH/CH 2 Cl 2 ) 268mg (80%) of product.

Abstract

The present invention provides a compound of formula (I) wherein R1-R5, R25, R26, Y and X2 are defined as in claim 1. The compounds activate human peroxisome proliferator activated receptors (hPPARs) and are useful for the treatment of associated disorders such as cardiovascular disease and hypercholesteremia.

Description

THIAZOLE AND OXAZOLE DERIVATIVES AS ACTIVATORS OF HUMAN PEROXISOME PROLIFERATOR ACTIVATED RECEPTORS
The present invention relates to certain novel compounds. In particular, the present invention relates to compounds that activate human peroxisome proliferator activated receptors ("hPPARs"). The present invention also relates to methods for preparing the compounds, their use in medicine, pharmaceutical compositions containing them and methods for the prevention or treatment of PPAR mediated diseases or conditions.
Several independent risk factors have been associated with cardiovascular disease. These include hypertension, increased fibrinogen levels, high levels of triglycerides, elevated LDL cholesterol, elevated total cholesterol, and low levels of HDL cholesterol. HMG CoA reductase inhibitors ("statins") are useful for treating conditions characterized by high LDL-c levels. It has been shown that lowering LDL-c is not sufficient for reducing the risk of cardiovascular disease in some patients, particularly those with normal LDL-c levels. This population pool is identified by the independent risk factor of low HDL-c. The increased risk of cardiovascular disease associated with low HDL-c levels has not yet been successfully addressed by drug therapy (i.e. currently there are no drugs on the market that are useful for raising HDL-c). (Bisgaier, C. L.; Pape, M. E. Curr. Pharm. Des. 1998, 4, 53-70).
Syndrome X (including metabolic syndrome) is loosely defined as a collection of abnormalities including hyperinsulinemia, obesity, elevated levels of trigycerides, uric acid, fibrinogen, small dense LDL particles, and plasminogen activator inhibitor 1 (PAI-1), and decreased levels of HDL-c.
NIDDM is described as insulin resistance which in turn causes anomalous glucose output and a decreaεe in glucose uptake by skeletal muscle. These factors eventually leaci to impaired glucose tolerance (IGT) and hyperinsulinemia. Peroxisome Proliferator Activated Receptors (PPARs) are ophan receptors belonging to the steroid/retinoid receptor superfamily of ligand-activated transcription factors. See, for example Willson T.M. and Wahli, W., Curr. Opin. Chem. Biol. (1997) Vol 1 pp 235-241 and Willson T.M. et. al., J. Med. Chem (2000) Vol 43 p527-549. The binding of agonist ligands to the receptor results in changes in the expression level of mRNA's encoded by PPAR target genes. Three mammalian Peroxisome Proliferator-Activated Receptors have been isolated and termed PPAR-alpha, PPAR-gamma, and PPAR-delta (also known as NUC1 or PPAR-beta). These PPARs regulate expression of target genes by binding to DNA sequence elements, termed PPAR response elements (PPRE). To date, PPRE's have been identified in the enhancers of a number of genes encoding proteins that regulate lipid metabolism suggesting that PPARs play a pivotal role in the adipogenic signaling cascade and lipid homeostasis (H. Keller and W. Wahli, Trends Endocrin. Met 291 -296, 4 (1993)).
It has now been reported that thiazolidinediones are potent and selective activators of PPAR-ga.f.me and bind directly to the PPAR-gamma receptor (J. M. Lehmann P . al., J. Biol. Chem. 12953-12956, 270 (1995)), providing evidence that PPAR-gamma is a possible target for the therapeutic actions of the thiazolidinediones.
Activators of the nuclear receptor PPARγ, for example troglitazone, have been shown in the clinic to enhance insulin-action, reduce serum glucose and have small but significant effects on reducing serum triglyceride levels in patients with Type 2 diabetes. See, for example, D. E. Kelly et al., Curr. Opin. Endocrinol. Diabetes, 90-96, 5 (2), (1998); M. D. Johnson et al., Ann. Pharmacother., 337-348, 32 (3), (1997); and M. Leutenegger et al., Curr. Ther. Res., 403-416, 58 (7), (1997).
The mechanism for this triglyceride lowering effect appears to be predominantly increased clearance of very low density lipoproteins (VLDL) through induction of liporotein lipase (LPL) gene expression. See, for example, B. Staels et al., Arterioscler. Thromb., Vase. Biol., 1756-1764, 17 (9), (1997).
Fibrates are a class of drugs which may lower serum triglycerides 20-50%, lower LDLc 10- 15%, shift the LDL particle size from the more atherogenic small dense to normal dense LDL, and increase HDLc 10- 5%. Experimental evidence indicates that the effects of fibrates on serum lipids are mediated through activation of PPARα. See, for example, B. Staels et al., Curr. Pharm. Des., 1-
14, 3 (1), (1997). Activation of PPARα results in transcription of enzymes that increase fatty acid catabolism and decrease de-novo fatty acid synthesis in the liver resulting in decreased triglyceride synthesis and VLDL production/secretion. In addition, PPARα activation decreases production of apoC-lll. Reduction in apoC-lll, an inhibitor of LPL activity, increases clearance of VLDL. See, for example, J. Auwerx et al., Atherosclerosis, (Shannon, Irel.), S29-S37, 124 (Suppl), (1996).
Certain compounds that activate or otherwise interact with one or more of the PPARs have been implicated in the regulation of triglyceride and cholesterol levels in animal models. See, for example, U.S. Patents 5,847,008 (Doebber et al.) and 5,859,051 (Adams et al.) and PCT publications WO 97/28149 (Leibowitz et al.) and WO99/04815 (Shimokawa et al.). In a recent report (Berger et al., J. Biol. Chem. 1999), vol. 274, pp. 6718-6725) it was stated that PPARD activation does not appear to modulate glucose or triglyceride levels.
In one aspect, the present invention provides compounds of formula (I) and pharmaceutically acceptable salts, solvates, and hydrolysable esters thereof wherein;
Figure imgf000003_0001
R1 and R2 are independently hydrogen or C,.3 alkyl;
X2 is O, S, or CH2; R3, R4, and R5 are independently H, C^alkyl, OCH3, CF3, OCF3, allyl, CN, or halogen;
Y is S or O; each R25 is independently CH3, OCH3, OCF3, CF3, or halogen; y is O, 1 , 2, 3, 4 or 5; and
R26 is selected from the group consisting of the moieties A through K depicted below:
Figure imgf000004_0001
wherein R12 is selected from the group consisting of C,.6alkyl, C.,.6alkylenearyl, and the moieties depicted below in Group II,
Figure imgf000004_0002
Group II
wherein R17 and R18 are independently hydrogen, halogen, hydroxy, -CN, Chalky!, C^ eperfluoroalkyl,
Figure imgf000004_0003
R19 is hydrogen or Chalky!;
R21 is
Figure imgf000004_0004
aryl, or -aryl-heteroaryl;
R22 is C,.6alkyl, aryl, or -C,.6alkylenearyl;
R23 is C^alkyl, C3.6cycloalkyl, or aryl;
R24 is Cι.6alkyl,
Figure imgf000004_0005
C3.6cycloalkyl, or aryl;
B
Figure imgf000004_0006
wherein Z is O, N or S (note that when Z is N, the depicted bond can be attached to the nitrogen in the ring as well as any of the carbons in the ring);
Figure imgf000004_0007
wherein R20 is
Figure imgf000004_0008
or 1-alkoxyC,.6alkyl;
— N O
Figure imgf000005_0001
wherein R13 and R14 are independently hydrogen, halogen, CN, perfluroC,.6aIkyl, perfluroOC,.
6alkyl, C,.salkyl, -OC.,.6alkyl, -C1.6alkyleneOC1.salkyl, -SC^alkyl, or aryl;
Figure imgf000005_0002
wherein R21 is independently as defined above;
/ R15 — N
R16
wherein R15 and R16 are independently hydrogen, C^alkyl, C3.6cycloaIkyl optionally substituted with 1 or 2 Cι.3alkyl groups, or R 2 as defined above;
H "
I (CH2)nPh wherein n is 1-3
J
— O— R21 wherein R21 is independently as defined above; and
K
— S— R21
wherein R21 is independently as defined above. As used herein "aryl" or in any phrase or term including "aryl" such as "-C^alkylenearyl", the "aryl" means a phenyl group or a 5 or 6 membered heteroaryl group. As used hereing "heteroaryl" means a 5 or 6 membered heteroaryl group. As used herein any such "aryl" or "heteroaryl" group may optionally be substittued with one or two substituents selected from the group consisting of halogen, CN, dimethylamino, perfluroC.,_6alkyl, perfluroOC,. 6alkyl, C,.6alkyl, -OC^alkyl, -C1_6alkyleneOCI.salkyl, and -SC,.6alkyl.
In another aspect, the present invention discloses a method for prevention or treatment of a disease or condition mediated by one or more human PPAR alpha, gamma or delta ("hPPARs") comprising administration of a therapeutically effective amount of a compound of this invention. hPPAR mediated diseases or conditions include dyslipidemia including associated diabetic dyslipidemia and mixed dyslipidemia, syndrome X (as defined in this application this embraces metabolic syndrome), heart failure, hypercholesteremia, cardiovascular disease including atherosclerosis, arteriosclerosis, and hypertriglycendemia, type II diabetes mellitus, type I diabetes, insulin resistance, hyperlipidemia, inflammation, epithelial hyperproliferative diseases including eczema and psoriasis and conditions associated with the lung and gut and regulation of appetite and food intake in subjects suffering from disorders such as obesity, anorexia bulimia, and anorexia nervosa. In particular, the compounds of this invention are useful in the treatment and prevention of diabetes and cardiovascular diseases and conditions including atherosclerosis, arteriosclerosis, hypertriglycendemia, and mixed dyslipidaemia.
In another aspect, the present invention provides pharmaceutical compositions comprising a compound of the invention, preferably in association with a pharmaceutically acceptable diluent or carrier. In another aspect, the present invention provides a compound of the invention for use in therapy, and in particular, in human medicine.
In another aspect, the present invention provides the use of a compound of the invention for the manufacture of a medicament for the treatment of a hPPAR mediated disease or condition.
As used herein, "a compound of the invention" means a compound of formula (I) or a pharmaceutically acceptable hydrolyzable ester or, solvate, thereof.
While hydrolyzable esters are included in the scope of this invention, the acids are preferred because the data suggests that while the esters are useful compounds, it may actually be the acids to which they hydrolyze that are the active compounds. Esters that hydrolyze readily can produce the carboxylic acid in the assay conditions or in vivo. Generally the carboxylic acid is active in both the binding and transient transfection assays, while the ester does not usually bind well but is active in the transient transfection assay presumably due to hydrolysis. Preferred hydrolysable esters are C^ alkyl esters wherein the alkyl group may be straight chain or branched chain. Methyl or ethyl esters are more preferred.
Preferably R1 and R2 are independently H or CH3. Most preferably R1 and R2 are either both H or both CH3.
Preferably X2 is O or S. More preferably X2 is S;
Preferably R3 is CH3 or H;
Preferably R4 and R5 are H.
Preferably Y is S. Preferably y is 1 or 2. When y is 2, preferably one R25 is halogen; more preferably one is halogen and the other is CF3. When y is 1 , preferably the R25 is in the para position on the ring and is more preferably CF3.
Preferably R26 is selected from the moieties shown below in Group III. Group III
Preferably R12 is selected from the moieties shown below in Group IV.
Figure imgf000007_0001
Group IV
Preferably R 3 or R14 are independently fluorine, bromine, phenyl, thienyl, CF3, OCF3, OCH3, SCH3, or t-butyl. Most preferably R14 is thienyl, OCH3, OCF3, CF3, or fluorine. Most preferably R14 is substituted para to the depicted open valence. Most preferably R13 is hydrogen or fluorine.
Preferably R17 and R18 are independently hydrogen, OH, OC,.3aIkyl, CN, halogen, CF3, COCH3, CH(OH)CH3, or OCF3. Most preferably R 7 is fluorine, chlorine, OC,.3alkyl, or COCH3 and R18 is OCH3 or hydrogen. Most preferably R17 is substituted para to the depicted open valence.
Preferably R20 is phenyl, methyl, OCH3, OH, or CH2OH.
Preferably R21 is -C,.3alkylenephenyl, phenyl-5-methyl-1 ,2,4-oxadiazol-3-yl, or phenyl optionally substituted by methyl or CN. Preferably R22 is C,.6alkyl, phenyl, or benzyl.
Preferably R23 is C,.salkyl, furanyl, thienyl, methoxymethyl, C3.6cyclalkyl, or phenyl optionally substituted by a halogen a methoxy or a dimethylamino group.
Preferably R24 is H, C,.6alkyl, cyclohexyl, m-methoxyphenyl, p-fluorophenyl, or - CH2CH2phenyl. Preferably R19 is hydrogen.
Particularly preferred compounds will be those is which most or all of the variables are selected from the preferred or most preferred groups for each variable.
While the preferred groups for each variable have generally been listed above separately for each variable, preferred compounds of this invention include those in which several or each variable in Formula (I) is selected from the preferred, more preferred, or most preferred groups for each variable. Therefore, this invention is intended to include all combinations of preferred, more preferred, and most preferred groups.
Suitable compounds of formula (1 ) include:
2-[4-({[4-{[4-(4-acetylphenyl)-1-piperazinyl]methyl}-2-(4-fluorophenyl)-1 ,3-thiazol-5- yl]methyl}sulfanyl)-2-methylphenoxy]-2-methylpropanoic acid,
2-methyl-2-{2-methyl-4-[({4-[4-(methylsulfanyl)benzyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol- 5-yl}methyl)suIfanyl]phenoxy}propanoic acid,
{2-methyl-4-[({4-(3-thienylmethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}acetic acid, {4-[({4-benzyl-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methyl)sulfanyI]-2,5- dimethylphenoxy}acetic acid, 2-{4-[({4-{[4-(4-acetylphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyl)sulfanyI]-2-methylphenoxy}propanoic acid,
2-{4-[({4-{[4-(4-acetylphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyl)sulfanyl]-2-ethyIphenoxy}propanoic acid, 2-{2-methyl-4-[({4-(2-thienylmethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}propanoic acid,
2-{4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol- 5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid,
2-{4-[({4-{[4-(4-ethoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyI)phenyl]-1 ,3-thiazol-5- yl}methyl)suIfanyl]-2-methylphenoxy}propanoic acid,
2-methyl-2-{2-methyl-4-[({4-{[4-(phenoxycarbonyl)-1-piperazinyl]methyl}-2-[4- (trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methyl)suIfanyl]phenoxy}propanoic acid,
2-{4-[({4-{[4-(4-acetylphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyI)sulfanyl]-2-propylphenoxy}propanoic acid, {2-methyl-4-[({4-[4-(3-thienyl)benzyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyl)sulfanyI]phenoxy}acetic acid,
2-(4-{[(2-(4-fluorophenyl)-4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-1 ,3-thiazol-5- yl)methyI]sulfanyl}-2-methylphenoxy)-2-methylpropanoic acid,
2-{4-[({4-{[4-(4-acetylphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyI]-1 ,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}-2-methylpropanoic acid,
2-{4-[({4-{[4-(2,4-dimethoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1 ,3- thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid,
{2-isopropyl-4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]- 1 ,3-thiazol-5-yI}methyl)sulfanyl]phenoxy}acetic acid, 2-{4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-
5-yI}methyl)sulfanyl]-2-propylphenoxy}propanoic acid ,
2-{4-[({4-benzyl-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methyl)sulfanyl]-2- methylphenoxy}propanoic acid,
2-{2-ethyl-4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1 ,3- thiazol-5-yl}methyI)sulfanyl]phenoxy}propanoic acid,
2-methyl-2-{2-methyl-4-t({4-[4-(trifluoromethyl)benzyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol- 5-yl}methyl)sulfanyl]phenoxy}propanoic acid,
2-{4-[({4-{[4-(4-fluorophenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyl)sulfanyl]-2-methylphenoxy}-2-methylpropanoic acid, {4-[({4-{[4-(4-acetylphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyI]-1 ,3-thiazol-5- yl}methyl)sulfanyI]-2-propylphenoxy}acetic acid,
{4-[({4-([1 ,1 '-biphenyl]-4-ylmethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyl)sulfanyl]-2-methylphenoxy}acetic acid,
2-{4-[({4-{[4-(4-fluorophenyl)-1-piperazinyI]methyl}-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyl)suIfanyl]-2-methylphenoxy}propanoic acid,
{4-[({4-{[4-(3-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazoI-5- yl}methyI)sulfanyl]-2-methylphenoxy}acetic acid, 2-{2-methyl-4-[({4-(3-thienylmethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}propanoic acid,
{4-[({4-{[4-(2-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyl)sulfanyl]-2-methylphenoxy}acetic acid, 2-{2-isopropyl-4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-
1 ,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic acid,
2-{4-[({4-(4-tert-butylbenzyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methyl)sulfanyl]-2- methylphenoxy}-2-methylpropanoic acid,
2-{4-[({4-{[4-(3-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol- 5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid,
2-{4-[({4-benzyl-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methyl)sulfanyl]-2,3- dimethylphenoxy}propanoic acid,
2-{4-[({4-{[4-(4-chlorophenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid, 2-{4-[({4-benzyl-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methyl)sulfanyl]-2- fluorophenoxy}propanoic acid,
2-{4-[({4-{[4-(2,4-difluorophenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol- 5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid,
{4-[({4-(2,4-difluorobenzyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methyl)sulfanyl]-2- methylphenoxy}acetic acid,
2-{4-[({4-{[4-(4-acetylphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyl)sulfanyl]-2-methylphenoxy}-2-methylpropanoic acid,
2-methyl-2-{2-methyl-4-[({4-(3-thienylmethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}propanoic acid, 2-{4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-
5-yl}methyl)suIfanyl]-2-methylphenoxy}propanoic acid,
{2-ethyl-4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1 ,3- thiazol-5-yl}methyl)sulfanyl]phenoxy}acetic acid,
2-{4-[({4-(4-methoxybenzyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methyl)sulfanyI]-2- methylphenoxy}-2-methylpropanoic acid,
2-methyl-2-{4-[({4-{[4-(2-pyrazinyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1 ,3- thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic acid,
2-{4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol- 5-yl}methyl)sulfanyl]-2-methylphenoxy}-2-methylpropanoic acid, 2-{4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-
5-yl}methyl)sulfanyl]phenoxy}-2-methylpropanoic acid,
2-methyl-2-{2-methyl-4-[({4-[4-(trifluoromethoxy)benzyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3- thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic acid,
2-{4-[({4-{[4-(4-isopropoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-l ,3- thiazol-5-yl}methyl)suIfanyl]-2-methylphenoxy}propanoic acid,
2-{2-methyl-4-[({4-{[4-(2-pyrimidinyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-l ,3- thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic acid, {2-methyl-4-[({4-(3-phenylpropyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}acetic acid,
[4-[({4-benzyl-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methyl)sulfanyl]-2- (trifluoromethyl)phenoxy]acetic acid, {2-methyl-4-[({4-{[4-(5-methyl-1 ,2,4-oxadiazol-3-yl)phenoxy]methyl}-2-[4-
(trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetic acid,
{4-[({4-benzyl-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methyl)sulfanyl]-5-chloro-2- methylphenoxy}acetic acid,
{4-[({4-benzyl-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methyl)sulfanyl]-2- methylphenoxy}acetic acid,
{4-[({4-(4-methoxybenzyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methyl)sulfanyl]-2- methylphenoxy}acetic acid,
{2,5-dimethyl-4-[({4-(3-thienylmethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}acetic acid, {2-methyl-4-[({4-{[4-(2-pyrazinyl)-1 -piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1 ,3- thiazol-5-yl}methyl)sulfanyl]phenoxy}acetic acid,
{4-[({4-benzyl-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methyl)sulfanyl]-2,3- dimethylpheήoxy}acetic acid,
[4-({[2-(4-chlorophenyl)-4-methyl-1 ,3-thiazol-5-yl]methyl}sulfanyl)-2-methylphenoxy]acetic acid,
{2-methyl-4-[({4-[(4-methyl-2-thienyl)methyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}acetic acid ,
{4-[({4-benzyl-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methyl)sulfanyl]-2- bromophenoxy}acetic acid, {2-methyl-4-[({4-[(2-phenylethoxy)methyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}acetic acid,
{2-methyl-4-[({4-(2-phenylethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}acetic acid, and pharmaceutically acceptable salts, solvates, and hydrolyzable esters thereof.
More preferred compounds of formula (1) include:
2-methyl-2-{2-methyl-4-[({4-(3-thienylmethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyl)sulfanyr]phenoxy}propanoic acid,
2-{4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol- 5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid,
{2-ethyl-4-[({4-{t4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1 ,3- thiazol-5-yl}methyl)sulfanyl]phenoxy}acetic acid,
2-{4-[({4-(4-methoxybenzyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methyl)sulfanyl]-2- methylphenoxy}-2-methylpropanoic acid, 2-methyl-2-{4-[({4-{[4-(2-pyrazinyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1 ,3- thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic acid,
2-{4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol- 5-yl}methyl)sulfanyl]-2-methylphenoxy}-2-methylpropanoic acid , 2-{4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol- 5-yl}methyl)sulfanyl]phenoxy}-2-methylpropanoic acid,
2-methyl-2-{2-methyl-4-[({4-[4-(trifluoromethoxy)benzyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3- thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic acid,
2-{4-[({4-{[4-(4-isopropoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1 ,3- thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid,
2-{2-methyl-4-[({4-{[4-(2-pyrimidinyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1 ,3- thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic acid, and pharmaceutically acceptable salts, solvates, and hydrolyzable esters thereof.
Preferably, the compounds of formula (I) are hPPAR agonists. The hPPAR agonists of formula (I) may be agonists of only one type ("selective agonists"), agonists for two PPAR subtypes ("dual agonists"), or agonists for all three subtypes ("pan agonists"). As used herein, by "agonist", or "activating compound", or "activator", or the like, is meant those compounds which have a pKi of at least 5.0 preferably at least 6.0 to the relevant PPAR, for example hPPARD. in the binding assay described below, and which achieve at least 30% activation of the relevant PPAR relative to the appropriate indicated positive control in the transfection assay described below at concentrations of 10"5 M or less. More preferably, the compounds of this invention achieve 30% activation of at least one human PPAR in the relevant transfection assay at concentrations of 10"8 M or less. More preferably the compounds of the invention achieve 30% activation of at least one human PPAR in the relevant transfection assay at concentrations of 10"7M or less.
Preferably the compounds of formula (1) are hPPARδ agonists. More preferably they are also agonists of at least one of PPARγ or PPARα. Most preferably they are pan hPPAR agonists. It will also be appreciated by those skilled in the art that the compounds of the present invention may also be utilized in the form of a pharmaceutically acceptable salt or solvate thereof.
The physiologically acceptable salts of the compounds of formula (I) include conventional salts formed from pharmaceutically acceptable inorganic or organic acids or bases as well as quaternary ammonium acid addition salts. More specific examples of suitable acid salts include hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, perchloric, fumaric, acetic, propionic, succinic, glycolic, formic, lactic, maleic, tartaric, citric, palmoic, malonic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, fumaric, toluenesulfonic, methanesulfonic, naphthalene-2-sulfonic, benzenesulfonic hydroxynaphthoic, hydroiodic, malic, steroic, tannic and the like. Other acids such as oxalic, while not in themselves pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable salts. More specific examples of suitable basic salts include sodium, lithium, potassium, magnesium, aluminium, calcium, zinc, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine and procaine salts. Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as "solvates". For example, a complex with water is known as a "hydrate". Solvates of the compound of formula (I) are within the scope of the invention. References hereinafter to a compound according to the invention include both compounds of formula (I) and their pharmaceutically acceptable salts and solvates.
The compounds of the invention and their pharmaceutically acceptable derivatives are conveniently administered in the form of pharmaceutical compositions. Such compositions may conveniently be presented for use in conventional manner in admixture with one or more physiologically acceptable carriers or excipients.
While it is possible that compounds of the present invention may be therapeutically administered as the raw chemical, it is preferable to present the active ingredient as a pharmaceutical formulation. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
Accordingly, the present invention further provides for a pharmaceutical formulation comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof together with one or more pharmaceutically acceptable carriers therefore and, optionally, other therapeutic and/or prophylactic ingredients. The formulations include those suitable for oral, parenteral (including subcutaneous e.g. by injection or by depot tablet, intradermal, intrathecal, intramuscular e.g. by depot and intravenous), rectal and topical (including dermal, buccal and sublingual) administration although the most suitable route may depend upon for example the condition and disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the compounds ("active ingredient") with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation. Formulations suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets (e.g. chewable tablets in particular for paediatric administration) each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.
A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with other conventional excipients such as binding agents, (for example, syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch or polyvinylpyrrolidone), fillers (for example, lactose, sugar, microcrystalline cellulose, maize-starch, calcium phosphate or sorbitol), lubricants (for example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica), disintegrants (for example, potato starch or sodium starch glycollate) or wetting agents, such as sodium lauryl sulfate. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. The tablets may be coated according to methods well-known in the art. Alternatively, the compounds of the present invention may be incorporated into oral liquid preparations such as aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, for example. Moreover, formulations containing these compounds may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents such as sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated edible fats; emulsifying agents such as lecithin, sorbitan mono-oleate or acacia; non- aqueous vehicles (which may include edible oils) such as almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; and preservatives such as methyl or propyl p- hydroxybenzoates or sorbic acid. Such preparations may also be formulated as suppositories, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of a sterile liquid carrier, for example, water-for-injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
Formulations for rectal administration may be presented as a suppository with the usual carriers such as cocoa butter, hard fat or polyethylene glycol.
Formulations for topical administration in the mouth, for example buccally or sublingually, include lozenges comprising the active ingredient in a flavoured basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a basis such as gelatin and glycerin or sucrose and acacia.
The compounds may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
In addition to the ingredients particularly mentioned above, the formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents. It will be appreciated by those skilled in the art that reference herein to treatment extends to prophylaxis as well as the treatment of established diseases or symptoms. Moreover, it will be appreciated that the amount of a compound of the invention required for use in treatment will vary with the nature of the condition being treated and the age and the condition of the patient and will be ultimately at the discretion of the attendant physician or veterinarian. In general, however, doses employed for adult human treatment will typically be in the range of 0.02-5000 mg per day, preferably 1-1500 mg per day. The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example as two, three, four or more sub-doses per day. The formulations according to the invention may contain between 0.1-99% of the active ingredient, conveniently from 30-95% for tablets and capsules and 3-50% for liquid preparations.
The compound of formula (I) for use in the instant invention may be used in combination with other therapeutic agents for example, statins and/or other lipid lowering drugs for example MTP inhibitors and LDLR upregulators. The compounds of the invention may also be used in combination with antidiabetic agents, e.g. metformin, sulfonylureas and/or PPAR gamma, PPAR alpha or PPAR alpha/gamma agonists (for example thiazolidinediones such as e.g. Pioglitazone and Rosiglitazone). The compounds may also be used in combination with antihypertensive agents such as angistensin antagonists e.g. telmisartan, calcium channel antagonists e.g. lacidipine and ACE inhibitors e.g. enalapril. The invention thus provides in a further aspect the use of a combination comprising a compound of formula (I) with a further therapeutic agent in the treatment of a hPPAR mediated disease.
When the compounds of formula (I) are used in combination with other therapeutic agents, the compounds may be administered either sequentially or simultaneously by any convenient route. The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above optimally together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the invention. The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations. When combined in the same formulation it will be appreciated that the two compounds must be stable and compatible with each other and the other components of the formulation and may be formulated for administration. When formulated separately they may be provided in any convenient formulation, conveniently in such a manner as are known for such compounds in the art.
When a compound of formula (I) is used in combination with a second therapeutic agent active against the same hPPAR mediated disease, the dose of each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art.
There is further provided processes for the preparation of compounds of 1. Unless otherwise indicated all definitions are as above. In general when X2 is O or S the compounds could be assembled by coupling through an alkylation step such as that shown below.
Figure imgf000014_0001
The esters are commercially available or made by the following general route when X2 is S.
Bs 1. CIS03H
R!? ^ L 1. cCsScCOOj3 i li\ γ I" RR" 22.. ZZnn oorr SSππ rreedduuccttiioonn ^ Kj f f RR<<
+ *- "Α
O *Xχ R&"^-- — ~ Ax°A R=^=-^SH
R1 R2 The heterocycle when Y is O or S and Z is N was generally made as shown below from an appropriate amide or thioamide:
Figure imgf000015_0001
In specific cases the overall coupling step could be carried out directly after chlorosulfonation 5 of the ester component without the need for formation of the chloride of the heterocyclic moiety, as shown below:
Figure imgf000015_0002
In some cases R9 was further elaborated through palladium coupling at the ester stage as shown below:
Figure imgf000015_0003
Alternatively R9 was elaborated after the coupling reaction by nucleophilic displacement of a mesylate shown below:
L Deprotection
Figure imgf000015_0004
Figure imgf000015_0006
Figure imgf000015_0005
Examples 0
The invention is further illustrated by the following Examples which should not be construed as constituting a limitation thereto.
Ethyl 4-(bromomethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thia2ole-5-carboxylate To a 2-L round-bottom flask equipped with an mechanical overhead stirrer, a reflux condenser and a N2 inlet was added ethyl 4-methyl-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazole-5-carboxylate (85g, 0.27moles, 1.Oeq) and dry carbon tetrachloride (750ml, 0.38M). Freshly recrystallized N-bromo succinimide (52.72g, 1.1 eq) was added as a solid, Benzoyl peroxide (6.5g, 10mol%) was added at room temperature all at once as a solid, and the reaction mixture was refluxed for 5 hrs. The reaction was monitored by 1H NMR and was determined to be composed of a 9:1 mixture of mono-bromination product (i.e. desired product) and di-bromination product with a 90% conversion. After cooling to 0 °C (to precipitate out the succinimide) the reaction was filtered through Celite and the solvent was removed under reduced pressure to yield a brown oil. The oil was crystallized using hexanes to yield 10Og (94%) of an off-white product of 90% purity.
1H NMR (CDCI3) 400MHz δ 8.10(d, 2H, J=8.20 Hz), 7.72(d, 2H, J=8.2G Hz), 4.99(s, 2H), 4.40(q, 2H, J=7.18 Hz), 1.41(t, 3H, J=7.18 Hz), TLC(15% EtOAc/Hexanes) Rf = 0.55
Ethyl 4-(bromomethyl)-2-phenyl-1 ,3-thiazole-5-carboxylate
The title compound was made using the same procedure as above.
Η NMR (CDCIg) 400MHz δ 7.98(dd, 2H, J=7.86, 1.54 Hz), 7.47(m, 3H), 4.99(s, 2H), 4.39(q, 2H, J=7.12 Hz), 1.40(t, 3H, J=7.12 Hz),
TLC(15% EtOAc/Hexanes) Rf = 0.50
Ethyl 4-(hydroxymethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-carboxylate
To a stirred solution of ethyl 4-(bromomethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazole-5- carboxylate (50g, 0.127moles, 1eq) in dry DMF (300ml) under a positive N2 flow was added silver trifluoroacetate (42.02g, 0.191 moles, 1.5eq) all at once as a solid. This was stirred at room temperature for 3.5 hrs. The reaction was partitioned between ethyl ether (1.5L) and water (500ml). The phases were separated and the organic phase was washed twice with water (500ml). After separation of the phases, the organic fraction was dried with Na2S04, filtered and concentrated in vacuo. The crude trifluoroacetate product was used without characterization. Ethanol (300ml) was added and the reaction was refluxed for 10 hrs. After cooling to room temperature the ethanol was removed in vacuo to yield 42g (100%) of the title compound. The product was used without purification.
1 H NMR (CDCI3) 400MHz δ 8.09(d, 2H, J=8.20 Hz), 7.73(d, 2H, J=8.20 Hz), 5.09(s, 2H), 4.41 (q, 2H, J=7.12 Hz), 1.40(t, 3H, J=7.12 Hz),
Ethyl 4-(hydroxymethyl)-2-phenyl-1 ,3-thiazole-5-carboxylate
The title compound was made using the same procedure as above.
1H NMR (CDCI3) 400MHz δ 7.95(m, 2H), 7.48(m, 3H), 5.09(s, 2H), 4.40(q, 2H, J=7.12 Hz), 1.41(t, 3H, J=7.12 Hz),
Ethyl 4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5- carboxylate To a 1-L round-bottom flask equipped with a magnetic stir-bar and a N2 inlet was added Ethyl 4-(hydroxymethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazole-5-carboxylate (42g, 0.127moles, 1eq) and dry CH2Cl2 (300ml) at room temperature. This was followed by the addition of 3,4-dihydro-2H-pyran (14ml, 0.152moles, 1.2eq) as a neat liquid and pyridinium p-toluenesulfonate (6.4g, 25.4mmoIes, 20mol%). The reaction mixture was stirred at room temperature overnight (10 hrs). The volatiles were then removed in vacuo and the residue was purified by flash silica gel chromatography (10% EtOAc/Hexanes to 30% EtOAc/Hexanes) to yield 34g (64%) of pure title compound.
1H NMR (CDCI3) 400MHz δ 8.09(d, 2H, J=8.20 Hz), 7.69(d, 2H, J=8.20 Hz), 5.18(d, 1 H, JD.30 Hz), 4.99(d, 1 H, J .30 Hz), 4.90(t, 1 H, J=3.42 Hz), 4.36(q, 2H, J=7.12 Hz), 3.98(m, 1 H), 3.56(m, 1 H), 1.69(m, 6H), 1.37(t, 3H, J=7.12 Hz),
TLC(30% EtOAc/Hexanes)= 0.64
Ethyl 2-phenyl-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3-thiazole-5-carboxylate
1H NMR (CDCI3) 400MHz δ 7.97(m, 2H), 7.43(m, 3H), 5.17(d, 1 H, J .13 Hz), 4.98(d, 1 H, J "13 Hz), 4.91 (t, 1 H, J=3.33 Hz), 4.35(q, 2H, J=7.12 Hz), 3.98(m, 1 H), 3.54(m, 1 H), 1.69(m, 6H), 1.36(t, 3H, J=7.12 Hz),
Ethyl 2-(4-fluorophenyl)-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3-thiazole-5-carboxylate
1H Nz δ 7.97(m, 2H), 7.11 (m, 2H), 5.16(d, 1 H, J .24 Hz), 4.97(d, 1 H, J .24 Hz), 4.90(t, 1 H, J=3.36 Hz), 4.34(q, 2H, J=7.13 Hz), 3.98(m, 1 H), 3.55(m, 1 H), 1.86(m, 2H), 1.70(m, 2H), 1.55(m, 2H), 1.36(t, 3H, J=7.13 Hz),
Suzuki Coupling
Ethyl 4-[4-(trifluoromethyl)benzyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-carboxylate To a solution of ethyl 4-(bromomethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazole-5-carboxylate
(0.25g, 0.63 mmol) in 4 ml of 2-methoxyethyl ether was added tetrakis(triphenyIphosphine)palladium(0), (0.02g, 0.019 mmol) and then sodium carbonate (0.13g, 1.2 mmol) in 0.5 ml water. After brief stirring, 4-(trifluoromethyl)phenyl boronic acid (0.13g, 0.7 mmol) in 1 ml ethanol was added. After heating at 110°C for 15 hours, the reaction was complete by HPLC and was treated with water (5 ml) and extracted with terf-butyl methyl ether (2 x 30ml). The organic layers were dried with magnesium sulfate and immediately loaded onto silica to give a crude residue which was purified on a Biotage FlashElute with a 40M silica cartridge, eluting with 10% ethyl acetate in hexanes to yield ethyl 4-[4-(trifluoromethyl)benzyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazole-5- carboxylate as a white solid (0.09g, 35%). 1H NMR (CDCI3): δ 8.18 (d, 2 H), 7.78 (d, 2 H), 7.58 (m, 4 H), 4.68 (s, 2 H), 4.40 (q, 2 H), 1.40
(t, 3 H); MS m/z 460 (M+1).
The following compounds were made using the the same palladium catalyzed coupling procedure using the appropriate boronic acid.
Ethyl 4-[4-(trifluoromethoxy)benzyl1-2-[4-(trifluorornethy phenyl]-1,3-thiazole-5-carboχylate From ethyl 4-(bromomethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazole-5-carboxylate (0.25g, 0.63 mmol), ethyl 4-[4-(trifluoromethoxy)benzyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazole-5- carboxylate (0.12g, 43%) was obtained as a light yellow solid.
1H NMR (CDCI3): δ 8.18 (d, 2 H), 7.77 (d, 2 H), 7.46 (d, 2 H), 7.18 (d, 2 H), 4.60 (s, 2 H) 4.40 (q, 2 H), 1.40 (t, 3 H); MS m/z 476 (M+1 ).
Ethyl 4-[4-methoxybenzyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-carboxylate
From ethyl 4-(bromomethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazole-5-carboxylate (0.25g, 0.63 mmol), ethyl 4-[4-methoxybenzyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazole-5-carboxylate (0.16g, 63%) was obtained as a yellow semi-solid.
1H NMR (CDCI3): δ 8.18 (d, 2 H), 7.70 (d, 2 H), 7.40 (d, 2H), 6.80 (d, 2 H), 4.57 (s, 2 H), 4.40 (q, 2 H), 3.80 (s, 3 H), 1.40 (t, 3 H); MS m/z 422 (M+1 ).
Ethyl 4-[4-(methylsulfanyl)benzyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-carboxylate From ethyl 4-(bromomethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazole-5-carboxylate (0.4g,
1.01 mmol), ethyl 4-[4-(methylsulfanyl)benzyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazole-5-carboxylate (0.44g, 100%) was obtained as a light yellow solid. H NMR (CDCI3): δ 8.11 (d, 2 H), 7.71 (d, 2 H), 7.38 (d, 2 H), 7.21 (d, 2 H), 4.52 (s, 2 H), 4.38 (q, 2 H), 2.49 (s, 3 H), 1.40 (t, 3 H); MS m/z 438 (M+1 ).
Ethyl 4-[4-tert-butylbenzyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-carboxylate
From ethyl 4-(bromomethyI)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazole-5-carboxylate (0.4g, 1.01 mmol), ethyl 4-[4-terf-butylbenzyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazole-5-carboxylate (0.24g, 54%) was obtained as a white solid. 1H NMR (CDCI3): δ 8.11 (d, 2 H), 7.73 (d, 2 H), 7.56 (d, 1 H), 7.49 (d, 1 H), 7.34 (m, 2 H), 4.58
(s, 2 H), 4.40 (q, 2 H), 1.40 (t, 3 H), 1.27 (s, 9 H); MS m/z 448 (M+1 ).
Ethyl 4-[3-thienylmethyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-carboxylate
From ethyl 4-(bromomethyI)-2-[4-(trifluoromethyl)phenyI]-1 ,3-thiazole-5-carboxylate (0.4g, 1.01 mmol), ethyl 4-[3-thienylmethyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazole-5-carboxylate (0.4g 100%) was obtained as a yellow solid.
1H NMR (CDCI3): δ 8.12 (d, 2 H), 7.77 (d, 2 H), 7.40 (d, 1 H), 7.28 (d, 1 H), 7.20 (s, 1 H), 4.61 (s, 2 H), 4.41 (q, 2 H), 1.40 (t, 3 H); MS m/z 398 (M+1 ).
Ethyl 4-[2-furylmethyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazole-5-carboxylate
From ethyl 4-(bromomethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazole-5-carboxylate (0.4g, 1.01 mmol), ethyl 4-[2-furylmethyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazole-5-carboxylate (0.204g, 53%) was obtained as a white solid.
MS m/z 382 (M+1 ); HPLC RT 4.072 (C18 4.2x100mm, 0-100% ACN/H20 (0.1% TFA), 6min @ 2ml/min @254/220nm). Ethyl 4-r3-furylmethyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-carboxylate
From ethyl 4-(bromomethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazole-5-carboxylate (0.4g, 1.01 mmol), ethyl 4-[3-furylmethyl]-2-t4-(trifluoromethyl)phenyl]-1 ,3-thiazole-5-carboxylate (0.217g, 56%) was obtained as a white solid. MS m/z 382 (M+1 ); HPLC RT 4.091 (C18 4.2x100mm, 0-100% ACN/H20 (0.1 % TFA), 6min
@ 2ml/min @254/220nm).
Ethyl 4-[2-thienylmethyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-carboxylate
From ethyl 4-(bromomethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazoIe-5-carboxylate (0.4g, 1.01 mmol), ethyl 4-[2-thienylmethyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazole-5-carboxyIate (0.248g, 62%) was obtained as a yellow solid.
MS m/z 398 (M+1 ); HPLC RT 4.224 (C18 4.2x100mm, 0-100% ACN/H20 (0.1 % TFA), 6min @ 2ml/min @254/220nm).
Ethyl 4-[(4-methyl-2-thienyl)methyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-carboxylate
From ethyl 4-(bromomethyI)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazole-5-carboxylate (0.6g, 1.52 mmol), ethyl 4-[(4-methyl-2-thienyl)methyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazoie-5- carboxylate (0.5g, 81 %) was obtained as a yellow solid.
MS m/z 412 (M+1 ); HPLC RT 4.682 (C18 4.2x100mm, 0-100% ACN/HzO (0.1 % TFA), 6min @ 2ml/min @254/220nm).
Ethyl 4-[2,4-difluorobenzyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-carboxylate
From ethyl 4-(bromomethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazole-5-carboxylate (0.6g, 1.52 mmol), ethyl 4-[2,4-difluorobenzyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazole-5-carboxylate (0.222g, 35%) was obtained as a white solid.
MS m/z 428 (M+1 ); HPLC RT 4.618 (C18 4.2x100mm, 0-100% ACN/H20 (0.1 % TFA), 6min @ 2ml/min @254/220nm).
4-[(Tetrahydro-2H-pyran-2-yloxy)methyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methanol To a stirred solution of lithium aluminum hydride (95%, 3.3g, 81.84mmoles, 1eq) in dry ethyl ether (300ml) at 0°C was added ethyl 4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-[4- (trifluoromethyl)phenyl]-1 ,3-thiazole-5-carboxylate (34g, 81.84mmoles, 1eq) in dry ethyl ether (50ml) dropwise via an addition funnel maintaining the internal reaction temperature below 5°C. This was stirred at 0 °C for 1 hr. At 0 °C 3.5ml water was added dropwise very carefully and was then allowed to warm to room temperature. This was followed by the addition 3.5ml 5N NaOH and 10ml water. The mixture was stirred at room temperature for 2hrs. At this point a fine white precipitate formed. The reaction was filtered through Celite and the resulting aluminum salts were washed with 500ml EtOAc. The ether/EtOAc solution was concentrated in vacuo to 30.6g (100%) of titled alcohol.
1H NMR (CDCI3) 400MHz δ 8.07(d, 2H, J=8.20 Hz), 7.72(d, 2H, J=8.20 Hz), 4.93(m, 4H), 4.78(t, 1 H, J=3.32 Hz), 3.90(m, 1 H), 3.61 (m, 1 H), 1.73(m, 6H), TLC(30% EtOAc/Hexanes)= 0.20 The following intermediates were reduced as above for 4-[(Tetrahydro-2H-pyran-2- yloxy)methyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methanol.
{4-[(Tetrahydro-2H-pyran-2-yloxy)methyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methanol
1H NMR (CDCI3) 400MHz δ 8.07(d, 2H, J=8.20 Hz), 7.72(d, 2H, J=8.20 Hz), 4.93(m, 4H), 4.78(t, 1 H, J=3.32 Hz), 3.90(m, 1 H), 3.61 (m, 1 H), 1.73(m, 6H), TLC(30% EtOAc/Hexanes)= 0.20
{2-(4-Fluorophenyl)-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3-thiazol-5-yl}methanol
1H NMR (CDCI3) 400MHz δ 7.89(m, 2H), 7.09(m, 2H), 4.81 (m, 5H), 3.84(m, 1 H), 3.55(m, 1 H), 1.67(m, 6H),
{2-Phenyl-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3-thiazol-5-yl}methanol 1 H NMR (CDCI3) 400MHz δ 7.96(m, 2H), 7.47(m, 3H), 4.92(m, 4H), 4.79(t, 1 H, J=3.45 Hz);
3.91 (m, 1 H), 3.60(m, 1 H), 1.73(m, 6H),
{2-(4-{trifuloromethyl}phenyl)-4-[(2-phenylethoxy)methyl]-1,3-thiazol-5-yl}methanol
1H (CDCI3) 300MHz δ 7.99(d, 2H, J=8.79 Hz), 7.67(d, 2H, J=8.79 Hz), 7.26(m, 5H), 4.78(s, 2H), 4.71 (s, 2H), 3.84(t, 2H, J=6.94 Hz), 2.95(t, 2H, J=6.94 Hz), 2.63(s, 1 H),
[2-(4-{trifuloromethyl}phenyl)-4-(3-phenylpropyl)-1,3-thiazol-5-yl]methanol
1H NMR (CDCI3) 300MHz δ 8.02(d, 2H, J=8J9 Hz), 7.67(d, 2H, J=8.79 Hz), 7.23(m, 4H), 4.76(s, 2H), 2.84(t, 2H, 7.28 Hz), 2.67(t, 2H, 7.28 Hz), 2.12(m, 2H),
[4-benzyl-2-(4-{trifluoromethyl}phenyl)-1,3-thiazol-5-yl]methanol
1H (CDCI3) 300MHz δ 8.01 (d, 2H, J=8.79 Hz), 7.65(d, 2H, J=8.79 Hz), 7.26(m, 5H), 4.78(s, 2H), 4.15(s, 2H),
TLC(20% EtOAc/Hexanes) Rf= 0.18 MS(ES+) M+H= 350
f2-(4-{trifluoromethyl}phenyl)-4-(2-phenylethyl)-1,3-thiazol-5-yl]methanol
1H (CDCI3) 300MHz δ 8.06(d, 2H, J=9.61 Hz), 7.70(d, 1 H, J=9.48 Hz), 7.23(m, 4H), 7.06(m, 2H), 4.40(d, 2H, J=5.63 Hz), 3.07(s, 4H), 1.08(s, 1 H), TLC(20% EtOAc/Hexanes) Rf= 0.18
MS(ES+) M+H= 364
j -[(Benzyloxy)methyl]-2-(4-{trifluoromethyl}phenyl)-1,3-thiazol-5-yl]methanol
1H (CDCI3) 300MHz δ 8.02(d, 2H, J=8.79 Hz), 7.68(d, 2H, J=8J9 Hz), 7.35(m, 5H), 4.82(m, 4H), 4.68(s, 2H), TLC(20% EtOAc/Hexanes) Rf= 0.14
[4-(4-Bromobenzyl)-2-(4-{trifluoromethyl}phenyl)-1,3-thiazol-5-yl]methanol
1H NMR (CDCI3) 300MHz δ 7.99(d, 2H, J=8.10 Hz), 7.66(d, 2H, J=8.10 Hz), 7.40(d, 2H, J=8.38 Hz), 7.15(d, 2H, J=8.38 Hz), 4.81(s, 2H), 4.10(s, 2H), TLC(20% EtOAc/Hexanes) Rf= 0.14
{4-[4-(trifluoromethyl)benzyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methanol
From ethyl 4-[4-(trifluoromethyl)benzyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazole-5-carboxylate (0.096g, 0.21 mmol), {4-[4-(trifluoromethyl)benzyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yljmethanol (0.09g, 100%) was obtained as a white solid.
1H NMR (CDCI3): 5 8.16 (d, 2 H), 7.73 (d, 2 H), 7.59 (d, 2 H), 7.44 (d, 2 H), 4.90 (d, 2 H), 4.26 (t, 2 H); MS m/z 418 (M+1).
{4-[4-(trifluoromethoxy)benzyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methanol
From ethyl 4-[4-(trifluoromethoxy)benzyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazole-5- carboxylate (0.123g 0.26 mmol), {4-[4-(trifluoromethoxy)benzyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3- thiazoI-5-yl}methanol (0.13g, 99%) was obtained as a white solid.
1H NMR (CDCI3): δ 8.07 (d, 2 H), 7.71 (d, 2 H), 7.38 (d, 2 H), 7.18 (d, 2 H), 4.80 (d, 2 H), 4.20 (s, 2 H); MS m/z 434 (M+1 ).
{4-(4-methoxybenzyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methanol
From ethyl 4-[4-methoxybenzyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazole-5-carboxylate ( 0.16g, 0.38 mmol), {4-(4-methoxybenzyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methanol (0.06g, 40%) was obtained as a white solid.
MS m/z 380 (M+1); HPLC RT 3.552 (C18 4.2x100mm, 0-100% ACN/H20 (0.1% TFA), 6min @ 2ml/min @254/220nm).
{4-[4-(methylsulfanyl)benzyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methanol From ethyl 4-[4-(methylsulfanyl)benzyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazole-5- carboxylate (0.44g, 1.0 mmol), {4-[4-(methylsulfanyl)benzyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yI}methanol (0.3g, 76%) was obtained as a white solid.
MS m/z 396 (M+1 ); HPLC RT 3.699 (C18 4.2x100mm, 0-100% ACN/H20 (0.1 % TFA), 6min
@ 2ml/min @254/220nm).
{4-(4-tert-butylbenzyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methanol
From ethyl 4-[4-terf-butylbenzyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazoIe-5-carboxylate
(0.24g, 0.54 mmol), {4-(4-terf-butylbenzyI)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methanol
(0.13g, 64%) was obtained as a white solid. MS m/z 406 (M+1 ); HPLC RT 4.002 (C184.2x100mm, 0-100% ACN/H20 (0.1 % TFA), 6min
@ 2m!/min @254/220nm). {4-(3-thienylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methanol
From ethyl 4-[3-thienylmethyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazole-5-carboxylate (0.44g, 1.11 mmol), {4-(3-thienyImethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methanol ( 0.098g, 25%) was obtained as a yellow solid. MS m/z 356 (M+1 ); HPLC RT 3.513 (C184.2x100mm, 0-100% ACN/HzO (0.1% TFA), 6min
@ 2ml/min @254/220nm).
{4-(2-furylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methanol
From ethyl 4-[2-furylmethyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazole-5-carboxylate ( 0.204g, 0.53 mmol), {4-(2-furylmethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methanol (0.162g, 89%) was obtained as a white solid.
MS m/z 340 (M+1 ); HPLC RT 3.382 (C18 4.2x100mm, 0-100% ACN/H20 (0.1% TFA), 6min @ 2ml/min @254/220nm).
{4-(3-furylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methanol
From ethyl 4-[3-furylmethyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazole-5-carboxylate (0.217g 0.57 mmol), {4-(3-furylmethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methanol (0.180g, 88%) was obtained as a white solid.
MS m/z 340 (M+1); HPLC RT 3.385 (C184.2x100mm, 0-100% ACN/H20 (0.1% TFA), 6min @ 2ml/min @254/220nm).
{4-(2-thierιylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methanol
From ethyl 4-[2-thienylmethyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazole-5-carboxylate ( 0.248g, 0.62 mmol), {4-(2-thienylmethyI)-2-[4-(trifluoromethyl)phenyI]-1 ,3-thiazol-5-yl}methanol (0.186g, 87%) was obtained as a yellow solid.
MS m/z 356 (M+1); HPLC RT 3.528 (C18 4.2x100mm, 0-100% ACN/H20 (0.1 % TFA), 6min @ 2ml/min @254/220nm).
{4-[(4-Methyll-2-thienyl)methyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}metharιol From ethyl 4-[(4-methyl-2-thienyl)methyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazole-5- carboxylate (0.5g, 1.22 mmol), {4-[(4-methyl-2-thienyl)methyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-
5-yl}methanol (0.084g, 19%) was obtained as a yellow solid.
MS m/z 370 (M+1 ); HPLC RT 3.913 (C18 4.2x100mm, 0-100% ACN/H20 (0.1 % TFA), 6min
@ 2ml/min @254/220nm).
{4-(2,4-difluorobenzyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methanol
From ethyl 4-[2,4-difluorobenzyl]-2-[4-(trifluoromethyl)phenyI]-1 ,3-thiazole-5-carboxylate
(0.46g, 1.08 mmol), {4-(2,4-difluorobenzyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methanol
(0.222g, 54%) was obtained as a white solid. MS m/z 386 (M+1); HPLC RT 3.900 (C18 4.2x100mm, 0-100% ACN/H20 (0.1% TFA), 6min
@ 2ml/min @254/220nm). 5-(Chloromethyl)-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-[4-(trifluoromethyl)phenvn-1,3- thiazole
To a 500-ml round-bottom flask equipped with a magnetic stir-bar, an addition funnel and a N2 inlet was added 4-[(Tetrahydro-2H-pyran-2-yloxy)methyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methanol (15g, 40.17mmoles, 1eq) and dry CH2CI2 (150ml, 0.27M). Methanesulfonyl chloride (3.73ml, 48.20mmoles, 1.2eq) was added neat all at once followed by the dropwise addition of triethylamine (8.44ml, 60.26mmoles, 1.5eq) over 10 minutes. This solution was stirred at room temperature for 1 hr. The reaction was transferred to a separatory funnel and washed with water and brine. After the phases were separated the CH2CI2 fraction was dried over Na2S04 and the solvent was removed in vacuo. This yielded 15.74g (100%) of a brown oil. The crude product was used as is and required no purification.
1H NMR (CDCI3) 300MHz δ 8.08(d, 2H, J=8.20 Hz), 7.73(d, 2H, J=8.20 Hz), 5.00(m, 3H), 4.80(m, 2H), 3.97(m, 1 H), 3.64(m, 1 H), 1.77(m, 6H),
TLC(25% EtOAc/Hexanes) Rf = 0.64
The following intermediates were also prepared using the above mesylation/chloride displacement procedure:
5-(Chloromethyl)-2-(4-fluorophenyl)-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3-thiazole 1H NMR (CDCI3) 400MHz δ 7.90(m, 2H), 7.11 (m, 2H), 4.94(s, 2H), 4.91 (d, 1H, JD.45 Hz),
4.76(t, 1 H, J=3.39 Hz), 4.72(d, 1 H, J .45 Hz), 3.92(m, 1 H), 3.58(m, 1 H), 1.69(m, 6H),
[5-(Chloromethyl)-2-phenyl-1 ,3-thiazol-4-yl]methyl tetrahydro-2H-pyran-2-yl ether
1H NMR (CDCI3) 300MHz δ 7.95(m, 2H), 7.47(m, 3H), 4.98(m, 3H), 4.80(m, 2H), 3.98(m, 1 H), 3.63(m, 1 H), l .73(m, 6H),
TLC(25% EtOAc/Hexanes) Rf = 0.57
5-(Chloromethyl)-2-(4-{trifluoromethyl}phenyl)-4-[4-(3-thienyl)benzyl]-1,3-thiazole H NMR (CDCI3) 300MHz δ 8.06(d, 2H, J=8.23 Hz), 7.71 (d, 2H, J=8.23 Hz), 7.58(d, 2H, J=8.23 Hz), 7.41 (m, 5H), 4.84(s, 2H), 4.26(s, 2H), TLC(20% EtOAc/Hexanes) Rf= 0.66
4-[(Benzyloxy)methyl]-5-(chloromethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole
1H NMR (CDCI3) 300MHz δ 8.03(d, 2H, J=8.79 Hz), 7.69(d, 2H, J=8.79 Hz), 7.37(m, 5H), 4.90(s, 2H), 4.77(s, 2H), 4.66(s, 2H)
4-Benzyl-5-(chloromethyl)-2-(4-{trifluoromethyl}phenyl)-1,3-thiazole
1H (CDCI3) 300MHz δ 8.02(d, 2H, J=8.79 Hz), 7.67(d, 2H, J=8.79 Hz), 7.26(m, 5H), 4.77(s, 2H), 4.21 (s, 2H), TLC(20% EtOAc/Hexanes) Rf= 0.66 5-(Chloromethyl)-2-(4-{trifluoromethyl}phenyl)-4-(2-phenylethyl)-1 ,3-thiazole
1H (CDCI3) 300MHz δ 8.05(d, 2H, J=8.79 Hz), 7.70(d, 2H, J=8.79 Hz), 7.22(m, 5H), 4.46(s, 2H), 3.09(s, 4H),
TLC(20% EtOAc/Hexanes) Rf= 0.67
5-(Chloromethyl)-2-(4-{trifluoromethyl}phenyl)-4-[(2-phenylethoxy)methyl]-1 ,3-thiazole H NMR (CDCI3) 300MHz δ 8.01 (d, 2H, J=8.79 Hz), 7.68(d, 2H, J=8.79 Hz), 7.26(m, 5H), 4.76(s, 2H), 4.74(s, 2H), 3.78(t, 2H, J=6.94 Hz), 2.94(t, 2H, J=6.94 Hz), TLC(20% EtOAc/Hexanes) Rf= 0.56
5-(Chloromethyl)-2-(4-{trifluoromethyl}phenyl)-4-(3-phenylpropyl)-1 ,3-thiazole
TLC(20% EtOAc/Hexanes) Rf= 0.63
4-(4-Bromobenzyl)-5-(chloromethyl)-2-(4-{trifluoromethyl}phenyl)-1 ,3-thiazole 1H NMR (CDCI3) 300MHz δ 8.00(d, 2H, J=8.10 Hz), 7.67(d, 2H, J=8.10 Hz), 7.42(d, 2H,
J=8.38 Hz), 7.18(d, 2H, J=8.38 Hz), 4.77(s, 2H), 4.14(s, 2H), TLC(20% EtOAc/Hexanes) Rf= 0.66
4-([1,1'-Bιphenyl]-4-ylmethyl)-5-(chloromethyl)-2-(4-{trifluoromethyl}phenyl)-1 ,3-thiazole 1H NMR (CDCI3) 300MHz δ 8.07(d, 2H, J=8.23 Hz), 7.72(d, 2H, J=8.23 Hz), 7.57(m, 4H),
7.39(m, 5H), 4.85(s, 2H), 4.28(s, 2H),
TLC(20% EtOAc/Hexanes) Rf= 0.69
5-(chloromethyl)-4-[4-(trifluoromethyl)benzyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazole From {4-t4-(trifluoromethyl)benzyl]-2-[4-(trifluoromethyI)phenyl]-1 ,3-thiazoI-5-yl}methanoI
(0.09g, 0.216 mmol), 5-(chloromethyl)-4-[4-(trifluoromethyl)benzyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3- thiazole (0.087g, 93%) was obtained as a yellow oil and immediately taken on without purification.
5-(chloromethyl)-4-[4-(trifluoromethoxy)benzyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole From {4-[4-(trifluoromethoxy)benzyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methanol
(0.13g, 0.3 mmol), 5-(chIoromethyl)-4-[4-(trifluoromethoxy)benzyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3- thiazole (0.135g, 100%) was obtained as a yellow oil and immediately taken on without purification.
5-(chloromethyl)-4-(4-methoxybenzyl)-2-[4-(trifluoromethyl)pherιyl]-1 ,3-thiazole From {4-(4-methoxybenzyl)-2-[4-(trifluoromethyI)phenyI]-1 ,3-thiazol-5-yl}methanol (0.06g,
0.158 mmol), 5-(chloromethyl)-4-(4-methoxybenzyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazole (0.08g, 100%) was obtained as a yellow oil and immediately taken on without purification.
5-(chloromethyl)-4-[4-(methylsulfanyl)benzvπ-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazole From {4-[4-(methylsulfanyl)benzyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methanol (0.3g, 0.76 mmol), 5-(chloromethyl)-4-[4-(methylsulfanyl)benzyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3- thiazole (0.33g, 100%) was obtained as a yellow oil and immediately taken on without purification.
MS m/z 414 (M+1 ).
4-(4-tert-butylbenzyl)-5-(chloromethyl)-2-[4-(trifluoronrιethyl)phenyl]-1 ,3-thiazole
From {4-(4-ferf-butylbenzyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methanol (0.13g, 0.32 mmol), 4-(4-terf-butylbenzyl)-5-(chloromethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazole (0.151 g, 100%) was obtained as a yellow oil and immediately taken on without purification. MS m/z 424 (M+1).
5-(chloromethyl)-4-(3-thienylmethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazole
From {4-(3-thienylmethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}r .ethanol (0.098g, 0.28 mmol), 5-(chloromethyl)-4-(3-thienylmethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazole (0.105g, 100%) was obtained as a yellow oil and immediately taken on without purification. MS m/z 374 (M+1 ).
5-(chloromethyl)-4-(2-furylmethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazole
From {4-(2-furyImethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5-yI}methanol (0.162g, 0.48 mmol), 5-(chloromethyl)-4-(2-furylmethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazole (0.097g, 57%) was obtained as a yellow oil and immediately taken on without purification. MS m/z 358 (M+1).
5-(chloromethyl)-4-(3-furylmethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazole From {4-(3-furylmethyI)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methanol (0.18g, 0.53 mmol), 5-(chloromethyl)-4-(3-furylmethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazole (0.172g, 91 %) was obtained as a yellow oil and immediately taken on without purification. MS n/z 358 (M+1).
5-(chloromethyl)-4-(2-thienylmethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazole
From {4-(2-thienylmethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5-yI}methanol (0.186g, 0.52 mmol), 5-(chloromethyl)-4-(2-thienylmethyl)-2-[4-(trifluoromethyI)phenyl]-1 ,3-thiazole (0.185g, 95%) was obtained as a yellow oil and immediately taken on without purification.
MS m/z 374 (M+1).
5-(chloromethyl)-4-[(4-methyl-2-thienyl)methyl]-2-[4-(trifluoronnethyl)phenyl]-1 ,3-thiazole
From {4-t(4-methyl-2-thienyI)methyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methanol (0.084g, 0.23 mmol), 5-(chloromethyl)-4-[(4-methyl-2-thienyl)methyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3- thiazole (0.123g, 100%) was obtained as a yellow oil and immediately taken on without purification.
5-(chloromethyl)-4-(2,4-difluorobenzyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazole From {4-(2,4-difluorobenzyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methanol (0.222g, 0.58 mmol), 5-(chloromethyl)-4-(2,4-difluorobenzyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazole (0.279g, 100%) was obtained as a yellow oil and immediately taken on without purification.
Ethyl 2-methyl-2-phenoxypropanoate
To a solution of potassium t-butoxide (1 M in THF, 531ml, 0.531 moles, 1eq) precooled to 0°C (ice bath) was added phenol (50g, 0.531 moles, 1eq) in dry THF (50ml) dropwise via an addition funnel over 20 minutes maintaining the internal temperature of the reaction below 5 degrees centigrade. Ethyl-2-bromoisobutyrate (70.14ml, 0.9eq, 0.478moles) in dry THF (20ml) was added dropwise over 10 minutes maintaining the internal reaction temperature below 5 °C. After the addition was complete, the ice bath was removed and the reaction was allowed to warm to room temperature. The reaction was brought to reflux and maintained at this reflux temperature for 8 hours. Following the cooling of the reaction to 0°C the volatiles were removed in vacuo. The residue was then partitioned between EtOAc and 1N NaOH. The phases were separated and the organic phase was washed with 1N NaOH, H20, brine and dried over Na2S04. After filtration the solution was concentrated under reduced pressure to yield 83g (75%) of clean title compound.
1H NMR (CDCI3) 400MHz δ 7.21 (m, 2H), 6.95(t, 1 H, J=7.41 Hz), 6.82(m, 2H), 4.21 (q, 2H, J=7.13 Hz), 1.57(s, 6H), 1.22(t, 3H, J=7.13 Hz),
Ethyl (2-ethylphenoxy)acetate
To a stirred solution of 2-ethylphenol (5ml, 42.4mmoles, 1eq) in dry DMF (120ml, 0.35M) was added potassium carbonate (6.45g, 46.6mmoles, 1.1eq) and ethylbromoacetate (4.7ml, 42.2mmoles, 1eq) and heated to 60 °C overnight. After cooling to room temperature the reaction mixture was partitioned between ethyl ether and 1 N NaOH. The phases were separated and the organic portion was washed twice with 1 N NaOH, twice with H20, brine, dried over Na2S04, filtered and concentrated in vacuo to yield 7.2g (82%) of product.
1H NMR (CDCI3) 400MHz δ 7.14(m, 2H), 6.92(t, 1 H, J=8.24 Hz), 6.70(d, 1 H, J=8.24 Hz), 4.62(s, 2H), 4.24(q, 2H, J=7.14 Hz), 2.70(q, 2H, J=7.51 Hz), 1.27(t, 3H, J=7.14 Hz), 1.21(t, 3H, J=7.51 Hz),
The following were compounds were made using the same alkylation procedure:
Ethyl (2-isopropylphenoxy)acetate
1H NMR (CDCI3) 400MHz δ 7.23(d, 1 H, J=7.69 Hz), 7.11 (t, 1 H, J=7.69 Hz), 6.96(t, 1 H, J=7.69 Hz), 6.70(d, 1.H, J=7.69 Hz), 4.62(s, 2H), 4.25(q, 2H, J=7.14 Hz), 3.41 (m, 1 H), 1.26(m, 9H),
Ethyl (2-propylphenoxy)acetate
1H NMR (CDCI3) 400MHz δ 7.12(m, 2H), 6.90(t, 1 H, J=8.24 Hz), 6.69(d, 1H, J=8.24 Hz), 4.61 (s, 2H), 4.24(q, 2H, J=7.14 Hz), 2.64(t, 2H, J=7.33 Hz), 1.64(m, 2H), 1.27(t, 3H, J=7.14 Hz), 0.94(t, 3H, J=7.33 Hz), Ethyl [4-(chlorosulfonyl)-2-ethylphenoxy]acetate
To a 250ml round-bottom flask containing chlorosulfonic acid (30m!) cooled to 0°C was added ethyl (2-ethylphenoxy)acetate (7.2g, 34.6mmoles) dropwise. Once the addition was complete the ice- bath was removed and the reaction was allowed to warm to room temperature at which the reaction was stirred for 3 hours. The reaction was then slowly added to ice and, once the excess chlorosulfonic acid was quenched, the mixture was diluted with CH2CI2 (200ml). The phases were separated and the aqueous fraction was washed with CH2CI2 twice. The combined organic fractions were dried over Na2S04 and filtered and concentrated in vacuo to yield 7.2g (70%) of crude product. The crude product was used with no purification. 1H NMR (CDCI3) 400MHz δ 7.84(m, 2H), 6.79(d, 1 H, J=8.24 Hz), 4.75(s, 2H), 4.26(q, 2H,
J=7.14 Hz), 2.77(q, 2H, J=7.51 Hz), 1.26(m, 6H),
The following were compounds were made using the same chlorosulfonation procedure:
Ethyl [4-(chiorosulfonyl)-2-methylphenoxy]acetate H NMR (d6-DMSO) 300MHz δ 7.41 (m, 2H), 6.79(d, 1 H, J=8.23 Hz), 4.82(s, 2H), 4.16(q, 2H, J=7.17 Hz), 2.21 (s, 3H), 1.21 (t, 3H, J=7.17 Hz),
Ethyl 2-[4-(chlorosulfonyl)-2-methylphenoxy]propanoate H NMR (d6-DMSO) 300MHz δ 7.44(m, 1H), 7.39(dd, 1H, J=8.23, 2.39 Hz), 6.74(d, 1H,
J=8.23 Hz), 4.96(q, 1 H, J=6.81 Hz), 4.13(q, 2H, J=7.08 Hz), 2.20(s, 3H), 1.54(d, 3H, J=6.81 Hz), 1.18(t, 3H, J=7.08 Hz),
Ethyl 2-[4-(chlorosulforιyl)-2-isopropylphenoxy]proparιoate 1H NMR (CDCI3) 400MHz δ 7.81 (m, 2H), 6.76(d, 1 H, J=8.42 Hz), 4.87(q, 1 H, J=6.78 Hz),
4.21 (q, 2H, J=7.14 Hz), 3.40(m, 1H), 1.65(d, 3H, J=6.78 Hz), 1.24(m, 9H),
Ethyl [4-(chlorosulfonyl)-2-isopropylphenoxy]acetate
1H NMR (CDCI3) 400MHz δ 7.84(m, 2H), 6.80(d, 1H, J=8.42 Hz), 4.75(s, 2H), 4.26(q, 2H, J=7.14 Hz), 3.42(m, 1 H), 1.27(m, 9H),
Ethyl 2-[4-(chlorosulfonyl)-2-propylphenoxy]propanoate
1H NMR (CDCI3) 400MHz δ 7.80(m, 2H), 6.75(d, 1 H, J=8.42 Hz), 4.85(q, 1 H, J=6J8 Hz), 4.21 (q, 2H, J=7.14 Hz), 2.69(t, 2H, J=7.51 Hz), 1.66(m, 5H), 1.23(t, 3H, J=7.14 Hz), 0.95(t, 3H, J=7.51 Hz),
Ethyl r4-(chlorosulfonyl)-2-propylphenoxy]acetate
1H NMR (CDCI3) 400MHz δ 7.83(m, 2H), 6.79(d, 1 H, J=8.42 Hz), 4.73(s, 2H), 4.26(q, 2H, J=7.14 Hz), 2.70(t, 2H, J=7.51 Hz), 1.67(m, 2H), 1.29(t, 3H, J=7.14 Hz), 0.95(t, 3H, J=7.51 Hz),
Ethyl 2-[4-(chlorosulfonyl)-2-ethylphenoxy]propanoate 1H NMR (CDCI3) 400MHz δ 7.81 (m, 2H), 6.75(d, 1 H, J=8.42 Hz), 4.86(q, 1 H, J=6.78 Hz), 4.21 (q, 2H, J=7.08 Hz), 2.75(m, 2H), 1.68(d, 3H, J=6.78 Hz), 1.23(m, 6H),
Ethyl 2-[4-(chlorosulfonyl)phenoxy]-2-methylpropanoate To a 3-L three-neck round-bottom flask equipped with a magnetic stir-bar, low temperature thermometer with thermometer adapter, addition funnel and a N2 inlet was added ethyl 2-methyl-2- phenoxypropanoate (83g, 0.399moles, 1eq) and dry CH2CI2 (1 L, 0.4M). After cooling the reaction to 0 °C (ice bath) chlorosulfonic acid (26.5ml, 0.399moles, 1eq) in dry CH2CI2 (50ml) was added dropwise over 30 minutes via addition funnel maintaining the internal temperature below 5°C. Following this dropwise addition the reaction was allowed to stir at 0 °C for 3 hours. The reaction was monitored by
HPLC and after 3 hours complete conversion was observed [(C-18, 3μm) 0%-95% Acetonitrile/Water over 8 minutes Rt= 2.96minutes]. At this point dry DMF (124ml, 4eq) was added slowly maintaining the internal temperature below 5°C. This was followed by the dropwise addition of thionyl chloride (43.77ml, 0.599moles, 1.5eq) in dry CH2CI2 (50ml) over 25minut.es maintaining the internal temperature below 5°C. After stirring at 0°C for 1.5 hours and monitoring by HPLC [(C-18, 3μm) 0%- 95% Acetonitrile/Water over 8 minutes Rt= 5.97minutes] the reaction was allowed to warm to room temperature. The reaction mixture was then washed with 0.1 N HCI and the phases were separated, with discarding the aqueous fraction. The organic fraction was washed with 0.1 N HCI, H20, brine and dried over Na2S04. The solution was filtered and concentrated in vacuo to yield 119.95g (98%) of pure sulfonyl chloride.
1H NMR (CDCI3) 400MHz δ 7.89(d, 2H, J=9.31 Hz), 6.89(d, 2H, J=9.31 Hz), 4.21 (q, 2H, J=7.16 Hz), 1 66(s, 6H), 1.20(t, 3H, J=7.16 Hz),
HPLC (C-18, 3μm) 0%-95% Acetonitrile/Water over 8 minutes Rt= 5.97minutes
Ethyl 2-methyl-2-(4-sulfanylphenoxy)propanoate
To a 3-L three-neck round-bottom flask equipped with an overhead mechanical stirrer, addition funnel and a N2 inlet was added ethyl 2-[4-(chlorosulfonyl)phenoxy]-2-methylpropanoate (53g, 0.1 3moles, 1 eq) and absolute EtOH (500ml). Tin powder (325mesh, 123.06g, 1.04moles, 6 eq) was added as a solid. The overhead stirrer was adjusted so that the rotor is as close as possible to the bottom of the round-bottom flask and stirring speed was accelerated to a very high setting before adding the HCI to prevent the clumping of the tin metal. Hydrogen chloride (4N in dioxane, 300ml) was added dropwise over the course of 1 hour. The reaction mixture was refluxed for 4 hours at which point the hot ethanolic solution was poured into a 2-L Erlenmeyer flask containing CH2CI2 (1 L) and ice. After stirring for 10 minutes the biphasic mixture was filtered through Celite. After transferring to a separatory funnel the phases were separated and the aqueous fraction was washed with CH2CI2 (2x 100ml). The combined organic fractions were dried over Na2S04, filtered and concentrated n vacuo. A bright yellow oil with a white precipitate suspended res ulted. This yellow mixture was dissolved in a minimum amount of CH2CI2 and filtered once again through Celite to yield 30g (75%) of a bright yellow oil. 1H NMR (CD3OD) 300MHz δ 7.18(m, 2H), 6.73(d, 2H, J=8.00 Hz), 4.23(q, 2H, J=7.17 Hz),
3.69(s, 1 H), 1.59(s, 6H), 1.26(t, 3H, J=7.17 Hz), The following were compounds were made using the same reduction procedure:
Ethyl (2-methyl-4-sulfanylphenoxy)acetate 1H NMR (CDCI3) 400MHz δ 7.15(m, 2H), 6.63(d, 1 H, J=8.23 Hz), 4.64(s, 2H), 4.29(q, 2H,
J=7.17 Hz), 3.36(s, 1 H), 2.29(s, 3H), 1.33(t, 3H, J=7.17 Hz),
Ethyl 2-(2-methyl-4-sulfanylphenoxy)propanoate
1H NMR (CDCI3) 400MHz δ 7.12(d, 1 H, J=2.39 Hz), 7.04(dd, 1 H, J=8.37, 2.39 Hz), 6.56(d, 1 H, J=8.37 Hz), 4.67(q, 1 H, J=6.72 Hz), 4.19(q, 2H, J=7.12 Hz), 3.31(s, 1 H), 2.22(s, 3H), 1.61 (d, 3H, J=6J2 Hz), 1.23(t, 3H, J=7.12 Hz),
TLC(20% EtOAc/Hexanes) Rf = 0.60
Ethyl (2-ethyl-4-sulfanylphenoxy)acetate 1H NMR (CDCI3) 400MHz δ 7.13(d, 1 H, J=2.20 Hz), 7.08(dd, 1 H, J=8.42, 2.38 Hz), 6.58(d,
1 H, J=8.42 Hz), 4.59(s, 2H), 4.24(q, 2H, J=7.14 Hz), 3.33(s, 1 H), 2.64(q, 2H, J=7.51 Hz), 1.28(t, 3H, J=7.14 Hz), 1.18(t, 3H, J=7.51 Hz),
Ethyl 2-(2-ethyl-4-sulfanylphenoxy)propanoate 1H NMR (CDCI3) 400MHz δ 7.15(d, 1 H, J=2.20 Hz), 7.07(dd, 1 H, J=8.42, 2.20 Hz), 6.55(d,
1 H, J=8.42 Hz), 4.74(q, 1 H, J=6J8 Hz), 4.17(m, 2H), 3.32(s, 1 H), 2.61 (q, 2H, J=7.51 Hz), 1.61(d, 3H, J=6.59 Hz), 1.19(m, 6H),
The following four compounds were made in the same way and used without further purification.
Ethyl (2-propyl-4-sulfanylphenoxy)acetate Ethyl 2-(2-propyl-4-sulfanylphenoxy)propanoate Ethyl (2-isopropyl-4-sulfanylphenoxy)acetate Ethyl 2-(2-isopropyl-4-sulfanylphenoxy)propanoate
Ethyl 2-methyl-2-{4-[({4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-[4-(trifluoromethyl)phenyn-1,3- thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoate
To a 250ml round-bottom flask equipped with a magnetic stir-bar and N2 inlet was added 5- (chloromethyl)-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazole (7.87g, 20.09mmoles, 1eq) and dry CH3CN (100ml, 0.27M). Solid cesium carbonate (16.4g, 50.22mmoles, 2.5eq) was added all at once followed by the quick addition of ethyl 2-methyl-2-(4- sulfanylphenoxy)propanoate (5.79g, 24.11 mmoles, 1.2eq) in dry CH3CN (10ml). The reaction was allowed to stir at room temperature for 2 hours at which point the solvent was removed under reduced pressure. The resulting residue was partitioned between EtOAc and 1 N NaOH. After the phases were separated the organic fraction was washed with H20, brine and dried over Na2S04. After filtration the volatiles were removed in vacuo to yield the titled compound in >100% yield. Sometimes because of the difficult separation between the thiophenol and the product, the crude product was carried forward without purification.
The following compounds were made using the same alkylation procedure. Where selectivity was an issue the alkylations were carried out below room temperature.:
Ethyl 2-{2-methyl-4-[({2-phenyl-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}propanoate 1H NMR (CDCI3) 300MHz δ 7.93(m, 2H), 7.44(m, 3H), 7.28(d, 1 H, J=2.J,9 Hz), 7.15(dd, 1 H,
J=8.23, 2.39 Hz), 6.61 (d, 1 H, J=8.23 Hz), 4.72(m, 3H), 4.50(d, 1 H, J .21 Hz), 4.32(s, 2H), 4.23(q, 2H, J=7.08 Hz), 3.93(m, 1 H), 3.59(m, 1 H), 2.26(s, 3H), 1.71 (m, 9H), 1.28(t, 3H, J=7.08 Hz),
Ethyl 2-{2-methyl-4-[({4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-[4-(trifluoromethyl)phenyl]-1,3- thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoate
1H NMR (CDCI3) 300MHz δ 8.04(d, 2H, J=8.23 Hz), 7.70(d, 2H, J=8.23 Hz), 7.27(d, 1 H,
J=2.39 Hz), 7. 5(dd, 1 H, J=8.49, 2.39 Hz), 6.60(d, 1 H, J=8.49 Hz), 4.73(m, 3H), 4.51 (d, 1 H, JD.21 Hz), 4.32(s, 2H), 4.20(q, 2H, J=7.17 Hz), 3.93(m, 1 H), 3.60(m, 1 H), 2.27(m, 3H), 1.71 (m, 9H), 1.27(t, 3H, J=7.17 Hz), TLC(30% EtOAc/Hexanes)= 0.73
Ethyl 2-{4-[({2-(4-fluorophenyl)-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3-thiazol-5- yl}methyl)sulfanyl]-2-methylphenoxy}propanoate H NMR (CDCl3) 400MHz δ 7.88(m, 2H), 7.19(d, 1 H, J=2.24 Hz), 7.08(m, 3H), 6.54(d, 1 H, J=8.45 Hz), 4.65(m, 3H), 4.44(m, 1 H), 4.24(s, 2H), 4.16(q, 2H, J=7.13 Hz), 3.86(m, 1 H), 3.53(m, 1 H), 2.21 (s, 3H), 1.66(m, 9H), 1.20(t, 3H, J=7.13 Hz),
Ethyl {2-ethyl-4-[({4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-[4-(trifluoromethyl)phenyl]-1,3- thiazol-5-yl}methyl)sulfanyl]phenoxy}acetate 1H NMR (CDCI3) 400MHz δ 7.98(d, 2H, J=8.24 Hz), 7.64(d, 2H, J=8.24 Hz), 7.20(d, H,
J=2.20 Hz), 7.15(dd, 1H, J=8.42, 2.20 Hz), 6.60(d, H, J=8.42 Hz), 4.63(m, 4H), 4.42(d, 1 H, J .27 Hz), 4.24(m, 4H), 3.87(m, 1 H), 3.54(m, 1 H), 2.64(q, 2H, J=7.51 Hz), 1.66(m, 6H), 1.26(t, 3H, J=7.14 Hz), 1.15(t, 3H, J=7.51 Hz),
Ethyl 2-{2-ethyl-4-[({4-[(tetrahydro-2H-pyrarι-2-yloxy)rnethyl]-2-[4-(trifluoromethyl)phenyl].l,3- thiazol-5-yl}methyl)sulfanyl3phenoxy}propanoate
1H NMR (CDCI3) 400MHz δ 7.98(d, 2H, J=8.24 Hz), 7.64(d, 2H, J=8.24 Hz), 7.17(d, 1 H, J=2.38 Hz), 7.11 (dd, 1 H, J=8.42, 2.38 Hz), 6.56(d, 1 H, J=8.42 Hz), 4.71 (q, 1 H, J^6.78 Hz), 4.66(t, 1 H, J=3.39 H/), ^.60(d, 1 H, J .27 Hz), 4.41(d, 1 H, J .27 Hz), 4.26(s, 2H), 4.16(q, 2H, J=7.14 Hz), 3.87(m, 1H), 3.54(m, 1 H), 2.62(q, 2H, J=7.51 Hz), 1.60(m, 9H), 1.20(t, 3H, J=7.14 Hz), 1.15(t, 3H, J=7.51 Hz), Ethyl {2-propyl-4-[({4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-[4-(trifluoromethyl)phenyl]-1,3- thiazol-5-yl}methyl)sulfanyl]phenoxy}acetate
1H NMR (CDCI3) 400MHz δ 7.97(d, 2H, J=8.20 Hz), 7.64(d, 2H, J=8.20 Hz), 7.16(m, 2H), 6.59(d, 1 H, J-8.24 Hz), 4.66(m, 1 H), 4.61 (m, 3H), 4.43(d, 1 H, J .27 Hz), 4.23(m, 4H), 3.88(m, 1 H), 3.54(m, 1 H), 2.57(t, 2H, J=7.33 Hz), 1.68(m, 8H), 1.26(t, 3H, J=7.14 Hz), 0.88(t, 3H, J=7.33 Hz),
Ethyl 2-{2-propyl-4-[({4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-[4-(trifluoromethyl)phenyl]-1,3- thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoate
1H NMR (CDCI3) 400MHz δ 7.97(d, 2H, J=8.24 Hz), 7.64(d, 2H, J=8.24 Hz), 7.17(d, 1 H, J=2.38 Hz), 7.11(dd, 1 H, J=8.42, 2.38 Hz), 6.55(d, 1H, J=8.42 Hz), 4.70(q, 1H, J=6.78 Hz), 4.66(t, 1 H, J=3.39 Hz), 4.62(d, 1 H, J .27 Hz), 4.43(d, 1 H, J .27 Hz), 4.25(s, 2H), 4.15(q, 2H, J=7.14 Hz), 3.88(m, 1 H), 3.54(m, 1 H), 2.56(t, 2H, J=7.33 Hz), 1.60(m, 11 H), 1.21(t, 3H, J=7.14 Hz), 0.88(t, 3H, J=7.33 Hz),
Ethyl {2-isopropyl-4-[({4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-[4-(trifluoromethyl)phenyl]- 1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetate
1H NMR (CDCI3) 400MHz δ 7.98(d, 2H, J=8.24 Hz), 7.64(d, 2H, J=8.24 Hz), 7.20(d, 1 H, J=2.38 Hz), 7.15(dd, 1 H, J=8.42, 2.38 Hz), 6.60(d, 1 H, J=8.42 Hz), 4.65(t, 1 H, J=3.48 Hz), 4.60(s, 2H), 4.56(d, IH, J .09 Hz), 4.38(d, 1H, J .09 Hz), 4.23(m, 4H), 3.87(m, 1 H), 3.53(m, 1H), 3.32(m, 1 H), 1.66(m, 6H), 1.26(t, 3H, J=7.14 Hz), 1.15(d, 6H, J=6.96 Hz),
Ethyl 2-{4-[({4-(2-furylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2- methylphenoxy}propanoate
From 5-(chloromethyl)-4-(2-furylmethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazole (0.097g, 0.27 mmol), ethyl 2-{4-[({4-(2-furylmethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyI)suIfanyl]-2-methylphenoxy}propanoate (0.091 g, 60%) was obtained as a white solid.
1H NMR (CDCI3): δ 8.00 (d, 2 H), 7.68 (d, 2 H), 7.23 (m, 2 H), 6.62 (m 2 H), 6.30 (s, 1 H), 6.02 (s, 1 H), 4.76 (q, 1 H), 4.21 (q, 2 H), 4.17 (s, 2 H), 3.98 (s, 2 H), 2.29 (s, 3 H), 1.63 (s, 3 H), 1.24 (t, 3 H); MS m/z 562 (M+1 ).
Ethyl 2-{4-[({4-(3-fuiylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanvn-2- methylphenoxy}propanoate
From 5-(chloromethyl)-4-(3-furylmethyI)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazole (0.172g, 0.48 mmol), ethyl 2-{4-[({4-(3-furylmethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- y|}methyl)sulfanyl]-2-methylphenoxy}propanoate (0.177g, 65%) was obtained as a white solid. 1H NMR (CDCI3): δ 8.00 (d, 2 H), 7.70 (d, 2 H), 7.28 (m, 2 H), 7.16, (d, 1 H), 6.61 (m, 2 H),
6.31 (s, 1 H), 4.78 (q, 1 H), 4.27 (q, 2 H), 4.18 (s, 2 H), 3.68 (s, 2 H), 2.22 (s, 3 H), 1.68 (s, 3 H), 1.30 (t, 3 H); MS /z 578 (M+1).
Ethyl 2-{4-[({4-(2-thienylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2- methylphenoxy}propanoate From 5-(chloromethyl)-4-(3-furylmethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazole (0.185g, 0.50 mmol), ethyl 2-{4-[({4-(2-thienylmethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyl)sulfanyl]-2-methyIphenoxy}propanoate (0.21 g, 73%) was obtained as a yellow solid.
1H NMR (CDCI3): δ 8.01 (d, 2 H), 7.70 (d, 2 H), 7.20 (s, 1 H), 7.17 (m, 1 H), 6.93 (m, 1 H), 6.80 (s, 1 H), 6.60 (m, 2 H), 4.74 (q, 1 H), 4.20 (q, 2 H), 4.19 (s, 2 H), 4.17 (s, 2 H), 2.29 (s, 3 H), 1.67 (s, 3 H), 1.30 (t, 3 H); MS m/z 578 (M+1 ).
Ethyl 2-methyl-2-{4-[({4-[4-(trifluoromethoxy)benzyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}propanoate From 5-(chloromethyl)-4-[4-(trifluoromethoxy)benzyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazole
(0.166g, 0.37 mmol) (prepared as in U16097-118-2), ethyl 2-methyI-2-{4-[({4-[4- (trifluoromethoxy)benzyl]-2-[4-(trifluoromethyl)phenyI]-1 ,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}propanoate (0.21 Og, 87%) was obtained as a white solid.
MS m/z 656 (M+1 ); HPLC RT 4.862 (C18 4.2x100mm, 0-100% ACN/H20 (0.1 % TFA), 6min @ 2ml/min @254/220nm).
Ethyl 2-methyl-2-{4-[({4-[(4-methyl-2-thienyl)methyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}propanoate
From 5-(chloromethyl)-4-(2-thienylmethyI)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazole (0.062g, 0.16 m ol), ethyl 2-methyl-2-{4-[({4-[(4-methyl-2-thienyl)methyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3- thiazol-5-yl}methyl)sulfanyl]pfιenoxy}propanoate (0.17g, 100%) was obtained as a yellow oil.
MS m/z 592 (M+1); HPLC RT 4.534 (C18 4.2x100mm, 0-100% ACN/H20 (0.1 % TFA), 6min @ 2ml/min @254/220nm).
Ethyl {2-methyl-4-[({4-[(4-methyl-2-thienyl)methyl]-2-[4-(trifluoromethyl)phenyl1-1,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}acetate
From 5-(chloromethyl)-4-(2-thienylmethyl)-2-[4-(trifluoromethyl)phenyl]-l ,3-thiazole (0.062g, 0.16 mmol), ethyl {2-methyl-4-[({4-[(4-methyl-2-thienyl)methyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol- 5-yl}methyl)sulfanyl]phenoxy}acetate (0.13g, 100%) was obtained as a yellow oil. MS m/z 578 (M+1); HPLC RT 4.338 (C18 4.2x100mm, 0-100% ACN/H20 (0.1 % TFA), 6min
@ 2ml/min @254/220nm).
Ethyl {4-[({4-(2,4-difluorobenzyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanvn- 2-methylphenoxy}acetate From 5-(chloromethyl)-4-(2,4-difluorobenzyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazole
(0.139g, 0.34 mmol), ethyl {4-[({4-(2,4-difluorobenzyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyl)sulfanyl]-2-methylphenoxy}acetate, (0.1 g, 49%) was obtained as a white solid.
MS m/z 594 (M+1 ); HPLC RT 4.337 (C18 4.2x100mm, 0-100% ACN/H20 (0.1% TFA), 6min @ 2ml/min @254/220nm).
Ethyl {4-[({4-(4-methoxybenzyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl1-2- methylphgnoxy}acetate From 5-(chloromethyl)-4-(4-methoxybenzyI)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazole (0.09g, 0.4 mmol) (prepared as in U17097-118-3), ethyl {4-[({4-(4-methoxybenzyl)-2-[4- (trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}acetate (0.160g, 68%) was obtained as a white solid. MS m/z 588 (M+1); HPLC RT 4.631 (C18 4.2x100mm, 0-100% ACN/H20 (0.1 % TFA), 6min
@ 2ml/min @254/220nm).
2-Methyl-4-[({4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol- 5-yl}methyl)sulfanyl]phenol 1H NMR (CDCI3) 400MHz δ 7.97(d, 2H, J=8.10 Hz), 7.63(d, 2H, J=8.10 Hz), 7.16(d, 1 H,
J=2.24 Hz), 7.06(dd, 1 H, J=8.28, 2.24 Hz), 6.63(d, 1 H, J=8.28 Hz), 4.64(t, 1 H, J=3.53 Hz), 4.59(d, 1 H, J .24 Hz), 4.40(d, 1 H, J .24 Hz), 4.23(s, 2H), 3.86(m, 1 H), 3.53(m, 1 H), 2.16(s, 3H), 1.66(m, 6H),
2-Methyl-4-[({4-(4-trifluoromethyl)benzyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]phenol
From 5-(chloromethyl)-4-[4-(trifluoromethyl)benzyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazole (0.82g, 0.19 mmol), 2-methyl-4-[({4-(4-trifluoromethyl)benzyl]-2-[4-(trifluoromethyl)phenyI]-1 ,3-thiazol- 5-yl}methyl)suIfanyl]phenol (0.021 g, 21 %) was obtained as a white solid.
1H NMR (CDCI3): δ 8.00 (d, 2 H), 7.69 (d, 2 H), 7.52 (d, 2 H), 7.29 (d, 2 H), 7.18 (s, 1 H), 7.16 (d 1 H), 6.70 (d, 1 H), 4.15 (s, 2 H), 4.00 (s, 2 H), 2.20 (s, 3 H); MS m/z 540 (M+ t).
2- ethyl-4-[({4-(4-trifluoromethoxy)benzyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]phenol
From 5-(chloromethyl)-4-[4-(trifluoromethoxy)benzyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazole (0.147g, 0.33 mmol), 2-methyl-4-[({4-(4-trifluoromethoxy)benzyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3- thiazol-5-yl}methyl)sulfanyl]phenol (0.048g, 27%) was obtained as a white solid.
1H NMR (CDCI3): δ 8.01 (d, 2 H), 7.71 (d, 2H), 7.13 (m, 6 H), 6.69 (d, 1 H), 4.18 (s, 2 H), 3.96 (s, 2 H), 2.22 (s, 3 H); MS m/z 556 (M+1).
4-[({4-(4-methoxybenzyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfarιyl]-2- methylphenol
From 5-(chloromethyl)-4-(4-methoxybenzyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazole (0.063g, 0.16 mmol), 4-[({4-(4-methoxybenzyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methyl)sulfanyl]-2- methylphenol (0.022g, 28%) was obtained as a white solid. 1H NMR (CDCI3): δ 8.00 (d, 2 H), 7.68 (d, 2 H), 7.19 (s, 1 H), 7.09 (m, 3 H), 6.82 (d, 2 H), 6.70
(d, 1 H), 4.14 (s, 2 H), 3.90 (s, 2 H), 2.20 (s, 3 H); MS m/z 502 (M+1 ).
2- ethyl-4-[({4-(4-methylsulfanyl)benzyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]phenol From 5-(chloromethyl)-4-[4-(methylsulfanyl)benzyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazole (0.33g, 0.78 mmol), 2-methyl-4-[({4-(4-methylsulfanyl)benzyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol- 5-yl}methyl)sulfanyl]phenol (0.296g, 72%) was obtained as a white solid.
MS m/z 518 (M+1 ).
4-[({4-(4-terf-butylbenzyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2- methylphenol
From 4-(4-terf-butylbenzyl)-5-(chloromethyl)-2-[4-(trifluoromethyI)phenyl]-1 ,3-thiazole (0.151 g, 0.36 mmol), 4-[({4-(4-terf-butylbenzyI)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methyl)sulfanyl]-2- methylphenol (0.113g, 60%) was obtained as a white solid. MS m/z 528 (M+1 ).
2-Methyll-4-[({4-(3-thienylmethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyl)sulfanyl]phenol
From 5-(chloromethyl)-4-(3-thienylmethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazole (0.105g, 0.28 mmol), 2-methyl-4-[({4-(3-thienylmethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyI)suIfanyl]phenol (0.072g, 54%) was obtained as a yellow oil . MS m/z 478 (M+1 ).
The following three compounds were also prepared by the same route but were carried on without purification:
Ethyl 2-{2-isopropyl-4-[({4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-[4-(trifluoromethyl)phenyl]- 1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoate
4-[({4-[(Tetrahydro-2tf-pyran-2-yloxy)methyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]phenol
4-[({2-(4-Fluorophenyl)-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3-thiazol-5- yl}methyl)sulfanyl]-2-methylphenol
Ethyl 2-{2-methyl-4-[({4-[4-(trifluoromethoxy)benzyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}propanoate
From 2-methyl-4-[({4-(4-trifluoromethoxy)benzyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazoI-5- yl}methyl)sulfanyl]phenol (0.17g, 0.31 mmol), ethyl 2-{2-methyl-4-[({4-[4-(trifIuoromethoxy)benzyI]-2- [4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoate (0.17g, 83%) was obtained as a white solid.
MS m/z 656 (M+1 ); HPLC RT 4.553 (C18 4.2x100mm, 0-100% ACN/H20 (0.1 % TFA), 6min @ 2ml/min @254/220nm).
Methyl {2-methyl-4-[({4-[4-(trifluoromethoxy)benzyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thjazol-5: yl}methyl)sulfanyl]phenoxy}acetate
From 2-methyl-4-[({4-(4-trifluoromethoxy)benzyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- y|}methyl)sulfanyl]phenol (0.17g, 0.31 mmol), methyl {2-methyl-4-[({4-[4-(trifluoromethoxy)benzyl]-2-[4- (trifluoromethyI)phenyl]-1 ,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetate (0.15g, 80%) was obtained as a white solid. MS m/z 628 (M+1 ); HPLC RT 4.398 (C18 4.2x100mm, 0-100% ACN/HzO (0.1 % TFA), 6min @ 2ml/min @254/220nm).
Ethyl 2-{2-methyl-4-[({4-(3-thienylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}propanoate
From 2-methyI-4-[({4-(3-thienylmethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyl)sulfanyl]phenol, ethyl 2-{2-methyl-4-[({4-(3-thienylmethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3- thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoate (0.225g, 0.47 mmol), (0.255g, 91 %) was obtained as a yellow oil.
MS m/z 578 (M+1 ); HPLC RT 4.412 (C18 4.2x100mm, 0-100% ACN/H20 (0.1% TFA), 6min @ 2ml/min @254/220nm).
Methyl {2-methyl-4-[({4-(3-thienylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}acetate
From 2-methyl-4-[({4-(3-thienyimethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyl)sulfanyl]phenoI, methyl {2-methyl-4-[({4-(3-thienylmethyl)-2-[4-(trifluoromethyI)phenyl]-1 , 3- thiazol-5-yl}methyl)sulfanyl]phenoxy}acetate (0.225g, 0.47 mmol), (0.259g, 94%) was obtained as a yellow oil. MS m/z 550 (M+1); HPLC RT 4.243 (C18 4.2x100mm, 0-100% ACN/H20 (0.1 % TFA), 6min
@ 2ml/min @254/220nm).
Ethyl 2-{4-[({4-(hydroxymethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}-2-methylpropanoate To a stirred solution of crude ethyl {2-methyl-4-[({4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-[4-
(trifluoromethyl)pheny]]-1 ,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetate (11.98g, 20.09mmoles, 1 eq) in MeOH (100ml, 0.20M) was added as a solid p-toluenesulfonic acid (800mg, 25mol%) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. The MeOH was removed in vacuo and the residue was purified by silica gel chromatography (15% EtOAc/Hexanes to 30% EtOAc/Hexanes) to yield 8g (78%) of pure titled alcohol.
1H NMR (CDCI3) 400MHz δ 7.96(d, 2H, J=8.06 Hz), 7.65(d, 2H, J=8.06 Hz), 7.23(d, 2H, J=8.79 Hz), β.73(d, 2H, J=8.79 Hz), 4.44(s, 2H), 4.17(m, 4H), 2.33(br s, 1 H), 1.56(s, 6H), 1.21(t, 3H, J=7.14 Hz),
TLC(30% EtOAc/Hexanes) Rf = 0.32 4-[({4-(Hydroxymethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2- methylphenol
1H NMR (CDCI3) 400MHz δ 7.95(d, 2H, J=7.93 Hz), 7.64(d, 2H, J=7.93 Hz), 7.15(d, 1 H, J=2.07 Hz), 6.98(dd, 1 H, J=8.10, 2.07 Hz), 6.62(d, 1 H, J=8.10 Hz), 4.39(s, 2H), 4.11(s, 2H), 2.14(s, 3H),
Hhyl 2-{4-[({4-(hydroxymethyQ-2-[4-(triflu^^ gropylphenoxy}propanoate 1H NMR (CDCI3) 400MHz δ 7.97(d, 2H, J=8.06 Hz), 7.66(d, 2H, J=8.06 Hz), 7.13(d, 1 H, J=2.38 Hz), 7.10(dd, 1 H, J=8.24, 2.38 Hz), 6.55(d, 1 H, J=8.24 Hz), 4.70(q, 1 H, J=6.78 Hz), 4.43(s, 2H), 4.14(m, 4H), 2.55(t, 2H, J=7.33 Hz), 2.19(br s, 1 H), 1.55(m, 5H), 1.21 (t, 3H, J=7.14 Hz), 0.85(t, 3H, J=7.33 Hz),
Methyl {4-[({4-(hydroxymethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2- isopropylphenoxy}acetate
1H NMR (CDCl3) 400MHz δ 7.97(d, 2H, J=8.42 Hz), 7.66(d, 2H, J=8.42 Hz), 7.15(m, 2H), 6.60(d, 1 H, J=8.79 Hz), 4.64(s, 2H), 4.38(s, 2H), 4.15(s, 2H), 3.77(s, 3H), 3.31 (m, 1 H), 2.03(br s, 1 H), 1.12(d, 6H, J=6.96 Hz),
Ethyl 2-{4-[({4-(hydroxymethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2- isopropylphenoxy}propanoate
1H NMR (CDCI3) 400MHz δ 7.97(d, 2H, J=8.24 Hz), 7.66(d, 2H, J=8.24 Hz), 7.15(d, 1 H, J=2.38 Hz), 7.11 (dd, 1 H, J=8.42, 2.38 Hz), 6.56(d, 1 H, J=8.42 Hz), 4.73(q, 1 H, J=6.78 Hz), 4.38(s, 2H), 4.14(m, 4H), 3.30(m, 1 H), 1.60(d, 3H, J=6.78 Hz), 1.17(m, 9H),
Ethyl 2-{4-[({4-(hydroxymethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2- methylphenoxy}propanoate 1H NMR (CDCI3) 300MHz δ 8.00(d, 2H, J=8.23 Hz), 7.69(d, 2H, J=8.23 Hz), 7.22(d, 1 H,
J=2.39 Hz), 7.12(dd, 1 H, J=8.23, 2.39 Hz), 6.59(d, 1 H, J=8.23 Hz), 4.74(q, 1 H, J=6.77 Hz), 4.51 (s, 2H), 4.19(m, 4H), 3.68(br s, 1 H), 2.26(s, 3H), 1.65(d, 3H, J=6J7 Hz), 1.26(t, 3H, J=7.17 Hz), TLC(50% EtOAc/Hexanes) Rf = 0.40
The following four compounds were deprotected as above but used without further purification:
Ethyl 2-[4-({[2-(4-fluorophenyl)-4-(hydroxymethyl)-1,3-thiazol-5-yl]methyl}sulfanyl)-2- methylphenoxy]propanoate
Ethyl {2-ethyl-4-[({4-(hydroxymethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}acetate
Ethyl 2-{2-ethyl-4-[({4-(hydroxymethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}propanoate
Ethyl {4-[({4-(hydroxymethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl1-2- propylphenoxy}acetate
Ethyl {[tert-butyl(diphenyl)silyl]oxy}acetate To a 500ml round-bottom flask equipped with a magnetic stir-bar, N2 inlet was added ethyl glycolate (10g, 96.0mmoles, 1eq) and dry CH2CI2 (200ml, 0.5M). This was followed by the addition of triethylamine (40ml, 0.288moles, 3eq) and DMAP (1.17g, 9.6mmoles, 10mol%) followed by the dropwise addition of TBDPSCI (27.5ml, 0.106moles, 1.1eq) in dry CH2CI2 (20ml). The reaction mixture was allowed to stir at room temperature overnight at which time the reaction mixture was diluted with CH2Cl2 and washed with 1N HCI, saturated sodium bicarbonate, H20 and dried over Na2S04. After filtration the volatiles were removed in vacuo to yield 30g (91 %) of titled compound.
1H NMR (CDCI3) 300MHz δ 7.69(m, 4H), 7.39(m, 6H), 4.23(s, 2H), 4.14(q, 2H, J=7.14 Hz), 1.22(t, 3H, J=7.14 Hz), 1.08(m, 9H), TLC(20% EtOAc/Hexanes) Rf= 0.67
{[tert-Butyl(diphenyl)silyl]oxy}acetic acid
To a stirred solution of ethyl {[tert-butyl(diphenyl)silyl]oxy}acetate (20g, 58.4mmoles, 1eq) in THF (100ml, 0.58M) was added 1N NaOH (6ml, 0.117moIes, 2eq) and was allowed to stir at room temperature overnight. The THF was removed in vacuo and the residue was partitioned between
CH2Cl2 and 1 N HCI until a pH of 2 was reached. The phases were separated and the aqueous phase was washed twice with CH2CI2. The combined organic fractions were dried over Na2S04, filtered and concentrated in vacuo to yield 17g (90%) of product.
1H NMR (CDCI3) 300MHz δ 7.68(m, 4H), 7.41 (m, 6H), 4.22(s, 2H), 1.11(s, 9H), TLC(5% Me0H/CH2CI2) Rf= 0.37
{[tert-Butyl(diphenyl)silyl]oxy}acetyl chloride
In a 500ml round-bottom flask was mixed {[tert-butyl(diphenyl)silyl]oxy}acetic acid (17g, 54.0mmoles, 1eq), thionyl chloride (11.7g, 0.162moles, 3eq) and dry CH2CI2 (120ml, 0.45M). This mixture was refluxed for 5 hours. After cooling to room temperature the volatiles were removed in vacuo. The resulting residue was washed twice with toluene and the toluene was subsequently removed in vacuo to remove excess thionyl chloride. This resulted in 18g (100%) of titled compound. H NMR (CDCI3) 300MHz δ 7.72(m, 4H), 7.44(m, 6H), 4.54(s, 2H), 1.11 (m, 9H),
Ethyl 4-{[tert-butyl(diphenyl)silyl1oxy}-3-oxobutanoate
To a 1-L round-bottom flask equipped with a magnetic stir-bar, addition funnel, low temperature thermometer with thermometer adapter and a N2 inlet was added monoethyl malonate (14.53g, 0.11moles, 2eq) in dry THF (150ml, 0.73M) and 20mg of 2,2'-dipyridyl. After cooling the reaction mixture to -78°C (dry ice/acetone), 7-BuLi (2.5M in Hexanes, 88ml, 0.22moles, 4eq) was added at a rate to maintain the internal temperature below -10°C. Once the addition was complete the reaction was allowed to warm to -10°C by removal of the cold bath. The reaction remained a light pink color; this designates that there was ample amount of n-BuLi to deprotonate the monoethyl malonate. (If the color had turned yellow the reaction would have had to have been re-cooled to - 78°C and additional n-BuLi would have had to have been added followed be re-warming to -10°C.) At this point the reaction mixture was cooled to -78°C followed by the dropwise addition of neat {[tert- Butyl(diphenyl)silyl]oxy}acetyl chloride (18g, 54mmoles, 1eq) over a period of 15 minutes maintaining the internal reaction temperature below -60°C. This was allowed to stir at -78°C for 10 minutes at which point the reaction was transferred to a separatory funnel containing diethyl ether (900ml) and 1N HCI (450ml). This was agitated and vented until further gas evolution ceased after which the phases were separated and the organic phase was washed with saturated sodium bicarbonate, brine and dried over Na2S04. This was then filtered, concentrated in vacuo and purified by silica gel chromatography (5% EtOAc/Hexanes to 20% EtOAc/Hexanes) to yield 12.2g (60%) of product.
1H NMR (CDCy 300MHz δ 7.63(m, 4H), 7.41 (m, 6H), 4.19(m, 4H), 3.63(s, 2H), 1.27(t, 3H, J=7.14 Hz), 1.08(s, 9H),
TLC(20% EtOAc/Hexanes) Rf= 0.53
The following compounds were made according to W. Wierenga (J.Org.Chem. 1979 vol 44 p
310):
Ethyl 4-(4-bromophenyl)-3-oxobutanoate
1H NMR (CDCy 300MHz δ 7.45(d, 2H, J=8.38 Hz), 7.10(d, 2H, J=8.38 Hz), 4.17(q, 2H, J=7.14 Hz), 3.79(s, 2H), 3.45(s, 2H), 1.26(t, 3H, J=7.14 Hz),
Ethyl 3-oxo-4-(2-phenylethoxy)butanoate
1H NMR (CDCy 300MHz δ 7.26(m, 5H), 4.15(q, 4H, J=7.14 Hz), 3.71(;, 2H, J=6.94 Hz), 3.46(s, 2H), 2.92(t, 2H, J=6.94 Hz), 1.27(t, 3H, J=7.14 Hz),
Ethyl 3-oxo-6-phenylhexanoate
1H NMR (CDCy 300MHz δ 7.22(m, 5H), 4.18(q, 2H, J=7.14 Hz), 3.39(s, 2H), 2.62(t, 2H, J=7.28 Hz), 2.53(t, 2H, J=7.28 Hz), 1.92(m, 2H), 1.25(t, 3H, J=7.14 Hz),
Ethyl 3-oxo-4-phenylbutanoate
1H (CDCy 300MHz 7.29(m, 5H), 4.18(q, 2H, J=7.14 Hz), 3.83(s, 2H), 3.44(s, 2H), 1.26(t, 3H, J=7.14 Hz),
TLC(20% EtOAc/Hexanes) Rf= 0.36
Ethyl 4-(benzyloxy)-3-oxobutanoate
1H (CDCI3) 300MHz 7.35(m, 5H), 4.59(s, 2H), 4.16(q, 4H, J=7.14 Hz), 3.53(s, 2H), 1.26(t, 3H, J=7.14 Hz),
Ethyl 3-oxo-5-phenylpentanoate 1H NMR (CDCI3) 300MHz 7.24(m, 5H), 4.18(q, 2H, J=7.14 Hz), 3.42(s, 2H), 2.90(m, 4H),
1.27(t, 3H, J=7.14 Hz)
Ethyl 4-{[tert-butyl(diphenyl)silyl]oxy}-2-chloro-3-oxobutanoate
To a 100ml round-bottom flask equipped with a magnetic stir-bar and a N2 inlet was added ethyl 4-{[tert-butyl(diphenyl)silyl]oxy}-3-oxobutanoate (4g, 10.4mmoles, 1eq) and dry CH2CI2 (25ml, 0.42M) at room temperature. This was followed by the addition of neat sulfuryl chloride (0.833ml, 10.4mmoles, 1eq) and the reaction was allowed to stir overnight at room temperature. After dilution with CH2CI2 (50ml) the reaction mixture was treated with saturated sodium bicarbonate until bubbling ceased. The phases were separated and the organic fraction was washed with sat. NaHC03, brine and dried over Na2S04. After filtration and concentration in vacuo was yielded 4.2g (96%) of crude chloride. This crude product was used without purification.
1H NMR (CDCI3) 400MHz δ 7.62(m, 4H), 7.41 (m, 6H), 5.26(s, 1 H), 4.40(m, 2H), 4.25(m, 2H), 1.28(t, 3H, J=7.14 Hz), 1.09(s, 9H),
The following intermediates were made by the same procedure as that used for Ethyl 4-{[tert- butyl(diphenyl)silyl]oxy}-2-ch!oro-3-oxobutanoate
Ethyl 4"(banzyloxy)-2-chloro-3-oxobutanoate
1H (CDCI3) 300MHz δ 7.36(m, 5H), 5.10(s, 1 H), 4.59(s, 2H), 4.32(s, 2H), 4.23(q, 2H, J=7.23 Hz), 1.28(t, 3H, J=7.14 Hz),
Ethyl 2-chloro-3-oxo-6-phenylhexanoate H (CDCy 300MHz δ 7.23(m, 5H), 4.75(s, 1 H), 4.27(q, 2H, J=7.14 Hz), 2.72(t, 2H, J=7.28 Hz), 2.63(t, 2H, J=7.28 Hz), 1.97(m, 2H, J=7.28 Hz), 1.28(t, 3H, J=7.14 Hz),
Ethyl 2-chloro-3-oxo-4-(2-phenylethoxy)butanoate
1H NMR (CDCy 300MHz δ 7.25(m, 5H), 5.03(s, 1 H), 4.29(m, 2H), 4.24(q, 2H, J=7.14 Hz), 3.73(t, 2H, J=7.00 Hz), 2.91 (t, 2H, J=7.00 Hz), 1.29(t, 3H, J=7.14 Hz),
Ethyl 2-chloro-3-oxo-4-phenylbutanoate 1H (CDCy 300MHz 7.29(m, 5H), 4.87(s, 1 H), 4.23(m, 2H, J=7.14, 7.00, 7.14, 1.10, 1.24,
1.24, 0.82 Hz), 4.02(d, 2H, J=4.53 Hz), 1.31 (t, 3H, J=7.14 Hz), TLC 20% EtOAc/Hexanes) Rf= 0.51
Ethyl 2-chloro-3-oxo-5-phenylpentanoate 1H (CDCy 300MHz 7.25(m, 5H), 4.76(s, 1 H), 4.25(q, 2H, J=7.14 Hz), 2.99(m, 4H), 1.31(t,
3H, J=7.14 Hz),
TLC(20% EtOAc/Hexanes) Rf= 0.46
Ethyl 4-(4-bromophenyl)-2-chloro-3-oxobutanoate 1H NMR (CDCy 300MHz δ 7.48(d, 2H, J=8.51 Hz), 7.10(d, 2H, J=8.51 Hz), 4.84(s, 1 H),
4.25(q, 2H, J=7.14 Hz), 3.97(s, 2H), 1.29(t, 3H, J=7.14 Hz), TLC(20% EtOAc/Hexanes) Rf= 0.58
Ethyl 4-({[tert-butyl(diphenyl)silyl]oχy}methyl)-2-(4-{trifluoromethyl}phenyl)-1,3-thiazole^- carboxylate To a 500ml round-bottom flask equipped with a magnetic stir-bar was mixed ethyl 4-{[tert- butyl(diphenyI)silyl]oxy}-2-chloro-3-oxobutanoate (20.4g, 52.88mmoles, 1eq), 4- trifluoromethylthiobenzamide (12.2g, 59.5mmoles, 1.1eq), 1 ,2-dichloroethane (150ml, 0.44M) and H20 (3ml). This mixture was refluxed for 12 hrs. After cooling to room temperature, the reaction mixture was diluted with CH2CI2 (100ml) and washed with sat. NaHC03. Once the phases were separated, the organic phase was washed with water, brine and dried over Na2S04. This was then filtered, concentrated in vacuo and purified via silica gel chromatography (5% EtOAc/Hexanes to 20% EtOAc/Hexanes) to yield 20.3g (76%) of the titled compound.
1H NMR (CDCy 400MHz δ 8.07(d, 2H, J=8.37 Hz), 7.76(m, 4H), 7.71 (d, 2H, J=8.37 Hz), 7.37(m, 6H), 5.24(s, 2H), 4.26(q, 2H, J=7.18 Hz), 1.29(t, 3H, J=7.18 Hz), 1.11 (s, 9H), TLC(20% EtOAc/Hexanes) Rf = 0.72
Ethyl 4-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-phenyl-1,3-thiazole-5-carboxylate
Analogous procedure to that used for ethyl 4-({[terf-butyI(diphenyl)silyl]oxy}methyl)-2-(4- {trifluoromethyl}phenyl)-1 ,3-thiazole-5-carboxylate except thiobenzamide is the starting material.
1H NMR (CDCI3) 400MHz δ 7.98(m, 2H), 7.76(m, 4H), 7.40(m, 9H), 5.21 (s, 2H), 4.23(q, 2H, J=7.12 Hz), 1.28(t, 3H, J=7.12 Hz), 1.08(s, 9H), TLC(20% EtOAc/Hexanes) Rf = 0.67
The following intermediates were made using the same procedure as Ethyl 4-({[tert- butyl(diphenyl)silyl]oxy}methyl)-2-(4-{trifluoromethyl}phenyl)-1 ,3-thiazole-5-carboxylate:
Ethyl 2-(4-{trifluoromethyl}phenyl)-4-[(2-phenylethoxy)methyl]-1,3-thiazole-5-carboxylate
1H (CDCI3) 300MHz δ 8.10(d, 2H, J=8.79 Hz), 7.71(d, 2H, J=8.79 Hz), 7.23(m, 5H), 5.02(s, 2H), 4.37(q, 2H, J=7.14 Hz), 3.86(t, 2H, J=7.42 Hz), 2.99(t, 2H, J=7.42 Hz), 1.41 (t, 3H, J=7.14 Hz),
Ethyl 2-(4-{trifluoromethyl}phenyl)-4-(3-phenylpropyl)-1,3-thiazole-5-carboxylate
1H (CDCI3) 300MHz δ 8.08(d, 2H, J=8.24 Hz), 7.71 (d, 2H, J=8.24 Hz), 7.23(m, 5H), 4.34(q, 2H, J=7.14 Hz), 3.25(t, 2H, J=7.69 Hz), 2.71 (t, 2H, J=7.69 Hz), 2.13(m, 2H), 1.35(t, 3H, J=7.14 Hz),
Ethyl 4-[(benzyloxy)methyl]-2-(4-{trifluoromethyl}phenyl)-1,3-thiazole-5-carboxylate
1H (CDCy 300MHz δ 8.12(d, 2H, J=8J9 Hz), 7.72(d, 2H, J=8.79 Hz), 7.35(m, 5H), 5.04(s, 2H), 4.74(s, 2H), 4.36(q, 2H, J=7.10 Hz), 1.38(t, 3H, J=7.14 Hz), TLC(20% EtOAc/Hexanes) Rf= 0.49
Ethyl 4-(4-bromobenzyl)-2-(4-{trifluoromethyl}phenyl)-1,3-thiazole-5-carboxylate
1H NMR (CDCI3) 300MHz δ 8.07(d, 2H, J=8J9 Hz), 7.69(d, 2H, J=8J9 Hz), 7.43(d, 2H, J=8.51 Hz), 7.28(d, 2H, J=8.51 Hz), 4.51(s, 2H), 4.38(q, 2H, J=7.14 Hz), 1.39(t, 3H, J=7.14 Hz), TLC(20% EtOAc/Hexanes) Rf= 0.66
Ethyl 4-(2-phenylethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-carboxylate 1H (CDCI3) 300MHz 8.10(d, 2H, J=8.79 Hz), 7J2(d, 2H, J=8.79 Hz), 7.24(m, 5H), 4.37(q, 2H, J=7.14 Hz), 3.51 (m, 2H), 3.10(m, 2H), 1.40(t, 3H, J=7.14 Hz), MS(ES+) M+H= 405.99
Ethyl 4-benzyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-carboxylate
1H (CDCy 300MHz 8.08(d, 2H, J=8.79 Hz), 7.70(d, 2H, J=8J9 Hz), 7.42(d, 2H, J=9.61 Hz), 7.23(m, 3H), 4.58(s, 2H), 4.38(q, 2H, J=7.14 Hz), 1.39(t, 3H, J=7.14 Hz), TLC(20% EtOAc/Hexanes) Rf= 0.57 MS(ES+) M+H= 391.9
{4-({[tert-Butyl(diphenyl)silyl]oxy}methyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methanol
Analogous reduction as in the synthesis of 4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-[4- (trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methanol. 1H NMR (CDCy 400MHz δ 7.97(d, 2H, J=8.03 Hz), 7.68(m, 6H), 7.41 (m, 6H), 4.97(s, 2H),
4.84(s, 2H), 1.08(s, 9H),
[4-({[tert-Butyl(diphenyl)silyl]oxy}methyl)-2-phenyl-1,3-thiazol-5-yl]methanol
Analogous reduction as in the synthesis of 4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-[4- (trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methanol. H NMR (CDCI3) 300MHz δ 7.90(m, 2H), 7.75(m, 4H), 7.45(m, 9H), 5.00(s, 2H), 4.86(s, 2H), 1.13(s, 9H),
The following compounds were all made by the general alkylation procedure with the appropriate thiols made above and the alkyl halides made from either {4-({[terf-
Butyl(diphenyl)silyl]oxy}methyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methanol or {4-({[terf- Butyl(diphenyl)silyl]oxy}methyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methanol via the chlorides as described above.
Ethyl [4-({[4-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-phenyl-1,3-thiazol-5-yl1methyl}sulfanyl)-2- methylphenoxy]acetate
1H NMR (CDCI3) 400MHz δ 7.85(m, 2H), 7.68(m, 4H), 7.39(m, 9H), 7.12(d, 1 H, J=2.39 Hz), 7.03(dd, 1 H, J=8.37, 2.39 Hz), 6.50(d, 1 H, J=8.37 Hz), 4.61 (s, 2H), 4.55(s, 2H), 4.24(q, 2H, J=7.12 Hz), 4.10(s, 2H), 2.18(s, 3H), 1.26(t, 3H, J=7.12 Hz), 1.05(s, 9H), TLC(20% EtOAc/Hexanes) Rf = 0.43
Ethyl 2-{4-[({4-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-[4-(trifluoromethyl)phenyl]-1,3.thiazol-5- y methyl)sulfanyl]-2-methylphenoxy}propanoate
1H NMR (CDCy 400MHz δ 7.94(d, 2H, J=8.20 Hz), 7.67(m, 6H), 7.39(m, 6H), 7.11(d, 1 H, J=2.39 Hz), 7.00(dd, 1 H, J=8.37, 2.39 Hz), 6.49(d, 1 H, J=8.37 Hz), 4.65(m, 2H), 4.17(q, 2H, J=7.18 Hz), 4.09(s, 2H), 2.17(s, 3H), 1.60(d, 3H, J=6.84 Hz), 1.21(t, 3H, J=7.18 Hz), 1.05(s, 9H), TLC(20% EtOAc/Hexanes) Rf = 0.57
Ethyl 2-[4-({[4-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-phenyl-1 ,3-thiazol-5-yl]methyl}sulfanyl)- 2-methylphenoxy]propanoate 1H NMR (CDCI3) 400MHz δ 7.85(m, 2H), 7.68(m, 4H), 7.38(m, 9H), 7.11 (d, 1 H, J=2.39 Hz),
6.99(dd, 1 H, J=8.55, 2.39 Hz), 6.49(d, 1 H, J=8.55 Hz), 4.64(m, 3H), 4.16(q, 2H, J=7.12 Hz), 4.07(s, 2H), 2.17(s, 3H), 1.59(d, 3H, J=6.84 Hz), 1.20(t, 3H, J=7.12 Hz), 1.05(m, 9H), Ti.C(20% EtOAc/Hexanes) Rf = 0.48
Ethyl {4-[({3-({[tert-butyl(diphenyl)silyl]oxy}methyl)-5-[4-(trifluoromethyl)phenyl]-2- thienyl}methyl)sulfanyl]-2-methylphenoxy}acetate
1H NMR (CDCI3) 400MHz δ 7.94(d, 2H, J=8.20 Hz), 7.66(m, 6H), 7.38(m, 6H), 7.11 (d, 1 H, J=2.22 Hz), 7.03(dd, 1 H, J=8.37, 2.22 Hz), 6.50(d, 1H, J=8.37 Hz), 4.63(s, 2H), 4.56(s, 2H), 4.23(q, 2H, J=7.12 Hz), 4.10(s, 2H), 2.18(s, 3H), 1.27(t, 3H, J=7.12 Hz), 1.04(s, 9H), TLC(20% EtOAc/Hexanes) Rf = 0.50
Ethyl [4-({[4-(hydroxymethyl)-2-(4-{trifluoromethyl}phenyl)-1,3-thiazol-5-yl]methyl}sulfanyl)-2- methylphenoxy]acetate
1H NMR (CDCI3) 300MHz δ 7.97(d, 2H, J=8.23 Hz), 7.67(d, 2H, J=8.23 Hz), 7.22(d, 1 H, J=2.39 Hz), 7.14(dd, 1 H, J=8.23, 2.39 Hz), 6.61 (d, 1 H, J=8.23 Hz), 4.63(s, 2H), 4.50(s, 2H), 4.26(q, 2H, J=7.17 Hz), 4.18(s, 2H), 2.83(s, 1 H), 2.25(s, 3H), 1.29(t, 3H, J=7.17 Hz), TLC(50% EtOAc/Hexanes) Rf= 0.51
(4-Bromophenyl)acetyl chloride To a stirred solution of 4-bromophenyIacetic acid (10g, 46.5mmoles, 1eq) in dry CH2CI2
(100ml, 0.47M) was added thionyl chloride (20.2ml, 0.280moles, 6eq) and refluxed for 36 hours. After cooling to room temperature the reaction was concentrated in vacuo to yield 10.86g (100%) of acid chloride. H (CDCy 300MHz δ 7.50(d, 2H, J=8.38 Hz), 7.14(d, 2H, J=8.38 Hz), 4.09(s, 2H),
4-Phenylbutanoyl chloride
1H NMR (CDCy 300MHz δ 7.25(m, 5H), 2.90(t, 2H, J=7.28 Hz), 2.69(t, 2H, J=7.28 Hz), 2.05(m, 2H),
(2-Phenylethoxy)acetyl chloride
1H NMR (CDCy 300MHz δ 7.26(m, 5H), 4.39(s, 2H), 3.80(t, 2H, J=6.94 Hz), 2.93(t, 2H, J=6.94 Hz)
r4-([1,1'-Biphenyl]-4-ylmethyl)-2-(4-{trifluoromethyl}phenyl)-1,3-thiazol-5-yl]methanol To a stirred solution of [4-(4-Bromobenzyl)-2-(4-{trifluoromethyl}phenyl)-1 ,3-thiazol-5- yl]methanol (0.33g, OJδmmoles, 1eq) in dry 1 ,2-dimethoxyethane (5ml, 0.16M) was added tetrakis(triphenylphosphino) palladium I (0.45g, 0.39mmoles, 0.5eq) and stirred for 5 minutes at room temperature. Phenylboronic acid (0.143g, 1.2mmoles, 1.5eq) was then added followed by the addition of sodium carbonate (2M aqueous solution, 2.3ml, 4.68mmoles, 6eq). The reaction mixture was heated at 100 degrees centigrade for 13 hours at which point, after cooling to room temperature, the reaction was partitioned between EtOAc and water. After separation of the phases the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated in vacuo to yield after purification by silica gel chromatography (CH2CI2 to 2% MeOH/CH2Cl2) 268mg (80%) of product.
1H NMR (CDCI3) 400MHz δ 8.03(d, 2H, J=8.20 Hz), 7.67(d, 2H, J=8.20 Hz), 7.54(m, 4H), 7.36(m, 5H), 4.85(s, 2H), 4.22(s, 2H),
The following intermediate was prepared in using the same procedure:
{2-(4-{trifluoromethyl}phenyl)-4-[4-(3-thienyl)benzyl]-1,3-thiazol-5-yl}methanol
1H NMR (CDCy 400MHz δ 8.03(d, 2H, J=8.20 Hz), 7.67(d, 2H, J=8.20 Hz), 7.52(d, 2H, J=8.37 Hz), 7.35(m, 5H), 4.84(s, 2H), 4.20(s, 2H),
The following componds were made by the same prcedure for phenol alkylation.
Ethyl {2-methyl-4-[({4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-[4-(trifluoromethyl)phenyl]-1,3- thiazol-5-yl}methyl)sulfanyl]phenoxy}acetate
To a 250ml round-bottom flask equipped with a magnetic stir-bar and N2 inlet was added 5- (chloromethyl)-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazole (7.87g, 20.09mmoles, 1eq) and dry CH3CN (100ml, 0.27M). Solid cesium carbonate (16.4g, 50.22mmoles, 2.5eq) was added all at once followed by the quick addition of ethyl 2-methyl-2-(4- sulfanylphenoxy)propanoate (5.79g, 24.11 mmoles, 1.2eq) in dry CH3CN (10ml). The reaction was allowed to stir at room temperature for 2 hours at which point the solvent was removed under reduced pressure. The resulting residue was partitioned between EtOAc and 1 N NaOH. After the phases were separated the organic fraction was washed with H20, brine and dried over Na2S04. After filtration the volatiles were removed in vacuo to yield the titled compound in >100% yield. Because of the difficult separation between the thiophenol and the product, the crude product was carried forward without purification.
4-[({4-(Bromomethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2- methylphenol 1H NMR (CDCI3) 400MHz δ 8.01 (d, 2H, J=8.10 Hz), 7.68(d, 2H, J=8.10 Hz), 7.17(d, 1 H,
J=2.41 Hz), 7.08(dd, 1 H, J=8.10, 2.41 Hz), 6.67(d, 1 H, J=8.10 Hz), 4.63(s, 2H), 4.14(s, 2H),
Ethyl Σ^-^^^^-methoxyphenyO-l iperazinyllmethyll-Σ-^-ftrifluoromethyQphenylJ-l^ th_iazol-5-yl}methyl)sulfanyllphenoxy}-2-methylpropanoate To a 500ml 3-neck round-bottom flask equipped with a magnetic stir-bar, low temperature thermometer with thermometer adapter, addition funnel and N2 inlet was added ethyl 2-{4-[({4- (hydroxymethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}-2- methylpropanoate (16g, 31.28mmoles, 1eq) and dry CH2CI2 (120ml, 0.26M) and cooled to 0°C. Methanesulfonyl chloride (2.91 ml, 37.54mmoles, 1.2eq) was added neat all at once. Triethylamine (6.6ml, 46.92mmoles, 1.5eq) was added dropwise over 20 minutes maintaining the internal temperature below 5°C and was stirred at 0°C for 30 minutes. The reaction mixture was transferred to a separatory funnel and washed with H20, brine and the organic fraction was dried over Na2S04.
After filtration the solvent was removed under reduced pressure to yield the corresponding mesylate in quantitative yield. Because of the unstable nature of the mesylate, the product was not characterized and was progressed onto the next stage without purification.
To the crude mesylate dissolved in dry THF (200ml, 0.16M) was added 4-methoxyphenyl piperazins (13g, 62.56mmoles, 2eq) and the reaction mixture was refluxed for .5 hours. After cooling to room temperature the solvent was removed in vacuo to yield a yellow solid residue. The residue was washed with a minimal amount of EtOAc and filtered through Celite to remove the 4- methoxyphenyl piperazine hydrochloride salt. The EtOAc was removed in vacuo and the resulting solid was filtered through a "plug" of silica gel using 30% EtOAc/Hexanes to yield 20.37g (95%)of a light-yellow solid.
1H NMR (CDCI3) 400MHz δ 7.96(d, 2H, J=8.24 Hz), 7.63(d, 2H, J=8.24 Hz), 7.27(d, 2H, J=8.79 Hz), 6.87(d, 2H, J=9.16 Hz), 6.80(d, 2H, J=9.16 Hz), 6.74(d, 2H, J=8.79 Hz), 4.32(s, 2H), 4.17(q, 2H, J=7.14 Hz), 3.73(s, 3H), 3.56(s, 2H), 3.06(br s, 4H), 2.59(br s, 4H), 1.55(s, 6H), 1.21 (t, 3H, J=7.14 Hz), HPLC (C-18, 3μm) 0%-95% Acetonitrile/Water over 8 minutes Rt= 6.06minutes
The follow intermediates were made using the same alkylation conditions:
4-[({4-{[4-(4-Methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyi)sulfanyl]-2-methylphenol
1H NMR (CDCI3) 400MHz δ 7.94(d, 2H, J=8.10 Hz), 7.64(d, 2H, J=8.10 Hz), 7.16(d, 1 H, J=2.07 Hz), 7.07(dd, 1 H, J=8.10, 2.07 Hz), 6.86(m, 2H), 6.80(d, 2H, J=8.97 Hz), 6.66(d, 1 H, J=8.10 Hz), 4.27(s, 2H), 3.73(s, 3H), 3.59(s, 2H), 3.15(br s, 4H), 2.67(br s, 4H), 2.16(s, 3H),
Ethyl [2-methyl-4-({[2-(4-{trifluoromethyl}phenyl)-4-(4-morpholinylmethyl)-1,3-thiazol-5- yl]methyl}sulfanyl)phenoxy]acetate
1H NMR (CDCy 300MHz δ 8.02(d, 2H, J=8.23 Hz), 7.69(d, 2H, J=8.23 Hz), 7.27(m, 1 H), 7.17(dd, 1 H, J=8.23, 2.39 Hz), 6.62(d, 1 H, J=8.23 Hz), 4.64(s, 2H), 4.36(s, 2H), 4.25(q, 2H, J=7.17 Hz), 3.72(t, 4H, J=4.51 Hz), 3.53(s, 2H), 2.48(t, 4H, J=4.51 Hz), 2.27(s, 3H), 1.32(t, 3H, J=7.17 Hz), TLC(50% EtOAc/Hexanes) Rf= 0.26
Ethyl [4-({[4-[(4-benzyl-1 -piperazinyl)methyl]-2-(4-{trifluoromethyl}phenyl)-1 ,3-thiazol-5- vnmethyl}sulfanyl)-2-methylphenoxy]acetate
1H NMR (CDCy 300MHz δ 8.02(d, 2H, J=8.76 Hz), 7.68(d, 2H, J=8J6 Hz), 7.31 (m, 6H), 7.16(dd, 1 H, J=8.49, 2.39 Hz), 6.62(d, 1 H, J=8.49 Hz), 4.63(s, 2H), 4.35(s, 2H), 4.27(q, 2H, J=7.17 Hz), 3.54(m, 4H), 2.51 (br s, 8H), 2.27(s, 3H), 1.32(t, 3H, J=7.17 Hz), TLC(50% EtOAc/Hexanes)= 0.19
Ethyl 2-{4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl1-1,3- thiazoi-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoate
1H NMR (CDCy 400MHz δ7.99(d, 2H, J=8.20 Hz), 7.66(d, 2H, J=8.20 Hz), 7.23(d, 1 H, J=2.39 Hz), 7.13(dd, 1 H, J=8.37, 2.39 Hz), 6.89(d, 2H, J=9.23 Hz), 6.83(d, 2H, J=9.23 Hz), 6.57(d, 1 H, J=8.37 Hz), 4.70(q, 1 H, J=6.84 Hz), 4.34(s, 2H), 4.17(q, 2H, J=7.18 Hz), 3.76(s, 3H), 3.58(s, 2H), 3.09(m, 4H), 2.63(m, 4H), 2.24(s, 3H), 1.62(d, 3H, J=6.84 Hz), 1.21(t, 3H, J=7.18 Hz),
TLC(30% EtOAc/Hexanes)= 0.29
Ethyl {2-methyl-4-[({2-(4-{trifluoromethyl}phenyl)-4-[(4-phenyl-1-piperazinyl)methyl]-1,3-thiazol- 5-yl}methyl)sulfanyl]phenoxy}acetate
1H NMR (CDCI3) 300MHz δ 8.04(d, 2H, J=8.23 Hz), 7.70(d, 2H, J=8.23 Hz), 7.29(m, 3H), 7.21 (dd, 1 H, J=8.23, 2.39 Hz), 6.92(m, 3H), 6.63(d, 1 H, J=8.23 Hz), 4.64(s, 2H), 4.38(s, 2H), 4.27(q, 2H, J=7.17 Hz), 3.63(s, 2H), 3.21 (m, 4H), 2.66(m, 4H), 2.28(s, 3H), 1.32(t, 3H, J=7.17 Hz), TLC(50% EtOAc/Hexanes) Rf = 0.52
Ethyl 4"{[5-({[4-(2-ethoxy-2-oxoethoxy)-3-methylphenyl]sulfanyl}methyl)-2 (4- {trifluoromethyl}phenyl)-1,3-thiazol-4-yl]methyl}-1-piperazinecarboxylate 1H NMR (CDCI3) 300MHz δ 7.99(d, 2H, J=8.23 Hz), 7.68(d, 2H, J=8.23 Hz), 7.25(m, 1 H),
7.17(dd, 1 H, J=8.49, 2.12 Hz), 6.61 (d, 1 H, J=8.49 Hz), 4.64(s, 2H), 4.28(m, 4H), 4.14(t, 2H, J=7.17 Hz), 3.50(m, 6H), 2.44(br s, 4H), 2.26(s, 3H), 1.29(t, 3H, J=7.17 Hz), TLC(50% EtOAc/Hexanes) Rf = 0.17
Ethyl {2-methyl-4-[({2-(4-{trifluoromethyl}phenyl)-4-[(4-phenyl-1-piperidinyl)methyl]-1,3-thiazol- 5-yl}methyl)sulfanyl]phenoxy}acetate H NMR (CDCl3) 300MHz δ 8.04(d, 2H, J=8.23 Hz), 7.70(d, 2H, J=8.23 Hz), 7.27(m, 7H), 6.64(d, 1 H, J=8.49 Hz), 4.64(s, 2H), 4.41 (s, 2H), 4.28(q, 2H, J=7.17 Hz), 3.60(s, 2H), 3.02(m, 2H), 2.53(m, 1 H), 2.30(s, 3H), 2.18(m, 2H), 1.84(m, 4H), 1.32(t, 3H, J=7.17 Hz), TLC(50% EtOAc/Hexanes) Rf = 0.48
Ethyl {2-methyl-4-[({2-(4-{trifluoromethyl}phenyl)-4-[(4-methyl-1-piperidinyl)methyl]-1,3-thiazol- 5-yl}methyl)sulfanyl]phenoxy}acetate H NMR (CDCl3) 300MHz δ 8.02(d, 2H, J=8.23 Hz), 7.68(d, 2H, J=8.23 Hz), 7.28(d, 1 H, J=2.39 Hz), 7.19(dd, 1 H, J=8.49, 2.39 Hz), 6.62(d, 1 H, J=8.49 Hz), 4.64(s, 2H), 4.38(s, 2H), 4.28(q, 2H, J=7.17 Hz), 3.51 (s, 2H), 2.84(m, 4H), 2.28(s, 3H), 2.02(m, 4H), 1.61(m, 4H), 1.30(m, 8H), 0.94(d, 3H, J=6.11 Hz),
TLC(50% EtOAc/Hexanes) Rf = 0.36
Ethyl (2-methyl-4-{[(2-(4-{trifluoromethyl}phenyl)-4-{[4-(2-methylphenyl)-1-piperazinyl]jττgthyl]^ 1J3-thiazol-5-yl)methyl]sulfanyl}phenoxy)acetate 1H (CDCI3) 400MHz δ 7.99(d, 2H, J=8.20 Hz), 7.66(d, 2H, J=8.20 Hz), 7.25(m, 1 H), 7.16(m, 3H), 6.98(m, 2H), 6.60(d, 1 H, J=8.55 Hz), 4.60(s, 2H), 4.37(s, 2H), 4.23(q, 2H, J=7.12 Hz), 3.59(s, 2H), 2.93(s, 4H), 2.63(s, 4H), 2.29(s, 3H), 2.24(s, 3H), 1.27(t, 5H, J=7.12 Hz),
TLC(50% EtOAc/Hexanes) Rf = 0.73
Ethyl [4-({[4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-(4-{trifluoromethyl}phenyl)-1,3- thiazol-5-yl]methyl}sulfanyl)-2-methylphenoxy]acetate H (CDCI3) 400MHz δ 7.99(d, 2H, J=8.20 Hz), 7.65(d, 2H, J=8.20 Hz), 7.24(dd, 1 H, J=2.39 Hz), 7.16(dd, 1 H, J=8.37, 2.39 Hz), 6.84(m, 4H), 6.58(d, 1 H, J=8.37 Hz), 4.59(s, 2H), 4.33(s, 2H), 4.23(q, 2H, J=7.18 Hz), 3.75(s, 3H), 3.57(s, 2H), 3.07(m, 4H), 2.62(s, 4H), 2.24(s, 3H), 1.27(t, 3H, J=7.18 Hz),
TLC(50% EtOAc/Hexanes) Rf = 0.44
Ethyl (2-methyl-4-{[(2-(4-{trifluoromethyl}phenyl)-4-{[4-(3-methylphenyl)-1-piperazinyl]methyl}- 1,3-thiazol-5-yl)methyl]sulfanyl}phenoxy)acetate
1H (CDCI3) 400MHz δ 7.99(d, 2H, J=8.20 Hz), 7.66(d, 2H, J=8.20 Hz), 7.24(m, 1 H), 7.14(m, 2H), 6.70(s, 3H), 6.59(d, 1 H, J=8.55 Hz), 4.60(s, 2H), 4.33(s, 2H), 4.23(q, 2H, J=7.12 Hz), 3.57(s, 2H), 3.16(br s, 4H), 2.62(br s, 4H), 2.30(s, 3H), 2.24(s, 3H), 1.26(t, 3H, J=7.12 Hz),
TLC(50% EtOAc/Hexanes) Rf = 0.64
Ethyl (2-methyl-4-{[(2-(4-{trifluoromethyl}phenyl)-4-{[4-(4-methylphenyl)-1-piperazinyl]methyl}- 1,3-thiazol-5-yl)methyl]sulfanyl}phenoxy)acetate
1H (CDCI3) 400MHz δ 7.99(d, 2H, J=8.20 Hz), 7.65(d, 2H, J=8.20 Hz), 7.24(d, 1 H, J=2.39 Hz), 7.15(dd, 1 H, J=8.37, 2.39 Hz), 7.04(d, 2H, J=8.55 Hz), 6.82(d, 2H, J=8.55 Hz), 6.58(d, 1 H, J=8.37 Hz), 4.60(s, 2H), 4.32(s, 2H), 4.23(q, 2H, J=7.12 Hz), 3.57(s, 2H), 3.10(s, 4H), 2.60(s, 4H), 2.26(s, 3H), 2.23(s, 3H), 1.26(t, 3H, J=7.12 Hz),
TLC(50% EtOAc/Hexanes) Rf = 0.64
Ethyl [4-({[4-{[4-(2-furoyl)-1-piperazinyl]methyl}-2-(4-{trifluoromethyl}phenyl)-1,3-thiazol-5- yl]methyl}sulfanyl)-2-methylphenoxy]acetate
1H (CDCy 400MHz δ 7.98(d, 2H, J=8.20 Hz), 7.65(d, 2H, J=8.20 Hz), 7.46(m, 1 H), 7.22(d, 1 H, J=2.39 Hz), 7.13(dd, 1 H, J=8.37, 2.39 Hz), 6.96(d, 1 H, J=3.42 Hz), 6.59(d, 1 H, J=8.37 Hz), 6.46(m, 1 H), 4.62(s, 2H), 4.29(s, 2H), 4.21 (q, 2H, J=7.12 Hz), 3.80(s, 4H), 3.50(s, 2H), 2.53(s, 4H), 2.23(s, 3H), 1.26(t, 3H, J=7.18 Hz), TLC(50% EtOAc/Hexanes) Rf = 0.06
Ethyl (2-methyl-4-{[(2-(4-{trifluoromethyl}phenyl)-4-{[4-(2-pyridinyl)-1-piperazinyl]methyj}: ;3: thiazol-5-yl)methyl]sulfanyl}phenoxy)acetate
1H (CDCy 400MHz δ 8.16(m, 1 H), 7.98(d, 2H, J=8.20 Hz), 7.63(d, 2H, J=8.20 Hz), 7.45(s, 1 H), 7.25(d, 1 H, J=2.22 Hz), 7.15(dd, 1 H, J=8.37, 2.22 Hz), 6.56(m, 3H), 4.60(s, 2H), 4.33(s, 2H), 4.21 (q, 2H, J^7.12 Hz), 3.53(m, 6H), 2.57(s, 4H), 2.23(s, 3H), 1.27(t, 3H, J=7.12 Hz), TLC(50% EtOAc/Hexanes) R, = 0.25
Ethyl [4-({[4-{[4-(4-chlorobenzyl)-1-piperazinyl]methyl}-2-(4-{trifluoromethyl}phenyl)-1,3-thiazol- 5-yl]methyl}sulfanyl)-2-methylphenoxy]acetate 1H (CDCI3) 400MHz δ 7.96(d, 2H, J=8.20 Hz), 7.64(d, 2H, J=8.20 Hz), 7.25(m, 5H), 7.13(dd,
1 H, J=8.37, 2.39 Hz), 6.58(d, 1 H, J=8.37 Hz), 4.59(s, 2H), 4.31(s, 2H), 4.22(q,"2H, J=7.18 Hz), 3.52(s, 2H), 3.42(s, 2H), 2.48(br s, 8H), 2.20(s, 3H), 1.26(t, 3H, J=7.18 Hz), TLC(50% EtOAc/Hexanes) Rf = 0.23
Ethyl [4-({[4-{[4-(4-acetylphenyl)-1-piperazinyl]methyl}-2-(4-{trifluoromethyl}phenyl)-1,3-thiazol- 5-yl]methyl}sulfanyl)-2-methylphenoxy]acetate
1H (CDCy 400MHz δ 7.98(d, 2H, J=8.20 Hz), 7.85(d, 2H, J=9.06 Hz), 7.66(d, 2H, J=8.20 Hz), 7.24(d, 1 H, J=2.39 Hz), 7.16(dd, 1 H, J=8.20, 2.39 Hz), 6.84(d, 2H, J=9.06 Hz), 6.58(d, 1 H, J=8.20 Hz), 4.61 (s, 2H), 4.31 (s, 2H), 4.22(q, 2H, J=7.18 Hz), 3.58(s, 2H), 3.33(br s, 4H), 2.60(br s, 4H), 2.50(m, 3H), 2.24(s, 3H), 1.27(t, 3H, J=7.18 Hz), TLC(50% EtOAc/Hexanes) Rf = 0.23
Ethyl [4-({[4-{[4-(2-hydroxyethyl)-1-piperazinyl]methyl}-2-(4-{trifluoromethyl}phenyl)-1,3-thiazol- 5-yl]methyl}sulfanyl)-2-methylphenoxy]acetate 1H (CDCy 400MHz δ 7.97(d, 2H, J=8.20 Hz), 7.64(d, 2H, J=8.20 Hz), 7.23(d, 1 H, J=2.22
Hz), 7.14(dd, I H, J=8.37, 2.22 Hz), 6.58(d, 1 H, J=8.37 Hz), 4.60(s, 2H), 4.30(s, 2H), 4.22(q, 2H, J=7.12 Hz), 3.60(m, 2H), 3.50(s, 2H), 2.94(s, 1 H), 2.53(m, 10H), 2.23(s, 3H), 1.26(t, 3H, J=7.12 Hz),
Ethyl (2-methyl-4-{[(2-(4-{trifluoromethyl}phenyl)-4-{[(3-pyridinylmethyl)amino]methyl}-1,3- thiazol-5-yl)methyl]sulfanyl}phenoxy)acetate
1H (CDCI3) 400MHz δ 8.55(m, 1 H), 8.50(m, 1 H), 7.98(d, 2H, J=8.20 Hz), 7.71 (m, 1 H), 7.65(m, 2H), 7.24(m, 1 H), 7.17(m, 1 H), 7.10(m, 1 H), 6.55(d, 1 H, J=8.37 Hz), 4.58(s, 2H), 4.22(q, 2H, J=7.12 Hz), 4.12(s, 2H), 3.77(s, 2H), 3.63(s, 2H), 2.64(br s, 1 H), 2.21(s, 3H), 1.27(t, 3H, J=7.12 Hz),
Ethyl (4-{[(4-{[4-(4-methoxyphenyl)-1 -piperazinyl]methyl}-2-phenyl-1 ,3-thiazol-5- yl)methyl]sulfanyl}-2-methylphenoxy)acetate H NMR (CDCy 400MHz δ7.88(m, 2H), 7.40(m, 3H), 7.25(d, 1 H, J=2.39 Hz), 7.17(dd, 1 H, J=8.37, 2.39 Hz), 6.89(d, 2H, J=9.06 Hz), 6.81 (d, 2H, J=9.06 Hz), 6.58(d, 1 H, J=8.37 Hz), 4.59(s, 2H), 4.32(s, 2H), 4.23(q, 2H, J=7.12 Hz), 3.74(s, 3H), 3.56(s, 2H), 3.06(m, 4H), 2.62(m, 4H), 2.24(s, 3H), 1.27(t, 3H, J=7.12 Hz),
Ethyl 2-(4-{[(4-{[4-(4-methoxyphenyl)-1 -piperazinyl]methyl}-2-phenyl-1 ,3-thiazol-5- y|)methyl]sulfanyl}-2-methylphenoxy)propanoate H NMR (CDCI3) 400MHz δ7.88(m, 2H), 7.40(m, 3H), 7.25(d, 1 H, J=2.39 Hz), 7.14(dd, 1 H, J=8.37, 2.39 Hz), 6.89(d, 2H, J=9.40 Hz), 6.82(d, 2H, J=9.40 Hz), 6.57(d, 1 H, J=8.37 Hz), 4.70(q, 1 H, J=6.84 HZ), 4.32(s, 2H), 4.17(q, 2H, J=7.18 Hz), 3.76(s, 3H), 3.56(s, 2H), 3.08(m, 4H), 2.63(m, 4H), 2.23(m, 3H), 1.61 (d, 3H, J=6.84 Hz), 1.25(t, 3H, J=7.18 Hz),
Ethyl {2-methyl-4-[({2-(4-{trifluoromethyl}phenyl)-4-[(pentylamino)methyl]-1,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}acetate
1H (CDCI3) 400MHz δ 7.97(d, 2H, J=8.20 Hz), 7.65(d, 2H, J=8.20 Hz), 7.20(d, 1H, J=2.39 Hz), 7.12(dd, 1 H, J=8.37, 2.39 Hz), 6.58(d, 1 H, J=8.37 Hz), 4.60(s, 2H), 4.23(q, 2H, J=7.18 Hz), 4.18(s, 2H), 3.64(s, 2H), 2.58(t, 2H, J=6.92 Hz), 2.22(s, 3H), 1.50(m, 2H), 1.28(m, 7H), 0.87(t, 3H, J=6.92 Hz),
Ethyl 2-{4-[({4-{[4-(4-hydroxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3- thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoate
1H NMR (CDCI3) 300MHz δ 8.08(d, 2H, J=8.28 Hz), 7.75(d, 2H, J=8.28 Hz), 7.27(d, 1 H, J=2.21 Hz;, 7 17(dd, 1 H, J=8.28, 2.21 Hz), 6.87(d, 2H, J=8.83 Hz), 6.73(d, 2H, J=8.83 Hz), 6.66(d, 1 H, J=8.28 Hz), 4.83(q, 1 H, J=6.81 Hz), 4.34(s, 2H), 4.15(q, 2H, J=7.08 Hz), 3.47(s, 2H), 3.00(t, 4H, J=4.83 Hz), 2.57(t, 4H, J=4.83 Hz), 2.20(s, 3H), 1.57(d, 3H, J=6.81 Hz), 1.20(t, 3H, J=7.08 Hz),
Ethyl 2-{4-[({4-{[4-(3,4-dimethoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]- 1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoate H NMR (CDCy 300MHz δ 8.06(d, 2H, J=8.28 Hz), 7.72(d, 2H, J=8.28 Hz), 7.26(d, 1 H,
J=2.21 Hz), 7.16(dd, 1 H, J=8.55, 2.21 Hz), 6.82(d, 1 H, J=8.55 Hz), 6.64(m, 2H), 6.47(dd, 1 H, J=8.55, 2.21 Hz), 4.81 (q, 1 H, J=6.99 Hz), 4.34(s, 2H), 4.14(q, 2H, J=7.17 Hz), 3.82(s, 3H), 3.77(s, 3H), 3.52(s, 2H), 3.07(t, 4H, J=4.55 Hz), 2.63(t, 4H, J=4.55 Hz), 2.20(s, 3H), 1.57(d, 3H, J=6.99 Hz), 1.18(t, 3H, J=7.17 Hz),
Ethyl 2-(4-{[(4-{[4-(4-methoxyphenyl)-1 -piperazinyl]methyl}-2-phenyl-1 ,3-thiazol-5- yl)methyl]sulfanyl}phenoxy)-2-methylpropanoate
1H NMR (CDCI3) 400MHz δ 7.87(m, 2H), 7.40(m, 3H), 7.28(d, 2H, J=8.°y Hz), 6.89(d, 2H, J=9.23 Hz), 6.82(d, 2H, J=9.23 Hz), 6.75(d, 2H, J=8.89 Hz), 4.33(s, 2H), 4.19(q, 2H, J=7.18 Hz), 3.76(s, 3H), 3.56(s, 2H), 3.09(br s, 4H), 2.65(br s, 4H), 1.58(s, 6H), 1.20(t, 3H, J=7.18 Hz),
Ethyl {4-[({4-{[4-(4-methoxyphenyl)-1 -piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1 ,3- thiazol-5-yl}methyl)sulfanyl]phenoxy}acetate
1H NMR (CDCy 400MHz δ7.99(d, 2H, J=8.20 Hz), 7.66(d, 2H, J=8.20 Hz), 7.35(d, 2H, J=8.89 Hz), 6.88(d, 2H, J=9.40 Hz), 6.83(m, 4H), 4.58(s, 2H), 4.34(s, 2H), 4.24(q, 2H, J=7.18 Hz), 3.76(s, 3H), 3.57(s, 2H), 3.08(m, 4H), 2.63(m, 4H), 1.27(t, 3H, J=7.18 Hz),
Ethyl 2-{4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-l!3 thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoate 1H NMR (CDCy 400MHz δ 7.99(d, 2H, J=8.20 Hz), 7.66(d, 2H, J=8.20 Hz), 7.32(d, 2H,
J=8.89 Hz), 6.89(d, 2H, J=9.23 Hz), 6.83(d, 2H, J=9.23 Hz), 6.79(d, 2H, J=8.89 Hz), 4.70(q, 1 H, J=6.78 Hz), 4.33(s, 2H), 4.16(q, 2H, J=7.09 Hz), 3.75(s, 3H), 3.57(s, 2H), 3.08(m, 4H), 2.63(m, 4H), 1.60(d, 3H, J=6.78 Hz), 1.24(t, 3H, J=7.09 Hz),
Ethyl 2-(4-{[(4-{[4-(4-methoxyphenyl)-1 -piperazinyl]methyl}-2-phenyl-1 ,3-thiazol-5- yl)methyl]sulfanyl}phenoxy)propanoate
1H NMR (CDCI3) 400MHz j57.87(m, 2H), 7.39(m, 3H), 7.32(d, 2H, J=8.85 Hz), 6.87(d, 2H, J=9.06 Hz), 6.82(d, 2H, J=9.06 Hz), 6.77(d, 2H, J=8.85 Hz), 4.69(q, 1H, J=6.78 Hz), 4.31 (s, 2H), 4.18(q, 2H, J=7.12 Hz), 3.75(s, 3H), 3.54(s, 2H), 3.08(m, 4H), 2.62(m, 4H), 1.59(d, 3H, J=6J8 Hz), 1.20(t, 3H, J=7.12 Hz),
Ethyl 2-{4-[({4-{[4-(3-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3- thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}-2-methylpropanoate H NMR (CDCy 400MHz δ 7.96(d, 2H, J=8.28 Hz), 7.63(d, 2H, J=8.28 Hz), 7.21 (d, 1H, J=2.41 Hz), 7.13(t, 1 H, J=8.10 Hz), 7.07(dd, 1 H, J=8.45, 2.41 Hz), 6.53(m, 2H), 6.43(t, 1 H, J=2.24 Hz), 6.38(dd, 1 H, J=8.10, 2.24 Hz), 4.31 (s, 2H), 4.18(q, 2H, J=7.16 Hz), 3.75(s, 3H), 3.55(s, 2H), 3.16(t, 4H, J=4.83 Hz), 2.58(t, 4H, J=4.83 Hz), 2.17(s, 3H), 1.57(s, 6H), 1.22(t, 3H, J=7.16 Hz),
Ethyl 2-{4-[({4-{[4-(4-fluorophenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3- thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}-2-methylpropanoate 1H NMR (CDCI3) 400MHz δ 7.96(d, 2H, J=8.28 Hz), 7.62(d, 2H, J=8.28 Hz), 7.21(d, 1H,
J=2.41 Hz), 7.06(dd, 1 H, J=8.45, 2.41 Hz), 6.91 (m, 2H), 6.83(m, 2H), 6.53(d, 1 H. J=8.45 Hz), 4.30(s, 2H), 4. i3(q, 2H, J=7.16 Hz), 3.55(s, 2H), 3.06(t, 4H, J=4.66 Hz), 2.57(t, 4H, J=4.66 Hz), 2.15(s, 3H), 1.55(s, 6H), 1.21(t, 3H, J=7.16 Hz),
Ethyl 2-{4-[({4-{[4-(3-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3- thiazol-5-yl}methyl)sulfanyllphenoxy}-2-methylpropanoate
1H NMR (CDCI3) 400MHz δ 7.96(d, 2H, J=8.10 Hz), 7.63(d, 2H, J=8.10 Hz), 7.26(d, 2H, J=8.79 Hz), 7.14(t, 1H, J=8.28 Hz), 6.74(d, 2H, J=8.79 Hz), 6.51(dd, 1 H, J=8.28, 2.24 Hz), 6.43(t, 1 H, J=2.24 Hz), 6.39(dd, 1H, J=8.28, 2.24 Hz), 4.31(s, 2H), 4.16(q, 2H, J=7.07 Hz), 3.74(s, 3H), 3.54(s, 2H), 3.17(t, 4H, J=4.66 Hz), 2.58(t, 4H, J=4.66 Hz), 1.56(s, 6H), 1.20(t, 3H, J=7.07 Hz),
Ethyl 2-{4-[({4-{[4-(4-chlorophenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3- thiazol-5-yl}methyl)sulfanyl]phenoxy}-2-methylpropanoate
1H NMR (CDCy 400MHz δ 7.96(d, 2H, J=8.10 Hz), 7.63(d, 2H, J=8.10 Hz), 7.27(d, 2H, J=8.79 Hz), 7.15(d, 2H, J=9.14 Hz), 6.80(d, 2H, J=9.14 Hz), 6.73(d, 2H, J=8.79 Hz), 4.30(s, 2H), 4.17(q, 2H, J=7.16 Hz), 3.54(s, 2H), 3.12(t, 4H, J=4.74 Hz), 2.57(m, 4H), 1.55(s 6H), 1.17(t, 3H, J=7.16 Hz),
Ethyl 2-{4-[({4-{[4-(4-acetylphenyl)-1-piperazinyl]methyl}-2-r4-(trifluoromethyl)phenyl]-1,3- thiazol-5-yl}methyl)sulfanyl]phenoxy}-2-methylpropanoate 1H NMR (CDCy 400MHz δ 7.95(d, 2H, J=8.28 Hz), 7.83(d, 2H, J=9.14 Hz), 7.62(d, 2H, J=8.28 Hz), 7.26(d, 2H, J=8.62 Hz), 6.82(d, 2H, J=9.14 Hz), 6.73(d, 2H, J=8.62 Hz), 4.29(s, 2H), 4.17(q, 2H, J=7.07 Hz), 3.53(s, 2H), 3.32(t, 4H, J=4.66 Hz), 2.57(br s, 4H), 2.48(s, 3H), 1.55(s, 6H), 1.17(t, 3H, J=7.07 Hz),
Ethyl 2-{4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3- thiazol-5-yl}methyl)sulfanyl]phenoxy}-2-methylpropanoate
1H NMR (CDCI3) 400MHz δ 7.96(d, 2H, J=8.28 Hz), 7.63(d, 2H, J=8.28 Hz), 7.26(d, 2H, J=8J9 Hz), 6.87(d, 2H, J=9.14 Hz), 6.81 (d, 2H, J=9.14 Hz), 6.73(d, 1 H, J=8.79 Hz), 4.32(s, 2H), 4.17(q, 2H, J=7.16 Hz), 3.73(s, 3H), 3.54(s, 2H), 3.06(t, 4H, J=4.83 Hz), 2.60(br s, 4H), 1.55(s, 6H), 1.20(t, 3H, J=7.16 Hz),
Ethyl 2-(4-{[(2-(4-fluorophenyl)-4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-1,3-thiazol-5- yl)methyl]sulfanyl}-2-methylphenoxy)-2-methylpropanoate 1H NMR (CDCy 400MHz δ 7.84(m, 2H), 7.20(d, 1 H, J=2.20 Hz), 7.07(m, 3H), 6.87(d, 2H,
J=9.16 Hz), 6.81 (d, 2H, J=9.16 Hz), 6.54(d, 1 H, J=8.42 Hz), 4.29(s, 2H), 4.19(q, 2H, J=7.14 Hz), 3.75(s, 3H), 3.54(s, 2H), 3.07(t, 4H, J=4.76 Hz), 2.61 (br s, 4H), 2.15(s, 3H), 1.54(s, 6H), 1.21 (t, 3H, J=7.14 Hz),
Ethyl 2-[4-({[4-{[4-(4-acetylphenyl)-1 -piperazinyl]methyl}-2-(4-fluorophenyl)-1 ,3-thiazol-5- yl]methyl}sulfanyl)-2-methylphenoxy]-2-methylpropanoate
1H NMR (CDCI3) 400MHz δ 7.84(m, 4H), 7.20(d, 1 H, J=2.38 Hz), 7.07(m, 3H), 6.83(d, 2H, J=9.16 Hz), 6.53(d, 1 H, J=8.42 Hz), 4.28(s, 2H), 4.18(q, 2H, J=7.14 Hz), 3.53(s, 2H), 3.33(t, 4H, J=4.58 Hz), 2.58(br s, 4H), 2.48(s, 3H), 2.16(s, 3H), 1.58(s, 6H), 1.23(t, 3H, J=7.14 Hz),
Ethyl 2-(4-{[(2-(4-fluorophenyl)-4-{[4-(3-methoxyphenyl)-1-piperazinyl]methyl}-1,3-thiazol-5- yl)methyl]sulfanyl}-2-methylphenoxy)-2-methylpropanoate
1H NMR (CDCI3) 400MHz δ 7.85(m, 2H), 7.20(d, 1 H, J=2.38 ), 7.14(t, 1 H, J=8.24 Hz), 7.07(m, 3H), 6.53(m, 2H), 6.44(t, 1 H, J=2.29 Hz), 6.39(dd, 1 H, J=8.06, 2.38 Hz), 4.29(s, 2H), 4.19(q, 2H, J=7.14 Hz), 3.76(s, 3H), 3.53(s, 2H), 3.17(t, 4H, J=4.67 Hz), 2.59(br s, 4H), 2.16(s, 3H), 1.55(s, 6H), 1.21(t, 3H, J=7.14 Hz),
Ethyl 4-{[5-({[4-(2-ethoxy-1 ,1 -dimethyl-2-oxoethoxy)-3-methylphenyl]sulfanyl}methyl)-2-(4- fluorophenyl)-1,3-thiazol-4-yl]methyl}-1-piperazinecarboxylate 1H NMR (CDCI3) 400MHz δ 7.82(m, 2H), 7.18(d, 1 H, J=2.38 Hz), 7.06(m, 3H), 6.53(d, 1 H,
J=8.61 Hz), 4.25(s, 2H), 4.19(q, 2H, J=7.14 Hz), 4.10(q, 2H, J=7.08 Hz), 3.45(m, 6H), 2.40(br s, 4H), 2.16(s, 3H), 1.55(s, 6H), 1.21 (m, 6H),
Ethyl 2-{4-[({4-{[4-(4-methoxyphenyl)-1^iperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-lJ3= thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}-2-methylpropanoate 1H NMR (CDCl3) 400MHz δ 7.96(d, 2H, J=8.28 Hz), 7.63(d, 2H, J=8.28 Hz), 7.21 (d, 1 H, J=2.24 Hz), 7.07(dd, 1 H, J=8.45, 2.24 Hz), 6.86(d, 2H, J=9.14 Hz), 6.80(d, 2H, J=9.14 Hz), 6.53(d, 1 H, J=8.45 Hz), 4.31 (s, 2H), 4.17(q, 2H, J=7.16 Hz), 3J2(s, 3H), 3.55(s, 2H), 3.05(t, 4H, J=4.66 Hz), 2.59(t, 4H, J=4.66 Hz), 2.16(s, 3H), 1.55(s, 6H), 1.20(t, 3H, J=7.16 Hz),
Ethyl 2-{4-[({4-{[4-(4-acetylphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1t3- thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}-2-methylpropanoate H NMR (CDCI3) 400MHz δ 7.95(d, 2H, J=8.10 Hz), 7.82(d, 2H, J=8.97 Hz), 7.62(d, 2H, J=8.10 Hz), 7.19(d, 1 H, J=2.41 Hz), 7.06(dd, 1 H, J=8.45, 2.41 Hz), 6.82(d, 2H, J=8.97 Hz), 6.52(d, 1 H, J=8.45
Figure imgf000051_0001
Hz), 2.54(t, 4H, J=4.66 Hz), 2.47(s, 3H), 2.14(s, 3H), 1.55(s, 6H), 1.18(t, 3H, J=7.07 Hz),
Ethyl 2-{4-[({4-[(4-acetyl-1-piperazinyl)methyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]-2-methylphenoxy}propanoate 1H NMR (CDCI3) 300MHz δ 8.00(d, 2H, J=8.23 Hz), 7.68(d, 2H, J=8.23 Hz), 7.27(d, 1 H,
J=2.39 Hz), 7.14(dd, 1 H, J=8.23, 2.39 Hz), 6.59(d, 1 H, J=8.23 Hz), 4J3(q, 1 H, J=6.72 Hz), 4.30(s, 2H), 4.20(q, 2H, J=7.17 Hz), 3.65(t, 2H, J=4.65 Hz), 3.54(s, 2H), 3.45(t, 2H, J=4.65Hz), 2.48(t, 4H, J=4.65 Hz), 2.26(s, 3H), 2.09(s, 3H), 1.65(d, 3H, J=6.72 Hz), 1.25(dd, 3H, J=7.17 Hz),
2-Methyl-2-{4-[({4-{[4-(phenoxycarbonyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]- 1 ,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic acid
1H NMR (CDCy 400MHz δ 7.95(d, 2H, J=8.28 Hz), 7.65(d, 2H, J=8.28 Hz), 7.33(m, 2H), 7.26(d, 2H, J=8.79 Hz), 7.17(t, 1 H, J=7.59 Hz), 7.06(d, 2H, J=7.59 Hz), 6.74(d, 2H, J=8.79 Hz), 4.32(s, 2H), 4.18(q, 2H, J=7.07 Hz), 3.61 (m, 6H), 2.51 (br s, 4H), 1.57(s, 6H), 1.20(t, 3H, J=7.07 Hz),
tert-Butyl 4-({5-({[4-(2-ethoxy-1 ,1 -dimethyl-2-oxoethoxy)phenyl]sulfanyl}methyl)-2-[4- (trifluoromethyl)phenyl]-1 ,3-thiazol-4-yl}methyl)-1-piperazinecarboxylate H NMR (CDCI3) 400MHz δ 7.94(d, 2H, J=8.28 Hz), 7.63(d, 2H, J=8.28 Hz), 7.24(d, 2H, J=8.79 Hz), 6.72(d, 2H, J=8.79 Hz), 4.29(s, 2H), 4.18(q, 2H, J=7.07 Hz), 3.44(m, 6H), 2.43(br s, 4H), 1.56(s, 6H), 1.42(s, 9H), 1.19(t, 3H, J=7.07 Hz),
Ethyl 2-methyl-2-{4-[({4-{[4-(2-pyrazinyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyn-1,3- thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoate
1H NMR (CDCI3) 400MHz δ 8.12(s, 1 H), 8.04(s, 1 H), 7.94(d, 2H, J=8.28 Hz), 7.83(s, 1 H), 7.65(d, 2H, J=8.28 Hz), 7.26(d, 2H, J=8J9 Hz), 6.73(d, 2H, J=8.79 Hz), 4.32(s, 2H), 4.17(q, 2H, J=7.07 Hz), 3.62(m, 6H), 2.64(br s, 4H), 1.56(s, 6H), 1.18(t, 3H, J=7.07 Hz),
Ethyl 2-{4-[({4-{[4-(2-methoxyphenyl)-1-piperazmyl]methyl)-2-[4-(trifluoromethyl)phenyn-1.3- thiazol-5-yl}methyl)sulfanyl]phenoxy}-2-methylpropanoate 1H NMR (CDCy 400MHz δ 7.96(d, 2H, J=8.28 Hz), 7.64(d, 2H, J=8.28 Hz), 7.27(d, 2H,
J=8.97 Hz), 6.98(m, 1 H), 6.90(m, 2H), 6.83(m, 1 H), 6.73(d, 2H, J=8.97 Hz), 4.35(s, 2H), 4.17(q, 2H, J=7.07 Hz), 3.83(s, 3H), 3.60(s, 2H), 3.11(br s, 4H), 2.72(br s, 4H), 1.58(s, 6H), 1.18(t, 3H, J=7.07 Hz),
tert-Butyl 4-({5-({[4-(2-methoxy-2-oxoethoxy)-3-methylphenyl]sulfanyl}methyl)-2-[4- (trifluoromethyl)phenyl]-1,3-thiazol-4-yl}methyl)-1-piperazinecarboxylate
1H NMR (CDCy 400MHz δ 7.90(d, 2H, J=8.28 Hz), 7.58(d, 2H, J=8.28 Hz), 7.16(d, 1 H, J=2.24 Hz), 7.08(dd, 1 H, J=8.45, 2.24 Hz), 6.52(d, 1 H, J=8.45 Hz), 4.56(s, 2H), 4.20(s, 2H), 3.70(s, 3H), 3.44(s, 2H), 3.36(t, 4H, J=4.48 Hz), 2.32(br s, 4H), 2.17(s, 3H), 1.38(s, 9H),
Ethyl 2-{2-methyl-4-[({4-{[4-(4-pyridinyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3- thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoate
1H NMR (CDCy 300MHz δ 8.28(d, 2H, J=6.37 Hz), 8.02(d, 2H, J=8.23 Hz), 7.69(d, 2H, J=8.23 Hz), 7.28(d, 1 H, J=2.39 Hz), 7.16(dd, 1 H, J=8.49, 2.39 Hz), 6.68(d, 2H, J=6.37 Hz), 6.60(d, 1 H, J=8.49 Hz), 4.73(q, 1 H, J=6.72 Hz), 4.32(s, 2H), 4.20(q, 2H, J=7.08 Hz), 3.59(s, 2H), 3.34(t, 4H, J=5.04 Hz), 2.58(t, 4H, J=5.04 Hz), 2.26(s, 3H), 1.65(d, 3H, J=6.72 Hz), 1.25(t, 3H, J=7.08 Hz),
Ethyl 2-{4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3- thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoate
1H NMR (CDCI3) 400MHz δ7.99(d, 2H, J=8.20 Hz), 7.66(d, 2H, J=8.20 Hz), 7.23(d, 1 H, J=2.39 Hz), 7.13(dd, 1 H, J=8.37, 2.39 Hz), 6.89(d, 2H, J=9.23 Hz), 6.83(d, 2H, J=9.23 Hz), 6.57(d, 1 H, J=8.37 Hz), 4.70(q, 1 H, J=6.84 Hz), 4.34(s, 2H), 4.17(q, 2H, J=7.18 Hz), 3.76(s, 3H), 3.58(s, 2H), 3.09(m, 4H), 2.63(m, 4H), 2.24(s, 3H), 1.62(d, 3H, J=6.84 Hz), 1.21(t, 3H, J=7.18 Hz),
TLC(30% EtOAc/Hexanes)= 0.29
Ethyl 2-{4-[({4-{[4-(2,4-difluorophenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3- thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoate
1H NMR (CDCy 300MHz δ 8.03(d, 2H, J=8.28 Hz), 7.69(d, 2H, J=8.28 Hz), 7.27(d, 1 H, J=2.21 Hz), 7.17(dd, 1 H, J=8.28, 2.21 Hz), 6.86(m, 3H), 6.61 (d, 1 H, J=8.28 Hz), 4.73(q, 1 H, J=6J1 Hz), 4.36(s, 2H), 4.21 (q, 2H, J=7.17 Hz), 3.62(s, 2H), 3.06(t, 4H, J=4.55 Hz), 2.67(t, 4H, J=4.55 Hz), 2.27(s, 3H), 1.65(d, 3H, J=6.71 Hz), 1.26(t, 3H, J=7.17 Hz),
Ethyl 2-{2-methyl-4-[({4-({4-[4-(trifluoromethoxy)phenyl]-1-piperazinyl}methyl)-2-[4- (trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoate
1H NMR (CD3OD) 400MHz δ 7.97(d, 2H, J=8.24 Hz), 7.63(d, 2H, J=8.24 Hz), 7.19(s, 1 H), 7.10(dd, 1 H, J=8.42, 2,20 Hz), 7.03(d, 2H, J=9.16 Hz), 6.85(d, 2H, J=9.16 Hz), 6.57(d, 1 H, J=8.42 Hz), 4.73(q, 1 H, J=6.78 Hz), 4.27(s, 2H), 4.07(m, 2H), 3.41 (s, 2H), 3.03(br s, 4H), 2.48(br s, 4H), 2.13(s, 3H), 1.51 (d, 3H, J=6.78 Hz), 1.11(t, 3H, J=7.14 Hz),
Ethyl 2-{4-[({4-{[4-(4-ethoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3: thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoate 1H NMR (CD3OD) 400MHz δ 8.01 (d, 2H, J=8.28 Hz), 7.70(d, 2H, J=8.28 Hz), 7.21 (d, 1 H, J=2.24 Hz), 7.11 (dd, 1 H, J=8.45, 2.24 Hz), 6.86(d, 2H, J=9.14 Hz), 6.76(d, 2H, J=9.14 Hz), 6.61 (d, 1 H, J=8.45 Hz), 4.77(q, 1 H, J=6.72 Hz), 4.29(s, 2H), 4.10(q, 2H, J=7.16 Hz), 3.91 (q, 2H, J=6.98 Hz), 3.40(s, 2H), 2.96(t, 4H, J=4.83 Hz), 2.50(t, 4H, J=4.83 Hz), 2.14(s, 3H), 1.52(d, 3H, J=6.72 Hz), 1.30(t, 3H, J=6.98 Hz), 1.14(t, 3H, J=7.1β Hz),
Ethyl 2-{2-methyl-4-[({4-{[4-(4-propoxyphenyl)-1-piperazinyl]methyl}-2-[4- (trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoate
1H NMR (CD3OD) 400MHz δ 7.96(d, 2H, J=8.10 Hz), 7.63(d, 2H, J=8.10 Hz), 7.18(s, 1 H), 7.09(d, 1 H, J=8.45 Hz), 6.81 (d, 2H, J=8.97 Hz), 6.73(d, 2H, J=8.97 Hz), 6.56(d, 1 H, J=8.45 Hz), 4.71 (q, 1 H, J=6.47 Hz), 4.25(s, 2H), 4.06(q, 2H, J=7.07 Hz), 3.76(t, 2H, J=7.41 Hz), 3.39(s, 2H), 2.92(br s, 4H), 2.48(br s, 4H), 2.12(s, 3H), 1.67(m, 2H), 1.49(d, 3H, J=6.47 Hz). 1.11 (t, 3H, J=7.07 Hz), 0.94(t, 3H, J=7.41 Hz),
Ethyl 2-{4-[({4-{[4-(4-isopropoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3- thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoate
1H NMR (CD3OD) 400MHz δ 7.96(d, 2H, J=8.28 Hz), 7.64(d, 2H, J=8.28 Hz), 7.18(d, 1 H, J=2.24 Hz), 7.09(dd, 1 H, J=8.45, 2.24 Hz), 6.81(d, 2H, J=9.14 Hz), 6.73(d, 2H, J=9.14 Hz), 6.57(d, 1 H, J=8.45 Hz), 4.71 (q, 1 H, J=6.78 Hz), 4.36(m, 1 H), 4.24(s, 2H), 4.06(q, 2H, J=7.16 Hz), 3.39(s, 2H), 2.92(t, 4H, J=4.57 Hz), 2.47(t, 4H, J=4.57 Hz), 2.11(s, 3H), 1.48(d, 3H, J=6J8 Hz), 1.19(d, 6H, J=6.21 Hz), 1.11 (t, 3H, J=7.16 Hz),
Ethyl 4-({5-({[4-(2-ethoxy-1 ,1 -dimethyl-2-oxoethoxy)phenyl]sulfanyl}methyl)-2-[4- (trifluoromethyl)phenyl]-1,3-thiazol-4-yl}methyl)-1-piperazinecarboxylate 1H NMR (CDCI3) 400MHz δ 7.94(d, 2H, J=8.28 Hz), 7.63(d, 2H, J=8.28 Hz), 7.24(m, 2H),
6.72(d, 2H, -8.79 Hz), 4.30(s, 2H), 4.18(q, 2H, J=7.07 Hz), 4.10(q, 2H, J=7.13 Hz), 3.49(m, 6H), 2.46(br s, 4H), 1.58(s, 6H), 1.21 (m, 6H),
Ethyl 4-({5-({[4-(2-methoxy-2-oxoethoxy)-3-methylphenyl]sulfanyl}methyl)-2-[4- (trifluoromethyl)phenyl]-1 ,3-thiazol-4-yl}methyl)-1-piperazinecarboxylate
1H NMR (CDCI3) 400MHz δ 7.95(d, 2H, J=8.10 Hz), 7.64(d, 2H, J=8.10 Hz), 7.20(d, 1H, J=2.21 Hz), 7.13(dd, 1 H, J=8.45, 2.21 Hz), 6.57(d, 1 H, J=8.45 Hz), 4.62(s, 2H), 4.30(s, 2H), 4.10(q, 2H, J=7.16 Hz), 3/77(s, 3H), 3.49(m, 6H), 2.45(br s, 4H), 2.21 (s, 3H), 1.23(t, 3H, J=7.16 Hz),
Methyl {4-[({4-{[4-(3-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1, 3- thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}acetate
1H NMR (CDCI3) 400MHz δ 7.97(d, 2H, J=8.28 Hz), 7.64(d, 2H, J=8.28 Hz), 7.21(d, 1 H, J=2.24 Hz), 7.14(m, 2H), 6.57(d, 1 H, J=8.45 Hz), 6.49(dd, 1 H, J=8.10, 2.20 Hz), 6.40(s, 2H), 4.60(s, 2H), 4.33(s, 2H), 3.76(s, 6H), 3.59(s, 2H), 3.21 (br s, 4H), 2.68(br s, 4H), 2.21 (s, 3H), Methyl {4-[({4-{[4-(4-acetylphenyl)-1 -piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1 ,3- thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}acetate
1H NMR (CDCy 400MHz δ 7.93(d, 2H, J=8.28 Hz), 7.82(d, 2H, J=8.97 Hz), 7.61 (d, 2H, J=8.28 Hz), 7.20(d, 1 H, J=2.24 Hz), 7.13(dd, 1 H, J=8.45, 2.24 Hz), 6.80(d, 2H, J=8.97 Hz), 6.55(d, 1 H, J=8.45 Hz), 4.57(s, 2H), 4.27(s, 2H), 3.73(s, 3H), 3.52(s, 2H), 3.27(t, 4H, J=4.83 Hz), 2.54(t, 4H, J=4.83 Hz), 2.45(s, 3H), 2.20(s, 3H),
Methyl {4-[({4-{[4-(2-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1, 3- thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}acetate H NMR (CDCI3) 400MHz δ 7.97(d, 2H, J=8.10 Hz), 7.65(d, 2H, J=8.10 Hz), 7.21 (m, 1 H),
7.15(dd, 1 H, J=8.45, 2.07 Hz), 6.98(br s, 1 H), 6.89(m, 2H), 6.83(d, 1 H, J=7.41 Hz), 6.57(d, 1 H, J=8.45 Hz), 4.61 (s, 2H), 4.35(s, 2H), 3.83(s, 3H), 3.75(s, 3H), 3.61 (s, 2H), 3.11 (br s, 4H), 2.70(br s, 4H), 2.22(s, 3H),
Methyl {2-methyl-4-[({4-{[4-(2-pyrazinyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3- thiazol-5-yl}methyl)sulfanyl]phenoxy}acetate
1H NMR (CDCy 400MHz δ 8.07(s, 1 H), 7.99(m, 1 H), 7.94(d, 2H, J=8.10 Hz), 7.77(d, 1 H, J=2.59 Hz), 7.60(d, 2H, J=8.10 Hz), 7.20(d, 1 H, J=2.24Hz), 7.12(dd, 1 H, J=8.45, 2.24 Hz), 6.54(d, 1 H, J=8.45 Hz), 4.58(s, 2H), 4.26(s, 2H), 3.73(s, 3H), 3.52(m, 6H), 2.52(t, 4H, J=4.83 Hz), 2.19(s, 3H),
Ethyl (4-{[(4-{[4-(4-methoxyphenyl)-1 -piperazinyl]methyl}-2-phenyl-1 ,3-thiazol-5- yl)methyl]sulfanyl}-2-methylphenoxy)acetate
1H NMR (CDCI3) 400MHz δ7.88(m, 2H), 7.40(m, 3H), 7.25(d, 1 H, J=2.39 Hz), 7.17(dd, 1 H, J=8.37, 2.39 Hz), 6.89(d, 2H, J=9.06 Hz), 6.81 (d, 2H, J=9.06 Hz), 6.58(d, 1 H, J=8.37 Hz), 4.59(s, 2H), 4.32(s, 2H), 4.23(q, 2H, J=7.12 Hz), 3.74(s, 3H), 3.56(s, 2H), 3.06(m, 4H), 2.62(m, 4H), 2.24(s, 3H), 1.27(t, 3H, J=7.12 Hz),
Ethyl 2-(4-{[(4-{[4-(4-methoxyphenyl)-1 -piperazinyl]methyl}-2-phenyl-1 ,3-thiazol-5- yl)methyl]sulfanyl}-2-methylphenoxy)propanoate 1H NMR (CDCI3) 400MHz δ7.88(m, 2H), 7.40(m, 3H), 7.25(d, 1 H, J=2.39 Hz), 7.14(dd, 1 H,
J=8.37, 2.39 Hz), 6.89(d, 2H, J=9.40 Hz), 6.82(d, 2H, J=9.40 Hz), 6.57(d, 1 H, J=8.37 Hz), 4.70(q, 1 H, J=6.84 Hz), 4.32(s, 2H), 4.17(q, 2H, J=7.18 Hz), 3.76(s, 3H), 3.56(s, 2H), 3.08(m, 4H), 2.63(m, 4H), 2.23(m, 3H), 1.61 (d, 3H, J=6.84 Hz), 1.25(t, 3H, J=7.18 Hz),
Ethyl 2-(4-{[(4-{[4-(4-methoxyphenyl)-1 ■piperazinyl]methyl}-2-phenyl-1 ,3-thiazol-5- yl)methyl]sulfanyl}phenoxy)-2-methylpropanoate
1H NMR (CDCl3) 400MHz δ 7.87(m, 2H), 7.40(m, 3H), 7.28(d, 2H, J=8.89 Hz), 6.89(d, 2H, J=9.23 Hz), 6.82(d, 2H, J=9.23 Hz), 6.75(d, 2H, J=8.89 Hz), 4.33(s, 2H), 4.19(q, 2H, J=7.18 Hz), 3.76(s, 3H), 3.56(s, 2H), 3.09(br s, 4H), 2.65(br s, 4H), 1.58(s, 6H), 1.20(t, 3H, J=7.18 Hz), Ethyl 2-{4-[({4-{[4-(2-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3- thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoate
1H NMR (CDCI3) 300MHz δ 8.03(d, 2H, J=8.28 Hz), 7.69(d, 2H, J=8.28 Hz), 7.28(d, 1 H, J=2.21 Hz), 7.17(dd, 1 H, J=8.28, 2.21 Hz), 7.00(m, 3H), 6.88(d, 1 H, J=7.73 Hz), 6.61 (d, 1 H, J=8.28 Hz), 4.74(q, 1 H, J=6.81 Hz), 4.39(s, 2H), 4.21 (q, 2H, J=7.17 Hz), 3.89(s, 3H), 3.63(s, 2H), 3.12(br s, 4H), 2.72(br s, 4H), 2.27(s, 3H), 1.65(d, 3H, J=6.81 Hz), 1.26(t, 3H, J=7.17 Hz),
Ethyl 2-[2-methyl-4-({[2-[4-(trifluoromethyl)phenyl]-4-({4-[3-(trifluoromethyl)phenyl]-1- piperazinyl}methyl)-1,3-thiazol-5-yl]methyl}sulfanyl)phenoxy]propanoate 1H NMR (CDCI3) 300MHz δ 8.03(d, 2H, J=8.28 Hz), 7.70(d, 2H, J=8.28 Hz), 7.36(t, 1 H,
J=8.00 Hz), 7.29(d, 1 H, J=2.21 Hz), 7.13(m, 4H), 6.61 (d, 1 H, J=8.28 Hz), 4.74(q, 1 H, J=6.90 Hz), 4.36(s, 2H), 4.18(q, 2H, J=7.08 Hz), 3.62(s, 2H), 3.26(t, 4H, J=4.83 Hz), 2.65(t, 4H, J=4.83 Hz), 2.26(s, 3H), 1.65(d, 3H, J=6.90 Hz), 1.27(t, 3H, J=7.08 Hz),
Ethyl 2-{2-methyl-4-[({4-({4-[2-oxo-2-(1 -pyrrolidinyl)ethyl]-1 -piperazinyl}methyl)-2-[4- (trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoate H NMR (CDCy 300MHz δ 7.96(d, 2H, J=8.28 Hz), 7.63(d, 2H, J=8.28 Hz), 7.20(d, 1H, J=2.21 Hz), 7.10(dd, 1 H, J=8.28, 2.21 Hz), 6.56(d, 1 H, J=8.28 Hz), 4.69(q, 1 H, J=6.71 Hz), 4.30(s, 2H), 4.16(q, 2H, J=7.08 Hz), 3.47(m, 8H), 3.10(s, 2H), 2.54(m, 6H), 2.20(s, 3H), 1.85(m, 4H), 1.60(d, 3H, J=6.71 Hz), 1.20(t, 3H, J=7.08 Hz),
Ethyl 2-{2-methyl-4-[({4-{[4-(2 yrimidinyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]- 1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoate
1H NMR (CDCl3) 300MHz δ 8.31 (d, 2H, J=4.69 Hz), 8.01 (d, 2H, J=8.28 Hz), 7.68(d, 2H, J=8.28 Hz), 7.27(d, 1 H, J=2.21 Hz), 7.16(dd, 1H, J=8.28, 2.21 Hz), 6.60(d, 1 H, J=8.28 Hz), 6.48(t, 1 H, J=4.69 Hz), 4.74(q, 1 H, J=6J1 Hz), 4.35(s, 2H), 4.20(q, 2H, J=7.08 Hz), 3.85(t, 4H, J=4.97 Hz), 3.57(s, 2H), 2.54(t, 4H, J=4.97 Hz), 2.24(s, 3H), 1.64(d, 3H, J=6J1 Hz), 1.24(t, 3H, J=7.08 Hz),
Ethyl 2-{2-methyl-4-[({4-{[4-(2-pyrazinyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3- thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoate
1H NMR (CDCl3) 300MHz δ 8.14(m, 1H), 8.06(m, 1 H), 8.01 (d, 2H, J=8.28 Hz), 7.85(d, 1 H, J=2.48 Hz), 7.67(d, 2H, J=8.28 Hz), 7.27(d, 1 H, J=2.21 Hz), 7.15(dd, 1 H, J=8.28, 2.21 Hz), 6.59(d, 1 H, J=8.28 Hz), 4J3(q, 1 H, J=6.71 Hz), 4.33(s, 2H), 4.16(q, 2H, J=7.17 Hz), 3.60(m, 6H), 2.58(t, 4H, J=4.83 Hz), 2.25(s, 3H), 1.64(d, 3H, J=6.71 Hz), 1.25(t, 3H, J=7.17 Hz),
Ethyl 2-[2-methyl-4-({[2-[4-(trifluoromethyl)phenyl]-4-({4-[4-(trifluoromethyl)phenyl]-1- piperazinyl}methyl)-1,3-thiazol-5-yl]methyl}sulfanyl)phenoxy]propanoate
1H NMR (CDCy 300MHz δ 8.03(d, 2H, J=8.28 Hz), 7.70(d, 2H, J=8.28 Hz), 7.51 (d, 2H, J=8.55 Hz), 7.28(d, 1 H, J=2.21 Hz), 7.18(dd, 1 H, J=8.28, 2.21 Hz), 6.94(d, 2H, J=8.55 Hz), 6.61 (d, 1 H, J=8.28 Hz), 4.74(q, 1 H, J=6.71 Hz), 4.35(s, 2H), 4.21 (q, 2H, J=7.17 Hz), 3.62(s, 2H), 3.33(t, 4H, J=4.55 Hz), 2.66(t, 4H, J=4.55 Hz), 2.27(s, 3H), 1.66(d, 3H, J=6.71 Hz), 1.26(t, 3H, J=7.17 Hz), Ethyl 2-{4-[({4-[(4-acetyl-1-piperazinyl)methyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]-2-isopropylphenoxy}propanoate
1H NMR (CDCI3) 400MHz δ 7.94(d, 2H, J=8.10 Hz), 7.64(d, 2H, J=8.10 Hz), 7.17(d, 1 H, J=2.24 Hz), 7.11 (dd, 1 H, J=8.45, 2.24 Hz), 6.54(d, 1 H, J=8.45 Hz), 4.72(q, 1 H, J=6.78 Hz), 4.23(s, 2H), 4.14(q, 2H, J=7.13 Hz), 3.59(s, 2H), 3.42(br s, 4H), 3.30(m, 1 H), 2.42(br s, 4H), 2.04(s, 3H), 1 ,59(d, 3H, J=6.78 Hz), 1.17(m, 9H),
Ethyl 2-{4-[({4-{[4-(4-fluorophenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3- thiazol-5-yl}methyl)sulfanyl]-2-isopropylphenoxy}propanoate
1H NMR (CDCI3) 400MHz δ 7.97(d, 2H, J=8.28 Hz), 7.64(d, 2H, J=8.28 Hz), 7.20(d, 1 H, J=2.24 Hz), 7.13(dd, 1 H, J=8.45, 2.24 Hz), 6.92(m, 2H), 6.83(m, 2H), 6.55(d, 1 H, J=8.45 Hz), 4.71 (q, 1 H, J=6.78 Hz), 4.28(s, 2H), 4.14(q, 2H, J=7.18 Hz), 3.48(s, 2H), 3.31 (m, 1 H), 3.07(t, 4H, J=4.83 Hz), 2.59(br s, 4H), 1.59(d, 3H, J=6.78 Hz), 1.15(m, 9H),
Ethyl 2-{2-isopropyl-4-[({4-(4-morpholinylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}propanoate
1H NMR (CDCI3) 400MHz δ 7.95(d, 2H, J=8.28 Hz), 7.63(d, 2H, J=8.28 Hz), 7.19(d, 1 H, J=2.24 Hz), 7.12(dd, 1 H, J=8.45, 2.24 Hz), 6.55(d, 1 H, J=8.45 Hz), 4.71 (q, 1 H, J=6.78 Hz), 4.26(s, 2H), 4.14(q, 2H, J=7.13 Hz), 3.67(m, 4H), 3.41(s, 2H), 3.30(m, 1 H), 2.42(br s, 4H), 1.59(d, 3H, J=6J8 Hz), 1.16(m, 9H),
Ethyl 2-{2-methyl-4-[({4-(1 -piperazinylmethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}propanoate 1H NMR (CDCI3) 300MHz δ 8.01 (d, 2H, J=8.23 Hz), 7.67(d, 2H, J=8.23 Hz), 7.27(d, 1 H,
J=2.39 Hz), 7.15(dd, 1 H, J=8.23, 2.39 Hz), 6.59(d, 1 H, J=8.23 Hz), 4.73(q, 1 H, J=6.64 Hz), 4.34(s, 2H), 4.20(q, 2H, J=7.08 Hz), 3.52(s, 2H), 2.91 (t, 4H, J=4.91 Hz), 2.46(m, 4H), 2.33(br s, 1 H), 2.26(s, 3H), 1.64(d, 3H, J=6.64 Hz), 1.25(t, 3H, J=7.08 Hz),
tert-Butyl 4-({5-({[4-(2-ethoxy-1-methyl-2-oxoethoxy)-3-methylphenyl]sulfanyl}methyl)-2-[4- (trifluoromethyl)phenyl]-1,3-thiazol-4-yl}methyl)-1-piperazinecarboxylate H NMR (CDCy 300MHz δ 8.01 (d, 2H, J=8.23 Hz), 7.68(d, 2H, J=8.23 Hz), 7.27(d, 1 H, J=2.39 Hz), 7.15(dd, 1 H, J=8.49, 2.39 Hz), 6.60(d, 1 H, J=8.49 Hz), 4.74(q, 1 H, J=6.72 Hz), 4.33(s, 2H), 4.22(q, 2H, J=7.08 Hz), 3.54(s, 2H), 3.46(m, 4H), 2.44(m, 4H), 2.27(s, 3H), 1.65(d, 3H, J=6J2 Hz), 1.48(s, 9H), 1.26(t, 3H, J=7.08 Hz),
Ethyl 2-{4-[( 4-{[4-(4-chlorophenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromeihyl)phenyl]-1,3- thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoate
1H NMR (CDCy 300MHz δ 8.03(d, 2H, J=8.23 Hz), 7.70(d, 2H, J=8.23 Hz), 7.22(m, 4H), 6.86(d, 2H, J=9.03 Hz), 6.61 (d, 1 H, J=8.49 Hz), 4.73(q, 1 H, J=6.81 Hz), 4.36(s, 2H), 4.18(q, 2H, J=7.08 Hz), 3.61 (s, 2H), 3.17(m, 4H), 2.64(m, 4H), 2.27(s, 3H), 1.65(d, 3H, J=6 84 Hz), 1.27(t, 3H, J=7.08 Hz),
Ethyl 2-{4-[({4-[(3,5-dimethyl-1-piperazinyl)methyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]-2-methylphenoxy}propanoate
1H NMR (CDCI3) 300MHz δ 8.01(d, 2H, J=8.23 Hz), 7.68(d, 2H, J=8.23 Hz), 7.27(d, 1 H, J=2.39 Hz), 7.15(dd, 1 H, J=8.49, 2.39 Hz), 6.60(d, 1 H, J=8.49 Hz), 4.74(q, 1 H, J=6.72 Hz), 4.35(s, 2H), 4.21 (q, 2H, J=7.08 Hz), 3.53(s, 2H), 2.96(m, 2H), 2J8(m, 2H), 2.26(s, 3H), 1.73(m, 2H), 1.65(d, 3H, J=6.72 Hz), 1.26(t, 3H, J=7.08 Hz), 1.09(d, 6H, J=6.37 Hz),
Ethyl 2-{4-[({4-{[4-(4-fluorophenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3- thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoate
1H NMR (CDCy 300MHz δ 8.03(d, 2H, J=8.49 Hz), 7.70(d, 2H, J=8.49 Hz), 7.28(d, 1 H, J=2.39 Hz), 7.18(dd, 1H, J=8.23, 2.39 Hz), 6.94(m, 4H), 6.62(d, 1 H, J=8.23 Hz), 4.74(q, 1H, J=6J2 - Hz), 4.37(s, 2H), 4.21 (q, 2H, J=7.08 Hz), 3.63(s, 2H), 3.14(t, 4H, J=4.51 Hz), 2.67(t, 4H, J=4.51 Hz), 2.28(s, 3H), 1.65(d, 3H, J=6.72 Hz), 1.26(t, 3H, J=7.08 Hz),
Ethyl 2-{4-[({4-{[4-(4-acetylphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3- thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoate 1H NMR (CDCl3) 300MHz δ 8.02(d, 2H, J=8.23 Hz), 7.89(d, 2H, J=8.76 Hz), 7.69(d, 2H,
J=8.23 Hz), 7.28(br s, 1 H), 7.17(dd, 1 H, J=8.23, 2.39 Hz), 6.88(d, 2H, J=8.76 Hz), 6.60(d, 1 H, J=8.23 Hz), 4.73(q, 1 H, J=6.81 Hz), 4.34(s, 2H), 4.18(q, 2H, J=7.17 Hz), 3.60(s, 2H), 3.37(m, 4H), 2.63(m, 4H), 2.54(s, 3H), 2.26(s, 3H), 1.65(d, 3H, J=6.81 Hz), 1.27(t, 3H, J=7.17 Hz),
Ethyl 4-({5-({[4-(2-ethoxy-1-methyl-2-oxoethoxy)-3-methylphenyl]sulfanyl}methyl)-2-[4- (trifluoromethyl)phenyl]-1,3-thiazol-4-yl}methyl)-1-piperazinecarboxylate
1H NMR (CDCI3) 300MHz δ 8.00(d, 2H, J=8.23 Hz), 7.68(d, 2H, J=8.23 Hz), 7.27(d, 1 H, J=2.39 Hz), 7.14(dd, 1 H, J=8.23, 2.39 Hz), 6.60(d, 1 H, J=8.23 Hz), 4.73(q, 1 H, J=6.81 Hz), 4.31 (s, 2H), 4.18(m, 4H), 3.50(m, 6H), 2.44(m, 4H), 2.26(s, 3H), 1.65(d, 3H, J=6.81 Hz), 1.26(m, 6H),
Ethyl 2-{2-methyl-4-[({4-(4-morpholinylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}propanoate
1H NMR (CDCI3) 300MHz δ 8.01 (d, 2H, J=8.23 Hz), 7.68(d, 2H, J=8.23 Hz), 7.27(d, 1 H, J=2.39 Hz), 7.16(dd, 1 H, J=8.49, 2.39 Hz), 6.60(d, 1 H, J=8.49 Hz), 4.73(q, 1 H, J=6.72 Hz), 4.34(s, 2H), 4.21 (q, 2H, J=7.08 Hz), 3.73(t, 4H, J=4.51 Hz), 3.54(s, 2H), 2.49(t, 4H, J=4.51 Hz), 2.26(s, 3H), 1.65(d, 3H, J=6J2 Hz), 1.26(t, 3H, J=7.08 Hz),
Ethyl 2-{4-[({4-{[4-(3-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3- thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoate 1H NMR (CDCy 300MHz δ 8.04(d, 2H, J=8.23 Hz), 7.70(d, 2H, J=8.23 Hz), 7.28(m, 1 H),
7.18(m, 2H), 6.62(d, 1 H, J=8.23 Hz), 6.56(dd, 1 H, J=8.23, 2.39 Hz), 6.50(t, 1 H, J=2.26 Hz), 6.45(dd, 1 H, J=8.23, 2.39 Hz), 4.74(q, 1 H, J=6.81 Hz), 4.37(s, 2H), 4.21 (q, 2H, J=7.08 Hz), 3.82(s, 3H), 3.61 (s, 2H), 3.22(t, 4H, J=4.65 Hz), 2.65(t, 4H, J=4.65 Hz), 2.28(s, 3H), 1.66(d, 3H, J=6.81 Hz), 1.26(t, 3H, J=7.08 Hz),
Ethyl 2-{4-[({4-[(4-acetyl-1-piperazinyl)methyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]-2-propylphenoxy}propanoate
1H NMR (CDCy 400MHz δ 7.95(d, 2H, J=8.06 Hz), 7.63(d, 2H, J=8.06 Hz), 7.16(d, 1 H, J=2.38 Hz), 7.11(dd, 1 H, J=8.24, 2.38 Hz), 6.55(d, 1H, J=8.24 Hz), 4J0(q, 1H, J=6.84 Hz), 4.23(s, 2H), 4.13(q, 2H, J=7.14 Hz), 3.59(br s, 2H), 3.47(s, 2H), 3.40(t, 2H, J=4.58 Hz), 2.55(t, 2H, J=7.33 Hz), 2.40(m, -,H), 2.05(s, 3H), 1.56(m, 5H), 1.20(t, 3H, J=7.14 Hz), 0.86(t, 3H, ..=7.33 Hz),
Ethyl 2-{4-[({4-{[4-(4-fluorophenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3- thiazol-5-yl}methyl)sulfanyl]-2-propylphenoxy}propanoate
1H NMR (CDCI3) 400MHz δ 7.97(d, 2H, J=8.24 Hz), 7.64(d, 2H, J=8.24 Hz), 7.19(d, 1 H, J=2.38 Hz), 7.14(dd, 1 H, J=8.42, 2.38 Hz), 6.93(m, 2H), 6.84(m, 2H), 6.56(d, 1 H, J=8.42 Hz), 4.69(q, 1 H, J=6.78 Hz), 4.30(s, 2H), 4.14(q, 2H, J=7.14 Hz), 3.54(s, 2H), 3.07(t, 4H, J=4.58 Hz), 2.58(m, 6H), 1.57(m, 5H), 1.22(t, 3H, J=7.14 Hz), 0.86(t, 3H, J=7.33 Hz),
Ethyl 2-{4-[({4-(4-morpholinylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]-2-propylphenoxy}propanoate
1H NMR (CDCI3) 400MHz δ 7.95(d, 2H, J=8.24 Hz), 7.63(d, 2H, J=8.24 Hz), 7.17(d, 1 H, J=2.38 Hz), 7.12(dd, 1 H, J=8.42, 2.38 Hz), 6.55(d, 1 H, J=8.42 Hz), 4.69(q, 1 H, J=6.78 Hz), 4.27(s, 2H), 4.14(q, 2H, J=7.14 Hz), 3.66(t, 4H, J=4.67 Hz), 3.45(s, 2H), 2.56(t, 2H, J=7.33 Hz), 2.42(m, 4H), 1.56(m, 5H), 1.21 (t, 3H, J=7.14 Hz), 0.86(t, 3H, J=7.33 Hz),
Methyl {4-[({4-[(4-acetyl-1 -piperazinyl)methyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyl)sulfanyl]-2-isopropylphenoxy}acetate
1H NMR (CDCy 400MHz δ 7.95(d, 2H, J=8.61 Hz), 7.64(d, 2H, J=8.61 Hz), 7.20(d, 1 H, J=2.20 Hz), 7.15(dd, 1 H, J=8.42, 2.20 Hz), 6.59(d, 1 H, J=8.42 Hz), 4.63(s, 2H), 4.25(s, 2H), 3.76(s, 3H), 3.56(s, 2H), 3.41 (m, 4H), 3.31 (m, 1 H), 2.38(m, 4H), 2.05(s, 3H), 1.11 (d, 6H, J=6J8 Hz),
Methyl {4-[({4-{[4-(4-fluorophenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1 ,3- thiazol-5-yl}methyl)sulfanyl]-2-isopropylphenoxy}acetate
1H NMR (CDCI3) 400MHz δ 7.98(d, 2H, J=8.24 Hz), 7.65(d, 2H, J=8.24 Hz), 7.23(d, 1 H, J=2.20 Hz), 7.18(dd, 1 H, J=8.42, 2.20 Hz), 6.94(m, 2H), 6.83(m, 2H), 6.60(d, 1 H, J=8.42 Hz), 4.61 (s, 2H), 4.30(s, 2H), 3.76(s, 3H), 3.49(s, 2H), 3.34(m, 1 H), 3.07(t, 4H, J=4.58 Hz), 2.59(m, 4H), 1.13(d, 6H, J=6.96 Hz),
j/|ethyl {2-isopropyl-4-[({4-(4-morpholinylrrιethyl)-2-[4-(trifluoromethyl)pheriyl]-1,3-thiazol-5- yj}methyl)sulfanyl]phenoxy}acetate 1H NMR (CDCI3) 400MHz δ 7.96(d, 2H, J=8.24 Hz), 7.64(d, 2H, J=8.24 Hz), 7.21 (d, 1 H, J=2.38 Hz), 7.16(dd, 1 H, J=8.42, 2.38 Hz), 6.59(d, 1 H, J=8.42 Hz), 4.62(s, 2H), 4.28(s, 2H), 3.76(s, 3H), 3.66(t, 4H, J=4.58 Hz), 3.41 (s, 2H), 3.32(m, 1 H), 2.42(m, 4H), 1.15(d, 6H, J=6.96 Hz),
Methyl {2-isopropyl-4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4- (trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetate
1H NMR (CDCy 400MHz δ 7.98(d, 2H, J=8.24 Hz), 7.65(d, 2H, J=8.24 Hz), 7.23(d, 1 H, J=2.20 Hz), 7.18(dd, 1 H, J=8.42, 2.20 Hz), 6.87(d, 2H, J=9.16 Hz), 6.81 (d, 2H, J=9.16 Hz), 6.60(d, 1 H, J=8.42 Hz), 4.61 (m, 2H), 4.31 (s, 2H), 3.77(s, 3H), 3.74(s, 3H), 3.50(s, 2H), 3.33(m, 1 H), 3.05(m, 4H), 2.60(br s, 4H), 1.15(d, 6H, J=6.96 Hz),
Methyl {4-[({4-{[4-(4-acetylphenyl)-1 -piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1 ,3- thiazol-5-yl}methyl)sulfanyl]-2-isopropylphenoxy}acetate
1H NMR (CDCI3) 400MHz δ 7.95(d, 2H, J=8.28 Hz), 7.84(d, 2H, J=9.14 Hz), 7.62(d, 2H, J=8.28 Hz), 7.21 (d, 1 H, J=2.24 Hz), 7.16(dd, 1 H, J=8.45, 2.24 Hz), 6.80(d, 2H, J=9.14 Hz), 6.58(d,
1H, J=8.45 Hz), 4.59(s, 2H), 4.27(s, 2H), 3.73(s, 3H), 3.46(s, 2H), 3.30(m, 5H), 2.54(t, 4H, J=4.57 Hz), 2.47(s, 3H), 1.12(d, 6H, J=6.90 Hz),
Methyl {2-isopropyl-4-[({4-{[4-(3-methoxyphenyl)-1-piperazinyl]methyl}-2-[4- (trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetate
1H NMR (CDCI3) 400MHz δ 7.98(d, 2H, J=8.28 Hz), 7.65(d, 2H, J=8.28 Hz), 7.24(d, 1 H, J=2.38 Hz), 7.19(dd, 1 H, J=8.42, 2.38 Hz), 7.14(t, 1 H, J=8.24 Hz), 6.60(d, 1 H, J=8.42 Hz), 6.51 (dd, 1 H, J=8.24, 2.38 Hz), 6.44(t, 1 H, J=2.29 Hz), 6.39(dd, 1 H, J=8.24, 2.38 Hz), 4.62(s, 2H), 4.30(s, 2H), 3.75(m, 6H), 3.48(s, 2H), 3.34(m, 1 H), 3.16(t, 4H, J=4.67 Hz), 2.57(t, 4H, J=4.67 Hz), 1.14(d, 6H, J=6.78 Hz),
Ethyl 2-{2-isopropyl-4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4- (trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoate
1H NMR (CDCI3) 400MHz δ 8.04(d, 2H, J=8.24 Hz), 7.71 (d, 2H, J=8.24 Hz), 7.16(m, 2H), 6.87(d, 2H, J=9.16 Hz), 6.78(d, 2H, J=9.16 Hz), 6.64(d, 1 H, J=8.42 Hz), 4.81 (q, 1 H, J=6.71 Hz), 4.27(s, 2H), 4.11 (q, 2H, J=7.08 Hz), 3.69(s, 3H), 3.28(m, 3H), 2.96(t, 4H, J=4.94 Hz), 2.51 (t, 4H, J=4.94 Hz;, 1.54(d, 3H, J=6.71 Hz), 1.12(m, 9H),
Ethyl 2-{4-[({4-{[4-(4-acetylphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3- thiazol-5-yl}methyl)sulfanyl]-2-isopropylphenoxy}propanoate
1H NMR (CDCI3) 400MHz δ 7.96(d, 2H, J=8.28 Hz), 7.83(d, 2H, J=9.14 Hz), 7.64(d, 2H, J=8.28 Hz), 7.19(d, 1 H, J=2.24 Hz), 7.12(dd, 1 H, J=8.45, 2.24 Hz), 6.81(d, 2H, J=9.14 Hz), 6.55(d, 1H, J=8.45 Hz), 4.71(q, 1 H, J=6J8 Hz), 4.26(s, 2H), 4.12(q, 2H, J=7.16 Hz), 3.47(s, 2H), 3.29(m, 5H), 2.56(br s, 4H), 2.48(s, 3H), 1.58(d, 3H, J=6.78 Hz), 1.15(m, 9H), Ethyl 2-{2-isopropyl-4-[({4-{[4-(3-methoxyphenyl)-1-piperazinyl]methyl}-2-[4- (trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoate
1H NMR (CDCI3) 400MHz δ 7.98(d, 2H, J=8.24 Hz), 7.65(d, 2H, J=8.24 Hz), 7.21 (d, 1 H, J=2.38 Hz), 7.14(m, 2H), 6.58(d, 1 H, J=8.61 Hz), 6.51(dd, 1 H, J=8.24, 2.20 Hz), 6.43(t, 1H, J=2.29 Hz), 6.39(dd, 1H, J=8.24, 2.20 Hz), 4.72(q, 1H, J=6.78 Hz), 4.29(s, 2H), 4.15(q, 2H, J=7.14 Hz), 3.76(s, 3H), 3.48(s, 2H), 3.33(m, 1 H), 3.16(br s, 4H), 2.59(br s, 4H), 1.60(d, 3H, J=6.78 Hz), 1.16(m, 9H),
Ethyl {4-[({4-(4-morpholinylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]-2-propylphenoxy}acetate
1H NMR (CDCI3) 400MHz δ 7.95(d, 2H, J=8.24 Hz), 7.63(d, 2H, J=8.24 Hz), 7.19(m, 2H), 6.58(d, 1 H, J=8.24 Hz), 4.59(s, 2H), 4.28(s, 2H), 4.21 (q, 2H, J=7.14 Hz), 3.66(t, 4H, J=4.49 Hz), 3.45(s, 2H), 2.56(t, 2H, J=7.33 Hz), 2.42(m, 4H), 1.56(m, 2H), 1.24(t, 3H, J=7.14 Hz), 0.87(t, 3H, J=7.33 Hz),
Ethyl {4-[({4-{[4-(4-acetylphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol- 5-yl}methyl)sulfanyl]-2-ethylphenoxy}acetate
1H NMR (CDCy 400MHz δ 7.97(d, 2H, J=8.24 Hz), 7.83(d, 2H, J=9.16 Hz), 7.63(d, 2H, J=8.24 Hz), 7.21 (d, 1 H, J=2.20 Hz), 7.16(dd, 1 H, J=8.42, 2.20 Hz), 6.82(d, 2H, J=9.16 Hz), 6.59(d, 1 H, J=8.42 Hz), 4.59(s, 2H), 4.29(s, 2H), 4.21(q, 2H, J=7.14 Hz), 3.52(s, 2H), 3.31 (t, 4H, J=4.80 Hz), 2.64(q, 2H, J=7.51 Hz), 2.55(t, 4H, J=4.80 Hz), 2.47(s, 3H), 1.24(t, 3H, J=7.14 Hz), 1.14(t, 3H, J=7.51 Hz),
Ethyl {2-ethyl-4-[({4-{[4-(3-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]- 1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetate
1H NMR (CDCy 400MHz δ 7.98(d, 2H, J=8.24 Hz), 7.65(d, 2H, J=8.24 Hz), 7.22(s, 1 H), 7.16(m, 2H), 6.60(d, 1 H, J=8.42 Hz), 6.51 (d, 1 H, J=8.42 Hz), 6.44(s, 1 H), 6.39(dd, 1 H, J=8.24, 1.28 Hz), 4.60(s, 2H), 4.32(s, 2H), 4.22(q, 2H, J=7.14 Hz), 3.76(s, 3H), 3.52(s, 2H), 3.16(t, 4H, J=4.67 Hz), 2.65(q, 2H, J=7.51 Hz), 2.57(t, 4H, J=4.67 Hz), 1.26(t, 3H, J=7.14 Hz), 1.16(t, 3H, J=7.51 Hz),
Ethyl {4-[({4-[(4-acetyl-1 -piperazinyl)methyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyl)sulfanyl]-2-ethylphenoxy}acetate
1H NMR (CDCI3) 400MHz δ 7.93(d, 2H, J=8.28 Hz), 7.61 (d, 2H, J=8.28 Hz), 7.16(d, 1H, J=2.24 Hz), 7.12(dd, 1 H, J=8.28, 2.24 Hz), 6.56(d, 1 H, J=8.28 Hz), 4.58(s, 2H), 4.20(m, 4H), 3.55(t, 4H, J=4.91 Hz), 3.43(s, 2H), 3.37(t, 4H, J=4.91 Hz), 2.60(q, 2H, J=7.50 Hz), 2.02(s, 3H), 1.22(t, 3H, J=7.14 Hz), 1.11 (t, 3H, J=7.50 Hz),
Ethyl {2-ethyl-4-[({4-{[4-(4-fluorophenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyπ-1,3- thiazol-5-yl}methyl)sulfanyl]phenoxy}acetate 1H NMR (CDCI3) 400MHz δ 8.03(d, 2H, J=8.28 Hz), 7.69(d, 2H, J=8.28 Hz), 7.25(m, 2H), 6.93(m, 4H), 6.64(d, 1 H, J=8.28 Hz), 4.64(s, 2H), 4.36(s, 2H), 4.26(q, 2H, J=7.08 Hz), 3.58(s, 2H), 3.11 (t, 4H, J=4.97 Hz), 2.66(m, 6H), 1.29(t, 3H, J=7.08 Hz), 1.19(t, 3H, J=7.54 Hz),
Ethyl {2-ethyl-4-[({4-(4-morpholinylmethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}acetate
1H NMR (CDCI3) 400MHz δ 8.01 (d, 2H, J=8.28 Hz), 7.68(d, 2H, J=8.28 Hz), 7.24(m, 2H), 6.63(d, 1 H, J=8.28 Hz), 4.64(s, 2H), 4.34(s, 2H), 4.26(q, 2H, J=7.17 Hz), 3.70(t, 4H, J=4.42 Hz), 3.49(s, 2H), 2.67(q, 2H, J=7.54 Hz), 2.46(t, 4H, J=4.42 Hz), 1.30(t, 3H, J=7.17 Hz), 1.19(t, 3H, J=7.54 Hz),
Ethyl 2-{2-ethyl-4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4- (trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoate
1H NMR (CDCI3) 400MHz δ 8.03(d, 2H, J=8.28 Hz), 7.70(d, 2H, J=8.28 Hz), 7.26(d, 1 H, J=2.21 Hz), 7.19(dd, 1 H, J=8.28, 2.21 Hz), 6.93(d, 2H, J=9. 1 Hz), 6.86(d, 2H, J=9.11 Hz), 6.62(d,
1 H, J=8.28 Hz), 4.76(q, 1 H, J=6.90 Hz), 4.36(s, 2H), 4.19(q, 2H, J=7.17 Hz), 3.80(s, 3H), 3.58(s, 2H), 3.11 (t, 4H, J=4.69 Hz), 2.67(m, 6H), 1.65(d, 3H, J=6.90 Hz), 1.24(m, 6H),
Ethyl 2-{4-[({4-{[4-(4-acetylphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3- thiazol-5-yl}iτιethyl)sulfanyl]-2-ethylphenoxy}propanoate
1H NMR (CDCy 400MHz δ 8.02(d, 2H, J=8.28 Hz), 7.89(d, 2H, J=8.83 Hz), 7.69(d, 2H, J=8.28 Hz), 7.25(d, 1 H, J=2.21 Hz), 7.18(dd, 1 H, J=8.28, 2.21 Hz), 6.88(d, 2H, J=8.83 Hz), 6.61 (d, 1 H, J=8.28 Hz), 4.76(q, 1 H, J=6.90 Hz), 4.33(s, 2H), 4.18(q, 2H, J=7.17 Hz), 3.57(s, 2H), 3.36(m, 4H), 2.66(m, 6H), 2.53(s, 3H), 1.65(d, 3H, J=6.90 Hz), 1.23(m, 6H),
Ethyl 2-{2-ethyl-4-[({4-{[4-(3-methoxyphenyl)-1 -piperazinyl]methyl}-2-[4- (trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoate
1H NMR (CDCI3) 400MHz δ 8.03(d, 2H, J=8.28 Hz), 7.70(d, 2H, J=8.28 Hz), 7.26(d, 1 H, J=2.21 Hz), 7.18(m, 2H), 6.62(d, 1 H, J=8.28 Hz), 6.56(dd, 1 H, J=8.00, 1.66 Hz), 6.49(m, 1 H), 6.44(dd, 1 H, J=8.00, 1.66 Hz), 4.76(q, 1 H, J=6.62 Hz), 4.35(s, 2H), 4.19(q, 2H, J=7.17 Hz), 3.81(s, 3H), 3.57(s, 2H), 3.21 (t, 4H, J=4.83 Hz), 2.66(m, 6H), 1.65(d, 3H, J=6.62 Hz), 1.24(m, 6H),
Ethyl 2-{4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3- thiazol-5-yl}methyl)sulfanyl]-2-propylphenoxy}propanoate 1H NMR (CDCI3) 400MHz δ 7.97(d, 2H, J=8.24 Hz), 7.64(d, 2H, J=8.24 Hz), 7.19(d, 1 H,
J=2.38 Hz), 7.14(dd, 1 H, J=8.42, 2.38 Hz), 6.88(d, 2H, J=9.16 Hz), 6.81 (d, 2H, J=9.16 Hz), 6.56(d, 1 H, J=8.42 Hz), 4.70(q, 1 H, J=6.78 Hz), 4.31 (s, 2H), 4.15(q, 2H, J=7.14 Hz), 3.74(s, 3H), 3.54(s, 2H), 3.05(t, 4H, J=4.85 Hz), 2.57(m, 6H), 1.56(m, 5H), 1.20(t, 3H, J=7.14 Hz), 0.86(t, 3H, J=7.33 Hz),
Ethyl 2-{4-[({4-{[4-(4-acetylphenyl)-1 -piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1 ,3; thiazol-5-yl}methyl)sulfanyl]-2-propylphenoxy}propanoate Η NMR (CDCI3) 400MHz δ 7.95(d, 2H, J=8.24 Hz), 7.84(d, 2H, J=9.14 Hz), 7.63(d, 2H, J=8.24 Hz), 7.17(d, 1 H, J=2.24 Hz), 7.12(dd, 1H, J=8.45, 2.24 Hz), 6.82(d, 2H, J=9.14 Hz), 6.54(d, 1 H, J=8.45 Hz), 4.68(q, 1 H, J=6.78 Hz), 4.27(s, 2H), 4.13(q, 2H, J=7.07 Hz), 3.51 (m, 2H), 3.31 (t, 4H, J=4.91 Hz), 2.55(m, 6H), 2.47(s, 3H), 1.55(m, 5H), 1.17(t, 3H, J=7.07 Hz), 0.85(t, 3H, J=7.41 Hz),
Ethyl 2-{4-[({4-{[4-(3-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3- thiazol-5-yl}methyl)sulfanyl]-2-propylphenoxy}propanoate
1H NMR (CDCI3) 400MHz δ 7.97(d, 2H, J=8.28 Hz), 7.64(d, 2H, J=8.28 Hz), 7.15(m, 3H), 6.56(d, 1 H, J=8.45 Hz), 6.50(dd, 1 H, J=8.10, 2.07 Hz), 6.43(t, 1 H, J=2.07 Hz), 6.39(dd, 1 H, J=8.10, 2.07 Hz), 4.70(q, 1 H, J=6J2 Hz), 4.29(s, 2H), 4.14(q, 2H, J=7.07 Hz), 3.76(s, 3H), 3.52(s, 2H), 3.16(t, 4H, J=4.83 Hz), 2.58(m, 6H), 1.57(m, 5H), 1.19(t, 3H, J=7.07 Hz), 0.87(t, 3H, J=7.33 Hz),
Ethyl 2-(4-{[(2-(4-fluorophenyl)-4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-1,3-thiazol-5- yl)methyQsu!fanyl}-2-methylphenoxy)propanoate 1H NMR (CDCI3) 400MHz δ 7.85(m, 2H), 7.22(d, 1 H, J=2.38 Hz), 7.09(m, 3H), 6.87(d, 2H,
J=9.16 Hz), 6.81 (d, 2H, J=9.16 Hz), 6.56(d, 1 H, J=8.42 Hz), 4.68(q, 1 H, J=6.78 Hz), 4.30(s, 2H), 4.16(q, 2H, J=7.20 Hz), 3.74(s, 3H), 3.53(s, 2H), 3.07(t, 4H, J=4.58 Hz), 2.62(br s, 4H), 2.21 (s, 3H), 1.60(d, 3H, J=6.78 Hz), 1.20(t, 3H, J=7.20 Hz),
Ethyl 2-[4-({[4-{[4-(4-acetylphenyl)-1-piperazinyl]methyl}-2-(4-fluorophenyl)-1,3-thiazol-5- yl]methyl}sulfanyl)-2-methylphenoxy]propanoate
1H NMR (CDCy 400MHz δ 7.85(m, 4H), 7.23(d, 1 H, J=2.38 Hz), 7.09(m, 3H), 6.83(d, 2H, J=9.16 Hz), 6.55(d, 1 H, J=8.42 Hz), 4.68(q, 1 H, J=6.78 Hz), 4.27(s, 2H), 4.16(q, 2H, J=7.14 Hz), 3.52(s, 2H), 3.32(t, 4H, J=4.94 Hz), 2.59(br s, 4H), 2.49(s, 3H), 2.21 (s, 3H), 1.60(d, 3H, J=6.78 Hz), 1.21 (t, 3H, J=7.14 Hz),
Ethyl 2-(4-{[(2-(4-fluorophenyl)-4-{[4-(3-methoxyphenyl)-1-piperazinyl]methyl}-1,3-thiazol-5- yl)methy!ji3u!fanyl}-2-methylphenoxy)propanoate
1H NMR (CDCy 400MHz δ 7.85(m, 2H), 7.23(d, 1 H, J=2.20 Hz), 7.11(m, 4H), 6.56(d, 1 H, J=8.24 Hz), 6.51 (dd, 1 H, J=8.24, 2.20 Hz), 6.44(t, 1 H, J=2.20 Hz), 6.39(dd, 1 H, J=8.24, 2.20 Hz), 4.69(q, 1 H, J=6J8 Hz), 4.29(s, 2H), 4.16(q, 2H, J=7.14 Hz), 3.76(s, 3H), 3.52(s, 2H), 3.16(t, 4H, J=4.76 Hz), 2.60(br s, 4H), 2.21 (s, 3H), 1.59(d, 3H, J=6.78 Hz), 1.22(t, 3H, J=7.14 Hz),
Ethyl 4-{[5-({[4-(2-ethoxy-1-methyl-2-oxoethoxy)-3-methylphenyl]sulfanyl}methyl)-2-(4- fluorophenvQ-1,3-thiazol-4-yl]methyl}-1-piperazinecarboxylate
1H NMR (CDCI3) 400MHz δ 7.83(m, 2H), 7.20(d, 1 H, J=2.20 Hz), 7.08(m, 3H), 6.55(d, 1 H, J=8.42 Hz), 4.68(q, 1 H, J=6.78 Hz), 4.23(s, 2H), 4.16(q, 2H, J=7.14 Hz), 4.09(q, 2H, J=7.14 Hz), 3.42(m, 6H), 2.38(br s, 4H), 2.18(s, 3H), 1.57(d, 3H, J=6.78 Hz), 1.13(m, 6H),
Ethyl {2-ethyl-4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]- 1 ,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetate 1H NMR (CDCI3) 400MHz δ 7.98(d, 2H, J=8.24 Hz), 7.65(d, 2H, J=8.24 Hz), 7.22(s, 1 H), 7.17(d, 1 H, J=8.42 Hz), 6.87(d, 2H, J=9.16 Hz), 6.81 (d, 2H, J=9.16 Hz), 6.59(d, 1 H, J=8.42 Hz), 4.60(s, 2H), 4.32(s, 2H), 4.22(q, 2H, J=7.14 Hz), 3.74(s, 3H), 3.53(s, 2H), 3.05(t, 4H, J=4.76 Hz), 2.62(m, 6H), 1.26(t, 3H, J=7.14 Hz), 1.16(t, 3H, J=7.33 Hz),
Ethyl 2-{4-[({4-[(4-acetyl-1-piperazinyl)methyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]-2-ethylphenoxy}propanoate
1H NMR (CDCy 400MHz δ 7.99(d, 2H, J=8.28 Hz), 7.68(d, 2H, J=8.28 Hz), 7.22(d, 1 H, J=2.21 Hz), 7.15(dd, 1 H, J=8.28, 2.21 Hz), 6.60(d, 1 H, J=8.28 Hz), 4.75(q, 1 H, J=6.81 Hz), 4.29(s, 2H), 4.19(q, 2H, J=7.17 Hz), 3.62(t, 2H, J=4.69 Hz), 3.50(s, 2H), 3.43(t, 2H, J=4.69 Hz), 2.66(q, 2H, J=7.45 Hz), 2.43(br s, 4H), 2.09(s, 3H), 1.64(d, 3H, J=6.81 Hz), 1.22(m, 6H),
Ethyl 2-{2-ethyl-4-[({4-{[4-(4-fluorophenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]- 1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoate 1H NMR (CDCy 400MHz δ 8.03(d, 2H, J=8.28 Hz), 7.69(d, 2H, J=8.28 Hz), 7.26(d, 1 H,
J=2.21 Hz), 7.19(dd, 1 H, J=8.55, 2.21 Hz), 6.94(m, 4H), 6.62(d, 1 H, J=8.55 Hz), 4.75(q, 1 H, J=6.90 Hz), 4.35(s, 2H), 4.19(q, 2H, J=7.17 Hz), 3.58(s, 2H), 3.12(t, 4H, J=4.97 Hz), 2.66(m, 6H), 1.64(d, 3H, J=6.90 Hz), 1.24(m, 6H),
Ethyl 2-{2-ethyl-4-[({4-(4-morpholinylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}propanoate
1H NMR (CDCy 400MHz δ 8.01 (d, 2H, J=8.28 Hz), 7.68(d, 2H, J=8.28 Hz), 7.24(d, 1 H, J=2.21 Hz), 7.16(dd, 1 H, J=8.28, 2.21 Hz), 6.60(d, 1 H, J=8.28 Hz), 4.75(q, 1 H, J=6.62 Hz), 4.32(s, 2H), 4.17(s, 2H), 3.70(t, 4H, J=4.42 Hz), 3.49(s, 2H), 2.66(q, 2H, J=7.54 Hz), 2.45(t, 4H, J=4.42 Hz), 1.63(d, 3H, J=6.62 Hz), 1.22(m, 6H),
Ethyl {4-[({4-{[4-(4-methoxyphenyl)-1 -piperazinyl]methyl}-2-[4-(trif luoromethyl)phenyl]-1 ,3- thiazol-5-yl}methyl)sulfanyl]-2-propylphenoxy}acetate
1H NMR (CDCI3) 400MHz δ 8.03(d, 2H, J=8.28 Hz), 7.69(d, 2H, J=8.28 Hz), 7.23(m, 2H), 6.89(m, 4H), 6.64(d, 1 H, J=8.28 Hz), 4.62(s, 2H), 4.36(s, 2H), 4.26(q, 2H, J=7.08 Hz), 3.79(s, 3H), 3.60(s, 2H), 3.11 (m, 4H), 2.64(m, 6H), 1.62(m, 2H), 1.30(t, 3H, J=7.08 Hz), 0.93(t, 3H, J=7.45 Hz),
Ethyl {4-[({4-{[4-(4-acetylphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol- 5-yl}methyl)sulfanyl]-2-propylphenoxy}acetate H NMR (CDCI3) 400MHz δ 8.02(d, 2H, J=8.28 Hz), 7.89(d, 2H, J=9.11 Hz), 7.69(d, 2H,
J=8.28 Hz), 7.24(m, 2H), 6.87(d, 2H, J=9.11 Hz), 6.64(d, 1 H, J=8.28 Hz), 4.62(ε 2H), 4.34(s, 2H), 4.26(q, 2H, J=7.17 Hz), 3.58(s, 2H), 3.35(t, 4H, J=4.97 Hz), 2.62(m, 6H), 2.54(s, 3H), 1.61 (m, 2H), 1.29(t, 3H, J=7.17 Hz), 0.91 (t, 3H, J=7.45 Hz),
Ethyl {4-[({4-{[4-(3-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1 !3. thiazol-5-yl}methyl)sulfanyl]-2-propylphenoxy}acetate 1H NMR (CDCI3) 400MHz δ 7.97(d, 2H, J=8.28 Hz), 7.64(d, 2H, J=8.2C Hz), 7.17(m, 3H), 6.58(d, 1 H, J=8.10 Hz), 6.51 (dd, 1 H, J=8.10, 2.07 Hz), 6.43(t, 1 H, J=2.07 Hz), 6.38(dd, 1 H, J=8.10, 2.07 Hz), 4.58(s, 2H), 4.30(s, 2H), 4.21 (q, 2H, J=7.13 Hz), 3.75(s, 3H), 3.53(s, 2H), 3.15(t, 4H, J=4.66 Hz), 2.57(m, 6H), 1.57(m, 2H), 1.24(t, 3H, J=7.13 Hz), 0.87(t, 3H, J=7.41 Hz),
Ethyl {4-[({4-[(4-acetyl-1 -piperazinyl)methyl]-2-[4-(trif luoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyl)sulfanyl]-2-propylphenoxy}acetate H NMR (CDCI3) 400MHz δ 7.93(d, 2H, J=8.28 Hz), 7.62(d, 2H, J=8.28 Hz), 7.14(m, 2H), 6.57(d, 1 H, J=8.28 Hz), 4.58(s, 2H), 4.20(m, 4H), 3.56(t, 2H, J=4.91 Hz), 3.45(s, 2H), 3.38(t, 2H, J=4.91 Hz), 2.55(t, 2H, J=7.33 Hz), 2.37(m, 4H), 2.03(s, 3H), 1.53(m, 2H), 1.22(t, 3H, J=7.16 Hz), 0.85(t, 3H, J=7.33 Hz),
Ethyl {4-[({4-{[4-(4-fluorophenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol- 5-yl}methyl)sulfanyl]-2-propylphenoxy}acetate H NMR (CDCI3) 400MHz δ 7.97(d, 2H, J=8.28 Hz), 7.64(d, 2H, J=8.28 Hz), 7.19(m, 2H),
6.92(m, 2H), d.83(m, 2H), 6.58(d, 1H, J=8.28 Hz), 4.56(s, 2H), 4.29(s, 2H), 4.20(q, 2H, J=7.13 Hz), 3.53(s, 2H), 3.06(t, 4H, J=4.91 Hz), 2.57(m, 6H), 1.55(m, 2H), 1.24(t, 3H, J=7.13 Hz), 0.86(t, 3H, J=7.41 Hz),
Ethyl 2-{4-[({4-{[4-(2,4-dimethoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]- 1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoate
1H NMR (CDCy 300MHz δ 8.02(d, 2H, J=8.28 Hz), 7.67(d, 2H, J=8.28 Hz), 7.26(d, 1 H, J=2.21 Hz), 7.16(dd, 1 H, J=8.55, 2.21 Hz), 6.87(d, 1 H, J=8.55 Hz), 6.60(d, 1 H, J=8.55 Hz), 6.50(d, 1 H, J=2.48 Hz), 6.42(dd, 1 H, J=8.55, 2.48 Hz), 4.72(q, 1 H, J=6.90 Hz), 4.38(s, 2H), 4.21 (q, 2H, J=7.08 Hz), 3.85(s, 3H), 3.79(s, 3H), 3.61 (s, 2H), 3.04(br s, 4H), 2.70(br s, 4H), 2.26(s, 3H), 1.63(d, 3H, J=6.90 Hz), 1.24(t, 3H, J=7.04 Hz),
phenyl 4-({5-({[4-(2-ethoxy-1 ,1 -dimethyl-2-oxoethoxy)phenyl]thio}methyl)-2-[4- (trifluoromethyl)phenyl]-1,3-thiazol-4-yl}methyl)piperazine-1-carboxylate ^o a 500ml 3-neck round-bottom flask equipped with a magnetic stir-bεr low temperature thermometer with thermometer adapter, addition funnel and N2 inlet was added ethyl 2-{4-[({4- (hydroxymethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}-2- methylpropanoate (300mg, 0.59mmoles, 1eq) and dry CH2CI2 (4ml, 0.15M) and cooled to 0 °C. Methanesulfonyl chloride (0.055ml, 0.71 mmoles, 1.2eq) was added neat all at once. Triethylamine (0.12ml, 0.89mmoles, 1.5eq) was added dropwise maintaining the internal temperature below 5°C and was stirred at 0 °C for 30 minutes. The reaction mixture was transferred to a separatory funnel and washed with H20, brine and the organic fraction was dried over Na2S04. After filtration the solvent was removed under reduced pressure to yield the corresponding mesylate in quantitative yield. Because of the unstable nature of the mesylate, the product was not characterized and was progressed onto the next stage without purification. To the crude mesylate dissolved in dry THF (3ml, 0.20M) was added piperazine (559mg, 5.9mmoles, 10eq) and the reaction mixture was refluxed for 5 hours. After cooling to room temperature the solvent was removed in vacuo. The residue was partitioned between EtOAc and H20 and after the phases were separated the organic fraction was dried over Na2S04, filtered and concentrated in vacuo to yield a quantitative amount of product. The product was used without characterization and purification.
The crude piperazine was dissolved in dry CH2CI2 (5ml, 0.12M) and to it was added phenylchloroformate (0.08ml, 0.65mmoles, 1.1eq) and triethylamine (0.248ml, 1.8mmoles, 3eq) and was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc and washed with 0.1 N HCI twice, H20, brine, dried over Na2S04, filtered and concentrated in vacuo to yield after silica gel chromatography 125mg (32% over three steps) of product.
1H NMR (CDCI3) 400MHz δ 7.95(d, 2H, J=8.28 Hz), 7.65(d, 2H, J=8.28 Hz), 7.33(m, 2H), 7.26(d, 2H, J=8.79 Hz), 7.17(t, 1 H, J=7.59 Hz), 7.06(d, 2H, J=7.59 Hz), 6.74(d, 2H, J=8.79 Hz), 4.32(s, 2H), 4.18(q, 2H, J=7.07 Hz), 3.61 (m, 6H), 2.51 (br s, 4H), 1.57(s, 6H), 1.20(t, 3H, J=7.07 Hz),
The following compounds were made the same procedure used for phenyl 4-({5-({[4-(2- ethoxy-1 ,1-dimethyl-2-oxoethoxy)phenyl]thio}methyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-4- yl}methyl)piperazine-1-carboxylate except no extra base was used when the other reactant was an isocyanate.
Phenyl 4-({5-({[4-(2-ethoxy-1-methyl-2-oxoethoxy)-3-methylphenyl]sulfanyl}methyl)-2-[4- (trifluoromethyl)phenyl]-1,3-thiazol-4-yl}methyl)-1-piperazinecarboxylate
1H NMR (CDCy 300MHz δ 7.97(d, 2H, J=8.28 Hz), 7.77(d, 2H, J=8.28 Hz), 7.60(m, 5H), 7.20(d, 1 H, J=2.21 Hz), 7.10(dd, 1 H, J=8.55, 2.21 Hz), 6.57(d, 1 H, J=8.55 Hz), 4J4(q, 1 H, J=6.71 Hz), 4.20(m, 4H), 3.48(s, 2H), 3.06(br s, 4H), 2.56(br s, 4H), 2.24(s, 3H), 1.65(d, 3H, J=6.71 Hz), 1.25(t, 3H, J=7.04 Hz),
benzyl 4-({5-({[4-(2-ethoxy-1-methyl-2-oxoethoxy)-3-methylphenyl]thio}methyl)-2-[4- (trifluoromethyl)phenyll-1,3-thiazol-4-yl}methyl)piperazine-1-carboxylate 1H NMR (CDCl3) 300MHz δ 8.01 (d, 2H, J=8.00 Hz), 7.69(d, 2H, J=8.00 Hz), 7.36(m, 5H),
7.26(d, 1 H, J=2.21 Hz), 7.15(dd, 1 H, J=8.55, 2.21 Hz), 6.60(d, 1 H, J=8.55 Hz), 5.16(s, 2H), 4.74(q, 1 H, J=6.62 Hz), 4.31 (s, 2H), 4.21 (q, 2H, J=7.08 Hz), 3.55(m, 6H), 2.47(br s, 4H), 2.26(s, 3H), 1.65(d, 3H, J=6.62 Hz), 1.25(t, 3H, J=7.08 Hz),
Isopropyl 4-{[5-({[4-(2-ethoxy-1-methyl-2-oxoethoxy)-3-methylphenyl]sulfanyl}methyl)-2-(4- fluorophenyl)-1,3-thiazol-4-yl]methyl}-1-piperazinecarboxylate
1H NMR (CDCI3) 400MHz δ 7.84(m, 2H), 7.22(d, 1 H, J=2.20 Hz), 7.09(m, 3H), 6.55(d, 1 H, J=8.42 Hz), 4.89(m, 1 H), 4.68(q, 1 H, J=6J8 Hz), 4.26(s, 2H), 4.16(q, 2H, J=7.20 Hz), 3.47(m, 6H), 2.40(br s, 4H), 2.22(s, 3H), 1.61(d, 3H, J=6.78 Hz), 1.27(m, 9H), Ethyl 2-{4-[({4-{[4-(cyclopentylcarbonyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3- thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoate
1H NMR (CDCIg) 300MHz δ 8.00(d, 2H, J=8.28 Hz), 7.67(d, 2H, J=8.28 Hz), 7.24(d, 1 H, J=2.21 Hz), 7.14(dd, 1 H, J=8.28, 2.21 Hz), 6.59(d, 1 H, J=8.28 Hz), 4.73(q, 1 H, J=6.71 Hz), 4.31 (s, 2H), 4.19(q, 2H, J=7.17 Hz), 3.65(br s, 2H), 3.50(br s, 4H), 2.87(m, 1 H), 2.45(t, 4H, J=4.69 Hz), 2.23(s, 3H), 1.73(m, 11 H), 1.24(t, 3H, J=7.17 Hz),
Ethyl 2-{4-[({4-{[4-(cyclopropylcarbonyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3- thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoate 1H NMR (CDCy 300MHz δ 8.00(d, 2H, J=8.28 Hz), 7.68(d, 2H, J=8.28 Hz), 7.27(d, 1H,
J=2.21 Hz), 7.15(dd, 1 H, J=8.28, 2.21 Hz), 6.59(d, 1 H, J=8.28 Hz), 4.73(q, 1 H, J=6J1 Hz), 4.31 (s, 2H), 4.20(q, 2H, J=7.08 Hz), 3.67(br s, 4H), 3.55(s, 2H), 2.49(br s, 4H), 2.26(s, 3H), 1 J4(m, 1 H), 1.64(d, 3H, J=6J1 Hz), 1.25(t, 3H, J=7.08 Hz), 1.00(m, 2H), 0.76(m, 2H),
Ethyl 2-{4-[({4-{[4-(cyclobutylcarbonyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3- thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoate
1H NMR (CDCI3) 300MHz δ 7.99(d, 2H, J=8.28 Hz), 7.67(d, 2H, J=8.28 Hz), 7.24(d, 1 H, J=2.21 Hz), 7.13(dd, 1 H, J=8.28, 2.21 Hz), 6.58(d, 1 H, J=8.28 Hz), 4.73(q, 1 H, J=6.71 Hz), 4.28(s, 2H), 4.19(q, 2H, J=7.17 Hz), 3.64(t, 2H, J=4.83 Hz), 3.52(s, 2H), 3.36(t, 2H, J=4.83 Hz), 3.24(m, 1 H), 2.47(m, 4H), 2.08(m, 9H), 1.63(d, 3H, J=6J1 Hz), 1.24(t, 3H, J=7.17 Hz),
Methyl 4-({5-({[4-(2-ethoxy-1-methyl-2-oxoethoxy)-3-methylphenyl]sulfanyl}methyl)-2-[4- (trifluoromethyl)phenyl]-1,3-thiazol-4-yl}methyl)-1-piperazinecarboxylate
1H NMR (CDCI3) 300MHz δ 8.00(d, 2H, J=8.28 Hz), 7.68(d, 2H, J=8.28 Hz), 7.26(d, 1 H, J=2.21 Hz), 7.14(dd, 1 H, J=8.28, 2.21 Hz), 6.59(d, 1 H, J=8.28 Hz), 4J3(q, 1 H, J=6.71 Hz), 4.31 (s, 2H), 4.20(q, 2H, J=7.17 Hz), 3.71 (s, 3H), 3.50(m, 6H), 2.44(br s, 4H), 2.26(s, 3H), 1.65(d, 3H, J=6.71 Hz), 1.25(t, 3H, J=7.17 Hz),
Ethyl 2-{2-methyl-4-[({4-{[4-(3-methylbutanoyl)-1-piperazinyl]methyl}-2-[4- (trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoate
1H NMR (CDCI3) 300MHz δ 8.00(d, 2H, J=8.28 Hz), 7.67(d, 2H, J=8.28 Hz), 7.24(d, 1 H, J=2.21 Hz), 7.14(dd, 1 H, J=8.55, 2.48 Hz), 6.59(d, 1 H, J=8.55 Hz), 4.73(q, 1 H, J=6.71 Hz), 4.30(s, 2H), 4.20(q, 2H, J=7.08 Hz), 3.65(br s, 2H), 3.54(s, 2H), 3.47(t, 2H, J=4.69 Hz), 2.45(t, 4H, J=4.83 Hz), 2.26(s, 3H), 2.12(m, 3H), 1.64(d, 3H, J=6J1 Hz), 1.24(t, 3H, J=7.08 Hz), 0.96(d, 6H, J=6.35 Hz),
Ethyl 2-{4-[({4-{[4-(4-fluorobenzoyl)-1-piperazinyl]methyl}-2-r4-(trifluoromethyl)phenyl]-1,3- thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoate
1H NMR (CDCI3) 300MHz δ 8.00(d, 2H, J=8.28 Hz), 7.69(d, 2H, J=8.28 Hz), 7.43(m, 2H), 7.24(d, 1 H, J=2.39 Hz), 7.11 (m, 3H), 6.59(d, 1 H, J=8.55 Hz), 4.73(q, 1 H, J=6J1 Hz), 4.30(s, 2H), 4.19(q, 2H, J=7.17 Hz), 3.65(m, 6H), 2.53(m, 4H), 2.25(s, 3H), 1.64(d, 3H, J=6.71 Hz), 1.25(t, 3H, J=7.1 Hz), Ethyl 2-{2-methyl-4-[({4-{[4-(propylsulfonyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]- 1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoate
1H NMR (CDCI3) 300MHz δ, 8.00(d, 2H, J=8.28 Hz), 7.68(d, 2H, J=8.28 Hz), 7.26(d, 1 H, J=2.21 Hz), 7.15(dd, 1 H, J=8.28, 2.21 Hz), 6.59(d, 1 H, J=8.28 Hz), 4J4(q, 1 H, J=6.71 Hz), 4.28(s, 2H), 4.20(q, 2H, J=7.08 Hz), 3.55(s, 2H), 3.30(t, 4H, J=4.55 Hz), 2.89(m, 2H), 2.56(t, 4H, J=4.28 Hz), 2.26(s, 3H), 1.87(m, 2H), 1.65(d, 3H, J=6.62 Hz), 1.25(t, 3H, J=7.04 Hz), 1.07(t, 3H, J=7.17 Hz).
Ethyl 2-{4-[({4-[(4-butyryl-1-piperazinyl)methyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]-2-methylphenoxy}propanoate
1H NMR (CDCI3) 300MHz δ 8.00(d, 2H, J=8.28 Hz), 7.67(d, 2H, J=8.2fj Hz), 7.26(d, 1 H, J=2.21 Hz), 7.14(dd, 1 H, J=8.55, 2.21 Hz), 6.59(d, 1 H, J=8.55 Hz), 4.73(q, 1 H, J=6J1 Hz), 4.30(s, 2H), 4.20(q, 2H, J=7.08 Hz), 3.64(m, 2H), 3.54(s, 2H), 3.45(t, 2H, J=4.83 Hz), 2.45(t, 4H, J=4.83 Hz), 2.31 (t, 2H, J=7.31 Hz), 2.25(s, 3H), 1.66(m, 5H), 1.24(t, 3H, J=7.08 Hz), 0.98(t, 3H, J=7.31 Hz),
Ethyl 2-{2-methyl-4-[({4-[(4-pentanoyl-1-piperazinyl)methyl]-2-[4-(trifluoromethyl)phenyl]-1,3- thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoate H NMR (CDCI3) 300MHz δ 8.00(d, 2H, J=8.28 Hz), 7.67(d, 2H, J=8.28 Hz), 7.26(d, 1 H, J=2.21 Hz), 7.14(dd, 1 H, J=8.28, 2.21 Hz), 6.58(d, 1 H, J=8.28 Hz), 4J3(q, 1 H, J=6.71 Hz), 4.30(s, 2H), 4.19(q, 2H, J=7.27 Hz), 3.64(m, 2H), 3.54(s, 2H), 3.46(t, 2H, J=4.83 Hz), 2.45(t, 4H, J=4.83 Hz), 2.32(t, 2H, J=7.45 Hz), 2.24(s, 3H), 1.61 (m, 5H), 1.37(m, 2H), 1.24(t, 3H, J=7.27 Hz), 0.93(t, 3H, J=7.45 Hz),
Ethyl 2-{4-[({4-{[4-(4-methoxybenzoyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3- thiazol-5-yl}rnethyl)sulfanyl]-2-methylphenoxy}propanoate
1H NMR (CDCy 300MHz δ 8.00(d, 2H, J=8.28 Hz), 7.67(d, 2H, J=8.28 Hz), 7.40(d, 2H, J=8.83 Hz), 7.24(d, 1 H, J=2.21 Hz), 7.14(dd, 1 H, J=8.28, 2.21 Hz), 6.92(d, 2H, J=8.83 Hz), 6.59(d, 1 H, J=8.28 Hz), 4.73(q, 1 H, J=6J1 Hz), 4.30(s, 2H), 4.19(q, 2H, J=7.08 Hz), 3.84(s, 3H), 3.63(m, 6H), 2.49(br s, 4H), 2.25(s, 3H), 1.64(d, 3H, J=6J1 Hz), 1.24(t, 3H, J=7.08 Hz),
Ethyl 2-{4-[({4-[(4-benzoyl-1-piperazinyl)methyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]-2-methylphenoxy}propanoate
1H NMR (CDCI3) 300MHz δ 7.99(d, 2H, J=8.55 Hz), 7.67(d, 2H, J=8.55 Hz), 7.41 (m, 5H), 7.24(d, 1 H, J=2.21 Hz), 7.15(dd, 1 H, J=8.55, 2.21 Hz), 6.59(d, 1 H, J=8.55 Hz), 4.73(q, 1 H, J=6J1 Hz), 4.30(s, 2H), 4.19(q, 2H, J=7.04 Hz), 3.83(br s, 2H), 3.56(s, 2H), 3.39(br s, 2H), 2.50(br s, 4H), 2.25(s, 3H), 1.64(d, 3H, J=6.71 Hz), 1.24(t, 3H, J=7.04 Hz),
isobutyl 4-({5-({[4-(2-ethoxy-1-methyl-2-oxoethoxy)-3-methylphenyl]sulfanyl}methyl)-2-[4- (trifluoromethyl)phenyl]-1,3-thiazol-4-yl}methyl)-1-piperazinecarboxylate 1H NMR (CDCI3) 300MHz δ, 8.00(d, 2H, J=8.28 Hz), 7.68(d, 2H, J=8.28 Hz), 7.26(d, 1H,
J=2.21 Hz), 7.14(dd, 1 H, J=8.28, 2.21 Hz), 6.59(d, 1 H, J=8.55 Hz), 4.73(q, 1 H, J=6J1 Hz), 4.32(s, 2H), 4.20(q, 2H, J=7.08 Hz), 3.88(d, 2H, J=6.62 Hz), 3.53(m, 6H), 2.46(br s, 4H), 2.25(s, 3H), 1.94(m, 1 H), 1.65(d, 3H, J=6.62 Hz), 1.25(t, 3H, J=7.17 Hz), 0.95(d, 6H, J=6.62 Hz).
Ethyl 2-{2-methyl-4-[({4-{[4-(2-thienylcarbonyl)-1-piperazinyl]methyl}-2-[4- (trifluoroinet!f yl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanϋate
1H NMR (CDCI3) 300MHz δ 8.01 (d, 2H, J=8.28 Hz), 7.68(d, 2H, J=8.28 Hz), 7.45(d, 1 H, J=4.97 Hz), 7.30(d, 1 H, J=3.59 Hz), 7.25(d, 1 H, J=2.21 Hz), 7.15(dd, 1 H, J=8.28, 2.21 Hz), 7.05(m, 1 H), 6.60(d, 1 H, J=8.28 Hz), 4.74(q, 1 H, J=6.71 Hz), 4.31(s, 2H), 4.19(q, 2H, J=7.08 Hz), 3.78(t, 4H, J=4.69 Hz), 3.56(s, 2H), 2.55(t, 4H, J=4.69 Hz), 2.25(s, 3H), 1.65(d, 3H, J=6J1 Hz), 1.25(t, 3H, J=7.08 Hz),
Phenyl 4-{[5-({[4-(2-ethoxy-1-methyl-2-oxoethoxy)-3-methylphenyl]sulfanyl}methyl)-2-(4- fluorophenyl)^ ,3-thiazpl-4-yl]methyl}-1-piperazinecarboxylate
1H NMR (CDCy 400MHz δ 7.85(m, 2H), 7.33(m, 2H), 7.15(m, 7H), 6.57(d, 1H, J=8.61 Hz), 4.69(q, 1 H, J=6.78 Hz), 4.27(s, 2H), 4.14(q, 2H, J=7.14 Hz), 3.63(br s, 4H), 3.50(s, 2H), 2.49(br s, 4H), 2.23(s, 3H), 1.60(d, 3H, J=6.78 Hz), 1.22(t, 3H, J=7.14 Hz),
Ethyl 2-{4-[({4-({4-[4-(dimethylamino)benzoyl]-1 -piperazinyl}methyl)-2-[4- (trifluorosiiethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoate 1H NMR (CDCy 300MHz δ 8.01 (d, 2H, J=8.28 Hz), 7.68(d, 2H, J=8.28 Hz), 7.37(d, 2H,
J=8.83 Hz), 7.25(d, 1 H, J=2.21 Hz), 7.15(dd, 1 H, J=8.28, 2.21 Hz), 6.68(d, 2H, J=8.83 Hz), 6.60(d, 1H, J=8.28 Hz), 4.73(q, 1H, J=6.71 Hz), 4.32(s, 2H), 4.20(q, 2H, J=7.17 Hz), 3.67(br s, 4H), 3.55(s, 2H), 3.02(s, 6H), 2.51 (br s, 4H), 2.26(s, 3H), 1.65(d, 3H, J=6J1 Hz), 1.25(t, 3H, J=7.17 Hz),
Ethyl 2-{4-[({4-{[4-(cyclohexylcarbonyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3- thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoate H NMR (CDCy 300MHz δ 8.00(d, 2H, J=8.28 Hz), 7.68(d, 2H, J=8.28 Hz), 7.26(d, 1 H, J=2.21 Hz), 7.14(dd, 1 H, J=8.28, 2.21 Hz), 6.59(d, 1 H, J=8.28 Hz), 4.73(q, 1 H, J=6.71 Hz), 4.30(s, 2H), 4.20(q, 2H, J=7.08 Hz), 3.58(m, 6H), 2.47(m, 5H), 2.26(s, 3H), 1.63(m, 11 H), 1.27(m, 5H),
Ethyl 2-{2-methyl-4-[({4-({4-[(methylamino)carbonyl]-1-piperazinyl}methyl)-2-[4- (trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoate
1H. NMR (CDCy 300MHz δ 8.01 (d, 2H, J=8.28 Hz), 7.67(d, 2H, J=8.28 Hz), 7.27(d, 1 H, J=2.21 Hz), 7.14(dd, 1 H, J=8.55, 2.21 Hz), 6.53(d, 1 H, J=8.55 Hz), 4.84(m, 1H), 4.70(q, 1H, J=6.90 Hz), 4.25(m, 4H), 3.52(m, 2H), 3.29(m, 4H), 2.80(d, 3H, J=4.42 Hz), 2.35(t, 4H, J=4.83 Hz), 2.22(s, 3H), 1.64(d, 3H, J=6.90 Hz), 1.25(t, 3H, J=7.17 Hz),
Ethyl 2-{4-[({4-({4-[(fert-butylamino)carbonyn-1 -piperazinyl>methyl)-2-[4- (trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoate 1H NMR (CDCI3) 300MHz δ 8.00(d, 2H, J=8.28 Hz), 7.67(d, 2H, J=8.28 Hz), 7.27(d, 1 H,
J=2.21 Hz), 7.14(dd, 1 H, J=8.28, 2.21 Hz), 6.56(d, 1 H, J=8.28 Hz), 4.72(q, 1 H, J=6.81 Hz), 4.42(s, 1 H), 4.33(d, 1 H, J .63 Hz), 4.26(d, 1 H, J=63 Hz), 4.20(q, 2H, J=7.08 Hz), 3.53(s, 2H), 3.29(m, 4H), 2.40(t, 4H, J=4.69 Hz), 2.25(s, 3H), 1.63(d, 3H, J=6.81 Hz), 1.35(s, 9H), 1.25(t, 3H, J=7.09 Hz),
Ethyl 2-{4-[({4-({4-[(4-methoxyanilino)carbonyl]-1-piperazinyl}methyl)-2-[4- (trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoate
1H NMR (CDCy 300MHz δ 8.05(d, 2H, J=8.28 Hz), 7.73(d, 2H, J=8.28 Hz), 7.23(m, 4H), 6.84(d, 2H, J=6.90 Hz), 6.66(d, 1 H, J=8.55 Hz), 4.83(q, 1 H, J=6.76 Hz), 4.36(d, 1 H, J=63 Hz), 4.30(d, 1 H, J= 63 Hz), 4.16(q, 2H, J=7.08 Hz), 3.75(s, 3H), 3.46(m, 6H), 2.43(t, 4H, J=4.83 Hz), 2.21 (s, 3H), 1.58(d, 3H, J=6.76 Hz), 1.20(t, 3H, J=7.08 Hz),
Ethyl 2-{2-methyl-4-[({4-[(4-{[(2-phenylethyl)amino]carbonyl}-1-piperazinyl)methyl]-2-[4- (trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoate
1H NMR (CDCy 300MHz δ 8.01 (d, 2H, J=8.28 Hz), 7.68(d, 2H, J=8.28 Hz), 7.24(m, 7H), 6.57(d, 1 H, J=8.55 Hz), 4.74(m, 2H), 4.33(d, 1 H, J .35 Hz), 4.26(d, 1 H, J .35 Hz), 4.20(q, 2H, J=7.04 Hz), 3.50(m, 4H), 3.28(m, 4H), 2.84(t, 2H, J=7.04 Hz), 2.38(t, 4H, J=4.83 Hz), 2.25(s, 3H), 1.65(d, 3H, J=6.62 Hz), 1.26(t, 3H, J=7.04 Hz),
Ethyl 2-{2-methyl-4-[({4-{[4-(phenylsulfonyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]- 1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoate 1H NMR (CDCy 300MHz δ 7.97(d, 2H, J=8.28 Hz), 7.77(d, 2H, J=8.28 Hz), 7.59(m, 5H),
7.20(d, 1 H, J=2.21 Hz), 7.10(dd, 1 H, J=8.55, 2.21 Hz), 6.58(d, 1 H, J=8.55 Hz), 4.73(q, 1 H, J=6.71 Hz), 4.19(m, 4H), 3.48(s, 2H), 3.07(br s, 4H), 2.56(br s, 4H), 2.25(s, 3H), 1.65(d, 3H, J=6.71 Hz), 1.25(t, 3H, J=7.04 Hz),
Ethyl 2-{2-methyl-4-[({2-[4-(trifluoromethyl)phenyl]-4-[(4-{[4-(trifluoromethyl)phenyl]sulfonyl}-1- piperazinyl)methyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoate
1H NMR (CDCI3) 300MHz δ 7.98(d, 2H, J=8.28 Hz), 7.90(d, 2H, J=8.55 Hz), 7.81 (d, 2H, J=8.55 Hz), 7.67(d, 2H, J=8.28 Hz), 7.21 (d, 1 H, J=2.21 Hz), 7.10(dd, 1H, J=8.28, 2.21 Hz), 6.58(d, 1 H, J=8.28 Hz), 4.74(q, 1 H, J=6.71 Hz), 4.21 (m, 4H), 3.49(s, 2H), 3.09(br s, 4H), 2.58(br s, 4H), 2.24(s, 3H), 1.66(d, 3H, J=6.71 Hz), 1.26(t, 3H, J=7.17 Hz),
Ethyl 2-{4-[({4-({4-[(4-methoxyphenyl)sulfonyl]-1-piperazinyl}methyl)-2-[4- (trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoate H NMR (CDCI3) 300MHz δ 7.97(d, 2H, J=8.28 Hz), 7.67(m, 4H), 7.20(d, 1 H, J=2.21 Hz), 7.09(dd, 1 H, J=8.55, 2.21 Hz), 6.99(d, 2H, J=8.83 Hz), 6.58(d, 1 H, J=8.55 Hz), 4.74(q, 1 H, J=6.71 Hz), 4.20(m, 4H), 3.87(s, 3H), 3.49(s, 2H), 3.05(br s, 4H), 2.54(br s, 4H), 2.24(s, 3H), 1.66(d, 3H, J=6.71 Hz), 1.25(t, 3H, J=7.04 Hz),
hyl 2-{4-[({4-{[4-(ethylsulfonyl)-1-piperazinyπmethyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol- 5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoate 1H NMR (CDCy 300MHz δ 8.00(d, 2H, J=8.28 Hz), 7.68(d, 2H, J=8.28 Hz), 7.26(d, 1 H, J=2.48 Hz), 7.15(d, 1 H, J=2.48 Hz), 6.59(d, 1 H, J=8.28 Hz), 4.74(q, 1 H, J=6.81 Hz), 4.28(s, 2H), 4.20(q, 2H, J=7.17 Hz), 3.55(s, 2H), 3.32(t, 4H, J=4.69Hz), 2.96(q, 2H, J=7.45 Hz), 2.55(br s, 4H), 2.25(s, 3H), 1.65(d, 3H, J=6.81 Hz), 1.38(t, 3H, J=7.45 Hz), 1.25(1, 3H, J=7.17 Hz),
Ethyl 2-{2-methyl-4-[({4-{[4-(methylsulfonyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]- 1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoate
1H NMR (CDCy 300MHz δ 8.00(d, 2H, J=8.55 Hz), 7.68(d, 2H, J=8.55 Hz), 7.26(d, 1 H, J=2.21 Hz), 7.15(dd, 1 H, J=8.55, 2.21 Hz), 6.59(d, 1H, J=8.55 Hz), 4.73(q, 1 H, J=6J1 Hz), 4.27(s, 2H), 4.20(q, 2H, J=7.17 Hz), 3.56(s, 2H), 3.24(t, 4H, J=4.55 Hz), 2.78(s, 3H), 2.58(t, 4H, J=4.55 Hz), 2.24(s, 3H), 1.64(d, 3H, J=6J1 Hz), 1.25(t, 3H, J=7.17 Hz),
Ethyl 2-{4-[({4-[(4-{[4-(acetylamino)phenyl]sulfonyl}-1-piperazinyl)methyl]-2-[4- (trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoate 1H NMR (CDCI3) 300MHz δ 8.40(s, 1 H), 7.96(d, 2H, J=8.28 Hz), 7.66(m, 6H), 7.16(d, 1 H,
J=2.21 Hz), 7.07(dd, 1H, J=8.28, 2.21 Hz), 6.56(d, 1H, J=8.28 Hz), 4.73(q, 1 H, J=6.71 Hz), 4.22(m, 4H), 3.51 (s, 2H), 3.03(br s, 4H), 2.55(br s, 4H), 2.19(m, 6H), 1.65(d, 3H, J=6.71 Hz), 1.27(t, 3H, J=7.04 Hz),
Ethyl 2-{4-[({4-({4-[(4-fluorophenyl)sulfonyl]-1-piperazinyl}methyl)-2-[4-(trifluoromethyl)phenyl]- 1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoate
1H NMR (CDCI3) 300MHz δ 7.97(d, 2H, J=8.28 Hz), 7.77(m, 2H), 7.66(d, 2H, J=8.28 Hz), 7.22(m, 3H), 7.10(dd, 1 H, J=8.55, 2.21 Hz), 6.58(d, 1H, J=8.55 Hz), 4.74(q, 1 H, J=6.81 Hz), 4.20(m, 4H), 3.49(s, 2H), 3.07(br s, 4H), 2.57(t, 4H, J=4.42 Hz), 2.24(s, 3H), 1.65(d, 3H, J=6.81 Hz), 1.27(t, 3H, J=7.17 Hz),
Ethyl 2-{4-[({4-{[4-(2-furoyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]-2-methylphenoxy}propanoate
1H NMR (CDCI3) 300MHz δ 8.00(d, 2H, J=8.28 Hz), 7.67(d, 2H, J=8.28 Hz), 7.48(s, 1 H), 7.24(d, 1 H, J=2.21 Hz), 7.15(dd, 1 H, J=8.28, 2.21 Hz), 6.99(d, 1 H, J=3.59 Hz), 6.60(d, 1 H, J=8.28
Hz), 6.48(m, 1 H), 4.73(q, 1 H, J=6.71 Hz), 4.31 (s, 2H), 4.20(q, 2H, J=7.08 Hz), 3.83(br s, 4H), 3.55(s, 2H), 2.54(t, 4H, J=4.83 Hz), 2.25(s, 3H), 1.64(d, 3H, J=6J1 Hz), 1.24(t, 3H, J=7.08 Hz),
Ethyl 2-{4-[({4-({4-[(isopropylamino)carbonyl]-1-piperazinyl}methyl)-2-[4- (trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy>propanoate
1H NMR (CDCI3) 300MHz δ, 8.01 (d, 2H, J=8.28 Hz), 7.67(d, 2H, J=8.28 Hz), 7.27(d, 1 H, J=1.93 Hz), 7.14(ddd, 1 H, J=8.55, 2.21 , 0.55 Hz), 6.55(d, 1 H, J=8.28 Hz), 4.72(q, 1 H, J=6.81 Hz), 4.47(d, 1 H, J=7.17 Hz), 4.26(m, 4H), 3.99(m, 1H), 3.52(m, 2H), 3.29(m, 4H), 2.37(t, 4H, J=4.69 Hz), 2.24(s, 3H), 1.64(d, 3H, J=6.62 Hz), 1.25(t, 3H, J=7.17 Hz), 1.15(m, 6H), Ethyl 2-{4-[({4-{I4-(methoxyacetyl)-1-piperazinyl]methyl}-2-[4-(trifluorometiιyl)phenyl1-1,3- thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoate
1H NMR (CDCI3) 300MHz δ 8.00(d, 2H, J=8.28 Hz), 7.67(d, 2H, J=8.28 Hz), 7.24(d, 1 H, J=2.21 Hz), 7.14(dd, 1 H, J=8.28, 2.21 Hz), 6.58(d, 1 H, J=8.28 Hz), 4.73(q, 1 H, J=6.71 Hz), 4.29(s, 2H), 4.20(q, 2H, J=7.17 Hz), 4.10(s, 2H), 3.64(m, 2H), 3.54(s, 2H), 3.48(m, 2H), 3.42(s, 3H), 2.47(m, 4H), 2.25(s, 3H), 1.64(d, 3H, J=6.71 Hz), 1.24(t, 3H, J=7.17 Hz),
Ethyl 2-{4-[({4-[(4-isobutyryl-1-piperazinyl)methyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]-2-methylphenoxy}propanoate 1H NMR (CDCy 300MHz δ 8.00(d, 2H, J=8.28 Hz), 7.68(d, 2H, J=8.28 Hz), 7.24(d, 1 H,
J=2.48 Hz), 7.14(dd, 1 H, J=8.55, 2.48 Hz), 6.59(d, 1 H, J=8.55 Hz), 4J4(q, 1 H, J=6.71 Hz), 4.30(s, 2H), 4.20(q, 2H, J=7.17 Hz), 3.58(m, 6H), 2.79(m, 1 H), 2.46(t, 4H, J=4.55 Hz), 2.24(s, 3H), 1.64(d, 3H, J=6.71 Hz), 1.24(t, 3H, J=7.17 Hz), 1.13(d, 6H, J=6J1 Hz),
Ethyl 2-{4-[({4-{[4-(2,2-dimethylpropanoyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]- 1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoate
1H NMR (CDCI3) 300MHz δ 8.00(d, 2H, J=8.28 Hz), 7.68(d, 2H, J=8.28 Hz), 7.24(d, 1H, J=2.21 Hz), 7.15(dd, 1 H, J=8.28, 2.21 Hz), 6.60(d, 1 H, J=8.28 Hz), 4.73(q, 1 H, J=6.71 Hz), 4.31 (s, 2H), 4.20(q, 2H, J=7.08 Hz), 3.66(t, 4H, J=4.69 Hz), 3.52(s, 2H), 2.48(t, 4H, J=4.69 Hz), 2.26(s, 3H), 1.65(d, 3H, J=6.71 Hz), 1.27(m, 12H),
Ethyl 2-{4-[({4-({4-[(4-fluoroanilino)carbonyl]-1-piperazinyl}methyl)-2-[4- (trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoate
1H NMR (CDCy 300MHz δ 8.04(d, 2H, J=8.28 Hz), 7.69(d, 2H, J=8.28 Hz), 7.33(m, 2H), 7.17(dd, 1 H, J=8.55, 2.21 Hz), 6.96(m, 2H), 6.52(d, 1 H, J=8.55 Hz), 4.72(q, 1 H, J=6.90 Hz), 4.27(m, 4H), 3.59(d, 1 H, J .52 Hz), 3.51 (d, 1 H, J .52 Hz), 3.34(m, 4H), 2.33(t, 4H, J=4.97Hz), 2.22(s, 3H), 1.62(d, 3H, J=6.90 Hz), 1.26(t, 3H, J=7.17 Hz),
Ethyl 2-{4-[({4-({4-[(3-methoxyanilino)carbonyl]-1-piperazinyl}methyl)-2-[4- (trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoate
1H NMR (CDCy 300MHz δ 8.04(d, 2H, J=8.28 Hz), 7.69(d, 2H, J=8.28 Hz), 7.31 (d, 1 H,
J=2.21 Hz), 7.16(m, 2H), 6.89(m, 2H), 6.59(dd, 1 H, J=8.28, 2.21 Hz), 6.53(m, 1 H), 473(q, 1H, J=6.90
Hz), 4.27(m, 4H), 3.79(s, 3H), 3.56(m, 2H), 3.37(m, 4H), 2.36(t, 4H, J=4.69 Hz), 2.23(s, 3H), 1.63(d,
3H, J=6.90 Hz), 1.26(t, 3H, J=7.17 Hz),
Ethyl 2-{4-[({4-{[4-(aminocarbonyl)-1 -piperazinyl]methyl}-2-[4-(trif luoromethyl)phenyl]-1 ,3- thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoate
1H NMR (CDCI3) 300MHz δ 8.01 (d, 2H, J=8.28 Hz), 7.68(d, 2H, J=8.28 Hz), 7.26(d, 1H,
J=2.21 Hz), 7.15(dd, 1 H, J=8.55, 2.21 Hz), 6.56(d, 1 H, J=8.55 Hz), 4.83(s, 2H), 4.71 (q, 1 H, J=6.81 Hz), 4.26(m, 4H), 3.55(m, 2H), 3.34(m, 4H), 2.41 (t, 4H, J=4.55 Hz), 2.24(s, 3H), 1.63(d, 3H, J=6.81
Hz), 1.25(t, 3H, J=7.04 Hz), Ethyl 2-{4-[({4-({4-[(cyclohexylamino)carbonyl]-1-piperazinyl}methyl)-2-[4- (trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoate
1H NMR (CDCI3) 300MHz δ 8.00(d, 2H, J=8.28 Hz), 7.67(d, 2H, J=8.28 Hz), 7.26(d, 1 H, J=2.21 Hz), 7.14(dd, 1 H, J=8.55, 2.21 Hz), 6.54(d, 1 H, J=8.55 Hz), 4.72(q, 1 H, J=6.81 Hz), 4.49(d, 1 H, J=7.45 Hz), 4.25(m, 4H), 3.64(m, 1 H), 3.52(m, 2H), 3.28(m, 4H), 2.38(t, 4H, J=4.83 Hz), 2.24(s, 3H), 1.95(m, 2H), 1.65(m, 7H), 1.38(m, 2H), 1.24(t, 3H, J=7.04 Hz), 1.10(m, 2H),
Ethyl 2-{2-msthyl-4-[({4-({4-[(propylamino)carbonyl]-1-piperazinyl}methyl)-2-[4- (trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoate
1H NMR (CDCy 300MHz δ 8.01 (d, 2H, J=8.00 Hz), 7.68(d, 2H, J=8.00 Hz), 7.27(d, 1 H, J=2.21 Hz), 7.14(dd, 1 H, J=8.28, 2.21 Hz), 6.54(d, 1 H, J=8.28 Hz), 4.75(m, 2H), 4.26(m, 4H), 3.53(m, 2H), 3.33(m, 4H), 3.19(m, 2H), 2.36(t, 4H, J=4.69 Hz), 2.23(s, 3H), 1.64(d, 3H, J=6.90 Hz), 1.52(m, 2H), 1.25(t, 3H, J=7.17 Hz), 0.92(t, 3H, J=7.45 Hz),
Ethyl 2-{4-[({4-({4-[(ethylamino)carbonyl]-1-piperazinyl}methyl)-2-[4-(trifluoromethyl)phenyl]- 1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoate
1H NMR (CDCy 300MHz δ 8.02(d, 2H, J=8.28 Hz), 7.69(d, 2H, J=8.28 Hz), 7.27(d, 1 H, J=2.21 Hz), 7.15(dd, 1H, J=8.55, 2.21 Hz), 6.54(d, 1H, J=8.55 Hz), 4.72(m, 2H), 4.26(m, 4H), 3.54(m, 2H), 3.29(m, 6H), 2.38(t, 4H, J=4.28 Hz), 2.25(s, 3H), 1.65(d, 3H, J=6.90 Hz), 1.26(t, 3H, J=7.04 Hz), 1.15(t, 3H, J=7.31 Hz),
Ethyl [2-methyl-4-({[4-{[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]methyl}-2 (4- {trifluoromethyl}phenyl)-1,3-thiazol-5-yl]methyl}sulfanyl)phenoxy]acetate To a stirred solution of ethyl [4-({[4-(hydroxymethyl)-2-(4-{trifluoromethyl}phenyl)-1 ,3-thiazol-5- yl]methyl}sulfanyl)-2-methylphenoxy]acetate (40mg, 0.08mmoles, 1eq) in dry toluene (2ml) was added 3-(5-methyl-1 ,2,4-oxadiazol-3-yl)phenol (15mg, 0.088mmoles, 1.1eq) followed by triphenylphosphine (25mg, 0.096mmoles, 1.2eq) as a solid. Diisopropylazodicarboxylate (0.017ml, 0.088mmoles, 1.1 eq) was then added dropwise and the reaction was stirred for 2 hours at room temperature. The reaction was then partitioned between EtOAc and H20. After the separation of the phases the organic phase was washed with 0.1 N NaOH, brine, dried over Na2S04, filtered, concentrated in vacuo and purified via flash chromatography (10% EtOAc/Hexanes to 35% EtOAc/Hexanes) to yield 40mg (76%) of product.
1H (CDCy 400MHz δ 8.02(d, 2H, J=8.20 Hz), 7.68(m, 4H), 7.38(t, 1 H, J=7.95 Hz), 7.19(d, 1 H, J=1.54), 7.12(dd, 1 H, J=8.37, 2.39 Hz), 7.06(dd, 1 H, J=8.20, 2.39 Hz), 6.57(d, 1 H, J=8.20 Hz), 4.95(s, 2H), 4.59(s, 2H), 4.27(s, 2H), 4.22(q, 2H, J=7.12 Hz), 2.65(s, 3H), 2.18(s, 3H), 1.25(t, 3H, J=7.12 Hz). TLC(50% EtOAc/Hexanes) Rf = 0.76
The following compounds were made using the general Mitsunobu reaction conditions detailed above: Ethyl 2-{2-methyl-4-[({4-{[3-(5-methyl-1 ,2,4-oxadiazol-3-yl)phenoxy]methyl}-2-[4- (trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoate
1H NMR (CDCI3) 400MHz δ 8.03(d, 2H, J=8.20 Hz), 7.69(m, 4H), 7.39(m, 1 H), 7.20(m, 1 H), 7.09(m, 2H), 6.55(d, 1 H, J=8.37 Hz), 4.99(d, 1 H, J .62 Hz), 4.95(d, 1 H, J .62 Hz), 4.70(q, 1 H, J=6.78 Hz), 4.16(q, 2H, J=7.18 Hz), 2.65(m, 3H), 2.18(s, 3H), 1.61 (d, 3H, J=6.78 Hz), 1.20(t, 3H, J=7.18 Hz),
Ethyl (2-methyl-4-{[(4-{[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]methyl}-2-phenyl-1,3-thiazol-5- yl)methyl]sulfanyl}phenoxy)acetate H NMR (CDCI3) 400MHz δ 7.91 (m, 2H), 7.69(m, 2H), 7.40(m, 4H), 7.20(d, 1 H, J=2.39 Hz), 7.13(dd, 1 H, J=8.37, 2.39 Hz), 7.07(dd, 1 H, J=8.37, 2.39 Hz), 6.57(d, 1 H, J=8.37 Hz), 5.29(s, 2H), 4.59(s, 2H), 4.27(s, 2H), 4.23(q, 2H, J=7.18 Hz), 2.65(s, 3H), 2.19(s, 3H), 1.27(t, 3H, J=7.18 Hz).
Ethyl [2-methyl-4-({[2-(4-{trifluoromethyl}phenyl)-4-(phenoxymethyl)-1,3-thiazol-5- yl]methyl}sulfanyl)phenoxy]acetate 1H NMR (CDCy 300MHz δ 8.04(d, 2H, J=8.23 Hz), 7.71(d, 2H, J=8.23 Hz), 7.34(m, 2H),
7.23(d, 1 H, J=2.39 Hz), 7.15(dd, 1 H, J=8.49, 2.39 Hz), 7.00(m, 3H), 6.59(d, 1 H, J=8.49 Hz), 4.94(s, 2H), 4.64(s,.2H), 4.27(m, 4H), 2.26(s, 3H), 1.32(t, 3H, J=7.17 Hz). TLC(30% EtOAc/Hexanes) Rf= 0.71
Ethyl [2-methyl-4-({[4-[(2-methylphenoxy)methyl]-2-(4-{trifluoromethyl}phenyl)-1,3-thiazol-5- yl]methyl}sulfanyl)phenoxy]acetate
1H (CDCy 300MHz δ 8.05(d, 2H, J=8.23 Hz), 7.72(d, 2H, J=8.23 Hz), 7.21 (m, 4H), 6.93(m, 2H), 6.59(d, 1 H, J=8.49 Hz), 5.00(s, 2H), 4.64(s, 2H), 4.29(m, 4H), 2.26(m, 6H), 1.32(t, 3H, J=7.17 Hz). TLC(20% EtOAc/Hexanes) Rf = 0J0
Ethyl [2-methyl-4-({[4-[(3-methylphenoxy)methyl]-2-(4-{trifluoromethyl}phenyl)-1,3-thiazol-5- yl]methyl}sulfanyl)phenoxy]acetate
1H (CDCy 300MHz δ 8.05(d, 2H, J=8.49 Hz), 7.71 (d, 2H, J=8.49 Hz), 7.35(m, 1 H), 7.26(dd, 1 H, J=2.39, 0.53 Hz), 7.21 (t, 1 H, J=7.43 Hz), 7.15(ddd, 1 H, J=8.49, 2.39, 0.53 Hz), 6.81 (m, 2H), 6.60(d, 1 H, J=8.49 Hz), 4.92(s, 2H), 4.65(s, 2H), 4.29(m, 4H), 2.38(s, 3H), 2.25(s, 3H), 1.32(t, 3H, J=7.17 Hz). TLC(20% EtOAc/Hexanes) Rf = 0.70
Ethyl [2-methyl-4-({[4-[(4-methylphenoxy)methyl]-2-(4-{trifluoromethyl}phenyl)-1,3-thiazol-5- yl]methyl}sulfanyl)phenoxy]acetate H (CDCy 300MHz δ 8.04(d, 2H, J=8.23 Hz), 7.71 (d, 2H, J=8.23 Hz), 7.27(dd, 1 H, J=2.39,
0.80 Hz), 7.14(m, 3H), 6.88(d, 2H, J=8.49 Hz), 6.60(d, 1 H, J=8.23 Hz), 4.92(s, 2H), 4.64(s, 2H), 4.29(m, 4H), 2.33(s, 3H), 2.26(s, 3H), 1.32(t, 3H, J=7.17 Hz). TLC(20% EtOAc/Hexanes) Rf = 0.70
Ethyl [4-({[4-[(3-cyanophenoxy)methyπ-2-(4-{trifluoromethyl}phenyl)-1,3-thiazol-5- yj]methyl}sulfanyl)-2-methylphenoxy'|acetate 1H (CDCI3) 300MHz δ 8.03(d, 2H, J=8.23 Hz), 7.71(d, 2H, J=8.23 Hz), 7.24(m, 6H), 6.61 (d, 1 H, J=8.23 Hz), 4.88(s, 2H), 4.67(s, 2H), 4.28(m, 4H), 2.24(s, 3H), 1.31 (t, 3H, J=7.17 Hz) . TLC(20% EtOAc/Hexanes) R, = 0.52
Ethyl [4-({[4-[(4-cyanophenoxy)methyl]-2-(4-{trifluoromethyl}phenyl)-1,3-thiazol-5- yl]methyl}sulfanyl)-2-methylphenoxy]acetate
1H (CDCI3) 300MHz δ 8.03(d, 2H, J=8.23 Hz), 7.73(d, 2H, J=8.23 Hz), 7.61 (d, 2H, J=9.03 Hz), 7.23(dd, 1 H, J=2.39, 0.53 Hz), 7.14(ddd, 1 H, J=8.49, 2.39, 0.53 Hz), 7.01 (d, 2H, J=9.03 Hz), 6.59(d, 1 H, J=8.49 Hz), 4.91 (s, 2H), 4.66(s, 2H), 4.28(m, 4H), 2.25(s, 3H), 1.32(t, 3H, J=7.17 Hz) . TLC(20% EtOAc/Hexanes) Rf = 0.52
Ethyl [2-methyl-4-({[4-{[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]methyl}-2-(4- {trifluoro}methylphenyl)-1,3-thiazol-5-yl]methyl}sulfanyl)phenoxy]acetate
1H (CDCI3) 400MHz δ 7.99(m, 4H), 7.67(d, 2H, J=8.20 Hz), 7.21(dd, 1 H, J=2.39, 0.68 Hz), 7.10(m, 1 H), 7.02(m, 2H), 6.54(d, H, J=8.37 Hz), 4.90(s, 2H), 4.59(s, 2H), 4.23(m, 4H), 2.62(s, 3H), 2.20(s, 3H), 1.26(t, 3H, J=7.18 Hz) . TLC(50% EtOAc/Hexanes) Rf = 0.68
Ethyl (2-methyl-4-{[(4-{[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]methyl}-2-phenyl-1,3-thiazol-5- yl)methyl]sulfanyl}phenoxy)acetate 1H NMR (CDCy 400MHz δ 7.98(d, 2H, J=8.89 Hz), 7.89(m, 2H), 7.42(m, 3H), 7.21 (d, 1 H,
J=2.39 Hz), 7.10(dd, 1 H, J=8.37, 2.39 Hz), 7.02(d, 2H, J=8.89 Hz), 6.54(d, 1 H, J=8.37 Hz), 4.89(s, 2H), 4.59(s, 2H), 4.23(q, 2H, J=7.18 Hz), 3.47(s, 2H), 2.62(s, 3H), 2.20(s, 3H), 1.27(t, 3H, J=7.18 Hz),
Ethyl 2-{2-methyl-4-[({4-{[4-(5-methyl-1)2,4-oxadiazol-3-yl)phenoxy]methyl}-2-[4- (trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoate
1H NMR (CDCI3) 300MHz δ 8.04(m, 4H), 7.71 (d, 2H, J=8.23 Hz), 7.25(d, 1 H, J=2.39 Hz), 7.11(dd, 1 H, J=8.49, 2.39 Hz), 7.06(d, 2H, J=9.03 Hz), 6.57(d, 1 H, J=8.49 Hz), 4.97(d, 1 H, J .68 Hz), 4.91 (d, 1 H, J .68 Hz), 4.73(q, 1 H, J=6.81 Hz), 4.29(s, 2H), 4.20(q, 2H, J=7.17 Hz), 2.67(s, 3H), 2.23(s, 3H), 1.65(d, 3H, J=6.81 Hz), 1.25(t, 3H, J=7.17 Hz),
Ethyl 2-(2-methyl-4-{[(4-{[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]methyl}-2-phenyl-1,3-thiazol- 5-yl)methyl]sulfanyl}phenoxy)propanoate
1H NMR (CDCI3) 400MHz δ 7.99(d, 2H, J=9.06 Hz), 7.89(m, 2H), 7.42(m, 3H), 7.20(d, 1 H, J=2.22 Hz), 7.06(dd, 1 H, J=8.37, 2.22 Hz), 7.02(d, 2H, J=9.06 Hz), 6.52(d, 1 H, J=8.37 Hz), 4.89(d, 1 H, J .62 Hz), 4.85(d, 1 H, J .62 Hz), 4.68(q, 1 H, J=6.78 Hz), 4.23(s, 2H), 4.17(q, 2H, J=7.12 Hz), 2.62(s, 2H), 2.19(s, 3H), 1.61 (d, 3H, J=6.78 Hz), 1.21 (t, 3H, J=7.12 Hz),
4-(Chloromethyl)-2-methylphenyl methyl ether
To a stirred solution of (4-methoxy-3-methyIphenyl)methanol (2.31g, 15 tδmmoles, 1eq) in anhydrous CH2CI2 (50ml, 0.3M) was added hexachloroethane (3.59g, 15.18mmoles, 1eq) and triphenylphosphine (3.98g, 15.18mmoles, 1eq). This mixture was stirred at room temperature overnight at which point the reaction was transferred to a separatory funnel and washed with H20, brine, dried over Na2S04, filtered, concentrated in vacuo and filtered through a plug of silica gel (30% EtOAc/Hexanes) to yield 2.59g (100%) of product.
1H NMR (CDCI3) 400MHz δ 7.16(m, 2H), 6.76(d, 1 H, J=8.10 Hz), 4.52(s, 2H), 3.81 (s, 3H), 2.19(s, 3H),
(4-Methoxy-3-methylbenzyl)(triphenyl)phosphoniιιm chloride
To a 250ml round-bottom flask equipped with a magnetic stir-bar and N2 inlet was added 4- (Chloromethyl)-2-methylphenyl methyl ether (2.59g, 15.18mmoles, 1eq), dry toluene (50ml, 0.3M) and triphenylphosphine (3.98g, 15.1 δmmoles, 1eq). The reaction mixture was refluxed overnight. After cooling to room temperature the solvent was removed in vacuo, the residue washed with hexanes and the solid/liquid mixture was filtered to yield 4.48g (71 %) of solid product.
1H NMR (CDCy 400MHz δ 7.66(m, 15H), 6.93(m, 1 H), 6.54(m, 2H), 5.24(d, 2H, J .79 Hz),
3.68(s, 3H), 1.90(s, 3H),
4-[(Tetrahydro-2H-pyran-2-yloxy)methyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5- carbaldehyde
To a stirred mixtureof pyridinium chlorochromate (6.9g, 32.12mmoles, 4eq) in dry CH2CI2
(40ml, 0.2M) was added {4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-[4-(trifluoroπιethyl)phenyl]-1 ,3- thiazol-5-yl}methanol (3.0g, 8.03mmoles, 1eq) in CH2CI2 (10ml). The mixture was stirred at room temperature for 4 hours at which time the reaction mixture was quenched by allowing it to stir with sat.
NaHC03. Once the quenching had ceased the reaction was filtered through Celite and the filtrate was transferred to a separatory funnel where the phases were separated. The organic phase was dried over Na2S04 and concentrated in vacuo to yield 2.18g (73%) of clean aldehyde. The crude product was used without purification.
1H NMR (CDCI3) 400MHz δ 10.39(s, 1 H), 8.09(d, 2H, J=8.28 Hz), 7.70(d, 2H, J=8.28 Hz), 5.22(d, 1 H, J .97 Hz), 4.96(d, 1 H, J .97 Hz), 4.83(m, 1 H), 3.87(m, 1 H), 3.58(m, 1 H), 1.81 (m, 2H), 1.61 (m, 4H),
5-[(E)-2-(4-Methoxy-3-methylphenyl)ethenyl]-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-[4- (trifluoromethyl)phenyl]-1 ,3-thiazole
To a suspension of NaH (60% dispersion in mineral oil, 242mg, 6.32mmoles, 1.4eq) in dry CH2CI2 (15ml) was added (4-Methoxy-3-methylbenzyl)(triphenyl)phosphonium chloride (2.62g, 6.32mmoles, 1.4eq). This was allowed to stir at room temperature for 1.5 hours followed by the dropwise addition of 4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazole- 5-carbaldehyde (1.68g, 4.51 mmoles, 1eq) in anhydrous carbon tetrachloride (25ml). The resulting reaction mixture was refluxed overnight at which point (after cooling to room temperature) the reaction was washed with 1 N NaOH, H20, brine, dried over Na2S04 and concentrated in vacuo to yield a >100% yield of a light green oil. The crude material was used without purification. 1H NMR (CDCI3) 400MHz δ 8.05(d, 2H, J=8.24 Hz), 7.68(d, 2H, J=8.24 Hz), 7.29(m, 3H), 6.85(m, 2H), 4.98(d, 1 H, J=12.09 Hz), 4.81 (m, 2H), 4.01 (m, 1 H), 3.86(s, 3H), 3.62(m, 1 H), 2.26(s, 3H), 1.72(m, 6H),
{5-[2-(4-Methoxy-3-methylphenyl)ethyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-4-yl}methanol
To a stirred solution of 5-[(E)-2-(4-Methoxy-3-methylphenyl)ethenyl]-4-[(tetrahydro-2H-pyran- 2-yloxy)methyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazole (2.20g, 4.51 mmoles, 1eq) in EtOH (50ml, 0.1 M) was added 10%Pd/C (500mg). The system was degassed using an aspirator and H2 was introduced via a balloon. The reaction was heated to 60 °C overnight which, after cooling to room temperature, was filtered through Celite, washed with EtOAc and concentrated in vacuo. This reaction yielded after chromatography 760mg (41 %) of clean alcohol.
1H NMR (CDCy 400MHz δ 7.98(d, 2H, J=8.24 Hz), 7.66(d, 2H, J=8.24-Hz), 6.91 (m, 2H), 6.72(d, 11-i, J^8.10 Hz), 4.54(s, 2H), 3.80(s, 3H), 3.11 (t, 2H, J=7.42 Hz), 2.87(t;2H, J=7.42 Hz), 2.18(s, 3H), 2.05(br s, 1 H),
4-(Bromomethyl)-5-[2-(4-methoxy-3-methylphenyl)ethyl]-2-[4-(trifluoromethyl)phenyl]-1,3- thiazole
To a 100ml round-bottom flask equipped with a magnetic stir-bar and N2 inlet was added {5- [2-(4-Methoxy-3-methylphenyl)ethyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-4-yl}methanol (0.708g, 1.74mmoles, 1eq), CH2CI2 (20ml), carbon tetrabromide (0.634g, 1.91 mmoles, 1.1 eq) and triphenylphosphine (0.501 g, 1.91 mmoles, 1.1 eq) in that order. The reaction was stirred overnight at which time it was diluted with CH2CI2 and washed with H20, brine, dried over Na2S04, concentrated in vacuo and purified via silica gel chromatography to yield 573mg (70%) of product. H NMR (CDCy 400MHz δ 7.97(d, 2H, J=8.10 Hz), 7.64(d, 2H, J=8.10 Hz), 6.94(m, 2H), 6.73(d, 1 H, J=8.10 Hz), 4.46(m, 2H), 3.79(m, 3H), 3.12(t, 2H, J= 7.24 Hz), 2.91 (t, 2H, J=7.24 Hz), 2.19(s, 3H),
4-(2-{4-(Bror.ιomethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}ethyl)-2-methylphenol
To a 50ml round-bottom flask equipped with a magnetic stir-bar, an addition funnel and N2 inlet was added 4-(Bromomethyl)-5-[2-(4-methoxy-3-methylphenyl)ethyl]-2-[4-(trifluoromethyl)phenyl]- 1 ,3-thiazole (468mg, LOmmoles, 1eq) and dry CH2CI2 (15ml, 0.1 M). The mixture was cooled to -78°C (dry ice/acetone) after which boron tribromide (1M in CH2CI2, 3ml, 3.0mmoles, 3eq) was added dropwise over the course of 15minutes. After the addition was complete, the cold bath was removed and the reaction was allowed to warm to room temperature and stirred for 1 hour. After this time, the reaction was cooled to 0°C and quenched very carefully with water. Once the reaction was quenched, it was transferred to a separatory funnel where the phases were separated. The aqueous fraction was washed three times with CH2CI2 and the combined organic fractions were dried over Na2S04, filtered, concentrated in vacuo to yield a quantitative yield of the titled phenol. The product was used without purification. 1H NMR (CDCI3) 400MHz δ 7.96(d, 2H, J=8.28 Hz), 7.65(d, 2H, J=8.28 Hz), 6.93(m, 1 H), 6.85(d, 1 H, J=8.10 Hz), 6.68(d, 1 H, J=8.10 Hz), 5.42(br s, 1 H), 4.45(s, 2H), 3.10(t, 2H, J=7.41 Hz), 2.89(t, 2H, J=7.41 Hz), 2.20(s, 3H),
The following compounds were made by amine displacement as described above for General
Alkylation with an Amine:
4-(2-{4-{[4-(4-Methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}ethyl)-2-methylphenol 1H NMR (CDCy 400MHz δ 7.94(d, 2H, J=8.28 Hz), 7.59(d, 2H, J=8.28 Hz), 6.91 (d, 1 H,
J=2.24 Hz), 6.86(d, 2H, J=9.31 Hz), 6.80(d, 2H, J=9.31 Hz), 6J4(dd, 1 H, J=8.10, 2.24 Hz), 6.58(s, 1 H), 6.51 (d, 1 H, J=8.10 Hz), 3.73(s, 3H), 3.58(s, 2H), 3.12(t, 2H, J=7.50 Hz), 3.05(t, 4H, J=4.48 Hz), 2.84(t, 2H, J=7.50 Hz), 2.64(t, 4H, J=4.48 Hz), 2.20(s, 3H),
1-{4-[4-({5-[2-(4-Hydroxy-3-methylphenyl)ethyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-4- yl}methyl)-1-piperazinyl]phenyl}ethanone
1H NMR (CD3OD) 400MHz δ 8.07(d, 2H, J=8.28 Hz), 7.85(d, 2H, J=9.14 Hz), 7.73(d, 2H, J=8.28 Hz), 6.92(d, 2H, J=9.14 Hz), 6.88(d, 1H, J=2.24 Hz), 6.77(dd, 1 H, J=8.28, 2.24 Hz), 6.60(d, 1 H, J=8.28 Hz), 3.49(s, 2H), 3.32(t, 4H, J=4.83 Hz), 3.18(t, 2H, J=7.07 Hz), 2.88(t, 2H, J=7.07 Hz), 2.51 (t, 4H, J=4.83 Hz), 2.47(s, 3H), 2.10(s, 3H),
4-(2-{4-{[4-(3-Methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}ethyl)-2-methylphenol
1H NMR (CD3OD) 400MHz δ 8.07(d, 2H, J=8.10 Hz), 7J2(d, 2H, J=8.10 Hz), 7.09(t, 1H, J=8.28 Hz), 6.88(s, 1 H), 6.77(dd, 1 H, J=8.45, 2.24 Hz), 6.59(d, 1 H, J=8.45 Hz), 6.51 (dd, 1 H, J=8.28, 2.24 Hz), 6.46(t, 1 H, J=2.24 Hz), 6.38(dd, 1 H, J=8.28, 2.24 Hz), 3.72(s, 3H), 3.49(s, 2H), 3.18(t, 2H, J=6.47 Hz), 3.09(br s, 4H), 2.87(t, 2H, J=6.47 Hz), 2.52(br s, 4H), 2.10(s, 3H),
4-(2-{4-{[4-(4-Chlorophenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}ethyl)-2-methylphenol
1H NMR (CD3OD) 400MHz δ 8.07(d, 2H, J=8.10 Hz), 7.73(d, 2H, J=8.10 Hz), 7.15(d, 2H, J=9.14 Hz), 6.89(m, 3H), 6.77(dd, 1 H, J=8.45, 2.41 Hz), 6.59(d, 1 H, J=8.45 Hz), 3.49(s, 2H), 3.18(t, 2H, J=7.16 Hz), 3.09(t, 4H, J=5.09 Hz), 2.87(t, 2H, J=7.16 Hz), 2.53(t, 4H, J=5.09 Hz), 2.10(s, 3H),
2-[4-(2-{4-{[4-(4-Methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyiiphenyl]-1,3-thiazol- 5-yl}ethyl)-2-methylphenoxy]-2-methylpropanoic acid
To a 25ml round-bottom flask equipped with a magnetic stir-bar and N2 inlet was added 4-(2- {4-{[4-(4-Methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}ethyl)-2- methylphenol (53mg, 0.094mmoles, 1eq) in acetone (2ml, 0.05M) followed by the addition of 2- trichloromethyl-2-propanol (33mg, 0.188mmoles, 2eq) and NaOH (pellets, 30mg, 0.752mmoles, 8eq). This was stirred at room temperature overnight after which the acetone was removed in vacuo and the resulting residue was partitioned between EtOAc and 1 N HCI. The phases were then separated and the organic fraction was washed with brine, dried over Na2S04 and concentrated in vacuo to yield after chromatography 23mg (40%) of product.
1H NMR (CDCy 400MHz δ 7.95(d, 2H, J=8.28 Hz), 7.62(d, 2H, J=8.28 Hz), 6.88(m, 5H), 6.67(br s, 1 H), 6.54(br s, 1 H), 3.72(s, 3H), 3.61(s, 2H), 3.23(m, 8H), 2.80(m, 4H), 2.15(s, 3H), 1.54(s, 6H),
MS(ES-) M-H= 652.2
The following compounds were also made by alkylation of a phenol with trichloromethyl-2- propanol as above:
2-[4-(2-{4-{[4-(4-Chlorophenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}ethyl)-2-methylphenoxy]-2-methylpropanoic acid
1H NMR (CD3OD) 400MHz δ 7.99(d, 2H, J=8.28 Hz), 7.66(d, 2H, J=8.28 Hz), 7.55(s, 1 H), 7.14(d, 2H, J=8.10 Hz), 6.91 (s, 1 H), 6.82(d, 2H, J=8.10 Hz), 6.66(br s, 1 H), 3.55(s, 2H), 3.28(m, 2H) buried under MeOH signal, 3.12(br s, 4H), 2.85(s, 2H), 2.65(br s, 4H), 2.13(s, 3H), 1.52(s, 6H), MS(ES+) M+H= 659.0
2-[4-(2-{4-{[4-(3-Methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol- 5-yl}ethyl)-2-methylphenoxy]-2-methylpropanoic acid H NMR (CD3OD) 400MHz δ 8.02(d, 2H, J=8.10 Hz), 7.68(d, 2H, J=8.10 Hz), 7.09(t, 1 H, J=8.10 Hz), 6.92(s, 1 H), 6.76(m, 2H), 6.50(dd, 1 H, J=8.10, 2.07 Hz), 6.42(t, 1 H, J=2.07 Hz), 6.37(dd, 1 H, J=8.10, 2.07 Hz), 3.72(s, 3H), 3.51 (s, 2H), 3.28(m, 2H) buried under MeOH signal, 3.12(m, 4H), 2.83(t, 2H, J=7.16 Hz), 2.61 (m, 4H), 2.15(s, 3H), 1.48(s, 6H), MS(ES-) M-H= 652.1
2-[4-(2-{4-{[4-(4-Acetylphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}ethyl)-2-methylphenoxy]-2-methylpropanoic acid
1H NMR (CD3OD) 400MHz δ 8.01 (d, 2H, J=8.10 Hz), 7.82(d, 2H, J=9.14 Hz), 7.67(d, 2H, J=8.10 Hz), 6.90(m, 3H), 6.66(m, 2H), 3.61 (s, 2H), 3.37(br s, 4H), 3.13(t, 2H, J=6.81 Hz), 2.82(t, 2H, J=6.81 Hz), 2.68(br s, 4H), 2.44(s, 3H), 2.11 (s, 3H), 1.50(s, 6H),
2-Methyll-2-{2-methyl-4-[({4-[4-(trifluoromethyl)benzyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-
5-yl}methyl)sulfanyl]phenoxy}propanoic acid From 2-methyl-4-[({4-(4-trifluoromethyl)benzyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyl)sulfanyl]phenol (0.021 g, 0.04 mmol), 2-methyl-2-{2-methyl-4-[({4-[4-(trifluoromethyl)benzyI]-
2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5-yI}methyl)suIfanyl]phenoxy}propanoic acid (0.006g, 25%) was obtained as a white solid.
1H NMR (CD3OD): δ 8.02 (d, 2 H), 7.78 (d, 2 H), 7.60 (d, 2 H), 7.30 (d, 2 H), 7.23 (s, 1 H), 7.16 (d, 1 H), 6.73 (d, 1 H), 4.29 (s, 2 H), 4.00 (s, 2 H), 2.17 (s, 3H), 1.61 (s, 6 H); 9F NMR (CD3OD): δ - 64.18 (s), -64.73 (s); MS m/z 626 (M+1); HPLC RT 4.273 (C18 4.2x100mm, 0-100% ACN/H20 (0.1 % TFA), 6min @ 2ml/min @254/220nm).
2-Methyll-2-{2-methyl-4-[({4-[4-(trifluoromethoxy)benzyl]-2-[4-(trifluoromethyl)phenyl]-1,3- thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic acid
From 2-methyI-4-[({4-(4-trifluoromethoxy)benzyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyl)sulfanyl]phenol (0.048g, 0.086 mmol), 2-methyl-2-{2-methyl-4-[({4-[4- (trifluoromethoxy)benzyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yI}methyl)sulfanyl]phenoxy}propanoic acid (0.013g, 23%) was obtained as a white solid. 1H NMR (CD3OD): δ 8.04 (d, 2 H), 7.74 (d, 2 H), 7.20 (m, 6 H), 6.72 (d, 1 H), 4.26 (s, 2 H),
3.95 (s, 2 H), 2.15 (s, 3 H), 1.61 (s, 6 H); 19F NMR (CD3OD): δ -59.86 (s), -64.72 (s); MS m/z 642
(M+1 ); HPLC RT 4.307 (C18 4.2x100mm, 0-100% ACN/H20 (0.1% TFA), 6min @ 2ml/min
@254/220nm).
2-{4-[({4-(4-methoxybenzyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2- methylphenoxy}-2-methylpropanoic acid
From 4-[({4-(4-methoxybenzyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methyl)sulfanyl]-2- methylphenol (0.022g, 0.04 mmol), 2-{4-[({4-(4-methoxybenzyl)-2-[4-(trifluoromethyI)phenyl]-1 ,3- thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}-2-methylpropanoic acid (0.003g, 12%) was obtained as a white solid. 1H NMR (CD3OD): δ 8.04 (d, 2 H), 7.76 (d, 2 H), 7.19 (s, 1 H), 7.14 (d, 1 H), 7.02 (d, 2 H), 6.81
(d, 2 H), 6.69 (d, 1 H), 4.21 (s, 2 H), 3.83 (s, 2 H), 3.78 (s, 3 H), 2.17 (s, 3 H), 1.60 (s, 6 H); MS m/z
588 (M+1); HPLC RT 4.136 (C18 4.2x100mm, 0-100% ACN/H20 (0.1 % TFA), 6min @ 2ml/min
@254/220nm).
2-Methyll-2-{2-methyl-4-[({4-[4-(methylsulfanyl)benzyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol- 5-yl}methyl)sulfanyl]phenoxy}propanoic acid
From 2-methyl-4-[({4-(4-methylsulfanyl)benzyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyl)sulfanyl]phenol (0.296g, 0.57 mmol), 2-methyl-2-{2-methyI-4-[({4-[4-(methylsulfanyl)benzyl]- 2-[4-(trifluoromethyl)phenyI]-1 ,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic acid (0.087g, 25%) was obtained as a white solid.
1H NMR (CD3OD): δ 8.04 (d, 2 H), 7.78 (d, 2 H), 7.13 (m, 6 H), 6.70 (d, 1 H), 4.22 (s, 2 H), 3.87 (s, 2 H), 2.47 (s, 3 H), 2.15 (s, 3 H), 1.60 (s, 6 H); MS m/z 604 (M+1); HPLC RT 4.220 (C18 4.2x100mm, 0-100% ACN/H20 (0.1 % TFA), 6min @ 2ml/min @254/220nm).
2-{4-[({4-(4-tert-butylbenzyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2- methylphenoxy}-2-methylpropanoic acid
From 4-[({4-(4-ferf-butyIbenzyl)-2-[4-(trifluoromethyI)phenyl]-1 ,3-thiazol-5-yl}methyl)sulfanyl]- 2-methylphenol (0.113g, 0.21 mmol), 2-{4-[({4-(4-terf-butylbenzyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3- thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}-2-methylpropanoic acid (0.012g, 9%) was obtained as a white solid. 1H NMR (CD3OD): δ 8.04 (d, 2 H), 7.76 (d, 2 H), 7.29 (d, 2 H), 7.22 (s, 1 H), 7.16 (d, 1 H), 7.03 (d, 2 H), 6.74 (d, 1 H); MS m/z 614 (M+1); HPLC RT 4.464 (C18 4.2x100mm, 0-100% ACN/H20 (0.1% TFA), 6min @ 2ml/min @254/220nm).
2-Methyll-2-{2-methyl-4-[({4-(3-thienylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}propanoic acid
From 2-methyl-4-[({4-(3-thienylmethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyI)sulfanyl]phenol (0.072g, 0.15 mmol), 2-methyl-2-{2-methyl-4-[({4-(3-thienylmethyl)-2-[4- (trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic acid (0.039g, 46%) was obtained as a cream solid.
1H NMR (CD3OD): δ 8.05 (d, 2 H), 7.76 (d, 2 H), 7.37 (t, 1 H), 7.20 (s, 1 H), 7.15 (d, 1H), 7.02 (s, 1 H), 6.96 (d, 1 H), 6.70 (d, 1 H), 4.23 (s, 2 H), 3.96 (s, 2 H), 2.20 (s, 3 H), 1.60 (s, 6 H); MS m/z 564 (M+1); HPLC RT 4. 12 (C18 4.2x100mm, 0-100% ACN/H20 (0.1% TFA), 6min @ 2ml/min @254/220nm). Ethyl 2-{2-methyl-4-[({4-[4-(trifluoromethoxy)benzyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}propanoate
FτOm 2-methyl-4-[({4-(4-trifluoromethoxy)benzyI]-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyl)sulfanyl]phenoI (0.17g, 0.31 mmol), ethyl 2-{2-methyl-4-[({4-[4-(trifluoromethoxy)benzyl]-2- [4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoate (0.17g, 83%) was obtained as a white solid. MS m/z 656 (M+1 ); HPLC RT 4.553 (C18 4.2x100mm, 0-100% ACN/H20 (0.1 % TFA), 6min @ 2ml/min @254/220nm).
Methyl {2-methyl-4-[({4-[4-(trifluoromethoxy)benzyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}acetate From 2-methyl-4-[({4-(4-trifluoromethoxy)benzyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyl)sulfanyl]phenol (0.17g, 0.31 mmol), methyl {2-methyl-4-[({4-[4-(trifluoromethoxy)benzyl]-2-[4- (trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetate (0.15g, 80%) was obtained as a white solid. MS m/z 628 (M+1); HPLC RT 4.398 (C184.2x100mm, 0-100% ACN/H20 (0.1% TFA), 6min @ 2ml/min @254/220nm).
Ethyl 2-{2-methyl-4-[({4-(3-thienylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyll)sulfanyllphenoxy}propanoate
From 2-methyI-4-[({4-(3-thienylmethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyl)sulfanyl]phenol, ethyl 2-{2-methyl-4-[({4-(3-thienylmethyl)-2-[4-(trifluoromethyl)phenyl]-l ,3- thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoate (0.225g, 0.47 mmol), (0.255g, 91 %) was obtained as a yellow oil.
MS m/z 578 (M+1 ); HPLC RT 4.412 (C18 4.2x100mm, 0-100% ACN/H20 (0.1 % TFA), 6min @ 2ml/min @254/220nm).
Methyl {2-methyl-4-[({4-(3-thienylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- y|}methyl)sulfanyl]phenoxy}acetate From 2-methyl-4-[({4-(3-thienylmethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyl)sulfanyI]phenol, methyl {2-methyl-4-[({4-(3-thienylmethyI)-2-[4-(trifluoromethyl)phenyl]-1 , 3- thiazol-5-yl}methyl)sulfanyl]phenoxy}acetate (0.225g, 0.47 mmol), (0.259g, 94%) was obtained as a yellow oil. MS m/z 550 (M+1 ); HPLC RT 4.243 (C18 4.2x100mm, 0-100% ACN/H20 (0.1% TFA), 6min
@ 2ml/min @254/220nm).
The following 2compounds were made by the Mitsunobu reaction of 4-[({4-{[4-(4- Methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyI)phenyl]-1 ,3-thiazol-5-yl}methyl)sulfanyl]-2- methylphenol with R and S Methyl lactate:
Methyl (2S)-2-{4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]- 1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoate
1H NMR (CDCI3) 400MHz δ 7.97(d, 2H, J=8.24 Hz), 7.64(d, 2H, J=8.24 Hz), 7.21 (d, 1 H, J=2.20 Hz), 7.11 (dd, 1H, J=8.42, 2.20 Hz), 6.86(d, 2H, J=9.16 Hz), 6.80(d, 2H, J=9.16 Hz), 6.54(d, 1 H, J=8.42 Hz), 4J0(q, 1 H, J=6.78 Hz), 4.30(s, 2H), 3.74(s, 3H), 3.69(s, 3H), 3.55(s, 2H), 3.06(br s, 4H), 2.62(br s, 4H), 2.21 (s, 3H), 1.60(d, 3H, J=6.78 Hz),
Methyl (2R)-2-{4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]- 1 ,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoate
1H NMR (CDCI3) 400MHz δ 7.97(d, 2H, J=8.24 Hz), 7.64(d, 2H, J=8.24 Hz), 7.22(d, 1 H,
J=2.01 Hz), 7.12(dd, 1 H, J=8.42, 2.01 Hz), 6.88(d, 2H, J=9.16 Hz), 6.80(d, 2H, J=9.16 Hz), 6.55(d,
1 H, J=8.42 Hz), 4J0(q, 1 H, J=6J8 Hz), 4.32(s, 2H), 3.73(s, 3H), 3.69(s, 3H), 3.55(s, 2H), 3.06(t, 4H,
J=4.76 Hz), 2.61 (br s, 4H), 2.22(s, 3H), 1.60(d, 3H, J=6.78 Hz),
2-{4-[({4-{[4-(4-Methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}-2-methylpropanoic acid
To a stirred solution of ethyl 2-{4-[({4-{[4-(4-methoxyphenyI)-1-piperazinyl]methyI}-2-[4-
(trifluoromethyl)phenyI]-1 ,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}-2-methylpropanoate (77.0g, 0.112moles, 1eq) in THF (600ml, 0.19M) was added MeOH (50ml) and a 1 N LiOH solution (6.18g in
250ml H20, 2.3eq). The mixture was refluxed for 5 hrs after which the THF was removed in vacuo.
The residue was diluted with EtOAc and to it was added 1N HCI until a pH of about 5 was reached.
The phases were separated and the organic fraction was concentrated in vacuo, then titrated with isopropyl acetate twice which was subsequently removed in vacuo each time. The crude product was then recrystallized from EtOH to yield 52g (71 %) of a white solid.
1H NMR (CD3OD) 400MHz δ 8.08(d, 2H, J=8.24 Hz), 7.75(d, 2H, J=8.24 Hz), 7.25(d, 2H, J=8.61 Hz), 6.94(d, 2H, J=9.16 Hz), 6.82(m, 4H), 4.28(s, 2H), 3.72(s, 3H), 3.59(s, 2H), 3.16(t, 4H, J=4.94 Hz), 2.96(t, 4H, J=4.94 Hz), 1.54(s, 6H),
CHN Analysis: Theory (C, 60.26%; H, 5.21%; N, 6.39%) Found (C, 60.11%; H, 5.31%; N, 6.23%)
HPLC (C-18, 3μm) 0%-95% Acetonitrile/Water over 8 minutes R,= 5.48minutes {4-[({4-benzyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2,5- dimethylphenoxy}acetic acid
Mass spec: calculated for C28H24F3N03S2: 543. Found: 544 (MH+). HPLC trace: retention time = 13.5 min (Alltima C18, 5 micron, 250mm column, Gradient elution with 70- 100% CH3CN/H20).
2-{4-[({4-benzyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2- methylphenoxy}propanoic acid
Elemental analysis calculated for C28H24F3N03S2: C: 61.8%, H: 4.5%, N: 2.6%. Found: C: 61.77%, H: 4.64%, N: 2.51 %. HPLC trace: retention Time .7 min (Alltima C18, 5 micron, 250 mm column, gradient elution with 70-100% CH3CN/H20).
2-{4-[({4-benzyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2,3- dimethylphenoxy}propanoic acid Elememtal analysis calculated for C29H26F3N03S2: C: 62.4%, H: 4.7%, N: 2.5%. Found: C:
62.58%, H: 4.93%, N: 2.44%. HPLC trace: retention time= 14.7 min (Alltima C18, 5 micron, 250 mm column using gradient elution with 70-100%CH3CN/H2O).
2-{4-[({4-benzyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2- fluorophon 'xy}propanoic acid
Mass spec calculated for C27H21F4N03S2: 547. Found: 548 (MH+). HPLC, Trace: retention time = 12.1 min (Alltima C18, 5 micron, 250 mm column using gradient elution with 70-100% CH3CN/H20).
(2S)-2-{4-[({4-{[4-(4-Methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3- thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid
1H NMR (CD3OD) 400MHz δ 8.07(d, 2H, J=8.24 Hz), 7.74(d, 2H, J=8.24 Hz), 7.19(d, 1 H, J=2.20 Hz), 7.09(dd, 1 H, J=8.42, 2.20 Hz), 6.91 (d, 2H, J=9.16 Hz), 6.80(d, 2H, J=9.16 Hz), 6.62(d, 1 H, J=8.42 Hz), 4.68(q, 1 H, J=6.78 Hz), 4.28(s, 2H), 3.71 (s, 3H), 3.48(s, 2H), 3.05(t, 4H, J=4.76 Hz), 2.69(t, 4H, J=4J6 Hz), 2.18(s, 3H), 1.57(d, 3H, J=6J8 Hz),
Chiral HPLC (Chiralpak, 2cm) 75% Carbon Dioxide/25% Methanol over 65minutes Rt@.88 minutes
(2R)-2-{4-[({4-{[4-(4-Methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3- thiazol-5-yl}methyl)sulfanyn-2-methylphenoxy}propanoic acid
1H NMR (CD3OD) 400MHz δ 8.11 (d, 2H, J=8.24 Hz), 7.76(d, 2H, J=8.24 Hz), 7.15(d, 1 H, J=2.20 Hz), 7.08(dd, 1 H, J=8.42, 2.20 Hz), 6.93(d, 2H, J=9.16 Hz), 6.82(d, 2H, J=9.16 Hz), 6.67(d, 1 H, J=8.42 Hz), 4.57(q, 1 H, J=6.78 Hz), 4.24(s, 2H), 3.71 (s, 3H), 3.54(s, 2H), 3.17(t, 4H, J=4J6 Hz), 3.02(t, 4H, J=4.76 Hz), 2.18(s, 3H), 1.55(d, 3H, J=6J8 Hz), Chiral HPLC (Chiralpak, 2cm) 75% Carbon Dioxide/25% Methanol over 65minutes R.T.58 minutes 2-(4-{[(2-(4-Fluorophenyl)-4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-1,3-thiazol-5- yl)methyl]sulfanyl}-2-methylphenoxy)-2-methylpropanoic acid
1H NMR (CD3OD) 400MHz δ 7.95(m, 2H), 7.18(m, 3H), 7.05(br s, 1 H), 6.93(d, 2H, J=8.61 Hz), 6.81 (d, 2H, J=8.61 Hz), 6.69(br s, 1 H), 4.22(s, 2H), 3.72(s, 3H), 3.55(s, 2H), 3.17(br s, 4H), 2.93(br s, 4H), 2.14(s, 3H), 1 ,59(s, 6H),
[4-({[4-[(4-Benzyl-1-piperazinyl)methyl]-2-(4-{trifluoromethyl}phenyl)-1,3-thiazol-5- yl]methyl}sulfanyl)-2-methylphenoxy]acetic acid
1H (CD3OD) 300MHz δ 8.15(d, 2H, J=8.23 Hz), 7.81 (d, 2H, J=8.23 Hz), 7.48(m, 5H), 7.24(s, 2H), 6.74(s, 1 H), 4.55(s, 2H), 4.28(s, 2H), 4.15(s, 2H), 3.46(s, 2H), 3.06(s, 4H), 2.49(s, 4H), 2.09(s, 3H) . MS(ES-) M-H= 625.98. TLC(10% MeOH/CH2CI2) Rf = 0.35
{2-Methyi-4-[({2-(4-{trifluoromethyl}phenyl)-4-[(4-methyl-1-piperidinyl)methyl]-1,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}acetic acid 1H (CD3OD) 300MHz δ 8.20(d, 2H, J=7.97 Hz), 7.85(d, 2H, J=7.97 Hz), 7.27(s, 1 H), 7.08(s,
1 H), 6.68(s, 1 H), 4.62(s, 2H), 4.29(s, 2H), 3.70(s, 2H), 2.86(s, 2H), 2.26(s, 3H), 1.90(s, 2H), 1.48(m, 5H), 1.06(s, 3H) . MS(ES-) M-H= 548.91. TLC(10% MeOH/CH2CI2) Rf = 0.24
[2-Methyl-4-({[4-{[4-(5-methyl-1 ,2,4-oxadiazol-3-yl)phenoxy]methyl}-2-(4- {trifluoromethyl}phenyl)-1,3-thiazol-5-yl]methyl}sulfanyl)phenoxy]acetic acid
1H (CDCy 400MHz δ 8.03(d, 2H, J=8.03 Hz), 7.93(d, 2H, J=8.89 Hz), 7.70(d, 2H, J=8.03 Hz), 7.19(d, 1 H, J=2.22 Hz), 7.07(dd, 1 H, J=8.37, 2.22 Hz), 6.96(d, 2H, J=8.89 Hz), 6.53(d, 1 H, J=8.37 Hz), 4.88(s, 2H), 4.64(s, 2H), 4.27(s, 2H), 2.65(s, 3H), 2.17(s, 3H) . TLC(5% MeOH/CH2CI2) Rf = 0.13. MS(ES-) M-H= 625.92
r2-Methyl-4-({r4-{[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]methyl}-2-(4- {trifluoromethyl}phenyl)-1,3-thiazol-5-yl]methyl}sulfanyl)phenoxy]acetic asid H (CDCI3) 400MHz δ 8.04(d, 2H, J=8.20 Hz), 7.69(m, 3H), 7.37(s, 2H), 7.16(dd, 1 H, J=8.20, 2.22 Hz), 7.05(dd, 1 H, J=8.20, 2.22 Hz), 6.91 (d, 1 H, J=2.22 Hz), 6.62(d, 1 H, J=8.20 Hz), 4.72(s, 2H), 4.43(s, 2H), 4.19(s, 2H), 2.73(s, 3H), 2.09(s, 3H) . TLC(5% MeOH/CH2Cl2) R{ = 0.13. MS(ES") M-H= 625.86
(2-Methyl-4-{[(2-(4-{trifluoromethyl}phenyl)-4-{[4-(2-methylphenyl)-1-piperazinyl]methyl}-1 ,3- thiazol-5-yl)methyl]sulfanyl}phenoxy)acetic acid 1H (CDCy 400MHz δ 8.10(d, 2H, J=8.03 Hz), 7.73(d, 2H, J=8.03 Hz), 7.16(m, 4H), 7.01 (br s,
2H), 6.73(d, 1 H, J=8.37 Hz), 4.79(s, 2H), 4.08(s, 2H), 3.80(m, 4H), 3.53(m, 2H), 3.24(m, 4H), 2.40(s, 3H), 2.18(s, 3H) . TLC(5% MeOH/CH2CI2) Rf = 0.10. MS(ES") M-H= 625.94
^-({^-{^^-Methoxypheny -l-piperazinvπmethyiy-Σ^-ftrifluoromethy^phenyQ-l^-thiazoNg- yj1methyl}sulfanyl)-2-methylphenoxy1acetic acid 1H (CDCI3) 400MHz δ 8.04(d, 2H, J=8.20 Hz), 7.72(d, 2H, J=8.20 Hz), 7.12(s, 1 H), 6.96(m, 3H), 6.81 (d, 2H, J=8.89 Hz), 6.74(d, 1 H, J=8.37 Hz), 4.76(s, 2H), 4.05(s, 2H), 3J4(s, 3H), 3.38(m, 10H), 2.16(s, 3H) . TLC(5% MeOH/CH2CI2) Rf = 0.13. MS(ES") M-H= 641.90
(2-Methyl-4-{[(2-(4-{trifluoromethyl}phenyl)-4-{[4-(3-methylphenyl)-1-piperazinyl]methyl}-1,3- thiazol-5-yl)methyl]sulfanyl}phenoxy)acetic acid
1H (CDCy 400MHz δ 8.05(d, 2H, J=8.20 Hz), 7.72(d, 2H, J=8.20 Hz), 7.20(s, 1 H), 7.06(d, 2H, J=9.06 Hz), 6.91 (m, 3H), 6.72(d, 1 H, J=8.37 Hz), 4.77(s, 2H), 4.06(s, 2H), 3.54(br s, 8H), 3.27(s, 2H), 2.30(s, 3H), 2.16(s, 3H) . TLC(5% MeOH/CH2CI2) Rf = 0.10. MS(ES') M-H= 625.99
(∑-Methyl^^^^-ftrifluoromethy^pheny ^^^^-methylphenyQ-l-piperazinyllmethy -I.S- thiazol-5-yl)methyl]sulfanyl}phenoxy)acetic acid
1H (CDCI3) 400MHz δ 8.03(d, 2H, J=8.20 Hz), 7.71 (d, 2H, J=8.20 Hz), 7.02(m, 6H), 6.71 (d, 1 H, J=8.55 Hz), 4.76(s, 2H), 4.08(s, 2H), 3.52(br s, 8H), 3.31 (s, 2H), 2.27(s, 3H), 2.16(s, 3H) . TLC(5% MeOH/CH2CI2) Rf = 0.10. MS(ES") M-H= 625.94
[4-({[4-{[4-(2-Furoyl)-1-piperazinyl]methyl}-2-(4-{trifluoromethyl}phenyl)-1,3-thiazol-5- yl]methyl}sulfanyl)-2-methylphenoxy]acetic acid
1H (CDCy 400MHz δ 8.02(d, 2H, J=8.20 Hz), 7.71 (d, 2H, J=8.20 Hz), 7.48(d, 1 H, J=2.05 Hz), 7.16(dd, 1 H, J=8.20, 2.05 Hz), 7.07(m, 1 H), 6.90(d, 1 H, J=2.39 Hz), 6.74(d, 1 H, J=8.20 Hz),
6.49(m, 1H), 4J7(s, 2H), 4.62(s, 2H), 4.05(s, 2H), 3.46(s, 2H), 3.27(s, 2H), 3.05(br s, 4H), 2.15(s, 3H) . TLC(5% MeOH/CH2CI2) Rf = 0.10. MS(ES") M-H= 629.83
(2-Methyl-4-{[(2-(4-{trifluoromethylphenyl)-4-{[4-(2-pyridinyl)-1-piperazinyl]methyl}-1,3-thiazol-5- yl)methyl]sulfanyl}phenoxy)acetic acid
1H (CDCI3) 400MHz δ 8.22(m, 1 H), 7.99(d, 2H, J=8.20 Hz), 7.68(d, 2H, J=8.20 Hz), 7.60(s, 1 H), 7.20(dd, 1 H, J=8.37, 2.39 Hz), 7.14(s, 1 H), 6.76(m, 1 H), 6.68(m, 1 H), 4.68(s, 2H), 4.14(s, 2H), 3.72(br s, 4H), 3.59(s, 2H), 2.87(br s, 4H), 2.17(s, 3H) . TLC(5% MeOH/CH2CI2) Rf = 0.10. MS(ES") M-H= 612.99
[4-({[4-{[4-(4-Chlorobenzyl)-1-piperazinyl]methyl}-2-(4-{trifluoromethyl}phenyl)-1,3-thiazol-5- yl]methyl}sulfanyl)-2-methylphenoxy]acetic acid H (CDCI3) 400MHz δ 8.04(d, 2H, J=8.20 Hz), 7.70(d, 2H, J=8.20 Hz), 7.41 (m, 4H), 7.14(m, 1 H), 7.03(m, 1 H), 6.69(d, 1 H, J=8.37 Hz), 4.72(s, 2H), 4.02(s, 2H), 3.18(m, 12H), 2.10(s, 3H) . TLC(5% MeOH/CH2CI2) Rf = 0.10. MS(ES") M-H= 659.78
[4.({[4-{[4-(4-acetylphenyl)-1-piperaziny|]methyl}-2-(4-{trifluorornethyl}phenyl)-1 ,3-thiazq|-5 : yl]methyl}sulfanyl)-2-methylphenoxy]acetic acid H (CDCI3) 400MHz δ 7.97(d, 2H, J=8.03 Hz), 7.85(d, 2H, J=8.89 Hz), 7.70(d, 2H, J=8.03 Hz), 7.16(dd, 1 H, J=8.37, 2.22 Hz), 6.86(m, 3H), 6.75(d, 1 H, J=8.37 Hz), 4.77(s, 2H), 4.04(s, 2H), 3.80(m, 4H), 3.45(m, 4H), 3.29(s, 2H), 2.51 (s, 3H), 2.17(s, 3H) . TLC(5% MeOH/CH2CI2) Rf = 0.10. MS(ES-) M-H= 653.99
(4-{[(4-{[4-(4-Methoxyphenyl)-1-piperazinyl]methyl}-2-phenyl-1,3-thiazol-5-yl)methyl]sulfanyl}-2- methylphenoxy)acetic acid
1H NMR (CDCy 400MHz 9.94(s, 1H), 7.84(m, 2H), 7.41 (m, 3H), 7.11(d, 1 H, J=2.22 Hz), 7.06(dd, 1 H, J=8.37, 2.22 Hz), 6.79(m, 4H), 6.60(d, 1 H, J=8.37 Hz), 4.54(s, 2H), 4.18(s, 2H), 3.76(s,
2H), 3.22(m, 8H), 2.18(s, 3H) . HPLC(C-18, 3μm) 1%MeOH/0-90% CH3CN/Water (0.1% TFA)/(50mM Et3N/TFA) 4min run Rt=2.67 min
2-{4-[({4-{[4-(4-Methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid
1H NMR (CDCy 400MHz δ9.69(s, 1H), 7.96(d, 2H, J=8.20 Hz), 7.65(d, 2H, J=8.20 Hz), 7.07(d, 1H, J=2.05 Hz), 7.02(dd, 1H, J=8.55, 2.05 Hz), 6.87(d, 2H, J=9.23 Hz), 6.80(d, 2H, J=9.23 Hz), 6.66(d, 1 H, J=8.55 Hz), 4.66(q, 1 H, J=6.95 Hz), 4.10(d, 1 H, J .70 Hz), 4.05(d, 1 H, J .70 Hz), 3.74(s, 3H), 3.57(d, 1 H, J .18 Hz), 3.51 (d, 1 H, J .18 Hz), 3.15(br s, 4H), 2.96(br s, 4H), 2.17(s, 3H),
1.59(d, 3H, J=6.95 Hz) . HPLC(C-18, 3μm) 1%MeOH/0-90% CH3CN/Water (0.1 % TFA)/(50mM Et3N/TFA) 4min run R,=2.91 min
2-(4-{[(4-{[4-(4-Methoxyphenyl)-1-piperazinyl]methyl}-2-phenyl-1,3-thiazol-5-yl)methyl]sulfanyl>- 2-methylphenoxy)propanoic acid
1H NMR (CDCy 400MHz δ7.81(m, 2H), 7.34(m, 3H), 7.09(m, 1 H), 6.90(m, 1H), 6.79(m, 4H), 6.48(d, 1 H, J=8.37 Hz), 4.35(m, 1 H), 4.16(s, 2H), 3.70(s, 3H), 3.32(s, 2H), 3.00(m, 4H), 2.60(m, 4H), 2.09(s, 3H), 1.34(m, 3H) . HPLC(C-18, 3μm) 1%MeOH/0-90% CH3CN/Water (0.1 % TFA)/(50mM Et3N/TFA) 4min run R,=2.78 min
{2-Methyl-4-[({2-(4-{trifluoromethyl}phenyl)-4-[(4-phenyl-1-piperazinyl)methyl]-1,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}acetic acid
1H (CD3OD) 300MHz δ 8.16(d, 2H, J=8.49 Hz), 7.81 (d, 2H, J=8.49 Hz), 7.26(br s, 3H), 7.09(br s, 1 H), 6.98(d, 2H, J=7.96 Hz), 6.88(m, 1 H), 6.66(br s, 1 H), 4.57(s, 2H), 4.29(s, 2H), 3.55(s, 2H), 3.26(br s, 4H), 2.91 (br s, 4H), 2.23(s, 3H) . MS(ES") M-H= 611.85. TLC(10% MeOH/CH2Cl2) Rf = 0.30
[4-({[4-{[4-(Ethoxycarbonyl)-1-piperazinyl]methyl}-2-(4-{trifluoromethyl}phenyl)-1,3-thiazol-5- yl]methyl}sulfanyl)-2-methylphenoxy]acetic acid H (CD3OD) 300MHz δ 8.14(d, 2H, J=8.23 Hz), 7.81 (d, 2H, J=8.23 Hz), 7.26(s, 1H), 7.12(s, 1 H), 6.71 (s, 1 H), 4.63(s, 2H), 4.32(s, 2H), 4.16(q, 2H, J=7.08 Hz), 3.55(br s, 4H), 3.44(s, 2H), 2.60(br s, 4H), 2.25(s, 3H), 1.30(t, 3H, J=7.08 Hz) . MS(ES") M-H= 607.86. TLC(10% MeOH/CH2CI2) Rf = 0.28 {2-Methyl-4-[({2-(4-{trifluoromethyl}phenyl)-4-[(4-phenyl-1-piperidinyl)methyl]-1,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}acetic acid
1H (CD3OD) 300MHz δ 8.14(d, 2H, J=8.23 Hz), 7.77(d, 2H, J=8.23 Hz), 7.28(s, 7H), 6.75(d, 1 H, J=8.23 Hz), 4.45(s, 2H), 4.34(s, 2H), 3.53(s, 2H), 3.08(m, 2H), 2.57(m, 1 H), 2.35(m, 2H), 2.22(s, 3H), 1.80(m, 4H) . MS(ES") M-H= 610.91. TLC(10% MeOH/CH2CI2) Rf = 0.30
[4-({[4-{[(Cyclopropylmethyl)amino]methyl}-2-(4-{trifluoromethyl}phenyl)-1,3-thiazol-5- yl]methyl}sulfanyl)-2-methylphenoxy]acetic acid
1H NMR 300MHz δ 8.08(d, 2H, J=8.20 Hz), 7.74(d, 2H, J=8.20 Hz), 7.14(dd, 1 H, J=8.49, 2.39 Hz), 7.01 (s, 1 H), 6.72(d, 1 H, J=8.49 Hz), 4.77(s, 2H), 4.03(s, 2H), 3.29(s, 2H), 2.77(d, 2H, J=7.43 Hz), 2.17(s, 3H), 1.17(m, 1 H), 0.62(m, 2H), 0.28(m, 2H) . MS(ES") M-H= 520.90. HPLC(C-18, 3μm) 1 %MeOH/0-90% CH3CN/Water (0.1 % TFA)/(50mM Et3N/TFA) 4min run Rt=2.67 min
{2-Methyl-4-[({2-(4-{trifluoromethyl}phenyl)-4-[(pentylamino)methyl]-1,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}acetic acid
1H NMR 300MHz δ 8.06(d, 2H, J=8.23 Hz), 7.69(d, 2H, J=8.23 Hz), 7.05(m, 2H), 6.66(d, 1 H, J=8.23 Hz), 4.67(s, 2H), 4.06(s, 2H), 3.35(s, 2H), 2.78(t, 2H, J=6.64 Hz), 2.17(s, 3H), 1.71 (m, 2H), 1.22(m, 4H), 0.83(t, 3H, J=6.64 Hz) . MS(ES") M-H= 536.90. HPLC(C-18, 3μm) 1%MeOH/0-90% CH3CN Water (0.1 % TFA)/(50mM Et3N/TFA) 4min run Rt=2.80 min
4-({[4-{[4-(2-Hydroxyethyl)-1-piperazinyl]methyl}-2-(4-{trifluoromethyl}phenyl)-1,3-thiazol-5- yl]methyl}sulfanyl)-2-methylphenoxy]acetic acid
1H NMR (CD3OD) 300MHz δ 8.16(d, 2H, J=8.23 Hz), 7.80(d, 2H, J=8.23 Hz), 7.26(m, 2H), 6.80(d, 1 H, J=8.49 Hz), 4.76(s, 2H), 4.40(s, 2H), 3.95(m, 2H), 3.84(s, 2H), 3.54(br s, 4H), 3.33(m, 2H), 3.20(br s, 4H), 2.22(s, 3H) . HPLC(C-18, 3μm) 1 %MeOH/0-90% CH3CN/Water (0.1 % TFA)/(50mM Et3N/TFA) 4min run Rt=2.48 min
(2-Methyl-4-{[(2-(4-{trifluoromethyl}phenyl)-4-{[(3-pyridinylmethyl)amino]methyl}-1,3-thiazol-5- yl)methyl]sulfanyl}phenoxy)acetic acid 1H NMR (CDCy 300MHz δ 8.58(d, 1 H, J=1.59 Hz), 8.48(dd, 1 H, J=4J8, 1.59 Hz), 8.03(m,
3H), 7.66(d, 2H, J=8.23 Hz), 7.24(m, 1 H), 7.06(d, 1 H, J=2.39 Hz), 6.99(d, 1 H, J=2.39 Hz), 6.59(d, 1 H, J=8.49 Hz), 4.61 (s, 2H), 4.04(s, 2H), 3.93(s, 2H), 3.28(s, 2H), 2.13(s, 3H) . MS(ES") M-H= 557.80.
HPLC(C-18, 3μm) 1 %MeOH/0-90% CH3CN/Water (0.1 % TFA)/(50mM Et3N/TFA) 4min run R,=2.44 min
^({^- (S-Hydroxy-l-piperidinyOmethyπ-∑^-ltrifluoromethy pheny -I .S-thiazol-S- vπmethyi}sulfanyl)-2-methylphenoxy]acetic acid
1H NMR (CDCI3) 300MHz δ 8.00(d, 2H, J=8.37 Hz), 7.69(d, 2H, J=8.37 Hz), 7.23(dd, 1 H, J=8.55, 2.20 Hz), 6.94(d, 1 H, J=2.20 Hz), 6.69(d, 1 H, J=8.55 Hz), 4.68(s, 2H), 4.21 (s, 2H), 3.16(m, 7H), 2.12(s, 3H), 1.63(m, 4H) . MS(ES") M-H= 550.8. HPLC(C-18, 3μm) 1%MeOH/0-90% CH3CN/Water (0.1 % TFA)/(50mM Et3N/TFA) 4min run R,=2.58 min
[4-({[4-[(4-Hydroxy-1-piperidinyl)methyl]-2-(4-{trifluoromethyl}phenyl)-1,3-thiazol-5- yl]methyl}sulfanyl)-2-methylphenoxy]acetic acid
1H NMR (CDCI3) 300MHz δ 7.97(d, 2H, J=8.23 Hz), 7.65(d, 2H, J=8.23 Hz), 7.11 (m, 2H), 6.58(d, 1 H, J=8.23 Hz), 4.53(s, 2H), 4.18(s, 2H), 3.86(br s, 1H), 3.62(m, 2H), 3.12(m, 2H), 2.95(m, 2H), 2.15(s, 3H), 2.04(m, 2H), 1.77(m, 2H) . HPLC(C-18, 3μm) 1 %MeOH/0-90% CH3CN/Water (0.1 % TFA)/(50mM Et3N/TFA) 4min run R,=2.54 min
[4-({[4-{[2-(hydroxymethyl)-1-piperidinyl]methyl}-2-(4-{trifluoromethyl}phenyl)-1,3-thiazol-5- yl]methyl}sulfanyl)-2-methylphenoxy]acetic acid
MS(ES-) M-H= 564.94. HPLC(C-18, 3μm) 1 %MeOH/0-90% CH3CN/Water (0.1% TFA)/(50mM Et3N/TFA) 4min run R,=2.66 min
[4-({[4-{[4-(Hydroxymethyl)-1-piperidinyl]methyl}-2-(4-{trifluoromethyl}phenyl)-1,3-thiazol-5- yl]methyi}sulfanyl)-2-methylphenoxy]acetic acid
Η NMR (CDCy 400MHz δ 7.94(d, 2H, J=8.20 Hz), 7.64(d, 2H, J=8.20 Hz), 7.13(dd, 1 H, J=8.55, 2.39 Hz), 7.06(d, 1 H, J=2.39 Hz), 6.58(d, 1 H, J=8.55 Hz), 4.60(s, 2H), 4.45(s, 2H), 4.18(s, 2H), 3.56(m, 6H), 2.75(br s, 1 H), 2.11 (s, 3H), 1.68(m, 4H) . MS(ES") M-H= 564.93. HPLC(C-18, 3μm) 1 %MeOH/0-90% CH3CN/Water (0.1% TFA)/(50mM Et3N/TFA) 4min run R,=2.56 min
[2-Methyl-4-({[2-(4-{trifluoromethyl}phenyl)-4-(4-morpholinylmethyl)-1,3-thiazol-5- ylImethyl}sulfanyl)phenoxy]acetic acid 1H NMR (CD3OD) 300MHz δ 8.11 (d, 2H, J=8.23 Hz), 7.79(d, 2H, J=8.23 Hz), 7.25(br s, 1 H),
7.17(dd, 1 H, J=8.23, 2.39 Hz), 6.74(d, 1H, J=8.23 Hz), 4.46(s, 2H), 4.32(s, 2H), 3.69(br s, 4H), 3.47(s, 2H), 2.50(br s, 4H), 2.23(s, 3H) . MS(ES') M-H= 536.43. TLC(20% MeOH/CH2CI2) Rf= 0.39
[4-({[4-[(Cyclohexylamino)methyl]-2-(4-{trifluoromethyl}phenyl)-1,3-thiazol-5- yl]methyl}sulfanyl)-2-methylphenoxy]acetic acid
1H NMR (CDCy 400MHz δ 8.01 (d, 2H, J=8.20 Hz), 7.66(d, 2H, J=8.20 Hz), 7.04(m, 2H), 6.61 (d, 1 H, J=8.20 Hz), 4.64(s, 2H), 4.14(s, 2H), 3.39(s, 2H), 2.86(m, 1 H), 2.14(s, 3H), 2.01 (m, 2H), 1 J3(m, 2H), 1.48(m, 4H), 1.08(m, 2H) . MS(ES") M-H= 548.7-. HPLC(C-18, 3μm) 1%MeOH/0-90% CH3CN Water (0.1% TFA)/(50mM Et3N/TFA) 4min run R,=2.75 min
j^-Methyl-4-({[4-{[(2-methylcyclohexyl)amino]rnethyl}-2-(4-{trifluoromethyl}phenyl)-1,3-thjazol 5-yl]methyl}sulfanyl)phenoxy]acetic acid
1H NMR 400MHz δ 7.98(d, 2H, J=8.20 Hz), 7.68(d, 2H, J=8.20 Hz), 7.09(dd, 1 H, J=8.37, 2.39 Hz), 6.98(d, 1 H, J=2.39 Hz), 6.65(d, 1 H, J=8.37 Hz), 4.66(s, 2H), 4.15(d, 1 H, J .70 Hz), 4.00(d, 1 H, J 70 Hz), 3.53(d, 1 H, J .04 Hz), 3.33(d, 1 H, J .04 Hz), 2.53(m, 1 H), 2.10(s, 3H), 1.74(m, 7H), 1.37(m, 2H), 1.03(d, 3H, J=6.32 Hz) . MS(ES") M-H= 562.80. HPLC(C-18, 3μm) 1 %MeOH/0-90% CH3CN/Water (0.1 % TFA)/(50mM Et3N/TFA) 4min run Rt=2.87 min
[2-Methyl-4-({[4-{[(3-methylcyclohexyl)amino]methyl}-2-(4-{trifluoromethyl}phenyl)-1,3-thiazol- 5-yl]methyl}sulfanyl)phenoxy]acetic acid
1H NMR 400MHz δ 8.01(d, 2H, J=8.20 Hz), 7.68(d, 2H, J=8.20 Hz), 7.05(m, 2H), 6.62(d, 1 H, J=8.37 Hz), 4.68(s, 2H), 4.29(s, 2H), 3.32(s, 2H), 2.90(m, 1 H), 2.15(s, 3H), 2.00(m, 5H), 1.56(m, 4H), 0.89(d, 3H, J=6.32 Hz). MS(ES") M-H= 562.9. HPLC(C-18, 3μm) 1 %MeOH/0-90% CH3CN/Water (0.1% TFA)/(50mM Et3N/TFA) 4min run R,=2.85 min
[2-Methyl-4-({[4-{[(4-methylcyclohexyl)amino]methyl}-2-(4-{trifluoromethyi phenyl)-1,3-thiazol- 5-yl]methyl}sulfanyl)phenoxy]acetic acid
1H NMR 400MHz δ 7.99(d, 2H, J=8.20 Hz), 7.64(d, 2H, J=8.20 Hz), 7.02(m, 2H), 6.59(d, 1 H, J=8.03 Hz), 4.58(s, 2H), 4.16(s, 2H), 3.44(s, 2H), 2.90(br s, 1 H), 2.12(s, 3H), 2.01 (m, 3H), 1.62(m, 6H), 0.90(d, 3H, J=6.84 Hz). MS(ES") M-H= 562.90. HPLC(C-18, 3μm) 1 %MeOH/0-90% CH3CN/Water (0.1 % TFA)/(50mM Et3N/TFA) 4min run Rt=2.85 min
[2-Methyl-4-({[4-[(2-methylphenoxy)methyl]-2-(4-{trifluoromethyl}phenyl)-1,3-thiazol-5- yl]methyl}sulfanyl)phenoxy]acetic acid 1H (CDCI3) 300MHz δ 8.03(d, 2H, J=8.23 Hz), 7.72(d, 2H, J=8.23 Hz), 7.17(m, 4H), 6.91 (m,
2H), 6.59(d, 1 H, J=8.49 Hz), 4.96(s, 2H), 4.67(s, 2H), 2.25(s, 3H), 2.21 (s, 3H). MS(ES") M-H= 557.8
[2-Methyl-4-({[4-[(3-methylphenoxy)methyl]-2-(4-{trifluoromethyl}phenyl)-1,3-thiazol-5- yl]methyl}sulfanyl)phenoxy]acetic acid H (CDCy 300MHz δ 8.06(d, 2H, J=8.23 Hz), 7.73(d, 2H, J=8.23 Hz), 7.26(dd, 1 H, J=2.39,
0.53 Hz), 7.20(t, 1 H, J=7.83 Hz), 7.12(ddd, 1 H, J=8.49, 2.39, 0.53 Hz), 6.80(m, 3H), 6.61(d, 1 H, J=8.49 Hz), 4.86(s, 2H), 4.67(s, 2H), 4.32(s, 2H), 2.36(s, 3H), 2.23(s, 3H). MS(ES") M-H= 557.83
[2-Methyll-4-({[4-[(4-Methyllphenoxy)methyl]-2-(4-{trifluoromethyl}phenyl)-1,3-thiazol-5- yl]methyl}sulfanyl)phenoxy]acetic acid
MS(ES-) M-H= 557.8
CHN Analysis: Theory 1.5H20 (C, 57.33%; H, 4.64%; N, 2.39%) Found (C, 57.34%; H, 4.24%; N, 2.37%)
[4-({[4-[(3-Cyanophenoxy)methyl]-2-(4-{trifluoromethyl}phenyl)-1,3-thiazol-5- vπmethyl}sulfanyl)-2-Methyllphenoxy]acetic acid
1H (CDCy 300MHz δ 8.05(d, 2H, J=8.23 Hz), 7.74(d, 2H, J=8.23 Hz), 7.38(m, 2H), 7.17(m, 4H), 6.67(d, 1 H, J=8.23 Hz), 4.76(s, 2H), 4.72(s, 2H), 4.25(s, 2H), 2.23(s, 3H). MS(ES") M-H= 569.2 [4-({[4-[(4-Cyanophenoxy)methyl]-2-(4-{trifluoromethyl}phenyl)-1,3-thiazol-5- yl]methyl}sulfanyl)-2-methylphenoxy]acetic acid
1H (CDCI3) 300MHz δ 9.94(s, 1 H), 8.03(d, 2H, J=8.23 Hz), 7.73(d, 2H, J=8.23 Hz), 7.60(d, 2H, J=9.03 Hz), 7.27(d, 1 H, J=2.12 Hz), 7.10(dd, 1 H, J=8.49, 2.12 Hz), 7.00(d, 2H, J=9.03 Hz), 6.61 (d, 1 H, J=8.49 Hz), 4.85(s, 2H), 4.69(s, 2H), 4.25(s, 2H), 2.21 (s, 3H). MS(ES") M-H= 569.2
(2-Methyl-4-{[(4-{[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]methyl}-2-phenyl-1,3-thiazol-5- yl)methyl]sulfanyl}phenoxyacetic acid
1H (CDCI3) 400MHz 7.95(d, 2H, J=9.06 Hz), 7.87(m, 2H), 7.43(m, 3H), 7.20(d, 1 H, J=2.39 Hz), 7.05(dd, 1 H, J=8.55, 2.39 Hz), 6.95(d, 2H, J=9.06 Hz), 6.52(d, 1 H, J=8.55 Hz), 4.80(s, 2H), 4.61 (s, 2H), 4.24(s, 2H), 2.63(s, 3H), 2.17(s, 3H). MS(ES") M-H= 558.40
2-(2-Methyl-4-{[(4-{[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]methyl}-2-phenyl-1,3-thiazol-5- yl)methyl]sulfanyl}phenoxy)propanoic acid 1H (CDCI3) 400MHz δ 7.93(d, 2H, J=9.06 Hz), 7.85(m, 2H), 7.40(m, 3H), 7.19(d, 1 H, J=2.22
Hz), 7.02(dd, 1 H, J=8.37, 2.22 Hz), 6.94(d, 2H, J=9.06 Hz), 6.52(d, 1 H, J=8.37 Hz), 4.81 (d, 1 H, J .79 Hz), 4.74(d, 1 H, J .79 Hz), 4.68(q, 1 H, J=6.78 Hz), 4.21 (s, 2H), 2.62(m, 3H), 2.16(s, 3H), 1.61 (d, 3H, J=6.78 Hz). MS(ES-) M-H= 571.50
2-{2-Methyl-4-[({4-{[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]methyl}-2-[4-
(trifluoromethyl)phenyll-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic acid
1H NMR (CDCI3) 400MHz δ 7.99(d, 2H, J=8.20 Hz), 7.67(m, 3H), 7.47(m, 1 H), 7.36(t, 1 H, J=8.03 Hz), 7.10(dd, 1 H, J=8.37, 2.39 Hz), 7.04(dd, 1 H, J=8.37, 2.39 Hz), 6.99(m, 1 H), 6.61 (d, 1 H, J=8.37 Hz), 4.75(q, 1H, J=6.84 Hz), 4.62(d, 1 H, J .45 Hz), 4.43(d, 1 H, J .45 Hz), 4.23(d, 1H, J .70 Hz), 4.16(d, 1 H, J .70 Hz), 2.70(s, 3H), 2.12(s, 3H), 1.68(d, 3H, J=6.84 Hz). MS(ES+) M+H= 642.00
2-(2-Methyl-4-{[(4-{[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]methyl}-2-phenyl-1,3-thiazol-5- yl)methyl]sulfanyl}phenoxy)propanoic acid
1H NMR (CDCI3) 400MHz δ 7.90(m, 2H), 7.67(t, 1H, J=7.52Hz), 7.46(m, 1 H), 7.42(m, 3H), 7.35(t, 1 H, J=7.52 Hz), 7.08(dd, 1 H, J=8.37, 2.39 Hz), 7.04(d, 1 H, J=8.37 Hz), 7.00(d, 1 H, J=2.39 Hz), 6.61 (d, 1 H, J=8.37 Hz), 4.73(q, 1 H, J=6.84 Hz), 4.58(d, 1 H, J .45 Hz), 4.43(d, 1 H, J .45 Hz), 4.20(d, 1 H, J .70 Hz), 4.15(d, 1 H, J .70 Hz), 2.69(s, 3H), 2.12(s, 3H), 1.66(d, 3H, J=6.84 Hz). MS(ES+) M+H= 573.80
[2-Methyl-4-({[2-(4-{trifluoromethyl}phenyl)-4-(phenoxymethyl)-1,3-thiazol-5- yl]methyl}sulfanyl)phenoxy]acetic acid
1H (CDCI3) 300MHz δ 8.02(d, 2H, J=8.23 Hz), 7.70(d, 2H, J=8.23 Hz), 7.33(m, 2H), 7.22(s, 1 H), 7.12(d, 1 H, J=9.03 Hz), 6.98(m, 3H), 6.58(d, 1 H, J=8.49 Hz), 4.87(s, 2H), 4.63(s, 2H), 4.30(s, 2H), 2.22(s, 3H). TLC(5% MeOH/CH2CI2) Rf = 0.17 (2-Methyl-4-{[(4-{[3-(5-methyl-1 ,2,4-oxadiazol-3-yl)phenoxy]methyl}-2-phenyl-1,3-thiazol-5- yl)methyl]sulfanyl}phenoxy)acetic acid
1H NMR (CDCI3) 400MHz δ 7.91 (m, 2H), 7.95(d, 1 H, J=7.69 Hz), 7.47(m, 1 H), 7.42(m, 3H), 7.35(t, 1 H, J=7.95 Hz), 7.13(dd, 1 H, J=8.37, 2.39 Hz), 7.04(s, 2H), 6.60(d, 1 H, J=8.37 Hz), 4.67(s, 2H), 4.57(s, 2H), 4.20(s, 2H), 2.69(s, 3H), 2.12(s, 3H), MS(ES+) M+H= 560.30
2-{2-Methyl-4-[({4-{[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]methyl}-2-[4- (trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic acid 1H (CDC13) 400MHz δ 7.94(m, 4H), 7.66(d, 2H, J=8.20 Hz), 7.18(d, 1 H, J=2.22 Hz), 7.03(dd,
1 H, J=8.20, 2.22 Hz), 6.94(d, 2H, J=8.89 Hz), 6.53(d, 1 H, J=8.20 Hz), 4.85(d, 1 H, J .79 Hz), 4.80(d, 1 H, J .79 Hz), 4.69(q, 1 H, J=6.84 Hz), 4.26(d, 1 H, J .70 Hz), 4.21 (d, 1 H, J .70 Hz), 2.63(m, 3H), 2.18(s, 3H), 1.62(d, 3H, J=6.84 Hz), MS(ES-) M-H= 640.00
{2-Ethyl-4-[({4-{[4-(4-fluorophenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3- thiazol-5-yl}methyl)sulfanyl]phenoxy}acetic acid
1H NMR (CDCI3) 400MHz δ 7.98(d, 2H, J=8.06 Hz), 7.67(d, 2H, J=8.06 Hz), 7.11(dd, 1 H, J=8.61 , 2.20 Hz), 7.02(d, 1 H, J=2.20 Hz), 6.93(m, 2H), 6.82(m, 2H), 6.68(d, 1 H, J=8.61 Hz), 4.62(s, 2H), 4.12(s, 2H), 3.44(s, 2H), 3.25(m, 4H), 3.02(br s, 4H), 2.58(q, 2H, J=7.51 Hz), 1.10(t, 3H, J=7.51 Hz),
MS(ES-) M-H= 644.5
{4-[({4-[(4-Acetyl-1-piperazinyl)methyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]-2-ethylphenoxy}acetic acid
1H NMR (CDCI3) 300MHz δ 8.04(d, 2H, J=8.28 Hz), 7.75(d, 2H, J=8.28 Hz), 7.22(dd, 1 H, J=8.55: 2 21 Hz), 7.03(s, 1 H), 6.74(d, 1 H, J=8.55 Hz), 4.74(s, 2H), 4.13(s, 2H), 3.76(br s, 4H), 3.36(s, 2H), 2.99(br s, 2H), 2.72(br s, 2H), 2.61 (q, 2H, J=7.45 Hz), 2.09(s, 3H), 1.12(t, 3H, J=7.45 Hz),
MS(ES+) M+H= 594.1
{4-[({4-{[4-(4-Acetylphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]-2-ethylphenoxy}acetic acid
1H NMR (CDCy 400MHz δ 7.95(d, 2H, J=8.42 Hz), 7.84(d, 2H, J=8.97 Hz), 7.67(d, 2H, J=8.42 Hz), 7.14(dd, 1 H, J=8.42, 2.20 Hz), 6.95(s, 1 H), 6.80(d, 2H, J=8.97 Hz), 6.70(d, 1 H, J=8.42 Hz), 4.66(s, 2H), 4.08(s, 2H), 3.54(br s, 4H), 3.38(s, 2H), 3.06(br s, 4H), 2.56(q, 2H, J=7.60 Hz), 2.49(s, 3H), 1.08(t, 3H, J=7.60 Hz),
{2-Ethyl-4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-li3- thiazol-5-yl}methyl)sulfanyl]phenoxy}acetic acid 1H NMR (CDCy 400MHz δ 7.97(d, 2H, J=8.28 Hz), 7.68(d, 2H, J=8.28 Hz), 7.15(dd, 1 H,
J=8.45, 2.24 Hz), 6.94(d, 1 H, J=2.24 Hz), 6.88(d, 2H, J=9.14 Hz), 6.79(d, 2H, J=9.14 Hz), 6.72(d, 1 H, J=8.45 Hz), 4.66(s, 2H), 4.08(s, 2H), 3.72(s, 3H), 3.32(m, 6H), 3.09(br s, 4H), 2.56(q, 2H, J=7.50 Hz), 1.08(t, 3H, J=7.50 Hz), MS(ES-) M-H= 656.2
2-(4-{[(2-(4-FluorophenyO-4-{[4-(phenoxycarbonyl)-1-piperazinyl]methyl}-1,3-thiazol-5- yl)methyl]sulfanyl}-2-methylphenoxy)propanoic acid H NMR (CDCy 400MHz δ 7.91 (m, 2H), 7.35(m, 3H), 7.19(m, 3H), 7.12(br s, 1 H), 7.07(d, 2H, J=8.79 Hz), 6.67(br s, 1 H), 4.58(br s, 1 H), 4.27(s, 2H), 3.59(m, 4H), 3.41 (s, 2H), 2.51 (br s, 4H), 2.19(s, 3H), 1.54(d, 1 H, J=6.59 Hz), MS(ES-) M-H= 620.4
2-(4-{[(2-(4-Fluorophenyl)-4-{[4-(isopropoxycarbonyl)-1-piperazinyl]methyl}-1,3-thiazol-5- yl)methyl]sulfanyl}-2-methylphenoxy)propanoic acid
1H NMR (CDCI3) 400MHz δ 7.94(m, 2H), 7.19(m, 3H), 7.05(br s, 1 H), 6.64(d, 1 H, J=8.42 Hz), 4.69(br s, 1 H), 4.47(br s, 1 H), 4.21 (s, 2H), 3.50(br s, 4H), 3.36(s, 2H), 2.64(br s, 4H), 2.18(s, 3H), 1.57(d, 3H, J=5.68 Hz), 1.22(d, 6H, J=6.23 Hz), MS(ES-) M-H= 586.2
2-[4-({[4-{[4-(Ethoxycarbonyl)-1-piperazinyl]methyl}-2-(4-fluorophenyl)-1,3-thiazol-5- yl]methyl}sulfanyl)-2-methylphenoxy]propanoic acid
1H NMR (CD3OD) 400MHz δ 7.93(m, 2H), 7.19(m, 3H), 7.09(br s, 1 H), 6.67(br s, 1 H), 4J0(br s, 1 H), 4.21 (s, 2H), 4.10(q, 2H, J=7.14 Hz), 3.49(m, 4H), 3.37(s, 2H), 2.60(br s, 4H), 2.18(s, 3H), 1.58(br s, 3H), 1.23(t, 3H, J=7.14 Hz),
MS(ES-) M-H= 572.2
2-(4-{[(2-(4-Fluorophenyl)-4-{[4-(3-methoxyphenyl)-1-piperazinyl]methyl}-1,3-thiazol-5- yl)methyl]sulfanyl}-2-methylphenoxy)propanoic acid
1H NMR (CDCI3) 400MHz δ 7.84(m, 2H), 7.13(m, 4H), 6.92(br s, 1 H), 6.72(br s, 1 H), 6.44(m, 3H), 4.38(br s, 1 H), 4.00(s, 2H), 3.74(s, 3H), 3.40(m, 6H), 3.03(m, 4H), 2.17(s, 3H), 1.61 (m, 3H), MS(ES-) M-H= 606.2
2-[4-({[4-{[4-(4-Acetylphenyl)-1-piperazinyl1methyl}-2-(4-fluorophenyl)-1,3-thiazol-5- yl]methyl}sulfanyl)-2-methylphenoxy]propanoic acid
1H NMR (CD3OD) 400MHz δ 7.94(m, 2H), 7.85(d, 2H, J=8.97 Hz), 7.18(m, 3H), 7.03(br s, 1 H), 6.92(d, 2H, J=8.97 Hz), 6.67(br s, 1H), 4.61(br s, 1 H), 4.19(s, 2H), 3.41(m, 6H), 2.73(br s, 4H), 2.48(s, 3H), 2.17(s, 3H), 1.61 (br s, 3H), MS(ES") M-H= 618.2
2-(4-{[(2-(4-Fluorophenyl)-4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-1,3-thiazol-5- y|)methyl]sulfanyl}-2-methylphenoxy)propanoic acid 1H NMR (CD3OD) 400MHz δ 7.97(m, 2H), 7.18(m, 3H), 7.02(br s, 1 H), 6.91 (d, 2H, J=8.79 Hz), 6.81 (d, 2H, J=8.79 Hz), 6.62(br s, 1 H), 4.66(br s, 1 H), 4.17(s, 2H), 3.72(s, 3H), 3.41 (s, 2H), 3.15(br s, 4H), 2.92(br s, 4H), 2.18(s, 3H), 1.59(br s, 3H),
MS(ES-) M-H= 606.2
{4-[({4-[(4-Acetyl-1-piperazinyl)methyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]-2-propylphenoxy}acetic acid
1H NMR (CD3OD) 400MHz δ 8.07(d, 2H, J=8.28 Hz), 7.75(d, 2H, J=8.28 Hz), 7.21 (dd, 1 H, J=8.45, 2.41 Hz), 7.09(d, 1 H, J=2.41 Hz), 6.74(d, 1 H, J=8.45 Hz), 4.65(s, 2H), 4.26(s, 2H), 3.60(br s, 4H), 3.53(s, 2H), 2.75(t, 2H, J=4J4 Hz), 2.69(t, 2H, J=4.74 Hz), 2.52(t, 2H, J=7.41 Hz), 2.07(s, 3H), 1.50(m, 2H), 0.80(t, 3H, J=7.41 Hz),
MS(ES') M-H= 606.3
{4-[({4-{[4-(3-Methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- ' yl}methyl)suifanyl]-2-propylphenoxy}acetic acid H NMR (CD3OD) 400MHz δ 8.11 (d, 2H, J=8.28 Hz), 7.77(d, 2H, J=8.28 Hz), 7.19(dd, 1 H, J=8.28, 2.41 Hz), 7.13(t, 1 H, J=8.45 Hz), 7.08(d, 1 H, J=2.41 Hz), 6.73(t, 1 H, J=8.45 Hz), 6.54(dd, 1 H, J=8.28, 2.41 Hz), 6.49(t, 1 H, J=2.33 Hz), 6.45(dd, 1 H, J=8.28, 2.41 Hz), 4.58(s, 2H), 4.26(s, 2H), 3.73(s, 3H), 3.69(s, 2H), 3.31 (m, 4H), 3.11 (t, 4H, J=4.66 Hz), 2.52(t, 2H, J=7.33 Hz), 1.49(s, 2H), 0.80(t, 3H, J=7.33 Hz),
MS(ES-) M-H= 670.3
{4-[({4-{[4-(4-Acetylphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]-2-propylphenoxy}acetic acid 1H NMR (CDCy 400MHz δ 7.93(d, 2H, J=8.45 Hz), 7.82(d, 2H, J=8.97 Hz), 7.68(d, 2H,
J=8.45 Hz), 7.19(dd, 1 H, J=8.45, 2.41 Hz), 6.78(m, 4H), 4.73(s, 2H), 4.03(s, 2H), 3.71 (t, 4H, J=5.09 Hz), 3.28(m, 6H), 2.47(m, 5H), 1.46(m, 2H), 0.86(t, 3H, J=7.24 Hz), MS(ES") M-H= 682.1
{4-[({4-{[4-(4-Methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]-2-propylphenoxy}acetic acid H NMR (CD3OD) 400MHz δ 8.11 (d, 2H, J=8.10 Hz), 7.77(d, 2H, J=8.10 Hz), 7.19(dd, 1 H, J=8.62, 2.24 Hz), 7.08(d, 1 H, J=2.24 Hz), 6.93(d, 2H, J=9.14 Hz), 6.82(d, 2H, J=9.14 Hz), 6.74(d, 1 H, J=8.62 Hz), 4.59(s, 2H), 4.26(s, 2H), 3.73(s, 2H), 3.71 (s, 3H), 3.18(m, 8H), 2.52(t, 2H, J=7.33 Hz), 1.48(m, 2H), 0.80(t, 3H, J=7.33 Hz),
MS(ES+) M+H= 672.2
2-{2-Ethy>-4-[({4-{[4-(3-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)pheny| - ,3- thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic acid 1H NMR (CDCl3) 400MHz δ 7.95(d, 2H, J=8.28 Hz), 7.66(d, 2H, J=8.28 Hz), 7.12(m, 2H),
6.90(s, 1 H), 6J6(d, 1 H, J=8.28 Hz), 6.45(m, 3H), 4.80(q, 1 H, J=6.90 Hz), 4.02(s, 2H), 3.73(s, 3H), 3.35(m, 4H), 3.21 (d, 1 H, J .66 Hz), 3.15(d, 1 H, J .66 Hz), 2.95(br s, 4H), 2.55(s, 2H), 1.62(d, 3H, J=6.90 Hz), 1.07(t, 3H, J=7.50 Hz), MS(ES-) M-H= 670.0
2-{4-[({4-{[4-(4-Acetylphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]-2-ethylphenoxy}propanoic acid
1H NMR (CDCy 400MHz δ 7.93(d, 2H, J=8.28 Hz), 7.82(d, 2H, J=8.97 Hz), 7.65(d, 2H, J=8.28 Hz), 7.08(dd, 1 H, J=8.62, 2.41 Hz), 6.87(d, 1H, J=2.41 Hz), 6.79(d, 2H, J=8.97 Hz), 6.72(d, 1 H, J=8.62 Hz), 4.80(q, 1 H, J=6.72 Hz), 4.04(d, 1 H, J .66 Hz), 3.98(d, 1 H, J .66 Hz), 3.49(br s, 4H), 3.28(d, 1 H, J .83 Hz), 3.14(d, 1 H, J .83 Hz), 3.00(br s, 4H), 2.54(m, 5H), 1.63(d, 3H, J=6.72 Hz), 1.06(t, 3H, J=7.50 Hz),
MS(ES-) M-H=682.2
2-{2-Ethyl-4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3- thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic acid
1H NMR (CDCy 400MHz δ 7.97(d, 2H, J=8.45 Hz), 7.66(d, 2H, J=8.45 Hz), 7.10(dd, 1 H, J=8.45, 2.24 Hz), 6.94(d, 1 H, J=2.24 Hz), 6.89(d, 2H, J=9.14 Hz), 6.80(d, 2H, J=9.14 Hz), 6.75(d, 1 H, J=8.45 Hz), 4.77(q, 1 H, J=6.72 Hz), 4.04(s, 2H), 3.73(s, 3H), 3.25(m, 6H), 2.96(br s, 4H), 2.57(s, 2H), 1.61 (d, 3H, J=6.72 Hz), 1.09(t, 3H, J=7.50 Hz), MS(ES-) M-H= 670.3
2-{2-Ethyl-4-[({4-(4-morpholinylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)su lfanyl]phenoxy}propanoic acid H NMR (CDCy 400MHz δ 8.01 (d, 2H, J=8.42 Hz), 7.70(d, 2H, J=8.42 Hz), 7.13(dd, 1 H, J=8.42, 2.20 Hz), 6.86(s, 1 H), 6.76(d, 1 H, J=8.42 Hz), 4.84(q, 1 H, J=6.65 Hz), 4.04(d, 1 H, J .47 Hz), 3.98(d, 1 H, J .47 Hz), 3.87(br s, 4H), 3.21 (d, 1 H, J .83 Hz), 3.08(d, 1 H, J .83 Hz), 2.95(br s, 4H), 2.55(s, 2H), 1.64(d, 3H, J=6.65 Hz), 1.07(t, 3H, J=7.51 Hz),
MS(ES-) M-H=565.0
2-{2-Ethyl-4-[({4-{[4-(4-fluorophenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3- thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic acid
1H NMR (CD3OD) 400MHz δ 8.12(d, 2H, J=8.24 Hz), 7.78(d, 2H, J=8.24 Hz), 7.17(dd, 1 H, J=8.61 , 2.20 Hz), 7.10(d, 1 H, J=2.20 Hz), 6.98(m, 4H), 6.71 (d, 1 H, J=8.61 Hz), 4.71 (q, 1 H, J=6.90 Hz), 4.27(s, 2H), 3.66(s, 2H), 3.20(m, 8H), 2.59(q, 2H, J=7.51 Hz), 1.57(d, 3H, J=6.90 Hz), 1.09(t, 3H, J=7.51 Hz),
MS(ES-) M-H= 658.0
2-{4-[({4 (4 Acetyl-1-piperazinyl)methyl]-2-[4-(trifluoromethyl)phenyl]-1,3-'ϊ: iazol-5- yl}methyl)sulfanyl]-2-ethylphenoxy}propanoic acid H NMR (CD3OD) 400MHz δ 8.10(d, 2H, J=8.24 Hz), 7.77(d, 2H, J=8.24 Hz), 7.19(t, 1 H,
J=2.38 Hz), 7.09(d, 1 H, J=2.38 Hz), 6.71 (d, 1 H, J=8.24 Hz), 4.80(q, 1 H, J=6.78 Hz), 4.26(s, 2H), 3.65(m, 6H), 3.56(d, 1 H, J .92 Hz), 3.51 (d, 1 H, J .92 Hz), 2.83(m, 4H), 2.58(q, 2H, J=7.60 Hz), 2.09(s, 3H), 1.60(d, 3H, J=6.78 Hz), 1.09(t, 3H, J=7.60 Hz), MS(ES-) M-H= 606.0
{2-Ethyl-4-[({4-(4-morpholinylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}acetic acid
1H NMR (CDCy 300MHz δ 8.05(d, 2H, J=8.28 Hz), 7.75(d, 2H, J=8.28 Hz), 7.19(dd, 1 H, J=8.55, 2.21 Hz), 6.98(s, 1 H), 6.76(d, 1 H, J=8.55 Hz), 4.74(s, 2H), 4.12(s, 2H), 3.95(br s, 4H), 3.32(s, 2H), 3.06(br s, 4H), 2.61 (q, 2H, J=7.54 Hz), 1.14(t, 3H, J=7.54 Hz), MS(ES-) M-H= 551.3
2-{2-lsopropyl-4-[({4-(4-morpholinylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}propanoic acid
1H NMR (CD3OD) 400MHz δ 8.11 (d, 2H, J=8.24 Hz), 7.78(d, 2H, J=8.24 Hz), 7.25(dd, 1 H, J=8.42, 2.38 Hz), 7.00(d, 1 H, J=2.38 Hz), 6.74(d, 1 H, J=8.42 Hz), 4.88(q, 1 H, J=6.78 Hz), 4.25(s, 2H), 3.84(m, 5H), 3.66(d, 1 H, J .28 Hz), 3.22(m, 5H), 1.60(d, 3H, J=6.78 Hz), 1.05(m, 6H), , MS(ES") M-H= 579.0
2-{4-[({4-{[4-(4-Fluorophenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]-2-isopropylphenoxy}propanoic acid
1H NMR (CD3OD) 400MHz δ 8.13(d, 2H, J=8.06 Hz), 7.79(d, 2H, J=8.06 Hz), 7.26(d, 1 H, J=8.42 Hz), 7.06(s, 1 H), 6.99(m, 4H), 6.75(d, 1 H, J=8.42 Hz), 4.88(q, 1 H, J=6.78 Hz), 4.29(s, 2H), 3.91 (d, 1 H, J .10 Hz), 3.80(d, 1 H, J .10 Hz), 3.33(m, 9H), 1.60(d, 3H, J=6.78 Hz), 1.08(m, 6H),
MS(ES-) M-H= 672.0
2-{4-[({4-[(4-Acetyl-1-piperazinyl)methyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]-2-isopropylphenoxy}propanoic acid
MS(ES-) M-H= 620.0
2-{2-lsopropyl-4-[({4-{[4-(3-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]- 1 ,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic acid
1H NMR (CD3OD) 400MHz δ 8.13(d, 2H, J=8.06 Hz), 7.79(d, 2H, J=8.06 Hz), 7.26(d, 1 H, J=8.42 Hz), 7.16(t, 1 H, J=8.42 Hz), 7.06(s, 1 H), 6.74(d, 1 H, J=8.42 Hz), 6.56(d, 1 H, J=8.42 Hz), 6.50(br s, 2H), 4.90(q, 1 H, J=6.78 Hz), 4.27(s, 2H), 3.89(d, 1 H, J .10 Hz), 3.79(d, 1 H, J .10 Hz), 3.74(s, 3H), 3.34(m, 9H), 1.60(d, 3H, J=6.78 Hz), 1.07(m, 6H),
MS(ES-) M-H= 684.1
2-{4-[({4-{[4-(4-Acetylphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]-2-isopropylphenoxy}propanoic acid 1H NMR (CD3OD) 400MHz δ 8.13(d, 2H, J=8.24 Hz), 7.91(d, 2H, J=8.97 Hz), 7.78(d, 2H,
J=8.24 Hz), 7.25(d, 1 H, J=8.97 Hz), 7.04(m, 3H), 6.74(d, 1 H, J=8.24 Hz), 4.89(q, 1 H, J=6.78Hz), 4.28(s, 2H), 3.90(d, 1 H, J .55 Hz), 3.79(d, 1 H, J .55 Hz), 3.60(br s, 4H), 3.32(m, 5H), 2.50(s, 3H), 1.61(d, 3H, J=6.78 Hz), 1.07(d, 6H, J=7.51 Hz), MS(ES-) M-H= 696.2
2-{2-lsopropyl-4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]- 1 ,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic acid
1H NMR (CD3OD) 400MHz δ 8.13(d, 2H, J=8.24 Hz), 7.79(d, 2H, J=8.24 Hz), 7.27(d, 1 H, J=8.61 Hz), 7.05(s, 1 H), 6.95(d, 2H, J=8.79 Hz), 6.84(d, 2H, J=8.79 Hz), 6.75(d, 1 H, J=8.61 Hz), 4.88(m, 1 H) buried under MeOH signal, 4.28(s, 2H), 3.90(d, 1 H, J .28 Hz), 3.80(d, 1 H, J .28 Hz), 3.71 (s, 3H), 3.56(br s, 4H), 3.28(m, 1 H) buried under MeOH signal, 2.96(br s, 4H), 1.58(d, 3H, J=6.59 Hz), 1.07(m, 6H),
MS(ES') M-H= 684.1
{2-lsopropyl-4-[({4-(4-morpholinylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}acetic acid
1H NMR (CD3OD) 400MHz δ 8.12(d, 2H, J=8.06 Hz), 7.79(d, 2H, J=8.06 Hz), 7.27(d, 1 H, J=8.42 Hz), 7.04(s, 1 H), 6.80(d, 1 H, J=8.42 Hz), 4.76(s, 2H), 4.27(s, 2H), 3.87(m, 6H), 3.22(m, 5H), 1.07(d, 6H, J=6/78 Hz),
MS(ES-) M-H= 565.0
{4-[({4-{[4-(4-Fluorophenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]-2-isopropylphenoxy}acetic acid
1H NMR (CD3OD) 400MHz δ 8.13(d, 2H, J=8.06 Hz), 7.79(d, 2H, J=8.06 Hz), 7.28(d, 1 H, J=8.42 Hz), 7.09(s, 1 H), 6.98(m, 4H), 6.81 (d, 1 H, J=8.42 Hz), 4.74(s, 2H), 4.28(s, 2H), 3.89(s, 2H), 3.61 (br s, 4H), 3.29(m, 1 H) buried under MeOH signal, 3.02(br s, 4H), 1.07(d, 6H, J=6.78 Hz), MS(ES') M-H= 658.0
{4-[({4-[(4-Acetyl-1-piperazinyl)methyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]-2-isopropylphenoxy}acetic acid H NMR (CD3OD) 400MHz δ 8.13(d, 2H, J=8.06 Hz), 7.79(d, 2H, J=8.06 Hz), 7.28(d, 1 H,
J=8.42 Hz), 7.03(br s, 1 H), 6.80(d, 1 H, J=8.42 Hz), 4.76(s, 2H), 4.27(s, 2H), 3.80(m, 6H), 3.21 (m, 5H), 2.11 (s, 3H), 1.06(d, 6H, J=6.78 Hz), MS(ES') M-H= 606.2
2-{4-[({4-{[4-(4-Methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]-2-propylphenoxy}propanoic acid
1H NMR (CD3OD) 400MHz δ 8.12(d, 2H, J=8.28 Hz), 7.79(d, 2H, J=8.28 Hz), 7.23(dd, 1 H, J=8.45, 2.24 Hz), 7.09(d, 1 H, J=2.24 Hz), 6.95(d, 2H, J=9.14 Hz), 6.84(d, 2H, J=9.14 Hz), 6.71 (d, 1 H, J=8.45 Hz), 4.81 (q, 1H, J=6.72 Hz), 4.29(s, 2H), 3.98(d, 1H, J .14 Hz), 3.90(d, 1H, J .14 Hz), 3.71 (s, 3H), 3.50(br s, 4H), 3.21 (m, 4H), 2.50(t, 2H, J=7.33 Hz), 1.58(d, 3H, J=6.72 Hz,, 1.48(m, 2H), 0.79(t, 3H, J=7.33 Hz), MS(ES-) M-H= 684.0
{4-[({4-(4-Morpholinylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2- propylphenoxy}acetic acid
1H NMR (CD3OD) 400MHz δ 8.10(d, 2H, J=8.79 Hz), 7.78(d, 2H, J=8.79 Hz), 7.20(dd, 1 H, J=8.42, 2.20 Hz), 7.08(d, 1 H, J=2.20 Hz), 6.75(d, 1 H, J=8.42 Hz), 4.63(s, 2H), 4.26(s, 2H), 3.79(t, 4H, J=4.21 Hz), 3.64(s, 2H), 2.97(t, 4H, J=4.21 Hz), 2.53(t, 2H, J=7.42 Hz), 1.50(s, 2H), 0.82(t, 3H, J=7.42 Hz),
MS(ES') M-H= 658.0
{4-[({4-{[4-(4-Fluorophenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]-2-propylphenoxy}acetic acid
1H NMR (CDCI3) 400MHz δ 7.97(d, 2H, J=8.24 Hz), 7.67(d, 2H, J=8.24 Hz), 7.12(dd, 1 H, J=8.42, 2.20 Hz), 7.01 (d, 1 H, J=2.20 Hz), 6.93(m, 2H), 6.83(m, 2H), 6.69(d, 1 H, J=8.42 Hz), 4.62(s, 2H), 4.12(s, 2H), 3.45(s, 2H), 3.26(t, 4H, J=4.85 Hz), 3.04(t, 4H, J=4.85 Hz), 2.52(t, 2H, J=7.33 Hz), 1.51(s, 2H), 0.83(t, 3H, J=7.33 Hz),
2-{4-[({4-[(3,5-Dimethyl-1-piperazinyl)methyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}met y!)sι;!fanyl]-2-methylphenoxy}propanoic acid 1H NMR (CDCI3) 400MHz δ 8.03(d, 2H, J=8.23 Hz), 7.71 (d, 2H, J=8.23 Hz), 7.20(m, 2H),
6.66(d, 1 H, J=8.55 Hz), 4.72(q, 1 H, J=6.64 Hz), 4.26(d, 1 H, J .87 Hz), 4.18(d, 1 H, J .87 Hz), 3.34(m, 2H), 3.05(m, 2H), 2.71 (m, 2H), 2.21 (s, 3H), 1.97(m, 2H), 1.63(d, 3H, J=6.64 Hz), 1.35(m, 6H), MS(ES+) M+H= 580.1
HPLC(C-18 3μm) 1 %MeOH/ 0-99% Acetonitrile/Water (0.1 %TFA) 5min run Rt= 3.98
2-{4-[({4-{[4-(4-Chlorophenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid H NMR (CDCI3) 400MHz δ 10.42(s, 1 H), 7.92(d, 2H, J=8.20 Hz), 7.64(d, 2H, J=8.20 Hz), 7.15(d, 2H, J=9.06 Hz), 7.01 (d, 1 H, J=2.20 Hz), 6.96(d, 1 H, J=8.37 Hz), 6.72(d, 2H, J=9.06 Hz), 6.59(d, 1 H, J=8.37 Hz), 4.64(q, 1 H, J=6.78 Hz), 4.09(s, 2H), 3.58(d, 1 H, J .18 Hz), 3.49(d, 1 H, J .18 Hz), 3.26(m, 4H), 3.05(m, 4H), 2.13(s, 3H), 1.56(d, 3H, J=6.78 Hz),
MS(ES+) M+H= 662.0
HPLC(C-18 3μm) 1 %MeOH/ 0-99% Acetonitrile/Water (0.1%TFA) 5min run Rt= 4.13
2-{4-[({4-{[4-(te/ -Butoxycarbonyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1 ,3- thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid
1H NMR (CDCy 400MHz δ 10.07(s, 1H), 7.93(d, 2H, J=8.23 Hz), 7.63(d, 2H, J=8.23 Hz), 7.04(s, 1 H), 6.98(d, 1 H, J=8.37 Hz), 6.58(d, 1 H, J=8.37 Hz), 4.65(q, 1 H, J=6.78 Hz), 4.12(d, 1 H, J .70 Hz), 4.05(d, 1 H, J .70 Hz), 3.47(m, 6H), 2.73(m, 4H), 2.14(s, 3H), 1.57(d, 3H, J=6.78 Hz), 1.38(s, 9H), MS(ES+) M+H= 652.0 HPLC(C-18 3μm) 1%MeOH/ 0-99% Acetonitrile/Water (0.1%TFA) 5min run Rt= 4.16
2-{2-Methyl-4-[({4-(1-piperazinylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}propanoic acid
1H NMR (CDCy 400MHz δ 9.26(br s, 1 H), 7.97(br s, 2H), 7.63(br s, 2H), 7.10(br s, 2H), 6.67(br s, 1 H), 4.56(br s, 1 H), 4.11 (br s, 2H), 3.39(br s, 2H), 2.98(br s, 4H), 2.41 (br s, 4H), 2.07(br s, 3H), 1.44(br s, 3H),
MS(ES+) M+H= 552
HPLC(C-18 3μm) 1 %MeOH/ 0-99% Acetonitrile/Water (0.1 %TFA) 5min run Rt= 3.80
{2-lsopropyl-4-[({4-{[4-(3-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]- 1 ,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetic acid
1H NMR (CD3OD) 400MHz δ 8.13(d, 2H, J=8.06 Hz), 7.79(d, 2H, J=8.06 Hz), 7.28(d, 1 H, J=8.24 Hz), 7.15(m, 1 H), 7.09(s, 1H), 6.80(d, 1H, J=8.24 Hz), 6.52(m, 3H), 4.74(s, 2H), 4.28(s, 2H), 3.88(s, 2H), 3.73(m, 3H), 3.48(br s, 4H), 3.29(m, 1 H) buried under MeOH signal, 3.05(s, 4H), 1.06(d, 6H, J=6.59 Hz),
MS(ES-) M-H= 670.0
{4-[({4-{[4-(4-Acetylphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]-2-isopropylphenoxy}acetic acid
1H NMR (CD3OD) 400MHz δ 8.13(d, 2H, J=7.87 Hz), 7.91 (d, 2H, J=8.79 Hz), 7.78(d, 2H, J=7.87 Hz), 7.27(d, 1 H, J=8.24 Hz), 7.09(br s, 1 H), 7.02(d, 2H, J=8.24 Hz), 6.80(d, 1 H, J=8J9 Hz), 4.74(s, 2H), 4.29(s, 2H), 3.89(s, 2H), 3.62(br s, 4H), 3.30(m, 5H), 2.51 (s, 3H), 1.07(d, 6H, J=6.78 Hz),
MS(ES-) M-H= 682.0
{2-lsopropyl-4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]- 1 ,3-thiazolι-5"yl}methyl)sulfanyl]phenoxy}acetic acid
1H NMR (CD3OD) 400MHz δ 8.13(d, 2H, J=8.06 Hz), 7.79(d, 2H, J=8.06 Hz), 7.29(d, 1 H, J=8.45 Hz), 7.09(s, 1 H), 6.98(d, 2H, J=8.45 Hz), 6.83(m, 3H), 4.73(s, 2H), 4.30(s, 2H), 3.90(s, 3H), 3.35(m, 11 H), 1.07(d, 6H, J=6.59 Hz), MS(ES-) M-H= 670.0
2-{4-[({4-(4-Morpholinylmethyl)-2-[4-(trifluoromethyl)phenyn-1,3-thiazol-5-yl}methyl)sulfanyl1-2- propylphenoxy}propanoic acid 1H NMR (CD3OD) 400MHz δ 8.18(d, 2H, J=8.00 Hz), 7.84(d, 2H, J=8.00 Hz), 7.30(dd, 1 H,
J=8.55, 2.48 Hz), 7.11(d, 1 H, J=2.48 Hz), 6.78(d, 1 H, J=8.55 Hz), 4.91 (s, 1 H) buried under MeOH signal, 4.33(s, 2H), 3.94(m, 6H), 3.24(br s, 4H), 2.56(t, 2H, J=7.45 Hz), 1.59(m, 5H), 0.86(t, 3H, J=7.45 Hz),
MS(ES-) M-H= 579.0 2-{4-[({4-{[4-(4-Fluorophenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]-2-propylphenoxy}propanoic acid
1H NMR (CD3OD) 400MHz δ 8.18(d, 2H, J=8.28 Hz), 7.85(d, 2H, J=8.28 Hz), 7.30(dd, 1 H, J=8.55, 2.21 Hz), 7.16(d, 1 H, J=2.21 Hz), 7.06(m, 4H), 6.78(d, 1 H, J=8.55 Hz), 4.89(br s, 1 H) hidden under MeOH signal, 4.35(s, 2H), 4.06(d, 1 H, J .35 Hz), 3.98(d, 1 H, J .35 Hz), 3.68(br s, 4H), 3.08(br s, 4H), 2.56(t, 2H, J=7.45 Hz), 1.57(m, 5H), 0.86(t, 3H, J=7.45 Hz), MS(ES-) M-H= 672.0
2-{4-[({4-[(4-Acetyl-1-piperazinyl)methyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]-2-propylphenoxy}propanoic acid
1H NMR (CD3OD) 400MHz δ 8.17(d, 2H, J=8.28 Hz), 7.84(d, 2H, J=8.28 Hz), 7.29(dd, 1 H, J=8.55, 2.21 Hz), 7.10(d, 1 H, J=2.21 Hz), 6.77(d, 1 H, J=8.55 Hz), 4.93(q, 1 H, J=6.78 Hz), 4.32(s, 2H), 3.86(m, 6H), 3.27(m, 4H), 2.56(m, 2H), 2.18(s, 3H), 1.66(d, 3H, J=6.78 Hz), 1.54(m, 2H), 0.85(t, 3H, J=7.31 Hz), MS(ES') M-H= 620.0
2-{4-[({4-{[4-(3-Methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]-2-propylphenoxy}propanoic acid
1H NMR (CD3OD) 400MHz δ 8.18(d, 2H, J=8.55 Hz), 7.85(d, 2H, J=8.55 Hz), 7.30(dd, 1 H, J=8.55, 2.21 Hz), 7.22(t, 1 H, J=8.55 Hz), 7.16(d, 1 H, J=2.21 Hz), 6.77(d, 1 H, J=8.55 Hz), 6.58(m, 3H), 4.80(m, 1 H), 4.34(s, 2H), 4.06(d, 1 H, J .07 Hz), 3.97(d, 1 H, J .07 Hz), 3.79(s, 3H), 3.60(br s, 4H), 3.08(br s, 4H), 2.56(t, 2H, J=7.17 Hz), 1.58(m, 5H), 0.85(t, 3H, J=7.17 Hz),
MS(ES-) M-H= 684.1
2-{4-[({4-{[4-(4-Acetylphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]-2-propylphenoxy}propanoic acid
1H NMR (CD3OD) 400MHz δ 8.12(d, 2H, J=8.28 Hz), 7.91(d, 2H, J=9.14 Hz), 7.78(d, 2H, J=8.28 Hz), 7.22(dd, 1 H, J=8.28, 2.24 Hz), 7.10(d, 1 H, J=2.24 Hz), 7.03(d, 2H, J=9.14 Hz), 6.71(d, 1H, J=8.28 Hz), 4.81 (q, 1 H, J=6.72 Hz), 4.29(s, 2H), 3.99(d, 1 H, J=.14 Hz), 3.91(d, 1H, J .14 Hz), 3.60(br s, 4H), 3.33(m, 4H), 2.48(m, 5H), 1.59(d, 3H, J=6.72 Hz), 1.48(m, 2H), 0.78(t, 3H, J=7.41 Hz),
MS(ES") M-H= 696.1
2-{2-Methyl-4-[({4-{[4-(2-pyrimidinyl)"1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3- thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic acid 1H NMR (CD3OD) 300MHz δ 8.35(d, 2H, J=4.69 Hz), 8.13(d, 2H, J=8.28 Hz), 7.80(d, 2H,
J=8.28 Hz), 7.21 (s, 1 H), 7.13(d, 1 H, J=8.28 Hz), 6.71 (d, 1 H, J=8.28 Hz), 6.63(t, 1 H, J=4.69 Hz), 4.59(m, 1 H), 4.31 (s, 2H), 3.86(t, 4H, J=4.69 Hz), 3.50(s, 2H), 2.69(t, 4H, J=4.69 Hz), 2.22(s, 3H), 1.59(d, 3H, J=6.78 Hz),
MS(ES-) M-H= 628.5 2-{4-[({4-{[4-(2,4-Dimethoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3- thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid
1H NMR (CD3OD) 300MHz δ 8.17(d, 2H, J=8.00 Hz), 7.80(d, 2H, J=8.00 Hz), 7.20(br s, 1 H), 7.04(br s, 1 H), 6.92(d, 1 H, J=8.55 Hz), 6.67(br s, 1 H), 6.56(m, 1 H), 6.48(m, 1 H), 4.59(br s, 1 H), 4.27(s, 2H), 3.84(s, 3H), 3.78(s, 3H), 3.55(s, 2H), 3.07(m 8H), 2.21 (s, 3H), 1.56(br s, 3H), MS(ES-) M-H= 685.6
2-{2-Methyl-4-[({4-({4-[2-oxo-2-(1-pyrrolidinyl)ethyl]-1-piperazinyl}methyl)-2-[4- (trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic acid MS(ES-) M-H= 660.7
CHN Analysis 0.3 H20 (Theoretical %C=53.62, %H=6.05, %N=7.82; Found %C=53.33, %H=6.01 , %N=7.95)
2-[2-Methyl-4-({[2-[4-(trifluoromethyl)phenyl]-4-({4-[3-(trifluoronnethyl)phenyl]-1- piperazinyl}methyl)-1,3-thiazol-5-yl]methyl}sulfanyl)phenoxy]propanoic acid H NMR (CD3OD) 300MHz δ 8.09(d, 2H, J=8.28 Hz), 7J7(d, 2H, J=8.28 Hz), 7.40(s, 1 H), 7.19(m, 4H), 7.07(d, 1 H, J=7.73 Hz), 6.71 (d, 1 H, J=8.28 Hz), 4.47(m, 1 H), 4.33(s, 2H), 3.53(s, 2H), 3.23(m, 4H), 2.64(m, 4H), 2.22(s, 3H), 1.57(d, 3H, J=6J8 Hz),
MS(ES-) M-H= 694.5
2-{4-[({4-{[4-(2-Methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid
1H NMR (CD3OD) 300MHz δ 8.09(d, 2H, J=8.28 Hz), 7.77(d, 2H, J=8.28 Hz), 7.25(s, 1 H), 7.17(s, 1 H), 6.96(m, 4H), 6.70(s, 1 H), 4.51 (m, 1 H), 4.34(s, 2H), 3.86(s, 3H), 3.57(s, 2H), 3.07(br s, 4H), 2.76(br s, 4H), 2.23(br s, 3H), .54(br s, 3H), MS(ES-) M-H= 656.5
2-{4-[({4-[(4-Acetyl-1-piperazinyl)methyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid 1H NMR (CDCI3) 400MHz δ 7.93(d, 2H, J=8.20 Hz), 7.63(d, 2H, J=8.20 Hz), 7.02(m, 2H),
6.57(d, 1 H, J=8.20 Hz), 4.65(q, 1H, J=6.78 Hz), 4.16(d, 1 H, J .87 Hz), 4.09(d, 1 H, J .87 Hz), 3.55(m, 6H), 2.74(m, 4H), 2.11 (s, 3H), 1.98(s, 3H), 1.55(d, 3H, J=6.78 Hz), MS(ES+) M+H= 594.0
HPLC(C-18 3μm) 1 %MeOH/ 0-99% Acetonitrile/Water (0.1 %TFA) 5min run Rt= 3.79
2-{2-Methyl-4-[({4-{[4-(4-pyridinyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3- thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic acid
1H NMR (CD3OD) 400MHz δ 8.01 (d, 2H, J=8.20 Hz), 7.95(d, 2H, J=8.20 Hz), 7.64(d, 2H, J=8.20 Hz), 7.16(d, 1 H, J=2.22 Hz), 7.09(dd, 1 H, J=8.37, 2.22 Hz), 6.97(d, 2H, J=8.20 Hz), 6.63(d, 1 H, J=8.37 Hz), 4.48(q, 1 H, J=6.78 Hz), 4.19(s, 2H), 3.57(t, 4H, J=5.10Hz), 3.48(s, 2H), 2.46(t, 4H, J=5.10 Hz), 2.14(s, 3H), 1.54(d, 3H, J=6.78 Hz), MS(ES+) M+H= 629.0
HPLC(C-18 3μm) 1 %MeOH/ 0-99% Acetonitrile/Water (0.1 %TFA) 5min run R,= 4.22
2-{4-[({4-{[4-(3-Methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid
1H NMR (CDCI3) 400MHz δ 10.57(s, 1 H), 7.91 (d, 2H, J=8.20 Hz), 7.63(d, 2H, J=8.20 Hz), 7.11(t, 1H, J=8.20 Hz), 6.98(m, 2H), 6.60(d, 1H, J=8.20 Hz), 6.41 (dd, 2H, J=8.20, 2.22 Hz), 6.35(t, 1H, J=2.22 Hz), 4.65(q, 1 H, J=6.84 Hz), 4.10(s, 2H), 3.72(s, 3H), 3.59(d, 1 H, J .18 Hz), 3.49(d, 1 H, J .18 Hz), 3.35 m, 4H), 3.10(m, 4H), 2.12(s, 3H), 1.55(d, 3H, J=6.84 Hz), MS(ES+) M+H= 658.0
HPLC(C-18 3μm) 1%MeOH/ 0-99% Acetonitrile/Water (0.1%TFA) 5min run Rt= 4.09
2-{2-Methyl-4-[({4-(4-morpholinylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}propanoic acid 1H NMR (CDCy 400MHz δ 11.61(s, 1 H), 8.00(d, 2H, J=8.23 Hz), 7.69(d, 2H, J=8.23 Hz),
7.10(dd, 1 H, J=8.37, 2.20 Hz), 6.83(d, 1 H, J=2.20 Hz), 6.71 (d, 1 H, J=8.37 Hz), 4.84(q, 1 H, J=6.72 Hz), 4.12(m, 4H), 3.84(m, 2H), 3.43(m, 3H), 3.19(m, 2H), 2.88(m, 1 H), 2.10(s, 3H), 1.61(d, 3H, J=6.72 Hz),
MS(ES+) M+H= 553.0 HPLC(C-18 3μm) 1%MeOH/ 0-99% Acetonitrile/Water (0.1%TFA) 5min run R,= 3.89
2-{4-[({4-{[4-(Ethoxycarbonyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid
1H NMR (CDCl3) 400MHz δ 10.39(s, 1H), 7.93(d, 2H, J=8.23 Hz), 7.64(d, 2H, J=8.23 Hz), 7.05(d, 1 H, J=2.39 Hz), 6.97(d, 1 H, J=8.37 Hz), 6.57(d, 1 H, J=8.37 Hz), 4.65(q, 1 H, J=6.78 Hz),
4.09(q, 4H, J=7.06 Hz), 3.58(m, 4H), 3.39(m, 2H), 2.74(m, 4H), 2.14(s, 3H), 1.57(d, 3H, J=6.78 Hz), 1.21(t, 3H, J=7.06 Hz),
MS(ES+) M+H= 624.0
HPLC(C-18 3μm) 1 %MeOH/ 0-99% Acetonitrile/Water (0.1 %TFA) 5min run Rt= 3.93
2-{4-[({4-{[4-(4-Acetylphenyl)-1-piperazinyl3methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazoI-5- yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid
1H NMR (CDCy 400MHz δ 9.84(s, 1 H), 7.91(d, 2H, J=8.20 Hz), 7.81(d, 2H, J=8.89 Hz), 7.63(d, 2H, J=8.20 Hz), 7.00(d, 1 H, J=2.20 Hz), 6.93(dd, 1 H, J=8.37, 2.20 Hz), 6.76(d, 2H, J=8.89 Hz), 6.58(d, 1 H, J=8.37 Hz), 4.66(q, 1 H, J=6.78 Hz), 4.08(s, 2H), 3.45(m, 6H), 2.96(m, 4H), 2.47(s, 3H), 2.13(s, 3H), 1.59(d, 3H, J=6.78 Hz),
MS(ES+) M+H= 670.0
HPLC(C-18 3μm) 1 %MeOH/ 0-99% Acetonitrile/Water (0.1 %TFA) 5min run Rt= 4.03 2-{4-[({4-{[4-(4-Fluorophenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid
1H NMR (CDCI3) 400MHz δ 7.92(d, 2H, J=8.23 Hz), 7.62(d, 2H, J=8.23 Hz), 7.05(s, 1 H), 6.89(m, 2H), 6.75(m, 2H), 6.55(d, 1 H, J=8.23 Hz), 4.59(m, 1 H), 4.17(m, 2H), 3.53(m, 2H), 3.21 (m, 4H), 2.97(m, 4H), 2.12(s, 3H), 1.51(d, 3H, J=6.78 Hz), MS(ES+) M+H= 646.0
HPLC(C-18 3μm) 1 %MeOH/ 0-99% Acetonitrile/Water (0.1 %TFA) 5min run Rt= 4.11
2-{4-[({4-({4-[(4-Fluorophenyl)sulfonyl]-1-piperazinyl}methyl)-2-[4-(trifluoromethyl)phenyl]-1,3- thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid
1H NMR (CD3OD) 400MHz δ 8.03(d, 2H, J=8.20 Hz), 7.83(t, 2H, J=7.69 Hz), 7.73(d, 2H, J=8.20 Hz), 7.33(t, 2H, J=7.69 Hz), 7.17(s, 1 H), 7.08(d, 1 H, J=8.20 Hz), 6.64(d, 1 H, J=8.20 Hz), 4.67(br s, 1 H), 4.22(s, 2H), 3.37(s, 2H), 2.99(br s, 4H), 2.50(br s, 4H), 2.16(s, 3H), 1.57(d, 3H, J=6.84 Hz), MS(ES-) M-H= 708.0
2-{2-Methyl-4-[({4-{[4-(3-methylbutanoyl)-1-piperazinyl]methyl}-2-[4-(trifluorømethyl)phenyl]- 1 ,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic acid
1H NMR (CD3OD) 400MHz δ 8.12(d, 2H, J=8.28 Hz), 7.80(d, 2H, J=8.28 Hz), 7.23(d, 1 H, J=2.21 Hz), 7.17(dd, 1 H, J=8.28, 2.21 Hz), 6.72(d, 1 H, J=8.28 Hz), 4J2(q, 1 H, J=6.44 Hz), 4.32(s, 2H), 3.63(br s, 4H), 3.44(s, 2H), 2.59(br s, 4H), 2.31 (d, 2H, J=6.90 Hz), 2.21 (s, 3H), 2.06(m, 1 H), 1.62(d, 3H, J=6.44 Hz), 0.98(d, 6H, J=6.90 Hz),
MS(ES-) M-H= 634.0
2-{4-[({4-{[4-(Cyclohexylcarbonyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3- thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid
1H NMR (CD3OD) 400MHz δ 8.06(d, 2H, J=8.10 Hz), 7.74(d, 2H, J=8.10 Hz), 7.16(d, 1 H, J=2.24 Hz), 7.09(dd, 1 H, J=8.45, 2.24 Hz), 6.64(d, 1 H, J=8.45 Hz), 4.68(q, 1 H, J=6.78 Hz), 4.25(s, 2H), 3.60(br s, 4H), 3.42(s, 2H), 2.62(br s, 4H), 2.16(s, 3H), 1.72(m, 5H), 1.56(d, 3H, J=6.72 Hz), 1.31 (m, 6H),
MS(ES-) M-H= 661.0
2-{2-Methyl-4-[({4-{[4-(2-pyrazinyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3- thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic acid 1H NMR (CD3OD) 300MHz δ
8.17(m, 4H), 7.81 (m, 3H), 7.26(br s, 1 H), 7.13(br s, 1 H), 6.75(br s, 1 H), 4.68(br s, 1 H), 4.32(s, 2H), 3.65(br s, 4H), 3.48(s, 2H), 2.64(br s, 4H), 2.20(s, 3H), 1.60(br s, 3H), MS(ES-) M-H= 628.3
2-{4-[({4-({4-[4-(dimethylamino)benzoyl]-1..piperazinyl}methyl)^ thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid 1H NMR (CD3OD) 400MHz δ,
8.12(d, 2H, J=8.28 Hz), 7.80(d, 2H, J=8.28 Hz), 7.35(d, 2H, J=9.11 Hz), 7.21 (d, 1 H, J=2.21 Hz), 7.14(d, 1 H, J=8.55 Hz), 6.78(d, 2H, J=9.11 Hz), 6J0(d, 1 H, J=8.55 Hz), 4.68(q, 1 H, J=6.62 Hz), 4.31 (s, 2H), 3.70(br s, 4H), 3.45(s, 2H), 3.02(s, 6H), 2.63(br s, 4H), 2.19(s, 3H), 1.59(d, 3H, J=6.62 Hz),
MS(ES-) M-H= 697.0
2-{4-[({4-{[4-(2-Furoyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid 1H NMR (CD3OD) 400MHz δ 8.06(d, 2H, J=8.28 Hz), 7.73(d, 2H, J=8.2S Hz), 7.65(m, 1 H),
7.16(d, 1 H, J=2.20 Hz), 7.07(d, 1 H, J=8.55 Hz), 7.01 (d, 1 H, J=3.62 Hz), 6.63(d, 1 H, J=8.45 Hz), 6.55(m, 1 H), 4.66(q, 1 H, J=6.55 Hz), 4.25(s, 2H), 3.77(br s, 4H), 3.39(s, 2H), 2.59(br s, 4H), 2.14(s, 3H), 1.54(d, 3H, J=6.55 Hz), MS(ES") M-H= 644.1
2-{4-[({4-{[4-(Cyclopentylcarbonyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3- thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid
1H NMR (CD3OD) 400MHz δ 8.13(d, 2H, J=8.28 Hz), 7.80(d, 2H, J=8.28 Hz), 7.23(d, 1 H, J=2.39 Hz), 7.15(d, 1 H, J=8.28 Hz), 6.71 (br s, 1 H), 4.73(q, 1 H, J=6.78 Hz), 4.31 (s, 2H), 3.67(br s, 4H), 3.45(s, 2H), 3.06(m, 1 H), 2.62(br s, 4H), 2.22(s, 3H), 1.75(m, 14H), MS(ES-) M-H= 646.2
2-{4-[({4-{[4-(Cyclobutylcarbonyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3- thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid 1H NMR (CD3OD) 400MHz δ 8.09(d, 2H, J=8.20 Hz), 7.77(d, 2H, J=8.20 Hz), 7.18(d, 1 H,
J=2.22 Hz), 7.13(dd, 1 H, J=8.55, 2.22 Hz), 6.68(d, 1 H, J=8.55 Hz), 4.71 (q, 1 H, J=6.75 Hz), 4.28(s, 2H), 3.60(br s, 2H), 3.46(br s, 2H), 3.41 (s, 2H), 2.57(t, 4H, J=4.44 Hz), 2.22(m, 6H), 2.00(m, 2H), 1.83(m, 2H), 1.60(d, 3H, J=6.75 Hz), MS(ES') M-H= 633.1
2-{4-[({4-{[4-(Cyclopropylcarbonyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3- thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid
1H NMR (CD3OD) 400MHz δ 8.10(d, 2H, J=8.23 Hz), 7.76(d, 2H, J=8.23 Hz), 7.21 (d, 1 H, J=2.20 Hz), 7.11 (d, 1 H, J=8.20 Hz), 6.67(s, 1 H), 4.68(q, 1 H, J=6.84 Hz), 4.28(s, 2H), 3.68(br s, 4H), 3.42(s, 2H), 2.59(br s, 4H), 2.19(s, 3H), 1 ,95(m, 1 H), 1.57(d, 3H, J=6.84 Hz), 0.84(m, 4H), MS(ES") M-H= 619.1
2-{2-Methyl-4-[({4-{[4-(2-thienylcarbonyl)-l-piperazinyl]methyl}-2-[4-(trifluoromethyl)pheny|]- 1I3-thiazol-5-yl}methyl)sulfanyl]phenoχy}propanoic acid 1H NMR (CD3OD) 300MHz δ 8.10(d, 2H, J=8.20 Hz), 7.76(d, 2H, J=8.20 Hz), 7.63(d, 1H, J=5.13 Hz), 7.37(d, 1 H, J=5.13 Hz), 7.22(br s, 1 H), 7.10(br s, 1 H), 7.02(br s, 1 H), 6.64(br s, 1 H), 4.67(br s, 1 H), 4.27(s, 2H), 3J4(br s, 4H), 3.40(s, 2H), 2.53(br s, 4H), 2.16(br s, 3H), 1.57(br s, 3H),
MS(ES-) M-H= 660.1
2-{4-[({4-{[4-(2,4-Difluorophenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol- 5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid
1H NMR (CD3OD) 300MHz δ 8.10(d, 2H, J=8.28 Hz), 7.73(d, 2H, J=8.28 Hz), 7.20(br s, 1 H), 6.92(m, 4H), 6.60(d, 1 H, J=8.55 Hz), 4.59(br s, 1 H), 4.23(s, 2H), 3.44(s, 2H), 3.06(br s, 4H), 2.80(br s, 4H), 2.17(s, 3H), 1.53(d, 3H, J=6.35 Hz), MS(ES") M-H= 661.2
2-[2-Methyl-4-({[2-[4-(trifluoromethyl)phenyl]-4-({4-[4-(trifluoromethyl)phenyl]-1- piperazinyl}methyl)-1 ,3-thiazol-5-yl]methyl}sulfanyl)phenoxy]propanoic acid 1H NMR (CD3OD) 300MHz δ 8.11 (d, 2H, J=8.28 Hz), 7.78(d, 2H, J=8.28 Hz), 7.49(d, 2H,
J=8.55 Hz), 7.24(d, 1 H, J=2.39 Hz), 7.15(d, 1 H, J=8.55 Hz), 7.04(d, 2H, J=8.55 Hz), 6.71 (d, 1 H, J=8.55 Hz), 4.55(br s, 1 H), 4.32(s, 2H), 3.51 (s, 2H), 3.31 (m, 4H), 2.68(t, 4H, J=4.97 Hz), 2.22(s, 3H), 1.59(d, 3H, J=6.07 Hz),
MS(F.S-) M-H= 694.5
2-{4-[({4-{[4-(lsobutoxycarbonyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol- 5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid
1H NMR (CD3OD) 400MHz δ 8.13(d, 2H, J=8.28 Hz), 7.80(d, 2H, J=8.28 Hz), 7.22(d, 1 H, J=2.21 Hz), 7.15(dd, 1 H, J=8.28, 2.21 Hz), 6.71 (d, 1 H, J=8.28 Hz), 4.75(q, 1 H, J=6.90 Hz), 4.31 (s, 2H), 3.89(d, 2H, J=6.90 Hz), 3.57(br s, 4H), 2.68(t, 4H, J=4.69 Hz), 2.22(s, 3H), 1.96(m, 1 H), 1.62(d, 3H, J=6.90 Hz), 0.96(d, 6H, J=6.90 Hz),
MS(ES-) M-H= 650
2-{4-[({4-({4-[(Benzyloxy)carbonyl]-1-piperazinyl}methyl)-2-[4-(trifluoromethyl)phenyl]-1,3- thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid
1H NMR (CD3OD) 400MHz δ 8.06(d, 2H, J=8.03 Hz), 7.73(d, 2H, J=8.03 Hz), 7.30(m, 5H), 7.15(br s, 1 H), 7.08(dd, 1 H, J=8.20, 2.22 Hz), 6.64(d, 1 H, J=8.20 Hz), 5.08(s, 2H), 4.65(q, 1 H, J=6.72 Hz), 4.23(s, 2H), 3.51 (br s, 4H), 3.37(s, 2H), 2.57(br s, 4H), 2.15(s, 3H), 1.55(d, 3H, J=6.72 Hz),
MS(ES') M-H= 684.0
2-(4-[({4-{[4-(Methoxycarbonyl)-1-piperazinynmethyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid
1H NMR (CD3OD) 400MHz δ 8.06(d, 2H, J=8.37 Hz), 7.74(d, 2H, J=8.37 Hz), 7.16(d, 1 H, J=2.21 Hz), 7.10(dd, 1 H, J=8.55, 2.39 Hz), 6.66(d, 1 H, J=8.55 Hz), 4.59(br s, 1 H), 4.25(s, 2H), 3.65(s, 3H), 3.45(t, 4H, J=4.79 Hz), 3.38(s, 2H), 2.49(br s, 4H), 2.17(s, 3H), 1.55(d, 3H, J=6.32 Hz), MS(ES-) M-H= 608.0 2-{2-Methyl-4-[({4-{[4-(phenoxycarbonyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]- 1 ,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic acid
1H NMR (CD3OD) 400MHz δ 8.08(d, 2H, J=8.20 Hz), 7.75(d, 2H, J=8.20 Hz), 7.34(m, 2H), 7.19(m, 2H), 7.13(dd, 1 H, J=8.20, 2.22 Hz), 7.06(m, 2H), 6.66(d, 1 H, J=8.20 Hz), 4.69(q, 1 H, J=6.78 Hz), 4.27(s, 2H), 3.69(br s, 2H), 3.54(br s, 2H), 3.43(s, 2H), 2.62(br s, 4H), 2.17(s, 3H), 1.54(d, 3H, J=6.78 Hz),
MS(ES-) M-H= 670.0
2-{2-Methyl-4-[({4-{[4-(phenylsulfonyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3- thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic acid
1H NMR (CD3OD) 400MHz δ 8.01 (d, 2H, J=8.20 Hz), 7.72(m, 4H), 7.63(d, 1 H, J=8.20 Hz), 7.56(M, 2H), 7.13(d, 1 H, J=2.22Hz), 7.05(dd, 1 H, J=8.20, 2.22 Hz), 6.62(d, 1 H, J=8.20 Hz), 4.70(q, 1 H, J=6.61 Hz), 4.19(s, 2H), 3.34(s, 2H), 2.97(br s, 4H), 2.51 (br s, 4H), 2.13(s, 3H), 1.57(d, 3H, J=6.61 Hz),
MS(ES-) M-H= 690.0
2-{2-Methyl-4-[({2-[4-(trifluoromethyl)phenyl]-4-[(4-{[4-(trifluoromethyl)phenyl]sulfonyl}-1- piperazinyl)methyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic acid 1H NMR (CD3OD) 400MHz δ 8.01 (d, 2H, J=8.20 Hz), 7.91 (m, 4H), 7.71(d, 2H, J=8.20 Hz),
7.15(d, 1 H, J=2.22 Hz), 7.08(dd, 1 H, J=8.20, 2.22 Hz), 6.62(d, 1 H, J=8.20 Hz), 4.71 (q, 1 H, J=6.58Hz), 4.20(s, 2H), 3.33(s, 2H), 3.01 (br s, 4H), 2.49(br s, 4H), 2.14(s, 3H), 1.57(d, 3H, J=6.58 Hz), MS(ES-) M-H= 758.0
2-{4-[({4-({4-[(4-Methoxyphenyl)sulfonyl]-1-piperazinyl}methyl)-2-[4-(trifluoromethyl)phenyl]- 1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid
Hi NMR (CDjOD) 400MHz δ 8.02(d, 2H, J=8.37 Hz), 7.72(d, 2H, J=8.37 Hz), 7.66(d, 2H, J=8J2 Hz), 7.14(d, 1 H, J=2.21 Hz), 7.07(m, 3H), 6.63(d, 1 H, J=8.37 Hz), 4.71 (q, 1 H, J=6.72 Hz), 4.20(s, 2H), 3.84(s, 3H), 3.35(s, 2H), 2.97(br s, 4H), 2.53(t, 4H, J=4.61 Hz), 2.14(s, 3H), 1.58(d, 3H, J=6.72 Hz),
MS(ES-) M-H= 720.0
2-{2-Methyl-4-[({4-{[4-(propylsulfonyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3- thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic acid 1H NMR (CD3OD) 400MHz δ 8.07(d, 2H, J=8.20 Hz), 7.75(d, 2H, J=8.20 Hz), 7.19(s, 1 H),
7.13(d, 1 H, J=8.20 Hz), 6.66(d, 1H, J=8.20 Hz), 4.70(q, 1 H, J=6.67 Hz), 4.26(s, 2H), 3.40(s, 2H), 3.22(br s, 4H), 2.95(t, 2H, J=7.43 Hz), 2.54(br s, 4H), 2.17(s, 3H), 1.76(m, 2H), 1.57(d, 3H, J=6.67 Hz), 1.02(t, 3H, J=7.43 Hz), MS(ES-) M-H= 656.0 2-{4-[({4-{[4-(Ethylsulfonyl)-1-piperazinylImethyl}-2-[4-(trifluoromethyl)phenylI-1,3-thiazol-5- yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid
1H NMR (CD3OD) 400MHz δ 8.07(d, 2H, J=8.03 Hz), 7.74(d, 2H, J=8.03 Hz), 7.19(s, 1 H), 7.11 (d, 1 H, J=8.03 Hz), 6.65(d, 1 H, J=8.03 Hz), 4.64(q, 1 H, J=6.49 Hz), 4.26(s, 2H), 3.39(s, 2H), 3.23(br s, 4H), 2.99(q, 2H, J=7.41 Hz), 2.51 (br s, 4H), 2.16(s, 3H), 1.55(d, 3H, J=6.49 Hz), 1.27(t, 3H, J=7.41 Hz),
MS(ES-) M-H= 642.0
2-{2-Methyl-4-[({4-{[4-(methylsulfonyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3- thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic acid
1H NMR (CD3OD) 400MHz δ 8.06(d, 2H, J=8.03 Hz), 7.74(d, 2H, J=8.03 Hz), 7.19(s, 1 H), 7.13(dd, 1 H, J=8.03, 2.22 Hz), 6.66(d, 1 H, J=8.03 Hz), 4.65(q, 1 H, J=6.84 Hz), 4.27(s, 2H), 3.40(s, 2H), 3.17(t, 4H, J=4.19 Hz), 2.80(s, 3H), 2.53(t, 4H, J=4.19 Hz), 2.17(s, 3H), 1.56(d, 3H, J=6.84 Hz),
MS(ES-) M-H= 628.0
2-{4-[({4-{[4-(4-Fluorobenzoyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid
1H NMR (CD3OD) 300MHz δ 8.09(d, 2H, J=8.28 Hz), 7.76(d, 2H, J=8.28 Hz), 7.52(M, 2H), 7.22(M, 3H), 7.13(dd, 1 H, J=8.28, 2.20 Hz), 6.68(d, 1 H, J=8.28 Hz), 4.67(q, 1 H, J=6.81 Hz), 4.32(s, 2H), 3.79(br s, 4H), 3.66(s, 2H), 2.90(br s, 4H), 2.17(s, 3H), 1.59(d, 3H, J=6.81 Hz), MS(ES") M-H= 671.9
2-{4-[({4-[(4-{[4-(Acetylamino)phenyllsulfonyl}-1-piperazinyl)methyl]-2-[4- (trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid 1H NMR (CD3OD) 400MHz δ 8.07(d, 2H, J=8.28 Hz), 7.83(d, 2H, J=8.83 Hz), 7.77(d, 2H,
J=8.28 Hz), 7.71 (d, 2H, J=8.83 Hz), 7.18(d, 1 H, J=2.20 Hz), 7.10(dd, 1 H, J=8.28, 2.20 Hz), 6.68(d, 1 H, J=8.28 Hz), 4.71 (q, 1 H, J=6.53 Hz), 4.26(s, 2H), 3.42(s, 2H), 3.03(br s, 4H), 2.56(t, 4H, J=4.83 Hz), 2.20(m, 6H), 1.63(d, 3H, J=6.53 Hz), MS(ES-) M-H= 747.0
2-{4-[({4-({4-[(4-Fluoroanilino)carbonyl]-1-piperazinyl}methyl)-2-[4-(trifluoromethyl)phenyl1-1,3- thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid MS(ES-) M-H= 687.5
2-{4-[({4-{f4-(4-Methoxybenzoyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol- 5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid
1H NMR (CD3OD) 300MHz δ 8.02(d, 2H, J=8.20 Hz), 7.69(d, 2H, J=8.20 Hz), 7.38(d, 2H, J=8.79 Hz), 7.12(d, 1 H, J=2.24 Hz), 7.06(dd, 1 H, J=8.28, 2.24 Hz), 6.95(d, 2H, J=8J9 Hz), 6.61 (d, 1 H, J=8.28 Hz), 4.58(q, 1 H, J=6.78 Hz), 4.25(s, 2H), 3.78(s, 3H), 3.71 (br s, 4H), 3.64(s, 2H), 2.88(br s, 4H), 2.10(s, 3H), 1.52(d, 3H, J=6.78 Hz),
MS(ES-) M-H= 683.6 2-{4-[({4-({4-[(3-Methoxyanilino)carbonyl]-1-piperazinyl}methyl)-2-[4-(trifluoromethyl)phenyl]- 1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid
1H NMR (CDCI3) 300MHz δ 8.04(d, 2H, J=8.28 Hz), 7.69(d, 2H, J=8.28 Hz), 7.31 (d, 1 H, J=2.21 Hz), 7.16(m, 2H), 6.89(m, 2H), 6.59(dd, 1 H, J=8.28, 2.21 Hz), 6.53(d, 1 H, J=8.28 Hz), 4.73(q, 1 H, J=6.90 Hz), 4.33(d, 1 H, J .63 Hz), 4.23(d, 1 H, J .63 Hz), 3.79(s, 3H), 3.45(m, 6H), 2.36(t, 4H, J=4.69 Hz), 2.24(s, 3H), 1.64(d, 3H, J=6.90 Hz),
MS(ES-) M-H= 699.6
2-{4-[({4-{[4-(Aminocarbonyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid
1H NMR (CD3OD) 400MHz δ 8.15(d, 2H, J=8.28 Hz), 7.83(d, 2H, J=8.28 Hz), 7.27(d, 1 H, J=2.48 Hz), 7.19(dd, 1 H, J=8.55, 2.48 Hz), 6.74(d, 1 H, J=8.55 Hz), 4.65(br s, 1 H), 4.36(s, 2H), 3.57(s, 2H), 3.48(br s, 4H), 2.64(br s, 4H), 2.24(s, 3H), 1.62(d, 3H, J=6.62 Hz), MS(ES') M-H= 593.1
2-{4-[({4-({4-[(Cyclohexylamino)carbonyl]-1-piperazinyl}methyl)-2-[4-(trifluoromethyl)phenyl]- 1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid
1H NMR (CD3OD) 400MHz δ 8.15(d, 2H, J=8.28 Hz), 7.81 (d, 2H, J=8.28 Hz), 7.24(br s, 1 H), 7.13(br s, 1 H), 6.73(br s, 1 H), 4.75(br s, 1 H), 4.30(s, 2H), 3.52(m, 7H), 2.68(br s, 4H), 2.24(s, 3H), 1.75(m, 7H), 1.26(m, 6H),
MS(ES-) M-H= 675.0
2-{2-Methyl-4-[({4-({4-[(propylamino)carbonyl]-1-piperazinyl}methyl)-2-[4- (trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic acid
1H NMR (CD3OD) 400MHz δ 8.15(d, 2H, J=8.00 Hz), 7.81 (d, 2H, J=8.00 Hz), 7.25(d, 1 H, J=2.21 Hz), 7.15(dd, 1 H, J=8.55, 2.21 Hz), 6.70(d, 1 H, J=8.55 Hz), 4.68(q, 1 H, J=6.53 Hz), 4.30(s, 2H), 3.60(s, 2H), 3.48(br s, 4H), 3.14(t, 2H, J=7.45 Hz), 2.73(t, 4H, J=5.10 Hz), 2.22(s, 3H), 1.63(d, 3H, J=6.53 Hz), 1.52(s, 2H), 0.93(t, 3H, J=7.45 Hz), MS(ES-) M-H= 635.3
2-{4-[({4-({4-[(Ethylamino)carbonyl]-1-piperazinyl}methyl)-2-[4-(trifluoromethyl)phenyl]-1,3- thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid
1H NMR (CD3OD) 400MHz δ 8.15(d, 2H, J=8.28 Hz), 7.81 (d, 2H, J=8.28 Hz), 7.25(d, 1 H, J=2.48 Hz), 7.14(dd, 1H, J=8.28, 2.48 Hz), 6.70(d, 1 H, J=8.28 Hz), 4.67(br s, 1 H), 4.29(s, 2H), 3.56(s, 2H), 3.46(br s, 4H), 3.22(q, 2H, J=7.17 Hz), 2.68(t, 4H, J=4.92 Hz), 2.21 (s, 3H), 1.61 (d, 3H, J=6.35 Hz), 1.14(t, 3H, J=7.17 Hz), MS(ES") M-H= 621.1
2-{2-Methyl-4-[({4-({4-[(methylamino)carbonyl]-1-piperazinyl}methyl)-2-[4-
(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanynphenoxy}propanoic acid 1H NMR (CD3OD) 400MHz δ 8.05(d, 2H, J=8.20 Hz), 7.72(d, 2H, J=8.20 Hz), 7.17(d, 1H, J=2.22 Hz), 7.09(dd, 1 H, J=8.37, 2.22 Hz), 6.61 (d, 1 H, J=8.37 Hz), 4.66(q, 1 H, J=6J5 Hz), 4.20(s, 2H), 3.56(s, 2H), 3.42(br s, 4H), 2.69(m, 7H), 2.15(s, 3H), 1.58(d, 3H, J=6J5 Hz),
MS(ES-) M-H= 607.0
2-{4-[({4-({4-[(lsopropylamino)carbonyl]-1-piperazinyl}methyl)-2-[4-(trifluoromethyl)phenyl]-1,3- thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid
1H NMR (CD3OD) 400MHz δ 8.09(d, 2H, J=8.20 Hz), 7.75(d, 2H, J=8.20 Hz), 7.17(br s, 1 H), 7.08(d, 1 H, J=8.20 Hz), 6.64(d, 1 H, J=8.20 Hz), 4.63(q, 1 H, J=6.49 Hz), 4.23(s, 2H), 3.84(m, 1 H), 3.46(m, 6H), 2.68(br s, 4H), 2.16(s, 3H), 1.57(d, 3H, J=6.49 Hz), 1.10(d, 6H, J=6.32 Hz), MS(ES-) M-H= 635.0
2-{4-[({4-({4-[(tert-Butylamino)carbonyl]-1-piperazinyl}methyl)-2-[4-(trifluoromethyl)phenyl]-1,3- thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid 1H NMR (CD3OD) 400MHz δ 8.08(d, 2H, J=8.20 Hz), 7.75(d, 2H, J=8.20 Hz), 7.16(d, 1 H,
J=2.22 Hz), 7.07(dd, 1 H, J=8.37, 2.22 Hz), 6.64(d, 1 H, J=8.37 Hz), 4.61 (q, 1 H, J=6J5 Hz), 4.21 (s, 2H), 3.44(m, 6H), 2.71 (br s, 4H), 2.16(s, 3H), 1.55(d, 3H, J=6.75 Hz), 1.27(s, 9H), MS(ES-) M-H= 649.0
2-{2-Methyl-4-[({4-[(4-{[(2-phenylethyl)amino]carbonyl}-1-piperazinyl)methyl]-2-[4- (trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic acid
1H NMR (CD3OD) 400MHz δ 8.08(d, 2H, J=8.03 Hz), 7.75(d, 2H, J=8.03 Hz), 7.17(s, 7H), 6.64(d, 1 H, J=8.55 Hz), 4.61 (q, 1 H, J=6.84 Hz), 4.24(s, 2H), 3.43(m, 9H), 2.76(1, 2H, J=7.52 Hz), 2.62(br s, 4H), 2.16(s, 3H), 1.56(d, 3H, J=6.67 Hz), MS(ES-) M-H= 697.0
2-{4-[({4-[(4-Benzoyl-1-piperazinyl)methyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid H NMR (CD3OD) 300MHz δ 8.03(d, 2H, J=8.28 Hz), 7.70(d, 2H, J=8.28 Hz), 7.42(m, 5H), 7.13(d, 1 H, J=2.24 Hz), 7.07(dd, 1 H, J=8.45, 2.24 Hz), 6.62(d, 1 H, J=8.45 Hz), 4.61 (q, 1 H, J=6.78 Hz), 4.26(s, 2H), 3.83(br s, 4H), 3.62(s, 2H), 2.86(br s, 4H), 2.11 (s, 3H), 1.53(d, 3H, J=6.78 Hz), MS(ES') M-H= 653.7
2-{2-Methyl-4-[({4-{[4-(4-propoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3- thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic acid
1H NMR (CD3OD) 400MHz δ 8.11 (d, 2H, J=7.69 Hz), 7.77(d, 2H, J=7.69 Hz), 7.15(s, 1 H), 7.08(dd, i H, ..'=8.61 , 2.20 Hz), 6.93(d, 2H, J=8.97 Hz), 6.82(d, 2H, J=8.97 Hz), c.67(d, 1 H, J=8.61 Hz), 4.57(q, 1 H, J=6J8 Hz), 4.24(s, 2H), 3.85(t, 2H, J=7.01 Hz), 3.55(s, 2H), 3.18(br s, 4H), 3.03(br s, 4H), 2.16(s, 3H), 1.73(m, 2H), 1.54(d, 3H, J=6.78 Hz), 1.00(t, 3H, J=7.01 Hz), MS(ES-) M-H= 684.0 2-{4-[({4-{[4-(4-Ethoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}met yl)sulfanyl]-2-methylphenoxy}propanoic acid
1H NMR (CD3OD) 400MHz δ 8.11 (d, 2H, J=8.06 Hz), 7.77(d, 2H, J=8.06 Hz), 7.15(s, 1 H), 7.08(dd, 1 H, J=8.42, 2.20 Hz), 6.92(d, 2H, J=8.97 Hz), 6.81 (d, 2H, J=8.97 Hz), 6.67(d, 1 H, J=8.42 Hz), 4.59(q, 1 H, J=6J8 Hz), 4.24(s, 2H), 3.95(q, 2H, J=6J8 Hz), 3.54(s, 2H), 3.17(br s, 4H), 3.04(br s, 4H), 2.17(s, 3H), 1.55(d, 3H, J=6J8 Hz), 1.32(t, 3H, J=6J8 Hz), MS(ES") M-H= 671.0
2-{2-Methyl-4-[({4-({4-[4-(trifluoromethoxy)phenyl]-1-piperazinyl}methyl)-2-[4- (trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic acid
1H NMR (CD3OD) 400MHz δ 8.10(d, 2H, J=8.28 Hz), 7.75(d, 2H, J=8.28 Hz), 7.15(d, 1 H, J=2.24 Hz), 7.12(d, 2H, J=9.14 Hz), 7.08(dd, 1 H, J=8.45, 2.24 Hz), 7.00(d, 2H, J=9.31 Hz), 6.66(d, 1 H, J=8.45 Hz), 4.59(q, 1 H, J=6.72 Hz), 4.24(s, 2H), 3.54(s, 2H), 3.27(m, 4H), 2.97(t, 4H, J=4.83 Hz), 2.16(s, 3H), 1.54(d, 3H, J=6J2 Hz), MS(ES") M-H= 710.0
2-{4-[({4-{[4-(3,4-Dimethoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3- thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid
1H NMR (CD3OD) 300MHz δ 8.17(d, 2H, J=8.28 Hz), 7.82(d, 2H, J=8.28 Hz), 7.20(br s, 1 H), 7.12(br s, 1 H), 6.89(d, 1 H, J=8.83 Hz), 6.72(m, 2H), 6.55(dd, 1 H, J=8.83, 2.76 Hz), 4.66(br s, 1 H),
4.29(s, 2H), 3.84(s, 3H), 3.80(s, 3H), 3.57(s, 2H), 3.25(br s, 4H), 3.07(br s, 4H), 2.23(s, 3H), 1.61 (br s, 3H),
MS(ES-) M-H= 686.0
2-{4-[({4-{[4-(4-Hydroxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid
1H NMR (CD3OD) 300MHz δ 8.14(br s, 2H), 7.80(br s, 2H), 7.24(br s, 1 H), 7.12(br s, 1 H), 6.92(br s, 2H), 6.76(br s, 2H), 6.63(sbr , 1 H), 4.54(br s, 1H), 4.31 (br s, 2H), 3.67 (br s, 2H), 3.06(br s, 8H), 2.23(br s, 3H), 1.60(br s, 3H), MS(ES-) M-H= 642.3
2-{4-[({4-{[4-(3-Hydroxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid
1H NMR (CD3OD) 300MHz δ 8.15(d, 2H, J=8.28 Hz), 7.81(d, 2H, J=8.28 Hz), 7.22(d, 1 H, J=2.21 Hz), 7.15(dd, 1 H, J=8.28, 2.21 Hz), 7.08(t, 1 H, J=8.14 Hz), 6.71 (d, 1H, J=8.28 Hz), 6.49(dd, 1 H, JD4, 2.21 Hz), 6.45(t, 1 H, J=2.21 Hz), 6.39(dd, 1 H, J=8.14, 2.21 Hz), 4.74(q, 1 H, J=6.81 Hz), 4.30(s, 2H), 3.85(s, 2H), 3.36(m, 4H), 3.24(m, 4H), 2.21 (s, 3H), 1.61(d, 3H, J=6.81 Hz),
MS(ES-) M-H= 642.0
2^{4-[({4-{[4-(2-Hydroxyphenyl)-1-piperazinyllmethyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thjazoU5; y }methyl)sulfanyl]-2-methylphenoxy}propanoic acid 1H NMR (CD3OD) 300MHz δ 8.20(d, 2H, J=8.00 Hz), 7.80(d, 2H, J=8.00 Hz), 7.23(br s, 1 H), 7.01(m, 3H), 6.82(m, 2H), 6.66(br s, 1 H), 4.74(br s, 1 H), 4.26(s, 2H), 3.56(s, 2H), 3.12(m, 8H), 2.19(s, 3H), 1.58(br s, 3H),
MS(ES-) M-H= 642.1
2-{4-[({4-[(4-Butyryl-1-piperazinyl)methyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid
1H NMR (CD3OD) 400MHz δ 8.05(d, 2H, J=8.55 Hz), 7.72(d, 2H, J=8.55 Hz), 7.17(d, 1 H, J=2.22 Hz), 7.08(d, 1 H, J=8.55 Hz), 6.64(s, 1 H), 4.56(q, 1H, J=6.55 Hz), 4.26(s, 2H), 3.54(br s, 4H), 3.38(s, 2H), 2.46(br s, 4H), 2.33(t, 2H, J=7.43 Hz), 2.16(s, 3H), 1.58(m, 5H), 0.93(t, 3H, J=7.43 Hz), MS(ES-) M-H= 620.0
2-{2-Methyl-4-[({4-[(4-pentanoyl-1-piperazinyl)methyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol- 5-yl}methyl)sulfanyl]phenoxy}propanoic acid 1H NMR (CD3OD) 400MHz δ 8.06(d, 2H, J=8.20 Hz), 7.74(d, 2H, J=8.20 Hz), 7.17(d, 1 H,
J=2.22 Hz), 7.10(dd, 1 H, J=8.20, 2.22 Hz), 6.65(d, 1 H, J=8.20 Hz), 4.68(q, 1 H, J=6J5 Hz), 4.25(s, 2H), 3.56(br s, 4H), 3.40(s, 2H), 2.56(br s, 4H), 2.36(t, 2H, J=7.35 Hz), 2.16(s, 3H), 1.54(m, 5H), 1.34(m, 2H), 0.90(t, 3H, J=7.35 Hz), MS(ES-) M-H= 634.0
2-{4-[({4-{[4-(Methoxyacetyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid
1H NMR (CD3OD) 300MHz δ 8.07(d, 2H, J=8.37 Hz), 7.75(d, 2H, J=8.37 Hz), 7.18(d, 1 H, J=2.20 Hz), 7.11 (d, 1 H, J=8.37 Hz), 6.65(d, 1 H, J=8.37 Hz), 4.68(q, 1 H, J=6J2 Hz), 4.26(s, 2H), 4.12(s, 2H), 3.57(br s, 2H), 3.46(br s, 2H), 3.39(s, 2H), 3.35(s, 3H), 2.53(t, 4H, J=4.79 Hz), 2.16(s, 3H), 1.56(d, 3H, J=6.72 Hz),
MS(ES-) M-H= 622.0
2-{4-[({4-[(4-lsobutyryl-1-piperazinyl)methyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid
1H NMR (CD3OD) 300MHz δ 8.10(d, 2H, J=8.28 Hz), 7.76(d, 2H, J=8.28 Hz), 7.20(d, 1 H, J=2.21 Hz), 7.13(dd, 1 H, J=8.55, 2.21 Hz), 6.69(d, 1 H, J=8.55 Hz), 4.67(q, 1 H, J=6.81 Hz), 4.31 (s, 2H), 3.76(br s, 4H), 3.69(s, 2H), 2.92(m, 5H), 2.20(s, 3H), 1.59(d, 3H, J=6.81 Hz), 1.10(d, 6H, J=6.62 Hz), MS(ES-) M-H= 620.4
2-{4-[({4-{[4-(2,2-Dimethylpropanoyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3- thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid
1H NMR (CD3OD) 300MHz δ 8.10(d, 2H, J=8.28 Hz), 7.76(d, 2H, J=8.28 Hz), 7.19(d, 1H, J=2.21 Hz), 7.13(dd, 1 H, J=8.28, 2.21 Hz), 6.69(d, 1 H, J=8.28 Hz), 4.68(q, 1 H, J=6.71 Hz), 4.32(s, 2H), 3.83(br s, 4H), 3.71 (s, 2H), 2.98(t, 4H, J=4.83 Hz), 2.20(s, 3H), 1.60(d, 3H, J=6.71 Hz), 1.28(s, 9H),
MS(ES-) M-H= 634.2
2-Methyl-2-[4-({[2-[4-(trifluoromethyl)phenyl]-4-({4-[3-(trifluoromethyl)phenyl]-1- piperazinyl}methyl)-1,3-thiazol-5-yl]methyl}sulfanyl)phenoxy]propanoic acid
1H NMR (CD3OD) 400MHz δ 8.10(d, 2H, J=8.06 Hz), 7.76(d, 2H, J=8.06 Hz), 7.40(t, 1 H, J=7.69 Hz), 7.28(d, 2H, J=8J9 Hz), 7.18(s, 2H), 7.09(d, 1H, J=7.69 Hz), 6.81 (d, 2H, J=8.79 Hz), 4.31 (s, 2H), 3.59(s, 2H), 3.31 (t, 4H, J=4.94 Hz), 2.88(t, 4H, J=4.94 Hz), 1.54(s, 6H), MS(ES")M-H=694.5
CHN Analysis (Theoretical %C=56.97, %H=4.49, %N=6.04; Found %C=56.69, %H=4.66, %N=5.77)
{4-[({4-{[4-(terf-Butoxycarbonyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol- 5-yl}methyl)sulfanyl]-2-methylphenoxy}acetic acid
1H NMR (CD3OD) 400MHz δ 8.05(d, 2H, J=8.28 Hz), 7.73(d, 2H, J=8.28 Hz), 7.18(s, 1 H), 7.11(br s, 1 H), 6.66(br s, 1 H), 4.54(s, 2H), 4.26(s, 2H), 3.42(m, 6H), 2.50(br s, 4H), 2.19(s, 3H), 1.43(s, 9H),
MS(ES-) M-H= 636.5
{2-Methyl-4-[({4-{[4-(2-pyrazinyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol- 5-yl}methyl)sulfanyl]phenoxy}acetic acid
1H NMR (CD3OD) 400MHz δ 8.21 (s, 1 H), 8.09(d, 3H, J=8.10 Hz), 7.80(s, 1 H), 7.75(d, 2H, J=8.28 Hz), 7.19(d, 1 H, J=2.07 Hz), 7.13(dd, 1 H, J=8.45, 2.24 Hz), 6.70(d, 1 H, J=8.45 Hz), 4.57(s, 2H), 4.27(s, 2H), 3.66(br s, 4H), 3.53(s, 2H), 2.77(br s, 4H), 2.17(s, 3H), MS(ES") M-H= 612.4
{4-[({4-{[4-(2-Methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]-2-methylphenoxy}acetic acid 1H NMR (CD3OD) 400MHz δ 8.10(d, 2H, J=8.28 Hz), 7.75(d, 2H, J=8.28 Hz), 7.18(d, 1 H,
J=2.20 Hz), 7.02(s, 2H), 6.92(dd, 2H, J=8.10, 2.20 Hz), 6.86(s, 1 H), 6.62(d, 1 H, J=8.45 Hz), 4.48(s, 2H), 4.25(s, 2H), 3.81 (s, 3H), 3.55(s, 2H), 3.11 (br s, 4H), 2.96(br s,'4H), 2.17(s, 3H), MS(ES-) M-H= 640.5
{4-[({4-{[4-(3-Methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]-2-methylphenoxy}acetic acid
1H NMR (CD3OD) 400MHz δ 8.10(d, 2H, J=8.28 Hz), 7.75(d, 2H, J=8.28 Hz), 7.18(d, 1 H, J=2.24 Hz), 7.10(s, 2H), 6.67(d, 1 H, J=8.23 Hz), 6.53(dd, 1 H, J=8.28, 2.24 Hz), 6.47(t, 1 H, J=2.24 Hz), 6.43(dd, 1 H, J=8.28, 2.24 Hz), 4.52(s, 2H), 4.25(s, 2H), 3J2(s, 3H), 3.58(s, 2H), 3.24(t, 4H, J=5.09 Hz), 2.98(t, 4H, J=5.09 Hz), 2.17(s, 3H),
MS(ES-) M-H= 642.0 2-Methyl-2-{4-[({4-{[4-(phenoxycarbonyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]- 1 ,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic acid
1H NMR (CD3OD) 400MHz δ 8.07(d, 2H, J=8.28 Hz), 7.73(d, 2H, J=8.28 Hz), 7.34(t, 2H, J=7.59 Hz), 7.27(d, 2H, J=8.45 Hz), 7.18(t, 1 H, J=7.59 Hz), 7.06(d, 2H, J=7.59 Hz), 6.80(d, 2H, J=8.45 Hz), 4.33(s, 2H), 3.68(br s, 2H), 3.53(br s, 2H), 3.44(s, 2H), 2.56(br s, 4H), 1.52(s, 6H),
CHN Analysis 1 MeOH(Theoretical %C=58.02, %H=5.16, %N=5.97; Found %C=58.33, %H=5.09, %N=5J2)
2-{4-[({4-{[4-(terf-Butoxycarbonyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3- thiazol-5-yl}methyl)sulfanyl]phenoxy}-2-methylpropanoic acid
1H NMR (CD3OD) 400MHz δ 8.04(d, 2H, J=8.28 Hz), 7.71 (d, 2H, J=8.28 Hz), 7.22(d, 2H, J=8.10 Hz), 6.78(d, 2H, J=8.10 Hz), 4.27(s, 2H), 3.40(m, 6H), 2.49(br s, 4H), 1.50(s, 6H), 1.41 (s, 9H),
MS(ES') M-H= 650.5
2-Methyl-2-{4-[({4-{[4-(2-pyrazinyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3- thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic acid
1H NMR (CD3OD) 400MHz δ 8.21 (s, 1 H), 8.07(m, 3H), 7.79(s, 1 H), 7.73(d, 2H, J=8.28 Hz), 7.25(d, 2H, J=8.10 Hz), 6.79(d, 2H, J=8.10 Hz), 4.30(s, 2H), 3.65(br s, 4H), 3.53(s, 2H), 2.72(br s, 4H), 1.53(s, 6H),
MS(ES-) M-H= 627.6
2-{4-[({4-{[4-(2-Methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}-2-methylpropanoic acid 1H NMR (CD3OD) 400MHz δ 8.10(d, 2H, J=8.28 Hz), 7J4(d, 2H, J=8.28 Hz), 7.21 (d, 2H,
J=8.42 Hz), 7.00(m, 1 H), 6.92(m, 2H), 6.86(m, 1 H), 6J8(d, 2H, J=8.42 Hz), 4.27(s, 2H), 3.81 (s, 3H), 3.59(s, 2H), 3.14(br s, 4H), 3.01 (br s, 4H), 1.51 (s, 6H), MS(ES-) M-H= 656.0
2-{4-[({4-{[4-(Ethoxycarbonyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}-2-methylpropanoic acid
1H NMR (CD3OD) 400MHz δ 8.05(d, 2H, J=8.10 Hz), 7.72(d, 2H, J=8.10 Hz), 7.24(d, 2H, J=8.42 Hz), 6.79(d, 2H, J=8.42 Hz), 4.30(s, 2H), 4.09(q, 2H, J=7.16 Hz), 3.44(m, 6H), 2.50(s, 4H), 1.52(s, 6H), 1.21 (t, 3H, J=7.16 Hz), MS(ES") M-H= 621.7
2-{4-[({4-{[4-(4-lsopropoxyphenyl)-1-piperazinyllmethyl}-2-[4-(trifluoromethyl)phenyl]-1,3- thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid H NMR (CD3OD) 400MHz δ 8.13(d, 2H, J=8.06 Hz), 7.79(d, 2H, J=8.06 Hz), 7.13(m, 2H), 6.92(d, 2H, J=8.97 Hz), 6.81 (d, 2H, J=8.97 Hz), 6.67(d, 1 H, J=8.42 Hz), 4.61 (q, 1 H, J=6.78 Hz), 4.46(m, 1 H), 4.25(s, 2H), 3.56(s, 2H), 3.19(br s, 4H), 3.06(br s, 4H), 2.17(s, 3H), 1.55(d, 3H, J=6.78 Hz), 1.24(d, 6H, J=6.87 Hz), MS(ES-) M-H= 685.0
[4-({[4-(ri,1'-Biphenyl]-4-ylmethyl)-2-(4-{trifluoromethyl}phenyl)-1,3-thiazol-5- yl]methyl}sulfanyl)-2-methylphenoxy]acetic acid
TLC(5% MeOH/CH2Cl2) Rf= 0.16 MS(ES-) M-H= 603
{2-Methyl-4-[({2-(4-{trifluoromethyl}phenyl)-4-[4-(3-thienyl)benzyl]-1,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}acetic acid
1H NMR (CDCy 300MHz δ 7.93(d, 2H, J=8.23 Hz), 7.61(d, 2H, J=8.23 Hz), 7.44(d, 2H, J=8.23 Hz), 7.36(s, 1 H), 7.29(m, 2H), 7.08(m, 3H), 6.54(d, 1 H, J=8.23 Hz), 4.52(s, 2H), 4.06(s, 2H), 3.90(s, 2H), 2.15(s, 3H), TLC(5% MeOH/CH2CI2) Rf= 0.18
MS(ES') M-H= 609
[4-({[4-Benzyl-2-(4-{trifluoromethyl}phenyl)-1,3-thiazol-5-yl]methyl}sulfanyl)phenoxy]acetic acid
1H NMR (CD3OD) 300MHz δ 8.04(d, 2H, J=8.23 Hz), 7.75(d, 2H, J=8.23 Hz), 7.34(d, 2H, J=8J6 Hz), 7.20(m, 5H), 6.88(d, 2H, J=9.76 Hz), 4.66(s, 2H), 4.25(s, 2H), 3.93(s, 2H), MS(ES") M-H= 513.86 TLC(20% MeOH/CH2CI2) Rf= 0.37
2-[4-({[4-Benzyl-2-(4-{trifluoromethyl}phenyl)-1,3-thiazol-5- yl]methyl}sulfanyl)phenoxy]propanoic acid
1H NMR (CDCI3) 300MHz δ 8.02(d, 2H, J=8.23 Hz), 7.69(d, 2H, J=8.23 Hz), 7.26(m, 7H), 6.83(d, 2H, J=8.76 Hz), 4.80(q, 1 H, J=6J2 Hz), 4.14(s, 2H), 3.90(m, 2H), 1.68(d, 3H, J=6.72 Hz), MS(ES') M-H= 528.43 TLC(20% MeOH/CH2CI2) Rf= 0.60
[2-Methyl-4-({[2-(4-{trifluoromethyl}phenyl)-4-(2-phenylethyl)-1,3-thiazol-5- yl]methyl}sulfanyl)phenoxy]acetic acid H (CDCI3) 300MHz δ 7.99(d, 2H, J=8.79 Hz), 7.67(d, 2H, J=8.93 Hz), 7.18(m, 8H), 6.60(d, 1 H, J=8.51 Hz), 4.64(s, 2H), 3.85(s, 2H), 2.90(m, 2H), 2.80(m, 2H), 2.23(s, 3H),
[4-({[4-[(Benzyloxy)methyl]-2-(4-{trifluoromethyl}phenyl)-1,3-thiazol-5-yl]methyl}sulfanyl -2- methylphenoxyjacetic acid H (CDCy 300MHz δ 7.99(d, 2H, J=8J9 Hz), 7.67(d, 2H, J=8.79 Hz), 7.33(m, 4H), 7.28(s, 2H), 7.18(dd, 1 H, J=2.33, 0.55 Hz), 7.08(ddd, 1 H, J=8.38, 2.33, 0.55 Hz), 6.56(d, 1 H, J=8.38 Hz), 4.63(s, 2H), 4.53(s, 2H), 4.39(s, 2H), 4.19(s, 2H), 2.21 (s, 3H), [2-Methyl-4-({[2-(4-{trifluoromethyl}phenyl)-4-(3-phenylpropyl)-1,3-thiazol-5- yl]methyl}sulfanyl)phenoxy]acetic acid
1H NMR (CDCI3) 300MHz δ 7.82(m, 2H), 7.50(m, 2H), 6.94(m, 8H), 3.95(s, 2H), 2.55(m, 4H), 1.99(m, 7H),
{2-Methyl-4-[({2-(4-{trifluoromethyl}phenyl)-4-[(2-phenylethoxy)methyl]-1,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}acetic acid
'H NMR (CDCI3) 300MHz δ 7.92(m, 2H), 7.62(m, 2H), 7.20(m, 7H), 7.05(br s, 1H), 4.55(s, 2H), 4.38(s, 2H), 4.09(s, 2H), 3.66(br s, 2H), 2.87(br s, 2H), 2.17(s, 3H), TLC(5% MeOH/Dichloromethane) Rf= 0.65
[4-({[4-(4-Bromobenzyl)-2-(4-{trifluoromethyl}phenyl)-1,3-thiazol-5-yl]methyl}sulfanyl)-2- methylphenoxyjacetic acid H NMR (CDCI3) 400MHz δ 7.82(d, 2H, J=8.20 Hz), 7.53(d, 2H, J=8.20 Hz), 7.22(d, 2H, J=8.55 Hz), 7.05(m, 1 H), 6.97(dd, 1 H, J=8.37, 2.39 Hz), 6.88(d, 2H, J=8.55 Hz), 6.47(d, 1 H, J=8.37 Hz), 4.47(s, 2H), 3.72(s, 2H), 3.36(s, 2H), 2.08(s, 3H), TLC(5% MeOH/CH2CI2) Rf= 0.16
[4-({[4-Benzyl-2-(4-{triflurormethyl}phenyl)-1,3-thiazol-5-yl]methyl}sulfanyl)-2- methylphenoxyjacetic acid H (CDCI3) 300MHz δ 7.97(d, 2H, J=8.79 Hz), 7.64(d, 2H, J=9.48 Hz), 7.21 (m, 8H), 6.58(d, 1 H, J=8.38 Hz), 4.65(s, 2H), 4.1 1 (s, 2H), 3.93(s, 2H), 2.22(s, 3H), MS(ES+) M+H= 529.99
2-{4-[({4-{[3-(5-Methyl-1 ,2,4-oxadiazol-3-yl)phenoxy]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3- thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic acid
1H NMR (CDCy 400MHz δ 8.01 (d, 2H, J=8.03 Hz), 7.68(m, 3H), 7.43(m, 1 H), 7.36(t, 1 H, J=8.03 Hz), 7.20(d, 2H, J=8.89 Hz), 7.05(dd, 1 H, J=8.20, 2.39 Hz), 6.79(d, 2H, J=8.89 Hz), 4.76(q, 1 H, J=6.78 Hz), 4.66(d, 1 H, J .28 Hz), 4.36(d, 1 H, J .28 Hz), 4.24(d, 1 H, J .70 Hz), 4.15(d, 1 H, J JO Hz), 2.71 (s, 3H), 1.67(m, 3H), MS(ES+) M+H= 628.0
2-{4-[({4-{[4-(4-Methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl1-2-methylphenoxy}propanoic acid 1H NMR (CDCy 400MHz δ 9.03(br s, 1 H), 7.96(d, 2H, J=8.20 Hz), 7.67(d, 2H, J=8.20 Hz),
7.15(d, 2H, J=8.72 Hz), 6.81 (m, 6H), 4.12(s, 2H), 3.73(s, 3H), 3.50(s, 2H), 3.27(br s, 4H), 3.15(br s, 4H), 1.63(s, 6H),
HPLC(C-18, 3μm) 1 %MeOH/0-90% CH3CN/Water (0.1 % TFA)/(50mM Et3N/TFA) 4min run Rt=2.89 min 2-(4-{[(4-{[4-(4-Methoxyphenyl)-1-piperazinyl]methyl}-2-phenyl-1,3-thiazol-5- yl)methyl]sulfanyl}phenoxy)-2-methylpropanoic acid
1H NMR (CDCl3) 400MHz δ 7.87(m, 2H), 7.44(m, 3H), 7.15(d, 2H, J=8.55 Hz), 6.82(m, 6H), 4.08(s, 2H), 3.73(s, 3H), 3.46(s, 2H), 3.31 (m, 4H), 3.18(m, 4H), 1.65(s, 6H), HPLC(C-18, 3μm) 1 %MeOH/0-90% CH3CN/Water (0.1 % TFA)/(50mM Et3N/TFA) 4min run
Rt=2.74 min
{4-[({4-{[4-(4-Methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)su If anyl] phenoxy}acetic acid 1H NMR (CDCy 400MHz δ 10.00(s, 1 H), 7.96(d, 2H, J=8.20 Hz), 7.66(d, 2H, J=8.20 Hz),
7.27(d, 2H, J=8.72 Hz), 6.82(m, 6H), 4.51 (s, 2H), 4.22(s, 2H), 3.80(s, 2H), 3J2(s, 3H), 3.21 (m, 8H), HPLC(C-18, 3μm) 1%MeOH/0-90% CH3CN/Water (0.1 % TFA)/(50mM Et3N/TFA) 4min run Rt=2.74 min
(4-{[(4-{[4-(4-Methoxyphenyl)-1-piperazinyl]methyl}-2-phenyl-1,3-thiazol-5- yl)methyl]sulfanyl}phenoxy)acetic acid
1H NMR (CDCy 400MHz δ 9.49(br s, 1 H), 7.86(m, 2H), 7.42(m, 3H), 7.24(d, 2H, J=8.55 Hz), 6.80(m, 6H), 4.50(s, 2H), 4.22(s, 2H), 3.81 (s, 2H), 3.71 (s, 3H), 3.24(m, 8H),
HPLC(C-18, 3μm) 1 %MeOH/0-90% CH3CN/Water (0.1% TFA)/(50mM Et3N/TFA) 4min run Rt=2.55 min
2-{4-[({4-{[4-(4-Methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}propanoic acid H NMR (CDCI3) 400MHz δ9.31(s, 1H), 7.96(d, 2H, J=8.20 Hz), 7.68(d, 2H, J=8.20 Hz), 7.18(d, 2H, J=8.55 Hz), 6.82(m, 6H), 4.73(q, 1 H, J=6.67 Hz), 4.16(d, 1 H, J .87 Hz), 4.10(d, 1 H, J .87 Hz), 3.72(s, 3H), 3.58(d, 1 H, J .53 Hz), 3.51 (d, 1 H, J .53 Hz), 3.24(m, 8H), 1.59(d, 3H, J=6.67 Hz), HPLC(C-18, 3μm) 1 %MeOH/0-90% CH3CN/Water (0.1 % TFA)/(50mM Et3N/TFA) 4min run R,=2.80 min
2-(4-{[(4-{[4-(4-Methoxyphenyl)-1-piperazinyl]methyl}-2-phenyl-1,3-thiazol-5- yl)methyl]sulfanyl}phenoxy)propanoic acid
1H NMR (CDCI3) 400MHz δ8.42(s, 1 H), 7.84(m, 2H), 7.40(m, 3H), 7.17(d, 2H, J=8.72 Hz), 6.81 (m, 6H), 4.69(q, 1 H, J=6.67 Hz), 4.11 (d, 1 H, J .18 Hz), 4.07(d, 1 H, J .18 Hz), 3.73(s, 3H), 3.57(d, 1 H, J .87 Hz), 3.49(d, 1 H, J .87 Hz), 3.18(m, 8H), 1.59(d, 3H, J=6.67 Hz), HPLC(C-18, 3μm) 1 %MeOH/0-90% CH3CN/Water (0.1 % TFA)/(50mM Et3N/TFA) 4min run
R,=2.63 min
£4-[({4-{[3-(5-Methyl-1,2>4-oxadiazol-3-yl)phenoxy]methyl}-2-[4-(trifluoromethyl)phenyl]-lJ3- thiazol-5-yl}methyl)sulfanyl]phenoxy}acetic acid H NMR (CDCI3) 400MHz δ 10.17(s, 1 H), 8.02(d, 2H, J=8.20 Hz), 7.67(m, 3H), 7.46(m, 1 H), 7.36(t, 1 H, J=7.95 Hz), 7.22(d, 2H, J=8.72 Hz), 7.06(dd, 1 H, J=8.37, 2.39 Hz), 6.79(d, 2H, J=8.72 Hz), 4.69(s, 2H), 4.58(s, 2H), 4.22(s, 2H), 2.73(s, 3H),
MS(ES+) M+H= 614.00
2-Methyl-2-{4-[({4-{[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]methyl}-2-[4- (trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic acid
1H (CDCI3) 400MHz δ 7.98(d, 2H, J=8.03 Hz), 7.92(d, 2H, J=9.06 Hz), 7.67(d, 2H, J=8.03 Hz), 7.18(d, 2H, J=9.06 Hz), 6.96(d, 2H, J=8.75 Hz), 6.74(d, 2H, J=8.75 Hz), 4.98(s, 2H), 4.29(s, 2H), 2.66(s, 3H), 1.57(s, 6H)
MS(ES-) M-H= 640.00
2-Methyl-2-(4-{[(4-{[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]methyl}-2-phenyl-1,3-thiazol-5- yl)methyl]sulfanyl}phenoxy)propanoic acid 1H NMR (CDCI3) 400MHz j57.93(d, 2H, J=9.06 Hz), 7.86(m, 2H), 7.42(m, 3H), 7.17(d, 2H,
J=8.72 Hz), 6.96(d, 2H, J=9.06 Hz), 6.73(d, 2H, J=8.72 Hz), 4.92(s, 2H), 4.27(s, 2H), 2.66(s, 3H), 1.57(s, 6H),
MS(ES') M-H= 571.50
{4-[({4-{[4-(5-Methyl-1 ,2,4-oxadiazol-3-yl)phenoxy]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3- thiazol-5-yl}methyl)sulfanyl]phenoxy}acetic acid
1H NMR (CDCI3) 400MHz δ 7.98(d, 2H, J=8.20 Hz), 7.93(d, 2H, J=9.06 Hz), 7.66(d, 2H, J=8.20 Hz), 7.28(d, 2H, J=8.89 Hz), 6.96(d, 2H, J=9.06 Hz), 6.76(d, 2H, J=8.89 Hz), 4.86(s, 2H), 4.60(s, 2H), 4.25(s, 2H), 2.62(s, 3H), MS(ES") M-H= 611.80
(4-{[(4-{[4-(5-Methyl-1,2,4-oxadiazol-3-yl)phenoxy]methyl}-2-phenyl-1,3-thiazol-5- yl)methyl]sulfanyl}phenoxy)acetic acid
1H NMR (CDCI3) 400MHz 7.92(d, 2H, J=9.06 Hz), 7.83(m, 2H), 7.39(m, 3H), 7.23(d, 2H, J=8.90 Hz), 6.95(d, 2H, J=9.06 Hz), 6.76(d, 2H, J=8.90 Hz), 4.70(s, 2H), 4.54(s, 2H), 4.18(s, 2H), 2.60(s, 3H),
MS(ES+) M+H= 546.20
2-{4-[({4-{[4-(5-Methyl-1,2,4-oxadiazol-3-yl)phenoxy]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3- thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic acid
1H NMR (CDCI3) 400MHz δ7.97(d, 2H, J=8.20 Hz), 7.92(d, 2H, J=8.89 Hz), 7.65(d, 2H, J=8.20 Hz), 7.22(d, 2H, J=8.89 Hz), 6.94(d, 2H, J=8.89 Hz), 6.73(d, 2H, J=8.89 Hz), 4.86(d, 1 H, J .79 Hz), 4.80(d, 1 H, J .96 Hz), 4.66(q, 1 H, J=6.89 Hz), 4.26(d, 1H, J .87 Hz), 4.20(d, 1 H, J .87 Hz), 2.62(s, 3H), 1.58(d, 3H, J=6.89 Hz), MS(ES-) M-H= 626.00 2-(4-{[(4-{[4-(5-Methyl-1 ,2,4-oxadiazol-3-yl)phenoxy]methyl}-2-phenyl-1,3-thiazol-5- yl)methyl]sulfanyl}phenoxy)propanoic acid
1H NMR (CDCI3) 400MHzδ7.93(d, 2H, J=9.06 Hz), 7.85(m, 2H), 7.41 (m, 3H), 7.24(d, 2H, J=8.89 Hz), 6.95(d, 2H, J=9.06 Hz), 6.74(d, 2H, J=8.89 Hz), 4.82(s, 2H), 4.68(q, 1 H, J=6.89 Hz), 4.25(d, 1 H, J .87 Hz), 4.19(d, 1 H, J .87 Hz), 2.64(s, 3H), 1.61(d, 3H, J=6.89 Hz), MS(ES-) M-H= 558.30
2-{4-[({4-{[4-(4-Acetylphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}-2-methylpropanoic acid 1H NMR (CD3OD) 400MHz δ 8.04(d, 2H, J=8.10 Hz), 7.85(d, 2H, J=9. 4 Hz), 7.72(d, 2H,
J=8.10 Hz), 7.25(d, 2H, J=8.79 Hz), 6.93(d, 2H, J=9.14 Hz), 6.81 (d, 2H, J=8.79 Hz), 4.32(s, 2H), 3.47(s, 2H), 3.35(t, 4H, J=4.91 Hz), 2.59(t, 4H, J=4.91 Hz), 2.47(s, 3H), 1.47(s, 6H), MS(ES-) M-H= 668.1
2-{4-[({4-{[4-(4-Chlorophenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}-2-methylpropanoic acid
1H NMR (CD3OD) 400MHz δ 8.05(d, 2H, J=8.10 Hz), 7.73(d, 2H, J=8.10 Hz), 7.24(d, 2H, J=8.79 Hz), 7.15(d, 2H, J=8.97 Hz), 6.90(d, 2H, J=8.97 Hz), 6.80(d, 2H, J=8.79 Hz), 4.30(s, 2H), 3.57(s, 2H), 3.18(t, 4H, J=5.00 Hz), 2.77(t, 4H, J=5.00 Hz), 1.49(s, 6H), CHN Analysis: Theory (C, 58.04%; H, 4.72%; N, 6.35%) Found (C, 57.65%; H, 4.80%; N,
6.13%)
2-{4-[({4-{[4-(3-Methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}-2-methylpropanoic acid 1H NMR (CD3OD) 400MHz δ 7.98(d, 2H, J=7.93 Hz), 7.63(d, 2H, J=7.93 Hz), 7.12(m, 3H),
6.73(m, 2H), 6.47(m, 1 H), 6.38(m, 2H), 4.18(s, 2H), 3.70(s, 3H), 3.50(s, 2H), 3.14(br s, 4H), 2J6(sbr ,
4H), 1.49(s, 6H),
CHN Analysis: Theory (C, 60.26%; H, 5.21%; N, 6.39%) Found (C, 59.83%; H, 5.29%; N,
6.32%)
2-(4-{[(2-(4-Fluorophenyl)-4-{[4-(phenoxycarbonyl)-1-piperazinyl]methyl}-1,3-thiazol-5- yl)methyl]sulfanyl}-2-methylphenoxy)-2-methylpropanoic acid
1H NMR (CDCl3) 400MHz δ 7.93(m, 2H), 7.35(m, 3H), 7.19(m, 4H), 7.08(m, 2H), 6.69(br s, 1 H), 4.27(s, 2H), 3.60(br s, 4H), 3.39(s, 2H), 2.54(br s, 4H), 2.14(s, 3H), 1.55(s, 6H), MS(ES-) M-H= 634.1
2-{4-r({4-{[4-(4-Methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl)methyl)sulfanyl]-2-methylphenoxy}-2-methylpropanoic acid
1H NMR (CD3OD) 400MHz δ 8.05(br s, 2H), 7.66(d, 2H, J=8.28 Hz), 7.15(s, 1 H), 6.84(m, 6H), 4.19(s, 2H), 3.44(s, 2H) 3.69(s, 3H), 3.10(m, 4H), 2.82(br s, 4H), 2.10(s, 3H), 1.52(s, 6H), MS(ES+) M+H= 672.2 2-{4-[({4-{[4-(4-Acetylphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]-2-methylphenoxy}-2-methylpropanoic acid
1H NMR (CD3OD) 400MHz δ 7.97(d, 2H, J=8.10 Hz), 7.80(d, 2H, J=8.42 Hz), 7.65(d, 2H, J=8.10 Hz), 7.16(br s, 1 H), 7.01 (br s, 1 H), 6.84(d, 2H, J=8.42 Hz), 6.60(br s, 1 H), 4.23(s, 2H), 3.44(s, 2H), 3.27(br s, 4H), 2.55(br s, 4H), 2.44(s, 3H), 2.11 (s, 3H), 1.52(s, 6H), MS(ES+) M+H= 684.2
2-{4-[({4-{[4-(3-Methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]-2-methylphenoxy}-2-methylpropanoic acid
1H NMR (CD3OD) 400MHz δ 7.96(d, 2H, J=8.10 Hz), 7.61 (d, 2H, J=8.10 Hz), 7.03(m, 3H), 6.38(m, 4H), 4.18(s, 2H), 3.69(s, 3H), 3.33(s, 2H), 3.11 (m, 4H), 2.66(br s, 4H), 2.09(s, 3H), 1.50(s, 6H),
MS(ES-) M-H= 670.0
2-{4-[({4-{[4-(4-Fluorophenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]-2-methylphenoxy}-2-methylpropanoic acid
1H NMR (CD3OD) 400MHz δ 8.08(d, 2H, J=8.24 Hz), 7.73(d, 2H, J=8.24 Hz), 7.18(br s, 1 H), 7.04(br s, 1 H), 6.92(m, 4H), 6.72(br s, 1 H), 4.26(s, 2H), 3.58(s, 2H), 3.14(br s, 4H), 2.84(br s, 4H), 2.10(s, 3H), 1.60(s, 6H),
MS(ES-) M-H= 658.4
2-Methyl-2-{2-methyl-4-[({4-{[4-(phenoxycarbonyl)-1-piperazinyl]methyl}-2-[4- (trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic acid H NMR (CD3OD) 400MHz δ 8.04(br s, 2H), 7.71 (br s, 2H), 7.34(m, 2H), 7.19(m, 3H), 7.04(m,
3H), 4.28(s, 2H), 3.65(s, 2H), 3.45(br s, 4H), 2.47(br s, 4H), 2.12(s, 3H), 1.61 (s, 6H), MS(ES-) M-H= 684.0
2-[4-({[4-{[4-(4-Acetylphenyl)-1-piperazinyl]methyl}-2-(4-fluorophenyl)-1,3-thiazol-5- yπmethyl}sulfanyl)-2-methylphenoxy]-2-methylpropanoic acid H NMR (CD3OD) 400MHz δ 7.93(m, 2H), 7.86(d, 2H, J=9.16 Hz), 7.18(m, 3H), 7.07(br s, 1 H), 6.95(d, 2H, J=9.16 Hz), 6.69(br s, 1 H), 4.23(s, 2H), 3.42(m, 6H), 2.69(br s, 4H), 2.49(s, 3H), 2.13(s, 3H), 1.56(s, 6H),
MS(ES-) M-H= 632.3
2- 4-{[(2-(4-Fluorophenyl)-4-{[4-(3-methoxyphenyl)-1-piperazinyl]methyl>-1,3-thiazol-5- yj)methyl]sulfanyl}-2-methylphenoxy)-2-methylpropanoic acid
1H NMR (CD3OD) 400MHz δ 7.96(m, 2H), 7.19(m, 3H), 7.12(t, 1 H, J=8.24 Hz), 7.01 (br s, 1 H), 6.66(br s, 1 H), 6.54(dd, 1 H, J=8.24, 2.20 Hz), 6.47(t, 1 H, J=2.20 Hz), 6.43(dd, 1 H, J=8.24, 2.20 Hz), 4.20(s, 2H), 3.73(s, 3H), 3.55(s, 2H), 3.24(br s, 4H), 2.91 (br s, 4H), 2.13(s, 3H), 1.56(s, 6H), MS(ES-) M-H= 620.0 2-[4-({[4-{[4-(Ethoxycarbonyl)-1-piperazinyl]methyl}-2-(4-fluorophenyl)-1,3-thiazol-5- yl]methyl}sulfanyl)-2-methylphenoxy]-2-methylpropanoic acid
1H NMR (CD3OD) 400MHz δ 7.94(m, 2H), 7.19(m, 3H), 7.00(br s, 1 H), 6.66(br s, 1 H), 4.23(s, 2H), 4.09(q, 2H, J=7.05 Hz), 3.48(m, 6H), 2.49(br s, 4H), 2.13(s, 3H), 1.56(s, 6H), 1.23(t, 3H, J=7.05 Hz),
MS(ES-) M-H= 586.2
2-(4-{[(2-(4-Fluorophenyl)-4-{[4-(isopropoxycarbonyl)-1-piperazinyl]methyl}-1,3-thiazol-5- yl)methyl]sulfanyl}-2-methylphenoxy)-2-methylpropanoic acid
1H NMR (CDCy 400MHz δ 7.90(m, 2H), 7.18(m, 3H), 7.07(br s, 1 H), 6.74(br s, 1 H), 4.64(m, 1 H), 4.26(s, 2H), 3.44(t, 4H, J=4.58 Hz), 3.36(s, 2H), 2.43(br s, 4H), 2.13(s, 3H), 1.55(s, 6H), 1.22(d, 6H, J=6.23 Hz),
MS(ES-) M-H= 600.0
2-{2-methyl-4-[({4-[4-(trifluoromethoxy)benzyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}propanoic acid
From ethyl 2-{2-methyl-4-[({4-[4-(trifluoromethoxy)benzyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3- thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoate (0.167g, 0.25 mmol), 2-{2-methyI-4-[({4-[4- (trifluoromethoxy)benzyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}propanoic acid (0.066g, 41 %) was obtained as a white solid.
1H NMR (CD3OD): δ 8.05 (d, 2 H), 7.77 (d, 2 H), 7.20 (m, 6 H), 6.71 (d, 1 H), 4.80 (q, 1 H),
4.25 (s, 2 H), 3.93 (s, 2 H), 2.20 (s, 3 H), 1.60 (d, 3 H); 19F NMR (CD3OD): δ -59.87 (s) -64.72 (s); MS m/z 628 (M+1); Anal. Calcd. for C29H23FNOS2: C, 55.5; H, 3.69; N, 2.23%; found: C, 55.27; H, 3.80; N, 2.21 %.
{2-methyl-4-[({4-[4-(trifluoromethoxy)benzyll-2-[4-(trifluoromethyl)phenyll-1,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}acetic acid
From methyl {2-methyl-4-[({4-[4-(trifluoromethoxy)benzyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3- thiazol-5-yl}methyl)sulfanyl]phenoxy}acetate (0.15g, 0.24 mmol), {2-methyl-4-[({4-[4-
(trifluoromethoxy)benzyI]-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetic acid ( 0.053g, 36%) was obtained as a white solid.
1H NMR (CD3OD): δ 8.05 (d, 2 H), 7.77 (d, 2 H), 7.20 (m, 6 H), 6.71 (d, 1 H), 4.70 (s, 2 H), 4.27 (s, 2 H), 3.94 (s, 2 H), 2.20 (s, 3 H); 19F NMR (CD3OD): δ -59.88 (s) -64.72 (s); MS m/z 614 (M+1 ); Anal. Calcd. for C28H21F6N04S2: C, 54.81 ; H, 3.45; N, 2.28%; found: C, 54.64; H, 3.46; N, 2.23%.
2-{2-methyl-4-[({4-(3-thienylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}propanoic acid From ethyl 2-{2-methyl-4-[({4-(3-thienylmethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}propanoate (0.255g, 0.44 mmol), 2-{2-methyl-4-[({4-(3-thienylmethy|)-2-[4- (trifluoromethyl)phenyl]-1 ,3-thiazoi-5-yl}methyl)sulfanyl]phenoxy}propanoic acid (0.058g, 24%) was obtained as a white solid.
1H NMR (CD3OD): δ 8.05 (d, 2 H), 7.77 (d, 2 H), 7.33 (t, 1 H), 7.18 (m, 2 H), 6.95 (m, 2 H), 6.69 (d, 1 H), 4.80 (q, 1 H), 4.22 (s, 2 H), 3.95 (s, 2 H), 2.20 (s, 3 H), 1.61 (d, 3 H); MS m/z 550 (M+1); HPLC RT 4.056 (C18 4.2x100mm, 0-100% ACN/H20 (0.1 % TFA), 6min @ 2ml/min @254/220nm). Anal. Calcd. for C26H22F3N03S3: C, 56.82; H, 4.03; N, 2.55%; found: C, 56.84; H, 4.16; N, 2.53%.
{2-methyl-4-[({4-(3-thienylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}acetic acid From methyl {2-methyl-4-t({4-(3-thienylmethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyl)sulfanyr]phenoxy}acetate (0.259g, 0.47 mmol), {2-methyl-4-[({4-(3-thienylmethyl)-2-[4- (trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methyl)sulfanyI]phenoxy}acetic acid (0.138g, 55%) was obtained as a white solid.
1H NMR (CD3OD): δ 8.05 (d, 2 H), 7.77 (d, 2 H), 7.33 (t, 1 H), 7.18 (m, 2 H), 6.95 (m, 2 H), 6.69 (d, 1 H), 4.70 (s, 2 H), 4.24 (s, 2 H), 3.95 (s, 2 H), 2.21 (s, 3 H); MS m/z 536 (M+1); HPLC RT
3.979 (C18 4.2x100mm, 0-100% ACN/H20 (0.1% TFA), 6min @ 2ml/min @254/220nm). Anal. Calcd. for C25H20F3NO3S3: C, 56.06; H, 3.76; N, 2.61%; found: C, 55.90; H, 3.88; N, 2.62%.
2-{4-[({4-(2-furylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2- methy!ρhanoxy}propanoic acid
From ethyl 2-{4-[({4-(2-furylmethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyl)sulfanyl]-2-methylphenoxy}propanoate (0.091 g, 0.16 mmol), 2-{4-[({4-(2-furylmethyl)-2-[4- (trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid (0.019g, 22%) was obtained as a white solid. 1H NMR (CD3OD): δ 8.05 (d, 2 H), 7.77 (d, 2 H), 7.37 (s, 1 H), 7.21 (s, 1 H), 7.17 (d, 1 H), 6.72
(d, 1 H), 6.31 (s, 1 H), 5.99 (s, 1 H), 4.80 (q, 1 H), 4.22 (s, 2 H), 3.97 (s, 2 H), 2.22 (s, 3 H), 1.63 (d, 3 H); MS m/z 534 (M+1 ); HPLC RT 3.929 (C18 4.2x100mm, 0-100% ACN/H20 (0.1 % TFA), 6min @ 2ml/min @254/220nm). Anal. Calcd. for C2SH22F3N04S2: C, 58.53; H, 4.16; N, 2.62%; found: C, 58.04; H, 4.76; N, 2.47%
2.{4-[({4-(3-furylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2- methylphenoxy}propanoic acid
From ethyl 2-{4-[({4-(3-furylmethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyl)sulfanyl]-2-methylphenoxy}propanoate (0.177g, 0.32 mmol), 2-{4-[({4-(3-furylmethyl)-2-[4- (trifluorόmethyl)phenyl]-1 ,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}prop&noic acid (0.030g, 18%) was obtained as a white solid.
1H NMR (CD3OD): δ 8.05 (d, 2 H), 7.77 (d, 2 H), 7.39 (s, 1 H), 7.20 (m, 3 H), 6.70 (d, 1 H), 6.29 (s, 1 H), 4.80 (q, 1 H), 4.22 (s, 2 H), 3.70 (s, 2 H), 2.20 (s, 3 H), 1.62 (d, 3 H); MS m/z 534 (M+1 ); HPLC RT 3.966 (C18 4.2x100mm, 0-100% ACN/H20 (0.1% TFA), 6min @ 2ml/min @254/220nm). Anal. Calcd. for C26H22F3N04S2: C, 58.53; H, 4.16; N, 2.62%; found: C, 58.38; H, 4.30; N, 2.54% 2-{2-methyl-4-[({4-(2-thienylmethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}propanoic acid
From ethyl 2-{4-[({4-(2-thienylmethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyl)sulfanyl]-2-methylphenoxy}propanoate (0.21 g, 0.36 mmol), 2-{2-methyl-4-[({4-(2- thienylmethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic acid (0.019g, 10%) was obtained as a white solid.
1H NMR (CD3OD): δ 8.05 (d, 2 H), 7.77 (d, 2 H), 7.20 (m, 3 H), 6.91 (t, 1 H), 6.79 (s, 1 H), 6.69 (d, 1 H), 4.80 (q, 1 H), 4.24 (s, 2 H), 4.09 (s, 2 H), 2.20 (s, 3 H), 1.62 (d, 3 H); MS m/z 550 (M+1 ); HPLC RT 4.074 (C18 4.2x100mm, 0-100% ACN/HzO (0.1% TFA), 6min @ 2ml/min @254/220nm).
2-methyl-2-{4-[({4-[4-(trifluoromethoxy)benzyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}propanoic acid
From ethyl 2-methyI-2-{4-[({4-[4-(trifluoromethoxy)benzyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3- thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoate (0.21 Og, 0.32 mmol), 2-methyl-2-{4-[({4-[4- (trifluoromethoxy)benzyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}propanoic acid (0.035g, 17%) was obtained as a cream solid.
1H NMR (CD3CI3): δ 8.05 (d, 2 H), 7.77 (d, 2 H), 7.28 (d, 2 H), 7.22 (d, 2 H), 7.13 (d, 2 H), 6.86
(d, 2 H), 4.19 (s, 2 H), 3.96 (s, 2 H), 1.63 (s, 6 H); 19F NMR (CD3CI3): δ -58.26 (s) -63.16 (s); MS m/z 628 (M+1 ); HPLC RT 4.526 (C18 4.2x100mm, 0-100% ACN/H20 (0.1% TFA), 6min @ 2ml/min @254/220nm). Anal. Calcd. for C29H23F6N04S2: C, 55.5; H, 3.69; N, 2.23%; found: C, 55.78; H, 3.83; N, 2.10%
{2-Methyll-4-[({4-[(4-methyl-2-thienyl)methyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}acetic acid From ethyl {2-methyl-4-[({4-[(4-methyl-2-thienyl)methyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3- thiazol-5-yl}methyl)sulfanyl]phenoxy}acetate (0.13g, 0.23 mmol), {2-methyl-4-[({4-[(4-methyl-2- thienyl)methyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methyl)sulfanyI]phenoxy}acetic acid (0.011g, 9%) was obtained as a cream solid.
1H NMR (CD3CI3): δ 8.01 (d, 2 H), 7.68 (d, 2 H), 7.24 (s, 1 H), 7.15 (d, 2 H), 6.72 (s, 1 H), 6.64 (d, 1 H), 4.75 (s, 2 H), 4.19 (s, 2 H), 4.05 (s, 2 H), 2.20 (s, 3 H), 2.29 (s, 3 H); MS m/z 550 (M+1); HPLC RT 4.366 (C18 4.2x100mm, 0-100% ACN/H20 (0.1% TFA), 6min @ 2ml/min @254/220nm).
{4-[({4-(2,4-difluorobenzyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2- methylphenoxy}acetic acid From ethyl {4-[({4-(2,4-difluorobenzyl)-2-[4-(trifluoromethyI)phenyl]-1 ,3-thiazoI-5- y|}methyI)sulfanyl]-2-methylphenoxy}acetate, (0.1 g, 0.17 mmol), {4-[({4-(2,4-difluorobenzyl)-2-[4- (trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}acetic acid (0.027g, 28%) was obtained as a cream solid.
1H NMR (CD3CI3): δ 7.99 (d, 2 H), 7.68 (d, 2 H), 7.22 (s, 1 H), 7.13 (m, 2 H), 6.79 (m, 2 H), 6.62 (d, 1 H), 4.70 (s, 2 H), 4.20 (s, 2 H), 3.86 (s, 2 H), 2.23 (s, 3 H); 19F NMR (CD3CI3): δ -63.15 (s) - 114.03 (s) -114.06 (s); MS m/z 566 (M+1 ); HPLC RT 4.356 (C18 4.2x100mm, 0-100% ACN/H20 (0.1 % TFA), 6min @ 2ml/min @254/220nm). Anal. Calcd. for C27H20F5NO3S2.0.5H2O: C, 56.44; H, 3.68; N, 2.44%; found: C, 56.40; H, 3.79; N, 2.20%
{4-[({4-(4-methoxybenzyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2- methylphenoxy}acetic acid
From ethyl {4-[({4-(4-methoxybenzyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyI)sulfanyl]-2-methylphenoxy}acetate (0.160g 0.27 mmol), {4-[({4-(4-methoxybenzyl)-2-[4- (trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}acetic acid (0.005g, 3%) was obtained as a cream solid. H NMR (CD3CI3): δ 8.01 (d, 2 H), 7.68 (d, 2 H), 7.23 (s, 1 H), 7.11 (m, 3 H), 6.82 (d, 2 H), 6.62
(d, 1 H), 4.90 (s, 2.H), 4.17 (s, 2 H), 3.90 (s, 2 H), 3.80 (s, 3 H), 2.25 (s, 3 H); MS m/z 560.
2-Methyll-2-{4-[({4-r(4-methyl-2-thienyl)methyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}propanoic acid From ethyl 2-methyl-2-{4-[({4-[(4-methyl-2-thienyl)methyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3- thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoate (0.17g 0.29 mmol), 2-methyI-2-{4-[({4-[(4-methyl-2- thienyl)methyl]-2-[4-(trifluoromethyI)phenyl]-1 ,3-thiazol-5-yl}methyl)suIfanyI]phenoxy}propanoic acid (0.002g, 1.2%) was obtained as a cream solid.
1H NMR (CD3CI3): δ 8.01 (d, 2 H), 7.78 (d, 2 H), 7.28 (d, 2 H), 6.86 (d 2 H), 6.73 (s, 1 H), 6.63 (s, 1 H), 4.18 (s, 2 H), 3.99 (s, 2 H), 2.21 (s, 3 H), 1.63 (s, 6 H); MS m/z 564 (M+1 ); HPLC RT 4.413 (C18 4.2x100mm, 0-100% ACN/H20 (0.1 % TFA), 6min @ 2ml/min @254/220nm).
The following is an alternative procedure for the synthesis of Ethyl 2-{4-[({4-(hydroxymethyl)- 2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}-2-methylpropanoate
Ethyl 2-[4-(chlorosulfonyl)phenoxy]-2-methylpropanoate
Cool a solution of the ethyl 2-methyl-2-phenoxypropanoate, (1.0 wt, 1.0 eq), in dichloromethane (7.5 vols) to 0°C with stirring under a nitrogen atmosphere. Slowly add neat chlorosulfonic acid (0.78 wt, 1.4 eq) to the reaction mixture at a rate such that the reaction temperature never rises above 5.0 °C. The addition typically takes 30 minutes to complete. Following the completion of the addition, stir the reaction mixture at 0-1 °C. Follow the course of the reaction by HPLC. The reaction is typically complete after 30 minutes. At this point, slowly treat the reaction mixture with DMF (1.75 L) (1.40 wt, 4.0 eq). The addition of DMF to the reaction mixture is very exothermic. Adjust the rate of addition so that the reaction temperature never rises above 10.0 °C. The addition of DMF to the reaction mixture takes approximately 30 minutes. Following the completio.ii of the DMF addition, re-cool the reaction mixture to 0.5 to 1°C. Treat the cooled reaction mixture with neat thionyl chloride (619 mL, 1.01 kg) (0.86 wt, 1.5 eq). Adjust the rate of addition so that the process temperature never reaches 5°C. The addition of thionyl chloride to the reaction mixture is not very exothermic at all. Hence, the addition of thionyl chloride is typically complete in 5 minutes. Following the completion of the DMF addition, warm the reaction mixture to 20°C with stirring. Follow the course of the reaction via HPLC. After 2.0 h, the reaction is typically complete. At this point, cool the reaction mixture to 0-1 °C and carefully treat the reaction mixture with water (8.8 L) (7.5 vols). [Note: The addition of water may be somewhat exothermic depending upon how much unreacted thionyl chloride is left in the reaction mixture.] Separate the organic layer and wash the organic layer with aqueous 0.1 N HCI solution (2 X 7.5 vols). Separate the organic layer, concentrate the organic layer to a minimum stir volume, treat the organic layer with isopropyl acetate (1 X 5.0 vols) and then concentrate the resulting solution via vacuum distillation to afford the titled compound as a translucent bronze colored oil.
Yield (% theory): 85-98%.
1H NMR (400 MHz, CDCI3) δ 7.90 (2H, bd), 6.90 (2H, bd), 4.22 (2H, q, J=7.0 Hz), 1.67 (6H, s), 1.20 (3H, t, J=7.0 Hz)
Diethyl 2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-4,5-dicarboxylate
Heat a solution of the 4-fluorobenzenecarbothioamide, (1.0 wt, 1.0 eq), in absolute ethanol (3 vols) to 50 °C with stirring under a nitrogen atmosphere. Add diethyl 2-chloro-3-oxosuccinate (1.2 wt, 1.1 eq), in one portion. Some warming is seen during the addition which is typically complete in less then 30 minutes. After the addition is complete, heat the reaction mixture to about 68°C. Hold the reaction mixture at 67-69°C for 6 h and then cool the reaction mixture to ambient temperature overnight. Dilute the resulting yellow hazy solution slowly with aqueous 50% ethanol solution (3 vols), stir at ambient temperature for 4h, and then cool the reaction mixture to <5°C. Filter the solids. Wash the wet cake with aqueous 50% ethanol solution (3 vols) and dry at 45 °C to constant weight to afford the title compound as an off-white to white colored solid. Yield (% theory): 78-83%.
1H NMR (300 MHz, CDCI3) δ 8.14 (2H, d, J=8.2Hz), 7.76 (2H, d, J=8.2Hz), 4.52 (2H, q, J=7.1 Hz), 4.43 (2H, q, J=7.1 Hz), 1.47 (3H, t, J=7.1 Hz), 1.42 (3H, t, J=7.1 Hz).
{5-Hydroxymethyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-4-yl}methanol
To a suspension of lithium aluminum hydride (0.14 wt) in THF (3.4 vols), add a solution of the diethyl 2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazole-4,5-dicarboxylate (1.0 wt, 1.0 eq), dissolved in THF (2 vols) at a rate such that the temperature of the reaction mixture is maintained at below -10°C. The addition time is 1.5-3.0 hr. After the addition is complete, stir the reaction mixture at ambient temperature for 18 h. Quench the reaction by adding aqueous 16% sulfuric aciα (2.4 vols). Charge ethyl acetate (5 vols) with stirring to the reaction mixture followed with water (5 vols). Filter the resulting two phase mixture through celite (0.4 wt). Separate the layers and wash the organic layer with water (4 X 4 vols) and with brine (2 X 4 vol). Reduce the total volume of the reaction mixture via vacuum distillation to leave the solid suspended in ethyl acetate (1-1.5 vols). Dilute the slurry with dichloromethane (5 vols) and stir the suspension for at least 6 h. Filter the tan-colored solid. Wash the wet cake with dichloromethane ( 2 vols) and dry the wet cake at 45°C under mild vacuum to afford the title compound as an off-white solid. Yield (% theory): 65-85%. 1H NMR (300 MHz, CD3OD) δ 8.15(2H, d, J=8.3Hz), 7.79(2H, d, J=8.3Hz), 4.92 (2H, s), 4.90
(2H, s), 4.77(2H, s). Ethyl 2-{4-[({4-(hydroxymethyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)- sulfanyl]phenoxy}-2-methylpropanoate .
To a stirred suspension of zinc dust (0.75 wt, 3.5 eq) in isopropyl acetate (5 vols), add a solution of DME (0.5 vol) and water (0.5 eq). Heat the resulting solution from room temperature to 40°C. Treat the reaction mixture with a solution of ethyl 2-[4-(chlorosulfonyl)phenoxy]-2- methylpropanoate (1.0 wt, 1.0 eq) and dichlorodimethylsilane (0.32 wt, 0.75 eq) in isopropyl acetate (3 vols) over a period of 2 h as this addition is mildly exothermic. After the addition is complete, increase the process temperature to 60°C. Treat the suspension at 60°C slowly with neat dichlorodimethylsilane (0.95 wt, 2.3 eq) over a period of 1 h. When the reduction of the sulfonylchloride is deemed complete (by HPLC), treat the reaction mixture with f5-Hydroxymethyl-2- [4-(trifluoromethyl)phenyl]-1 ,3-thiazol-4-yl}methanol (1.04 wt, 1.1 eq) in one portion at 60°C. After the addition is complete, increase the process temperature to 89°C and stir the reaction mixture at this temperature for 3 to 5 h then cool to ambient temperature. Filter the reaction mixture to remove unreacted zinc residue, wash the filtrate with water (2 X 8 vols) and concentrate the organic layer to about 3.5 volumes via vacuum distillation at 40-45°C. Dissolve the resultant, somewhat syrupy, residue in ethanol (2 vols) and treat the resulting solution with iso-octane (2vols). Cool the clear yellow-tinted solution to ambient temperature to induce crystallization of the product. Collect the solid via filtration. Wash the wet cake with iso-octane/EtOH (9:1 , 1 vol) and dry under vacuum (-21 Torr) at 60 °C for 12 h to afford the title compound as an off-white solid. Yield (% theory): 45-55%.
1H NMR (400 MHz, CDCI3) δ 7.96 (2H, d, J=8.5 Hz), 7.66 (2H, d, J=8.5 Hz), 7.24 (2H, d, J=8.8 Hz), 6.74 (2H, d, J=8.8 Hz), 4.45 (2H, d, J=3.5 Hz), 4.19 (2H, q, J=7.2 Hz), 4.16 (2H, s), 2.30 (1H, br s), 1.57 (6H, s), 1.20 (3H, t, J=7.2 Hz).
The following intermediates and ligands were prepared for the binding and transfection assays described below:
i) 2-{2-methyl-4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyllphenoxy}acetic acid This compound was used as a PPARdelta reference in the transfection assays described below and was prepared according to the following method:
Figure imgf000123_0001
Chlorosulfonic acid (15mL) was cooled to 0°C. then 10.0 g (0.05M) of ethyl (2- methylphenoxyacetate was added over 10 m. The reaction mixture was stirred at 0-5°C for 30m, the bath was removed and stirring continued for 2 h. The reaction mixture was poured into ice, forming a white solid which was washed with ice water and dried under high vacuum affording the title compound (12.846 g ,86%).
Figure imgf000124_0001
To a well stirred solution of LiAIH4 (1.52 g, 40 mmol) in dry THF (50 mL) at 0 °C, was slowly added a solution of ethyl 4-methyl-2-[4-(trifluoromethyl)phenyl]-thiazole-5-carboxylate (12.6 g, 40 mmol) in dry THF (50 mL). The mixture was stirred at room temperature for 2 hs. The reaction was quenched by slow addition at 0 °C of water (2 mL), 5N NaOH (2 mL) and water (6 mL). The precipitate was filtered, washed with EtOAc, MeOH, CH2CI2and THF. After evaporation, a yellow solid was obtained, that was crystallyzed from MeOH-water to afford intermediate 1 depicted above (9.90 g, 36 mmol, 90%) as a yellow solid mp 120-122 °C.
Figure imgf000124_0002
To a cold (0°C) stirred solution of intermediate 1 (8.2g, 30 mmol) and Et3N (6.07 g, 8.36 mL,
60 mmol), in dry CH2CI2 (120 mL) was slowly added MeS02Cl (5.49 g, 3.71 mL, 48 mmol). After 2 hs at 0°C more Et3N (6 mmol) and MeS02CI (4.8 mmol) were added. After 2 more h a tic (hexane:EtOAc, 1 :1 ) showed complete reaction. The reaction mixture was diluted with CH2CI2 (120 mL) and washed with NaHC03 (sat.) (2 x 240 mL) and water (2 x 240 mL), dried, filtered and evaporated to afford intermediate 2 (8.0 g, 27 mmol, 90%) as a yellow solid.
2-{2-methyl-4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}acetic acid:
Figure imgf000124_0003
Intermediate A (4.68g, 16mM) was refluxed with 9.6 g of tin powder in ethanol (20mL) and dioxane/HCI (20 mL). After 3 h the reaction mixture was poured into ice and CH2CI2 (200mL) and filtered. The phases were separated and the aqueous layer was extracted 2X 50 mL CH2CI2. The combined organic layers were dried (MgS04), filtered and evaporated to yield 3.5g (97%). This material readily forms disulfides and therefore was used immediately. It was dissolved in acetonitrile (50mL) with intermediate C (4.0g, 14.0mM) and Cs2C03 (10.1g, 31.0 mM) and stirred for 1 h then diluted with ether (200mL) and water (200mL). The phases were separated and the organic phase was washed 2X NaOH 0.1 N (50mL), dried (MgS04), filtered and evaporated to afford crude product (6.57 g, ) which was slurried in hexane:ether (1 :1 ) and filtered to yield pure intermediate D (5.0g, 74%). This material was hydrolyzed as described below to prepare the title compound. A solution of the corresponding ester (Intermediate D) (1 mmol) in THF (10 mL) (in some cases few drops of MeOH were added to help solubility), was treated with 1 N LiOH in water (2mL, 2 mmol), and stirred 16 h at room temperature (when reactions were slow, the temperature was elevated to 50°C). The solution was neutralized with 1 N HCI (2 mL, 2 mmol) and the organic solvent evaporated to afford an aqueous solution with an insoluble product. If the insoluble was a solid, it was filtered and dried to afford the final product. If the insoluble was an oil, it was extracted with EtOAc (30 mL). The organic solution was separated, washed with water (2 x 30 mL), dried, filtered, and evaporated to afford the final product.
Binding Assay:
Compounds were tested for their ability to bind to hPPAR gamma hPPARalpha or PPARdelta using a Scintillation Proximity Assay (SPA). The PPAR ligand binding domain (LBD) was expressed in E. coli as polyHis tagged fusion proteins and purified. The LBD was then labeled with biotin and immobilized on streptavidin-modified scintillation proximity beads. The beads were then incubated with a constant amount of the appropriate radioligand (3H-BRL 49653 for PPARgamma, radiolabelled 2-(4-(2 (2,3-D'tritio-1 -heptyl-3-(2,4~difluorophenyl)ureido)ethyI)phenoxy)-2-meth;. Ibutanoic acid for hPPAR alpha (see WO 00/08002.) and labelled GW2433 (see Brown, P. J et al . Chem. Biol., 4, 909- 918 (1997). For the structure and synthesis of this ligand) for PPAR delta) and variable concentrations of test compound, and after equilibration the radioactivity bound to the beads was measured by a scintillation counter. The amount of nonspecific binding, as assessed by control wells containing 50 μM of the corresponding unlabeled ligand, was subtracted from each data point. For each compound tested, plots of ligand concentration vs. CPM of radioligand bound were constructed and apparent Ki values were estimated from nonlinear least squares fit of the data assuming simple competitive binding. The details of this assay have been reported elsewhere (see, Blanchard, S. G. et. al. Development of a Scintillation Proximity Assay for Peroxisome Proliferator-Activated Receptor gamma Ligand Binding Domain. Anal. Biochem., 257, 112-119 (1998)).
Transfection assay: Compounds were screened for functional potency in transient transfection assays in CV-1 cells for their ability to activate the PPAR subtypes (transactivation assay). A previously established chimeric receptor system was utilized to allow comparison of the relative transc ptional activity of the receptor subtypes on the same target gene and to prevent endogenous receptor activation from complicating the interpretation of results. See, for example, Lehmann, J. M.; Moore, L. B.; Smith- Oliver, T. A.; Wilkison, W. O.; Willson, T. M.; Kliewer, S. A., An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPARgammaJ, J. Biol. Chem., 270, 12953-6 (1995). The ligand binding domains for murine and human PPAR alpha, PPAR gamma, and PPAR delta were each fused to the yeast transcription factor GAL4 DNA binding domain. CV-1 cells were transiently transfected with expression vectors for the respective PPAR chimera along with a reporter construct containing five copies of the GAL4 DNA binding site driving expression of secreted placenta! alkaline phosphatase (SPAP) and beta-galactosidase. After 16 h, the medium was exchanged to DME medium supplemented with 10% delipidated fetal calf serum and the test compound at the appropriate concentration. After an additional 24h, cell extracts were prepared and assayed for alkaline phosphatase and D-galactosidase activity. Alkaline phosphatase activity was corrected for transfection efficiency using the beta-galactosidase activity as an internal standard (see, for example, Kliewer, S. A., et. al. Cell 83, 813-819 (1995)). Rosiglitazone (BRL 49653) was used as a positive control in the hPPAR gamma assay. The positive control for PPAR de a assays was 2-{2- methyl-4-[({4-methyl-2-{trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methyl)sulfanyI]phenoxy}acetic acid. The positive control in the hPPARalpha transfection assay was 2-[4-(2-(3-(4-fluorophenyl)-1- heptylureido)ethyl)-phenoxy]-2-methylpropionic acid, which can be prepared as described in Brown, Peter J., et. al. Synthesis Issue 7, 778-782 ( 997), or patent publication WO 9736579.
All of the above examples of this invention were agonists of at least one hPPAR subtype.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, solvate, or hydrolyzable ester thereof wherein:
Figure imgf000127_0001
R1 and R2 are independently hydrogen or C.,_3 alkyl;
X2 is O, S, or CH2;
R3, R4, and R5 are independently H, C,.3alkyl, OCH3, CF3, OCF3, CN, allyl, or halogen;
Y is S or O; each R25 is independently CH3, OCH3, CF3, or halogen; y is 0, 1 , 2, 3, 4 or 5; and
R2S is selected from the group consisting of the moieties A through K depicted below:
— N N — R'z wherein R12 is selected from the group consisting of C,.6alkyl, C,.6alkylenearyl, and the moieties depicted below in Group II,
Figure imgf000127_0002
Group II
wherein R17 and R18 are independently hydrogen, halogen, hydroxy, -CN, Chalky!, cι- gperfluoroalkyl,
Figure imgf000127_0003
perfluoroOC1.6alkyl, or C,.6hydroxyalkyl; R19 is hydrogen or Chalky!;
R21 is C,.6alkyl, -C,.6alkylenearyl, aryl, or -aryl-heteroaryl; R22 is Chalky!, aryl, or -C,_6alkylenearyl; R23 is Chalky), C3.6cycloalkyl, or aryl; R24 is Chalky!, -C^alkylenearyl, C3.6cycloalkyl, or aryl; B
Figure imgf000128_0001
wherein Z is O, N or S (note that when Z is N, the depicted bond can be attached to the nitrogen in the ring as well as any of the carbons in the ring);
- -,R20
wherein R20 is C,.6alkyl, aryl, -OC.,_6aIkyl, hydroxy, C,..6hydroxyalkyI, or l-alkoxyC^alkyl;
-N O
Figure imgf000128_0002
wherein R13 and R14 are independently hydrogen, halogen, CN, perfluroC.,..salkyl, perfluroOC,. ial yl, Chalky!, -OC,.6alkyl, -C1.6alkyleneOC1.6alkyl, -SC,..βalkyl, or aryl;
F
Figure imgf000128_0003
wherein R21 is independently as defined above;
Figure imgf000128_0004
wherein R15 and R16 are independently hydrogen, C.,.6alkyl, C3.6cycloalkyl optionally substituted with 1 or 2 C.,_3alkyl groups, or R12 as defined above; H =N
i (CH2)nPh wherein n is 1-3
— O— R21 wherein R21 is independently as defined above; and
K
— S— R21
wherein R21 is independently as defined above.
2. A compound according to claim 1 wherein R and R2 are independently H or CH3.
3. A compound according to claim 2 wherein R1 and R2 are either both H or both CH3.
4. A compound according to any of claims 1 -3 wherein X2 is O or S.
5. A compound according to any of claims 1 -4 wherein R3 is CH3 or H.
6. A compound according to any of claims 1-5 wherein R4 and R5 are H.
7. A compound according to any preceding claim wherein Y is S.
8. A compound according to any of claims 1-8 wherein y is 1 or 2.
9. A compound according to claim 8 wherein each R25 is independently halogen or CF3.
10. A compound according to any preceding claim wherein R26 is selected from the group consisting of
Figure imgf000129_0001
wherein R12, Z, R13, and R14 are as defined in Claim 1.
11. A compound according to any preceeding claim wherein R13 and R14 are independently fluorine, bronime, phenyl, thienyl, CF3, OCF3, OCH3, SCH3, or t-butyl, R17 and R18 are independently hydrogen, OH, CN, OC^a^y!, halogen, CF3, COCH3, CH(OH)CH3, or OCF3, R21 is phenyl optionally substituted by methyl or CN, -C^alkylenephenyl, or phenyl-5-methyl-1 ,2,4-oxadiazol-3-yl, R22 is C,. 6alkyl, phenyl, or benzyl, R23 is C,„6alkyl, furanyl, thienyl, phenyl optionally substituted by a halogen a methoxy or a dimethylamino group, methoxymethylcyclopropyl, or C3.scyclalkyl, and R24 is H, C.,.6alkyl, cyclohexyl, m-methoxyphenyl, p-fluorophenyl, or -CH2CH2phenyl.
12. A compound according to Claim 11 wherein R2S is
-N N— R12 and R12 is selected from the moieties shown in Group IV.
Figure imgf000130_0001
Group IV
13. A compound according to Claim 12 wherein R17 is fluorine, chlorine, OC,.3alkyl or COCH3 and R18 is OCH3 or hydrogen, and R19 is hydrogen.
14. A compound according to Claim 10 wherein R26 is
Figure imgf000130_0002
15. A compound according to Claim 14 wherein R14 is thienyl, OCH3, OCF3, CF3, or fluorine, and R13 is hydrogen or fluorine.
16. A compound of formula (I) selected from:
2-[4-({[4-{[4-(4-acetylphenyl)-1-piperazinyl]methyl}-2-(4-fluorophenyl)-1 ,3-thiazol-5- yl]methyl}sulfanyl)-2-methylphenoxy]-2-methylpropanoic acid,
2-methyl-2-{2-methyl-4-[({4-[4-(methylsulfanyl)benzyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol- 5-yl}methyl)suIfanyl]phenoxy}propanoic acid,
{2-methyl-4-[({4-(3-thienylmethyI)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}acetic acid, {4-[({4-benzyl-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methyI)sulfanyl]-2,5- dimethylphenoxyjacetic acid,
2-{4-[({4-{[4-(4-acetylphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyl)suIfanyl]-2-methyIphenoxy}propanoic acid, 2-{4-[({4-{[4-(4-acetylphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}metfιyl)sulfanyl]-2-ethylphenoxy}propanoic acid,
2-{2-methyl-4-[({4-(2-thienylmethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}propanoic acid, 2-{4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyI]-1 ,3-thiazol-
5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid,
2-{4-[({4-{[4-(4-ethoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyI)phenyl]-1 ,3-thiazol-5- yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid,
2-methyl-2-{2-methyl-4-[({4-{[4-(phenoxycarbonyl)-1-piperazinyl]methyl}-2-[4- (trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic acid,
2-{4-[({4-{[4-(4-acetylphenyl)-1-piperazinyI]methyl}-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyl)sulfanyl]-2-propylphenoxy}propanoic acid,
{2-methyl-4-[({4-[4-(3-thienyl)benzyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}acetic acid, 2-(4-{[(2-(4-fluorophenyl)-4-{[4-(4-methoxyphenyl)-1 -piperazinyl]methyl}-1 ,3-thiazol-5- yl)methyl]sulfanyl}-2-methylphenoxy)-2-methylpropanoic acid,
2-{4-[({4-{[4-(4-acetylphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}-2-methylpropanoic acid,
2-{4-[({4-{[4-(2,4-dimethoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1 ,3- thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid,
{2-isopropyl-4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]- 1 ,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetic acid,
2-{4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-t4-(trifluoromethyl)phenyl]-1 ,3-thiazol- 5-yl}methyl)sulfanyl]-2-propylphenoxy}propanoic acid, 2-{4-[({4-benzyl-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methyl)sulfanyl]-2- methylphenoxy}propanoic acid,
2-{2-ethyl-4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1 ,3- thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic acid,
2-methyl-2-{2-methyl-4-[({4-[4-(trifluoromethyl)benzyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol- 5-yl}methyl)sulfanyl]phenoxy}propanoic acid,
2-{4-[({4-{[4-(4-fluorophenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyl)sulfanyl]-2-methylphenoxy}-2-methylpropanoic acid ,
{4-[({4-{[4-(4-acetylphenyl)-1-piperazinyl]methyI}-2-[4-(trifluoromethyI)phenyl]-1 ,3-thiazol-5- yl}methyl)sulfanyl]-2-propylphenoxy}acetic acid, {4-[({4-([1 ,1 '-biphenyl]-4-ylmethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyl)sulfanyl]-2-methylphenoxy}acetic acid,
2-{4-[({4-{[4-(4-fluorophenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid,
{4-[({4-{[4-(3-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1 ,3-thia∑ol-5- y|}methyl)sulfanyl]-2-methylphenoxy}acetic acid,
2-{2-methyl-4-[({4-(3-thienylmethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}propanoic acid, {4-[({4-{[4-(2-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyl)sulfanyl]-2-methylphenoxy}acetic acid,
2-{2-isopropyl-4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]- 1 ,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic acid, 2-{4-[({4-(4-tert-butylbenzyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methyl)sulfanyl]-2- methylphenoxy}-2-methylpropanoic acid,
2-{4-[({4-{[4-(3-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol- 5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid,
2-{4-[({4-benzyl-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5-y)}methyl)sulfanyl]-2,3- dimethylphenoxy}propanoic acid,
2-{4-[({4-{t4-(4-chlorophenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid,
2-{4-[({4-benzyl-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methyl)sulfanyl]-2- fluorophenoxy}propanoic acid, 2-{4-[({4-{[4-(2,4-difluorophenyl)-1 -piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-
5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid,
{4-[({4-(2,4-difluorobenzyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methyl)sulfanyl]-2- methylphenoxyjacetic acid,
2-{4-[({4-{[4-(4-acetylphenyl)-1-piperazinyl]methyi}-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyl)sulfanyl]-2-methylphenoxy}-2-methylpropanoic acid,
2-methyl-2-{2-methyl-4-[({4-(3-thienylmethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazoi-5- yl}methyl)sulfanyl]phenoxy}propanoic acid,
2-{4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol- 5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid, {2-ethyl-4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1 ,3- thiazol-5-yl}methyl)sulfanyl]phenoxy}acetic acid,
2-{4-[({4-(4-methoxybenzyl)-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-y!}methyl)sulfanyl]-2- methylphenoxy}-2-methylpropanoic acid,
2-methyl-2-{4-[({4-{[4-(2-pyrazinyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1 ,3- thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic acid,
2-{4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol- 5-yl}methyl)sulfanyl]-2-methylphenoxy}-2-methylpropanoic acid,
2-{4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol- 5-yl}methyl)sulfanyl]phenoxy}-2-methylpropanoic acid, 2-methyl-2-{2-methyl-4-[({4-[4-(trifluoromethoxy)benzyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3- thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic acid,
2-{4-[({4-{[4-(4-isopropoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1 ,3- thiazol-5-yl}methyl)suIfanyl]-2-methylphenoxy}propanoic acid,
2-{2-methyl-4-[({4-{[4-(2-pyrimidinyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1 ,3- thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic acid.
{2-methyl-4-[({4-(3-phenylpropyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol~5- yl}methyl)sulfanyl]phenoxy}acetic acid, [4-[({4-benzyl-2-t4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methyI)suIfanyl]-2- (trifluoromethyl)phenoxy]acetic acid,
{2-methyl-4-[({4-{[4-(5-methyl-1 ,2,4-oxadiazol-3-yl)phenoxy]methyl}-2-[4- (trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methyl)sulfanyl]phenoxy}acetic acid, {4-[({4-benzyl-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methyl)sulfanyl]-5-chloro-2- methylphenoxy}acetic acid,
{4-[({4-benzyl-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methyl)sulfanyl]-2- methylphenoxy}acetic acid,
{4-[({4-(4-methoxybenzyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methyl)sulfanyl]-2- methylphenoxy}acetic acid,
{2,5-dimethyI-4-[({4-(3-thienylmethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}acetic acid,
{2-methyl-4-[({4-{[4-(2-pyrazinyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1 ,3- thiazol-5-yl}methyl)sulfanyI]phenoxy}acetic acid, {4-[({4-benzyl-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methyl)sulfanyl]-2,3- dimethylphenoxy}acetic acid,
[4-({[2-(4-chIorophenyl)-4-methyl-1 ,3-thiazol-5-yl]methyl}sulfanyl)-2-methylphenoxy]acetic acid,
{2-methyl-4-[({4-[(4-methyl-2-thienyl)methyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yI}methyπsulfanyl]phenoxy}acetic acid,
{4-t({4-benzyl-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methyl)sulfanyl]-2- bromophenoxy}acetic acid,
{2-methyl-4-[({4-[(2-phenylethoxy)methyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}acetic acid, {2-methyl-4-[({4-(2-phenylethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}acetic acid, and pharmaceutically acceptable salts, solvates, and hydrolyzable esters thereof.
17. A compound of formula (I) selected from: 2-methyl-2-{2-methyl-4-[({4-(3-thienylmethyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5- yl}methyl)sulfanyl]phenoxy}propanoic acid,
2-{4-[({4-{[4-(4-methoxyphenyi)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol- 5-yl}methyl)suIfanyl]-2-methylphenoxy}propanoic acid,
{2-ethyl-4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1 ,3- thiazol-5-yl}methyl)suIfanyl]phenoxy}acetic acid,
2-{4-[({4-(4-methoxybenzyl)-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-5-yl}methyl)sulfanyl]-2- methylphenoxy}-2-methyIpropanoic acid ,
2-methyl-2-{4-[({4-{[4-(2-pyrazinyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyi)phenyI]-1 ,3- thiazol-5-yl}methyl)sulfanyI]phenoxy}propanoic acid, 2-{4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyI]methyl}-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol-
5-yl}methyI)sulfanyl]-2-methylphenoxy}-2-methyIpropanoic acid,
2-{4-[({4-{[4-(4-methoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1 ,3-thiazol- 5-yl}methyl)sulfanyl]phenoxy}-2-methylpropanoic acid, 2-methyl-2-{2-methyl-4-[({4-[4-(trifluoromethoxy)benzyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3- thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic acid,
2-{4-[({4-{[4-(4-isopropoxyphenyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1 ,3- thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy}propanoic acid,
2-{2-methyl-4-[({4-{[4-(2-pyrimidinyl)-1-piperazinyl]methyl}-2-[4-(trifluoromethyl)phenyl]-1 ,3- thiazol-5-yl}methyl)sulfanyl]phenoxy}propanoic acid, and pharmaceutically acceptable salts, solvates, or hydrolyzable esters thereof
18. A compound according to any preceding claim which is a hPPARδ agonist.
19 A compound according to Claim 18 which is also a hPPARα or hPPARgamma agonist.
20. A compound according to any preceding claim which is a hPPAR pan agonist.
21. A compound according to any of claims 1-20 for use in therapy.
22. A pharmaceutical composition comprising a compound according to any of claims 1- 20.
23. A pharmaceutical composition according to claim 22 further comprising a pharmaceutically acceptable diluent or carrier.
24. Use of a compound according to any of claims 1 -20 for the manufacture of a medicament for the treatment of a hPPAR disease or condition.
25. Use according to claim 24 wherein the hPPAR mediated disease or condition is dyslipidemia, syndrome X, heart failure, hypercholesteremia, cardiovascular disease, type II diabetes mellitus, type I diabetes, insulin resistance, hyperlipidemia, obesity, anorexia bulimia and anorexia nervosa
26. A method of treating a hPPAR mediated disease or condition in a patient comprising the administration of a therapeutically effective amount of a compound according to any of claims 1- 20.
27. A method according to claim 26 wherein the hPPAR mediated disease or condition is dyslipidemia, syndrome X, heart failure, hypercholesteremia, cardiovascular disease, type II diabetes mellitus, type I diabetes, insulin resistance, hyperlipidemia, obesity, anorexia bulimia and anorexia nervosa.
PCT/US2001/051056 2000-12-20 2001-12-19 Thiazole and oxazole derivatives as activators of human peroxisome proliferator activated receptors WO2002059098A1 (en)

Priority Applications (7)

Application Number Priority Date Filing Date Title
JP2002559400A JP4234431B2 (en) 2000-12-20 2001-12-19 Thiazole and oxazole derivatives as activators of human peroxisome proliferator-activated receptors
DK01994514T DK1349843T3 (en) 2000-12-20 2001-12-19 Thiazole and oxazole derivatives as activators of human peroxisome profilerator-activated receptors
EP01994514A EP1349843B1 (en) 2000-12-20 2001-12-19 Thiazole and oxazole derivatives as activators of human peroxisome proliferator activated receptors
AT01994514T ATE293611T1 (en) 2000-12-20 2001-12-19 THIAZOLE AND OXAZOLE DERIVATIVES AS ACTIVATORS OF HUMAN PEROXISOME PROLIFERATOR ACTIVATED RECEPTORS
DE60110262T DE60110262T2 (en) 2000-12-20 2001-12-19 THIAZOL AND OXAZOLE DERIVATIVES ACTIVATED AS HUMAN PEROXISOM PROLIFERATOR ACTIVATED RECEPTORS
US11/550,060 US7229998B2 (en) 2000-12-20 2006-10-17 Thiazole and oxazole derivatives as activators of human peroxisome proliferator activated receptors
US11/753,848 US7449468B2 (en) 2000-12-20 2007-05-25 Thiazole and oxazole derivatives as activators of human peroxisome proliferator activated receptors

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB0031103.5 2000-12-20
GBGB0031103.5A GB0031103D0 (en) 2000-12-20 2000-12-20 Chemical compounds

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US10451295 A-371-Of-International 2001-12-19
US11/550,060 Continuation US7229998B2 (en) 2000-12-20 2006-10-17 Thiazole and oxazole derivatives as activators of human peroxisome proliferator activated receptors

Publications (1)

Publication Number Publication Date
WO2002059098A1 true WO2002059098A1 (en) 2002-08-01

Family

ID=9905490

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2001/051056 WO2002059098A1 (en) 2000-12-20 2001-12-19 Thiazole and oxazole derivatives as activators of human peroxisome proliferator activated receptors

Country Status (9)

Country Link
EP (1) EP1349843B1 (en)
JP (1) JP4234431B2 (en)
AT (1) ATE293611T1 (en)
DE (1) DE60110262T2 (en)
DK (1) DK1349843T3 (en)
ES (1) ES2240558T3 (en)
GB (1) GB0031103D0 (en)
PT (1) PT1349843E (en)
WO (1) WO2002059098A1 (en)

Cited By (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003015776A1 (en) * 2001-08-13 2003-02-27 Janssen Pharmaceutica N.V. 2,4,5-trisubstituted thiazolyl derivatives and their antiinflammatory activity
WO2003072102A1 (en) 2002-02-25 2003-09-04 Eli Lilly And Company Peroxisome proliferator activated receptor modulators
WO2004000785A2 (en) * 2002-06-19 2003-12-31 Smithkline Beecham Corporation Phenyloxyalkanonic acid derivatives as hppar activators
WO2004022551A1 (en) * 2002-09-06 2004-03-18 Takeda Pharmaceutical Company Limited Furan or thiophene derivative and medicinal use thereof
WO2004026849A1 (en) * 2002-09-19 2004-04-01 Smithkline Beecham Corporation Process for preparing substituted phenoxy-acetic acids from phenols
WO2004037776A2 (en) 2002-10-28 2004-05-06 Novo Nordisk A/S Novel compounds and their use as prar-modulators
WO2004037775A1 (en) 2002-10-28 2004-05-06 Novo Nordisk A/S Novel compounds useful in treating ppar mediated diseases
WO2004076428A1 (en) * 2003-02-27 2004-09-10 Aventis Pharma Deutschland Gmbh 4-(3- (2-phenyl-oxazol-4-ylmethoxy)-cyclohexyloxy)-butane acid derivatives and related compounds as ppar modulators for treating diabetes of type 2 and atherosclerosis
JP2005035966A (en) * 2002-09-06 2005-02-10 Takeda Chem Ind Ltd Furan or thiophene derivative and its pharmaceutical use
US7091245B2 (en) 2002-09-05 2006-08-15 Novo Novdisk A/S Compounds, their preparation and use
US7105551B2 (en) 2000-12-20 2006-09-12 Smithkline Beecham Corporation Thiazole derivatives for treating PPAR related disorders
US7129268B2 (en) 2002-10-28 2006-10-31 Novo Nordisk A/S Peroxisome proliferator activated receptor-active arylene acetic acid derivatives
WO2007003581A1 (en) 2005-06-30 2007-01-11 Novo Nordisk A/S Phenoxy acetic acids as ppar delta activators
US7196107B2 (en) 2000-12-20 2007-03-27 Smithkline Beecham Corporation Thia-and oxazoles and their use as ppars activators
FR2910893A1 (en) * 2006-12-29 2008-07-04 Genfit Sa New Phenylthiazolyl/phenyloxazolyl derivatives are peroxisome proliferator-activated receptor agonist useful to treat e.g. diabetic, dyslipidemia, cardiovascular disease, hypertension, inflammatory diseases and cerebral ischaemia
US7709528B2 (en) 2002-10-28 2010-05-04 High Point Pharmaceuticals, Llc Compounds, their preparation and use
EP2213289A1 (en) 2006-09-07 2010-08-04 Nycomed GmbH Combination treatment for diabetes mellitus
US7943613B2 (en) 2005-12-22 2011-05-17 High Point Pharmaceuticals, Llc Compounds, their preparation and use
US7943612B2 (en) 2006-03-09 2011-05-17 High Point Pharmaceuticals, Llc Compounds that modulate PPAR activity, their preparation and use
US7968723B2 (en) 2004-05-05 2011-06-28 High Point Pharmaceuticals, Llc Compounds, their preparation and use
US8053598B2 (en) 2004-05-05 2011-11-08 High Point Pharmaceuticals, Llc Compounds, their preparation and use
WO2012122368A1 (en) * 2011-03-08 2012-09-13 The Regents Of The University Of California Deoxycytidine kinase binding compounds
US8404726B2 (en) 2006-04-18 2013-03-26 Nippon Chemiphar Co. Ltd. Activating agent for peroxisome proliferator activated receptor δ
US8648208B2 (en) 2008-04-15 2014-02-11 Nippon Chemiphar Co. Ltd. Activating agent for peroxisome proliferator activated receptor
WO2015068156A1 (en) 2013-11-05 2015-05-14 Ben-Gurion University Of The Negev Research And Development Authority Compounds for the treatment of diabetes and disease complications arising from same
US9579335B2 (en) 2010-10-19 2017-02-28 Indiana University Research And Technology Corporation Treatment of cystic diseases
US9663448B2 (en) 2007-06-04 2017-05-30 Ben-Gurion University Of The Negev Research And Development Authority Tri-aryl compounds and compositions comprising the same
US10456406B2 (en) 2013-09-09 2019-10-29 Vtv Therapeutics Llc Use of a PPAR-δ agonist for reducing loss of muscle strength, muscle mass, or type I muscle fibers in an immobilized limb
US11446307B2 (en) 2020-11-02 2022-09-20 Trethera Corporation Crystalline forms of a deoxycytidine kinase inhibitor and uses thereof
WO2022245986A1 (en) * 2021-05-19 2022-11-24 Stinginn Inc Small molecular inhibitors of sting signaling compositions and methods of use
US11931365B2 (en) 2022-01-25 2024-03-19 Reneo Pharmaceuticals, Inc. Use of PPAR-delta agonists in the treatment of disease

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BRPI0610177A2 (en) * 2005-05-25 2016-11-29 Nippon Chemiphar Co compound or a salt thereof, and peroxisome proliferator activated receptor activator
JP2009132620A (en) * 2006-03-07 2009-06-18 Astellas Pharma Inc Phenylthiazole derivative

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5972881A (en) * 1995-09-18 1999-10-26 Ligand Pharmaceuticals Incorporated Treating NIDDM with RXR agonists
WO2000008002A1 (en) * 1998-08-07 2000-02-17 Glaxo Group Limited SUBSTITUTED OXAZOLES AND THIAZOLES DERIVATIVES AS hPPAR GAMMA AND hPPAR ALPHA ACTIVATORS
WO2001000603A1 (en) * 1999-06-25 2001-01-04 Glaxo Group Limited Thiazole and oxazole derivatives and their pharmaceutical use
WO2001040207A1 (en) * 1999-12-02 2001-06-07 Glaxo Group Limited Substituted oxazoles and thiazoles derivatives as hppar alpha activators

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5972881A (en) * 1995-09-18 1999-10-26 Ligand Pharmaceuticals Incorporated Treating NIDDM with RXR agonists
WO2000008002A1 (en) * 1998-08-07 2000-02-17 Glaxo Group Limited SUBSTITUTED OXAZOLES AND THIAZOLES DERIVATIVES AS hPPAR GAMMA AND hPPAR ALPHA ACTIVATORS
WO2001000603A1 (en) * 1999-06-25 2001-01-04 Glaxo Group Limited Thiazole and oxazole derivatives and their pharmaceutical use
WO2001040207A1 (en) * 1999-12-02 2001-06-07 Glaxo Group Limited Substituted oxazoles and thiazoles derivatives as hppar alpha activators

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
D. BISHOP-BAILEY: "Peroxisome Proliferator Activated Receptors in the Cardiovascular System", BRITISH JOURNAL OF PHARMACOLOGY, vol. 129, no. 5, March 2000 (2000-03-01), pages 823 - 34, XP001079321 *
J. M. LEHMANN ET. AL.: "An Antidiabetic Thiazolidinedione is a High Affinity Ligand for Peroxisome Proliferator-activated Receptor gamma.", JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 270, no. 22, 2 June 1995 (1995-06-02), pages 12953 - 6, XP000577082 *
W. R. OLIVER ET. AL.: "A Selective Peroxisome Proliferator -activated Receptor delta Agonist Promotes Reverse Cholesterol Transport.", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE USA, vol. 98, no. 9, 24 April 2001 (2001-04-24), pages 5306 - 11, XP001080446 *

Cited By (60)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7105551B2 (en) 2000-12-20 2006-09-12 Smithkline Beecham Corporation Thiazole derivatives for treating PPAR related disorders
US7196107B2 (en) 2000-12-20 2007-03-27 Smithkline Beecham Corporation Thia-and oxazoles and their use as ppars activators
WO2003015776A1 (en) * 2001-08-13 2003-02-27 Janssen Pharmaceutica N.V. 2,4,5-trisubstituted thiazolyl derivatives and their antiinflammatory activity
EA007933B1 (en) * 2001-08-13 2007-02-27 Янссен Фармацевтика Н.В. 2,4,5-trisubstituted thiazolyl derivatives and their antiinflammatory activity
HRP20040098B1 (en) * 2001-08-13 2012-08-31 Janssen Pharmaceutica N.V. 2,4,5-TRlSUBSTITUTED THIAZOLYL DERIVATIVES AND THEIR ANTIINFLAMMATORY ACTIVITY
US7138403B2 (en) 2001-08-13 2006-11-21 Janssen Pharmaceutica N.V. 2,4,5-trisubstituted thiazolyl derivatives and their antiinflammatory activity
WO2003072102A1 (en) 2002-02-25 2003-09-04 Eli Lilly And Company Peroxisome proliferator activated receptor modulators
US7241793B2 (en) 2002-06-19 2007-07-10 Smithkline Beecham Corporation Phenyloxyalkanonic acid derivatives as hPPAR activators
WO2004000785A2 (en) * 2002-06-19 2003-12-31 Smithkline Beecham Corporation Phenyloxyalkanonic acid derivatives as hppar activators
WO2004000785A3 (en) * 2002-06-19 2004-10-14 Smithkline Beecham Corp Phenyloxyalkanonic acid derivatives as hppar activators
US7091245B2 (en) 2002-09-05 2006-08-15 Novo Novdisk A/S Compounds, their preparation and use
JP2005035966A (en) * 2002-09-06 2005-02-10 Takeda Chem Ind Ltd Furan or thiophene derivative and its pharmaceutical use
WO2004022551A1 (en) * 2002-09-06 2004-03-18 Takeda Pharmaceutical Company Limited Furan or thiophene derivative and medicinal use thereof
US7553867B2 (en) 2002-09-06 2009-06-30 Takeda Pharmaceutical Company Limited Furan or thiophene derivative and medicinal use thereof
JP2006502191A (en) * 2002-09-19 2006-01-19 スミスクライン ビーチャム コーポレーション Process for producing substituted phenoxy-acetic acid from phenols
WO2004026849A1 (en) * 2002-09-19 2004-04-01 Smithkline Beecham Corporation Process for preparing substituted phenoxy-acetic acids from phenols
US7129268B2 (en) 2002-10-28 2006-10-31 Novo Nordisk A/S Peroxisome proliferator activated receptor-active arylene acetic acid derivatives
WO2004037775A1 (en) 2002-10-28 2004-05-06 Novo Nordisk A/S Novel compounds useful in treating ppar mediated diseases
WO2004037776A2 (en) 2002-10-28 2004-05-06 Novo Nordisk A/S Novel compounds and their use as prar-modulators
US7709528B2 (en) 2002-10-28 2010-05-04 High Point Pharmaceuticals, Llc Compounds, their preparation and use
WO2004076428A1 (en) * 2003-02-27 2004-09-10 Aventis Pharma Deutschland Gmbh 4-(3- (2-phenyl-oxazol-4-ylmethoxy)-cyclohexyloxy)-butane acid derivatives and related compounds as ppar modulators for treating diabetes of type 2 and atherosclerosis
US7335671B2 (en) 2003-02-27 2008-02-26 Sanofi-Aventis Deutschland Gmbh Arylcycloalkyl-substituted alkanoic acid derivatives, processes for their preparation and their use as pharmaceuticals
US7872034B2 (en) 2003-02-27 2011-01-18 Sanofi-Aventis Deutschland Gmbh Arylcycloalkyl-substituted alkanoic acid derivatives, processes for their preparation and their use as pharmaceuticals
US7968723B2 (en) 2004-05-05 2011-06-28 High Point Pharmaceuticals, Llc Compounds, their preparation and use
US8053598B2 (en) 2004-05-05 2011-11-08 High Point Pharmaceuticals, Llc Compounds, their preparation and use
US7943669B2 (en) 2005-06-30 2011-05-17 High Point Pharmaceuticals, Llc Phenoxy acetic acids as PPAR delta activators
US8217086B2 (en) 2005-06-30 2012-07-10 High Point Pharmaceuticals, Llc Phenoxy acetic acids as PPAR delta activators
EP2298742A1 (en) 2005-06-30 2011-03-23 High Point Pharmaceuticals, LLC Phenoxy acetic acids as PPAR delta activators
WO2007003581A1 (en) 2005-06-30 2007-01-11 Novo Nordisk A/S Phenoxy acetic acids as ppar delta activators
US8426473B2 (en) 2005-06-30 2013-04-23 High Point Pharnaceuticals, LLC Phenoxy acetic acids as PPAR delta activators
US9855274B2 (en) 2005-12-22 2018-01-02 Vtv Therapeutics Llc Phenoxy acetic acids and phenyl propionic acids as PPAR delta agonists
US10471066B2 (en) 2005-12-22 2019-11-12 Vtv Therapeutics Llc Phenoxy acetic acids and phenyl propionic acids as PPAR delta agonists
US10947180B2 (en) 2005-12-22 2021-03-16 Vtv Therapeutics Llc Phenoxy acetic acids and phenyl propionic acids as PPAR delta agonists
EP2386540A1 (en) 2005-12-22 2011-11-16 High Point Pharmaceuticals, LLC Novel compounds, their preparation and use
US9663481B2 (en) 2005-12-22 2017-05-30 Vtv Therapeutics Llc Phenoxy acetic acids and phenyl propionic acids as PPARδ agonists
US7943613B2 (en) 2005-12-22 2011-05-17 High Point Pharmaceuticals, Llc Compounds, their preparation and use
US11420929B2 (en) 2005-12-22 2022-08-23 Vtv Therapeutics Llc Phenoxy acetic acids and phenyl propionic acids as PPAR delta agonists
US8362016B2 (en) 2005-12-22 2013-01-29 High Point Pharmaceuticals, Llc Phenyl propionic acids as PPAR delta activators
US8551993B2 (en) 2005-12-22 2013-10-08 High Point Pharmaceuticals, Llc Phenoxy acetic acids as PPAR delta activators
US7943612B2 (en) 2006-03-09 2011-05-17 High Point Pharmaceuticals, Llc Compounds that modulate PPAR activity, their preparation and use
US8404726B2 (en) 2006-04-18 2013-03-26 Nippon Chemiphar Co. Ltd. Activating agent for peroxisome proliferator activated receptor δ
EP2213289A1 (en) 2006-09-07 2010-08-04 Nycomed GmbH Combination treatment for diabetes mellitus
FR2910893A1 (en) * 2006-12-29 2008-07-04 Genfit Sa New Phenylthiazolyl/phenyloxazolyl derivatives are peroxisome proliferator-activated receptor agonist useful to treat e.g. diabetic, dyslipidemia, cardiovascular disease, hypertension, inflammatory diseases and cerebral ischaemia
WO2008087367A2 (en) * 2006-12-29 2008-07-24 Genfit Substituted (phenylthiazolyl)-phenyl-propan-1-one and (phenyloxazodyl)-phenyl-propan-1-one derivatives, preparations and uses of same
WO2008087367A3 (en) * 2006-12-29 2008-11-06 Genfit Substituted (phenylthiazolyl)-phenyl-propan-1-one and (phenyloxazodyl)-phenyl-propan-1-one derivatives, preparations and uses of same
US10214481B2 (en) 2007-06-04 2019-02-26 Ben-Gurion University Of The Negev Research And Development Aithority Telomerase activating compounds and methods of use thereof
US9663448B2 (en) 2007-06-04 2017-05-30 Ben-Gurion University Of The Negev Research And Development Authority Tri-aryl compounds and compositions comprising the same
US9670138B2 (en) 2007-06-04 2017-06-06 Ben-Gurion University Of The Negev Research And Development Authority Telomerase activating compounds and methods of use thereof
US8648208B2 (en) 2008-04-15 2014-02-11 Nippon Chemiphar Co. Ltd. Activating agent for peroxisome proliferator activated receptor
US9579335B2 (en) 2010-10-19 2017-02-28 Indiana University Research And Technology Corporation Treatment of cystic diseases
US9688673B2 (en) 2011-03-08 2017-06-27 The Regents Of The University Of California Deoxycytidine kinase binding compounds
WO2012122368A1 (en) * 2011-03-08 2012-09-13 The Regents Of The University Of California Deoxycytidine kinase binding compounds
US11096946B2 (en) 2013-09-09 2021-08-24 Vtv Therapeutics Llc Use of a PPAR-δ agonist for reducing loss of muscle strength, muscle mass, or type I muscle fibers in an immobilized limb
US10456406B2 (en) 2013-09-09 2019-10-29 Vtv Therapeutics Llc Use of a PPAR-δ agonist for reducing loss of muscle strength, muscle mass, or type I muscle fibers in an immobilized limb
EP3756661A1 (en) 2013-09-09 2020-12-30 vTv Therapeutics LLC Use of a ppar-delta agonist for treating muscle atrophy
US10111880B2 (en) 2013-11-05 2018-10-30 Ben-Gurion University Of The Negev Research And Development Authority Compounds for the treatment of diabetes and disease complications arising from same
WO2015068156A1 (en) 2013-11-05 2015-05-14 Ben-Gurion University Of The Negev Research And Development Authority Compounds for the treatment of diabetes and disease complications arising from same
US11446307B2 (en) 2020-11-02 2022-09-20 Trethera Corporation Crystalline forms of a deoxycytidine kinase inhibitor and uses thereof
WO2022245986A1 (en) * 2021-05-19 2022-11-24 Stinginn Inc Small molecular inhibitors of sting signaling compositions and methods of use
US11931365B2 (en) 2022-01-25 2024-03-19 Reneo Pharmaceuticals, Inc. Use of PPAR-delta agonists in the treatment of disease

Also Published As

Publication number Publication date
DE60110262T2 (en) 2006-03-09
DE60110262D1 (en) 2005-05-25
ATE293611T1 (en) 2005-05-15
EP1349843B1 (en) 2005-04-20
DK1349843T3 (en) 2005-08-15
PT1349843E (en) 2005-09-30
GB0031103D0 (en) 2001-01-31
JP2004520377A (en) 2004-07-08
EP1349843A1 (en) 2003-10-08
ES2240558T3 (en) 2005-10-16
JP4234431B2 (en) 2009-03-04

Similar Documents

Publication Publication Date Title
EP1349843B1 (en) Thiazole and oxazole derivatives as activators of human peroxisome proliferator activated receptors
JP3490704B2 (en) Thiazole and oxazole derivatives and their pharmaceutical use
EP1343773B1 (en) Thiazole derivatives for traeing ppar related disorders
US6498174B1 (en) Substituted oxazoles and thiazoles derivatives as hPPARγ and hPPARα activators
EP1392674B1 (en) Furan and thiophene derivatives that activate human peroxisome proliferator activated receptors
EP1343772B1 (en) Thia- and oxazoles and their use as ppars activators
AU2002246713A1 (en) Thiazole derivatives for treating PPAR related disorders
US20040147571A1 (en) Substituted oxazoles and thiazoles as hppar alpha agonists
EP1513796B1 (en) Phenyloxyalkanoic acid derivatives as hppar activators
US7439259B2 (en) Thiazole derivatives for treating PPAR related disorders
US7229998B2 (en) Thiazole and oxazole derivatives as activators of human peroxisome proliferator activated receptors
AU2002253385A1 (en) Furan and thiophene derivatives that activate human peroxisome proliferator actvated receptors

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SD SE SG SI SK SL TJ TM TN TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 2002559400

Country of ref document: JP

WWE Wipo information: entry into national phase

Ref document number: 2001994514

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 2001994514

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWE Wipo information: entry into national phase

Ref document number: 10451295

Country of ref document: US

WWG Wipo information: grant in national office

Ref document number: 2001994514

Country of ref document: EP