WO2007056366A2 - Compounds and compositions as ppar modulators - Google Patents

Compounds and compositions as ppar modulators Download PDF

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Publication number
WO2007056366A2
WO2007056366A2 PCT/US2006/043342 US2006043342W WO2007056366A2 WO 2007056366 A2 WO2007056366 A2 WO 2007056366A2 US 2006043342 W US2006043342 W US 2006043342W WO 2007056366 A2 WO2007056366 A2 WO 2007056366A2
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Prior art keywords
phenyl
methyl
thiazol
acetic acid
trifluoromethyl
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PCT/US2006/043342
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French (fr)
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WO2007056366A3 (en
Inventor
Robert Epple
Christopher Cow
Mihai Azimioara
Ross Russo
Yongping Xie
Xing Wang
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Irm Llc
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Application filed by Irm Llc filed Critical Irm Llc
Priority to BRPI0618335-2A priority Critical patent/BRPI0618335A2/en
Priority to CA002626483A priority patent/CA2626483A1/en
Priority to JP2008540130A priority patent/JP2009514964A/en
Priority to EP06837062A priority patent/EP1945620A2/en
Priority to US12/092,962 priority patent/US20090192203A1/en
Priority to AU2006311675A priority patent/AU2006311675A1/en
Publication of WO2007056366A2 publication Critical patent/WO2007056366A2/en
Publication of WO2007056366A3 publication Critical patent/WO2007056366A3/en

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    • 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
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    • 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
    • C07D263/34—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/46—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
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    • 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
    • C07D277/32—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • 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 invention provides compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with the activity of the Peroxisome Proliferator-Activated Receptor (PPAR) families.
  • PPAR Peroxisome Proliferator-Activated Receptor
  • Peroxisome Proliferator Activated Receptors are members of the nuclear hormone receptor super family, which are ligand-activated transcription factors regulating gene expression. Certain PPARs are associated with a number of disease states including dyslipidemia, hyperlipidemia, hypercholesteremia, atherosclerosis, atherogenesis, hypertriglyceridemia, heart failure, myocardial infarction, vascular diseases, cardiovascular diseases, hypertension, obesity, inflammation, arthritis, cancer, Alzheimer's disease, skin disorders, respiratory diseases, ophthalmic disorders, IBDs (irritable bowel disease), ulcerative colitis and Crohn's disease. Accordingly, molecules that modulate the activity of PPARs are useful as therapeutic agents in the treatment of such diseases.
  • the present invention provides compounds of Formula I: in which n is selected from 0, 1, 2 and 3; p is selected from O 5 1 5 2 and 3;
  • Y is selected from O 5 S, NR 73 and CR 7a R 7 b5 wherein R 7a and R 7 b are independently selected from hydrogen and C 1 -C 6 alkyl;
  • Z is selected from CR8 a R8 b and S; wherein R8 a and R8 b are independently selected from hydrogen and C h alky!;
  • W is selected from O and S;
  • Ri is selected from -X1CR9R 1 0X2CO 2 R 1 1, -X 1 SCR9R10X 2 CO2R11 and - X1OCR 9 R 1 0X 2 CO 2 R 11 ; wherein X 1 and X 2 are independently selected from a bond and Ci- 4 alkylene; and R 9 and Rio are independently selected from hydrogen, C 1 -C 6 alkyl and Ci- 4 alkoxy; or R 9 and Ri 0 together with the carbon atom to which R9 and Rio are attached form C3-i 2 cycloalkyl; and Rn is selected from hydrogen and C 1 -C 6 alkyl; each
  • R 2 is independently selected from halo, C 1 -C 6 alkyl, C ⁇ - ⁇ alkenyl, C 1 -C 4 alkoxy, Ci- 4 alkylthio 5 Ca- ⁇ cycloalkyl, C 3-8 heterocycloalkyl, C ⁇ -ioaryl and Cs-ioheteroaryl; wherein any aryl, heteroaryl, cycloalkyl or heterocycloalkyl of R 2 is optionally substituted with 1 to 3 radicals independently selected from halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 - 6 alkenyl, C 1 -C 6 alkylthio, halo-substituted- C 1 -C 6 alkyl, halo-substituted- C 1 -C 6 alkoxy, -C(O)R 14a and NRi 4a Ri4b; wherein Ri 4a and Ri 4b are independently selected from hydrogen and C 1 -C
  • R 3 and R 4 are independently selected from hydrogen and C 1 -C 6 alkyl
  • R 5 and R 6 are independently selected from hydrogen, C 1 -C 6 alkyl, Ca-i ⁇ cycloalkyl, Ca-sheterocycloalkyl, Cg-ioaryl and Cs-isheteroaryl;
  • any aryl, heteroaryl, cycloalkyl and heterocycloalkyl of R5 and R 6 is optionally substituted with 1 to 3 radicals independently selected from halo, nitro, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, hydroxy- C 1 -C 6 alkyl, halo-substituted- C 1 -C 6 alkyl, halo-substituted- C 1 -C 6 alkoxy, C 3 -i2cycloalkyl, C 3 -C 8 heterocycloalkyl, C ⁇ -ioaryl, Cs-nheteroaryl, -XS(O) 0-2 R 12 , -XS(O) 0-2 XR 13 , -XNR 12 R 12 , -XNR 12 S(O) 0-2 R 12 , -XNR 12 C(O)R 12 ,
  • the present invention provides a pharmaceutical composition that contains a compound of Formula I or a N-oxide derivative, individual isomers and mixture of isomers thereof; or a pharmaceutically acceptable salt thereof, in admixture with one or more suitable excipients.
  • the present invention provides a method of treating a disease in an animal in which modulation of PPAR activity can prevent, inhibit or ameliorate the pathology and/or symptomology of the diseases, which method comprises administering to the animal a therapeutically effective amount of a compound of Formula I or a N-oxide derivative, individual isomers and mixture of isomers thereof, or a pharmaceutically acceptable salt thereof.
  • the present invention provides the use of a compound of
  • the present invention provides a process for preparing compounds of Formula I and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixture of isomers thereof, and the pharmaceutically acceptable salts thereof.
  • Alkyl as a group and as a structural element of other groups, for example halo-substituted-alkyl and alkoxy, can be either straight-chained or branched.
  • C 1 -C 6 alkoxy includes, methoxy, ethoxy, and the like.
  • Halo-substituted alkyl includes trifluoromethyl, pentafluoroethyl, and the like.
  • Aryl means a monocyclic or fused bicyclic aromatic ring assembly containing six to ten ring carbon atoms.
  • aryl can be phenyl or naphthyl, preferably phenyl.
  • Arylene means a divalent radical derived from an aryl group.
  • Heteroaryl is as defined for aryl where one or more of the ring members are a heteroatom.
  • heteroaryl includes pyridyl, indolyl, indazolyl, quinoxalinyl, quinolinyl, benzofuranyl, benzopyranyl, benzothiopyranyl, benzo[l,3]dioxole, imidazolyl, benzo- imidazolyl, pyrimidinyl, furanyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, thienyl, etc.
  • C 6 -ioarylCo- 4 alkyl means an aryl as described above connected via a alkylene grouping. For example, includes phenethyl, benzyl, etc.
  • Cycloalkyl means a saturated or partially unsaturated, monocyclic, fused bicyclic or bridged polycyclic ring assembly containing the number of ring atoms indicated.
  • Ca-iocycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • Ca-sheterocycloalkyl as used in this application to describe compounds of the invention includes morpholino, pyrrolidinyl, piperazinyl, piperidinyl, piperidinylone,
  • Halogen (or halo) preferably represents chloro or fluoro, but can also be bromo or iodo.
  • Treatment refers to a method of alleviating or abating a disease and/or its attendant symptoms.
  • the present invention provides compounds, compositions and methods for the treatment of diseases in which modulation of PPAR activity can prevent, inhibit or ameliorate the pathology and/or symptomology of the diseases, which method comprises administering to the animal a therapeutically effective amount of a compound of Formula I.
  • n is selected from 0, 1, 2 and 3;
  • p is selected from 0, 1 and 2;
  • Y is selected from O and S;
  • Z is selected from CR ⁇ aR ⁇ b and S; wherein Rg 3 and Rg b are independently selected from hydrogen and C 1 -C 6 alkyl;
  • W is selected from O and S;
  • Ri is selected from ⁇ XiCR 9 RioX 2 C0 2 Ri i, -XISCR 9 R 1O X 2 CO 2 R I i and - X1OCR9R10X2CO 2 R11; wherein Xi and X 2 are independently selected from a bond and Ci- 4alkylene; and R 9 and Rio are independently selected from hydrogen, C 1 -C 6 alkyl and Ci- 4alkoxy; or R 9 and Rio together with the carbon atom to which R 9 and Rio are attached form C3-i 2 cycloalkyl; and Rn is selected from hydrogen and C 1 -C 6 alkyl; each
  • R 2 is independently selected from C 1 -C 6 alkyl, Ci-ealkenyl, Ci- 4 alkoxy, Ci- 4 alkylthio, C 3 -i 2 cycloalkyl, C3 -8 heterocycloalkyl, C ⁇ -ioaryl and Cs-ioheteroaryl; wherein any aryl, heteroaryl, cycloalkyl or heterocycloalkyl OfR 2 is optionally substituted with 1 to 3 radicals independently selected from halo, d- ⁇ alkoxy, C 1 -C 6 alkylthio, halo-substituted-Ci. ⁇ alkoxy, -C(O)Ri4a and NRi4 a Ri4b; wherein R ⁇ a and R ⁇ b are independently selected from hydrogen and C 1 -C 6 alkyl;
  • R3 and R4 are independently selected from hydrogen and C 1 -C 6 alkyl
  • Rs is Ce-ioaryl optionally substituted with 1 to 3 radicals independently selected from halo, nitro, cyano, C 1 -C 6 alkyl, Ci- ⁇ alkoxy, d- ⁇ alkylthio, hydroxy-C 1 -C 6 alkyl, halo-substituted-C 1 -C 6 alkyl, halo-substituted-C] ⁇ alkoxy, C 3 -i 2 cycloalkyl, Cs-gheterocycloalkyl, C ⁇ -ioaryl, Cs-uheteroaryl and -XNR 12 R 12 ; wherein R 12 is selected from hydrogen and Ci- ⁇ alkyl; and
  • Re is selected from hydrogen and methyl.
  • Ri is selected from -CH 2 CR 5 R 6 CO 2 H, -
  • each R 2 is indepedently selected from methyl, ethyl, cyclopropyl, methoxy, furanyl, phenyl, pyridinyl, thienyl, pyrrolidinyl and benzo[l,3]dioxolyl; wherein said pyridinyl or phenyl of R 2 is optionally substituted with 1 to 3 radicals independently selected from halo, methyl-carbonyl, dimethyl-amino, methoxy, halo-substituted-methoxy, methyl-thio, ethenyl, hexenyl and propyloxy.
  • Preferred compounds of Formula I are selected from: (5-Cyclopropyl-2-methyl-4- ⁇ 3-[4-(4-trifluoromethyl-phenyl)-thiazol-2-yl]-propoxy ⁇ -phenoxy)-acetic acid; (3- ⁇ 3-[4-(4- Trifluoromethyl-phenyl)-thiazol-2-yl]-propoxy ⁇ -phenyl)-acetic acid; (2-Methyl-4- ⁇ 3-[4-(4- trifluoromethyl-phenyl)-thiazol-2-yl]-propoxy ⁇ -phenoxy)-acetic acid; 2-Methyl-2-(4- ⁇ 3-[4 ⁇ (4-trifluoromethyl-phenyl)-thiazol-2-yl]-propoxy ⁇ -phenoxy)-propionic acid; (2- Cyclopropyl-3- ⁇ 3-[4-(4-trifluoromethyl-phenyl)-thiazol-2-yl]-propoxy ⁇ -
  • Compounds of the invention modulate the activity of PPARs and, as such, are useful for treating diseases or disorders in which PPARs contributes to the pathology and/or symptomology of the disease.
  • This invention further provides compounds of this invention for use in the preparation of medicaments for the treatment of diseases or disorders in which PPARs contributes to the pathology and/or symptomology of the disease.
  • Such compounds may therefore be employed for the treatment of prophylaxis, dyslipidemia, hyperlipidemia, hypercholesteremia, atherosclerosis, atherogenesis, hypertriglyceridemia, heart failure, hyper cholesteremia, myocardial infarction, vascular diseases, cardiovascular diseases, hypertension, obesity, cachexia, HIV wasting syndrome, inflammation, arthritis, cancer, Alzheimer's disease, anorexia, anorexia nervosa, bulimia, skin disorders, respiratory diseases, ophthalmic disorders, IBDs (irritable bowel disease), ulcerative colitis and Crohn's disease.
  • prophylaxis dyslipidemia, hyperlipidemia, hypercholesteremia, atherosclerosis, atherogenesis, hypertriglyceridemia, heart failure, hyper cholesteremia, myocardial infarction, vascular diseases, cardiovascular diseases, hypertension, obesity, cachexia, HIV wasting syndrome, inflammation, arthritis, cancer, Alzheimer's disease, anorexia, anorexia nervosa,
  • dyslipidemia deslipidemia, hyperlipidemia, hypercholesteremia, atherosclerosis, atherogenesis, hypertriglyceridemia, cardiovascular diseases, hypertension, obesity, inflammation, cancer, skin disorders, EBDs (irritable bowel disease), ulcerative colitis and Crohn's disease.
  • Compounds of the invention can also be employed to treat long term critical illness, increase muscle mass and/or muscle strength, increase lean body mass, maintain muscle strength and function in the elderly, enhance muscle endurance and muscle function, and reverse or prevent frailty in the elderly.
  • the compounds of the present invention may be employed in mammals as hypoglycemic agents for the treatment and prevention of conditions in which impaired glucose tolerance, hyperglycemia and insulin resistance are implicated, such as ty ⁇ e-1 and ty ⁇ e-2 diabetes, Impaired Glucose Metabolism (IGM), Impaired Glucose Tolerance (IGT), Impaired Fasting Glucose (EFG), and Syndrome X.
  • IGM Impaired Glucose Metabolism
  • IGM Impaired Glucose Tolerance
  • IGF Impaired Fasting Glucose
  • the present invention further provides a method for preventing or treating any of the diseases or disorders described above in a subject in need of such treatment, which method comprises administering to said subject a therapeutically effective amount (See, "Administration and Pharmaceutical Compositions ", infra) of a compound of the invention or a pharmaceutically acceptable salt thereof.
  • a therapeutically effective amount See, "Administration and Pharmaceutical Compositions ", infra) of a compound of the invention or a pharmaceutically acceptable salt thereof.
  • the required dosage will vary depending on the mode of administration, the particular condition to be treated and the effect desired.
  • the present invention also concerns: i) a compound of the invention or a pharmaceutically acceptable salt thereof for use as a medicament; and ii) the use of a compound of the invention or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for preventing or treating any of the diseases or disorders described above.
  • compounds of the invention will be administered in therapeutically effective amounts via any of the usual and acceptable modes known in the art, either singly or in combination with one or more therapeutic agents.
  • a therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. In general, satisfactory results are indicated to be obtained systemically at daily dosages of from about 0.03 to 2.5mg/kg per body weight.
  • An indicated daily dosage in the larger mammal, e.g. humans, is in the range from about 0.5mg to about lOOmg, conveniently administered, e.g. in divided doses up to four times a day or in retard form.
  • Suitable unit dosage forms for oral administration comprise from ca. 1 to 50mg active ingredient.
  • Compounds of the invention can be administered as pharmaceutical compositions by any conventional route, in particular enterally, e.g., orally, e.g., in the form of tablets or capsules, or parenterally, e.g., in the form of injectable solutions or suspensions, topically, e.g., in the form of lotions, gels, ointments or creams, or in a nasal or suppository form.
  • Pharmaceutical compositions comprising a compound of the present invention in free form or in a pharmaceutically acceptable salt form in association with at least one pharmaceutically acceptable carrier or diluent can be manufactured in a conventional manner by mixing, granulating or coating methods.
  • oral compositions can be tablets or gelatin capsules comprising the active ingredient together with a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and or polyvinylpyrollidone; if desired d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or e) absorbents, colorants, flavors and sweeteners.
  • diluents e.g., lactose, dextrose, sucrose,
  • compositions can be aqueous isotonic solutions or suspensions, and suppositories can be prepared from fatty emulsions or suspensions.
  • the compositions can be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they can also contain other therapeutically valuable substances.
  • Suitable formulations for transdermal applications include an effective amount of a compound of the present invention with a carrier.
  • a carrier can include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host.
  • transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
  • Matrix transdermal formulations can also be used.
  • Suitable formulations for topical application, e.g., to the skin and eyes, are preferably aqueous solutions, ointments, creams or gels well-known in the art. Such can contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
  • This invention also concerns a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound as described herein in combination with one or more pharmaceutically acceptable carriers.
  • Compounds of the invention can be administered in therapeutically effective amounts in combination with one or more therapeutic agents (pharmaceutical combinations).
  • the present invention also relates to pharmaceutical combinations, such as a combined preparation or pharmaceutical composition (fixed combination), comprising: 1) a compound of the invention as defined above or a pharmaceutical acceptable salt thereof; and 2) at least one active ingredient selected from:
  • anti-diabetic agents such as insulin, insulin derivatives and mimetics; insulin secretogogues such as the sulfonylureas, e.g., Glipizide, glyburide and Amaryl; insulinotropic sulfonylurea receptor ligands such as meglitinides, e.g., nateglinide and repaglinide; insulin sensitizer such as protein tyrosine phosphatase- IB (PTP 7 IB) inhibitors such as PTP-112; GSK3 (glycogen synthase kinase-3) inhibitors such as SB-517955, SB- 4195052, SB-216763, NN-57-05441 and NN-57-05445; RXR ligands such as GW-0791 and AGN- 194204; sodium-dependent glucose co-transporter inhibitors such as T- 1095; glycogen phosphorylase A inhibitors such as BAY
  • hypolipidemic agents such as 3-hydroxy-3-methyl-glutaryl coenzyme A
  • HMG-CoA reductase inhibitors e.g., lovastatin, pitavastatin, simvastatin, pravastatin, cerivastatin, mevastatin, velostatin, fluvastatin, dalvastatin, atorvastatin, rosuvastatin and rivastatin; squalene synthase inhibitors; FXR (farnesoid X receptor) and LXR (liver X receptor) ligands; cholestyramine; f ⁇ brates; nicotinic acid and aspirin; [0030] c) an anti-obesity agent or appetite regulating agent such as phentermine, leptin, bromocriptine, dexamphetamine, amphetamine, fenfluramine, dexfenfluramine, sibutramine, orlistat, dexfenfluramine, mazindol, phentermine, phendi
  • anti-hypertensive agents e.g., loop diuretics such as ethacrynic acid, furosemide and torsemide; diuretics such as thiazide derivatives, chlorithiazide, hydrochlorothiazide, amiloride; angiotensin converting enzyme (ACE) inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perinodopril, quinapril, ramipril and trandolapril; inhibitors of the Na-K-ATPase membrane pump such as digoxin; neutralendopeptidase (NEP) inhibitors e.g.
  • loop diuretics such as ethacrynic acid, furosemide and torsemide
  • diuretics such as thiazide derivatives, chlorithiazide, hydrochlorothiazide, amilor
  • ECE inhibitors e.g. SLV306
  • ACE/NEP inhibitors such as omapatrilat, sampatrilat and fasidotril
  • angiotensin II antagonists such as candesartan, eprosartan, irbesartan, losartan, telmisartan and valsartan, in particular valsartan
  • renin inhibitors such as aliskiren, terlakiren, ditekiren, RO 66-1132, RO-66-1168
  • ⁇ -adrenergic receptor blockers such as acebutolol, atenolol, betaxolol, bisoprolol, metoprolol, nadolol, propranolol, sotalol and timolol
  • inotropic agents such as digoxin, dobutamine and milrinone
  • calcium channel blockers such as digoxin, dobutamine and milrin
  • thrombin inhibitors such as Ximelagatran
  • aldosterone inhibitors such as anastrazole, fadrazole, eplerenone
  • a chemotherapeutic agent such as aromatase inhibitors e.g. femara, anti- estrogens, topoisomerase I inhibitors, topoisomerase II inhibitors, microtubule active agents, alkylating agents, antineoplastic antimetabolites, platin compounds, compounds decreasing the protein kinase activity such as a PDGF receptor tyrosine kinase inhibitor preferably Imatinib ( ⁇ N- ⁇ 5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2-methyl ⁇ henyl ⁇ -4-(3- pyridyl)-2-pyrimidine-amine ⁇ ) described in the European patent application EP-A-O 564 409 as example 21 or 4-Methyl-N-[3-(4-methyl-imidazol-l-yl)-5-trifluoromethyl-phenyl]-3-
  • aromatase inhibitors e.g. femara, anti-
  • tegaserod tegaserod
  • imatinib vildagliptin
  • metformin a thiazolidone derivative
  • glitazone such as pioglitazone, rosiglitazone, or ⁇ Rj-I-
  • the pharmaceutical combinations contains a therapeutically effective amount of a compound of the invention as defined above, in a combination with a therapeutically effective amount of another therapeutic agent as described above, e.g., each at an effective therapeutic dose as reported in the art.
  • Combination partners (1) and (2) can be administered together, one after the other or separately in one combined unit dosage form or in two separate unit dosage forms.
  • the unit dosage form may also be a fixed combination.
  • the structure of the active agents identified by generic or trade names may be taken from the actual edition of the standard compendium "The Merck Index" or the Physician's Desk Reference or from databases, e.g. Patents International (e.g. IMS World Publications) or Current Drugs. The corresponding content thereof is hereby incorporated by reference.
  • the invention concerns a pharmaceutical composition (fixed combination) comprising a therapeutically effective amount of a compound as described herein, in combination with a therapeutically effective amount of at least one active ingredient selected from the above described group a) to m), or, in each case a pharmaceutically acceptable salt thereof.
  • IGM Impaired Glucose Metabolism
  • ITT Impaired Glucose Tolerance
  • IGF Impaired Fasting Glucose
  • Such therapeutic agents include estrogen, testosterone, a selective estrogen receptor modulator, a selective androgen receptor modulator, insulin, insulin derivatives and mimetics; insulin secretagogues such as the sulfonylureas, e.g., Glipizide and Amaryl; insulinotropic sulfonylurea receptor ligands, such as meglitinides, e.g., nateglinide and repaglinide; insulin sensitizers, such as protein tyrosine phosphatase- IB (PTP-IB) inhibitors, GSK3 (glycogen synthase kinase-3) inhibitors or RXR ligands; biguanides, such as metformin; alpha-glucosidase inhibitors, such as acarbose; GLP-I (glucagon like peptide- 1), GLP-I analogs, such as Exendin-4, and GLP-I mimetics; DPPIV
  • hypolipidemic agents such as 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors, e.g., lovastatin, pitavastatin, simvastatin, pravastatin, cerivastatin, mevastatin, velostatin, fluvastatin, dalvastatin, atorvastatin, rosuvastatin, fluindostatin and rivastatin, squalene synthase inhibitors or FXR (liver X receptor) and LXR (farnesoid X receptor) ligands, cholestyramine, fibrates, nicotinic acid and aspirin.
  • a compound of the present invention may be administered either simultaneously, before or after the other active ingredient, either separately by the same or different route of administration or together in the same pharmaceutical formulation.
  • the invention also provides for pharmaceutical combinations, e.g. a kit, comprising: a) a first agent which is a compound of the invention as disclosed herein, in free form or in pharmaceutically acceptable salt form, and b) at least one co-agent.
  • the kit can comprise instructions for its administration.
  • co-administration or “combined administration” or the like as utilized herein are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.
  • pharmaceutical combination as used herein means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non- fixed combinations of the active ingredients.
  • fixed combination means that the active ingredients, e.g. a compound of Formula I and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage.
  • non-fixed combination means that the active ingredients, e.g. a compound of Formula I and a co- agent, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the 2 compounds in the body of the patient.
  • cocktail therapy e.g. the administration of 3 or more active ingredients.
  • the present invention also includes processes for the preparation of compounds of the invention.
  • reactive functional groups for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions.
  • Conventional protecting groups can be used in accordance with standard practice, for example, see T. W. Greene and P. G. M. Wuts in "Protective Groups in Organic
  • n, p, Ri, R 2 , R3, R 4 , Rs, Re, Y, Z and W are as defined for Formula I in the Summary of the Invention; and Q is a halogen, preferably Cl, I or Br.
  • Compounds of 2 are formed by reacting a compound of formula 1 with a halogen (Q) (for example, Br 2 , and the like) under suitable acidic conditions (for example, acetic acid, and the like), a suitable solvent (for example, dichloromethane, and the like). The reaction is carried out in the temperature range of about 10 to about SO 0 C and takes up to about 12 hours to complete.
  • n, p, R x , R 2 , R 3 , R 4 , R5, Rg, Y, Z and W are as defined for
  • R 2 ' is selected from Ca-galkenyl, cyclopropyl, C 6 -ioaryl and C 5- ioheteroaryl.
  • Q is a halogen, preferably Cl, I or Br; and R 30 is, independently selected from hydrogen, C 1 -C 6 alkyl or the R 30 radicals can be cyclized.
  • Compounds of Formula I are prepared by reacting a compound of formula 2 with a compound of formula 3 in the presence of a suitable catalyst (e.g., Pd(Ph ⁇ ) 4 , or the like), a suitable base (e.g., Na 2 COj 5 or the like) and a suitable solvent (e.g., water, ethanol, DME or the like and mixtures thereof).
  • a suitable catalyst e.g., Pd(Ph ⁇ ) 4 , or the like
  • a suitable base e.g., Na 2 COj 5 or the like
  • a suitable solvent e.g., water, ethanol, DME or the like and mixtures thereof.
  • n, p, Ri, R 2 , R3, R 4 , R 5 , R 6 , Rg, Ri 0 , Xi, X2, Y, Z and W are as defined for Formula I.
  • Compounds of Formula I are prepared by reacting a compound of formula 4 in the presence of a suitable base (e.g., lithium hydroxide, or the like) and a suitable solvent (e.g., THF, water or the like). The reaction is carried out in the temperature range of about 0 0 C to about 50 0 C and takes up to about 30 hours to complete.
  • a suitable base e.g., lithium hydroxide, or the like
  • a suitable solvent e.g., THF, water or the like
  • n, p, Ri, R 2 , R 3 , R 4 , R 5 , R 6 , Y, Z and W are as defined for
  • n, p, Rj, R 2 , R 3 , R 4 , R 5 , R 6 , Y, Z and W are as defined for
  • n, p, Rj, R 2 , R 3 , R 4 , Y and Z are as defined for Formula I in the
  • Q is a halogen, preferably Cl, I or BT.
  • Compounds of formula 11 and 12 are formed by reacting a compound of formula 5 with a compound of formula 9 or 10, respectively. The reaction proceeds in the presence of a suitable solvent (for example, acetonitrile, acetone, and the like), a suitable inorganic base (for example, CS 2 CO 3 , K2CO3, and the like). The reaction is carried out in the temperature range of about 10 to about 100 0 C and takes up to about 24 hours to complete.
  • a suitable solvent for example, acetonitrile, acetone, and the like
  • a suitable inorganic base for example, CS 2 CO 3 , K2CO3, and the like.
  • n, p, Ri, R2, R3, R 4 , Y and Z are as defined for Formula I in the
  • Compounds of formula 12 are formed by reacting a compound of formula 11 with a suitable reactant (for example, sodium cyanide, potassium cyanide, and the like), in a suitable solvent (for example, DMF, DMSO, ethanol, water, and the like). The reaction is carried out in the temperature range of about 0 to about 100 0 C and takes up to about 12 hours to complete.
  • a suitable reactant for example, sodium cyanide, potassium cyanide, and the like
  • a suitable solvent for example, DMF, DMSO, ethanol, water, and the like.
  • n, p, Ri, R 2 , R 3 , R4, Y and Z are as defined for Formula I in the
  • Compounds of formula 13 are formed by reacting a compound of formula 12 with a suitable solvent (for example, DMF, and the like) and a suitable reagent (for example, thioacetamide, and the like) under suitable acidic conditions (for example, HCl, and the like).
  • a suitable solvent for example, DMF, and the like
  • a suitable reagent for example, thioacetamide, and the like
  • acidic conditions for example, HCl, and the like
  • compounds of formula 13 are formed by reacting a compound of formula 12 with a suitable solvent (for example, pyridine, and the like) and a suitable reagent (for example, H 2 S, and the like) under suitable basic conditions (for example, triethylamine, and the like).
  • a suitable solvent for example, pyridine, and the like
  • a suitable reagent for example, H 2 S, and the like
  • suitable basic conditions for example, triethylamine, and the like
  • Compounds of formula 14 are formed by reacting a compound of formula 12 with a suitable solvent (for example, methanol, ethanol, and the like) and a suitable reagent (for example, ⁇ SCVwater, and the like). The reaction is carried out in the temperature range of about 0 to about 5O 0 C and takes up to about 24 hours to complete.
  • a suitable solvent for example, methanol, ethanol, and the like
  • a suitable reagent for example, ⁇ SCVwater, and the like
  • n, p, R 1 , R 2 , R 3 , R 4 , R 5 , Re, Y, Z and W are as defined for
  • Formula I in the Summary of the Invention and Q is a halogen, preferably Cl, I or Br.
  • Compounds of formula I are formed by reacting a compound of formula 13 or 14 with a compound of formula 15 optionally in the presence of a suitable solvent (for example, ethanol, and the like). The reaction is carried out in the temperature range of about 50 to about 120 0 C and takes up to about 24 hours to complete. [0069] Detailed reaction conditions are described in the examples, infra.
  • a compound of the invention can be prepared as a pharmaceutically acceptable acid addition salt by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid.
  • a pharmaceutically acceptable base addition salt of a compound of the invention can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base.
  • the salt forms of the compounds of the invention can be prepared using salts of the starting materials or intermediates.
  • the free acid or free base forms of the compounds of the invention can be prepared from the corresponding base addition salt or acid addition salt from, respectively.
  • a compound of the invention in an acid addition salt form can be converted to the corresponding free base by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, and the like).
  • a suitable base e.g., ammonium hydroxide solution, sodium hydroxide, and the like.
  • a compound of the invention in a base addition salt form can be converted to the corresponding free acid by treating with a suitable acid
  • Compounds of the invention in unoxidized form can be prepared from N- oxides of compounds of the invention by treating with a reducing agent (e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, or the like) in a suitable inert organic solvent (e.g. acetonitrile, ethanol, aqueous dioxane, or the like) at 0 to 80 0 C.
  • a reducing agent e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, or the like
  • a suitable inert organic solvent e.g. acetonitrile, ethanol, aqueous dioxane, or the like
  • Prodrug derivatives of the compounds of the invention can be prepared by methods known to those of ordinary skill in the art (e.g., for further details see Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters, Vol.4, p. 1985).
  • appropriate prodrugs can be prepared by reacting a non-derivatized compound of the invention with a suitable carbamylating agent (e.g., 1,1-acyloxyalkylcarbanochloridate, para- nitrophenyl carbonate, or the like).
  • Hydrates of compounds of the present invention can be conveniently prepared, or formed during the process of the invention, as solvates (e.g., hydrates). Hydrates of compounds of the present invention can be conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents such as dioxin, tetrahydrofuran or methanol.
  • Compounds of the invention can be prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. While resolution of enantiomers can be carried out using covalent diastereomeric derivatives of the compounds of the invention, dissociable complexes are preferred (e.g., crystalline diastereomeric salts). Diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and can be readily separated by taking advantage of these dissimilarities.
  • the • diastereomers can be separated by chromatography, or preferably, by separation/resolution techniques based upon differences in solubility.
  • the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.
  • a more detailed description of the techniques applicable to the resolution of stereoisomers of compounds from their racemic mixture can be found in Jean Jacques,
  • the compounds of Formula I can be made by a process, which involves:
  • Step A (3-Hydroxy-phenyl)-acetic acid (10 g, 65.7 mmol) is dissolved in
  • Step B (3-hydroxy-phenyl)-acetic acid ethyl ester 1 (5.93 g, 32.9 mmol) and imidazole (6.72 g, 98.7 mmol) are dissolved in DMF (16 mL) and stirred at rt for 10 min. Then TBDMSCl (7.44 g, 49.4 mmol) dissolved in DMF (4 mL) is added slowly and the mixture is stirred at rt overnight. Then water (50 mL) is added and the mixture is extracted with ether twice.
  • Step C [3-(tert-Butyl-dimethyl-silanyloxy)-phenyl]-acetic acid ethyl ester
  • Step D [2-Bromo-5-(tert-butyl-dimethyl-silanyloxy)-phenyl]-acetic acid ethyl ester 3 (1.00 g, 2.68 mmol), potassium phosphate (1.99 g, 9.38 mmol) and cyclopropylboronic acid (0.35 g, 4.02 mmol) are dissolved in toluene (12 mL). Tricyclohexylphosphine (0.23 g, 0.80 mmol), palladium acetate (0.09 g, 0.40 mmol) and water (0.6 mL) are added and the mixture is heated to 100 0 C overnight.
  • Step E Crude [5-(fe/-f-butyl-dimethyl-silanyloxy)-2-cycIopropyl-phenyl]- acetic acid ethyl ester 4 is dissolved in a mixture of THF (5 mL) and TBAF (5 mL) and stirred at it for 90 min. Water (75 mL) is added and the mixture is extracted with EtOAc (100 mL) twice. The organic layers are combined, washed with 0.1 M HCl and brine, dried over MgSO 4 , filtered and concentrated.
  • Step A (3,5-Dihydroxy-phenyl)-acetic acid (5 g, 29.7 mmol) is dissolved in MeOH (30 mL). Catalytic amounts of thionyl chloride (-0.25 ml_) are added and the solution is stirred at rt overnight. The solvent is removed in vacuo to give (3,5-dihydroxy- phenyl)-acetic acid methyl ester 6 (5.44 g, quant.): MS calcd. for C 9 Hi i ⁇ 4 (M+H*) 183.1, found 183.0.
  • Step B (3,5-Dihydroxy-phenyl)-acetic acid methyl ester 6 (2.50 g, 13.9 mmol) and imidazole (3.78 g, 55.5 mmol) are dissolved in DMF (10 mL) and stirred at rt for 10 min. Then TBDMSCl (1.67 g, 11.1 mmol) dissolved in DMF (4 mL) is added slowly and the mixture is stirred at rt for 8 h. Then water (50 mL) is added and the mixture is extracted with ether twice. The organic layers are combined, washed with water and brine, dried over MgSO 4 J filtered and concentrated.
  • Step C [3-(tert-Butyl-dimethyl-silanyloxy)-5-hydroxy-phenyl]-acetic acid methyl ester 7 (1.81 g, 6.1 mmol) and triethyl amine (0.85 mL, 6.1 mmol) are dissolved in DCM (30 mL) and cooled to 0 0 C. Triflic anhydride (1.03 mL, 6.1 mmol) dissolved in DCM (20 mL) is added dropwise, then the mixture is stirred at 0 0 C for 3 h. The solution is washed with saturated bicarbonate, water and brine. The organic layer is dried over MgSO 4 , filtered and concentrated.
  • Step D [3-(terr-Butyl-dimethyl-silanyloxy)-5-trifluoro- methanesulfonyloxy-phenyl]-acetic acid methyl ester 8 (0.5 g, 1.13 mmol), potassium phosphate (0.84 g, 3.96 mmol) and cyclopropylboronic acid (0.13 g, 1.472 mmol) are dissolved in toluene (6 mL). Tricyclohexylphosphine (32 mg, 0.11 mmol), palladium acetate (13 mg, 0.06 mmol) and water (0.3 mL) are added and the mixture is heated to 100 0 C overnight.
  • Step E Crude [3-(ter ⁇ butyl-dimethyl-silanyloxy)-5-cyclopropyl-phenylJ- acetic acid methyl ester 9 (0.22 g, 0.69 mmol) is dissolved in a mixture of THF (5 mL) and TBAF (5 mL) and stirred at rt for 90 min. Water (75 mL) is added and the mixture is extracted with EtOAc (100 mL) twice. The organic layers are combined, washed with 0.1 M HCl and brine, dried over MgS ⁇ 4, filtered and concentrated.
  • Step A (3-Hydroxy-phenyl)-acetic acid (3.0 g, 19.7 mmol) is dissolved in
  • Step B tert-Butylamine (5 mL, 48 mmol) is dissolved in toluene (40 mL) and cooled to -30°C, then bromine (1.2 mL, 24 mmol) is added dropwise and stirred at -30°C for 0.5 h. The mixture is cooled to -78°C and a solution of (3-hydroxy-phenyl)-acetic acid methyl ester 11 (4 g, 24 mmol) in DCM (20 mL) is added dropwise and stirred at rt for 16 h.
  • Step A (4-Bromo-3-hydroxy-phenyl)-acetic acid methyl ester 12 (751 mg, 2.09 mmol) and TBDMSCl (346 mg, 2.30 mmol) are dissolved in DCM (4 mL). Triethylamine (0.44 mL, 3.13 mmol) and DMAP (25 mg, 0.21 mmol) are added and the mixture is stirred at rt for 2 h. Water (10 mL) is added and the mixture is extracted with DCM.
  • Step B [4-Bromo-3-(/er/-butyl-dimethyl-silanyloxy)-phenyl]-acetic acid methyl ester 14 (663 mg, 1.85 mmol), potassium phosphate (1.37 g, 6.47 mmol) and cyclo- propylboronic acid (0.19 g, 2.22 mmol) are dissolved in toluene (40 mL). Tricyclohexylphosphine (42 mg, 0.18 mmol), palladium acetate (26 mg, 0.09 mmol) and water (2 mL) are added and the mixture is heated to 100 0 C overnight.
  • Step C [3-(fer ⁇ Butyl-dimethyl-silanyloxy)-4-cyclopropyl-phenyl]-acetic acid methyl ester 15 (479 mg, 1.49 mmol) is dissolved in a mixture of THF (20 mL) and TBAF (1.8 mL, 1.79 mmol) and stirred at rt for 90 min. 1 N HCl (40 mL) is added and the mixture is extracted with EtOAc (40 mL).
  • Step A (2-Methylphenoxy)acetic acid ethyl ester (66.03 g, 340 mmol) is dissolved in dichloroethane (400 mL).
  • Aluminum chloride 100.02 g, 750 mmol
  • Acetyl chloride 35 mL, 493 mmol
  • the rate of addition is adjusted to maintain a relatively slow emission of hydrogen chloride gas.
  • the resulting dark brown solution is allowed to cool off to rt, then is poured over 300 g of crushed ice.
  • Step B (4-Acetyl-2-methyl-phenoxy) -acetic acid ethyl ester 18 ⁇ 76.5 g, 324 mmol), 77% mCPBA ⁇ 100.3 g, 407 mmol) and p-TsOH (13 g, 68 mmol) in dichloroethane (450 mL) are heated to 50 0 C for 30 h. The reaction mixture is then washed with 1 M KI (2x500 mL) and NaHSO 3 (2x500 mL) . The organic layer is dried (MgSO 4 ) , filtered and concentrated to afford 19 as a brown syrup .
  • Step C A solution of (4-acetoxy-2-methyl-phenoxy) -acetic acid ethyl ester 19 (from step B above) in dry MeOH (400 mL) is combined with a 0.5 M solution of NaOMe in MeOH (650 mL, 325 mmol) and stirred for 2 h at rt . The solution is neutralized with 1 M HCl and washed with H 2 O (2x500 mL) .
  • Step A Intermediate 20 (5 g, 26 mmol) is dissolved in DCM (100 mL) . Bromine (1.44 mL, 28 mmol) in DCM (20 mL) is added dropwise and stirred at rt for 2 h. The mixture is washed with aqueous saturated NaHCO 3 (2x100 mL) and brine (20 mL) , dried over MgSO 4 , filtered, and concentrated.
  • Step B ( (5-Brotno-4-hydroxy-2-methyl-phenoxy) -acetic acid methyl ester 21 (25.5 mmol) and TBDMSCl (4.23 g, 28.0 mmol) are dissolved in DCM (100 mL) . Triethylamine (5.4 mL, , 38.2 mmol) and DMAP (311 mg, 2.5 mmol) are added and the mixture is stirred at rt for 2 h.
  • Step C [5-Bromo-4- ( text-butyl-dimethyl-silanyloxy) -2-methyl- phenoxy] -acetic acid methyl ester 22 (2.75 g, 7.0 mmol), potassium phosphate (5.2 g, 24.5 mmol) and cyclopropylboronic acid (0.72 g, 8.4 mmol) are dissolved in toluene (80 mL) . Tricyclohexylphosphine (157 mg, 0.7 mmol), palladium acetate (98 mg, 0.35 mmol) and water (4 mL) are added and the mixture is heated to 100 0 C overnight.
  • Step D [4- ( tert-Butyl-dimethyl-silanyloxy) -5-cyclopropyl-2- methyl-phenoxy] -acetic acid methyl ester 23 (1.0 g, 3.1 mmol) is dissolved in a mixture of THF (30 mL) and TBAF (3.7 mL, 3.7 mmol) and stirred at rt for 90 min. 1 N HCl (40 mL) is added and the mixture is extracted with EtOAc (40 mL) . The organic layer is washed with 1 N HCl and brine, dried over MgSO 4 , filtered and concentrated. The residue is triturated with hexanes to afford (5-cyclopropyl ⁇ 4-hydroxy-2-methyl-phenoxy) - acetic acid methyl ester 24 as an off-white powder: 1 H-NMR
  • Step A 4- (Benzyloxy) phenol (5.0 g, 25 mmol) is dissolved in DMF (40 mL) . To the solution is added NaH (60% dispersion, 1.1 g, 27.5 mmol) in portions while it is kept at rt . After stirring the suspension for 30 min at rt methyl - ⁇ - bromoisobutyrate (9.05 g, 50 mmol) is added dropwise. The mixture is stirred at 50 0 C for 3 h, then concentrated. The remainder is diluted with water (200 mL) and extracted with EtOAc (3x150 mL) . The organic layer is separated and dried over MgSO 4 , filtered and concentrated.
  • Step B 2 - (4-Benzyloxy-phenoxy) -2-methyl-propionic acid methyl ester 27 (0.5 g, 1.7 mmol) is dissolved in EtOH (15 mL) . After addition of a catalytic amount of palladium (0) on charcoal the mixture is aubjected to 1 atm hydrogen and stirred for 5 h at rt .
  • Step A (4-Hydroxy-2-methyl-phenoxy) -acetic acid methyl ester 20 (3.0 g, 15.3 mmol) and 1, 2-dibromoethane (13.2 mL, 153 mmol) are dissolved in dry acetone (100 mL) . Cs 2 CO 3 (25 g, 76.5 mmol) is added and the mixture is heated at reflux for 16 h.
  • Step B [4- (2-Bromo-ethoxy) -2-methyl-phenoxy] -acetic acid methyl ester 29 (100 mg, 0.33 mmol), and NaCN (16 mg, 0.33 mmol) are dissolved in DMSO (3 mL) and stirred at rt for 6 h. The mixture is diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL) .
  • Step C [4- (2-Cyano-ethoxy) -2-methyl-phenoxy] -acetic acid methyl ester 30 (236 mg, 0.95 mmol) and thioacetamide (178 tng, 2.37 mmol) are dissolved in dimethylformamide (0.8 mL) .
  • HCl 0.9 mL of 4N in dioxane, 3.61 mmol is added and the mixture is heated at 100° C for 2 h. The mixture is cooled and poured into a saturated solution of NaHCO 3 (50 mL) and extracted with EtOAc (50 mL) .
  • Step A (4-Hydroxy-2-methyl-phenoxy) -acetic acid methyl ester 20 (500 mg, 2.55 mmol) and chloroacetonitrile (0.16 mL, 2.55 mmol) are dissolved in dry acetonitrile (10 mL) . Cesium carbonate (1.6 g, 5.1 mmol) is added and the mixture is stirred at rt for 16 h. The mixture is filtered and concentrated to afford (4-cyanomethoxy-2-methyl-phenoxy) - acetic acid methyl ester 39 as a colorless glass.
  • Step B (4-Cyanomethoxy-2-methyl-phenoxy) -acetic acid methyl ester 39 (5.85 g, 24.8 mmol) and thioacetamide (4.76 g, 63.3 mmol) are dissolved in dimethylformamide (15 mL) .
  • HCl 24 mL of 4N in dioxane, 95 mmol
  • the mixture is heated at 100 °C for 2 h.
  • the mixture is cooled and poured into a saturated solution of NaHCO 3 (20 mL) and extracted with EtOAc (50 mL) .
  • the organic layer is washed with water, then brine, dried (MgSO 4 ) , filtered and concentrated.
  • Step A (4-Hydroxy-2 -methyl-phenoxy) -acetic acid methyl ester 20 (5 g, 25.5 tn ⁇ iol) is dissolved in dichloromethane (100 mL) . Bromine (1.44 mL, 28.0 mmol) in dichloromethane (20 mL) is added and the mixture is stirred at rt for 3 h. Then the mixture is washed with water, saturated solutions of NaHCO 3 and sodium bisulfite, dried (MgSO 4 ) , filtered and concentrated.
  • Step B (5-Bromo-4-hydroxy-2-methyl-phenoxy) -acetic acid methyl ester 41 (3.0 g, 9.31 mmol) and chloroacefonitrile (0.62 mil, 9.78 mmol) are dissolved in dry acetonitrile (50 mL) . Cesium carbonate (6.07 g, IB.62 mmol) is added and the mixture is stirred at rt for 2 Ii. The mixture is filtered and concentrated to afford crude (5-br ⁇ mo-4-cyanomethoxy-2-methyl- phenoxy) -acetic acid methyl ester 42 which is used in the next step without further purification. MS calcd. for C 12 Hi 3 BrNO 4
  • Step C (5-Bromo-4-cyanomethoxy-2-methyl-phenoxy) -acetic acid methyl ester 42 (9.3 mmol) and thioacetamide (1.75 g, 23.2 mmol) are dissolved in dimethylformamide (7 mL) .
  • HCl (9 mL of 4N in dioxane, 35.3 mmol) is added and the mixture is heated at 100° C for 2 h.
  • the mixture is cooled and poured into a saturated solution of NaHCO 3 (20 mL) and extracted with EtOAc (20 mL) .
  • the organic layer is washed with water, then brine, dried (MgSO 4 ), filtered and concentrated.
  • Step A 4-Hydroxybenzaldehyde (7.03 g, 57.6 mmol) is dissolved in acetonitrile (60 mL) . Powdered potassium carbonate (11.98 g, 86.7 mmol) is added while stirring, followed by dropwise addition of the benzyl bromide (7 mL, 59 mmol) . The mixture is vigorously stirred under nitrogen for 3 h.
  • Step B 4-Benzyloxy-benzaldehyde 44 (1.24 g, 5.84 mmol) and ethyl ethoxyacetate (1.2 mL, 8.8 mmol) are dissolved in dry THF (30 mil) . Solid potassium teirt-but ⁇ xide (1.45 g, 12.9 mmol) is added and the mixture is stirred under nitrogen overnight. The resulting suspension is filtered through Celite 545. The solids are thoroughly washed with THF. The combined organic solutions are concentrated to yield 3- (4- benzyloxy-phenyl) -2-ethoxy-acrylic acid ethyl ester 45 as an oil.
  • Step C 3- (4-Benzyloxy-phenyl) -2-ethoxy-acrylic acid ethyl ester 45 (0.80 g, 2.45 mmol) is dissolved in ethanol (40 mL) .
  • the solution is degassed with nitrogen, then treated with a catalytic amount of 5% palladium black on carbon (0.28 g, 0.13 mmol) .
  • the solution is shaken under 60 psi hydrogen for 5 h.
  • Step A 4-Bromo-3-methyl-phenol (25.11 g, 134 mmol) is dissolved in acetonitrile (125 mL) . Powdered potassium carbonate (25.69 g, 186 mmol) is added while stirring, followed by dropwise addition of benzyl bromide (17 mL, 143 mmol) . The mixture is vigorously stirred under nitrogen for 6 h.
  • Step B 4-Benzyloxy-l-bromo-2-methyl-benzene 49 (24.0 g, 86.6 tntnol) , tri-o-tolyl-phosphane (15.00 g, 49.3 tnmol) , ethyl diisopropylamine (35 mL, 212 mmol) and methyl acrylate (35 mL, 388 tnmol) are dissolved in propionitrile (200 mL) . The mixture is degassed with argon. Solid palladium (II) acetate (4.00 g, 17.8 mmol) is added and the mixture is heated to 100°C for 18 h/ The mixture is cooled and filtered through a plug of Celite 545.
  • II Solid palladium
  • Step C 3- (4-Benzyloxy-2-methyl-phenyl) -acrylic acid ethyl ester 50 from Step B above is dissolved in ethyl acetate (200 mL) and ethanol (20 mL) . The solution is degassed with nitrogen, then treated with 5% palladium black on carbon (1.15 g, 1.08 mmol, 1 mol%) . The solution is shaken under 40 psi hydrogen for 15 h.
  • Step B 4-Benzyloxy-bromobenzene 52 (1.30 g, 5.2 mmol), tri- o-tolyl-phosphane (0.98 g, 3.2 mmol), ethyl diisopropylamine (2 mL, 12.1 mmol) and methyl methacrylate (2.20 mL, 20.7 mmol) are dissolved in propionitrile (100 mL) .
  • the mixture is degassed with argon.
  • Solid palladium(II) acetate (0.26 g, 1.2 mmol) is added and the mixture is heated to 100 0 C for 18 h. The mixture is cooled and filtered through a plug of Celite 545.
  • Step C The 1:1 olefin mixture 53 from Step B above is dissolved in ethyl acetate (50 mL) and ethanol (10 mL) . The solution is degassed with nitrogen, then treated with a catalytic amount of 5% palladium black on carbon (0.50 g, 7 ⁇ nol%) . The .solution is shaken under 60 psi hydrogen for 15 h.
  • Step A 3- (3 -Hydroxy-phenyl) -propionic acid (24.88 g, 149.7 mmol) is dissolved in methanol (50 mL) . Thionyl chloride (5 ⁇ L, 68.7 mmol) is added dropwise with vigorous stirring. The mixture is stirred at 60 0 C for 3 h. Cooling and concentration yielded 3- (3 -hydroxy-phenyl) -propionic acid methyl ester 56
  • Step B 3- (3 -Hydroxy-phenyl) -propionic acid methyl ester 56 (3.16 g, 17.5 mmol) is dissolved in DCM (40 mL) . Powdered calcium carbonate (2.27 g, 22.7 mmol) is added. While the suspension is vigorously stirred, a solution of bromine (0.90 mL, 17.6 mmol) in DCM (30 mL) is added dropwise. After the addition is completed, the suspension is treated with 0.2 g sodium bisulfite in ' water (5 mL) .
  • Step C 3- (2-Bromo-5-hydroxy-phenyl) -propionic acid methyl ester 57 (4.45 g, 17.2 mmol) is dissolved in DCM (80 mL) . Imidazole (1.45 g, 21.3 mmol) is added and the mixture is stirred at rt until it became homogenous. te_rt-Butyl dimethylchlorosilane (2.66 g, 17.7 mmol) is added and the mixture is stirred at rt for 18 h.
  • Step D 3- [2-Bro ⁇ no-5- ( tert-butyl-dimethyl-silanyloxy) - phenyl] -propionic acid methyl ester 58 (5.74 g, 15.4 mmol) is dissolved in toluene (165 mL) . Cy ⁇ lopropylboroni ⁇ acid (2.22 g, 25.8 mmol), potassium phosphate (11.71 g, 55.2 mtnol) , and tricyclohexyl-phosphane (1.81 g, 6.5 mmol) are added, followed by water (10 mL) .
  • Step E 3- [5- ( tert-Butyl-dimethyl-silanyloxy) -2-cyclopropyl- phenyl] -propionic acid methyl ester 59 (2.87 g, 8.6 mmol) is dissolved in THF (30 mL) . A I M solution of tetra- ( ⁇ - butyl) ammonium fluoride in THF (10 mL, 10 mmol) is added. The mixture is stirred at rt for 4 h.
  • Step A 3- (4-Hydroxy-2-methyl -phenyl) -propionic acid methyl ester 51 (2.50 g, 12.9 tnmol) is dissolved in DCM (60 mL) and cooled to 0 0 C. Powdered calcium carbonate (2.27 g, 22.7 mmol) is added. While the suspension is vigorously stirred, a solution of bromine (0.90 mL, 17.6 mmol) in DCM (20 mL) is added dropwise.
  • the suspension is warmed up to rt and treated with 0.2 g sodium bisulfite and 5 mL water, followed by drying over MgSO 4 , filtration and concentration to yield 3- (5-bromo-4-hydroxy-2- methyl-phenyl) -propionic acid methyl ester 61 (3.67 g, quant.) as a colourless oil that slowly solidified.
  • Step B 3- (5-Bromo-4 -hydroxy-2-methyl-phenyl) -propionic acid methyl ester 61 (from Step A above) is dissolved in DCM (45 mL) ., Imidazole (1.12 g, 16.5 mmol) is added and the mixture is stirred at rt until it became homogenous. tert-Butyl dimethylchlorosilane (2.10 g, 13.9 mmol) is added and the mixture is stirred at rt for 18 h.
  • Step C 3- [5-Brom ⁇ -4- ( fcerfc-butyl-dimethyl-silanyloxy) -2- methyl-phenyl] -propionic acid methyl ester 62 (4.67 g, 12.1 mmol) is dissolved in toluene (70 mL) . Cyclopropylboronic acid (1.95 g, 22.7 mmol), potassium phosphate (9.15 g, 43.1 mmol) , and tricyclohexyl-phosphane (1.44 g, 5.13 mmol) are added, followed by water (10 mL) . The mixture is degassed with argon.
  • Step D 3- [4- ( te-rt-Butyl-dimethyl-silanyloxy) -5-cyclopropyl- 2-methyl-phenyl] -propionic acid methyl ester 63 (4.23 g, 12.1 mmol) is dissolved in THF (60 mL) .
  • Step A N-Bromosuccinimide (7.5G g, 42.5 mmol) is suspended in DCM (50 mL) . tert-Butylamine (5 mL, 47.5 mmol) is added in one portion. After 45 min, the white precipitate is filtered off and the clear filtrate is used as such.
  • Step B 3- (2-Bromo-3-hydroxy-phenyl) -propionic acid methyl ester 65 (0.86 g, 3.32 mmol) is dissolved in DCM (15 mL) .
  • Step C 3- [2-Bromo-3- ( tert-butyl-dimethyl-silanyloxy) - phenyl] -propionic acid methyl ester 67 (1.18 g, 3.16 mmol) is dissolved in toluene (25 mL) . Cyclopropylboronic acid (0.55 g, 6.4 mmol), potassium phosphate (2.60 g, 12.2 mmol), and tricyclohexyl-phosphane (0.38 g, 1.36 mmol) are added, followed by water (5 mL) . The mixture is degassed with argon.
  • Step D 3- [3- ( tejrfc-Butyl-dimethyl-silanyloxy) -2-cyclopropyl- phenyl] -propionic acid methyl ester 68 (0.72 g, 2.2 mmol) is dissolved in THF (3 mL) . A I M solution of tetra- ⁇ n ⁇ butyl) ammonium fluoride in THF (4 mL, 4 mmol) is added and the mixture is stirred at rt for 18 h.
  • Step A 4-Benzyloxy-phenol (32.04 g, 160 mmol) is dissolved in of DCM (550 tnL) and methanol (20 mL) . Powdered calcium carbonate (21.83 g, 218 mmol) is suspended into the solution. While stirring vigorously, a solution of bromine (8.30 mL, 162 mmol) in DCM (50 mL) is added dropwise. After the addition is completed, the suspension is stirred at rt for 30 min, then the solids are' filtered off. The filtrate is dried over solid NaHCO 3 and MgSO 4 , then filtered and concentrated to yield an oil.
  • Step B 4-Benzyloxy-2-bromo-phenol 71 (43.6 g, 156 mmol) is dissolved in DCM (400 mL) . Imidazole (14.9 g, 219 mmol) is added and the mixture is stirred at rt until homogenous. text-Butyl dimethylchlorosilane (23.6 g, 156.6 mmol) is added and the mixture is stirred at rt for 18 h.
  • Step C (4-Benzyloxy-2-bromo-phenoxy) - tert-butyl-dimethyl-
  • Step D (4-Benzyloxy-2-methyl-phenoxy) - tert-butyl-dimethyl- silane 73 (5.03 g, 15.3 mmol) is dissolved in THF (30 mL) . A 1 M solution of tetra- (z ⁇ -butyl) ammonium fluoride in THP (18 mL, 18 mmol) is added. Then the mixture is stirred at rt for 4 h.
  • Step E 4-Benzyloxy-2-methyl-phenol 74 (3.06 g, 14.3 mmol) is dissolved in acetonitrile (60 mL) . Powdered cesium carbonate (8.71 g, 26.7 mmol) is added to the vigorously stirred solution. 2-Bromo-2-methyl-propionic acid methyl ester (2.20 mL, 17.0 mmol) is added and the mixture is stirred at 60 0 C for 6 h.
  • Step F 2- (4-Benzyloxy-2-methyl-phenoxy) -2-methyl-propionic
  • Step B 2 , 5-Dimethylhydroquinone 79 (3.73 g, 27 ⁇ ntnol) is dissolved in dimethylformamide (20 mL) and acetonitrile (60 iriL) . Powdered cesium carbonate (9.16 g, 28.1 g) is added to the vigorously stirred solution, followed by 2 -bromo-2-methyl- propionic acid methyl ester (3.50 mL>, 27.0 tnmol) . The mixture is stirred at 75 0 C for 18 h.
  • Step A 2, 5-Dimethylphenol (10.04 g, 82.2 mmol) is dissolved in methanol (40 tnL) .
  • Sodium thiocyanate (15.87 g, 195.8 mmol) and sodium bromide (7.37 g, 71.6 mmol) are added and the mixture is stirred at 0 0 C.
  • Bromine (4.50 tnL, 87.6 mmol) dissolved in methanol (40 mL) is added dropwise while stirring vigorously. Upon the completion of the addition, the mixture is stirred at 50 0 C for 1 h. The mixture is cooled and concentrated. The residue is taken up in ethyl acetate and filtered.
  • Step B 2,5-Dimethyl-4-thiocyanato-phenol 82 (5.75 g, 32.1 mmol) is dissolved in acetonitrile (25 mL) . Powdered cesium carbonate (15.32 g, 47.0 mmol) is added. Then 2-bromo-2- methyl-propionic acid methyl ester (4.50 mL, 34.8 mmol) is added and the mixture is stirred at 60 0 C for 18 h.
  • Step C 2- (2, 5-dimethyl-4-thiocyanato-phenoxy) -2-methyl- propionic acid methyl ester 83 (3.88 g, 13.9 mmol) is dissolved in methanol (50 mL) . Potassium dihydrogenphosphate (0.23 g, 1.69 mmol), water (6 mL) , and dithiothreitol (2.80 g, 18.2 mmol) are added and the mixture is stirred at reflux for 3 h. After cooling and concentration, the residue is taken up in ethyl acetate, washed with water and brine, dried over Na 2 SO 4 and concentrated to yield an oil.
  • Step A 2 , 5-Ditnethyl-4-thiocyanato-phenol 82 (1.50 g, 8.4 mmol) is dissolved in methanol (30 mL) . Potassium dihydrogenphosphate (0.32 g, 2.35 mmol), water (4 mL) , and dithiothreitol (2.17 g, 14.1 mmol) are added and the mixture is stirred at reflux for 3 h. After cooling and concentration, the residue is taken up in ethyl acetate, washed with water and brine, dried over Na 2 SO 4 and concentrated to yield an oil.
  • Step B 4-Mercapto ⁇ 2,5-dimethyl-phenol 88 (0.44 g,- 2.85 mmol) is dissolved in acetonitrile (5 mL) . Powdered cesium carbonate (1.55 g, 4.8 mmol) is added. Then 2-bromo-2-methyl- propionic acid methyl ester (0.350 mL, 2.7 mmol) is added and the mixture is stirred at 25 0 C for 3 h.
  • Step A 4-Methoxy-2, 5-dimethyl-benzaldehyde (1.24 g, 7.55 mmol) is dissolved in dry dichloromethane (12 mL) .
  • neat boron tribromide (1.75 g, 18.5 mmol) is added dropwise, with stirring. A tan-coloured precipitate started to form.
  • the suspension is stirred at room temperature for 5 d.
  • the homogenous mixture is poured over 150 g ice. After the ice melted, the solid phenol 90 is isolated by filtration and dried (1.28 g, quantitative) .
  • Step B 4-Hydroxy-2, 5-dimethyl-benzaldehyde 90 (30.56 g, , 0.2 mol) is dissolved in acetonitrile (150 mL) . Benzyl bromide (24 mL, 0.2 mol) is added, followed by powdered potassium carbonate (36.92 g, 0.27 mol). The mixture is stirred at 60 0 C for 18h. Cooling and concentration, followed by silica gel chromatography (0-20% ethyl acetate in hexanes) yielded 4- benzyloxy-2, 5-dimethyl-benzaldehyde 91 as a colorless oil.
  • Step C 4-Benzyloxy-2, 5-dimethyl -benzaldehyde 91 (4.77 g, , 20 tnmol) is dissolved in diethyl ether (30 mL) .
  • Sodium borohydride (1.0 g, 27 mmol) is added in one portion, followed by 5 mL absolute ethanol .
  • the mixture is vigorously stirred for 3h at room temperature, then carefully poured over 100 mL IN aqueous HCl. Extraction with ethyl acetate, washing with water and brine, then concentration yielded (4-benzyloxy-2, 5- dimethyl-phenyl) -methanol 92 as a soft solid.
  • Step D (4-Benzyloxy-2 , 5-dimethyl-phenyl) -methanol 92 (4.79 g, 19.7 mmol) and ethyl diisopropylatnine (6.0 mL, 34.4 mmol) are dissolved in dichloromethane (80 mL) .
  • Step E Acetic acid 4-benzyloxy-2, 5-dimethyl-benzyl ester 93 (0.56 g, 2 raraol) is dissolved in dry dichloromethane (5 mL) .
  • (1-Methoxy-2-methyl-propenyloxy) -trimethylsilane (1 mL, 5 mraol) and magnesium perchlorate (0.09 g, 0.4 mraol) are added and the suspension is stirred overnight.
  • Step P 3- (4-Benzyloxy-2, 5-dimethyl-phenyl) -2, 2-dimethyl- propionic acid methyl ester 94 (0.45 g, 1.4 mmol) is dissolved in ethanol (20 mL) . Palladium black on carbon (5%; 0.16 g, 5 mol%) is added and the mixture is vigorously stirred under 1 atm. hydrogen for 18h. Filtration and concentration yielded 3- (4-hydroxy-2, 5-dimethyl-phenyl) -2, 2-dimethyl-propionic acid methyl ester 95 as an oil (0.11 g, 34%) .
  • Intormediat ⁇ 97 2- [4- (2-Bromo-ethoxy) -2, 5-dimethyl-phenoxy] - 2-methyl-propionic acid methyl ester.
  • Step C Intermediate 80 (0.25 g, 1.05 mmol) , 1, 2-dibromoethane (0.90 mL, 10.5 tnraol) and Cs 2 CO 3 (1.7 g, 5.25 mmol) are suspended in dry acetonitrile (7 mL) . The mixture is heated to 80 0 C overnight. The reaction mixture is cooled to room temperature, filtered and the solvent is removed in vacuo.
  • Step A Benzoyloxyacetonitrile (10 g, 62 mmol) and thioacetamide (11.6 g, 155 mmol are dissolved in DMF (40 mL) .
  • Step B Benzoic acid thiocarbamoylmethyl ester 100 (2.8 g, 14.3 mmol) and l-biphenyl-4-yl-2-bromo-ethanone (3.9 g, 14.3 mmol) are dissolved in MeOH (20 mL) and heated at reflux for 16 Ir. Concentrated H 2 SO 4 (2 mL) is added and the reflux continued for 24 h. The mixture is cooled and poured into water (100 mL) and extracted with EtOAc (2 x 80 mL) . The organic layers are combined and washed with water (100 mL) , sat.
  • Step C (4-Biphenyl-4-yl-thiazol-2-yl) -methanol 101 (860 mg, 3.22 mmol) is dissolved in dry THF (20 mL) , then thionyl chloride (0.47 mL, 6.43 mmol) is added and the mixture is stirred at rt for 2 h. The mixture is poured into a saturated solution of NaHCO 3 (20 mL) and extracted with EtOAc (20 mL) . The organic layer is washed with brine, dried (MgSO 4 ) , filtered and evaporated to give 4-Biphenyl-4-yl-2- chloromethyl-thiazole 102 (0.50 g, 55%) as a beige powder.
  • Step C 4-hydroxy-thiobutyramide 104 (7.0 g, 59 mmol) and 2 ⁇ bromo-1- (4-trifluoromethyl-phenyl) -ethanone (15.7 g, 59 mmol) are dissolved in EtOH (50 mL) and heated to 80 "C for 5 h. The mixture is concentrated and purified by flash chromatography (EtOAc/Hexanes gradient) to afford 3- [4- (4-trifluoromethyl- phenyl) -thiazol-2-yl] -propan-1-ol 105 as a colorless solid: MS calcd. for Ci 3 Hi 3 F 3 NOS (M+H + ) 288.1, found 288.1.
  • Step D 3- [4- (4-Trifluoromethyl-phenyl) -thiazol-2-yl] -propan- 1-ol 105 (2.5 g, 8.7 mmol) and ethyldiisopropylamine (3.5 mL, 21.2 mmol) are dissolved in dichloromethane (35 mL) .
  • Mesyl chloride (0.85 mL, 11.0 mmol) are added dropwise and the mixture is stirred at rfe overnight. Then the mixture is diluted with DCM and washed with H 2 O and brine. The organic layer is dried (MgSO 4 ) , filtered and concentrated to afford the mesylate 106 as a light-brown oil: MS calcd. for Ci 4 H 15 F 3 NO 3 S 2 (M+H + ) 366.0, found 366.1.
  • Step A 3-Cyano-propionic acid methyl ester (3.0 g, 2.7 mmol) is dissolved in methanol (6 mL) and stirred in an ice-bath. Concentrated sulfuric acid (12 mL) is added slowly, then the ice-bath is removed and the mixture is stirred overnight at rt .
  • Step B Succinamic acid methyl ester 107 (0.7 g, 5.3 mmol) and 2-bromo-l- (4-trifluoromethyl-phenyl) -ethanone (0.71 g, 2.7 mmol) are stirred neat at 80 "C for 4 h. Then the mixture is dissolved in EtOAc and washed with H 2 O and brine. The organic layer is dried (MgSO 4 ), filtered and concentrated.
  • Step C The 3- [4- (4-trifluoromethyl-phenyl) -oxazol-2-yl] - propionic acid methyl ester 108 (0.26 g, 0.87 mmol) is placed in a flame-dried flask, dissolved in THF/DCM 1:1 (5 mL) and flushed with. argon. After cooling to O 0 C, lithium aluminiumtetrahydride (0.87 mL IM in THF, 0.87 mmol) is added dropwise over a period of 45 min. Sodium sulfate decahydrate (0.28 g, 0.87 mmol ⁇ is added slowly in portions, the ice-bath is removed and the mixture is stirred at rt for 20 min.
  • Step A Malonamic acid methyl ester (22.0 g, 187 mmol) and 2- Bromo-l- (4-trifluoromethyl-phenyl) -ethanone (10 g, 37.4 mmol) are heated to 130 "C with stirring for 2 h. Water (30 mL) is added and the product is extracted with EtOAc (2 x 40 mL) .
  • Step B [4- (4-Trifluoromethyl-phenyl) -oxazol-2-yl] -acetic acid methyl ester 110 (1.8 g, 6.31 mmol) is dissolved in dry THF (40 mL) . Sodium borohydride (377 mg, 10.1 mmol) is added and the mixture is heated at reflux for 16 h. The reaction is poured into 1 N HCl (20 mL) and extracted with EtOAc (2 x 50 mL) .
  • Step B 2, 2-Dimethyl-malonamic acid ethyl ester 113 (3.0 g, 11.4 mmol) and 2-bromo-l- (4-trifluoromethyl-phenyl) -ethanone (2.7 g, 17.1 mmol) are heated to 130°C with vigorous stirring for 2 h. Then water (30 mL) is added and the product is extracted with EtOAc (2 x 40 mL) .
  • Step C 2-Methyl-2- [4- (4-trifluoromethyl-phenyl) -oxazol-2-yl] - propionic acid ethyl ester 114 (2.6 g, 7.94 mmol) is dissolved in dry THF (40 mL) . Sodium, borohydride (1.5 g, 40.2 mmol)- is added and the mixture is heated at reflux for 64 h. The reaction is poured into 1 N HCl (20 mL) and extracted with EtOAc (2 x 50 mL) .
  • Step A Cyano-acetic acid benzyl ester (2 g, 11.4 mrnol) and thioacetamide (2.14 g, 28.5 mmol are dissolved in DMF (7 mL) .
  • HCl (10.8 mL of 4N in dioxane, 43.3 mmol) is added and the mixture is heated at 100 "C for 2 h.
  • the mixture is cooled, poured into water (30 mL) and extracted with EtOAc (50 mL) .
  • the organic layer is washed with water (20 mL) , sat.
  • Step B Thiocarbamoyl-acetic acid benzyl ester 116 (0.8 g, 3.8 mmol) and 2-Bromo-l- (4-trifluoromethyl-phenyl) -ethanone (1.0 g, 3.81 mmol) are dissolved in EtOH (20 mL) and heated at reflux for 2 h. The mixture is cooled and filtered to afford [4- (4-Trifluoromethyl-phenyl) -thiazol-2-yl] -acetic acid ethyl ester 117. MS calcd. for Ci 4 Hi 3 F 3 NO 2 S (M+H + ) 316.1, found 316.0.
  • Step C [4- (4-Trifluoromethyl-phenyl) -thiazol-2-yl) -acetic acid ethyl ester 117 (397 mg, 1.26 mmol) is dissolved in dry THF (10 mL) , then LiAlH 4 (1.26 mL of 1 M in THF, 1.26 mmol) is added and the mixture is stirred at rt for 1 h. The reaction is quenched by slow addition of water (5 mL) and extracted with EtOAc (20 mL) .
  • Example Al (5-Cyclopropyl-2-methyl-4- ⁇ 3- [4- (4- trifluoromethyl-phenyl) -thiazol-2-yl] -propoxy ⁇ -phenoxy) -acetic acid.
  • Step A Intermediate 105 (25 mg, 0.09 mraol) , intermediate 24 (26 mg, 0.11 mmol) and triphenylphosphine (35 mg, 0.14 mmol) are dissolved in dry DCM (1 mL) and cooled to 0 0 C. After the slow addition of diethyl azodicarboxylate (29 ⁇ L, 0.18 mmol) the solution is stirred at room temperature overnight. The solvent is removed to afford crude (5-cy ⁇ lopropyl-2-methyl-4- ⁇ 3- [4- (4-trifluoromethyl-phenyl) -thiazol-2-yl] -propoxy ⁇ - phenoxy) -acetic acid methyl ester which is used without further purification in step B.
  • Step B The crude (5-cyclopropyl-2-methyl-4- ⁇ 3- [4- (4- trifluoromethyl-phenyl) -thiazol-2-yl] -propoxy ⁇ -phenoxy) -acetic acid methyl ester is dissolved in THF (1.8 tnL) , a solution of 1 M LiOH in H 2 O (0.6 mL) is added and the mixture is stirred overnight at room temperature. The mixture is acidified with 1 M HCl (0.7 mL) , DCM (10 mL) is added and the organic layer washed with H 2 O (3x5 mL) .
  • Example Bl 2- (2 , 3-Dimethyl-4- ⁇ 3- [4- (4-trifluoromethyl- phenyl) -thiazol-2-yl] -propoxy ⁇ -phenoxy) -2-methyl-propionic acid.
  • Step A Methanesulfonic acid 3- [4- (4-trifluoromethyl-phenyl) - thiazol-2-yl] -propyl ester 106 (37 mg, 0.10 mmol) and 2-(4- hydroxy-2 , 3 -dimethyl-phenoxy) -2-methyl-propionic acid methyl ester 78 (23.8 mg, 0.10 mmol) are dissolved in dry acetonitrile (2 mL) . Powdered cesium carbonate (50 mg, 0.16 mmol) is added and the solution is vigorously stirred at 55°C for 6 h.
  • Step B The crude 2- (2 , 3-dimethyl-4- ⁇ 3- [4- (4-trifluoromethyl- phenyl) -thiazol-2-yl] -propoxy ⁇ -phenoxy) -2-methyl-propionic acid methyl ester is dissolved in dioxane (1.5 mL) . Lithium hydroxide monohydrate (0.10 g, excess) and water (0.5 mL) are added. The mixture is stirred at 60 0 C for 2 h. Cooling to room temperature, concentration, acidification with 1 N HCl, and purification on reversed-phase HPLC (H 2 O/MeCN gradient) afforded the title compound Bl as a colorless oil: 1 H-NMR
  • Example Cl (2-Methyl-4- ⁇ 2- [4- (4-trifluoromethyl-phenyl) - thiazol-2-yl] -ethoxy ⁇ -phenoxy) -acetic acid.
  • Step A [2-Methyl-4 ⁇ (2-thio . carbamoyl-ethoxy) -phenoxy] -acetic acid methyl ester 31 (22 tng, 0.08 mmol) and 2-bromo-1- (4- trifluoromethyl-phenyl) -ethanone (20 tng, 0.075 mmol) are dissolved in MeOH (1 mL) and heated at 160° C by subjection to microwave irradiation in a sealed tube for 10 minutes to afford crude (2-methyl-4- ⁇ 2- [4- (4-trifluoromethyl-phenyl) - thiazol-2-yl] -ethoxy ⁇ -phenoxy) -acetic acid methyl ester which is used without further purification in step B.
  • Step B To the crude (2-methyl-4- ⁇ 2- [4- (4-trifluoromethyl- phenyl) -thiazol-2 -yl] -ethoxy ⁇ -phenoxy) -acetic acid methyl ester in MeOH is added THP (2 mL) and 1 N LiOH (1 mL) . The mixture is stirred at rt for 16 h, then acidified with 1 N HCl and extracted with EtOAc (10 mL) .
  • Example Dl ⁇ 4 ' -Methoxy-4-methyl-6- [4- (4-trifluoromethyl- phenyl) -thiazol-2-ylmethoxy] -biphenyl-3-yloxy ⁇ -acetic acid.
  • Step A ⁇ 2-Methyl-4-thiocarbamoylmethoxy-phenoxy) -acetic acid methyl ester 40 (315 mg, 1.17 mmol) and 2-brotno-l- (4- trifluoromethyl-phenyl) -ethanone (298 mg, 1.11 mmol) are dissolved in EtOH (5 mL) and heated at reflux for 2 h.
  • Step B ⁇ 2-Methyl-4- [4- (4-trifluoromethyl-phenyl) -thiazol-2- ylmethoxy] -phenoxy ⁇ -acetic acid ethyl ester (220 mg, 0.48 ⁇ vmol) is dissolved in dichloromethane (3 mL) . Bromine (62 ⁇ L, 1.2 inmol) is predissolved in AcOH (0.2 mL) , then is added to the solution. The mixture is stirred at rt for 3 h, then is poured into water (10 mL) and extracted with dichloromethane (10 mL) .
  • Step C ⁇ 5-Bromo-2-methyl-4- [4- (4-trifluoromethyl-phenyl) - thiazol-2-ylmethoxy] -phenoxy ⁇ -acetic acid ethyl ester (20 mg, 0.04 mmol) , 4 -methoxyphenylboronic acid (7.2 mg, 0.05 mmol) and sodium carbonate (13 mg, 0.12 mmol) are dissolved in a mixture of water (120 ⁇ L) , ethanol (90 ⁇ L) and 1,2- dimethoxyethane (360 ⁇ L) . The mixture is degassed with Argon for 2 minutes.
  • Step D To the solution of ⁇ 4- [4- ⁇ 4-tnethoxy-phenyl) -5- (4- trifluoromethoxy-phenyl) -thiazol-2-ylmethoxy] -2-methyl- phenoxy ⁇ -acetic acid methyl ester from Step C is added THF (1 mL) and a solution of 1 M LiOH in H 2 O (0.2 mL) . The mixture is stirred for 1 h at rt, then it is acidified with 1 M HCl (0.3 mL) . EtOAc (20 mL) is added and the organic layer is washed with brine (10 mL) .
  • Example El ⁇ 4 ' -Methoxy- ⁇ -methyl- ⁇ - [4- (4-nitro-phenyl) - thiazol-2-ylmethoxy] -biphenyl-3-yloxy ⁇ -acetic acid.
  • Step A (5-Bromo-2-methyl-4-thiocarbamoylmethoxy-phenoxy) - acetic acid methyl ester 43 (50 tng, 0.14 tnmol) and 2-bromo-l- (4-nitro-phenyl) -ethanone (40 mg, 0.17 mraol) are dissolved in EtOH (1 mL) and heated at reflux for 2 h.
  • Step B ⁇ 5-Bromo-2-methyl-4- [4- (4-nitro-phenyl) -thiazol-2- ylmethoxy] -phenoxy ⁇ -acetic acid ethyl ester (26 mg, 0.053 mmol) , 4-methoxyphenylboronic acid (8 mg, 0.053 mmol) and sodium carbonate (17 mg, 0.16 mmol) are dissolved in a mixture of water (120 ⁇ L) , ethanol (90 ⁇ L) and 1, 2-dimethoxyethane (360 ⁇ L) . The mixture is degassed with Argon for 2 minutes.
  • Step C To the solution of ⁇ 4 ' -methoxy-4-methyl-6- [4- (4-nitro- phenyl) -thiazol-2-ylmethoxy] -biphenyl-3-yloxy ⁇ -acetic acid ethyl ester from Step A is added THF (1 mL) and a solution of 1 M LiOH in H 2 O (0.2 mL) . The mixture is stirred for 1 h at rt. Then it is acidified with 1 M HCl (0.25 mL) , EtOAc (10 mL) is added and the organic layer is washed with brine.
  • Example Pl ⁇ 5-Cyclopropyl-2-methyl-4- [4- (4-trifluoromethyl- phenyl) -thiazol-2-ylmethoxy] -phenoxy ⁇ -acetic acid.
  • Step A Copper powder (19 mg, 0.29 mmol) is slurried in toluene (4 mL) . Iodine (0.8 mg, 0.0032 mmol) is added and stirred at rt until the brown color disappeared ( ⁇ 10 min) . Diiodomethane (10.4 ⁇ L, 0.129 mmol) and ⁇ 2-methyl-4- [4- (4- trifluoromethyl-phenyl) -thiazol-2-ylmethoxy] -5-vinyl-phenoxy ⁇ - acetic acid methyl ester (30 mg, 0.06 mmol, see example D4) are added and the mixture is heated at reflux for 3 h.
  • Step B ⁇ 5-Cy ⁇ lopropyl-2-methyl-4- [4- (4-trifluoromethyl- phenyl) -thiazol-2-ylmethoxy] -phenoxy ⁇ -acetic acid methyl ester is dissolved in THP (1 mL) and a solution of 1 M LiOH in H 2 O (0.2 mL) is added. The mixture is stirred for 1 h at rt . Then it is acidified with 1 M HCl (0.25 mL) , EtOAc (10 mL) is added and the organic layer is washed with brine.
  • Example Gl ⁇ 5-Ethyl-2-methyl-4- [4- (4-trifluoromethyl- phenyl) -thiazol-2-ylmethoxy] -phenoxy ⁇ -acetic acid.
  • Step A ⁇ 2-Methyl-4- [4- (4-trifluoromethyl-phenyl) -thiazol-2- ylmethoxy] -5-vinyl-phenoxy ⁇ -acetic acid methyl ester (40 mg, 0.09 mmol) and 1, 4-cyclohexadiene (40 ⁇ L, 0.43 mmol) are dissolved in dry MeOH (5 mL) . Palladium on charcoal (10 mg) is added and the mixture is stirred at rt for 16 h.
  • Step B ⁇ 5-Ethyl -2-methyl-4- [4- (4-trifluoromethyl-phenyl) - thiazol-2-ylmethoxy] -phenoxy ⁇ -acetic acid methyl ester is dissolved in THF (1 mL) and a solution of 1 M LiOH in H 2 O (0.2 mL) is added. The mixture is stirred for 1 h at rt . Then it is acidified with 1 M HCl (0.25 mL) , EtOAc (10 mL) is added and the organic layer is washed with brine .
  • Example Hl [4- (4-Biphenyl-4-yl-thiazol-2-ylmethoxy) -5- cyclopropyl-2-methyl-phenoxy] -acetic acid.
  • Step A (5-Cyclopropyl-4-hydroxy-2-methyl-phenoxy) -acetic acid methyl ester 24 (40 mg, 0.17 mmol) and 4-Biphenyl-4-yl-2- chloromethyl-thiazole 102 (48 mg, 0.17 mmol) are dissolved in dry acetonitrile ⁇ 5 mL) .
  • Cs 2 CO 3 110 mg, 0.34 mmol is added and the mixture is heated at reflux for 1 h to afford [4- (4- biphenyl-4-yl-thiazol-2-ylmethoxy) -5-cyclopropyl-2-methyl- phenoxy] -acetic acid methyl ester, which is used in Step B without further purification.
  • Step B To the solution of [4- (4-Biphenyl-4-yl-thiazol-2- ylmethoxy) -5-cyclopropyl-2-methyl-phenoxy] -acetic acid methyl ester from Step A is added THF (1 ml.) and a solution of 1 M LiOH in H 2 O (0.2 mL) . The mixture is stirred for 1 h at rt. Then it is acidified with 1 M HCl (0.25 mL) , EtOAc (10 mL) is added and the organic layer is washed with brine .
  • Example II 2- (2 , 5-Dimethyl-4- ⁇ 2- [4- (4-trifluoromethyl- phenyl) -thiazol-2-ylsulfanyl] -ethoxy ⁇ -phenoxy) -2-methyl- propionic acid.
  • Step A The mercaptothiazole 119 (0.65 g, 2.49 mmol) , the bromide 97 (0.55 g, 1.66 mmol) and K 2 CO 3 (0.28 g, 1.99 mmol) are suspended in dry acetonitrile (15 tnL) in a sealed tube. The mixture is stirred vigorously and heated to reflux overnight. Then the reaction mixture is cooled to room temperature, filtered and the solvent is removed in vacuo. The remainder is dissolved in EtOAc and washed with water twice, the organic layer is dried (MgSO 4 ) and concentrated.
  • Step B THF (3 mL) and 1 N LiOH (1 mL) are added to the solution derived from step A. The mixture is stirred at 50 0 C for 5 h, then acidified with 1 N HCl (-1.5 mL) . The reaction mixture is extracted with DCM (3 mL) , the organic layer is separated and concentrated in vacuo.
  • Transfection assays are used to assess the ability of compounds of the invention to modulate the transcriptional activity of the PPARs. Briefly, expression vectors for chimeric proteins containing the DNA binding domain of yeast GAL4 fused to the ligand-binding domain (LBD) of either PPAR ⁇ , PPAR ⁇ or PPAR ⁇ are introduced via transient transfection into mammalian cells, together with a reporter plasmid where the luciferase gene is under the control of a GAL4 binding site. Upon exposure to a PPAR modulator, PPAR transcriptional activity varies, and this can be monitored by changes in luciferase levels. If transfected cells are exposed to a PPAR agonist, PPAR-dependent transcriptional activity increases and luciferase levels rise.
  • LBD ligand-binding domain
  • Penicillin/Streptomycin/Fungizome DMEM Media.
  • the cells are harvested by washing with PBS (30ml) and then dissociating using trypsin (0.05%; 3ml).
  • the trypsin is inactivated by the addition of assay media (DMEM, CA-dextran fetal bovine serum (5%).
  • DMEM assay media
  • the cells are spun down and resuspended to 170,000cells/ml.
  • a Transfection mixture of GAL4-PPAR LBD expression plasmid (l ⁇ g), UAS-luciferase reporter plasmid (l ⁇ g), Fugene (3:1 ratio; 6 ⁇ L) and serum -free media (200 ⁇ L) was prepared and incubated for 15- 40 minutes at room temperature.
  • Transfection mixtures are added to the cells to give 0;16M cells/mL, and cells (50 ⁇ l/well) are then plated into 384 white, solid-bottom, TC-treated plates. The cells are further incubated at 37 0 C, 5.0% CO 2 for 5-7 hours. A 12-point series of dilutions (3 fold serial dilutions) are prepared for each test compound in DMSO with a starting compound concentration of lO ⁇ M. Test compound (500nl) is added to each well of cells in the assay plate and the cells are incubated at 37 0 C 5 5.0% CO 2 for 18-24 hours. The cell lysis/luciferase assay buffer, Bright-GloTM (25%; 25 ⁇ l; Promega), is added to each well. After a further incubation for 5 minutes at room temperature, the luciferase activity is measured.
  • Raw luminescence values are normalized by dividing them by the value of the DMSO control present on each plate. Normalized data is analyzed and dose-response curves are fitted using Prizm graph fitting program. EC50 is defined as the concentration at which the compound elicits a response that is halfway between the maximum and minimum values. Relative efficacy (or percent efficacy) is calculated by comparison of the response elicited by the compound with the maximum value obtained for a reference PPAR modulator.
  • Compounds of Formula I in free form or in pharmaceutically acceptable salt form, exhibit valuable pharmacological properties, for example, as indicated by the in vitro tests described in this application.
  • Compounds of the invention preferably have an EC50 for PPAR ⁇ and/or PP ARa and/or PPAR ⁇ , of less than 5 ⁇ M, more preferably less than 1 ⁇ M, more preferably less than 500nm, more preferably less than 10OnM.
  • Compounds of the invention preferably have an EC50 for PPAR ⁇ that is less than or equal to PP ARa which in turn has an EC50 that is at least 10-fold less than PPAR ⁇ .

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Abstract

The invention provides compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with the activity of the Peroxisome Proliferator-Activated Receptor (PPAR) families.

Description

COMPOUNDS AND COMPOSITIONS AS PPAR MODULATORS
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of priority to U.S. Provisional Patent
Application Number 60/734,683, filed 07 November 2005. The full disclosure of this application is incorporated herein by reference in its entirety and for all purposes.
BACKGROUND OF THE INVENTION
Field of the Invention
[0002] The invention provides compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with the activity of the Peroxisome Proliferator-Activated Receptor (PPAR) families.
Background
[0003] Peroxisome Proliferator Activated Receptors (PPARs) are members of the nuclear hormone receptor super family, which are ligand-activated transcription factors regulating gene expression. Certain PPARs are associated with a number of disease states including dyslipidemia, hyperlipidemia, hypercholesteremia, atherosclerosis, atherogenesis, hypertriglyceridemia, heart failure, myocardial infarction, vascular diseases, cardiovascular diseases, hypertension, obesity, inflammation, arthritis, cancer, Alzheimer's disease, skin disorders, respiratory diseases, ophthalmic disorders, IBDs (irritable bowel disease), ulcerative colitis and Crohn's disease. Accordingly, molecules that modulate the activity of PPARs are useful as therapeutic agents in the treatment of such diseases.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides compounds of Formula I:
Figure imgf000003_0001
in which n is selected from 0, 1, 2 and 3; p is selected from O5 15 2 and 3;
Y is selected from O5 S, NR73 and CR7aR7b5 wherein R7a and R7b are independently selected from hydrogen and C1-C6alkyl;
Z is selected from CR8aR8b and S; wherein R8a and R8b are independently selected from hydrogen and Chalky!;
W is selected from O and S;
Ri is selected from -X1CR9R10X2CO2R11, -X1SCR9R10X2CO2R11 and - X1OCR9R10X2CO2R11; wherein X1 and X2 are independently selected from a bond and Ci- 4alkylene; and R9 and Rio are independently selected from hydrogen, C1-C6alkyl and Ci- 4alkoxy; or R9 and Ri 0 together with the carbon atom to which R9 and Rio are attached form C3-i2cycloalkyl; and Rn is selected from hydrogen and C1-C6alkyl; each
R2 is independently selected from halo, C1-C6alkyl, C∑-βalkenyl, C1-C4alkoxy, Ci- 4alkylthio5 Ca-^cycloalkyl, C3-8heterocycloalkyl, Cβ-ioaryl and Cs-ioheteroaryl; wherein any aryl, heteroaryl, cycloalkyl or heterocycloalkyl of R2 is optionally substituted with 1 to 3 radicals independently selected from halo, C1-C6alkyl, C1-C6alkoxy, C2-6alkenyl, C1-C6alkylthio, halo-substituted- C1-C6alkyl, halo-substituted- C1-C6alkoxy, -C(O)R14a and NRi4aRi4b; wherein Ri4a and Ri4b are independently selected from hydrogen and C1-C6alkyl;
R3 and R4 are independently selected from hydrogen and C1-C6alkyl;
R5 and R6 are independently selected from hydrogen, C1-C6alkyl, Ca-i∑cycloalkyl, Ca-sheterocycloalkyl, Cg-ioaryl and Cs-isheteroaryl;
[0004] wherein any aryl, heteroaryl, cycloalkyl and heterocycloalkyl of R5 and R6 is optionally substituted with 1 to 3 radicals independently selected from halo, nitro, cyano, C1-C6alkyl, C1-C6alkoxy, C1-C6alkylthio, hydroxy- C1-C6alkyl, halo-substituted- C1-C6alkyl, halo-substituted- C1-C6alkoxy, C3-i2cycloalkyl, C3-C8heterocycloalkyl, Cβ-ioaryl, Cs-nheteroaryl, -XS(O)0-2R12 , -XS(O)0-2XR13 , -XNR12R12, -XNR12S(O)0-2R12, -XNR12C(O)R12, - XC(O)NR12R12, -XNR12C(O)R13, -XC(O)NR12R13, -XC(O)R13, -XNR12XR13 and - XOXR13; wherein any aryl, heteroaryl, cycloalkyl or heterocycloalkyl substituent is further optionally substituted with 1 to 3 radicals independently selected from halo, nitro, cyano, Ci- βalkyl, Cuβalkoxy, C1-C6alkylthio, hydroxy-Ci-δalkyl, halo-substituted-Ci-6alkyl and halo- substituted-Ci-6alkoxy; wherein X is a bond or Ci-4alkylene; R12 is selected from hydrogen and C1-C6alkyl; and R13 is selected from C3-i2cycloalkyl, Cs^heterocycloalkyl, Cβ-ioaryl and C5-i0heteroaryl; wherein any aryl, heteroaryl, cycloalkyl or heterocycloalkyl of R13 is optionally substituted with 1 to 3 radicals independently selected from halo, nitro, cyano, Ci- βalkyl, C1-C6alkoxy, halo-substituted-C1-C6alkyl and halo-substituted-C1-C6alkoxy; with the proviso that either R5 or Re, but not both R5 and Re, must be hydrogen or methyl; and the N- oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixture of isomers thereof; and the pharmaceutically acceptable salts and solvates (e.g. hydrates) of such compounds.
[0005] In a second aspect, the present invention provides a pharmaceutical composition that contains a compound of Formula I or a N-oxide derivative, individual isomers and mixture of isomers thereof; or a pharmaceutically acceptable salt thereof, in admixture with one or more suitable excipients.
[0006] In a third aspect, the present invention provides a method of treating a disease in an animal in which modulation of PPAR activity can prevent, inhibit or ameliorate the pathology and/or symptomology of the diseases, which method comprises administering to the animal a therapeutically effective amount of a compound of Formula I or a N-oxide derivative, individual isomers and mixture of isomers thereof, or a pharmaceutically acceptable salt thereof.
[0007] In a fourth aspect, the present invention provides the use of a compound of
Formula I in the manufacture of a medicament for treating a disease in an animal in which PPAR activity activity contributes to the pathology and/or symptomology of the disease. [0008] In a fifth aspect, the present invention provides a process for preparing compounds of Formula I and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixture of isomers thereof, and the pharmaceutically acceptable salts thereof. DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0009] "Alkyl" as a group and as a structural element of other groups, for example halo-substituted-alkyl and alkoxy, can be either straight-chained or branched. C1-C6alkoxy includes, methoxy, ethoxy, and the like. Halo-substituted alkyl includes trifluoromethyl, pentafluoroethyl, and the like.
[0010] "Aryl" means a monocyclic or fused bicyclic aromatic ring assembly containing six to ten ring carbon atoms. For example, aryl can be phenyl or naphthyl, preferably phenyl. "Arylene" means a divalent radical derived from an aryl group.
"Heteroaryl" is as defined for aryl where one or more of the ring members are a heteroatom.
For example heteroaryl includes pyridyl, indolyl, indazolyl, quinoxalinyl, quinolinyl, benzofuranyl, benzopyranyl, benzothiopyranyl, benzo[l,3]dioxole, imidazolyl, benzo- imidazolyl, pyrimidinyl, furanyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, thienyl, etc. "C6-ioarylCo-4alkyl" means an aryl as described above connected via a alkylene grouping. For example,
Figure imgf000005_0001
includes phenethyl, benzyl, etc.
[0011] "Cycloalkyl" means a saturated or partially unsaturated, monocyclic, fused bicyclic or bridged polycyclic ring assembly containing the number of ring atoms indicated.
For example, Ca-iocycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
"Heterocycloalkyl" means cycloalkyl, as defined in this application, provided that one or more of the ring carbons indicated, are replaced by a moiety selected from -O-, -N=, -NR-,
-C(O) -, -S-, -S(O) - or -S(O)2-, wherein R is hydrogen, Ci-4alkyl or a nitrogen protecting group. For example, Ca-sheterocycloalkyl as used in this application to describe compounds of the invention includes morpholino, pyrrolidinyl, piperazinyl, piperidinyl, piperidinylone,
1 ,4-dioxa-8-aza-spiro[4.5]dec-8-yl, etc.
[0012] "Halogen" (or halo) preferably represents chloro or fluoro, but can also be bromo or iodo.
[0013] "Treat", "treating" and "treatment" refer to a method of alleviating or abating a disease and/or its attendant symptoms. Description of the Preferred Embodiments
[0014] The present invention provides compounds, compositions and methods for the treatment of diseases in which modulation of PPAR activity can prevent, inhibit or ameliorate the pathology and/or symptomology of the diseases, which method comprises administering to the animal a therapeutically effective amount of a compound of Formula I. In one embodiment, with reference to compounds of Formula I, n is selected from 0, 1, 2 and 3; p is selected from 0, 1 and 2;
Y is selected from O and S;
Z is selected from CRβaRβb and S; wherein Rg3 and Rgb are independently selected from hydrogen and C1-C6alkyl;
W is selected from O and S;
Ri is selected from ~XiCR9RioX2C02Ri i, -XISCR9R1OX2CO2RI i and - X1OCR9R10X2CO2R11; wherein Xi and X2 are independently selected from a bond and Ci- 4alkylene; and R9 and Rio are independently selected from hydrogen, C1-C6alkyl and Ci- 4alkoxy; or R9 and Rio together with the carbon atom to which R9 and Rio are attached form C3-i2cycloalkyl; and Rn is selected from hydrogen and C1-C6alkyl; each
R2 is independently selected from C1-C6alkyl, Ci-ealkenyl, Ci-4alkoxy, Ci- 4alkylthio, C3-i2cycloalkyl, C3-8heterocycloalkyl, Cβ-ioaryl and Cs-ioheteroaryl; wherein any aryl, heteroaryl, cycloalkyl or heterocycloalkyl OfR2 is optionally substituted with 1 to 3 radicals independently selected from halo, d-βalkoxy, C1-C6alkylthio, halo-substituted-Ci. βalkoxy, -C(O)Ri4a and NRi4aRi4b; wherein Rπa and R^b are independently selected from hydrogen and C1-C6alkyl;
R3 and R4 are independently selected from hydrogen and C1-C6alkyl;
Rs is Ce-ioaryl optionally substituted with 1 to 3 radicals independently selected from halo, nitro, cyano, C1-C6alkyl, Ci-^alkoxy, d-βalkylthio, hydroxy-C1-C6alkyl, halo-substituted-C1-C6alkyl, halo-substituted-C]^alkoxy, C3-i2cycloalkyl, Cs-gheterocycloalkyl, Cβ-ioaryl, Cs-uheteroaryl and -XNR12R12; wherein R12 is selected from hydrogen and Ci- βalkyl; and
Re is selected from hydrogen and methyl. [0015] In another embodiment, Ri is selected from -CH2CR5R6CO2H, -
OCRsR6CO2H, -SCR5R6CO2H, -CR5R6CH2CO2H and -CR5R6CO2H; wherein R5 and R6 are independently selected from hydrogen, methyl, methoxy and ethoxy; or R5 and R6 together with the carbon atom to which R5 and R6 are attached form cyclopentyl. [0016] In another embodiment, each R2 is indepedently selected from methyl, ethyl, cyclopropyl, methoxy, furanyl, phenyl, pyridinyl, thienyl, pyrrolidinyl and benzo[l,3]dioxolyl; wherein said pyridinyl or phenyl of R2 is optionally substituted with 1 to 3 radicals independently selected from halo, methyl-carbonyl, dimethyl-amino, methoxy, halo-substituted-methoxy, methyl-thio, ethenyl, hexenyl and propyloxy.
Preferred compounds of Formula I are selected from: (5-Cyclopropyl-2-methyl-4- {3-[4-(4-trifluoromethyl-phenyl)-thiazol-2-yl]-propoxy}-phenoxy)-acetic acid; (3-{3-[4-(4- Trifluoromethyl-phenyl)-thiazol-2-yl]-propoxy}-phenyl)-acetic acid; (2-Methyl-4-{3-[4-(4- trifluoromethyl-phenyl)-thiazol-2-yl]-propoxy}-phenoxy)-acetic acid; 2-Methyl-2-(4-{3-[4~ (4-trifluoromethyl-phenyl)-thiazol-2-yl]-propoxy} -phenoxy)-propionic acid; (2- Cyclopropyl-3- {3-[4-(4-trifluoromethyl-phenyl)-thiazol-2-yl]-propoxy} -phenyl)-acetic acid; (4-Cyclopropyl-3-{3-[4-(4-trifluoromethyl-phenyl)-thiazol-2-yl]-propoxy}-phenyl)-acetic acid; (±)-2-Ethoxy-3-(4- {3-[4-(4-trifluoromethyl-phenyl)-thiazol-2-yl]-propoxy} -phenyl)- ptopionic acid; (±)-2-Methoxy-3-(4- {3-[4-(4-trifluoromethyl-phenyl)-thiazol-2-yl] - propoxy}-phenyl)-propionic acid; (3-{3-[4-(4-Trifluoromethyl-phenyl)-oxazol-2-yl]- propoxy} -phenyl)-acetic acid; (2-Methyl-4- {3-[4-(4-trifluoromethyl-phenyl)-oxazol-2-yl]- propoxy} -phenoxy)-acetic acid; (5-Cyclopropyl-2-methyl-4-{3-[4-(4-trifluoromethyl- phenyl)-oxazol-2-yl]-ρroρoxy} -phenoxy)-acetic acid; 2-Methyl-2-(4-{3-[4-(4- trifluoτomethyl-phenyl)-oxazol-2-yl]-propoxy}-phenoxy)-propionic acid; (2-Cyclopropyl-3- {3-[4-(4-trifluoromethyl-phenyl)-oxazol-2-yl]-propoxy}-phenyl)-acetic acid; (4- Cyclopropyl-3-{3-[4-(4-trifluoromethyl-phenyl)-oxazol-2-yl]-propoxy}-phenyl)-acetic acid; (3-{2-[4-(4-Trifluoromethyl-phenyl)-oxazol-2-yl]-ethoxy}-phenyl)-acetic acid; (3-{2-[4-(4- Trifluoromethoxy-phenyl)-oxazol-2-yl]-ethoxy} -phenyl)-acetic acid; (2-Cyclopropyl-3- {2- [4-(4-trifluoromethoxy-phenyl)-oxazol-2-yl]-ethoxy} -phenyl)-acetic acid; (4-Cyclopropyl-3- {2-[4-(4-trifluoromethoxy-phenyl)-oxazol-2-yl]-ethoxy}-phenyl)-acetic acid; (2- Cyclopropyl-3-{2-methyl-2-[4-(4-trifluoromethyl-phenyl)-oxazol-2-yl]-propoxy}-phenyl)- acetic acid; (4-Cyclopropyl-3- {2-methyl-2-[4-(4-trifluoromethyl-phenyl)-oxazol-2-yl]- propoxy}-phenyl)-acetic acid; 3-(2-Methyl-4- {3-[4-(4-trifluoromethyl-phenyl)-thiazol-2-yl]- propoxy} -phenyl)-propionic acid; 3-(2-Cyclopropyl-5- {3 -[4-(4-trifluoromethyl-phenyl)- thiazol-2-yl]-propoxy} ~phenyl)-proρionic acid; 3-(5-CycIopropyl-2-methyl-4- {3-[4-(4- trifluoromethyl-phenyl)-thiazol-2-yl]-propoxy}-phenyl)-propionic acid; 3-(4-Cyclopropyl-3- {3-[4-(4-trifluoromethyl-phenyl)-thiazol-2-yl]-propoxy} -phenyl)-propionic acid; 2-Methyl- 2-(3-methyl-4-{3-[4-(4-trifluoromethyl-phenyl)-thiazol-2-yl]-propoxy}-phenoxy)-propionic acid; (±)-2-Methyl-3-(4- {3-[4-(4-trifluoromethyl-phenyl)-thiazol-2-yl]-propoxy} -phenyl)- propionic acid; (±)-3 -(4- {3-[4-(4-Trifluoromethyl-phenyl)-thiazol-2-yl]-propoxy} -phenyl)- butyric acid; 2-Methyl-2-(2-methyl-4- {3-[4-(4-trifluoromethyl-phenyl)-thiazol-2-yl]- propoxy } -phenoxy)-propionic acid; 2-(2,3 -Dimeihyl-4- {3 -[4-(4-trifluoromethyl-phenyl)- thiazol-2-yl]-proρoxy}-phenoxy)-2-methyl-propionic acid; (±)-2-Ethoxy-3-(2-methyl-4-{3- [4-(4-trifluoromethyl-phenyi)-thiazol-2-yl]-propoxy } -phenyl)-propionic acid; 2-(2,5- Dimethyl-4-{3-[4-(4-trifluoromethyl-phenyl)-thiazol-2-yl]-propylsulfanyl}-phenoxy)-2- methyl-propionic acid; (2,5-Dimethyl-4-{3-[4-(4-trifluoromethyl-phenyI)-thiazol-2-yl]- propoxy}-phenoxy)-acetic acid; (2,5-Dimethyl-4- {3-[4-(4-trifluoromethyl-phenyl)-thiazol-2- yl] -propylsulfanyl} -phenoxy)-acetic acid; 2-(2,5-Dimethyl-4- {3 -[4-(4-trifluoromethyl- phenyl)-thiazol-2-yl]-propoxy}-phenoxy)-2-methyl-proρionic acid; (3-Methoxy-4- {3-[4-(4- txifluoromethyl-phenyl)-thiazol-2-yl]-proρoxy}-phenyl)-acetic acid; (4-Methoxy-3- {3-[4-(4- trifluoromethyl-phenyl)-thiazol-2-yl]-propoxy} -phenyl)-acetic acid; (±)-3-(2,5-Dimethyl-4- {3-[4-(4-trifluoromethyl-phenyl)-thiazol-2-yl]-propoxy}-phenyl)-2-ethoxy-propionic acid; 3-(2,5-Dimethyl-4-{3-[4-(4-trifluoromefhyl-phenyl)-thiazol-2-yl]-propoxy}-phenyl)-2,2- dimethyl-propionic acid; 2-(2,5-Dimethyl-4- {3-[4-(4-trifluoromethyl-phenyl)-thiazol-2-yl]- propoxy} -phenylsulfanyl)-2-methyl-propionic acid; (2-Methyl-4- {2-[4-(4-trifluoromethyl- phenyl)-fhiazol-2-yl]-etiioxy} -phenoxy)-acetic acid; (2-Methyl-4- {2-[4-(4-trifluoromethoxy- phenyl)-thiazol-2-yl]-ethoxy}-phenoxy)-acetic acid; (2-Methyl-4-{2-[5-methyl-4-(4- trifluoromethyl-phenyl)-thiazol-2-yl]-ethoxy}-ρhenoxy)-acetic acid; (2-Methyl-4-{2-[4-(3- trifluoromethyl-phenyl)-thiazol-2-yl]-ethoxy} -phenoxy)-acetic acid; (4- {2-[4-(4-Methoxy- pheπyl)-thiazol-2-yl]-ethoxy} -2-methyl-phenoxy)-acetic acid; {2-Methyl-4-[2-(4- naρhthalen-2-yl-thiazol-2-yl)-ethoxy]-phenoxy}-acetic acid; (2-Methyl-4- {3-[4-(4- trifluoromethyl-phenyl)-thiazol-2-yl]-propoxy} -phenoxy)-acetic acid; (2-Methyl-4- {3-[4-(4- trifluoromethoxy-phenyl)-thiazol-2-yl]-propoxy}-phenoxy)-acetic acid;(2-Methyl-4-{3-[5- methyl -4-(4-trifluoromethyl-phenyl)-thiazol-2-yl]-propoxy} -phenoxy)-acetic acid; (2- Methyl-4- {3-[4-(3-trifluoromethyl-phenyl)-thiazol-2-yl]-propoxy} -phenoxy)-acetic acid; (4- {3-[4-(4-Methoxy-phenyl)-thiazol-2-yl]-propoxy}-2-methyl-phenoxy)-acetic acid; {2- Methyl-4-[3-(4-naphthalen-2-yl-thiazol-2-yl)-propoxy]-phenoxy}-acetic acid; (2-Methyl-4- {4-[4-(4-trifluoromethyl-phenyl)-thiazol-2-yl]-butoxy}-phenoxy)-acetic acid; (2-Methyl-4- {4-[4-(4-trifluoromethoxy-phenyl)-thiazol-2-yl]-butoxy} -phenoxy)-acetic acid; (2-Methyl-4- {4-[5-methyl-4-(4-trifluoromeihyl-phenyl)-thiazol-2-yl]-butoxy}-phenoxy)-acetic acid; (2- Methyl-4-{4-[4-(3-trifluoromethyl-phenyl)-thiazol-2-yl]-butoxy}-phenoxy)-acetic acid; (4- {4-[4-(4-Methoxy-phenyl)-thiazol-2-yl]-butoxy} -2-methyl-phenoxy)-acetic acid; {2-Methyl- 4-[4-(4-naphthalen-2-yl-thiazol-2-yl)-butoxy]-phenoxy}-acetic acid; (5-Cycloproρyl-2- methyl-4-{2-[4-(4-trifluoromethyl-phenyl)-thiazol-2-yl]-ethoxy}-phenoxy)-acetic acid; {5- Cyclopropyl-2-methyl-4-[2-(4-naphthalen-2-yl-thiazol-2-yl)-ethoxy]-phenoxy}-acetic acid; (5-Cyclopropyl-2-methyl-4-{2-[5-methyl-4-(4-trifluoromethyl-phenyl)-thiazol-2-yl]- ethoxy}-phenoxy)-acetic acid; (3-{2-[4-(4-Trifluoromethyl-phenyl)-thiazol-2-yl]-ethoxy}- phenyl)-acetic acid; {3-[2-(4-Naphthalen-2-yl-thiazol-2-yl)-ethoxy]-phenyl}-acetic acid; (3- {2-[5-Methyl-4-(4-trifluoromethyl-phenyl)-thiazol-2-yl]-ethoxy } -phenyl)-acetic acid; (2- Cyclopropyl-3 - {2-[4-(4-trifluoromethyl-phenyl)-thiazol-2-yl]-ethoxy} -phenyl)-acetic acid; {2-Cyclopropyl-3-[2-(4-naphthalen-2-yl-thiazol-2-yl)-ethoxy]-phenyl}-acetic acid; (2- Cyclopropyl-3-{2-[5-methyl-4-(4-trifluoromethyl-phenyl)-thiazol-2-yl]-ethoxy}-phenyl)- acetic acid; (4-Cyclopropyl-3-{2-[4-(4-trifluoromethyl-phenyl)-thiazol-2-yl]-ethoxy} - phenyl)-acetic acid; {4-Cyclopropyl-3-[2-(4-naphthalen-2-yl-thiazol-2-yl)-ethoxy]-phenyl} - acetic acid; (4-Cyclopropyl-3- {2-[5-methyl-4-(4-trifluoromethyl-phenyl)-thiazol-2-yl]- ethoxy} -phenyl)-acetic acid; 2-Methyl-2-(4- {2-[4-(4-trifluoromethyl-phenyl)-thiazol-2-yl]- ethoxy} -phenoxy)-propionic acid; 2-Methyl-2- {4-[2-(4-naphthalen-2-yl-thiazol-2-yl)- ethoxy]-phenoxy} -propionic acid; 2-Methyl-2-(4- {2-[5-methyl-4-(4-trifluoromethyl- phenyl)-thiazol-2-yl]-ethoxy}-phenoxy)-propionic acid; {4'-Methoxy-4-methyl-6-[4-(4- trifluoromethyl-phenyl)-thiazol-2-ylmethoxy]-biphenyl-3-yloxy} -acetic acid; {4-Methyl-4'- trifluoroπiethoxy-6-[4-(4-trifluoromethyl-phenyl)-thiazol-2-ylmethoxy]-biphenyl-3-yloxy}- acetic acid; {4-Methyl-4'-methylsulfanyl-6-[4-(4-trifluoromethyl-ρhenyl)-thiazol-2- ylmethoxy]-biphenyl-3-yloxy}-acetic acid; {2-Methyl-4-[4-(4-trifluoromethyl-phenyl)- thiazol-2-ylmethoxy]-5-vinyl-phenoxy} -acetic acid; {5-Hex-l -enyl-2-methyl-4-[4-(4- trifluoromethyl-phenyl)-thiazol-2-ylmethoxy]-phenoxy}-acetic acid; {5-Furan-3-yl-2- methyl-4-[4-(4-trifluoromethyl-phenyl)-thiazol-2-ylmethoxy]-phenoxy} -acetic acid; {5-(6- Methoxy-pyridin-3-yl)-2-methyl-4-[4-(4-trifluoromethyl-ρhenyl)-thiazol-2-ylmethoxy]- phenoxy} -acetic acid; {4-Methyl-4'-propoxy-6-[4-(4-trifluoromethyl-phenyl)-thiazol-2- ylmethoxy]-biphenyl-3-yloxy} -acetic acid; {3'-Chloro-4'-methoxy-4-methyl-6-[4-(4- trifluoromethyl-phenyl)-thiazol-2-ylmethoxy]-biρhenyl-3-yloxy}-acetic acid; {5- Benzo[ 1 ,3]dioxol-5-yl-2-tnethyl-4-[4-(4-trifluoromethyl-phenyl)-thiazol-2-ylmethoxy] - phenoxy} -acetic acid; {4'-Acetyl-4-methyl-6-[4-(4-trifluoromethyl-phenyl)-thiazol-2- ylmethoxy]-biphenyl-3-yloxy}-acetic acid; {4'-Dimethylamino-4-methyl-6-[4-(4- trifluoromethyl-phenyl)-thiazol-2-ylmethoxy]-biphenyl-3-yloxy} -acetic acid; {2-Methyl-5- thioρhen-2-yl-4-[4-(4-trifluoromethyl-phenyl)-thiazol-2-ylmethoxy]-phenoxy}-acetic acid; {4-Methyl-4'-methylsulfanyl-6-[4-(4-trifluoromethoxy-phenyl)-thiazol-2-ylmethoxy]- biphenyl-3-yloxy} -acetic acid; {3'-Methoxy-4-methyl-6-[4-(4-trifluoromethoxy-phenyl)- thiazol-2-ylmethoxy]-biphenyl-3-yloxy}-acetic acid; {2-Methyl-5-pyrrolidin-l-yl-4-[4-(4- trifluoromethyl-phenyl)-thiazol-2-ylmethoxyJ-phenoxy} -acetic acid; (±)-(4'-Methoxy-4- methyl-6- { 1 -[4-(4-trifluoromethyl-phenyl)-thiazol-2-yl]-ethoxy} -biphenyl-3-yloxy)-acetic acid; (4'-Methoxy-4-methyl-6- {2-[4-(4-trifluoromethyl-ρhenyl)-thiazol-2-yl]-ethoxy} - biphenyl-3-yloxy)-acetic acid; (2-Methyl-4- {2-[4-(4-trifluoromethyl-pheπyl)-thiazol-2-yl]- ethoxy} -5-vinyl-phenoxy)-acetic acid; {4'-Methoxy-4-methyl-6-[4-(4-nitro-phenyl)-thiazol- 2-ylmethoxy]-biphenyl-3-yloxy} -acetic acid; {4'-Methoxy-6-[4-(4-methoxy-phenyl)-thiazol- 2-ylmethoxy]-4-methyl-biphenyl-3 -yloxy} -acetic acid; [4'-Methoxy-4-methyl-6-(4-p-tolyl- thiazol-2-ylmethoxy)-biphenyl-3-yloxy]-acetic acid; {6-[4-(4-Chloro-phenyl)-thiazol-2- ylmethoxy]-4'-methoxy-4-methyl-biphenyl-3-yloxy}-acetic acid; {6-[4-(4-Diethylamino- phenyl)-thiazol-2-ylmethoxy]-4'-methoxy-4-methyl-biρhenyl-3-yloxy} -acetic acid; {6-[4-(4- Cyano-phenyl)-thiazol-2-ylmethoxy]-4'-methoxy-4-methyl-biphenyl-3-yloxy}-acetic acid; [6-(4-Biphenyl-4-yl-thiazol-2-ylmethoxy)-4'-methoxy-4-methyl-biphenyl-3-yloxy]-acetic acid; [4'-Methoxy-4-methyl-6-(4-naphthalen-2-yl-thiazol-2-yIinethoxy)-biphenyl-3-yloxy]- acetic acid; {4'-Methoxy-6-[4-(3-methoxy-phenyl)-thiazol-2-ylmethoxy]-4-methyl-biphenyl- 3-yloxy} -acetic acid; {5-Cyclopropyl-2-methyl-4-[4-(4-trifluoromethyl-phenyl)-thiazol-2- ylmethoxy]-phenoxy} -acetic acid; {5-Ethyl-2-methyl-4-[4-(4-trifluoromethyl-phenyl)- thiazol-2-ylmethoxy]-phenoxy}-acetic acid; [4-(4-Biphenyl-4-yl-miazol-2-ylmethoxy)-5- cyclopropyl-2-methyl-phenoxy]-acetic acid; 2-(2,5-Dimethyl-4- {2-[4-(4-trifluoromethyl- phenyl)-thiazol-2-ylsulfanyl]-ethoxy}-phenoxy)-2-methyl-propionic acid; and 2-(2,5-
Dimethyl-4-{3-[4-(4-trifluoromethyl-phenyl)-thiazol-2-ylsulfanyl]-propoxy}-phenoxy)-2- methyl-propionic acid.
[0017] Further preferred compounds of Formula I are detailed in the Examples, infra.
Pharmacology and Utility
[0018] Compounds of the invention modulate the activity of PPARs and, as such, are useful for treating diseases or disorders in which PPARs contributes to the pathology and/or symptomology of the disease. This invention further provides compounds of this invention for use in the preparation of medicaments for the treatment of diseases or disorders in which PPARs contributes to the pathology and/or symptomology of the disease. [0019] Such compounds may therefore be employed for the treatment of prophylaxis, dyslipidemia, hyperlipidemia, hypercholesteremia, atherosclerosis, atherogenesis, hypertriglyceridemia, heart failure, hyper cholesteremia, myocardial infarction, vascular diseases, cardiovascular diseases, hypertension, obesity, cachexia, HIV wasting syndrome, inflammation, arthritis, cancer, Alzheimer's disease, anorexia, anorexia nervosa, bulimia, skin disorders, respiratory diseases, ophthalmic disorders, IBDs (irritable bowel disease), ulcerative colitis and Crohn's disease. Preferably for the treatment of prophylaxis, dyslipidemia, hyperlipidemia, hypercholesteremia, atherosclerosis, atherogenesis, hypertriglyceridemia, cardiovascular diseases, hypertension, obesity, inflammation, cancer, skin disorders, EBDs (irritable bowel disease), ulcerative colitis and Crohn's disease.
[0020] Compounds of the invention can also be employed to treat long term critical illness, increase muscle mass and/or muscle strength, increase lean body mass, maintain muscle strength and function in the elderly, enhance muscle endurance and muscle function, and reverse or prevent frailty in the elderly.
[0021] Further, the compounds of the present invention may be employed in mammals as hypoglycemic agents for the treatment and prevention of conditions in which impaired glucose tolerance, hyperglycemia and insulin resistance are implicated, such as tyρe-1 and tyρe-2 diabetes, Impaired Glucose Metabolism (IGM), Impaired Glucose Tolerance (IGT), Impaired Fasting Glucose (EFG), and Syndrome X. Preferably type-1 and type-2 diabetes, Impaired Glucose Metabolism (IGM), Impaked Glucose Tolerance (IGT) and Impaired Fasting Glucose (IFG).
[0022] In accordance with the foregoing, the present invention further provides a method for preventing or treating any of the diseases or disorders described above in a subject in need of such treatment, which method comprises administering to said subject a therapeutically effective amount (See, "Administration and Pharmaceutical Compositions ", infra) of a compound of the invention or a pharmaceutically acceptable salt thereof. For any of the above uses, the required dosage will vary depending on the mode of administration, the particular condition to be treated and the effect desired. The present invention also concerns: i) a compound of the invention or a pharmaceutically acceptable salt thereof for use as a medicament; and ii) the use of a compound of the invention or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for preventing or treating any of the diseases or disorders described above.
Administration and Pharmaceutical Compositions
[0023] In general, compounds of the invention will be administered in therapeutically effective amounts via any of the usual and acceptable modes known in the art, either singly or in combination with one or more therapeutic agents. A therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors. In general, satisfactory results are indicated to be obtained systemically at daily dosages of from about 0.03 to 2.5mg/kg per body weight. An indicated daily dosage in the larger mammal, e.g. humans, is in the range from about 0.5mg to about lOOmg, conveniently administered, e.g. in divided doses up to four times a day or in retard form. Suitable unit dosage forms for oral administration comprise from ca. 1 to 50mg active ingredient. [0024] Compounds of the invention can be administered as pharmaceutical compositions by any conventional route, in particular enterally, e.g., orally, e.g., in the form of tablets or capsules, or parenterally, e.g., in the form of injectable solutions or suspensions, topically, e.g., in the form of lotions, gels, ointments or creams, or in a nasal or suppository form. Pharmaceutical compositions comprising a compound of the present invention in free form or in a pharmaceutically acceptable salt form in association with at least one pharmaceutically acceptable carrier or diluent can be manufactured in a conventional manner by mixing, granulating or coating methods. For example, oral compositions can be tablets or gelatin capsules comprising the active ingredient together with a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and or polyvinylpyrollidone; if desired d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or e) absorbents, colorants, flavors and sweeteners. Injectable compositions can be aqueous isotonic solutions or suspensions, and suppositories can be prepared from fatty emulsions or suspensions. The compositions can be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they can also contain other therapeutically valuable substances. Suitable formulations for transdermal applications include an effective amount of a compound of the present invention with a carrier. A carrier can include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host. For example, transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin. Matrix transdermal formulations can also be used. Suitable formulations for topical application, e.g., to the skin and eyes, are preferably aqueous solutions, ointments, creams or gels well-known in the art. Such can contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
[0025] This invention also concerns a pharmaceutical composition comprising a therapeutically effective amount of a compound as described herein in combination with one or more pharmaceutically acceptable carriers. [0026] Compounds of the invention can be administered in therapeutically effective amounts in combination with one or more therapeutic agents (pharmaceutical combinations).
[0027] Thus, the present invention also relates to pharmaceutical combinations, such as a combined preparation or pharmaceutical composition (fixed combination), comprising: 1) a compound of the invention as defined above or a pharmaceutical acceptable salt thereof; and 2) at least one active ingredient selected from:
[0028] a) anti-diabetic agents such as insulin, insulin derivatives and mimetics; insulin secretogogues such as the sulfonylureas, e.g., Glipizide, glyburide and Amaryl; insulinotropic sulfonylurea receptor ligands such as meglitinides, e.g., nateglinide and repaglinide; insulin sensitizer such as protein tyrosine phosphatase- IB (PTP7IB) inhibitors such as PTP-112; GSK3 (glycogen synthase kinase-3) inhibitors such as SB-517955, SB- 4195052, SB-216763, NN-57-05441 and NN-57-05445; RXR ligands such as GW-0791 and AGN- 194204; sodium-dependent glucose co-transporter inhibitors such as T- 1095; glycogen phosphorylase A inhibitors such as BAY R3401 ; biguanides such as metformin; alpha- glucosidase inhibitors such as acarbose; GLP-I (glucagon like peptide-1), GLP-I analogs such as Exendin-4 and GLP-I mimetics; DPPIV (dipeptidyl peptidase IV) inhibitors such as DPP728, LAF237 (vildagliptin - Example 1 of WO 00/34241), MK-0431, saxagliptin, GSK23 A ; an AGE breaker; a thiazolidone derivative (glitazone) such as pioglitazone, rosiglitazone, or (R)-I- {4-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]- benzenesulfonyl}-2,3-dihydro-lH-indole-2-carboxylic acid described in the patent application WO 03/043985, as compound 19 of Example 4, a non-glitazone type PPARγ agonist e.g. GI-262570;
[0029] b) hypolipidemic agents such as 3-hydroxy-3-methyl-glutaryl coenzyme A
(HMG-CoA) reductase inhibitors, e.g., lovastatin, pitavastatin, simvastatin, pravastatin, cerivastatin, mevastatin, velostatin, fluvastatin, dalvastatin, atorvastatin, rosuvastatin and rivastatin; squalene synthase inhibitors; FXR (farnesoid X receptor) and LXR (liver X receptor) ligands; cholestyramine; fϊbrates; nicotinic acid and aspirin; [0030] c) an anti-obesity agent or appetite regulating agent such as phentermine, leptin, bromocriptine, dexamphetamine, amphetamine, fenfluramine, dexfenfluramine, sibutramine, orlistat, dexfenfluramine, mazindol, phentermine, phendimetrazine, diethylpropion, fluoxetine, bupropion, topiramate, diethylpropion, benzphetamine, phenylpropanolamine or ecopipam, ephedrine, pseudoephedrine or cannabinoid receptor antagonists;
[00311 d) anti-hypertensive agents, e.g., loop diuretics such as ethacrynic acid, furosemide and torsemide; diuretics such as thiazide derivatives, chlorithiazide, hydrochlorothiazide, amiloride; angiotensin converting enzyme (ACE) inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perinodopril, quinapril, ramipril and trandolapril; inhibitors of the Na-K-ATPase membrane pump such as digoxin; neutralendopeptidase (NEP) inhibitors e.g. thiorphan, terteo-thiorphan, SQ29072; ECE inhibitors e.g. SLV306; ACE/NEP inhibitors such as omapatrilat, sampatrilat and fasidotril; angiotensin II antagonists such as candesartan, eprosartan, irbesartan, losartan, telmisartan and valsartan, in particular valsartan; renin inhibitors such as aliskiren, terlakiren, ditekiren, RO 66-1132, RO-66-1168; β-adrenergic receptor blockers such as acebutolol, atenolol, betaxolol, bisoprolol, metoprolol, nadolol, propranolol, sotalol and timolol; inotropic agents such as digoxin, dobutamine and milrinone; calcium channel blockers such as amlodipine, bepridil, diltiazem, felodipine, nicardipine, nimodipine, nifedipine, nisoldipine and verapamil; aldosterone receptor antagonists; and aldosterone synthase inhibitors; [0032] e) a HDL increasing compound;
[0033] f) Cholesterol absorption modulator such as Zetia® and KT6-971 ;
[0034] g) Apo-Al analogues and mimetics;
10035] h) thrombin inhibitors such as Ximelagatran;
[0036] i) aldosterone inhibitors such as anastrazole, fadrazole, eplerenone;
[0037] j) Inhibitors of platelet aggregation such as aspirin, clopidogrel bisulfate;
[0038] k) estrogen, testosterone, a selective estrogen receptor modulator, a selective androgen receptor modulator;
[0039] 1) a chemotherapeutic agent such as aromatase inhibitors e.g. femara, anti- estrogens, topoisomerase I inhibitors, topoisomerase II inhibitors, microtubule active agents, alkylating agents, antineoplastic antimetabolites, platin compounds, compounds decreasing the protein kinase activity such as a PDGF receptor tyrosine kinase inhibitor preferably Imatinib ( { N-{5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylρhenyl}-4-(3- pyridyl)-2-pyrimidine-amine }) described in the European patent application EP-A-O 564 409 as example 21 or 4-Methyl-N-[3-(4-methyl-imidazol-l-yl)-5-trifluoromethyl-phenyl]-3-
(4-pyridin-3-yl-pyτimidin-2-ylamino)-benzamide described in the patent application WO
04/005281 as example 92; and
[0040] m) an agent interacting with a 5-HT3 receptor and/or an agent interacting with 5-HT4 receptor such as tegaserod described in the US patent No. 5510353 as example
13, tegaserod hydrogen maleate, cisapride, cilansetron;
[0041] or, in each case a pharmaceutically acceptable salt thereof; and optionally a pharmaceutically acceptable carrier.
[0042] Most preferred combination partners are tegaserod, imatinib, vildagliptin, metformin, a thiazolidone derivative (glitazone) such as pioglitazone, rosiglitazone, or ^Rj-I-
{4-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-benzenesulfonyl}-2>3- dihydro-lH-indole-2-carboxylic acid, a sulfonylurea receptor ligand, aliskiren, valsartan, orlistat or a statin such as pravastatin, simvastatin, fluvastatin or pravastatin. [0043] Preferably the pharmaceutical combinations contains a therapeutically effective amount of a compound of the invention as defined above, in a combination with a therapeutically effective amount of another therapeutic agent as described above, e.g., each at an effective therapeutic dose as reported in the art. Combination partners (1) and (2) can be administered together, one after the other or separately in one combined unit dosage form or in two separate unit dosage forms. The unit dosage form may also be a fixed combination. [0044] The structure of the active agents identified by generic or trade names may be taken from the actual edition of the standard compendium "The Merck Index" or the Physician's Desk Reference or from databases, e.g. Patents International (e.g. IMS World Publications) or Current Drugs. The corresponding content thereof is hereby incorporated by reference. Any person skilled in the art is fully enabled to identify the active agents and, based on these references, likewise enabled to manufacture and test the pharmaceutical indications and properties in standard test models, both in vitro and in vivo. [0045] In another preferred aspect the invention concerns a pharmaceutical composition (fixed combination) comprising a therapeutically effective amount of a compound as described herein, in combination with a therapeutically effective amount of at least one active ingredient selected from the above described group a) to m), or, in each case a pharmaceutically acceptable salt thereof. Ϊ0046] A pharmaceutical composition or combination as described herein for the manufacture of a medicament for the treatment of for the treatment of dyslipidemia, hyperlipidemia, hypercholesteremia, atherosclerosis, hypertriglyceridemia, heart failure, myocardial infarction, vascular diseases, cardiovascular diseases, hypertension, obesity, inflammation, arthritis, cancer, Alzheimer's disease, skin disorders, respiratory diseases, ophthalmic disorders, inflammatory bowel diseases, IBDs (irritable bowel disease), ulcerative colitis, Crohn's disease, conditions in which impaired glucose tolerance, hyperglycemia and insulin resistance are implicated, such as type-1 and type-2 diabetes, Impaired Glucose Metabolism (IGM), Impaired Glucose Tolerance (IGT), Impaired Fasting Glucose (IFG), and Syndrome-X.
[0047] Such therapeutic agents include estrogen, testosterone, a selective estrogen receptor modulator, a selective androgen receptor modulator, insulin, insulin derivatives and mimetics; insulin secretagogues such as the sulfonylureas, e.g., Glipizide and Amaryl; insulinotropic sulfonylurea receptor ligands, such as meglitinides, e.g., nateglinide and repaglinide; insulin sensitizers, such as protein tyrosine phosphatase- IB (PTP-IB) inhibitors, GSK3 (glycogen synthase kinase-3) inhibitors or RXR ligands; biguanides, such as metformin; alpha-glucosidase inhibitors, such as acarbose; GLP-I (glucagon like peptide- 1), GLP-I analogs, such as Exendin-4, and GLP-I mimetics; DPPIV (dipeptidyl peptidase IV) inhibitors, e.g. isoleucin-thiazolidide; DPP728 and LAF237, hypolipidemic agents, such as 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors, e.g., lovastatin, pitavastatin, simvastatin, pravastatin, cerivastatin, mevastatin, velostatin, fluvastatin, dalvastatin, atorvastatin, rosuvastatin, fluindostatin and rivastatin, squalene synthase inhibitors or FXR (liver X receptor) and LXR (farnesoid X receptor) ligands, cholestyramine, fibrates, nicotinic acid and aspirin. A compound of the present invention may be administered either simultaneously, before or after the other active ingredient, either separately by the same or different route of administration or together in the same pharmaceutical formulation.
[0048] The invention also provides for pharmaceutical combinations, e.g. a kit, comprising: a) a first agent which is a compound of the invention as disclosed herein, in free form or in pharmaceutically acceptable salt form, and b) at least one co-agent. The kit can comprise instructions for its administration. [0049] The terms "co-administration" or "combined administration" or the like as utilized herein are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time. The term "pharmaceutical combination" as used herein means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non- fixed combinations of the active ingredients. The term "fixed combination" means that the active ingredients, e.g. a compound of Formula I and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients, e.g. a compound of Formula I and a co- agent, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the 2 compounds in the body of the patient. The latter also applies to cocktail therapy, e.g. the administration of 3 or more active ingredients.
Processes for Making Compounds of the Invention
[0050] The present invention also includes processes for the preparation of compounds of the invention. In the reactions described, it can be necessary to protect reactive functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups can be used in accordance with standard practice, for example, see T. W. Greene and P. G. M. Wuts in "Protective Groups in Organic
Chemistry", John Wiley and. Sons, 1991.
[0051] Compounds of Formula I, in which R4 is cyclic (e.g. cycloalkyl, heterocycloalkyl, aryl and heteroaryl), can be prepared by proceeding as in reaction schemes
Ia and Ib:
Reactions Scheme Ia
Figure imgf000018_0001
in which n, p, Ri, R2, R3, R4, Rs, Re, Y, Z and W are as defined for Formula I in the Summary of the Invention; and Q is a halogen, preferably Cl, I or Br. Compounds of 2 are formed by reacting a compound of formula 1 with a halogen (Q) (for example, Br2, and the like) under suitable acidic conditions (for example, acetic acid, and the like), a suitable solvent (for example, dichloromethane, and the like). The reaction is carried out in the temperature range of about 10 to about SO0C and takes up to about 12 hours to complete.
Reactions Scheme Ib
Figure imgf000019_0001
[0052] in which n, p, Rx, R2, R3, R4, R5, Rg, Y, Z and W are as defined for
Formula I in the Summary of the Invention and R2' is selected from Ca-galkenyl, cyclopropyl, C6-ioaryl and C5-ioheteroaryl. Q is a halogen, preferably Cl, I or Br; and R30 is, independently selected from hydrogen, C1-C6alkyl or the R30 radicals can be cyclized. Compounds of Formula I are prepared by reacting a compound of formula 2 with a compound of formula 3 in the presence of a suitable catalyst (e.g., Pd(Ph^)4, or the like), a suitable base (e.g., Na2COj5 or the like) and a suitable solvent (e.g., water, ethanol, DME or the like and mixtures thereof). The reaction is carried out in the temperature range of about 120 to about 2000C (microwave) and takes up to about 20 minutes to complete or a corresponding rime and temperature for conventional heating.
[0053] Compounds of Formula I, in which Ri is defined by -X1CR9R10X2CO2R11
(shown below), -Xi SCR9RIOX2CO2RH and -X1OCR9R10X2CO2R11, wherein R7 is an alkyl group e.g., methyl or ethyl for a compound of formula 4 converting to hydrogen in formula I, can be prepared by proceeding as in reaction scheme 2: Reactions Scheme 2
Figure imgf000020_0001
Figure imgf000020_0002
[0054] in which n, p, Ri, R2, R3, R4, R5, R6, Rg, Ri0, Xi, X2, Y, Z and W are as defined for Formula I. Compounds of Formula I are prepared by reacting a compound of formula 4 in the presence of a suitable base (e.g., lithium hydroxide, or the like) and a suitable solvent (e.g., THF, water or the like). The reaction is carried out in the temperature range of about 00C to about 500C and takes up to about 30 hours to complete. [0055] Compounds of Formula I can be prepared by proceeding as in reaction scheme 3:
Reactions Scheme 3
Figure imgf000020_0003
[0056] in which n, p, Ri, R2, R3, R4, R5, R6, Y, Z and W are as defined for
Formula I in the Summary of the Invention; and Q is a halogen, preferably Cl, I or Br. Compounds of I are formed by reacting a compound of formula 5 with a compound of formula 6 or formula 7 (where OMs is a mesylate formed from the corresponding alcohol using mesylation conditions known to one of skill in the art). The reaction proceeds in the presence of a suitable solvent (for example, acetonitrile, acetone, and the like), a suitable inorganic base (for example, CS2CO3, and the like). The reaction is carried out in the temperature range of about 10 to about 8O0C and takes up to about 12 hours to complete. [0057] Compounds of Formula I can be prepared by proceeding as in reaction scheme 4:
Reactions Scheme 4
Figure imgf000021_0001
[0058] in which n, p, Rj, R2, R3, R4, R5, R6, Y, Z and W are as defined for
Formula I in the Summary of the Invention. Compounds of formula I are formed by reacting a compound of formula 5 with a compound of formula 8. The reaction proceeds in the presence of a suitable solvent (for example, DCM, THF, and the like), suitable activation reagents (for example, triphenylphosphine/diethylazodicarboxylate, and the like). The reaction is carried out in the temperature range of about 0 to about 3O0C and takes up to about 12 hours to complete.
[0059] Compounds of Formula I can be prepared by proceeding as in reaction scheme 5:
Reactions Scheme 5
Figure imgf000022_0001
[0060] in which n, p, Rj, R2, R3, R4, Y and Z are as defined for Formula I in the
Summary of the Invention; and Q is a halogen, preferably Cl, I or BT. Compounds of formula 11 and 12 are formed by reacting a compound of formula 5 with a compound of formula 9 or 10, respectively. The reaction proceeds in the presence of a suitable solvent (for example, acetonitrile, acetone, and the like), a suitable inorganic base (for example, CS2CO3, K2CO3, and the like). The reaction is carried out in the temperature range of about 10 to about 1000C and takes up to about 24 hours to complete.
[0061] Compounds of Formula I can be prepared by proceeding as in reaction scheme 6:
Reactions Scheme 6
Figure imgf000022_0002
(11) <12>
[0062] in which n, p, Ri, R2, R3, R4, Y and Z are as defined for Formula I in the
Summary of the Invention; and Q is a halogen, preferably Cl, I or Br. Compounds of formula 12 are formed by reacting a compound of formula 11 with a suitable reactant (for example, sodium cyanide, potassium cyanide, and the like), in a suitable solvent (for example, DMF, DMSO, ethanol, water, and the like). The reaction is carried out in the temperature range of about 0 to about 1000C and takes up to about 12 hours to complete. [0063] Compounds of Formula I can be prepared by proceeding as in reaction scheme 7a and 7b:
Reactions Scheme 7a
Figure imgf000023_0001
Reactions Scheme 7b
Figure imgf000023_0002
[0064] in which n, p, Ri, R2, R3, R4, Y and Z are as defined for Formula I in the
Summary of the Invention. Compounds of formula 13 are formed by reacting a compound of formula 12 with a suitable solvent (for example, DMF, and the like) and a suitable reagent (for example, thioacetamide, and the like) under suitable acidic conditions (for example, HCl, and the like). The reaction is carried out in the temperature range of about 0 to about 12O0C and takes up to about 6 hours to complete.
[0065] Alternatively, compounds of formula 13 are formed by reacting a compound of formula 12 with a suitable solvent (for example, pyridine, and the like) and a suitable reagent (for example, H2S, and the like) under suitable basic conditions (for example, triethylamine, and the like). The reaction is carried out in the temperature range of about 0 to about 5O0C and takes up to about 6 hours to complete.
[0066] Compounds of formula 14 are formed by reacting a compound of formula 12 with a suitable solvent (for example, methanol, ethanol, and the like) and a suitable reagent (for example, ^SCVwater, and the like). The reaction is carried out in the temperature range of about 0 to about 5O0C and takes up to about 24 hours to complete. [0067] Compounds of Formula I can be prepared by proceeding as in reaction scheme 8: Reactions Scheme 8 O
R5 Rβ Q
Figure imgf000024_0001
(13/14) I
[0068] in which n, p, R1, R2, R3, R4, R5, Re, Y, Z and W are as defined for
Formula I in the Summary of the Invention; and Q is a halogen, preferably Cl, I or Br. Compounds of formula I are formed by reacting a compound of formula 13 or 14 with a compound of formula 15 optionally in the presence of a suitable solvent (for example, ethanol, and the like). The reaction is carried out in the temperature range of about 50 to about 1200C and takes up to about 24 hours to complete. [0069] Detailed reaction conditions are described in the examples, infra.
Additional Processes for Making Compounds of the Invention
[0070] A compound of the invention can be prepared as a pharmaceutically acceptable acid addition salt by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid. Alternatively, a pharmaceutically acceptable base addition salt of a compound of the invention can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base. Alternatively, the salt forms of the compounds of the invention can be prepared using salts of the starting materials or intermediates.
[0071] The free acid or free base forms of the compounds of the invention can be prepared from the corresponding base addition salt or acid addition salt from, respectively. For example a compound of the invention in an acid addition salt form can be converted to the corresponding free base by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, and the like). A compound of the invention in a base addition salt form can be converted to the corresponding free acid by treating with a suitable acid
(e.g., hydrochloric acid, etc.).
[0072] Compounds of the invention in unoxidized form can be prepared from N- oxides of compounds of the invention by treating with a reducing agent (e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, or the like) in a suitable inert organic solvent (e.g. acetonitrile, ethanol, aqueous dioxane, or the like) at 0 to 800C.
[0073] Prodrug derivatives of the compounds of the invention can be prepared by methods known to those of ordinary skill in the art (e.g., for further details see Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters, Vol.4, p. 1985). For example, appropriate prodrugs can be prepared by reacting a non-derivatized compound of the invention with a suitable carbamylating agent (e.g., 1,1-acyloxyalkylcarbanochloridate, para- nitrophenyl carbonate, or the like).
[0074] Protected derivatives of the compounds of the invention can be made by means known to those of ordinary skill in the art. A detailed description of techniques applicable to the creation of protecting groups and their removal can be found in T. W.
Greene, "Protecting Groups in Organic Chemistry", 3rd edition, John Wiley and Sons, Inc.,
1999.
[0075] Compounds of the present invention can be conveniently prepared, or formed during the process of the invention, as solvates (e.g., hydrates). Hydrates of compounds of the present invention can be conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents such as dioxin, tetrahydrofuran or methanol.
[0076] Compounds of the invention can be prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. While resolution of enantiomers can be carried out using covalent diastereomeric derivatives of the compounds of the invention, dissociable complexes are preferred (e.g., crystalline diastereomeric salts). Diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and can be readily separated by taking advantage of these dissimilarities. The • diastereomers can be separated by chromatography, or preferably, by separation/resolution techniques based upon differences in solubility. The optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization. A more detailed description of the techniques applicable to the resolution of stereoisomers of compounds from their racemic mixture can be found in Jean Jacques,
Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley
And Sons, Inc., 1981.
[0077] In summary, the compounds of Formula I can be made by a process, which involves:
[0078] (a) that of reaction schemes 1 to 8; and
[0079] (b) optionally converting a compound of the invention into a pharmaceutically acceptable salt;
[0080] (c) optionally converting a salt form of a compound of the invention to a non-salt form;
[0081] (d) optionally converting an unoxidized form of a compound of the invention into a pharmaceutically acceptable N-oxide;
[0082] (e) optionally converting an N-oxide form of a compound of the invention to its unoxidized form;
[0083] (f) optionally resolving an individual isomer of a compound of the invention from a mixture of isomers;
[0084] (g) optionally converting a non-derivatized compound of the invention into a pharmaceutically acceptable prodrug derivative; and
[0085] (h) optionally converting a prodrug derivative of a compound of the invention to its non-derivatized form.
[0086] Insofar as the production of the starting materials is not particularly described, the compounds are known or can be prepared analogously to methods known in the art or as disclosed in the Examples hereinafter.
[0087] One of skill in the art will appreciate that the above transformations are only representative of methods for preparation of the compounds of the present invention, and that other well known methods can similarly be used. Examples
[0088] The present invention is further exemplified, but not limited, by the following intermediates and examples that illustrate the preparation of compounds of Formula I according to the invention.
Figure imgf000027_0001
Br2 Step C
Figure imgf000027_0002
Intermediate 5: (2-Cyclopropyl-5-hydroxy-phenyl)-acetic acid ethyl ester.
[0089] Step A: (3-Hydroxy-phenyl)-acetic acid (10 g, 65.7 mmol) is dissolved in
EtOH (50 mL). Catalytic amounts of thionyl chloride (~0.5 mL) are added and the solution is stirred for 6 h at rt. The solvent is removed in vacuo to give (3-hydroxy-phenyl)-acetic acid ethyl ester 1 (11.8 g, quant.): MS calcd. for Ci0Hi3O3 (M+H+) 181.1, found 181.0.
[0090] Step B: (3-hydroxy-phenyl)-acetic acid ethyl ester 1 (5.93 g, 32.9 mmol) and imidazole (6.72 g, 98.7 mmol) are dissolved in DMF (16 mL) and stirred at rt for 10 min. Then TBDMSCl (7.44 g, 49.4 mmol) dissolved in DMF (4 mL) is added slowly and the mixture is stirred at rt overnight. Then water (50 mL) is added and the mixture is extracted with ether twice. The organic layers are combined, washed with water and brine, dried over MgSO4, filtered and concentrated to give [3 -(ter/-buryl-dimethyl-silanyloxy)-phenyl] -acetic acid ethyl ester 2 as an oil: 1H-NMR (400 MHz, CDCl3) δ = 6.97 (t, J= 7.8 Hz3 IH), 6.67 (d, J= 7.6 Hz, IH), 6.59 (s, IH), 6.54 (d, J= 8.1 Hz, IH), 3.95 (q, J= 7.1 Hz, 2H), 3.35 (s, 2H), 1.05 (t, J= 7.1 Hz, 3H), 0.79 (s, 9H), 0.00 (s, 6H); MS calcd. for C16H27O3Si (IVH-H+) 295.2, found 295.1. [0091] Step C: [3-(tert-Butyl-dimethyl-silanyloxy)-phenyl]-acetic acid ethyl ester
2 (9.20 g, 31.2 mmol) and potassium acetate (3.10 g, 31.2 mmol) are dissolved in acetic acid (120 mL) and cooled to 15°C. Bromine (1.60 mL, 31.2 mmol) dissolved in HOAc (60 mL) is added at a rate that kept the temperature at approx. 15°C, then the mixture is stirred at this temperature for 2 h. Insoluble salts are filtered and the solution is concentrated. The remainder is taken up in ether and washed with saturated bicarbonate, water and brine. The organic layer is dried over MgSO4, filtered and concentrated. The remainder is purified by flash chromatography (EtOAc/Hexanes gradient) to afford [2-bromo-5-(terΛbutyl-dimethyl- silanyloxy)-phenyl]-acetic acid ethyl ester 3 as a colourless oil: 1H-NMR (400 MHz, CDCl3) δ = 7.19 (d, J = 8.6 Hz, IH), 6.61 (d, J= 2.9 Hz, IH)5 6.44 (dd, J= 8.6 Hz, J= 2.9 Hz, IH), 3.99 (q, J= 7.1 Hz, 2H), 3.51 (s, 2H), 1.07 (t,J= 7.1 Hz, 3H), 0.78 (s, 9H), 0.00 (s," 6H); MS calcd. for Ci6H26O3BrSi (M+H*) 373.1, found 373.0.
[0092] Step D: [2-Bromo-5-(tert-butyl-dimethyl-silanyloxy)-phenyl]-acetic acid ethyl ester 3 (1.00 g, 2.68 mmol), potassium phosphate (1.99 g, 9.38 mmol) and cyclopropylboronic acid (0.35 g, 4.02 mmol) are dissolved in toluene (12 mL). Tricyclohexylphosphine (0.23 g, 0.80 mmol), palladium acetate (0.09 g, 0.40 mmol) and water (0.6 mL) are added and the mixture is heated to 1000C overnight. Then the mixture is diluted with EtOAc (160 mL) and washed with water and brine successively. The organic layer is dried over MgSO4, filtered and concentrated to afford crude [5-(tert-butyl-dimethyl- silanyloxy)-2-cyclopropyl-phenyl]-acetic acid ethyl ester 4 as a colourless oil: 1H-NMR (400 MHz, CDCl3) δ = 6.91 (d5 J= 8.3 Hz, IH), 6.72 (d, /= 2.6 Hz, IH), 6.65 (dd, J= 8.3 Hz, J- 2.6 Hz, IH), 4.15 (q, J= 7.1 Hz, 2H), 3.76 (s, 2H)5 1.84 (m, IH)5 1.24 (t, J= 7.1 Hz, 3H), 0.97 (s, 9H), 0.87 (m, 2H)5 0.57 (m, 2H), 0.00 (s, 6H); MS calcd. for C19H31O3S1 (MH-H+) 335.2, found 335.1.
[0093] Step E: Crude [5-(fe/-f-butyl-dimethyl-silanyloxy)-2-cycIopropyl-phenyl]- acetic acid ethyl ester 4 is dissolved in a mixture of THF (5 mL) and TBAF (5 mL) and stirred at it for 90 min. Water (75 mL) is added and the mixture is extracted with EtOAc (100 mL) twice. The organic layers are combined, washed with 0.1 M HCl and brine, dried over MgSO4, filtered and concentrated. The remainder is purified by reverse phase HPLC (H2CVMeCN gradient) to afford (2-cyclopropyl-5-hydroxy-phenyl)-acetic acid ethyl ester 5 as an oil: 1H-NMR (400 MHz, CDCl3) δ = 6.92 (d, J= 8.3 Hz, IH), 6.71 (d, J= 2.6 Hz, IH), 6.64 (dd, J= 8.3 Hz, J= 2.6 Hz, IH), 4.16 (q, J= 7.1 Hz, 2H), 3.76 (s, 2H), 1.80 (m, IH), 1.25 (t, J = 7.1 Hz, 3H), 0.85 (m, 2H), 0.55 (m, 2H); MS calcd. for Ci3H17O3 (M+H"1") 221.1, found 221.0.
Figure imgf000029_0001
Tf2O Step C
Figure imgf000029_0002
Intermediate 10: (3-Cyclopropyl-5-hydroxy-phenyl)-acetic acid methyl ester.
[0094] Step A: (3,5-Dihydroxy-phenyl)-acetic acid (5 g, 29.7 mmol) is dissolved in MeOH (30 mL). Catalytic amounts of thionyl chloride (-0.25 ml_) are added and the solution is stirred at rt overnight. The solvent is removed in vacuo to give (3,5-dihydroxy- phenyl)-acetic acid methyl ester 6 (5.44 g, quant.): MS calcd. for C9Hi iθ4 (M+H*) 183.1, found 183.0.
10095] Step B: (3,5-Dihydroxy-phenyl)-acetic acid methyl ester 6 (2.50 g, 13.9 mmol) and imidazole (3.78 g, 55.5 mmol) are dissolved in DMF (10 mL) and stirred at rt for 10 min. Then TBDMSCl (1.67 g, 11.1 mmol) dissolved in DMF (4 mL) is added slowly and the mixture is stirred at rt for 8 h. Then water (50 mL) is added and the mixture is extracted with ether twice. The organic layers are combined, washed with water and brine, dried over MgSO4J filtered and concentrated. The crude product is dissolved in DCM/hexanes 1:9 and filtered to give a mixture of bisilylated sideproduct and [3-(førf-butyl-dimethyl-silanyloxy)- 5-hydroxy-phenyl]-acetic acid methyl ester 7 as a colourless oil: MS calcd. for CiSH2SO4Si (MH-H+) 297.1. found 297.1.
[0096] Step C: [3-(tert-Butyl-dimethyl-silanyloxy)-5-hydroxy-phenyl]-acetic acid methyl ester 7 (1.81 g, 6.1 mmol) and triethyl amine (0.85 mL, 6.1 mmol) are dissolved in DCM (30 mL) and cooled to 00C. Triflic anhydride (1.03 mL, 6.1 mmol) dissolved in DCM (20 mL) is added dropwise, then the mixture is stirred at 00C for 3 h. The solution is washed with saturated bicarbonate, water and brine. The organic layer is dried over MgSO4, filtered and concentrated. The remainder is purified by flash chromatography (EtOAc/Hexanes gradient) to afford [3-(tert-butyl-dirnethyl-silanyloxy)-5- trifluoromethanesulfonyloxy-phenyl] -acetic acid methyl ester 8 as a colourless oil: 1H-NMR (400 MHz, CDCl3) δ = 6.61 (s, IH), 6.58 (s, IH), 6.44 (s, IH), 3.49 (s, 3H), 3.37 (s, 2H), 0J6 (s, 9H), 0.00 (s, 6H); MS calcd. for Ci6H24F3O6SSi (M-HH+) 429.1, found 429.1.
[0097] Step D: [3-(terr-Butyl-dimethyl-silanyloxy)-5-trifluoro- methanesulfonyloxy-phenyl]-acetic acid methyl ester 8 (0.5 g, 1.13 mmol), potassium phosphate (0.84 g, 3.96 mmol) and cyclopropylboronic acid (0.13 g, 1.472 mmol) are dissolved in toluene (6 mL). Tricyclohexylphosphine (32 mg, 0.11 mmol), palladium acetate (13 mg, 0.06 mmol) and water (0.3 mL) are added and the mixture is heated to 1000C overnight. Then the mixture is diluted with EtOAc (100 mL) and washed with water and brine successively. The organic layer is dried over MgSO4, filtered and concentrated to afford crude [3-(tert-butyl-dimethyl-silanyloxy)-5-cyclopropyl-phenyl]-acetic acid methyl ester 9 as a colourless oil: MS calcd. for Ci8H29θ3Si (M-HH+) 321.2, found 321.1.
[0098] Step E: Crude [3-(ter^butyl-dimethyl-silanyloxy)-5-cyclopropyl-phenylJ- acetic acid methyl ester 9 (0.22 g, 0.69 mmol) is dissolved in a mixture of THF (5 mL) and TBAF (5 mL) and stirred at rt for 90 min. Water (75 mL) is added and the mixture is extracted with EtOAc (100 mL) twice. The organic layers are combined, washed with 0.1 M HCl and brine, dried over MgSθ4, filtered and concentrated. The remainder is purified by reverse- phase HPLC (H∑O/MeCN gradient) to afford (3-Cyclopropyl-5-hydroxy-ρhenyl)- acetic acid methyl ester 10 as an oil: 1H-NMR (400 MHz, CDCl3) δ = 6.56 (s, IH), 6.55 (s, IH), 6.43 (s, IH), 3.69 (s, 3H), 3.53 (s, 2H), 1.81 (m, IH), 0.92 (m, 2H), 0.66 (m, 2H); MS calcd. for Ci2Hi5O3 (M+H+) 207.1, found 207.1.
Figure imgf000031_0001
Intermediates 12 and 13: (4-Bromo-3-hydroxy-phenyl)-acetic acid methyl ester and (2- bromo-3-hydroxy-phenyl)-acetic acid methyl ester.
[0099] Step A: (3-Hydroxy-phenyl)-acetic acid (3.0 g, 19.7 mmol) is dissolved in
MeOH (50 mL). Catalytic amounts of thionyl chloride (~0.1 mL) are added and the solution is stirred for 6 h at rt. The solvent is removed in vacuo to give (3-hydroxy-phenyl)-acetic acid methyl ester 11 (3.2 g, quant): MS calcd. for C9HnO3 (MH-H+) 167.1, found 167.0.
[00100] Step B: tert-Butylamine (5 mL, 48 mmol) is dissolved in toluene (40 mL) and cooled to -30°C, then bromine (1.2 mL, 24 mmol) is added dropwise and stirred at -30°C for 0.5 h. The mixture is cooled to -78°C and a solution of (3-hydroxy-phenyl)-acetic acid methyl ester 11 (4 g, 24 mmol) in DCM (20 mL) is added dropwise and stirred at rt for 16 h. 1 N HCl (20 mL) is added and the mixture is extracted with DCM (50 mL) and washed with a saturated solution OfNaHCO3 (50 mL), then brine (20 mL). The organic layer is dried over MgSO4, filtered and concentrated. The regioisomers are separated and purified by reverse phase HPLC (H2θ/MeCN gradient) to afford 12 (4-bromo-3-hydroxy-phenyl)-acetic acid methyl ester: 1H-NMR (400 MHz, CDCl3) δ = 7.39 (d, J= 8.4 Hz, IH), 6.95 (d, J= 2.0 Hz, IH), 6.73 (dd, J= 2.0, 8.4 Hz, IH), 3.70 (s, 3H), 3.55 (s, 2H); MS calcd. for C9Hi0BrO3 (M+H*) 244.9, found 245.0 and 13 (2-bromo-3-hydroxy-phenyl)-acetic acid methyl ester: 1H-NMR (400 MHz, CDCl3) δ = 7.17 (t, J= 8.0 Hz, IH), 6.94 (dd, J = 1.2, 8.0 Hz, IH), 6.86 (dd, J= 1.2, 8.0 Hz, IH), 3.79 (s, 2H), 3.72 (s, 3H); MS calcd. for C9Hi0BrO3 (M+H+) 244.9, found 245.0.
Figure imgf000032_0001
12 14 15
TBAF Step C
Figure imgf000032_0002
16
Intermediate 16: (4-Cyclopropyl-3-hydroxy-phenyl)-acetic acid methyl ester.
[00101] Step A: (4-Bromo-3-hydroxy-phenyl)-acetic acid methyl ester 12 (751 mg, 2.09 mmol) and TBDMSCl (346 mg, 2.30 mmol) are dissolved in DCM (4 mL). Triethylamine (0.44 mL, 3.13 mmol) and DMAP (25 mg, 0.21 mmol) are added and the mixture is stirred at rt for 2 h. Water (10 mL) is added and the mixture is extracted with DCM. The organic layer is washed with 1 N HCl and brine, dried over MgSO4, filtered, concentrated and purified by flash chromatography (EtOAc/Hexanes gradient) to afford [4- bromo-3-(tert-butyl-dimethyl-silanyloxy)-phenyl]-acetic acid methyl ester 14 as an oil: MS calcd. for Cj5H24BrO3Si OMH-H+) 359.1, found 359.0.
[00102] Step B: [4-Bromo-3-(/er/-butyl-dimethyl-silanyloxy)-phenyl]-acetic acid methyl ester 14 (663 mg, 1.85 mmol), potassium phosphate (1.37 g, 6.47 mmol) and cyclo- propylboronic acid (0.19 g, 2.22 mmol) are dissolved in toluene (40 mL). Tricyclohexylphosphine (42 mg, 0.18 mmol), palladium acetate (26 mg, 0.09 mmol) and water (2 mL) are added and the mixture is heated to 1000C overnight. The mixture is diluted with EtOAc (160 mL) and washed with water and brine successively. The organic layer is dried over MgSO4, filtered, concentrated and purified by flash chromatography (EtOAc/Hexanes gradient) to afford [3-(ter^butyl-dimethyl-silanyloxy)-4-cyclopropyl- phenyl]-acetic acid methyl ester 15 as a colourless oil: 1H-NMR (400 MHz, CDCl3) δ = 6.77 (d, J= 2.4 Hz, IH), 6.73 (m, 2H), 3.67 (s, 3H), 3.53 (s, 2H), 2.10 (m, IH), 1.03 (s, 9H)30.89 (m, 2H), 0.61 (m, 2H), 0.23 (s, 6H); MS calcd. for Ci8H29O3Si (M+H+) 321.2, found 321.1.
[00103] Step C: [3-(fer^Butyl-dimethyl-silanyloxy)-4-cyclopropyl-phenyl]-acetic acid methyl ester 15 (479 mg, 1.49 mmol) is dissolved in a mixture of THF (20 mL) and TBAF (1.8 mL, 1.79 mmol) and stirred at rt for 90 min. 1 N HCl (40 mL) is added and the mixture is extracted with EtOAc (40 mL). The organic layer is washed with 1 N HCl and brine, dried over MgSO4, filtered and concentrated to afford (4-cyclopropyl-3-hydroxy- phenyl)-acetic acid methyl ester 16 (0.42 g, quant.) as an oil: 1H-NMR (400 MHz, CDCl3) δ = 7.00 (d, J= 7.6 Hz5 IH), 6.79 (d, J = 1.6 Hz, IH), 6.75 (dd, J= 1.6, 7.6 Hz, IH), 3.69 (s, 3H), 3.55 (s, 2H), 1.79 (m, IH), 0.95 (m, 2H), 0.63 (m, 2H). MS calcd. for Ci2Hi5O3 (M+H*) 207.1, found 207.0.
Figure imgf000033_0001
17
Intermediate 17: (2-Cyclopropyl-3-hydroxy-phenyl)-acetic acid methyl ester.
[00104] Following the procedure for Intermediate 16, except substituting bromide
13 for bromide 12, the title compound is prepared as a clear liquid: 1H-NMR (400 MHz, CDCl3) δ = 7.12 (t, J= 1.6 Hz, IH), 6.82 (dd, J= 1.2, 8.4 Hz, IH), 6.78 (dd, J= 1.2, 7.6 Hz, IH), 3.86 (s, 2H), 3.70 (s, 3H), 1.62 (m, IH), 1.10 (m, 2H), 0.63 (m, 2H). MS calcd. for Ci2Hi5O3 (MH-H+) 207.1, found 207.0.
Figure imgf000034_0001
18 19
Step C NaOMs
Figure imgf000034_0002
20
Intermediate 20. (4-Hydroxy-2-methyl-phenoxy)-acetic acid methyl ester.
[00105] Step A: (2-Methylphenoxy)acetic acid ethyl ester (66.03 g, 340 mmol) is dissolved in dichloroethane (400 mL). Aluminum chloride (100.02 g, 750 mmol) is added and the light-brown mixture is stirred for 10 minutes at it. Acetyl chloride (35 mL, 493 mmol) is added dropwise using an addition funnel. The rate of addition is adjusted to maintain a relatively slow emission of hydrogen chloride gas. The resulting dark brown solution is allowed to cool off to rt, then is poured over 300 g of crushed ice. The mixture is diluted with DCM (300 mL) and washed successively with water, saturated NaHCθ3 solution, water, saturated NH4Cl solution, and brine. The organic layer is dried over Na2SO4, filtered and concentrated to afford 18 as a brown oil that solidified as a crystalline mass: 1H-NMR (400MHz5 CDCl3) δ = 7.79 (d, J= 2.0 Hz, IH), 7.77 (dd, J= 2.0, 8.4 Hz, IH), 6.69 (d, J= 8.4 Hz, IH), 4.71 (s, 2H), 4.26 (q, J= 7.2 Hz, 2H), 2.54 (s, 3H), 2.32 (s, 2H), 1.29 (t, J= 7.2 Hz, 3H).
Step B: (4-Acetyl-2-methyl-phenoxy) -acetic acid ethyl ester 18 {76.5 g, 324 mmol), 77% mCPBA {100.3 g, 407 mmol) and p-TsOH (13 g, 68 mmol) in dichloroethane (450 mL) are heated to 500C for 30 h. The reaction mixture is then washed with 1 M KI (2x500 mL) and NaHSO3 (2x500 mL) . The organic layer is dried (MgSO4) , filtered and concentrated to afford 19 as a brown syrup .
Step C: A solution of (4-acetoxy-2-methyl-phenoxy) -acetic acid ethyl ester 19 (from step B above) in dry MeOH (400 mL) is combined with a 0.5 M solution of NaOMe in MeOH (650 mL, 325 mmol) and stirred for 2 h at rt . The solution is neutralized with 1 M HCl and washed with H2O (2x500 mL) . The organic layer is dried (Na2SO4) , filtered and concentrated to afford 20 as a light-brown solid: 1H-NMR (400MHz, CDCl3) δ= 6.58 (d, J = 2.8 Hz, IH) , 6.54 (d, J= 8.4 Hz), 6.50 (dd, J = 2.8, 8.4 Hz, IH), 4.7 (br. s, IH), 4.54 (s, 2H), 3.73 (s, 3H), 2.17 (s, 3H). MS calcd. for C10Hi3O4 (M+H+) 197.1, found 197.4.
Figure imgf000035_0001
20 21 22
Figure imgf000035_0002
24 23
Intermediate 24: (5-Cyclopropyl-4-hydroxy-2-methyl-phenoxy) - acetic acid methyl ester.
Step A: Intermediate 20 (5 g, 26 mmol) is dissolved in DCM (100 mL) . Bromine (1.44 mL, 28 mmol) in DCM (20 mL) is added dropwise and stirred at rt for 2 h. The mixture is washed with aqueous saturated NaHCO3 (2x100 mL) and brine (20 mL) , dried over MgSO4, filtered, and concentrated. The residue is recrystallized from EtOAc/Hexanes to afford 21 (5-bromo-4- hydroxy-2-methyl-phenoxy) -acetic acid methyl ester: 1H-NMR (400 MHz, CDCl3) δ = 7.01 (s, IH), 6.98 (s, IH), 5.31 (s, IH), 4.74 (s, 2H), 3.97 (s, 3H), 2.39 (s, 3H); MS calcd. for Cx0Hi2BrO4 (M+H+) 275.0, found 297.0 (M+Na+) .
Step B: ( (5-Brotno-4-hydroxy-2-methyl-phenoxy) -acetic acid methyl ester 21 (25.5 mmol) and TBDMSCl (4.23 g, 28.0 mmol) are dissolved in DCM (100 mL) . Triethylamine (5.4 mL, , 38.2 mmol) and DMAP (311 mg, 2.5 mmol) are added and the mixture is stirred at rt for 2 h. The mixture is washed with 1 N HCl and brine, dried over MgSO4, filtered, concentrated and purified by flash chromatography (EtOAc/Hexanes gradient) to afford [5- bromo-4- ( tert-butyl-dimethyl-silanyloxy) -2-methyl-phenoxy] - acetic acid methyl ester 22 as an oil: MS calcd. for C16H26BrO4Si (M+H+) 389.1, found 389.0.
Step C: [5-Bromo-4- ( text-butyl-dimethyl-silanyloxy) -2-methyl- phenoxy] -acetic acid methyl ester 22 (2.75 g, 7.0 mmol), potassium phosphate (5.2 g, 24.5 mmol) and cyclopropylboronic acid (0.72 g, 8.4 mmol) are dissolved in toluene (80 mL) . Tricyclohexylphosphine (157 mg, 0.7 mmol), palladium acetate (98 mg, 0.35 mmol) and water (4 mL) are added and the mixture is heated to 1000C overnight. The mixture is diluted with EtOAc (140 mL) and washed with water and brine successively. The organic layer is dried over MgSO4, filtered, and concentrated to afford crude [4- (tert-butyl-dimethyl- silanyloxy) -5-cyclopropyl-2-methyl-phenoxy] -acetic acid methyl ester 23 which is used directly in the next step: MS calcd. for Ci9H3xO4Si (M+H+) 351.2, found 351.2.
Step D: [4- ( tert-Butyl-dimethyl-silanyloxy) -5-cyclopropyl-2- methyl-phenoxy] -acetic acid methyl ester 23 (1.0 g, 3.1 mmol) is dissolved in a mixture of THF (30 mL) and TBAF (3.7 mL, 3.7 mmol) and stirred at rt for 90 min. 1 N HCl (40 mL) is added and the mixture is extracted with EtOAc (40 mL) . The organic layer is washed with 1 N HCl and brine, dried over MgSO4, filtered and concentrated. The residue is triturated with hexanes to afford (5-cyclopropyl~4-hydroxy-2-methyl-phenoxy) - acetic acid methyl ester 24 as an off-white powder: 1H-NMR
(400 MHz, CDCl3) δ = 6.67 (s, IH), 6.50 (s, IH), 4.56 (s, 2H), 3.80 (S, 3H), 2.22 (s, 3H), 1.76 (m, IH), 0.94 (m, 2H), 0.59
(m, 2H). MS calcd. for C13Hi7O4 (M+H+) 237.1, found 237.0.
Figure imgf000037_0001
Intermediate 25: (4-Hydroxy-phenoxy) -acetic acid methyl ester .
(4-Hydroxy-phenoxy) -acetic acid (10.98 g, 65.3 mmol) is dissolved in methanol (50 mL) . Catalytic concentrated sulfuric acid (0.2 mL) is added and the mixture is heated to reflux overnight. Cooling, treatment with solid NaHCO3 and activated charcoal, drying over MgSO4, filtration and concentration yielded a white solid (12.86 g, quant.) : 1H-NMR
(400 MHz, CDCl3) δ = 7.80 (d, J = 9.2 Hz, 2H), 6.75 (d, J = 9.2 Hz, 2H), 4.58 (s, 2H), 3.80 (s, 3H). MS calcd. for C9H11O4
(M+H+) 183.1, found 183.0.
Figure imgf000037_0002
Intermediate 26: (3-Cyclopropyl-4-hydroxy-phenoxy) -acetic acid methyl ester.
Following the procedure for intermediate 24, except substituting intermediate 25 for intermediate 20 in step A, the title compound is prepared as a clear solid: 1H-NMR (400 MHz, CDCl3) δ = 6.77 (dd, J = 1.2, 7.6 Hz, IH), 6.68 (m, 2H), 4.56 (s, 2H), 3.80 (s, 3H), 1.81 (τn, IH), 0.96 (m, 2H), 0.64 (m, 2H) . MS calσd. for C12Hi5O4 (M+H+) 223.1, found 223.0.
Figure imgf000038_0001
Intermediate 28: 2- (4-Hydroxy-phenoxy) -2-methyl-propionic acid methyl ester.
Step A: 4- (Benzyloxy) phenol (5.0 g, 25 mmol) is dissolved in DMF (40 mL) . To the solution is added NaH (60% dispersion, 1.1 g, 27.5 mmol) in portions while it is kept at rt . After stirring the suspension for 30 min at rt methyl -α- bromoisobutyrate (9.05 g, 50 mmol) is added dropwise. The mixture is stirred at 500C for 3 h, then concentrated. The remainder is diluted with water (200 mL) and extracted with EtOAc (3x150 mL) . The organic layer is separated and dried over MgSO4, filtered and concentrated. The crude product is purified by flash chromatography (silica, Hex/EtOAc gradient) to afford 2- (4 -benzyloxy-phenoxy) -2 -methyl -propionic acid methyl ester 27 as a clear oil: 1H-NMR (400MHz, CDCl3) δ = 7.44-7.33 (m, 5H), 6.85 (m, 4H), 5.01 (s, 2H), 3.78 (s, 3H), 1.55 (s, 6H) . MS calculated for C18H2IO4 (M+H+) 301.1, found 301.4.
Step B: 2 - (4-Benzyloxy-phenoxy) -2-methyl-propionic acid methyl ester 27 (0.5 g, 1.7 mmol) is dissolved in EtOH (15 mL) . After addition of a catalytic amount of palladium (0) on charcoal the mixture is aubjected to 1 atm hydrogen and stirred for 5 h at rt . Then the mixture is filtered through Celite 545 , the solvent is removed and the remainder dried on high vacuum to yield 2- (4 -hydroxy-phenoxy) -2-methyl-propionic acid methyl ester 28 as a brown oil: 1H-NMR (400MHz, CDCl3) δ = 6.76 (d, J = 9.0 Hz, 2H), 6.69 (d, J = 9.0 Hz, 2H) , 3.78 (s, 3H) , 1,53 (s, 6H) . MS calculated for C11H13O4 (M+H+) 211.1, found 211.3.
Figure imgf000039_0001
31
Intermediate 31: [2-Methyl-4- (2-thiocarbamoyl-ethoxy) - phenoxy] -acetic acid methyl ester.
Step A: (4-Hydroxy-2-methyl-phenoxy) -acetic acid methyl ester 20 (3.0 g, 15.3 mmol) and 1, 2-dibromoethane (13.2 mL, 153 mmol) are dissolved in dry acetone (100 mL) . Cs2CO3 (25 g, 76.5 mmol) is added and the mixture is heated at reflux for 16 h. The mixture is cooled, filtered, concentrated and purified by flash chromatography (EtOAc/Hexanes gradient) to afford [4- (2-bromo-ethoxy) -2-methyl-phenoxyl -acetic acid methyl ester 29 as a white powder: 1H-NMR (400 MHz, CDCl3) δ = 6.70 (s, IH), 6.59 (m, 2H), 4.53 (s, 2H), 4.15 (t, J= 6.4 Hz, 2H), 3.73 (s, 3H), 3.53 (t, J = 6.4 Hz, 2H), 2.20 (s, 3H). MS calcd. for Ci2H16BrO4 (M+H+) 303.0, found 303.0
Step B: [4- (2-Bromo-ethoxy) -2-methyl-phenoxy] -acetic acid methyl ester 29 (100 mg, 0.33 mmol), and NaCN (16 mg, 0.33 mmol) are dissolved in DMSO (3 mL) and stirred at rt for 6 h. The mixture is diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL) . The organic layers are combined, washed with water (20 mL) and brine (20 mL) , dried (MgSO4) , filtered, and concentrated to give crude [4- (2-cyano-ethoxy) -2-methyl- phenoxy] -acetic acid methyl ester 30: 1H-NMR (400 MHz, CDCl3) δ = 6.89 (s, IH), 6.58 (s, 2H), 4.53 (s, 2H), 4.06 (t, J = 6.4 Hz, 2H)7 3,72 (S, 3H), 2.71 (t, J = 6.4 Hz, 2H), 2.20 (s, 3H). MS calcd. for C13Hi5NO4 (M+H+) 250.1, found 250.1.
Step C: [4- (2-Cyano-ethoxy) -2-methyl-phenoxy] -acetic acid methyl ester 30 (236 mg, 0.95 mmol) and thioacetamide (178 tng, 2.37 mmol) are dissolved in dimethylformamide (0.8 mL) . HCl (0.9 mL of 4N in dioxane, 3.61 mmol) is added and the mixture is heated at 100° C for 2 h. The mixture is cooled and poured into a saturated solution of NaHCO3 (50 mL) and extracted with EtOAc (50 mL) . The organic layer is washed with water, then brine, dried (MgSO4) , filtered and evaporated to give [2- methyl-4- (2 -thiocarbatnoyl-ethoxy) -phenoxy] -acetic acid methyl ester 31 as a red oil. MS calcd. for Ci3Hi8NO4S (M+H+) 284.1, found 284.1.
Intermediate 32: [2-Methyl-4- (3-thiocarbamoyl-propoxy) - phenoxy] -acetic acid methyl ester.
Following the procedure of Intermediate 31, except substituting 1,3 dibromopropane for 1, 2-dibromoethane, the title compound is prepared a red oil: MS calcd. for Ci4H20NO4S (M+H4") 298.1, found 298.1.
Figure imgf000040_0002
33 Intermediate 33: [2-Methyl-4- (3-thiocarbamoyl-propoxy) - phenoxy] -acetic acid methyl ester.
Following the procedure of Intermediate 31, except substituting 1,4 dibroraobutane for 1,2-dibromoethane, the title compound is prepared a red oil: 1H-NMR (400 MHz, CDCl3) δ = 6.65 (s, IH), 6.56 (m, 2H), 4.52 (s, 2H), 3.86 (t, J = 6.4 Hz, 2H), 3.72 (s, 3H), 2;67 (t, J-= 7.2 Hz, IH), 2.19 (s, 3H), 1.88 (m, 2H), 1.75 (m, 3H). MS calcd. for C15H22NO4S (M+H+) 312.1, found 312.1.
Figure imgf000041_0001
34
Intermediate 34: [5-Cyclopropyl-2-methyl-4- (2-thiocarbamoyl- ethoxy) -phenoxy] -acetic acid methyl ester.
Following the procedure of Intermediate 31, except substituting (5-cyclopropyl-4-hydroxy-2-methyl-phenoxy) -acetic acid methyl ester 24 for (4-Hydroxy-2-methyl -phenoxy) -acetic acid methyl ester 20, the title compound is prepared a red oil. MS calcd. for Ci6H22NO4S (M+H+) 324.1, found 324.1.
Figure imgf000041_0002
Intermediate 35: [3- (2-Thiocarbamoyl-ethoxy) -phenyl] -acetic acid methyl ester.
Following the procedure of Intermediate 31, except substituting (3 -hydroxy-phenyl) -acetic acid methyl ester 11 for (4-Hydroxy-2-methyl-phenoxy) -acetic acid methyl ester 20, the title compound is prepared a red oil: 1H-NMR (400 MHz, CDCl3) δ s= 7.12 (t, J = 8.8 Hz, IH) , 6.76 (m, 3H) , 4.13 (t, J = 6.4 Hz, 2H) , 3.63 (s, 3H), 3.53 (m, 3H) , 2.76 (t, J" = 6.4 Hz, IH) . MS calcd. for C12H16NO3S (M+H+) 254.1, found 254.1.
Figure imgf000042_0001
36
Intermediate 36: [4-Cycloρropyl-3- (2-thiocarbamoyl-ethoxy) - phenyl] -acetic acid methyl ester.
Following the procedure of Intermediate 31, except substituting (4-Cyclopropyl-3-hydroxy-phenyl) -acetic acid methyl ester 16 for (4-Hydroxy-2-methyl-phenoxy) -acetic acid methyl ester 20, the title compound is prepared a red oil. MS calcd. for Ci5H20NO3S (M+H+) 294.1, found 294.1.
Figure imgf000042_0002
Intermediate 37: [2-Cyclopropyl-3- (2-thiocarbamoyl-ethoxy) - phenyl] -acetic acid methyl ester.
Following the procedure of Intermediate 31, except substituting (2-Cyclopropyl-3-hydroxy-phenyl) -acetic acid methyl ester 17 for (4-Hydroxy-2-methyl-phenoxy) -acetic acid methyl ester 20, the title compound is prepared a red oil. MS calcd. for C15H20NO3S (M+H+) 294.1, found 294.1.
Figure imgf000042_0003
38 Intermediate 38: 2-Methyl-2- [4- (2-thiocarbamoyl-ethoxy) - phenoxy] -propionic acid methyl ester.
Following the procedure of Intermediate 31, except substituting 2- (4-Hydroxy-phenoxy) -2-methyl-propionic acid methyl ester 28 for (4-Hydroxy-2-methyl-phenoxy) -acetic acid methyl ester 20, the title compound is prepared a red oil. MS calcd. for C14H20NO4S (M+H+) 298.1, found 298.1.
Figure imgf000043_0001
Intermediate 40. (2-Methyl-4-thiocarbamoylmethoxy-phenoxy) - acetic acid methyl ester.
Step A: (4-Hydroxy-2-methyl-phenoxy) -acetic acid methyl ester 20 (500 mg, 2.55 mmol) and chloroacetonitrile (0.16 mL, 2.55 mmol) are dissolved in dry acetonitrile (10 mL) . Cesium carbonate (1.6 g, 5.1 mmol) is added and the mixture is stirred at rt for 16 h. The mixture is filtered and concentrated to afford (4-cyanomethoxy-2-methyl-phenoxy) - acetic acid methyl ester 39 as a colorless glass. 1H-NMR (400MHz, CDCl3) 6.76 (s, IH), 6.67 (d, J" = 8.4 Hz, IH), 6.60 (d, J= 8.4 Hz, IH), 4.62 (s, 2H), 4.54 (s, 2H), 3.72 (S, 3H), 2.21 (s, 3H). MS calcd. for C12H14NO4 (M+H+) 236.1, found 236.1.
Step B: (4-Cyanomethoxy-2-methyl-phenoxy) -acetic acid methyl ester 39 (5.85 g, 24.8 mmol) and thioacetamide (4.76 g, 63.3 mmol) are dissolved in dimethylformamide (15 mL) . HCl (24 mL of 4N in dioxane, 95 mmol) is added and the mixture is heated at 100 °C for 2 h. The mixture is cooled and poured into a saturated solution of NaHCO3 (20 mL) and extracted with EtOAc (50 mL) . The organic layer is washed with water, then brine, dried (MgSO4) , filtered and concentrated. The residue is triturated with, diσhloromethane and filtered to give (2- Methyl-4-thiocarbamoylmethoxy-phenoxy) -acetic acid methyl ester 40 as a beige powder: 1H-NMR (400MHz, DMSO-d6) 6.84 (d, J = 2.8 Hz, IH), 6.78 (d, J = 8.8 Hz1 IH), 6.71 <dd, J = 8.8, 2.8 Hz, IH), 4.73 (s, 2H), 4.67 (s, 2H), 3.70 (ε, 3H), 2.18 (s, 3H). MS calcd. for C12H15NO4S (M+H+) 270.1, found 270.3.
Figure imgf000044_0001
Step C
Figure imgf000044_0002
Intermediate 43. (5-Bromo-2-methyl-4-thiocarbatnoylmethoxy- phenoxy) -acetic acid methyl ester.
Step A: (4-Hydroxy-2 -methyl-phenoxy) -acetic acid methyl ester 20 (5 g, 25.5 tnπiol) is dissolved in dichloromethane (100 mL) . Bromine (1.44 mL, 28.0 mmol) in dichloromethane (20 mL) is added and the mixture is stirred at rt for 3 h. Then the mixture is washed with water, saturated solutions of NaHCO3 and sodium bisulfite, dried (MgSO4) , filtered and concentrated. The residue is purified by flash chromatography (EtOAc/Hexanes gradient) to afford the (5-bromo-4-hydroxy-2- methyl-phenoxy) -acetic acid methyl ester 41. 1H-NMR (400MHz, CDCl3) 7.01 (S, IH), 6.98 (s, IH), 5.32 (br . S, IH), 4.74 (s, 2H), 3.98 (s, 3H), 2.39 (s, 3H). MS calcd. for Ci0H12BrO4 (M+H+) 275.0, found 297.0 (+Na+).
Step B: (5-Bromo-4-hydroxy-2-methyl-phenoxy) -acetic acid methyl ester 41 (3.0 g, 9.31 mmol) and chloroacefonitrile (0.62 mil, 9.78 mmol) are dissolved in dry acetonitrile (50 mL) . Cesium carbonate (6.07 g, IB.62 mmol) is added and the mixture is stirred at rt for 2 Ii. The mixture is filtered and concentrated to afford crude (5-brσmo-4-cyanomethoxy-2-methyl- phenoxy) -acetic acid methyl ester 42 which is used in the next step without further purification. MS calcd. for C12Hi3BrNO4
(M+H+) 314.0, found 313.9.
Step C: (5-Bromo-4-cyanomethoxy-2-methyl-phenoxy) -acetic acid methyl ester 42 (9.3 mmol) and thioacetamide (1.75 g, 23.2 mmol) are dissolved in dimethylformamide (7 mL) . HCl (9 mL of 4N in dioxane, 35.3 mmol) is added and the mixture is heated at 100° C for 2 h. The mixture is cooled and poured into a saturated solution of NaHCO3 (20 mL) and extracted with EtOAc (20 mL) . The organic layer is washed with water, then brine, dried (MgSO4), filtered and concentrated. The residue is recrystallized from dichloromethane/hexanes to give (5-Bromo- 2-methyl-4-thiocarbamoylmethoxy-phenoxy) -acetic acid methyl ester 43 as a beige powder. 1H-NMR (400MHz, CDCl3) 8.27 (s, IH), 7.68 (s, IH), 6.91 (s, IH), 6.76 (s, IH), 4.85 (s, 2H), 4.61 (s, 2H), 3.81 (s, 3H), 2.25 (s, 3H). MS calcd. for Ci2Hi5BrNO4S (M+H+) 348.0, found 347.9.
Figure imgf000045_0001
Intermediate 46: (±) -2-Ethoxy-3- (4 -hydroxy-phenyl) -propionic acid ethyl ester.
Step A: 4-Hydroxybenzaldehyde (7.03 g, 57.6 mmol) is dissolved in acetonitrile (60 mL) . Powdered potassium carbonate (11.98 g, 86.7 mmol) is added while stirring, followed by dropwise addition of the benzyl bromide (7 mL, 59 mmol) . The mixture is vigorously stirred under nitrogen for 3 h. Filtration and concentration yielded 4-benzyloxy- benzaldehyde 44 (12.4 g, quant.) as a white solid: 1H-NMR (400 MHz, CDCl3) δ = 9.89 (s, IH), 7.84 (d, J" = 8.8 Hz, 2H), 7.40 (in, 5H), 7.08 (d, J = 8.8 Hz, 2H), 5.16 (s, 2H). MS calcd. for Ci4Hi3O2 (M+H+) 213.1, found 213.2.
Step B: 4-Benzyloxy-benzaldehyde 44 (1.24 g, 5.84 mmol) and ethyl ethoxyacetate (1.2 mL, 8.8 mmol) are dissolved in dry THF (30 mil) . Solid potassium teirt-butσxide (1.45 g, 12.9 mmol) is added and the mixture is stirred under nitrogen overnight. The resulting suspension is filtered through Celite 545. The solids are thoroughly washed with THF. The combined organic solutions are concentrated to yield 3- (4- benzyloxy-phenyl) -2-ethoxy-acrylic acid ethyl ester 45 as an oil. The crude material is used as such in the next step: 1H-NMR (400 MHz, CDCl3) δ = 7.75 (d, J= 8.8 Hz, 2H), 7.37 (m, 5H), 6.96 (d, ιT = 8.8 Hz, 2H), 6.95 (s, IH), 5.09 (s, 2H), 4.29 (q, J = 7.2 Hz, 2H), 3.98 (q, J" = 7.1 Hz, 2H), 1.35 (m, 6H). MS calcd. for C20H23O4 (M+H+) 327.2, found 327.2.
Step C: 3- (4-Benzyloxy-phenyl) -2-ethoxy-acrylic acid ethyl ester 45 (0.80 g, 2.45 mmol) is dissolved in ethanol (40 mL) .
The solution is degassed with nitrogen, then treated with a catalytic amount of 5% palladium black on carbon (0.28 g, 0.13 mmol) . The solution is shaken under 60 psi hydrogen for 5 h.
Filtration and concentration yielded (±) -2-ethoxy-3- (4- hydroxy-phenyl) -propionic acid ethyl ester 46 as an oil. 1H- NMR (400 MHz, CDCl3) δ = 7.10 (d, J" = 8.4 Hz, 2H), 6.74 (d, J = 8.4 Hz, 2H), 4.18 (q, J = 7.2 Hz, 2H), 3.97 (t, J = 6.9 Hz, IH), 3.60 (m, IH), 3.36 (m, IH), 2.94 (d, J = 6.6 Hz, 2H), 1.23 (t, J = 7.2 Hz, 3H), 1.17 (t, J" = 7.0 Hz, 3H). MS calcd. for C13H19O4 (M+H+) 239.1, found 239.1.
Figure imgf000046_0001
Intermediate 47 : (±) -2-Ethoxy-3- (4-hydroxy-2-methyl-phenyl) - propionic acid ethyl ester.
Following the procedure for Intermediate 46, except substituting 4-hydroxy-2-methylbenzaldehyde for 4- hydroxybenzaldehyde, the title compound is prepared as a clear oil: MS calcd. for C14H20NaO4 (M+Na+) 275.1, found 275.1.
Figure imgf000047_0001
48
Intermediate 48: (±) -2-Ethoxy-3- (4-hydroxy-2 , 5-dimethyl- phenyl) -propionic acid ethyl ester.
Following the procedure for Intermediate 46, except substituting 4-hydroxy-2 , 5-dimethylbenzaldehyde for 4- hydroxybenzaldehyde, the title compound is prepared as a clear oil: MS calcd. for Ci4H20NaO4 (M+Na+) 275.1, found 275.2.
<^CO2CH,
Figure imgf000047_0002
Intermediate 51: 3- (4-Hydroxy-2-methyl-phenyl) -propionic acid methyl ester.
Step A: 4-Bromo-3-methyl-phenol (25.11 g, 134 mmol) is dissolved in acetonitrile (125 mL) . Powdered potassium carbonate (25.69 g, 186 mmol) is added while stirring, followed by dropwise addition of benzyl bromide (17 mL, 143 mmol) . The mixture is vigorously stirred under nitrogen for 6 h. Filtration through a plug of Celite 545 and concentration yielded 4-benzyloxy-1-bromo-2-methyl-benzene 49 as an off- white solid: 1H-NMR (400 MHz, CDCl3) δ = 7.35 (m, 6H), 6.87 (d, J = 2.8 Hz, IH), 6.68 (dd, J = 8.8, 2.8 Hz, IH), 5.02 (s, 2H) , 2.36 (s, 3H) .
Step B: 4-Benzyloxy-l-bromo-2-methyl-benzene 49 (24.0 g, 86.6 tntnol) , tri-o-tolyl-phosphane (15.00 g, 49.3 tnmol) , ethyl diisopropylamine (35 mL, 212 mmol) and methyl acrylate (35 mL, 388 tnmol) are dissolved in propionitrile (200 mL) . The mixture is degassed with argon. Solid palladium (II) acetate (4.00 g, 17.8 mmol) is added and the mixture is heated to 100°C for 18 h/ The mixture is cooled and filtered through a plug of Celite 545. Concentration and silica gel purification (0-40% gradient of ethyl acetate in hexanes) yielded 3-(4~ benzyloxy-2-methyl-phenyl) -acrylic acid ethyl ester 50 as an oil (30.8 g, quant.): 1H-NMR (400 MHz, CDCl3) δ = 7.92 (d, J" = 15.8 Hz, IH), 7.52 (d, J = 9.4 Hz, IH), 7.39 (m, 5H), 6.82 (m, 2H), 6.26 (d, J" = 15.8 Hz, IH), 5.08 (s, 2H), 3.80 (s, 3H), 2.42 (s, 3H). MS calcd. for C18H19O3 (M+H+) 283.2, found 283.2.
Step C: 3- (4-Benzyloxy-2-methyl-phenyl) -acrylic acid ethyl ester 50 from Step B above is dissolved in ethyl acetate (200 mL) and ethanol (20 mL) . The solution is degassed with nitrogen, then treated with 5% palladium black on carbon (1.15 g, 1.08 mmol, 1 mol%) . The solution is shaken under 40 psi hydrogen for 15 h. Filtration and concentration yielded 3- (4- hydroxy-2-methyl-phenyl) -propionic acid methyl ester 51 as an oil: 1H-NMR (400 MHz, CDCl3) δ = 6.98 (d, J = 8.1 Hz , IH), 6.64 (d, J = 2.6 Hz, IH) , 6.60 (dd, J = 8.1, 2.6 Hz, IH) , 4.93 (S, IH),, 3.68 (s, IH), 2.86 (t , J"= 8.8 Hs, 2H), 2.55 (d, J = 8.8 Hz, 2H), 2.26 (s, 3H). MS calcd. for C11H14NaO3 (M+Na+) 217.1, found 217.1.
Figure imgf000049_0001
52 53 54
Intermediate 54: (±) -3- (4-Hydroxy-phenyl) -2-methyl-propionic acid methyl ester.
Step A: 4-Bromophenol (3.55 g, 20.5 mmol) is dissolved in acetonitrile (50 mL) . Powdered potassium carbonate (3.86 g, 27.9 mmol) is added while stirring, followed by dropwise addition of benzyl bromide (2.4 mL, 20.2 mmol). The mixture is vigorously stirred under nitrogen for 6 h. Filtration and concentration yielded 4-benzyloxy-bromobenzene 52 (5.52 g, quant.) as an oil that slowly solidified: 1H-NMR (400 MHz, CDCl3) δ = 7.37, (m, 7H), 6.87 (m, 2H), 5.07 (s, 2H).
Step B: 4-Benzyloxy-bromobenzene 52 (1.30 g, 5.2 mmol), tri- o-tolyl-phosphane (0.98 g, 3.2 mmol), ethyl diisopropylamine (2 mL, 12.1 mmol) and methyl methacrylate (2.20 mL, 20.7 mmol) are dissolved in propionitrile (100 mL) . The mixture is degassed with argon. Solid palladium(II) acetate (0.26 g, 1.2 mmol) is added and the mixture is heated to 1000C for 18 h. The mixture is cooled and filtered through a plug of Celite 545. Concentration and silica gel purification (10-60% gradient of ethyl acetate in hexanes) yielded a 1:1 mixture of isomeric olefins 53 as an oil. Used the mixture as such in the next step: MS calcd. for C18H19O3 (M+H+) 283.1, found 283.1.
Step C: The 1:1 olefin mixture 53 from Step B above is dissolved in ethyl acetate (50 mL) and ethanol (10 mL) . The solution is degassed with nitrogen, then treated with a catalytic amount of 5% palladium black on carbon (0.50 g, 7 τnol%) . The .solution is shaken under 60 psi hydrogen for 15 h. Filtration and concentration yielded (±) -3- (4-hydroxy- phenyl) -2-methyl-propionic acid methyl ester 54 as an oil: 1H-NMR (400 MHz, CDCl3) δ = 7.01 (d, J" = 8.6 Hz, 2H) , 6.74 (d, J = 8.6 Hz, 2H) , 3.63 (s, 3H) , 2.94 (dd, J = 13.1, 6.7 Hz, IH) , 2.69 (dqd, J" = 7.4, 6.8, 6.7 Hz, IH)', 2.60 (dd, J = 13.1, 7.4 Hz, IH) , 1.14 (d, J = 6.8 Hz, 3H) . MS calcd. for
C11H14NaO3 (M+Na+) 217.1, found 217.1.
Figure imgf000050_0001
Intermediate 55: (±) -3- (4-Hydroxy-phenyl) -butyric acid methyl ester.
Following the procedure for Intermediate 54, except substituting methyl crotonate for methyl methacrylate in Step B, the title compound is prepared as a clear liquid: 1H-NMR
(400 MHz, CDCl3) δ = 7.08 (d, J = 8.9 Hz, 2H), 6.75 (d, J = 8.6 Hz, 2H), 4.91 (s, IH), 3.62 (s, 3H), 3.22 (m, IH), 2.55
(m, 2H) , 1.27 (d, J" = 7.0 Hz, 3H) . MS calcd. for C11H14NaO3
(M+Na+) 217.1, found 217.1.
Figure imgf000050_0002
Intermediate 60: 3- (2-Cyclopropyl-5-hydroxy-phenyl) -propionic acid methyl ester.
Step A: 3- (3 -Hydroxy-phenyl) -propionic acid (24.88 g, 149.7 mmol) is dissolved in methanol (50 mL) . Thionyl chloride (5 π\L, 68.7 mmol) is added dropwise with vigorous stirring. The mixture is stirred at 600C for 3 h. Cooling and concentration yielded 3- (3 -hydroxy-phenyl) -propionic acid methyl ester 56
(29.26 g, quant.) as an oil: 1H-NMR (400 MHz, CDCl3) δ = 7.15
(dd, J = 8.4, 7.6 Hz, IH), 6.75 (d, J" = 7.6 Hz, IH), 6.69 (m,
2H), 3.68 (s, 3H), 2.90 (t, J = 7.6 Hz, 2H), 2.63 (t, J" = 7.6
Hz, 2H) .
Step B: 3- (3 -Hydroxy-phenyl) -propionic acid methyl ester 56 (3.16 g, 17.5 mmol) is dissolved in DCM (40 mL) . Powdered calcium carbonate (2.27 g, 22.7 mmol) is added. While the suspension is vigorously stirred, a solution of bromine (0.90 mL, 17.6 mmol) in DCM (30 mL) is added dropwise. After the addition is completed, the suspension is treated with 0.2 g sodium bisulfite in' water (5 mL) . The organic layer is dried over MgSO4, filtered and concentrated to yield 3- (2-bromo-5- hydroxy-phenyl) -propionic acid methyl ester 57 as a colourless oil. XH-NMR (400 MHz, CDCl3) δ = 7.36 (d, J = 8.6 Hz, IH), 6.76 (d, J= 3.0 Hz, IH) , 6.60 (dd, J" = 8.6, 3.0 Hz, IH) , 5.46 (s, IH), 3.69 (s, 3H), 3.00 (t, J = 7.9 Hz, 2H), 2.65 (t, J = 7.9 Hz, 2H) .
Step C: 3- (2-Bromo-5-hydroxy-phenyl) -propionic acid methyl ester 57 (4.45 g, 17.2 mmol) is dissolved in DCM (80 mL) . Imidazole (1.45 g, 21.3 mmol) is added and the mixture is stirred at rt until it became homogenous. te_rt-Butyl dimethylchlorosilane (2.66 g, 17.7 mmol) is added and the mixture is stirred at rt for 18 h. Washing with water, drying over MgSO4 and concentration yielded 3- [2-bromo-5- ( text-butyl- dimethyl-silanyloxy) -phenyl] -propionic acid methyl ester 58 as an oil: 1H-NMR (400 MHz, CDCl3) (two major rotamers are present; the data is given for the most abundant isomer) δ = 7.35 (d, J = 8.6 Hz, IH), 6.74 (d, J = 2.9 Hz, IH), 6.58 (dd, J = 8.6, 2.9 Hz, IH), 3.69 (s, 3H), 2.99 (t, -J = 8.2 Hz, 2H), 2.63 (t, J = 8.2 Hz, 2H), 0.97 (s, 9H), 0.18 (s, 6H). MS calcd. for C16H26BrO3Si (M+H+) 373.1, found 373.1. Step D: 3- [2-Broτno-5- ( tert-butyl-dimethyl-silanyloxy) - phenyl] -propionic acid methyl ester 58 (5.74 g, 15.4 mmol) is dissolved in toluene (165 mL) . Cyσlopropylboroniσ acid (2.22 g, 25.8 mmol), potassium phosphate (11.71 g, 55.2 mtnol) , and tricyclohexyl-phosphane (1.81 g, 6.5 mmol) are added, followed by water (10 mL) . The mixture is degassed with argon. Palladium (II) acetate (0.70 g, 3.1 mmol) is added. The mixture is heated to 95°C for 3.5 h. Cooling, separation of the organic layer, drying over MgSO4 and concentration, followed by silica gel chromatography (0-25% gradient, ethyl acetate in hexanes) yielded 3- [5- ( tejrt-butyl-dimethyl- silanyloxy) -2-cyclopropyl-phenyl] -propionic acid methyl ester 59 as an oil: 1H-NMR (400 MHz, CDCl3) δ = 6.84 (d, J = 8.3 Hz, 1H> , 6.63 (d, J = 2.5 Hz, IH), 6.59 (dd, J = 8.3, 2.5 Hz, IH), 3.70 (S, 3H), 3.08 <t, J = 7.8 Hz, 2H), 2.64 (t, J = 7.8 Hz, 2H), 1.83 (m, IH), 0.97 (s, 9H), 0.88 (m, 2H), 0.58 (m, 2H), 0.16 (S, 6H). MS calcd. for Ci9H31O3Si (M+H+) 335.2, found 335.2.
Step E: 3- [5- ( tert-Butyl-dimethyl-silanyloxy) -2-cyclopropyl- phenyl] -propionic acid methyl ester 59 (2.87 g, 8.6 mmol) is dissolved in THF (30 mL) . A I M solution of tetra- (π- butyl) ammonium fluoride in THF (10 mL, 10 mmol) is added. The mixture is stirred at rt for 4 h. Concentration to dryness and purification by silica gel chromatography (10-60% gradient, ethyl acetate in hexanes) yielded 3- (2-σyclopropyl- 5-hydroxy-phenyl) -propionic acid methyl ester 60: 1H-NMR (400 MHz, CDCl3) δ = 6.87 (d, J = 8.3 Hz, IH) , 6.65 (d, J" = 2.7 Hs, IH), 6.60 (dd, J = 8.3, 2.7 Hz, IH), 4.96 (s, IH), 3.70 (s, 3H), 3.09 (t, J - 7.8 Hz, 2H), 2.65 (t, J = 7.8 Hz, 2H), 1.82
(m, IH), 0.88 (m, 2H), 0.58 (m, 2H). MS calcd. for Ci3Hi7O3
(M+H+) 221.1, found 221.1.
Figure imgf000053_0001
. OH >-B Pd/L Step C OH
Figure imgf000053_0002
DMS
64 63
Intermediate 64: 3- (5 -Cyclopropyl-4-hydroxy-2-methyl-phenyl) - propionic acid methyl ester.
Step A: 3- (4-Hydroxy-2-methyl -phenyl) -propionic acid methyl ester 51 (2.50 g, 12.9 tnmol) is dissolved in DCM (60 mL) and cooled to 00C. Powdered calcium carbonate (2.27 g, 22.7 mmol) is added. While the suspension is vigorously stirred, a solution of bromine (0.90 mL, 17.6 mmol) in DCM (20 mL) is added dropwise. After the addition is completed, the suspension is warmed up to rt and treated with 0.2 g sodium bisulfite and 5 mL water, followed by drying over MgSO4, filtration and concentration to yield 3- (5-bromo-4-hydroxy-2- methyl-phenyl) -propionic acid methyl ester 61 (3.67 g, quant.) as a colourless oil that slowly solidified. 1H-NMR (400 MHz, CDCl3) δ = 7.21 (s, IH),.6.82 (s, IH), 5.30 (s, IH), 3.69 <S, 3H), 2.85 (t, J" = 7.5 Hz, 2H), 2.54 (t, J" = 7.5 Hz, 2H), 2.24 (s, 3H) .
Step B: 3- (5-Bromo-4 -hydroxy-2-methyl-phenyl) -propionic acid methyl ester 61 (from Step A above) is dissolved in DCM (45 mL) ., Imidazole (1.12 g, 16.5 mmol) is added and the mixture is stirred at rt until it became homogenous. tert-Butyl dimethylchlorosilane (2.10 g, 13.9 mmol) is added and the mixture is stirred at rt for 18 h. Washing with water, drying the organic phase over MgSO4 and concentration yielded 3- [5- bromo-4- ( te-trt-butyl-dimethyl-silanyloxy) -2-methyl-phenyl] - propionic acid methyl ester 62 as an oil: 1H-NMR (400 MHz, CDCl3) δ = 7.25 (s, IH), 6.65 (s, IH), 3.68 (s, 3H), 2.83 (t, J = 7.6 Hz, 2H) , 2.54 (t, J= 7.6 Hz, 2H) , 2.21 (s, 3H) , 1.03 (s, 9H) , 0.23 (s, 6H) .
Step C: 3- [5-Bromσ-4- ( fcerfc-butyl-dimethyl-silanyloxy) -2- methyl-phenyl] -propionic acid methyl ester 62 (4.67 g, 12.1 mmol) is dissolved in toluene (70 mL) . Cyclopropylboronic acid (1.95 g, 22.7 mmol), potassium phosphate (9.15 g, 43.1 mmol) , and tricyclohexyl-phosphane (1.44 g, 5.13 mmol) are added, followed by water (10 mL) . The mixture is degassed with argon. Palladium(II) acetate (0.55 g, 2.45 mmol) is added. The mixture is heated to 95°C for 3.5 h. Cooling, separation of the organic layer, drying over MgSO4 and concentration, followed by silica gel chromatography (0-20% gradient, ethyl acetate in hexanes) yielded 3- [4- ( teαrfc-butyl- dimethyl-silanyloxy) -5-cyclopropyl-2-methyl-phenyl] -propionic acid methyl ester 63 as an oil: 1H-NMR (400 MHz, CDCl3) δ = 6.56 (s, IH), 6.54 (s, IH), 3.67 (s, 3H), 2.81 (t, J = 7.7 Hz, 2H), 2.51 (t, J = 7.7 Hz, 2H), 2.21 (S, 3H), 1.76 (m, IH), 1.01 (s, 9H)1 0.85 (m, 2H), 0.57 (m, 2H), 0.22 (s, 6H). MS calcd. for C20H33O3Si (M+H+) 349.2, found 349.2.
Step D: 3- [4- ( te-rt-Butyl-dimethyl-silanyloxy) -5-cyclopropyl- 2-methyl-phenyl] -propionic acid methyl ester 63 (4.23 g, 12.1 mmol) is dissolved in THF (60 mL) . A I M solution of tetra-
(n-butyl) ammonium fluoride in THF (18 mL, 18 mmol) is added. The mixture is stirred at rt for 4 h. Concentration to dryness and purification by silica gel chromatography (10-30% gradient, ethyl acetate in hexanes) yielded 3- (5-cyclopropyl- 4-hydroxy-2-methyl-phenyl) -propionic acid methyl ester 64: 1H-NMR (400 MHz, CDCl3) δ = 6.84 (s, IH), 6.67 (s, IH), 5.30
(s, IH), 3.68 (S, 3H), 2.84 (t, J = 7.7 Hs , 2H), 2.53 (t, J = 7.7 Hz, 2H), 2.24 (s, 3H), 1.74 (m, IH), 0.93 (m, 2H), 0.60
(m, 2H) . MS calcd . for Ci4Hi9O3 (M+H+) 235 . 1 , found 235 . 1 .
Figure imgf000055_0001
56 65 66
Figure imgf000055_0002
69
Intermediate 69: 3- (2-Cyclopropyl-3-hydroxy-phenyl) -propionic acid methyl ester.
Step A: N-Bromosuccinimide (7.5G g, 42.5 mmol) is suspended in DCM (50 mL) . tert-Butylamine (5 mL, 47.5 mmol) is added in one portion. After 45 min, the white precipitate is filtered off and the clear filtrate is used as such.
3- (3-Hydroxy-phenyl) -propionic acid methyl ester (7.56 g, 42 mmol) is dissolved in DCM (25 mL) and cooled to -78°C. The clear filtrate prepared above is added dropwise with stirring.
After 30 min, the mixture is warmed up and concentrated to yield a mixture of 65 and 66. Trituration with DCM resulted in the precipitation of dibrominated sideproduct and is filtered off. Silica gel chromatography purification (10-100% ethyl acetate in hexanes) of the- filtrate yielded 3- (2-bromo-3- hydroxy-phenyl) -propionic acid methyl ester 65 and 3-(4-bromo- 3-hydroxy-phenyl) -propionic acid methyl ester 66: 65: 1H-NMR
(400 MHz, CDCl3) δ = 7.14 (t, J" = 7.8 Hz, IH), 6.90 (dd, J = 8.2, 1.4 Hz, IH), 6.82 (dd, J" = 7.4, 1.4 Hz, IH), 5.68 (s, IH) , 3.69 (s, 3H) , 3.07 (t, J = 8.0 Hz, 2H) , 2.65 (t, J - 8.0
Hz, 2H) . 66: 1H-NMR (400 MHz, CDCl3) δ = 7.35 (d, J = 8.4
Hz, IH) , 6.87 (d, 'J = 2.0 Hz, IH) , 6.66 (dd, J = 8.4, 2.0 Ha,
IH) , 5.45 (S, IH) , 3.67 (s, 3H) , 2.88 (t, J = 7.6 Hz, 2H) , 2.61 (t, J" = 7.6 Hz, 2H) .
Step B: 3- (2-Bromo-3-hydroxy-phenyl) -propionic acid methyl ester 65 (0.86 g, 3.32 mmol) is dissolved in DCM (15 mL) .
Imidazole (0.36 g, 5.3 mmol) is added and the mixture is stirred at rt until homogenous. tert-Butyl dimethyl- chlorosilane (0.55 g, 3.6 mmol) is added and the mixture is stirred at rt for 18 h. Washing with water, drying over MgSO4 and concentration yielded 3- [2-brσmσ-3- ( tert-butyl-dimethyl- silanyloxy) -phenyl] -propionic acid methyl ester 67 as an oil:
1H-NMR (400 MHz, CDCl3) δ = 7.07 (t,. J = 7.6 Hz, IH), 6.83
(dd, J = 7.6, 1.2 Hz, IH), 6.28 (dd, J = 8.0, 1.6 Hz, IH),
3.67 (s, 3H), 3.06 (t, J = 7.6 Hz, 2H), 2.63 (t, J = 7.6 Hz,
2H) , 1.03 (s, 9H) , 0.34 (s, 6H) . MS calcd. for C16H26BrO3Si
(M+H+) 373.1, found 372.6.
Step C: 3- [2-Bromo-3- ( tert-butyl-dimethyl-silanyloxy) - phenyl] -propionic acid methyl ester 67 (1.18 g, 3.16 mmol) is dissolved in toluene (25 mL) . Cyclopropylboronic acid (0.55 g, 6.4 mmol), potassium phosphate (2.60 g, 12.2 mmol), and tricyclohexyl-phosphane (0.38 g, 1.36 mmol) are added, followed by water (5 mL) . The mixture is degassed with argon.
Palladium (II) acetate (0.16 g, 0.71 mmol) is added and the mixture is heated to 95°C for 4 h. Cooling, separation of the organic layer, drying over MgSO4 and concentration, followed by silica gel chromatography (0-30% gradient, ethyl acetate in hexanes) yielded 3- [3- ( tert-butyl-dimethyl-silanyloxy) -2- cyclopropyl-phenyl] -propionic acid methyl ester 68 as an oil:
1H-NMR (400 MHz, CDCl3) δ = 7.01 (t, J = 7.8 Hz, IH), 6.75
(d, J = 7.6 Hz, IH), 6.64 (d, J" = 8.0, Hz, IH), 3.68 (s, 3H),
3.17 (t, J = 7.9 Hz, 2H), 2.63 (t, J = 7.9 Hz, 2H), 1.54 (m,
IH), 1.03 (s, 9H), 0.96 (m, 2H), 0.62 (m, 2H), 0.34 (s, 6H).
MS calcd. for C19H31O3Si (M+H+) 335.2, found 335.2. Step D: 3- [3- ( tejrfc-Butyl-dimethyl-silanyloxy) -2-cyclopropyl- phenyl] -propionic acid methyl ester 68 (0.72 g, 2.2 mmol) is dissolved in THF (3 mL) . A I M solution of tetra- {n~ butyl) ammonium fluoride in THF (4 mL, 4 mmol) is added and the mixture is stirred at rt for 18 h. Concentration to dryness and purification by silica gel chromatography (5-50% gradient, ethyl acetate in hexanes) yielded 3- (2-cyclopropyl -3 -hydroxy- phenyl) -propionic acid methyl ester 69: 1H-NMR (400 MHz, CDCl3) δ = 7.09 (t, J = 7.9 Hz, IH), 6.76 (dd, J" = 8.1, 0.9 Hz1 IH), 6.72 (d, J = 7.6 Hz, IH), 5.93 (s, IH), 3.69 (s, 3H), 3.15 (t, J = 7.8 Hz, 2H), 2.63 (t, J" = 7.8 Hz, 2H), 1.59 (m, IH), 1.14 (m, 2H), 0.65 (m, 2H). MS calcd. for C13H17O3 (M+H+) 221.1, found 221.1.
Figure imgf000057_0001
Intermediate 70: 3- (4 -Cyclopropyl-3 -hydroxy -phenyl) -propionic acid methyl ester.
Following the procedure for Intermediate 69, except substituting intermediate 66 for intermediate 65 in step B, the title compound is prepared as a clear oil: 1H-NMR (400 MHz, CDCl3) δ = 6.99 (d, J = 7.7 Hz, IH), 6.71 (d, J = 1.5 Hz, IH) , 6.69 (dd, J = 7.7, 1.5 Hz, IH) 1 5.47 (s, IH) , 3.67 (s, 3H) , 2.88 (t, .7 = 7.6 Hz, 2H) , 2.61 (t, J = 7.6 Hz, 2H), 1.76
(m, IH) , 0.94 (m, 2H) , 0.62 (m, 2H) . MS calcd. for Ci3HnO3
(M+H+) 221.1, found 221.1.
with the methyl group at 2 . 19 ppm) MS calcd . for Ci3Hi7O4 (M+H+ ) 225 . 1 , found 225 . 1 .
Figure imgf000058_0001
Intermediate 78: 2- (4-Hydroxy-2, 3-dimethyl-phenoxy) -2-methyl- propionic acid methyl ester.
Following the procedure for • Intermediate 77, except substituting the appropriate hydroquinone, the title compound is prepared as a clear liquid: 1H-NMR (400 MHz, CDCl3) δ = 6.50 {s, 2H), 4.55 (s, IH), 2.05 (s, 3H), 2.04 (s, 3H), 1.52 (s, 6H). MS calcd. for Ci3H18NaO4 (M+Na+) 261.1, found 261.1.
Figure imgf000058_0002
Intermediate 80 : 2- (4-Hydroxy-2 , 5-dimethyl-phenoxy) -2-methyl- propionic acid methyl ester.
Step A: 2, 5-Dimethylquinone (5.41 g, 39.7 mmol) is suspended in diethyl ether (70 mL) . Water (100 mL) is added, followed by solid sodium dithionite (20.30 g, 116.6 mmol). The resulting mixture is shaken vigorously. The initially yellow mixture turned deep red, then colourless. Separation of the organic layer, washing with water and brine, drying over Na2SO4 and concentration yielded 2,5-dimethylhydroquinone 79 as a white solid: 1H-NMR (400 MHz:, DMSO-ds) δ = 8.32 (s, 2H), 6.45 (S, 2H), 1.99 (s, 6H).
60
Figure imgf000059_0001
Intermediate 76: 2- (4-Hydroxy-2-methyl-phenoxy) -2-methyl- propionic acid methyl ester.
Step A: 4-Benzyloxy-phenol (32.04 g, 160 mmol) is dissolved in of DCM (550 tnL) and methanol (20 mL) . Powdered calcium carbonate (21.83 g, 218 mmol) is suspended into the solution. While stirring vigorously, a solution of bromine (8.30 mL, 162 mmol) in DCM (50 mL) is added dropwise. After the addition is completed, the suspension is stirred at rt for 30 min, then the solids are' filtered off. The filtrate is dried over solid NaHCO3 and MgSO4, then filtered and concentrated to yield an oil. Recrystallization from diethyl ether/petroleum ether at -200C yielded 4-benzyloxy-2-bromo-phenol 71 as a colourless oil that slowly solidified: 1H-NMR (400 MHz, CDCl3) δ = 7.38 (m, 5H), 7.10 (d, J = 2.8 Hz, IH), 6.94 (d, J = 8.9 Hz, IH) , 6.87 (dd, J" = 8.9, 2.8 Hz, IH) , 4.99 (s, 2H) .
Step B: 4-Benzyloxy-2-bromo-phenol 71 (43.6 g, 156 mmol) is dissolved in DCM (400 mL) . Imidazole (14.9 g, 219 mmol) is added and the mixture is stirred at rt until homogenous. text-Butyl dimethylchlorosilane (23.6 g, 156.6 mmol) is added and the mixture is stirred at rt for 18 h. Washing with water, drying over MgSO4 and concentration yielded (4- benzyloxy-2-bromo-phenoxy) -tert-butyl-dimethyl-silane 72 as an oil: 1H-NMR (400 MHz, CDCl3) δ = 7.40 (m, 5H), 7.10 (s, IH), 6.79 <s, 2H), 4.98 (s, 2H), 1.03 (a, 9H), 0.22 (s, 6H).
Step C: (4-Benzyloxy-2-bromo-phenoxy) - tert-butyl-dimethyl-
57 silane 72 (10.05 g, 25.6 mraol) is dissolved in dimethylformamide (45 πiL) . The mixture is degassed with argon. Dichloro bis (triphenylphosphino) palladium (II) (3.49 g, 4.97 mmol) is added, followed by tetramethyltin (5.0 mL, 36.3 ramol) . The mixture is heated to 1000C for 3 h, after which it became homogenous. Cooling, concentration, and silica gel chromatography purification (0-50% gradient, ethyl acetate in hexanes) yielded (4-benzyloxy-2-methyl-phenoxy) - teirt-butyl- dimethyl-silane 73 as a white solid: 1H-NMR (400 MHz, CDCl3) δ = 7.42 (m, 2H), 7.37 (m, 2H), 7.31 (m, IH), 6.79 (d, J= 2.2 HK, IH), 6.67 (m, 2H), 4.99 (s, 2H), 2.18 (s, 3H), 1.01 (s, 9H), 0.18 (s, 6H). MS calcd. for C20H29O2Si (M+H+) 329.2, found 329.2,
Step D: (4-Benzyloxy-2-methyl-phenoxy) - tert-butyl-dimethyl- silane 73 (5.03 g, 15.3 mmol) is dissolved in THF (30 mL) . A 1 M solution of tetra- (zι-butyl) ammonium fluoride in THP (18 mL, 18 mmol) is added. Then the mixture is stirred at rt for 4 h. Concentration to dryness and purification by silica gel chromatography (10-30% gradient, ethyl acetate in hexanes) yielded 4-benzyloxy-2-methyl-phenol 74: 1H-NMR (400 MHz, CDCl3) δ = 7.42 (nα, 4H), 7.31 (m, IH), 6.78 (s, IH), 6.69 (s, 2H), 4.99 (S, 2H), 2.27 (s, 3H).
Step E: 4-Benzyloxy-2-methyl-phenol 74 (3.06 g, 14.3 mmol) is dissolved in acetonitrile (60 mL) . Powdered cesium carbonate (8.71 g, 26.7 mmol) is added to the vigorously stirred solution. 2-Bromo-2-methyl-propionic acid methyl ester (2.20 mL, 17.0 mmol) is added and the mixture is stirred at 600C for 6 h. Filtration and concentration yielded 2- (4-benzyloxy-2- methyl-phenoxy) -2-methyl-propionic acid methyl ester 75 (5.11 g, quant.) as an oil: 1H-NMR (400 MHz, CDCl3) δ = 7.37 (m, 5H), 6.80 (d, J = 2.4 Hz, IH), 6.65 (d, J" = 2.8 Hz, IH), 6.64 (s, IH), 4.98 <S, 2H), 3.80 (s, 3H), 2.21 (s, 3H), 1.54 (s, 6H). MS calcd. for Ci9H22NaO4 (M+Na+) 337.2, found 337.2.
Step F: 2- (4-Benzyloxy-2-methyl-phenoxy) -2-methyl-propionic
58 acid methyl ester 75 (5.11 g, 14.3 mmol) is dissolved in ethanol (120 mL) . The solution is degassed with nitrogen, then treated with a catalytic amount of 5% palladium black on carbon (1.50 g, 4 mol%) . The solution is shaken under 60 psi hydrogen for 15 h. Filtration and concentration yielded an oil. Silica gel chromatography (hexanes to 60% ethyl acetate in hexanes) afforded 2- (4-hydroxy-2-methyl7phenoxy) -2-methyl- propionic acid methyl ester 76 (3.42 g, quant . ) as an oil: 1H-NMR (400 MHz, CDCl3) δ = 6.64 (d, J= 3.0 Hz, IH), 6.59 (d, J = 8.7 Hz, IH), 6.51 (dd, J = 8.7, 3.1 Hz, IH), 4.62 (a, IH), 3.80 (s, 3H), 2.19 (s, 3H), 1.53 (s, 6H). MS calcd. for Ci2Hi6NaO4 (M+Na*) 247.1, found 247.1.
Figure imgf000061_0001
77
Intermediate 77: 2- (4 -Hydroxy-2-methyl-phenoxy) -2-methyl- propionic acid methyl ester.
2-Methyl-hydroquinone (1.01 g, 8.13 mmol) is dissolved in acetonitrile (15 mL) . Powdered cesium carbonate (2.86 g, 8.78 mmol) is added to the vigorously stirred solution. 2-Bromo-2- methyl-propionic acid methyl ester (1.10 mL, 8.50 mmol) dissolved in acetonitrile (5 mL) is added dropwise. The mixture is stirred at rt for 6 h. Filtration and concentration, followed by purification by silica gel chromatography (10-70% gradient, ethyl acetate in hexanes) yielded 2- (4-hydroxy-2-methyl-phenoxy) -2-methyl-propionic acid methyl ester 77 as and oil: 1H-NMR (400 MHz, CDCl3) δ = 6.61 (m, 3H), 4.53 (s, IH), 3.73 (s, 3H), 2.19 (s, 3H), 1.53 (s, 6H) . The structure is confirmed by a NOESY experiment (the resonance at 1.53 ppm has a medium-strength positive nOe with the aromatic signals around 6.61 ppm, no nOe is observed
59 Step B: 2 , 5-Dimethylhydroquinone 79 (3.73 g, 27 τntnol) is dissolved in dimethylformamide (20 mL) and acetonitrile (60 iriL) . Powdered cesium carbonate (9.16 g, 28.1 g) is added to the vigorously stirred solution, followed by 2 -bromo-2-methyl- propionic acid methyl ester (3.50 mL>, 27.0 tnmol) . The mixture is stirred at 750C for 18 h. Filtration and concentration, followed by purification by silica gel chromatography (5-30% gradient, ethyl acetate in hexanes) yielded 2- (4-hydroxy-2 , 5- dimethyl-phenoxy) -2-methyl-ρropionic acid methyl ester 80 as and oil. The chromatography also yielded recovered hydroquinone 79. 80: 1H-NMR (400 MHz, CDCl3) δ = 6.57 (s, IH), 6.50 (s, IH), 4.44 <s, IH), 2.15 (s, 3H), 2.14 (s, 3H), 1.52 (s, 6H) . MS calcd. for Ci3H18NaO4 (M+Na+) 261.1, found 261.1.
H3CO2C^(X
OK
81
Intermediate 81: (4 -Hydroxy-2 , 5-dimethyl-phenoxy) -acetic acid methyl ester.
Following the procedure for Intermediate 80, except substituting the appropriate bromoacetate, the title compound is prepared as a clear glass: 1H-NMR (400 MHz, CDCl3) δ = 6.60 (S, IH), 6.53 (S, IH), 4.58 (s, 2H), 3.80 (s, 3H), 2.22 (s, 3H) , 2.19 (s, 3H) .
H3CO2C. Br
A
Figure imgf000062_0001
Intermediate 84 : 2- (4-Mercapto-2, 5-dimethyl-phenoxy) -2- methyl-propionic acid methyl ester.
Step A: 2, 5-Dimethylphenol (10.04 g, 82.2 mmol) is dissolved in methanol (40 tnL) . Sodium thiocyanate (15.87 g, 195.8 mmol) and sodium bromide (7.37 g, 71.6 mmol) are added and the mixture is stirred at 00C. Bromine (4.50 tnL, 87.6 mmol) dissolved in methanol (40 mL) is added dropwise while stirring vigorously. Upon the completion of the addition, the mixture is stirred at 500C for 1 h. The mixture is cooled and concentrated. The residue is taken up in ethyl acetate and filtered. The filtrate is washed with saturated aqueous NaHCθ3, water, and brine, dried over Na2SO4 and concentrated to afford 2 , 5-dimethyl-4-thiocyanato-phenol 82 as an oil that solidified upon drying under high vacuum: 1H-NMR (400 MHz, CDCl3) δ = 7.38 (s, IH), 6.73 (s, IH), 5.22 (s, IH), 2.45 (s, 3H) , 2.21 (s, 3H) .
Step B: 2,5-Dimethyl-4-thiocyanato-phenol 82 (5.75 g, 32.1 mmol) is dissolved in acetonitrile (25 mL) . Powdered cesium carbonate (15.32 g, 47.0 mmol) is added. Then 2-bromo-2- methyl-propionic acid methyl ester (4.50 mL, 34.8 mmol) is added and the mixture is stirred at 600C for 18 h. Filtration and concentration, followed by silica gel chromatography (0- 50% ethyl acetate in hexanes) yielded 2- (2, 5-dimethyl-4- thiocyanato-phenoxy) -2-methyl-propionic acid methyl ester 83 as an oil: 1H-NMR (400 MHz, CDCl3) (rotamers are present; the data given is for the most abundant isomer) δ = 7.39 (s, IH), 6.50 (S, IH), 3.78 (s, 3H)7 2.42 (s, 3H), 2.20 (s, 3H), 1.62 (s, 6H). MS calcd. for C14H17NNaO3S (M+Na+) 302.1, found 302.1.
Step C: 2- (2, 5-dimethyl-4-thiocyanato-phenoxy) -2-methyl- propionic acid methyl ester 83 (3.88 g, 13.9 mmol) is dissolved in methanol (50 mL) . Potassium dihydrogenphosphate (0.23 g, 1.69 mmol), water (6 mL) , and dithiothreitol (2.80 g, 18.2 mmol) are added and the mixture is stirred at reflux for 3 h. After cooling and concentration, the residue is taken up in ethyl acetate, washed with water and brine, dried over Na2SO4 and concentrated to yield an oil. Silica gel chromatography purification (0-65% ethyl acetate in hexanes) afforded 2- (4-mercapto-2,5-dimethyl-phenoxy) -2-methyl- propionic acid methyl ester 84 as a colourless oil : 1H-NMR (400 MHz, CDCl3) δ = 7.09 (s, IH), 6.47 (s, IH), 3.79 (s, IH), 3.10 (S, IH), 2.24 (s, 3H), 2.15 (s, 3H), 1.56 (s, 6H).
Figure imgf000064_0001
85
Intermediate 85: (4-Mercaρto-2, 5-dimethyl-phenoxy) -acetic acid methyl ester.
Following the procedure for Intermediate 84, except substituting the appropriate bromoacetate, the title compound is prepared as a clear liquid: 1H-NMR (400 MHz, CDCl3) δ = 7.11 (s, IH), 6.53 (s, IH), 4.61 (s, 2H), 3.80 (s, 3H), 3.11 (s, IH), 2.30 (S, 3H), 2.21 (S, 3H).
Figure imgf000064_0002
86
Intermediate 86: (4-Hydroxy-3-methoxy-phenyl) -acetic acid methyl ester.
(4-Acetoxy-3-meth.oxy-ph.enyl) -acetic acid (2.0 g, 8.9 mmol) is dissolved in methanol (15 mL) . Thionyl chloride (1.5 mL, 20.6 mmol) is added dropwise with vigorous stirring. The mixture is stirred at 500C overnight. Cooling and concentration yielded (4-hydroxy-3-methoxy-phenyl) -acetic acid methyl ester 86 (1.8 g, quant.) as an oil: 1H-NMR (400 MHz, CDCl3) δ = 6.86 (d, J = 8.0 Hz, IH), 6.80 (d, J = 1.7 Hz, IH), 6.76 (dd, J= 8.0, 1.8 Hz, IH), 5.10 (br. s, IH), 3.88 (s, 3H), 3.69 (s, 3H) , 3 . 55 ( S , 2H) .
Figure imgf000065_0001
Intermediate 87: (3-Hydroxy-4-methoxy-piienyl) -acetic acid methyl ester .
(3 -Hydroxy-4-methoxy-phenyl) -acetic acid (5.0 g, 27.4 mmol) is dissolved in methanol (30 mL) . Thionyl chloride (2.0 xtiL], 27.5 mmol) is added dropwise with vigorous stirring. The mixture is stirred at 500C overnight. Cooling and concentration yielded (3-hydroxy-4-methoxy-phenyl) -acetic acid methyl ester 87 as an oil: 1H-NMR (400 MHz, CDCl3) δ = 6.86 (d, J = 2.0 Hz, IH), 6-80 (d, J = 8.2 Hz, IH), 6.75 (dd, J" = 8.2,' 2.0 Hz, IH), 3.87 (S, 3H), 3.68 (s, 3H), 3.53 (s, 2H).
Figure imgf000065_0002
Intermediate 89 : 2- (4-Hydroxy-2, 5-dimethyl-phenylsulfanyl) -2- methyl-propionic acid methyl ester.
Step A: 2 , 5-Ditnethyl-4-thiocyanato-phenol 82 (1.50 g, 8.4 mmol) is dissolved in methanol (30 mL) . Potassium dihydrogenphosphate (0.32 g, 2.35 mmol), water (4 mL) , and dithiothreitol (2.17 g, 14.1 mmol) are added and the mixture is stirred at reflux for 3 h. After cooling and concentration, the residue is taken up in ethyl acetate, washed with water and brine, dried over Na2SO4 and concentrated to yield an oil. Silica gel chromatography purification (0-65% ethyl acetate in hexanes) afforded A- mercapto-2, 5-dimethyl-phenol 88 as a colourless wax: 1H-NMR (400 MHz, CDCl3) δ = 7.10 (s, IH), 6.63 (s, IH), 4.81 (s, IH), 3.08 (s, IH), 2.28 (s, 3H), 2.17 (s, 3H). MS σalσd. for C8H11O2S (M+H+) 155.1, found 155.0.
Step B: 4-Mercapto~2,5-dimethyl-phenol 88 (0.44 g,- 2.85 mmol) is dissolved in acetonitrile (5 mL) . Powdered cesium carbonate (1.55 g, 4.8 mmol) is added. Then 2-bromo-2-methyl- propionic acid methyl ester (0.350 mL, 2.7 mmol) is added and the mixture is stirred at 250C for 3 h. Filtration and concentration, followed by silica gel chromatography (10-50% ethyl acetate in hexanes) yielded 2- (4-hydroxy-2, 5-dimethyl- phenylsulfanyl) -2-methyl-propionic acid methyl ester 89 as a wax: 1H-NMR (400 MHz, CDCl3) δ - 7.17 (s, IH), 6.66 (s, IH), 4.94 (s, IH), 3.67 (s, 3H), 2.36 (s, 3H), 2.18 (s, 3H), 1.46 (s, 6H). MS calcd. for Ci3H19O3S (M+Na+) 255.1, found 255.1.
Figure imgf000066_0001
Intermediate 95. 3- (4-Hydroxy-2, 5-dimethyl-phenyl) -2, 2~ dimethyl-propionic acid methyl ester.
Step A: 4-Methoxy-2, 5-dimethyl-benzaldehyde (1.24 g, 7.55 mmol) is dissolved in dry dichloromethane (12 mL) . neat boron tribromide (1.75 g, 18.5 mmol) is added dropwise, with stirring. A tan-coloured precipitate started to form. The suspension is stirred at room temperature for 5 d. The homogenous mixture is poured over 150 g ice. After the ice melted, the solid phenol 90 is isolated by filtration and dried (1.28 g, quantitative) . 1H-NMR (400 MHz, dmso-de) δ = 10.40 (S IH), 9.98 (s, IH), 7.54 (s, IH), 6.68 (s, IH), 3.36 (s, IH), 2.49 (s, 3H), 2.13 (s, 3H).
Step B: 4-Hydroxy-2, 5-dimethyl-benzaldehyde 90 (30.56 g, , 0.2 mol) is dissolved in acetonitrile (150 mL) . Benzyl bromide (24 mL, 0.2 mol) is added, followed by powdered potassium carbonate (36.92 g, 0.27 mol). The mixture is stirred at 600C for 18h. Cooling and concentration, followed by silica gel chromatography (0-20% ethyl acetate in hexanes) yielded 4- benzyloxy-2, 5-dimethyl-benzaldehyde 91 as a colorless oil. 1H-NMR (400 MHz, CDCl3) δ = 10.13 (s, IH), 7.61 (s, IH), 7.43 (m, 5H), 6.72 (s, IH), 5.15 (S, 2H), 2.63 (s, 3H), 2.28 (s, 3H). MS calcd. for C16H17O2 (M+H+) 241.1, found 241.1.
Step C: 4-Benzyloxy-2, 5-dimethyl -benzaldehyde 91 (4.77 g, , 20 tnmol) is dissolved in diethyl ether (30 mL) . Sodium borohydride (1.0 g, 27 mmol) is added in one portion, followed by 5 mL absolute ethanol . The mixture is vigorously stirred for 3h at room temperature, then carefully poured over 100 mL IN aqueous HCl. Extraction with ethyl acetate, washing with water and brine, then concentration yielded (4-benzyloxy-2, 5- dimethyl-phenyl) -methanol 92 as a soft solid. 1H-NMR (400 MHz, CDCl3) δ = 7.39 (m, 5H),' 7.11 (s, IH), 6.73 (s, IH), 5.07 (s, 2H), 4.61 (s, 2H), 2.35 (s, 3H), 2.25 (s, 3H).
Step D: (4-Benzyloxy-2 , 5-dimethyl-phenyl) -methanol 92 (4.79 g, 19.7 mmol) and ethyl diisopropylatnine (6.0 mL, 34.4 mmol) are dissolved in dichloromethane (80 mL) . Acetic anhydride
(2.5 mL, 26.4 mmol) is added in one portion and the mixture is stirred at room temperature for 18h. Washing with IN HCl, water, saturated aqueous NaHCO3, saturated aqueous NH4Cl and brine, followed by drying over MgSO4 and concentration yields acetic acid 4-benzyloxy-2, 5-dimethyl-benzyl ester 93 as an oil
(4.93 g, quant.). XH-NMR (400 MHz, CDCl3) δ = 7.39 (m, 5H), 7.11 (s, IH) , 6.73 (s, IH) , 5.07 (s, 2H) , 5.04 (s, 2H) , 2.32 (s, 3H) , 2.24 (s, 3H) , 2.07 (s, 3H) .
Step E: Acetic acid 4-benzyloxy-2, 5-dimethyl-benzyl ester 93 (0.56 g, 2 raraol) is dissolved in dry dichloromethane (5 mL) . (1-Methoxy-2-methyl-propenyloxy) -trimethylsilane (1 mL, 5 mraol) and magnesium perchlorate (0.09 g, 0.4 mraol) are added and the suspension is stirred overnight. Filtration and silica gel chromatography- (0-30% ethyl acetate in hexanes) yielded 3- (4-benzyloxy-2, 5-dimethyl-phenyl) -2, 2-dimethyl- propionic acid methyl ester 94 as an oil. 1H-NMR (400 MHz, CDCl3) δ = 7.37 (m, 5H), 6.81 (s, IH), 6.67 (s, IH), 5.02 (s, 2H), 2.82 (S, 3H), 2.25 (s, 3H), 2.20 (s, 3H), 1.18 (s, 6H).
Step P: 3- (4-Benzyloxy-2, 5-dimethyl-phenyl) -2, 2-dimethyl- propionic acid methyl ester 94 (0.45 g, 1.4 mmol) is dissolved in ethanol (20 mL) . Palladium black on carbon (5%; 0.16 g, 5 mol%) is added and the mixture is vigorously stirred under 1 atm. hydrogen for 18h. Filtration and concentration yielded 3- (4-hydroxy-2, 5-dimethyl-phenyl) -2, 2-dimethyl-propionic acid methyl ester 95 as an oil (0.11 g, 34%) . 1H-NMR (400 MHz, CDCl3) δ = 6.75 (s, IH), 6.56 (s, IH), 3.67 (s, 3H), 2.80 (s, 2H), 2.20 (s, 3H)1 2.16 (s, 3H), 1.17 (s, 6H).
Figure imgf000068_0001
96
Intermediate 96: (±) -2-Methoxy-3- (4-hydroxy-2-methyl-phenyl) - propionic acid ethyl ester.
Following the procedure for Intermediate 46, except substituting the appropriate methoxyacetate, the title compound is prepared as a clear oil: 1H-NMR (400 MHz, CDCl3) δ = 7.04 (d, J = 8.4 Hz, 2H), 6.73 (d, J = 8.4 Hz, 2H), 5.35 (s, IH), 3.96 (dd, J = 5.4, 7.3 Hz, IH), 3.72 (S, 3H), 3.35 ( s , 3H) , 2 . 96 (tn, 2H) . MS calcd . for C11Hi4NaO4 (M+Na+) 233 . 1 , found 233 . 1 .
Figure imgf000069_0001
80 97
Intormediatβ 97 : 2- [4- (2-Bromo-ethoxy) -2, 5-dimethyl-phenoxy] - 2-methyl-propionic acid methyl ester.
Step C: Intermediate 80 (0.25 g, 1.05 mmol) , 1, 2-dibromoethane (0.90 mL, 10.5 tnraol) and Cs2CO3 (1.7 g, 5.25 mmol) are suspended in dry acetonitrile (7 mL) . The mixture is heated to 800C overnight. The reaction mixture is cooled to room temperature, filtered and the solvent is removed in vacuo. The remainder is purified by flash chromatography (silica, DCM/MeOH gradient) to afford 2- [4- (2-bromo-ethoxy) -2-methyl- phenoxy] -2-methyl-propionic acid methyl ester 97 (0.24 g, 66%) as a colourless oil: 1H-NMR (400 MHz, CDCl3) δ = 6.59 (s, IH), 6.52 (S, IH), 4.22 (t, J = 6.2 Hz, 2H), 3.80 (s, 3H), 3.62 (t, J = 6.2 Hz, 2H), 2.18 (s, 3H), 2.15 (s, 3H), 1.53 (s, 6H). MS calculated for Ci5H22BrO4 (M+H+) 345.1, found 345.0.
>OCC Br
98
Intermediate 98: 2- [4- (3-Broτno-prσpoxy) -2 , 5-dimethyl- phenoxy] -2-methyl-propionic acid methyl ester.
Following the procedure for Intermediate 97, except substituting 1,3-dibromopropane for 1, 2-dibromoethane, the title compound is prepared as a clear oil: 1H-ISIMR (400 MHz, CDCl3) δ = 6.49 (s, IH), 6.40 (s, IH), 3.90 (t, J = 5.7 Hz, 2H), 3.68 (S, 3H), 3.49 (t, J = 6.5 Hz, 2H), 2.18. (m, 2H), 2 . 07 ( s , 3H ) , 1 . 99 ( s , 3H ) , 1 . 40 ( s , 6H) . MS calculated for C16H24BrO4 (M+H+ ) 359 . 1 , found 359 . 0 .
Figure imgf000070_0001
Intermediate 102. 4-Biphenyl-4-yl-2-chloromethyl-thiazole.
Step A: Benzoyloxyacetonitrile (10 g, 62 mmol) and thioacetamide (11.6 g, 155 mmol are dissolved in DMF (40 mL) .
HCl (60 mli of 4N in dioxane, 235 mmol) is added and the mixture is heated at 100° C for 2 h. The mixture is cooled and poured into water (100 rtiL) and extracted with EtOAc (80 mL) . The organic layer is washed with water (100 mL) , sat. NaHCO3
(2 x 100 mL) then brine (100 mL) , dried (MgSO4) , filtered and evaporated to give crude benzoic acid thiocarbamoylmethyl ester 100 which is used in Step B without further purification. MS calcd. for C9Hi0NO2S (M+H+) 196.0, found 196.0.
Step B: Benzoic acid thiocarbamoylmethyl ester 100 (2.8 g, 14.3 mmol) and l-biphenyl-4-yl-2-bromo-ethanone (3.9 g, 14.3 mmol) are dissolved in MeOH (20 mL) and heated at reflux for 16 Ir. Concentrated H2SO4 (2 mL) is added and the reflux continued for 24 h. The mixture is cooled and poured into water (100 mL) and extracted with EtOAc (2 x 80 mL) . The organic layers are combined and washed with water (100 mL) , sat. NaHCO3 (2 x 100 mL) and brine (100 mL) , dried (MgSO4), filtered and evaporated and purified by flash chromatography (EtOAc/Hexanes gradient) to afford (4-Biphenyl-4-yl-thiazol-2- yl) -methanol 101 (0.86 g, 23%). MS calcd. for Ci5H14NOS (M+H+) 268.1, found 268.1.
Step C: (4-Biphenyl-4-yl-thiazol-2-yl) -methanol 101 (860 mg, 3.22 mmol) is dissolved in dry THF (20 mL) , then thionyl chloride (0.47 mL, 6.43 mmol) is added and the mixture is stirred at rt for 2 h. The mixture is poured into a saturated solution of NaHCO3 (20 mL) and extracted with EtOAc (20 mL) . The organic layer is washed with brine, dried (MgSO4) , filtered and evaporated to give 4-Biphenyl-4-yl-2- chloromethyl-thiazole 102 (0.50 g, 55%) as a beige powder. 1H- NMR (400MHz, CDCl3) 7.96 (d, J = 8.4 Hz, 2H), 7.66 (m, 4H), 7.55 (s, IH), 7.46 (t, J = 8.0 Hz, 2H), 7.37 (t, J = 8.8 Hz, IH), 4.94 (s, 2H). MS calcd. for Ci6Hi3ClNS (M+H+) 286.0, found 286.0.
H2S
Hor^^a NH2 step A Step B 5
103 104
Figure imgf000071_0001
Intermediate 106. Methanesulfonic acid 3- [4- (4- trifluoromethyl -phenyl) -thiazol-2-yl] -propyl ester.
Step A: Potassium cyanide (25.4 g, 0.39 mol) is suspended into a mixture of ethanol (120 mL) and water (40 mL) . 3- Chloropropanol (26.8 mL, 0.32 tnol) is added and the mixture is heated to reflux for 90 min. After filtering insoluble material the remaining oil is distilled (100 mTorr, 75* C) to give 4-hydroxy-butyronitrile 103 (10 g, 37%) as a colouless oil : 1H-NMR (400MHz , CDCl3) 3 . 69 ( t , J = 5 . 8 Hz , 2H) , 2 . 46 ( t ,
J = 7 . 1 Hz , 2H) , 1 . 84 (quint , J = 6 . 5 Hz , 2H) .
Step B: 4-hydroxy-butyrσnitrile 103 (7.5 g, 90 mmol) ia dissolved in pyridine (60 mL) . Triethylamine (25 mL) is added and the solution is flushed with nitrogen. Then hydrogen sulfide gas is bubbled steadily through the solution for 3.5 h. Concentration yielded 4-hydroxy-thiobutyramide 104 as a yellow oil: 1H-NMR (400MHz, CDCl3) 3.78 (t, <J = 5.8 Hz, 2H), 2.51 (t, J = 7.1 Hz, 2H) , 1.91 (quint, J = 6-5 Hz, 2H) .
Step C: 4-hydroxy-thiobutyramide 104 (7.0 g, 59 mmol) and 2~ bromo-1- (4-trifluoromethyl-phenyl) -ethanone (15.7 g, 59 mmol) are dissolved in EtOH (50 mL) and heated to 80 "C for 5 h. The mixture is concentrated and purified by flash chromatography (EtOAc/Hexanes gradient) to afford 3- [4- (4-trifluoromethyl- phenyl) -thiazol-2-yl] -propan-1-ol 105 as a colorless solid: MS calcd. for Ci3Hi3F3NOS (M+H+) 288.1, found 288.1.
Step D: 3- [4- (4-Trifluoromethyl-phenyl) -thiazol-2-yl] -propan- 1-ol 105 (2.5 g, 8.7 mmol) and ethyldiisopropylamine (3.5 mL, 21.2 mmol) are dissolved in dichloromethane (35 mL) . Mesyl chloride (0.85 mL, 11.0 mmol) are added dropwise and the mixture is stirred at rfe overnight. Then the mixture is diluted with DCM and washed with H2O and brine. The organic layer is dried (MgSO4) , filtered and concentrated to afford the mesylate 106 as a light-brown oil: MS calcd. for Ci4H15F3NO3S2 (M+H+) 366.0, found 366.1.
Figure imgf000073_0001
Step C LAH
Figure imgf000073_0002
Intermediate 109. 3- [4- (4-Trifluoromethyl-phenyl) -oxazol-2- yl] -propan-1-ol .
Step A: 3-Cyano-propionic acid methyl ester (3.0 g, 2.7 mmol) is dissolved in methanol (6 mL) and stirred in an ice-bath. Concentrated sulfuric acid (12 mL) is added slowly, then the ice-bath is removed and the mixture is stirred overnight at rt . The acid is quenched by adding solid NaHC03 and water, the product is extracted with EtOAc and dried to give succinamic acid methyl ester 107 as a white solid: 1H-NMR (400MHz, CDCl3) 5.64 {s, br, NH2) , 3.51 (s, 3H), 2.49 (t, J = 6.7 Hz, 2H), 2.39 (t, J = 6.1 Hz, 2H) .
Step B: Succinamic acid methyl ester 107 (0.7 g, 5.3 mmol) and 2-bromo-l- (4-trifluoromethyl-phenyl) -ethanone (0.71 g, 2.7 mmol) are stirred neat at 80 "C for 4 h. Then the mixture is dissolved in EtOAc and washed with H2O and brine. The organic layer is dried (MgSO4), filtered and concentrated. The mixture is purified by flash chromatography (EtOAc/Hexanes gradient) to afford 3- [4- (4-trifluoromethyl-phenyl) -oxazol-2-yl] - propionic acid methyl ester 108 as a colorless oil: 1H-NMR (400MHz, CDCl3) 7.84 (s, IH), 7.76 (d, J = 8.2 Hz, 2H), 7.58 (d, J = 8.2 Hz, 2H), 3.67 (s, 3H), 3.10 (t, J" = 7.5 Hz, 2H), 2.83 (t, J" = 7.5 Hz, 2H). MS calcd. for Ci4Hi3F3NO3 (M+H+) 300.1, found 300.0.
Step C: The 3- [4- (4-trifluoromethyl-phenyl) -oxazol-2-yl] - propionic acid methyl ester 108 (0.26 g, 0.87 mmol) is placed in a flame-dried flask, dissolved in THF/DCM 1:1 (5 mL) and flushed with. argon. After cooling to O0C, lithium aluminiumtetrahydride (0.87 mL IM in THF, 0.87 mmol) is added dropwise over a period of 45 min. Sodium sulfate decahydrate (0.28 g, 0.87 mmol} is added slowly in portions, the ice-bath is removed and the mixture is stirred at rt for 20 min. Then the mixture is filtered through celite and washed with DCM and EtOAc. The solvents are removed in vacuo to yield 3- [4- (4- trifluoromethyl-phenyl) -oxazol-2-yl] -propan-1-ol 109 (0.24 g, quant.) as a colorless glass: 1H-NMR (400MHz, CDCl3) 7.84 (s, IH)1, 7.74 (d, J = 8.2 HZ, 2H), 7.57 <d, J = S.2 Hz, 2H), 3.73 (t, J = 5.6 Hz, 2H), 2.91 (t, J = 7.1 Hz, 2H), 2.02 (m, 2H). MS calcd. for C13Hi3F3NO2 (M+H+) 272.1, found 272.0.
Figure imgf000074_0001
Intermediate 111. 2- [4- (4-Trifluoromethyl -phenyl) -oxazol-2- yll -ethanol .
Step A: Malonamic acid methyl ester (22.0 g, 187 mmol) and 2- Bromo-l- (4-trifluoromethyl-phenyl) -ethanone (10 g, 37.4 mmol) are heated to 130 "C with stirring for 2 h. Water (30 mL) is added and the product is extracted with EtOAc (2 x 40 mL) . The organic layers are combined, washed with water (30 mL) and brine (30 mL) , dried (MgSO4) , filtered, concentrated and purified by flash chromatography (EtOAc/Hexanes gradient) to afford [4- (4-Trifluoromethyl-phenyl) -oxazol-2-yl] -acetic acid methyl ester 110 as a colorless oil: 1H-NMR (400MHz, CDCl3) 7.98 (s, IH), 7.83 (d, J" = 8.0 Hz, 2H), 7.65 (d, J = 8.0 Hz, 2H), 3.94 (s, 2H), 3.78 (s, 3H). MS calcd. for CI3HHF3NO3 (M+H+) 286.1, found 286.1. Step B: [4- (4-Trifluoromethyl-phenyl) -oxazol-2-yl] -acetic acid methyl ester 110 (1.8 g, 6.31 mmol) is dissolved in dry THF (40 mL) . Sodium borohydride (377 mg, 10.1 mmol) is added and the mixture is heated at reflux for 16 h. The reaction is poured into 1 N HCl (20 mL) and extracted with EtOAc (2 x 50 mL) . The organic layers are combined and washed with 1 N HCl, dried (MgSO4) , filtered and evaporated to afford the title compound 111: 1H-NMR (400MHz, CDCl3) 7.94 (s, IH), 7.82 (d, J = 8.0 Hz, 2H), 7.65 (d, J= 8.0 Hz, 2H), 4.10 (m,3H), 3.77 (s, IH). MS calcd. for C12HnF3NO2 (M+H+) 258.1, found 258.1.
Figure imgf000075_0001
Intermediate 112. 2- [4- (4-Trifluoromethoxy-phenyl) -oxazol-2- yl] -ethanol .
Following the procedure of Intermediate 111, except substituting 2-Broτno-l- (4-trifluoromethoxy-phenyl) -ethanone for 2-Bromo-l- (4-trifluoromethyl-phenyl) -ethanone, the title compound is prepared a red oil. 1H-NMR (400MHz, CDCl3) 7.78 (s, IH), 7.66 (d, J = 8.0 Hs, 2H), 7.17 (d, J = 8.0 Hz, 2H), 4.01 (t, J = 5.6 Hz, 2H) , 2.98 (t, J = 5.6 Hz, 2H) . MS calcd. for Ci2H11FjNO3 (M+H+) 274.1, found 274.1.
Figure imgf000075_0002
Intermediate 115. 2-Methyl-2- [4- (4-trifluoromethyl-phenyl) oxazol-2-yl] -propan-1-ol. Step A: Cyano-dimethyl-acetic acid ethyl ester (3 g, 21.2 mmol) is dissolved in EtOH (5 mL) , then concentrated H2SO4 (20 mL) is added and the mixture is stirred at rt for 16 h. The reaction is poured into water (100 mL) and NaHCO3 is added portionwise to neutral pH. Then the mixture is extracted with EtOAc (3 x 60 mli) . The organic layers are combined and washed with brine, dried (MgSO4) , filtered and evaporated to afford 2 , 2-dimethyl-malonamic acid ethyl ester 113 as a clear oil. 1H-NMR (400MHz, CDCl3) 4.11 (q, J = 7.2 Hz, 2H), 1.38 (S, 6H) , 1.20 (t, J" = 7.2 Hz, 3H) .
Step B: 2, 2-Dimethyl-malonamic acid ethyl ester 113 (3.0 g, 11.4 mmol) and 2-bromo-l- (4-trifluoromethyl-phenyl) -ethanone (2.7 g, 17.1 mmol) are heated to 130°C with vigorous stirring for 2 h. Then water (30 mL) is added and the product is extracted with EtOAc (2 x 40 mL) . The organic layers are combined, washed with water (30 mL) and brine (30 mL) , dried (MgSO4) , filtered, concentrated and purified by flash chromatography (EtOAc/Hexanes gradient) to afford 2-methyl-2- [4- (4-trifluoromethyl-phenyl) -oxazol-2-yl] -propionic acid ethyl ester 114 as a colorless oil. MS calcd. for CIeHi7F3NO3 <M+H+) 328.1, found 328.1.
Step C: 2-Methyl-2- [4- (4-trifluoromethyl-phenyl) -oxazol-2-yl] - propionic acid ethyl ester 114 (2.6 g, 7.94 mmol) is dissolved in dry THF (40 mL) . Sodium, borohydride (1.5 g, 40.2 mmol)- is added and the mixture is heated at reflux for 64 h. The reaction is poured into 1 N HCl (20 mL) and extracted with EtOAc (2 x 50 mL) . The organic layers are combined and washed with 1 N HCl, dried (MgSO4), filtered and evaporated to afford the title compound 115: 1H-NMR (400MHz, CDCl3) 7.85 (s, IH), 7.74 (d, J = 8.0 Hz, 2H), 7.57 (d, J = 8.0 Hz, 2H), 3.69 (s, 2H), 1.32 (s, 6H). MS calcd. for Cx4H15F3NO2 (M+H+) 286.1, found 286.1.
Figure imgf000077_0001
Step A
Figure imgf000077_0002
Intermediate 118: 2- [4- (4-Trifluoromethyl-phenyl) -thiazol-2- yl] -ethanol .
Step A: Cyano-acetic acid benzyl ester (2 g, 11.4 mrnol) and thioacetamide (2.14 g, 28.5 mmol are dissolved in DMF (7 mL) . HCl (10.8 mL of 4N in dioxane, 43.3 mmol) is added and the mixture is heated at 100 "C for 2 h. The mixture is cooled, poured into water (30 mL) and extracted with EtOAc (50 mL) . The organic layer is washed with water (20 mL) , sat. NaHCO3 (2 x 20 mL) then brine (20 mL) , dried (MgSO4) , filtered and evaporated to give exude Thiσcarbamoyl-acetic acid benzyl ester 116 which is used in Step B without further purification. MS calcd. for Ci0Hi2NO2S (M+H+) 210.1, found 210.0.
Step B: Thiocarbamoyl-acetic acid benzyl ester 116 (0.8 g, 3.8 mmol) and 2-Bromo-l- (4-trifluoromethyl-phenyl) -ethanone (1.0 g, 3.81 mmol) are dissolved in EtOH (20 mL) and heated at reflux for 2 h. The mixture is cooled and filtered to afford [4- (4-Trifluoromethyl-phenyl) -thiazol-2-yl] -acetic acid ethyl ester 117. MS calcd. for Ci4Hi3F3NO2S (M+H+) 316.1, found 316.0.
Step C: [4- (4-Trifluoromethyl-phenyl) -thiazol-2-yl) -acetic acid ethyl ester 117 (397 mg, 1.26 mmol) is dissolved in dry THF (10 mL) , then LiAlH4 (1.26 mL of 1 M in THF, 1.26 mmol) is added and the mixture is stirred at rt for 1 h. The reaction is quenched by slow addition of water (5 mL) and extracted with EtOAc (20 mL) . The organic layer is washed with 1 N HCl (10 mL) , dried (MgSO4) , filtered, evaporated and purified by flash column chromatography (EtOAc/Hexane gradient) to afford 2- [4- (4 -Trif luorσmethyl -phenyl) -thiazol-2-yl] -ethanol 118 as a white powder. 1H-NMR (400MHz, CDCl3) 7.97 (d, J = 8.0 Hz, 2H), 7.66 (d, J" = 8.0 Hz, 2H), 7.48 (s, IH) , 5.47 (m, IH) , 4.09 (t, J = 5.6 Hz, 2H) , 3.28 (t, J = 6.0 Hz, 2H) . MS calcd. for C12H11F3NOS (M+H+) 274.0, found 274.0.
Intermediate 119 : 4- (4- (trifluoromethyl) phenyl ) thiazole-2- thiol .
Figure imgf000078_0001
2-Bromo-l- (4-trifluoromethyl-phenyl) -ethanone (10 g, 37.4 mmol) and ammonium dithiocarbamate (4.2 g, 37.4 mmol) are dissolved in dry acetone (100 mL) and heated at reflux for 2 h. The solution is cooled and stirred at rt for 2 h, then filtered and washed with acetone to give 4- (4-
(trifluoromethyl) phenyl) thiazole-2 -thiol 119 as a white solid: 1H-NMR (400 MHz, DMSO-d6) δ = 7.99 (d, J = 8.4 Hz, 2H), 7.79
(d, J = a.4 Hz, 2H), 7.47 (s, IH). MS calculated for C15H13N2S
(M+H+) 262.1, found 262.0. -
Figure imgf000078_0002
Example Al. (5-Cyclopropyl-2-methyl-4-{3- [4- (4- trifluoromethyl-phenyl) -thiazol-2-yl] -propoxy} -phenoxy) -acetic acid.
Step A: Intermediate 105 (25 mg, 0.09 mraol) , intermediate 24 (26 mg, 0.11 mmol) and triphenylphosphine (35 mg, 0.14 mmol) are dissolved in dry DCM (1 mL) and cooled to 00C. After the slow addition of diethyl azodicarboxylate (29 μL, 0.18 mmol) the solution is stirred at room temperature overnight. The solvent is removed to afford crude (5-cyσlopropyl-2-methyl-4- {3- [4- (4-trifluoromethyl-phenyl) -thiazol-2-yl] -propoxy}- phenoxy) -acetic acid methyl ester which is used without further purification in step B.
Step B: The crude (5-cyclopropyl-2-methyl-4- {3- [4- (4- trifluoromethyl-phenyl) -thiazol-2-yl] -propoxy} -phenoxy) -acetic acid methyl ester is dissolved in THF (1.8 tnL) , a solution of 1 M LiOH in H2O (0.6 mL) is added and the mixture is stirred overnight at room temperature. The mixture is acidified with 1 M HCl (0.7 mL) , DCM (10 mL) is added and the organic layer washed with H2O (3x5 mL) . The organic layer is dried (MgSO4) , filtered, concentrated and purified on reverse phase HPLC (H2O/MeCN gradient) to afford the title compound Al as a colorless glass: 1H-NMR (400MHz, CD3OD) δ = 7.77 (d, J = 7.9 Hz, 2H), 7.44 (d, J = 7.9 Hz, 2H), 7.24 (s, IH), 6.45 (s, IH), 6.09 (s, IH), 4.36 (s, 2H), 3.86 (t, J" = 6.0 Hz, 2H), 3.11 (t, J = 7.7 Hz, 2H), 2.16 (m, 2H), 2.01 (s, 3H)-, 1.91 (m, IH), 0.69 (m, 2H), 0.37 (m, 2H). MS calcd. for C25H25F3NO4S (M+H+) 492.1, found 492.2.
By repeating the procedures described in the above examples, using appropriate starting materials, the following compounds of Formula I, as identified in Table 1, are obtained.
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0003
Figure imgf000089_0001
UOH Step B
Figure imgf000089_0002
Bl
Example Bl. 2- (2 , 3-Dimethyl-4- {3- [4- (4-trifluoromethyl- phenyl) -thiazol-2-yl] -propoxy} -phenoxy) -2-methyl-propionic acid.
Step A: Methanesulfonic acid 3- [4- (4-trifluoromethyl-phenyl) - thiazol-2-yl] -propyl ester 106 (37 mg, 0.10 mmol) and 2-(4- hydroxy-2 , 3 -dimethyl-phenoxy) -2-methyl-propionic acid methyl ester 78 (23.8 mg, 0.10 mmol) are dissolved in dry acetonitrile (2 mL) . Powdered cesium carbonate (50 mg, 0.16 mmol) is added and the solution is vigorously stirred at 55°C for 6 h. Filtration and concentration yielded crude 2- (2,3- diraethy1-4- {3- [4- (4-trifluoromethyl-phenyl) -thiazol-2-yl] - propoxy} -phenoxy) -2-methyl-propionic acid methyl ester which is used without further purification in Step B.
Step B: The crude 2- (2 , 3-dimethyl-4- {3- [4- (4-trifluoromethyl- phenyl) -thiazol-2-yl] -propoxy} -phenoxy) -2-methyl-propionic acid methyl ester is dissolved in dioxane (1.5 mL) . Lithium hydroxide monohydrate (0.10 g, excess) and water (0.5 mL) are added. The mixture is stirred at 600C for 2 h. Cooling to room temperature, concentration, acidification with 1 N HCl, and purification on reversed-phase HPLC (H2O/MeCN gradient) afforded the title compound Bl as a colorless oil: 1H-NMR
(400 MHz, CDCl3) δ = 7.99 (d, J = 8.1 Hz, 2H), 7.67 (d, J" = 8.1 Hz, 2H), 7.46 (s, IH), 6.72 (d, J" = B.8 Hz, IH), 6.61 (d, J = 8.7 Hz, IH), 4.05 (t, J = 6.0 Hz, 2H), 3.30 (t, J" = 7.4 Hz, 2H), 2.37 (m, 2H), 2.18 (s, 6H), 1.54 (s, 6H). 19F-NMR
(376 MHz, CDCl3) δ = -62.49. MS calcd. for C25H27F3NO4S (M+H+) 494.2, found 494.2.
By repeating the procedures described in the above examples, using appropriate starting materials, the following compounds of Formula I, as identified in Table 2, are obtained.
Table 2
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000094_0002
Cl Example Cl: (2-Methyl-4- {2- [4- (4-trifluoromethyl-phenyl) - thiazol-2-yl] -ethoxy} -phenoxy) -acetic acid.
Step A: [2-Methyl-4~ (2-thio.carbamoyl-ethoxy) -phenoxy] -acetic acid methyl ester 31 (22 tng, 0.08 mmol) and 2-bromo-1- (4- trifluoromethyl-phenyl) -ethanone (20 tng, 0.075 mmol) are dissolved in MeOH (1 mL) and heated at 160° C by subjection to microwave irradiation in a sealed tube for 10 minutes to afford crude (2-methyl-4- {2- [4- (4-trifluoromethyl-phenyl) - thiazol-2-yl] -ethoxy} -phenoxy) -acetic acid methyl ester which is used without further purification in step B.
Step B: To the crude (2-methyl-4- {2- [4- (4-trifluoromethyl- phenyl) -thiazol-2 -yl] -ethoxy} -phenoxy) -acetic acid methyl ester in MeOH is added THP (2 mL) and 1 N LiOH (1 mL) . The mixture is stirred at rt for 16 h, then acidified with 1 N HCl and extracted with EtOAc (10 mL) . The organic layer is dried (MgSO4) , filtered, concentrated and purified on reverse phase HPLC (H2O/MeCN gradient) to afford the title compound Cl as a colorless glass: 1H-NMR (400MHz, CDCl3) δ = 8.21 (d, J = 7.6 Hz, 2H), 7.88 (d, J = 7.6 Hz, 2H), 7.71 (s, IH), 7.03 (s, IH), 6.93 (S, 2H), 4.84 (s, 2H), 4.55 (t, J = 6.4 Hz, 2H), 3.74 (t, J = 6.4 Hz, 2H), 2.39 (s, 3H). MS calcd. for C2IHIBF3NO4S (M+H+) 438.1, found 438.1.
By repeating the procedures described in the above examples, using appropriate starting materials, the following compounds of Formula I, as identified in Table 3, are obtained.
Table 3
Figure imgf000096_0001
Figure imgf000097_0001
δ
8.4 (m, J= 6.0
δ
δ 7.6
I H), 2.4 (s,
2.08 (s,
452.1,
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
UOH Step D
Figure imgf000107_0002
Example Dl: {4 ' -Methoxy-4-methyl-6- [4- (4-trifluoromethyl- phenyl) -thiazol-2-ylmethoxy] -biphenyl-3-yloxy}-acetic acid.
Step A: {2-Methyl-4-thiocarbamoylmethoxy-phenoxy) -acetic acid methyl ester 40 (315 mg, 1.17 mmol) and 2-brotno-l- (4- trifluoromethyl-phenyl) -ethanone (298 mg, 1.11 mmol) are dissolved in EtOH (5 mL) and heated at reflux for 2 h. The mixture is cooled and the resulting precipitate is collected by filtration, washed with MeOH, and dried under vacuum to give {2-Methyl-4- [4- {4-trifluoromethyl-phenyl) -thiazol-2- ylmethoxy] -phenoxy} -acetic acid ethyl ester: 1H-NMR (400MHz, CDCl3) 8.01 (d, J" = 8.0 Hz, 2H), 7.68 (d, J = 8.0 Hz, 2H), 7.61 (S, IH), 6.89 (d, J = 2.4 Hz, IH), 6.7.6 (dd, J = 2.8, 8.4 Hz, IH), 6.67 (d, J = 8.8 Hz, IH), 5.37 (s, 2H), 4.59 (s, 2H), 4.25 (q, J" = 7.2 Hz, 2H), 2.29 (s, 3H), 1.29 (t, J" = 7.2 Hs, 3H). MS calcd. for C22H2IF3NO4S (M+H+) 452.1, found 452.4.
Step B: {2-Methyl-4- [4- (4-trifluoromethyl-phenyl) -thiazol-2- ylmethoxy] -phenoxy} -acetic acid ethyl ester (220 mg, 0.48 πvmol) is dissolved in dichloromethane (3 mL) . Bromine (62 μL, 1.2 inmol) is predissolved in AcOH (0.2 mL) , then is added to the solution. The mixture is stirred at rt for 3 h, then is poured into water (10 mL) and extracted with dichloromethane (10 mL) . The organic layer is washed successively with saturated solutions of NaHCO3 and " sodium bisulfite, dried (MgSOa) , filtered and concentrated. The residue is triturated with hexanes and filtered to afford {5-bromo-2-methyl-4- [4- (4- trifluoromethyl -phenyl) -thiazol-2-ylmethoxy] -phenoxy} -acetic acid ethyl ester: 1H-NMR (400MHz, CDCl3) 7.95 (d, J = 8.0 Hz, 2H), 7.62 (d, J = 8.0 Hz, 2H), 7.58 (s, IH), 6.88 (s, IH), 6.83 (s, IH), 5.37 (s, 2H), 4.53 (s, 2H), 4.20 (q, J" = 7.2 Hz, 2H), 2.19 (s, 3H), 1.24 (t, J = 7.2 Hz, 3H). MS calcd. for C22H20BrF3NO4S (M+H+) 530.0, found 530.2.
Step C: {5-Bromo-2-methyl-4- [4- (4-trifluoromethyl-phenyl) - thiazol-2-ylmethoxy] -phenoxy} -acetic acid ethyl ester (20 mg, 0.04 mmol) , 4 -methoxyphenylboronic acid (7.2 mg, 0.05 mmol) and sodium carbonate (13 mg, 0.12 mmol) are dissolved in a mixture of water (120 μL) , ethanol (90 μL) and 1,2- dimethoxyethane (360 μL) . The mixture is degassed with Argon for 2 minutes. Pd (PPh3) 4 (10 mol%) is added and the mixture is subjected to microwave irradiation (1800C) for 5 min in a sealed tube to give crude {4 ' -methoxy-4-methyl-6- [4- (4- trifluoromethyl -phenyl) -thiazol-2-ylmethoxy] -biphenyl-3- yloxy} -acetic acid ethyl ester, which is used without further purification in Step B. MS calcd. for C29H27F3NO5S (M+H+) 558.2, found 558.3
Step D: To the solution of {4- [4- {4-tnethoxy-phenyl) -5- (4- trifluoromethoxy-phenyl) -thiazol-2-ylmethoxy] -2-methyl- phenoxy} -acetic acid methyl ester from Step C is added THF (1 mL) and a solution of 1 M LiOH in H2O (0.2 mL) . The mixture is stirred for 1 h at rt, then it is acidified with 1 M HCl (0.3 mL) . EtOAc (20 mL) is added and the organic layer is washed with brine (10 mL) . The organic layer is dried (MgSO4) , filtered, concentrated and purified on reverse phase HPLC (H2O/MeCN gradient) to afford the title compound Dl as a white solid: 1H-NMR (400MHz, CDCl3) δ = 7.97 (d, <J = 8.0 Hz, 2H), 7.67 (d, J- = 8.0 Hz, 2H), 7.55 (s, IH), 7.49 (d, J ~ 8.4 Hz, 2H), 6.98 (s, IH), 6.94 (d, J = 8.4 Hz, 2H), 6.78 (s, IH), 5.29 (S, 2H), 4.69 (s, 2H), 3.85 (s, 3H), 2.33 (S, 3H). MS calcd. for C27H23F3NO5S (M+H+) 530.1, found 530.3.
By repeating the procedures described in the above examples, using appropriate starting materials, the following compounds of Formula I, as identified in Table 4, are obtained.
Table 4
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Ill
Figure imgf000113_0001
T7US2006/043342
δ
Hz, IH), 6.94 6.84 (s, 3H).
δ
7.61
2H), 2.12
493.1,
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Example El: {4 ' -Methoxy-^-methyl-δ- [4- (4-nitro-phenyl) - thiazol-2-ylmethoxy] -biphenyl-3-yloxy} -acetic acid.
Step A: (5-Bromo-2-methyl-4-thiocarbamoylmethoxy-phenoxy) - acetic acid methyl ester 43 (50 tng, 0.14 tnmol) and 2-bromo-l- (4-nitro-phenyl) -ethanone (40 mg, 0.17 mraol) are dissolved in EtOH (1 mL) and heated at reflux for 2 h. The mixture is cooled, the resulting precipitate is filtered and washed to afford {5-bromo-2-methyl-4- [4- (4-nitro-phenyl) -thiazol-2- ylmethoxy] -phenoxy} -acetic acid ethyl ester as a white powder which is used in Step B without further purification. MS calcd. for C2IH20BrN2O6S (M+H+) 507.1, found 506.9.
Step B: {5-Bromo-2-methyl-4- [4- (4-nitro-phenyl) -thiazol-2- ylmethoxy] -phenoxy} -acetic acid ethyl ester (26 mg, 0.053 mmol) , 4-methoxyphenylboronic acid (8 mg, 0.053 mmol) and sodium carbonate (17 mg, 0.16 mmol) are dissolved in a mixture of water (120 μL) , ethanol (90 μL) and 1, 2-dimethoxyethane (360 μL) . The mixture is degassed with Argon for 2 minutes. Pd(PPh3) 4 (10 mol%) is added and the mixture is subjected to microwave irradiation (1800C) for 5 min in a sealed tube to give crude {4 ' -methoxy-4-methyl-6- [4- (4-nitro-phenyl) -thiazol- 2-ylmethoxy] -biphenyl-3-yloxy} -acetic acid ethyl ester, which is used directly in Step C. MS calcd. for C28H27N2O7S (M+H+) 535 . 2 , found 535 . 1 .
Step C: To the solution of {4 ' -methoxy-4-methyl-6- [4- (4-nitro- phenyl) -thiazol-2-ylmethoxy] -biphenyl-3-yloxy} -acetic acid ethyl ester from Step A is added THF (1 mL) and a solution of 1 M LiOH in H2O (0.2 mL) . The mixture is stirred for 1 h at rt. Then it is acidified with 1 M HCl (0.25 mL) , EtOAc (10 mL) is added and the organic layer is washed with brine. The organic layer is dried (MgSO4) , filtered, concentrated and purified on reverse phase HPLC (H2O/MeCN gradient) to afford the title compound El as a white solid: 1H-NMR (400MHz, DMSO- d6) δ = 8.21 (s, IH), 8.07 (d, J" = 8.8 Hz, 2H), 7.97 (d, J = 8.8 Hz, 2H), 7.26 (d, J = 8.4 Hz, 2H), S.91 (s, IH), 6.75 (d, J = 8.8 Hz, 2H), 6.55 (s, IH), 5.18 (s, 2H), 4.48 (a, 2H), 3.55 (s, 3H), 1.99 (S, 3H)-. MS calcd. for C2SH23N2O7S (M+H+) 507.1, found 507.1.
By repeating the procedures described in the above examples, using appropriate starting materials, the following compounds of Formula I, as identified in Table 5, are obtained.
Table 5
Figure imgf000117_0001
Figure imgf000118_0001
δ
7.50
2H),
δ
2H)1 5.21 (s,
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Pl
Example Pl: {5-Cyclopropyl-2-methyl-4- [4- (4-trifluoromethyl- phenyl) -thiazol-2-ylmethoxy] -phenoxy} -acetic acid.
Step A; Copper powder (19 mg, 0.29 mmol) is slurried in toluene (4 mL) . Iodine (0.8 mg, 0.0032 mmol) is added and stirred at rt until the brown color disappeared (~ 10 min) . Diiodomethane (10.4 μL, 0.129 mmol) and {2-methyl-4- [4- (4- trifluoromethyl-phenyl) -thiazol-2-ylmethoxy] -5-vinyl-phenoxy} - acetic acid methyl ester (30 mg, 0.06 mmol, see example D4) are added and the mixture is heated at reflux for 3 h. Then it is cooled, filtered and concentrated to afford {5- cyclopropyl-2-methyl-4- [4- (4-trifluoromethyl-phenyl) -thiazol- 2-ylmethoxy] -phenoxy} -acetic acid methyl ester which is used in Step B without further purification. MS calcd. for C24H23F3NO4S (M+H+) 478.1, found 478.1.
Step B: {5-Cyσlopropyl-2-methyl-4- [4- (4-trifluoromethyl- phenyl) -thiazol-2-ylmethoxy] -phenoxy} -acetic acid methyl ester is dissolved in THP (1 mL) and a solution of 1 M LiOH in H2O (0.2 mL) is added. The mixture is stirred for 1 h at rt . Then it is acidified with 1 M HCl (0.25 mL) , EtOAc (10 mL) is added and the organic layer is washed with brine. The organic layer is dried (MgSO4) , filtered, concentrated and purified on reverse phase HPLC (H2O/MeCN gradient) to afford the title compound Fl as a white solid: 1H-NMR (400MHz, DMSO-d6) δ = 8.39 (s, IH) , 8.19 (d, J = 8.0 Hz, 2H) , 7.83 (d, J = 8.4 Hz, 2H) , 6.98 (s, IH) , 6.35 (S, IH), 5.46 (s, 2H) , 4.63 (s, 2H) , 2.15 (S, 3H) , 0.91 (m, 2H), 0.64 (m, 2H) . MS calcd. for C23H2IF3NO4S (M+H+) 464.1, found 464.0.
Figure imgf000122_0001
LiOH Step B
Figure imgf000122_0002
Gl
Example Gl: {5-Ethyl-2-methyl-4- [4- (4-trifluoromethyl- phenyl) -thiazol-2-ylmethoxy] -phenoxy} -acetic acid.
Step A: {2-Methyl-4- [4- (4-trifluoromethyl-phenyl) -thiazol-2- ylmethoxy] -5-vinyl-phenoxy} -acetic acid methyl ester (40 mg, 0.09 mmol) and 1, 4-cyclohexadiene (40 μL, 0.43 mmol) are dissolved in dry MeOH (5 mL) . Palladium on charcoal (10 mg) is added and the mixture is stirred at rt for 16 h. The mixture is filtered and concentrated to afford {5-Ethyl-2- methyl-4- [4- (4-trifluoromethyl-phenyl) -thiazol-2-ylmethoxy] - phenoxy} -acetic acid methyl ester which is used in Step B without further purification. MS calcd. for C23H23F3NO4S (M+H+) 466.1, found 466.1.
Step B: {5-Ethyl -2-methyl-4- [4- (4-trifluoromethyl-phenyl) - thiazol-2-ylmethoxy] -phenoxy} -acetic acid methyl ester is dissolved in THF (1 mL) and a solution of 1 M LiOH in H2O (0.2 mL) is added. The mixture is stirred for 1 h at rt . Then it is acidified with 1 M HCl (0.25 mL) , EtOAc (10 mL) is added and the organic layer is washed with brine . The organic layer is dried (MgSO4) , filtered, concentrated and purified on reverse phase HPLC (H2O/MeCN gradient) to afford the title compound Gl as a white solid: 1H-NMR (400MHz, DMSO-d6) δ = 8.38 (s, IH), 8.19 (d, J = 8.0 Hz, 2H), 7.82 (d, J = 8.4 Hz, 2H), 6.98 (S, IH), 6.72 (s, IH), 5.44 (s, 2H), 4.63 (s, 2H), 2.60 (q, J = 7.2 Hz, 2H), 2.17 (s, 3H), 1.16 (t, JT = 7.2 Hz, 3H). MS calσd, for C22H2IF3NO4S (M+H+) 452.1, found 452.1.
Figure imgf000123_0001
Bl
Example Hl: [4- (4-Biphenyl-4-yl-thiazol-2-ylmethoxy) -5- cyclopropyl-2-methyl-phenoxy] -acetic acid.
Step A: (5-Cyclopropyl-4-hydroxy-2-methyl-phenoxy) -acetic acid methyl ester 24 (40 mg, 0.17 mmol) and 4-Biphenyl-4-yl-2- chloromethyl-thiazole 102 (48 mg, 0.17 mmol) are dissolved in dry acetonitrile {5 mL) . Cs2CO3 (110 mg, 0.34 mmol) is added and the mixture is heated at reflux for 1 h to afford [4- (4- biphenyl-4-yl-thiazol-2-ylmethoxy) -5-cyclopropyl-2-methyl- phenoxy] -acetic acid methyl ester, which is used in Step B without further purification. MS calcd. for C29H28NO4S (M+H+) 486.2, found 486.1.
Step Bs To the solution of [4- (4-Biphenyl-4-yl-thiazol-2- ylmethoxy) -5-cyclopropyl-2-methyl-phenoxy] -acetic acid methyl ester from Step A is added THF (1 ml.) and a solution of 1 M LiOH in H2O (0.2 mL) . The mixture is stirred for 1 h at rt. Then it is acidified with 1 M HCl (0.25 mL) , EtOAc (10 mL) is added and the organic layer is washed with brine . The organic layer is dried (MgSO4) , filtered, concentrated and purified on reverse phase HPLC (H20/MeCN gradient) to afford the title compound Hl as a white solid: 1H-NMR (400MHz, CDCl3) δ = 7.98
(d, σ = 8.4 Hz, 2H), 7.67 (d, J = 8.4 Hz, 2H), 7.65 (d, J" = 7.6 Hz, 2H), 7.54 (s, IH), 7.46 (t, J = 7.2 HZ, 2H), 7.36 (t, J = 7.2 Hz, IH), 6.81 (s, IH), 6.38 (s, IH), 5.43 (s, 2H), 4.61 (S, 2H), 2.26 (s, 3H), 2.21 (m, IH), 0.97 (m, 2H), 0.64
(m, 2H) . MS calcd . for C28H26NO4S (M+H+) 472 . 2 , found 472 . 1 .
Figure imgf000124_0001
Example II: 2- (2 , 5-Dimethyl-4- {2- [4- (4-trifluoromethyl- phenyl) -thiazol-2-ylsulfanyl] -ethoxy} -phenoxy) -2-methyl- propionic acid.
Step A: The mercaptothiazole 119 (0.65 g, 2.49 mmol) , the bromide 97 (0.55 g, 1.66 mmol) and K2CO3 (0.28 g, 1.99 mmol) are suspended in dry acetonitrile (15 tnL) in a sealed tube. The mixture is stirred vigorously and heated to reflux overnight. Then the reaction mixture is cooled to room temperature, filtered and the solvent is removed in vacuo. The remainder is dissolved in EtOAc and washed with water twice, the organic layer is dried (MgSO4) and concentrated. The remainder is purified by flash chromatography (silica, DCM/MeOH gradient) to afford the 2- (2, 5-dimethyl-4- {2- [4- (4- trifluoromethyl-phenyl) -thiazol-2-ylsulfanyl] -ethoxy}- phenoxy) -2-methyl-propionic acid methyl ester as a colourless oil.
Step B: THF (3 mL) and 1 N LiOH (1 mL) are added to the solution derived from step A. The mixture is stirred at 500C for 5 h, then acidified with 1 N HCl (-1.5 mL) . The reaction mixture is extracted with DCM (3 mL) , the organic layer is separated and concentrated in vacuo. The remainder is taken up in DMSO (1 mL) and purified on reverse phase HPLC (H2O/MeCN gradient) to afford the title compound Il as a white solid: 1H-NMR (600 MHz, CDCl3) δ = 7.96 (d, J = 8.0 Hz, 2H), 7.66 (d, J = 8.4 Hz, 2H), 7.47 (s, IH), 6.68 (s, IH), 6.64 (s, IH), 4.32 (t, J = 6.4 Hz, 2H), 3.71 (t, J = 6.4 Hz, 2H), 2.16 (s, 3H), 2.14 (s, 3H), 1.54 (s, 6H). MS calculated for C24H25F3NO4S2 (M+H+) 512.1, found 512.0.
By repeating the procedures described in the above examples, using appropriate starting materials, the following compounds of Formula I, as identified in Table 6, are obtained.
Table 6
Figure imgf000125_0001
Figure imgf000126_0001
Transcriptional Assay
[00106] Transfection assays are used to assess the ability of compounds of the invention to modulate the transcriptional activity of the PPARs. Briefly, expression vectors for chimeric proteins containing the DNA binding domain of yeast GAL4 fused to the ligand-binding domain (LBD) of either PPARδ, PPARα or PPARγ are introduced via transient transfection into mammalian cells, together with a reporter plasmid where the luciferase gene is under the control of a GAL4 binding site. Upon exposure to a PPAR modulator, PPAR transcriptional activity varies, and this can be monitored by changes in luciferase levels. If transfected cells are exposed to a PPAR agonist, PPAR-dependent transcriptional activity increases and luciferase levels rise.
[00107] 293T human embryonic kidney cells (8x106) are seeded in a 175cm2 flask a day prior to the start of the experiment in 10% FBS, 1%
Penicillin/Streptomycin/Fungizome, DMEM Media. The cells are harvested by washing with PBS (30ml) and then dissociating using trypsin (0.05%; 3ml). The trypsin is inactivated by the addition of assay media (DMEM, CA-dextran fetal bovine serum (5%). The cells are spun down and resuspended to 170,000cells/ml. A Transfection mixture of GAL4-PPAR LBD expression plasmid (lμg), UAS-luciferase reporter plasmid (lμg), Fugene (3:1 ratio; 6μL) and serum -free media (200μL) was prepared and incubated for 15- 40 minutes at room temperature. Transfection mixtures are added to the cells to give 0;16M cells/mL, and cells (50μl/well) are then plated into 384 white, solid-bottom, TC-treated plates. The cells are further incubated at 370C, 5.0% CO2 for 5-7 hours. A 12-point series of dilutions (3 fold serial dilutions) are prepared for each test compound in DMSO with a starting compound concentration of lOμM. Test compound (500nl) is added to each well of cells in the assay plate and the cells are incubated at 370C5 5.0% CO2 for 18-24 hours. The cell lysis/luciferase assay buffer, Bright-Glo™ (25%; 25μl; Promega), is added to each well. After a further incubation for 5 minutes at room temperature, the luciferase activity is measured.
[00108] Raw luminescence values are normalized by dividing them by the value of the DMSO control present on each plate. Normalized data is analyzed and dose-response curves are fitted using Prizm graph fitting program. EC50 is defined as the concentration at which the compound elicits a response that is halfway between the maximum and minimum values. Relative efficacy (or percent efficacy) is calculated by comparison of the response elicited by the compound with the maximum value obtained for a reference PPAR modulator.
[00109] Compounds of Formula I, in free form or in pharmaceutically acceptable salt form, exhibit valuable pharmacological properties, for example, as indicated by the in vitro tests described in this application. Compounds of the invention preferably have an EC50 for PPARδ and/or PP ARa and/or PPARγ, of less than 5μM, more preferably less than 1 μM, more preferably less than 500nm, more preferably less than 10OnM. Compounds of the invention preferably have an EC50 for PPARδ that is less than or equal to PP ARa which in turn has an EC50 that is at least 10-fold less than PPARγ.
[00110] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference for all purposes.

Claims

WE CLAIM:
1. A compound of Formula I:
Figure imgf000129_0001
I in which n is selected from 0, 1, 2 and 3; p is selected from 0, 1, 2 and 3;
Y is selected from O, S, NR73 and CR7aR7b; wherein R7a and R?b are independently selected from hydrogen and C1-C6alkyl;
Z is selected from CRg3RBb and S; wherein R83 and Rgb are independently selected from hydrogen and C1-C6alkyl;
W is selected from O and S;
Ri is selected from -X1CRgRiOX2CO2Rn, -XISCR9R1OX2CO2RI i and - X1OCR9R10X2CO2R11; wherein Xi and X2 are independently selected from a bond and Ci- 4alkylene; and Kg and Rto are independently selected from hydrogen, C^alkyl and Cj. 4alkoxy; or R9 and Rio together with the carbon atom to which R9 and Rio axe attached form C3_i2cycloalkyl; and Rn is selected from hydrogen and C1-C6alkyl; each
R2 is independently selected from halo, C1-C6alkyl, C2-6alkenyl, Ci-4alkoxy, C|. 4alkylthio, C3-12cycloalkyl, C3-8heterocycloalkyl, Cβ-ioaryl and C5-ioheteroaryl; wherein any aryl, heteroaryl, cycloalkyl or heterocycloalkyl OfR2 is optionally substituted with 1 to 3 radicals independently selected from halo, C1-C6alkyl, C1-C6alkoxy, C2-6alkenyl, Ci-salkylthio, halo-substituted-C1-C6alkyl, halo-substituted-C1-C6alkoxy, -C(O)RH3 and NRi4aRi4b; wherein Ri4a and Ri4b are independently selected from hydrogen and C1-C6alkyl;
R3 and R4 are independently selected from hydrogen and C1-C6alkyl;
R5 and Rg are independently selected from hydrogen, C1-C6alkyl, C3-12cycloalkyl, C3^heterocycloalkyl, Ce-ioaryl and C5-i3heteroaryl; wherein any aryl, heteroaryl, cycloalkyl and heterocycloalkyl of Rs and Re is optionally substituted with 1 to 3 radicals independently selected from halo, nitro, cyano, Cj- βalkyl, C1-C6alkoxy, C1-C6alkylthio, hydroxy-C1-C6alkyl, halo-substituted-C1-C6alkyl, halo- substituted-Ci-6alkoxy, Cs-ucycloalkyl, Qj-sheterocycloalkyl, Cβ-ioaryl, Cs.i3heteroaryl, - XS(O)0-2R12 , -XS(O)0-2XR13 , -XNR12R12, -XNR12S(O)0-2R12, -XNR12C(O)R12, - XC(O)NR12R12, -XNR12C(O)R13, -XC(O)NR12R13, -XC(O)R13, -XNR12XR13 and - XOXR13; wherein any aryl, heteroaryl, cycloalkyl or heterocycloalkyl substituent is further optionally substituted with 1 to 3 radicals independently selected from halo, nitro, cyano, Cu 6alkyl, C1-C6aIkoxy, C1-C6alkylthio, hydroxy-Ci.6alkyl, halo-substituted-C1-C6alkyl and halo- substituted-Ci-«alkoxy; wherein X is a bond or C1-C6alkylene; R12 is selected from hydrogen and C1-C6alkyl; and R13 is selected from C3-12cycloalkyl, Cs-βheterocycloalkyl, Cβ-ioaryl and Cs-ioheteroaryl; wherein any aryl, heteroaryl, cycloalkyl or heterocycloalkyl of R13 is optionally substituted with 1 to 3 radicals independently selected from halo, nitro, cyano, Cj. βalkyl, C1-C6alkoxy, halo-substituted-C1-C6alkyl and halo-substituted-Ci-έalkoxy; with the proviso that either Rs or R^, but not both Rs and Re, must be hydrogen or methyl; and the pharmaceutically acceptable salts, hydrates, solvates, isomers and prodrugs thereof.
2. The compound of claim 1 in which: n is selected from O, 1, 2 and 3; p is selected from 0, 1 and 2;
Y is selected from O and S;
Z is selected from CRβaRβb and S; wherein Rsa and Rgb are independently selected from hydrogen and C1-C6alkyl; i
W is selected from O and S;
Ri is selected from -XiCR9R1OX2CO2Rn, -X1SCR9R10X2CO2R11 and - XiOCR9Ri0X2Cθ2Rπ; wherein X1 and X2 are independently selected from a bond and Ci- 4alkylene; and Rg and Rio are independently selected from hydrogen, Ci-4alkyl and Ci- 4alkoxy; or R9 and Rio together with the carbon atom to which Rg and Rio are attached form C3.12cycloa.kyl; and Ru is selected from hydrogen and C1-C6alkyl; each
R2 is independently selected from C1-C6alkyl, C2^alkenyl, Ci-4alkoxy, Ci- 4alkylthio, C3-12cycloalkyl, C3-8heterocycloalkyl, Cό-ioaryl and Cs-iQheteroaryl; wherein any aryl, heteroaryl, cycloalkyl or heterocycloalkyl OfR2 is optionally substituted with 1 to 3 radicals independently selected from halo, C1-C6alkoxy, C1-C6alkylthio, halo-substituted-Ci. βalkoxy, -C(0)Ri4a and NRi4aRi4b; wherein Rj43 and Rπb are independently selected from hydrogen and C1-C6alkyl;
R3 and R4 are independently selected from hydrogen and Ci.6alkyl;
R5 is Cg-ioaryl optionally substituted with 1 to 3 radicals independently selected from halo, nitro, cyano, C1-C6alkyl, C1-C6alkoxy, C1-C6alkylthio, hydroxy-C1-C6alkyl, halo-substituted-C1-C6alkyl, halo-substituted-C^alkoxy, C3.i2cycloalkyl, Cs-sheterocycloalkyl, Cβ-ioaryl, Cs-πheteroaryl and -XNR12R12; wherein R12 is selected from hydrogen and Ci. βalkyl; and
Re is selected from hydrogen and methyl.
3. The compound of claim 2 in which Ri is selected from -CH2CR5R6CO2H, — OCR5RsCO2H, -SCR5ReCO2H, -CR5RsCH2COaH and -CR5ReCO2H; wherein R5 and R6 are independently selected from hydrogen, methyl, methoxy and ethoxy; or R5 and Rg together with the carbon atom to which R5 and R^ are attached form cyclopentyl.
4. The compound of claim 3 in which each R2 is independently selected from methyl, ethyl, cyclopropyl, methoxy, furanyl, phenyl, pyridinyl, thienyl, pyrrolidinyl and benzo[l,3]dioxolyl; wherein said pyridinyl or phenyl of R2 is optionally substituted with 1 to 3 radicals independently selected from halo, methyl-carbonyl, dimethyl-amino, methoxy, halo-substituted-methoxy, methyl-thio, ethenyl, hexenyl and propyloxy.
5. The compound of claim 1 selected from: (5-Cyclopropyl-2-methyl-4-{3-[4-(4- trifluoromethyl-phenyl)-thiazol-2-yl]-propoxy}-phenoxy)-acetic acid; (3-{3-[4-(4- Trifluoromethyl-phenyl)-thiazol-2-yl]-propoxy} -phenyl)-acetic acid; (2-MethyI-4- {3-[4-(4- trifluoromethyl-phenyl)-thiazol-2-yl]-propoxy}-phenoxy)-acetic acid;2-Methyl-2-(4-{3-[4- (4-trifluoromethyl-phenyl)-thiazol-2-yl]-ρropoxy} -phenoxy)-propionic acid; (2- Cyclopropyl-3- {3-[4-(4-trifluoromethyl-phenyl)-thiazol-2-yl]-propoxy} -phenyl) -acetic acid; (4-Cyclopropyl-3-{3-[4-(4-trifluoromethyl-phenyl)-thiazol-2-yl]-propoxy}-phenyl)-acetic acid; (±)-2-Ethoxy-3-(4-{3-[4-(4-trifluoromethyl-phenyl)-thiazol-2-yl]-propoxy}-phenyl)- propionic acid; (-t)-2-Methoxy-3-(4- {3-[4-(4-trifluoromethyl-phenyl)-thiazol-2~yl]- propoxy}-phenyl)-propionic acid; (3-{3-[4-(4-Trifluoromethyl-phenyl)-oxazol-2-yl]- propoxy}-phenyl)-acetic acid; (2-Methyl-4-{3-[4-(4-trifluoromethyl-phenyl)-oxazol-2-yl]- propoxy}-phenoxy)-acetic acid; (5-Cyclopropyl-2-methyl-4-{3-[4-(4-trifluoromethyl- phenyl)-oxazol-2-yl]-propoxy}-ρhenoxy)-acetic acid; 2-Methyl-2-(4-{3-[4-(4- trifluoromethyl-phenyl)-oxazol-2-yl]-propoxy}-phenoxy)-propionic acid; (2-Cyclopropyl-3- {3 -[4-(4-trifluoromethyl-phenyl)-oxazol-2-yl]-proρoxy } -phenyl)-acetic acid; (4- Cyclopropyl-3 - {3-[4-(4-trifluoromethyl-phenyl)-oxazol-2-yl]-propoxy} -phenyl)-acetic acid; (3-{2-[4-(4-Trifluoromethyl-phenyl)-oxazol-2-yl]-ethoxy}-phenyl)-acetic acid; (3-{2-[4-(4- Trifluoromethoxy-phenyl)-oxazol-2-yl]-ethoxy} -phenyl)-acetic acid; (2-Cyclopropyl-3- {2- [4-(4-trifluoromethoxy-phenyl)-oxazol-2-yl]-ethoxy} -phenyl)-acetic acid; (4-Cyclopropyl-3- {2-[4-(4-trifluoromethoxy-phenyl)-oxazol-2-yl]-eihoxy} -phenyl)-acetic acid; (2- Cyclopropyl-3-{2-methyl-2-[4-(4-trifluoronieihyl-phenyl)-oxazol-2-yl]-propoxy}-phenyl)- acetic acid; (4-Cyclopropyl-3-{2-methyl-2-[4-(4-trifluoromethyl-phenyl)-oxazol-2-yl]- propoxy} -phenyl)-acetic acid; 3-(2-Methyl-4- {3-[4-(4-trifluoromethyl-phenyl)-thiazol-2-yl]- propoxy} -phenyl)-propionic acid; 3-(2-Cyclopropyl-5- {3-[4-(4-trifluoromethyl-phenyl)- thiazol-2-yl]-propoxy} -phenyl)-propionic acid; 3-(5-Cyclopropyl-2-methyl-4- {3-[4-(4- trifluoromethyl-phenyl)-thiazol-2-yl]-propoxy}-phenyl)-propionic acid; 3-(4-Cyclopropyl-3- {3-[4-(4-trifluoromethyl-phenyl)-thiazol-2-yl]-propoxy} -phenyl)-propionic acid; 2-Methyl- 2-(3-methyl-4-{3-[4-(4-trifluoromethyl-phenyl)-thiazol-2-yl]-propoxy}-phenoxy)-propionic acid; (-t)-2-Methyl-3-(4-{3-[4-(4-trifluoromethyl-phenyl)-thiazol-2-yl]-propoxy}-phenyl)- propionic acid; (±)-3 -(4- {3-[4-(4-Trifluoromethyl-phenyl)-thiazol-2-yl]-propoxy} -phenyl)- butyric acid; 2-Methyl-2-(2-methyl-4-{3-[4-(4-trifluoromethyl-phenyl)-thiazol-2-yl]- propoxy} -phenoxy)-propionic acid; 2-(2, 3-Dimethyl-4- {3 -[4-(4-trifluoromethyl-phenyl)- thiazol-2-yl]-propoxy}-phenoxy)-2-methyl-propionic acid; (±)-2-Ethoxy-3-(2-methyl-4-{3- [4-(4-trifluoromethyl-phenyl)-thiazol-2-yl]-propoxy}-phenyl)-propionic acid; 2-(2,5- Dimethyl-4-{3-[4-(4-trifluoromethyl-ρhenyl)-thiazol-2-yl]-propylsulfanyl}-phenoxy)-2- methyl-propionic acid; (2,5-Dimethyl-4- {3-[4-(4-trifluoromethyl-phenyl)-thiazol-2-yl]- propoxy } -phenoxy)-acetic acid; (2,5-Dimethyl-4- {3 -[4-(4-trifluoromethyl-phenyl)-thiazol-2- yl]-propylsulfanyl}-phenoxy)-acetic acid; 2-(2,5-Dimethyl-4-{3-[4-(4-trifluoromethyl- phenyl)-thiazol-2-yl]-propoxy}-phenoxy)-2-methyl-propionic acid; (3-Methoxy-4-{3-[4-(4- trifluoromethyl-phenyl)-thiazol-2-yl]-propoxy}-phenyl)-acetic acid; (4-Methoxy-3-{3-[4-(4- trifluoromethyl-phenyl)-thiazol-2-yl]-propoxy}-phenyl)-acetic acid; (±)-3-(2,5-Dimethyl-4- {3-[4-(4-trifluoromethyl-phenyl)-thiazol-2-yl]-propoxy}-phenyl)-2-ethbxy-propionic acid; 3-(2,5-Dimeihyl-4-{3-[4-(4-trifluoromethyl-phenyl)-thiazol-2-yl]-propoxy}-phenyl)-2,2- dimethyl-propionic acid; 2-(2,5-Dimethyl-4- {3-[4-(4-trifluoromethyl-phenyl)-thiazol-2-yl]- propoxy} -ρhenylsuIfanyl)-2-methyl-propionic acid; (2-Methyl-4- {2-[4-(4-trifluoromethyl- phenyl)-thiazol-2-yl]-ethoxy}-phenoxy)-acetic acid; (2-Methyl-4- {2-[4-(4-trifluoromethoxy- phenyl)-thiazol-2-yl]-ethoxy}-phenoxy)-acetic acid; (2-Methyl-4- {2-[5-methyl-4-(4- trifluoromethyl-phenyl)-thiazol-2-yl]-ethoxy} -phenoxy)-acetic acid; (2-Methyl-4- {2-[4-(3- trifluoromethyl-phenyl)-thiazol-2-yl]-ethoxy} -phenoxy)-acetic acid; (4- {2-[4-(4-Methoxy- phenyl)-thiazol-2-yl]-ethoxy}-2-methyl-phenoxy)-acetic acid; {2-Methyl-4-[2-(4- naphthalen-2-yl-thiazol-2-yl)-ethoxy]-phenoxy} -acetic acid; (2-Methyl-4- {3-[4-(4- trifluoromethyl-phenyl)-thiazol-2-yl]-propoxy}-phenoxy)-acetic acid; (2-Methyl-4-{3-[4-(4- trifluoromethoxy-phenyl)-thiazol-2-yl]-proρoxy}-phenoxy)-acetic acid;(2-Methyl-4-{3-[5- methyl-4-(4-trifluoromethyl-phenyl)-thiazol-2-yl] -propoxy } -phenoxy)-acetic acid; (2- Methyl-4-{3-[4-(3-trifluoromethyl-phenyl)-thiazol-2-yl]-propoxy}-phenoxy)-acetic acid; (4- {3-[4-(4-Methoxy-phenyl)-thiazol-2-yl]-propoxy} -2-methyl-phenoxy)-acetic acid; {2- Methyl-4-[3-(4-naphthalen-2-yl-thiazol-2-yl)-propoxy]-phenoxy}-acetic acid; (2-Methyl-4- {4-[4-(4-tτifluoromethyl-phenyl)-thiazol-2-yl]-butoxy} -phenoxy)-acetic acid; (2-Methyl-4- {4-[4-(4-trifluoromethoxy-phenyl)-thiazol-2-yl]-butoxy} -phenoxy)-acetic acid; (2-Methyl-4- {4-[5-methyl-4-(4-trifluoromethyl-phenyl)-thiazol-2-yl]-butoxy} -phenoxy)-acetic acid; (2- Methyl-4- {4-[4-(3-trifluoromethyl-phenyl)-thiazol-2-yl]-butoxy}-phenoxy)-acetic acid; (4- {4-[4-(4-Methoxy-phenyl)-thiazol-2-yl]-butoxy} -2-methyl-phenoxy)-acetic acid; {2-Methyl- 4-[4-(4-naphthalen-2-yl-thiazol-2-yl)-butoxy]-phenoxy}-acetic acid; (5-Cyclopropyl-2- methyl-4- {2-[4-(4-trifluoromethyl-phenyl)-thiazol-2-yl]-ethoxy} -phenoxy)-acetic acid; {5- Cyclopropyl-2-methyl-4-[2-(4-naphthalen-2-yl-thiazol-2-yl)-ethoxy]-ρhenoxy}-acetic acid; (5-Cyclopropyl-2-methyl-4-{2-[5-methyl-4-(4-trifluoromethyl-phenyl)-thiazol-2-yl]- ethoxy}-phenoxy)-acetic acid; (3-{2-[4-(4-Trifluoromethyl-phenyl)-thiazol-2-yl]-ethoxy}- phenyl)-acetic acid; {3-[2-(4-Naphthalen-2-yl-thiazol-2-yl)-ethoxy]-phenyl}-acetic acid; (3- {2-[5-Methyl-4-(4-trifluoromethyl-phenyl)-thiazol-2-yl]-ethoxy} -phenyl)-acetic acid; (2- Cyclopropyl-3 - {2-[4-(4-trifluoromethyl-phenyl)-thiazol-2-yl]-ethoxy } -phenyl)-acetic acid; {2-Cyclopropyl-3-[2-(4-naphthalen-2-yl-thiazol-2-yl)-ethoxy]-phenyl}-acetic acid; (2- Cyclopropyl-3 - {2-[5-methyl-4-(4-trifluoromethyl-phenyl)-thiazol-2-yl]-ethoxy} -phenyl)- acetic acid; (4-Cyclopropyl-3- {2-[4-(4-trifluoromethyl-phenyl)-thiazol-2-yl]-ethoxy} - phenyl)-acetic acid; {4-Cyclopropyl-3-[2-(4-naphthalen-2-yl-ihiazol-2-yl)-ethoxy]-phenyl} - acetic acid; (4-Cyclopropyl-3- {2-[5-methyl-4-(4-trifluoromethyl-phenyl)-thiazol-2-yl]- ethoxy} -phenyl)-acetic acid; 2-Methyl-2-(4- {2-[4-(4-trifluoromethyl-phenyl)-thiazol-2-yl]- ethoxy} -phenoxy)-propionic acid; 2-Methyl-2- {4-[2-(4-naphthalen-2-yl-thiazol-2-yl)- ethoxy]-phenoxy } -propionic acid; 2-Methyl-2-(4- {2-[5-methyl-4-(4-trifluoromethyl- phenyl)-thiazol-2-yl]-ethoxy}-phenoxy)-propionic acid; {4'-Methoxy-4-methyl-6-[4-(4- trifluoromethyl-phenyl)-thiazol-2-ylmethoxy]-biphenyl-3-yloxy } -acetic acid; {4-Methyl-4'- trifluoromethoxy-6-[4-(4-trifluoromethyl-phenyl)-thiazol-2-ylmethoxy] -biphenyl-3 -yloxy } - acetic acid; {4-Methyl-4'-methylsulfanyl-6-[4-(4-trifluoromethyl-phenyl)-thiazol-2- ylmethoxy]-biphenyl-3-yloxy}-acetic acid; {2-Methyl-4-[4-(4-trifluoromethyl-phenyl)- thiazol-2-ylmethoxy]-5-vinyl-phenoxy}-acetic acid; {5-Hex-l -enyl-2-methyl-4-[4-(4- trifluoromethyl-phenyl)-thiazol-2-ylme1hoxy]-phenoxy} -acetic acid; {5-Furan-3-yl-2- methyl-4-[4-(4-trifluoromethyl-phenyl)-thiazol-2-ylmethoxy]-phenoxy}-acetic acid; {5-(6- Methoxy-pyτidin-3-yl)-2-methyl-4-[4-(4-trifluoromethyl-phenyl)-thiazol-2-ylmethoxy]- phenoxy} -acetic acid; {4-Methyl-4'-propoxy-6-[4-(4-trifluoromethyl-phenyl)-thiazol-2- ylmethoxy)-biphenyl-3-yloxy} -acetic acid; {3'-Chloro-4'-methoxy-4-methyl-6-[4-(4- trifluoromethyl-phenyl)-thiazol-2-ylmethoxy]-biphenyl-3-yloxy} -acetic acid; { 5- Benzo[l,3]dioxol-5-yl-2-methyl-4-[4-(4-trifluoromethyl-phenyl)-thiazol-2-ylmethoxy]- phenoxy} -acetic acid; {4'-Acetyl-4-methyl-6-[4-(4-trifluoromethyl-phenyl)-thiazol-2- ylmethoxy]-biphenyl-3-yloxy} -acetic acid; {4'-Dimethylamino-4-methyl-6-[4-(4- trifluoromethyl-phenyl)-thiazol-2-ylmethoxy]-biphenyl-3-yloxy}-acetic acid; {2-Methyl-5- thiophen-2-yl-4-[4-(4-trifluoromethyl-phenyl)-thiazol-2-ylmethoxy]-phenoxy}-acetic acid; {4-Methyl-4'-methylsulfanyl-6-[4-(4-trifluoromethoxy-phenyl)-thiazol-2-ylmethoxy]- biphenyl-3 -yloxy} -acetic acid; {3'-Methoxy-4-methyl-6-[4-(4-trifluoromethoxy-phenyl)- thiazol-2-ylmethoxy]-biphenyl-3-yloxy}-acetic acid; {2-Methyl-5-pyrrolidin-l-yl-4-[4-(4- trifluoromethyl-phenyl)-thiazol-2-ylmethoxy]-phenoxy} -acetic acid; (±)-(4'-Methoxy-4- methyl-6- { 1 -[4-(4-trifluoromethyl-phenyl)-thiazol-2-yl]-ethoxy} -biphenyl-3-yloxy)-acetic acid; (4'-Methoxy-4-methyl-6- {2-[4-(4-trifluoromethyl-phenyl)-thiazol-2-yl]-ethoxy} - biphenyl-3-yloxy)-acetic acid; (2-Methyl-4- {2-[4-(4-trifluoromethyl-phenyl)-thiazol-2-yl]- ethoxy}-5-vinyl-phenoxy)-acetic acid; {4'-Methoxy-4-methyl-6-[4-(4-nitro-phenyl)-thiazol- 2-ylmethoxy]-biphenyl-3-yloxy} -acetic acid; {4'-Methoxy-6-[4-(4-methoxy-phenyl)-thiazol- 2-ylmethoxy] -4-methyl-biphenyl-3 -yloxy } -acetic acid; [4'-Methoxy-4-methyl-6-(4-p-tolyl- thiazol-2-ylmethoxy)-biphenyl-3 -yloxy]-acetic acid; { 6-[4-(4-Chloro~phenyl)-thiazol-2- ylmemoxy]-4'-memoxy-4-methyl-biρhenyl-3-yloxy}-acetic acid; {6-[4-(4-Diethylamino- phenyl)-thiazol-2-ylmethoxy]-4'-methoxy-4-methyl-biphenyI-3-yloxy} -acetic acid; {6-[4-(4- Cyano-phenyl)-thiazol-2-ylmethoxy]-4'-methoxy-4-methyl-biphenyl-3-yloxy}-acetic acid; [6-(4-Biphenyl-4-yl-thiazol-2-ylmethoxy)-4'-methoxy-4-methyl-biphenyl-3-yloxy]-acetic acid; [4'-Methoxy-4-methyl-6-(4-naphthalen-2-yl-thiazol-2-ylmethoxy)-biphenyl-3-yloxy]- acetic acid; {4'-Methoxy-6-[4-(3 -methoxy-phenyl)-thiazol-2-ylmethoxy] -4-methyl-biphenyl- 3-yloxy} -acetic acid; {5-Cyclopropyl-2-methyl-4-[4-(4-trifluoromethyl-phenyl)-thiazol-2- ylmethoxy]-phenoxy}-acetic acid; {5-Ethyl-2-methyl-4-[4-(4-trifluoromethyl-phenyl)- thiazol-2-ylmethoxy]-phenoxy} -acetic acid; [4-(4-Biphenyl-4-yl-thiazol-2-ylmethoxy)-5- cyclopropyl-2-methyl-phenoxy]-acetic acid; 2-(2,5-Dimethyl-4- {2-[4-(4-trifluoromethyl- phenyl)-miazol-2-ylsulfanyl]-ethoxy}-phenoxy)-2-methyl-propionic acid; and 2-(2,5- Dimethyl-4-{3-[4-(4-trifluoromethyl-phenyl)-thiazol-2-ylsulfanyl]-propoxy}-phenoxy)-2- methyl-propionic acid.
6. A method for treating a disease or disorder in an animal in which modulation of PPAR activity can prevent, inhibit or ameliorate the pathology and/or symptomology of the disease, which method comprises administering to the animal a therapeutically effective amount of a compound of Claim 1.
7. The method of claim 6 in which the PPAR activity is at least one PPAR selected from PP ARa, PPARδ and PP ARy.
8. The method of claim 7 in which the PPAR activity is both PP ARa and PPARδ.
9. The method of claim 6 in which the disease or disorder is selected from the treatment of prophylaxis, dyslipidemia, hyperlipidemia, hypercholesteremia, atherosclerosis, atherogenesis, hypertriglyceridemia, heart failure, myocardial infarction, vascular diseases, cardiovascular diseases, hypertension, obesity, cachexia, inflammation, arthritis, cancer, anorexia, anorexia nervosa, bulimia, Alzheimer's disease, skin disorders, respiratory diseases, ophthalmic disorders, irritable bowel diseases, ulcerative colitis, Crohn's disease, tyρe-1 diabetes, type-2 diabetes and Syndrome X.
10. The method of claim 6 in which the disease or disorder is selected from HIV wasting syndrome, long term critical illness, decreased muscle mass and/or muscle strength, decreased lean body mass, maintenance of muscle strength and function in the elderly, diminished muscle endurance and muscle function, and frailty in the elderly.
11. The use of a compound according to any of claims 1 to 5 in the manufacture of a medicament for treating a disease in an animal in which PPAR activity contributes to the pathology and/or symptomology of the disease.
12. The use of claim 11 in which the PPAR activity is at least one PPAR selected from PP ARa, PPARδ and PP ARy.
13. The use of claim 12 in which the PPAR activity is both PP ARa and PPARδ.
14. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any of claim 1 to 5 in combination with one or more pharmaceutically acceptable excipients.
15. A pharmaceutical combination, especially a pharmaceutical composition, comprising: 1) a compound of any of claims 1 to 5 or a pharmaceutical acceptable salt thereof; and 2) at least one active ingredient selected from: a) anti-diabetic agents such as insulin, insulin derivatives and mimetics; insulin secretogogues such as the sulfonylureas, e.g., Glipizide, glyburide and Amaryl; insulinotropic sulfonylurea receptor ligands such as meglitinides, e.g., nateglinide and repaglinide; insulin sensitizer such as protein tyrosine phosphatase- IB (PTP-IB) inhibitors such as PTP-112; GSK3 (glycogen synthase kinase-3) inhibitors such as SB-517955, SB- 4195052, SB-216763, NN-57-05441 andNN-57-05445; RXR ligands such as GW-0791 and AGN- 194204; sodium-dependent glucose co-transporter inhibitors such as T-1095; glycogen phosphorylase A inhibitors such as BAY R3401; biguanides such as metformin; alpha- glucosidase inhibitors such as acarbose; GLP-I (glucagon like peptide-1), GLP-I analogs such as Exendin-4 and GLP-I mimetics; dipeptidyl peptidase IV inhibitors such as DPP728, vildagliptin, MK-0431, saxagliptin, GSK23A ; an AGE breaker; a thiazolidone derivative (glitazone) such as pioglitazone, rosiglitazone, or (R)-I- {4-[5-methyl-2-(4-trifluorornethyl- phenyl)-oxazol-4-ylmethoxy]-benzenesulfonyl}-2,3-dihydro-lH/-indole-2-carboxylic acid, a non-glitazone type PPARγ agonist e.g. GI-262570; b) hypolipidemic agents such as 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG- CoA) reductase inhibitors, e.g., lovastatin, pitavastatin, simvastatin, pravastatin, cerivastatin, mevastatin, velostatin, fluvastatin, dalvastatin, atorvastatin, rosuvastatin and rivastatin; squalene synthase inhibitors; FXR (farnesoid X receptor) and LXR (liver X receptor) ligands; cholestyramine; fibrates; nicotinic acid and aspirin; c) an anti-obesity agent or appetite regulating agent such as phentermine, leptin, bromocriptine, dexamphetamine, amphetamine, fenfluramine, dexfenfluramine, sibutramine, orlistat, dexfenfluramine, mazindol, phentermine, phendimetrazine, diethylpropion, fluoxetine, bupropion, topiramate, diethylpropion, benzphetamine, phenylpropanolamine or ecopipam, ephedrine, pseudoephedrine or cannabinoid receptor antagonists; d) anti-hypertensive agents, e.g., loop diuretics such as ethacrynic acid, furosemide and torsemide; diuretics such as thiazide derivatives, chlorithiazide, hydrochlorothiazide, amiloride; angiotensin converting enzyme (ACE) inhibitors such as benazepril, captopril, enalapril, fosinopril, lisiπopril, moexipril, perinodopril, quinapril, ramipril and trandolapril; inhibitors of the Na-K- ATPase membrane pump such as digoxin; neutralendopeptidase (NEP) inhibitors e.g. thiorphan, terteo-thiorphan, SQ29072; ECE inhibitors e.g. SLV306; ACE/NEP inhibitors such as omapatrilat, sampatrilat and fasidotril; angiotensin II antagonists such as candesartan, eprosartan, irbesartan, losartan, telmisartan and valsartan, in particular valsartan; renin inhibitors such as aliskiren, terlakiren, ditekiren, RO 66-1132, RO- 66-1168; β-adrenergic receptor blockers such as acebutolol, atenolol, betaxolol, bisoprolol, metoprolol, nadolol, propranolol, sotalol and timolol; inotropic agents such as digoxin, dobutamine and milrinone; calcium channel blockers such as amlodipine, bepridil, diltiazem, felodipine, nicardipine, nimodipine, nifedipine, nisoldipine and verapamil; aldosterone receptor antagonists; and aldosterone synthase inhibitors; e) a HDL increasing compound; f) a cholesterol absorption modulator such as Zetia® and KT6-971; g) Apo-Al analogues and mimetics; h) thrombin inhibitors such as Ximelagatran; i) aldosterone inhibitors such as anastrazole, fadrazole, eplerenone; j) Inhibitors of platelet aggregation such as aspirin, clopidogrel bisulfate; k) estrogen, testosterone, a selective estrogen receptor modulator, a selective androgen receptor modulator;
1) a chemotherapeutic agent such as aromatase inhibitors e.g. femara, anti- estrogens, topoisomerase I inhibitors, topoisomerase II inhibitors, microtubule active agents, alkylating agents, antineoplastic antimetabolites, platin compounds, compounds decreasing the protein kinase activity such as a PDGF receptor tyrosine kinase inhibitor preferably Imatinib or 4-Methyl-N-[3-(4-methyl-imidazol-l-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin- 3-yl-pyrimidin-2-ylamino)-benzamide; and m) an agent interacting with a 5-HTa receptor and/or an agent interacting with 5- HT4 receptor such as tegaserod, tegaserod hydrogen maleate, cisapride, cilansetron; or, in each case a pharmaceutically acceptable salt thereof; and optionally a pharmaceutically acceptable carrier.
16. A pharmaceutical composition according to claim 14 or a combination according to claim 15, for the treatment or prevention of dyslipidemia, hyperlipidemia, hypercholesteremia, atherosclerosis, hypertriglyceridemia, heart failure, myocardial infarction, vascular diseases, cardiovascular diseases, hypertension, obesity, inflammation, arthritis, cancer, Alzheimer's disease, skin disorders, respiratory diseases, ophthalmic disorders, inflammatory bowel diseases, IBDs (irritable bowel disease), ulcerative colitis, Crohn's disease, conditions in which impaired glucose tolerance, hyperglycemia and insulin resistance are implicated, such as type-1 and type-2 diabetes, Impaired Glucose Metabolism (IGM), Impaired Glucose Tolerance (IGT), Impaired Fasting Glucose (IFG), and Syndrome- X.
17. A compound according to any of claims 1 to 5, or a pharmaceutical composition according to claim 10 or a combination according to claim 11, for use as a medicament.
18. Use of a compound according to any of claims 1 to 5, or a pharmaceutical composition according to claim 14 or a combination according to claim 15, for the manufacture of a medicament for the treatment or prevention of dyslipidemia, hyperlipidemia, hypercholesteremia, atherosclerosis, hypertriglyceridemia, heart failure, myocardial infarction, vascular diseases, cardiovascular diseases, hypertension, obesity, inflammation, arthritis, cancer, Alzheimer's disease, skin disorders, respiratory diseases, ophthalmic disorders, inflammatory bowel diseases, IBDs (irritable bowel disease), ulcerative colitis, Crohn's disease, conditions in which impaired glucose tolerance, hyperglycemia and insulin resistance are implicated, such as type-1 and type-2 diabetes, Impaired Glucose Metabolism (IGM), Impaired Glucose Tolerance (IGT), Impaired Fasting Glucose (IFG), and Syndrome-X.
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