EP1937647A1 - Condensed pyrazole derivatives as ppar agonists ii - Google Patents

Condensed pyrazole derivatives as ppar agonists ii

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Publication number
EP1937647A1
EP1937647A1 EP06779567A EP06779567A EP1937647A1 EP 1937647 A1 EP1937647 A1 EP 1937647A1 EP 06779567 A EP06779567 A EP 06779567A EP 06779567 A EP06779567 A EP 06779567A EP 1937647 A1 EP1937647 A1 EP 1937647A1
Authority
EP
European Patent Office
Prior art keywords
phenyl
methyl
phenoxy
indazol
trifluoromethyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP06779567A
Other languages
German (de)
French (fr)
Inventor
Andrew Ayscough
Stephen Thompson
Susanne Taylor
Nawaz Mohammed Khan
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Inpharmatica Ltd
Original Assignee
Inpharmatica Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB0519874.2A external-priority patent/GB0519874D0/en
Priority claimed from GB0614578A external-priority patent/GB0614578D0/en
Application filed by Inpharmatica Ltd filed Critical Inpharmatica Ltd
Publication of EP1937647A1 publication Critical patent/EP1937647A1/en
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles

Definitions

  • This invention relates to compounds which are useful for treating disorders mediated by peroxisome- proliferator-activated receptor (PPAR) subtype ⁇ (PP AR ⁇ ).
  • PPAR peroxisome- proliferator-activated receptor subtype ⁇
  • the high fat diet of modern society combined with a largely sedentary lifestyle has resulted in an increase in the population that are overweight or obese. Being overweight or obese increases the risk of coronary heart disease, hypertension, dyslipidemia, atherosclerosis, type-II diabetes, stroke, osteoarthritis, restrictive pulmonary disease, sleep apnoea, certain types of cancers and inflammatory disorders.
  • the standard treatment for obesity is calorific restriction and increase of physical exercise. However, such approaches are rarely successful and pharmaceutical treatments are required to correct these metabolic disorders.
  • the three peroxisome-proliferator-activated receptor (PPAR) subtypes, PPAR ⁇ , PP ARa and PP AR ⁇ , are nuclear receptors that regulate glucose and lipid homeostasis.
  • PP AR ⁇ agonists might be useful in the treatment of various components of the metabolic syndrome including dyslipidemia, obesity and insulin resistance by increasing fatty acid consumption in skeletal muscle and adipose tissue.
  • PP AR ⁇ agonists have shown cholesterol lowering activity and elevation of high-density lipoprotein cholesterol (HDL-C) levels in diabetic mice suggesting they may have beneficial effects on dyslipidemia (2).
  • a potent PP AR ⁇ agonist has also been shown to increase HDL-C while decreasing elevated trigylceride (TG) and insulin levels in obese rhesus monkeys (3).
  • the same compound also attenuates weight gain and insulin resistance in mice fed high-fat diets by increasing the expression of genes in skeletal muscle that promote lipid catabolism and mitochondrial uncoupling, thereby increasing ⁇ -oxidation of fatty acids in skeletal muscle (4).
  • a series of studies have demonstrated the expression of PPAR ⁇ in a number of neural cell types including optic nerve oligodendrocytes and sciatic nerve Schwann cells.
  • a PPAR ⁇ agonist has demonstrated neuroprotective effects on cerebellar neurons suggesting a role in the treatment of neurodegenerative diseases including Alzheimer's disease and Parkinson's disease and may also be of use in the enhancement of learning and memory function (9).
  • Studies with a PPAR ⁇ agonist show a reduction in the clinical signs of murine experimental autoimmune encephalomyelitis, commonly used as a model for multiple sclerosis (10).
  • PPAR ⁇ agonists are expected to be therapeutically useful, e.g. in the treatment of metabolic syndrome, obesity, type-II diabetes, dyslipidemia, wound healing, inflammation, neurodegenerative disorders and multiple sclerosis.
  • WO2005/060958 discloses compounds based on various ring systems which are modulators of PPAR ⁇ .
  • WO2005/065638 discloses triazole, oxadiazole and thiadiazole compounds which are modulators of PPAR ⁇ .
  • R is a carboxylic acid or a derivative thereof;
  • R 1 and R 2 are independently H or alkyl, or together R 1 and R 2 form an alkylene group;
  • L 1 is a single bond, NH, NCH 3 , O, S, CH 2 or CH, wherein when L 1 is CH the dashed line indicates a double bond and R 2 is absent, otherwise the dashed line is a single bond;
  • R 8 and R 9 are independently H, halo, alkyl or alkoxy; L 2 is O or S;
  • L 3 is CH 2 or CH 2 CH 2 ;
  • R 10 and R 11 are independently H, halo, CF 3 , OCF 3 , alkyl or alkoxy; Y 1 is CH or N; Y 2 is CH or N; and R 12 and R 13 are independently H, halo, CF 3 , OCF 3 , alkyl or alkoxy; and pharmaceutically acceptable derivatives thereof.
  • the invention also provides a compound of formula (I), or a pharmaceutically acceptable derivative thereof, for use in therapy.
  • the invention further provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable derivative thereof, in combination with a pharmaceutically acceptable carrier, excipient or diluent.
  • the invention further provides a method for the treatment of a disease or condition mediated by PPAR ⁇ , comprising the step of administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable derivative thereof, to a patient.
  • the invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable derivative thereof, in the manufacture of a medicament for the treatment of a disease or condition mediated by PPAR ⁇ .
  • the invention also provides a composition comprising PPAR ⁇ and a compound of formula (I) 5 or a pharmaceutically acceptable derivative thereof.
  • the invention also provides a crystal of PPAR ⁇ and a compound of formula (I), or a pharmaceutically acceptable derivative thereof.
  • Such crystals can be used for X-ray diffraction studies of PPAR ⁇ inhibition, e.g. to provide atomic structural information in order to aid rational design of further agonists.
  • pharmaceutically acceptable derivative includes any pharmaceutically acceptable salt, solvate or hydrate thereof.
  • pharmaceutically acceptable salt includes a salt prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic or organic acids and bases.
  • inorganic acids suitable for use in this invention include, but are not limited to hydrochloric, hydrobromic, hydroiodic, sulfuric, and phosphoric acids.
  • Appropriate organic acids for use in this invention include, but are not limited to aliphatic, aromatic, carboxylic and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, citric, succinic, glycolic, glucuronic, maleic, furoic, glutamic, benzoic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic, benzenesulfonic, stearic, sulfanilic, algenic, and galacturonic.
  • inorganic bases suitable for use in this invention include metallic salts made from aluminium, calcium, lithium, magnesium, potassium, sodium, and zinc.
  • Appropriate organic bases may be selected, for example, from N,N-dibenzylethylenediamine ? chloroprocaine, choline, diethanolamine, ethylenediamine, meglumaine (N-methylglucamine), and procaine.
  • the compounds of the invention may exist in a number of diastereomeric and enantiomeric forms. Diastereomeric and enantiomeric forms of the polyphenols of the invention may be differentiated by the direction in which they rotate plane-polarised light.
  • a dextrorotatory (d) substance rotates plane- polarised light in a clockwise or positive (+) direction.
  • a levorotatory (1) substance rotates plane- polarised light in a counterclockwise or negative (— ) direction.
  • the invention encompasses pure diastereomers and enantiomers as well as mixtures, including racemic mixtures, of diastereomers and enantiomers.
  • R is a carboxylic acid or a derivative thereof.
  • carboxylic acids include esters (e.g. of the fo ⁇ nula -CO 2 R 4 ).
  • R 4 is alkyl (e.g. C h alky!) or arylalkyl (e.g. benzyl).
  • R 4 is independently H, alkyl (e.g. C 1-6 alkyl) or arylalkyl (e.g. benzyl).
  • R is a carboxylic acid, i.e. -CO 2 H.
  • R 1 is H or methyl.
  • R 1 may be substituted or unsubstituted. Where substituted, R 1 may be substituted by one or more Sub 1 , defined below.
  • R 2 is H or methyl.
  • R 1 and R 2 are both H or both methyl.
  • R 2 may be substituted or unsubstituted. Where substituted, R 2 may be substituted by one or more Sub 1 , defined below.
  • L 1 is O, S or NH.
  • L 1 may be substituted or unsubstituted. Where substituted, L 1 may be substituted by one or more Sub 1 , defined below.
  • L 2 is O or S, e.g. S.
  • R 8 and R 9 are independently selected from the group consisting of R 8 and R 9
  • R 8 and R 9 are both H, or R 8 is methyl and R 9 is H.
  • R 8 and R 9 may be independently substituted or unsubstituted. Where substituted, R 8 or R 9 may be substituted by one or more Sub 1 , defined below.
  • L 3 is -CH 2 -.
  • L 3 may be substituted or unsubstituted. Where substituted, L 3 may be substituted by one or more Sub 1 , defined below.
  • R 10 is CF 3 substituted at the 4-position and R 11 is H.
  • R 10 and R 11 may be independently substituted or unsubstituted. Where substituted, R 10 or R 11 may be substituted by one or more Sub 1 , defined below.
  • Y 1 is CH.
  • Y 1 may be substituted or unsubstituted. Where substituted, Y 1 may be substituted by Sub 1 , defined below.
  • Y 2 is CH.
  • Y 2 may be substituted or unsubstituted. Where substituted, Y 2 may be substituted by Sub 1 , defined below.
  • Sub 1 defined below.
  • R 12 and R 13 are both H, or R 12 is H and R 13 is attached to group Y 1 (when Y 1 is CH) and is alkyl, alkoxy, Cl, F, CF 3 or OCF 3 .
  • Preferred compounds of formula (I) are those of formula (II): wherein R 1 , R 2 , L 1 , R 8 , R 9 , L 2 , L 3 , R 10 , R 11 , R 12 and R 13 are defined above; and pharmaceutically acceptable derivatives thereof.
  • Especially preferred compounds of the invention are the compounds of example 1 below, i.e.: ⁇ 2-Methyl-4-[l-(4-trifluoromethyl-phenyl)-lH-indazol-3-ylmethylsulfanyl]-phenoxy ⁇ -acetic acid
  • Preferred compounds of the invention have an EC5 0 in the PPAR ⁇ GAL4 assay of biological assay 1 of ⁇ l uM, preferably ⁇ 10O nM.
  • Preferred compounds of the invention up-regulate one or more of the target genes identified in biological assay 3 below (i.e. FATP, LCAD, CPTl, PDK4, UCP2, UCP3, PGC-Ia and GLUT4) by at least 2 fold at sub-micromolar concentrations.
  • Preferred compounds of the invention demonstrate one or more of the following effects when compared to vehicle treated animals:
  • (v) up-regulate one or more of the target genes identified in biological assay 3 below (i.e. FATP 5 LCAD, CPTl, PDK4, UCP2, UCP3, PGC-Ia and GLUT4) by at least 2 fold at sub- micromolar concentrations.
  • Preferred compounds of the invention have an EC5 0 in the PPAR ⁇ GAL4 assay of biological assay 1 at least ten times lower than its EC 50 in the PP ARa GAL4 assay or the PPAR ⁇ GAL4 assay, preferably both, of biological assay 1.
  • the invention is useful for the treatment of a disease or condition mediated by PPAR ⁇ .
  • Diseases and conditions mediated by PPAR ⁇ include: metabolic syndrome, and components thereof including dyslipidaemia, obesity and insulin resistance; type-II diabetes; wound healing; inflammation; neurodegenerative disorders; and multiple sclerosis.
  • the present invention is useful for the treatment of coronary heart disease, hypertension, hyperlipidaemia, type-II diabetes mellitus, stroke, osteoarthritis, restrictive pulmonary disease, sleep apnoea and cancer.
  • treatment includes prophylactic treatment.
  • a “patient” means an animal, preferably a mammal, preferably a human in need of treatment.
  • the amount of the compound of the invention administered should be a therapeutically effective amount where the compound or derivative is used for the treatment of a disease or condition and a prophylactically effective amount where the compound or derivative is used for the prevention of a disease or condition.
  • terapéuticaally effective amount refers to the amount of compound needed to treat or ameliorate a targeted disease or condition.
  • prophylactically effective amount used herein refers to the amount of compound needed to prevent a targeted disease or condition.
  • the exact dosage will generally be dependent on the patient's status as the time of administration. Factors that may be taken into consideration when determining dosage include the severity of the disease state in the patient, the general health of the patient, the age, weight, gender, diet, time and frequency of administration, drug combinations, reaction sensitivities and the patient's tolerance or response to therapy. The precise amount can be determined by routine experimentation, but may ultimately lie with the judgement of the clinician.
  • an effective dose will be from 0.01 mg/kg/day (mass of drug compared to mass of patient) to 50 mg/kg/day, preferably 0.05 mg/kg/day to 10 mg/kg/day.
  • Compositions may be administered individually to a patient or may be administered in combination with other agents, drugs or hormones.
  • the compounds of the invention may be administered as a medicament by mucosal or parenteral routes, including intravenous, intramuscular, intraperitoneal, subcutaneous, transdermal, airway (aerosol), oral, intranasal, rectal, vaginal and topical (including buccal and sublingual) administration.
  • the compounds of the invention will generally be provided in injectable form.
  • the compounds of the invention will generally be provided in the form of tablets or capsules, as a powder or granules, or as an aqueous solution or suspension.
  • Tablets for oral use may include the active ingredients mixed with pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavouring agents, colouring agents and preservatives.
  • Suitable inert diluents include sodium and calcium carbonate, sodium and calcium phosphate and lactose.
  • Corn starch and alginic acid are suitable disintegrating agents.
  • Suitable binding agents include starch and gelatin.
  • Suitable lubricating agents include magnesium stearate, stearic acid or talc.
  • the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate, to delay absorption in the gastrointestinal tract.
  • Capsules for oral use include hard gelatin capsules in which the active ingredient is mixed with a solid diluent, and soft gelatin capsules wherein the active ingredients are mixed with water or an oil such as peanut oil, liquid paraffin or olive oil.
  • compositions for use with the invention may comprise pharmaceutically acceptable carriers, such as sugars or salts, or excipients. They may also contain diluents, such as water, saline, glycerol, etc. Additionally, auxiliary substances, such as wetting or emulsifying agents, pH buffering substances, and the like, may be present.
  • pharmaceutically acceptable carriers and excipients are available in Gennaro (2000) Remington: The Science and Practice of Pharmacy, 20th edition (ISBN: 0683306472).
  • halogen includes fluorine, chlorine, bromine and iodine.
  • alkyl alkylene, alkenyl, or alkynyl are used herein to refer to both straight and branched chain acyclic forms. Cyclic analogues thereof are referred to as cycloalkyl, etc.
  • alkyl includes monovalent, straight or branched, saturated, acyclic hydrocarbyl groups.
  • Preferred alkyl are Ci -lo alkyl, more preferably still more preferably C 1-4 alkyl, such as methyl, ethyl, n-propyl, i-propyl or t-butyl groups.
  • cycloalkyl includes monovalent, saturated, cyclic hydrocarbyl groups.
  • Preferred cycloalkyl are C 3-6 CyClOaIlCyI, such as cyclopentyl and cyclohexyl.
  • alkoxy means alkyl-O-.
  • alkenyl includes monovalent, straight or branched, unsaturated, acyclic hydrocarbyl groups having at least one carbon-carbon double bond and preferably no carbon-carbon triple bonds.
  • Preferred alkenyl are C 2- ioalkenyl, more preferably C 2- 6alkenyl, still more preferably C2 -4 alkenyl.
  • cycloalkenyl includes monovalent, unsaturated, cyclic hydrocarbyl groups having at least one carbon-carbon double bond and preferably no carbon-carbon triple bonds.
  • Preferred cycloalkenyl are C 3 . 6 cycloalkenyl, preferably Cs- ⁇ cycloalkenyl.
  • alkynyl includes monovalent, straight or branched, unsaturated, acyclic hydrocarbyl groups having at least one carbon-carbon triple bond and preferably no carbon-carbon double bonds.
  • Preferred alkynyl are C 2-10 alkynyl, more preferably C2- 6 alkynyl, still more preferably C 2-4 alkynyl.
  • alkylene includes divalent, straight or branched, saturated, acyclic hydrocarbyl groups.
  • Preferred alkylene are Cj.ioalkylene, more preferably still more preferably C 1-4 alkylene, such as methylene, ethylene, n-propylene, i-propylene or t-butylene groups.
  • aryl includes monovalent, aromatic, cyclic hydrocarbyl groups, such as phenyl or naphthyl (e.g. 1-naphthyl or 2-naphthyl). rn general, the aryl groups may be monocyclic or polycyclic fused ring aromatic groups. Preferred aryl are C 6 -C 14 aryl.
  • aryl groups are monovalent derivatives of aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, chrysene, coronene, fluoranthene, fluorene, ⁇ s-indacene, s- indacene, indene, naphthalene, ovalene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene and rubicene.
  • arylalkyl means alkyl substituted with an aryl group, e.g. benzyl.
  • heteroaryl includes monovalent, heteroaromatic, cyclic hydrocarbyl groups additionally containing one or more heteroatoms selected from O, S or N.
  • the heteroaryl groups may be monocyclic or polycyclic (e.g. bicyclic) fused ring heteroaromatic groups.
  • Preferred heteroaryl groups are 5-13 membered (preferably 5-10 membered) and contain 1, 2, 3 or 4 heteroatoms selected from O, S or N.
  • Monocyclic heteroaromatic groups include 5- or 6-membered heteroaromatic groups containing 1, 2, 3 or 4 heteroatoms selected from O, S or N.
  • monocyclic heteroaryl groups are pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, tetrazolyl and succinimidyl.
  • Bicyclic heteroaromatic groups include 9- to 13-membered fbsed-ring heteroaromatic groups containing 1, 2, 3, 4 or more heteroatoms selected from O, S or N.
  • Examples of bicyclic heteroaromatic groups are benzofuryl, [2,3-dihydro]benzofuryl, benzothienyl, benzotriazolyl, indolyl, isoindolyl, benzimidazolyl, imidazo[l,2-a]pyridyl, benzothiazolyl, benzoxazolyl, benzopyranyl, [3,4-dihydro]benzopyranyl, quinazolinyl, naphthyridinyl, pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl, pyrido[4,3-b] ⁇ yridyl, quinolinyl, isoquinolinyl, 5,6,7,8-t
  • heteroaryl groups are monovalent derivatives of acridine, carbazole, /?-carboline, chromene, cinnoline, furan, imidazole, indazole, indole, indolizine, isobenzofuran, isochromene, isoindole, isoquinoline, isotbiazole, isoxazole, naphthyridine, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, thiophene and xanthene.
  • Preferred heteroaryl groups are five- and six-membered monovalent derivatives, such as the monovalent derivatives of furan, imidazole, isothiazole, isoxazole, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine and thiophene.
  • the five-membered monovalent derivatives are particularly preferred, i.e. the monovalent derivatives of furan, imidazole, isothiazole, isoxazole, pyrazole, pyrrole and thiophene.
  • heteroarylalkyl means alkyl substituted with an heteroaryl group.
  • heteroalkylene includes alkylene groups in which up to three carbon atoms, preferably up to two carbon atoms, more preferably one carbon atom, are each replaced independently by O, S or
  • -CH 2 - is replaced by -O-, -S- or -NR 6 -, where R 6 is H, alkyl, aryl, -C(O)-alkyl, -C(O)-aryl, -S(O) 2 -alkyl or-S(O) 2 -aryl.
  • R 6 is preferably H or alkyl ⁇ e.g. C 1-6 alkyl).
  • alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, alkylene, aryl, arylalkyl, heteroaryl, heteroarylalkyl and heteroalkylene groups of the compounds of the invention may be substituted or unsubstituted, preferably unsubstituted.
  • substituents there will generally be 1 to 3 substituents, preferably 1 or 2 substituents, more preferably 1 substituent.
  • Z 3 is independently O, S or NR 5 ;
  • R s is H or C 1-6 alkyl, optionally substituted by 1 to 3 substituents Sub 2 .
  • the group may be substituted by both ends of an alkylene or heteroalkylene chain (e.g. on the same carbon atom of the group) to form a cyclic moiety.
  • a phenyl group or a six-membered ring heteroaryl group e.g. pyridyl
  • substitution at the meta and para positions is preferred, with para substitution being especially preferred.
  • composition comprising X may consist exclusively of X or may include something additional e.g. X + Y.
  • Method B (A) Water containing 0.1% formic acid and (B) acetonitrile containing 0.1% formic acid as the mobile phase (gradient: 0.00 minutes, 95% A; linear gradient to 100% B at 4.45 minutes; then hold until 5.15 minutes; 5.16 minutes 95% A; then hold until 6 minutes).
  • Flow rate 1.5 ml/minute to column & to UV detector, flow split after UV detector such that 0.25ml/rninute to MS detector and 0.75 ml/minute to waste; injection volume 5 ⁇ l; Auxiliary Detectors:- Agilent 1100 Series variable wavelength UV detector (serial # JP33322024) wavelength 220nm.
  • Flow rate lml/minute to column & to UV detector, flow split after UV detector such that 0.25ml/minute to MS detector and 0.75ml/minute to waste; injection volume 5 ⁇ l; Auxiliary Detectors:- Agilent 1100 Series variable wavelength UV detector (serial # JP33322024) wavelength 220nm.
  • reaction mixture was warmed to room temperature and stirred for 2 hours before being quenched (water, IM hydrochloric acid), extracted (3 x ethyl acetate), the combined organic extracts were washed (brine), dried (Na 2 SO 4 ), filtered and the solvent removed in vacuo.
  • the resultant crude residue was taken, up in tetrahydrofuran (10ml), ⁇ zs-l,2-(diphenylphos ⁇ hino)ethane (250mg, 0.6263mmol) and JV- chlorosuccinimide (163mg, 1.253mmol) were added and the reaction stirred for 2 hours.
  • reaction was cooled to O 0 C, sodium thiocyanate dihydrate (5.4Og, 46.16mmol), sodium bromide (1.48g, 14.43mmol) and bromine (0.71ml, 14.43mmol) in methanol (20ml) were added, the reaction warmed to room temperature and stirred for 8 hours.
  • the reaction mixture was poured into saturated sodium bicarbonate solution, extracted (3 x dichloromethane), the organic extracts washed (water, brine), dried (Na 2 SO 4 ), filtered and the solvent removed in vacuo.
  • Intermadiate 8a (4-Acetyl-2-methyl-phenoxy) ⁇ acetic acid ethyl ester
  • Example Ia ⁇ 2-Methyl-4-[l -(4-trifluoromethyl-phenyl)-lH-indazol-3-ylmethylsulfanyl]-phenoxy ⁇ - acetic acid
  • Example Ib ⁇ 4-[5-Fluoro-l -(4-trifluoromethyl-phenyl)- 1 H-indazol-3 -yhnethylsulfanyl]-2-methyl- phenoxy ⁇ -acetic acid
  • Example Id ⁇ 4-[5-methoxy-l-(4-trifluoromethyl-phenyl)-lH-indazol-3-yhnethylsulfanyl]-2-methyl- phenoxy ⁇ -acetic acid
  • Example Ie ⁇ 4-[5-chloro-l-(4-trifluoromethyl-phenyl)-lH-indazol-3-yhnethylsulfanyl]-2-methyl- phenoxy ⁇ -acetic acid
  • Example Ig ⁇ 4-[7-Fluoro- 1 -(4-trifluoromethyl-phenyl)- 1 H-indazol-3-ylmethylsulfanyl]-2-methyl- phenoxy ⁇ -acetic acid
  • Example Ii ⁇ 4-[6-Chloro- 1 -(4-trifluoromethyl-phenyl)- 1 H-indazol-3 -ylmethylsulfanyl]-2-methyl- phenoxy ⁇ -acetic acid
  • Example 2a ⁇ 2-Methyl-4-[ 1 -(4-trifluoromethoxy-phenyl)- 1 H-indazol-3 -ylmethoxyj-phenoxy ⁇ - acetic acid
  • Example 2b 2-Methyl-2- ⁇ 2-methyl-4-[ 1 -(4-trifluoromethoxy-phenyl)- 1 H-indazol-3 -ylmethoxy]- phenoxy ⁇ -propionic acid
  • Example 2c ⁇ 2-Methyl-4-[l-(4-trifluoromethyl-phenyl)-lH-indazol-3-ylmethoxy]-phenoxy ⁇ -acetic acid
  • Example 2d 2- ⁇ 2-Methyl-4-[l -(4-trifluoromethoxy-phenyl)- 1 H-indazol-3-ylmethoxy]-phenoxy ⁇ - propionic acid
  • Example 2e ⁇ 2-Chloro-4-[ 1 -(4-trifluoromethyl-phenyl)- 1 H-indazol-3 -ylmethoxyj-phenoxy ⁇ -acetic acid
  • Example 2f ⁇ 2-Fluoro-4-[l-(4-trifluoromethyl-phenyl)-lH-indazol-3-yhnethoxy]-phenoxy ⁇ -acetic acid
  • Example 2g ⁇ 2-Methyl-4- [ 1 -(4-trifluoromethoxy-phenyl)- 1 H-pyrazolo[4,3 -c]pyridin-3 -ylmethoxy]- phenoxy ⁇ -acetic acid
  • the cells are then again washed with PBS prior to the addition of 100 ⁇ l reduced serum medium (OptiMEM; Invitrogen). Compounds were added (10 ⁇ l in 2 % DMSO in OptiMEM) to achieve final concentrations between 0-30 ⁇ M. The cells were then returned to the incubator for a further 24 hours. 100 ⁇ l of luciferase reagent (Bright GIo, Promega) was added directly to each well, and the luminescence determined using a suitable luminometer.
  • OptiMEM reduced serum medium
  • OptiMEM reduced serum medium
  • Compounds were added (10 ⁇ l in 2 % DMSO in OptiMEM) to achieve final concentrations between 0-30 ⁇ M.
  • the cells were then returned to the incubator for a further 24 hours. 100 ⁇ l of luciferase reagent (Bright GIo, Promega) was added directly to each well, and the luminescence determined using a suitable luminometer.
  • Biological assay 2 Binding assay Compounds were tested for their ability to bind to PPAR ⁇ using a scintillation proximity assay (SPA).
  • the PPAR ⁇ LBD (S139-Y441) was expressed in E. coli as an N-terminal GST fusion, with a hexhistidine tag immediately N-terminal to the PPAR ⁇ LBD.
  • the purified protein was incubated with 3 H GW2433 (for details of synthesis see reference 13) in the presence of varying concentrations of the compound to be tested in the presence of 5 % DMSO. After 1 hour incubation at room temperature Yttrium silicate copper SPA bead were added and the incubation continued for a further 1 hour. After equilibration the radioactivity bound to the beads was determined by scintillation counting. Apparent Ki values were obtained by fitting the data by nonlinear regression analysis, assuming simple competitive binding. Non-specific binding was determined in the presence of excess unlabelled GW2433.
  • C2C12 cells (ECACC, Salisbury, UK) were grown in Dulbecco's modified Eagle's medium supplemented with 200units penicillin/50 ⁇ M streptomycin and 10% fetal calf serum.
  • For cellular stimulation cells were seeded onto 6cm dishes and grown until confluent. La order to induce differentiation the medium was changed to Dulbecco's modified Eagle's medium supplemented with 200units penicillin/50 ⁇ M streptomycin and 2% horse serum. After 4 day of differentiation the cells were treated with the appropriate compound concentration (in a final of 0.1% DMSO) in the above mentioned medium for 24h.
  • RNA samples were homogenised into Trizol solution (Invitrogen) and total RNA was extracted using a standard protocol. RNA was cleaned using the manufaturer's protocol (Sigma Aldrich, St Louis, USA). cDNA was synthesized from 500ng total RNA using random hexamers and multiscribe reverse transcriptase (Applied Biosystems) according to the manufacturer's protocol. Real time PCR was performed on the resulting cDNA using Applied Biosystems' Taqman method. The following genes were analysed to determine whether favourable PPAR ⁇ -induced ⁇ -oxidation and energy uncoupling can be detected in the skeletal muscle samples: FATB, UCP2, UCP3, PGCl ⁇ , PDK4, CPTl, LCAD, GLUT4.

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Abstract

The invention discloses compounds of formula (I) wherein: R is a carboxylic acid or a derivative thereof; R1 and R2 are independently H or alkyl, or together R1 and R2 form an alkylene group; L1 is a single bond, NH, NCH3, O, S, CH2 or CH, wherein when L1 is CH the dashed line indicates a double bond and R2 is absent, otherwise the dashed line is a single bond; R8 and R9 are independently H, halo, alkyl or alkoxy; L2 is O or S; L3 is CH2 or CH2CH2; R10 and R11 are independently H, halo, CF3, OCF3, alkyl or alkoxy; Y1 is CH or N; Y2 is CH or N; and R12 and R13 are independently H, halo, CF3, OCF3, alkyl or alkoxy; or a pharmaceutically acceptable derivative thereof, useful for treating disorders mediated by peroxisome-proliferator-activated receptor (PPAR) subtype δ (PPARδ). The compounds of the invention are therefore useful in the treatment of metabolic syndrome, obesity, type-II diabetes, dyslipidemia, wound healing, inflammation, neurodegenerative disorders and multiple sclerosis.

Description

CONDENSED PYRAZOLE DERIVATIVES AS PPAR AGONISTS II
All documents cited herein are incorporated by reference in their entirety.
TECHNICAL FIELD
This invention relates to compounds which are useful for treating disorders mediated by peroxisome- proliferator-activated receptor (PPAR) subtype δ (PP ARδ).
BACKGROUND OF THE INVENTION
The high fat diet of modern society combined with a largely sedentary lifestyle has resulted in an increase in the population that are overweight or obese. Being overweight or obese increases the risk of coronary heart disease, hypertension, dyslipidemia, atherosclerosis, type-II diabetes, stroke, osteoarthritis, restrictive pulmonary disease, sleep apnoea, certain types of cancers and inflammatory disorders. The standard treatment for obesity is calorific restriction and increase of physical exercise. However, such approaches are rarely successful and pharmaceutical treatments are required to correct these metabolic disorders.
The three peroxisome-proliferator-activated receptor (PPAR) subtypes, PPARγ, PP ARa and PP ARδ, are nuclear receptors that regulate glucose and lipid homeostasis.
Pharmacological evidence gained with small molecule agonists and genetic studies has uncovered several important roles of PP ARδ in regulating lipid metabolism and energy homeostasis (1). The data indicate that PP ARδ agonists might be useful in the treatment of various components of the metabolic syndrome including dyslipidemia, obesity and insulin resistance by increasing fatty acid consumption in skeletal muscle and adipose tissue.
PP ARδ agonists have shown cholesterol lowering activity and elevation of high-density lipoprotein cholesterol (HDL-C) levels in diabetic mice suggesting they may have beneficial effects on dyslipidemia (2). A potent PP ARδ agonist has also been shown to increase HDL-C while decreasing elevated trigylceride (TG) and insulin levels in obese rhesus monkeys (3). The same compound also attenuates weight gain and insulin resistance in mice fed high-fat diets by increasing the expression of genes in skeletal muscle that promote lipid catabolism and mitochondrial uncoupling, thereby increasing β-oxidation of fatty acids in skeletal muscle (4).
Genetic studies provide data that accord with that of the pharmacological experiments described above. Overexpression of constitutively active PP ARδ in mouse adipose tissue protects against either genetic or high-fat-diet-induced hyperlipidemia, steatosis and obesity and increases the expression of genes that are involved in fatty acid oxidation and energy dissipation (5). Conversely, PPARδ null mice display an obese phenotype and reduced energy uncoupling when fed a high-fat diet. Recently, overexpression of constitutively active PPARδ in mouse skeletal muscle was found to induce differentiation of mitochondria-rich, oxidative type 1 muscle fibres (6). As a result, these transgenic animals are resistant to diet-induced obesity and their exercise endurance is improved. Studies on PPARδ +/- mice show a delay in wound healing (7) and further animal model studies with a PPARδ agonist have demonstrated an enhancement in barrier repair and a reduction in inflammation (8).
A series of studies have demonstrated the expression of PPARδ in a number of neural cell types including optic nerve oligodendrocytes and sciatic nerve Schwann cells. A PPARδ agonist has demonstrated neuroprotective effects on cerebellar neurons suggesting a role in the treatment of neurodegenerative diseases including Alzheimer's disease and Parkinson's disease and may also be of use in the enhancement of learning and memory function (9). Studies with a PPARδ agonist show a reduction in the clinical signs of murine experimental autoimmune encephalomyelitis, commonly used as a model for multiple sclerosis (10).
Consequently, PPARδ agonists are expected to be therapeutically useful, e.g. in the treatment of metabolic syndrome, obesity, type-II diabetes, dyslipidemia, wound healing, inflammation, neurodegenerative disorders and multiple sclerosis. There is therefore a need for new and improved compounds which are PPARδ agonists. WO2005/060958 discloses compounds based on various ring systems which are modulators of PPARδ.
WO2005/065638 discloses triazole, oxadiazole and thiadiazole compounds which are modulators of PPARδ.
DISCLOSURE OF THE INVENTION Compounds of formula (I) defined below, and pharmaceutically acceptable derivatives thereof, have been found to be agonists of PPARδ. Compounds of formula (I) or pharmaceutically acceptable derivatives thereof are thus useful in the treatment of conditions and diseases mediated by PPARδ, in particular metabolic syndrome, obesity, type-II diabetes, dyslipidemia, wound healing, inflammation, neurodegenerative disorders and multiple sclerosis. The invention therefore provides a compound of formula (I):
wherein:
R is a carboxylic acid or a derivative thereof; R1 and R2 are independently H or alkyl, or together R1 and R2 form an alkylene group;
L1 is a single bond, NH, NCH3, O, S, CH2 or CH, wherein when L1 is CH the dashed line indicates a double bond and R2 is absent, otherwise the dashed line is a single bond;
R8 and R9 are independently H, halo, alkyl or alkoxy; L2 is O or S;
L3 is CH2 or CH2CH2;
R10 and R11 are independently H, halo, CF3, OCF3, alkyl or alkoxy; Y1 is CH or N; Y2 is CH or N; and R12 and R13 are independently H, halo, CF3, OCF3, alkyl or alkoxy; and pharmaceutically acceptable derivatives thereof.
The invention also provides a compound of formula (I), or a pharmaceutically acceptable derivative thereof, for use in therapy. The invention further provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable derivative thereof, in combination with a pharmaceutically acceptable carrier, excipient or diluent.
The invention further provides a method for the treatment of a disease or condition mediated by PPARδ, comprising the step of administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable derivative thereof, to a patient. The invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable derivative thereof, in the manufacture of a medicament for the treatment of a disease or condition mediated by PPARδ.
The invention also provides a composition comprising PPARδ and a compound of formula (I)5 or a pharmaceutically acceptable derivative thereof.
The invention also provides a crystal of PPARδ and a compound of formula (I), or a pharmaceutically acceptable derivative thereof. Such crystals can be used for X-ray diffraction studies of PPARδ inhibition, e.g. to provide atomic structural information in order to aid rational design of further agonists.
Compounds of Formula (I) and Derivatives
The term "pharmaceutically acceptable derivative" includes any pharmaceutically acceptable salt, solvate or hydrate thereof. The term "pharmaceutically acceptable salt" includes a salt prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic or organic acids and bases.
Examples of inorganic acids suitable for use in this invention include, but are not limited to hydrochloric, hydrobromic, hydroiodic, sulfuric, and phosphoric acids. Appropriate organic acids for use in this invention include, but are not limited to aliphatic, aromatic, carboxylic and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, citric, succinic, glycolic, glucuronic, maleic, furoic, glutamic, benzoic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic, benzenesulfonic, stearic, sulfanilic, algenic, and galacturonic.
Examples of inorganic bases suitable for use in this invention include metallic salts made from aluminium, calcium, lithium, magnesium, potassium, sodium, and zinc. Appropriate organic bases may be selected, for example, from N,N-dibenzylethylenediamine? chloroprocaine, choline, diethanolamine, ethylenediamine, meglumaine (N-methylglucamine), and procaine. The compounds of the invention may exist in a number of diastereomeric and enantiomeric forms. Diastereomeric and enantiomeric forms of the polyphenols of the invention may be differentiated by the direction in which they rotate plane-polarised light. A dextrorotatory (d) substance rotates plane- polarised light in a clockwise or positive (+) direction. A levorotatory (1) substance rotates plane- polarised light in a counterclockwise or negative (— ) direction. The invention encompasses pure diastereomers and enantiomers as well as mixtures, including racemic mixtures, of diastereomers and enantiomers.
R is a carboxylic acid or a derivative thereof. Derivatives of carboxylic acids include esters (e.g. of the foπnula -CO2R4). R4 is alkyl (e.g. Chalky!) or arylalkyl (e.g. benzyl). R4 is independently H, alkyl (e.g. C1-6alkyl) or arylalkyl (e.g. benzyl).
Preferred Compounds Group R
Preferably, R is a carboxylic acid, i.e. -CO2H.
Group R1
Preferably, R1 is H or methyl. R1 may be substituted or unsubstituted. Where substituted, R1 may be substituted by one or more Sub1, defined below.
Group R2
Preferably, R2 is H or methyl.
In a particular preferred embodiment, R1 and R2 are both H or both methyl. R2 may be substituted or unsubstituted. Where substituted, R2 may be substituted by one or more Sub1, defined below.
Group L1
Preferably, L1 is O, S or NH. L1 may be substituted or unsubstituted. Where substituted, L1 may be substituted by one or more Sub1, defined below.
Group L2
Preferably, L2 is O or S, e.g. S. Groups R8 and R9
Preferably, R8 and R9 are both H, or R8 is methyl and R9 is H.
R8 and R9 may be independently substituted or unsubstituted. Where substituted, R8 or R9 may be substituted by one or more Sub1, defined below.
Group L3 Preferably, L3 is -CH2-.
L3 may be substituted or unsubstituted. Where substituted, L3 may be substituted by one or more Sub1, defined below.
Groups R10 and R"
Preferably, R10 is CF3 substituted at the 4-position and R11 is H. R10 and R11 may be independently substituted or unsubstituted. Where substituted, R10 or R11 may be substituted by one or more Sub1, defined below.
Group Y1 Preferably, Y1 is CH.
Y1 may be substituted or unsubstituted. Where substituted, Y1 may be substituted by Sub1, defined below.
Group Y2 Preferably, Y2 is CH.
Y2 may be substituted or unsubstituted. Where substituted, Y2 may be substituted by Sub1, defined below. Groups R12 and R13
Preferably, R12 and R13 are both H, or R12 is H and R13 is attached to group Y1 (when Y1 is CH) and is alkyl, alkoxy, Cl, F, CF3 or OCF3.
Preferred compounds of formula (I) are those of formula (II): wherein R1, R2, L1, R8, R9, L2, L3, R10, R11, R12 and R13 are defined above; and pharmaceutically acceptable derivatives thereof. Especially preferred compounds of the invention are the compounds of example 1 below, i.e.: {2-Methyl-4-[l-(4-trifluoromethyl-phenyl)-lH-indazol-3-ylmethylsulfanyl]-phenoxy}-acetic acid
{4-[5-Fluoro- 1 -(4-trifluoromethyl-phenyl)- 1 H-indazol-3-ylmethylsulfanyl]-2-methyl- phenoxy} -acetic acid
{4-[5-trifluoromethoxy-l-(4-trifluoromethyl-phenyl)-lH-indazol-3-ylmethylsulfanyl]-2- methyl-phenoxy} -acetic acid
{4-[5-methoxy-l-(4-trifluoromethyl-phenyl)-lH-indazol-3-ylmethylsulfanyl]-2-methyl- phenoxy} -acetic acid
{4-[5-chloro- 1 -(4-trifluoromethyl-phenyl)- 1 H-indazol-3-ylmethylsulfanyl]-2-methyl- phenoxy} -acetic acid; and {4-[5-methyl-l-(4-trifluoromethyl-phenyl)-lH-indazol-3-ylmethylsulfanyl]-2-methyl- phenoxy} -acetic acid.
Preparation
Methods for the preparation of the compounds of the invention are disclosed in detail below in the examples. In general, compounds of the invention may be prepared by the reaction scheme described below. O2, 4A mol.sieves
Intermediates 2
LiAIH41 THF1 O-C NCS, PPh3, THFrDCM (3:1)
Intermediates 3 Intermediates 4
Intermediates 7 Examples 1
LiAIH4, THF, 0°C tort
Intermediate S Intermediate 6
Diseases and Conditions
Compounds of formula (T), and pharmaceutically acceptable derivatives thereof, have been found to be agonists of PPARδ. Preferred compounds of the invention have an EC50 in the PPARδ GAL4 assay of biological assay 1 of<l uM, preferably <10O nM.
Preferred compounds of the invention up-regulate one or more of the target genes identified in biological assay 3 below (i.e. FATP, LCAD, CPTl, PDK4, UCP2, UCP3, PGC-Ia and GLUT4) by at least 2 fold at sub-micromolar concentrations. Preferred compounds of the invention demonstrate one or more of the following effects when compared to vehicle treated animals:
(i) improve lipid profiles through increasing HDL-cholesterol levels and/or reduce total cholesterol;
(ii) reduce triglyceride levels; (ili) reduce glucose serum levels and improve oral glucose tolerance;
(iv) maintenance of body weight and/or promotion of lean tissue over fat mass from the results from the DEXA scanning and monitoring of body weight; and/or
(v) up-regulate one or more of the target genes identified in biological assay 3 below (i.e. FATP5 LCAD, CPTl, PDK4, UCP2, UCP3, PGC-Ia and GLUT4) by at least 2 fold at sub- micromolar concentrations.
Preferred compounds of the invention have an EC50 in the PPARδ GAL4 assay of biological assay 1 at least ten times lower than its EC50 in the PP ARa GAL4 assay or the PPARγ GAL4 assay, preferably both, of biological assay 1. The invention is useful for the treatment of a disease or condition mediated by PPARδ. Diseases and conditions mediated by PPARδ include: metabolic syndrome, and components thereof including dyslipidaemia, obesity and insulin resistance; type-II diabetes; wound healing; inflammation; neurodegenerative disorders; and multiple sclerosis. Since being overweight or obese increases certain risk factors, the present invention is useful for the treatment of coronary heart disease, hypertension, hyperlipidaemia, type-II diabetes mellitus, stroke, osteoarthritis, restrictive pulmonary disease, sleep apnoea and cancer.
As used herein, "treatment" includes prophylactic treatment. As used herein, a "patient" means an animal, preferably a mammal, preferably a human in need of treatment.
The amount of the compound of the invention administered should be a therapeutically effective amount where the compound or derivative is used for the treatment of a disease or condition and a prophylactically effective amount where the compound or derivative is used for the prevention of a disease or condition.
The term "therapeutically effective amount" used herein refers to the amount of compound needed to treat or ameliorate a targeted disease or condition. The term "prophylactically effective amount" used herein refers to the amount of compound needed to prevent a targeted disease or condition. The exact dosage will generally be dependent on the patient's status as the time of administration. Factors that may be taken into consideration when determining dosage include the severity of the disease state in the patient, the general health of the patient, the age, weight, gender, diet, time and frequency of administration, drug combinations, reaction sensitivities and the patient's tolerance or response to therapy. The precise amount can be determined by routine experimentation, but may ultimately lie with the judgement of the clinician. Generally, an effective dose will be from 0.01 mg/kg/day (mass of drug compared to mass of patient) to 50 mg/kg/day, preferably 0.05 mg/kg/day to 10 mg/kg/day. Compositions may be administered individually to a patient or may be administered in combination with other agents, drugs or hormones. The compounds of the invention may be administered as a medicament by mucosal or parenteral routes, including intravenous, intramuscular, intraperitoneal, subcutaneous, transdermal, airway (aerosol), oral, intranasal, rectal, vaginal and topical (including buccal and sublingual) administration.
For parenteral administration, the compounds of the invention will generally be provided in injectable form. For oral administration, the compounds of the invention will generally be provided in the form of tablets or capsules, as a powder or granules, or as an aqueous solution or suspension.
Tablets for oral use may include the active ingredients mixed with pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavouring agents, colouring agents and preservatives. Suitable inert diluents include sodium and calcium carbonate, sodium and calcium phosphate and lactose. Corn starch and alginic acid are suitable disintegrating agents. Suitable binding agents include starch and gelatin. Suitable lubricating agents include magnesium stearate, stearic acid or talc. The tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate, to delay absorption in the gastrointestinal tract.
Capsules for oral use include hard gelatin capsules in which the active ingredient is mixed with a solid diluent, and soft gelatin capsules wherein the active ingredients are mixed with water or an oil such as peanut oil, liquid paraffin or olive oil.
Compositions for use with the invention may comprise pharmaceutically acceptable carriers, such as sugars or salts, or excipients. They may also contain diluents, such as water, saline, glycerol, etc. Additionally, auxiliary substances, such as wetting or emulsifying agents, pH buffering substances, and the like, may be present. A thorough discussion of pharmaceutically acceptable carriers and excipients is available in Gennaro (2000) Remington: The Science and Practice of Pharmacy, 20th edition (ISBN: 0683306472).
Chemical Groups
The term "halogen" (or "halo") includes fluorine, chlorine, bromine and iodine.
Unless indicated explicitly otherwise, where combinations of groups are referred to herein as one moiety, e.g. arylalkyl, the last mentioned group contains the atom by which the moiety is attached to the rest of the molecule.
The terms "alkyl", "alkylene", "alkenyl", or "alkynyl" are used herein to refer to both straight and branched chain acyclic forms. Cyclic analogues thereof are referred to as cycloalkyl, etc.
The term "alkyl" includes monovalent, straight or branched, saturated, acyclic hydrocarbyl groups. Preferred alkyl are Ci-loalkyl, more preferably still more preferably C1-4alkyl, such as methyl, ethyl, n-propyl, i-propyl or t-butyl groups.
The term "cycloalkyl" includes monovalent, saturated, cyclic hydrocarbyl groups. Preferred cycloalkyl are C3-6CyClOaIlCyI, such as cyclopentyl and cyclohexyl.
The term "alkoxy" means alkyl-O-. The term "alkenyl" includes monovalent, straight or branched, unsaturated, acyclic hydrocarbyl groups having at least one carbon-carbon double bond and preferably no carbon-carbon triple bonds. Preferred alkenyl are C2-ioalkenyl, more preferably C2-6alkenyl, still more preferably C2-4alkenyl.
The term "cycloalkenyl" includes monovalent, unsaturated, cyclic hydrocarbyl groups having at least one carbon-carbon double bond and preferably no carbon-carbon triple bonds. Preferred cycloalkenyl are C3.6cycloalkenyl, preferably Cs-βcycloalkenyl.
The term "alkynyl" includes monovalent, straight or branched, unsaturated, acyclic hydrocarbyl groups having at least one carbon-carbon triple bond and preferably no carbon-carbon double bonds. Preferred alkynyl are C2-10alkynyl, more preferably C2-6alkynyl, still more preferably C2-4alkynyl. The term "alkylene" includes divalent, straight or branched, saturated, acyclic hydrocarbyl groups. Preferred alkylene are Cj.ioalkylene, more preferably still more preferably C1-4alkylene, such as methylene, ethylene, n-propylene, i-propylene or t-butylene groups.
The term "aryl" includes monovalent, aromatic, cyclic hydrocarbyl groups, such as phenyl or naphthyl (e.g. 1-naphthyl or 2-naphthyl). rn general, the aryl groups may be monocyclic or polycyclic fused ring aromatic groups. Preferred aryl are C6-C14aryl.
Other examples of aryl groups are monovalent derivatives of aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, chrysene, coronene, fluoranthene, fluorene, αs-indacene, s- indacene, indene, naphthalene, ovalene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene and rubicene. The term "arylalkyl" means alkyl substituted with an aryl group, e.g. benzyl.
The term "heteroaryl" includes monovalent, heteroaromatic, cyclic hydrocarbyl groups additionally containing one or more heteroatoms selected from O, S or N. In general, the heteroaryl groups may be monocyclic or polycyclic (e.g. bicyclic) fused ring heteroaromatic groups. Preferred heteroaryl groups are 5-13 membered (preferably 5-10 membered) and contain 1, 2, 3 or 4 heteroatoms selected from O, S or N.
Monocyclic heteroaromatic groups include 5- or 6-membered heteroaromatic groups containing 1, 2, 3 or 4 heteroatoms selected from O, S or N. Examples of monocyclic heteroaryl groups are pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, tetrazolyl and succinimidyl.
Bicyclic heteroaromatic groups include 9- to 13-membered fbsed-ring heteroaromatic groups containing 1, 2, 3, 4 or more heteroatoms selected from O, S or N. Examples of bicyclic heteroaromatic groups are benzofuryl, [2,3-dihydro]benzofuryl, benzothienyl, benzotriazolyl, indolyl, isoindolyl, benzimidazolyl, imidazo[l,2-a]pyridyl, benzothiazolyl, benzoxazolyl, benzopyranyl, [3,4-dihydro]benzopyranyl, quinazolinyl, naphthyridinyl, pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl, pyrido[4,3-b]ρyridyl, quinolinyl, isoquinolinyl, 5,6,7,8-tetrahydroquinolinyl, 5,6,7,8-tetrahydroisoquinolinyl and phthalimidyl.
Other examples of heteroaryl groups are monovalent derivatives of acridine, carbazole, /?-carboline, chromene, cinnoline, furan, imidazole, indazole, indole, indolizine, isobenzofuran, isochromene, isoindole, isoquinoline, isotbiazole, isoxazole, naphthyridine, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, thiophene and xanthene. Preferred heteroaryl groups are five- and six-membered monovalent derivatives, such as the monovalent derivatives of furan, imidazole, isothiazole, isoxazole, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine and thiophene. The five-membered monovalent derivatives are particularly preferred, i.e. the monovalent derivatives of furan, imidazole, isothiazole, isoxazole, pyrazole, pyrrole and thiophene.
The term "heteroarylalkyl" means alkyl substituted with an heteroaryl group.
The term "heteroalkylene" includes alkylene groups in which up to three carbon atoms, preferably up to two carbon atoms, more preferably one carbon atom, are each replaced independently by O, S or
N.
Where reference is made to a carbon atom of an alkyl group or other group being replaced by an O, S, or N atom, what is intended is that:
— CH- — N — is replaced by I
-CH= is replaced by -N=; or
-CH2- is replaced by -O-, -S- or -NR6-, where R6 is H, alkyl, aryl, -C(O)-alkyl, -C(O)-aryl, -S(O)2-alkyl or-S(O)2-aryl. R6 is preferably H or alkyl {e.g. C1-6alkyl).
Substitution
The alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, alkylene, aryl, arylalkyl, heteroaryl, heteroarylalkyl and heteroalkylene groups of the compounds of the invention may be substituted or unsubstituted, preferably unsubstituted.
Where substituted, there will generally be 1 to 3 substituents, preferably 1 or 2 substituents, more preferably 1 substituent. Preferred substituents are Sub1, where Sub1 is independently halogen, trihalomethyl, -NO2, -CN, -N+(R^2O', -CO2H, -CO2R5, -SO3H, -SORS, -SO2R8, -SO3R3, -OC(=O)ORS, -C(=O)H, -C(=O)RS, -0C(=0)R5, -NRS 2, -C(O)NH2, -C(=O)NRS 2, -N(RS)C(=O)ORS, -N(RS)C(=O)NRS 2, -OC(=O)NRS 2, -N(RS)C(=O)RS, -C(=S)NRS 2, -NRSC(=S)RS, -SO2NRS 2, -NR5SO2R5, -N(R5)C(=S)NRS 2, -N(RS)SO2NRS 2, -Rs or -Z3R5. Z3 is independently O, S or NR5; R5 is independently H or C1-6alkyl, C3-6cycloalkyl, C2-6alkenyl, C3-6cycloalkenyl, C3-6alkynyl, C6-i4aryl, heteroaryl having 5-13 members, Cβ-MarylQ-ealkyl, or heteroarylC1-6alkyl where the heteroaryl has 5-13 members, where Rs is optionally substituted itself (preferably unsubstituted) by 1 to 3 substituents Sub2, where Sub2 is independently halogen, trihalomethyl, -NO2, -CN, -N+(Cj -6alkyl)2O", -CO2H, -CO2C1-6alkyl, -SO3H, -SOC]-6alkyl, -SO2C1-6alkyl, -SO3C1-6alkyl, -OC(=O)OC1-6alkyl, -C(=O)H, -C(=O)C1-6alkyl, -OC(=O)C1-6alkyl, -N(C1-6alkyl)2, -C(=0)NH2, -C(=O)N(C1-6alkyl)2, -N(C1-6alkyl)C(==O)O(C1-6alkyl), -N(C1-6alkyl)C(=O)N(C1-6alkyl)2, -OC(=O)N(Ci-6alkyl)2, -N(C1-5alkyl)C(=O)C1-6alkyl, -C(=S)N(C1-6alkyl)2, -N(C1-6alkyl)C(=S)C1-6alkyl, -SO2N(C1-6alkyl)2, -N^Lealky^SOzCLsalkyl, -N(C1-6alkyl)C(=S)N(C1-6alkyl)2, -N(C1-6alkyl)SO2N(Ci-6alkyl)2, C1-6alkyl or -Z'C1-6alkyl, where Z4 is O, S or N(C1-6alkyl).
Preferably, Rs is H or C1-6alkyl, optionally substituted by 1 to 3 substituents Sub2. In addition, where a group has at least 2 positions which may be substituted, the group may be substituted by both ends of an alkylene or heteroalkylene chain (e.g. on the same carbon atom of the group) to form a cyclic moiety.
Where a phenyl group or a six-membered ring heteroaryl group (e.g. pyridyl) is substituted, substitution at the meta and para positions is preferred, with para substitution being especially preferred.
General
The term "comprising" means "including" as well as "consisting" e.g. a composition "comprising" X may consist exclusively of X or may include something additional e.g. X + Y.
The term "about" in relation to a numerical value x means, for example, x+10%. The word "substantially" does not exclude "completely" e.g. a composition which is "substantially free" from Y may be completely free from Y. Where necessary, the word "substantially" may be omitted from the definition of the invention.
MODES FOR CARRYING OUT THE INVENTION
Materials and Methods 400 MHz ^H nuclear magnetic resonance (NMR) spectra were recorded on a Bruker Avance spectrometer. In the nuclear magnetic resonance (NMR) spectra the chemical shifts (δ) are expressed in ppm relative to the residual solvent peak. Abbreviations have the following significances: br = broad signal, s = singlet; d = doublet; t = triplet; m = multiplet; q = quartet; dd = doublet of doublets; ddd= doublet of double doublets. Other patterns are unabbreviated. The thin layer chromatography (TLC) Rp values were determined using Merck silica plates.
High Pressure Liquid Chromatography - Mass Spectrometry (LC-MS) conditions for determination of retention times (Rp) and associated mass ions were as follows. Mass Spectrometer (MS): Waters
ZQ (Waters Ltd) Serial No. LAA623 Ionization Mode: Electrospray (Positive Ion); Full Scan m/z 100 - 900, scanning for O.όsec with an interscan delay of 0.4 sec in centroid Mode. Electrospray (Negative Ion); Full Scan m/z 100 - 900, scanning for 0.6sec with an interscan delay of 0.4 sec in centroid mode. Liquid Chromatograph (LC): Agilent 1100 series binary pump (Serial # DE33214258), degasser (Serial # JP13211877) & well plate auto sampler (Serial # DE33402913). Phenomenex Luna Cl 8(2), 3μ (4.6mm x 150mm) reverse phase column (Method A) and Phenomenex Luna Cl 8(2), 3μ (4.6mm x 50mm) reverse phase column (Method B) operated under gradient elution conditions using the methods and solvents described below.
Method A
(A) Water containing 0.1% formic acid and (B) acetonitrile containing 0.1% formic acid as the mobile phase (gradient: 0.00 minutes, 95% A; linear gradient to 100% B at 12 minutes; then hold until 13.15 minutes). Flow rate 1 ml/minute to column & to UV detector, flow split after UV detector such that 0.25 ml/minute to MS detector and 0.75 ml/minute to waste; injection volume 5μl; Auxiliary Detectors:- Agilent 1100 Series variable wavelength UV detector (serial # JP33322024) wavelength = 220nm.
Method B (A) Water containing 0.1% formic acid and (B) acetonitrile containing 0.1% formic acid as the mobile phase (gradient: 0.00 minutes, 95% A; linear gradient to 100% B at 4.45 minutes; then hold until 5.15 minutes; 5.16 minutes 95% A; then hold until 6 minutes). Flow rate 1.5 ml/minute to column & to UV detector, flow split after UV detector such that 0.25ml/rninute to MS detector and 0.75 ml/minute to waste; injection volume 5μl; Auxiliary Detectors:- Agilent 1100 Series variable wavelength UV detector (serial # JP33322024) wavelength = 220nm.
Method C
(A) Water containing 0.1% formic acid and (B) acetonitrile containing 0.1% formic acid as the mobile phase (gradient: 0.00 minutes, 80% A; linear gradient to 100% B at 12 minutes; then hold until 13.15 minutes). Flow rate lml/minute to column & to UV detector, flow split after UV detector such that 0.25ml/minute to MS detector and 0.75ml/minute to waste; injection volume 5μl; Auxiliary Detectors:- Agilent 1100 Series variable wavelength UV detector (serial # JP33322024) wavelength = 220nm.
Method D
(A) Water containing 0.1% formic acid and (B) acetonitrile containing 0.1% formic acid as the mobile phase (gradient: 0.00 minutes, 80% A; linear gradient to 100% B at 4.45 minutes; then hold until 5.15 minutes; 5.16 minutes 80% A; then hold until 6 minutes). Flow rate 1.5ml/minute to column & to UV detector, flow split after UV detector such that 0.25ml/minute to MS detector and 0.75ml/minute to waste; injection volume 5μl; Auxiliary Detectors:- Agilent 1100 Series variable wavelength UV detector (serial # JP33322024) wavelength = 220nm. Preparation
Intermediate 1
Intermediate Ia: lH-Indazole-3-carboxylic acid methyl ester
To a stirred suspension of indazole-3-carboxylic acid (2.43g, 15mmol) in dichloromethane (100ml), under an inert atmosphere, were added oxalyl chloride (2.62ml, 30mmol) and dimethylformamide (ImI) and the reaction stirred for 2 hours. Methanol (100ml) was then added slowly and the reaction stirred overnight. The solvent was evaporated in vacuo to give a crude residue which was taken up in dichloromethane, washed (water, brine), dried (Na2SO4), filtered and the solvent removed in vacua to give the title compound (2.63g, 99%) as a yellow solid.
1H NMR (400MHz, DMSO-D6) δ 8.03 (IH, dt, J = 1.1 and 8.2 Hz); 7.67 (IH, dt, J = 0.8 and 8.4 Hz); 7.46 (IH, m); 7.31 (IH, m); 3.93 (3H, s)
Intermediate Ib: 5-Fluoro-lH-indazole-3-carboxylic acid methyl ester
To a stirred suspension of 5-fluoroisatin (2g, 12.11mmol) in water (10ml) was added a solution of sodium hydroxide (509mg, 12.72mmol) in water (lOrnl), the reaction mixture heated at 5O0C for 30 minutes, cooled and then treated with sodium nitrite (836mg, 12.11mmol). This mixture was then added over 10 minutes to solution of concentrated sulphuric acid (2.26g) in water (200ml) at O0C, whilst maintaining the temperature below 50C. After a further 15 minutes, a solution of tin (II) chloride (5.51g, 29.06mmol) in concentrated hydrochloric acid was added, stirring continued at 50C for 30 minutes, the reaction warmed to room temperature and stirred for 1 hour. The reaction mixture was then filtered, the resultant brown precipitate dissolved in a mixture of ethyl acetate, methanol and tetrahydrofuran, dried (Na2SO4), filtered and the solvent removed in vacuo. The resultant crude residue was suspended in methanol (150ml), concentrated sulphuric acid (500μl) added and the reaction heated at reflux for 16 hours. The solvent was removed in vacuo to give a crude residue which was purified by column chromatography eluting initially with 20% ethyl acetate/petroleum ether and then gradually increasing it to 30% ethyl acetate/petroleum ether to give the title compound (1.1 Ig, 47%) as a yellow solid. 1H NMR (400MHz, DMSO-D6) δ = 7.74 (IH, d, J = 3.1Hz); 7.71 (IH3 d, J = 3.0Hz); 7.37 (IH, td, J = 2.5 & 9.2Hz); 3.92 (3H, s).
Intermediate Ic: Synthesis of S-trifluoromethoxy-lH-indazole-S-carboxylic acid methyl ester
By proceeding in a similar manner to 5-Fluoro~lH-indazole-3-carboxylic acid methyl ester (Intermediate Ib) above, but using 5-trifluoromethoxyisatin, there was prepared 5-trifluoromethoxy- lH-indazole-3-carboxylic acid methyl ester (Intermediate Ic) (1.27g, 40%) as a pale yellow solid.
1H NMR (400MHz, DMSO-D6) δ = 7.96 (IH, m); 7.82 (IH, d, J = 9.1Hz); 7.47 (IH, m); 3.94 (3H, s). Intermediate Id: 5-methoxy-lH-indazole-3-carboxylic acid methyl ester
By proceeding in a similar manner to 5-Fluoro-lH-indazole-3-carboxylic acid methyl ester (Intermediate Ib) above, but using 5-methoxyisatin, there was prepared 5-methoxy-lH-indazole-3- carboxylic acid methyl ester (Intermediate Id) (LlOg, 44%) as an orange solid. 1H NMR (400MHz, CDCl3) δ = 7.53 (IH, d, J = 9.2Hz); 7.48 (IH, d, J = 2.4Hz); 7.07 (IH, dd, J = 2.4 & 9.1Hz); 3.99 (3H, s); 3.85 (3H, s).
Intermediate Ie: S-chloro-lH-indazole-S-carboxylic acid methyl ester
By proceeding in a similar manner to 5-Fluoro-lH-indazole-3-carboxylic acid methyl ester (Intermediate Ib) above, but using 5-chloroisatin, there was prepared 5-chloro-lH-indazole-3- carboxylic acid methyl ester (Intermediate Ie) (0.98g, 38%) as a yellow solid. 1H NMR (400MHz5 DMSO-D6) δ = 8.06 (IH, dd, J = 0.8 and 2.0Hz); 7.73 (IH, d, J = 8.9Hz); 7.48 (IH, dd, J = 2.0 & 8.9Hz); 3.94 (3H, s).
Intermediate If: S-methyl-lH-indazole-S-carboxylic acid methyl ester
By proceeding in a similar manner to 5-Fluoro-lH-indazole-3-carboxylic acid methyl ester (Intermediate Ib) above, but using 5-methylisatin, there was prepared 5-methyl-lH-indazole-3- carboxylic acid methyl ester (Intermediate If) (1.22g, 53%) as an orange solid.
1H NMR (400MHz, DMSO-D6) δ = 7.85 (IH, m); 7.56 (IH, d, J = 8.5Hz); 7.28 (IH, dd, 1.5 & 8.5Hz); 3.91 (3H, s); 2.45 (3H, s). Intermediate Ig: 7-Fluoro-lH-indazole-3-carboxylic acid methyl ester
By proceeding in a similar manner to 5-Fluoro-lH-indazole-3-carboxylic acid methyl ester (Intermediate Ib) above, but using 7-Fluoroisatin, there was prepared 7-Fluoro-lH-indazole-3- carboxylic acid methyl ester (Intermediate Ig) (418mg, 24%) as a white solid. LCMS: Method B RT = 2.79 min. m/z = 195 (ES+, M+H)
Intermediate Ih: 4-Chloro-lH-indazole-3-carboxylic acid methyl ester
By proceeding in a similar manner to 5-Fluoro-lH-indazole-3-carboxylic acid methyl ester (Intermediate Ib) above, but using 4-Chloroisatin, there was prepared 4-Chloro-lH-indazole-3- carboxylic acid methyl ester (Intermediate Ih) (151mg, 13%) as a light yellow solid.
LCMS: Method B RT = 2.83 min. m/z = 211 (ES+, M+H) Intermediate Ii: 6-Chloro-lH-indazole-3 -carboxylic acid methyl ester
By proceeding in a similar manner to S-Fluoro-lH-indazole-S-carboxylic acid methyl ester (Intermediate Ib) above, but using 6-Chloroisatin, there was prepared 6-Chloro-lH-indazole-3- carboxylic acid methyl ester (Intermediate Ii) (200mg, 17%) as an orange solid. LCMS: Method B RT = 3.06 min. m/z = 211 (ES+, M+H)
Intermediate 2
Intermediate 2a: l-(4-Trifluoromethyl-phenyl)-lH-indazole-3-carboxylic acid methyl ester
To a stirred solution of lH-Indazole-3-carboxylic acid methyl ester (Intermediate Ia) (1.89g, 10.73mmol) in dichloromethane (150ml) was added 4-trifluoromethylbenzeneboronic acid (4.08g,
21.46mmol), pyridine (1.74ml, 21.46mmol), copper (II) acetate (2.92g, lό.lOmmol) and 4A molecular sieves (8.2g). The reaction mixture was stirred open to air for a further 48 hours. The reaction mixture was filtered through a pad of celite and the filtrate concentrated in vacuo to give a crude residue which was purified by column chromatography eluting initially with 5% diethyl ether/petroleum ether and then gradually increasing it to 20% diethyl ether/petroleum ether to give the title compound (1.61g, 47%) as an off-white solid.
1H NMR (400MHz, CDCl3) δ 8.28 (IH, dt, J = 1.0 and 8.2 Hz); 7.87 (2H, m); 7.77 (2H, m); 7.71 (IH, dt, J = 0.8 and 8.5 Hz); 7.47 (IH, m); 7.36 (IH, m); 4.02 (3H, s).
Intermediate 2b: 5-Fluoro-l-(4-trifluoromethyl-phenyl)-lH-indazole-3-carboxylic acid methyl ester
By proceeding in a similar manner to l-(4-Trifluoromethyl-plienyl)-lH-indazole-3-carboxylic acid methyl ester (Intermediate 2a) but using S-Fluoro-lH-indazole-S-carboxylic acid methyl ester (Intermediate Ib), there was prepared 5-Fluoro-l-(4-trifluoromethyl-phenyl)-lH-indazole-3- carboxylic acid methyl ester (Intermediate 2b) (196mg) as a yellow solid.
LCMS: Method B RT = 4.33 min. m/z = 339 (ES+, M+H)
Intermediate 2c: 5-trifluoromethoxy-l-(4-trifluoromethyl-phenyl)-lH-indazole-3-carboxylic acid methyl ester
By proceeding in a similar manner to l-(4-Trifluoromethyl-phenyl)-lH-indazole-3-carboxylic acid methyl ester (Intermediate 2a) but using S-Fluoro-lH-indazole-S-carboxylic acid methyl ester (Intermediate Ic), there was prepared 5-trifluoromethoxy-l-(4-trifluoromethyl-phenyl)-lH-indazole- 3-carboxylic acid methyl ester (Intermediate 2c) (185mg) as a yellow solid.
LCMS: Method B RT = 4.62 min. m/z = 405 (ES+, M+H)
Intermediate 2d: 5-methoxy-l-(4-trifluoromethyl-phenyl)-lH-indazole-3-carboxylic acid methyl ester
By proceeding in a similar manner to l-(4-Trifluoromethyl-phenyl)-lH-indazole-3-carboxylic acid methyl ester (Intermediate 2a) but using 5-methoxy-lH-indazole-3-carboxylic acid methyl ester (Intermediate Id), there was prepared 5-Fluoro-l-(4-trifluoromethyl-phenyl)-lH-indazole-3- carboxylic acid methyl ester (Intermediate 2d) (206mg) as a yellow solid.
LCMS: Method B RT = 4.31 min. m/z = 351 (ES+, M+H) Intermediate 2e: 5-chloro-l-(4-trifluoromethyl-phenyl)-lH-indazole-3-carboxylic acid methyl ester
By proceeding in a similar manner to l-(4-Trifluoromethyl-phenyl)-lH-indazole-3-carboxylic acid methyl ester (Intermediate 2a) but using S-chloro-lH-indazole-S-carboxylic acid methyl ester (Intermediate Ie), there was prepared 5-chloro-l-(4-trifluoromethyl-phenyl)-lH-indazole-3- carboxylic acid methyl ester (Intermediate 2e) (193mg) as a yellow solid.
LCMS: Method B RT = 4.55 min. m/z = 355/357 (ES+, M+H)
Intermediate 2f: 5-methyl-l-(4-trifluoromethyl-phenyl)-lH-indazole-3-carboxylic acid methyl ester
By proceeding in a similar manner to l-(4-Trifluoromethyl-phenyl)-lH-indazole-3-carboxylic acid methyl ester (Intermediate 2a) but using 5-methyl-lH-indazole-3-carboxylic acid methyl ester (Intermediate If), there was prepared 5-methyl-l-(4-trifluoromethyl-phenyl)-lH-indazole-3- carboxylic acid methyl ester (Intermediate 2f) (165mg) as a yellow solid.
LCMS: Method B RT = 4.49 min. m/z = 335 (ES+, M+H) Intermediate 2g: 7-Fluoro-l-(4-trifluoromethyl-phenyl)-lH-indazole-3-carboxylic acid methyl ester
By proceeding in a similar manner to l-(4-Trifluoromethyl-phenyl)-lH-indazole-3-carboxylic acid methyl ester (Intermediate 2a) but using T-Fluoro-lH-indazole-S-carboxylic acid methyl ester (Intermediate Ig), there was prepared 7-Fluoro-l-(4-trifluoromethyl-phenyl)-lH-indazole-3- carboxylic acid methyl ester (Intermediate 2g) (230mg, 68%) as a white solid.
LCMS: Method B RT = 4.33 min. m/z = 339 (ES+, M+H)
Intermediate 2h: 4-Chloro-l-(4-trifluoromethyl-phenyl)-lH-indazole-3-carboxylic acid methyl ester
By proceeding in a similar manner to l-(4-Trifluoromethyl-phenyl)-lH-indazole-3-carboxylic acid methyl ester (Intermediate 2a) but using 4-Chloro-lH-indazole-3-carboxylic acid methyl ester (Intermediate Ih), there was prepared 4-Chloro-l-(4-trifluoromethyl-phenyl)-lH-indazole-3- carboxylic acid methyl ester (Intermediate 2h) (128mg, 52%) as a yellow oil.
LCMS: Method B RT = 4.42 min. m/z = 355 (ES+, M+H)
Intermediate 2i: 6-Chloro-l-(4-trifluoromethyl-phenyl)-lH-indazole-3-carboxylic acid methyl ester
By proceeding in a similar manner to l-(4-Trifluoromethyl-phenyl)-lH-indazole-3-carboxylic acid methyl ester (Intermediate 2a) but using 6-Chloro-lH-indazole-3-carboxylic acid methyl ester (Intermediate Ii), there was prepared 6-Chloro-l-(4-trifluoromethyl-phenyl)-lH-indazole-3- carboxylic acid methyl ester (Intermediate 2i) (80mg, 24%) as a yellow oil.
LCMS: Method B RT = 4.05 min. m/z = 355 (ES+, M+H) Intermediate 2i: l-(4-Trifluoromethoxy-phenyl)-lH-indazole-3-carboxylic acid methyl ester
By proceeding in a similar manner to l-(4-Trifluoromethyl-phenyl)-lH-indazole-3-carboxyIic acid methyl ester (Intermediate 2a) but using lH-Indazole-3-carboxylic acid methyl ester (Intermediate Ia) and 4-Trifluoromethoxybenzeneboronic acid, there was prepared l-(4-Trifluoromethoxy-phenyl)- lH-indazole-3-carboxylic acid methyl ester (Intermediate 2j) (441mg, 46%) as a clear oil.
LCMS: Method B RT = 4.36 min. m/z = 337 (ES+, M+H)
Intermediate 2k: 7-Fluoro-l-(4-trifluoromethoxy-phenyl)-lH-indazole-3-carboxylic acid methyl ester
By proceeding in a similar manner to l-(4-Trifluoromethyl-phenyl)-lH-indazole-3-carboxylic acid methyl ester (Intermediate 2a) but using 7-Fluoro-lH-indazole-3-carboxylic acid methyl ester (Intermediate Ig) and 4-Trifluoromethoxybenzeneboronic acid, there was prepared 7-Fluoro-l-(4- trifluoromethoxy-phenyl)-lH-indazole-3-carboxylic acid methyl ester (Intermediate 2k) (145mg, 32%) as a white solid.
LCMS: Method B RT = 4.35 min. m/z = 355 (ES+, M+H) Intermediate 21: 1 -(4-Chloro-phenyl)- 1 H-indazole-3-carboxylic acid methyl ester
By proceeding in a similar manner to l-(4-Trifluoromethyl-phenyl)-lH-indazole-3-carboxylic acid methyl ester (Intermediate 2a) but using lH-indazole-3-carboxylic acid methyl ester (Intermediate Ia) and 4-Chloro-phenylboronic acid, there was prepared l-(4-Chloro-phenyl)-lH-indazole-3- carboxylic acid methyl ester (Intermediate 21) (505mg, 62%) as a yellow solid. LCMS: Method B RT = 4.23 min. m/z = 287/289 (ES+, M+H)
Intermediate 2m: l-(4-Trifluoromethyl-phenyl)-lH-pyrazolo[4,3-c]pyridine-3-carboxylic acid ethyl ester
To a stirred solution of l-(4-Trifluoromethyl-phenyl)-l,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-3,5- dicarboxylic acid 5-tert-butyl ester 3-ethyl ester (Intermediate 14a) (369mg, 0.901 lmmol) in dichloromethane (8ml) was added trifluoroacetic acid (2ml) and the reaction stirred for 3 hours. The solvent was removed in vacuo to give a crude residue which was taken up in dichloromethane, washed (saturated sodium bicarbonate solution, brine), dried (Na2SO4) and the solvent removed in vacuo. The crude residue was taken up in cumene (50ml) before adding 10% Palladium on carbon (500mg) and heating at reflux overnight. The reaction mixture was cooled to room temperature, filtered through a pad of celite and the filtrate concentrated in vacuo. The crude residue was purified by flash column chromatography eluting with 33% diethyl ether/petroleum ether gradually increasing it to 66% diethyl ether/petroleum ether to yield the title compound (222mg, 73%) as an off-white solid. LCMS: Method B RT = 3.48 min m/z = 336 (ES+, M+H)
Intermediate 2n: l-(4-Trifluoromethoxyl-phenyl)-lH-pyrazolo[4,3-c]pyridine-3-carboxylic acid ethyl ester
By proceeding in a similar manner to l-(4-Trifluoromethyl-phenyl)-lH-pyrazolo[4,3-c]pyridine-3- carboxylic acid ethyl ester (Intermediate 2m) but using l-(4-Trifluoromethoxy-phenyl)- 1,4,6,7- tetrahydro-pyrazolo^S-cjpyridine^S-dicarboxylic acid 5-tert-butyl ester 3-ethyl ester (Intermediate 14b), there was prepared l-(4-Trifluoromethoxy-phenyl)-lH-pyrazolo[4,3-c]pyiidine-3-carboxylic acid ethyl ester (Intermediate 2n) (1.09Og, 87%) as an off white solid.
LCMS: Method B RT - 4.65 min m/z = 351 (ES+, M+H)
Intermediate 3
Intermediate 3 a: [ 1 -(4-Trifiuoromethyl-phenyl)- 1 H-indazol-3 -yl]-methanol
To a stirred solution of l-(4-Trifluoromethyl-phenyl)-lH-indazole-3-carboxylic acid methyl ester (Intermediate 2a) (1.73g, 5.40mmol) in tetrahydrofuran (60ml) at O0C, under an inert atmosphere, was added lithium aluminium hydride (820mg, 21.61mmol) portionwise, the reaction mixture was warmed to room temperature and stirred for 2 hours before being quenched (water, IM HCl), extracted (3 x ethyl acetate), the combined organic extracts were washed (brine), dried (Na2SO4), filtered and the solvent removed in vacuo. The resultant crude residue was purified by flash column chromatography eluting with 10% ethyl acetate/petroleum ether and then gradually increasing it to 20% ethyl acetate/petroleum ether to give the title compound (1.0Ig, 64%) as a white solid.
1H NMR (400MHz, CDCl3) δ 7.83 (3H, m); 7.72 (3H, m); 7.44 (IH, m); 7.23 (IH, m); 5.08 (2H, d, J = 5.5 Hz)
Intermediate 3b: [5-Fluoro-l-(4-trifluoromethyl-phenyl)-lH-indazol-3-yl]-methanol
By proceeding in a similar manner to [l-(4-Trifluoromethyl-phenyl)-lH-indazol-3-yl]-methanol (Intermediate 3a) but using 5-Fluoro-l-(4-trifluoromethyl-phenyl)-lH-indazole-3-carboxylic acid methyl ester (Intermediate 2b), there was prepared [5-Fluoro-l-(4-trifluoromethyl-phenyl)-lH- indazol-3-yl]-methanol (Intermediate 3b) (167mg) as a clear waxy solid.
LCMS: Method B RT = 3.79 min. m/z = 311 (ES+, M+H)
Intermediate 3c: [5-trifluoromethoxy- 1 -(4-trifluoromethyl-phenyl)- 1 H-indazol-3-yl]-methanol
By proceeding in a similar manner to [l-(4-Trifluoromethyl-phenyl)-lH-indazol-3-yl]-methanol (Intermediate 3a) but using 5-trifluoromethoxy- 1 -(4-trifluoromethyl-phenyl)- lH-indazole-3- carboxylic acid methyl ester (Intermediate 2c), there was prepared [5-trifluoromethoxy- 1 -(4- trifluoromethyl-phenyl)-lH-indazol-3-yl]-methanol (Intermediate 3c) (206mg) as a clear waxy solid.
LCMS: Method B RT = 4.18 min. m/z = 377 (ES+, M+H)
Intermediate 3d: [5-methoxy-l-(4-trifluoromethyl-phenyl)-lH-indazol-3-yl]-methanol
By proceeding in a similar manner to [l-(4-Trifluoromethyl-phenyl)-lH-indazol-3-yl]-methanol (Intermediate 3a) but using 5-methoxy-l-(4-trifluoromethyl-phenyl)-lH-indazole-3-carboxylic acid methyl ester (Intermediate 2d), there was prepared [5-methoxy-l-(4-trifluoromethyl-phenyl)-lH- indazol-3-yl]-methanol (Intermediate 3d) (184mg) as a clear waxy solid.
LCMS: Method B RT = 3.74 min. m/z = 323 (ES+, M+H)
Intermediate 3e: [5-chloro-l -(4-trifluoromethyl-phenyl)-lH-indazol-3-yl]-methanol
By proceeding in a similar manner to [l-(4-Trifluoromethyl-phenyl)-lH-indazol-3-yl]-methanol (Intermediate 3a) but using 5-chloro-l-(4-trifluoromethyl-phenyl)-lH-indazole-3-carboxylic acid methyl ester (Intermediate 2e), there was prepared [5-chloro-l -(4-trifluoromethyl-phenyl)- IH- indazol-3-yl]-methanol (Intermediate 3e) (177mg) as a clear waxy solid.
LCMS: Method B RT = 4.03 min. m/z = 327/329 (ES+, M+H)
Intermediate 3f: [5-methyl-l-(4-trifluoromethyl-phenyl)-lH-indazol-3-yl]-methanol
By proceeding in a similar manner to [l-(4-Trifluoromethyl-phenyl)-lH-indazol-3-yl]-methanol (Intermediate 3a) but using 5-methyl-l-(4-trifluoromethyl-phenyl)-lH-indazole-3-carboxylic acid methyl ester (Intermediate 2f), there was prepared [5-methyl-l-(4-trifluoromethyl-phenyl)-lH- indazol-3-yl]-methanol (Intermediate 3f) (152mg) as a clear waxy solid.
LCMS: Method B RT = 3.94 min. m/z = 307 (ES+, M+H) Intermediate 3g: [7-Fluoro-l-(4-trifluoromethyl-phenyl)-lH-indazol-3-yl]-methanol
By proceeding in a similar manner to [l-(4-Trifluoromethyl-phenyl)-lH-indazol-3-yl]-methanol (Intermediate 3 a) but using 7-Fluoro-l-(4-trifluoromethyl-phenyl)-lH-indazole-3-carboxylic acid methyl ester (Intermediate 2g), there was prepared [7-Fluoro-l-(4-trifluoromethyl-phenyl)-lH- indazol-3-yl]-methanol (Intermediate 3g) (225mg) as a clear waxy solid.
LCMS: Method B RT = 3.79 min. m/z = 311 (ES+, M+H)
Intermediate 3h: [4-Chloro- 1 -(4-trifluoromethyl-phenyl)- 1 H-indazol-3 -yl]-methanol
By proceeding in a similar manner to [l-(4-Trifluoromethyl-phenyl)-l H-indazol-3 -yl]-methanol (Intermediate 3 a) but using 4-Chloro-l -(4-trifluoromethyl-phenyl)- lH-indazole-3-carboxylic acid methyl ester (Intermediate 2h), there was prepared [4-CUoro-l -(4-trifluoromethyl-phenyl)- IH- indazol-3-yl]-methanol (Intermediate 3h) (105mg, 94%) as a light yellow solid.
LCMS: Method B RT = 3.95 min. m/z = 327/329 (ES+, M+H)
Intermediate 3i: [6-Chloro -l-(4-trifluoromethyl-phenyl)-lH-indazol-3-yl]-methanol
By proceeding in a similar manner to [l-(4-Trifluoromethyl-phenyl)-lH-indazol-3-yl]-methanol (Intermediate 3a) but using 6-Chloro-l-(4-trifluoromethyl-phenyl)-lH-indazole-3-carboxylic acid methyl ester (Intermediate 2i), there was prepared [6-Chloro-l -(4-trifluoromethyl-phenyl)- IH- indazol-3-yl]-methanol (Intermediate 3i) (60mg, 80%) as an off white solid. LCMS: Method B RT = 4.05 min. m/z = 327/329 (ES+, M+H) Intermediate 3i: [ 1 -(4-Trifluoromethoxy-phenyl)- 1 H-indazol-3 -yl]-methanol
By proceeding in a similar manner to [l-(4-Trifluoromethyl-phenyl)-lH-indazol-3-yl]-methanol (Intermediate 3 a) but using l-(4-Trifluoromethoxy-phenyl)-lH-indazole-3-carboxylic acid methyl ester (Intermediate 2j), there was prepared [l-(4-Trifluoromethoxy-phenyl)-lH-indazol-3-yl]- methanol (Intermediate 3j) (389mg, 99%) as a clear waxy solid.
LCMS: Method B RT = 3.78 min. m/z = 309 (ES+, M+H)
Intermediate 3k: [7-Fluoro- 1 -(4-trifluoromethoxy-phenyl)- 1 H-indazol-3 -yl]-methanol
By proceeding in a similar manner to [l-(4-Trifluoromethyl-phenyl)-lH-indazol-3-yl]-methanol (Intermediate 3a) but using 7-Fluoro-l-(4-trifluoromethoxy-phenyl)-lH-indazole-3-carboxylic acid methyl ester (Intermediate 2k), there was prepared [7-Fluoro-l -(4-trifluoromethoxy-phenyl)- IH- indazol-3-yl]-methanol (Intermediate 3k) (94mg, 70%) as a clear waxy crystals.
LCMS: Method B RT = 3.80 min. m/z = 327 (ES+, M+H) Intermediate 31: [l-(4-Chloro-phenyl)-lH-indazol-3-yl]-methanol
By proceeding in a similar manner to [l-(4-Trifluoromethyl-phenyl)-l H-indazol-3 -yl]-methanol (Intermediate 3 a) but using l-(4-Chloro-ρhenyl)-lH-indazole-3-carboxylic acid methyl ester (Intermediate 21), there was prepared [l-(4-Chloro-phenyl)-lH-indazol-3-yl]-methanol (Intermediate 31) (448mg, 107%) as a clear waxy solid.
LCMS: Method B RT = 3.56 min. m/z = 259/261 (ES+, M+H)
Intermediate 4 Intermediate 4a: 3-Chloromethyl-l-(4-trifluoromethyl-phenyl)-lH-indazole
To a stirred solution of [l-(4-Trifluoromethyl-phenyl)-lH-indazol-3-yl]-methanol (Intermediate 3a) in 3:1 (v:v) tetrahydrofuran:dichloromethane (40ml), under an inert atmosphere, was added JV- chlorosuccinimide (692mg, 5.184mmol) and triphenylphosphine (1.36g, 5.184mmol) and the reaction stirred overnight. The solvent was removed in vacuo to give a crude residue which was taken up in dichloromethane, washed (saturated sodium bicarbonate solution, water, brine), dried (Na2SO4), filtered and the solvent removed in vacuo. The resultant crude residue was purified by flash column chromatography eluting with 5% ethyl acetate/petroleum ether to give the title compound (960mg, 89%) as a white solid. 1H NMR (400MHz, CDCl3) δ = 7.87 (IH, dt, J = 0.9 and 8.1 Hz); 7.82 (2H, d, J = 8.4 Hz); 7.72 (3H, m); 7.45 (IH, m); 7.27 (IH, m); 4.97 (2H, s).
Intermediate 4b: 3-Chloromethyl-5-fluoro-l -(4-trifluoromethyl-phenyl)-lH-indazole
By proceeding in a similar manner to 3-Chloromethyl-l-(4-trifluoromethyl-phenyl)-lH-indazole (Intermediate 4a) but using [5-Fluoro-l-(4-trifluoromethyl-phenyl)-lH-indazol-3-yl]-methanol (Intermediate 3b) there was prepared 3-Chloromethyl-5-fluoro-l-(4-trifluoromethyl-phenyl)-lH- indazole (Intermediate 4b) (127mg) as a white solid.
LCMS: Method B RT = 4.58 min. m/z = 329/331 (ES+, M+H) Intermediate 4c: S-Chloromethyl-S-trifluorometlioxy- 1 -(4-trifluoromethyl-phenyl)- 1 H-indazole
By proceeding in a similar manner to 3-Chloromethyl-l-(4-trifluoromethyl-phenyl)-lH-indazole (Intermediate 4a) but using [5-trifluoromethoxy-l-(4-trifluoromethyl-phenyl)-lH-indazol-3-yl]- methanol (Intermediate 3c) there was prepared 3-Chloromethyl-5-trifluoromethoxy-l-(4- trifluoromethyl-phenyl)-l H-indazole (Intermediate 4c) (119mg) as a white solid.
LCMS: Method B RT = 4.82 min. m/z = 395/397 (ES+, M+H)
Intermediate 4d: 3-Chloromethyl-5-methoxy-l -(4-trifluoromethyl-phenyl)-l H-indazole
By proceeding in a similar manner to 3 -Chloromethyl-1 -(4-trifluoromethyl-phenyl)- 1 H-indazole (Intermediate 4a) but using [5-methoxy-l-(4-trifluoromethyl-phenyl)-lH-indazol-3-yl]-methanol (Intermediate 3d) there was prepared 3-Chloromethyl-5-methoxy-l-(4-trifluoromethyl-phenyl)-lH- indazole (Intermediate 4d) (20mg) as a white solid.
LCMS: Method B RT = 4.56 min. m/z = 341/343 (ES+, M+H) Intermediate 4e: 3-Chloromethyl-5-chloro-l-(4-trifluoromethyl-phenyl)-lH-indazole
By proceeding in a similar manner to 3-Chloromethyl-l-(4-trifluoromethyl-phenyl)-lH-indazole (Intermediate 4a) but using [5-chloro-l-(4-trifluoromethyl-phenyl)-lH-indazol-3-yl]-methanol (Intermediate 3e) there was prepared 3-Chloromethyl-5-chloro-l-(4-trifluoromethyl-plienyl)-lH- indazole (Intermediate 4e) (129mg) as a clear waxy solid.
LCMS: Method B RT = 4.80 min. m/z = 345/347/349 (ES+, M+H)
Intermediate 4f: 3-Chloromethyl-5-methyl-l -(4-trifluoromethyl-phenyl)-lH-mdazole
By proceeding in a similar manner to 3-Chloromethyl-l-(4-trifluoromethyl-phenyl)-lH-indazole (Intermediate 4a) but using [5-methyl-l-(4-trifluoromethyl-phenyl)-lH-indazol-3-yl]-methanol (Intermediate 3f) there was prepared 3-Chloromethyl-5-methyl-l-(4-trifluoromethyl-phenyl)-lH- indazole (Intermediate 4f) (121mg) as a clear waxy solid.
LCMS: Method B RT = 4.76 min. m/z = 325/327 (ES+, M+H) Intermediate 4g: 3-Chloromethyl-7-fl.uoro- 1 -(4-trifluoromethyl-phenyl)- 1 H-indazole
By proceeding in a similar manner to 3-Chloromethyl-l -(4-trifluoromethyl-phenyl)- 1 H-indazole (Intermediate 4a) but using [7-Fluoro-l -(4-trifluoromethyl-phenyl)- lH-indazol-3-yl]-methanol (Intermediate 3g) there was prepared 3 -Chloromethyl-7-fluoro-l -(4-trifluoromethyl-phenyl)- IH- indazole (Intermediate 4g) (195mg, 83%) as a white solid.
LCMS: Method B RT = 4.58 min. m/z = 345/347 (ES+, M+H) Intermediate 4h: 4-Chloro-3-chloromethyl-l-(4-trifluoromethyl-phenyl)-lH-indazole
By proceeding in a similar manner to 3-Chloromethyl-l-(4-trifluoromethyl-phenyl)-lH-mdazole (Intermediate 4a) but using [4-Chloro-l-(4-trifluoromethyl-phenyl)-lH-indazol-3-yl]-methanol (Intermediate 3h) there was prepared 4-Chloro-3-cMoromethyl-l-(4-trifluoromethyl-phenyl)-lH- indazole (Intermediate 4h) (91mg, 85%) as a yellow crystals.
LCMS: Method B RT = 4.27 min. m/z = 329/331 (ES+, M+H)
Intermediate 4i: 6-Chloro-3 -chloromethyl- 1 -(4-trifluoromethyl-phenyl)- 1 H-indazole
By proceeding in a similar manner to 3-Chlorornethyl-l -(4-trifluoromethyl-phenyl)- IH-indazole (Intermediate 4a) but using [6-Chloro-l -(4-trifluoromethyl-phenyl)- lH-indazol-3-yl]-methanol (Intermediate 3i) there was prepared 6-Chloro-3 -chloromethyl- 1 -(4-trifluoromethyl-phenyl)- IH- indazole (Intermediate 4i) (40mg, 77%) as a yellow solid.
LCMS: Method B RT = 4.79 min. m/z = 345/347/349 (ES+, M+H) Intermediate 4j: 3 -Chloromethyl- 1 -(4-trifluoromethoxy-phenyl)- 1 H-indazole
By proceeding in a similar manner to 3-Chloromethyl-l-(4-trifluoromethyl-phenyl)-lH-indazole (Intermediate 4a) but using [l-(4-Trifluoromethoxy-phenyl)-lH-indazol-3-yl]-methanol (Intermediate 3j) there was prepared 3-Chloromethyl-l-(4-trifluoromethoxy-phenyl)-lH-indazole (Intermediate 4j) (286mg, 71%) as a white solid. LCMS: Method B RT = 4.63 min: m/z = 327/329 (ES+, M+H)
Intermediate 4k: 3-Chloromethyl-7-fluoro- 1 -(4-trifluoromethoxy-phenyl)- 1 H-indazole
By proceeding in a similar manner to 3-Chloromethyl-l-(4-trifluoromethyl-phenyl)-lH-indazole (Intermediate 4a) but using [7-Fluoro-l -(4-trifluoromethoxy-phenyl)- lH-indazol-3-yl]-methanol (Intermediate 3k) there was prepared 3-Chloromethyl-7-fluoro-l-(4-trifluoromethoxy-phenyl)-lH- indazole (Intermediate 4k) (69mg, 62%) as a white crystals.
LCMS: Method B RT = 4.58 min. m/z = 345/347 (ES+, M+H) Intermediate 41: 3-Chloromethyl- 1 -(4-chloro-phenyl)- 1 H-indazole
By proceeding in a similar manner to 3 -Chloromethyl-l-(4-trifluoromethyl-phenyl)-l H-indazole (Intermediate 4a) but using [l-(4-Chloro-phenyl)-lH-indazol-3-yl]-methanol (Intermediate 31) there was prepared 3-Chloromethyl-l-(4-chloro-phenyl)-lH-indazole (Intermediate 41) (89mg, 19%) as a white crystals. LCMS: Method B RT = 4.54 min. m/z = 277/279/281 (ES+5 M+H)
Intermediate 4m: 3-Chloromethyl-l-(4-trifluoromethyl-phenyl)-lH-pyrazolo[4,3-c]pyridine
To a stirred solution of l-(4-Trifluoromethyl-phenyl)-lH-pyrazolo[433-c]pyridine-3-carboxylic acid ethyl ester (Intermediate 2m) (210mg, 0.6263mmol) in tetrahydrofuran (10ml) at O0C, under an inert atmosphere, was added lithium aluminium hydride (95mg, 2.505mmol) portionwise. The reaction mixture was warmed to room temperature and stirred for 2 hours before being quenched (water, IM hydrochloric acid), extracted (3 x ethyl acetate), the combined organic extracts were washed (brine), dried (Na2SO4), filtered and the solvent removed in vacuo. The resultant crude residue was taken, up in tetrahydrofuran (10ml), όzs-l,2-(diphenylphosρhino)ethane (250mg, 0.6263mmol) and JV- chlorosuccinimide (163mg, 1.253mmol) were added and the reaction stirred for 2 hours. The solvent was removed in vacuo to give a crude residue which was taken up in dichloromethane, washed (saturated sodium bicarbonate solution, water, brine), dried (Na2SO4), filtered and the solvent removed in vacuo. The resultant crude residue was purified by flash column chromatography eluting with 20% ethyl acetate/petroleum ether gradually increasing to 40% ethyl acetate/petroleum ether to yield the title compound (64mg, 33%) as a pale orange film.
LCMS: Method B RT = 3.09.min m/z = 312/314 (ES+, M+H)
Intermediate 4n: 3-Chloromethyl-l-(4-trifluoromethoxy-phenyl)-lH-pyrazolo[4,3-c]pyridine
By proceeding in a similar manner to 3-Chloromethyl- 1 -(4-trifluoromethyl-phenyl)- lH-pyrazolo[4,3- c]pyridine (Intermediate 4m) but using l-(4-Trifluoromethoxy-phenyl)-lH-pyrazolo[4,3-c]pyridine- 3-carboxylic acid ethyl ester (Intermediate 2n), there was prepared 3-Chloromethyl-l-(4- trifluoromethoxy-phenyl)-lH-pyrazolo[4,3-c]pyridine (Intermediate 4n) (55mg, 54%) as an off white solid. LCMS: Method B RT = 3.02 min m/z = 328/330 (ES+, M+H)
Intermediate 5
4-hydroxy-3 -methylphenylthiocyanate
To a stirred solution of ocresol (10ml, 96.17mmol) and sodium thiocyanate dihydrate (36.03g, 307.7mmol) in methanol (100ml) at O0C, was added sodium bromide (9.89g, 96.17mmol) and bromine (4.73ml, 96.17mmol) in methanol (100ml) slowly, the reaction was warmed to room temperature and stirred overnight. The reaction was cooled to O0C, sodium thiocyanate dihydrate (5.4Og, 46.16mmol), sodium bromide (1.48g, 14.43mmol) and bromine (0.71ml, 14.43mmol) in methanol (20ml) were added, the reaction warmed to room temperature and stirred for 8 hours. The reaction mixture was poured into saturated sodium bicarbonate solution, extracted (3 x dichloromethane), the organic extracts washed (water, brine), dried (Na2SO4), filtered and the solvent removed in vacuo. The resultant crude residue was purified by flash column chromatography eluting initially with 10% diethyl ether/petroleum ether and then gradually increasing it to 30% diethyl ether/petroleum ether to give the title compound (8.96g, 56% isolated yield) as waxy orange solid.
1H NMR (400MHz, CDCl3) δ 7.27 (IH, m); 7.21 (IH, m); 6.74 (IH, d, J = 8.4 Hz); 5.31 (IH, bs); 2.18 (3H, s).
Intermediate 6
4-Mercapto-2-methyl-phenol
To a stirred solution of 4-hydroxy-3-methylphenylthiocyanate (Intermediate 5) (8.95g, 54.17mmol) in tetrahydrofuran (250ml) at O0C, under an inert atmosphere, was added lithium aluminium hydride (2.26g, 59.59mmol) portionwise, the reaction warmed to room temperature and stirred overnight. The reaction mixture was quenched (water, IM HCl), extracted (3 x ethyl acetate), the combined organic extracts were washed (brine), dried (Na2SO4), filtered and the solvent removed in vacuo. The resultant crude residue was purified by flash column chromatography eluting initially with 10% diethyl ether/petroleum ether and then gradually increasing it to 50% diethyl ether/petroleum ether to give the title compound (4.25g, 56%) as a waxy white solid.
1H NMR (400MHz, DMSO-D6) δ = 9.33 (IH, s); 7.08 (IH, m); 6.99 (IH, m); 6.74 (IH, d, J = 8.3 Hz); 4.85 (IH, s); 2.12 (3H, s).
Intermediate 7
Intermediate 7a: {2-Methyl-4-[ 1 -(4-trifluoromethyl-phenyl)- 1 H-indazol-3-yhnethylsulfanyl]- phenoxy} -acetic acid tert-butyl ester
To a stirred solution of 4-Mercapto-2-methyl-phenol (Intermediate 6) (477mg, 3.400mmol) in acetonitrile (25ml) under an inert atmosphere, was added cesium carbonate (1.1 Ig, 3.40mmol) and 3-
Chloromethyl-l-(4-trifluoromethyl-phenyl)-lH-indazole (Intermediate 4a) (960mg, 3.090mmol) in acetonitrile (25ml) and the reaction was stirred for 2 hours. Cesium carbonate (1.71g, 5.250mmol) and t-butylbromoacetate (666μl) were added, the reaction mixture was stirred overnight and the solvent removed in vacuo. The reaction mixture was partitioned between dichloromethane and water. The organic layer was collected, washed (brine), dried (Na2SO4), filtered and the solvent removed in vacuo. The resultant crude residue was purified by flash column chromatography eluting with 20% ethyl acetate/petroleum ether to give the title compound (1.6Og, 98%) as a colourless oil.
1H NMR (400MHz, CDCl3) δ 7.70 (6H, m); 7.39 (IH, m); 7.18 (IH, m); 7.10 (2H, m); 4.42 (2H, s); 4.35 (2H, s); 2.13 (3H, s); 1.39 (9H, s).
Intermediate 7b: {4-[5-Fluoro-l-(4-trifluoromethyl-phenyl)-lH-indazol-3-yhnethylsulfanyl]-2- methyl-phenoxy} -acetic acid tert-butyl ester
By proceeding in a similar manner to 2-Methyl-4-[l-(4-trifluoromethyl-phenyl)-lH-indazol-3- ylmethylsulfanyrj-phenoxy} -acetic acid tert-butyl ester (Intermediate 7a) but using 3-Chloromethyl- 5-fluoro-l-(4-trifluoromethyl-phenyl)-lH-indazole (Intermediate 4b) there was prepared {4-[5- Fluoro- 1 -(4-trifluoromethyl-phenyl)-l H-indazol-3 -yhnethylsulfanyl]-2-methyl-ρhenoxy} -acetic acid tert-butyl ester (Intermediate 7b) (207mg) as a colourless oil. LCMS: Method B RT = 5.13 min. m/z = 547 (ES+, M+H)
Intermediate 7c: {4-[5-trifluoromethoxy- 1 -(4-trifluoromethyl-phenyl)- lH-indazol-3- ylmethylsulfanyl]-2-methyl-ρhenoxy} -acetic acid tert-butyl ester
By proceeding in a similar manner to 2-Methyl-4-[l -(4-trifluoromethyl-phenyl)- lH-indazol-3- ylmethylsulfanyl]-phenoxy} -acetic acid tert-butyl ester (Intermediate 7a) but using 3-Chloromethyl- 5-trifluoromethoxy-l-(4-trifluorometh.yl-phenyl)-lH-indazole (Intermediate 4c) there was prepared {4-[5-trifluoromethoxy-l-(4-trifluoromethyl-phenyl)-lH-indazol-3-ylmethylsulfanyl]-2-methyl- phenoxy} -acetic acid tert-butyl ester (Intermediate 7c) (123mg) as a colourless oil.
LCMS: Method B RT = 5.25 min. m/z = 613.15 (ES+, M+H)
Intermediate 7d: {4-[5-methoxy- 1 -(4-trifluoromethyl-phenyl)- 1 H-indazol-3 -ylrnethylsulfanyl]-2- methyl-phenoxy} -acetic acid tert-butyl ester
By proceeding in a similar manner to 2-Methyl-4-[l -(4-trifluoromethyl-phenyl)- 1 H-indazol-3 - ylmethylsulfanyl]-phenoxy} -acetic acid tert-butyl ester (Intermediate 7a) but using 3-Chloromethyl- 5-methoxy-l-(4-trifluoromethyl-phenyl)-lH-indazole (Intermediate 4d) there was prepared {4-[5- methoxy-l-(4-trifluoromethyl-phenyl)-lH-indazol-3-yhnethylsulfanyl]-2-methyl-phenoxy}-acetic acid tert-butyl ester (Intermediate 7d) (34mg) as a colourless oil.
LCMS: Method B RT = 5.12 min. m/z = 559 (ES+, M+H) Intermediate 7e: {4-[5-chloro- 1 -(4-trifluoromethyl-phenyl)- 1 H-indazol-3 -ylmethylsulfanyl]-2- methyl-phenoxy} -acetic acid tert-butyl ester
By proceeding in a similar manner to 2-Methyl-4-[l-(4-trifluoromethyl-phenyl)-lH-indazol-3- ylmethylsulfanyl]-phenoxy} -acetic acid tert-butyl ester (Intermediate 7a) but using 3-Chloromethyl- 5-chloro-l-(4-trifluoromethyl-phenyl)-lH-indazole (Intermediate 4e) there was prepared {4-[5- cUoro-l-(4-Mfluoromethyl-phenyl)-lH-indazol-3-ylmethylsulfanyl]-2-methyl-phenoxy}-acetic acid tert-butyl ester (Intermediate 7e) (143mg) as a colourless oil.
LCMS: Method B RT = 5.28 min. m/z = 563/565 (ES+, M+H)
Intermediate 7f: {4-[5-methyl-l-(4-trifluoromethyl-phenyl)-lH-indazol-3-ylmethylsulfanyl]-2- methyl-phenoxy} -acetic acid tert-butyl ester
By proceeding in a similar manner to 2-Methyl-4-[l-(4-trifluoromethyl-phenyl)-lH-indazol-3- ylmethylsulfanyl]-phenoxy} -acetic acid tert-butyl ester (Intermediate 7a) but using 3-Chloromethyl- 5-methyl-l-(4-trifluoromethyl-phenyl)-lH-indazole (Intermediate 4f) there was prepared {4-[5- methyl- 1 -(4-trifluoromethyl-phenyl)- lH-indazol-3-yhnethylsulfanyl]-2-methyl-phenoxy} -acetic acid tert-butyl ester (Intermediate 7f) (184mg) as a colourless oil.
LCMS: Method B RT = 5.26 min. m/z = 543(ES+, M+H)
Intermediate 7g: {4-[7-Fluoro-l-(4-trifluoromethyl-phenyl)-lH-indazol-3-ylmethylsulfanyl]-2- methyl-phenoxy} -acetic acid tert-butyl ester
By proceeding in a similar manner to 2-Methyl-4-[l-(4-trifluoromethyl-phenyl)-lH-indazol-3- ylmethylsulfanylj-phenoxy} -acetic acid tert-butyl ester (Intermediate 7a) but using 3-Chloromethyl- 7-fluoro-l-(4-trifluoromethyl-phenyl)-lH-indazole (Intermediate 4g) there was prepared {4-[7- Fluoro-l-(4-trifluoromethyl-phenyl)-lH-indazol-3-ylmethylsulfanyl]-2-meth.yl--phenoxy}-acetic acid tert-butyl ester (Intermediate 7g) (1 lOmg) as a colourless oil.
LCMS: Method B RT = 5.17 min. m/z = 547 (ES+, M+H)
Intermediate 7h: {4-[4-Chloro-l-(4-trifluoromethyl-phenyl)-lH-indazol-3-yhnethylsulfanyl]-2- methyl-phenoxy} -acetic acid tert-butyl ester
By proceeding in a similar manner to 2-Methyl-4-[l-(4-trifluoromethyl-phenyl)-lH-indazol-3- ylmethylsulfanyl]-phenoxy} -acetic acid tert-butyl ester (Intermediate 7a) but using 4-Chloro-3- chloromethyl-l-(4-trifluoromethyl-phenyl)-lH-indazole (Intermediate 4h) there was prepared {4-[4- Chloro- 1 -(4-trifluoromethyl-phenyl)- 1 H-indazol-3-yhnethylsulfanyl]-2-methyl-phenoxγ} -acetic acid tert-butyl ester (Intermediate Th) (93mg, 69%) as a colourless oil.
LCMS: Method B RT = 5.32 min. m/z = 563 (ES+, M+H)
Intermediate 7i: {4-[6-CMoro-l-(4-trifluoromethyl-phenyl)-lH-indazol-3-ylmethylsulfanyl]-2- methyl-phenoxy} -acetic acid tert-butyl ester
By proceeding in a similar manner to 2-Memyl-4-[l-(4-trifluoromemyl-phenyl)-lH-indazol-3- ylmethylsulfanyl]-phenoxy} -acetic acid tert-butyl ester (Intermediate 7a) but using 6-Chloro-3- chloromethyl-l-(4-trifluoromethyl-phenyl)-lH-indazole (Intermediate 4i) there was prepared {4-[6- CWoro-l-(4-trifluoromethyl-phenyl)-lH-mdazol-3-ylmemylsulfanyl]-2-methyl-phenoxy}-acetic acid tert-butyl ester (Intermediate 7i) (35mg, 62%) as a colourless oil.
LCMS: Method B RT = 5.29 min. m/z = 564 (ES+, M+H)
Intermediate 7j: {2-Methyl-4-[l-(4-trifluoromethoxy-phenyl)-lH-indazol-3-yhnethylsulfanyl]- phenoxy} -acetic acid tert-butyl ester
By proceeding in a similar manner to 2-Methyl-4-[l-(4-trifluoromethyl-phenyl)-lH-indazol-3- ylmethylsulfanyl]-phenoxy} -acetic acid tert-butyl ester (Intermediate 7a) but using 3-Chloromethyl- l-(4-trifluoromethoxy-phenyl)-lH-indazole (Intermediate 4j) there was prepared {2-Methyl-4-[l-(4- trifluoromethoxy-phenyl)-lH-indazol-3-ylmethylsulfanyl]-phenoxy} -acetic acid tert-butyl ester (Intermediate 7j) (217mg, 93 %) as a light yellow oil.
LCMS: Method B RT = 5.19 min. m/z = 545 (ES+, M+H)
Intermediate 7k 2-Methyl-2- {2-methyl-4-[ 1 -(4-trifluoromethoxy-phenyl)- 1 H-indazol-3 - ylmethylsulfanyl]-phenoxy} -propionic acid tert-butyl ester
By proceeding in a similar manner to 2-Methyl-4-[l-(4-trifluoromemyl-phenyl)-lH-indazol-3- ylmethylsulfanylj-phenoxy} -acetic acid tert-butyl ester (Intermediate 7a) but using 3-Chloromethyl- l-(4-trifluoromethoxy-phenyl)-lH-indazole (Intermediate 4j) and t-butyl bromoisobutyrate there was prepared 2-Methyl-2- {2-methyl-4-[ 1 -(4-trifluoromethoxy-phenyl)- 1 H-indazol-3 -ylmethylsulfanyl]- phenoxy} -propionic acid tert-butyl ester (Intermediate 7k) (204mg, 83%) as a colourless oil.
LCMS: Method B RT = 5.43 min. m/z = 573 (ES+, M+H)
Intermediate 71: {4-[7-Fluoro-l-(4-trifluoromethoxy-phenyl)-lH-indazol-3-ylmethylsulfanyl]-2- methyl-phenoxy} -acetic acid tert-butyl ester
By proceeding in a similar manner to 2-Methyl-4-[l-(4-trifluoromethyl-phenyl)-lH-indazol-3- ylmethylsulfanylj-phenoxy} -acetic acid tert-butyl ester (Intermediate 7a) but using 3-Chloromethyl- 7-fluoro-l-(4-trifluoromethoxy-ρhenyl)-lH-indazole (Intermediate 4k) there was prepared {4-[7- Fluoro- 1 -(4-trifluoromethoxy-phenyl)- 1 H-indazol-3 -yhnethylsulfanyl]-2-methyl-phenoxy } -acetic acid tert-butyl ester (Intermediate 71) (151mg) as a colourless oil.
LCMS: Method B RT = 5.15 min. m/z = 563 (ES+, M+H)
Intermediate 7m: {4-[l-(4-Chloro-ρhenyl)-lH-indazol-3-yhnethylsulfanyl]-2-methyl-phenoxy}- acetic acid tert-butyl ester
By proceeding in a similar manner to 2-Methyl-4-[l-(4-trifluoromethyl-phenyl)-lH-indazol-3- ylmethylsulfanylj-phenoxy} -acetic acid tert-butyl ester (Intermediate 7a) but using 3-Chloromethyl- l-(4-chloro-phenyl)-lH-indaxole (Intermediate 41) there was prepared {4-[l-(4-Chloro-phenyl)-lH- indazol-3-ylmethylsulfanyl]-2-methyl-phenoxy} -acetic acid tert-butyl ester (Intermediate 7m) (50mg) as a colourless oil.
LCMS: Method B RT = 5.20 min. m/z = 495/497 (ES+, M+H)
Intermediate 7n: {4-[ 1 -(4-Trifluoromethyl-phenyl)- 1 H-indazol-3 -ylmethylsulfanylj-phenoxy} -acetic acid tert-butyl ester
By proceeding in a similar manner to 2-Methyl-4-[l-(4-trifluoromethyl-phenyl)-lH-indazol-3- ylmethylsulfanyl]-phenoxy} -acetic acid tert-butyl ester (Intermediate 7a) but using 3-Chloromethyl- l-(4-trifluoromethyl-phenyl)-lH-indazole (Intermediate 4a) and thiophenol there was prepared {4- [l-(4-Trifluoromethyl-phenyl)-l H-indazol-3 -ylmethylsulfanylj-phenoxy} -acetic acid tert-butyl ester (Intermediate 7n) (75mg, 63%) as a white solid.
LCMS: Method B RT = 5.03 min. m/z = 515 (ES+, M+H)
Intermediate 7o: 2-Methyl-2-{4-[l-(4-trifluoromethyl-phenyl)-lH-indazol-3-ylmethylsulfanyl]- phenoxy} -propionic acid tert-butyl ester
By proceeding in a similar manner to 2-Methyl-4-[l-(4-trifluoromethyl-phenyl)-lH-indazol-3- ylmethylsulfanyl]-phenoxy} -acetic acid tert-butyl ester (Intermediate 7a) but using 3-Chloromethyl- l-(4-trifluoromethyl-phenyl)-lH-indazole (Intermediate 4a), Thiophenol and t-butyl bromoisobutyrate there was prepared 2-Methyl-2-{4-[l-(4-trifluoromethyl-phenyl)-lH-indazol-3- ylmethylsulfanyl]-phenoxy} -propionic acid tert-butyl ester (Intermediate 7o) (20mg, 16%) as a yellow oil.
LCMS: Method D RT = 4.80 min. m/z = 543 (ES+, M+H)
Intermediate 7p: {2-Methyl-4-[l-(4-trifluoromethyl-phenyl)-lH-pyrazolo[4,3-c]pyridin-3- ylmethylsulfanyl]-phenoxy} -acetic acid tert-butyl ester
By proceeding in a similar manner to 2-Methyl-4-[l-(4-trifluoromethyl-phenyl)-lH-indazol-3- ylmethylsulfanyl]-phenoxy} -acetic acid tert-butyl ester (Intermediate 7a) but using 3-Chloromethyl- l-(4-trifluoromethyl-phenyl)-lH-pyrazolo[4,3-c]pyridine (Intermediate 4m), there was prepared {2- Methyl-4-[l-(4-trifluoromethyl-phenyl)-lH-pyrazolo[4,3-c]pyridin-3-ylmethylsulfanyl]-phenoxy}- acetic acid tert-butyl ester (Intermediate 7p) (46mg) as a pale yellow oil.
LCMS: Method B RT = 4.30 min m/z = 530 (ES+, M+H)
Intermediate 8
Intermadiate 8a: (4-Acetyl-2-methyl-phenoxy)~acetic acid ethyl ester
To a stirred solution of 4'-hydroxy-3'-methylacetophenone (3g, 20mmol) in acetonitrile (50ml), under an inert atmosphere, was added ethyl bromoacetate (2.45ml, 22mmol) and cesium carbonate (7.17g, 22mmol). The reaction was heated to 5O0C and stirred for 2 hours. The reaction mixture was cooled to room temperature before partitioning between ethyl acetate and water. The organic phase was collected and washed with brine, dried (Na2SO4), filtered and the filtrate concentrated in vacuo to yield the title compound (4.72g, 100%) as a pale yellow oil.
LCMS: Method B RT = 3.41 min. m/z = 237 (ES+, M+H)
Intermediate 8b: 2-(4-Acetyl-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester
By proceeding in a similar manner to (4-Acetyl-2-methyl-phenoxy)-acetic acid ethyl ester (Intermediate 8a) but using ethyl-2-bromoisobutyrate, there was prepared 4-Acetyl-2-methyl- phenoxy)-acetic acid ethyl ester (Intermediate 8b) (2.6Ig) as a pale yellow oil.
LCMS: Method B RT = 3.89 min. m/z = 265 (ES+, M+H) Intermediate 8c: 2-(4-Acetyl-2-methyl-phenoxy)-propionic acid ethyl ester
By proceeding in a similar manner to (4-Acetyl-2-methyl-phenoxy)-acetic acid ethyl ester (Intermediate 8 a) but using 4'Hydroxy-3'-Methylacetophenone and DL-Ethyl-2-Brornopropionate there was prepared {2-(4-Acetyl-2-methyl-phenoxy)-propionic acid ethyl ester (Intermediate 8c) (1.645g, 99%) as a clear oil.
LCMS: Method B RT = 3.71 min. m/z = 251 (ES+, M+H)
Intermediate 9
Intermediate 9a: (4-Acetoxy-2-methyl-phenoxy)-acetic acid ethyl ester
To a stirred solution of (4-Acetyl-2-methyl-phenoxy)-acetic acid ethyl ester (Intermediate 8a) (4.72g, 20mmol) in dichloromethane (100ml) was added p-toluenesulfonic acid mono-hydrate (380mg, 2mmol). The reaction was heated to reflux before adding 70-75% 3-chloroperoxybenzoic acid (14.8Og, 60mmol) portionwise over 40 minutes. The reaction was maintained at reflux for a further 7 hours, cooled to room temperature and stirring continued overnight. Dichloromethane (30ml) was then added, the reaction mixture filtered and the filtrate slowly added to a stirred a stirred solution of potassium iodide (l:5w/v; 150ml). After 10 minutes, the organic layer was collected and added to stirred a solution of potassium iodide (l:5w/v; 150ml). Stirring was continued for a further 10 minutes. The organic layer was collected, washed (10% sodium sulfite solution, water, brine), dried (Na2SO4) and the solvent removed in vacuo to yield the title compound (4.76g, 94%) as an orange oil.
LCMS: Method B RT = 3.54 min. m/z = 275 (ES+, M+H)
Intermediate 9b: 2-(4-Acetoxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester
By proceeding in a similar manner to (4-Acetoxy-2-methyl-phenoxy)-acetic acid ethyl ester (Intermediate 9a), but using 2-(4-Acetyl-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (Intermediate 8b), there was prepared 2-(4-Acetoxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (Intermediate 9b) (2.8Ig) as an orange oil. LCMS: Method B RT = 3.96 min. m/z = 281 (ES+, M+H)
Intermediate 9c: 2-(4-Acetoxy-2-methyl-phenoxy)-propionic acid ethyl ester
By proceeding in a similar manner to (4-Acetoxy-2-methyl-phenoxy)-acetic acid ethyl ester (Intermediate 9a), but using 2-(4-Acetyl-2-methyl-phenoxy)-propionic acid ethyl ester (Intermediate 8c), there was prepared 2-(4-Acetoxy-2-methyl-phenoxy)-propionic acid ethyl ester (Intermediate 9c) (936mg, 53%) as a clear oil.
LCMS: Method B RT = 3.85 min. m/z = 267 (ES+, M+H) Intermediate 10
Intermediate IQa: (4-Hydroxy-2-methyl-phenoxy)-acetic acid ethyl ester
To a stirred solution of (4-Acetoxy-2-methyl-ρhenoxy)-acetic acid ethyl ester (Intermediate 9a) in ethanol (50ml) was added sodium ethoxide (1.35g, 19.81mmol). The reaction was heated to 450C and stirred for 1.5 hours. The reaction mixture was then cooled to room temperature, neutralised
(cone, hydrochloric acid) and the solvent removed in vacuo. The crude residue was partitioned between ethyl acetate and water. The organic layer was washed (water, brine), dried (Na2SO4) and the solvent removed in vacuo. The crude residue was triturated with dichloromethane/petroleum ether to yield the title compound (3.57g, 90%) as a brown solid.
LCMS: Method B RT = 2.93 min. m/z = 211 (ES+, M+H)
Intermediate IQb: 2-(4-Hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester
By proceeding in a similar manner to (4-Hydroxy-2-methyl-phenoxy)-acetic acid ethyl ester (Intermediate 10a) but using 2-(4-Acetoxy-2-niethyl-phenoxy)-2-methyl-propionic acid ethyl ester (Intermediate 9b), there was prepared 2-(4-Hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (2.1Og) as a waxy white solid.
LCMS: Method B RT = 3.38 min. m/z = 239 (ES+, M+H)
Intermediate IQc: 2-(4-Hydroxy-2-methyl-phenoxy)-propionic acid ethyl ester
By proceeding hi a similar manner to (4-Hydroxy-2-methyl-phenoxy)-acetic acid ethyl ester (Intermediate 10a) but using 2-(4-Acetoxy-2-methyl-ρhenoxy)-propionic acid ethyl ester (Intermediate 9c), there was prepared 2-(4-Hydroxy-2-methyl-phenoxy)-propionic acid ethyl ester (Intermediate 10c) (680mg, 86%) as a brown oil. LCMS: Method B RT = 3.26 min. m/z = 225 (ES+, M+H)
Intermediate IQd: (2-Chloro-4-hydroxy-phenoxy)-acetic acid ethyl ester
To a stirred solution of (2-Chloro-4-methoxy-phenoxy)-acetic acid ethyl ester
(Intermediate 12a) (lOOmg, 0.41mmol) in dichloromethane (ImI), under an inert atmosphere, at - 780C, was added drop wise IM Boron tribromide (1.6ml, l.βmmol). The reaction mixture was stirred at -780C for 30 minutes then warmed to room temperature and stirred for 2hrs. The reaction mixture was then quenched (ice water), stirred for 30 minutes, extracted (2 x dichloromethane), the organic layers washed (water, brine), dried (Na2SO4) and the solvent removed in vacuo to give the title compound (75mg, 80%) as a pale yellow oil.
LCMS: Method B RT = 3.11 min. m/z = 231/233 (ES+, M+H) Intermediate IQe: (2-Fluoro-4-hydroxy-phenoxy)-acetic acid ethyl ester
By proceeding in a similar manner to (2-Chloro-4-hydroxy-phenoxy)-acetic acid ethyl ester (Intermediate 12a) but using (2-Fluoro-4-methoxy-phenoxy)-acetic acid ethyl ester (Intermediate 12b) there was prepared (2-Fluoro-4-hydroxy-phenoxy)-acetic acid ethyl ester (Intermediate 1Oe) (159 g, 74%) as a clear oil.
LCMS: Method B RT = 2.89 min. m/z = 215 (ES+, M+H) Intermediate 11
Intermediate 11a: {2-Methyl-4-[l-(4-trifluoromethoxy-phenyl)-lH-indazol-3-yhnethoxy]-phenoxy}- acetic acid ethyl ester
To a stirred solution of (4-Hydroxy-2-methyl-phenoxy)-acetic acid ethyl ester (Intermediate 10a) (110mg, 0.5250mmol) in acetonitrile (10ml) was added cesium carbonate (342mg, 1.05mmol) and 3- Chloromethyl-l-(4-trifluoromethoxy-plienyl)-lH-indazole (Intermediate 4j) (163mg, 0.5mmol). The reaction was heated at reflux for 1 hour. The reaction mixture was cooled to room temperature, partitioned between ethyl acetate and water. The organic phase was collected and washed (brine), dried (Na2SO4) and the solvent removed in vacuo. The crude residue was purified by flash column chromatography eluting with 10% diethyl ether/petroleum ether gradually increasing it to 20% diethyl ether/petroleum ether to yield the title compound (223mg, 89%) as a pale yellow oil.
LCMS: Method B RT = 4.90 min. m/z = 501 (ES+, M+H) Intermediate lib: 2-Methyl-2-{2-methyl-4-[l-(4-trifluoromethoxy-phenyl)-lH-indazol-3- ylmethoxy]-phenoxy} -propionic acid ethyl ester
By proceeding in a similar manner to {2-Methyl-4-[l-(4-trifluoromethoxy-phenyl)-lH-indazol-3- ylmethoxy]-phenoxy} -acetic acid ethyl ester (Intermediate Ha) but using 2-(4-Hydroxy-2-methyl- phenoxy)-2-methyl-propionic acid ethyl ester (Intermediate 10b), there was prepared 2-Methyl-2-{2- methyl-4-[ 1 -(4-trifluor omethoxy-phenyl)- 1 H-indazol-3 -ylmethoxy] -phenoxy} -propionic acid ethyl ester (Intermediate 1 Ib) (252mg) as a pale yellow oil.
LCMS: Method B RT = 5.13 min. m/z = 529 (ES+, M+H)
Intermediate lie: {2-Methyl-4-[l-(4-trifluoromethyl-phenyl)-lH-indazol-3-yhnethoxy]-phenoxy}- acetic acid ethyl ester
By proceeding in a similar manner to {2-Methyl-4-[l-(4-trifluoromethoxy-phenyl)-lH-indazol-3- ylmethoxyj-phenoxy} -acetic acid ethyl ester (Intermediate lla) but vising 3-Chloromethyl-l-(4- trifluoromethyl-phenyl)-lH-indazole (Intermediate 4a), there was prepared {2-Methyl-4-[l-(4- trifluoromethyl-phenyl)-lH-indazol-3-yhnethoxy]-phenoxy} -acetic acid ethyl ester (Intermediate lie) (332mg) as a pale yellow oil.
LCMS: Method B RT = 4.89 min. m/z = 485 (ES+, M+H)
Intermediate Hd: 2-{2-Methyl-4-[l-(4-trifluoromethoxy-phenyl)-lH-indazol-3-yhnethoxy]- phenoxy} -propionic acid ethyl ester
By proceeding in a similar manner to {2-Methyl-4-[l-(4-trifluoromethoxy-phenyl)-lH-indazol-3- ylmethoxyj-phenoxy} -acetic acid ethyl ester (Intermediate lla) but using 2-(4-Hydroxy-2-methyl- phenoxy)-propionic acid ethyl ester (Intermediate 10a), there was prepared 2-{2-Methyl-4-[l-(4- trifluoromethoxy-phenyl)-lH-indazol-3-yhnethoxy]-phenoxy} -propionic acid ethyl ester (Intermediate l id) (144mg, 90%) as a pale yellow oil. LCMS: Method B RT = 5.08 min. m/z = 515 (ES+, M+H)
Intermediate lie: {2-Chloro-4-[l-(4-trifluoromethyl-phenyl)-lH-indazol-3-yhnethoxy]-phenoxy}- acetic acid ethyl ester
By proceeding in a similar manner to {2-Methyl-4-[l-(4-trifluoromethoxy-phenyl)-lH-indazol-3- ylmethoxy]-phenoxy} -acetic acid ethyl ester (Intermediate lla) but using (2-Chloro-4-hydroxy- phenoxy)-acetic acid ethyl ester (Intermediate 1Od), there was prepared {2-Chloro-4-[l-(4- trifluoromethyl-plienyl)-lH-indazol-3-ylniethoxy]-phenoxy}-acetic acid ethyl ester (Intermediate lie) (88mg, 55%) as an off white solid.
LCMS: Method B RT = 4.91 min. nα/z = 505 (ES+, M+H)
Intermediate Hf: {2-Fluoro-4-[ 1 -(4-trifluoromethyl-phenyl)- 1 H-indazol-3 -ylmethoxy]-phenoxy } - acetic acid ethyl ester
By proceeding in a similar manner to {2-Methyl-4-[l-(4-trifluoromethoxy-phenyl)-lH-indazol-3- yhnethoxy]-phenoxy} -acetic acid ethyl ester (Intermediate lla) but using (2-Fluoro-4-hydroxy- phenoxy)-acetic acid ethyl ester (Intermediate 1Oe), there was prepared {2-Fluoro-4-[l-(4- trifluoromethyl-phenyl)-l H-indazol-3 -ylmethoxy]-phenoxy} -acetic acid ethyl ester (Intermediate 1 If) (241mg) as a clear oil which crystallised on standing.
LCMS: Method B RT = 4.81 min. m/z = 489 (ES+, M+H)
Intermediate Hg: {2-Methyl-4-[ 1 -(4-trifluoromethoxy-phenyl)-l H-pyrazolo[4,3 -c]pyridin-3 - ylmethoxy]-phenoxy} -acetic acid ethyl ester
By proceeding in a similar manner to {2-Methyl-4-[l-(4-trifluoromethoxy-phenyl)-l H-indazol-3 - ylmethoxyj-phenoxy) -acetic acid ethyl ester (Intermediate lla but using 3-Chloromethyl-l-(4- trifluoromethoxy-phenyl)-lH-pyrazolo[4,3-c]pyridine (Intermediate 4n) and (4-Hydroxy-2-methyl- phenoxy)-acetic acid ethyl ester (Intermediate 10a), there was prepared {2-Methyl-4-[l-(4- trifluoromethoxy-phenyO-lH-pyrazolo^jS-cjpyridin-S-ylniethoxyj-phenoxyl-acetic acid ethyl ester (Intermediate llg) (12mg, 16%) as a clear oil.
LCMS: Method B RT = 3.67 min m/z = 502 (ES+, M+H) Intermediate 12
Intermediate 12a: (2-Chloro-4-rnethoxy-phenoxy)-acetic acid ethyl ester
To a stirred solution of 2-Chloro-4-methoxyphenol (200mg, 1.26mmol) in acetonitrile (5ml), under an inert atmosphere, was added ethyl bromoacetate (147ul, 1.32mmol) and cesium carbonate (4.52mg, 1.39mmol), the reaction heated to 5O0C and stirred for 16 hours. The reaction mixture was cooled to room temperature, partitioned between ethyl acetate and water and the layers separated. The organic phase was washed (Brine), dried (Na2SO4) and the solvent removed in vacuo to give the title compound (307mg, 100%) as a pale yellow oil.
LCMS: Method B RT = 3.76 min. m/z = 245/247 (ES+, M+H) Intermediate 12b: (2-Fluoro-4-methoxy-phenoxy)-acetic acid ethyl ester
By proceeding in a similar manner to (2-Chloro-4-methoxy-phenoxy)-acetic acid ethyl ester (Intermediate 12a)) but using 2-Fluoro-4-methoxyphenol there was prepared (2-Fluoro-4-methoxy- phenoxy)-acetic acid ethyl ester (Intermediate 12b) (231 g, 101%) as a clear oil.
LCMS: Method B RT = 3.57 min. m/z = 229 (ES+, M+H) Intermediate 13
Intermediate 13 a: 3-Ethoxyoxalyl-4-oxo-piperidine-l-carboxylic acid tert-butyl ester
To a stirred solution of IM lithium bis(trimethylsilyl)amide in tetrahydrofuran (50ml, 50mmol) in diethyl ether (50ml) at -780C, under an inert atmosphere, was added N-BOC-4-piperidone (9.96g, 50mmol) in diethyl ether (50ml) dropwise. The reaction mixture was stirred for 30 minutes. To this was added, a solution of diethyl oxalate (6.79ml, 50mmol) in diethyl ether (20ml). The reaction mixture was warmed to room temperature and stirred overnight. The reaction was then quenched (water), neutralised (IM hydrochloric acid), the layers separated and the aqueous layer was extracted (ethyl acetate). The combined organic layers were washed (brine), dried (Na2SO4) and the solvent removed in vacuo to yield the title compound (10.89g, 73%) as a yellow oil.
LCMS: Method B RT = 3.55. m/z = 298 (ES-, M-H) Intermediate 14
Intermediate 14a: lAό^-Tefrahyάϊo-pyrazolo^S-ctøyridine-SjS-dicarboxylic acid 5-tert-butyl ester 3 -ethyl ester
To a stirred solution of 3-Ethoxyoxalyl-4-oxo-piperidine-l-carboxylic acid tert-butyl ester (Intermediate 12a) (2.93g, 9.792mmol) in acetic acid (40ml) was added hydrazine hydrate (0.48ml, 9.792mmol) and the reaction heated at reflux for 1.5 hours. The reaction mixture was cooled to room temperature and the solvent removed in vacuo. The crude residue was taken up in ethyl acetate, washed (saturated sodium bicarbonate solution, brine), dried (Na2SO4) and the solvent removed in vacuo. The crude residue was purified by flash column chromatography eluting with 33% ethyl acetate/petroleum ether gradually increasing it to 50% ethyl acetate/petroleum ether to yield the title compound (1.67g, 58%) as an off-white foam. LCMS: Method B RT = 3.11 min m/z = 296 (ES+, M+H) Intermediate 15
Intermediate 15a: l-(4-Trifluoromethyl-phenyl)-l,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-3,5- dicarboxylic acid 5-tert-butyl ester 3-ethyl ester
By proceeding in a similar manner to l-(4-Trifluoromethyl-phenyl)-lH-indazole-3-carboxylic acid methyl ester (Intermediate 2a) but using l^^jT-Tetrahydro-pyrazolo^jS-cJpyridme-SjS-dicarboxylic acid 5-tert-butyl ester 3-ethyl ester (Intermediate 14a), there was prepared l-(4-Trifmoromethyl- phenyl)-l,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-3,5-dicarboxylic acid 5-tert-butyl ester 3-ethyl ester (Intermediate 15a) (1.03g) as a white solid.
LCMS: Method B RT = 4.50 min m/z = 440 (ES+, M+H)
Intermediate 15b: l-(4-Trifluoromethoxy-phenyl)-l,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-3,5- dicarboxylic acid 5-tert-butyl ester 3-ethyl ester
By proceeding in a similar manner to l-(4-Trifluoromethyl-phenyl)-lH-indazole-3-carboxylic acid methyl ester (Intermediate 2a) but using l,4,6,7-Tetrahydro-pyrazolo[4,3-c]pyridine-3,5-dicarboxylic acid 5-tert-butyl ester 3-ethyl ester (Intermediate 14a) and 4-trifluoromethoxy-benzeneboronic acid, there was prepared l-(4-Trifluoromethoxy-phenyl)-l,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-3,5- dicarboxylic acid 5-tert-butyl ester 3-ethyl ester (Intermediate 15b) (1.615g, 34%) as a white solid.
LCMS: Method B RT = 4.56 min m/z = 456 (ES+, M+H) Example 1
Example Ia: {2-Methyl-4-[l -(4-trifluoromethyl-phenyl)-lH-indazol-3-ylmethylsulfanyl]-phenoxy} - acetic acid
{2-Methyl-4-[ 1 -(4-trifluoromethyl-phenyl)- 1 H-indazol-3 -ylmethylsulfanyl]-phenoxy} -acetic acid tert-butyl ester (Intermediate 7a) (1.6g, 3.03mmol) was dissolved in 4M hydrogen chloride in 1,4- dioxane (20ml), the reaction mixture was stirred overnight and the solvent was removed in vacuo. The resultant crude residue was azeotroped (4 x diethyl ether), triturated with cyclohexane, filtered and dried in vacuo to give the title compound (1.2Og, 84%) as a white solid. 1H NMR (400MHz, CDCl3) δ 8.00 (5H, M); 7.62 (IH, m); 7.38 (IH, t, J = 7.2 Hz); 7.21 (2H, m); 6.78 (IH, d, J = 8.4 Hz); 4.58 (2H, s); 4.55 (2H, s); 2.14 (3H, s)
LCMS: Method A RT = 12.80 min. m/z = 473(ES+, M+H)
Example Ib: {4-[5-Fluoro-l -(4-trifluoromethyl-phenyl)- 1 H-indazol-3 -yhnethylsulfanyl]-2-methyl- phenoxy} -acetic acid
A solution of {4-[5-Fluoro-l-(4-trifluoromethyl-phenyl)-lH-indazol-3-yhnethylsulfanyl]-2-methyl- phenoxy} -acetic acid tert-butyl ester (Intermediate 7b) in 20% trifluoroacetic acid/dichloromethane (10ml) was stirred for 16 hours and then concentrated in vacuo. The resultant crude residue was azetroped (4 x dichloromethane), then triturated with diethyl ether/petroleum ether to give the title compound (128mg) as a white solid. 1H NMR (400MHz, DMSO-D6) δ = 7.97 (IH, dd, J = 3.9 & 9.3Hz); 7.90 (4H, m); 7.73 (IH, dd, J = 2.4 & 8.8Hz); 7.45 (IH, dt, J = 2.5 & 9.1 Hz); 7.18 (2H, m); 6.78 (IH, d, J = 8.4 Hz); 4.67 (2H5 s); 4.51 (2H, s); 2.10 (3H, s)
LCMS: Method A RT = 12.88 min. m/z = 491 (ES+, M+H); m/z = 489(ES-, M-H) Example Ic: {4-[5-trifluorometiioxy-l-(4-trifluoiOniethyl-plienyl)-lH-indazol-3-ylmethylsulfanyl]- 2-methyl-phenoxy} -acetic acid
A solution of {4-[5-Mfluoromethoxy-l-(4-trifluoroniethyl-phenyl)-lH-indazol-3-ylmethylsulfanyl]- 2-methyl-phenoxy} -acetic acid tert-butyl ester (Intermediate 7c) in 20% trifluoroacetic acid/dichloromethane (10ml) was stirred for 16 hours and then concentrated in vacuo. The resultant crude residue was dissolved in dichloromethane, washed (water, brine), dried (Na2SO4) and the solvent removed in vacuo to give a brown oil which was purified by flash column chromatography, eluting initially with ethyl acetate and then gradually increasing to acetic acid/methanol/ethyl acetate (1:10:89, v/v/v) to give the title compound (75mg) as a white solid. 1H NMR (400MHz, DMSO-D6) δ = 8.09 (IH, d, J = 9.1 Hz); 7.99 (5H, m); 7.59 (IH, m); 7.24 (2H, m); 6.82 (IH, d, J = 8.4 Hz); 4.71 (2H, s); 4.62 (2H, s); 2.15 (3H, s)
LCMS: Method A RT = 13.43 min. m/z = 557 (ES+, M+H); m/z = 555 (ES-, M-H)
Example Id: {4-[5-methoxy-l-(4-trifluoromethyl-phenyl)-lH-indazol-3-yhnethylsulfanyl]-2-methyl- phenoxy} -acetic acid
By proceeding in a manner similar to {4-[5-Fluoro-l-(4-trifluoromethyl-ρhenyl)-lH-indazol-3- ylmetfa.ylsulfanyl]-2-methyl-phenoxy}-acetic acid, but using 4-[5-methoxy-l-(4-trifluoromethyl- phenyl)-lH-indazol-3-ylmethylsulfanyl]-2-methyl-plienoxy}-acetic acid tert-butyl ester (Intermediate 7d), there was prepared the title compound (23mg) as a white solid.
1H NMR (400MHz, DMSO-D6) δ = 7.91 (5H, m); 7.25 (IH, d, J = 2.3 Hz); 7.19 (3H,m); 6.75 (IH, d, J = 8.1 Hz); 4.56 (2H, s); 4.50 (2H, s); 3.79 (3H, s); 2.10 (3H, s)
LCMS: Method A RT = 12.83 min. m/z = 503 (ES+, M+H); m/z = 501 (ES-, M-H).
Example Ie: {4-[5-chloro-l-(4-trifluoromethyl-phenyl)-lH-indazol-3-yhnethylsulfanyl]-2-methyl- phenoxy} -acetic acid
By proceeding in a manner similar to {4-[5-Fluoro-l-(4-trifluoromethyl-phenyl)-lH-indazol-3- yhnethylsulfanyl]-2-methyl-phenoxy}-acetic acid, but using 4-[5-chloro-l-(4-trifluoromethyl- phenyl)-lH-indazol-3-yhnethylsulfanyl]-2-methyl-phenoxy} -acetic acid tert-butyl ester (Intermediate 7e), there was prepared the title compound (91mg) as a white solid. 1H NMR (400MHz, DMSO-D6) δ = 7.97-7.87 (6H3 M); 7.55 (IH, dd, J = 2.2 & 8.8 Hz); 7.17 (2H,m); 6.75 (IH, d, J = 8.4 Hz); 4.64 (2H, s); 4.52 (2H, s); 2.09 (3H, s)
LCMS: Method A RT = 13.39 min. m/z = 507/509 (ES+, M+H); m/z - 505/507 (ES-, M-H).
Example If: {4-[5-memyl-l-(4-trifluoromethyl-phenyl)-lH-indazol-3-yhnethylsulfanyl]-2-methyl- phenoxy} -acetic acid
By proceeding in a manner similar to {4-[5-Fluoro-l-(4-trifluoromethyl-phenyl)-lH-indazol-3- ylmethylsulfanyl]-2-methyl-phenoxy} -acetic acid, but using 4-[5-methyl-l-(4-trifluoromethyl- phenyl)-lH-indazol-3-ylmethylsulfanyl]-2-methyl-phenoxy} -acetic acid tert-butyl ester (Intermediate 7f), there was prepared the title compound (124mg) as a white solid. 1H NMR. (400MHz, DMSO-D6) δ = 7.91 (4H, m); 7.85 (IH, d, J = 8.7Hz); 7.61 (IH, s); 7.38 (IH, dd, J = 1.5 & 8.8Hz); 7.18 (2H,m); 6.75 (IH, d, J = 8.5 Hz); 4.67 (2H, s); 4.49 (2H, s); 2.44 (3H, s); 2.10 (3H, s)
LCMS: Method A RT = 13.32 min. m/z = 487 (ES+, M+H); m/z = 485 (ES-, M-H).
Example Ig: {4-[7-Fluoro- 1 -(4-trifluoromethyl-phenyl)- 1 H-indazol-3-ylmethylsulfanyl]-2-methyl- phenoxy} -acetic acid
By proceeding in a similar manner to {4-[5-Fluoro-l-(4-trifluoromethyl-phenyl)-lH-indazol-3- ylmethylsulfanyl]-2-methyl-phenoxy}-acetic acid (Example Ib) but using {4-[7-Fluoro-l-(4- trifluoromethyl-phenyl)-lH-indazol-3-ybnethylsulfanyl]-2-methyl-phenoxy}-acetic acid tert-butyl ester (Intermediate 7g) there was prepared {4-[7-Fluoro-l -(4-trifluoromethyl-phenyl)- lH-indazol-3- yhnethylsulfanyl]-2-methyl-phenoxy} -acetic acid (Example Ig) (96mg, 98%) as a clear semi-solid.
IH 400 MHz (dl-CDC13): δ = 7.68 (2H, d, J= 8.77Hz); 7.57 (2H, dd, J = 3.61, 8.77Hz); 7.50-7.46 (IH, m); 7.12 (4H, m); 6.53 (IH, d, J= 8.25Hz); 4.59 (2H, s); 4.33 (2H, s); 2.13 (3H, s)
LCMS: Method A RT = 12.91min. m/z = 491(ES+, M+H); m/z = 489(ES-, M-H) Example Ih: {4-[4-Chloro-l-(4-trifluoromethyl-phenyl)-lH-indazol-3-yhnethylsulfanyl]-2-methyl- phenoxy} -acetic acid
By proceeding in a similar manner to {4-[5-Fluoro-l-(4-trifluoromeihyl-phenyl)-lH-indazol-3- ylmethylsulfanyl]-2-methyl-phenoxy}-acetic acid (Example Ib) but using 4-[4-Chloro-l-(4- trifluoromethyl-phenyl)- 1 H-indazol-3 -ylmethylsulfanyl]-2-methyl-phenoxy} -acetic acid tert-butyl ester (Intermediate 7h) there was prepared {4-[4-Chloro-l-(4-trifluorometh.yl-phenyl)-lH-indazol-3- ylmethylsulfanyl]-2-methyl-phenoxy} -acetic acid (Example Ih) (78mg, 96%) as an off white solid.
1H 400 MHz (d1-MeOD): δ = 7.87 (2H, d, J= 7.81Hz); 7.79 (IH, d, J = 8.93Hz); 7.73 (2H, d, J = 8.93Hz); 7.49 (IH, t, J = 7.81Hz); 7.33 (IH, d, J = 7.26Hz); 7.16 (IH, d, J= 7.25Hz); 7.02 (IH, s); 6.72 (IH, d, J = 7.81Hz); 4.65 (2H, s); 4.54 (2H, s); 2.13 (3H, s) LCMS: Method C RT = 13.08 min. m/z = 507(ES+, M+H); m/z = 505(ES-, M-H)
Example Ii: {4-[6-Chloro- 1 -(4-trifluoromethyl-phenyl)- 1 H-indazol-3 -ylmethylsulfanyl]-2-methyl- phenoxy} -acetic acid
By proceeding in a similar manner to {4-[5-Fluoro-l-(4-trifluoromethyl-phenyl)-lH-indazol-3- ylmethylsulfanyl]-2-methyl-phenoxy}-acetic acid (Example Ib) but using {4-[6-Chloro-l-(4- trifluoromethyl-phenyl)-lH-indazol-3-ylmethylsulfanyl]-2-methyl-phenoxy}-acetic acid tert-butyl ester (Intermediate 7i) there was prepared {4-[6-Chloro-l-(4-trifluoromethyl-phenyl)-lH-indazol-3- ylmethylsulfanyl]-2-methyl-phenoxy} -acetic acid (Example Ii) (20mg, 72%) as a clear crystals.
IH 400 MHz (dl-CDCI3): δ = 7.74-7.58 (6H, m); 7.15-7.08 (3H, m); 6.53 (IH, d, J = 8.45Hz); 4.59 (2H, s); 4.32 (2H, s); 2.13 (3H, s)
LCMS: Method A RT = 13.03 min. m/z = 507 (ES+, M+H); m/z = 505 (ES-, M-H) Example Ii: {2-Methyl-4-[l-(4-trifluoromethoxy-phenyl)-lH-indazol-3-ylmethylsulfanyl]- phenoxy} -acetic acid
By proceeding in a similar manner to {4-[5-Fluoro-l-(4-trifluoromethyl-phenyl)-lH-indazol-3- ylmethylsulfanyl]-2-methyl-phenoxy} -acetic acid (Example Ib) but using 2-Methyl-4-[l-(4- trifluoromethoxy-phenyl)-lH-indazol-3-ylmethylsulfanyl]-pb.enoxy} -acetic acid tert-butyl ester (Intermediate 7j) there was prepared {2-Methyl-4-[l-(4-trifluoromethoxy-phenyl)-lH-indazol-3- ylmethylsulfanyl]-phenoxy} -acetic acid (Example Ij) (217mg, 98%) as a clear semi-solid.
IH 400 MHz (dl-CDC13): δ = 7.70 (IH, d, J = 7.52Hz); 7.60-7.55 (3H, m); 7.37 (IH, t, J 7.52= Hz); 7.29 (2H, d, J = 8.36Hz); 7.18-7.10 (3H, m); 6.54 (IH, d, J= 8.36Hz); 4.58 (2H, s); 4.36 (2H, s); 2.13 (3H, s)
LCMS: Method A RT = 12.96 min. m/z = 489(ES+, M+H); m/z = 487(ES-, M-H)
Example lfc 2-Methyl-2- {2-methyl-4-[ 1 -(4-trifluoromethoxy-phenyl)- 1 H-indazol-3 - yhnethylsulfanyl]-phenoxy} -propionic acid
By proceeding in a similar manner to {4-[5-Fluoro-l-(4-trifluoromethyl-phenyl)-lH-indazol-3- ylmethylsulfanyl]-2-methyl-phenoxy} -acetic acid (Example Ib) but using 2-Methyl-2-{2-methyl-4- [ 1 -(4-trifluoromethoxy-phenyl)- 1 H-indazol-3 -ylmethylsulfanyl]-phenoxy} -propionic acid tert-butyl ester (Intermediate 7k) there was prepared 2-Methyl-2-{2-methyl-4-[l-(4-trifluoromethoxy-phenyl)- lH-indazol-3-ylmethylsulfanyl]-phenoxy}-propionic acid (Example Ik) (96mg, 98%) as a clear semi-solid. IH 400 MHz (dl-CDC13): δ = 7.7O(1H, d, J= 8.10Hz); 7.61-7.56 (3H, m); 7.37 (IH, t, J = 7.45Hz); 7.29 (2H, d, J = 8.10Hz); 7.17-7.13 (2H, m); 7.05 (IH3 dd, J = 8.75, 2.60Hz); 6.72 (IH, d, J = 8.20Hz); 4.38 (2H, s); 2.08 (3H, s); 1.50 (6H, s)
LCMS: Method A RT = 13.53 min. m/z = 517(ES+, M+H); m/z = 515(ES-, M-H) Example 11: {4-[ 1 -(4-Chloro-phenyl)- 1 H-indazol-3 -ylmethylsulfanyl]-2-methyl-phenoxy} -acetic acid
By proceeding in a similar manner to {4-[5-Fluoro-l-(4-trifluoromethyl-phenyl)-lH-indazol-3- ylmethylsulfanyl]-2-methyl-phenoxy} -acetic acid (Example Ib) but using {4-[l-(4-Chloro-phenyl)- 1 H-indazol-3 -ylmethylsulfanyl]-2-methyl-phenoxy} -acetic acid tert-butyl ester (Intermediate 71) there was prepared {4-[l-(4-Chloro-phenyl)-lH-indazol-3-ylmethylsulfanyl]-2-methyl-phenoxy}- acetic acid (Example 11) (22mg, 50%) as a clear semi-solid.
IH 400 MHz (dl-CDC13): δ = 7.70 (IH, d, J= 8.15Hz); 7.58 (IH, d, J = 8.60Hz); 7.49 (2H, d, J = 8.60Hz); 7.43-7.33 (3H, m); 7.17-7.09 (3H, m); 6.54 (IH, d, J = 9.05Hz); 4.57 (2H, s); 4.36 (2H, s); 2.13 (3H, s)
LCMS: Method A RT = 12.80 min. m/z = 439(ES+, M+H); m/z = 437(ES-, M-H)
Example Im: {4-[ 1 -(4-Trifluoromethyl-phenyl)- 1 H-indazol-3 -ylmethylsulfanyl]-phenoxy} -acetic acid
By proceeding in a similar manner to {4-[5-Fluoro-l-(4-trifluoromethyl-phenyl)-lH-mdazol-3- yhnethylsulfanyl]-2-methyl-phenoxy}-acetic acid (Example Ib) but using {4-[l-(4-Trifluoromethyl- phenyl)-lH-indazol-3-ylmethylsulfanyl]-phenoxy} -acetic acid tert-butyl ester (Intermediate 7m) there was prepared {4-[l-(4-Trifluoromethyl-phenyl)-lH-indazol-3-ylmethylsulfanyl]-phenoxy}- acetic acid (Example Im) (85mg) as a white solid.
IH 400 MHz (dl-CDC13): δ = 7.70 (6H, m); 7.40 (IH, t, J = 7.66Hz); 7.27 (2H, d, J = 9.04Hz); 7.18 (IH, m); 7.18 (2H, d, J = 8.60Hz); 4.57 (2H, s); 4.37 (2H, s LCMS: Method A RT = 12.46 min. m/z = 459(ES+, M+H); m/z = 457(ES-, M-H)
Example In: 2-Methyl-2-{4-[l-(4-trifluoromethyl-phenyl)-lH-indazol-3-ylmethylsulfanyl]- phenoxy} -propionic acid
By proceeding in a similar manner to {4-[5-Fluoro-l-(4-trifluoromethyl-phenyl)-lH-indazol-3- yhnethylsulfanyl]-2-methyl-phenoxy} -acetic acid (Example Ib) but using 2-Methyl-2-{4-[l-(4- trifluoromethyl-phenyl)-lH-indazol-3-ylmethylsulfanyl]-phenoxy}-propionic acid tert-butyl ester (Intermediate 7n) there was prepared {2-Methyl-2-{4-[l-(4-trifluoromethyl-phenyl)-lH-indazol-3- ylmethylsulfanylj-phenoxy} -propionic acid (Example In) (96mg, 98%) as a clear semi-solid.
IH 400 MHz (dl-CDC13): δ = 7.71-7.65(6H, m); 7.39 (IH, t, J = 7.79Hz); 7.23 (2H, d, J = 8.76Hz); 7.17 (lH,t , J = 7.52Hz); 6.74 (2H, d, J= 8.77Hz); 4.39 (2H, s); 1.49 (6H, s)
LCMS: Method A RT = 13.05 min. m/z = 487(ES+, M+H); m/z = 485(ES-, M-H)
Example lo: {4-[7-Fluoro- 1 -(4-trifluoromethoxy-phenyl)- 1 H-indazol-3 -ylmethylsulfanyl]-2-methyl- phenoxy} -acetic acid
By proceeding in a similar manner to {2-Methyl-4-[l-(4-trifluoromethyl-phenyl)-lH-indazol-3- ylmethylsulfanyl]-phenoxy} -acetic acid (Example Ia) but using {4-[7-Fluoro-l-(4-trifluoromethoxy- phenyl)-lH-indazol-3-ylmethylsulfanyl]-2-methyl-phenoxy}-acetic acid tert-butyl ester (Intermediate 7o) there was prepared {4-[7-Fluoro-l-(4-trifluoromethoxy-phenyl)-lH-indazol-3- ylmethylsulfanyl]-2-methyl-phenoxy}-acetic acid (Example lo) (66mg, 48%) as an of white solid.
IH 400 MHz (dl-CDC13): δ = 7.46(3H, m); 7.24 (2H, d, J = 8.38Hz); 7.08 (4H, m); 6.54 (IH, d, J = 8.03Hz); 4.59 (2H, s); 4.33 (2H, s); 2.13(3H, s)
LCMS: Method A RT = 12.91 min. m/z = 507 (ES+, M+H), m/z = 505 (ES-, M-H)
Example Ijx {2-Methyl-4-[ 1 -(4-trifluoromethyl-phenyl)- 1 H-pyrazolo[4,3 -c]pyridin-3 - ylmethylsulfanyl]-phenoxy} -acetic acid hydrochloride
By proceeding in a similar manner to {2-Methyl-4-[l-(4-trifluoromethyl-phenyl)-lH-indazol-3- ylmethylsulfanyl]-phenoxy} -acetic acid (Example Ia), but using {2-Methyl-4-[l-(4-trifluoromethyl- pheny^-lH-pyrazolo^^-cJpyridin-S-yhnethylsulfanyy-phenoxyJ-acetic acid tert-butyl ester (Intermediate 7p), there was prepared {2-Methyl-4-[l-(4-trifluoromethyl-phenyl)-lH-pyrazolo[4,3- c]pyridin-3-yhnethylsulfanyl]-phenoxy}-acetic acid hydrochloride (Example Ip) (15mg) as a white solid.
1H NMR (400MHz3 DMSOd6) δ = 9.52 (IH, s); 8.64 (IH, d, J = 6.5Hz); 8.21 (IH, d, J = 6.5Hz); 7.94 (2H, d, J = 8.5Hz); 7.87 (2H, d, J = 8.5Hz); 7.10 (2H, m); 6.70 (IH, d, J = 8.5 Hz); 4.63 (2H, s); 4.59 (2H, s); 2.04 (3H, s)
LCMS: Method A RT = 8.49 min m/z = 474 (ES+, M+H) Example 2
Example 2a: {2-Methyl-4-[ 1 -(4-trifluoromethoxy-phenyl)- 1 H-indazol-3 -ylmethoxyj-phenoxy } - acetic acid
To a stirred solution of {2-Methyl-4-[l-(4-trifluoromethoxy-phenyl)-lH-indazol-3-ylmethoxy]- phenoxy} -acetic acid ethyl ester (Intermediate l la) in tetrahydrofuran:methanol:water (4:4:1, 18ml) was added lithium hydroxide monohydrate. The reaction was heated to 5O0C and stirred for 1 hour. The solvent was removed in vacuo. The crude residue was acidified (IM hydrochloric acid), filtered and dried in vacuo. The precipitate was then triturated with diethyl ether/petroleum ether to yield the title compound (10.69g) as a white solid
1H NMR (400MHz, DMSOd6) δ = 12.91 (<1H, bs); 7.98-7.88 (4H5 m); 7.61 (2H, d, J - 8.2 Hz); 7.55 (IH, m); 7.32 (IH, m); 6.96 (IH, d, J = 2.6 Hz); 6.89 (IH, dd, J = 2.9 & 8.7 Hz); 6.78 (IH, d, J = 8.9 Hz); 5.46 (2H, s); 4.61 (2H, s); 2.18 (3H, s)
LCMS: Method A RT = 12.92 min m/z = 473 (ES+, M+H)
Example 2b: 2-Methyl-2- {2-methyl-4-[ 1 -(4-trifluoromethoxy-phenyl)- 1 H-indazol-3 -ylmethoxy]- phenoxy} -propionic acid
By proceeding in a similar manner to {2-Methyl-4-[l-(4-trifluoromethyl-phenyl)-lH-indazol-3- ylmethoxy]-phenoxy} -acetic acid (Example 2a) but using 2-Methyl-2-{2-methyl-4-[l-(4- trifluoromethoxy-phenyl)-lH-indazol-3-yhnethoxy]-phenoxy}-propionic acid ethyl ester (Intermediate l ib), there was prepared 2-Methyl-2-{2-methyl-4-[l-(4-trifluoromethoxy-phenyl)-lH- indazol-3-ylmethoxy]-phenoxy}-propionic acid (Example 2b) (174mg) as a white solid. 1H NMR (400MHz, DMSO-d6) δ = 7.97-7.88 (4H, m); 7.61 (2H, d, J = 8.3 Hz); 7.55 ); 7.32 (IH, t, J = 7.5Hz); 6.95 (IH, d, J = 2.9 Hz); 6.89 (IH, dd, J = 3.1 & 8.8 Hz); 6.75 (IH, d, J = 8.9 Hz); 5.44 (2H, s); 2.14 (3H, s); 1.43 (6H, s)
LCMS: Method A RT = 12.92 min m/z = 473 (ES+, M+H)
Example 2c: {2-Methyl-4-[l-(4-trifluoromethyl-phenyl)-lH-indazol-3-ylmethoxy]-phenoxy}-acetic acid
By proceeding in a similar manner to {2-Methyl-4-[l-(4-trifluoromethoxy-phenyl)-lH-indazol-3- ylmethoxyj-phenoxy} -acetic acid (Example 2a) but using {2-Methyl-4-[l-(4-trifluoromethyl- phenyl)-lH-indazol-3-ylmethoxy]-phenoxy}-acetic acid ethyl ester (Intermediate lie), there was prepared {2-Methyl-4-[l-(4-trifluoromethoxy-phenyl)-lH-indazol-3-yhnethoxy]-phenoxy}-acetic acid (Example 2c) (207mg, 67%) as a white solid.
1R NMR (400MHz, DMSOd6) δ = 12.91 (<1H, bs); 8.07 (2H, d, J = 8.7 Hz); 7.99 (2H, d, J = 9.0 Hz); 7.96 (2H, d, J = 8.8 Hz); 7.59 (IH, m); 7.36 (IH, t, J = 7.4 Hz); 6.96 (IH, d, J = 2.9 Hz); 6.89 (IH, dd, J = 3.0 & 8.8 Hz); 6.78 (IH, d, J = 8.8 Hz); 5.46 (2H, s); 4.62 (2H, s); 2.18 (3H, s)
LCMS: Method A RT = 12.76 min m/z = 457 (ES+, M+H)
Example 2d: 2- {2-Methyl-4-[l -(4-trifluoromethoxy-phenyl)- 1 H-indazol-3-ylmethoxy]-phenoxy} - propionic acid
By proceeding in a similar manner to {2-Methyl-4-[l-(4-trifluoromethyl-phenyl)-lH-indazol-3- ylmethoxy]-phenoxy} -acetic acid (Example 2c) but using 2-{2-Methyl-4-[l-(4-trifluoromethoxy- phenyl)-lH-indazol-3-ylmethoxy]-phenoxy}-propionic acid ethyl ester (Intermediate lid), there was prepared 2-{2-Methyl-4-[l-(4-trifluoromethoxy-phenyl)-lH-indazol-3-ylmethoxy]-phenoxy}- propionic acid (Example 2d) (116mg, 88%) as a white solid.
IH 400 MHz (dl-CDC13): δ = 7.85 (IH, d, J= 8.38Hz); 7.67 (2H, d, J= 8.87Hz); 7.61 (IH, d, J= 8.38Hz); 7.38 (IH, t, J= 7.39Hz); 7.30 (2H5 d, J= 8.38Hz); 7.17 (IH, t, J= 7.39Hz); 6.83 (IH, d, J = 2.46Hz); 6.75 (IH, dd, J = 2.95, 8.87Hz); 6.62 (IH, d, J = 8.87Hz); 5.36 (2H, s); 4.56 (IH, q, J= 6.90Hz); 2.16 (3H, s); 1.51 (3H, d, J= 6.37Hz). LCMS: Method C RT = 12.72 min m/z = 487 (ES+, M+H)
Example 2e: {2-Chloro-4-[ 1 -(4-trifluoromethyl-phenyl)- 1 H-indazol-3 -ylmethoxyj-phenoxy} -acetic acid
By proceeding in a similar manner to {2-Methyl-4-[ 1 -(4-trifluoromethyl-phenyl)- 1 H-indazol-3 - ylmethoxyj-phenoxy} -acetic acid (Example 2a) but using {2-Chloro-4-[l-(4-trifluoromethyl- phenyl)-lH-indazol-3-ylmethoxy]-phenoxy}-acetic acid ethyl ester (Intermediate lie), there was prepared {2-Chloro-4-[l -(4-trifluoromethyl-phenyl)-lH-indazol-3-ylmethoxy]-phenoxy} -acetic acid (Example 2e) (66mg, 85%) as a white solid.
IH 400 MHz (dl-CDC13): δ = 7.90-7.80 (3H, m); 7.77-7.68 (3H, m); 7.44 (IH, t, J = 7.66Hz); 7.24 (IH, t, J = 7.57Hz); 7.13 (IH, d, J = 2.96Hz); 6.89 (IH, dd, J= 2.59, 8.88Hz); 6.83 (IH, d, J= 8.88Hz); 5.41 (2H, s); 4.59 (2H, s).
LCMS: Method A RT = 13.07 min. m/z = 477 (ES+, M+H), m/z = 475 (ES-, M-H)
Example 2f: {2-Fluoro-4-[l-(4-trifluoromethyl-phenyl)-lH-indazol-3-yhnethoxy]-phenoxy}-acetic acid
By proceeding in a similar manner to {2-Methyl-4-[l-(4-trifluoromethyl-phenyl)-lH-indazol-3- ylmethoxyj-phenoxy} -acetic acid (Example 2a) but using (2-Fluoro-4-[l-(4-trifluoromethyl-phenyl)- lH-indazol-3-ylmethoxy]-phenoxy} -acetic acid ethyl ester (Intermediate Hf), there was prepared {2- Fluoro-4-[l-(4-trifluoromethyl-phenyl)-lH-indazol-3-yknethoxy]-phenoxy}-acetic acid (Example 2f) (226mg, 100%) as a white solid.
IH 400 MHz (dl-CDC13): δ = 7.79-7.58 (6H, m) 7.35 (IH, t, J = 8.14Hz); 7.13 (IH, t, J = 7.58Hz); 6.81 (IH, t, J = 9.26Hz); 6.71 (IH, dd, J= 2.80, 12.35Hz); 6.62 (IH, d, J= 8.70Hz); 5.27 (2H, s); 4.45 (2H, s). LCMS: Method C RT - 12.67 min m/z = 461 (ES+, M+H), m/z = 459 (ES-, M-H)
Example 2g: {2-Methyl-4- [ 1 -(4-trifluoromethoxy-phenyl)- 1 H-pyrazolo[4,3 -c]pyridin-3 -ylmethoxy]- phenoxy} -acetic acid
By proceeding in a similar manner to {2-Methyl-4-[l-(4-trifluoromethyl-phenyl)-lH-indazol-3- ylmethoxyj-phenoxy} -acetic acid (Example 2a) but using {2-Methyl-4-[l-(4-trifluoromethoxy- phenyl)-lH-pyrazolo[4,3-c]pyridin-3-yhnethoxy]-phenoxy}-acetic acid ethyl ester (Intermediate Hg), there was prepared {2-Methyl-4-[l-(4-trifluoromethoxy-phenyl)-lH-pyrazolo[4,3-c]pyridin-3- ylmethoxy]-ρhenoxy} -acetic acid (Example 2g) (9mg, 79%) as a white solid. IH 400 MHz (dl-MeOD): δ = 9.27 (IH, bs); 8.41 (IH, d, J = 6.67Hz); 7.88 (IH3 d, J = 6.67Hz); 7.83 (2H, d, J = 8.58Hz); 7.47 (2H, d, J = 8.58Hz); 6.86 (IH, d, J = 2.48Hz); 6.78 (IH, dd, J = 2.95,8.86Hz); 6.67 (lH,d , J = 8.86Hz); 5.48 (2H, s); 4.51 (2H, s); 2.15 (3H, s).
LCMS: Method A RT = 8.51 min. m/z = 474 (ES+, M+H), m/z = 472 (ES-, M-H) Biological Assays
Biological Assay 1: Transactivation assay
Compounds were screened for their functional potency in transiently transfected HEK293 cells for their ability to activate PPAR subtypes. Cells were cultured in DMEM (Invitrogen) supplemented with 10 % foetal calf serum, glutamine, penicillin and streptomycin and plated at 10 000 cells/well of a 96-well solid white plate and incubated at 37 °C/5 % CO2 for 24 hours. Media was removed and the cells washed with PBS. Cells were then transiently transfected using Fugene (Roche) with 50 ng pFACMV-PPARδ (plasmid encoding amino acids 1-147 of the GAL4 DNA binding domain, fused to amino acids 147-441 of PPARδdownstream of CMV promoter) and 250 ng pFR-Luc (reporter plasmid containing 5 X GAL4 response elements upstream of a luciferase gene), using a ratio of 3:1 Fugene:DNA. 100 μl of this transfection mixture in DMEM (without foetal calf serum) was added to each well, and the incubation continued for a further 24 hours. The cells are then again washed with PBS prior to the addition of 100 μl reduced serum medium (OptiMEM; Invitrogen). Compounds were added (10 μl in 2 % DMSO in OptiMEM) to achieve final concentrations between 0-30 μM. The cells were then returned to the incubator for a further 24 hours. 100 μl of luciferase reagent (Bright GIo, Promega) was added directly to each well, and the luminescence determined using a suitable luminometer.
To measure the selectivity of compounds, their ability to transactivate GAL4 fusions of PP ARa LBD and PP ARy LBD was determined. The activity of compounds was expressed as a percentage relative to control compounds: PPARγ rosiglitazone (BRL 49653), PPARδ GW501516 (11) or PP ARa KCL1999000269 (12). EC50 values were calculated by fitting of the data to a sigmoidal dose response curve.
The compounds of the invention of examples la-f exhibited EC50 values in the PPARδ GAL4 assay < 100 nM.
Biological assay 2: Binding assay Compounds were tested for their ability to bind to PPARδ using a scintillation proximity assay (SPA). The PPARδ LBD (S139-Y441) was expressed in E. coli as an N-terminal GST fusion, with a hexhistidine tag immediately N-terminal to the PPARδ LBD. The purified protein was incubated with 3H GW2433 (for details of synthesis see reference 13) in the presence of varying concentrations of the compound to be tested in the presence of 5 % DMSO. After 1 hour incubation at room temperature Yttrium silicate copper SPA bead were added and the incubation continued for a further 1 hour. After equilibration the radioactivity bound to the beads was determined by scintillation counting. Apparent Ki values were obtained by fitting the data by nonlinear regression analysis, assuming simple competitive binding. Non-specific binding was determined in the presence of excess unlabelled GW2433.
Biological assay 3: C2C12 assay
C2C12 cells (ECACC, Salisbury, UK) were grown in Dulbecco's modified Eagle's medium supplemented with 200units penicillin/50μM streptomycin and 10% fetal calf serum. For cellular stimulation cells were seeded onto 6cm dishes and grown until confluent. La order to induce differentiation the medium was changed to Dulbecco's modified Eagle's medium supplemented with 200units penicillin/50μM streptomycin and 2% horse serum. After 4 day of differentiation the cells were treated with the appropriate compound concentration (in a final of 0.1% DMSO) in the above mentioned medium for 24h. Cells were lysed in 250μl lysis solution and total RNA was extracted according to the manufacturer's protocol (Sigma Aldrich, St Louis, USA). cDNA was synthesized from 500ng total RNA using random hexamers and multiscribe reverse transcriptase (Applied Biosystems) according to the manufacturer's protocol. Real time PCR was performed on the resulting cDNA using Applied Biosystems' Taqman method. In order to assess the beneficial effects of PPARδ agonists on β-oxidation and energy dissipation in muscle cells the following surrogate marker genes were analysed by real time quantitative PCR: FATP, LCAD, CPTl, PDK4, UCP2, UCP3, PGC-Ia and GLUT4. Relative transcription levels were normalised to 18s ribosomal RNA levels.
Biological assay 4: In vivo study
In vivo studies were performed in ob/ob mice approximately 6 weeks old. Animals were fed for 14 days on a high fat diet and randomised, by weight into groups. Compound or vehicle was administered daily by oral gavage for up to 4 weeks. The body weight and food intake was monitored daily and an oral glucose tolerance test performed periodically during the study. Blood samples were also taken for analysis to determine fasting levels of insulin, serum glucose, triglyceride, total and HDL-cholesterol and free fatty acids. Prior to termination all animals were subjected to DEXA scanning to assess body fat content. Following termination liver and muscle (gastrocnemius) tissue were excised from each animal for analysis of RNA. Tissues were homogenised into Trizol solution (Invitrogen) and total RNA was extracted using a standard protocol. RNA was cleaned using the manufaturer's protocol (Sigma Aldrich, St Louis, USA). cDNA was synthesized from 500ng total RNA using random hexamers and multiscribe reverse transcriptase (Applied Biosystems) according to the manufacturer's protocol. Real time PCR was performed on the resulting cDNA using Applied Biosystems' Taqman method. The following genes were analysed to determine whether favourable PPARδ-induced β-oxidation and energy uncoupling can be detected in the skeletal muscle samples: FATB, UCP2, UCP3, PGClα, PDK4, CPTl, LCAD, GLUT4.
It will be understood that the invention is described above by way of example only and modifications may be made while remaining within the scope and spirit of the invention.
REFERENCES
1 J. P. Berger et al, PPARs: therapeutic targets for metabolic disease, Trends Pharmacol Sci. (2005), 26(5), 244-251.
2 M.D. Leibowitz et al., Activation of PPARδ alters lipid metabolism in db/db mice, FEBS Lett. (2000), 473, 333-336.
3 W.R. Oliver et al, Proc. Natl. Acad. ScL USA (2001), 98, 5306-5311.
4 T. Tanaka et al., Activation of peroxisome proliferator-activated receptor delta induces fatty acid beta-oxidation in skeletal muscle and attenuates metabolic syndrome, Proc. Natl. Acad. ScL USA, (2003), 100, 15924-15929.
5 W.-X. Wang et al., Peroxisome-proliferator-activated receptor delta activates fat metabolism to prevent obesity, Cell (2003), 113, 159-170.
6 W.-X. Wang et al., Regulation of Muscle Fiber Type and Running Endurance by PPARδ, PLoS Biol. (2004), 2, 1532-1539.
7 Michalik et al, Impaired skin wound healing in peroxisome proliferator-activated receptor (PPAR)CC and PPARβ mutant mice, J. Cell. Biol (2001), 154, 799-819.
8 M. Schmuth et al, Peroxisome Proliferator-Activated Receptor (PPAR)-β/δ Stimulates Differentiation and Lipid Accumulation in Keratinocytes, J. Invest. Dermatol (2004), 122, 971-983
9 SJ. Roberts-Thompson et al, Effect of the peroxisome proliferator-activated receptorβ activator GW0742 in rat cultured cerebellar granule neurons, J. Neuroscience Research (2004), 77 (2), 240-249.
10 P.E. Polak et al, Protective effects of a peroxisome proliferator-activated receptor-β/δ agom'st in experimental autoimmune encephalomyelitis, J. Neuroimmunol (2005), In Press
11 M. Sznaidman et al, Novel Selective Small Molecule Agonists for Peroxisome Proliferator- Activated Receptor - Synthesis and Biological Activity, Biorg. Med. Chem. Lett. (2003), 13, 1517- 1521.
12 M. Nomura et al, Design, Synthesis, and Evaluation of Substituted Phenylpropanoic Acid Derivatives as Human Peroxisome Proliferator Activated Receptor Activators. Discovery of Potent and Human Peroxisome Proliferator Activated Receptor ctSubtype-Selective Activators, J. Med. Chem. (2003), 46, 3581.
13 P, Brown et al, Identification of peroxisome proliferator-activated receptor ligands from a biased chemical library, Chemistry & Biology (1997), 4, 909-918.

Claims

1. A compound of formula (T) :
wherein:
R is a carboxylic acid or a derivative thereof;
R1 and R2 are independently H or alkyl, or together R1 and R2 form an alkylene group;
L1 is a single bond, NH, NCH3, O, S, CH2 or CH, wherein when L1 is CH the dashed line indicates a double bond and R2 is absent, otherwise the dashed line is a single bond;
R8 and R9 are independently H, halo, alkyl or alkoxy; L2 is O or S; L3 is CH2 or CH2CH2;
R10 and R11 are independently H, halo, CF3, OCF3, alkyl or alkoxy; Y1 is CH or N; Y2 is CH or N; and
R12 and R13 are independently H5 halo, CF3, OCF3, alkyl or alkoxy; or a pharmaceutically acceptable derivative thereof.
2. A compound of claim 1 wherein R is a carboxylic acid.
3. A compound of claim 1 or claim 2 wherein R1 is H or methyl.
4. A compound of any of claims 1 -3 wherein R2 is H or methyl.
5. A compound of any of claims 1 -4 wherein L1 is O, S or NH.
6. A compound of any of claims 1-5 wherein R8 and R9 are both H.
7. A compound of any of claims 1-5 wherein R8 is methyl and R9 is H.
8. A compound of any of claims 1-7 wherein R10 is CF3 substituted at the 4-position and R11 is H.
9. A compound of any of claims 1-8 wherein Y1 is CH.
10. A compound of any of claims 1 -9 wherein Y2 is CH.
11. A compound of any of claims 1-10 wherein R12 and R13 are both H.
12. A compound of any of claims 1-10 wherein R12 is H and R13 is attached to group Y1 (when Y1 is CH) and is alkyl, alkoxy, Cl, F, CF3 or OCF3.
13. A compound of formula (II) :
wherein R1, R2, L1, R8, R9, L2, L3, R10, R11, R12 and R13 are as defined in any one of claims 1-11; or a pharmaceutically acceptable derivative thereof.
14. A compound of claim 1 which is: {2-Methyl-4-[ 1 -(4-trifluoromethyl-phenyl)- 1 H-indazol-3-yhnethylsulfanyl]-phenoxy} -acetic acid;
{4-[5-Fluoro-l-(4-trifluoromethyl-phenyl)-lH-indazol-3-yhnethylsulfanyl]-2-methyl- phenoxy} -acetic acid;
{4-[5-trifluoromethoxy-l-(4-trifiuoromethyl-phenyl)-lH-indazol-3-ymiethylsulfanyl]-2- methyl-phenoxy} -acetic acid;
{4-[5-methoxy-l -(4-trifluoromethyl-phenyl)- 1 H-indazol-3-yhnethylsulfanyl]-2-methyl- phenoxy} -acetic acid;
{4-[5-chloro-l-(4-trifluoromethyl-phenyl)-lH-indazol-3-yhnethylsulfanyl]-2-methyl- phenoxy} -acetic acid; or {4-[5-methyl-l-(4-trifluoromethyl-phenyl)-lH-indazol-3-yhnethylsulfanyl]-2-methyl- phenoxy} -acetic acid.
15. A compound of claim 1 which is:
{4-[7-Fluoro-l-(4-trifluoromethyl-phenyl)-lH-indazol-3-ylmethylsulfanyl]-2-methyl-phenoxy}- acetic acid; {4-[4-Chloro-l-(4-trifluoromethyl-phenyl)-lH-indazol-3-ylmethylsulfanyl]-2-methyl-phenoxy}- acetic acid; {φfό-Cωoro-l-C^trifluoromethyl-pheny^-lH-indazol-S-ylmethylsulfanylJ^-methyl-phenoxy}- acetic acid;
{2-Metibyl-4-[l-(4-trifluorome1hoxy-phenyl)-lH-indazol-3-ylrnethylsulfanyl]-phenoxy}-acetic acid;
2-Me&yl-2- {2-methyl-4-[l -(4-trifluo^ propionic acid;
{4-[l-(4-Chloro-phenyl)-lH-indazol-3-ylmethylsulfanyl]-2-methyl-phenoxy}-acetic acid; {4-[ 1 -(4-Trifluoromethyl-phenyl)- 1 H-indazol-3 -ylmethylsulfanyl]-phenoxy} -acetic acid;
2-Methyl-2- {4-[ 1 -(4-trifluoromethyl-phenyl)- 1 H-indazol-3-ylmethylsulfanyl]-phenoxy} -propionic acid; {4-[7-Fluoro-l-(4-trifluorometiboxy-phenyl)-lH-indazol-3-ylme1iiylsulfanyl]-2-methyl-phenoxy}- acetic acid;
{2-Meώyl-4-[l-(4-trifluoromethyl-phenyl)-lH-pyrazolo[4,3-c]pyridin-3-ylmethylsulfanyl]- phenoxy} -acetic acid hydrochloride;
{2-Methyl-4-[l-(4-trifluoromethoxy-phenyl)-lH-indazol-3-ylmethoxy]-phenoxy}-acetic acid; 2-Methyl-2- {2-methyl-4-[ 1 -(4-trifluoromethoxy-phenyl)- 1 H-indazol-3 -yhnethoxy]-phenoxy} - propionic acid;
{2-Methyl-4-[l-(4-trifluoromethyl-phenyl)-lH-indazol-3-ylmethoxy]-phenoxy}-acetic acid; 2- {2-Methyl-4-[ 1 -(4-trifluoromethoxy-phenyl)- 1 H-indazol-3-yhnethoxy]-phenoxy} -propionic acid; {2-Chloro-4-[l -(4-trifluoromethyl-phenyl)- lH-indazol-3-yhnethoxy]-phenoxy} -acetic acid; {2-Fluoro-4-[l-(4-trifluoromethyl-phenyl)-lH-indazol-3-yknethoxy]-phenoxy}-acetic acid; or
{2-Methyl-4-[ 1 -(4-trifluoromethoxy-phenyl)- 1 H-pyrazolo[4,3-c]pyridin-3 -yhnethoxy]-phenoxy} - acetic acid.
16. A compound of any of claims 1 - 15 for use in therapy.
17. A pharmaceutical composition comprising a compound of any of claims 1-15 in combination with a pharmaceutically acceptable carrier, excipient or diluent.
18. A method for the treatment of a disease or condition mediated by PPARδ, comprising the step of administering a therapeutically effective amount of a compound of any of claims 1-15 to a patient.
19. The use of a compound of any of claims 1-15 in the manufacture of a medicament for the treatment of a disease or condition mediated by PPARδ.
K
20. The method of claim 18 or the use of claim 19 wherein the disease or condition is: metabolic syndrome, or a component thereof, e.g. dyslipidaemia, obesity or insulin resistance; type-II diabetes; wound healing; inflammation; a neurodegenerative disorder; or multiple sclerosis.
21. The method of claim 18 or the use of claim 19 wherein the disease or condition is: coronary heart disease; hypertension; hyperlipidaemia; type-II diabetes mellitus; stroke; osteoarthritis; restrictive pulmonary disease; sleep apnoea or cancer.
22. A crystal of PPARδ and a compound of any of claims 1-15.
7ZJ
EP06779567A 2005-09-29 2006-09-28 Condensed pyrazole derivatives as ppar agonists ii Withdrawn EP1937647A1 (en)

Applications Claiming Priority (3)

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GBGB0519874.2A GB0519874D0 (en) 2005-09-29 2005-09-29 PPAR Agonists II
GB0614578A GB0614578D0 (en) 2006-07-21 2006-07-21 Agonists IIA
PCT/GB2006/003608 WO2007036727A1 (en) 2005-09-29 2006-09-28 Condensed pyrazole derivatives as ppar agonists ii

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WO2009078981A2 (en) * 2007-12-13 2009-06-25 Sri International Ppar-delta ligands and methods of their use
CN103319395B (en) * 2013-04-08 2014-09-24 武汉罗化科技有限公司 Industrialization preparation method for 4-fluoroisatin and product thereby
CN113264931B (en) * 2020-02-17 2022-06-07 成都先导药物开发股份有限公司 Preparation method of 1,4,6, 7-tetrahydro-5H-pyrazolo [4,3-c ] pyridine derivative

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