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WO2004043368A2 - Sulfonamides - Google Patents

Sulfonamides Download PDF

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Publication number
WO2004043368A2
WO2004043368A2 PCT/US2003/035357 US0335357W WO2004043368A2 WO 2004043368 A2 WO2004043368 A2 WO 2004043368A2 US 0335357 W US0335357 W US 0335357W WO 2004043368 A2 WO2004043368 A2 WO 2004043368A2
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WO
WIPO (PCT)
Prior art keywords
phenyl
chloro
methyl
oxy
pyrrolidinyl
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PCT/US2003/035357
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French (fr)
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WO2004043368A3 (en
Inventor
Linda S. Barton
Christopher T. Louer
John Jeffrey Mcatee
Michael J. Neeb
Ning Wang
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Smithkline Beecham Corporation
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Application filed by Smithkline Beecham Corporation filed Critical Smithkline Beecham Corporation
Priority to AU2003295408A priority Critical patent/AU2003295408A1/en
Publication of WO2004043368A2 publication Critical patent/WO2004043368A2/en
Publication of WO2004043368A3 publication Critical patent/WO2004043368A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to sulfonamides, pharmaceutical compositions containing them and their use as urotensin II antagonists
  • cardiovascular homeostasis The integrated control of cardiovascular homeostasis is achieved through a combination of both direct neuronal control and systemic neurohormonal activation. Although the resultant release of both contractile and relaxant factors is normally under stringent regulation, an aberration in this status quo can result in cardiohemodynamic dysfunction with pathological consequences.
  • the principal mammalian vasoactive factors that comprise this neurohumoral axis namely angiotensin-II, endothelin-1, norepinephrine, all function via an interaction with specific G- protein coupled receptors (GPCR).
  • GPCR G- protein coupled receptors
  • this peptide has significant hemodynamic and endocrine actions in diverse end-organ systems and tissues:
  • osmoregulation effects which include the modulation of transepithelial ion (Na + , Cl " ) transport. Although a diuretic effect has been described, such an effect is postulated to be secondary to direct renovascular effects (elevated GFR)
  • Urotensin-II receptor Compounds that antagonize the Urotensin-II receptor may be useful in the treatment of congestive heart failure, stroke, ischemic heart disease (angina, myocardial ischemia), cardiac arrhythmia, hypertension (essential and pulmonary), COPD, fibrosis (e.g. pulmonary fibrosis), restenosis, atherosclerosis, dyslipidemia, asthma, (Hay DWP, Luttmann MA, Douglas SA: 2000, Br J Pharmacol: 131; 10-12) neurogenic inflammation and metabolic vasculopathies all of which are characterized by abnormal vasoconstriction and/or myocardial dysfunction.
  • Urotensin antagonists may provide end organ protection in hypersensitive cohorts in addition to lowering blood pressure.
  • U-II and GPR14 are both expressed within the mammalian CNS (Ames et. al. Nature 1999, 401, 282), they also may be useful in the treatment of addiction, schizophrenia, cognitive disorders/Alzheimers disease, (Gartlon J. Psychopharmacology (Berl) 2001 June; 155(4):426-33), impulsivity, anxiety, stress, depression, pain, migraine, neuromuscular function, parkinsons, movement disorders, sleep-wake cycle, and incentive motivation (Clark et al.Brain Research 923 (2001) 120-127. Functional U-II receptors are expressed in rhabdomyosarcomas cell lines and therefore may have oncological indications.
  • Urotensin may also be implicated in various metabolic diseases such as diabetes (Ames et. al. Nature 1999, 401, 282, Nothacker et al., Nature Cell Biology 1: 383-385, 1999) and in various gastrointestinal disorders, bone, cartilage, and joint disorders (e.g. arthritis and osteoporosis); and genito-urinary disorders. Therefore, these compounds may be useful for the prevention (treatment) of gastric reflux, gastric motility and ulcers, arthritis, osteoporosis and urinary incontinence.
  • diabetes Ames et. al. Nature 1999, 401, 282, Nothacker et al., Nature Cell Biology 1: 383-385, 1999
  • these compounds may be useful for the prevention (treatment) of gastric reflux, gastric motility and ulcers, arthritis, osteoporosis and urinary incontinence.
  • this invention provides for sulfonamides and pharmaceutical compositions containing them.
  • this invention provides for the use of sulfonamides as antagonists of urotensin II, and as inhibitors of urotensin II.
  • this invention provides for the use of sulfonamides for treating conditions associated with urotensin II imbalance.
  • this invention provides for the use of sulfonamides for the treatment of congestive heart failure, stroke, ischemic heart disease (angina, myocardial ischemia), cardiac arrhythmia, hypertension (essential and pulmonary), renal disease (acute and chronic renal failure/end stage renal disease) along with peripheral vascular disease (male erectile dysfunction, diabetic retinopathy, intermittent claudication/ischemic limb disease) and ischemic/hemorrhagic stroke, COPD, restenosis, asthma, neurogenic inflammation, migraine, metabolic vasculopathies, bone/cartilage/joint diseases, arthritis and other inflammatory diseases, fibrosis (e.g.
  • pulmonary fibrosis sepsis
  • atherosclerosis dyslipidemia
  • addiction schizophrenia, cognitive disorders/Alzheimers disease, impulsivity, anxiety, stress, depression, parkinsons, movement disorders, sleep-wake cycle, incentive motivation, pain, neuromuscular function, diabetes, gastric reflux, gastric motility disorders, ulcers and genitourinary diseases.
  • the urotensin antagonist may be administered alone or in conjunction with one or more other therapeutic agents, said agents being selected from the group consisting of endothelin receptor antagonists, angiotensin converting enzyme (ACE) inhibitors, A-IJ receptor antagonists, vasopeptidase inhibitors, diuretics, digoxin, and dual non-selective ⁇ -adrenoceptor and c -adrenoceptor antagonists.
  • ACE angiotensin converting enzyme
  • the present invention provides for compounds of Formula (I):
  • R j is hydrogen, halogen, or C . alkyl
  • Ar is phenyl, pyrazolyl, thiazolyl, dibenzofuranyl, benzodioxolyl, quinolinyl, or naphthalenyl, all of which may be substituted or unsubstituted by one or two of the following: halogen, CN, SCC j .6 alkyl), CF 3 , OCF 3 , SCF3, C . alkyl, Ph, OPh, C g alkoxy, C0 2 (C 1 . 6 alkyl), NR 5 R 6 , NR 5 COR 6 , CONR 5 R 6 , COR5, N0 2 , ⁇ .3 alkylenedioxy, CH 2 OH or CH 2 CN;
  • R 2 is hydrogen, halogen, or CF3.
  • R5 and Rg are independently hydrogen or C . alkyl
  • R9 is hydrogen or Cj.g alkyl; or a pharmaceutically acceptable salt thereof.
  • alkyl includes all straight chain and branched isomers. Representative examples thereof include methyl, ethyl, n-propyl, wo-propyl, n-butyl, sec-butyl, wo-butyl, t-butyl, n-pentyl and n-hexyl.
  • halogen' and halo' include fluorine, chlorine, bromine and iodine, and fluoro, chloro, bromo and iodo, respectively.
  • Ar is phenyl.
  • Preferred substituents for Ar are hydrogen, CN, halogen, CF3, C0 2 CH3, C ⁇ _ 2 alkoxy,
  • R 2 is preferably hydrogen, Cl, or CF3.
  • R j is preferably hydrogen, BR, or Cl.
  • R9 is preferably Cj_ 2 alkyl.
  • Preferred compounds are : 5-chloro-N-[3- ⁇ [(3R)-l-methyl-3-pyrrolidinyl]oxy ⁇ -4-(trifluoromethyl)phenyl]-3-[4- (trifluoromethyl)phenyl]-2-thiophenesulfonamide;
  • 2-thiophenesulfonamide 4-(4-biphenylyl)-5-chloro-N-(4-chloro-3- ⁇ [(3R)-l-methyl-3-pyrrolidinyl]oxy ⁇ phenyl)-2- thiophenesulfonamide; 5-chloro-N-(4-chloro-3- ⁇ [(3R)-l-methyl-3-pyrrolidinyl]oxy ⁇ phenyl)-4-[4-(phenyloxy)phenyl]- 2-thiophenesulfonamide;
  • 2-thiophenesulf onamide N-[3- ⁇ [(3R)-l-methyl-3-pyrrolidinyl]oxy ⁇ -4-(trifluoromethyl)phenyl]-5-phenyl-2- thiophenesulfonamide; 5-[3-(methyloxy)phenyl]-N-[3- ⁇ [(3R)-l-methyl-3-pyrrolidinyl]oxy ⁇ -4- (trifluoromethyl)phenyl]-2-thiophenesulfonamide;
  • More Preferred compounds are: 5-chloro-3-(4-cyanophenyl)-N-[3- ⁇ [(3R)-l-methyl-3-pyrrolidinyl]oxy ⁇ -4-
  • the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active form. All of these compounds and their diastereoisomers are contemplated to be within the scope of the present invention.
  • Compounds of Formula (I) may be prepared as outlined in Scheme 1.
  • Sulfonyl chlorides when not commercially available, can prepared by methods known in the art: Shahripour, A.B. et al. Bioorg. Med. Chem. 2002, 10, 31; Cross, P.E. et al. /. Med. Chem. 1978, 21, 845; Huntress et al J. Amer. Chem. Soc. 1941, 63, 3446; Hashimoto, H. et al J. Med. Chem. 2002, 45, 1511; O'Brien, P. M. et al. J.Me ⁇ Chem. 2000, 43, 156; Brandish, D. J.Med.Chem. 1999, 22, 4584.
  • Compounds of Formula (I) and their pharmaceutically acceptable salts may be administered in a standard manner for the treatment of the indicated diseases, for example orally, parenterally, sub-lingually, transdermally, rectally, via inhalation or via buccal administration.
  • a syrup formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, peanut oil, olive oil, glycerine or water with a flavoring or coloring agent.
  • a liquid carrier for example, ethanol, peanut oil, olive oil, glycerine or water with a flavoring or coloring agent.
  • any pharmaceutical carrier routinely used for preparing solid formulations may be used. Examples of such carriers include magnesium stearate, terra alba, talc, gelatin, agar, pectin, acacia, stearic acid, starch, lactose and sucrose.
  • compositions are in the form of a capsule, any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatin capsule shell.
  • composition is in the form of a soft gelatin shell capsule
  • any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example aqueous gums, celluloses, silicates or oils and are incorporated in a soft gelatin capsule shell.
  • Typical parenteral compositions consist of a solution or suspension of the compound or salt in a sterile aqueous or non-aqueous carrier optionally containing a parenterally acceptable oil, for example polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil, or sesame oil.
  • compositions for inhalation are in the form of a solution, suspension or emulsion that may be administered as a dry powder or in the form of an aerosol using a conventional propellant such as dichlorodifluoromethane or trichlorofluoromethane.
  • a typical suppository formulation comprises a compound of Formula (1) or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent, for example polymeric glycols, gelatins, cocoa-butter or other low melting vegetable waxes or fats or their synthetic analogues.
  • Typical transdermal formulations comprise a conventional aqueous or non-aqueous vehicle, for example a cream, ointment, lotion or paste or are in the form of a medicated plaster, patch or membrane.
  • the composition is in unit dosage form, for example a tablet, capsule or metered aerosol dose, so that the patient may administer to themselves a single dose.
  • Each dosage unit for oral administration contains suitably from 0.1 mg to 500 mg/Kg, and preferably from 1 mg to 100 mg/Kg, and each dosage unit for parenteral administration contains suitably from 0.1 mg to 100 mg, of a compound of Formula (I) or a pharmaceutically acceptable salt thereof calculated as the free acid.
  • Each dosage unit for intranasal administration contains suitably 1-400 mg and preferably 10 to 200 mg per person.
  • a topical formulation contains suitably 0.01 to 1.0% of a compound of Formula (I).
  • the daily dosage regimen for oral administration is suitably about 0.01 mg/Kg to 40 mg/Kg, of a compound of Formula (I) or a pharmaceutically acceptable salt thereof calculated as the free acid.
  • the daily dosage regimen for parenteral administration is suitably about 0.001 mg/Kg to 40 mg/Kg, of a compound of the Formula (I) or a pharmaceutically acceptable salt thereof calculated as the free acid.
  • the daily dosage regimen for intranasal administration and oral inhalation is suitably about 10 to about 500 mg/person.
  • the active ingredient may be administered from 1 to 6 times a day, sufficient to exhibit the desired activity.
  • sulphonamide analogs may be used for the treatment of congestive heart failure, stroke, ische ic heart disease (angina, myocardial ischemia), cardiac arrhythmia, hypertension (essential and pulmonary), renal disease (acute and chronic renal failure/end stage renal disease) along with peripheral vascular disease (male erectile dysfunction, diabetic retinopathy, intermittent claudication/ischemic limb disease) and ischemic/hemorrhagic stroke, COPD, restenosis, asthma, neurogenic inflammation, migraine, metabolic vasculopathies, bone/cartilage/joint diseases, arthritis and other inflammatory diseases, fibrosis (e.g.
  • the urotensin antagonist may be administered alone or in conjunction with one or more other therapeutic agents, said agents being selected from the group consisting of endothelin receptor antagonists, angiotensin converting enzyme (ACE) inhibitors, A-D. receptor antagonists, vasopeptidase inhibitors, diuretics, digoxin, and dual non-selective D-adrenoceptor and o. ⁇ -adrenoceptor antagonists.
  • ACE angiotensin converting enzyme
  • HEK-293 cell membranes containing stable cloned human and rat GPR-14 (20 ug/assay) were incubated with 200 pM [1251] h-U-II (200 Ci/mmol "1 in the presence of increasing concentrations of test compounds in DMSO (0.1 nM to 10 uM), in a final incubation volume of 200 ul (20 mM Tris-HCl, 5 mM MgC12). Incubation was done for 30 minutes at room temperature followed by filtration GF/B filters with Brandel cell harvester.
  • HEK-293-GPR14 cells in T150 flask were prelabeled overnight with 1 uCi myo-[ 3 H] inositol per ml of inositol free Dulbecco's modified Eagel's medium. After labeling, the cells were washed twice with Dulbecco's phosphate-buffered saline (DPBS) and then incubated in DPBS containing 10 mM LiCl for 10 min at 37°C.
  • DPBS Dulbecco's phosphate-buffered saline
  • the experiment was initiated by the addition of increasing concentrations of h-U-II (1 pM to l ⁇ M ) in the absence and presence of three different concentrations (0.3, 1 and 10 uM) of test compounds and the incubation continued for an additional 5 min at 37°C after which the reaction was terminated by the addition of 10% (final concentration) trichloroacetic acid and centrifugation.
  • the supernatants were neutralized with lOOul of 1M Trizma base and the inositol phosphates were separated on AG 1-X8 columns (0.8 ml packed, 100-200 mesh) in formate phase. Inositol monophosphate was eluted with 8 ml of 200 mM ammonium formate.
  • Example 565 Using the general procedure oultined in Example 565, the following compounds were prepared.
  • the reaction mixture was placed under argon atmosphere and heated to 120 °C in the microwave for 600 sec.
  • the solvent was removed by evaporation and the residue was purified by preparative HPLC (Xterra Prep RP, 75 x 30 mm, 25 mL/min, A: acetonitrile B: water, 0.1% TFA; A: 10 to 90% during 10 min, UN detection at 214 nm) to give 12 mg (9%) of the title compound as a free base.
  • the hydrochloride salt was formed from by dissolving the substrate in methanol, adding hydrochloric acid in ether (IM) and evaporating the volatile materials to give a solid.
  • Aniline CF3 (80 mg, 0.31 mmol) was dissolved in 2 mL of methylene chloride and treated with methyl 3-(chlorosulfonyl)-4-phenyl-5-(trifluoromethyl)-2-thiophenecarboxylate (118 mg, 0.307 mmol) and pyridine (0.025 mL, 0.31 mmol) with vigorous stirring at room temperature. The reaction mixture was maintained for 18 hours, and then the solvent was removed under reduced pressure.
  • Examples 210-214 The following examples were prepared according to the representative procedure in Example 209 using the appropriate sulfonyl chlorides as starting material, and in some cases using acetonitrile rather than methylene chloride as the solvent.
  • EXAMPLE 215 Formulations for pharmaceutical use incorporating compounds of the present invention can be prepared in various forms and with numerous excipients. Examples of such formulations are given below.
  • Step 1 Blend ingredients No. 1, No. 2, No. 3 and No. 4 in a suitable mixer/blender.
  • Step 2 Add sufficient water portion-wise to the blend from Step 1 with careful mixing after each addition. Such additions of water and mixing until the mass is of a consistency to permit its conversion to wet granules.
  • Step 3 The wet mass is converted to granules by passing it through an oscillating granulator using a No. 8 mesh (2.38 mm) screen.
  • Step 4 The wet granules are then dried in an oven at 140°F (60°C) until dry.
  • Step 5 The dry granules are lubricated with ingredient No. 5.
  • Step 6 The lubricated granules are compressed on a suitable tablet press.
  • a compound of Formula I (1 mg to 100 mg) is aerosolized from a metered dose inhaler to deliver the desired amount of drag per use.
  • a pharmaceutical composition for parenteral administration is prepared by dissolving an appropriate amount of a compound of formula I in polyethylene glycol with heating. This solution is then diluted with water for injections Ph Eur. (to 100 ml). The solution is then sterilized by filtration through a 0.22 micron membrane filter and sealed in sterile containers.
  • Ph Eur. to 100 ml
  • the above specification and Examples fully disclose how to make and use the compounds of the present invention.
  • the present invention is not limited to the particular embodiments described hereinabove, but includes all modifications thereof within the scope of the following claims.
  • the various references to journals, patents and other publications which are cited herein comprise the state of the art and are incorporated herein by reference as though fully set forth.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Abstract

The present invention relates to sulfonamides, pharmaceutical compositions containing them, and their use as antagonists of urotensin II.

Description

SULFONAMIDES
FIELD OF THE INVENTION
The present invention relates to sulfonamides, pharmaceutical compositions containing them and their use as urotensin II antagonists
BACKGROUND OF THE INVENTION
The integrated control of cardiovascular homeostasis is achieved through a combination of both direct neuronal control and systemic neurohormonal activation. Although the resultant release of both contractile and relaxant factors is normally under stringent regulation, an aberration in this status quo can result in cardiohemodynamic dysfunction with pathological consequences.
The principal mammalian vasoactive factors that comprise this neurohumoral axis, namely angiotensin-II, endothelin-1, norepinephrine, all function via an interaction with specific G- protein coupled receptors (GPCR). Urotensin-II, represents a novel member of this neurohumoral axis.
In the fish, this peptide has significant hemodynamic and endocrine actions in diverse end-organ systems and tissues:
• smooth muscle contraction both vascular and non-vascular in origin including smooth muscle preparations from the gastrointestinal tract and genitourinary tract. Both pressor and depressor activity has been described upon systemic administration of exogenous peptide
• osmoregulation: effects which include the modulation of transepithelial ion (Na+, Cl") transport. Although a diuretic effect has been described, such an effect is postulated to be secondary to direct renovascular effects (elevated GFR)
• metabolism: urotensin-II influences prolactin secretion and exhibits a lipolytic effect in fish (activating triacylglycerol lipase resulting in the mobilization of non-esterified free fatty acids)
(Pearson, et. al. Proc. Natl. Acad. Sci. (U.S.A.) 1980, 77, 5021; Conlon, et. al. J. Exp. Zool. 1996, 275, 226.) In studies with human Urotensin-II it was found that it:
• was an extremely potent and efficacious vasoconstrictor
• exhibited sustained contractile activity that was extremely resistant to wash out
• had detrimental effects on cardiac performance (myocardial contractility) Human Urotensin-II was assessed for contractile activity in the rat-isolated aorta and was shown to be the most potent contractile agonist identified to date. Based on the in vitro pharmacology and in vivo hemodynamic profile of human Urotensin-II it plays a pathological role in cardiovascular diseases characterized by excessive or abnormal vasoconstriction and myocardial dysfunction. (Ames et. al. Nature 1999, 401, 282; Douglas & Ohlstein (2000). Trends Cardiovasc. Med., 10(6):229-37).
Compounds that antagonize the Urotensin-II receptor may be useful in the treatment of congestive heart failure, stroke, ischemic heart disease (angina, myocardial ischemia), cardiac arrhythmia, hypertension (essential and pulmonary), COPD, fibrosis (e.g. pulmonary fibrosis), restenosis, atherosclerosis, dyslipidemia, asthma, (Hay DWP, Luttmann MA, Douglas SA: 2000, Br J Pharmacol: 131; 10-12) neurogenic inflammation and metabolic vasculopathies all of which are characterized by abnormal vasoconstriction and/or myocardial dysfunction. Urotensin antagonists may provide end organ protection in hypersensitive cohorts in addition to lowering blood pressure.
Since U-II and GPR14 are both expressed within the mammalian CNS (Ames et. al. Nature 1999, 401, 282), they also may be useful in the treatment of addiction, schizophrenia, cognitive disorders/Alzheimers disease, (Gartlon J. Psychopharmacology (Berl) 2001 June; 155(4):426-33), impulsivity, anxiety, stress, depression, pain, migraine, neuromuscular function, parkinsons, movement disorders, sleep-wake cycle, and incentive motivation (Clark et al.Brain Research 923 (2001) 120-127. Functional U-II receptors are expressed in rhabdomyosarcomas cell lines and therefore may have oncological indications. Urotensin may also be implicated in various metabolic diseases such as diabetes (Ames et. al. Nature 1999, 401, 282, Nothacker et al., Nature Cell Biology 1: 383-385, 1999) and in various gastrointestinal disorders, bone, cartilage, and joint disorders (e.g. arthritis and osteoporosis); and genito-urinary disorders. Therefore, these compounds may be useful for the prevention (treatment) of gastric reflux, gastric motility and ulcers, arthritis, osteoporosis and urinary incontinence.
SUMMARY OF THE INVENTION
In one aspect this invention provides for sulfonamides and pharmaceutical compositions containing them. In a second aspect, this invention provides for the use of sulfonamides as antagonists of urotensin II, and as inhibitors of urotensin II.
In another aspect, this invention provides for the use of sulfonamides for treating conditions associated with urotensin II imbalance. In yet another aspect, this invention provides for the use of sulfonamides for the treatment of congestive heart failure, stroke, ischemic heart disease (angina, myocardial ischemia), cardiac arrhythmia, hypertension (essential and pulmonary), renal disease (acute and chronic renal failure/end stage renal disease) along with peripheral vascular disease (male erectile dysfunction, diabetic retinopathy, intermittent claudication/ischemic limb disease) and ischemic/hemorrhagic stroke, COPD, restenosis, asthma, neurogenic inflammation, migraine, metabolic vasculopathies, bone/cartilage/joint diseases, arthritis and other inflammatory diseases, fibrosis (e.g. pulmonary fibrosis), sepsis, atherosclerosis, dyslipidemia, addiction, schizophrenia, cognitive disorders/Alzheimers disease, impulsivity, anxiety, stress, depression, parkinsons, movement disorders, sleep-wake cycle, incentive motivation, pain, neuromuscular function, diabetes, gastric reflux, gastric motility disorders, ulcers and genitourinary diseases. The urotensin antagonist may be administered alone or in conjunction with one or more other therapeutic agents, said agents being selected from the group consisting of endothelin receptor antagonists, angiotensin converting enzyme (ACE) inhibitors, A-IJ receptor antagonists, vasopeptidase inhibitors, diuretics, digoxin, and dual non-selective β-adrenoceptor and c -adrenoceptor antagonists.
Other aspects and advantages of the present invention are described further in the following detailed description of the preferred embodiments thereof.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides for compounds of Formula (I):
Figure imgf000004_0001
Formula (I)
wherein: Rj is hydrogen, halogen, or C . alkyl;
Ar is phenyl, pyrazolyl, thiazolyl, dibenzofuranyl, benzodioxolyl, quinolinyl, or naphthalenyl, all of which may be substituted or unsubstituted by one or two of the following: halogen, CN, SCCj.6 alkyl), CF3, OCF3, SCF3, C . alkyl, Ph, OPh, C g alkoxy, C02(C1.6 alkyl), NR5R6, NR5COR6, CONR5R6, COR5, N02, ^.3 alkylenedioxy, CH2OH or CH2CN;
R2 is hydrogen, halogen, or CF3.
R5 and Rg are independently hydrogen or C . alkyl;
R9 is hydrogen or Cj.g alkyl; or a pharmaceutically acceptable salt thereof.
When used herein, the term "alkyl" includes all straight chain and branched isomers. Representative examples thereof include methyl, ethyl, n-propyl, wo-propyl, n-butyl, sec-butyl, wo-butyl, t-butyl, n-pentyl and n-hexyl.
When used herein, the terms halogen' and halo' include fluorine, chlorine, bromine and iodine, and fluoro, chloro, bromo and iodo, respectively. Preferably Ar is phenyl. Preferred substituents for Ar are hydrogen, CN, halogen, CF3, C02CH3, Cι_2alkoxy,
C=0, NHCOCH3, CH20, Cι.2a]kyl„ SCH3, O-CF3, CH2CN, -C(CH3)3, NH3, Ph, OPh,
N02, CH2OH, or N-C(O)0-CH(CH3)3. R2 is preferably hydrogen, Cl, or CF3.
Rj is preferably hydrogen, BR, or Cl.
R9 is preferably Cj_2 alkyl.
Preferred compounds are : 5-chloro-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-(trifluoromethyl)phenyl]-3-[4- (trifluoromethyl)phenyl]-2-thiophenesulfonamide;
5,5'-dichloro-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-(trifluoromethyl)phenyl]-2,3 - bithiophene-2'-sulforiamide; 5-chloro-3-(2,4-dichlorophenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4- (trifluoromethyl)phenyl]-2-thiophenesulfonamide; 5-chloro-3-(2,4-difluorophenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4- (trifluoromethyl)phenyl]-2-thiophenesulfonamide; 5-chloro-3-(2-methylphenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4- (trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-3-(2,5-dimethylphenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-3-(2-chlorophenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-3-[5-chloro-2-(methyloxy)phenyl]-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-3-(2,5-difluorophenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-3-[2-methyl-4-(methyloxy)phenyl]-N-t3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4- (trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-3-dibenzo[b,d]furan-2-yl-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-3-[2-methyl-8-(methyloxy)-5-quinolinyl]-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-
4-(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-3-(6-methyl-l,3-benzodioxol-5-yl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-(trifluoromethyl)phenyl]-3-{4-
[(trifluoromethyl)oxy]phenyl}-2-thiophenesulfonamide; -chloro-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-(trifluoromethyl)phenyl]-3-[2- (trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-4-[3-(cyanomethyl)phenyl]-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-4-[4-(cyanomethyl)phenyl]-N-[3-{ [(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-3-[2-(cyanomethyl)phenyl]-N-[3-{ [(3R)- 1 -methyl-3-pyrrolidinyl]oxy } -4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-3-[4-(cyanomethyl)phenyl]-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-3-[4-(l,l-dimethylethyl)phenyl]-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4- (trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-3-[4-(dimethylamino)phenyl]-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -[5-chloro-2-({ [3-{ [(3R)-l-methyl-3-ρyrrolidinyl]oxy }-4-
(trifluoromethyl)phenyl]amino } sulfonyl)-3-thienyl]benzamide; 5-chloro-3-(3-chloro-4-fluorophenyl)-N-(4-chloro-3-{[(3R)-l-methyl-3- pyrrolidinyl]oxy}phenyl)-2-thiophenesulfonamide; 5-chloro-4-(3-chloro-4-fluorophenyl)-N-(4-chloro-3-{[(3S)-l-methyl-3- pyrrolidinyl]oxy}phenyl)-2-thiophenesulfonamide; 4-chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-5-[4-
(cyanomethyl)phenyl] -2-thiophenesulf onamide ; 4-chloro-N-(4-chloro-3- { [(3R)- 1 -methyl-3-pyrrolidinyl] oxy }phenyl)-5-(4-methylphenyl)-2- thiophenesulfonamide; 5-chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-4-phenyl-2- thiophenesulfonamide;
4-(2-aminophenyl)-5-chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-2- thiophenesulf onamide ; 4-(3-aminophenyl)-5-chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-2- thiophenesulfonamide; 5-chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-4-[4-(methyloxy)phenyl]-
2-thiophenesulfonamide; 4-(4-biphenylyl)-5-chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-2- thiophenesulfonamide; 5-chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-4-[4-(phenyloxy)phenyl]- 2-thiophenesulfonamide;
5-chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-4-[4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; N-{3-[2-chloro-5-({ [3-{ [(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]amino } sulfonyl)-3-thienyl]phenyl } acetamide; 5-chloro-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-(trifluoromethyl)phenyl]-4-[4-
(methylthio)phenyl]-2-thiophenesulfonamide; 5-chloro-4-[2-methyl-8-(methyloxy)-5-quinolinyl]-N-[3-{ [(3R)-l-methyl-3-pyrrolidinyl]oxy}-
4-(trifluoromethyl)phenyl]-2-thiophenesulfonamide; 5-chloro-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-(trifluoromethyl)phenyl]-4-[2- (trifluoromethyl)phenyl]-2-thiophenesulfonamide;
5-chloro-4-dibenzo[b,d]furan-4-yl-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; 5-chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-4-[2-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; N-[3-(2-chloro-5-{[(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)amino]sulfonyl}-
3-thienyl)phenyl]acetamide; 5-chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-4-[2-methyl-8-
(methyloxy)-5-quinolinyl]-2-thiophenesulfonamide; 4-chloro-5-[3-(hydroxymethyl)phenyl]-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; 5-(3-aminophenyl)-4-chloro-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; 4-chloro-5-dibenzo[b,d]furan-4-yl-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4- (trifluoromethyl)phenyl]-2-thiophenesulfonamide;
4-chloro-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-(trifluoromethyl)phenyl]-5-[4-
(methylthio)phenyl]-2-thiophenesulfonamide; 4-chlorό-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-(trifluoromethyl)phenyl]-5-[2-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; N-[3-{ [(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-(trifluoromethyl)phenyl]-5-[4-
(methylthio)phenyl]-2-thiophenesulfonamide; 5-(6-methyl-l,3-benzodioxol-5-yl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; 5-[3-(cyanomethyl)phenyl]-N-[3-{ [(3R)-l-methyl-3-pyrrolidinyl]oxy}-4- (trifluoromethyl)phenyl]-2-thiophenesulfonamide;
5-[4-(cyanomethyl)phenyl]-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; 4-chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-5-[2-
(trifluororriethyl)phenyl]-2-thiophenesulfonamide; 4-chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-5-dibenzo[b,d]furan-4-yl-
2-thiophenesulf onamide ; N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-(trifluoromethyl)phenyl]-5-phenyl-2- thiophenesulfonamide; 5-[3-(methyloxy)phenyl]-N-[3-{ [(3R)-l-methyl-3-pyrrolidinyl]oxy}-4- (trifluoromethyl)phenyl]-2-thiophenesulfonamide;
N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-(trifluoromethyl)phenyl]-5-[3-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; 2,5-dichloro-4-[3-(methyloxy)phenyl]-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-3-thiophenesulfonamide; 5-chloro-4-(3-cyanophenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; 5-chloro-4-[3-(methyloxy)phenyl]-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; 5-chloro-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-(trifluoromethyl)phenyl]-4-[3-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; 5-chloro-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-(trifluoromethyl)phenyl]-3-(2- naphthalenyl)-2-thiophenesulfonamide; 5-chloro-3-(3,5-difluorophenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4- (trifluoromethyl)phenyl]-2-thiophenesulfonamide; ;
3-[5-chloro-2-({ [3-{ [(3R)-l-methyl-3-pyrrolidinyl]oxy }-4-
(trifluoromethyl)phenyl]amino}sulfonyl)-3-thienyl]benzoic acid; 5-chloro-3-(3-chlorophenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl] -2-thiophenesulf onamide ; 5-chloro-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-(trifluoromethyl)phenyl]-3-{3- t(trifluoromethyl)oxy]phenyl } -2-thiophenesulf onamide ; 5-chloro-3-(3,4-dichlorophenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; 5-chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-3-(3-cyanophenyl)-2- thiophenesulfonamide;
5-chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-3-[3-(methyloxy)phenyl]-
2-thiophenesulfonamide; 5-chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-3-(3-chlorophenyl)-2- thiophenesulfonamide; 5-chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-3-(3-fluorophenyl)-2- thiophenesulfonamide; N-{3-[3-chloro-5-({ [3-{ [(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl] amino } sulf onyl)-2-thienyl]phenyl } acetamide ; N-{2-[2-chloro-5-({ [3-{ [(3R)-l-methylpyrrolidin-3-yl]oxy}-4- (trifluoromethyl)phenyl]amino}sulfonyl)-3-thienyl]phenyl}acetamide;
Methyl 3-({ [3-{ [(3R)-l-methyl-3-pyrrolidinyl]oxy }-4-(trifluoromethyl) phenyl]amino}sulfonyl)-4-phenyl-5-(trifluoromethyl)-2-thiophenecarboxylate; ; N-[3-{ [(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-(trifluoromethyl)phenyl]-4-phenyl-5-
(trifluoromethyl)-3-thiophenesulfonamide; 3-(3-cyanophenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-(trifluoromethyl)phenyl]-2- thiophenesulfonamide; and N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-(trifluoromethyl)phenyl]-5-(2-methyl-l,3-thiazol-
4-yl)-2-thiophenesulfonamide.
More Preferred compounds are: 5-chloro-3-(4-cyanophenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; 3-(4-acetylphenyl)-5-chloro-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4- (trifluoromethyl)phenyl]-2-thiophenesulfonamide;
5-chloro-3-(4-chlorophenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; 5-chloro-3-[4-(methyloxy)phenyl]-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; 5-chloro-3-(4-formylphenyl)-N-[3-{ [(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; N-{4-[5-chloro-2-({ [3-{ [(3R)-l-methyl-3-pyrrolidinyl]oxy }-4-
(trifluoromethyl)phenyl]amino}sulfonyl)-3-thienyl]phenyl}acetamide; 5-chloro-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-(trifluoromethyl)phenyl]-4-[4- (trifluoromethyl)phenyl]-2-thiophenesulfonamide;
4-(4-acetylphenyl)-5-chloro-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; 5-chloro-4-(4-fluorophenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; 5-chloro-4-[4-(methyloxy)phenyl]-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; N-{4-[2-chloro-5-({ [3-{ [(3R)-l-methyl-3-pyrrolidinyl]oxy }-4-
(trifluoromethyl)phenyl]amino}sulfonyl)-3-thienyl]phenyl}acetamide; ; 5-chloro-4-(2,4-dichlorophenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4- (trifluoromethyl)phenyl]-2-thiophenesulfonamide;
5-chloro-4-(2,4-difluorophenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; N-{3-[5-chloro-2-({[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]amino}sulfonyl)-3-thienyl]phenyl}acetamide; -chloro-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-(trifluoromethyl)phenyl]-3-[4-
(methylthio)phenyl]-2-thiophenesulfonamide; -chloro-4-[4-( 1 , 1 -dimethylethyl)phenyl]-N-[3-{ [(3R)- 1 -methyl-3-pyrrolidinyl]oxy }-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-4-[4-(dimethylamino)phenyl]-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-5-[3-fluoro-4-
(methyloxy)phenyl]-2-thiophenesulfonamide; -chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-5-(2-fluorophenyl)-2- thiophenesulfonamide; -chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-4-(4-cyanophenyl)-2- thiophenesulf onamide ; -chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-4-(4-chlorophenyl)-2- thiophenesulfonamide; -chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-4-(4-fluorophenyl)-2- thiophenesulfonamide; -chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-4-[3-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-4-(3-chlorophenyl)-2- thiophenesulfonamide; -chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-4-[3-(methyloxy)phenyl]-
2-thiophenesulfonamide; -Chloro-4-(2-methylphenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-4-(2,5-dimethylphenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-4-[2-(methyloxy)phenyl]-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-(trifluoromethyl)phenyl]-4-{4- [(trifluoromethyl)oxy]phenyl}-2-thiophenesulfonamide; -chloro-4-[2-methyl-4-(methyloxy)phenyl]-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -[3,4-bis(methyloxy)phenyl]-5-chloro-N-(4-chloro-3-{[(3R)-l-methyl-3- pyrrolidinyl]oxy}phenyl)-2-thiophenesulfonamide; 5-chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-4-[2-methyl-4-
(methyloxy)phenyl]-2-thiophenesulfonamide; 5-chloro-4-[4-(hydroxymethyl)phenyl]-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; 5-chloro-4-[3-(hydroxymethyl)phenyl]-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; 4-(4-aminophenyl)-5-chloro-N- [3- { [(3R)- 1 -methyl-3-pyrrolidinyl] oxy } -4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; 4-(2-aminophenyl)-5-chloro-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4- (trifluoromethyl)phenyl]-2-thiophenesulfonamide;
5-chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-4-[2-
(cyanomethyl)phenyl]-2-thiophenesulfonamide; N-(4-bromo-3-{[(3R)-l-methylpyrrolidin-3-yl]oxy}phenyl)-5-chloro-4-(3-chloro-4- fluorophenyl)thiophene-2-sulfonamide; 4-chloro-5-[3-(cyanomethyl)phenyl]-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; 4-chloro-N-[3-{ [(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-(trifluoromethyl)phenyl]-5-{4-
[(trifluoromethyl)oxy]phenyl}-2-thiophenesulfonamide; 4-chloro-5-[2-methyl-8-(methyloxy)-5-quinolinyl]-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}- 4-(trifluoromethyl)phenyl]-2-thiophenesulfonamide;
N-{3-[5-({[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-(trifluoromethyl)phenyl]amino}sulfonyl)-
2-thienyl]phenyl } acetamide ; N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-(trifluoromethyl)phenyl]-5-{4-
[(trifluoromethyl)oxy]phenyl}-2-thiophenesulfonamide; 5-[2-(cyanomethyl)phenyl]-N-[3-{ [(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; 4-chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-5-(4-chlorophenyl)-2- thiophenesulfonamide; 5-[3,5-bis(trifluoromethyl)phenyl]-4-chloro-N-(4-chloro-3-{[(3R)-l-methyl-3- pyrrolidinyl]oxy}phenyl)-2-thiophenesulfonamide;
4-chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-5-(4-fluorophenyl)-2- thiophenesulf onamide ; 4-chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}ρhenyl)-5-[4-(methyloxy)phenyl]-
2-thiophenesulfonamide; -chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-5-(2-methylphenyl)-2- thiophenesulfonamide; -chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-5-[2-methyl-4-
(methyloxy)phenyl]-2-thiophenesulfonamide; -chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-5-(4-cyanophenyl)-2- thiophenesulfonamide; -chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-5-{3-
[(trifluoromethyl)oxy]phenyl } -2-thiophenesulf onamide ; -[3,4-bis(methyloxy)phenyl]-4-chloro-N-(4-chloro-3-{[(3R)-l-methyl-3- pyrrolidinyl]oxy}phenyl)-2-thiophenesulfonamide; -chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-5-[2-
(cyanomethyl)phenyl]-2-thiophenesulfonamide; -(3-cyanophenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-(trifluoromethyl)phenyl]-2- thiophenesulfonamide; -bromo-2-chloro-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-(trifluoromethyl)phenyl]-5-[3-
(trifluoromethyl)phenyl]-3-thiophenesulfonamide; -chloro-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-(trifluoromethyl)phenyl]-3-phenyl-2- thiophenesulfonamide; -chloro-3-[3-(methyloxy)phenyl]-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4- (trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-3-(4-fluorophenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -[3,5-bis(trifluoromethyl)phenyl]-5-chloro-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-3-(3-fluorophenyl)-N-[3-{ [(3R)-l-methyl-3-pyrrolidinyl]oxy }-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -(3-acetylphenyl)-5-chloro-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -[3,4-bis(methyloxy)phenyl]-5-chloro-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4- (trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-3-(3,5-dichlorophenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-3-(3-fluoro-4-methylρhenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; 5-chloro-3-(3,4-difluorophenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; 5-chloro-3-(3,4-dimethylphenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; 3-(l,3-benzodioxol-5-yl)-5-chloro-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; 5-chloro-4-(3,5-dichlorophenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; 4-chloro-5-(4-methylphenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4- (trifluoromethyl)phenyl]-2-thiophenesulfonamide;
4-chloro-5-[2-(methyloxy)phenyl] -N- [3- { [(3R)- 1 -methyl-3-pyrrolidinyl]oxy } -4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; 4-chloro-5-(2-fluorophenyl)-N-[3-{ [(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; 4-chloro-5-(3,4-dimethylphenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; 4-chloro-N-[3-{[(3R)-l-methyl-3-pyrrolidmyl]oxy}-4-(trifluoromethyl)phenyl]-5-phenyl-2- thiophenesulfonamide; 4-chloro-5-[5-chloro-2-(methyloxy)phenyl]-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4- (trifluoromethyl)phenyl]-2-thiophenesulfonamide;
4-chloro-5-[3-methyl-4-(methyloxy)phenyl]-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; N-{3-[2-chloro-5-({ [3-{ [(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]amino}sulfonyl)-3-thienyl]phenyl}-2-methylpropanamide; N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-(trifluoromethyl)phenyl]-5-[l-methyl-5-
(trifluoromethyl)- 1 H-pyrazol-3-yl] -2-thiophenesulf onamide ; 4-(3-cyanoρhenyl)-N-[3-{ [(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-(trifluoromethyl)ρhenyl]-2- thiophenesulf onamide ; 5-chloro-N-(4-chloro-3- { [(3R)- 1 -methyl-3-pyrrolidinyl]oxy }phenyl)-4-(3,5-dichlorophenyl)-2- thiophenesulfonamide;
5-chloro-4-(4-cyanophenyl)-N- [3- { [(3R)- 1 -methyl-3-pyrrolidinyl]oxy } -4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; 5-chloro-4-(4-chlorophenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-4-(4-formylphenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-4-[2-(cyanomethyl)phenyl]-N-[3-{[(3R)-l-methyl-3-ρyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-3-[3-(cyanomethyl)phenyl]-N-[3-{[(3R)-l-methyl-3-ρyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-4-(3,4-difluorophenyl)-2- thiophenesulf onamide ; -chloro-4-(2,5-difluorophenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4- (trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-4-(2-chlorophenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-4-[5-chloro-2-(methyloxy)phenyl]-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-4-(6-methyl-l,3-benzodioxol-5-yl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-4-(3,4-dichlorophenyl)-2- thiophenesulfonamide; -chloro-4-(3-chloro-4-fluorophenyl)-N-(4-chloro-3-{[(3R)-l-methyl-3- pyrrolidinyljoxy }phenyl)-2-thiophenesulfonamide; -chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-4-(6-methyl-l,3- benzodioxol-5-yl)-2-thiophenesulfonamide; -chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-4-(4-methyl-3- nitrophenyl)-2-thiophenesulfonamide; -chloro-5-[2-(cyanomethyl)phenyl]-N-[3-{ [(3R)- 1 -methyl-3-pyrrolidinyl]oxy } -4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-5-[4-(cyanomethyl)phenyl]-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-5-[2-methyl-4-(methyloxy)phenyl]-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4- (trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-5-(5-methyl-l,3-benzodioxol-4-yl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -dibenzo[b,d]furan-4-yl-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -(3-acetylphenyl)-4-chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-2- thiophenesulfonamide; -chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-5-[3-
(trifluoromethyl)phenyl]-2-thiophenesulf onamide; -chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-5-(3-fluorophenyl)-2- thiophenesulfonamide; -chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-5-(3-cyanophenyl)-2- thiophenesulfonamide; -chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-5-[3-(methyloxy)phenyl]- 2-thiophenesulfonamide; -chloro-N-(4-chloro-3- { [(3R)- 1 -methyl-3-pyrrolidinyl]oxy }phenyl)-5-(6-methyl- 1,3- benzodioxol-5-yl)-2-thiophenesulfonamide; -chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-5-(2,4-difluorophenyl)-2- thiophenesulfonamide; -chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-5-(3,4-dichlorophenyl)-2- thiophenesulfonamide; -chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-5-(3-chlorophenyl)-2- thiophenesulf onamide ; -chloro-5-(3-chloro-4-fluorophenyl)-N-(4-chloro-3-{[(3R)-l-methyl-3- pyrrolidinyl]oxy}phenyl)-2-thiophenesulfonamide; -bromo-2-chloro-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-(trifluoromethyl)phenyl]-5- phenyl-3-thiophenesulfonamide; -chloro-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-(trifluoromethyl)phenyl]-4-phenyl-2- thiophenesulfonamide; -chloro-3-(3-cyanophenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-(trifluoromethyl)phenyl]-3-[3-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-3-(3-chloro-4-fluorophenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4- (trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-3-(4-methyl-3-nitrophenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-4-(3-chloro-4-fluorophenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-4-(3,4-dichlorophenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; ' -[3,4-bis(methyloxy)phenyl]-5-chloro-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-4-(3,4-difluorophenyl)-N-[3-{ [(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-4-(4-methyl-3-nitrophenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-5-[3-(methyloxy)phenyl]-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4- (trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-5-[4-(methyloxy)phenyl]-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-5-(4-fluorophenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-5 -(4-cyanophenyl)-N- [3- { [(3R)- 1 -methyl-3-pyrrolidinyl] oxy } -4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-5-(2-methylphenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-(trifluoromethyl)phenyl]-5-[3- (trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-5-(3-methylphenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -(3-acetylphenyl)-4-chloro-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-5-(3-cyanophenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-5-(2,4-difluorophenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-5-(4-chlorophenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4- (trifluoromethyl)phenyl]-2-thiophenesulfonamide; -[3,4-bis(methyloxy)phenyl]-4-chloro-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-5-(3,4-dichlorophenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; 5-[3,5-bis(trifluoromethyl)phenyl]-4-chloro-N-[3-{t(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; 4-chloro-5-(3-fluorophenyl)-N-t3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; 4-chloro-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-(trifluoromethyl)phenyl]-5-{3-
[(trifluoromethyl)oxy]phenyl}-2-thiophenesulfonamide; and 4-chloro-5-[3-fluoro-4-(methyloxy)phenyl]-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide.
The compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active form. All of these compounds and their diastereoisomers are contemplated to be within the scope of the present invention. Compounds of Formula (I) may be prepared as outlined in Scheme 1.
Scheme 1
Figure imgf000018_0001
Conditions: a) MeCN, py, rt; b) ArB(OH)2, Pd°, heating. (X is Br or Cl)
Anilines A and B have been previously described: WO 2002089792 Al, which is incorporated by reference herein.
Figure imgf000018_0002
Aniline A Aniline B
Sulfonyl chlorides, when not commercially available, can prepared by methods known in the art: Shahripour, A.B. et al. Bioorg. Med. Chem. 2002, 10, 31; Cross, P.E. et al. /. Med. Chem. 1978, 21, 845; Huntress et al J. Amer. Chem. Soc. 1941, 63, 3446; Hashimoto, H. et al J. Med. Chem. 2002, 45, 1511; O'Brien, P. M. et al. J.MeάChem. 2000, 43, 156; Brandish, D. J.Med.Chem. 1999, 22, 4584.
Substituted benzenesulfonyl chlorides used in the synthesis of the title compounds which were not available commercially and were prepared by methods known to those practiced in the art.
With appropriate manipulation, including the use of alternative nitrogen protecting grouρ(s), the synthesis of the remaining compounds of Formula (I) was accomplished by methods analogous to those above and to those described in the Experimental section. In order to use a compound of the Formula (I) or a pharmaceutically acceptable salt thereof for the treatment of humans and other mammals it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
Compounds of Formula (I) and their pharmaceutically acceptable salts may be administered in a standard manner for the treatment of the indicated diseases, for example orally, parenterally, sub-lingually, transdermally, rectally, via inhalation or via buccal administration.
Compounds of Formula (I) and their pharmaceutically acceptable salts which are active when given orally can be formulated as syrups, tablets, capsules and lozenges. A syrup formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, peanut oil, olive oil, glycerine or water with a flavoring or coloring agent. Where the composition is in the form of a tablet, any pharmaceutical carrier routinely used for preparing solid formulations may be used. Examples of such carriers include magnesium stearate, terra alba, talc, gelatin, agar, pectin, acacia, stearic acid, starch, lactose and sucrose. Where the composition is in the form of a capsule, any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatin capsule shell. Where the composition is in the form of a soft gelatin shell capsule any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example aqueous gums, celluloses, silicates or oils and are incorporated in a soft gelatin capsule shell. Typical parenteral compositions consist of a solution or suspension of the compound or salt in a sterile aqueous or non-aqueous carrier optionally containing a parenterally acceptable oil, for example polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil, or sesame oil. Typical compositions for inhalation are in the form of a solution, suspension or emulsion that may be administered as a dry powder or in the form of an aerosol using a conventional propellant such as dichlorodifluoromethane or trichlorofluoromethane. A typical suppository formulation comprises a compound of Formula (1) or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent, for example polymeric glycols, gelatins, cocoa-butter or other low melting vegetable waxes or fats or their synthetic analogues.
Typical transdermal formulations comprise a conventional aqueous or non-aqueous vehicle, for example a cream, ointment, lotion or paste or are in the form of a medicated plaster, patch or membrane.
Preferably the composition is in unit dosage form, for example a tablet, capsule or metered aerosol dose, so that the patient may administer to themselves a single dose.
Each dosage unit for oral administration contains suitably from 0.1 mg to 500 mg/Kg, and preferably from 1 mg to 100 mg/Kg, and each dosage unit for parenteral administration contains suitably from 0.1 mg to 100 mg, of a compound of Formula (I) or a pharmaceutically acceptable salt thereof calculated as the free acid. Each dosage unit for intranasal administration contains suitably 1-400 mg and preferably 10 to 200 mg per person. A topical formulation contains suitably 0.01 to 1.0% of a compound of Formula (I).
The daily dosage regimen for oral administration is suitably about 0.01 mg/Kg to 40 mg/Kg, of a compound of Formula (I) or a pharmaceutically acceptable salt thereof calculated as the free acid. The daily dosage regimen for parenteral administration is suitably about 0.001 mg/Kg to 40 mg/Kg, of a compound of the Formula (I) or a pharmaceutically acceptable salt thereof calculated as the free acid. The daily dosage regimen for intranasal administration and oral inhalation is suitably about 10 to about 500 mg/person. The active ingredient may be administered from 1 to 6 times a day, sufficient to exhibit the desired activity.
These sulphonamide analogs may be used for the treatment of congestive heart failure, stroke, ische ic heart disease (angina, myocardial ischemia), cardiac arrhythmia, hypertension (essential and pulmonary), renal disease (acute and chronic renal failure/end stage renal disease) along with peripheral vascular disease (male erectile dysfunction, diabetic retinopathy, intermittent claudication/ischemic limb disease) and ischemic/hemorrhagic stroke, COPD, restenosis, asthma, neurogenic inflammation, migraine, metabolic vasculopathies, bone/cartilage/joint diseases, arthritis and other inflammatory diseases, fibrosis (e.g. pulmonary fibrosis), sepsis, atherosclerosis, dyslipidemia, addiction, schizophrenia, cognitive disorders/ Alzheimers disease, impulsivity, anxiety, stress, depression, pain, neuromuscular function, diabetes, gastric reflux, gastric motility disorders, ulcers and genitourinary diseases. The urotensin antagonist may be administered alone or in conjunction with one or more other therapeutic agents, said agents being selected from the group consisting of endothelin receptor antagonists, angiotensin converting enzyme (ACE) inhibitors, A-D. receptor antagonists, vasopeptidase inhibitors, diuretics, digoxin, and dual non-selective D-adrenoceptor and o.χ-adrenoceptor antagonists.
No unacceptable toxicological effects are expected when compounds of the invention are administered in accordance with the present invention.
The biological activity of the compounds of Formula (I) are demonstrated by the following tests: Radioligand binding:
HEK-293 cell membranes containing stable cloned human and rat GPR-14 (20 ug/assay) were incubated with 200 pM [1251] h-U-II (200 Ci/mmol"1 in the presence of increasing concentrations of test compounds in DMSO (0.1 nM to 10 uM), in a final incubation volume of 200 ul (20 mM Tris-HCl, 5 mM MgC12). Incubation was done for 30 minutes at room temperature followed by filtration GF/B filters with Brandel cell harvester. ^^I labeled
U-II binding was quantitated by gamma counting. Nonspecific binding was defined by •'••"I U- II binding in the presence of 100 nM of unlabeled human U-II. Analysis of the data was performed by nonlinear least square fitting. Ca2+-mobilization: A microtitre plate based Ca2+-mobilization FLIPR assay (Molecular Devices,
Sunnyvale, CA) was used for the functional identification of the ligand activating HEK-293 cells expressing (stable) recombinant GPR-14. The day following transfection, cells were plated in a poly-D-lysine coated 96 well black/clear plates. After 18-24 hours the media was aspirated and Fluo 3AM-loaded cells were exposed to various concentrations (10 nM to 30 uM) of test compounds followed by h-U-II. After initiation of the assay, fluorescence was read every second for one minute and then every 3 seconds for the following one minute. The inhibitory concentration at 50% (IC50)was calculated for various test compounds. Inositol phosphates assays:
HEK-293-GPR14 cells in T150 flask were prelabeled overnight with 1 uCi myo-[3H] inositol per ml of inositol free Dulbecco's modified Eagel's medium. After labeling, the cells were washed twice with Dulbecco's phosphate-buffered saline (DPBS) and then incubated in DPBS containing 10 mM LiCl for 10 min at 37°C. The experiment was initiated by the addition of increasing concentrations of h-U-II (1 pM to lμM ) in the absence and presence of three different concentrations (0.3, 1 and 10 uM) of test compounds and the incubation continued for an additional 5 min at 37°C after which the reaction was terminated by the addition of 10% (final concentration) trichloroacetic acid and centrifugation. The supernatants were neutralized with lOOul of 1M Trizma base and the inositol phosphates were separated on AG 1-X8 columns (0.8 ml packed, 100-200 mesh) in formate phase. Inositol monophosphate was eluted with 8 ml of 200 mM ammonium formate. Combined inositol di and tris phosphate was eluted with 4ml of 1M ammonium formate/ 0.1 M formic acid. Eluted fractions were counted in beta scintillation counter. Based on shift from the control curve KB was calculated. Activity for the compounds of this invention range from (radioligand binding assay): Ki = l nM - 10000 nM.
The following Examples are illustrative but not limiting embodiments of the present invention.
Example 1 5-chloro-4-(3-chloro-4-fluorophenylVN-(4-chloro-3-f r(3R)-l-methyl-3- pyrrolidinvnoxy)phenyl)-2-thiophenesulfonamide:
Figure imgf000022_0001
4-bromo-5-chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-2- thiophenesulfonamide (synthesized as outlined in WO 2002090348) (100 mg, 0.21 mmol) was dissolved in 4 mL of dioxane and treated with [l,l'-Bis(diphenylphosphino)ferrocene] dichloropalladium(π) complex with dichloromethane (1:1) {Pd DPPF} (25 mg, 0.031 mmol), potassium carbonate (0.31 mL of a 2.0 M aqueous solution, 0.62 mmol), and (3-dichloro-4- fluorophenyl)boronic acid (37 mg, 0.21 mmol). This suspension was stirred vigorously and heated to 185 °C for 600 sec in a Personal Chemistry Microwave Reactor at the Normal power level. The reaction mixture was filtered through a 0.2 micron Acrodisk filter, concentrated, dissolved in DMSO and purified by preparative HPLC (X-Terra Prep RP ODS-A, 30 x 75 mm, 25 mL/min, A: acetonitrile B: water, A: 5% to 65% during 15 min, UN detection at 214 nm) to give 50 mg (44%) of the title compound as a brown solid. MS (ES) m/e 535 [M+H]+ Examples 2-152 The following compounds were prepared according to the procedure described in example 1 using the appropriate acid in place of 3,5-dichlorophenylboronic acid.
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0002
Example 153 5-chloro-3-(4-fluorophenyl)-N-r3-{r(3R)-l-methyl-3-pyrrolidinynoxyi-4- (trifluoromethyl)phenyll-2-thiophenesulfonamide:
Figure imgf000043_0001
The 3-bromo-5-chloro-N-[3-{[3R)-l-methyl-3-pyrrolidinyl]oxy}-4-(trifluoromethyl)phenyl]2- thiophenesulfonamide (25 mg, 0.05 mmol) and 4-fluorobenzeneboronic acid (7 mg, 0.05 mmol) were dissolved in a mixture of toluene and ethanol (4:1, 2.5 ml). (dppf)2PdCl2 (5.0 mg, 0.007 mmol, 14%) was added followed by 2M Na2C03 solution (0.13 ml, 0.26 mmol). The mixture was heated at 90°C for 18 h then concentrated in vacuo. The crude mixture was purified by preparative HPLC (YMC CombiPrep ODS-A, 50 x 20 mm, 20 mL/min, A: acetonitrile B: water, A: 10 to 90% over 10 min, UN detection at 214 nm) to give the title compound as a tan oil. MS (ES) m/e 534.8 [M+H]+. Examples 154-180
Using the general procedure oultined in Example 565, the following compounds were prepared.
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0002
Example 181 4-chloro-5-(4-methylphenyl)-N-r3-ir(3R)-l-methyl-3-pyrrolidinyl1oxyl-4- (trifluoromethyl)phenyn-2-thiophenesulfonamide:
Figure imgf000047_0001
To a solution of the product of Example 89 (0.1 g, 0.21 mmol) and (4-methylphenyl)boronic acid (46 mg, 0.30 mmol) in dry THF (2 ml) was added potassium fluoride (36 mg, 0.60 mmol), tris(dibenzylideneacetone)dipalladium (9.6 mg, 10 mol %) and tri- tertbutylphosphine-tetrafluoroborate (12 mg, 20 mol %). The reaction mixture was placed under an argon atmosphere and was heated to 60°C for 16 hours. The solvent was removed by evaporation and the residue was dissolved in DMSO, filtered, and purified by preparative HPLC (YMC CombiPrep ODS-A, 50 x 20 mm, 20 mL/min, A: acetonitrile B: water, A: 10 to 90% over 10 min, UN detection at 214 nm) to give 50 mg (42% yield) of the title compound as an oil. MS (ES) m/e 531 [M+H]+. The hydrochloride salt was formed from by dissolving the substrate in methanol, adding hydrochloric acid in ether (IM) and evaporating the volatile materials to give a solid.
Examples 182-197 Using the general procedure oultined in Example 181, the following compounds were prepared.
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0002
Example 198 4-chloro-N-r3-ir(3R)-l-methyl-3-pyrrolidinyl1oxy|-4-(trifluoromethyl)phenyll-5-i3- r(trifluoromethyl)oxy1phenyl|-2-thiophenesulfonamide:
Figure imgf000050_0001
To a solution of 4,5-dichloro-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4- (trifluoromethyl)phenyl]-2-thiophenesulfonamide (100 mg, 0.21 mmol) and 3- (trifluoromethoxy)benzene boronic acid (48 mg, 0.23 mmol) in anhydrous THF was added potassium flouride (36 mg, 0.63 mmol), tri-tertbutylphosphine-tetrafluoroborate (6.1 mg, 10 mol %), and tris(dibenzylideneacetone)dipalladium (4.8 mg, 5 mol %). The reaction mixture was placed under argon atmosphere and heated to 120 °C in the microwave for 600 sec. The solvent was removed by evaporation and the residue was purified by preparative HPLC (Xterra Prep RP, 75 x 30 mm, 25 mL/min, A: acetonitrile B: water, 0.1% TFA; A: 10 to 90% during 10 min, UN detection at 214 nm) to give 12 mg (9%) of the title compound as a free base.
The hydrochloride salt was formed from by dissolving the substrate in methanol, adding hydrochloric acid in ether (IM) and evaporating the volatile materials to give a solid.
Examples 199-206 Using the general procedure outlined in Example 198, the following compounds were prepared.
Figure imgf000051_0001
Figure imgf000052_0002
Example 207 N-\ 3-r2-chloro-5-(l 13-1 r(3RVl-methyl-3-Pyrrolidinyl]oxyl-4- (trifluoromethvDphenyllaminolsulfonyπ-S-thienyllphenyll^-methylpropanamide
Figure imgf000052_0001
A solution of 4-bromo-5-chloro-N-[3-{ [(3R)-l-methyl-3-pyrrolidinyl]oxy }-4- (trifluoromethyl)phenyl]-2-thiophenesulfonamide (676 mg, 1.30 mmol), (3- aminophenyl)boronic acid (200 mg, 1.30 mmol), and [1,1 - bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (100 mg, 0.13 mmol) in dioxane (5 mL) and aqueous 2 M sodium carbonate (1.3 mL, 2.6 mmol) was heated in a Personal Chemistry microwave reactor at normal power for 300 sec at 170 °C. The mixture was filtered through a 0.45 μm fritted funnel and purified by preparative HPLC [YMC CombiPrep ODS-A, 50 x 20 mm, 20 mL/min, A: acetonitrile (with 0.1% trifluoroacetic acid added), B: water (with 0.1% trifluoroacetic acid added), A: 10 to 90% over 10 min, UN detection at 214 nm] to give 4-(3-aminophenyl)-5-chloro-N-[3-{ [(3R)-l-methyl-3- pyrrolidinyl]oxy}-4-(trifluoromethyl)phenyl]-2-thiophenesulfonamide (311 mg, 45%) as a trifluoroacetate salt. MS (ES) m/e 532.2 [M+H]+.
To a solution of 4-(3-aminophenyl)-5-chloro-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4- (trifluoromethyl)phenyl]-2-thiophenesulfonamide (50 mg, 0.077 mmol) and triethylamine (23 mg, 0.23 mmol) in methylene chloride (1 mL) was added isobutyryl chloride (25 mg, 0.23 mmol). The reaction was maintained for 16 h at room temperature before being quenched with methanol. The solution was concentrated and the crude material purified by preparative HPLC [YMC CombiPrep ODS-A, 50 x 20 mm, 20 mL/min, A: acetonitrile (with 0.1% trifluoroacetic acid added), B: water (with 0.1% trifluoroacetic acid added), A: 10 to 90% over 10 min, UN detection at 214 nm] to provide the desired product (15 mg, 27%) as a trifluoroacetate salt. MS (ES) m/e 601.8 [M+H]+.
Example 208 N-I2-.2-chloro-5-({ r3-{ r(3R -l-methylpyrrolidin-3-ylloxyl-4-
(trifluoromethyl)phenvnaminoisulfonyl -3-thienynphenyl|acetamide
Figure imgf000053_0001
To a solution of 4-(2-aminophenyl)-5-chloro-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4- (trifluoromethyl)phenyl]-2-thiophenesulfonamide (18 mg, 0.024 mmol) and triethylamine (12 mg, 0.12 mmol) in methylene chloride (1 mL) was added acetic anhydride (2.5 mg, 0.024 mmol). The reaction was maintained at room temperature for 16 h. The solution was concentrated under reduced pressure and the remaining residue purified by preparative HPLC . [YMC CombiPrep ODS-A, 50 x 20 mm, 20 mL/min, A: acetonitrile (with 0.1% trifluoroacetic acid added), B: water (with 0.1% trifluoroacetic acid added), A: 10 to 90% over 10 min, UN detection at 214 nm] to give the desired product (7 mg, 42%) as a trifluoroacetate salt. MS
(ES) m/e 574.2 [M+H]+.
Example 209 Methyl 3-({ [3-{ r(3R)-l-methyl-3-pyrrolidinynoxy)-4-(trifluoromethyl phenvnaminolsulfonvD^-phenyl-S-ftrifluoromethyD^-thiophenecarboxylate:
Figure imgf000053_0002
Aniline CF3 (80 mg, 0.31 mmol) was dissolved in 2 mL of methylene chloride and treated with methyl 3-(chlorosulfonyl)-4-phenyl-5-(trifluoromethyl)-2-thiophenecarboxylate (118 mg, 0.307 mmol) and pyridine (0.025 mL, 0.31 mmol) with vigorous stirring at room temperature. The reaction mixture was maintained for 18 hours, and then the solvent was removed under reduced pressure. The residue was dissolved in 1 mL of DMSO and purified by preparative HPLC (YMC CombiPrep ODS-A, 50 x 20 mm, 20 mL/min, A: acetonitrile B: water, A: 5% to 95% during 12 min, UN detection at 214 nm) to give 58 mg (31%) of the title compound as a tan solid. MS (ES) m/e 609 [M+H]+
Examples 210-214 The following examples were prepared according to the representative procedure in Example 209 using the appropriate sulfonyl chlorides as starting material, and in some cases using acetonitrile rather than methylene chloride as the solvent.
Figure imgf000054_0001
EXAMPLE 215 Formulations for pharmaceutical use incorporating compounds of the present invention can be prepared in various forms and with numerous excipients. Examples of such formulations are given below.
Tablets/Ingredients Per Tablet
1.Active ingredient 40 mg
(Cpd of Form. I)
2.Corn Starch 20 mg 3.Alginic acid 20 mg
4.Sodium Alginate 20 mg
5.Mg stearate 1.3 mg
2.3 mg
Procedure for tablets:
Step 1: Blend ingredients No. 1, No. 2, No. 3 and No. 4 in a suitable mixer/blender.
Step 2: Add sufficient water portion-wise to the blend from Step 1 with careful mixing after each addition. Such additions of water and mixing until the mass is of a consistency to permit its conversion to wet granules. Step 3: The wet mass is converted to granules by passing it through an oscillating granulator using a No. 8 mesh (2.38 mm) screen.
Step 4: The wet granules are then dried in an oven at 140°F (60°C) until dry.
Step 5: The dry granules are lubricated with ingredient No. 5.
Step 6: The lubricated granules are compressed on a suitable tablet press.
Inhalant Formulation
A compound of Formula I, (1 mg to 100 mg) is aerosolized from a metered dose inhaler to deliver the desired amount of drag per use.
Parenteral Formulation A pharmaceutical composition for parenteral administration is prepared by dissolving an appropriate amount of a compound of formula I in polyethylene glycol with heating. This solution is then diluted with water for injections Ph Eur. (to 100 ml). The solution is then sterilized by filtration through a 0.22 micron membrane filter and sealed in sterile containers. The above specification and Examples fully disclose how to make and use the compounds of the present invention. However, the present invention is not limited to the particular embodiments described hereinabove, but includes all modifications thereof within the scope of the following claims. The various references to journals, patents and other publications which are cited herein comprise the state of the art and are incorporated herein by reference as though fully set forth.

Claims

What is claimed is:
1. A compound of Formula (I)
Figure imgf000057_0001
Formula (I)
wherein:
Rj is hydrogen, halogen, or C^g alkyl;
Ar is phenyl, pyrazolyl, thiazolyl, dibenzofuranyl, benzodioxolyl, quinolinyl, or naphthalenyl, all of which may be substituted or unsubstituted by one or two of the following: halogen, CN, S(Cχ_6 alkyl), CF , OCF3, SCF , Cχ_6 alkyl, Ph, OPh, C g alkoxy, C02(C1_6 alkyl), NR5R6,
NR5COR6, CONR5R6, COR5, N02, Cχ.3 alkylenedioxy, CH2OH or CH2CN;
R2 is hydrogen, halogen, or CF3.
R5 and Rg are independently hydrogen or Cχ.β alkyl; R9 is hydrogen or Cχ.g alkyl; or a pharmaceutically acceptable salt thereof.
2. A compound of Claim 1 wherein:
Ar is phenyl; substituted or unsubstituted by one or two of the following: hydrogen, CN, halogen, CF3, C02CH3, C^alkoxy, C=0, NHCOCH3, CH20, Cι_2alkyl„ SCH3, O-
CF3, CH2CN, -C(CH3)3, NH3, Ph, OPh, N02, CH2OH, or N-C(O)0-CH(CH3)3;
R2 is hydrogen, Cl, or CF3;
Rj is hydrogen, Br, or Cl; and
R9 is Cj_2 alkyl.
3. A compound of claim 1 selected from: 5-chloro-3-(4-cyanophenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; 3-(4-acetylphenyl)-5-chloro-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; 5-chloro-3-(4-chlorophenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; 5-chloro-3-[4-(methyloxy)phenyl]-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; 5-chloro-3-(4-formylphenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; N-{4-[5-chloro-2-({ [3-{ [(3R)-l-methyl-3-pyrrolidinyl]oxy }-4- (trifluoromethyl)phenyl]amino}sulfonyl)-3-thienyl]phenyl}acetamide; ;
5-chloro-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-(trifluoromethyl)ρhenyl]-4-[4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; 4-(4-acetylphenyl)-5-chloro-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; 5-chloro-4-(4-fluorophenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; 5-chloro-4-[4-(methyloxy)phenyl]-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; N-{4-[2-chloro-5-({ [3-{ [(3R)-l-methyl-3-pyrrolidinyl]oxy }-4- (trifluoromethyl)phenyl]amino } sulfonyl)-3-thienyl]phenyl } acetamide; ;
5-chloro-4-(2,4-dichlorophenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; 5-chloro-4-(2,4-difluorophenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; N-{3-[5-chloro-2-({[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]amino}sulfonyl)-3-thienyl]phenyl}acetamide; 5-chloro-N-[3-{[(3R)-l-methyl-3-ρyrrolidinyl]oxy}-4-(trifluoromethyl)phenyl]-3-[4-
(methylthio)phenyl]-2-thiophenesulfonamide; 5-chloro-4-[4-(l,l-dimethylethyl)phenyl]-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4- (trifluoromethyl)phenyl]-2-thiophenesulfonamide;
5-chloro-4-[4-(dimethylamino)phenyl]-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; 4-chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-5-[3-fluoro-4-
(methyloxy)phenyl]-2-thiophenesulfonamide; -chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-5-(2-fluorophenyl)-2- thiophenesulfonamide; -chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-4-(4-cyanophenyl)-2- thiophenesulf onamide ; -chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-4-(4-chlorophenyl)-2- thiophenesulfonamide; -chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-4-(4-fluorophenyl)-2- thiophenesulfonamide; -chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-4-[3- (trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-4-(3-chlorophenyl)-2- thiophenesulfonamide; -chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-4-[3-(methyloxy)phenyl]-
2-thiophenesulfonamide; -Chloro-4-(2-methylphenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-4-(2,5-dimethylphenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-4-[2-(methyloxy)phenyl]-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4- (trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-(trifluoromethyl)phenyl]-4-{4-
[(trifluoromethyl)oxy]phenyl}-2-thiophenesulfonamide; -chloro-4-[2-methyl-4-(methyloxy)phenyl]-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -[3,4-bis(methyloxy)phenyl]-5-chloro-N-(4-chloro-3-{[(3R)-l-methyl-3- pyrrolidinyl]oxy}phenyl)-2-thiophenesulfonamide; -chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-4-[2-methyl-4-
(methyloxy)phenyl]-2-thiophenesulfonamide; -chloro-4-[4-(hydroxymethyl)phenyl]-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4- (trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-4-[3-(hydroxymethyl)phenyl]-N-[3-{[(3R)-l-methyl-3-ρyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -(4-aminophenyl)-5-chloro-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; 4-(2-aminophenyl)-5-chloro-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; 5-chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-4-[2-
(cyanomethyl)phenyl]-2-thiophenesulfonamide; N-(4-bromo-3-{[(3R)-l-methylpyrrolidin-3-yl]oxy}phenyl)-5-chloro-4-(3-chloro-4- fluorophenyl)thiophene-2-sulfonamide; 4-chloro-5-[3-(cyanomethyl)phenyl]-N-[3-{ [(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thioρhenesulfonamide; 4-chloro-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-(trifluoromethyl)phenyl]-5-{4- [(trifluoromethyl)oxy]phenyl } -2-thiophenesulf onamide;
4-chloro-5-[2-methyl-8-(methyloxy)-5-quinolinyl]-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-
4-(trifluoromethyl)phenyl]-2-thiophenesulfonamide; N-{3-[5-({[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-(trifluoromethyl)phenyl]amino}sulfonyl)-
2-thienyl]phenyl}acetamide; N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-(trifluoromethyl)phenyl]-5-{4-
[(trifluoromethyl)oxy]phenyl}-2-thiophenesulfonamide; 5-[2-(cyanomethyl)phenyl]-N-[3-{ [(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; 4-chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-5-(4-chlorophenyl)-2- thiophenesulfonamide;
5-[3,5-bis(trifluoromethyl)phenyl]-4-chloro-N-(4-chloro-3-{[(3R)-l-methyl-3- pyrrolidinyl] oxy } phenyl)-2-thiophenesulf onamide ; 4-chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-5-(4-fluorophenyl)-2- thiophenesulfonamide; 4-chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-5-[4-(methyloxy)phenyl]-
2-thiophenesulf onamide ; 4-chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-5-(2-methylphenyl)-2- thiophenesulfonamide; 4-chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-5-[2-methyl-4- (methyloxy)phenyl]-2-thiophenesulfonamide;
4-chloro-N-(4-chloro-3- { [(3R)~ 1 -methyl-3-pyrrolidinyl] oxy } phenyl)-5-(4-cyanophenyl)-2- thiophenesulfonamide; 4-chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-5-{3-
[(trifluoromethyl)oxy]phenyl}-2-thiophenesulfonamide; -[3,4-bis(methyloxy)phenyl]-4-chloro-N-(4-chloro-3-{[(3R)-l-methyl-3- pyrrolidinyl]oxy}phenyl)-2-thiophenesulfonamide; -chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-5-[2-
(cyanomethyl)phenyl]-2-thioρhenesulfonamide; -(3-cyanophenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-(trifluoromethyl)phenyl]-2- thiophenesulfonamide; -bromo-2-chloro-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-(trifluoromethyl)phenyl]-5-[3-
(trifluoromethyl)phenyl]-3-thiophenesulfonamide; -chloro-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-(trifluoromethyl)phenyl]-3-ρhenyl-2- thiophenesulfonamide; -chloro-3-[3-(methyloxy)phenyl]-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-3-(4-fluorophenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -[3,5-bis(trifluoromethyl)phenyl]-5-chloro-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-3-(3-fluorophenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -(3-acetylphenyl)-5-chloro-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4- (trifluoromethyl)phenyl]-2-thiophenesulfonamide; -[3,4-bis(methyloxy)phenyl]-5-chloro-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-3-(3,5-dichlorophenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-3-(3-fluoro-4-methylphenyl)-N-[3-{ [(3R)- 1 -methyl-3-pyrrolidinyl]oxy } -4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-3-(3,4-difluorophenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-3-(3,4-dimethylphenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4- (trifluoromethyl)phenyl]-2-thiophenesulfonamide; -(l,3-benzodioxol-5-yl)-5-chloro-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-4-(3,5-dichlorophenyl)-N-[3-{ [(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; 4-chloro-5-(4-methylphenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)ρhenyl]-2-thiophenesulfonamide; 4-chloro-5-[2-(methyloxy)phenyl]-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; 4-chloro-5-(2-fluorophenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; 4-chloro-5-(3,4-dimethylphenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; 4-chloro-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-(trifluoromethyl)phenyl]-5-phenyl-2- thiophenesulfonamide;
4-chloro-5-[5-chloro-2-(methyloxy)phenyl]-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; 4-chloro-5-[3-methyl-4-(methyloxy)phenyl]-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; N-{3-[2-chloro-5-({ [3-{ [(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]amino}sulfonyl)-3-thienyl]phenyl}-2-methylpropanamide; N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-(trifluoromethyl)phenyl]-5-[l-methyl-5-
(trifluoromethyl)-lH-pyrazol-3-yl]-2-thiophenesulfonamide; 4-(3-cyanophenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-(trifluoromethyl)phenyl]-2- thiophenesulfonamide;
4. A compound of claim 1 selected from: 5-chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-4-(3,5-dichlorophenyl)-2- thiophenesulfonamide; 5-chloro-4-(4-cyanophenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4- (trifluoromethyl)phenyl]-2-thiophenesulfonamide; 5-chloro-4-(4-chlorophenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; 5-chloro-4-(4-formylphenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4- (trifluoromethyl)phenyl] -2-thiophenesulf onamide ;
5-chloro-4-[2-(cyanomethyl)phenyl]-N-[3- { [(3R)- 1 -methyl-3-pyrrolidinyl]oxy }-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; 5-chloro-3-[3-(cyanomethyl)phenyl]-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4- (trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-4-(3,4-difluorophenyl)-2- thiophenesulfonamide; -chloro-4-(2,5-difluorophenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-4-(2-chlorophenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-4-[5-chloro-2-(methyloxy)phenyl]-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-4-(6-methyl-l,3-benzodioxol-5-yl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4- (trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-4-(3,4-dichlorophenyl)-2- thiophenesulfonamide; -chloro-4-(3-chloro-4-fluorophenyl)-N-(4-chloro-3-{[(3R)-l-methyl-3- pyrrolidinyl]oxy}phenyl)-2-thiophenesulfonamide; -chloro-N-(4-chloro-3- { [(3R)- l-methyl-3-pyrrolidinyl]oxy }phenyl)-4-(6-methyl- 1,3- benzodioxol-5-yl)-2-thiophenesulfonamide; -chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-4-(4-methyl-3- nitrophenyl)-2-thiophenesulfonamide; -chloro-5-[2-(cyanomethyl)phenyl]-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4- (trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-5-[4-(cyanomethyl)phenyl]-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-5-[2-methyl-4-(methyloxy)phenyl]-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-5-(5-methyl-l,3-benzodioxol-4-yl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -dibenzo[b,d]furan-4-yl-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -(3-acetylphenyl)-4-chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-2- thiophenesulfonamide; -chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-5-[3-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-5-(3-fluorophenyl)-2- thiophenesulf onamide ; -chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-5-(3-cyanophenyl)-2- thiophenesulfonamide; -chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-5-[3-(methyloxy)phenyl]-
2-thiophenesulfonamide; -chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-5-(6-methyl-l,3- benzodioxol-5-yl)-2-thiophenesulfonamide; -chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-5-(2,4-difluorophenyl)-2- thiophenesulf onamide ; -chloro-N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-5-(3,4-dichlorophenyl)-2- thiophenesulfonamide; -chloro-N-(4-chloro-3-{ [(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-5-(3-chlorophenyl)-2- thiophenesulf onamide ; -chloro-5-(3-chloro-4-fluorophenyl)-N-(4-chloro-3-{ [(3R)-l-methyl-3- pyrrolidinyl]oxy}phenyl)-2-thiophenesulfonamide; -bromo-2-chloro-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-(trifluoromethyl)phenyl]-5- phenyl-3-thiophenesulfonamide; -chloro-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-(trifluoromethyl)phenyl]-4-phenyl-2- thiophenesulf onamide ; -chloro-3-(3-cyanophenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4- (trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-(trifluoromethyl)phenyl]-3-[3-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-3-(3-chloro-4-fluorophenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-3-(4-methyl-3-nitrophenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-4-(3-chloro-4-fluorophenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-4-(3 ,4-dichlorophenyl)-N- [3-{ [(3R)- 1 -methyl-3-pyrrolidinyl] oxy } -4- (trifluoromethyl)phenyl]-2-thiophenesulfonamide; -[3,4-bis(methyloxy)phenyl]-5-chloro-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-4-(3,4-difluorophenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)ρhenyl]-2-thiophenesulfonamide; -chloro-4-(4-methyl-3-nitrophenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-5-[3-(methyloxy)phenyl]-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-5-[4-(methyloxy)phenyl]-N-[3-{ [(3R)-l-methyl-3-pyrrolidinyl]oxy }-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-5-(4-fluorophenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-5-(4-cyanophenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4- (trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-5-(2-methylphenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-(trifluoromethyl)phenyl]-5-[3-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-5-(3-methylphenyl)-N-[3- { [(3R)- 1 -methyl-3-pyrrolidinyl]oxy } -4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -(3-acetylphenyl)-4-chloro-N-[3-{ [(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-5-(3-cyanophenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4- (trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-5-(2,4-difluorophenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-5-(4-chlorophenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -[3,4-bis(methyloxy)phenyl]-4-chloro-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-5-(3,4-dichlorophenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -[3,5-bis(trifluoromethyl)phenyl]-4-chloro-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4- (trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-5-(3-fluorophenyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; -chloro-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-(trifluoromethyl)phenyl]-5-{3-
[(trifluoromethyl)oxy]phenyl}-2-thiophenesulfonamide; and 4-chloro-5-[3-fluoro-4-(methyloxy)phenyl]-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4- (trifluoromethyl)phenyl]-2-thiophenesulfonamide.
5. A pharmaceutical composition comprising a compound of formula (I) of claim 1 and a pharmaceutically acceptable carrier or excipient.
6. A method of treating conditions associated with Urotensin-II imbalance by antagonizing the Urotensin-II receptor which comprises administering to a patient in need thereof, a compound of Formula I of claim 1.
7. A method according to Claim 6 wherein the disease is congestive heart failure, stroke, ischemic heart disease , angina, myocardial ischemia, cardiac arrhythmia, essential and pulmonary hypertension, renal disease, acute and chronic renal failure, end stage renal disease, peripheral vascular disease, male erectile dysfunction, diabetic retinopathy, intermittent claudication/ischemic limb disease, ischemic/hemorrhagic stroke, COPD, restenosis, asthma, neurogenic inflammation, migraine, metabolic vasculopathies, bone/cartilage/joint diseases, arthritis and other inflammatory diseases, fibrosis, pulmonary fibrosis, sepsis, atherosclerosis, dyslipidemia, addiction, schizophrenia, cognitive disorders, Alzheimers disease, impulsivity, anxiety, stress, depression, parkinsons, movement disorders, sleep-wake cycle, incentive motivation, pain, neuromuscular function, diabetes, gastric reflux, gastric motility disorders, ulcers and genitourinary diseases.
PCT/US2003/035357 2002-11-06 2003-11-06 Sulfonamides WO2004043368A2 (en)

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US7432258B2 (en) 2006-07-20 2008-10-07 Smithkline Beecham Corporation Morpholinyl and pyrrolidinyl analogs
US7750161B2 (en) 2003-09-26 2010-07-06 Daniel Bur Pyridine derivatives
US8067601B2 (en) 2004-10-12 2011-11-29 Actelion Pharmaceticals Ltd. 1-[2-(4-benzyl-4-hydroxy-piperidin-1 -yl )-ethyl]-3-(2-methyl-quinolin- 4-yl)- urea as crystalline sulfate salt
US9096558B2 (en) 2010-07-09 2015-08-04 Pfizer Limited N-sulfonylbenzamide compounds

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UA103319C2 (en) 2008-05-06 2013-10-10 Глаксосмитклайн Ллк Thiazole- and oxazole-benzene sulfonamide compounds

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7750161B2 (en) 2003-09-26 2010-07-06 Daniel Bur Pyridine derivatives
US8067601B2 (en) 2004-10-12 2011-11-29 Actelion Pharmaceticals Ltd. 1-[2-(4-benzyl-4-hydroxy-piperidin-1 -yl )-ethyl]-3-(2-methyl-quinolin- 4-yl)- urea as crystalline sulfate salt
US7432258B2 (en) 2006-07-20 2008-10-07 Smithkline Beecham Corporation Morpholinyl and pyrrolidinyl analogs
US7749998B2 (en) 2006-07-20 2010-07-06 Glaxosmithkline Llc Morpholinyl and pyrrolidinyl analogs
US9096558B2 (en) 2010-07-09 2015-08-04 Pfizer Limited N-sulfonylbenzamide compounds

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