WO2004043366A2 - Sulfonamides - Google Patents

Sulfonamides Download PDF

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Publication number
WO2004043366A2
WO2004043366A2 PCT/US2003/035307 US0335307W WO2004043366A2 WO 2004043366 A2 WO2004043366 A2 WO 2004043366A2 US 0335307 W US0335307 W US 0335307W WO 2004043366 A2 WO2004043366 A2 WO 2004043366A2
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WIPO (PCT)
Prior art keywords
alkyl
mmol
methyl
trifluoromethyl
hydrogen
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PCT/US2003/035307
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French (fr)
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WO2004043366A3 (en
Inventor
Jason W Dodson
Bahman Ghavimi-Alagha
Gerald R. Girard
Bryan W. King
John Jeffrey Mcatee
Michael J. Neeb
Ning Wang
Catherine C.K. Yuan
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Smithkline Beecham Corporation
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Priority to AU2003291303A priority Critical patent/AU2003291303A1/en
Publication of WO2004043366A2 publication Critical patent/WO2004043366A2/en
Publication of WO2004043366A3 publication Critical patent/WO2004043366A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom 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
    • C07D409/02—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 angiotensm- ⁇ , 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 + , CI " ) 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 H, 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-JJ 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 x is phenyl, thienyl, furanyl, pyrroyl, pyridinyl, oxazoyl, indoyl, triazinyl, imidazoyl, pyrimidinyl, oxadiazoyl, pyrazoyl, triazoyl, thiazoyl, thiadiazoyl, or pyrazinyl substituted or unsubstituted by one, two , three, four or five of any of the following: halogen, CF 3 , OCF 3 , OH, SCF 3 , NO 2 , CN, Ci_ 6 alkyl, C g alkoxy, C ⁇ 6 alkyl-CF 3 , O(CH 2 ) q Y, NR 5 R 6 , N(Ci.
  • 6 al y ⁇ CO ⁇ g alkyl 6 al y ⁇ CO ⁇ g alkyl
  • COR 10 CONR 7 R 8 , S(O)pC!.
  • 6 alkyl CO 2 H, CO 2 (C ⁇ _ 6 alkyl), C ⁇ _ 6 alkyl-CO 2 (C ⁇ _ 6 alkyl), C ⁇ g alkyl-NHCOR ⁇ , or CH(OH)C ⁇ _ 6 alkyl
  • R2 is hydrogen, halogen, CF3, CN, or C1.4 alkyl;
  • R3 and R4 are independently hydrogen, C ⁇ _g alkyl, benzyl, -C(Ri4)2-ORi2 > -COOR13, -
  • R5 and Rg are independently hydrogen or C ] _g alkyl, or taken together form a 5-7-member saturated heterocycle optionally containing an additional heteroatom selected from N, O or S and further substituted by hydrogen, C]_g alkyl, benzyl or OH;
  • R7 and Rg are independently hydrogen, Cj.g alkyl, or benzyl; or taken together form a 5-7- member saturated heterocycle optionally containing an additional heteroatom selected from N, O or S and further substituted by hydrogen, C j _g alkyl, benzyl or OH;
  • R9 is hydrogen, C g alkyl, or -(CH2) m Ri5;
  • Rjo is hydrogen or C]_g alkyl;
  • Rjl is C -6 alkyl or benzyl
  • Rl2 is hydrogen or C j.g alkyl;
  • Rj4 is hydrogen or Cj. alkyl
  • X is O, S, or CH 2 ;
  • Y is a 5-7 member saturated heterocycle containin up to 2 heteroatoms selected from N, O or S, optionally substituted by hydrogen, C j_g alkyl or benzyl; n is 0, 1 or 2; m is 1 or 2 ; p is 0, 1 or 2; q is O or 1; provided that when Rj4 is OH, m must be 2; further provided that the compound of Formula (I) is not: 3,5-dichloro-4-hydroxy-N-[3- ⁇ t(3R)-l-methyl-3-pyrrolidinyl]oxy ⁇ -4- (trifluoromethyl)phenyl]benzenesulfonamide; 5-[cyclohexyl(hydroxy)methyl]-N-[3- ⁇ [(3R)-l-methyl-3-pyrrolidinyl]oxy ⁇ -4-
  • alkyl includes all straight chain and branched isomers. Representative examples thereof include methyl, ethyl, n-propyl, is o-propyl, w-butyl, sec-butyl, wo-butyl, t-butyl, n-pentyl and n-hexyl.
  • Tialogen' and halo' include fluorine, chlorine, bromine and iodine, and fluoro, chloro, bromo and iodo, respectively.
  • 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.
  • Ri is preferably phenyl, thienyl, furanyl, pyrroyl, pyridinyl, oxazoyl, imidazoyl, pyrimidinyl, pyrazoyl, or thiazoylsubstituted or unsubstituted by one, two, or three, of any of the following: CI, Br, F. CF 3 , OH, NO 2 , CN, C ⁇ _ 3 alkyl, Ci _ 3 alkoxy, O(CH 2 ) q Y, NR 5 R 6 , COR 10 , CONR 7 R 8 , S(O)pC!_3 alkyl, CO 2 H, or CH(OH)C 1 . 4 alkyl.
  • R2 is preferably hydrogen, CI, Br, CF3, or C j _2 alkyl.
  • R3 and R4 are preferably hydrogen, C ⁇ _3 alkyl, -C(Rj4)2-OR ⁇ 2-
  • R7 and Rg are preferably hydrogen, C j _3 alkyl, or taken together form morpholine or piperidine.
  • R5 and Rg are preferably hydrogen or C ⁇ _3 alkyl, or taken together form morpholine, piperidine, or pyrrolidine.
  • R9 is preferably hydrogen, C j _3 alkyl.
  • RjO i preferably hydrogen, C1.3 alkyl.
  • R 2 is preferably hydrogen or C ]_3 alkyl.
  • R j 4 is preferably independently hydrogen or methyl.
  • X is preferably O.
  • Y is preferably tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperadinyl, azetidinyl all of which may be optionaly substituted by Cj_3 alkyl
  • n is preferably 1.
  • p is 0, 1 or 2
  • q is 0 or 1
  • Preferred compounds are:
  • H r hydrogen peroxide, trifluoroacetic acid; s) sodium hydride, 2(S)3(R)-N-Boc-hydroxyproline methyl ester; t) 4M HCl, dioxane; u) formaldehyde, sodium triacetoxyborohydride; v) hydrogen, palladium on carbon; w) RlSO 2 Cl, pyridine; x) lithium aluminum hydride or lithium borohydride
  • Sulfonyl chlorides when not commercially available, can be prepared by methods known in the art: Shahripour, A.B. et al. Bioorg. Med. Chem. 2002, 10, 31; Cross, P.E. et al. J. 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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, 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, 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-II receptor antagonists, vasopeptidase inhibitors, diuretics, digoxin, and dual non-selective ⁇ -adrenoceptor and cq-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. *25j labeled U-II binding was quantitated by gamma counting. Nonspecific binding was defined by 125j ⁇ j_ II binding in the presence of 100 nM of unlabeled human U-II. Analysis of the data was performed by nonlinear least square fitting. Ca 2+ -n ⁇ obilization:
  • a microtitre plate based Ca 2+ -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 Molecular Devices, Sunnyvale, CA
  • 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 IM 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 1 is illustrative but not limiting embodiments of the present invention.
  • Example 2 The compound of Example 2 (3.20 g, 9.6 mmole) and formaldehyde (37% wt. in water, 0.94 g, 11.5 mmole, 1.2 eq) was dissolved in CH 2 C1 2 (70 ml). Na(OAc) BH (3.01 g, 14.4 mmole, 1.5 eq) was added and the resultant mixture was stirred at rt overnight. The mixture was concentrated under reduced pressure and then partitioned between CH2CI2 and H2O. The organic layer was dried (MgSO4) and concentrated in vacuo.
  • LiBH4 (0.24 g, 1.1 mmol) was added to a solution of the compound of Example 5 (0.6 g, 1.0 mmol) and THF (10 mL) and the resultant mixture was stirred at rt overnight. The mixture was then diluted with MeOH and concentrated. The residue was dissolved in MeOH (10 mL), 2N HCl was added (10 mL) and the solution allowed to stand overnight.
  • Aniline A (39 mg, 0.15 mmol) was dissolved in 1 mL of methylene chloride and treated with 4- bromobenzenesulfonyl chloride (46.0 mg, 0.18 mmol) and pyridine (0.024 mL, 0.30 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 10-137 The following examples were prepared according to the representative procedure in Example 1? using the appropriate sulfonyl chlorides as starting material, in some cases using acetonitrile rather than methylene chloride as the solvent, and in some cases also substituting Aniline A for Aniline B.
  • 2,5-difluoro-4-trifluoromethyl-aniline 500 mg, 2.54 mmol was dissolved in 1 mL of acetonitrile, cooled to 0 °C, and treated with tetrafluoroboric acid (48% aqueous solution, 0.498 mL, 3.81 mmol) and tert-butyl nitrite (0.453 mL, 3.81 mmol).
  • This reaction was maintained at 0 °C for one hour.
  • a suspension of CuCl (377 mg, 3.81 mmol) in 3 mL of glacial acetic acid at 0 °C was saturated with sulfur dioxide gas by bubbling the gas through the suspension with vigorous stirring for 30 minutes.
  • Aniline A (186 mg, 0.715 mmol) was dissolved in 2 mL of methylene chloride and treated with the product of Example 134a [2,5-difluoro-4-trifluoromethyl-benzenesulfonyl chloride] (200 mg, 0.715 mmol) and pyridine (1.0 mL, 12.4 mmol) with vigorous stirring at room temperature. The reaction mixture was maintained for 18 hours, and then the solvent was removed under reduced pressure.
  • Aniline B (162 mg, 0.715 mmol) was dissolved in 2 mL of methylene chloride and treated with the product of Example 134a [2,5-difluoro-4-trifluoromethyl-benzenesulfonyl chloride] (200 mg, 0.715 mmol) and pyridine (1.0 mL, 12.4 mmol) with vigorous stirring at room temperature. The reaction mixture was maintained for 18 hours, and then the solvent was removed under reduced pressure.
  • Example 136a t3-(methyloxy)-4-(trifluoromethyl)aniline] (500 mg, 2.62 mmol) was dissolved in 1 mL of acetonitrile, cooled to 0 °C, and treated with tetrafluoroboric acid (48% aqueous solution, 0.512 mL, 3.92 mmol) and tert-butyl nitrite (0.466 mL, 3.92 mmol). This reaction was maintained at 0 °C for one hour.
  • tetrafluoroboric acid 48% aqueous solution, 0.512 mL, 3.92 mmol
  • tert-butyl nitrite 0.466 mL, 3.92 mmol
  • Aniline B (243 mg, 1.07 mmol) was dissolved in 2 mL of acetonitrile and treated with the product of Example 136b [3-(methyloxy)-4-(trifluoromethyl) benzenesulfonyl chloride] (294.3 mg, 1.07 mmol) and pyridine (1.0 mL, 12.4 mmol) with vigorous stirring at room temperature. The reaction mixture was maintained for 18 hours, and then the solvent was removed under reduced pressure.
  • Aniline A (278 mg, 1.07 mmol) was dissolved in 2 mL of acetonitrile and treated with the product of Example 136b [3-(methyloxy)-4-(trifluoromethyl) benzenesulfonyl chloride] (294.3 mg, 1.07 mmol) and pyridine (1.0 mL, 12.4 mmol) with vigorous stirring at room temperature. The reaction mixture was maintained for 18 hours, and then the solvent was removed under reduced pressure.
  • Aniline A (1.00 g, 3.84 mmol) was dissolved in 30 mL of acetonitrile and treated with the product of Example 138a [4-fluoro-3-(trifluoromethyl) benzenesulfonyl chloride] (1.9 g, 7.23 mmol) and pyridine (1.24 mL, 15.4 mmol) with vigorous stirring at room temperature. The reaction mixture was maintained for 18 hours, and then the solvent was removed under reduced pressure.
  • Example 142a [3-(methyloxy)-4-(trifluoromethyl)aniline] (2.00 g, 10.5 mmol) was dissolved in 22 mL of anhydrous dioxane and 4.5 mL of acetic acid and cooled to 0 °C. Then, a solution of bromine (0.592 mL, 11.6 mmol) in 20 mL of anhydrous dioxane was added dropwise over a 10 minute period. The reaction was allowed to warm to room temperature and stir for one hour, after which time it was poured into 100 mL of IM NaOH and 100 mL of 2M sodium carbonate.
  • the aqueous suspension was extracted with methylene chloride (3 x 100 mL) and the combined organic layers were washed with 0.5 M sodium carbonate (100 mL), washed with saturated sodium chloride (100 mL), dried over sodium sulfate, filtered, and concentrated to 2.69 g (95 %) of an orange oil which crystallized upon standing. This material was used directly in the next step without further purification.
  • Example 145a [2-bromo-5-(methyloxy)-4-(trifluoromethyl) aniline] (1.00 g, 3.70 mmol) was dissolved in 2 mL of acetonitrile, cooled to 0 °C, and treated with tetrafluoroboric acid (48% aqueous solution, 0.554 mL, 4.24 mmol) and tert-butyl nitrite (0.504 mL, 4.24 mmol). This reaction was maintained at 0 °C for one hour.
  • the aqueous suspension was extracted with ether (2 x 200 mL) and the combined organic layers were washed twice with water (400 mL), washed once with saturated NaCl (400 mL), dried over sodium sulfate, filtered, and concentrated to 1.29 g (99 %) of a brown oil which was used directly in the next step without further purification.
  • Aniline A (368 mg, 1.42 mmol) was dissolved in 10 mL of acetonitrile and treated with the product of Example 145b [2-bromo-5-(methyloxy)-4-(trifluoromethyl)benzenesulfonyl chloride] (500 mg, 1.42 mmol) and pyridine (0.458 mL, 5.66 rnmol) with vigorous stirring at room temperature. The reaction mixture was maintained for 18 hours, and then the solvent was removed under reduced pressure.
  • Aniline B (322 mg, 1.42 mmol) was dissolved in 10 mL of acetonitrile and treated with the product of Example 145b [2-bromo-5-(methyloxy)-4-(trifluoromethyl)benzenesulfonyl chloride] (500 mg, 1.42 mmol) and pyridine (0.458 mL, 5.66 mmol) with vigorous stirring at room temperature. The reaction mixture was maintained for 18 hours, and then the solvent was removed under reduced pressure.
  • Example 147a [4-(methyloxy)-3-(trifluoromethyl)aniline] (500 mg, 2.62 mmol) was dissolved in 1 mL of acetonitrile, cooled to 0 °C, and treated with tetrafluoroboric acid (48% aqueous solution, 0.512 mL, 3.92 mmol) and tert-butyl nitrite (0.466 mL, 3.92 mmol). This reaction was maintained at 0 °C for one hour. In the meantime, a suspension of CuCl (388 mg, 3.92 mmol) in 3 mL of glacial acetic acid at 0 °C was saturated with sulfur dioxide gas by bubbling the gas through the suspension with vigorous stirring for 30 minutes.
  • tetrafluoroboric acid 48% aqueous solution, 0.512 mL, 3.92 mmol
  • tert-butyl nitrite 0.466 mL, 3.92 mmol
  • Aniline B (124 mg, 0.545 mmol) was dissolved in 2 mL of acetonitrile and treated with the product of Example 147b [4-(methyloxy)-3-(trifluoromethyl) benzenesulfonyl chloride] (149 mg, 0.543 mmol) and pyridine (1.0 mL, 12.4 mmol) with vigorous stirring at room temperature. The reaction mixture was maintained for 18 hours, and then the solvent was removed under reduced pressure.
  • Aniline A (142 mg, 0.545 mmol) was dissolved in 2 mL of acetonitrile and treated with the product of Example 147b [4-(methyloxy)-3-(trifluoromethyl) benzenesulfonyl chloride] (149 mg, 0.543 mmol) and pyridine (1.0 mL, 12.4 mmol) with vigorous stirring at room temperature. The reaction mixture was maintained for 18 hours, and then the solvent was removed under reduced pressure.
  • Aniline A (50 mg, 0.192 mmol) was dissolved in 2 mL of acetonitrile and treated with the product of Example 143a [5-methyl-2-thiophenesulfonyl chloride] (44 mg, 0.220 mmol) and pyridine (0.031 mL, 0.385 mmol) with vigorous stirring at room temperature. The reaction mixture was maintained for 18 hours, and then the solvent was removed under reduced pressure.
  • Aniline A (264 mg, 1.02 mmol) was dissolved in 6 mL of dichloromethane and pyridine (0.330 mL, 4.08 mmol) and treated with a solution of the product of Example 151a [5-bromo-4- methyl-2-thiophenesulfonyl chloride] (280 mg, 1.02 mmol) in 4 mL of dichloromethane with vigorous stirring at room temperature. The reaction mixture was maintained for 72 hours, and then the solvent was removed under reduced pressure.
  • reaction mixture was heated at 110 ° C for 16 h, and then at 140 °C for 3 days, after which time an additional amount of cyclohexylmercaptan (0.035 mL, 0.288 mmol) and 3N NaOH (0.096 mL, 0.288 mmol) was added and heated at 130 °C for an additional 18 hours.
  • the reaction mixture was allowed to cool to room temperature, was 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 14.9 mg (26 %) of the title compound as an oil.
  • MS (ES) m/e 599 [M+H]+
  • 3-fluoro-4-(trifluoromethyl)aniline (3.0 g, 16.8 mmol) was dissolved in 6 mL of acetonitrile, cooled to 0 °C, and treated with tetrafluoroboric acid (48% aqueous solution, 3.30 mL, 25.3 mmol) and tert-butyl nitrite (2.96 mL, 25.3 mmol). This reaction was maintained at 0 °C for one hour. In the meantime, a suspension of CuCl (2.50 g, 25.3 mmol) in 20 mL of acetonitrile at 0 °C was saturated with sulfur dioxide gas by bubbling the gas through the suspension with vigorous stirring for 30 minutes.
  • Example 152 [4-bromo-5- (cyclohexylthio)-N- [3- ⁇ [(3R)- 1 -methyl-3-pyrrolidinyl] oxy ⁇ -4-(trifluoromethyl) phenyl]-2- thiophenesulfonamide] except that the product of Example 154b [3-fluoro-N-[3- ⁇ [(3R)-l- methyl-3-pyrrolidinyl]oxy ⁇ -4-(trifluoromethyl)phenyl]-4-(trifluoromethyl) benzene- sulfonamide] was used in place of 4-Bromo-5-chloro-thiophene-2-sulfonic acid [3-((R)-l- methyl-pyrrolidin-3-yloxy)-4-trifluoromethyl-phenyl]-amide to give 28 mg (47%) of the title compound as an oil. MS (ES) m/
  • the title compound was prepared by a method similar to that of Example 153 [4-bromo-5- (butylthio)-N-[3- ⁇ [(3R)-l-methyl-3-pyrrolidinyl]oxy ⁇ -4-(trifluoromethyl) phenyl]-2- thiophenesulfonamide] except that the product of Example 148b [3-fluoro-N-[3- ⁇ [(3R)-l- methyl-3-pyrrolidmyl]oxy ⁇ -4-(trifluoromethyl)phenyl]-4-(trifluoromethyl) benzene- sulfonamide] was used in place of 4-Bromo-5-chloro-thiophene-2-sulfonic acid [3-((R)-l- methyl-pyrrolidin-3-yloxy)-4-trifluoromethyl-phenyl]-amide to give 35 mg (61%) ofthe title compound as an oil.
  • the title compound was prepared by a method similar to that of Example 156 [3- (cyclohexyloxy)-N-[3- ⁇ [(3R)-l-methyl-3-pyrrolidinyl]oxy ⁇ -4-(trifluoromethyl) phenyl]-4- (trifluoromethyl)benzenesulfonamide] except that n-butanol was used in place of cyclohexanol to give 42 mg (62 %) ofthe title compound as an oil.
  • reaction mixture was warmed to room temperature and left standing at ambient temperature for 18 h.
  • the solvent was removed in vacuo and the residue was partitioned in 1:1
  • the mixture was concentrated to -10 mL on a steam bath, replenished with MeOH (15 mL), reconcentrated to -10 mL, repeated the MeOH process two more times to ensure the removal ofthe volatile borates, finally the solvent was removed in vacuo to provide the crude product as a solid (1.04 g).
  • the solid was dissolved in 2.5 ⁇ NaOH ( ⁇ 5 mL), filtered to remove 0.11 g of the starting anisole.
  • the filtrate was acidified (pH 1) with cone. HCl and the resulting precipitate was filtered to provide 0.62 g of product.
  • Example 159e The procedure in Example 159e was used to prepare the title compound. Isolated 34.9 mg (8%): mp 168-170 °C. MS (ES) m/e 549 [M+H] + .
  • Example 162 N-r3-(l-methyl-2(S)-methoxycarbonylpyrrolidin-3(R)-yloxy)-4-trifluoromethylphenyl1-2- bromo-4,5-dimethoxybenzenesulfonamide and N-r3-(l-methyl-2(R)- methoxycarbonylpyrrolidin-3(R)-yloxy -4-trifluoromethylphenyl]-2-bromo-4-5- dimethoxybenzenesulfonamide:
  • H2O2 50% in H20, 42 ml 1.46mole, 7 eq
  • the mixture was stirred and heated at 45°C for 2 hr and 65°C for 40 min before being cooled to rt and poured into ice/water (600 ml). The mixture was stirred overnight. Ether (250 ml) was added and the organic layer was separated. The organic layer was washed with 10% HCl, saturated NaHCO3, twice with brine, dried (MgSO4) and concentrated in vacuo to give the title compound as a yellow oil (17.10 g, 96%).
  • LiBH4 (0.24 g, 1.1 mmol) was added to a solution ofthe compound of Example 162 (0.6 g, 1.0 mmol) and THF (10 mL) and the resultant mixture was stirred at rt overnight. The mixture was then diluted with MeOH and concentrated. The residue was dissolved in MeOH (10 mL), 2N HCl was added (10 mL) and the solution allowed to stand overnight.
  • Example 168-169 Using the procedure outlined in Example 161, the following compounds were prepared.
  • Example 171 Using the procedure of Example 164, the following compound was prepared:
  • MeMgBr (3 M in ether, 0.40 mL, 1.2 mmol) was added to a solution of the product from Example 156 (0.12 g, 0.20 mmol) and THF (2 mL). The resultant mixture was maintained at rt for 2 h then quenched with water. The mixture was extracted with CH2CI2 and then ether.
  • Example 174-175 Using the procedure of Example 167, the following compounds were prepared:
  • Example 177 Following the procedure of Example 176, except substituting isobutyraldehyde for propionaldehyde gave the following compound:
  • Example 183a [2-chloro-3-thiophenecarboxylic acid] (2.1 g , 14.6 mmol ) was added slowly to chlorosulphonic acid (5.1 mL, 5.2 equiv.) at 0°C. The resulting mix was then heated at 95°C for 2h. After cooling, the mix was poured into ice (Caution, Slow! !). The product was collected by filtration; drying left 2.67 g (71% yield). _R (film) 1377.97 cm “1 and 1161.23 cm- 1 .
  • n-BuLi (1.9 mL, 1.6 M in hexane) was added dropwise to a solution of 3-bromo-2- chlorothiophene (550 mg, 2.8 mmol) in dry THF(10 mL) at -78°C under argon. The resulting mixture was stirred at-78°C for 5 min. then 1-iodopropane (2.4 g, 13.9 mmol) was added . The mixture was stirred at -78°C for another 15 min. and then was quenched by adding water. The reaction mix was extracted with ether and the ether extracts were washed with saturatd ⁇ aCl, dried (MgSO 4 ) and concentrated to a light yellow solid.
  • Chlorosulfonic acid (739 Dl, 11 mmol) was then added dropwise to a solution of this material in CH 2 C1 2 (28 mL) at room temperature The resulting mixture was stirred at rt for 18 h. The mixture was concentrated and azetroped with toluene (x2) to remove excess chlorosulfonic acid and kept in vacuum for several hours. The crude mixture was then dissolved in CH 2 C1 2 (28 mL) and added dropwise to a mixture containing Aniline A (1.4g, 2.78 mmol) and pyridine (899 uL, 11.2 mmol).
  • Aqueous K 3 PO 4 (0.27 mL, 3 M, 0.81 mmol) was added followed by the addition of 4- bromo-5-chloro-N-[3- ⁇ [(3R)-l-methyl-3-pyrrolidinyl]oxy ⁇ -4-(trifluoromethyl)phenyl]-2- thiophenesulfonamide (83 mg, 0.16 mmol) in DMF (2 mL) and Pd (dppf)Cl 2 . (13 mg, 0.016 mmol). The resulting mixture was heated at 60°C for 18 h. The reaction mixture was concentrated invacuo and the residue was dissolved in EtOAc washed with water, saturated ⁇ aCl, dried (MgSO 4 ) and concentrated.
  • Tribromoborane 25 g, 100 mmol was added dropwise to a solution of 2-bromo-5-nitroanisole (7.94 g, 34.2 mmol) in methylene chloride (100 mL) at 0 °C. The solution was allowed to warm to room temperature and react for 16 h. The reaction was then quenched by the addition of methanol (20 mL) and stirred for 3 h. The solvent was removed under reduced pressure and the remaining residue purified by column chromatography (400 g silica gel 60, 230-400 mesh, 5-20% ethyl acetate/hexanes as eluent) to give 2-bromo-5-nitrophenol (6.2 g, 83%). MS (ES) m/e 217.6 [M+H]+.
  • Diisopropyl azodicarboxylate (3.34 g, 16.5 mmol) was added dropwise to a solution of 2- bromo-5-nitrophenol (3.0 g, 13.8 mmol), (3S)-l-methyl-3-pyrrolidinol (1.4 g, 13.8 mmol), and triphenylphosphine (4.33 g, 16.5 mmol) in methylene chloride (100 mL). The reaction was maintained for 16 h at room temperature.
  • Examples 190-193 The following examples were prepared in an analogous fashion to the representative procedure in Example 189 using the appropriate sulfonyl chlorides as starting material.
  • Examples 195-201 The following examples were prepared according to the representative procedure in Example 194 using the appropriate alcohols as starting material. For some of the alcohol starting materials, the reactions required heating the dimethylformamide solution at 50 °C for 16 h.
  • Example 202 4-amino-N-r3-ir( ' 3R)-l-methyl-3-pyrrolidinyl1oxy ⁇ -4-(trifluoromethyl)phenyl1-5-(tetrahvdro-
  • Example 210-212 The following examples were prepared according to the representative procedure in Example 209 using the appropriate aldehydes as starting material.
  • Examples 214-215 The following examples were prepared according to the representative procedure in Example 209 using the appropriate aldehydes as starting material.
  • Triethylsilane (0.5 mL) was added to a solution of 5-[cyclopropyl(hydroxy)methyl]-N-[3- ⁇ [(3R)- 1 -methyl-3-pyrrolidinyl] oxy ⁇ -4-(trifluoromethyl)phenyl]-2-thiophenesulf onamide (15 mg, 0.025 mmol) in trifluoroacetic acid (0.5 mL) and methylene chloride (0.2 mL). The reaction was maintained at room temperature for 16 h. The solution was concentrated under reduced pressure.
  • Examples 219-228 Following the general procedure in Example 1?? except substituting 4-bromo-5-chloro-2- thiophenesulfonyl chloride, 3-bromo-5-chloro-2-thiophenesulfonyl chloride, 5-bromo-2- thiophenesulfonyl chloride, 4-bromo-2-thiophenesulfonyl chloride, or 4-bromo-2,5-dichloro-3- thiophenesulfonyl chloride for 4,5-dichloro-2-thiophenesulfonyl chloride and/or 4-chloro-3- ((R)-l-methylpyrrolidin-3-yloxy)anline or 4-bromo-3-((R)-l-methylpyrrolidin-3-yloxy)anline for 4-trifluoromethyl-3-((R)-l-methylpyrrolidin-3-yloxy)anline the following compounds could be prepared.
  • 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 drug 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.

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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 angiotensm-π, 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+, CI") transport. Although a diuretic effect has been described, such an effect is postulated to be secondary to direct renovascular effects (elevated GFR)
• metabolism: urotensin-H 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-ϋ 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 H, 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-JJ 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:
Rx is phenyl, thienyl, furanyl, pyrroyl, pyridinyl, oxazoyl, indoyl, triazinyl, imidazoyl, pyrimidinyl, oxadiazoyl, pyrazoyl, triazoyl, thiazoyl, thiadiazoyl, or pyrazinyl substituted or unsubstituted by one, two , three, four or five of any of the following: halogen, CF3, OCF3, OH, SCF3, NO2, CN, Ci_6 alkyl, C g alkoxy, C^6 alkyl-CF3, O(CH2)qY, NR5R6, N(Ci.6 al y^CO^ g alkyl), COR10, CONR7R8, S(O)pC!.6 alkyl, CO2H, CO2(Cι_6 alkyl), Cλ_6 alkyl-CO2(Cι_6 alkyl), C^g alkyl-NHCORπ, or CH(OH)Cι_6 alkyl; R2 is hydrogen, halogen, CF3, CN, or C1.4 alkyl;
R3 and R4 are independently hydrogen, C ι_g alkyl, benzyl, -C(Ri4)2-ORi2> -COOR13, -
CONR12, -C(R14)2-N(R12)2;
R5 and Rg, are independently hydrogen or C]_g alkyl, or taken together form a 5-7-member saturated heterocycle optionally containing an additional heteroatom selected from N, O or S and further substituted by hydrogen, C]_g alkyl, benzyl or OH;
R7 and Rg are independently hydrogen, Cj.g alkyl, or benzyl; or taken together form a 5-7- member saturated heterocycle optionally containing an additional heteroatom selected from N, O or S and further substituted by hydrogen, Cj_g alkyl, benzyl or OH;
R9 is hydrogen, C g alkyl, or -(CH2)mRi5; Rjo is hydrogen or C]_g alkyl; Rjl is C -6 alkyl or benzyl Rl2 is hydrogen or C j.g alkyl;
^13 s C 1-6 aikyi; Rj4 is hydrogen or Cj. alkyl; R 5 is phenyl, OH, or -(C=O)C1.3alkyl; X is O, S, or CH2;
Y is a 5-7 member saturated heterocycle containin up to 2 heteroatoms selected from N, O or S, optionally substituted by hydrogen, C j_g alkyl or benzyl; n is 0, 1 or 2; m is 1 or 2 ; p is 0, 1 or 2; q is O or 1; provided that when Rj4 is OH, m must be 2; further provided that the compound of Formula (I) is not: 3,5-dichloro-4-hydroxy-N-[3-{t(3R)-l-methyl-3-pyrrolidinyl]oxy}-4- (trifluoromethyl)phenyl]benzenesulfonamide; 5-[cyclohexyl(hydroxy)methyl]-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; 5-(cyclohexylmethyl)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-(trifluoromethyl)phenyl]-2- thiophenesulfonamide; N-(4-chloro-3-{ [(3R)-l-methyl-3-pyrrolidinyl]oxy }phenyl)-4-fluorobenzenesulfonamide; ; 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, is o-propyl, w-butyl, sec-butyl, wo-butyl, t-butyl, n-pentyl and n-hexyl.
When used herein, the terms Tialogen' and halo' include fluorine, chlorine, bromine and iodine, and fluoro, chloro, bromo and iodo, respectively.
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.
Ri is preferably phenyl, thienyl, furanyl, pyrroyl, pyridinyl, oxazoyl, imidazoyl, pyrimidinyl, pyrazoyl, or thiazoylsubstituted or unsubstituted by one, two, or three, of any of the following: CI, Br, F. CF3, OH, NO2, CN, Cι _3 alkyl, Ci _3 alkoxy, O(CH2)qY, NR5R6, COR10, CONR7R8, S(O)pC!_3 alkyl, CO2H, or CH(OH)C1.4 alkyl.
R2 is preferably hydrogen, CI, Br, CF3, or Cj_2 alkyl.
R3 and R4 are preferably hydrogen, C^_3 alkyl, -C(Rj4)2-OR^2-
R7 and Rg are preferably hydrogen, Cj_3 alkyl, or taken together form morpholine or piperidine. R5 and Rg are preferably hydrogen or Cι_3 alkyl, or taken together form morpholine, piperidine, or pyrrolidine.
R9 is preferably hydrogen, Cj_3 alkyl.
RjO i preferably hydrogen, C1.3 alkyl.
R 2 is preferably hydrogen or C ]_3 alkyl. Rj4 is preferably independently hydrogen or methyl.
X is preferably O.
Y is preferably tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperadinyl, azetidinyl all of which may be optionaly substituted by Cj_3 alkyl n is preferably 1. p is 0, 1 or 2 q is 0 or 1
Preferred compounds are:
N-[3-(l-methyl-2(S)-methoxycarbonylpyrrolidin-3(R)-yloxy)-4- trifluoromethylphenyl]-2-bromo-4,5-dimethoxybenzenesulfonamide;
N-t3-(2(S)-hydroxymethyl-l-methylpyrrolidin-3(R)-yloxy)-4-trifluoromethylphenyl]- 2-bromo-4,5-dimethoxybenzenesulfonamide; N-[3-(2(R)-hydroxymethyl- 1 -methylpyrrolidin-3 (R)-yloxy)-4-trifluoromethylphenyl]-
2-bromo-4,5-dimethoxybenzenesulfonamide;
N-[3-(2(S)-hydroxymethyl-l-methylρyrrolidin-3(R)-yloxy)-4-trifluoromethylphenyl]- 4,5-dimethoxybenzenesulfonamide;
N-[3-((R)-pyrrolidin-3-yloxy)-4-trifluoromethylphenyl]-2-bromo-4,5- dimethoxybenzenesulfonamide.
Compounds of Formula (I) may be prepared as outlined in Scheme 1.
Scheme 1
Figure imgf000007_0001
q) mercaptan, NaOH solution, DMF, heat. (X is CI or Br, Z from the list of substuients on Rl)
Scheme 2
Figure imgf000008_0001
Figure imgf000008_0002
H
Figure imgf000008_0003
r) hydrogen peroxide, trifluoroacetic acid; s) sodium hydride, 2(S)3(R)-N-Boc-hydroxyproline methyl ester; t) 4M HCl, dioxane; u) formaldehyde, sodium triacetoxyborohydride; v) hydrogen, palladium on carbon; w) RlSO2Cl, pyridine; x) lithium aluminum hydride or lithium borohydride
Scheme 3
Figure imgf000008_0004
y) RCHO, sodium cyanoborohydride or RBr, potassium iodide, potassium carbonate.
Scheme 4
Figure imgf000008_0005
z) cesium carbonate, DMF, ROH. aa) iron powder, HOAc. (R is alkyl)
Scheme 5
Figure imgf000008_0006
bb) n-BuLi, RCHO, THF, -78°C. cc) Triethylsilane, TFA, CH2C12, rt. (Y is halogen or hydrogen)
Sulfonyl chlorides, when not commercially available, can be prepared by methods known in the art: Shahripour, A.B. et al. Bioorg. Med. Chem. 2002, 10, 31; Cross, P.E. et al. J. 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.
Anilines A and B have been previously described: WO 2002089792 Al incorporated by reference herein.
Figure imgf000009_0001
Aniline A Anline B
With appropriate manipulation, including the use of alternative nitrogen protecting group(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, 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, 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-II receptor antagonists, vasopeptidase inhibitors, diuretics, digoxin, and dual non-selective β-adrenoceptor and cq-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. *25j labeled U-II binding was quantitated by gamma counting. Nonspecific binding was defined by 125j χj_ 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+-nιobilization:
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 IM 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 IM 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 = 1 nM - 10000 nM. (Example 6 = 21nm)
The following Examples are illustrative but not limiting embodiments of the present invention. Example 1
3-Fluoro-4-trifluoromethylnitrobenzene:
3-Fluoro-4-trifluoromethylaniline (15.10 g, 85.4 mmole) was dissolved on CF3CO2H
(85 ml). H2O2 (50% in H2O, 42 ml 1.46mole, 7 eq) was added dropwise over 35 min. The mixture was stirred and heated at 45 °C for 2 hr and 65 °C for 40 min before being cooled to it and poured into ice/water (600 ml). The mixture was stirred overnight. Ether (250 ml) was added and the organic layer was separated. The organic layer was washed with 10% HCl, saturated NaHCO3, twice with brine, dried (MgSO4) and concentrated in vacuo to give the title compound as a yellow oil (17.10 g, 96%).
Example 2
3-r2(S)-methoxycarbonylpyrrolidin-3 (R)-yloxyl -4-trifluoromethyl nitrobenzene :
A solution ofthe compound of Example 1 (3.14 g, 15 mmole) and 2(S)3(R)-N-tert- butoxycarbonylhydroxyproline methyl ester (3.68g, 15 mmole) in dry THF (75 ml) was cooled to 0°C and then NaH (60% in mineral oil, 1.20 g, 30 mmole) was added protionwise over 5 rnin. The mixture was stirred and allowed to warm to rt. Once at rt, the mixture was stirred an additional 2 hr. The solvent was removed under reduced pressure and then the residue was dissolved in MeOH (75 ml). 4M HCl in dioxane (20 ml) was added and the resultant mixture was stirred at rt overnight. The mixture was concentrated under reduced pressure and the residue partitioned between H O and CH2CI2. The aqueous layer was adjusted to pH 7 using aqueous Na CO3 and then was extracted with CH2C-2. The CH2CI2 layer was dried (MgSO4) and concentrated to give the title compound as a yellow oil (2.50 g, 50%). MS (ES) m/e 335.2
[M+H]+.
Example 3
3-ri-methyl-2(R S)-methoxycarbonylpyrrolidin-3(R)-yloxyl-4-trifluoromethyl nitrobenzene:
The compound of Example 2 (3.20 g, 9.6 mmole) and formaldehyde (37% wt. in water, 0.94 g, 11.5 mmole, 1.2 eq) was dissolved in CH2C12 (70 ml). Na(OAc) BH (3.01 g, 14.4 mmole, 1.5 eq) was added and the resultant mixture was stirred at rt overnight. The mixture was concentrated under reduced pressure and then partitioned between CH2CI2 and H2O. The organic layer was dried (MgSO4) and concentrated in vacuo. The crude mixture was purified by column chromatography (150 g silica gel 60, 230-400 mesh, CH2CI2 then 1% MeOH in CH2C12 then 2% MeOH in CH2C12 as eluent) to give 2.80 g (73%) of a mixture of diastereomers as a yellow oil. MS (ES) m/e 349.0 [M+H]+.
Example 4 3-ri-Methyl-2(R/S)-methoxycarbonylpyrrolidin-3(R)-yloxy1-4-trifluoromethyl aniline:
Pd-C (10 %, 0.9g) added to a solution the compound of Example 3 (1.96 g, 5.6 mmol) and MeOH (50 mL). The resulting mixture was shaken under a H2 atmosphere (50 psi) for 3h. The mixture was then filtered through a pad of Celite and the filtrate concentrated under reduced pressure to give 1.8 g (100%) of the title compound as a tan oil. MS (ES) m/e 319.2
[M+H]+.
Example 5 N-[3-( 1 -methyl-2(S)-methoxycarbonylpyrrolidin-3(R)-yloxy)-4-trifluoromethylphenyl]-2- bromo-4,5-dimethoxybenzenesulfonamide:
Pyridine (0.35 g, 4.4 mmol), followed by the compound of Example 4 (1.41 g, 4.4 mmol) was added to a solution of 2-bromo-4,5-dimethoxybenzenesulfonyl chloride (1.40 g, 4.4 mmol) and acetonitrile (10 mL). The resultant mixture was stirred at rt overnight. The mixture was concentrated and purified by silica gel chromatography COMBIFLASH CONDITIONS to give 1.24 g (47%) of N-[3-(l-methyl-2(S)-methoxycarbonylpyrrolidin-3(R)-yloxy)-4- trifluoromethylphenyl]-2-bromo-4,5-dimethoxybenzenesulfonamide. MS (ES+) m/e 597.2 [M+H]+. and XXX g (XX%) of N-[3-(l-methyl-2(R)-methoxycarbonylpyrrolidin-3(R)-yloxy)- 4-trifluoromethylphenyl]-2-bromo-4,5-dimethoxybenzenesulfonamide. MS (ES) m/e 597.2
[M+H]+.
Example 6 N-r3-(2(S)-hydroxymethyl-l-methylpyrrolidin-3(R)-yloxy)-4-trifluoromethylphenyl1-2-bromo- 4-5-dimethoxybenzenesulfonamide:
LiBH4 (0.24 g, 1.1 mmol) was added to a solution of the compound of Example 5 (0.6 g, 1.0 mmol) and THF (10 mL) and the resultant mixture was stirred at rt overnight. The mixture was then diluted with MeOH and concentrated. The residue was dissolved in MeOH (10 mL), 2N HCl was added (10 mL) and the solution allowed to stand overnight. The solution was then concentrated in vacuo and purified by preparative HPLC (YMC CombiPrep ODS-A, 50 x 20 mm, 20 mL/min, A: acetonitrile B: water, A: 10 to 90% during 10 min, UN detection at 214 nm) to give 100 mg (17%) of the title compound as a white solid. MS (ES) m/e 569.2
[M+H]+.
Example 7 Ν-[3-(2(R)-hydroxymethyl-l-methylpyrrolidin-3(R)-yloxy)-4-trifluoromethylphenyl]-2-bromo- 4,5-dimethoxybenzenesulfonamide:
L1BH4 (24 mg, 0.11 mmol) was added to a solution of the compound of Example 6 (60 mg, 0.1 mmol) and THF (1 mL). The resultant mixture was stirred at rt overnight. Satd NH4CI was added and the mixture extracted with C^C^- The organic layers were combined, dried (MgSO4) and concentrated in vacuo. The residue was dissolved in CH2CI2 (10 mL) and 2N HCl (2 mL) and stirred overnight. The mixture was concentrated under reduced pressure and purified by preparative HPLC (YMC CombiPrep ODS-A, 50 x 20 mm, 20 mL/min, A: acetonitrile B: water, A: 10 to 90% during 10 min, UN detection at 214 nm) to give 4.4 mg
(8%) of the title compound as a tan oil. MS (ES) m/e 569.2 [M+H]+. Example 8 N-r3-(2(S)-hvdroxymethyl-l-methylpyrrolidin-3(R)-yloxy)-4-trifluoromethylphenyll-3-4- dimethoxybenzenesulfonamide:
A solution of the compound of Example 6 (0.30 g, 0.50 mmol) and THF (2mL) was added dropwise to a solution of 1 M L1AIH4 in ether (1.0 mL, 1.0 mmol). The mixture was stirred at rt for 20 min and then another portion of L1AIH4 (2.0 mL, 2.0 mmol) was added. The mixture was stirred an additional 45 min before being quenched with water (0.22 mL) and NaF (0.38 g, 9.1 mmol). The mixture was filtered through a pad of Celite and the filtrate concentrated in vacuo. The residue was purified by preparative HPLC (YMC CombiPrep ODS-A, 50 x 20 mm, 20 mL/min, A: acetonitrile B: water, A:10 to 90% during 10 min, UN detection at 214 nm) to give 35 mg (14%) of the title compound as a tan solid. MS (ES) m/e 491.2 [M+H1+.
Example 9 4-bromo-Ν-r3-{ r(3R)-l-methyl-3-pyrrolidinvnoxyl-4-(trifluoromethyl)phenyll benzenesulfonamide:
Figure imgf000015_0001
Aniline A (39 mg, 0.15 mmol) was dissolved in 1 mL of methylene chloride and treated with 4- bromobenzenesulfonyl chloride (46.0 mg, 0.18 mmol) and pyridine (0.024 mL, 0.30 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 47.7 mg (66%) of the title compound as a pale yellow oil. MS (ES) m/e 479 [M+H]+
Examples 10-137 The following examples were prepared according to the representative procedure in Example 1? using the appropriate sulfonyl chlorides as starting material, in some cases using acetonitrile rather than methylene chloride as the solvent, and in some cases also substituting Aniline A for Aniline B.
Figure imgf000016_0001
Figure imgf000017_0001
Figure imgf000018_0001
Figure imgf000019_0001
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Example 138 4-amino-N-r3-ir(3R)-l-methyl-3-pyrrolidinyl1oxyl-4-(trifluoromethyl)phenyl1 benzenesulfonamide :
Figure imgf000032_0001
N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-(trifluoromethyl)phenyl]-4- nitrobenzenesulfonamide (216 mg, 0.487 mmol) was dissolved in 5 mL of methanol and the solution was degassed with argon. Then, the solution was treated with 10 % Pd on Carbon (21.6 mg) and the flask was flushed with hydrogen gas. The reaction was stirred under an atmosphere of hydrogen for 18 hours, and then the mixture was filtered through Celite and concentrated to dryness under vacuum to give 188.9 mg (93 %) of the title compound as a white powder. MS (ES) m/e 417 [M+H]+
Example 139 4-amino-2.5-bis(methyloxy)-N-r3-f r(3R)-l-methyl-3-pyrrolidinylloxy|-4- (trifluoromethyl)phenvnbenzenesulfonamide
Figure imgf000032_0002
2,5-bis(methyloxy)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-(trifluoromethyl)phenyl]-4- nitrobenzenesulfonamide (54.6 mg, 0.108mmol) was dissolved in 5 mL of methanol and the solution was degassed with argon. Then, the solution was treated with 10 % Pd on Carbon (5.5 mg) and the flask was flushed with hydrogen gas. The reaction was stirred under an atmosphere of hydrogen for 18 hours, and then the mixture was filtered through Celite and concentrated to dryness under vacuum to give 44.5 mg (87 %) of the title compound as a colorless film. MS (ES) m/e 476 [M+H]+
Example 140
2.5-difluoro-N-r3-ir(3R)-l-methyl-3-pyrrolidinvnoxyl-4-(trifluoromethyl) phenyl]-4- (trifluoromethyl)benzenesulfonamide
Figure imgf000032_0003
a) 2.5-difluoro-4-trifluoromethyl-benzenesulfonyl chloride
Figure imgf000033_0001
2,5-difluoro-4-trifluoromethyl-aniline (500 mg, 2.54 mmol) was dissolved in 1 mL of acetonitrile, cooled to 0 °C, and treated with tetrafluoroboric acid (48% aqueous solution, 0.498 mL, 3.81 mmol) and tert-butyl nitrite (0.453 mL, 3.81 mmol). This reaction was maintained at 0 °C for one hour. In the meantime, a suspension of CuCl (377 mg, 3.81 mmol) in 3 mL of glacial acetic acid at 0 °C was saturated with sulfur dioxide gas by bubbling the gas through the suspension with vigorous stirring for 30 minutes. When the diazotization reaction was complete after one hour, this solution was added dropwise to the suspension of CuCl, and the vigorous evolution of nitrogen gas was observed. The reaction was then allowed to warm to room temperature and stir for one hour, after which time it was poured onto 35 mL of an ice/water slurry, causing the product to precipitate as 401.1 mg (56 %) of an orange solid which was used directly in the next step without further purification, b) 2.5-difluoro-N-r3-ir('3R)-l-methyl-3-pyrrolidinvnoxyl-4-(trifluoromethyl) phenyl1-4- (trifluoromethyl)benzenesulfonamide
Figure imgf000033_0002
Aniline A (186 mg, 0.715 mmol) was dissolved in 2 mL of methylene chloride and treated with the product of Example 134a [2,5-difluoro-4-trifluoromethyl-benzenesulfonyl chloride] (200 mg, 0.715 mmol) and pyridine (1.0 mL, 12.4 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 2 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 10.9 mg (3%) of the title compound as a yellow solid. MS (ES) m/e 505 [M+H]+
Example 141 Ν-(4-chloro-3-ir(3R)-l-methyl-3-pyrrolidinyl1oxylphenyl)-2,5-difluoro-4- (trifluoromethyl)benzenesulfonamide
Figure imgf000034_0001
Aniline B (162 mg, 0.715 mmol) was dissolved in 2 mL of methylene chloride and treated with the product of Example 134a [2,5-difluoro-4-trifluoromethyl-benzenesulfonyl chloride] (200 mg, 0.715 mmol) and pyridine (1.0 mL, 12.4 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 2 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 72.4 mg (22%) ofthe title compound as a yellow solid. MS (ES) m/e 471 [M+H]+
Example 142 Ν-(4-chloro-3-{r(3R)-l-methyl-3-pyrrolidinylloxy}phenyl)-3-(methyIoxy)-4- (trifluoromethyl)benzenesulfonamide
Figure imgf000034_0002
a) 3-(methyloxy)-4-(trifluoromethyl)aniline
Figure imgf000034_0003
2-(methyloxy)-4-nitro-l-(trifluoromethyl)benzene (5.00 g, 22.6 mmol) was dissolved in 200 mL of methanol and the solution was degassed with argon. Then, the solution was treated with 10 % Pd on Carbon (800 mg) and the flask was flushed with hydrogen gas. The reaction was stirred under an atmosphere of hydrogen for 18 hours, and then the mixture was filtered through Celite and concentrated to dryness and under vacuum and crystallized to give 4.20 g
(97 %) of the product as a light orange crystalline solid. MS (ES) m/e 192 [M+H]+
b) 3-(methyloxy)-4-(trifluoromethyl)benzenesulfonyl chloride
The product of Example 136a t3-(methyloxy)-4-(trifluoromethyl)aniline] (500 mg, 2.62 mmol) was dissolved in 1 mL of acetonitrile, cooled to 0 °C, and treated with tetrafluoroboric acid (48% aqueous solution, 0.512 mL, 3.92 mmol) and tert-butyl nitrite (0.466 mL, 3.92 mmol). This reaction was maintained at 0 °C for one hour. In the meantime, a suspension of CuCl (388 mg, 3.92 mmol) in 3 mL of glacial acetic acid at 0 °C was saturated with sulfur dioxide gas by bubbling the gas through the suspension with vigorous stirring for 30 minutes. When the diazotization reaction was complete after one hour, this solution was added dropwise to the suspension of CuCl, and the vigorous evolution of nitrogen gas was observed. The reaction was then allowed to warm to room temperature and stir for one hour, after which time it was poured onto 35 mL of an ice/water slurry, causing the product to precipitate as 588.6 mg (82 %) of a water-insoluble brown oil which was separated from the aqueous layer via pipette, dissolved in diethyl ether, dried over anhydrous sodium sulfate, filtered, and concentrated to a crude oil which was used directly in the next step without further purification.
c) N-(4-chloro-3-{r("3R)-l-methyl-3-pyrrolidinynoxy}phenyl)-3-(methyloxy)-4- (trifluoromethyl)benzenesulfonamide
Figure imgf000035_0001
Aniline B (243 mg, 1.07 mmol) was dissolved in 2 mL of acetonitrile and treated with the product of Example 136b [3-(methyloxy)-4-(trifluoromethyl) benzenesulfonyl chloride] (294.3 mg, 1.07 mmol) and pyridine (1.0 mL, 12.4 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 2 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 207.2 mg (42%) of the title compound as a tan solid. MS (ES) m e 465 [M+H]+
Example 143 3-(methyloxy)-Ν-r3-{ r(3R)-l-methyl-3-pyrrolidinylloxy }-4-(trifluoromethyl) phenyll-4- (trifluoromethyl)benzenesulfonamide
Figure imgf000036_0001
Aniline A (278 mg, 1.07 mmol) was dissolved in 2 mL of acetonitrile and treated with the product of Example 136b [3-(methyloxy)-4-(trifluoromethyl) benzenesulfonyl chloride] (294.3 mg, 1.07 mmol) and pyridine (1.0 mL, 12.4 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 2 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 110.6 mg (21%) of the title compound as a tan solid. MS (ES) m/e 499 [M+H]+
Example 144 4-fluoro-Ν-r3-ir(3R)-l-methyl-3-pyrrolidinyl1oxyl-4-(trifluoromethyl)phenyl1-3- (trifluoromethyl)benzenesulfonamide
Figure imgf000036_0002
a) 4-fluoro-3-(trifluoromethyl)benzenesulfonyl chloride
Figure imgf000036_0003
4-fluoro-3-(trifluoromethyl)aniline (1.40 g, 7.82 mmol) was dissolved in 3 mL of acetonitrile, cooled to 0 °C, and treated with tetrafluoroboric acid (48% aqueous solution, 1.53 mL, 11.7 mmol) and tert-butyl nitrite (1.39 mL, 11.7 mmol). This reaction was maintained at 0 °C for one hour. In the meantime, a suspension of CuCl ( 1.16 g, 11.7 mmol) in 9 mL of glacial acetic acid at 0°C was saturated with sulfur dioxide gas by bubbling the gas through the suspension with vigorous stirring for 30 minutes. When the diazotization reaction was complete after one hour, this solution was added dropwise to the suspension of CuCl, and the vigorous evolution of nitrogen gas was observed. The reaction was then allowed to warm to room temperature and stir for one hour, after which time it was poured onto 200 mL of an ice/water slurry. The aqueous suspension was extracted with ether (2 x 200 mL) and the combined organic layers were washed twice with water (400 mL), washed once with saturated NaCl (400 mL), dried over sodium sulfate, filtered, and concentrated to 1.9 g (93%) of an orange oil which was used directly in the next step without further purification.
b) 4-fluoro-N-r3-ir('3RVl-methyl-3-pyrrolidinvnoxyl-4-(trifluoromethyl)phenyl1-3- (trifluoromethyl)benzenesulfonamide
Figure imgf000037_0001
Aniline A (1.00 g, 3.84 mmol) was dissolved in 30 mL of acetonitrile and treated with the product of Example 138a [4-fluoro-3-(trifluoromethyl) benzenesulfonyl chloride] (1.9 g, 7.23 mmol) and pyridine (1.24 mL, 15.4 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 5 mL of DMSO and purified by preparative HPLC (YMC CombiPrep ODS-A, 50 x 50 mm, 50 mL/min, A: acetonitrile B: water, A: 5% to 95% during 15 min, UN detection at 214 nm) to give 1.04 g (56%) of the title compound as a yellow foam. MS (ES) m/e 487 [M+H]+
Example 145 2-bromo-5-(methyloxy)-Ν-r3-ir(3R)-l-methyl-3-pyrrolidinyl1oxyl-4-(trifluoromethyl)phenyl1- 4-(trifluoromethyl)benzenesulfonamide
Figure imgf000037_0002
a) 2-bromo-5-(methyloxy)-4-(trifluoromethyl)aniline
Figure imgf000037_0003
The product of Example 142a [3-(methyloxy)-4-(trifluoromethyl)aniline] (2.00 g, 10.5 mmol) was dissolved in 22 mL of anhydrous dioxane and 4.5 mL of acetic acid and cooled to 0 °C. Then, a solution of bromine (0.592 mL, 11.6 mmol) in 20 mL of anhydrous dioxane was added dropwise over a 10 minute period. The reaction was allowed to warm to room temperature and stir for one hour, after which time it was poured into 100 mL of IM NaOH and 100 mL of 2M sodium carbonate. The aqueous suspension was extracted with methylene chloride (3 x 100 mL) and the combined organic layers were washed with 0.5 M sodium carbonate (100 mL), washed with saturated sodium chloride (100 mL), dried over sodium sulfate, filtered, and concentrated to 2.69 g (95 %) of an orange oil which crystallized upon standing. This material was used directly in the next step without further purification.
b) 2-bromo-5-(methyloxy)-4-(trifluoromethyl)benzenesulfonyl chloride
The product of Example 145a [2-bromo-5-(methyloxy)-4-(trifluoromethyl) aniline] (1.00 g, 3.70 mmol) was dissolved in 2 mL of acetonitrile, cooled to 0 °C, and treated with tetrafluoroboric acid (48% aqueous solution, 0.554 mL, 4.24 mmol) and tert-butyl nitrite (0.504 mL, 4.24 mmol). This reaction was maintained at 0 °C for one hour. In the meantime, a suspension of CuCl (420 mg, 4.24 mmol) in 3 mL of glacial acetic acid at 0 °C was saturated with sulfur dioxide gas by bubbling the gas through the suspension with vigorous stirring for 30 minutes. When the diazotization reaction was complete after one hour, this solution was added dropwise to the suspension of CuCl, and the vigorous evolution of nitrogen gas was observed. The reaction was then allowed to warm to room temperature and stir for one hour, after which time it was poured onto 200 mL of an ice/water slurry. The aqueous suspension was extracted with ether (2 x 200 mL) and the combined organic layers were washed twice with water (400 mL), washed once with saturated NaCl (400 mL), dried over sodium sulfate, filtered, and concentrated to 1.29 g (99 %) of a brown oil which was used directly in the next step without further purification.
c) 2-bromo-5-(methyloxy)-N-r3-{r(3R)-l-methyl-3-pyrrolidinylloxy}-4- (trifluoromethyl)phenvn-4-(trifluoromethyl)benzenesulfonamide
Figure imgf000038_0002
Aniline A (368 mg, 1.42 mmol) was dissolved in 10 mL of acetonitrile and treated with the product of Example 145b [2-bromo-5-(methyloxy)-4-(trifluoromethyl)benzenesulfonyl chloride] (500 mg, 1.42 mmol) and pyridine (0.458 mL, 5.66 rnmol) 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 3 mL of DMSO and purified by preparative HPLC (YMC CombiPrep ODS-A, 50 x 50 mm, 50 mL/min, A: acetonitrile B: water, A: 5% to 95% during 15 min, UN detection at 214 nm) to give 204.9 mg (25%) ofthe title compound as a pink solid. MS (ES) m/e 577 [M+H]+
Example 146 2-bromo-Ν-('4-chloro-3-{r(3R)-l-methyl-3-pyrrolidinynoxy)phenyl)-5-(methyloxy)-4- (trifluoromethyl)benzenesulfonamide
Figure imgf000039_0001
Aniline B (322 mg, 1.42 mmol) was dissolved in 10 mL of acetonitrile and treated with the product of Example 145b [2-bromo-5-(methyloxy)-4-(trifluoromethyl)benzenesulfonyl chloride] (500 mg, 1.42 mmol) and pyridine (0.458 mL, 5.66 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 3 mL of DMSO and purified by preparative HPLC (YMC CombiPrep ODS-A, 50 x 50 mm, 50 mL/min, A: acetonitrile B: water, A: 5% to 95% during 15 min, UN detection at 214 nm) to give 170.9 mg (22%) of the title compound as a beige solid. MS (ES) m/e 543 [M+H]+
Example 147 Ν-(4-chloro-3-{r(3R)-l-methyl-3-pyrrolidinyl1oxy|phenyl)-4-('methyloxy)-3- (trifluoromethyl)benzenesulfonamide
Figure imgf000039_0002
a) 4-(methyloxy)-3-(trifluoromethyl)aniline
Figure imgf000039_0003
l-(methyloxy)-4-nitro-2-(trifluoromethyl)benzene (7.00 g, 31.7 mmol) was dissolved in 200 mL of methanol and the solution was degassed with argon. Then, the solution was treated with 10 % Pd on Carbon (1.05 g) and the flask was flushed with hydrogen gas. The reaction was stirred under an atmosphere of hydrogen for 18 hours, and then the mixture was filtered through Celite and concentrated to dryness under vacuum to give 5.70 g (94 %) of the product as a dark brown solid which was used in the next step without further purification. b) 4-fmethyloxy)-3-(trifluoromethyl)benzenesulfonyl chloride
Figure imgf000040_0001
The product of Example 147a [4-(methyloxy)-3-(trifluoromethyl)aniline] (500 mg, 2.62 mmol) was dissolved in 1 mL of acetonitrile, cooled to 0 °C, and treated with tetrafluoroboric acid (48% aqueous solution, 0.512 mL, 3.92 mmol) and tert-butyl nitrite (0.466 mL, 3.92 mmol). This reaction was maintained at 0 °C for one hour. In the meantime, a suspension of CuCl (388 mg, 3.92 mmol) in 3 mL of glacial acetic acid at 0 °C was saturated with sulfur dioxide gas by bubbling the gas through the suspension with vigorous stirring for 30 minutes. When the diazotization reaction was complete after one hour, this solution was added dropwise to the suspension of CuCl, and the vigorous evolution of nitrogen gas was observed. The reaction was then allowed to warm to room temperature and stir for one hour, after which time it was poured onto 200 mL of an ice/water slurry. The aqueous suspension was extracted with ether (2 x 100 mL) and the combined organic layers were washed twice with water (200 mL), washed once with saturated NaCl (200 mL), dried over sodium sulfate, filtered, and concentrated to 298 mg (41 %) of an orange oil which was used directly in the next step without further purification.
c) N-(4-chloro-3-ir('3R)-l-methyl-3-pyrrolidinynoxy)phenyl)-4-fmethyloxy)-3- (trifluoromethvDbenzenesulfonamide
Figure imgf000040_0002
Aniline B (124 mg, 0.545 mmol) was dissolved in 2 mL of acetonitrile and treated with the product of Example 147b [4-(methyloxy)-3-(trifluoromethyl) benzenesulfonyl chloride] (149 mg, 0.543 mmol) and pyridine (1.0 mL, 12.4 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 2 mL of DMSO and purified by preparative HPLC (YMC CombiPrep ODS-A, 50 x 50 mm, 50 mL/min, A: acetonitrile B: water, A: 5% to 95% during 15 min, UN detection at 214 nm) to give 91.9 mg (36%) of the title compound as a tan solid. MS (ES) m/e 465 [M+H]+ Example 148 4-(methyloxy)-N-r3-ir(3R)-l-methyl-3-pyrrolidinyl1oxy)-4-(trifluoromethyl) phenyl1-3- (trifluoromethvDbenzenesulfonamide
Figure imgf000041_0001
Aniline A (142 mg, 0.545 mmol) was dissolved in 2 mL of acetonitrile and treated with the product of Example 147b [4-(methyloxy)-3-(trifluoromethyl) benzenesulfonyl chloride] (149 mg, 0.543 mmol) and pyridine (1.0 mL, 12.4 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 2 mL of DMSO and purified by preparative HPLC (YMC CombiPrep ODS-A, 50 x 50 mm, 50 mL/min, A: acetonitrile B: water, A: 5% to 95% during 15 min, UN detection at 214 nm) to give 73.0 mg (27%) of the title compound as a light brown solid. MS (ES) m/e 499 [M+H]+
Example 149 5-Methyl-thiophene-2-sulfonic acid f((R)- 1 -methyl-pyrrolidin-3-yloxy)- 4-trifluoromethyl-phenvn -amide
Figure imgf000041_0002
a) 5-methyl-2-thiophenesulfonyl chloride
Figure imgf000041_0003
A solution of 2-methylthiophene (507 mg, 5.16 mmol) in 5 mL of dichloromethane was added dropwise to a solution of chlorosulfonic acid (1.20 g, 10.3 mmol) in 5 mL of dichloromethane at -10 °C. The mixture was stirred at this temperature for 45 minutes and then poured onto an ice-water slurry and extracted twice with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated to give 180 mg (18 %) of the product which was used directly in the next step without further purification. b) 5-Methyl-thiophene-2-sulf onic acid K(R)-1 -methyl-pyrrolidin-3-yloxy)- 4-trifluoromethyl-phenvn-amide
Figure imgf000042_0001
Aniline A (50 mg, 0.192 mmol) was dissolved in 2 mL of acetonitrile and treated with the product of Example 143a [5-methyl-2-thiophenesulfonyl chloride] (44 mg, 0.220 mmol) and pyridine (0.031 mL, 0.385 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 15 min, UN detection at 214 nm) to give 32 mg (40%) ofthe title compound as a white microcrystalline solid. MS (ES) m/e 421 [M+H]+
Example 150 5-methyl-Ν-r3-{r(3R)-l-methyl-3-pyrrolidinvnoxyl-4-(trifluoromethyl)phenyll-Ν-r(5-methyl- 2-thienyl)sulfonyll-2-thiophenesulfonamide
Figure imgf000042_0002
Also isolated from the reaction mixture of Example 149b [5-Methyl-thiophene-2-sulfonic acid [((R)-l-methyl-pyrrolidin-3-yloxy)-4-trifluoromethyl-phenyl]-amide], was the title compound (16 mg, 15%) as a separate fraction from the preparative HPLC. MS (ES) m/e 581 [M+H]+
Example 151 5-bromo-4-methyl-N-r3-{ r(3R)-l-methyl-3-pyrrolidinyl1oxy l-4-(trifluoromethyl) phenyll-2- thiophenesulfonamide
Figure imgf000042_0003
a) 5-bromo-4-methyl-2-thiophenesulfonyl chloride
Figure imgf000043_0001
A solution of 2-bromo-3-methylthiophene (531 mg, 3.00 mmol) in 10 mL of dichloromethane was added dropwise to a solution of chlorosulfonic acid (1.05 g, 9.00 mmol) in 10 mL of dichloromethane at 0 °C. The mixture was stirred at this temperature for 60 minutes and then poured onto an ice-water slurry and extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to give 600 mg (73 %) of the product which was used directly in the next step without further purification.
b) 5-bromo-4-methyl-N-r3-(r('3R)-l-methyl-3-pyrrolidinvnoxy)-4-('trifluoromethyl) phenyll- 2-thiophenesulfonamide
Figure imgf000043_0002
Aniline A (264 mg, 1.02 mmol) was dissolved in 6 mL of dichloromethane and pyridine (0.330 mL, 4.08 mmol) and treated with a solution of the product of Example 151a [5-bromo-4- methyl-2-thiophenesulfonyl chloride] (280 mg, 1.02 mmol) in 4 mL of dichloromethane with vigorous stirring at room temperature. The reaction mixture was maintained for 72 hours, and then the solvent was removed under reduced pressure. The residue was dissolved in 1 mL of DMSO and purified by reverse phase preparative HPLC (YMC CombiPrep ODS-A, 50 x 20 mm, 20 mL/min, A: acetonitrile B: water, A: 5% to 95% during 15 min, UN detection at 214 nm) and then further purified by normal phase preparative HPLC (Biotage Flash 12+M, KP-Sil, SiO2, 12mm x 7.5 cm, 4 mL/min, A: MeOH, B: CH2C12, A: 5 to 15%, UN detection at 214 nm) to give 250 mg (47%) of the title compound as a white microcrystalline solid. MS (ES) m/e 499
[M+H]+ Example 152 4-bromo-5-(cyclohexylthio)-N-r3-{r(3R)-l-methyl-3-pyrrolidinvnoxy)-4- (trifluoromethyl)phenyl1-2-thiophenesulfonamide
Figure imgf000044_0001
4-Bromo-5-chloro-thiophene-2-sulfonic acid [3-((R)-l-methyl-pyrrolidin-3-yloxy)-4- trifluoromethyl-phenyl]-amide (50 mg, 0.096 mmol) was added as a solid to a mixture of cyclohexylmercaptan (0.013 mL, 0.106 mmol) and 3N NaOH solution (0.035 mL, 0.106 mmol) in DMF (1.0 mL) under argon with vigorous stirring. The reaction mixture was heated at 110 ° C for 16 h, and then at 140 °C for 3 days, after which time an additional amount of cyclohexylmercaptan (0.035 mL, 0.288 mmol) and 3N NaOH (0.096 mL, 0.288 mmol) was added and heated at 130 °C for an additional 18 hours. The reaction mixture was allowed to cool to room temperature, was 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 14.9 mg (26 %) of the title compound as an oil. MS (ES) m/e 599 [M+H]+
Example 153 4-bromo-5-(butylthio)-Ν-r3-{r(3R)-l-methyl-3-pyrrolidinvnoxy}-4-(trifluoromethyl)phenyll- 2-thiophenesulfonamide
Figure imgf000044_0002
The title compound was prepared by a method similar to that of Example 152 [4-bromo-5- (cyclohexylthio)-N-[3-{[(3R)-l-methyl-3-ρyrrolidinyl]oxy];-4-(trifluoromethyl) phenyl]-2- thiophenesulfonamide] except that butanethiol was used in place of cyclohexylmercaptan to give 11.5 mg (21%) ofthe title compound as an oil. MS (ES) m/e 573 [M+H]+
Example 154
3-(cyclohexylthio)-N-r3-{r(3R)-l-methylpyrrolidin-3-vnoxy}-4-(trifluoromethyl) phenvn-4-
(trifluoromethyl)benzenesulfonamide
Figure imgf000045_0001
a) 3-fluoro-4-(trifluoromethyl)benzenesulfonyl chloride
Figure imgf000045_0002
3-fluoro-4-(trifluoromethyl)aniline (3.0 g, 16.8 mmol) was dissolved in 6 mL of acetonitrile, cooled to 0 °C, and treated with tetrafluoroboric acid (48% aqueous solution, 3.30 mL, 25.3 mmol) and tert-butyl nitrite (2.96 mL, 25.3 mmol). This reaction was maintained at 0 °C for one hour. In the meantime, a suspension of CuCl (2.50 g, 25.3 mmol) in 20 mL of acetonitrile at 0 °C was saturated with sulfur dioxide gas by bubbling the gas through the suspension with vigorous stirring for 30 minutes. When the diazotization reaction was complete after one hour, this solution was added dropwise to the suspension of CuCl, and the vigorous evolution of nitrogen gas was observed. The reaction was then allowed to warm to room temperature and stir for one hour, after which time it was poured onto 100 mL of an ice/water slurry. The product precipitated out of solution and the solid was dissolved in diethyl ether, dried over sodium sulfate, filtered, and concentrated to 4.31 g (97 %) of an amber oil which was used directly in the next step without further purification.
b) 3-fluoro-N-r3-(r(3R)-l-methyl-3-pyrrolidinylloxyl-4-('trifluoromethvDphenyll-4- (trifluoromethyl)benzenesulfonamide
Figure imgf000045_0003
A 25-mL round-bottom flask equipped with an argon inlet and a magnetic stirring bar was charged with 3.0 g (13.6 mmol) of Aniline A and 6 mL of anhydrous methylene chloride. The contents ofthe flask were stirred at room temperature until all ofthe solids were dissolved, and 2.2 mL of anhydrous pyridine was added. The solution was stirred for 60 sec before 4.31 mg (16.4 mmol) of the product of Example 154a [3-fluoro-4-(trifluoromethyl)benzenesulfonyl chloride] was added and the resulting mixture was stirred and maintained at room temperature for 18 hours. The solvent was removed by rotary evaporation at reduced pressure and the crude oil was dissolved in DMSO and purified by preparative HPLC (YMC CombiPrep ODS-A 50 x 20 mm, 20mL/min, A: acetonitrile B: water, 10 - 90% over 10 min, UN detection at 214 nm) to give 4.41 g (67%) of the product as a pale amber oil.
c) 3-(cyclohexylthio)-Ν-r3-{r(3R)-l-methylpyrrolidin-3-yl1oxyl-4-(trifluoromethyl) phenyll- 4-(trifluoromethyl)benzenesulfonamide
Figure imgf000046_0001
The title compound was prepared by a method similar to that of Example 152 [4-bromo-5- (cyclohexylthio)-N- [3- { [(3R)- 1 -methyl-3-pyrrolidinyl] oxy } -4-(trifluoromethyl) phenyl]-2- thiophenesulfonamide] except that the product of Example 154b [3-fluoro-N-[3-{[(3R)-l- methyl-3-pyrrolidinyl]oxy}-4-(trifluoromethyl)phenyl]-4-(trifluoromethyl) benzene- sulfonamide] was used in place of 4-Bromo-5-chloro-thiophene-2-sulfonic acid [3-((R)-l- methyl-pyrrolidin-3-yloxy)-4-trifluoromethyl-phenyl]-amide to give 28 mg (47%) of the title compound as an oil. MS (ES) m/e 583 [M+H]+
Example 155
3-(butylthio)-N-r3-{r(3R)-l-methylpyrrolidin-3-vnoxyl-4-(trifluoromethyl) phenyl1-4- (trifluoromethyl)benzenesulfonamide
Figure imgf000046_0002
The title compound was prepared by a method similar to that of Example 153 [4-bromo-5- (butylthio)-N-[3-{ [(3R)-l-methyl-3-pyrrolidinyl]oxy }-4-(trifluoromethyl) phenyl]-2- thiophenesulfonamide] except that the product of Example 148b [3-fluoro-N-[3-{[(3R)-l- methyl-3-pyrrolidmyl]oxy}-4-(trifluoromethyl)phenyl]-4-(trifluoromethyl) benzene- sulfonamide] was used in place of 4-Bromo-5-chloro-thiophene-2-sulfonic acid [3-((R)-l- methyl-pyrrolidin-3-yloxy)-4-trifluoromethyl-phenyl]-amide to give 35 mg (61%) ofthe title compound as an oil. MS (ES) m/e 557 [M+H]+ Example 156 3-(cyclohexyloxy)-N-r3- j r(3R)-l-methyl-3-pyrrolidinyl1oxy }-4-(trifluoromethyl) phenyl]-4- (trifluoromethyl)benzenesulfonamide
Figure imgf000047_0001
The product of Example 154b [3-fluoro-N-[3-{ [(3R)-l-methyl-3-pyrrolidinyl]oxy }-4-
(trifluoromethyl)phenyl]-4-(trifluoromethyl) benzenesulfonamide] (50 mg, 0.103 mmol), sodium hydride (95 %, 12 mg, 0.500 mmol), and cyclohexanol (0.048 mL, 0.462 mmol) were combined in 1 mL of DMSO and heated to 200 °C for 7.5 minutes in a sealed microwave vial with a Personal Chemistry Microwave Reactor at Normal Power. Then, an additional amount of sodium hydride (9.9 mg, 0.412 mmol) and cyclohexanol (0.43 mL, 0.412 mmol) were added and the reaction was heated again in the microwave to 200 °C for 15 minutes. The reaction mixture was allowed to cool to room temperature, was 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, UV detection at 214 nm) to give 35.9 mg (62 %) of the title compound as an oil. MS (ES) m/e 567 [M+H]+
Example 157 3-(butyloxy)-N-r3-{r(3R)-l-methyl-3-pyrrolidinyl1oxyl-4-(trifluoromethyl) phenyl1-4- (trifluoromethyl)benzenesulfonamide
Figure imgf000047_0002
The title compound was prepared by a method similar to that of Example 156 [3- (cyclohexyloxy)-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-(trifluoromethyl) phenyl]-4- (trifluoromethyl)benzenesulfonamide] except that n-butanol was used in place of cyclohexanol to give 42 mg (62 %) ofthe title compound as an oil. MS (ES) m/e 541 [M+H]+ Example 158 3-( I T3- 1 T(3R)- 1 -methyl-3-pyrrolidinvn oxy I -4-(trifluoromethyl)phenyl1 amino 1 sulf onyl)-2- thiophenecarboxylic acid:
Figure imgf000048_0001
NaOH (2 mL, IM) was added to a solution of the product of Example 107?? [methyl 3-({ [3- { [(3R)- 1 -methyl-3-pyrrolidinyl] oxy } -4-(trifluoromethyl) phenyl] amino } sulf onyl)-2- thiophenecarboxylate] and methanol (1 mL) and the mixture maintained at rt for 48 h. The mixture was concentrated in vacuo and the purified by preparative HPLC (Phenomenx Luna Combi-HTS 5 μ C18, 75 x 30 mm, 40 mL/min, A: acetonitrile + 0.1% TFA, B: water + 0.1% TFA, A: 10 to 98% over 20 min, UN detection 214 nm) to provide the title compound as a solid. MS (ES) m/e 451.0 [M+H]+.
Example 159 2-Bromo-N-('4-fluoro-3-ir(3R)-l-methyl-3-pyrrolidinylloxylphenyl)-4.5-
Figure imgf000048_0002
bis(methyloxy)benzenesulfonamide: a) 5-Amino-2-fluorophenol
A solution of BBr3 (d = 2.658, 973 μL, 10.01 mmol) in CH2C12 (5 mL) was added slowly (10 min) to a stirred solution of 2-fluoro-5-aminoanisole (483.7 mg, 3.43 mmol) in dichloromethane (5 mL) at 0 °C under an argon atmosphere. The mixture was allowed to warm to ambient temperature, then stirred at that temperature for 18 h. The mixture was cooled in an ice-bath and cuatiously quenched with MeOH (20 mL), then evaporated in vacuo to a gummy residue. Redissolved the residue in MeOH (10 mL), re-evaporated in vacuo to the gummy residue, repeated the MeOH treatment two more times to expel the volatile borates. The resultant residue was dissolved in water (5 mL), saturated the solution with solid ΝaHCO3, then extracted with ethyl acetate. The ethyl acetate extract was washed with brine, dried (MgSO ), concentrated, in vacuo, to a crystalline solid (415.3 mg, 95%): mp 151-153 °C. MS m/e 128 [M+H[+. b) 4-Fluoro-3-hydroxyphenylcarbamic acid tert-butyl ester
A solution of di-tert-butyl dicarbonate (268.5 mg, 1.23 mmol) in THF (1.5 mL) was added to a solution of the product of Example 159a [5-amino-2-fluorophenol] (156.4 mg, 1.23 mmol) in THF (6 mL) at 0 °C. The reaction mixture was heated at reflux for 3 h, cooled to room temperature, then the solvent was removed in vacuo to provide the title compound (271.4 mg, 97%) as a glassy solid. MS (ES) m/e 311.4 [M+H]+.
c) (R)-r3-(l-Methyl-pyrrolidin-3-yloxy)-4-fluorophenyl1-carbamic acid
DIAD (d = 1.03, 487 μL, 2.39 mmol) was added to a cold (0 °C) solution of (S)-3-methyl- pyrrolidinol ((120.8 mg, 1.19 mmol), the product of Example 159b [2-fluoro-5-(tert-butoxy- crabomoyl)phenol] (271.4 mg, 1.19 mmol) and triphenylphosphine (626.5 mg, 2.39 mmol).
The reaction mixture was warmed to room temperature and left standing at ambient temperature for 18 h. The solvent was removed in vacuo and the residue was partitioned in 1:1
EtOAc/10%HCl (20 mL). The aqueous phase was separated, washed 2x10 mL of EtOAc, then made basic (pHIO) with 10% NaOH.The resulting precipitate was extracted with EtOAc, washed with water, brine, dried (MgSO4) and evaporated in vacuo to provide the desired product (359.1 mg, 97%) as a resin. MS (SE) e/m 311.4 [M+H]+.
d) 4-Fluoro-3-| r(3R)-l-methyl-3-pyrrolidinyl1oxy laniline dihydrochloride The product of Example 159c [(R)-[3-(l-methyl-pyrrolidin-3-yloxy)-4-fluorophenyl]-carbamic acid] (359.1 mg, 1.16 mmol) was dissolved in 1:1 TFA/DCM (3 mL), left standing at ambient temoperature for 18 h. The solvents were removed in vacou, dissolved the residue MeOH (2 mL) and treated with IM Et2O.HCl (3 mL) then evaporated in vacuo to provide the product as a solid. The crude product was triturated in DCM (5 mL) to provide a powdery solid, filtered under an argon atmosphere to give the product as the dihydrochloride salt (177.1 mg, 54%): mp 150-159 °C. MS (ES) e/m 211.2 [M+H]+.
e) 2-Bomo-N-f4-fluoro-3-{r(3,R)-l-methyl-3-pyrrolidinyl1oxylphenyl)-4.5- bis(methyloxy)benzenesulfonamide 2-Bromo-4,5-dimethoxybenzenesulfonyl chloride (98.3 mg, 0.31 mmol) was added in one portion to a stirred suspension of the product of Example 159d [4-fluoro-3-{[(3R)-l-methyl-3- pyrrolidinyljoxy} aniline dihydrochloride] (88.3 mg, 0.31 mmol) and pyridine (d = 0.978, 76 μL, 0.94 mmol) in acetonitrile (0.5 mL). The mixture was heated at 60 °C for 1 h, cooled and purifired preparative HPLC (Phenomenx Luna Combi-HTS 5 μ C18, 75 x 30 mm, 40 mL/min, A: acetonitrile + 0.1% TFA, B: water + 0.1% TFA, A: 10 to 98% over 20 min, UN detection 214 nm) to provide the product (144.3 mg) as the TFA salt. An aqueous solution (2 mL) ofthe TFA salt was made basic with saturated NaHCO3 and the resulting gummy precipitate was crystallized from MeOH to provide the title compound (55.1 mg, 36%); mp 125-127 °C. MS (ES) m/e 489 [M+H]+.
Example 160 2.6-Dichloro-N-(4-fluoro-3-{r(3R)-l-methyl-3-pyrrolidinyl1oxy)phenyl)-4- (trifluoromethyl)benzenesulfonamide:
Figure imgf000050_0001
2,6-Dichloro-4-trifluoromethyl-benzenesulfonyl chloride was reacted with 4-fluoro-3-{ [(3R)-1- methyl-3-pyrrolidinyl]oxy}aniline dihydrochloride in the exact manner as described in Example 159e to provide the title compound (61.3 mg, 43%): mp 92-95 °C. MS (ES) m/e 487 [M+H]+.
Example 161
2-Bromo-N-(4-bromo-3-{r(3R)-l-methyl-3-pyrrolidinynoxy|phenyl)-4.5- bis(methyloxy)benzenesulfonamide
Figure imgf000050_0002
a) 2-Bromo-5-nitroρhenol A solution of BBr3 (d = 2.658, 1.62 mL, 17.24 mmol) CH2C12 (5 mL) was added slowly (-15 min) to a stirred, cold (0 °C), solution of 2-bromo-5-nitroanisoIe (1.00 g, 4.31 mmol) in CH2C12 (10 mL) under an argon atmosphere. The mixture was allowed to warm room temperature and left standing at ambient temperature for 18 h. The mixture was cooled in an ice-bath and quenched, cautiously, with MeOH (15 mL). The mixture was concentrated to -10 mL on a steam bath, replenished with MeOH (15 mL), reconcentrated to -10 mL, repeated the MeOH process two more times to ensure the removal ofthe volatile borates, finally the solvent was removed in vacuo to provide the crude product as a solid (1.04 g). The solid was dissolved in 2.5Ν NaOH (~5 mL), filtered to remove 0.11 g of the starting anisole. The filtrate was acidified (pH 1) with cone. HCl and the resulting precipitate was filtered to provide 0.62 g of product. The material was purified by flash chromatography (Varian Bond Elute lOg Si cartridge, CH2C12) to provide clean product (0.54 g, 65%); mp 115-117 °C. MS (ES) m/e 218 [M+H]+.
b) (3R)-3-r(2-bromo-5-nitrophenyl)oxy1-l-methylpyrrolidine A solution of the product of Example 161a [2-bromo-5-nitrophenol] (1.2214 g, 5.50 mmol), (5)-3-methyl-pyrrolidinol (0.5668 g, 5.60 mmol), and triphenylphosphine (2.939 g, 11.20 mmol) in THF (20 mL) was treated with DIAD (d = 1.03, 2.2 mL, 11.20 mmol) in the exact manner as described Example 161c. Isolated 1.03 g (61%) of product as a solid. MS (ES) m/e 301.2 [M+Hf.
c) 4-Bromo-3-ir(3R)-l-methyl-3-pyrrolidinyl1oxy|aniline
A mixture of the product of Example 161b [(3R)-3-[(2-bromo-5-nitrophenyl)oxy]-l- methylpyrrolidine] (0.301 lg, 1.0 mmol) and SnCl2.2H2O (1.1282 g, 5.0 mmol)in EtOH (3.85 mL) was heated at 70 °C for 0.5 h, cooled and adjusted to pHlO-l 1 with 2.5N NaOH forming a gummy precipitate. The mixture was extracted EtOAc (3x10 mL), and the combined extracts were washed with water (10 mL), brine, dried (MgSO4), removed the solvent in vacuo to the product (0.2095 g, 77%) as a syrup. ME (ES) m/e 271 [M+Hf.
d) 2-Bromo-N-(4-bromo-3-{ r(i;R)-l-methyl-3-pyrrolidinynoxylphenyl)-4.5- bis(methyloxy)benzenesulfonamide
The procedure in Example 159e was used to prepare the title compound. Isolated 34.9 mg (8%): mp 168-170 °C. MS (ES) m/e 549 [M+H]+.
Example 162 N-r3-(l-methyl-2(S)-methoxycarbonylpyrrolidin-3(R)-yloxy)-4-trifluoromethylphenyl1-2- bromo-4,5-dimethoxybenzenesulfonamide and N-r3-(l-methyl-2(R)- methoxycarbonylpyrrolidin-3(R)-yloxy -4-trifluoromethylphenyl]-2-bromo-4-5- dimethoxybenzenesulfonamide:
Figure imgf000051_0001
a) 3-Fluoro-4-trifluoromethylnitrobenzene: 3-Fluoro-4-trifluoromethylaniline (15.10 g, 85.4 mmole) was dissolved on CF3CO2H (85 ml).
H2O2 (50% in H20, 42 ml 1.46mole, 7 eq) was added dropwise over 35 min. The mixture was stirred and heated at 45°C for 2 hr and 65°C for 40 min before being cooled to rt and poured into ice/water (600 ml). The mixture was stirred overnight. Ether (250 ml) was added and the organic layer was separated. The organic layer was washed with 10% HCl, saturated NaHCO3, twice with brine, dried (MgSO4) and concentrated in vacuo to give the title compound as a yellow oil (17.10 g, 96%).
b) 3-r2(S)-methoxycarbonylpyrrolidin-3(R)-yloxy1-4-trifluoromethyl nitrobenzene: A solution of the compound of Example 162a (3.14 g, 15 mmole) and 2(S)3(R)-N-tert- butoxycarbonylhydroxyproline methyl ester (3.68g, 15 mmole) in dry THF (75 ml) was cooled to 0°C and then NaH (60% in mineral oil, 1.20 g, 30 mmole) was added protionwise over 5 min. The mixture was stirred and allowed to warm to rt. Once at rt, the mixture was stirred an additional 2 hr. The solvent was removed under reduced pressure and then the residue was dissolved in MeOH (75 ml). 4M HCl in dioxane (20 ml) was added and the resultant mixture was stirred at rt overnight. The mixture was concentrated under reduced pressure and the residue partitioned between H2O and CH2CI2. The aqueous layer was adjusted to pH 7 using aqueous Na2CU3 and then was extracted with CH2CI2. The CH2CI2 layer was dried (MgSO4) and concentrated to give the title compound as a yellow oil (2.50 g, 50%). MS (ES) m/e 335.2 [M+H]+.
c) 3-ri-methyl-2(R S)-methoxycarbonylpyrrolidin-3(R)-yloxy1-4-trifluoromethyl nitrobenzene: The compound of Example 162b (3.20 g, 9.6 mmole) and formaldehyde (37% wt. in water, 0.94 g, 11.5 mmole, 1.2 eq) was dissolved in CH2C12 (70 ml). Na(OAc)3BH (3.01 g, 14.4 mmole, 1.5 eq) was added and the resultant mixture was stirred at rt overnight. The mixture was concentrated under reduced pressure and then partitioned between CH2CI2 and H2O. The organic layer was dried (MgSO4) and concentrated in vacuo. The crude mixture was purified by column chromatography (150 g silica gel 60, 230-400 mesh, CH2CI2 then 1% MeOH in
CH2C12 then 2% MeOH in CH2Cl2 as eluent) to give 2.80 g (73%) of a mixture of diastereomers as a yellow oil. MS (ES) m/e 349.0 [M+H]+.
d) 3-ri-Methyl-2(R S)-methoxycarbonylpyrrolidm-3(R)-yloxy1-4-trifluoromethyl aniline: Pd-C (10 %, 0.9g) added to a solution the compound of Example 162c (1.96 g, 5.6 mmol) and MeOH (50 mL). The resulting mixture was shaken under a H2 atmosphere (50 psi) for 3h.
The mixture was then filtered through a pad of Celite and the filtrate concentrated under reduced pressure to give 1.8 g (100%) of the title compound as a tan oil. MS (ES) m/e 319.2 [M+H]+.
e) N-r3-(l-methyl-2(S)-methoxycarbonylpyrrolidin-3(R)-yloxy)-4-trifluoromethylphenyll-2- bromo-4,5-dimethoxybenzenesulfonamide and N-r3-(l-methyl-2(R)- methoxycarbonylpyrrolidin-3('R)-yloxy)-4-trifluoromethylphenvn-2-bromo-4.5- dimethoxybenzenesulfonamide:
Pyridine (0.48 g, 6.0 mmol), followed by the compound of Example 162d (1.9 g, 6.0 mmol) was added to a solution of 2-bromo-4,5-dimethoxybenzenesulfonyl chloride (1.9 g, 6.0 mmol) and acetonitrile (30 mL). The resultant mixture was stirred at rt overnight. The mixture was concentrated and purified by 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 silica gel chromatography. Mixed fractions were further purified by purified by column chromatography (140 g silica gel 60, 230-400 mesh, 1-3% methanol in CH2C12 as eluent) to give to give 1.2 g (34%) of Ν-[3-(l-methyl-2(S)-methoxycarbonylpyrrolidin-3(R)-yloxy)-4- trifluoromethylphenyl]-2-bromo-4,5-dimethoxybenzenesulfonamide. MS (ES+) m/e 597.2 [M+H]+. and 0.27 g (8%) of N-[3-(l-methyl-2(R)-methoxycarbonylpyrrolidin-3(R)-yloxy)-4- trifluoromethylphenyl]-2-bromo-4,5-dimethoxybenzenesulfonamide. MS (ES) m/e 597.2
[M+H]+.
Examples 163-164 Using the procedure outlined in Example 162e, the following compounds were prepared.
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000054_0004
Example 165 N-r3-(2(S)-hvdroxymethyl-l-methylpyrrolidin-3(R)-yloxy)-4-trifluoromethylphenvn-2-bromo- 4.5-dimethoxybenzenesulfonamide:
Figure imgf000054_0002
LiBH4 (0.24 g, 1.1 mmol) was added to a solution ofthe compound of Example 162 (0.6 g, 1.0 mmol) and THF (10 mL) and the resultant mixture was stirred at rt overnight. The mixture was then diluted with MeOH and concentrated. The residue was dissolved in MeOH (10 mL), 2N HCl was added (10 mL) and the solution allowed to stand overnight. The solution was then concentrated in vacuo and purified by preparative HPLC (YMC CombiPrep ODS-A, 50 x 20 mm, 20 mL/min, A: acetonitrile B: water, A:10 to 90% during 10 min, UN detection at 214 nm) to give 100 mg (17%) of the title compound as a white solid. MS (ES) m/e 569.2 [M+H]+.
Example 166 Ν-r3-(2(R)-hydroxymethyl-l-methylpyrrolidin-3(R)-yloxy)-4-trifluoromethylphenyl1-2-bromo- 4.5-dimethoxybenzenesulfonamide:
Figure imgf000054_0003
L1BH4 (24 mg, 0.11 mmol) was added to a solution of the compound of Example 162 (60 mg, 0.1 mmol) and THF (1 mL). The resultant mixture was stirred at rt overnight. Satd NH4CI was added and the mixture extracted with CH2CI2. The organic layers were combined, dried
(MgSO4) and concentrated in vacuo. The residue was dissolved in CH2CI2 (10 mL) and 2N HCl (2 mL) and stirred overnight. The mixture was concentrated under reduced pressure and purified by preparative HPLC (YMC CombiPrep ODS-A, 50 x 20 mm, 20 mL/min, A: acetonitrile B: water, A: 10 to 90% during 10 min, UN detection at 214 nm) to give 4.4 mg (8%) of the title compound as a tan oil. MS (ES) m/e 569.2 [M+H]+. Example 167 N-[3-(2(S)-hvdroxymethyl-l-methylpyrrolidin-3(R)-yloxy)-4-trifluoromethylphenyl1-3.4- dimethoxybenzenesulfonamide:
Figure imgf000055_0001
A solution ofthe compound of Example 162 (0.30 g, 0.50 mmol) and THF (2mL) was added dropwise to a solution of 1 M LiAlH4 in ether (1.0 mL, 1.0 mmol). The mixture was stirred at rt for 20 min and then another portion of L1AIH4 (2.0 mL, 2.0 mmol) was added. The mixture was stirred an additional 45 min before being quenched with water (0.22 mL) and NaF (0.38 g, 9.1 mmol). The mixture was filtered through a pad of Celite and the filtrate concentrated in vacuo. The residue was purified by preparative HPLC (YMC CombiPrep ODS-A, 50 x 20 mm, 20 mL/min, A: acetonitrile B: water, A:10 to 90% during 10 min, UN detection at 214 nm) to give 35 mg (14%) ofthe title compound as a tan solid. MS (ES) m/e 491.2 [M+H]+.
Example 168-169 Using the procedure outlined in Example 161, the following compounds were prepared.
Figure imgf000055_0003
Example 170 N-r3-(l-Methyl-2(S)-N-methylamidepyrrolidin-3(R)-yloxy)-4-trifluoromethylphenyl1-4-5- dimethoxybenzenesulfonamide:
Figure imgf000055_0002
NaOH (40 mL, 1 M) was added to a solution of the compound of Example 162 (1.24 g, 2.08 mmol) and methanol (20 mL). The resultant mixture was stirred at rt for 16 h and then concentrated in vacuo. The residue was partitioned between water and CH2CI2 and acidified to pH = 3-4. The layers were separated and the aqueous washed with two more portions of CH2C12. The organic layers were combined, dried (MgSO4) and concentrated in vacuo to give 0.83 g of carboxylic acid. 200 mg (0.34 mol) of this product and methylamine (2 M in THF, 0.20 mL, 0.41 mol) were dissolved in MeCN (2 mL). BOP reagent (150 mg, 0.34 mmol) and triethylamine (34 mg, 0.34 mmol) were added. The resultant mixture was stirred at rt for 16 h and then concentrated in vacuo. The redidue was partitioned between EtOAc and 5% aqueous Na2CO3. The organic layere was separated, dried (MgSO ) and concentrated in vacuo. The crude product was purified by silica gel chromatography (35 g Redisep column, silica, 40 um, 60 A, 35 mL/min, A: MeOH, B: CH2C12, A: 0-1% for 25 min, 1-2% for 30 min, 2% for 10 min; detection at 214 nm) to give 90 mg (44%) of the title compound as a white solid. MS (ES) m/e
596.0 [M+H]+.
Example 171 Using the procedure of Example 164, the following compound was prepared:
Figure imgf000056_0002
Example 172 N-r3-(l-Methyl-2(,S)-N,N-dimethylmethylamidepyrrolidin-3(R)-yloxy)-4- trifluoromethylphenyl1-2-boromo-4.5-dimethoxybenzenesulfonamide:
Figure imgf000056_0001
Borane methylsulfide (2 M, 0.1 mL, 0.2 mmol) was added dropwise to a solution of the compound of Example 165 (20 mg, 0.033 mmol) and THF (2 mL). The resultant mixture was stirred at rt for 16 h before being 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 18 mg (93%) ofthe title compound as a clear oil. MS (ES) m/e 596.2 [M+H]+.
Example 173 Ν-r3-(2(S)-2,2-dimethylhydroxymethyl-l-methvpyrrolidin-3(R)-yloxy)-4- trifluoromethylphenvn-2-bromo-4-5-dimethoxybenzenesulfonamide:
Figure imgf000057_0001
MeMgBr (3 M in ether, 0.40 mL, 1.2 mmol) was added to a solution of the product from Example 156 (0.12 g, 0.20 mmol) and THF (2 mL). The resultant mixture was maintained at rt for 2 h then quenched with water. The mixture was extracted with CH2CI2 and then ether.
The organic layers were combined, dried (MgSO4) and concetrated in vacuo. The crude product was purfied by preparative HPLC (YMC CombiPrep ODS-A, 50 x 20 mm, 20 mL/min, A: acetonitrile B: water, A: 10 to 90% during 10 min, UN detection at 214 nm) to give 22 mg
(18%) of the title compound as a tan oil. MS (ES) m/e 597.0 [M+H]+.
Example 174-175 Using the procedure of Example 167, the following compounds were prepared:
Figure imgf000057_0002
Example 176 2-Bromo-4.5-dimethoxy-N-r3-((R)-l-propyl-pyrrolidin-3-yloxy)-4- trifluoromethyl-phenyl1- benzenesulfonamide:
Figure imgf000058_0001
To a mixture of N-[4-Trifluoromethyl-3-((R)-pyrrolidin-3-yloxy)-phenyl]-2-bromo-3,4- dimethoxy-benzenesulfonamide hydrochloride (75 mg, 0.133 mmole) and propionaldehyde ( 10 uL, 8 mg, 0.133 mmole) in EtOH (3 mL), was added NaBH3CN (11 mg, 0.173 mmole). The mixture was stirred at rt 18 hr. Solvent was evaporated and the mixture chromatographed on a normal-phase Gilson Automated Chromatography System using a solvent gradient of dichloromethane to 15% methanol- dichloromethane as elutant to provide 60 mg (80%) of the title compound. MS (ES) m/e 567 [M+H]+.
Example 177 Following the procedure of Example 176, except substituting isobutyraldehyde for propionaldehyde gave the following compound:
Figure imgf000058_0003
Example 178 N-r3-((R)-l-Benzyl-pyrrolidin-3-yloxy)-4-trifluoromethyl-phenyl1-2-bromo-4.5-dimethoxy- benzenesulfonamide:
Figure imgf000058_0002
To a mixture of N-[4-TrifluoromethyI-3-((R)-ρyrroIidin-3-yloxy)-phenyl]-2-bromo-3,4- dimethoxy-benzenesulfonamide hydrochloride (75 mg, 0.133 mmol), K2CO3 (55 mg, 0.4 mmol), and KI ( 22 mg, 0.133 mmol) in CH3CN (2 mL), was added benzyl bromide (17 uL, 25 mg, 0.146 mmol). The mixture was stirred at rt 18 hr. Solvent was evaporated and the mixture chromatographed on a normal-phase Gilson Automated Chromatography System using a solvent gradient of dichloromethane to 15% methanol- dichloromethane as elutant to obtain 40 mg (50%) of the title compound. MS (ES) m/e 615 [M+H]+.
Examples 179-182 Following the procedure of Example 178, except substituting phenethyl bromide, bromoethanol, l-bromo-2-butanonone and 2-methoxyethyl bromide for benzyl bromide gave the following compounds:
Figure imgf000059_0002
Example 183 Methyl 2-chloro-5-q [3-1 Ϊ(3R)-1 -methyl-3-pyrrolidinylloxy 1-4- (trifluoromethyl)phenynamino } sulfonyl)-3-thiophenecarboxylate:
Figure imgf000059_0001
a) 2-chloro-3-thiophenecarboxylic acid
Figure imgf000060_0001
A solution of 3-bromo-2-chlorothiophene (3.3 g, 17 mmol) in dry THF (20 mL) was added dropwise to a solution of n-butyllithium (7.4 mL, 1.6M in hexane) in dry THF (lOmL) at -
78°C under Argon. After stirring for 15 min, the reaction mixture was poured into crushed dry ice covered with ether. When the temperature had risen to 0°C, sodium hydroxide (2N, 150 mL) was added. The ether phase was extracted with sodium hydroxide (x3) and the combined aqueous was cooled at 0°C and acidified with 6N HCl. The product precipated and was collected by filtration; drying left 2.1 g (76%) as a white solid.
b) 2-chloro-5-(chlorosulfonyl)-3-thiophenecarboxylic acid
Figure imgf000060_0002
The product of Example 183a [2-chloro-3-thiophenecarboxylic acid] (2.1 g , 14.6 mmol ) was added slowly to chlorosulphonic acid (5.1 mL, 5.2 equiv.) at 0°C. The resulting mix was then heated at 95°C for 2h. After cooling, the mix was poured into ice (Caution, Slow! !). The product was collected by filtration; drying left 2.67 g (71% yield). _R (film) 1377.97 cm"1 and 1161.23 cm-1.
c) Methyl 2-chloro-5-({r3-ir('3RVl-methyl-3-pyrrolidinyl1oxy)-4- (trifluoromethyl)phenyl1aminolsulfonyl)-3-thiophenecarboxylate:
Figure imgf000060_0003
A solution of the product sulfonyl chloride from Example 183b (1.30g, 5 mmol) in CH2C12 (20mL) was added dropwise to a solution containing Aniline A (1.3 g, 5 mmol) and pyridine (1.6 mL, 20 mmol) in CH2C12 (25 mL) over 60 min. The resulting mixture was stirred at rt for 18h. The reaction mix was concentrated in vacuo, which left an orange yellow solid
(pyridinium salt) which was refluxed in MeOH saturated with HCl (30 ml) for 18h. The mixture was concentrated and the residue was dissolved in EtOAc and washed with 10% NaHCO3, saturated NaCl, dried (MgSO ) and concentrated. Purificaiton by silica gel chromatography (1-3% MeOH in CH2C12) gave 980mg of the title compound as a white solid.
MS (ES) m/e 499 [M+H]+.
Example 184
5-Chloro-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl1oxy)-4-(trifluoromethyl)phenvn-4-(4- morpholinylcarbonyl)-2-thiophenesulfonamide:
Figure imgf000061_0001
a) 2-chloro-5-α \3-\ r(3R)-l-methyl-3-ρyrrolidinylloxyl-4- (trifluoromethyl)phenyllamino ) sulfonyl)-3-thiophenecarboxylic acid:
Figure imgf000061_0002
A solution ofthe sulfonyl chloride from Example 183b ( 1.30 g, 5 mmol) in CH2C12 (20mL) was added dropwise to a solution containing Aniline A (1.3 g, 5 mmol) and pyridine (1.62 mL, 20 mmol) in CH2C12 (25 mL) over 60 min., the resulting mix was stirred at rt for 18h. The reaction mix was concentrated in vacuo which left an orange yellow solid (pyridinium salt) which was used as without further purification. MS (ES) m/e 485.0 [M+H]+.
b) 5-Chloro-N-[3-ir(3R)-l-methyl-3-pyrrolidinvnoxy}-4-Ctrifluoromethyl)phenyll-4-('4- morpholinylcarbonyl)-2-thiophenesulfonamide
Figure imgf000061_0003
A mixture ofthe carboxylic acid from Example 184a (242 mg, 0.5 mmol), morpholine (44 mg, 0.5 mmol), DIEA (96 ul, 0.55 mmol) and BOP (232 mg, 0.55 mmol) in DMF (2mL) was stirred at rt for 18 h. The reaction was concentrated invacuo and the reside was taken up in EtOAc and washed with water, saturated ΝaCl, dried (MgSO4) and concentrated. The residue was purified by preparative HPLC (Xterra Prep RP, 75 x 30 mm, 25 mL/min, A: acetonitrile(containing 0.1% TFA) B: water (containing 0.1%TFA), A:5- to 50% during 15min, UN detection at 214 nm). The product was then treated with HCl (IM in ether) to give the title compound as its HCl salt which was a light yellow solid. MS (ES) m/e 554.4 [M+H]+
Example 185 2-Chloro-NN-dimethyl-5-({[3-{r(3R)-l-methyl-3-pyrrolidinvnoxyl-4- (trifluoromethyl)phenyl1aπuno)sulfonyl)-3-thiophenecarboxamide:
Figure imgf000062_0001
Following the procedure of Example 184b replacing morpholine by dimethylamine gave the title compound as HCl salt which was a pale yellow solid. MS (ES) m/e 512.2 [M+H]+.
Example 186 Preparation of 5-chloro-N-[3- j [(3R)-l-methyl-3-pyrrolidinyl1oxyl-4-(trifluoromethyl)phenyl1- 4-propyl-2-thiophenesulfonamide :
Figure imgf000062_0002
n-BuLi (1.9 mL, 1.6 M in hexane) was added dropwise to a solution of 3-bromo-2- chlorothiophene (550 mg, 2.8 mmol) in dry THF(10 mL) at -78°C under argon. The resulting mixture was stirred at-78°C for 5 min. then 1-iodopropane (2.4 g, 13.9 mmol) was added .The mixture was stirred at -78°C for another 15 min. and then was quenched by adding water. The reaction mix was extracted with ether and the ether extracts were washed with saturatd ΝaCl, dried (MgSO4) and concentrated to a light yellow solid. Chlorosulfonic acid (739 Dl, 11 mmol) was then added dropwise to a solution of this material in CH2C12 (28 mL) at room temperature The resulting mixture was stirred at rt for 18 h. The mixture was concentrated and azetroped with toluene (x2) to remove excess chlorosulfonic acid and kept in vacuum for several hours. The crude mixture was then dissolved in CH2C12 (28 mL) and added dropwise to a mixture containing Aniline A (1.4g, 2.78 mmol) and pyridine (899 uL, 11.2 mmol). After stirring at rt for 18 h, the mixture was concentrated invacuo and the residue redissolved in CH2C12, washed with water then saturated ΝaCl, dried (MgSO ) and concentrated. The crude product was purified by silica gel chromatography (0-5% MeOH in CH2C12) to give 202 mg which was further purified by preparative HPLC (Xterra Prep RP, 75 x 30 mm, 25 mL/min, A: acetonitrile containing 0.1% TFA, B: water containing 0.1%TFA, A:5- to 75% during 15min, UN detection at 214 nm). The product was treated with HCl (IM in ether) to give the HCl salt as a pale yellow solid. MS (ES) m/e 483.2 [M+H]+.
Example 187 5-chloro-4-('3-methylbutyl)-N-r3- (3R)-l-methyl-3-ρyrrolidinvnoxyl-4- (trifluoromethyl)phenyl1-2-thiophenesulfonamide:
Figure imgf000063_0001
Following the procedure of Example 186, replacing 1-iodopropane by l-iodo-3-methylbutane gave the title compound as a pale yellow solid. MS (ES) m e 511.2 [M+H]+.
Example 188 5-chloro-N-[3-ir(3R)-l-methyl-3-pyrrolidinyl1oxyl-4-(trifluoromethyl)phenyll-4-(3,3.3- trifluoropropyl)-2-thiophenesulfonamide:
Figure imgf000063_0002
t-BuLi (0.44mL, 1.7 M in pentane, 0.748 mmol) was added rapidly to a solution of 3,3,3- trifluoro-1-iodo-propane ( 78 mg, 0.35 mmol) in Et2O (5 mL) at -78°C. After 3 min, 9- methoxy-9-BBΝ (0.82 mL, 1.0 M in THF, 0.82 mmol) was added followed by THF (5mL). The solution was stirred at -78°C for 10 min then allowed to warm to room temperature (1.5 h). Aqueous K3PO4 (0.27 mL, 3 M, 0.81 mmol) was added followed by the addition of 4- bromo-5-chloro-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-(trifluoromethyl)phenyl]-2- thiophenesulfonamide (83 mg, 0.16 mmol) in DMF (2 mL) and Pd (dppf)Cl2. (13 mg, 0.016 mmol). The resulting mixture was heated at 60°C for 18 h. The reaction mixture was concentrated invacuo and the residue was dissolved in EtOAc washed with water, saturated ΝaCl, dried (MgSO4) and concentrated. Purificaiton by dilica gel chromatographgy (1-4% MeOH in CH2C12) gave 100 mg which was further purified by preparative HPLC (Xterra Prep RP, 75 x 30 mm, 25 mL/min, A: acetonitrile containing 0.1% TFA, B: water containing 0.1%TFA, A: 5- to 72% during 14min, UN detection at 214 nm). The product was then treated with HCl (IM in ether) to give the title compounds as its HCl salt as a pale yellow solid. MS
(ES) m/e 536.0 [M+H]+.
Example 189 4-bromo-N-(4-bromo-3-{ r(3R)-l-methylpyrrolidin-3-yl1oxylphenyl)-5-chlorothiophene-2- sulfonamide
Figure imgf000064_0001
Tribromoborane (25 g, 100 mmol) was added dropwise to a solution of 2-bromo-5-nitroanisole (7.94 g, 34.2 mmol) in methylene chloride (100 mL) at 0 °C. The solution was allowed to warm to room temperature and react for 16 h. The reaction was then quenched by the addition of methanol (20 mL) and stirred for 3 h. The solvent was removed under reduced pressure and the remaining residue purified by column chromatography (400 g silica gel 60, 230-400 mesh, 5-20% ethyl acetate/hexanes as eluent) to give 2-bromo-5-nitrophenol (6.2 g, 83%). MS (ES) m/e 217.6 [M+H]+.
Diisopropyl azodicarboxylate (3.34 g, 16.5 mmol) was added dropwise to a solution of 2- bromo-5-nitrophenol (3.0 g, 13.8 mmol), (3S)-l-methyl-3-pyrrolidinol (1.4 g, 13.8 mmol), and triphenylphosphine (4.33 g, 16.5 mmol) in methylene chloride (100 mL). The reaction was maintained for 16 h at room temperature. The solvent was removed under reduced pressure and the remaining material purified by column chromatography (300 g silica gel 60, 230-400 mesh, 0-5% methanol/methylene chloride as eluent) to provide (3R)-3-[(2-bromo-5- nitrophenyl)oxy]-l-methylpyrrolidine (2.6 g, 63%). MS (ES) m/e 301.2 [M+H]+.
A mixture of iron (5 g) and iron (IH) chloride (5 g) was added to a solution of (3R)-3-[(2- bromo-5-nitrophenyl)oxy]-l-methylpyrrolidine (2.2 g, 7.3 mmol) in acetic acid (15 mL) and water (5 mL). After stirring for 18 h at room temperature, the mixture was filtered and concentrated. The remaining residue was dissolved in aqueous hydrochloric acid (6 mL of a 2 M aqueous solution) and ethyl acetate (10 mL). The layers were separated and the organic layer discarded. The aqueous layer was concentrated to give 4-bromo-3-{ [(3R)-l-methyl-3- pyrrolidinyljoxy } aniline as a hydrochloride salt (2.2 g, 100%). MS (ES) m/e 271.2 [M+H]+.
A solution of 4-bromo-5-chloro-2-thiophenesulfonyl chloride (382 mg, 1.29 mmol) in methylene chloride (2 mL) was added to a solution of 4-bromo-3-{[(3R)-l-methyl-3- pyrrolidinyl] oxy} aniline (350 mg, 1.29 mmol) and pyridine (306 mg, 3.87 mmol) in methylene chloride (8 mL) at -78 °C. After 1 h, the solution was allowed to warm to room temperature and stir for 15 h. The volatiles were removed under reduced pressure and the remaining crude material was 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 (16 mg, 28%) as a trifluoroacetate salt. MS (ES) m/e 529.0 [M+H]+.
Examples 190-193 The following examples were prepared in an analogous fashion to the representative procedure in Example 189 using the appropriate sulfonyl chlorides as starting material.
Figure imgf000065_0001
Example 194 5-[(l-methyl-3-pyrrolidinyl)oxy1-N-[3-{[('3R)-l-methyl-3-pyrrolidinynoxyl-4-
(trifluoromethyl)phenyn-4-nitro-2-thiophenesulfonamide
Figure imgf000066_0001
A solution of 5-chloro-4-nitro-2-thiophenesulfonyl chloride (1.0 g, 3.82 mmol) in methylene chloride (5 mL) was added to a solution of 3-{ [(3R)-l-methyl-3-pyrrolidinyl]oxy }-4-
(trifluoromethyl)aniline (0.83 g, 3.18 mmol) and pyridine (0.76 g, 9.54 mmol) in methylene chloride (20 mL) at -78 °C. The solution was allowed to warm to room temperature and stir for 16 h. The volatiles were removed in vacuo and the remaining crude material purified by column chromatography (250 g silica gel 60, 230-400 mesh, 5-25% methanol/methylene chloride as eluent) to provide 5-chloro-N-[3-{ [(3R)-l-methyl-3-pyrrolidinyl]oxy }-4-
(trifluoromethyl)phenyl]-4-nitro-2-thiophenesulfonamide (500 mg, 33%). MS (ES) m/e 486.0
[M+H]+.
To a mixture of 5-chloro-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4- (trifluoromethyl)phenyl]-4-nitro-2-thiophenesulfonamide (50 mg, 0.10 mmol) and cesium carbonate (134 mg, 0.41 mmol) in dimethylformamide (1 mL) was added l-methyl-3- pyrrolidinol (16 mg, 0.15 mmol). The reaction was allowed to stir for 18 h. The mixture was filtered through a 0.45 μm fritted funnel and the remaining 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 give the desired product (6.1 mg, 9%) as a trifluoroacetate salt and a mixture of diastereomers. MS (ES) m/e 551.2 [M+H]+.
Examples 195-201 The following examples were prepared according to the representative procedure in Example 194 using the appropriate alcohols as starting material. For some of the alcohol starting materials, the reactions required heating the dimethylformamide solution at 50 °C for 16 h.
Figure imgf000067_0001
Example 202 4-amino-N-r3-ir('3R)-l-methyl-3-pyrrolidinyl1oxy}-4-(trifluoromethyl)phenyl1-5-(tetrahvdro-
2H-pyran-4-yloxy)-2-thiophenesulfonamide
Figure imgf000068_0001
A mixture of N-[3-{ [(3R)-l-methyl-3-pyrrolidinyl]oxy }-4-(trifluoromethyl)phenyl]-4-nitro-5- (tetrahydro-2H-pyran-4-yloxy)-2-thiophenesulfonamide (8.2 mg, 0.012 mmol) and iron powder (spatula tip) in acetic acid (1 mL) was allowed to stir at room temperature for 18 h. The mixture was filtered and the remaining residue purified by preparative ΗPLC [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 (1.7 mg, 18%) as a trifluoroacetate salt. MS
(ES) m/e 522.2 [M+Η]+.
Example 203
N- \5-( { Ϊ3- { [(3R)- 1 -methyl-3-pyrrolidinvn oxy } -4-(trifluoromethyl)phenyll amino } sulfonyl)-2- (tetrahydro-2H-pyran-4-yloxy)-3-thienyπacetamide
Figure imgf000068_0002
To a solution of N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-(trifluoromethyl)phenyl]-4-nitro- 5-(tetrahydro-2H-pyran-4-yloxy)-2-thiophenesulfonamide (10 mg, 0.018 mmol) and acetic anhydride (0.5 mL) in acetic acid (2 mL) was added excess iron powder (spatula tip) and a catalytic amount of iron (III) chloride (spatula tip). The mixture was allowed to stir at room temperature for 18 h. The mixture was filtered and the remaining residue purified by preparative ΗPLC [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 (4.4 mg, 36%) as a trifluoroacetate salt. MS (ES) m/e 564.2 [M+Η]+. Example 204 5-chloro-N-(4-chloro-3-{r(3R)-l-methyl-3-pyrrolidinvnoxy}phenyl)-4-nitro-2- thiophenesulfonamide
Figure imgf000069_0001
A solution of 5-chloro-4-nitro-2-thiophenesulfonyl chloride (230 mg, 0.88 mmol) in methylene chloride (2 mL) was added to a solution of 4-chloro-3-{[(3R)-l-methyl-3- pyrrolidinyl] oxy} aniline (200 mg, 0.88 mmol) and pyridine (210 mg, 2.6 mmol) in methylene chloride (8 mL). The solution was maintained at room temperature for 16 h. The volatiles were removed under reduced pressure and the remaining residue dissolved in dimethylformamide, filtered through a 0.45 um 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 the desired product (40 mg, 8%) as a trifluoroacetate salt. MS (ES) m/e 452.0 [M+H]+.
Example 205 N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinylloxy}phenyl)-4-nitro-5-(tetrahydro-2H-pyran-4- yloxy)-2-thiophenesulfonamide
Figure imgf000069_0002
To a mixture of 5-chloro-N-(4-chloro-3-{ [(3R)-l-methyl-3-pyrrolidinyl]oxy }phenyl)-4-nitro-2- thiophenesulfonamide (25 mg, 0.044 mmol) and cesium carbonate (215 mg, 0.66 mmol) in dimethylformamide (1 mL) was added tetrahydro-2H-pyran-4-ol (45 mg, 0.44 mmol). The mixture was allowed to stir for 18 h. The mixture was filtered through a 0.45 μm fritted funnel and the remaining 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 give the desired product (3.7 mg, 13%) as a trifluoroacetate salt. MS (ES) m/e 518.2 [M+H]+. Example 206 5-hvdroxy-N-r3-{[(3R)-l-methyl-3-pyrrolidinyl1oxy}-4-(trifluoromethyl)phenyl1-4-nitro-2-
thiophenesulfonamide
Figure imgf000070_0001
A mixture of 5-chloro-N-[3-{ [(3R)-l-methyl-3-pyrrolidinyl]oxy }-4-(trifluoromethyl)phenyl]-4- nitro-2-thiophenesulfonamide (25 mg, 0.051 mmol), cesium carbonate (166 mg, 0.51 mmol), and l-methyl-4-piperidinol (29 mg, 0.25 mmol) in dimethylformamide (1 mL) was heated in a Personal Chemistry microwave reactor at normal power for 900 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 provide an unexpected 5-hydroxythiophene product (7 mg, 24%) as a trifluoroacetate salt with no incorporation of the l-methyl-4-piperidinol group. MS (ES) m/e
468.2 [M+H]+.
Example 207 4-amino-5-chloro-N-r3-{ [(3R)-l-methyl-3-pyrrolidinyl1oxy}-4-(trifluoromethyl)phenyl]-2- thiophenesulfonamide
Figure imgf000070_0002
To a solution of 5-chloro-N-[3-{ [(3R)-l-methyl-3-pyrrolidinyl]oxy }-4-
(trifluoromethyl)phenyl]-4-nitro-2-thiophenesulfonamide (40 mg, 0.082 mmol) in tetrahydrofuran (1 mL) and aqueous sodium carbonate (1 mL of a 2 M solution) was added sodium hydrosulfite portion wise (spatula tip). The pH of the solution was monitored closely and if necessary more aqueous sodium carbonate was added to keep the solution basic (pH>8). The progress of the reaction was followed by TLC and addition of sodium hydrosulfite was discontinued once all the starting material had been consumed. The reaction was diluted with ethyl acetate (10 mL) and water (3 mL) and the layers separated. The organic layer was washed with water (3 x 3 mL) and concentrated under reduced pressure. The remaining material was 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 (1 mg, 1.8%) as a trifluoroacetate salt. MS (ES) m/e 456.4 [M+H]+.
Example 2085-(4-methyl-l-piperazinyl)-Ν-[3-{r(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl1-4-nitro-2-thiophenesulfonamide
Figure imgf000071_0001
A solution of 5-chloro-N-[3-{ [(3R)-l-methyl-3-pyrrolidinyl]oxy }-4-(trifluoromethyl)phenyl]-4- nitro-2-thiophenesulfonamide (68 mg, 0.14 mmol) and 1-methylpiperazine (42 mg, 0.42 mmol) in dimethylformamide (1.5 mL) was heated in a Personal Chemistry microwave reactor at normal power for 600 sec at 200 °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 the desired product (22 mg, 24%) as a trifluoroacetate salt. MS (ES) m/e 550.0 [M+H]+.
Example 209 5-(l-hvdroxyethyl)-N-r3-ir(3R)-l-methyl-3-pyrrolidinyl1oxy}-4-(trifluoromethyl)phenyl]-2- thiophenesulfonamide
Figure imgf000071_0002
A solution of 5-bromo-2-thiophenesulfonyl chloride (0.503 g, 1.92 mmol) in methylene chloride (2 mL) was added to a solution of 3-{ [(3R)-l-methyl-3-pyrrolidinyl]oxy }-4- (trifluoromethyl)aniline (0.501 g, 1.92 mmol) and pyridine (0.456 g, 5.76 mmol) in methylene chloride (8 mL). The solution was maintained at room temperature for 16 h. The volatiles were removed in vacuo and the remaining crude material purified by column chromatography (200 g silica gel 60, 230-400 mesh, 50% ethylacetate/hexanes-5% methanol/methylene chloride as eluent) to provide 5-bromo-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4- (trifluoromethyl)phenyl]-2-thiophenesulfonamide (565 mg, 61%). MS (ES) m/e 485.0 [M+H]+.
To a solution of 5-bromo-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4- (trifluoromethyl)phenyl]-2-thiophenesulfonamide (85 mg, 0.18 mmol) in tetrahydrofuran (1 mL) at -78 °C was added rc-BuLi (0.24 mL of a 1.6 M solution in hexanes, 0.39 mmol). After 5 min, a solution of acetaldehyde (0.1 mL, excess) in tetrahydrofuran (0.1 mL) was added. Within 10 min the reaction was quenched by the addition of methanol. The solvent was removed 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 (52 mg, 53%) as a trifluoroacetate salt. MS
(ES) m/e 451.0 [M+H]+.
Example 210-212 The following examples were prepared according to the representative procedure in Example 209 using the appropriate aldehydes as starting material.
Figure imgf000072_0001
Example 213 4-bromo-5-( 1 -hydroxy ethyl)-N-[3- { \(3R)- 1 -methyl-3-pyrrolidinyll oxy } -4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide
Figure imgf000073_0001
To a solution of 3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-(trifluoromethyl)aniline (0.50 g, 1.92 mmol) and pyridine (1 mL) in methylene chloride (5 mL) was added 4,5-dibromo-2- thiophenesulfonyl chloride (0.65 g, 1.92 mmol). The solution was maintained at room temperature for 16 h. The volatiles were removed in vacuo and the remaining crude material purified by column chromatography (200 g silica gel 60, 230-400 mesh, 50% ethylacetate/hexanes-2% methanol/methylene chloride as eluent) to provide 4,5-dibromo-N-[3- { [(3R)-l-methyl-3-pyrrolidinyl]oxy }-4-(trifluoromethyl)phenyl]-2-thiophenesulfonamide (700 mg, 60%). MS (ES) m/e 563.0 [M+H]+.
To a solution of 4,5-dibromo-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4- (trifluoromethyl)phenyl]-2-thiophenesulfonamide (30 mg, 0.053 mmol) in tetrahydrofuran (3 mL) at -78 °C was added π-BuLi (0.20 mL of a 1.6 M solution in hexanes, 0.32 mmol). After 5 min, acetaldehyde (0.03 mL, 0.53 mmol) was added neat. Within 10 min the reaction was quenched by the addition of methanol and the solvent was removed under reduced pressure. The remaining material was dissolved in methanol (1 mL), 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 the desired product (5 mg,
20%) as a trifluoroacetate salt. MS (ES) m/e 529.2 [M+H]+.
Examples 214-215 The following examples were prepared according to the representative procedure in Example 209 using the appropriate aldehydes as starting material.
Figure imgf000073_0002
Figure imgf000074_0001
Example 216 5-(cvclopropylmethyl)-N-r3-{ [(3R)-l-methyl-3-pyrrolidinyl1oxy}-4-(trifluoromethyl)phenyn-
2-thiophenesulfonamide
Figure imgf000074_0002
Triethylsilane (0.5 mL) was added to a solution of 5-[cyclopropyl(hydroxy)methyl]-N-[3- { [(3R)- 1 -methyl-3-pyrrolidinyl] oxy } -4-(trifluoromethyl)phenyl]-2-thiophenesulf onamide (15 mg, 0.025 mmol) in trifluoroacetic acid (0.5 mL) and methylene chloride (0.2 mL). The reaction was maintained at room temperature for 16 h. The solution was concentrated under reduced pressure. The remaining crude material was dissolved in methanol (1 mL), 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 the desired product (8.4 mg, 57%) as a trifluoroacetate salt. MS (ES) m/e 461.2 [M+H]+.
Example 217
4-bromo-N- [3-1 (3R)- 1 -methyl-3-pyrrolidinyll oxy } -4-(trifluoromethyl)phenyl1-2-
thiophenesulfonamide
Figure imgf000074_0003
A solution of 4,5-dibromo-N-[3-{ [(3R)-l-methyl-3-pyrrolidinyl]oxy }-4- (trifluoromethyl)phenyl]-2-thiophenesulfonamide (50 mg, 0.089 mmol) and copper (I) bromide (13 mg, 0.089 mmol) in dimethylformamide (1 mL) was heated in a Personal Chemistry microwave reactor at normal power for 300 sec at 220 °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 the desired product (17 mg, 32%) as a trifluoroacetate salt. MS (ES) m/e 485.2 [M+H]+.
Example 218 4.5-dichloro-N-[3-{r(3R)-l-methyl-3-pyrrolidinyl1oxy}-4-(trifluoromethyl)phenyl1-2- thiophenesulfonamide:
Figure imgf000075_0001
To a solution of 4-trifluoromethyl-3-((R)-l-methylpyrrolidin-3-yloxy)anline (2.5 g, 9.6 mmol) in acetonitrile (50 ml) and pyridine (1.5 ml) was added 4,5-dichloro-2-thiophenesulfonyl chloride (3.4 g, 13.4 mmol) at 0°C. The reaction was allowed to warm to rt and the solvent was evaporated. The residue was purified by silica gel chromatography (35 g Redisep column, silica, 40 um, 60 A, 35 mL/min, 0-20% MeOH: CH2C12, detection at 214 nm) to give 2.80 g (62% yield) of the title compound as a light orange solid. MS (ESI) 475.0 (MH+).
Examples 219-228 Following the general procedure in Example 1?? except substituting 4-bromo-5-chloro-2- thiophenesulfonyl chloride, 3-bromo-5-chloro-2-thiophenesulfonyl chloride, 5-bromo-2- thiophenesulfonyl chloride, 4-bromo-2-thiophenesulfonyl chloride, or 4-bromo-2,5-dichloro-3- thiophenesulfonyl chloride for 4,5-dichloro-2-thiophenesulfonyl chloride and/or 4-chloro-3- ((R)-l-methylpyrrolidin-3-yloxy)anline or 4-bromo-3-((R)-l-methylpyrrolidin-3-yloxy)anline for 4-trifluoromethyl-3-((R)-l-methylpyrrolidin-3-yloxy)anline the following compounds could be prepared.
Figure imgf000075_0002
Figure imgf000076_0001
EXAMPLE 229 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 drug 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 ofthe art and are incorporated herein by reference as though fully set forth.

Claims

What is claimed is:
1. A compound of Formula (I) :
Figure imgf000079_0001
Formula (I) wherein:
R! is phenyl, thienyl, furanyl, pyrroyl, pyridinyl, oxazoyl, indoyl, triazinyl, imidazoyl, pyrimidinyl, oxadiazoyl, pyrazoyl, triazoyl, thiazoyl, thiadiazoyl, or pyrazinyl substituted or unsubstituted by one, two , three, four or five of any of the following: halogen, CF3, OCF3, OH, SCF3, NO2, CN, Cχ.6 alkyl, Cι _6 alkoxy, Cχ_6 alkyl-CF3, O(CH2)qY, NR5R6, N(Cχ_6 alkyl)CO(C1.6 alkyl), COR10, CONR7R8, S(O)pC1.6 alkyl, CO2H, CO2(C1.6 alkyl), Cχ.6 alkyl-CO2(C1.6 alkyl), Cχ.6 alkyl-NHCORn, or CH(OH)C!.6 alkyl;
R2 is hydrogen, halogen, CF3, CN, or Cχ.4 alkyl;
R3 and R4 are independently hydrogen, C χ_g alkyl, benzyl, -C(Rχ4)2-OR 2> -COOR13, -
CONR12, -C(R14)2-N(R12)2;
R5 and Rg, are independently hydrogen or Cχ.g alkyl, or taken together form a 5-7-member saturated heterocycle optionally containing an additional heteroatom selected from N, O or S and further substituted by hydrogen, C . alkyl, benzyl or OH;
R7 and Rg are independently hydrogen, Cχ_g alkyl, or benzyl; or taken together form a 5-7- member saturated heterocycle optionally containing an additional heteroatom selected from N, O or S and further substituted by hydrogen, Cχ_6 alkyl, benzyl or OH;
R9 is hydrogen, C .g alkyl, or -(CH2)mRi5;
R θ is hydrogen or C _g alkyl;
Rj 1 is Cχ.g alkyl or benzyl
Rχ2 is hydrogen or C χ.g alkyl;
Rχ3 is C χ_6 alkyl;
Rχ4 is hydrogen or C^alkyl;
Rχ5 is phenyl, OH, or
Figure imgf000079_0002
X is O, S, or CH2;
Y is a 5-7 member saturated heterocycle containin up to 2 heteroatoms selected from N, O or S, optionally substituted by hydrogen, C χ_g alkyl or benzyl; n is 0, 1 or 2; m is 1 or 2 ; p is 0, 1 or 2 q is 0 or 1 provided that when R is OH, m must be 2; further provided that the compound of Formula (I) is not: 3,5-dichloro-4-hydroxy-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4- (trifluoromethyl)phenyl]benzenesulfonamide; 5-[cyclohexyl(hydroxy)methyl]-N-[3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}-4-
(trifluoromethyl)phenyl]-2-thiophenesulfonamide; 5-(cyclohexylmethyl)-N-[3- { [(3R)- 1 -methyl-3-pyrrolidinyl] oxy } -4-(trifluoromethyl)phenyl]-2- thiophenesulfonamide;
N-(4-chloro-3-{[(3R)-l-methyl-3-pyrrolidinyl]oxy}phenyl)-4-fluorobenzenesulfonamide; ; or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 wherein: Ri is phenyl, thienyl, furanyl, pyrroyl, pyridinyl, oxazoyl, imidazoyl, pyrimidinyl, pyrazoyl, or thiazoylsubstituted or unsubstituted by one, two, or three, of any of the following: CI, Br, F. CF3, OH, NO2, CN, Ci _3 alkyl, Ci _3 alkoxy, O(CH2)qY, NR5R6, COR10,
CONR7R8, S(O)pCi_3 alkyl, CO2H, or CH(OH)C!.4 alkyl;
R2 is hydrogen, CI, Br, CF3, or C _2 alkyl; R3 and R4 are hydrogen, C _3 alkyl, -C(R 4)2-OR 2;
R7 and Rg are hydrogen, Ci .3 alkyl, or taken together form morpholine or piperidine;
R5 and Rg are hydrogen or C _3 alkyl, or taken together form morpholine, piperidine, or pyrrolidinel;
R9 is hydrogen, Cχ_3 alkyl; R o is hydrogen, Cχ_3 alkyl;
R 2 is hydrogen or C χ_3 alkyl;
Rχ4 is independently hydrogen or methyl;
X is O; Y is tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperadinyl, azetidinyl all of which may be optionaly substituted by C _3 alkyl; n is 1; p is 0, 1 or 2; and q is O or l.
3. A compound according to claim 1 chosen from the group consisting of:
N-[3-(l-methyl-2(S)-methoxycarbonylpyrrolidin-3(R)-yloxy)-4- trifluoromethylphenyl]-2-bromo-4,5-dimethoxybenzenesulfonamide; N-[3-(2(S)-hydroxymethyl-l-methylpyrrolidin-3(R)-yloxy)-4-trifluoromethylρhenyl]-
2-bromo-4,5-dimethoxybenzenesulfonamide;
N-[3-(2(R)-hydroxymethyl-l-methylpyrrolidin-3(R)-yloxy)-4-trifluoromethylphenyl]- 2-bromo-4,5-dimethoxybenzenesulfonamide;
N-[3-(2(S)-hydroxymethyl-l-methylpyrrolidin-3(R)-yloxy)-4-trifluoromethylphenyl]- 4,5-dimethoxybenzenesulfonamide;
N-[3-((R)-pyrrolidin-3-yloxy)-4-trifluoromethylphenyl]-2-bromo-4,5- dimethoxybenzenesulfona ide.
4. A pharmaceutical composition comprising a compound of formula (I) of claim 1 and a pharmaceutically acceptable carrier or excipient.
5. 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.
6. A method according to Claim 5 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.
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Cited By (6)

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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
CN107056768A (en) * 2017-03-14 2017-08-18 三峡大学 A kind of reversible proton pump inhibitor, preparation method and applications
CN108685910A (en) * 2018-06-08 2018-10-23 三峡大学 A kind of urease inhibitor
WO2022255499A1 (en) 2021-06-04 2022-12-08 学校法人京都薬科大学 Novel amp-activated protein kinase activator

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002089792A1 (en) * 2001-05-07 2002-11-14 Smithkline Beecham Corporation Sulfonamides

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002089792A1 (en) * 2001-05-07 2002-11-14 Smithkline Beecham Corporation Sulfonamides

Cited By (7)

* 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
CN107056768A (en) * 2017-03-14 2017-08-18 三峡大学 A kind of reversible proton pump inhibitor, preparation method and applications
CN108685910A (en) * 2018-06-08 2018-10-23 三峡大学 A kind of urease inhibitor
WO2022255499A1 (en) 2021-06-04 2022-12-08 学校法人京都薬科大学 Novel amp-activated protein kinase activator

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