WO2010150192A1 - Heterocyclic sulfonamides, uses and pharmaceutical compositions thereof - Google Patents

Heterocyclic sulfonamides, uses and pharmaceutical compositions thereof Download PDF

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Publication number
WO2010150192A1
WO2010150192A1 PCT/IB2010/052827 IB2010052827W WO2010150192A1 WO 2010150192 A1 WO2010150192 A1 WO 2010150192A1 IB 2010052827 W IB2010052827 W IB 2010052827W WO 2010150192 A1 WO2010150192 A1 WO 2010150192A1
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WIPO (PCT)
Prior art keywords
alkyl
compound
propane
pharmaceutically acceptable
mmol
Prior art date
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PCT/IB2010/052827
Other languages
French (fr)
Inventor
Anton Franz Joseph Fliri
Randall James Gallaschun
Christopher John O'donnell
Jacob Bradley Schwarz
Barbara Eileen Segelstein
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Pfizer Inc.
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Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=43127233&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2010150192(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to KR1020127001882A priority Critical patent/KR101401886B1/en
Priority to MX2011013884A priority patent/MX2011013884A/en
Priority to DK10732448.5T priority patent/DK2445883T3/en
Priority to NZ597226A priority patent/NZ597226A/en
Priority to RS20140543A priority patent/RS53626B1/en
Priority to CA2766104A priority patent/CA2766104C/en
Priority to AP2012006072A priority patent/AP3066A/en
Priority to CU2011000233A priority patent/CU24078B1/en
Priority to AU2010264095A priority patent/AU2010264095B2/en
Priority to JP2012516937A priority patent/JP5079933B1/en
Priority to ES10732448.5T priority patent/ES2517267T3/en
Priority to BRPI1014583-4A priority patent/BRPI1014583B1/en
Priority to CN201080033627.7A priority patent/CN102471271B/en
Priority to MEP-2014-107A priority patent/ME01903B/en
Priority to BR122019013104-0A priority patent/BR122019013104B1/en
Priority to MA34488A priority patent/MA33384B1/en
Priority to PL10732448T priority patent/PL2445883T3/en
Priority to EA201190320A priority patent/EA021057B1/en
Priority to SG2011092301A priority patent/SG176828A1/en
Priority to EP10732448.5A priority patent/EP2445883B1/en
Priority to SI201030724T priority patent/SI2445883T1/en
Priority to UAA201114874A priority patent/UA102310C2/en
Application filed by Pfizer Inc. filed Critical Pfizer Inc.
Publication of WO2010150192A1 publication Critical patent/WO2010150192A1/en
Priority to IL217083A priority patent/IL217083A/en
Priority to TNP2011000654A priority patent/TN2011000654A1/en
Priority to ZA2012/00367A priority patent/ZA201200367B/en
Priority to HRP20140867AT priority patent/HRP20140867T1/en

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    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
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    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/07—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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    • C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings 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
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Definitions

  • the present invention relates to a novel class of compounds having the structure of formula I as defined herein and pharmaceutical compositions comprising a compound of formula I or a pharmaceutically acceptable salt thereof.
  • the present invention also comprises methods of treating a subject by administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof to the subject. These compounds are useful for the conditions disclosed herein.
  • the present invention further comprises methods for making the compounds of formula I and corresponding intermediates.
  • the primary excitatory neurotransmitter in the mammalian central nervous system is the amino acid glutamate whose signal transduction is mediated by either ionotropic or metabotropic glutamate receptors (GIuR).
  • iGluR lonotropic glutamate receptors
  • AMPA ⁇ -amino-3-hydroxy-5-methylisoxazole-4-propionic acid
  • NMDA /V-methyl-D- aspartate
  • kainate Parsons, C. G., Danysz, W. and Lodge, D.
  • AMPA receptors proteinaceous homo- or heterotetramers comprised of any combination of four ca. 900 amino acid monomer subunits each encoded from a distinct gene (GIU AI - A4 ) with each subunit protein existing as one of two splice variants deemed "flip" and "flop", mediate the vast majority of excitatory synaptic transmissions in the mammalian brain and have long been proposed to be an integral component of the neural circuitry that mediates cognitive processes (Bleakman, D.
  • the present invention is directed to compounds, including the pharmaceutically acceptable salts of the compounds, having the structure of formula:
  • R 5 is hydrogen, or (CrC 6 )alkyl;
  • each R 8 is independently selected from the group consisting of hydrogen, (Ci-C ⁇ jalkyl, (C 6 -Cio)aryl, (d-CgJheteroaryl,
  • (Ci-C6>alkyl may be additionally optionally substituted with an optionally substituted (C 6 -Cio)aryl, (Ci-Cgjheteroaryl, (d-CgJheterocycloalkyl, or (C 3 -Cio)cycloalkyl; wherein said optional substituents may be independently substituted with from one, two, three or four radicals independently selected from halogen, hydroxyl, -CF 3 , -CN, (Ci-C 3 )alkyl, (Ci-C 3 )alkoxy, and amino; wherein each of said R 8 (C 6 -Ci 0 )aryl, (Ci-C 9 )heteroaryl, (Ci-Cg)heterocycloalkyl or (C 3 -Ci 0 )cycloalkyl substituents may be optionally additionally substituted with one, two, three or four radicals independently selected from halogen, hydroxyl, -CF 3 ,
  • R 11 is hydrogen or (Ci-C 6 )alkyl
  • ring "A” is (C 6 -Ci 0 )aryl, (CrC 9 )heteroaryl, (C 4 -Ci 0 )cycloalkyl, or (d-Cg)heterocycloalkyl; wherein two of said R 1 substituents on said (C 4 -Cio)cycloalkyl and (Ci-Cg)heterocycloalkyl may optionally be attached to the same carbon atom and may optionally be taken together to be oxo;
  • ring "B” is (C 6 -Cio)aryl, (d-Cg)heteroaryl, (C 4 -Ci o)cycloalkyl, or (Ci-Cg)heterocycloalkyl;
  • X is -O- or >C(R 4 ) 2 ;
  • alkyl refers to a linear or branched-chain saturated, mono- unsaturated and poly-unsaturated hydrocarbyl substituent (i.e., a substituent obtained from a hydrocarbon by removal of a hydrogen) containing from one to six carbon atoms; and in another embodiment, from one to four carbon atoms.
  • Mono- and poly-unsaturated substituents, a so called alkenyl has 2 to
  • the alkenyl group may exist as the pure E (entadel) form, the pure Z (zusammen) form, or any mixture thereof.
  • Poly-unsaturated includes multiple double bonds and one or more triple bonds.
  • Such triple bond containing alkyl grops, a so called alkynyl group has 2 to 6 carbon atoms. Examples of such saturated substituents include methyl, ethyl, propyl
  • alkynyl examples include ethynyl, propynyl, butynyl, 3,3-dimethylbutynyl and the like.
  • the number of carbon atoms in a hydrocarbyl substituent is indicated by the prefix “C x -Cy-,” wherein x is the minimum and y is the maximum number of carbon atoms in the substituent.
  • C x -Cy- refers to an alkyl substituent containing from 1 to 6 carbon atoms.
  • Cs-C ⁇ -cycloalkyl refers to saturated cycloalkyl containing from 3 to 6 carbon ring atoms.
  • perfluoro(Ci-C 6 )alkyl refers to an alkyl radical as described above substituted with one or more fluorine's including, but not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2- thfluoroethyl, and the like.
  • hydroxy refers to -OH.
  • the prefix "hydroxy” indicates that the substituent to which the prefix is attached is substituted with one or more hydroxy substituents.
  • Compounds bearing a carbon to which one or more hydroxy substituents include, for example, alcohols, enols and phenol.
  • cyano also referred to as "nitrile” means -CN, which also may be depicted as -C ⁇ N.
  • amino refers to -NH 2 .
  • alkoxy refers to an alkyl linked to an oxygen, which may also be represented as: -O-R, wherein the R represents the alkyl group. Examples of alkoxy include methoxy, ethoxy, propoxy and butoxy.
  • sulfonyl refers to -S(O)2-, which also may be depicted
  • alkyl-sulfonyl-alkyl refers to alkyl-S(O) 2 -alkyl.
  • alkylsulfonyl include methylsulfonyl, ethylsulfonyl, and propylsulfonyl.
  • cycloalkyl is defined to include saturated or unsaturated (non aromatic), bridged, polycyclic, spirocyclic or fused polycyclic 3 to 10 membered hydrocarbon rings (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, bicyclo[2.2.1]heptanyl, bicyclo[3.2.1]octanyl and bicyclo[5.2.0]nonanyl, etc.); optionally substituted by 1 to 5 suitable substituents.
  • the cycloalkyl group has 3 to 6 carbon atoms.
  • the cycloalkyl may optionally contain one, two or more non cumulative non aromatic double or triple bonds.
  • Spirocyclic rings are one particular kind of cycloalkyl that occurs when a ring is formed around one carbon atom as compared to a fused ring in which a ring is formed through two common carbon atoms.
  • aryl is defined to include all-carbon monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups having a completely conjugated pi-electron system.
  • the aryl group has 6, 8, 9 or 10 carbon atoms in the ring(s). More preferably, the aryl group has 6 or 10 carbon atoms in the ring(s). Most preferably, the aryl group has 6 carbon atoms in the ring(s).
  • (C 6 -Cio)aryl means aromatic radicals containing from 6 to 10 carbon atoms such as phenyl, naphthyl, tetrahydronaphthyl, anthracenyl, indanyl and the like.
  • the aryl group is optionally substituted by 1 to 5 suitable substituents.
  • heteroaryl is defined to include monocyclic or fused-ring polycyclic aromatic heterocyclic groups with one or more heteroatoms selected from O, S and N in one or more of said ring(s).
  • the heteroaryl group has 5 to 12 ring atoms including one to five heteroatoms independently selected from O, S, and N.
  • One or more of said rings of said heterocyclic group may contain no heteroatoms.
  • the heteroaryl group has 5 to 10 ring atoms including one to four heteroatoms. More preferably, the heteroaryl group has 5 to 8 ring atoms including one, two or three heteroatoms. Most preferably, the heteroaryl group has 6 to 8 ring atoms including one or two heteroatoms.
  • (Ci-Cg)heteroaryl means aromatic radicals containing at least one ring heteroatom independently selected from O, S and N and from 1 to 9 carbon atoms such as pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, furyl, imidazolyl, pyrrolyl, oxazolyl (e.g., 1 ,3-oxazolyl, 1 ,2-oxazolyl), thiazolyl (e.g., 1 ,2-thiazolyl, 1 ,3-thiazolyl), pyrazolyl, tetrazolyl, triazolyl (e.g., 1 ,2,3-triazolyl, 1 ,2,4-triazolyl), oxadiazolyl (e.g., 1 ,2,3-oxadiazolyl), thiadiazolyl (e.g., 1
  • heterocycloalkyl is defined to include a monocyclic, bridged, polycyclic, spirocyclic or fused polycyclic saturated or unsaturated non-aromatic 3 to 20 membered ring including 1 or more heteroatoms independently selected from O, S and N.
  • One or more of said rings of said bridged, polycyclic or fused heterocyclic group may contain no heteroatoms.
  • heterocycloalkyl rings examples include azetidinyl, tetrahydrofuranyl, imidazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, thiomorpholinyl, tetrahydrothiazinyl, tetrahydro-thiadiazinyl, morpholinyl, oxetanyl, tetrahydrodiazinyl, oxazinyl, oxathiazinyl, indolinyl, isoindolinyl, quinuclidinyl, chromanyl, isochromanyl, benzoxazinyl, and the like.
  • heterocycloalkyl rings are tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, imidazolidin-1 -yl, imidazolidin-2- yl, imidazolidin-4-yl, pyrrolidin-1 -yl, pyrrol id in-2-yl, pyrrol id in-3-yl, piperidin-1 - yl, piperidin-2-yl, piperidin-3-yl, piperazin-1-yl, piperazin-2-yl, piperazin-3-yl, 1 ,3-oxazol id in-3-yl, isothiazolidine, 1 ,3-thiazolidin-3-yl, 1 ,2 pyrazol id in-2-yl, 1 ,3-pyrazolidin-1 -yl, 1 ,2-tetrahydrothiazin-2-yl, 1 ,3 tetrahydrothia
  • each substituent is selected independent of the other. Each substituent therefore may be identical to or different from the other substituent(s).
  • asymmetric center When an asymmetric center is present in a compound of formula I (hereinafter understood to mean formula I, Ia, Ib, Ic, Id or Ie), hereinafter referred to as a "compound of the invention,” the compound may exist in the form of optical isomers (enantiomers).
  • the present invention comprises enantiomers and mixtures, including racemic mixtures of the compounds of formula I.
  • the present invention comprises diastereomehc forms (individual diastereomers and mixtures thereof) of compounds.
  • geometric isomers may arise.
  • the present invention comprises the tautomeric forms of compounds of formula I.
  • tautomeric isomerism 'tautomerism'
  • This can take the form of proton tautomerism in compounds of formula I containing, for example, an imino, keto, or oxime group, or so-called valence tautomerism in compounds which contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.
  • the various ratios of the tautomers in solid and liquid form is dependent on the various substituents on the molecule as well as the particular crystallization technique used to isolate a compound.
  • Suitable pharmaceutically acceptable acid addition salts of the compounds of the present invention when possible include those derived from inorganic acids, such as hydrochloric, hydrobromic, hydrofluoric, boric, fluoroboric, phosphoric, metaphosphoric, nitric, carbonic, sulfonic, and sulfuric acids, and organic acids such as acetic, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isothionic, lactic, lactobionic, maleic, malic, methanesulfonic, trifluoromethanesulfonic, succinic, toluenesulfonic, tartaric, and trifluoroacetic acids.
  • Suitable organic acids generally include, for example, aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids.
  • suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts.
  • base salts are formed from bases which form non-toxic salts, including aluminum, arginine, benzathine, choline, diethylamine, diolamine, glycine, lysine, meglumine, olamine, tromethamine and zinc salts.
  • hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.
  • the present invention also includes isotopically labelled compounds, which are identical to those recited in formula I, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that may be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chlorine, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 CI, respectively.
  • isotopically labelled compounds of the present invention for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Thtiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
  • lsotopically labelled compounds of formula I of this invention may generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples and Preparations below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.
  • ethers relates to compounds of the Formula I (or Ia, Ib, Ic, Id or Ie), wherein "Z" is -O- .
  • Another embodiment of the present invention (the so called thioethers) relates to a compound of the Formula I (or Ia, Ib, Ic, Id or Ie), wherein "Z" is -S-.
  • Another embodiment of the present invention (the so called sulfones) relates to a compound of the Formula I (or Ia, Ib, Ic, Id or Ie), wherein "Z" is -(SO 2 )-.
  • furans or pyrans relate to compounds of the Formula I (or Ia, Ib, Ic, Id or Ie), wherein X is -O-.
  • the present inventors have a particular interest is these furans and pyrans particularly as they can be segregated according to combinations with other embodiments of which the "Z" embodiments are of particular note.
  • cyclopentyls or cyclohexyls relate to compounds of the Formula I (or Ia, Ib, Ic, Id or Ie), wherein X is >C(R 4 )2, more specifically wherein each R 4 is hydrogen.
  • the present inventors also have a particular interest is these cyclopentyls or cyclohexyls particularly as they can be segregated according to combinations with other embodiments of which the "Z" embodiments are of particular note.
  • Another embodiment of the present invention relates to a compound of the Formula I (or Ia, Ib, Ic, Id or Ie), wherein R 1 is (Ci-C 6 )alkoxy, (Ci-C 6 )alkyl, cyano or halogen and is in the ortho or para position relative to Y.
  • the present inventors also have a heightened particular interest in these "B" phenyl compounds particularly as they can be segregated according to combinations with other embodiments of which the "X" "cyclopentyls” or “cyclohexyls” and/or the "Z” embodiments are of particular note. Each of these embodiments also form additional embodiments of interest with the "A" ring embodiments described above.
  • the present inventors also have a heightened particular interest in these "B" (d-C 9 )heteroaryl compounds particularly as they can be segregated according to combinations with other embodiments of which the "X" "cyclopentyls” or “cyclohexyls” and/or the "Z” embodiments are of particular note. Each of these embodiments also form additional embodiments of interest with the "A" ring embodiments described above.
  • the present inventors also have a heightened particular interest in these "B" (d-CgJheterocycloalkyl compounds particularly as they can be segregated according to combinations with other embodiments of which the "X" "cyclopentyls” or “cyclohexyls” and/or the "Z” embodiments are of particular note.
  • Each of these embodiments also form additional embodiments of interest with the "A" ring embodiments described above.
  • the present inventors also have a heightened particular interest in these "B" (C 4 -Ci 0 )cycloalkyl compounds particularly as they can be segregated according to combinations with other embodiments of which the "X" "cyclopentyls” or “cyclohexyls” and/or the "Z” embodiments are of particular note. Each of these embodiments also form additional embodiments of interest with the "A" ring embodiments described above.
  • Another embodiment of the present invention relates to a compound of the Formula I (or Ia, Ib, Ic, Id or Ie), wherein R 2 is (CrC ⁇ Jalkoxy, (d-C ⁇ Jalkyl, cyano or halogen.
  • Another embodiment of the present invention relates to a compound of the Formula I (or Ia, Ib, Ic, Id or Ie), wherein R 2 is hydrogen.
  • Another embodiment of the present invention relates to a compound of the Formula I (or Ia, Ib, Ic, Id or Ie), wherein R 4 is hydrogen.
  • Another embodiment of the present invention relates to a compound of the Formula I (or Ia, Ib, Ic, Id or Ie), wherein p is two and both R 4 are taken together to form oxo.
  • Another embodiment of the present invention relates to a compound of the Formula I (or Ia, Ib, Ic, Id or Ie), wherein p is two and each R 4 is (Ci-C ⁇ )alkyl.
  • Another embodiment of the present invention relates to a compound of the Formula I (or Ia, Ib, Ic, Id or Ie), wherein q is zero.
  • Another embodiment of the present invention relates to a compound of the Formula I (or Ia, Ib, Ic, Id or Ie), wherein Y is absent.
  • Another embodiment of the present invention relates to a compound of the Formula I (or Ia, Ib, Ic, Id or Ie), wherein Y is -O-.
  • Another embodiment of the present invention relates to a compound of the Formula I (or Ia, Ib, Ic, Id or Ie), wherein Y is >C(R 7 ) 2 .
  • Another embodiment of the present invention relates to a compound of the Formula I (or Ia, Ib, Ic, Id or Ie), wherein R 6 is (Ci-C 5 )alkyl-SO 2 -.
  • Another embodiment of the present invention relates to a compound of the Formula I (or Ia, Ib, Ic, Id or Ie), wherein R 6 is (C3-C 5 )cycloalkyl-SO2-.
  • Another embodiment of the present invention relates to a compound of the Formula I (or Ia, Ib, Ic, Id or Ie), wherein R 6 is [(Ci-C 3 )alkyl] 2 N-SO 2 -; wherein said (Ci-C 2 )alkyl moieties may optionally be taken together with the nitrogen atom to which they are attached to form a four to six membered heterocyclic ring.
  • Another embodiment of the invention also relates to each of the individual compounds described as Examples 1 -54 in the Examples section of this specification, and pharmaceutically acceptable salts thereof.
  • the compounds of Formula I and the pharmaceutically acceptable salts thereof are useful for the treatment of a variety of neurological and psychiatric disorders associated with glutamate dysfunction, including: acute neurological and psychiatric disorders such as cerebral deficits subsequent to cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage, dementia (including AIDS-induced dementia), Alzheimer's disease, Huntington's Chorea, amyotrophic lateral sclerosis, ocular damage, retinopathy, cognitive disorders, idiopathic and drug- induced Parkinson's disease, muscular spasms and disorders associated with muscular spasticity including tremors, epilepsy, convulsions, migraine (including migraine headache), urinary incontinence, substance tolerance, substance withdrawal (including, substances such as opiates, nicotine, tobacco products, alcohol, benzodiazepines, cocaine, sedatives, hypnotics, etc.), psychosis, schizophrenia, anxiety (including generalized
  • the invention provides a method for treating a condition in a mammal, such as a human, selected from the conditions above, comprising administering an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof to the mammal.
  • the mammal is preferably a mammal in need of such treatment or prevention.
  • treating means reversing, alleviating, modulating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
  • treatment refers to the act of treating as "treating” is defined immediately above.
  • the invention provides a method for treating a condition selected from migraine, anxiety disorders, schizophrenia, and epilepsy.
  • exemplary anxiety disorders are generalized anxiety disorder, social anxiety disorder, panic disorder, post-traumatic stress disorder and obsessive- compulsive disorder.
  • the invention provides a method for treating depression selected from Major Depression, Chronic Depression (Dysthymia), Seasonal Depression (Seasonal Affective Disorder), Psychotic Depression, and Postpartum Depression.
  • the invention provides a method for treating a sleep disorder selected from insomnia and sleep deprivation.
  • the invention comprises methods of treating a condition in a mammal, such as a human, by administering an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the condition is selected from the group consisting of atherosclerotic cardiovascular diseases, cerebrovascular diseases and peripheral arterial diseases, to the mammal.
  • a mammal such as a human
  • the mammal is preferably a mammal in need of such treatment or prevention.
  • Other conditions that can be treated in accordance with the present invention include hypertension and angiogenesis.
  • the present invention provides methods of treating neurological and psychiatric disorders associated with glutamate dysfunction, comprising administering to a mammal, preferably a mammal in need thereof, an amount of a compound of Formula I or a pharmaceutically acceptable salt thereof effective in treating such disorders.
  • the compound of Formula I or a pharmaceutically acceptable salt thereof is optionally used in combination with another active agent.
  • an active agent may be, for example, an atypical antipsychotic or an AMPA potentiator.
  • another embodiment of the invention provides methods of treating neurological and psychiatric disorders associated with glutamate dysfunction, comprising administering to a mammal an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof and further comprising administering another active agent.
  • another active agent refers to any therapeutic agent, other than the compound of Formula (I), or salt thereof, that is useful for the treatment of a subject disorder.
  • additional therapeutic agents include antidepressants, antipsychotics, anti-pain, anti- Alzheimer's and anti-anxiety agents.
  • Examples of particular classes of antidepressants that can be used in combination with the compounds of the invention include norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors (SSRIs), NK-1 receptor antagonists, monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase (RIMAs), serotonin and noradrenaline reuptake inhibitors (SNRIs), corticotropin releasing factor (CRF) antagonists, ⁇ -adrenoreceptor antagonists, and atypical antidepressants.
  • Suitable norepinephrine reuptake inhibitors include tertiary amine tricyclics and secondary amine tricyclics.
  • Suitable tertiary amine tricyclics and secondary amine tricyclics include amithptyline, clomipramine, doxepin, imipramine, thmipramine, dothiepin, butriptyline, iphndole, lofepramine, nortriptyline, protriptyline, amoxapine, desipramine and maprotiline.
  • suitable selective serotonin reuptake inhibitors include fluoxetine, fluvoxamine, paroxetine, and sertraline.
  • monoamine oxidase inhibitors include isocarboxazid, phenelzine, and tranylcyclopramine.
  • Suitable reversible inhibitors of monoamine oxidase include moclobemide.
  • suitable serotonin and noradrenaline reuptake inhibitors of use in the present invention include venlafaxine.
  • suitable atypical anti-depressants include bupropion, lithium, nefazodone, trazodone and viloxazine.
  • anti- Alheimer's agents include Dimebon, NMDA receptor antagonists such as memantine; and cholinesterase inhibitors such as donepezil and galantamine.
  • Suitable classes of anti-anxiety agents include benzodiazepines and serotonin 1A (5-HT1A) agonists or antagonists, especially 5-HT1A partial agonists, and corticotropin releasing factor (CRF) antagonists.
  • Suitable benzodiazepines include alprazolam, chlordiazepoxide, clonazepam, chlorazepate, diazepam, halazepam, lorazepam, oxazepam, and prazepam.
  • Suitable 5-HT1A receptor agonists or antagonists include buspirone, flesinoxan, gepirone and ipsapirone.
  • Suitable atypical antipsychotics include paliperidone, bifeprunox, ziprasidone, risperidone, aripiprazole, olanzapine, and quetiapine.
  • Suitable nicotine acetylcholine agonists include ispronicline, varenicline and MEM 3454.
  • Anti-pain agents include pregabalin, gabapentin, clonidine, neostigmine, baclofen, midazolam, ketamine and ziconotide.
  • the invention is also directed to pharmaceutical compositions comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the compounds of the Formula I may be prepared by the methods described below, together with synthetic methods known in the art of organic chemistry, or modifications and derivatisations that are familiar to those of ordinary skill in the art.
  • Scheme 1 refers to the preparation of compounds of the Formula I.
  • an aryl halide of Formula II wherein L 1 is iodo, bromo or a triflate, may be coupled to a suitably substituted aryl boronic acid of structure (R 1 J n -ArB(OH) 2 , wherein Ar represents a suitably substituted aryl or heteroaryl group and B is boron, under standard palladium catalyzed cross- coupling reaction conditions well known to one of ordinary skill in the art to provide the compound of Formula I.
  • the compounds of Formula Il may be prepared from the compounds of Formula III via displacement of L 2 , wherein L 2 may be halo, -OSO 2 CH 3 (-OMs), or -OSO 2 CF 3 (-OTf), with a reactant
  • Z is O or S.
  • Typical conditions involve reaction in an organic solvent such as acetonitrile in the presence of a base such as cesium carbonate at elevated temperature such as 15O 0 C.
  • a base such as cesium carbonate
  • Z is S
  • a reagent such as a peroxide (such as mCPBA) in a solvent such as methylene chloride at room temperature.
  • the compound of Formula III may be converted to a compound of Formula II, wherein L 2 is ZH and Z is O or S, by nucleophilic aromatic substitution (such as reaction with an aryl tin, such as SnAr) reaction with an appropriately substituted aryl reagent
  • L 2 is halo or -OSO 2 CF 3 (-OTf) according to methods analogous to those described in Withbroe, G. J.; Singer, R. A.; Sieser, J. E. "Streamlined Synthesis of the Bippyphos Family of Ligands and Cross-Coupling Applications” Org. Process Res. Dev. 2008, 12, 480-489.
  • Typical conditions involve reaction in an organic solvent such as ethanol in the presence of a base such as potassium hydroxide, a catalyst, such as a palladium (such as Pd2(dba) 3 ), and a ligand, such as 1 -[2-[bis(tert-butyl)phosphino]phenyl]-3,5- diphenyl-1 H-pyrazole (bippyphos), at elevated temperature such as 8O 0 C.
  • a base such as potassium hydroxide
  • a catalyst such as a palladium (such as Pd2(dba) 3 )
  • a ligand such as 1 -[2-[bis(tert-butyl)phosphino]phenyl]-3,5- diphenyl-1 H-pyrazole (bippyphos)
  • a compound of Formula I may be prepared from a compound of Formula II, wherein L 1 is a silyl group (such as trimethylsilyl) by first converting the silyl group to a halide, such as by reaction with a halogenating reagent such as potassium bromide/ ⁇ /-chlorosuccinimide (NCS) in the presence of an acid (such as acetic acid) followed by arylation as described above.
  • Suitable solvents for the halogenation include alcohols such as methanol or ethanol.
  • the reaction may be conducted at a temperature of about 1O 0 C to about 6O 0 C for about 10 to about 120 minutes.
  • NR 7 may be prepared by reaction of a compound of Formula Il wherein L 1 is NH 2 or OH by reaction with an aryl halide in the presence of a catalyst.
  • the compound of Formula Il may be prepared from a compound of Formula III by coupling with a suitably substituted Aryl Ghgnard in an ethereal solvent such as THF at about -3O 0 C to about room temperature.
  • a catalyst such as palladium or copper, may facilitate the reaction.
  • the compounds of Formula III are commercially available or may be made by methods well known to those skilled in the art or may be prepared by routine methods known in the art (such as those methods disclosed in standard reference books such as the COMPENDIUM OF ORGANIC SYNTHETIC METHODS, Vol. I-VI (published by Wiley-lnterscience)). Th e compounds of Formula I may be separated into the enantiomerically pure isomers according to methods well known to those skilled in the art and described in detail in the Example section herein.
  • the compounds of this invention may be used in the form of salts derived from inorganic or organic acids.
  • the acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is obtained.
  • Base salts can easily be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmaceutically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they may also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before. In either case, stoichiometric quantities of reagents are preferably employed in order to ensure completeness of the reaction and maximum product yields. Where a salt is intended to be administered to a patient (as opposed to, for example, being used in an in vitro context), the salt preferably is pharmaceutically acceptable.
  • pharmaceutically acceptable salt refers to a salt prepared by combining a compound of formula I with an acid whose anion, or a base whose cation, is generally considered suitable for human consumption.
  • Pharmaceutically acceptable salts are particularly useful as products of the methods of the present invention because of their greater aqueous solubility relative to the parent compound.
  • the salts of the compounds of this invention are non-toxic "pharmaceutically acceptable salts.”
  • a compound of the invention is administered in an amount effective to treat or prevent a condition as described herein.
  • the compounds of the invention are administered by any suitable route in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment or prevention intended.
  • Therapeutically effective doses of the compounds required to treat or prevent the progress of the medical condition are readily ascertained by one of ordinary skill in the art using preclinical and clinical approaches familiar to the medicinal arts.
  • the compounds of the invention may be administered orally.
  • Oral administration may involve swallowing so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth.
  • the compounds of the invention may be administered directly into the blood stream, into muscle, or into an internal organ.
  • Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intra urethra I, intrasternal, intracranial, intramuscular and subcutaneous.
  • Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
  • the compounds of the invention may be administered topically to the skin or mucosa, that is, dermally or transdermally.
  • the compounds of the invention may be administered intranasally or by inhalation.
  • the compounds of the invention may be administered rectally or vaginally.
  • the compounds of the invention may be administered directly to the eye or ear.
  • the dosage regimen for the compounds and/or compositions containing the compounds is based on a variety of factors, including the type, age, weight, sex and medical condition of the patient; the severity of the condition; the route of administration; and the activity of the particular compound employed. Thus, the dosage regimen may vary widely.
  • Dosage levels of the order from about 0.01 mg to about 100 mg per kilogram of body weight per day are useful in the treatment or prevention of the above- indicated conditions.
  • the total daily dose of a compound of the invention is typically from about 0.01 to about 100 mg/kg.
  • total daily dose of the compound of the invention is from about 0.1 to about 50 mg/kg, and in another embodiment, from about 0.5 to about 30 mg/kg (i.e., mg compound of the invention per kg body weight).
  • dosing is from 0.01 to 10 mg/kg/day. In another embodiment, dosing is from 0.1 to 1 .0 mg/kg/day.
  • Dosage unit compositions may contain such amounts or submultiples thereof to make up the daily dose.
  • the administration of the compound will be repeated a plurality of times in a day (typically no greater than 4 times). Multiple doses per day typically may be used to increase the total daily dose, if desired.
  • compositions may be provided in the form of tablets containing 0.01 , 0.05, 0.1 , 0.5, 1 .0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 75.0, 100, 125, 150, 175, 200, 250 or 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient.
  • a medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, or in another embodiment, from about 1 mg to about 100 mg of active ingredient.
  • doses may range from about 0.1 to about 10 mg/kg/minute during a constant rate infusion.
  • Suitable subjects according to the present invention include mammalian subjects. Mammals according to the present invention include, but are not limited to, canine, feline, bovine, caprine, equine, ovine, porcine, rodents, lagomorphs, primates, and the like, and encompass mammals in utero. In one embodiment, humans are suitable subjects. Human subjects may be of either gender and at any stage of development.
  • the invention comprises the use of one or more compounds of the invention for the preparation of a medicament for the treatment or prevention of the conditions recited herein.
  • a compound of the invention can be administered as the compound per se.
  • pharmaceutically acceptable salts of the compounds are suitable for medical applications because of their greater aqueous solubility relative to the parent compounds.
  • the present invention comprises pharmaceutical compositions.
  • Such pharmaceutical compositions comprise a compound of the invention or a pharmaceutically acceptable salt thereof presented with a pharmaceutically-acceptable carrier.
  • the carrier can be a solid, a liquid, or both, and may be formulated with the compound as a unit- dose composition, for example, a tablet, which can contain from 0.05% to 95% by weight of the active compounds.
  • a compound of the invention may be coupled with suitable polymers as targetable drug carriers. Other pharmacologically active substances can also be present.
  • the compounds of the present invention and the pharmaceutically acceptable salts thereof may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment or prevention intended.
  • the active compounds, pharmaceutically acceptable salts thereof and compositions may be administered orally, rectally, parenterally, or topically.
  • Oral administration of a solid dose form may be, for example, presented in discrete units, such as hard or soft capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of at least one compound of the present invention or a pharmaceutically acceptable salt thereof.
  • the oral administration may be in a powder or granule form.
  • the oral dose form is sub-lingual, such as, for example, a lozenge.
  • the compounds of formula I or a pharmaceutically acceptable salt thereof are ordinarily combined with one or more adjuvants.
  • Such capsules or tablets may contain a controlled-release formulation.
  • the dosage forms also may comprise buffering agents or may be prepared with enteric coatings.
  • oral administration may be in a liquid dose form.
  • Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art (e.g., water).
  • Such compositions also may comprise adjuvants, such as wetting, emulsifying, suspending, flavoring (e.g., sweetening), and/or perfuming agents.
  • the present invention comprises a parenteral dose form.
  • Parenteral administration includes, for example, subcutaneous injections, intravenous injections, intraperitoneally, intramuscular injections, intrasternal injections, and infusion.
  • injectable preparations e.g., sterile injectable aqueous or oleaginous suspensions
  • suitable dispersing, wetting agents, and/or suspending agents may be formulated according to the known art using suitable dispersing, wetting agents, and/or suspending agents.
  • Topical administration includes, for example, transdermal administration, such as via transdermal patches or iontophoresis devices, intraocular administration, or intranasal or inhalation administration.
  • Compositions for topical administration also include, for example, topical gels, sprays, ointments, and creams.
  • a topical formulation may include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas.
  • Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used.
  • Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol.
  • Penetration enhancers may be incorporated - see, for example, J Pharm Sci, 88 (10), 955-958, by Finnin and Morgan (October 1999).
  • Formulations suitable for topical administration to the eye include, for example, eye drops wherein the compound of this invention or a pharmaceutically acceptable salt thereof is dissolved or suspended in suitable carrier.
  • a typical formulation suitable for ocular or aural administration may be in the form of drops of a micronised suspension or solution in isotonic, pH- adjusted, sterile saline.
  • Other formulations suitable for ocular and aural administration include ointments, biodegradable (e.g. absorbable gel sponges, collagen) and non-biodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes.
  • a polymer such as crossed-l inked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysacchahde polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride.
  • a preservative such as benzalkonium chloride.
  • Such formulations may also be delivered by iontophoresis.
  • the active compounds of the invention or the pharmaceutically acceptable salts thereof are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant.
  • Formulations suitable for intranasal administration are typically administered in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as 1 ,1 ,1 ,2-tetrafluoroethane or 1 ,1 ,1 ,2,3,3,3- heptafluoropropane.
  • the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.
  • the present invention comprises a rectal dose form.
  • rectal dose form may be in the form of, for example, a suppository. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.
  • compositions of the invention may be prepared by any of the well-known techniques of pharmacy, such as effective formulation and administration procedures.
  • effective formulations and administration procedures are well known in the art and are described in standard textbooks.
  • Formulation of drugs is discussed in, for example, Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania, 1975; Liberman, et al., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Kibbe, et al., Eds., Handbook of Pharmaceutical Excipients (3 rd Ed.), American Pharmaceutical Association, Washington, 1999.
  • the compounds of the present invention and the pharmaceutically acceptable salts thereof can be used, alone or in combination with other therapeutic agents, in the treatment or prevention of various conditions or disease states.
  • the compound(s) of the present invention, pharmaceutically acceptable salts thereof and other therapeutic agent(s) may be may be administered simultaneously (either in the same dosage form or in separate dosage forms) or sequentially in any order.
  • An exemplary therapeutic agent may be, for example, a metabotropic glutamate receptor agonist.
  • the administration of two or more compounds "in combination" means that the two compounds are administered closely enough in time that the presence of one alters the biological effects of the other.
  • the two or more compounds may be administered simultaneously, concurrently or sequentially in any order. Additionally, simultaneous administration may be carried out by mixing the compounds prior to administration or by administering the compounds at the same point in time but at different anatomic sites or using different routes of administration.
  • kits that are suitable for use in performing the methods of treatment or prevention described above.
  • the kit contains a first dosage form comprising one or more of the compounds of the present invention or a pharmaceutically acceptable salt thereof and a container for the dosage, in quantities sufficient to carry out the methods of the present invention.
  • the kit of the present invention comprises one or more compounds of the invention or a pharmaceutically acceptable salt thereof.
  • a trial structure was obtained by direct methods for each compound.
  • reaction conditions length of reaction and temperature
  • reaction conditions may vary. In general, reactions were followed by thin layer chromatography or mass spectrometry, and subjected to work-up when appropriate. If non- product solids were present in the crude reaction mixture, filtration through Celite® may be employed. Purifications may vary between experiments: in general, solvents and the solvent ratios used for eluants/gradients were chosen to provide appropriate RfS or retention times.
  • Preparation 1 Synthesis of c/s-/V- ⁇ 4-[(6-bromopyridin-3-yl)oxy1tetrahydrofuran-3-yl)propane-
  • Step 1 Synthesis of frans-4-[(6-bromopyridin-3-yl)oxy]tetrahydrofuran- 3-ol.
  • Step 1 The title compound of Step 1 was prepared according to the general procedure for the synthesis of frans-4-(4-bromophenoxy)tetrahydrofuran-3-ol in Example 2, except that 6-bromopyridin-3-ol was used in place of 4- bromophenol, and the crude product was purified by silica gel chromatography (Gradient: 20% to 70% ethyl acetate in heptane). Yield:
  • Step 2 The title compound of Step 2 was prepared according to the general procedure for the synthesis of frans-2-(4-bromophenoxy)cyclopentyl methanesulfonate in Example 5, except that frans-4-[(6-bromopyhdin-3- yl)oxy]tetrahydrofuran-3-ol was used instead of trans-2-(4- bromophenoxy)cyclopentanol.
  • the product was obtained as a solid. Yield:
  • Step 3 Synthesis of cis-N- ⁇ 4-[(6-bromopyhdin-3-yl)oxy]tetrahydro- furan-3-yl ⁇ propane-2-sulfonamide. 7rans-4-[(6-bromopyridin-3-yl)oxy]tetrahydrofuran-3-yl methane sulfonate (591 .7 mg, 1 .75 mmol), propane-2-sulfonamide (647 mg, 5.25 mmol) and cesium carbonate (855 mg, 2.62 mmol) were combined in acetonitrile (8 ml_) and subjected to microwave irradiation for 55 minutes at 150 0 C.
  • Step 2 Synthesis of compound methyl 3-cyano-4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)benzoate. 4,4,4',4 ⁇ 5,5,5 ⁇ 5'-Octamethyl-2,2'-bi-1 ,3,2-dioxaborolane
  • Step 1 Synthesis of frans-2-(4-bromo-3-fluorophenoxy)cyclopentanol.
  • 4-Bromo-3-fluorophenol (8.00 g, 41 .9 mmol) and 6- oxabicyclo[3.1 .0]hexane (8.25 ml_, 95.2 mmol) were combined in butyronitrile (5.0 ml_) and treated with sodium carbonate (4.04 g, 38.1 mmol).
  • the reaction was subjected to microwave irradiation for 2 hours at 175°C, then filtered through Celite®.
  • Step 2 The title compound in Step 2 was prepared according to the general procedure for the synthesis of (1 R,2R)-2-(4-bromophenoxy)cyclohexyl acetate in Example 7, except that frans-2-(4-bromo-3-fluorophenoxy)cyclopentanol was used instead of frans-2-(4-bromophenoxy)cyclohexanol.
  • the less polar material from the chromatographic purification on silica gel provided (1 R,2R)-
  • Step 3 The title compound in Step 3 was prepared according to the general procedure for the synthesis of (1R,2R)-2-(4-bromophenoxy)cyclohexanol in Example 7, except that (1 R,2R)-2-(4-bromo-3-fluorophenoxy)cyclopentyl acetate was used instead of (1 R,2R)-2-(4-bromophenoxy)cyclohexyl acetate.
  • Step 4 The title compound in Step 4 was prepared according to the general procedure for the synthesis of frans-2-(4-bromophenoxy)cyclopentyl methanesulfonate in Example 5, except that (1 R,2R)-2-(4-bromo-3- fluorophenoxy)cyclopentanol was used instead of frans-2-(4- bromophenoxy)cyclopentanol.
  • the product was obtained as an oil, which was taken on to the following step without purification.
  • MS (GCMS) m/z 352, 354 (M+1 ).
  • Step 5 Synthesis of (1 R,2S)-2-azidocyclopentyl 4-bromo-3- fluorophenyl ether.
  • Step 5 The title compound in Step 5 was prepared according to the general procedure for the synthesis of c/s-2-azidocyclopentyl 4-bromophenyl ether in Example 5, except that (1 R,2R)-2-(4-bromo-3-fluorophenoxy)cyclopentyl methanesulfonate was employed in place of trans-2-(4- bromophenoxy)cyclopentyl methanesulfonate.
  • the product was isolated as a brown oil, which was used without purification in the following step.
  • Step 6 Synthesis of (1 S,2R)-2-(4-bromo-3- fluorophenoxy)cyclopentanamine.
  • Step 6 The title compound in Step 6 was prepared according to the general procedure for the synthesis of c/s-2-(4-bromophenoxy)cyclopentanamine in Example 5, except that (1 R,2S)-2-azidocyclopentyl 4-bromo-3-fluorophenyl ether was used instead of c/s-2-azidocyclopentyl 4-bromophenyl ether, and c/s-2-(4-bromophenoxy)cyclopentanamine was taken on to the following step without purification.
  • Step 7 Synthesis of ⁇ /-[(1 S,2R)-2-(4-bromo-3-fluorophenoxy)- cyclopentyl]propane-2-sulfonamide.
  • the title compound of Step 7 was prepared according to the general procedure for the synthesis of c/s- ⁇ /-[2-(4- bronnophenoxy)cyclopentyl]propane-2-sulfonannide in Example 5, except that (1 S,2R)-2-(4-bromo-3-fluorophenoxy)cyclopentanannine was used instead of c/s-2-(4-bromophenoxy)cyclopentanannine, and the chromatographic purification was carried out with a gradient of 0% to 10% methanol in dichloromethane, to provide the title compound as an off-white solid.
  • Step 1 Synthesis of te/t-butyl (methylsulfonyl) ⁇ 2-[4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]ethyl ⁇ carbamate.
  • Trifluoroacetic acid (10 mL) was added to a 0 0 C solution of te/t-butyl (methylsulfonyl) ⁇ 2-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]ethyl ⁇ carbamate (from the previous step, assumed 19.7 mmol) in dichloromethane (100 mL).
  • the reaction mixture was allowed to warm to room temperature and stir for 18 hours. It was then cooled to 0 0 C and brought to pH 10.5 with a 4N aqueous sodium hydroxide solution.
  • the title compound was prepared according to the general procedure for the synthesis of c/s- ⁇ /-[2-(4-bromophenoxy)cyclopentyl]propane-2- sulfonamide in Example 5, except that (1 S,2R)-2-(4-bromo-3- fluorophenoxy)cyclohexanamine was used in place of c/s-2-(4- bromophenoxy)cyclopentanamine, and the chromatographic purification employed 0% to 1 % methanol in dichloromethane as gradient.
  • Step 1 Synthesis of frans-2-[(6-bromopyridin-3-yl)oxy]cyclohexanol.
  • the title compound of Step 1 was prepared according to the general procedure for the synthesis of frans-2-(4-bromo-3- fluorophenoxy)cyclopentanol in Preparation 3, except that 6-bromopyhdin-3-ol was used instead of 4-bromo-3-fluorophenol, and 7-oxabicyclo[4.1.0]heptane in place of 6-oxabicyclo[3.1.0]hexane.
  • the aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with water (2 x 200 ml_) and saturated aqueous sodium chloride solution (200 ml_).
  • the organic layer was then extracted with aqueous 1 N hydrochloric acid (4 x 150 ml_), and the combined aqueous layers were washed with ethyl acetate (150 ml_).
  • Step 3 Synthesis of c/s- ⁇ /- ⁇ 2-[(6-bromopyhdin-3-yl)oxy]cyclohexyl ⁇ - propane-2-sulfonamide.
  • the title compound of Step 3 was prepared according to the general procedure for the synthesis of c/s- ⁇ /-[2-(4- bromophenoxy)cyclopentyl]propane-2-sulfonamide c/s- ⁇ /-[2-(4- bromophenoxy)cyclopentyl]propane-2-sulfonamide in Example 5, except that c/s-2-[(6-bromopyridin-3-yl)oxy]cyclohexanamine was used in place of c/s-2- (4-bromophenoxy)cyclopentanamine, and the 4-(dimethylamino)pyhdine was omitted.
  • silica gel chromatography in this case was carried out with an eluant of 2% methanol in dichloromethane, to provide c/s- ⁇ /- ⁇ 2-[(6- bromopyridin-3-yl)oxy]cyclohexyl ⁇ propane-2-sulfonamide as a beige foam. Yield: 7.96 g, 21.1 mmol, 72%.
  • Step 4 Isolation of ⁇ /- ⁇ (1 S,2R)-2-[(6-bromopyridin-3- yl)oxy]cyclohexyl ⁇ propane-2-sulfonamide.
  • the first-eluting compound was enantiomer [ ⁇ /- ⁇ (1R,2S)-2-[(6-bromopyridin-3- yl)oxy]cyclohexyl ⁇ propane-2-sulfonamide] and the second-eluting peak provided desired product ⁇ /- ⁇ (1 S,2R)-2-[(6-bromopyridin-3- yl)oxy]cyclohexyl ⁇ propane-2-sulfonamide upon removal of solvent in vacuo. Yield: 3.13 g, 8.30 mmol, 39%.
  • the absolute stereochemistry of these enantiomers was assigned by analogy to Example 5.
  • the title compound was prepared according to the general procedure for the synthesis of c/s- ⁇ /- ⁇ 4-[(6-bromopyridin-3-yl)oxy]tetrahydrofuran-3- yl ⁇ propane-2-sulfonamide in Preparation 1 , except that trans-4-(4- bromophenoxy)tetrahydrofuran-3-yl methanesulfonate was used in place of frans-4-[(6-bromopyridin-3-yl)oxy]tetrahydrofuran-3-yl methanesulfonate, and the chromatographic purification was carried out with a gradient of 15% to 35% acetone in heptane.
  • Step 1 Synthesis of frans- ⁇ /-(4-hydroxytetrahydrofuran-3-yl)propane- 2-sulfonamide. 3,6-Dioxabicyclo[3.1.0]hexane (1.90 g, 22.1 mmol), propane-2- sulfonamide (prepared according to the method of D. C. Johnson, Il and T. S. Widlanski, Tetrahedron Letters 2004, 45, 8483-8487) (3.13 g, 25.4 mmol), potassium carbonate (584 mg, 4.23 mmol) and benzylthethylammonium chloride (963 mg, 4.23 mmol) were suspended in dioxane (10 ml_) and heated at reflux for 120 hours.
  • dioxane 10 ml_
  • Step 2 Synthesis of frans-4-[(isopropylsulfonyl)amino]tetrahydrofuran- 3-yl methanesulfonate.
  • Triethylamine (1.99 ml_, 14.3 mmol) was added to a cooled (0 0 C) solution of frans-/V-(4-hydroxytetrahydrofuran-3-yl)propane-2-sulfonamide (1.99 g, 9.52 mmol) in dichloromethane (20 ml_).
  • Methanesulfonyl chloride (0.885 ml_, 11.4 mmol) was then added and the reaction was stirred at 0 0 C for 50 minutes.
  • Saturated aqueous sodium bicarbonate solution (10 ml_) was added, and the aqueous layer was extracted with methylene chloride.
  • Step 3 Synthesis of frans- ⁇ /-[4-(4-bromophenoxy)tetrahydrofuran-3- yl]propane-2-sulfonamide.
  • a solution of frans-4-[(isopropylsulfonyl)amino] tetrahydrofuran-3-yl methanesulfonate (546 mg, 1 .90 mmol) in acetonitrile (8 mL) was combined with 4-bromophenol (97%, 407 mg, 2.28 mmol) and cesium carbonate (929 mg, 2.85 mmol).
  • the reaction was irradiated in a microwave reactor at 160 0 C for 2 hours, then cooled to room temperature and treated with saturated aqueous sodium bicarbonate solution (10 ml_). The reaction was extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (Gradient: 20% to 50% ethyl acetate in heptane), to afford trans-N-[4-(4- bromophenoxy)tetrahydrofuran-3-yl]propane-2-sulfonamide. Yield: 626 mg, 1.72 17117101, 91 %.
  • Step 4 Synthesis of ⁇ /- ⁇ 1 -[4-frans-( ⁇ 4-[(isopropylsulfonyl)amino]- tetrahydrofuran-3-yl ⁇ oxy)phenyl]pyrrolidin-3-yl ⁇ acetamide.
  • Triethylamine (181.9 ml_, 1.31 mol) was added to a solution of trans-4- (4-bromophenoxy)tetrahydrofuran-3-ol from the previous step (354 g, assumed 300.6 g, 1.16 mol) in methylene chloride (2 L), and the reaction was cooled to 0 0 C in an ice bath.
  • Methanesulfonyl chloride (101.3 ml_, 1.31 mol) was then added drop-wise, while keeping the reaction temperature below 5 0 C, and the reaction was stirred at room temperature for 18 hours. Water (1.5 L) was added, and the aqueous layer was extracted with methylene chloride.
  • Step 3 Synthesis of c/s-3-azido-4-(4-bromophenoxy)tetrahydrofuran.
  • frans-4-(4-bromophenoxy)tetrahydrofuran-3-yl methanesulfonate 133.2 g, 0.395 mol
  • sodium azide (192.6 g, 2.96 mol)
  • the reaction was heated at 110 0 C for 66 hours.
  • the reaction was cooled to room temperature and water (12 L) was added. This reaction was carried out a total of three times on the same scale, and the combined batches were extracted with te/t-butyl methyl ether.
  • Step 6 Synthesis of ⁇ /-[(3S,4S)-4-(4-bromophenoxy)tetrahydrofuran-3- yl]propane-2-sulfonamide.
  • Step 7 Synthesis of ⁇ /-[(3S,4S)-4-(biphenyl-4-yloxy)tetrahydrofuran-3- yl]propane-2-sulfonamide.
  • Step 1 Synthesis of frans-2-(4-bromophenoxy)cyclopentanol. 6-Oxabicyclo[3.1.0]hexane (2.04 ml_, 23.5 mmol), 4-bromophenol (4.49 g, 26.0 mmol), cesium carbonate (99%, 8.93 g, 27.1 mmol) and benzylthethylammonium chloride (99%, 1.09 g, 4.74 mmol) were suspended in dioxane (65 mL) and heated at reflux for 18 hours. Additional 6- oxabicyclo[3.1 .0]hexane (0.50 mL, 5.8 mmol) was added, and heating was continued for 66 hours.
  • Step 2 The title compound of Step 2 was prepared according to the general procedure for the synthesis of frans-4-(4-bromophenoxy)tetrahydrofuran-3-yl methanesulfonate in Example 2, except that trans-2-(4- bromophenoxy)cyclopentanol was used in place of trans-4-(4- bromophenoxy)tetrahydrofuran-3-ol, and the reaction mixture was quenched by addition of saturated aqueous ammonium chloride solution. The organic layer was then washed with saturated aqueous ammonium chloride solution, washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo to provide product as a brown oil.
  • Step 3 Synthesis of c/s-2-azidocyclopentyl 4-bromophenyl ether.
  • frans-2-(4-bromophenoxy)cyclopentyl methanesulfonate 3.52 g, 10.5 mmol
  • dimethylformamide 22 mL
  • sodium azide 897 mg, 13.7 mmol
  • the reaction was cooled to room temperature and partitioned between ethyl acetate and 1 N aqueous lithium chloride solution.
  • Step 4 Synthesis of c/s-2-(4-bromophenoxy)cyclopentanamine.
  • a solution of c/s-2-azidocyclopentyl 4-bromophenyl ether from the previous step (2.59 g, 9.18 mmol) in tetrahydrofuran (63 ml_) and water (5.0 ml_) was treated with polymer-supported thphenylphosphine (3 mmol/g, 7.15 g, 21.5 mmol). The reaction was stirred for 18 hours, then filtered through Celite®.
  • the filter pad was rinsed with tetrahydrofuran, then with a mixture of methylene chloride and methanol, and the combined filtrates were concentrated in vacuo, and azeotroped with ethanol.
  • the residue was purified by chromatography on silica gel (Gradient: 0% to 10% methanol in ethyl acetate) to afford product as a light brown oil. Yield: 1.43 g, 5.58 mmol, 61 %.
  • Step 6 Isolation of ⁇ /-[(1 S,2R)-2-(4-bromophenoxy)cyclopentyl]- propane-2-sulfonamide. Separation of the enantiomers comprising c/s- ⁇ /-[2-(4- bromophenoxy)cyclopentyl]propane-2-sulfonamide (1.586 g, 4.38 mmol) was carried out by chiral chromatography. Column: Chiralpak® AD-H, 2.1 x 25 cm, 5 ⁇ m; Mobile phase: 75:25 carbon dioxide: methanol; Flow rate: 65 g/min.
  • the first-eluting compound was enantiomer ⁇ /-[(1 R,2S)-2-(4- bromophenoxy)cyclopentyl]propane-2-sulfonamide (767 mg, 2.12 mmol, 48%) and the second-eluting peak provided desired product ⁇ /-[(1 S,2R)-2-(4- bromophenoxy)cyclopentyl]propane-2-sulfonamide upon removal of solvent in vacuo. Yield: 758 mg, 2.09 mmol, 48%.
  • the absolute stereochemistry of these enantiomers was assigned by analogy to their higher homologues (see Example 7).
  • Step 7 Synthesis of compound ⁇ /- ⁇ (1 S,2R)-2-[(2'-cyanobiphenyl-4- yl)oxy]cyclopentyl ⁇ propane-2-sulfonamide.
  • the title compound of Step 7 was prepared according to the general procedure for the synthesis of Example 2, except that ⁇ /-[(1 S,2R)-2-(4- bromophenoxy)cyclopentyl]propane-2-sulfonamide was used instead of N- [(3S,4S)-4-(4-bromophenoxy)tetrahydrofuran-3-yl]propane-2-sulfonamide, and (2-cyanophenyl)boronic acid was added in place of phenylboronic acid.
  • Dimethoxyethane (1 .5 ml_) was added and the reaction mixture was purged three times with nitrogen/vacuum.
  • the reaction was subjected to microwave irradiation at 120 0 C for 2 hours, then solvent was removed in vacuo and the residue was partitioned between ethyl acetate and saturated aqueous sodium chloride solution.
  • the aqueous layer was extracted with ethyl acetate, and the organic layers were combined, dried over calcium sulfate, filtered, and concentrated in vacuo.
  • the residue was purified by preparative thin layer chromatography on silica gel (Eluant: 40% ethyl acetate in heptane), to afford the title compound as a yellow oil which subsequently solidified.
  • Step 1 Synthesis of frans-2-(4-bromophenoxy)cyclohexanol.
  • Sodium metal (2.58 g, 112 mmol) was combined with absolute ethanol (200 ml_) and allowed to react completely.
  • 4-Bromophenol (19.4 g, 112 mmol) was added, and the reaction was stirred for 20 minutes, at which point 7-oxabicyclo[4.1.0]heptane (10.0 g, 102 mmol) was added, and the solution was heated at reflux for 15 hours. After removal of solvent in vacuo, the residue was partitioned between water (300 ml_) and ethyl acetate (100 ml_).
  • aqueous layer was extracted with ethyl acetate (2 x 100 ml_), and the combined organic layers were washed with water (2 x 200 ml_), dried over magnesium sulfate, filtered, and concentrated under reduced pressure.
  • the resulting light tan solid was recrystallized from heptane (roughly 200 ml_) to provide frans-2-(4-bromophenoxy)cyclohexanol as a fluffy white solid. Yield: 12.5 g, 46.1 mmol, 45%.
  • frans-2-(4-Bromophenoxy)cyclohexanol (5.305 g, 19.56 mmol) was dissolved in ethyl acetate (196 ml_) and treated with vinyl acetate (3.37 g, 39.1 mmol), followed by lipase enzyme from Candida antarctica (Novozyme 435, Sigma L4777, lipase immobilized on acrylic resin, 5.3 g). The reaction was capped and stirred for 18 hours, then filtered through Celite® and rinsed with ethyl acetate (500 ml_).
  • Step 4 The title compound of Step 4 was prepared according to the general procedure for the synthesis of frans-2-(4-bromophenoxy)cyclopentyl methanesulfonate in Example 5, except that (1 R,2R)-2-(4- bromophenoxy)cyclohexanol was used instead of trans-2-(4- bromophenoxy)cyclopentanol.
  • (1 R,2R)-2-(4-bromophenoxy)cyclohexyl methanesulfonate was obtained as a light golden oil. Yield: 3.60 g, 10.3 mmol, quantitative.
  • Step 5 Synthesis of (1R,2S)-2-azidocyclohexyl 4-bromophenyl ether.
  • (1 R,2R)-2-(4-bromophenoxy)cyclohexyl methanesulfonate (3.55 g, 10.2 mmol) in dimethylformamide (21.8 ml_) and water (2.43 ml_) was added sodium azide (95%, 2.09 mg, 30.5 mmol) and the reaction was heated at 120 0 C for 23 hours. The reaction was cooled to room temperature, diluted with water (400 ml_) and extracted with ethyl acetate (4 x 400 ml_).
  • Step 6 Synthesis of (1 S,2R)-2-(4-bromophenoxy)cyclohexanamine.
  • the filter pad was rinsed with tetrahydrofuran (250 ml_), then with ethyl acetate (400 ml_), and the combined filtrates were concentrated in vacuo, and azeotroped with ethanol.
  • the residue was purified by chromatography on silica gel (Gradient: 0% to 10% methanol in dichloromethane) to afford (1 S,2R)-2-(4-bromophenoxy)cyclohexanamine as a yellow oil. Yield: 1.82 g, 6.74 mmol, 70%.
  • Step 7 Synthesis of ⁇ /-[(1 S,2R)-2-(4-bromophenoxy)cyclohexyl] propane-2-sulfonamide.
  • Step 7 The title compound of Step 7 was prepared according to the general procedure for the synthesis of c/s- ⁇ /-[2-(4- bromophenoxy)cyclopentyl]propane-2-sulfonamide in Example 5, except that (1 S,2R)-2-(4-bromophenoxy) cyclohexanamine was used in place of c/s-2-(4- bromophenoxy)cyclopentan-amine, and the product purification was carried out using a gradient of 0% to 1 % methanol in dichloromethane. ⁇ /-[(1 S,2R)-2- (4-bromophenoxy)cyclohexyl] propane-2-sulfonamide was obtained as a white foam.
  • the enantiomer of ⁇ /-[(1 S,2R)-2-(4-bromophenoxy)cyclohexyl]propane-2- sulfonamide was prepared using similar chemistry to that described above in this Step 7, but employing (1 S,2S)-2-(4-bromophenoxy)cyclohexanol as starting material instead of (1 R,2R)-2-(4-bromophenoxy)cyclohexanol.
  • the absolute stereochemistry of the enantiomer of ⁇ /-[(1 S,2R)-2-(4- bromophenoxy)cyclohexyl]propane-2-sulfonamide was established via X-ray crystallography.
  • Step 8 Synthesis of ⁇ /- ⁇ (1 S,2R)-2-[(2'-cyanobiphenyl-4- yl)oxy]cyclohexyl ⁇ propane-2-sulfonamide.
  • the title compound was prepared according to the general procedure for the synthesis of Example 2, except that ⁇ /-[(1 S,2R)-2-(4- bromophenoxy)cyclohexyl]propane-2-sulfonamide was used in place of N- [(3S,4S)-4-(4-bromophenoxy)tetrahydrofuran-3-yl]propane-2-sulfonamide, and the microwave irradiation was carried out at 140 0 C for 55 minutes.
  • Method A Aryl coupling, exemplified by synthesis of frans- ⁇ /- ⁇ 4-[(2'- ethoxybiphenyl-4-yl)oxy1tetrahvdrofuran-3-yl)propane-2-sulfonamide frans-/V-[4-(4-Bromophenoxy)tetrahydrofuran-3-yl]propane-2- sulfonamide (91 .1 mg, 0.250 mmol), (2-ethoxyphenyl)boronic acid (49.8 mg,
  • the boronic acid (0.1 mmol) was weighed into a vial and treated with a solution of c/s- ⁇ /-[4-(4-bromophenoxy)tetrahydrofuran-3-yl]propane-2- sulfonamide (18.2 mg, 0.05 mmol) in degassed ethanol (0.8 ml_).
  • a solution of sodium carbonate (26.5 mg, 0.25 mmol) in water (0.1 ml_) was added, and the reaction vial was purged twice with vacuum, then refilled with nitrogen.
  • Tetrakis(thphenylphosphine)palladium(0) (2.9 mg, 0.0025 mmol) in degassed toluene (0.1 ml_) was then added and the reaction was heated to
  • Murine ES cell line E14 with a targeted mutation in the Sox1 gene and a neuroectodermal marker that offers G418 resistance when the Sox1 gene is expressed (Stem Cell Sciences, West Mains Road, Edinburgh, Scotland EH9 3JQ) may be used in all experiments.
  • ES cells may be maintained undifferentiated as previously described (Methods For The Isolation And Maintenance Of Murine Embryonic Stem Cells; Roach-M-L, McNeish-J-D., Methods in Molecular Biology, 185, 1 -16 (2002)).
  • ES cells may be grown in stem cell culture media comprising a base medium of KnockoutTM D- MEM (Invitrogen 5791 Van Allen Way, Carlsbad, CA USA 92008,), supplemented with 15% ES qualified Fetal Bovine Serum (FBS) (Invitrogen), 0.2 mM L-Glutamine (Invitrogen), 0.1 mM MEM non-essential amino acids (Invitrogen), 30 ⁇ g/ml Gentamicin (G418) (Invitrogen), 1000 U/ml ESGROTM (CHEMICON International, Inc., 28820 Single Oak Drivejemecula, CA 92590) and 0.1 mM 2-mercaptoethanol (Sigma, 3050 Spruce St., St.
  • ES cells may then be plated on gelatin-coated dishes (BD Biosciences,2350 Qume Drive, San Jose, CA 95131 ), wherein the media is changed daily and the cells dissociated with 0.05% Trypsin EDTA (Invitrogen) every other day.
  • gelatin-coated dishes BD Biosciences,2350 Qume Drive, San Jose, CA 95131
  • Trypsin EDTA Invitrogen
  • ES cells may be weaned from FBS onto Knockout Serum ReplacementTM (KSR) (Invitrogen).
  • KSR Knockout Serum ReplacementTM
  • ES cells may be dissociated into a single cell suspension, then 3x10 6 cells plated in bacteriology dishes (Nunc 4014) and grown as a suspension culture in NeuroEB-l medium that consisted of KnockoutTM D-MEM (Invitrogen), supplemented with 10% KSR (Invitrogen), 0.2 mM L-Glutamine (Invitrogen), 0.1 mM MEM non-essential amino acids (Invitrogen), 30 ⁇ g/ml Gentamicin (Invitrogen), 1000 U/ml ESGROTM (CHEMICON International, Inc.), 0.1 mM 2-mercaptoethanol (Sigma) and 150ng/ml Transferrin (Invitrogen).
  • the plates may then be put on a Stovall Belly ButtonTM shaker in an atmospheric oxygen incubator.
  • the media may be changed on day 2 of EB formation with NeuroEB-l and on day 4 with NeuroEB-ll (NeuroEB-l plus 1 ⁇ g/ml mNoggin (R&D Systems, 614 McKinley Place N. E. Minneapolis, MN 55413)
  • EBs may be dissociated with 0.05% Trypsin EDTA, and 4x10 6 cells/100mm dish may then be plated on Laminin coated tissue culture dishes in NeuroEB-ll-G418 medium that consisted of a base medium of a 1 :1 mixture of D-MEM/F12 supplemented with N2 supplements and NeuroBasal Medium supplemented with B27 supplement and 0.1 mM L-Glutamine (all from Invitrogen).
  • the base medium may then be supplemented with 10ng/ml bFGF (Invitrogen), 1 ⁇ g/ml mNoggin, 500ng/ml SHH-N (ProSpecBio Rehovot Science Park, P.O. BOX 398, Rehovot 76103, Israel), 100ng/ml FGF-8b (R&D Systems), 1 ⁇ g/ml Laminin and 200 ⁇ g/ml G418 (Invitrogen) for selection of neuronal precursors expressing Sox-1.
  • the plates may then be put in an incubator containing 2% oxygen and maintained in these conditions. During the 6-day selection period, the NeuroEB-ll media should be changed daily.
  • the surviving neuronal precursor foci may then be dissociated with 0.05% Trypsin EDTA and the cells plated at a density of 1.5x10 6 cells/100mm Laminin coated dish in Neuroll-G418 medium.
  • the cells may then be dissociated every other day for expansion, and prepared for cryopreservation at passage 3 or 4.
  • the cryopreservation medium typically contains 50% KSR, 10% dimethyl sulfoxide (DMSO) (Sigma) and 40% Neuroll-G418 medium.
  • Neuronal precursors may be cryopreserved at a concentration of 4x10 6 cells/ml and 1 ml/cryovial in a controlled rate freezer overnight then transferred to an ultra-low freezer or liquid nitrogen for long-term storage.
  • Cryopreserved ES cell-derived neuronal precursors may be thawed by the rapid thaw method in a 37°C water-bath.
  • the cells are then transferred from the cryovial to a 100mm Laminin coated tissue culture dish that already contains Neuroll-G418 that has been equilibrated in a 2 percent oxygen incubator.
  • the media is changed with fresh Neuroll-G418 the next day.
  • the cells may be dissociated every other day as described above for expansion to generate enough cells to plate for the screen.
  • the cells are plated into 384-well poly-d-lysine coated tissue culture dishes (BD Biosciences) by the automated SelecT® (The Automation Partnership York Way, Royston, Hertfordshire SG8 5WY UK) at a cell density of 6K cells/well in differentiation medium Neurolll that contains a 4:1 ratio of the NeuroBasalMedium/B27:D-MEM/F12/N2 supplemented with 1 ⁇ M cAMP (Sigma), 200 ⁇ M Ascorbic Acid (Sigma), 1 ⁇ g/ml Laminin (Invitrogen) and 10ng/ml BDNF (R&D Systems, 614 McKinley Place N. E. Minneapolis, MN 55413). The plates are then put in an incubator with 2 percent oxygen and allowed to complete the differentiation process for 7 days. The cells could then be used over a 5-day period for the high throughput screen.
  • In vitro assays In vitro assays
  • the FLIPR assay may be performed using the following methods:
  • the pH may be adjusted to 7.4 with 1 M NaOH.
  • PA pluronic acid
  • results are analyzed by subtracting the minimum fluorescent FLIPR value after compound or agonist addition from the peak fluorescent value of the FLIPR response after agonist addition to obtain the change in fluorescence.
  • the change in fluorescence (RFUs, relative fluorescent units) are then analyzed using standard curve fitting algorithms.
  • the negative control is defined by the AMPA challenge alone, and the positive control is defined by the AMPA challenge plus a maximal concentration of cyclothiazide (10 uM or 32 uM).
  • Compounds are delivered as DMSO stocks or as powders. Powders are solubilized in DMSO. Compounds are then added to assay drug buffer as 40 ⁇ L top [concentration] (4X the top screening concentration).
  • the standard agonist challenge for this assay is 32 ⁇ M AMPA.
  • EC50 values of the compounds of the invention are preferably 10 micromolar or less, more preferably 1 micromolar or less, even more preferably 100 nanomolar or less.
  • Table 3 The data for specific compounds of the invention is provided below in Table 3.

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Abstract

The invention is directed to a class of compounds, including the pharmaceutically acceptable salts of the compounds, having the structure of formula (I) as defined in the specification. The invention is also directed to compositions containing and uses of the compounds of formula I.

Description

HETEROCYCLIC SULFONAMIDES, USES AND PHARMACEUTICAL
COMPOSITIONS THEREOF
Field of the Invention
The present invention relates to a novel class of compounds having the structure of formula I as defined herein and pharmaceutical compositions comprising a compound of formula I or a pharmaceutically acceptable salt thereof. The present invention also comprises methods of treating a subject by administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof to the subject. These compounds are useful for the conditions disclosed herein. The present invention further comprises methods for making the compounds of formula I and corresponding intermediates.
Background of the Invention The primary excitatory neurotransmitter in the mammalian central nervous system (CNS) is the amino acid glutamate whose signal transduction is mediated by either ionotropic or metabotropic glutamate receptors (GIuR). lonotropic glutamate receptors (iGluR) are comprised of three subtypes differentiated by their unique responses to the three selective iGluR agonists α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), /V-methyl-D- aspartate (NMDA) and kainate (Parsons, C. G., Danysz, W. and Lodge, D. (2002), in: lonotropic Glutamate Receptors as Therapeutic Targets (Danysz, W., Lodge, D. and Parsons, C. G. eds), pp 1 -30, F. P. Graham Publishing Co., Tennessee). AMPA receptors, proteinaceous homo- or heterotetramers comprised of any combination of four ca. 900 amino acid monomer subunits each encoded from a distinct gene (GIUAI-A4) with each subunit protein existing as one of two splice variants deemed "flip" and "flop", mediate the vast majority of excitatory synaptic transmissions in the mammalian brain and have long been proposed to be an integral component of the neural circuitry that mediates cognitive processes (Bleakman, D. and Lodge, D. (1998) Neuropharmacology of AMPA and Kainate Receptors. Neuropharmacology 37:1187-1204). The combination of various heterotetrameric possibilities, two splice forms for each of the four iGluR monomers and receptor subunit RNA editing with the heterogeneous distribution of AMPA receptors throughout the brain highlight the myriad of potential AMPA receptor responses within this organ (Black, M. D. (2005) Therapeutic Potential of Positive AMPA Modulators and Their Relationship to AMPA Receptor Subunits. A Review of Preclinical Data. Psychopharmacology 179:154-163). AMPA modulators have now become an active target for drug discovery (see Rogers, B. and Schmidt, C, (2006) Novel Approaches for the Treatment of Schizophrenia, Annual Reports in Medicinal Chemistry 3-21 ). Summary of the Invention
The present invention is directed to compounds, including the pharmaceutically acceptable salts of the compounds, having the structure of formula:
Figure imgf000003_0001
I wherein each R1 and each R2 and each R7 is independently selected from the group consisting of hydrogen, halogen, hydroxyl, -CF3, -CN, -(C=O)R8, -0-(C=O)-R8, -(NR8MC=O)-R8, -(C=O)-OR8, -(C=O)-N(R8)2, -OR8, -0-(C=O)-OR8, -O-(C=O)-N(R8)2, -NO2, -N(R8)2, -(NR8)-SO2-R8, -S(O)WR8, -SO2-N(R8)2, (CrC6)alkyl, (C6-Ci0)aryl, (Ci-C9)heteroaryl,
(d-CgJheterocycloalkyl, and (C3-Cio)cycloalkyl; wherein said (d-CβJalkyl, (C6-Cio)aryl, (d-C9)heteroaryl, (d-Cg)heterocycloalkyl, or (C3-Ci0)cycloalkyl are each independently optionally substituted with one, two, three or four R9; w is 0, 1 or 2; m is zero, one, two or three; n is zero, one, two or three; p is zero, one, two or three; q is zero, one, two or three; s is one and t is one; or one of s or t is one and the other of s or t is two;
R3 is hydrogen or (d-CβJalkyl; each R4 is independently selected from hydrogen, or (Ci-Cβjalkyl; wherein said (Ci-C6)alkyl may be optionally substituted with one, two, three or four halogen, -CN, or -OR9; or two R4 groups on the same carbon atom may be taken together to form an oxo (=O) radical or a (C3-C6)spirocycloalkyl;
R5 is hydrogen, or (CrC6)alkyl; R6 is (Ci-C6)alkyl-(C=O)-, [(Ci-C6)alkyl]2N-(C=O)-, (Ci-C6)alkyl-SO2-,
(C3-Cio)cycloalkyl-SO2-, or [(Ci-C6)alkyl]2N-SO2-; wherein said (d-C6)alkyl moieties of said [(Ci-C6)alkyl]2N-(C=O)- and [(Ci-C6)alkyl]2N-SO2- may optionally be taken together with the nitrogen atom to which they are attached to form a three to six membered heterocyclic ring; each R8 is independently selected from the group consisting of hydrogen, (Ci-Cβjalkyl, (C6-Cio)aryl, (d-CgJheteroaryl,
(CrC9)heterocycloalkyl, and (C3-Ci0)cycloalkyl; wherein said (d-C6)alkyl may be optionally substituted with one, two or three substituents independently selected from hydrogen, halo, -CN, perfluoro(Ci-C6)alkyl, hydroxy, amino, (Ci-C6)alkylamino, [(Ci-C6)alkyl]2amino, (Ci-C6)alkoxy, perfluoro(Ci-C6)alkoxy, HO-(C=O)-, (d-C6)alkyl-O-(C=O)-, formyl, (Ci-C6)alkyl-(C=O)-, H2N-(C=O)-, (d-C6)alkyl]-(NH)-(C=O)-,
[(Ci-C6)alkyl]2N-(C=O)-, (d-C6)alkyl-(C=O)-O-, H(C=O)-NH-,
(Ci-C6)alkyl(C=O)-NH-, (Ci-C6)alkyl(C=O)-[N((Ci-C6)alkyl)]-, (Ci-C6)alkyl-SO2-, (d-C6)alkyl-SO2-NH-, (Ci-C6)alkyl-SO2-[N((Ci-C6)alkyl)]-, H2N-SO2-, [(Ci-C6)alkyl]-NH-SO2-, and [(d-C6)alkyl]2N-SO2-; wherein said -A-
(Ci-C6>alkyl may be additionally optionally substituted with an optionally substituted (C6-Cio)aryl, (Ci-Cgjheteroaryl, (d-CgJheterocycloalkyl, or (C3-Cio)cycloalkyl; wherein said optional substituents may be independently substituted with from one, two, three or four radicals independently selected from halogen, hydroxyl, -CF3, -CN, (Ci-C3)alkyl, (Ci-C3)alkoxy, and amino; wherein each of said R8 (C6-Ci0)aryl, (Ci-C9)heteroaryl, (Ci-Cg)heterocycloalkyl or (C3-Ci0)cycloalkyl substituents may be optionally additionally substituted with one, two, three or four radicals independently selected from halogen, hydroxyl, -CF3, -CN, (Ci-C3)alkyl, (Ci-C3)alkoxy and amino; each R9 is independently selected from the group consisting of halogen, hydroxyl, -CF3, -CN, -(C=O)R10, -0-(C=O)-R10, -(NR10)-(C=O)-R10, -(C=O)-OR10, -(C=O)-N(R10)2, -OR10, -0-(C=O)-OR10, -O-(C=O)-N(R10)2, -NO2, -N(R10)2, -(NR10)-SO2-R10, -S(O)WR10, and -SO2-N(R10)2; each R10 is independently selected from the group consisting of hydrogen, (d-C6)alkyl, (C6-Ci0)aryl, (Ci-C9)heteroaryl,
(Ci-Cg)heterocycloalkyl and (C3-Ci 0)cycloalkyl; wherein said (Ci-C6)alkyl may be optionally substituted with one, two or three substituents independently selected from hydrogen, halo, -CN, perfluoro(Ci-C6)alkyl, hydroxy, amino, (CrCβJalkylamino, [(Ci-C6)alkyl]2amino, (Ci-C6)alkoxy, perfluoro(CrC6)alkoxy, HO-(C=O)-, (Ci-C6)alkyl-O-(C=O)-, formyl, (CrC6)alkyl-(C=O)-, H2N-(C=O)-, (d-C6)alkyl]-(NH)-(C=O)-,
[(CrC6)alkyl]2N-(C=O)-, (CrC6)alkyl-(C=O)-O-, H(C=O)-NH-,
(CrC6)alkyl(C=O)-NH-, (Ci-C6)alkyl(C=O)-[N((Ci-C6)alkyl)]-, (CrC6)alkyl-SO2-, (Ci-C6)alkyl-SO2-NH-, (Ci-C6)alkyl-SO2-[N((Ci-C6)alkyl)]-, H2N-SO2-, [(CrC6)alkyl]-NH-SO2-, and [(Ci-C6)alkyl]2N-SO2-; wherein said (CrC6)alkyl may also be additionally optionally substituted with an optionally substituted (C6-Cio)aryl, (Ci-Cgjheteroaryl, (Ci-Cgjheterocycloalkyl or (C3-Cio)cycloalkyl; wherein said optional substituents may be independently substituted from one, two, three or four radicals independently selected from halogen, hydroxyl, -CF3, -CN, (Ci-C3)alkyl, (Ci-C3)alkoxy, and amino; wherein each of said R10 (C6-Cio)aryl, (d-Cg)heteroaryl, (d-Cg)heterocycloalkyl, or (C3-Cio)cycloalkyl substituents may be optionally additionally substituted with one, two, three or four radicals independently selected from halogen, hydroxyl, -CF3, -CN, (Ci-C3)alkyl, (CrC3)alkoxy, and amino;
R11 is hydrogen or (Ci-C6)alkyl; ring "A" is (C6-Ci 0)aryl, (CrC9)heteroaryl, (C4-Ci 0)cycloalkyl, or (d-Cg)heterocycloalkyl; wherein two of said R1 substituents on said (C4-Cio)cycloalkyl and (Ci-Cg)heterocycloalkyl may optionally be attached to the same carbon atom and may optionally be taken together to be oxo; ring "B" is (C6-Cio)aryl, (d-Cg)heteroaryl, (C4-Ci o)cycloalkyl, or (Ci-Cg)heterocycloalkyl;
"X" is -O- or >C(R4)2;
"Y" is >NR11, -(NR11HC=O)-, >C=O, -O- or >C(R7)2; and "Z" is -O-. -S-, -(S=O)-, or -(SO2)-.
The term "alkyl" refers to a linear or branched-chain saturated, mono- unsaturated and poly-unsaturated hydrocarbyl substituent (i.e., a substituent obtained from a hydrocarbon by removal of a hydrogen) containing from one to six carbon atoms; and in another embodiment, from one to four carbon atoms. Mono- and poly-unsaturated substituents, a so called alkenyl, has 2 to
6 carbon atoms. The alkenyl group may exist as the pure E (entgegen) form, the pure Z (zusammen) form, or any mixture thereof. Poly-unsaturated includes multiple double bonds and one or more triple bonds. Such triple bond containing alkyl grops, a so called alkynyl group, has 2 to 6 carbon atoms. Examples of such saturated substituents include methyl, ethyl, propyl
(including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl and tert-butyl), pentyl, iso-amyl, hexyl and the like. Examples of unsaturated alkyl include ethenyl, 1 -propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-1- propenyl, 1 -butenyl, 2-butenyl, and the like. Examples of alkynyl include ethynyl, propynyl, butynyl, 3,3-dimethylbutynyl and the like. In some instances, the number of carbon atoms in a hydrocarbyl substituent (e.g., alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, etc.) is indicated by the prefix "Cx-Cy-," wherein x is the minimum and y is the maximum number of carbon atoms in the substituent. Thus, for example, "Ci-Cβ-alkyl" refers to an alkyl substituent containing from 1 to 6 carbon atoms. Illustrating further, Cs-Cβ-cycloalkyl refers to saturated cycloalkyl containing from 3 to 6 carbon ring atoms.
As used herein, the term "perfluoro(Ci-C6)alkyl" refers to an alkyl radical as described above substituted with one or more fluorine's including, but not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2- thfluoroethyl, and the like.
The term "hydroxy" or "hydroxyl" refers to -OH. When used in combination with another term(s), the prefix "hydroxy" indicates that the substituent to which the prefix is attached is substituted with one or more hydroxy substituents. Compounds bearing a carbon to which one or more hydroxy substituents include, for example, alcohols, enols and phenol.
The term "cyano" (also referred to as "nitrile") means -CN, which also may be depicted as -C≡N.
The term "carbonyl" means -C(O)-, >C=O, -(C=O)-, and which also may be depicted as:
Figure imgf000007_0001
The term "amino" refers to -NH2. The term "oxo" refers to =O.
The term "alkoxy" refers to an alkyl linked to an oxygen, which may also be represented as: -O-R, wherein the R represents the alkyl group. Examples of alkoxy include methoxy, ethoxy, propoxy and butoxy. The term "sulfonyl" refers to -S(O)2-, which also may be depicted
Figure imgf000008_0001
Thus, for example, "alkyl-sulfonyl-alkyl" refers to alkyl-S(O)2-alkyl. Examples of alkylsulfonyl include methylsulfonyl, ethylsulfonyl, and propylsulfonyl. As used herein, the term "cycloalkyl" is defined to include saturated or unsaturated (non aromatic), bridged, polycyclic, spirocyclic or fused polycyclic 3 to 10 membered hydrocarbon rings (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, bicyclo[2.2.1]heptanyl, bicyclo[3.2.1]octanyl and bicyclo[5.2.0]nonanyl, etc.); optionally substituted by 1 to 5 suitable substituents. Preferably, the cycloalkyl group has 3 to 6 carbon atoms. In one embodiment the cycloalkyl may optionally contain one, two or more non cumulative non aromatic double or triple bonds. Spirocyclic rings are one particular kind of cycloalkyl that occurs when a ring is formed around one carbon atom as compared to a fused ring in which a ring is formed through two common carbon atoms.
As used herein, the term "aryl" is defined to include all-carbon monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups having a completely conjugated pi-electron system. The aryl group has 6, 8, 9 or 10 carbon atoms in the ring(s). More preferably, the aryl group has 6 or 10 carbon atoms in the ring(s). Most preferably, the aryl group has 6 carbon atoms in the ring(s). For example, as used herein, the term "(C6-Cio)aryl" means aromatic radicals containing from 6 to 10 carbon atoms such as phenyl, naphthyl, tetrahydronaphthyl, anthracenyl, indanyl and the like. The aryl group is optionally substituted by 1 to 5 suitable substituents.
As used herein, the term "heteroaryl" is defined to include monocyclic or fused-ring polycyclic aromatic heterocyclic groups with one or more heteroatoms selected from O, S and N in one or more of said ring(s). The heteroaryl group has 5 to 12 ring atoms including one to five heteroatoms independently selected from O, S, and N. One or more of said rings of said heterocyclic group may contain no heteroatoms. Preferably, the heteroaryl group has 5 to 10 ring atoms including one to four heteroatoms. More preferably, the heteroaryl group has 5 to 8 ring atoms including one, two or three heteroatoms. Most preferably, the heteroaryl group has 6 to 8 ring atoms including one or two heteroatoms. For example, as used herein, the term "(Ci-Cg)heteroaryl" means aromatic radicals containing at least one ring heteroatom independently selected from O, S and N and from 1 to 9 carbon atoms such as pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, furyl, imidazolyl, pyrrolyl, oxazolyl (e.g., 1 ,3-oxazolyl, 1 ,2-oxazolyl), thiazolyl (e.g., 1 ,2-thiazolyl, 1 ,3-thiazolyl), pyrazolyl, tetrazolyl, triazolyl (e.g., 1 ,2,3-triazolyl, 1 ,2,4-triazolyl), oxadiazolyl (e.g., 1 ,2,3-oxadiazolyl), thiadiazolyl (e.g., 1 ,3,4- thiadiazolyl), quinolyl, isoquinolyl, benzothienyl, benzofuryl, indolyl, and the like. The heteroaryl group is optionally substituted by 1 to 5 suitable substituents.
As used herein, the term "heterocycloalkyl" is defined to include a monocyclic, bridged, polycyclic, spirocyclic or fused polycyclic saturated or unsaturated non-aromatic 3 to 20 membered ring including 1 or more heteroatoms independently selected from O, S and N. One or more of said rings of said bridged, polycyclic or fused heterocyclic group may contain no heteroatoms. Examples of such heterocycloalkyl rings include azetidinyl, tetrahydrofuranyl, imidazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, thiomorpholinyl, tetrahydrothiazinyl, tetrahydro-thiadiazinyl, morpholinyl, oxetanyl, tetrahydrodiazinyl, oxazinyl, oxathiazinyl, indolinyl, isoindolinyl, quinuclidinyl, chromanyl, isochromanyl, benzoxazinyl, and the like. Further examples of said heterocycloalkyl rings are tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, imidazolidin-1 -yl, imidazolidin-2- yl, imidazolidin-4-yl, pyrrolidin-1 -yl, pyrrol id in-2-yl, pyrrol id in-3-yl, piperidin-1 - yl, piperidin-2-yl, piperidin-3-yl, piperazin-1-yl, piperazin-2-yl, piperazin-3-yl, 1 ,3-oxazol id in-3-yl, isothiazolidine, 1 ,3-thiazolidin-3-yl, 1 ,2 pyrazol id in-2-yl, 1 ,3-pyrazolidin-1 -yl, 1 ,2-tetrahydrothiazin-2-yl, 1 ,3 tetrahydrothiazin-3-yl, 1 ,2- tetrahydrodiazin-2-yl, 1 ,3 tetrahydrodiazin-1 -yl, 1 ,4-oxazin-2-yl, 1 ,2,5- oxathiazin-4-yl and the like. The heterocycloalkyl ring is optionally substituted by 1 to 5 suitable substituents.
If substituents are described as being "independently selected" from a group, each substituent is selected independent of the other. Each substituent therefore may be identical to or different from the other substituent(s).
When an asymmetric center is present in a compound of formula I (hereinafter understood to mean formula I, Ia, Ib, Ic, Id or Ie), hereinafter referred to as a "compound of the invention," the compound may exist in the form of optical isomers (enantiomers). In one embodiment, the present invention comprises enantiomers and mixtures, including racemic mixtures of the compounds of formula I. In another embodiment, for compounds of formula I that contain more than one asymmetric center, the present invention comprises diastereomehc forms (individual diastereomers and mixtures thereof) of compounds. When a compound of formula I contains an alkenyl group or moiety, geometric isomers may arise.
The present invention comprises the tautomeric forms of compounds of formula I. Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism ('tautomerism') can occur. This can take the form of proton tautomerism in compounds of formula I containing, for example, an imino, keto, or oxime group, or so-called valence tautomerism in compounds which contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism. The various ratios of the tautomers in solid and liquid form is dependent on the various substituents on the molecule as well as the particular crystallization technique used to isolate a compound.
Suitable pharmaceutically acceptable acid addition salts of the compounds of the present invention when possible include those derived from inorganic acids, such as hydrochloric, hydrobromic, hydrofluoric, boric, fluoroboric, phosphoric, metaphosphoric, nitric, carbonic, sulfonic, and sulfuric acids, and organic acids such as acetic, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isothionic, lactic, lactobionic, maleic, malic, methanesulfonic, trifluoromethanesulfonic, succinic, toluenesulfonic, tartaric, and trifluoroacetic acids. Suitable organic acids generally include, for example, aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids.
Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts. In another embodiment, base salts are formed from bases which form non-toxic salts, including aluminum, arginine, benzathine, choline, diethylamine, diolamine, glycine, lysine, meglumine, olamine, tromethamine and zinc salts. In one embodiment, hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.
The present invention also includes isotopically labelled compounds, which are identical to those recited in formula I, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that may be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chlorine, such as 2H, 3H, 13C, 11C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36CI, respectively. Compounds of the present invention, and pharmaceutically acceptable salts of said compounds or which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically labelled compounds of the present invention, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Thtiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances, lsotopically labelled compounds of formula I of this invention may generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples and Preparations below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.
One embodiment of the present invention relates to compounds of the Formula:
Figure imgf000012_0001
Ia
Another embodiment of the present invention relates to compounds of the Formula:
Figure imgf000012_0002
Ib One skilled in the art will appreciate that compounds of formula I can exist as alternate stereoisomers including the following:
Figure imgf000013_0001
Another embodiment of the present invention (the so called ethers) relates to compounds of the Formula I (or Ia, Ib, Ic, Id or Ie), wherein "Z" is -O- .
Another embodiment of the present invention (the so called thioethers) relates to a compound of the Formula I (or Ia, Ib, Ic, Id or Ie), wherein "Z" is -S-.
Another embodiment of the present invention (the so called sulfoxides) relates to a compound of the Formula I (or Ia, Ib, Ic, Id or Ie), wherein "Z" is -(S=O)-. Another embodiment of the present invention (the so called sulfones) relates to a compound of the Formula I (or Ia, Ib, Ic, Id or Ie), wherein "Z" is -(SO2)-.
Another embodiment of the present invention (the so called furans or pyrans) relate to compounds of the Formula I (or Ia, Ib, Ic, Id or Ie), wherein X is -O-. The present inventors have a particular interest is these furans and pyrans particularly as they can be segregated according to combinations with other embodiments of which the "Z" embodiments are of particular note.
Another embodiment of the present invention (the so called cyclopentyls or cyclohexyls) relate to compounds of the Formula I (or Ia, Ib, Ic, Id or Ie), wherein X is >C(R4)2, more specifically wherein each R4 is hydrogen. The present inventors also have a particular interest is these cyclopentyls or cyclohexyls particularly as they can be segregated according to combinations with other embodiments of which the "Z" embodiments are of particular note. Another embodiment of the present invention relates to a compound of the Formula I (or Ia, Ib, Ic, Id or Ie), wherein ring "A" is phenyl; more specifically wherein n is zero, one or two; more specifically wherein R1 is selected from the group consisting of hydrogen, halogen, hydroxyl, -CF3, -CN, -(C=O)R8, -0-(C=O)-R8, -(NR8HC=O)-R8, -(C=O)-OR8, -(C=O)-N(R8)2, -OR8, -0-(C=O)-OR8, -O-(C=O)-N(R8)2, -NO2, -N(R8)2, -(NR8)-SO2-R8, -S(O)WR8, -SO2-N(R8)2, and (CrC6)alkyl; wherein said (Ci-C6)alkyl is optionally substituted with one, two, three or four R9. The present inventors also have a particular interest in these "A" phenyl compounds particularly as they can be segregated according to combinations with other embodiments of which the "cyclopentyls" or "cyclohexyls" and/or the "Z" embodiments are of particular note.
Another embodiment of the present invention relates to a compound of the Formula I (or Ia, Ib, Ic, Id or Ie), wherein ring "A" is (Ci-Cg)heteroaryl; more specifically wherein n is zero, one or two; and more specifically wherein R1 is selected from the group consisting of hydrogen, halogen, hydroxyl, -CF3, -CN, -(C=O)R8, -0-(C=O)-R8, -(NR8HC=O)-R8, -(C=O)-OR8, -(C=O)-N(R8)2, -OR8, -0-(C=O)-OR8, -O-(C=O)-N(R8)2, -NO2, -N(R8)2, -(NR8)-SO2-R8, -S(O)WR8, -SO2-N(R8)2, and (CrC6)alkyl; wherein said (CrC6)alkyl is optionally substituted with one, two, three or four R9. The present inventors also have a particular interest is these "A" (Ci-C9)heteroaryl compounds particularly as they can be segregated according to combinations with other embodiments of which the "X" "cyclopentyls" or "cyclohexyls" and/or the "Z" embodiments are of particular note.
Another embodiment of the present invention relates to a compound of the Formula I (or Ia, Ib, Ic, Id or Ie), wherein ring "A" is (d-CgJheterocycloalkyl; more specifically wherein n is zero, one or two; and more specifically wherein R1 is selected from the group consisting of oxo, hydrogen, halogen, hydroxyl, -CF3, -CN, -(C=O)R8, -0-(C=O)-R8, -(NR8HC=O)-R8, -(C=O)-OR8, -(C=O)-N(R8)2, -OR8, -0-(C=O)-OR8, -O-(C=O)-N(R8)2, -NO2, -N(R8)2, -(NR8)-SO2-R8, -S(O)WR8, -SO2-N(R8)2, and (CrC6)alkyl; wherein said (CrC6)alkyl is optionally substituted with one, two, three or four R9. The present inventors also have a particular interest in these "A" (Ci-Cg)heterocycloalkyl compounds particularly as they can be segregated according to combinations with other embodiments of which the "X" "cyclopentyls" or "cyclohexyls" and/or the "Z" embodiments are of particular note.
Another embodiment of the present invention relates to a compound of the Formula I (or Ia, Ib, Ic, Id or Ie), wherein ring "A" is (C4-Ci0)cycloalkyl; more specifically wherein n is zero, one or two; and more specifically wherein R1 is selected from the group consisting of oxo, hydrogen, halogen, hydroxyl, -CF3, -CN, -(C=O)R8, -0-(C=O)-R8, -(NR8)-(C=O)-R8, -(C=O)-OR8, -(C=O)-N(R8)2, -OR8, -0-(C=O)-OR8, -O-(C=O)-N(R8)2, -NO2, -N(R8)2, -(NR8)-SO2-R8, -S(O)WR8, -SO2-N(R8)2, and (d-C6)alkyl; wherein said (CrCβJalkyl is optionally substituted with one, two, three or four R9. The present inventors also have a particular interest is these "A" (C4-Cio)cycloalkyl compounds particularly as they can be segregated according to combinations with other embodiments of which the "X" "cyclopentyls" or "cyclohexyls" and/or the "Z" embodiments are of particular note.
Another embodiment of the present invention relates to a compound of the Formula I (or Ia, Ib, Ic, Id or Ie), wherein R1 is (Ci-C6)alkoxy, (Ci-C6)alkyl, cyano or halogen and is in the ortho or para position relative to Y.
Another embodiment of the present invention relates to a compound of the Formula I (or Ia, Ib, Ic, Id or Ie), wherein ring "B" is phenyl; more specifically wherein m is zero or one; more specifically wherein R2 is hydrogen, halogen, hydroxyl, -CF3, -CN, -(C=O)R8, -0-(C=O)-R8, -(NR8)- (C=O)-R8, -(C=O)-OR8, -(C=O)-N(R8)2, -OR8, -0-(C=O)-OR8, -0-(C=O)- N(R8)2, -NO2, -N(R8)2, -(NR8)-SO2-R8, -S(O)WR8, -SO2-N(R8)2, and (CrC6)alkyl; wherein said (CrC6)alkyl is optionally substituted with one, two, three or four R9. The present inventors also have a heightened particular interest in these "B" phenyl compounds particularly as they can be segregated according to combinations with other embodiments of which the "X" "cyclopentyls" or "cyclohexyls" and/or the "Z" embodiments are of particular note. Each of these embodiments also form additional embodiments of interest with the "A" ring embodiments described above.
Another embodiment of the present invention relates to a compound of the Formula I (or Ia, Ib, Ic, Id or Ie), wherein ring "B" is (Ci-Cg)heteroaryl; more specifically wherein m is zero or one; and more specifically wherein R2 is hydrogen, halogen, hydroxyl, -CF3, -CN, -(C=O)R8, -0-(C=O)-R8, -(NR8HC=O)-R8, -(C=O)-OR8, -(C=O)-N(R8)2, -OR8, -0-(C=O)-OR8, -O-(C=O)-N(R8)2, -NO2, -N(R8)2, -(NR8)-SO2-R8, -S(O)WR8, -SO2-N(R8)2, and (CrC6)alkyl; wherein said (Ci-C6)alkyl is optionally substituted with one, two, three or four R9. The present inventors also have a heightened particular interest in these "B" (d-C9)heteroaryl compounds particularly as they can be segregated according to combinations with other embodiments of which the "X" "cyclopentyls" or "cyclohexyls" and/or the "Z" embodiments are of particular note. Each of these embodiments also form additional embodiments of interest with the "A" ring embodiments described above. Another embodiment of the present invention relates to a compound of the Formula I (or Ia, Ib, Ic, Id or Ie), wherein ring "B" is (Ci-Cg)heterocycloalkyl; more specifically wherein n is zero or one; and more specifically wherein R2 is hydrogen, halogen, hydroxyl, -CF3, -CN, -(C=O)R8, -0-(C=O)-R8, -(NR8MC=O)-R8, -(C=O)-OR8, -(C=O)-N(R8)2, -OR8, -0-(C=O)-OR8, -O-(C=O)-N(R8)2, -NO2, -N(R8)2, -(NR8)-SO2-R8, -S(O)WR8, -SO2-N(R8)2, and (CrC6)alkyl; wherein said (d-C6)alkyl is optionally substituted with one, two, three or four R9. The present inventors also have a heightened particular interest in these "B" (d-CgJheterocycloalkyl compounds particularly as they can be segregated according to combinations with other embodiments of which the "X" "cyclopentyls" or "cyclohexyls" and/or the "Z" embodiments are of particular note. Each of these embodiments also form additional embodiments of interest with the "A" ring embodiments described above. Another embodiment of the present invention relates to a compound of the Formula I (or Ia, Ib, Ic, Id or Ie), wherein ring "B" is (C4-Ci0)cycloalkyl; more specifically wherein m is zero or one; and more specifically wherein R2 is hydrogen, halogen, hydroxyl, -CF3, -CN, -(C=O)R8, -0-(C=O)-R8, -(NR8HC=O)-R8, -(C=O)-OR8, -(C=O)-N(R8)2, -OR8, -0-(C=O)-OR8, -O-(C=O)-N(R8)2, -NO2, -N(R8)2, -(NR8)-SO2-R8, -S(O)WR8, -SO2-N(R8)2, and (CrCβJalkyl; wherein said (d-CβJalkyl is optionally substituted with one, two, three or four R9. The present inventors also have a heightened particular interest in these "B" (C4-Ci0)cycloalkyl compounds particularly as they can be segregated according to combinations with other embodiments of which the "X" "cyclopentyls" or "cyclohexyls" and/or the "Z" embodiments are of particular note. Each of these embodiments also form additional embodiments of interest with the "A" ring embodiments described above.
Another embodiment of the present invention relates to a compound of the Formula I (or Ia, Ib, Ic, Id or Ie), wherein R2 is (CrCβJalkoxy, (d-CβJalkyl, cyano or halogen. Another embodiment of the present invention relates to a compound of the Formula I (or Ia, Ib, Ic, Id or Ie), wherein R2 is hydrogen.
Another embodiment of the present invention relates to a compound of the Formula I (or Ia, Ib, Ic, Id or Ie), wherein R4 is hydrogen. Another embodiment of the present invention relates to a compound of the Formula I (or Ia, Ib, Ic, Id or Ie), wherein p is two and both R4 are taken together to form oxo.
Another embodiment of the present invention relates to a compound of the Formula I (or Ia, Ib, Ic, Id or Ie), wherein p is two and each R4 is (Ci-Cβ)alkyl.
Another embodiment of the present invention relates to a compound of the Formula I (or Ia, Ib, Ic, Id or Ie), wherein q is zero.
Another embodiment of the present invention relates to a compound of the Formula I (or Ia, Ib, Ic, Id or Ie), wherein Y is absent. Another embodiment of the present invention relates to a compound of the Formula I (or Ia, Ib, Ic, Id or Ie), wherein Y is -O-.
Another embodiment of the present invention relates to a compound of the Formula I (or Ia, Ib, Ic, Id or Ie), wherein Y is >C(R7)2.
Another embodiment of the present invention relates to a compound of the Formula I (or Ia, Ib, Ic, Id or Ie), wherein R6 is (Ci-C5)alkyl-(C=O)-.
Another embodiment of the present invention relates to a compound of the Formula I (or Ia, Ib, Ic, Id or Ie), wherein R6 is [(Ci-C3)alkyl]2N-(C=O)-, wherein said (Ci-C2)alkyl moieties may optionally be taken together with the nitrogen atom to which they are attached to form a four to six membered heterocyclic ring.
Another embodiment of the present invention relates to a compound of the Formula I (or Ia, Ib, Ic, Id or Ie), wherein R6 is (Ci-C5)alkyl-SO2-.
Another embodiment of the present invention relates to a compound of the Formula I (or Ia, Ib, Ic, Id or Ie), wherein R6 is (C3-C5)cycloalkyl-SO2-. Another embodiment of the present invention relates to a compound of the Formula I (or Ia, Ib, Ic, Id or Ie), wherein R6 is [(Ci-C3)alkyl]2N-SO2-; wherein said (Ci-C2)alkyl moieties may optionally be taken together with the nitrogen atom to which they are attached to form a four to six membered heterocyclic ring.
Another embodiment of the invention also relates to each of the individual compounds described as Examples 1 -54 in the Examples section of this specification, and pharmaceutically acceptable salts thereof.
Specific preferred compounds of the invention include:
Propane-2-sulfonic acid [(3S,4S)-4-(2'-cyano-biphenyl-4-yloxy)- tetrahydro-furan-3-yl]-amide; Propane-2-sulfonic acid [(3S,4S)-4-(2'-cyano-4'-fluoro-biphenyl-4- yloxy)-tetrahydro-furan-3-yl]-amide;
Propane-2-sulfonic acid [(3S,4S)-4-(2',4'-difluoro-biphenyl-4-yloxy)- tetrahydro-furan-3-yl]-amide;
Propane-2-sulfonic acid {(3S,4S)-4-[4-(5-cyano-thiophen-2-yl)- phenoxy]-tetrahydro-furan-3-yl}-amide;
Propane-2-sulfonic acid {(1 S,2R)-2-[4-(5-cyano-thiophen-2-yl)-3-fluoro- phenoxy]-cyclopentyl}-amide;
Propane-2-sulfonic acid {(1 S,2R)-2-[4-(5-cyano-thiophen-2-yl)- phenoxy]-cyclopentyl}-amide; Propane-2-sulfonic acid {(1 S,2R)-2-[3-fluoro-4-(2- methanesulfonylamino-ethyl)-phenoxy]-cyclopentyl}-amide;
Propane-2-sulfonic acid {(3S,4S)-4-[5-(2-cyano-phenyl)-pyhdin-2- yloxy]-tetrahydro-furan-3-yl}-amide;
Propane-2-sulfonic acid {(1 S,2R)-2-[6-(2-cyano-4-fluoro-phenyl)- pyhdin-3-yloxy]-cyclohexyl}-amide; and
Propane-2-sulfonic acid {(1 S,2R)-2-[6-(5-cyano-thiophen-2-yl)-pyhdin- 3-yloxy]-cyclohexyl}-amide; or pharmaceutically acceptable salts thereof.
Other specific compounds of the invention, and the pharmaceutically acceptable salts thereof, include the following: Propane-2-sulfonic acid [4-(4-benzyl-phenoxy)-tetrahydro-furan-3-yl]- amide;
Propane-2-sulfonic acid {4-[4-(1 -phenyl-ethyl)-phenoxy]-tetrahydro- furan-3-yl}-amide; Propane-2-sulfonic acid {4-[4-(hydroxy-phenyl-methyl)-phenoxy]- tetrahydro-furan-3-yl}-amide;
Propane-2-sulfonic acid [4-(4-benzoyl-phenoxy)-tetrahydro-furan-3-yl]- amide;
Propane-2-sulfonic acid [4-(4-phenoxymethyl-phenoxy)-tetrahydro- furan-3-yl]-amide;
Propane-2-sulfonic acid {4-[4-(pyrrol id ine- 1 -carbonyl)-phenoxy]- tetrahydro-furan-3-yl}-amide;
Propane-2-sulfonic acid {4-[3-fluoro-4-(2-oxo-pyrrolidin-1 -ylmethyl)- phenoxy]-tetrahydro-furan-3-yl}-amide; Propane-2-sulfonic acid {4-[4-(1 ,1 -dioxo-1 lambda*6*-isothiazolidin-2- ylmethyl)-phenoxy]-tetrahydro-furan-3-yl}-amide;
Propane-2-sulfonic acid [4-(4-phenoxy-phenoxy)-tetrahydro-furan-3-yl]- amide;
N-{4-[4-(Propane-2-sulfonylamino)-tetrahydro-furan-3-yloxy]-phenyl}- benzamide;
Propane-2-sulfonic acid {4-[4-(2-oxo-pyrrolidin-1-yl)-phenoxy]- tetrahydro-furan-3-yl}-amide;
2-[2-Fluoro-4-(tetrahydro-furan-3-yloxy)-phenyl]-isothiazolidine 1 ,1 - dioxide; compound with propane-2-sulfonic acid amide; N-[4-(2'-Cyano-biphenyl-4-yloxy)-tetrahydro-furan-3-yl]- methanesulfonamide;
3-[4-(2'-Cyano-biphenyl-4-yloxy)-tetrahydro-furan-3-yl]-1 ,1 -dimethyl- sulfonylurea;
Propane-2-sulfonic acid {4-[5-(2-cyano-phenyl)-pyridin-2-yloxy]- tetrahydro-furan-3-yl}-amide; and Propane-2-sulfonic acid {4-[5-(2-cyano-phenyl)-pyrimidin-2-yloxy]- tetrahydro-furan-3-yl}-amide.
The compounds of Formula I and the pharmaceutically acceptable salts thereof are useful for the treatment of a variety of neurological and psychiatric disorders associated with glutamate dysfunction, including: acute neurological and psychiatric disorders such as cerebral deficits subsequent to cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage, dementia (including AIDS-induced dementia), Alzheimer's disease, Huntington's Chorea, amyotrophic lateral sclerosis, ocular damage, retinopathy, cognitive disorders, idiopathic and drug- induced Parkinson's disease, muscular spasms and disorders associated with muscular spasticity including tremors, epilepsy, convulsions, migraine (including migraine headache), urinary incontinence, substance tolerance, substance withdrawal (including, substances such as opiates, nicotine, tobacco products, alcohol, benzodiazepines, cocaine, sedatives, hypnotics, etc.), psychosis, schizophrenia, anxiety (including generalized anxiety disorder, social anxiety disorder, panic disorder, post-traumatic stress disorder and obsessive compulsive disorder), mood disorders (including depression, mania, bipolar disorders), trigeminal neuralgia, hearing loss, tinnitus, macular degeneration of the eye, emesis, brain edema, pain (including acute and chronic pain states, severe pain, intractable pain, neuropathic pain, and post-traumatic pain), tardive dyskinesia, sleep disorders (including narcolepsy), attention deficit/hyperactivity disorder, attention deficit disorder, and conduct disorder. Accordingly, in one embodiment, the invention provides a method for treating a condition in a mammal, such as a human, selected from the conditions above, comprising administering an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof to the mammal. The mammal is preferably a mammal in need of such treatment or prevention. The term "treating", as used herein, unless otherwise indicated, means reversing, alleviating, modulating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term "treatment", as used herein, unless otherwise indicated, refers to the act of treating as "treating" is defined immediately above. As an example, the invention provides a method for treating a condition selected from migraine, anxiety disorders, schizophrenia, and epilepsy. Exemplary anxiety disorders are generalized anxiety disorder, social anxiety disorder, panic disorder, post-traumatic stress disorder and obsessive- compulsive disorder. As another example, the invention provides a method for treating depression selected from Major Depression, Chronic Depression (Dysthymia), Seasonal Depression (Seasonal Affective Disorder), Psychotic Depression, and Postpartum Depression. As another example, the invention provides a method for treating a sleep disorder selected from insomnia and sleep deprivation. In another embodiment, the invention comprises methods of treating a condition in a mammal, such as a human, by administering an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the condition is selected from the group consisting of atherosclerotic cardiovascular diseases, cerebrovascular diseases and peripheral arterial diseases, to the mammal. The mammal is preferably a mammal in need of such treatment or prevention. Other conditions that can be treated in accordance with the present invention include hypertension and angiogenesis.
In another embodiment, the present invention provides methods of treating neurological and psychiatric disorders associated with glutamate dysfunction, comprising administering to a mammal, preferably a mammal in need thereof, an amount of a compound of Formula I or a pharmaceutically acceptable salt thereof effective in treating such disorders.
The compound of Formula I or a pharmaceutically acceptable salt thereof is optionally used in combination with another active agent. Such an active agent may be, for example, an atypical antipsychotic or an AMPA potentiator. Accordingly, another embodiment of the invention provides methods of treating neurological and psychiatric disorders associated with glutamate dysfunction, comprising administering to a mammal an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof and further comprising administering another active agent.
As used herein, the term "another active agent" refers to any therapeutic agent, other than the compound of Formula (I), or salt thereof, that is useful for the treatment of a subject disorder. Examples of additional therapeutic agents include antidepressants, antipsychotics, anti-pain, anti- Alzheimer's and anti-anxiety agents. Examples of particular classes of antidepressants that can be used in combination with the compounds of the invention include norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors (SSRIs), NK-1 receptor antagonists, monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase (RIMAs), serotonin and noradrenaline reuptake inhibitors (SNRIs), corticotropin releasing factor (CRF) antagonists, α-adrenoreceptor antagonists, and atypical antidepressants. Suitable norepinephrine reuptake inhibitors include tertiary amine tricyclics and secondary amine tricyclics. Examples of suitable tertiary amine tricyclics and secondary amine tricyclics include amithptyline, clomipramine, doxepin, imipramine, thmipramine, dothiepin, butriptyline, iphndole, lofepramine, nortriptyline, protriptyline, amoxapine, desipramine and maprotiline. Examples of suitable selective serotonin reuptake inhibitors include fluoxetine, fluvoxamine, paroxetine, and sertraline. Examples of monoamine oxidase inhibitors include isocarboxazid, phenelzine, and tranylcyclopramine. Examples of suitable reversible inhibitors of monoamine oxidase include moclobemide. Examples of suitable serotonin and noradrenaline reuptake inhibitors of use in the present invention include venlafaxine. Examples of suitable atypical anti-depressants include bupropion, lithium, nefazodone, trazodone and viloxazine. Examples of anti- Alheimer's agents include Dimebon, NMDA receptor antagonists such as memantine; and cholinesterase inhibitors such as donepezil and galantamine. Examples of suitable classes of anti-anxiety agents that can be used in combination with the compounds of the invention include benzodiazepines and serotonin 1A (5-HT1A) agonists or antagonists, especially 5-HT1A partial agonists, and corticotropin releasing factor (CRF) antagonists. Suitable benzodiazepines include alprazolam, chlordiazepoxide, clonazepam, chlorazepate, diazepam, halazepam, lorazepam, oxazepam, and prazepam. Suitable 5-HT1A receptor agonists or antagonists include buspirone, flesinoxan, gepirone and ipsapirone. Suitable atypical antipsychotics include paliperidone, bifeprunox, ziprasidone, risperidone, aripiprazole, olanzapine, and quetiapine. Suitable nicotine acetylcholine agonists include ispronicline, varenicline and MEM 3454. Anti-pain agents include pregabalin, gabapentin, clonidine, neostigmine, baclofen, midazolam, ketamine and ziconotide.
The invention is also directed to pharmaceutical compositions comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
Detailed Description of the Invention
The compounds of the Formula I may be prepared by the methods described below, together with synthetic methods known in the art of organic chemistry, or modifications and derivatisations that are familiar to those of ordinary skill in the art.
During any of the following synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This can be achieved by means of conventional protecting groups, such as those described in T. W. Greene, Protective Groups in Organic Chemistry, John Wiley & Sons, 1999, which is hereby incorporated by reference.
As appreciated by the artisan, the use of Formula I is a convenience and the invention is understood to include each and every species falling thereunder as though individually set forth herein. Thus, the invention contemplates each species separately and any and all combinations of such species. More specifically, in the Scheme that follows, R1 through R11, m, n, p, q, s, t, w, A, B, X, Y, and Z are as defined above.
Scheme 1
Figure imgf000026_0001
Scheme 1 refers to the preparation of compounds of the Formula I. Referring to Scheme 1 , an aryl halide of Formula II, wherein L1 is iodo, bromo or a triflate, may be coupled to a suitably substituted aryl boronic acid of structure (R1Jn-ArB(OH)2, wherein Ar represents a suitably substituted aryl or heteroaryl group and B is boron, under standard palladium catalyzed cross- coupling reaction conditions well known to one of ordinary skill in the art to provide the compound of Formula I. [Suzuki, A., Journal of Organometallic Chemistry, 576, 147-169 (1999), Miyaura and Suzuki, Chemical Reviews, 95, 2457-2483 (1995).] The compounds of Formula Il may be prepared from the compounds of Formula III via displacement of L2, wherein L2 may be halo, -OSO2CH3 (-OMs), or -OSO2CF3 (-OTf), with a reactant
Figure imgf000027_0001
wherein Z is O or S. Typical conditions involve reaction in an organic solvent such as acetonitrile in the presence of a base such as cesium carbonate at elevated temperature such as 15O0C. In the case where Z is S the product Il or I may be further oxidized to afford >S=O or >SO2 with a reagent such as a peroxide (such as mCPBA) in a solvent such as methylene chloride at room temperature.
Alternately, the compound of Formula III may be converted to a compound of Formula II, wherein L2 is ZH and Z is O or S, by nucleophilic aromatic substitution (such as reaction with an aryl tin, such as SnAr) reaction with an appropriately substituted aryl reagent
Figure imgf000027_0002
wherein L2 is halo or -OSO2CF3 (-OTf) according to methods analogous to those described in Withbroe, G. J.; Singer, R. A.; Sieser, J. E. "Streamlined Synthesis of the Bippyphos Family of Ligands and Cross-Coupling Applications" Org. Process Res. Dev. 2008, 12, 480-489. Typical conditions involve reaction in an organic solvent such as ethanol in the presence of a base such as potassium hydroxide, a catalyst, such as a palladium (such as Pd2(dba)3), and a ligand, such as 1 -[2-[bis(tert-butyl)phosphino]phenyl]-3,5- diphenyl-1 H-pyrazole (bippyphos), at elevated temperature such as 8O0C.
Alternatively, a compound of Formula I may be prepared from a compound of Formula II, wherein L1 is a silyl group (such as trimethylsilyl) by first converting the silyl group to a halide, such as by reaction with a halogenating reagent such as potassium bromide/Λ/-chlorosuccinimide (NCS) in the presence of an acid (such as acetic acid) followed by arylation as described above. Suitable solvents for the halogenation include alcohols such as methanol or ethanol. The reaction may be conducted at a temperature of about 1O0C to about 6O0C for about 10 to about 120 minutes. Alternatively, a compound of Formula I wherein q is zero and Y is O or
NR7 may be prepared by reaction of a compound of Formula Il wherein L1 is NH2 or OH by reaction with an aryl halide in the presence of a catalyst.
Alternatively, when q is two or three, one skilled in the art will appreciate that numerous coupling reactions of two suitably functionalized alkyl groups may afford the compounds of Formula I. Such reactions are within the skill of the art.
The compound of Formula Il may be prepared from a compound of Formula III by coupling with a suitably substituted Aryl Ghgnard in an ethereal solvent such as THF at about -3O0C to about room temperature. A catalyst, such as palladium or copper, may facilitate the reaction.
The compounds of Formula III are commercially available or may be made by methods well known to those skilled in the art or may be prepared by routine methods known in the art (such as those methods disclosed in standard reference books such as the COMPENDIUM OF ORGANIC SYNTHETIC METHODS, Vol. I-VI (published by Wiley-lnterscience)). Th e compounds of Formula I may be separated into the enantiomerically pure isomers according to methods well known to those skilled in the art and described in detail in the Example section herein.
The compounds of this invention may be used in the form of salts derived from inorganic or organic acids. The acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is obtained.
Base salts can easily be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmaceutically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they may also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before. In either case, stoichiometric quantities of reagents are preferably employed in order to ensure completeness of the reaction and maximum product yields. Where a salt is intended to be administered to a patient (as opposed to, for example, being used in an in vitro context), the salt preferably is pharmaceutically acceptable. The term "pharmaceutically acceptable salt" refers to a salt prepared by combining a compound of formula I with an acid whose anion, or a base whose cation, is generally considered suitable for human consumption. Pharmaceutically acceptable salts are particularly useful as products of the methods of the present invention because of their greater aqueous solubility relative to the parent compound. For use in medicine, the salts of the compounds of this invention are non-toxic "pharmaceutically acceptable salts." Typically, a compound of the invention is administered in an amount effective to treat or prevent a condition as described herein. The compounds of the invention are administered by any suitable route in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment or prevention intended. Therapeutically effective doses of the compounds required to treat or prevent the progress of the medical condition are readily ascertained by one of ordinary skill in the art using preclinical and clinical approaches familiar to the medicinal arts.
The compounds of the invention may be administered orally. Oral administration may involve swallowing so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth.
In another embodiment, the compounds of the invention may be administered directly into the blood stream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intra urethra I, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
In another embodiment, the compounds of the invention may be administered topically to the skin or mucosa, that is, dermally or transdermally. In another embodiment, the compounds of the invention may be administered intranasally or by inhalation. In another embodiment, the compounds of the invention may be administered rectally or vaginally. In another embodiment, the compounds of the invention may be administered directly to the eye or ear. The dosage regimen for the compounds and/or compositions containing the compounds is based on a variety of factors, including the type, age, weight, sex and medical condition of the patient; the severity of the condition; the route of administration; and the activity of the particular compound employed. Thus, the dosage regimen may vary widely. Dosage levels of the order from about 0.01 mg to about 100 mg per kilogram of body weight per day are useful in the treatment or prevention of the above- indicated conditions. In one embodiment, the total daily dose of a compound of the invention (administered in single or divided doses) is typically from about 0.01 to about 100 mg/kg. In another embodiment, total daily dose of the compound of the invention is from about 0.1 to about 50 mg/kg, and in another embodiment, from about 0.5 to about 30 mg/kg (i.e., mg compound of the invention per kg body weight). In one embodiment, dosing is from 0.01 to 10 mg/kg/day. In another embodiment, dosing is from 0.1 to 1 .0 mg/kg/day. Dosage unit compositions may contain such amounts or submultiples thereof to make up the daily dose. In many instances, the administration of the compound will be repeated a plurality of times in a day (typically no greater than 4 times). Multiple doses per day typically may be used to increase the total daily dose, if desired.
For oral administration, the compositions may be provided in the form of tablets containing 0.01 , 0.05, 0.1 , 0.5, 1 .0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 75.0, 100, 125, 150, 175, 200, 250 or 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient. A medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, or in another embodiment, from about 1 mg to about 100 mg of active ingredient. Intravenously, doses may range from about 0.1 to about 10 mg/kg/minute during a constant rate infusion.
Suitable subjects according to the present invention include mammalian subjects. Mammals according to the present invention include, but are not limited to, canine, feline, bovine, caprine, equine, ovine, porcine, rodents, lagomorphs, primates, and the like, and encompass mammals in utero. In one embodiment, humans are suitable subjects. Human subjects may be of either gender and at any stage of development.
In another embodiment, the invention comprises the use of one or more compounds of the invention for the preparation of a medicament for the treatment or prevention of the conditions recited herein. For the treatment or prevention of the conditions referred to above, a compound of the invention can be administered as the compound per se. Alternatively, pharmaceutically acceptable salts of the compounds are suitable for medical applications because of their greater aqueous solubility relative to the parent compounds.
In another embodiment, the present invention comprises pharmaceutical compositions. Such pharmaceutical compositions comprise a compound of the invention or a pharmaceutically acceptable salt thereof presented with a pharmaceutically-acceptable carrier. The carrier can be a solid, a liquid, or both, and may be formulated with the compound as a unit- dose composition, for example, a tablet, which can contain from 0.05% to 95% by weight of the active compounds. A compound of the invention may be coupled with suitable polymers as targetable drug carriers. Other pharmacologically active substances can also be present.
The compounds of the present invention and the pharmaceutically acceptable salts thereof may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment or prevention intended. The active compounds, pharmaceutically acceptable salts thereof and compositions, for example, may be administered orally, rectally, parenterally, or topically. Oral administration of a solid dose form may be, for example, presented in discrete units, such as hard or soft capsules, pills, cachets, lozenges, or tablets, each containing a predetermined amount of at least one compound of the present invention or a pharmaceutically acceptable salt thereof. In another embodiment, the oral administration may be in a powder or granule form. In another embodiment, the oral dose form is sub-lingual, such as, for example, a lozenge. In such solid dosage forms, the compounds of formula I or a pharmaceutically acceptable salt thereof are ordinarily combined with one or more adjuvants. Such capsules or tablets may contain a controlled-release formulation. In the case of capsules, tablets, and pills, the dosage forms also may comprise buffering agents or may be prepared with enteric coatings. In another embodiment, oral administration may be in a liquid dose form. Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art (e.g., water). Such compositions also may comprise adjuvants, such as wetting, emulsifying, suspending, flavoring (e.g., sweetening), and/or perfuming agents.
In another embodiment, the present invention comprises a parenteral dose form. "Parenteral administration" includes, for example, subcutaneous injections, intravenous injections, intraperitoneally, intramuscular injections, intrasternal injections, and infusion. Injectable preparations (e.g., sterile injectable aqueous or oleaginous suspensions) may be formulated according to the known art using suitable dispersing, wetting agents, and/or suspending agents.
In another embodiment, the present invention comprises a topical dose form. "Topical administration" includes, for example, transdermal administration, such as via transdermal patches or iontophoresis devices, intraocular administration, or intranasal or inhalation administration. Compositions for topical administration also include, for example, topical gels, sprays, ointments, and creams. A topical formulation may include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. When the compounds of this invention and the pharmaceutically acceptable salts thereof are administered by a transdermal device, administration will be accomplished using a patch either of the reservoir and porous membrane type or of a solid matrix variety. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated - see, for example, J Pharm Sci, 88 (10), 955-958, by Finnin and Morgan (October 1999).
Formulations suitable for topical administration to the eye include, for example, eye drops wherein the compound of this invention or a pharmaceutically acceptable salt thereof is dissolved or suspended in suitable carrier. A typical formulation suitable for ocular or aural administration may be in the form of drops of a micronised suspension or solution in isotonic, pH- adjusted, sterile saline. Other formulations suitable for ocular and aural administration include ointments, biodegradable (e.g. absorbable gel sponges, collagen) and non-biodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes. A polymer such as crossed-l inked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysacchahde polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis.
For intranasal administration or administration by inhalation, the active compounds of the invention or the pharmaceutically acceptable salts thereof are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant. Formulations suitable for intranasal administration are typically administered in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as 1 ,1 ,1 ,2-tetrafluoroethane or 1 ,1 ,1 ,2,3,3,3- heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.
In another embodiment, the present invention comprises a rectal dose form. Such rectal dose form may be in the form of, for example, a suppository. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.
Other carrier materials and modes of administration known in the pharmaceutical art may also be used. Pharmaceutical compositions of the invention may be prepared by any of the well-known techniques of pharmacy, such as effective formulation and administration procedures. The above considerations in regard to effective formulations and administration procedures are well known in the art and are described in standard textbooks. Formulation of drugs is discussed in, for example, Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania, 1975; Liberman, et al., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Kibbe, et al., Eds., Handbook of Pharmaceutical Excipients (3rd Ed.), American Pharmaceutical Association, Washington, 1999.
The compounds of the present invention and the pharmaceutically acceptable salts thereof can be used, alone or in combination with other therapeutic agents, in the treatment or prevention of various conditions or disease states. The compound(s) of the present invention, pharmaceutically acceptable salts thereof and other therapeutic agent(s) may be may be administered simultaneously (either in the same dosage form or in separate dosage forms) or sequentially in any order. An exemplary therapeutic agent may be, for example, a metabotropic glutamate receptor agonist.
The administration of two or more compounds "in combination" means that the two compounds are administered closely enough in time that the presence of one alters the biological effects of the other. The two or more compounds may be administered simultaneously, concurrently or sequentially in any order. Additionally, simultaneous administration may be carried out by mixing the compounds prior to administration or by administering the compounds at the same point in time but at different anatomic sites or using different routes of administration.
The phrases "concurrent administration," "co-administration," "simultaneous administration," and "administered simultaneously" mean that the compounds are administered in combination.
The present invention further comprises kits that are suitable for use in performing the methods of treatment or prevention described above. In one embodiment, the kit contains a first dosage form comprising one or more of the compounds of the present invention or a pharmaceutically acceptable salt thereof and a container for the dosage, in quantities sufficient to carry out the methods of the present invention.
In another embodiment, the kit of the present invention comprises one or more compounds of the invention or a pharmaceutically acceptable salt thereof.
Three compounds of the invention were subjected to single crystal X- ray structure determination to elucidate their absolute stereochemistry. Crystallographic data is provided below.
Representative crystals were surveyed (see individual compounds below for characterization of data sets and diffractometers used). Friedel pairs were collected in order to facilitate the determination of the absolute configuration. Atomic scattering factors were taken from the International
Tables for Crystallography, Vol. C, pp. 219, 500, Kluwer Academic
Publishers, 1992. All crystallographic calculations were facilitated by the SHELXTL system, Version 5.1 , Bruker AXS, 1997. All diffractometer data were collected at room temperature. Pertinent crystal, data collection, and refinement are summarized in Table I for each compound.
A trial structure was obtained by direct methods for each compound.
These trial structures refined routinely. Hydrogen positions were calculated wherever possible. The methyl hydrogens were located by difference Fourier techniques and then idealized. Any hydrogens on nitrogen were located by difference Fourier techniques and allowed to refine. The hydrogen parameters were added to the structure factor calculations but were not refined. The shifts calculated in the final cycles of least squares refinement were all less than 0.1 of the corresponding standard deviations. Final R- indices are given for each structure. A final difference Fourier revealed no missing or misplaced electron density for any of these structures.
Absolute configurations were determined by the method of Flack, Acta Crystallogr., 1983 A39, 876. Coordinates, anisotropic temperature factors, distances and angles are shown below (Tables 1 -5) for each structure. Experimental Procedures
Experiments were generally carried out under inert atmosphere (nitrogen or argon), particularly in cases where oxygen- or moisture-sensitive reagents or intermediates were employed. Commercial solvents and reagents were generally used without further purification, including anhydrous solvents where appropriate (generally Sure-Seal™ products from the Aldrich Chemical Company, Milwaukee, Wisconsin). Mass spectrometry data is reported from either liquid chromatography-mass spectrometry (LCMS), atmospheric pressure chemical ionization (APCI) or gas chromatography- mass spectrometry (GCMS) instrumentation. Chemical shifts for nuclear magnetic resonance (NMR) data are expressed in parts per million (ppm, δ) referenced to residual peaks from the deuterated solvents employed.
For syntheses referencing procedures in other Examples, Preparations or Methods, reaction conditions (length of reaction and temperature) may vary. In general, reactions were followed by thin layer chromatography or mass spectrometry, and subjected to work-up when appropriate. If non- product solids were present in the crude reaction mixture, filtration through Celite® may be employed. Purifications may vary between experiments: in general, solvents and the solvent ratios used for eluants/gradients were chosen to provide appropriate RfS or retention times. Preparation 1 Synthesis of c/s-/V-{4-[(6-bromopyridin-3-yl)oxy1tetrahydrofuran-3-yl)propane-
2-sulfonamide
Step 1 . Synthesis of frans-4-[(6-bromopyridin-3-yl)oxy]tetrahydrofuran- 3-ol.
The title compound of Step 1 was prepared according to the general procedure for the synthesis of frans-4-(4-bromophenoxy)tetrahydrofuran-3-ol in Example 2, except that 6-bromopyridin-3-ol was used in place of 4- bromophenol, and the crude product was purified by silica gel chromatography (Gradient: 20% to 70% ethyl acetate in heptane). Yield:
5.24 g, 20.2 mmol, 61 %. 1H NMR (500 MHz, CDCI3) δ 3.79 (dd, J=9.9, 1 .9
Hz, 1 H), 3.87 (dd, J=10.4, 1 .8 Hz, 1 H), 4.00 (dd, J=9.9, 4.3 Hz, 1 H), 4.19 (dd, j=10.4, 4.7 Hz, 1 H), 4.38 (br m, 1 H), 4.59 (br s, 1 H), 4.68 (br d, J=4.4 Hz,
1 H), 7.14 (dd, J=8.7, 3.2 Hz, 1 H), 7.32 (dd, J=8.7, 0.5 Hz, 1 H), 8.01 (br d, J=3.1 Hz, 1 H).
Step 2. Synthesis of frans-4-[(6-bromopyridin-3-yl)oxy]tetrahydrofuran- 3-yl methanesulfonate.
The title compound of Step 2 was prepared according to the general procedure for the synthesis of frans-2-(4-bromophenoxy)cyclopentyl methanesulfonate in Example 5, except that frans-4-[(6-bromopyhdin-3- yl)oxy]tetrahydrofuran-3-ol was used instead of trans-2-(4- bromophenoxy)cyclopentanol. The product was obtained as a solid. Yield:
5.95 g, 17.6 mmol, 87%. 1 H NMR (400 MHz, CDCI3) δ 3.07 (s, 3H), 3.94 (br dd, J=10.5, 1 .8 Hz, 1 H), 4.00 (m, 1 H), 4.1 1 (dd, J=1 1 .1 , 4.1 Hz, 1 H), 4.18 (dd, J=10.6, 4.5 Hz, 1 H), 4.97 (br d, J=4.4 Hz, 1 H), 5.13 (br d, J=3.8 Hz, 1 H), 7.19
(dd, J=8.7, 3.2 Hz, 1 H), 7.35 (dd, J=8.7, 0.5 Hz, 1 H), 8.04 (dd, J=3.2, 0.5 Hz,
1 H).
Step 3. Synthesis of cis-N-{4-[(6-bromopyhdin-3-yl)oxy]tetrahydro- furan-3-yl}propane-2-sulfonamide. 7rans-4-[(6-bromopyridin-3-yl)oxy]tetrahydrofuran-3-yl methane sulfonate (591 .7 mg, 1 .75 mmol), propane-2-sulfonamide (647 mg, 5.25 mmol) and cesium carbonate (855 mg, 2.62 mmol) were combined in acetonitrile (8 ml_) and subjected to microwave irradiation for 55 minutes at 150 0C. The crude reaction mixture was combined with several similar reactions run under the same conditions (total starting material used: 1.527 g, 4.515 mmol) and shaken with saturated aqueous sodium bicarbonate solution (100 ml_). The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified via silica gel chromatography (Gradient: 5% to 40% ethyl acetate in heptane) to provide the title compound. Yield: 382 mg, 1.046 mmol, 23%. 1H NMR (400 MHz, CDCI3) δ 1.34 (d, J=6.8 Hz, 3H), 1.36 (d, J=6.8 Hz, 3H), 3.17 (septet, J=6.8 Hz, 1 H), 3.74 (dd, J=Q, 9 Hz, 1 H), 3.94 (dd, J=10.9, 1.5 Hz, 1 H), 4.14 (dd, J=8, 8 Hz, 1 H), 4.19 (dd, J=10.9, 4.3 Hz, 1 H), 4.27 (m, 1 H), 4.84 (m, 1 H), 5.66 (d, J=9.9 Hz, 1 H), 7.20 (dd, J=8.8, 3.2 Hz, 1 H), 7.40 (d, J=8.8 Hz, 1 H), 8.01 (d, J=3.2 Hz, 1 H).
Preparation 2 Synthesis of methyl 3-cvano-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- vDbenzoate Step 1. Synthesis of methyl 3-cyano-4-{[(trifluoromethyl)sulfonyl]oxy}- benzoate.
A solution of methyl 3-cyano-4-hydroxybenzoate [see P. Madsen et al, J. Medicinal Chemistry 2002, 45, 5755-5775] (4.18 g, 23.6 mmol) in dichloromethane (81 ml_) was treated with 4-(dimethylamino)pyhdine (432 mg, 3.54 mmol) and cooled to 0 0C. After addition of triethylamine (4.93 ml_, 35.4 mmol), the solution was treated drop-wise with trifluoromethanesulfonic anhydride (5.96 ml_, 35.4 mmol) and allowed to warm to room temperature. After 2 hours, the reaction was concentrated in vacuo, and repetitively treated with dichloromethane and concentrated until 17 grams of material remained. This was subjected to silica gel chromatography (Gradient: 0% to 10% ethyl acetate in heptane) to provide product as a colorless oil. Yield: 6.5O g, 21.0 mmol, 89%. 1H NMR (500 MHz, CDCI3) δ 4.00 (s, 3H), 7.60 (d, J=8.8 Hz, 1 H), 8.39 (dd, J=8.8, 2.1 Hz, 1 H), 8.45 (d, J=2.2 Hz, 1 H).
Step 2. Synthesis of compound methyl 3-cyano-4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)benzoate. 4,4,4',4\5,5,5\5'-Octamethyl-2,2'-bi-1 ,3,2-dioxaborolane
(bis(pinacolato)diboron, 5.81 g, 22.9 mmol), methyl 3-cyano-4- {[(trifluoromethyl)sulfonyl]oxy}benzoate (5.90 g, 19.1 mmol), potassium acetate (99%, 9.46 g, 95.4 mmol) and 1 ,1 '- [bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (1 .40 g, 1 .91 mmol) were combined in degassed dioxane (83 ml_) in a thick-walled reaction flask. The reaction was sealed and heated at 1000C for 18 hours, then treated with dichloromethane (100 ml_), stirred well and filtered through Celite®. The filter cake was rinsed with dichloromethane (2 x 100 ml_), and the combined filtrates were concentrated in vacuo and subjected to chromatography on silica gel (Gradient: 0% to 30% ethyl acetate in heptane). Fractions containing product were concentrated and subjected to recrystallization from 2-propanol to provide the title compound as a white solid. Yield: 3.395 g, 1 1 .82 mmol, 62%. 1H NMR (400 MHz, CDCI3) δ 1 .41 (s, 12H), 3.97 (s, 3H), 7.98 (d, J=7.8 Hz, 1 H), 8.20 (dd, J=I Λ, 1 .6 Hz, 1 H), 8.35 (br d, J=1 .6 Hz, 1 H). Preparation 3
Synthesis of Λ/-[(1 S,2f?)-2-(4-bromo-3-fluorophenoxy)cvclopentylipropane-2- sulfonamide
Step 1 . Synthesis of frans-2-(4-bromo-3-fluorophenoxy)cyclopentanol. 4-Bromo-3-fluorophenol (8.00 g, 41 .9 mmol) and 6- oxabicyclo[3.1 .0]hexane (8.25 ml_, 95.2 mmol) were combined in butyronitrile (5.0 ml_) and treated with sodium carbonate (4.04 g, 38.1 mmol). The reaction was subjected to microwave irradiation for 2 hours at 175°C, then filtered through Celite®. The filter cake was washed with ethyl acetate, then dichloromethane, and the combined filtrates were concentrated under reduced pressure to provide product as a dark brown oil. This material was used without additional purification. Yield: 1 1 .59 g, >41 .9 mmol, assumed quantitative. 1H NMR (400 MHz, CDCI3) δ 1.61 -1.89 (m, 5H), 2.02-2.24 (m, 2H), 4.30 (m, 1 H), 4.46 (m, 1 H), 6.63 (ddd, J=8.9, 2.8, 1.1 Hz, 1 H), 6.73 (dd, J=10.5, 2.8 Hz, 1 H), 7.40 (dd, J=8.9, 8.0 Hz, 1 H).
Step 2. Synthesis of (1 R,2R)-2-(4-bromo-3-fluorophenoxy)cyclopentyl acetate.
The title compound in Step 2 was prepared according to the general procedure for the synthesis of (1 R,2R)-2-(4-bromophenoxy)cyclohexyl acetate in Example 7, except that frans-2-(4-bromo-3-fluorophenoxy)cyclopentanol was used instead of frans-2-(4-bromophenoxy)cyclohexanol. The less polar material from the chromatographic purification on silica gel provided (1 R,2R)-
2-(4-bromo-3-fluorophenoxy)cyclopentyl acetate as an oil. Yield: 6.42 g, 20.2 mmol, 48% over 2 steps. 1H NMR (400 MHz, CDCI3) δ 1.67-1.75 (m, 1 H),
1.79-1.92 (m, 3H), 2.05-2.20 (m, 2H), 2.08 (s, 3H), 4.60 (m, 1 H), 5.14 (m, 1 H),
6.66 (ddd, J=8.9, 2.8, 1.1 Hz, 1 H), 6.78 (dd, J=10.5, 2.8 Hz, 1 H), 7.40 (dd, J=8.8, 8.1 Hz, 1 H).
Step 3. Synthesis of (1R,2R)-2-(4-bromo-3-fluorophenoxy)- cyclopentanol.
The title compound in Step 3 was prepared according to the general procedure for the synthesis of (1R,2R)-2-(4-bromophenoxy)cyclohexanol in Example 7, except that (1 R,2R)-2-(4-bromo-3-fluorophenoxy)cyclopentyl acetate was used instead of (1 R,2R)-2-(4-bromophenoxy)cyclohexyl acetate.
The product was obtained as a yellow oil. Yield: 5.29 g, 19.2 mmol, 95%. 1H
NMR (500 MHz, CDCI3) δ 1.62-1.68 (m, 2H), 1.71 -1.90 (m, 3H), 2.04-2.11 (m,
1 H), 2.15-2.22 (m, 1 H), 4.30 (m, 1 H), 4.47 (m, 1 H), 6.63 (ddd, J=8.9, 2.8, 1.1 Hz, 1 H), 6.73 (dd, J=10.5, 2.8 Hz, 1 H), 7.40 (dd, J=8.9, 8.1 Hz, 1 H).
Step 4. Synthesis of (1 R,2R)-2-(4-bromo-3-fluorophenoxy)cyclopentyl methanesulfonate.
The title compound in Step 4 was prepared according to the general procedure for the synthesis of frans-2-(4-bromophenoxy)cyclopentyl methanesulfonate in Example 5, except that (1 R,2R)-2-(4-bromo-3- fluorophenoxy)cyclopentanol was used instead of frans-2-(4- bromophenoxy)cyclopentanol. The product was obtained as an oil, which was taken on to the following step without purification. MS (GCMS) m/z 352, 354 (M+1 ). 1 H NMR (500 MHz, CDCI3) δ 1 .81 -2.00 (m, 4H), 2.16-2.26 (m, 2H), 3.04 (s, 3H), 4.77 (m, 1 H), 5.07 (m, 1 H), 6.65 (ddd, J=8.9, 2.8, 1 .1 Hz, 1 H), 6.74 (dd, J=10.2, 2.8 Hz, 1 H), 7.43 (dd, J=8.9, 8.0 Hz, 1 H).
Step 5. Synthesis of (1 R,2S)-2-azidocyclopentyl 4-bromo-3- fluorophenyl ether.
The title compound in Step 5 was prepared according to the general procedure for the synthesis of c/s-2-azidocyclopentyl 4-bromophenyl ether in Example 5, except that (1 R,2R)-2-(4-bromo-3-fluorophenoxy)cyclopentyl methanesulfonate was employed in place of trans-2-(4- bromophenoxy)cyclopentyl methanesulfonate. The product was isolated as a brown oil, which was used without purification in the following step. 1 H NMR (400 MHz, CDCI3) δ 1 .66-1 .75 (m, 1 H), 1 .88-2.08 (m, 5H), 3.74 (m, 1 H), 4.65 (m, 1 H), 6.66 (ddd, J=8.9, 2.8, 1 .1 Hz, 1 H), 6.75 (dd, J=10.4, 2.8 Hz, 1 H), 7.42 (dd, J=8.8, 8.0 Hz, 1 H).
Step 6: Synthesis of (1 S,2R)-2-(4-bromo-3- fluorophenoxy)cyclopentanamine.
The title compound in Step 6 was prepared according to the general procedure for the synthesis of c/s-2-(4-bromophenoxy)cyclopentanamine in Example 5, except that (1 R,2S)-2-azidocyclopentyl 4-bromo-3-fluorophenyl ether was used instead of c/s-2-azidocyclopentyl 4-bromophenyl ether, and c/s-2-(4-bromophenoxy)cyclopentanamine was taken on to the following step without purification. LCMS m/z 276.2 (M+1 ). 1 H NMR (500 MHz, CDCI3) δ 1 .5 (v br s, 2H), 1 .57-1 .66 (m, 2H), 1 .80-1 .87 (m, 2H), 1 .93-2.01 (m, 2H), 3.36 (m, 1 H), 4.41 (m, 1 H), 6.63 (ddd, J=8.9, 2.8, 1 .1 Hz, 1 H), 6.71 (dd, J=10.5, 2.8 Hz, 1 H), 7.40 (dd, J=8.8, 8.0 Hz, 1 H).
Step 7. Synthesis of Λ/-[(1 S,2R)-2-(4-bromo-3-fluorophenoxy)- cyclopentyl]propane-2-sulfonamide. The title compound of Step 7 was prepared according to the general procedure for the synthesis of c/s-Λ/-[2-(4- bronnophenoxy)cyclopentyl]propane-2-sulfonannide in Example 5, except that (1 S,2R)-2-(4-bromo-3-fluorophenoxy)cyclopentanannine was used instead of c/s-2-(4-bromophenoxy)cyclopentanannine, and the chromatographic purification was carried out with a gradient of 0% to 10% methanol in dichloromethane, to provide the title compound as an off-white solid. Yield: 4.15 g, 10.9 mmol, 54% from (1 R,2R)-2-(4-bromo-3- fluorophenoxy)cyclopentyl acetate (5 steps). 1H NMR (500 MHz, CDCI3) δ 1.36 (d, J=6.7 Hz, 3H), 1.39 (d, J=6.8 Hz, 3H), 1.62-1.69 (m, 1 H), 1.77-1.90 (m, 3H), 1.92-2.00 (m, 1 H), 2.10-2.15 (m, 1 H), 3.14 (septet, J=6.8 Hz, 1 H), 3.86 (m, 1 H), 4.56-4.60 (m, 2H), 6.61 (ddd, J=8.9, 2.8, 1.1 Hz, 1 H), 6.70 (dd, J=10.3, 2.8 Hz, 1 H), 7.43 (dd, J=8.8, 8.1 Hz, 1 H). The absolute configuration of Λ/-[(1 S,2R)-2-(4-bromo-3-fluorophenoxy)cyclopentyl]propane-2-sulfonamide was assigned by analogy to the stereochemistry of compounds in Example 7 and Preparation 6. Preparation 4
Synthesis of (2-cvano-4-fluorophenyl)boronic acid 2-Bromo-5-fluorobenzonitrile (6.00 g, 30.0 mmol) and triisopropyl borate (8.28 ml_, 36.0 mmol) were dissolved in a mixture of toluene (48 ml_) and tetrahydrofuran (12 ml_), and the solution was cooled in a dry ice/acetone bath. A solution of n-butyllithium in hexanes (2.5M, 14.4 ml_, 36.0 mmol) was added drop-wise over 1 hour, and the reaction was then allowed to warm to room temperature with stirring over 18 hours. The mixture was cooled in an ice bath and treated with a 2N aqueous hydrochloric acid solution until the pH reached 1 , then allowed to warm to room temperature, at which time the layers were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed twice with water, once with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting solid was recrystallized from ethyl acetate-heptane to provide (2-cyano-4- fluorophenyl)boronic acid as a white solid. Yield: 2.20 g, 13.3 mmol, 44%. 1H NMR (400 MHz, CD3OD) δ 7.43 (ddd, J=8.6, 8.6, 2.5 Hz, 1 H), 7.55 (dd, J=8.8, 2.5 Hz, 1 H), 7.69 (br s, 1 H).
Preparation 5
Synthesis of Λ/-(2-f4-(4.4.5.5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl1ethyl)methanesulfonamide
Step 1. Synthesis of te/t-butyl (methylsulfonyl){2-[4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]ethyl}carbamate.
4,4,5,5-Tetramethyl-1 ,3,2-dioxaborolane (4.29 mL, 29.6 mmol) was added slowly to a mixture of te/t-butyl [2-(4- iodophenyl)ethyl](methylsulfonyl)carbamate (see JP. Gardner and W.D. Miller, PCT Pat. Appl. Publ. WO 2001090055, 2001 ) (8.39 g, 19.7 mmol), triethylamine (9.64 mL, 69.1 mmol) and 1 ,1 '-
[bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (217 mg, 0.296 mmol) in acetonitrile (50 mL), and the reaction mixture was heated at 75 0C for 4 hours. After removal of solvent, the residue was mixed with water (240 mL) and extracted with methyl te/t-butyl ether. The combined organic layers were washed with saturated aqueous sodium chloride solution and with water, then dried over magnesium sulfate, filtered and concentrated in vacuo to provide synthesis of te/t-butyl (methylsulfonyl){2-[4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl]ethyl}carbamate, which was used without additional purification. Yield: assumed quantitative. LCMS m/z 326.1 (M+1 ). 1H NMR (400 MHz, CDCI3) δ 1.35 (s, 12H), 2.84 (s, 3H), 2.90 (t, J=6.8 Hz, 2H), 3.42 (dt, J=6.6, 6.6 Hz, 2H), 4.18 (br t, J=6 Hz, 1 H), 7.23 (d, J=8.1 Hz, 2H), 7.78 (d, J=8.1 Hz, 2H). Step 2. Synthesis of Λ/-{2-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]ethyl}methanesulfonamide.
Trifluoroacetic acid (10 mL) was added to a 00C solution of te/t-butyl (methylsulfonyl){2-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]ethyl}carbamate (from the previous step, assumed 19.7 mmol) in dichloromethane (100 mL). The reaction mixture was allowed to warm to room temperature and stir for 18 hours. It was then cooled to 0 0C and brought to pH 10.5 with a 4N aqueous sodium hydroxide solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified via silica gel chromatography (Gradient: 0% to 5% methanol in dichloromethane) to provide the title compound as an off-white solid. Yield: 2.5 g, 7.7 mmol, 39% over two steps. LCMS m/z 326.1 (M+1 ). 1H NMR (400 MHz, CDCI3) δ 1.35 (s, 12H), 2.84 (s, 3H), 2.90 (t, J=6.8 Hz, 2H), 3.42 (dt, J=6.6, 6.6 Hz, 2H), 4.18 (br t, J=6 Hz, 1 H), 7.23 (d, J=8.1 Hz, 2H), 7.78 (d, J=8.1 Hz, 2H). Preparation 6
Synthesis of Λ/-[(1 S,2f?)-2-(4-bromo-3-fluorophenoxy)cvclohexylipropane-2- sulfonamide
The title compound was prepared according to the general procedure for the synthesis of c/s-Λ/-[2-(4-bromophenoxy)cyclopentyl]propane-2- sulfonamide in Example 5, except that (1 S,2R)-2-(4-bromo-3- fluorophenoxy)cyclohexanamine was used in place of c/s-2-(4- bromophenoxy)cyclopentanamine, and the chromatographic purification employed 0% to 1 % methanol in dichloromethane as gradient. (1 S,2R)-2-(4- Bromo-3-fluorophenoxy)cyclohexanamine was synthesized according to the general procedures described for synthesis of (1 S,2R)-2-(4- bromophenoxy)cyclohexanamine in Example 7, except for the use of 4- bromo-3-fluorophenol in place of 4-bromophenol. The title compound was obtained as a white solid. 1H NMR (400 MHz, CDCI3) δ 1.33-1.53 (m, 4H), 1.35-1.38 (m, 6H), 1.78-1.89 (m, 3H), 2.04-2.10 (m, 1 H), 3.12 (septet, J=6.8 Hz, 1 H), 3.54 (m, 1 H), 4.44 (d, J=9.6 Hz, 1 H), 4.55 (m, 1 H), 6.67 (br dd, J=8.9, 2.8 Hz, 1 H), 6.75 (dd, J=10.2, 2.7 Hz, 1 H), 7.43 (dd, J=8.5, 8.5 Hz, 1 H). The absolute configuration of the title compound was established via X- ray crystallography. Preparation 7 Synthesis of /V-K 1 S,2f?)-2-[(6-bromopyridin-3-yl)oxy1cvclohexyl)propane-2- sulfonamide
Step 1. Synthesis of frans-2-[(6-bromopyridin-3-yl)oxy]cyclohexanol. The title compound of Step 1 was prepared according to the general procedure for the synthesis of frans-2-(4-bromo-3- fluorophenoxy)cyclopentanol in Preparation 3, except that 6-bromopyhdin-3-ol was used instead of 4-bromo-3-fluorophenol, and 7-oxabicyclo[4.1.0]heptane in place of 6-oxabicyclo[3.1.0]hexane. The crude product (preparation run in four batches) was recrystallized from heptane to provide trans-2-[(6- bromopyridin-3-yl)oxy]cyclohexanol as an off-white solid. Yield: 11.09 g, 40.75 mmol, 46%. 1H NMR (500 MHz, CDCI3) δ 1.27-1.46 (m, 4H), 1.76-1.80 (m, 2H), 2.09-2.13 (m, 2H), 2.41 (d, J=2.6 Hz, 1 H), 3.74 (m, 1 H), 4.00 (m, 1 H), 7.17 (dd, J=8.7, 3.1 Hz, 1 H), 7.37 (d, J=8.5 Hz, 1 H), 8.10 (d, J=3.0 Hz, 1 H). Step 2. Synthesis of c/s-2-[(6-bromopyhdin-3-yl)oxy]cyclohexanamine.
C/s-5-[(2-azidocyclohexyl)oxy]-2-bromopyridine, prepared from trans-2-
[(6-bromopyridin-3-yl)oxy]cyclohexanol by the general procedures described in Example 5 for the conversion of frans-2-(4-bromophenoxy)cyclopentanol to c/s-2-azidocyclopentyl 4-bromophenyl ether) (13.5 g, 45.4 mmol) was dissolved in tetrahydrofuran (292 ml_) and water (23 ml_), and the solution was treated with thphenylphosphine (23.8 g, 90.7 mmol). The reaction was stirred for 18 hours at room temperature, then partitioned between ethyl acetate (500 ml_) and water (200 ml_). The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with water (2 x 200 ml_) and saturated aqueous sodium chloride solution (200 ml_). The organic layer was then extracted with aqueous 1 N hydrochloric acid (4 x 150 ml_), and the combined aqueous layers were washed with ethyl acetate (150 ml_). The aqueous layer was then cooled in an ice bath and slowly treated with an aqueous 2N solution of sodium hydroxide, until the mixture was a cloudy white; it was then extracted with ethyl acetate (3 x 150 ml_), and the combined organic layers were washed with saturated aqueous sodium chloride solution (150 ml_), dried over sodium sulfate, filtered and concentrated in vacuo. C/s-2-[(6-bromopyridin-3-yl)oxy]cyclohexanamine was obtained as a yellow oil. Yield: 8.00 g, 29.5 mmol, 65%. 1H NMR (500 MHz, CDCI3) δ 1.34 (d, J=6.8 Hz, 3H), 1.35 (d, J=6.7 Hz, 3H), 1.35-1.52 (m, 4H), 1.79-1.85 (m, 3H), 2.02 (m, 1 H), 3.11 (septet, J=6.8 Hz, 1 H), 3.53 (m, 1 H), 4.59 (br s, 1 H), 4.68 (m, 1 H), 7.19 (dd, J=8.7, 3.1 Hz, 1 H), 7.38 (d, J=8.7 Hz, 1 H), 8.07 (d, J=3.2 Hz, 1 H).
Step 3. Synthesis of c/s-Λ/-{2-[(6-bromopyhdin-3-yl)oxy]cyclohexyl}- propane-2-sulfonamide. The title compound of Step 3 was prepared according to the general procedure for the synthesis of c/s-Λ/-[2-(4- bromophenoxy)cyclopentyl]propane-2-sulfonamide c/s-Λ/-[2-(4- bromophenoxy)cyclopentyl]propane-2-sulfonamide in Example 5, except that c/s-2-[(6-bromopyridin-3-yl)oxy]cyclohexanamine was used in place of c/s-2- (4-bromophenoxy)cyclopentanamine, and the 4-(dimethylamino)pyhdine was omitted. The silica gel chromatography in this case was carried out with an eluant of 2% methanol in dichloromethane, to provide c/s-Λ/-{2-[(6- bromopyridin-3-yl)oxy]cyclohexyl}propane-2-sulfonamide as a beige foam. Yield: 7.96 g, 21.1 mmol, 72%. 1H NMR (500 MHz, CDCI3) δ 1.34 (d, J=6.8 Hz, 3H), 1.35 (d, J=6.7 Hz, 3H), 1.35-1.52 (m, 4H), 1.79-1.85 (m, 3H), 2.02 (m, 1 H), 3.11 (septet, J=6.8 Hz, 1 H), 3.53 (m, 1 H), 4.59 (br s, 1 H), 4.68 (m, 1 H), 7.19 (dd, J=8.7, 3.1 Hz, 1 H), 7.38 (d, J=8.7 Hz, 1 H), 8.07 (d, J=3.2 Hz, 1 H).
Step 4. Isolation of Λ/-{(1 S,2R)-2-[(6-bromopyridin-3- yl)oxy]cyclohexyl}propane-2-sulfonamide.
Separation of the enantiomers comprising c/s-Λ/-{2-[(6-bromopyridin-3- yl)oxy]cyclohexyl}propane-2-sulfonamide (7.96 g, 21.1 mmol) was carried out by chiral chromatography. Column: Chiralpak® AD-H, 2.1 x 25 cm, 5 μm; Mobile phase: 70:30 carbon dioxide: methanol; Flow rate: 65 g/min. The first-eluting compound was enantiomer [Λ/-{(1R,2S)-2-[(6-bromopyridin-3- yl)oxy]cyclohexyl}propane-2-sulfonamide] and the second-eluting peak provided desired product Λ/-{(1 S,2R)-2-[(6-bromopyridin-3- yl)oxy]cyclohexyl}propane-2-sulfonamide upon removal of solvent in vacuo. Yield: 3.13 g, 8.30 mmol, 39%. The absolute stereochemistry of these enantiomers was assigned by analogy to Example 5. Preparation 8
Synthesis of c/s-/V-[4-(4-bromophenoxy)tetrahvdrofuran-3-ylipropane-2- sulfonamide
The title compound was prepared according to the general procedure for the synthesis of c/s-Λ/-{4-[(6-bromopyridin-3-yl)oxy]tetrahydrofuran-3- yl}propane-2-sulfonamide in Preparation 1 , except that trans-4-(4- bromophenoxy)tetrahydrofuran-3-yl methanesulfonate was used in place of frans-4-[(6-bromopyridin-3-yl)oxy]tetrahydrofuran-3-yl methanesulfonate, and the chromatographic purification was carried out with a gradient of 15% to 35% acetone in heptane. Yield: 238 mg, 0.65 mmol, 31 %. 1H NMR (400 MHz, CDCI3) δ 1.30 (d, J=6.8 Hz, 3H), 1.33 (d, J=6.8 Hz, 3H), 3.11 (septet, J=6.8 Hz, 1 H), 3.66 (dd, J=QA , 8.4 Hz, 1 H), 3.89 (dd, J=10.7, 1.7 Hz, 1 H), 4.07-4.13 (m, 2H), 4.19 (m, 1 H), 4.71 (m, 1 H), 5.12 (d, J=9.6 Hz, 1 H), 6.75 (d, J=9.0 Hz, 2H), 7.36 (d, J=9.0 Hz, 2H).
Example 1 Synthesis of Λ/-I1 -[4-frans-({4-[(isopropylsulfonyl)amino1tetrahvdrofuran-3- yl)oxy)phenylipyrrolidin-3-yl)acetamide
Figure imgf000048_0001
Step 1. Synthesis of frans-Λ/-(4-hydroxytetrahydrofuran-3-yl)propane- 2-sulfonamide. 3,6-Dioxabicyclo[3.1.0]hexane (1.90 g, 22.1 mmol), propane-2- sulfonamide (prepared according to the method of D. C. Johnson, Il and T. S. Widlanski, Tetrahedron Letters 2004, 45, 8483-8487) (3.13 g, 25.4 mmol), potassium carbonate (584 mg, 4.23 mmol) and benzylthethylammonium chloride (963 mg, 4.23 mmol) were suspended in dioxane (10 ml_) and heated at reflux for 120 hours. The reaction was cooled to room temperature, filtered, concentrated in vacuo and purified by silica gel chromatography (Gradient: 40% to 80% ethyl acetate in heptane), to afford trans-N-{4- hydroxytetrahydrofuran-3-yl)propane-2-sulfonamide as a solid. Yield: 3.76 g, 18.0 mmol, 81 %. 1H NMR (400 MHz, CDCI3) δ 1.38 (d, J=6.7 Hz, 3H), 1.40 (d, J=6.7 Hz, 3H) 2.91 (d, J=3.6 Hz, 1 H), 3.22 (septet, J=6.8 Hz, 1 H), 3.67- 3.71 (m, 2H), 3.82 (m, 1 H), 4.08-4.12 (m, 2H), 4.40 (m, 1 H), 4.77 (d, J=8.4 Hz, 1 H), 13C NMR (100 MHz, CDCI3) δ 16.44, 16.69, 54.18, 62.06, 71.47, 73.50, 77.64.
Step 2. Synthesis of frans-4-[(isopropylsulfonyl)amino]tetrahydrofuran- 3-yl methanesulfonate.
Triethylamine (1.99 ml_, 14.3 mmol) was added to a cooled (0 0C) solution of frans-/V-(4-hydroxytetrahydrofuran-3-yl)propane-2-sulfonamide (1.99 g, 9.52 mmol) in dichloromethane (20 ml_). Methanesulfonyl chloride (0.885 ml_, 11.4 mmol) was then added and the reaction was stirred at 0 0C for 50 minutes. Saturated aqueous sodium bicarbonate solution (10 ml_) was added, and the aqueous layer was extracted with methylene chloride. The combined organic layers were dried over sodium sulfate, filtered, concentrated in vacuo and purified by silica gel chromatography (Gradient: 10% to 50% ethyl acetate in heptane) to provide trans-4- [(isopropylsulfonyl)amino]tetrahydrofuran-3-yl methanesulfonate. Yield: 2.27 g, 7.90 mmol, 83%. 1H NMR (400 MHz, CDCI3) δ 1.40 (d, J=6.8 Hz, 3H), 1.41 (d, J=6.8 Hz, 3H), 3.14 (s, 3H), 3.25 (septet, J=6.8 Hz, 1 H), 3.77 (dd, J=9.5, 2.4 Hz, 1 H), 3.96 (dd, J=1 1.3, 2.2 Hz, 1 H), 4.08-4.16 (m, 2H), 4.21 (dd, J=1 1 .3, 5.1 Hz, 1 H), 4.77 (d, J=8.0 Hz, 1 H), 5.15 (m, 1 H). 13C NMR (100 MHz, CDCI3) δ 16.48, 16.54, 38.28, 54.28, 59.49, 71.83, 71.87, 83.97.
Step 3. Synthesis of frans-Λ/-[4-(4-bromophenoxy)tetrahydrofuran-3- yl]propane-2-sulfonamide. In a microwave vial, a solution of frans-4-[(isopropylsulfonyl)amino] tetrahydrofuran-3-yl methanesulfonate (546 mg, 1 .90 mmol) in acetonitrile (8 mL) was combined with 4-bromophenol (97%, 407 mg, 2.28 mmol) and cesium carbonate (929 mg, 2.85 mmol). The reaction was irradiated in a microwave reactor at 1600C for 2 hours, then cooled to room temperature and treated with saturated aqueous sodium bicarbonate solution (10 ml_). The reaction was extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (Gradient: 20% to 50% ethyl acetate in heptane), to afford trans-N-[4-(4- bromophenoxy)tetrahydrofuran-3-yl]propane-2-sulfonamide. Yield: 626 mg, 1.72 17117101, 91 %. LCMS m/z 361.9 (M-1 ). 1H NMR (400 MHz, CDCI3) δ 1.38 (d, J=6.9 Hz, 3H), 1.40 (d, J=6.8 Hz, 3H), 3.19 (septet, J=6.8 Hz, 1 H), 3.82 (br d, J=8.0, 1 H), 3.91 (dd, J=10.6, 1.7 Hz, 1 H), 4.02-4.08 (m, 2H), 4.24 (dd, J=10.5, 4.7 Hz, 1 H), 4.85 (br d, J=4.7 Hz, 1 H), 4.95 (br d, J=8.3 Hz, 1 H), 6.88 (d, J=9.0 Hz, 2H), 7.40 (d, J=9.0 Hz, 2H). 13C NMR (100 MHz, CDCI3) δ 16.45, 16.71 , 54.14, 58.70, 71 .45, 71 .81 , 82.07, 1 13.97, 1 17.20, 132.52, 155.75.
Step 4. Synthesis of Λ/-{1 -[4-frans-({4-[(isopropylsulfonyl)amino]- tetrahydrofuran-3-yl}oxy)phenyl]pyrrolidin-3-yl}acetamide.
To 2-methylbutan-2-ol (2.0 ml_) was added 2'-(dicyclohexylphosphino)- Λ/,Λ/-dimethylbiphenyl-2-amine (3.2 mg, 0.008 mmol) and ths(dibenzylideneacetone)dipalladium(0) (2.7 mg, 0.003 mmol). The purple reaction mixture was then degassed for 20 minutes and trans-N-[4-(4- bromophenoxy)tetrahydrofuran-3-yl]propane-2-sulfonamide (95 mg, 0.26 mmol) and /V-pyrrolidin-3-ylacetamide (67 mg, 0.52 mmol) were added. Next, potassium hydroxide (32 mg, 0.57 mmol) was added and the reaction was degassed for an additional 20 minutes. The brown reaction mixture was heated to reflux under nitrogen and turned yellow. The reaction was monitored by GC-MS and when the reaction was complete, saturated aqueous sodium bicarbonate solution (5 ml_) was added. The aqueous layer was extracted with ethyl acetate and the combined organics were dried over sodium sulfate, filtered, concentrated in vacuo, and purified by silica gel chromatography (Gradient: 50% to 70% ethyl acetate in heptane), to afford the diastereomeric mixture Λ/-{1 -[4-trans-({4-
[(isopropylsulfonyl)amino]tetrahydrofuran-3-yl}oxy)phenyl]pyrrolidin-3- yl}acetamide as a gum Yield: 97.5 mg, 0.236 mmol, 91 %. 1H NMR (400 MHz, CDCI3) δ 1.31 (d, J=6.8 Hz, 3H), 1.32 (d, J=6.8 Hz, 3H), 1.93 (s, 3H), 2.22 (m, 1 H), 2.64 (br s, 1 H), 3.07-3.13 (m, 2H), 3.19 (m, 1 H), 3.34-3.43 (m, 2H), 3.74 (dd, J=9.0, 1.8 Hz, 1 H), 3.85 (dd, J=10.3, 1.7 Hz, 1 H), 4.00-4.13 (m, 3H), 4.53 (m, 1 H), 4.69 (br s, 1 H), 5.67 (d, J=8.0 Hz, 1 H), 6.46 (d, J=8.8 Hz, 2H), 6.46 (1 H, pattern obscured by aromatic signal), 6.84 (d, J=9.0 Hz, 2H). 13C NMR (100 MHz, CDCI3) δ 16.37, 16.46, 22.98, 31 .44, 46.32, 49.31 , 53.61 , 53.88, 58.67, 71 .45, 71 .87, 82.80, 1 12.72, 1 17.00, 143.13, 147.98, 170.23.
Example 2 Λ/-r(3S,4S)-4-(biphenyl-4-yloxy)tetrahydrofuran-3-ylipropane-2-sulfonamide
Figure imgf000051_0001
Step 1. Synthesis of frans-4-(4-bromophenoxy)tetrahydrofuran-3-ol.
3,6-Dioxabicyclo[3.1.0]hexane (100 g, 1.16 mol), 4-bromophenol (241.1 g, 1.39 mol), cesium carbonate (492 g, 1.51 mol) and benzylthethylammonium chloride (52.9 g, 0.23 mol) were suspended in dioxane (1 L) and heated at reflux for 18 hours. The reaction was cooled to room temperature and diluted with ethyl acetate, then washed with saturated aqueous sodium carbonate solution. The aqueous layer was extracted with ethyl acetate, and the combined organic portions were dried over sodium sulfate, filtered and concentrated in vacuo, to provide crude product, which solidified on standing. This was used without purification in the next step. Yield: 354 g, >100%, assumed quantitative. Material from a smaller-scale experiment carried out in similar fashion was purified by silica gel chromatography for characterization (Gradient: 10% to 35% ethyl acetate in heptane), to afford frans-4-(4-bromophenoxy)tetrahydrofuran-3-ol as a solid. 1H NMR (400 MHz, CDCI3) δ 2.09 (br d, J=4.5 Hz, 1 H), 3.83 (m, 1 H), 3.91 (dd, J=10.3, 2.1 Hz, 1 H), 4.05 (dd, J=10.1 , 4.0 Hz, 1 H), 4.26 (dd, J=10.4, 4.9 Hz, 1 H), 4.41 (br s, 1 H), 4.67 (m, 1 H), 6.81 (d, J=9.0 Hz, 2H), 7.40 (d, J=9.1 Hz, 2H). Step 2. Synthesis of frans-4-(4-bromophenoxy)tetrahydrofuran-3-yl methanesulfonate.
Triethylamine (181.9 ml_, 1.31 mol) was added to a solution of trans-4- (4-bromophenoxy)tetrahydrofuran-3-ol from the previous step (354 g, assumed 300.6 g, 1.16 mol) in methylene chloride (2 L), and the reaction was cooled to 0 0C in an ice bath. Methanesulfonyl chloride (101.3 ml_, 1.31 mol) was then added drop-wise, while keeping the reaction temperature below 5 0C, and the reaction was stirred at room temperature for 18 hours. Water (1.5 L) was added, and the aqueous layer was extracted with methylene chloride. The organics were combined and dried over sodium sulfate, filtered and concentrated in vacuo to afford product as a brown oil. Yield: 399.6 g, 1.18 mol, quantitative. Material from a smaller-scale experiment carried out in similar fashion was triturated with ethanol for characterization. 1H NMR (400 MHz, CDCI3) δ 3.10 (s, 3H), 4.00 (br dd, J=10.4, 1.9 Hz, 1 H), 4.07 (m, 1 H), 4.16 (dd, J=11.1 , 3.9 Hz, 1 H), 4.23 (dd, J=10.5, 4.6 Hz, 1 H), 4.98 (br d, J=4.6 Hz, 1 H), 5.20 (m, 1 H), 6.85 (d, J=9.1 Hz, 2H), 7.42 (d, J=9.0 Hz, 2H).
Step 3. Synthesis of c/s-3-azido-4-(4-bromophenoxy)tetrahydrofuran. To a solution of frans-4-(4-bromophenoxy)tetrahydrofuran-3-yl methanesulfonate (133.2 g, 0.395 mol) in dimethylformamide (3 L) was added sodium azide (192.6 g, 2.96 mol) and the reaction was heated at 110 0C for 66 hours. The reaction was cooled to room temperature and water (12 L) was added. This reaction was carried out a total of three times on the same scale, and the combined batches were extracted with te/t-butyl methyl ether. The organic layers were then dried over sodium sulfate and concentrated in vacuo to afford product as a red-brown oil, contaminated with 18% dimethylformamide. Corrected yield: 286.7 g, 1.01 mol, 85%. 1H NMR (400 MHz, CDCI3) δ 3.93-3.97 (m, 2H), 4.00 (m, 1 H), 4.09 (dd, J=8.7, 5.8 Hz, 1 H), 4.17 (dd, J=10.0, 5.6 Hz, 1 H), 4.90 (ddd, J=5.4, 5.4, 4.4 Hz, 1 H), 6.83 (d, J=9.1 Hz, 2H), 7.41 (d, J=9.0 Hz, 2H).
Step 4. Synthesis of c/s-4-(4-bromophenoxy)tetrahydrofuran-3-amine.
A solution of c/s-3-azido-4-(4-bromophenoxy)tetrahydrofuran (286.7 g, 1 .01 mol) in tetrahydrofuran (1 .25 L) was cooled to 0 0C and treated with thphenylphosphine (278 g, 1 .06 mol). The reaction was allowed to warm to room temperature and stirred for 18 hours. Water (53 ml_) was added and the reaction was stirred at room temperature for 66 hours. Solvent was removed under reduced pressure and the residue was mixed with diethyl ether. The supernatant was decanted and concentrated in vacuo, providing a residue, which was filtered through a short plug of silica gel (Gradient: 0% to 5% methanol in methylene chloride) to afford c/s-4-(4- bromophenoxy)tetrahydrofuran-3-amine (155 g) and 366 grams of impure product. An acid /base extraction was carried out on the impure material, providing additional product (48.5 g). Total yield: 203.5 g, 0.788 mol, 68% over four steps. 1H NMR (300 MHz, CDCI3) δ 3.6 (m, 1 H), 3.7 (m, 1 H), 3.9 (m, 1 H), 4.0 (m, 1 H), 4.1 (m, 1 H), 4.6 (m, 1 H), 6.8 (m, 2H), 7.3 (m, 2H).
Step 5. Synthesis of (3S,4S)-4-(4-bromophenoxy)tetrahydrofuran-3- amine. A mixture of c/s-4-(4-bromophenoxy)tetrahydrofuran-3-amine (191 g,
0.74 mol) and (1 S)-(+)-10-camphorsulfonic acid (154.2 g, 0.66 mol) was dissolved in 2-propanol (2.4 L) and water (100 mL) at reflux. The clear solution was allowed to cool to room temperature over 18 hours, and the resulting crystals were isolated, washed and dried to afford the (+)- camphorsulfonic acid salt of (3S,4S)-4-(4-bromophenoxy)tetrahydrofuran-3- amine (139.2 g, 0.284 mol) with an e.e. (enantiomeric excess) of 85%. Recrystallization from 2-propanol (1 .2 L) and water (70 mL) afforded the (+)- camphorsulfonic acid salt of (3S,4S)-4-(4-bromophenoxy)tetrahydrofuran-3- amine, with an e.e. of 99%. Yield: 1 13.2 g, 0.23 mol, 31 %. 1H NMR (300 MHz, DMSO-CZ6) δ 0.74 (s, 3H), 1 .05 (s, 3H), 1 .23 (d, half of AB quartet J=10 Hz, 1 H), 1 .29 (d, half of AB quartet, J=10 Hz, 1 H), 1 .76-1 .94 (m, 2H), 2.19- 2.28 (m, estimated 2H), 2.35 (d, J=14.7 Hz, 1 H), 2.66-2.73 (m, estimated 1 H), 2.85 (d, J=14.7 Hz, 1 H), 3.78-3.84 (m, 2H), 3.96-4.10 (m, 3H), 5.04 (m, 1 H), 6.99 (d, J=8.8 Hz, 2H), 7.52 (d, J=9.0 Hz, 2H), 8.23 (br s, 3H). Additional (3S,4S)-4-(4-bromophenoxy)tetrahydrofuran-3-amine (+)-camphorsulfonic acid salt (13.6 g, 27.7 mmol) from another experiment was added and the combined batch (126.8 g, 0.258 mol) was washed with 2N aqueous sodium hydroxide solution and extracted three times with methylene chloride. The organic layers were combined and concentrated in vacuo, affording (3S,4S)- 4-(4-bromophenoxy)tetrahydrofuran-3-amine as a white solid with an e.e. of 99%. Yield: 65.6 g, 0.254 mmol, 98% for neutralization.
The combined mother liquors from above, enriched in (3R,4R)-4-(4- bromophenoxy)tetrahydrofuran-3-amine, were washed with 2N sodium hydroxide and extracted with methylene chloride. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give a residue (156.3 g, 0.606 mol of product and its enantiomer). This material was combined with (1 R)-(-)-10-camphorsulfonic acid (126.2 g, 0.54 mol) and dissolved in 2-propanol (1.65 L) and water (100 ml_) at reflux. The clear solution was allowed to cool to room temperature over 18 hours and the resulting crystals were isolated, washed and dried. This afforded the (-)- camphorsulfonic acid salt of (3R,4R)-4-(4-bromophenoxy)tetrahydrofuran-3- amine (152.6 g, 0.311 mol), with an e.e. of 90%. Recrystallization as above afforded the (-)-camphorsulfonic acid salt of (3R,4R)-4-(4- bromophenoxy)tetrahydrofuran-3-amine as a white solid, with an e.e. of 99%. Yield: 132.0 g, 0.27 mol, 36%. The mother liquor was concentrated in vacuo, washed with 2N sodium hydroxide and extracted with methylene chloride. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain a mixture of (3S,4S)-4-(4-bromophenoxy)tetrahydrofuran-3- amine and its enantiomer (67.7 g, 0.26 mol). Together with (1 S)-(+)-10- camphorsulfonic acid (54.6 g, 0.24 mol), this material was dissolved in 2- propanol (425 ml_) and water (17.5 ml_) at reflux. The clear solution was allowed to reach room temperature over 18 hours and the resulting crystals were isolated, washed and dried. This afforded additional (3S,4S)-4-(4- bromophenoxy)tetrahydrofuran-3-amine (+)-camphorsulfonic acid salt (48.0 g, 97.9 mmol), with an e.e. of 89-93% Recrystallization afforded (3S,4S)-4-(4- bromophenoxy)tetrahydrofuran-3-amine (+)-camphorsulfonic acid salt (40.0 g, 81.6 mmol, additional 11 %) with an e.e. of 99+%.
Step 6. Synthesis of Λ/-[(3S,4S)-4-(4-bromophenoxy)tetrahydrofuran-3- yl]propane-2-sulfonamide.
To a solution of (3S,4S)-4-(4-bromophenoxy)tetrahydrofuran-3-amine (65.6 g, 0.254 mol) in methylene chloride (500 ml_) was added 1 ,8- diazabicyclo[5.4.0]undec-7-ene (DBU, 53 ml_, 0.35 mol). The reaction mixture was cooled to 0 0C and propane-2-sulfonyl chloride (31.2 ml_, 0.28 mol) was added drop-wise. The mixture was then stirred at room temperature for 18 hours. The reaction was monitored by proton NMR: additional propane-2- sulfonyl chloride (2.8 ml_, 25 mmol) was added and the mixture was stirred at room temperature for an additional 18 hours. Again the reaction was monitored by NMR and additional propane-2-sulfonyl chloride (2.8 ml_, 25 mmol) was added. After 2.5 hours the reaction was complete according to NMR analysis. Water (500 ml_) was added and the layers were separated. The aqueous layer was extracted with methylene chloride, and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in methylene chloride and washed with aqueous hydrochloric acid (1 N, 2 x 300 ml_), dried over sodium sulfate, filtered and concentrated in vacuo to afford Λ/-[(3S,4S)-4-(4- bromophenoxy)tetrahydrofuran-3-yl]propane-2-sulfonamide as an orange/brown oil. Yield: 92.5 g, 0.254 mol, 100%. 1H NMR (300 MHz, CDCI3) δ 1.36 (d, J=7 Hz, 3H), 1.38 (d, J=7 Hz, 3H), 3.15 (septet, J=7 Hz, 1 H), 3.69 (dd, J=8.5, 8.5 Hz, 1 H), 3.93 (dd, J=10.6, 1.5 Hz, 1 H), 4.10-4.28 (m, 3H), 4.72-4.81 (m, 2H), 6.77 (d, J=9.1 Hz, 2H), 7.41 (d, J=9.1 Hz, 2H). The absolute configuration of this material was established via X-ray crystallographic analysis of a crystal of Λ/-[(3S,4S)-4-(4- bronnophenoxy)tetrahydrofuran-3-yl]propane-2-sulfonannide grown from a heptane / ethyl acetate solution. The results are described below.
A 0.90 A data set (maximum sin Θ/λ=0.56) was collected on a Bruker APEX diffractometer. The final R-index was 3.61 %.
Table 1. Crystal data and structure refinement
Empirical formula Ci3Hi8NO4SBr
Formula weight 364.25
Temperature 298(2) K
Wavelength 1.54178 A
Crystal system Monoclinic
Space group P2(1 )
Unit cell dimensions a = 5.9363(2) A α= 90°. b = 10.5879(3) A β= 103.2060(10)°. c = 12.8451 (3) A Y = 90°.
Volume 786.00(4) A3
Z 2
Density (calculated) 1.539 Mg/m3 Absorption coefficient 4.921 mm"1
F(OOO) 372
Crystal size 0.10 x 0.30 x 0.46 mm3
Theta range for data collection 3.53 to 58.95°.
Reflections collected 3091
Independent reflections 1793 [R(int) = 0.0354]
Completeness to theta = 58.95° 94.4 %
Absorption correction Empirical Absorption Correction
Refinement method Full-matrix least-squares on F2
Data / restraints / parameters 1793 / 1 / 182
Goodness-of-fit on F2 1.059 Final R indices [l>2sigma(l)] R1 = 0.0361 , wR2 = 0.0989
R indices (all data) R1 = 0.0363, wR2 = 0.0991 Absolute structure parameter 0.07(3) Extinction coefficient 0.0186(12)
Largest diff. peak and hole Q.334 and -0.419 e.A"3
Table 2. Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (A2x 103). U(eq) is defined as one third of the trace of the orthogonal ized U1J tensor.
X y Z U(eq)
0(1) 16729(5) -2517(4) 8631(3) 64(1)
C(2) 15699(8) -1365(5) 8185(4) 53(1)
C(3) 13507(7) -1173(4) 8572(3) 40(1)
C(4) 13927(7) -2000(5) 9573(4) 44(1)
C(5) 15252(8) -3101(5) 9223(4) 51(1)
0(6) 11551(5) -1714(3) 7853(2) 43(1)
C(7) 10585(7) -1088(4) 6917(3) 39(1)
C(8) 8713(8) -1672(5) 6277(3) 44(1)
C(9) 7541(9) -1109(5) 5335(4) 53(1)
C(10) 8294(10) 50(5) 5049(4) 53(1)
C(11) 10210(9) 625(5) 5669(4) 59(1)
C(12) 11377(9) 69(5) 6625(4) 52(1)
N(13) 11853(6) -2321(4) 9909(3) 49(1)
S(14) 11933(2) -2739(1) 11126(1) 44(1)
0(15) 14164(7) -3235(4) 11567(3) 68(1)
0(16) 9939(7) -3478(4) 11111 (3) 71(1)
C(17) 11817(10) -1310(5) 11862(4) 60(1)
C(18) 11798(15) -1658(9) 13017(5) 91(2)
C(19) 9823(14) -497(8) 11370(6) 94(2)
Br(20) 6647(1) 861(1) 3780(1) 84(1) Table 3. Bond lengths [Ai and angles [°1.
O(1)-C(2) 1.425(7) N(13)-C(4)-C(3) 113.7(4)
O(1)-C(5) 1.426(6) N(13)-C(4)-C(5) 116.2(4)
C(2)-C(3) 1.509(6) C(3)-C(4)-C(5) 100.7(4)
C(3)-O(6) 1.428(5) O(1)-C(5)-C(4) 104.2(4)
C(3)-C(4) 1.528(6) C(7)-O(6)-C(3) 119.1(3)
C(4)-N(13) 1.436(6) C(8)-C(7)-O(6) 115.1(4)
C(4)-C(5) 1.530(7) C(8)-C(7)-C(12) 120.8(4)
O(6)-C(7) 1.378(5) O(6)-C(7)-C(12) 124.0(4)
C(7)-C(8) 1.370(6) C(7)-C(8)-C(9) 120.4(5)
C(7)-C(12) 1.394(7) C(10)-C(9)-C(8) 119.0(5)
C(8)-C(9) 1.386(6) C(11)-C(10)-C(9) 121.0(5)
C(9)-C(10) 1.383(8) C(11)-C(10)-Br(20) 119.4(4)
C(10)-C(H) 1.373(7) C(9)-C(10)-Br(20) 119.6(4)
C(10)-Br(20) 1.904(5) C(10)-C(11)-C(12) 120.1(5)
C(11)-C(12) 1.396(7) C(11)-C(12)-C(7) 118.5(5)
N(13)-S(14) 1.615(3) C(4)-N(13)-S(14) 121.2(3)
S(14)-O(16) 1.415(4) O(16)-S(14)-O(15) 120.2(3)
S(14)-O(15) 1.417(4) O(16)-S(14)-N(13) 107.4(2)
S(14)-C(17) 1.794(6) O(15)-S(14)-N(13) 107.8(2)
C(17)-C(19) 1.483(9) O(16)-S(14)-C(17) 110.0(3)
C(17)-C(18) 1.532(8) O(15)-S(14)-C(17) 104.3(3)
C(2)-O(1)-C(5) 109.0(3) N(13)-S(14)-C(17) 106.4(2)
O(1)-C(2)-C(3) 107.8(4) C(19)-C(17)-C(18) 111.7(6)
O(6)-C(3)-C(2) 111.6(4) C(19)-C(17)-S(14) 112.8(4)
O(6)-C(3)-C(4) 105.5(3) C(18)-C(17)-S(14) 108.5(5)
C(2)-C(3)-C(4) 102.3(4)
Symmetry transformations used to generate equivalent atoms Table 4. Anisotropic displacement parameters (A2X 103). The anisotropic displacement factor exponent takes the form: -2ττ2 [ h2 a*2Un + ... + 2 h k a* b*U12]
Figure imgf000059_0001
0(1) 46(2) 70(2) 84(3) 20(2) 30(2) 10(2)
C(2) 46(3) 54(3) 59(3) 4(3) 15(2) -8(2)
C(3) 37(2) 44(2) 37(2) -1(2) 4(2) -3(2)
C(4) 33(2) 59(3) 37(2) 6(2) 2(2) -9(2)
C(5) 40(2) 51(3) 62(3) 13(3) 13(2) 3(2)
0(6) 43(2) 43(2) 37(2) 4(1) 1(1) -10(1)
C(7) 39(2) 44(2) 35(2) 1(2) 8(2) 0(2)
C(8) 45(2) 44(2) 42(2) -1(2) 8(2) -7(2)
C(9) 48(2) 66(3) 38(2) 3(2) -3(2) -4(2)
C(10) 67(3) 57(3) 34(2) 8(2) 7(2) 2(3)
C(11) 72(3) 56(4) 46(2) 7(3) 9(3) -8(3)
C(12) 58(3) 54(3) 44(2) 1(2) 9(2) -6(2)
N(13) 37(2) 81(3) 27(2) 8(2) 5(2) -7(2)
S(14) 48(1) 46(1) 38(1) 9(1) 8(1) 0(1)
0(15) 57(2) 88(3) 53(2) 19(2) -1(2) 23(2)
0(16) 69(2) 92(3) 52(2) 10(2) 15(2) -34(2)
C(17) 72(3) 68(4) 40(2) -2(3) 12(3) -2(3)
C(18) 116(5) 108(6) 48(3) -7(4) 17(3) -9(5)
C(19) 106(6) 93(5) 76(4) -10(4) 7(4) 36(4)
Br(20) 100(1) 84(1) 56(1) 25(1) -10(1) 3(1)
Table 5. Hydrogen coordinates (x 104) and isotropic displacf parameters (A: -χ103). X y Z U(eq)
H(2A) 15347 -1408 7411 80
H(2B) 16753 -666 8412 80
H(3A) 13257 -285 8730 80
H(4A) 14969 -1550 10157 80
H(5A) 16148 -3550 9838 80
H(5B) 14199 -3690 8779 80
H(8A) 8225 -2452 6477 80
H(9A) 6268 -1504 4900 80
H(11A) 10730 1387 5450 80
H(12A) 12656 462 7058 80
H(13A) 10543 -2290 9454 80
H(17A) 13237 -832 11873 80
H(18A) 11746 -902 13423 80
H(18B) 13173 -2126 13328 80
H(18C) 10462 -2166 13025 80
H(19A) 9846 254 11792 80
H(19B) 8408 -949 11342 80
H(19C) 9924 -270 10659 80
Step 7. Synthesis of Λ/-[(3S,4S)-4-(biphenyl-4-yloxy)tetrahydrofuran-3- yl]propane-2-sulfonamide.
To a microwave vial was added Λ/-[(3S,4S)-4-(4- bromophenoxy)tetrahydrofuran-3-yl]propane-2-sulfonannide (124 mg, 0.340 mmol), phenylboronic acid (63.5 mg, 0.521 mmol), dicyclohexyl(2',4',6'- triisopropylbiphenyl-2-yl)phosphine (XPhos, 16.2 mg, 0.034 mmol), palladium(ll) acetate (5.2 mg, 0.023 mmol) and potassium fluoride (99.6 mg, 1.71 mmol). The vial was capped, and purged three times with nitrogen/vacuum. A 1 :1 mixture of degassed methanol/toluene (1.5 mL) was added and the reaction was subjected to microwave irradiation at 1300C for 30 minutes. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate and saturated aqueous sodium chloride solution. The aqueous layer was extracted twice with ethyl acetate, and the organic layers were combined, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (Gradient: 10% to 25% ethyl acetate in heptane), to afford the title compound as a solid. Yield: 90 mg, 0.25 mmol, 73%. 1H NMR (400 MHz, CDCI3) δ 1.37 (d, J=6.8 Hz, 3H), 1.40 (d, J=6.8 Hz, 3H), 3.17 (septet, J=6.8 Hz, 1 H), 3.76 (dd, J=8.6, 8.6 Hz, 1 H), 4.01 (dd, J=10.6, 1.6 Hz, 1 H), 4.16-4.30 (m, 3H), 4.84 (m, 1 H), 5.09 (d, J=9.4 Hz, 1 H), 6.97 (d, J=8.7 Hz, 2H), 7.34 (t, J=7.4 Hz, 1 H), 7.44 (dd, J=7.6, 7.6 Hz, 2H), 7.55 (m, 4H). 13C NMR (100 MHz, CDCI3) δ 16.48, 16.55, 54.27, 55.35, 70.29, 71.96, 75.87, 115.85, 126.65, 126.88, 128.34, 128.68, 135.1 1 , 140.25, 155.93.
Example 3
Λ/-l(3S.4S)-4-r(2'-cvanobiphenyl-4-yl)oxy1tetrahvdrofuran-3-yl)propane-2- sulfonamide
Figure imgf000061_0001
The title compound was prepared according to the general procedure for the synthesis of Example 2, except that (2-cyanophenyl)boronic acid was used in place of phenylboronic acid, affording product as a solid. Yield: 675.3 mg, 1 .75 mmol, 85%. LCMS m/z 387.0 (M+1 ). 1H NMR (500 MHz, CDCI3) δ 1 .36 (d, J=6.8 Hz, 3H), 1 .39 (d, J=6.8 Hz, 3H), 3.19 (septet, J=6.8 Hz, 1 H), 3.77 (dd, J=8.8, 8.8 Hz, 1 H), 3.98 (dd, J=10.6, 1 .6 Hz, 1 H), 4.16 (dd, J=7.9, 7.9 Hz, 1 H), 4.21 (dd, J=10.6, 4.3 Hz, 1 H) 4.30 (m, 1 H), 4.82 (m, 1 H), 5.53 (d, J=9.6 Hz, 1 H), 7.03 (d, J=8.8 Hz, 2H), 7.43 (ddd, J=U, 7.7, 1 .1 Hz, 1 H), 7.48 (br d, J=7.9 Hz, 1 H), 7.51 (d, J=8.8 Hz, 2H), 7.63 (ddd, J=U, 7.7, 1 .4 Hz, 1 H), 7.75 (br dd, J=7.8, 1 .1 Hz, 1 H). 13C NMR (125 MHz, CDCI3) 5 16.19, 16.24, 53.89, 55.03, 69.86, 71 .62, 75.48, 110.47, 1 15.39, 1 18.53, 127.00, 129.53, 129.86, 131 .26, 132.58, 133.35, 144.32, 156.76.
Example 4 /V-{(3SΛS)-4-[4-(5-cvano-2-thienyl)phenoxy1tetrahydrofuran-3-yl)propane-2- sulfonamide
Figure imgf000062_0001
The title compound was prepared according to the general procedure for the synthesis of Example 2, except that (5-cyano-2-thienyl)boronic acid was used in place of phenylboronic acid, affording product as a solid. Yield: 365 mg, 0.93 mmol, 58%. LCMS m/z 393.5 (M+1 ). 1H NMR (500 MHz, CDCI3) δ 1.39 (d, J=6.8 Hz, 3H), 1.41 (d, J=6.8 Hz, 3H), 3.21 (septet, J=6.8 Hz, 1 H), 3.77 (dd, J=8.8, 8.8 Hz, 1 H), 3.99 (dd, J=10.7, 1.6 Hz, 1 H), 4.18 (dd, J=I Λ, 7.8 Hz, 1 H), 4.23 (dd, J=10.7, 4.3 Hz, 1 H), 4.30 (m, 1 H), 4.88 (m, 1 H), 5.31 (d, J=9.8 Hz, 1 H), 6.97 (d, J=8.9 Hz, 2H), 7.19 (d, J=3.9 Hz, 1 H), 7.53 (d, J=8.8 Hz, 2H), 7.58 (d, J=3.9 Hz, 1 H). 13C NMR (125 MHz, CDCI3) δ 16.35, 54.07, 55.26, 69.84, 71 .73, 75.84, 107.00, 1 14.23, 1 16.02, 122.36, 125.87, 127.67, 138.35, 151 .01 , 157.40.
Example 5 Λ/-{(1 S,2f?)-2-r(2'-cvanobiphenyl-4-yl)oxy1cvclopentyl)propane-2-sulfonamide
Figure imgf000062_0002
Step 1. Synthesis of frans-2-(4-bromophenoxy)cyclopentanol. 6-Oxabicyclo[3.1.0]hexane (2.04 ml_, 23.5 mmol), 4-bromophenol (4.49 g, 26.0 mmol), cesium carbonate (99%, 8.93 g, 27.1 mmol) and benzylthethylammonium chloride (99%, 1.09 g, 4.74 mmol) were suspended in dioxane (65 mL) and heated at reflux for 18 hours. Additional 6- oxabicyclo[3.1 .0]hexane (0.50 mL, 5.8 mmol) was added, and heating was continued for 66 hours. Again, 6-oxabicyclo[3.1 .0]hexane (0.50 mL, 5.8 mmol) was added, and the reaction mixture was heated at reflux for an additional 18 hours. The reaction was then cooled to room temperature, concentrated in vacuo and partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over calcium sulfate, filtered and concentrated under reduced pressure to afford a golden oil, which was purified via chromatography on silica gel (Gradient: 0% to 20% ethyl acetate in heptane) to provide product as an oil. Yield: 3.21 g, 12.5 mmol, 48%. GCMS m/z 256, 258 (M+). 1H NMR (400 MHz, CDCI3) δ 1 .64 (d, J=3.7 Hz, 1 H), 1 .60-1 .68 (m, 1 H), 1 .70-1 .88 (m, 3H), 2.07 (m, 1 H), 2.17 (m, 1 H), 4.30 (m, 1 H), 4.48 (m, 1 H), 6.80 (d, J=9.0 Hz, 2H), 7.37 (d, J=9.0 Hz, 2H). Step 2. Synthesis of frans-2-(4-bromophenoxy)cyclopentyl methanesulfonate.
The title compound of Step 2 was prepared according to the general procedure for the synthesis of frans-4-(4-bromophenoxy)tetrahydrofuran-3-yl methanesulfonate in Example 2, except that trans-2-(4- bromophenoxy)cyclopentanol was used in place of trans-4-(4- bromophenoxy)tetrahydrofuran-3-ol, and the reaction mixture was quenched by addition of saturated aqueous ammonium chloride solution. The organic layer was then washed with saturated aqueous ammonium chloride solution, washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo to provide product as a brown oil. Yield: 3.86 g, 1 1 .5 mmol, 98%. 1H NMR (400 MHz, CDCI3) δ 1 .79-2.00 (m, 4H), 2.14-2.26 (m, 2H), 3.03 (s, 3H), 4.78 (m, 1 H), 5.07 (m, 1 H), 6.82 (d, J=9.0 Hz, 2H), 7.39 (d, J=QA Hz, 2H).
Step 3. Synthesis of c/s-2-azidocyclopentyl 4-bromophenyl ether. To a solution of frans-2-(4-bromophenoxy)cyclopentyl methanesulfonate (3.52 g, 10.5 mmol) in dimethylformamide (22 mL) was added sodium azide (897 mg, 13.7 mmol) and the reaction was heated at 1000C for 18 hours. The reaction was cooled to room temperature and partitioned between ethyl acetate and 1 N aqueous lithium chloride solution. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over calcium sulfate, filtered and concentrated in vacuo to provide product as a brown oil, which was used in the next step without additional purification. Yield: 2.59 g, 9.18 mmol, 87%. 1H NMR (400 MHz, CDCI3) δ 1.65-1.73 (m, 1 H), 1.89-2.05 (m, 5H), 3.74 (m, 1 H), 4.66 (m, 1 H), 6.83 (d, J=9.0 Hz, 2H), 7.39 (d, J=9.0 Hz, 2H).
Step 4. Synthesis of c/s-2-(4-bromophenoxy)cyclopentanamine. A solution of c/s-2-azidocyclopentyl 4-bromophenyl ether from the previous step (2.59 g, 9.18 mmol) in tetrahydrofuran (63 ml_) and water (5.0 ml_) was treated with polymer-supported thphenylphosphine (3 mmol/g, 7.15 g, 21.5 mmol). The reaction was stirred for 18 hours, then filtered through Celite®. The filter pad was rinsed with tetrahydrofuran, then with a mixture of methylene chloride and methanol, and the combined filtrates were concentrated in vacuo, and azeotroped with ethanol. The residue was purified by chromatography on silica gel (Gradient: 0% to 10% methanol in ethyl acetate) to afford product as a light brown oil. Yield: 1.43 g, 5.58 mmol, 61 %. MS (APCI) m/z 257.9 (M+1 ). 1H NMR (400 MHz, CDCI3) δ 1.47 (br s, 2H), 1.56-1.68 (m, 2H), 1.78-1.88 (m, 2H), 1.91 -1.99 (m, 2H), 3.35 (ddd, J=8.6, 7.0, 4.7 Hz, 1 H), 4.42 (m, 1 H), 6.80 (d, J=9.0 Hz, 2H), 7.37 (d, J=9.0 Hz, 2H). Step 5. Synthesis of c/s-Λ/-[2-(4-bromophenoxy)cyclopentyl]propane-2- sulfonamide.
To a slurry of c/s-2-(4-bromophenoxy)cyclopentanamine (1.43 g, 5.58 mmol) in methylene chloride (38.5 ml_) was added 1 ,8- diazabicyclo[5.4.0]undec-7-ene (1.40 ml_, 9.36 mmol), then 4- (dimethylamino)pyridine (915 mg, 7.49 mmol). The reaction mixture was cooled to 0 0C and propane-2-sulfonyl chloride (0.937 ml_, 8.38 mmol) was added drop-wise. The mixture was then allowed to warm to room temperature and stir for 18 hours. The reaction was treated with 1 N aqueous hydrochloric acid, and the organic layer was washed with saturated aqueous sodium chloride solution, dried over calcium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (Gradient: 0% to 15% ethyl acetate in heptane) to provide product as a colorless gum. Yield: 1.586 g, 4.38 mmol, 78%.
Step 6. Isolation of Λ/-[(1 S,2R)-2-(4-bromophenoxy)cyclopentyl]- propane-2-sulfonamide. Separation of the enantiomers comprising c/s-Λ/-[2-(4- bromophenoxy)cyclopentyl]propane-2-sulfonamide (1.586 g, 4.38 mmol) was carried out by chiral chromatography. Column: Chiralpak® AD-H, 2.1 x 25 cm, 5 μm; Mobile phase: 75:25 carbon dioxide: methanol; Flow rate: 65 g/min. The first-eluting compound was enantiomer Λ/-[(1 R,2S)-2-(4- bromophenoxy)cyclopentyl]propane-2-sulfonamide (767 mg, 2.12 mmol, 48%) and the second-eluting peak provided desired product Λ/-[(1 S,2R)-2-(4- bromophenoxy)cyclopentyl]propane-2-sulfonamide upon removal of solvent in vacuo. Yield: 758 mg, 2.09 mmol, 48%. The absolute stereochemistry of these enantiomers was assigned by analogy to their higher homologues (see Example 7). The title compound, synthesized in the following step, proved significantly more potent than its enantiomer (prepared in the same way from Λ/-[(1 R,2S)-2-(4-bromophenoxy)cyclopentyl]propane-2-sulfonamide. On this basis, the (1 S,2R) configuration was assigned to Λ/-[(1 S,2R)-2-(4- bromophenoxy)cyclopentyl]propane-2-sulfonamide. MS (APCI) m/z 364.2 (M+1 ). 1 H NMR (500 MHz, CDCI3) δ 1.35 (d, J=6.8 Hz, 3H), 1.38 (d, J=6.8 Hz, 3H), 1.64 (m, 1 H), 1.79-1.98 (m, 4H), 2.12 (m, 1 H), 3.13 (septet, J=6.8 Hz, 1 H), 3.86 (m, 1 H), 4.59 (m, 1 H), 4.63 (d, J=9.5 Hz, 1 H), 6.78 (d, J=9.0 Hz, 2H), 7.39 (d, J=QA Hz, 2H). Data for Λ/-[(1 R2S)-2-(4- bromophenoxy)cyclopentyl]propane-2-sulfonamide: MS (APCI) m/z 362.2, 364.2 (M+1 ). 1H NMR (500 MHz, CDCI3) δ 1.35 (d, J=6.8 Hz, 3H), 1.38 (d, J=6.8 Hz, 3H), 1.58-1.68 (m, 1 H), 1.78-1.97 (m, 4H), 2.12 (m, 1 H), 3.13 (septet, J=6.8 Hz, 1 H), 3.86 (m, 1 H), 4.59 (m, 1 H), 4.64 (d, J=9.5 Hz, 1 H), 6.78 (d, J=QA Hz, 2H), 7.39 (d, J=9.0 Hz, 2H).
Step 7. Synthesis of compound Λ/-{(1 S,2R)-2-[(2'-cyanobiphenyl-4- yl)oxy]cyclopentyl}propane-2-sulfonamide. The title compound of Step 7 was prepared according to the general procedure for the synthesis of Example 2, except that Λ/-[(1 S,2R)-2-(4- bromophenoxy)cyclopentyl]propane-2-sulfonamide was used instead of N- [(3S,4S)-4-(4-bromophenoxy)tetrahydrofuran-3-yl]propane-2-sulfonamide, and (2-cyanophenyl)boronic acid was added in place of phenylboronic acid. After the reaction mixture was concentrated in vacuo, it was directly purified by silica gel chromatography in this case (Eluant: 25% ethyl acetate in heptane), to afford the product as a sticky white foam. Trituration with hexanes gave product as a white powder. Yield: 53 mg, 0.14 mmol, 82%. MS (APCI) m/z 382.9 (M-1 ). 1H NMR (400 MHz, CDCI3) δ 1 .36 (d, J=6.7 Hz, 3H), 1 .40 (d, J=6.8 Hz, 3H), 1 .66 (m, 1 H), 1 .82-2.03 (m, 4H), 2.15 (m, 1 H), 3.15 (septet, J=6.8 Hz, 1 H), 3.90 (m, 1 H), 4.70 (m, 2H), 7.01 (d, J=8.8 Hz, 2H), 7.42 (ddd, J=7.6, 7.6, 1 .2 Hz, 1 H), 7.50 (m, 1 H), 7.52 (d, J=8.8 Hz, 2H), 7.64 (ddd, J=U, 7.7, 1 .4 Hz, 1 H), 7.76 (m, 1 H).
Example 6 Λ/-{(1 S,2f?)-2-[4-(5-cvano-2-thienyl)phenoxy1cvclopentyl)propane-2- sulfonamide
Figure imgf000066_0001
To a microwave vial was added Λ/-[(1 S,2R)-2-(4- bromophenoxy)cyclopentyl]propane-2-sulfonamide (150.0 mg, 0.414 mmol), (5-cyano-2-thienyl)boronic acid (95.0 mg, 0.621 mmol), dicyclohexyl(2',4',6'- thisopropylbiphenyl-2-yl)phosphine (20.2 mg, 0.0410 mmol), palladium(ll) acetate (7.4 mg, 0.033 mmol) and potassium fluoride (120 mg, 2.07 mmol). Dimethoxyethane (1 .5 ml_) was added and the reaction mixture was purged three times with nitrogen/vacuum. The reaction was subjected to microwave irradiation at 120 0C for 2 hours, then solvent was removed in vacuo and the residue was partitioned between ethyl acetate and saturated aqueous sodium chloride solution. The aqueous layer was extracted with ethyl acetate, and the organic layers were combined, dried over calcium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative thin layer chromatography on silica gel (Eluant: 40% ethyl acetate in heptane), to afford the title compound as a yellow oil which subsequently solidified. Yield: 104 mg, 0.266 mmol, 64%. LCMS m/z 391.0 (M+1 ). 1H NMR (500 MHz, CDCI3) δ 1.36 (d, J=6.8 Hz, 3H), 1.39 (d, J=6.8 Hz, 3H), 1.66 (m, 1 H), 1.81 -1.94 (m, 3H), 1.99 (m, 1 H), 2.14 (m, 1 H), 3.15 (septet, J=6.8 Hz, 1 H), 3.89 (m, 1 H), 4.64 (d, J=9.5 Hz, 1 H), 4.69 (m, 1 H), 6.95 (d, J=8.7 Hz, 2H), 7.18 (d, J=4.0 Hz, 1 H), 7.54 (d, J=8.7 Hz, 2H), 7.57 (d, J=3.9 Hz, 1 H).
Example 7 Λ/-{(1 S,2f?)-2-[(2'-cvanobiphenyl-4-yl)oxy1cvclohexyl)propane-2-sulfonamide
Figure imgf000067_0001
Step 1. Synthesis of frans-2-(4-bromophenoxy)cyclohexanol. Sodium metal (2.58 g, 112 mmol) was combined with absolute ethanol (200 ml_) and allowed to react completely. 4-Bromophenol (19.4 g, 112 mmol) was added, and the reaction was stirred for 20 minutes, at which point 7-oxabicyclo[4.1.0]heptane (10.0 g, 102 mmol) was added, and the solution was heated at reflux for 15 hours. After removal of solvent in vacuo, the residue was partitioned between water (300 ml_) and ethyl acetate (100 ml_). The aqueous layer was extracted with ethyl acetate (2 x 100 ml_), and the combined organic layers were washed with water (2 x 200 ml_), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting light tan solid was recrystallized from heptane (roughly 200 ml_) to provide frans-2-(4-bromophenoxy)cyclohexanol as a fluffy white solid. Yield: 12.5 g, 46.1 mmol, 45%. 1H NMR (400 MHz, CDCI3) δ 1.26-1.46 (m, 4H), 1.75-1.79 (m, 2H), 2.08-2.14 (m, 2H), 2.52 (d, J=2.1 Hz, 1 H), 3.72 (m, 1 H), 3.96 (ddd, J=10.3, 8.6, 4.4 Hz, 1 H), 6.84 (d, J=9.0 Hz, 2H), 7.37 (d, J=9.0 Hz, 2H). Step 2. Synthesis of (1R,2R)-2-(4-bromophenoxy)cyclohexyl acetate. frans-2-(4-Bromophenoxy)cyclohexanol (5.305 g, 19.56 mmol) was dissolved in ethyl acetate (196 ml_) and treated with vinyl acetate (3.37 g, 39.1 mmol), followed by lipase enzyme from Candida antarctica (Novozyme 435, Sigma L4777, lipase immobilized on acrylic resin, 5.3 g). The reaction was capped and stirred for 18 hours, then filtered through Celite® and rinsed with ethyl acetate (500 ml_). Concentration of the filtrate in vacuo provided a pale yellow oil, which was purified via silica gel chromatography (Gradient: 0% to 10% ethyl acetate in heptane) to afford (1 R,2R)-2-(4- bromophenoxy)cyclohexyl acetate, the less polar product, as a colorless oil. Yield: 2.047 g, 6.54 mmol, 33%. Data for (1R,2R)-2-(4- bromophenoxy)cyclohexyl acetate: 1H NMR (400 MHz, CDCI3) δ 1.32-1.59 (m, 4H), 1.71-1.80 (m, 2H), 1.95 (s, 3H), 2.02-2.14 (m, 2H), 4.17 (ddd, J=9.6, 8.1 , 4.4 Hz, 1 H), 4.96 (m, 1 H), 6.84 (d, J=9.0 Hz, 2H), 7.36 (d, J=9.1 Hz, 2H). Enantiomeric alcohol (1 S,2S)-2-(4-bromophenoxy)cyclohexanol, the more polar product, was obtained as a white solid (3.57 g). Data for (1 S,2S)-2-(4- bromophenoxy)cyclohexanol: 1H NMR (400 MHz, CDCI3) δ 1.26-1.46 (m, 4H), 1.74-1.79 (m, 2H), 2.08-2.15 (m, 2H), 2.50 (br s, 1 H), 3.72 (ddd, J=10.6, 8.5, 4.6 Hz, 1 H), 3.96 (m, 1 H), 6.84 (d, J=9.0 Hz, 2H), 7.38 (d, J=9.0 Hz, 2H). The absolute configurations of these compounds were assigned on the basis of an X-ray crystal structure of the enantiomer of Λ/-[(1 S,2R)-2-(4- bromophenoxy)cyclohexyl]propane-2-sulfonamide (see step 7 below). Step 3. Synthesis of (1R,2R)-2-(4-bromophenoxy)cyclohexanol. A solution of (1 R,2R)-2-(4-bromophenoxy)cyclohexyl acetate (2.047 g, 6.54 mmol) in methanol (12.2 ml_) and water (0.32 ml_) was cooled to 00C and treated with lithium hydroxide hydrate (95%, 1.73 g, 39.2 mmol). The reaction was stirred at 00C for 15 minutes, then allowed to warm and stir at room temperature for 18 hours. The methanol was removed under reduced pressure, and the aqueous residue was partitioned between ethyl acetate (200 ml_) and water (100 ml_). After extraction of the aqueous layer with ethyl acetate (100 ml_), the combined organics were washed with saturated aqueous sodium chloride solution (100 ml_), dried over magnesium sulfate, filtered and concentrated in vacuo to provide (1 R,2R)-2-(4- bromophenoxy)cyclohexanol as a yellow oil. Yield: 1.76 g, 6.49 mmol, 99%. 1H NMR (400 MHz, CDCI3) δ 1.26-1.46 (m, 4H), 1.74-1.79 (m, 2H), 2.08-2.14 (m, 2H), 3.72 (ddd, J=10.5, 8.4, 4.7 Hz, 1 H), 3.96 (m, 1 H), 6.84 (d, J=9.0 Hz, 2H), 7.37 (d, J=9.0 Hz, 2H).
Step 4. Synthesis of (1 R,2R)-2-(4-bromophenoxy)cyclohexyl methanesulfonate.
The title compound of Step 4 was prepared according to the general procedure for the synthesis of frans-2-(4-bromophenoxy)cyclopentyl methanesulfonate in Example 5, except that (1 R,2R)-2-(4- bromophenoxy)cyclohexanol was used instead of trans-2-(4- bromophenoxy)cyclopentanol. (1 R,2R)-2-(4-bromophenoxy)cyclohexyl methanesulfonate was obtained as a light golden oil. Yield: 3.60 g, 10.3 mmol, quantitative. 1H NMR (400 MHz, CDCI3) δ 1.26-1.51 (m, 3H), 1.64-1.84 (m, 3H), 2.19 (m, 1 H), 2.30 (m, 1 H), 2.97 (s, 3H), 4.22 (ddd, J=10.2, 8.5, 4.6 Hz, 1 H), 4.64 (ddd, J=10.6, 8.4, 4.9 Hz, 1 H), 6.82 (d, J=9.1 Hz, 2H), 7.39 (d, J=9.1 Hz, 2H).
Step 5. Synthesis of (1R,2S)-2-azidocyclohexyl 4-bromophenyl ether. To a solution of (1 R,2R)-2-(4-bromophenoxy)cyclohexyl methanesulfonate (3.55 g, 10.2 mmol) in dimethylformamide (21.8 ml_) and water (2.43 ml_) was added sodium azide (95%, 2.09 mg, 30.5 mmol) and the reaction was heated at 120 0C for 23 hours. The reaction was cooled to room temperature, diluted with water (400 ml_) and extracted with ethyl acetate (4 x 400 ml_). The combined organic layers were washed with aqueous lithium chloride solution (1 N, 400 ml_), washed with water (400 ml_), and dried over magnesium sulfate. Filtration and removal of solvents in vacuo afforded (1R,2S)-2-azidocyclohexyl 4-bromophenyl ether as an orange oil, which was used in the next step without additional purification. Yield: 2.85 g, 9.62 mmol, 94%. 1H NMR (400 MHz, CDCI3) δ 1.36-1.48 (m, 2H), 1.62-1.76 (m, 4H), 1.96-2.07 (m, 2H), 3.63 (m, 1 H), 4.43 (m, 1 H), 6.85 (d, J=9.0 Hz, 2H), 7.39 (d, J=8.9 Hz, 2H).
Step 6. Synthesis of (1 S,2R)-2-(4-bromophenoxy)cyclohexanamine. A solution of (1 R,2S)-2-azidocyclohexyl 4-bromophenyl ether from the previous step (2.85 g, 9.62 mmol) in tetrahydrofuran (59 ml_) and water (4.6 ml_) was treated with polymer-supported thphenylphosphine (3 mmol/g, 7.87 g, 23.6 mmol). The reaction was stirred for 18 hours, then filtered through Celite®. The filter pad was rinsed with tetrahydrofuran (250 ml_), then with ethyl acetate (400 ml_), and the combined filtrates were concentrated in vacuo, and azeotroped with ethanol. The residue was purified by chromatography on silica gel (Gradient: 0% to 10% methanol in dichloromethane) to afford (1 S,2R)-2-(4-bromophenoxy)cyclohexanamine as a yellow oil. Yield: 1.82 g, 6.74 mmol, 70%. 1H NMR (400 MHz, CDCI3) δ 1.33-1.55 (m, 4H), 1.66-1.75 (m, 3H), 2.00 (m, 1 H), 2.07 (br s, 2H), 2.97 (m, 1 H), 4.39 (m, 1 H), 6.85 (d, J=9.0 Hz, 2H), 7.36 (d, J=9.0 Hz, 2H).
Step 7. Synthesis of Λ/-[(1 S,2R)-2-(4-bromophenoxy)cyclohexyl] propane-2-sulfonamide.
The title compound of Step 7 was prepared according to the general procedure for the synthesis of c/s-Λ/-[2-(4- bromophenoxy)cyclopentyl]propane-2-sulfonamide in Example 5, except that (1 S,2R)-2-(4-bromophenoxy) cyclohexanamine was used in place of c/s-2-(4- bromophenoxy)cyclopentan-amine, and the product purification was carried out using a gradient of 0% to 1 % methanol in dichloromethane. Λ/-[(1 S,2R)-2- (4-bromophenoxy)cyclohexyl] propane-2-sulfonamide was obtained as a white foam. Yield: 1.67 g, 4.44 mmol, 75%. 1H NMR (400 MHz, CDCI3) δ 1.36 (d, J=6.9 Hz, 3H), 1.37 (d, J=6.9 Hz, 3H), 1.37-1.48 (m, 4H), 1.77-1.88 (m, 3H), 2.06 (m, 1 H), 3.12 (septet, J=6.8 Hz, 1 H), 3.54 (m, 1 H), 4.48 (d, J=9.5 Hz, 1 H), 4.54 (m, 1 H), 6.84 (d, J=9.0 Hz, 2H), 7.39 (d, J=9.0 Hz, 2H). The enantiomer of Λ/-[(1 S,2R)-2-(4-bromophenoxy)cyclohexyl]propane-2- sulfonamide was prepared using similar chemistry to that described above in this Step 7, but employing (1 S,2S)-2-(4-bromophenoxy)cyclohexanol as starting material instead of (1 R,2R)-2-(4-bromophenoxy)cyclohexanol. The absolute stereochemistry of the enantiomer of Λ/-[(1 S,2R)-2-(4- bromophenoxy)cyclohexyl]propane-2-sulfonamide was established via X-ray crystallography.
Step 8. Synthesis of Λ/-{(1 S,2R)-2-[(2'-cyanobiphenyl-4- yl)oxy]cyclohexyl}propane-2-sulfonamide. The title compound was prepared according to the general procedure for the synthesis of Example 2, except that Λ/-[(1 S,2R)-2-(4- bromophenoxy)cyclohexyl]propane-2-sulfonamide was used in place of N- [(3S,4S)-4-(4-bromophenoxy)tetrahydrofuran-3-yl]propane-2-sulfonamide, and the microwave irradiation was carried out at 140 0C for 55 minutes. The crude reaction mixture was then filtered through Celite® and rinsed with methanol. Removal of solvent in vacuo provided a brown solid, which was dissolved in ethyl acetate (100 ml_) and washed with water (2 x 75 ml_). The aqueous layers were extracted with ethyl acetate (75 ml_), and the combined organic layers were washed with saturated aqueous sodium chloride solution (75 ml_), dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting colorless oil was purified by preparative thin layer chromatography on silica gel (Eluant: 1 % methanol in dichloromethane) to provide the title compound as a white foam. Yield: 72 mg, 0.18 mmol, 34%. LCMS m/z 399 (M+1 ). 1H NMR (400 MHz, CDCI3) δ 1.37 (d, J=7.2 Hz, 3H), 1.39 (d, J=7.0 Hz, 3H), 1.41 -1.55 (m, 4H), 1.79-1.94 (m, 3H), 2.16 (m, 1 H), 3.14 (septet, J=6.8 Hz, 1 H), 3.59 (m, 1 H), 4.52 (d, J=9.4 Hz, 1 H), 4.66 (m, 1 H), 7.06 (d, J=8.7 Hz, 2H), 7.42 (ddd, J=7.6, 7.6, 1.2 Hz, 1 H), 7.50 (m, 1 H), 7.52 (d, J=8.6 Hz, 2H), 7.64 (ddd, J=IJ, 7.7, 1.4 Hz, 1 H), 7.76 (m, 1 H). The biological activity of the title compound was >150 times improved over that of its enantiomer, which was prepared in the same way from the enantiomer of N- [(1 S,2R)-2-(4-bromophenoxy)cyclohexyl]propane-2-sulfonamide. Examples 8-54
Method A: Aryl coupling, exemplified by synthesis of frans-Λ/-{4-[(2'- ethoxybiphenyl-4-yl)oxy1tetrahvdrofuran-3-yl)propane-2-sulfonamide frans-/V-[4-(4-Bromophenoxy)tetrahydrofuran-3-yl]propane-2- sulfonamide (91 .1 mg, 0.250 mmol), (2-ethoxyphenyl)boronic acid (49.8 mg,
0.300 mmol), [1 ,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(ll)
(95%, 38.5 mg, 0.050 mmol), and sodium carbonate (63.6 mg, 0.600 mmol) were combined in dioxane (3.2 ml_) and water (0.8 ml_) and subjected to microwave irradiation for 20 minutes at 150 0C. The reaction was then filtered through Celite® and partitioned between water (10 ml_) and diethyl ether (10 ml_). The aqueous layer was extracted with additional diethyl ether (2 x 10 ml_), and the organic layers were combined, dried over sodium sulfate, filtered, concentrated in vacuo, and purified by silica gel chromatography
(Gradient: 15% to 35% ethyl acetate in heptane), to afford the title compound as a gum. Yield of pure fractions: 16.6 mg, 0.041 mmol, 16%. See Table 1 for characterization data.
Method B Coupling of bromoaromatic and boronic acid mediated by tetrakis(triphenylphosphine)palladium(0) A Suzuki coupling was carried via a method similar to that reported by
K. Kawaguchi et ai, Journal of Organic Chemistry 2007, 72, 51 19-5128 and corresponding supporting information.
Method C
Coupling of amine to bromoaromatic, mediated by ths(dibenzylideneacetone)dipalladium(0)
An amination reaction was carried out as described by X. Huang et ai, Journal of the American Chemical Society 2003, 125, 6653-6655. Method D Ester hydrolysis
Hydrolysis of the alkyl ester to the corresponding carboxylic acid was carried out under standard conditions, for instance with aqueous sodium hydroxide.
Method E Preparation of c/s-Λ/-{4-[(4-substituted)phenoxy1tetrahydrofuran-3- yllpropanesulfonamides
The boronic acid (0.1 mmol) was weighed into a vial and treated with a solution of c/s-Λ/-[4-(4-bromophenoxy)tetrahydrofuran-3-yl]propane-2- sulfonamide (18.2 mg, 0.05 mmol) in degassed ethanol (0.8 ml_). Next, a solution of sodium carbonate (26.5 mg, 0.25 mmol) in water (0.1 ml_) was added, and the reaction vial was purged twice with vacuum, then refilled with nitrogen. Tetrakis(thphenylphosphine)palladium(0) (2.9 mg, 0.0025 mmol) in degassed toluene (0.1 ml_) was then added and the reaction was heated to
800C for 16 hours. Next, the reaction was treated with an aqueous solution of sodium hydroxide (1 N, 1.5 ml_) and ethyl acetate (2.3 ml_) and the reaction vial was shaken and extracted three times with ethyl acetate. The combined organic layers were passed thru a solid phase extraction cartridge loaded with sodium sulfate, and the filtrate was concentrated in vacuo. The residue was dissolved in dimethyl sulfoxide (1 ml_) and purified by preparative HPLC
(Column: XBridge Ci8, 5 μm, 19 x 100 mm; Solvent A: 0.1 % ammonium hydroxide in water (v/v); Solvent B: 0.1 % ammonium hydroxide in acetonitrile
(v/v) using an appropriate gradient). Method F
Preparation of Λ/-r(1 S,2f?)-2-(Λ/',Λ/'-disubstituted-4- aminophenoxy)cvclohexylipropane-2-sulfonamides The amine (0.35 mmol) was weighed into a vial. In a dry box was added degassed 2-methyl-2-butanol (0.4 ml_), a spatula tip of dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine (XPhos, 0.7 mg, 0.0015 mmol), a spatula tip of ths(dibenzylideneacetone)dipalladium(0) (0.14 mg, 0.00025 mmol) and one potassium hydroxide pellet. The reaction was then flooded with nitrogen, evacuated using a vacuum, and refilled with nitrogen. After the mixture was shaken at room temperature for 15 minutes, it was treated with a solution of Λ/-[(1 S,2R)-2-(4- bromophenoxy)cyclohexyl]propane-2-sulfonamide (26.3 mg, 0.7 mmol) in degassed 2-methyl-2-butanol (0.4 ml_) and shaken at 100 0C for 18 hours. The reaction was then treated with water (1.5 ml_) and extracted with ethyl acetate (3 x 2.5 ml_). The organic layers were combined, passed thru a solid phase extraction cartridge loaded with sodium sulfate, and concentrated in vacuo. {Note: to remove any te/t-butoxycarbonyl protecting groups present after the coupling, a mixture of 1 :1 trifluoroacetic acid/dichloromethane (0.5 ml_) was added to the appropriate reactions, and then they were shaken at room temperature for 2 hours and concentrated in vacuo.} The residue was dissolved in dimethyl sulfoxide (1 ml_), and purified by preparative HPLC (Column: XBridge Ciβ, 5 μm, 19 x 50 mm; Solvent A: 0.1 % trifluoroacetic acid in water (v/v); Solvent B: 0.1 % trifluoroacetic acid in acetonitrile (v/v) using an appropriate gradient).
TABLE 1
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
(d,
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
TABLE 2
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
AColumn: Waters Sunfire Ci8 3.5 μm, 4.6x50 mm; Mobile phase A: 0.05% TFA in water; Mobile phase B: 0.05% TFA in CH3CN; Flow rate 2.0 mL/min.
Figure imgf000088_0001
BColumn: Waters Xterra Ci8 3.5 μm, 4.6x50 mm; Mobile phase A: 0.1 % NH4OH in water; Mobile phase B: 0.1 % NH4OH in CH3CN; Flow rate 2.0 mL/min.
Figure imgf000088_0002
Biological Protocols Growth and Maintenance of ES Cells
Murine ES cell line E14, with a targeted mutation in the Sox1 gene and a neuroectodermal marker that offers G418 resistance when the Sox1 gene is expressed (Stem Cell Sciences, West Mains Road, Edinburgh, Scotland EH9 3JQ) may be used in all experiments. ES cells may be maintained undifferentiated as previously described (Methods For The Isolation And Maintenance Of Murine Embryonic Stem Cells; Roach-M-L, McNeish-J-D., Methods in Molecular Biology, 185, 1 -16 (2002)). Briefly, ES cells may be grown in stem cell culture media comprising a base medium of Knockout™ D- MEM (Invitrogen 5791 Van Allen Way, Carlsbad, CA USA 92008,), supplemented with 15% ES qualified Fetal Bovine Serum (FBS) (Invitrogen), 0.2 mM L-Glutamine (Invitrogen), 0.1 mM MEM non-essential amino acids (Invitrogen), 30 μg/ml Gentamicin (G418) (Invitrogen), 1000 U/ml ESGRO™ (CHEMICON International, Inc., 28820 Single Oak Drivejemecula, CA 92590) and 0.1 mM 2-mercaptoethanol (Sigma, 3050 Spruce St., St. Louis, MO 63103). ES cells may then be plated on gelatin-coated dishes (BD Biosciences,2350 Qume Drive, San Jose, CA 95131 ), wherein the media is changed daily and the cells dissociated with 0.05% Trypsin EDTA (Invitrogen) every other day.
Neural In Vitro Differentiation of ES Cells Embrvoid Body Formation: Prior to embryoid body (EB) formation the
ES cells may be weaned from FBS onto Knockout Serum Replacement™ (KSR) (Invitrogen). To form EBs, ES cells may be dissociated into a single cell suspension, then 3x106 cells plated in bacteriology dishes (Nunc 4014) and grown as a suspension culture in NeuroEB-l medium that consisted of Knockout™ D-MEM (Invitrogen), supplemented with 10% KSR (Invitrogen), 0.2 mM L-Glutamine (Invitrogen), 0.1 mM MEM non-essential amino acids (Invitrogen), 30μg/ml Gentamicin (Invitrogen), 1000 U/ml ESGRO™ (CHEMICON International, Inc.), 0.1 mM 2-mercaptoethanol (Sigma) and 150ng/ml Transferrin (Invitrogen). The plates may then be put on a Stovall Belly Button™ shaker in an atmospheric oxygen incubator. The media may be changed on day 2 of EB formation with NeuroEB-l and on day 4 with NeuroEB-ll (NeuroEB-l plus 1 μg/ml mNoggin (R&D Systems, 614 McKinley Place N. E. Minneapolis, MN 55413)
Neuronal Precursor Selection and Expansion: On day 5 of EB formation, EBs may be dissociated with 0.05% Trypsin EDTA, and 4x106 cells/100mm dish may then be plated on Laminin coated tissue culture dishes in NeuroEB-ll-G418 medium that consisted of a base medium of a 1 :1 mixture of D-MEM/F12 supplemented with N2 supplements and NeuroBasal Medium supplemented with B27 supplement and 0.1 mM L-Glutamine (all from Invitrogen). The base medium may then be supplemented with 10ng/ml bFGF (Invitrogen), 1 μg/ml mNoggin, 500ng/ml SHH-N (ProSpecBio Rehovot Science Park, P.O. BOX 398, Rehovot 76103, Israel), 100ng/ml FGF-8b (R&D Systems), 1 μg/ml Laminin and 200μg/ml G418 (Invitrogen) for selection of neuronal precursors expressing Sox-1. The plates may then be put in an incubator containing 2% oxygen and maintained in these conditions. During the 6-day selection period, the NeuroEB-ll media should be changed daily. On day 6, the surviving neuronal precursor foci may then be dissociated with 0.05% Trypsin EDTA and the cells plated at a density of 1.5x106 cells/100mm Laminin coated dish in Neuroll-G418 medium. The cells may then be dissociated every other day for expansion, and prepared for cryopreservation at passage 3 or 4. The cryopreservation medium typically contains 50% KSR, 10% dimethyl sulfoxide (DMSO) (Sigma) and 40% Neuroll-G418 medium. Neuronal precursors may be cryopreserved at a concentration of 4x106 cells/ml and 1 ml/cryovial in a controlled rate freezer overnight then transferred to an ultra-low freezer or liquid nitrogen for long-term storage. Neuronal Differentiation: Cryopreserved ES cell-derived neuronal precursors may be thawed by the rapid thaw method in a 37°C water-bath. The cells are then transferred from the cryovial to a 100mm Laminin coated tissue culture dish that already contains Neuroll-G418 that has been equilibrated in a 2 percent oxygen incubator. The media is changed with fresh Neuroll-G418 the next day. The cells may be dissociated every other day as described above for expansion to generate enough cells to plate for the screen. For the screen, the cells are plated into 384-well poly-d-lysine coated tissue culture dishes (BD Biosciences) by the automated SelecT® (The Automation Partnership York Way, Royston, Hertfordshire SG8 5WY UK) at a cell density of 6K cells/well in differentiation medium Neurolll that contains a 4:1 ratio of the NeuroBasalMedium/B27:D-MEM/F12/N2 supplemented with 1 μM cAMP (Sigma), 200μM Ascorbic Acid (Sigma), 1 μg/ml Laminin (Invitrogen) and 10ng/ml BDNF (R&D Systems, 614 McKinley Place N. E. Minneapolis, MN 55413). The plates are then put in an incubator with 2 percent oxygen and allowed to complete the differentiation process for 7 days. The cells could then be used over a 5-day period for the high throughput screen. In vitro assays
Procedure fon AMPA ES Cell FLIPR Screen
On the day of the assay, the FLIPR assay may be performed using the following methods:
Assay buffer:
Compound g/L MMWW [[ccoonncceennttrraattiioonn ]]
NaCI 8.47 5588..4444 114455 mmMM
Glucose 1.8 118800..22 11 OO mmMM
KCI .37 7744..5566 55 mmMM
MgSO4 i mM M Stock 224466..4488 11 mmMM
HEPES 2.38 223388..33 11 OO mmMM
CaCI2 2 ml I M Stock 111100..9999 22 mmMM
The pH may be adjusted to 7.4 with 1 M NaOH. Prepare a 2 mM (approx.) stock solution of Fluo-4 AM (Invitrogen) dye in DMSO - 22 μl DMSO per 50 μg vial (440 μl_ per 1 mg vial). Make a 1 mM (approx.) Fluo-4 AM, PA working solution per vial by adding 22 μl of 20% pluronic acid (PA) (Invitrogen) in DMSO to each 50 μg vial (440 μl_ per 1 mg vial). Prepare a 250 mM Probenecid (Sigma) stock solution. Make 4 μM (approx.) dye incubation media by adding the contents of 2 50 μg vials per 11 ml DMEM high glucose without glutamine (220 ml DMEM per 1 mg vial). Add 110 μL probenecid stock per 11 ml media (2.5 mM final concentration). Dye concentrations ranging from 2 μM to 8 μM dye may be used without altering agonist or potentiator pharmacology. Add probenecid to the assay buffer used for cell washing (but not drug preparation) at 110 μl probenecid stock per 11 ml buffer.
Remove growth media from cell plates by flicking. Add 50 μl / well dye solution. Incubate 1 hour at 370C and 5% CO2. Remove dye solution and wash 3 times with assay buffer + probenecid (100 μl probenecid stock per 10 ml buffer), leaving 30 μL / well assay buffer. Wait at least 10-15 minutes. Compound and agonist challenge additions may be performed with the FLIPR (Molecular Devices, 1311 Orleans Ave, Sunnyvale, CA 94089). The first addition is for test compounds, which are added as 15 μL of a 4X concentration. The second addition is 15 μL of 4X concentration of agonist or challenge. This achieves 1 X concentration of all compounds only after second addition. Compounds are pretreated at least 5 minutes before agonist addition.
Several baseline images are collected with the FLIPR before compound addition, and images are collected for least one minute after compound addition. Results are analyzed by subtracting the minimum fluorescent FLIPR value after compound or agonist addition from the peak fluorescent value of the FLIPR response after agonist addition to obtain the change in fluorescence. The change in fluorescence (RFUs, relative fluorescent units) are then analyzed using standard curve fitting algorithms. The negative control is defined by the AMPA challenge alone, and the positive control is defined by the AMPA challenge plus a maximal concentration of cyclothiazide (10 uM or 32 uM).
Compounds are delivered as DMSO stocks or as powders. Powders are solubilized in DMSO. Compounds are then added to assay drug buffer as 40 μL top [concentration] (4X the top screening concentration). The standard agonist challenge for this assay is 32 μM AMPA. EC50 values of the compounds of the invention are preferably 10 micromolar or less, more preferably 1 micromolar or less, even more preferably 100 nanomolar or less. The data for specific compounds of the invention is provided below in Table 3.
Table 3
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
* Value represents the geometric mean of 2-5 EC50 determinations
When introducing elements of the present invention or the exemplary embodiment(s) thereof, the articles "a," "an," "the" and "said" are intended to mean that there are one or more of the elements. The terms "comprising," "including" and "having" are intended to be inclusive and mean that there may be additional elements other than the listed elements. Although this invention has been described with respect to specific embodiments, the details of these embodiments are not to be construed as limitations to the invention, the scope of which is defined by the appended claims.

Claims

1. A compound of formula I, or a pharmaceutically acceptable salt thereof,
Figure imgf000096_0001
I wherein each R1 and each R2 and each R7 is independently selected from the group consisting of hydrogen, halogen, hydroxyl, -CF3, -CN, -(C=O)R8, -0-(C=O)-R8, -(NR8MC=O)-R8, -(C=O)-OR8, -(C=O)-N(R8)2, -OR8, -0-(C=O)-OR8, -O-(C=O)-N(R8)2, -NO2, -N(R8)2, -(NR8)-SO2-R8, -S(O)WR8, -SO2-N(R8)2, (CrC6)alkyl, (C6-Ci0)aryl, (Ci-C9)heteroaryl,
(Ci-C9)heterocycloalkyl, and (C3-Ci 0)cycloalkyl; wherein said (Ci-C6)alkyl, (C6-Cio)aryl, (Ci-Cg)heteroaryl, (Ci-Cg)heterocycloalkyl, or (C3-Ci0)cycloalkyl are each independently optionally substituted with one, two, three or four R9; w is O, 1 or 2; m is zero, one, two or three; n is zero, one, two or three; p is zero, one, two or three; q is zero, one, two or three; s is one and t is one; or one of s or t is one and the other of s or t is two;
R3 is hydrogen or (CrC6)alkyl; each R4 is independently selected from hydrogen, or (Ci-C6)alkyl; wherein said (Ci-C6)alkyl may be optionally substituted with one, two, three or four halogen, -CN, or -OR9; or two R4 groups on the same carbon atom may be taken together to form an oxo (=O) radical or a (C3-C6)spirocycloalkyl; R5 is hydrogen, or (CrC6)alkyl;
R6 is (Ci-C6)alkyl-(C=O)-, [(Ci-C6)alkyl]2N-(C=O)-, (d-C6)alkyl-SO2-, (C3-Cio)cycloalkyl-SO2-, or [(Ci-C6)alkyl]2N-SO2-; wherein said (Ci-C6)alkyl moieties of said [(d-C6)alkyl]2N-(C=O)- and [(Ci-C6)alkyl]2N-SO2- may optionally be taken together with the nitrogen atom to which they are attached to form a four to six membered heterocyclic ring;
R8 is independently selected from the group consisting of hydrogen, (d-CβJalkyl, (C6-Cio)aryl, (Ci-Cg)heteroaryl, (Ci-Cg)heterocycloalkyl, and (C3-Cio)cycloalkyl; wherein said (d-CβJalkyl may be optionally substituted with one, two or three substituents independently selected from hydrogen, halo, -CN, perfluoro(Ci-C6)alkyl, hydroxy, amino, (Ci-C6)alkylamino, [(Ci-C6)alkyl]2amino, (d-C6)alkoxy, perfluoro(d-C6)alkoxy, HO-(C=O)-, (Ci-C6)alkyl-O-(C=O)-, formyl, (Ci-C6)alkyl-(C=O)-, H2N-(C=O)-, (Ci-C6)alkyl]-(NH)-(C=O)-, [(d-C6)alkyl]2N-(C=O)-, (d-C6)alkyl-(C=O)-O-, H(C=O)-NH-, (Ci-C6)alkyl(C=O)-NH-, (d-C6)alkyl(C=O)-[N((Ci-C6)alkyl)]-, (Ci-C6)alkyl-SO2-, (d-C6)alkyl-SO2-NH-, (Ci-C6)alkyl-SO2-[N((Ci-C6)alkyl)]-, H2N-SO2-, [(Ci-C6)alkyl]-NH-SO2-, and [(d-C6)alkyl]2N-SO2-; wherein said (d-CβJalkyl may be additionally optionally substituted with an optionally substituted (C6-Cio)aryl, (Ci-Cg)heteroaryl, (d-Cg)heterocycloalkyl, or (C3-Cio)cycloalkyl; wherein said optional substituents may be independently substituted with from one, two, three or four radicals independently selected from halogen, hydroxyl, -CF3, -CN, (Ci-C3)alkyl, (Ci-C3)alkoxy, and amino; wherein each of said R8 (C6-Ci0)aryl, (d-Cg)heteroaryl, (d-Cg)heterocycloalkyl or (C3-Ci0)cycloalkyl substituents may be optionally additionally substituted with one, two, three or four radicals independently selected from halogen, hydroxyl, -CF3, -CN, (Ci-C3)alkyl, (Ci-C3)alkoxy and amino; each R9 is independently selected from the group consisting of halogen, hydroxyl, -CF3, -CN, -(C=O)R10, -Q-(C=O)-R10, -(NR10)-(C=O)-R10, -(C=O)-OR10, -(C=O)-N(R10)2, -OR10, -0-(C=O)-OR10, -O-(C=O)-N(R10)2, -NO2, -N(R1V -(NR10)-SO2-R10, -S(O)WR10, -SO2-N(R10)2;
R10 is independently selected from the group consisting of hydrogen, (Ci-C6)alkyl, (C6-Ci0)aryl, (Ci-C9)heteroaryl, (Ci-C9)heterocycloalkyl and (C3-Cio)cycloalkyl; wherein said (CrC6)alkyl may be optionally substituted with one, two or three substituents independently selected from hydrogen, halo, -CN, perfluoro(Ci-C6)alkyl, hydroxy, amino, (Ci-C6)alkylamino, [(Ci-C6)alkyl]2amino, (CrC6)alkoxy, perfluoro(CrC6)alkoxy, HO-(C=O)-, (CrC6)alkyl-O-(C=O)-, formyl, (Ci-C6)alkyl-(C=O)-, H2N-(C=O)-, (CrC6)alkyl]-(NH)-(C=O)-, [(Ci-C6)alkyl]2N-(C=O)-, (CrC6)alkyl-(C=O)-O-, H(C=O)-NH-, (Ci-C6)alkyl(C=O)-NH-, (Ci-C6)alkyl(C=O)-[N((Ci-C6)alkyl)]-, (CrC6)alkyl-SO2-, (Ci-C6)alkyl-SO2-NH-, (Ci-C6)alkyl-SO2-[N((Ci-C6)alkyl)]-, H2N-SO2-, [(CrC6)alkyl]-NH-SO2-, and [(Ci-C6)alkyl]2N-SO2-; wherein said (d-CβJalkyl may also be additionally optionally substituted with an optionally substituted (C6-Ci0)aryl, (Ci-C9)heteroaryl, (Ci-C9)heterocycloalkyl or (C3-Cio)cycloalkyl; wherein said optional substituents may be independently substituted with from one, two, three or four radicals independently selected from halogen, hydroxyl, -CF3, -CN, (Ci-C3)alkyl, (Ci-C3)alkoxy, and amino; wherein each of said R10 (C6-Cio)aryl, (Ci-C9)heteroaryl, (Ci-C9)heterocycloalkyl, or (C3-Cio)cycloalkyl substituents may be optionally additionally substituted with one, two, three or four radicals independently selected from halogen, hydroxyl, -CF3, -CN, (Ci-C3)alkyl, (Ci-C3)alkoxy, and amino;
R11 is hydrogen or (Ci-C6)alkyl; ring "A" is (C6-Ci0)aryl, (CrC9)heteroaryl, (C4-Ci 0)cycloalkyl, or
(Ci-Cg)heterocycloalkyl; wherein two of said R1 substituents on said (C4-Cio)cycloalkyl and (Ci-C9)heterocycloalkyl may optionally be attached to the same carbon atom and may optionally be taken together to be oxo; ring "B" is (C6-Cio)aryl, (CrC9)heteroaryl, (C4-Ci o)cycloalkyl, or (Ci-Cg)heterocycloalkyl;
"X" is -O- or >C(R4)2; "Y" is absent, >NR11, -(NR11)-(C=O)-, >C=O, -O- or >C(R7)2; and "Z" is -O-. -S-, -(S=O)-, or -(SO2)-.
2. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein said compound has the regiochemistry of the Formula:
Figure imgf000099_0001
Ia
3. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein said compound has the stereochemistry of the Formula:
Figure imgf000099_0002
Ib
4. A compound according to any of the proceeding claims, or a pharmaceutically acceptable salt thereof, wherein "Z" is -O-.
5. A compound according to any of the proceeding claims, or a pharmaceutically acceptable salt thereof, wherein X is -O-.
6. The compound of any of the proceeding claims, or a pharmaceutically acceptable salt thereof, wherein ring "A" is phenyl; n is zero, one or two; R1 is selected from the group consisting of hydrogen, halogen, hydroxyl, -CF3, -CN, -(C=O)R8, -0-(C=O)-R8, -(NR8)-(C=O)-R8, -(C=O)-OR8, -(C=O)-N(R8)2, -OR8, -0-(C=O)-OR8, -O-(C=O)-N(R8)2, -NO2, -N(R8)2, -(NR8)-SO2-R8, -S(O)wR8, -SO2-N(R8)2, and (Ci-C6)alkyl; wherein said (CrC6)alkyl is optionally substituted with one, two, three or four R9.
7. The compound of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein ring "A" is (Ci-Cg)heteroaryl; n is zero, one or two; and wherein R1 is selected from the group consisting of hydrogen, halogen, hydroxyl, -CF3, -CN, -(C=O)R8, -0-(C=O)-R8, -(NR8)-(C=O)-R8, -(C=O)-OR8, -(C=O)-N(R8)2, -OR8, -0-(C=O)-OR8, -O-(C=O)-N(R8)2, -NO2, -N(R8)2, -(NR8)-SO2-R8, -S(O)wR8, -SO2-N(R8)2, and (CrC6)alkyl; wherein said (Ci-Cβjalkyl is optionally substituted with one, two, three or four R9.
8. The compound of any of the proceeding claims, or a pharmaceutically acceptable salt thereof, wherein ring "B" is phenyl; m is zero or one; R2 is hydrogen, halogen, hydroxyl, -CF3, -CN, -(C=O)R8, -0-(C=O)-R8, -(NR8HC=O)-R8, -(C=O)-OR8, -(C=O)-N(R8)2, -OR8, -0-(C=O)-OR8, -O-(C=O)-N(R8)2, -NO2, -N(R8)2, -(NR8)-SO2-R8, -S(O)WR8, -SO2-N(R8)2, and (CrC6)alkyl; wherein said (Ci-C6)alkyl is optionally substituted with one, two, three or four R9.
9. The compound of any of the proceeding claims, or a pharmaceutically acceptable salt thereof, wherein R2 is hydrogen and R4 is hydrogen.
10. The compound of any of the proceeding claims, or a pharmaceutically acceptable salt thereof, wherein q is zero.
11. The compound of any of the proceeding claims, or a pharmaceutically acceptable salt thereof, wherein Y is absent.
12. The compound of any of the proceeding claims, or a pharmaceutically acceptable salt thereof, wherein R6 is (Ci-C5)alkyl-(C=O)-.
13. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein said compound is:
Propane-2-sulfonic acid [(3S,4S)-4-(2'-cyano-biphenyl-4-yloxy)- tetrahydro-furan-3-yl]-amide; Propane-2-sulfonic acid [(3S,4S)-4-(2'-cyano-4'-fluoro-biphenyl-4- yloxy)-tetrahydro-furan-3-yl]-amide;
Propane-2-sulfonic acid [(3S,4S)-4-(2',4'-difluoro-biphenyl-4-yloxy)- tetrahydro-furan-3-yl]-amide;
Propane-2-sulfonic acid {(3S,4S)-4-[4-(5-cyano-thiophen-2-yl)- phenoxy]-tetrahydro-furan-3-yl}-amide;
Propane-2-sulfonic acid {(1 S,2R)-2-[4-(5-cyano-thiophen-2-yl)-3-fluoro- phenoxy]-cyclopentyl}-amide;
Propane-2-sulfonic acid {(1S,2R)-2-[4-(5-cyano-thiophen-2-yl)- phenoxy]-cyclopentyl}-amide; Propane-2-sulfonic acid {(1 S,2R)-2-[3-fluoro-4-(2- methanesulfonylamino-ethyl)-phenoxy]-cyclopentyl}-amide;
Propane-2-sulfonic acid {(3S,4S)-4-[5-(2-cyano-phenyl)-pyhdin-2- yloxy]-tetrahydro-furan-3-yl}-amide;
Propane-2-sulfonic acid {(1S,2R)-2-[6-(2-cyano-4-fluoro-phenyl)- pyhdin-3-yloxy]-cyclohexyl}-amide; or
Propane-2-sulfonic acid {(1 S,2R)-2-[6-(5-cyano-thiophen-2-yl)-pyhdin- 3-yloxy]-cyclohexyl}-amide.
14. A method for the treatment or prevention in a mammal of a condition selected from the group consisting of acute neurological and psychiatric disorders, stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage, dementia, Alzheimer's disease, Huntington's Chorea, amyotrophic lateral sclerosis, ocular damage, retinopathy, cognitive disorders, idiopathic and drug- induced Parkinson's disease, muscular spasms and disorders associated with muscular spasticity including tremors, epilepsy, convulsions, migraine, urinary incontinence, substance tolerance, substance withdrawal, psychosis, schizophrenia, anxiety, mood disorders, trigeminal neuralgia, hearing loss, tinnitus, macular degeneration of the eye, emesis, brain edema, pain, tardive dyskinesia, sleep disorders, attention deficit/hyperactivity disorder, attention deficit disorder, and conduct disorder, comprising administering a compound of any of the proceeding claims, or a pharmaceutically acceptable salt thereof, to the mammal.
15. A pharmaceutical composition comprising a compound of any of the proceeding claims, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
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WO2018172250A1 (en) 2017-03-21 2018-09-27 Bayer Pharma Aktiengesellschaft 2-methyl-quinazolines
WO2019201848A1 (en) 2018-04-18 2019-10-24 Bayer Pharma Aktiengesellschaft 2-methyl-aza-quinazolines
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WO2024033374A1 (en) 2022-08-11 2024-02-15 Syngenta Crop Protection Ag Novel arylcarboxamide or arylthioamide compounds
WO2024089216A1 (en) 2022-10-27 2024-05-02 Syngenta Crop Protection Ag Novel sulfur-containing heteroaryl carboxamide compounds

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US9056832B2 (en) 2010-09-17 2015-06-16 Purdue Pharma L.P. Pyridine compounds and the users thereof
US9611222B2 (en) 2010-09-17 2017-04-04 Purdue Pharma L.P. Pyridine compounds and the uses thereof
US20140005212A1 (en) * 2010-12-22 2014-01-02 Purdue Pharma L.P. Substituted Pyridines as Sodium Channel Blockers
US9656959B2 (en) * 2010-12-22 2017-05-23 Purdue Pharma L.P. Substituted pyridines as sodium channel blockers
WO2012137982A3 (en) * 2011-04-05 2013-04-04 Takeda Pharmaceutical Company Limited Sulfonamide derivative and use thereof
JP2014523851A (en) * 2011-04-05 2014-09-18 武田薬品工業株式会社 Sulfonamide derivatives and uses thereof
US9527807B2 (en) 2011-04-05 2016-12-27 Takeda Pharmaceutical Company Limited Sulfonamide derivative and use thereof
WO2012137982A2 (en) 2011-04-05 2012-10-11 Takeda Pharmaceutical Company Limited Sulfonamide derivative and use thereof
US11186567B2 (en) 2017-02-10 2021-11-30 University College Cardiff Consultants Limited AMPA receptor potentiators
WO2018172250A1 (en) 2017-03-21 2018-09-27 Bayer Pharma Aktiengesellschaft 2-methyl-quinazolines
US11298345B2 (en) 2018-03-01 2022-04-12 University College Cardiff Consultants Limited Compounds that modulates AMPA receptor function
WO2019201848A1 (en) 2018-04-18 2019-10-24 Bayer Pharma Aktiengesellschaft 2-methyl-aza-quinazolines
WO2023217989A1 (en) 2022-05-12 2023-11-16 Syngenta Crop Protection Ag Alkoxy heteroaryl- carboxamide or thioamide compounds
WO2023249875A1 (en) * 2022-06-21 2023-12-28 Alkermes, Inc. Substituted pyrrolidinyl and piperidinyl compounds and related methods of treatment
WO2024033374A1 (en) 2022-08-11 2024-02-15 Syngenta Crop Protection Ag Novel arylcarboxamide or arylthioamide compounds
WO2024089216A1 (en) 2022-10-27 2024-05-02 Syngenta Crop Protection Ag Novel sulfur-containing heteroaryl carboxamide compounds

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