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WO2010087761A1 - Composés 2-aza-bicyclo[2.2.2]octane et leurs utilisations - Google Patents

Composés 2-aza-bicyclo[2.2.2]octane et leurs utilisations Download PDF

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Publication number
WO2010087761A1
WO2010087761A1 PCT/SE2010/050070 SE2010050070W WO2010087761A1 WO 2010087761 A1 WO2010087761 A1 WO 2010087761A1 SE 2010050070 W SE2010050070 W SE 2010050070W WO 2010087761 A1 WO2010087761 A1 WO 2010087761A1
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Prior art keywords
methyl
compound
alkyl
azabicyclo
octan
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English (en)
Inventor
Jeffrey Scott Albert
Cristobal Alhambra
Todd Andrew Brugel
Janet Forst
Christopher R Holmquist
Jeffrey Gilbert Varnes
Xia Wang
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AstraZeneca AB
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AstraZeneca AB
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • This invention relates to 2-aza-bicyclo[2.2.2]octane compounds (and salts thereof).
  • This invention also relates to pharmaceutical compositions comprising such a compound, uses of such a compound (including, for example, treatment methods and medicament preparations), and processes for making such a compound.
  • novel treatments for schizophrenia and other psychotic diseases may result from increased NMDA activation in the central nervous system. In principle, this could be achieved by treatment with direct NMDA agonists; however, such compounds are known to cause neurotoxicity.
  • Glycine is a requisite co-agonist for NMDA receptor, and increases in its concentration may result in increased NMDA activation.
  • the concentration of glycine is regulated by the action of the glycine transporter. Treatment with compounds that modulate the glycine transporter may increase the synaptic glycine level and thus result in NMDAr potentiation and improvement in disease symptomology.
  • R 1 is selected from H and Ci-C ⁇ -alkyl; each R 2 is independently selected from halogen, -CN, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 6 -cycloalkyl, -SO 2 NR 3 R 4 , -NH 2 , -S-Ci-C 6 -alkyl, C 1 -C 6 - alkoxy, and Ci-C ⁇ -alkyl, wherein: the Ci-C ⁇ -alkyl and Ci-C ⁇ -alkoxy are optionally substituted with one or more halogens; each R 3 and R 4 is independently selected from H and Ci-C ⁇ -alkyl; and n is selected from 1, 2, and 3.
  • U.S. Patent Appl. Publ. No. 2009/0030033 discusses the use of such compounds for treating conditions, including schizophrenia, bi-polar disorder, mania and manic depression, anxiety, and other cognitive conditions.
  • This invention relates to, inter alia, 2-aza-bicyclo[2.2.2]octane compounds; treatment methods using the 2-aza-bicyclo[2.2.2]octane compounds ⁇ e.g., method for treating psychosis and other cognitive disorders and as pharmacological tools); uses of the 2-aza- bicyclo[2.2.2]octane compounds to make medicaments; compositions comprising the 2-aza- bicyclo[2.2.2]octane compounds ⁇ e.g., pharmaceutical compositions); methods for manufacturing the 2-aza-bicyclo[2.2.2]octane compounds; and intermediates used in such manufacturing methods.
  • a 1 may be phenyl optionally substituted with 1, 2, or 3 R 5 groups.
  • a 1 is a 5- or 6-membered heteroaryl optionally substituted with 1, 2, or 3 R 7 groups.
  • a 2 may be phenyl substituted with 1, 2, or 3 R 2 groups.
  • a 2 is a heteroaryl optionally substituted with 1, 2, or 3 R 6 groups.
  • R 1 is selected from hydrogen, Ci-C 6 -alkyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, Cs-Cg-cycloalkyl-Ci ⁇ -alkyl, aryl-Ci-C4-alkyl, heterocycloalkyl-Ci-C 4 - alkyl, heteroaryl-Ci-C 4 -alkyl, and C 3 -C 8 -alkenyl.
  • the C 3 -C 8 -cycloalkyl-Ci-C 4 -alkyl, aryl-C r C 4 -alkyl, and heteroaryl-Ci-C 4 -alkyl are optionally substituted with one or more independently selected halogens.
  • Each R 2 is independently selected from halogen, -CN, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 5- or 6-membered heterocyclyl, -SOR, -SO 2 R, -NH 2 , -SR, C 1 -C 6 - alkoxy, Ci-C 6 -alkyl, and C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl.
  • the Ci-C 6 -alkyl, Ci-C 6 -alkoxy, and C 3 - C 6 cycloalkyl are optionally substituted with one or more independently selected halogens.
  • the heterocyclyl is optionally substituted with 1, 2, or 3 R 6 groups.
  • Each R 5 is independently selected from Ci-C 6 -alkyl, C 3 -C8-cycloalkyl, C 1 -C 6 - alkoxy, -CN, halogen, -SO 2 R, -SOR, -SR, and heterocyclyl.
  • the C r C 6 -alkyl, C 3 -C 8 - cycloalkyl, and Ci-C 6 -alkoxy are optionally substituted with one or more independently selected halogens.
  • the heterocyclyl is optionally substituted with Ci-C 4 -alkyl or halogen.
  • Each R 6 is independently selected from Ci-C 6 -alkyl, Ci-C 6 -alkoxy, halogen, -SO 2 R, -SOR, -SR, phenyl, -CF 3 , -OCF 3 , -CN, and heterocyclyl.
  • the heterocyclyl is optionally substituted with Ci-C 4 -alkyl.
  • Each R 7 is independently selected from Ci-C 6 -alkyl, Ci-C4-alkoxy, -CF 3 , -OCF 3 , -CN, -SO 2 R, -SOR, -SR, phenyl, heterocyclyl, and d-C 4 -alkoxy.
  • the Ci-C 6 -alkyl, C 3 -C 8 -cycloalkyl, and Ci-C 4 -alkoxy are optionally substituted.
  • Each R is independently selected from Ci-C 6 -alkyl, C 3 -C8-cycloalkyl-Ci-C 6 - alkyl, and NR 3 R 4 .
  • Each R 3 and R 4 is independently selected from H and Ci-C 6 -alkyl.
  • This invention excludes compounds (and pharmaceutically acceptable salts thereof) that satisfy both the following A 1 and A 2 definitions: A 1 is phenyl; and
  • a 2 is phenyl substituted with 1, 2, or 3 groups selected from halogen, -CN, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, -SO 2 NR 3 R 4 , -NH 2 , -S-Ci- C 6 -alkyl, Ci-C 6 -alkoxy, and Ci-C 6 -alkyl, wherein: the Ci-C 6 -alkyl and Ci-C 6 -alkoxy are optionally substituted with one or more halogens.
  • composition comprises a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • composition also comprises a pharmaceutically acceptable carrier or diluent.
  • This invention also is directed, in part, to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in treating a condition (typically a disorder).
  • This invention also is directed, in part, to a method of using a compound of Formula (I) or a pharmaceutically acceptable salt thereof to treat a condition.
  • This invention also is directed, in part, to a method of treating a condition in a patient in need of such treatment.
  • the method comprises administering a compound of Formula (I) or a pharmaceutically acceptable salt thereof to the patient.
  • This invention also is directed, in part, to a use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament (e.g., a pharmaceutical composition) for treating a condition.
  • a 1 is phenyl (i.e., unsubstituted phenyl).
  • the compound corresponds to Formula (II):
  • a 2 is phenyl substituted with 1, 2, or 3 groups independently selected from halogen, -CN, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, -SO 2 NR 3 R 4 , -NH 2 , -S-Ci-C 6 -alkyl, Ci-C 6 -alkyl, Ci-C 6 -alkoxy, halo-Ci-C 6 -alkyl, and halo-Ci-C 6 -alkoxy.
  • a 1 is phenyl substituted with 1, 2, or 3 R 5 groups. In some such embodiments, A 1 is phenyl substituted with 1 R 5 group. In other embodiments, A 1 is phenyl substituted with 2 R 5 groups. And in other embodiments, A 1 is phenyl substituted with 3 R 5 groups. [29] In some embodiments, A 1 is a 5- or 6-membered heteroaryl (i.e., unsubstituted
  • the heteroaryl is 5-membered. In some such embodiments, the heteroaryl is imidazolyl. In other such embodiments, the heteroaryl is furanyl. In some embodiments, the heteroaryl that is substituted is 6-membered. In some such embodiments, the heteroaryl is selected from pyridinyl. [30] In some embodiments, A 1 is a 5- or 6-membered heteroaryl substituted with 1,
  • a 1 is 5- or 6-membered heteroaryl substituted with 1 R 7 group. In other embodiments, A 1 is 5- or 6-membered heteroaryl substituted with 2 R 7 groups. And in other embodiments, A 1 is 5- or 6-membered heteroaryl substituted with 3 R 7 groups.
  • the heteroaryl that is substituted is 5-membered. In some such embodiments, the heteroaryl that is substituted is imidazolyl. In other such embodiments, the heteroaryl that is substituted is furanyl. In some embodiments, the heteroaryl that is substituted is 6-membered. In some such embodiments, the heteroaryl that is substituted is pyridinyl.
  • a 2 is phenyl substituted with 1, 2, or 3 R 2 groups. In some such embodiments, A 2 is a phenyl substituted with 1 R 2 group. In other embodiments, A 2 is a phenyl substituted with 2 R 2 groups. And in other embodiments, A 2 is a phenyl substituted with 3 R 2 groups. Excluded from such embodiments, however, are compounds (and salts thereof) wherein both the following A 1 and A 2 definitions are satisfied:
  • a 1 is phenyl (i.e., the compound corresponds to Formula (II)); and A 2 is phenyl substituted with 1, 2, or 3 groups independently selected from halogen, -CN, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl,
  • a 2 is a heteroaryl (i.e., unsubstituted heteroaryl).
  • the heteroaryl is 5-membered.
  • a 2 is selected from oxazolyl, imidazolyl, thiazolyl, and isoxazolyl.
  • the heteroaryl is 6-membered.
  • a 2 is pyridinyl.
  • the heteroaryl is 9-membered.
  • a 2 is selected from imidazopyridinyl and benzoimidazolyl.
  • a 2 is heteroaryl substituted with 1, 2, or 3 R 6 groups. In some such embodiments, A 2 is a heteroaryl substituted with 1 R 6 group. In other embodiments, A 2 is a heteroaryl substituted with 2 R 6 groups. And in other embodiments, A 2 is a heteroaryl substituted with 3 R 6 groups.
  • the heteroaryl that is substituted is 5-membered. In some such embodiments, the heteroaryl is selected from oxazolyl, imidazolyl, thiazolyl, and isoxazolyl. In some embodiments, the heteroaryl that is substituted is 6-membered. In some such embodiments, the heteroaryl is pyridinyl. In some embodiments, the heteroaryl that is substituted is 9-membered. In some such embodiments, the heteroaryl is selected from imidazopyridinyl and benzoimidazolyl.
  • a 2 is a pyridinyl substituted with 1 R 6 group. In other embodiments, A 2 is a pyridinyl substituted with 2 R 6 groups. And in other embodiments, A 2 is a pyridinyl substituted with 3 R 6 groups.
  • each R is independently selected from Ci-C 6 -alkyl, C 3 -C 8 -cycloalkyl-Ci-C 6 -alkyl, and NR 3 R 4 .
  • an R is Ci-C 6 -alkyl. In some such embodiments, R is methyl. In other embodiments, R is ethyl. And, in other embodiments, R is propyl. [37] In some such embodiments, an R is C 3 -C 8 -cycloalkyl-Ci-C 6 -alkyl.
  • an R is NR 3 R 4 .
  • every R is independently selected Ci-C 6 -alkyl.
  • every R is independently selected C 3 -C 8 - cycloalkyl-Ci-C 6 -alkyl.
  • every R is independently selected NR 3 R 4 .
  • R 1 is selected from hydrogen, Ci-C 6 -alkyl, C 3 -C 6 cycloalkyl, 3-6 membered heterocycloalkyl, C 3 -C 8 -cycloalkyl-Ci-C 4 -alkyl, aryl-Ci-C 4 -alkyl, heterocycloalkyl-Ci-C 4 - alkyl, heteroaryl-Ci-C 4 -alkyl, and C 3 -C 8 -alkenyl.
  • the C 3 -C 8 -cycloalkyl-Ci-C 4 -alkyl, aryl-Ci- C 4 -alkyl, and heteroaryl-Ci-C 4 -alkyl are optionally substituted with one or more independently selected halogens.
  • R 1 is selected from hydrogen, d-C 6 -alkyl, C 3 -C 6 cycloalkyl, 3-6 membered heterocycloalkyl, C 3 -C 8 -cycloalkyl-Ci-C 4 -alkyl, aryl-Ci-C 4 -alkyl, heterocycloalkyl-Ci-C 4 -alkyl, heteroaryl-Ci-C 4 -alkyl, and C 3 -C 8 -alkenyl.
  • R 1 is hydrogen
  • R 1 is Ci-C 6 -alkyl. In some such embodiments, R 1 is methyl. In other such embodiments, R 1 is ethyl. In still other such embodiments, R 1 is propyl.
  • R 1 is C 3 -Cs alkenyl.
  • R 1 is C 3 -C 6 cycloalkyl.
  • R 1 is C 3 -Cg-cycloalkyl-Ci-C 4 -alkyl optionally substituted with one or more halogen.
  • R 1 is aryl-Ci-C4-alkyl optionally substituted with one or more halogen.
  • R 1 is heteroaryl-Ci-C 4 -alkyl optionally substituted with one or more halogen.
  • Each R 2 is independently selected from halogen, -CN, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 5- or 6- membered heterocyclyl (i.e., a 5- or 6-membered heterocycloalkyl, 5- or 6-membered heterocycloalkenyl, or 5- or 6-membered heteroaryl), -SOR, -SO 2 R, -NH 2 , -SR, Ci-C 6 -alkoxy, C r C 6 -alkyl, and Ci-C 4 -alkoxy-Ci-C 4 -alkyl.
  • the C 1 - C 6 -alkyl, Ci-C 6 -alkoxy, and C 3 -C 6 cycloalkyl are optionally substituted with one or more independently selected halogens.
  • the heterocyclyl is optionally substituted with 1, 2, or 3 R 6 groups.
  • Each R 2 is independently selected from halogen, -CN, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 5- or 6- membered heterocyclyl, -SOR, -SO 2 R, -NH 2 , -SR, C 1 -C 6 - alkoxy, and Ci-C 6 -alkyl.
  • Ci-C 6 -alkyl, Ci-C 6 -alkoxy, and C 3 -C 6 cycloalkyl are optionally substituted with one or more independently selected halogens.
  • the heterocyclyl is optionally substituted with 1, 2, or 3 R 6 groups.
  • each R 2 is selected from halogen, 5- or 6- membered heterocyclyl, -SO 2 R, -NH 2 , Ci-C 6 -alkoxy, Ci-C 6 -alkyl, and C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl.
  • the Ci-C 6 -alkyl and Ci-C 6 -alkoxy are optionally substituted with one or more independently selected halogens.
  • at least one R 2 is Ci-C 6 -alkyl optionally substituted with one or more halogens. In some such embodiments, for example, at least one R 2 is methyl. In other such embodiments, at least one R 2 is -CF3.
  • At least one R 2 is Ci -C 6 -alkoxy. In some such embodiments, for example, at least one R 2 is methoxy. [56] In some embodiments, at least one R 2 is Ci-C 4 -alkoxy-Ci-C 4 -alkyl. In some such embodiments, for example, at least one R 2 is methoxymethyl.
  • At least one R 2 is halogen. In some such embodiments, for example, at least one R 2 is chloro. In other such embodiments, at least one R 2 is bromo. In still other such embodiments, at least one R 2 is fluoro. [58] In some embodiments, at least one R 2 is -SO 2 R. In some such embodiments, for example, at least one R 2 is methylsulfonyl.
  • At least one R 2 is -NH 2 .
  • At least one R 2 is a 5- or 6- membered heterocyclyl.
  • at least one R 2 is a 5-membered heterocycloalkyl, such as, for example, a pyrrolidinyl.
  • at least one R 2 is a 5-membered heteroaryl, such as, for example, pyrazolyl.
  • each R 2 is different.
  • R 2 are the same.
  • Each R 3 and R 4 is independently selected from H and Ci-C 6 -alkyl. [64] In some embodiments, at least one R 3 is H.
  • every R 3 is H.
  • At least one R 3 is H, and at least one R 4 is H.
  • every R 3 and every R 4 is H.
  • at least one R is Ci-C ⁇ -alkyl.
  • every R 3 is independently selected Ci-C ⁇ -alkyl.
  • At least one R 3 is Ci-C ⁇ -alkyl, and at least one R 4 is Ci- Ce-alkyl.
  • every R 3 is Ci-C ⁇ -alkyl, and every R 4 is Ci-C ⁇ -alkyl. [72] In some embodiments, at least one R 3 is H, and at least one R 4 is Ci-C ⁇ -alkyl.
  • every R 3 is H, and every R 4 is independently selected Ci-Ce-alkyl.
  • Each R 5 is independently selected from Ci-C ⁇ -alkyl, Cs-Cs-cycloalkyl, C 1 -C 6 - alkoxy, -CN, halogen, -SO 2 R, -SOR, -SR, and heterocyclyl (i.e., a heterocycloalkyl, heterocycloalkenyl, or heteroaryl).
  • the Ci-C ⁇ -alkyl, Cs-Cg-cycloalkyl, and Ci-C ⁇ -alkoxy are optionally substituted with one or more independently selected halogens.
  • the heterocyclyl is optionally substituted with Ci-C 4 -alkyl or halogen.
  • At least one R 5 is halogen. In some such embodiments, for example, at least one R 5 is fluoro. In other such embodiments, for example, at least one R 5 is bromo. In still other such embodiments, for example, at least one R 5 is chloro.
  • At least one R 5 is Ci-C ⁇ -alkyl. In some such embodiments, for example, at least one R 5 is methyl.
  • At least one R 5 is Ci -C ⁇ -alkoxy. In some such embodiments, for example, at least one R 5 is methoxy. [78] In some embodiments, at least one R 5 is -SO 2 R. In some such embodiments, for example, at least one R 5 is propylsulfonyl. In other such embodiments, at least one R 5 is dimethylaminosulfonyl. In other such embodiments, at least one R 5 is cy clopropy lmethy lsulfony 1.
  • At least one R 5 is heteroaryl. In some such embodiments, for example, at least one R 5 is pyrazolyl. [80] In some embodiments, at least one R 5 is heteroaryl substituted with C 1 -C 4 - alkyl or halogen. In some such embodiments, for example, at least one R 5 is methylpyrazolyl.
  • each R 5 is different.
  • the R 5 are the same.
  • Each R 6 is independently selected from Ci-C ⁇ -alkyl, Ci-C ⁇ -alkoxy, halogen, -SO 2 R, -SOR, -SR, phenyl, -CF 3 , -OCF 3 , -CN, and heterocyclyl (i.e., heterocycloalkyl, heterocycloalkenyl, or heteroaryl).
  • the heterocyclyl is optionally substituted with Ci-C 4 -alkyl.
  • each R 6 is independently selected from Ci-C ⁇ -alkyl, Ci- C ⁇ -alkoxy, halogen, -SR, phenyl, and -CF 3 .
  • At least one R 6 is halogen. In some such embodiments, for example, at least one R 6 is fluoro. In other such embodiments, at least one R 6 is chloro. In still other such embodiments, at least one R 6 is bromo.
  • At least one R 6 is Ci-C ⁇ -alkyl. In some such embodiments, for example, at least one R 6 is methyl.
  • At least one R 6 is CF 3 .
  • At least one R 6 is Ci-C ⁇ -alkoxy. In some such embodiments, for example, at least one R 6 is methoxy.
  • At least one R 6 is phenyl
  • At least one R 6 is -SR. In some such embodiments, for example, at least one R 6 is methylsulfanyl.
  • each R 6 is different.
  • Each R 7 is independently selected from Ci-C ⁇ -alkyl, Ci-C 4 -alkoxy, -CF 3 , -OCF 3 , -CN, -SO 2 R, -SOR, -SR, phenyl, Ci-C 4 -alkoxy, and heterocyclyl ⁇ i.e., a heterocycloalkyl, heterocycloalkenyl, or heteroaryl).
  • the Ci-C ⁇ -alkyl, C 3 -C 8 -cycloalkyl, and Ci-C 4 -alkoxy are optionally substituted.
  • the Ci-C 6 - alkyl, C 3 -C8-cycloalkyl, and Ci-C4-alkoxy are optionally substituted with one or more independently selected halogen.
  • each R 7 is independently selected from Ci-C 6 -alkyl, C 1 - C 4 -alkoxy, -CN, -SO 2 R, -SOR, -SR, and Ci-C 4 -alkoxy.
  • Each Ci-C 6 -alkyl, C 3 -C 8 -cycloalkyl, and Ci-C 4 -alkoxy are optionally substituted with one or more independently selected halogens.
  • At least one R 7 is Ci-C 6 -alkyl optionally substituted with one or more halogens. In some such embodiments, for example, at least one R 7 is methyl. In other such embodiments, at least one R 7 is -CF 3 . [96] In some embodiments, at least one R 7 is Ci-C 4 -alkoxy optionally substituted with one or more halogens. In some such embodiments, for example, at least one R 7 is -OCF 3 .
  • At least one R 7 is phenyl.
  • At least one R 7 is heterocyclyl. [99] In some embodiments wherein more than one R 7 is present, each R 7 is different.
  • R 7 are the same.
  • a 1 is phenyl; and A 2 is phenyl substituted with 1, 2, or 3 R 2 groups. Excluded from such embodiments, however, are compounds wherein A 2 is phenyl substituted with 1, 2, or 3 groups independently selected from halogen, -CN, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, -SO 2 NR 3 R 4 , -NH 2 , -S-Ci-C 6 -alkyl, Ci-C 6 -alkyl, Ci- C 6 -alkoxy, halo-Ci-C 6 -alkyl, and halo-Ci-C 6 -alkoxy.
  • a 1 is phenyl (i.e., the compound corresponds in structure to Formula (II)), and A 2 is heteroaryl.
  • a 1 is phenyl; and A 2 is a heteroaryl substituted with 1, 2, or 3 R 6 groups.
  • the compound corresponds in structure to:
  • a 1 is phenyl substituted with 1, 2, or 3 R 5 groups; and A 2 is phenyl substituted with 1, 2, or 3 R 2 groups.
  • a 1 is phenyl substituted with 1, 2, or 3 R 5 groups; and A 2 is a heteroaryl.
  • a 1 is phenyl substituted with 1, 2, or 3 R 5 groups; and A 2 is a heteroaryl substituted with 1, 2, or 3 R 6 groups.
  • a 1 is a 5- or 6-membered heteroaryl; and A 2 is phenyl substituted with 1, 2, or 3 R 2 groups. [108] In some embodiments, A 1 is a 5- or 6-membered heteroaryl, and A 2 is a heteroaryl.
  • a 1 is a 5- or 6-membered heteroaryl; and A 2 is a heteroaryl substituted with 1, 2, or 3 R 6 groups.
  • a 1 is a 5- or 6-membered heteroaryl substituted with 1, 2, or 3 R 7 groups; and A 2 is phenyl substituted with 1, 2, or 3 R 2 groups.
  • a 1 is a 5- or 6-membered heteroaryl substituted with 1, 2, or 3 R 7 groups; and A 2 is a heteroaryl.
  • a 1 is a 5- or 6-membered heteroaryl substituted with 1, 2, or 3 R 7 groups; and A 2 is a heteroaryl substituted with 1, 2, or 3 R 6 groups.
  • the compound or salt is a compound or salt described in
  • the compound or salt is a compound corresponding in to the non-salt structure shown in Table 1 below or a pharmaceutically acceptable salt thereof.
  • the compound or salt is a compound shown in Table 2 below or a pharmaceutically acceptable salt thereof.
  • the compound or salt is a compound shown in Table 3 below or a pharmaceutically acceptable salt thereof.
  • the compound or salt is a single optical isomer, a racemic mixture, or any other mixture of optical isomers corresponding to a structure below or a pharmaceutically acceptable salt of such an isomer, racemic mixture, or other mixture of optical isomers:
  • the compound or salt is a single optical isomer, a racemic mixture, or any other mixture of optical isomers corresponding to the structure below or a pharmaceutically acceptable salt of such an isomer, racemic mixture, or other mixture of optical isomers:
  • the compound or salt could comprise, for example, the following isomer or a pharmaceutically acceptable salt thereof:
  • the compound or salt could alternatively comprise the following isomer or a pharmaceutically acceptable salt thereof:
  • the compound or salt could comprise a racemic mixture of the above two isomers (i.e., a mixture of the two isomers wherein the ratio of the two isomers is approximately 50:50) or a pharmaceutically acceptable salt thereof.
  • the compound or salt could comprise any other mixture of the above two isomers or a pharmaceutically acceptable salt thereof.
  • the compound or salt is a single optical isomer, a racemic mixture, or any other mixture of optical isomers corresponding to a structure below or a pharmaceutically acceptable salt of such an isomer, racemic mixture, or other mixture of optical isomers:
  • All the compounds of this invention include at least one chiral carbon, i.e., the carbon linking the 2-aza-bicyclo[2.2.2]octane group with A 1 and the amino:
  • Formula (I) is intended to encompass any single chiral isomer corresponding to Formula (I), as well as any mixture of chiral isomers (e.g., the racemate) corresponding to Formula (I).
  • Formula (I) encompasses a single chiral isomer corresponding to Formula (IA):
  • Formula (I) also encompasses a single chiral isomer corresponding to Formula (IB):
  • Formula (I) also encompasses a racemic mixture of the above chiral isomers (i.e., a mixture of the two isomers wherein the ratio of the two isomers is approximately 50:50). And Formula (I) encompasses any other mixture of the above two chiral isomers wherein the ratio of the two isomers is other than approximately 50:50.
  • a single chiral isomer corresponding to Formula (I) (or a salt thereof) is obtained by isolating it from a mixture of isomers (or a salt thereof) using, for example, chiral chromatographic separation.
  • a single chiral isomer of Formula (I) (or a salt thereof) is obtained through direct synthesis from, for example, a chiral starting material.
  • the ratio of one chiral isomer to its mirror chiral isomer is greater than about 9:1. In some such embodiments, the ratio is at least about 95:5. In other such embodiments, the ratio is at least about 98:2. In still yet other such embodiments, the ratio is at least about 99: 1. And in still yet other such embodiments, one chiral isomer is present without any detectible amount of its mirror chiral isomer.
  • Formula (IB) can alternatively be depicted as follows in Formula (IB-I):
  • Contemplated salts of the compounds of this invention include both acid addition salts.
  • a salt may be advantageous due to one or more of its chemical or physical properties, such as stability in differing temperatures and humidities, or a desirable solubility in water, oil, or other solvent.
  • a salt may be used to aid in the isolation or purification of the compound.
  • the salt is pharmaceutically acceptable.
  • an acid addition salt can be prepared using various inorganic or organic acids.
  • Such salts can typically be formed by, for example, mixing the compound with an acid (e.g., a stoichiometric amount of acid) using various methods known in the art. This mixing may occur in water, an organic solvent (e.g. , ether, ethyl acetate, ethanol, isopropanol, or acetonitrile), or an aqueous/organic mixture.
  • an organic solvent e.g. , ether, ethyl acetate, ethanol, isopropanol, or acetonitrile
  • examples of inorganic acids that typically may be used to form acid addition salts include hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric, and phosphoric acid.
  • organic acids include, for example, aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids.
  • organic salts include cholate, sorbate, laurate, acetate, trifluoroacetate, formate, propionate, succinate, glycolate, gluconate, digluconate, lactate, malate, tartaric acid (and derivatives thereof, e.g.
  • dibenzoyltartrate citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate, benzoate, anthranilic acid, mesylate, stearate, salicylate, p-hydroxybenzoate, phenylacetate, mandelate (and derivatives thereof), embonate (pamoate), ethanesulfonate, benzenesulfonate, pantothenate, 2- hydroxyethanesulfonate, sulfanilate, cyclohexylaminosulfonate, algenic acid, ⁇ - hydroxybutyric acid, galactarate, galacturonate, adipate, alginate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, dodecylsulfate, glycoheptanoate, glycerophosphate, heptanoate,
  • the salt is selected from acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edentate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, myethylsulfate, mutate, napsylate, nitrate, N-methylglucarnine ammonium salt, oleate,
  • the compounds of Formula (I) and salts thereof are intended to encompass any tautomer that may form.
  • a "tautomer” is any other structural isomer that exists in equilibrium resulting from the migration of a hydrogen atom, e.g. , amide-imidic acid tautomerism.
  • an amine of a compound of Formula (I) or a salt thereof may form an N-oxide.
  • Such an N-oxide is intended to be encompassed by the compounds of Formula (I) and salts thereof.
  • An N-oxide can generally be formed by treating an amine with an oxidizing agent, such as hydrogen peroxide or a per-acid (e.g., a peroxycarboxylic acid).
  • N-oxides also can be made by reacting the amine with m-CPBA, for example, in an inert solvent, such as dichloromethane. See L. W. Deady, Syn. Comm., 1 , pp. 509-514 (1977).
  • a compound of Formula (I) or salt thereof could form isolatable atropisomer in certain solvents at certain temperatures.
  • the compounds of Formula I and salts thereof are intended to encompass any such atropisomers.
  • Atropisomers can generally be isolated using, for example, chiral LC.
  • the compounds of Formula (I) and salts thereof are intended to encompass any isotopically-labeled (or "radio-labeled") derivatives of a compound of Formula (I) or salt thereof.
  • a derivative is a derivative of a compound of Formula (I) or salt thereof wherein one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature.
  • radionuclides examples include 2 H (also written as "D" for deuterium), 3 H
  • radionuclide (also written as "T” for tritium), 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 18 F, 35 S, 36 Cl, 82 Br, 75 Br, 76 Br, 77 Br, 123 I, 124 I, 125 I, and 131 L.
  • the radionuclide that is used will depend on the specific application of that radio-labeled derivative. For example, for in vitro receptor labeling and competition assays, 3 H or 14 C are often useful. For radio-imaging applications, 11 C or 18 F are often useful. In some embodiments, the radionuclide is 3 H. In some embodiments, the radionuclide is 14 C. In some embodiments, the radionuclide is 11 C. And in some embodiments, the radionuclide is 18 F.
  • the compounds of Formula (I) and salts thereof are intended to cover all solid- state forms of the compounds of Formula (I) and salts thereof.
  • the compounds of Formula (I) and salts thereof also are intended to encompass all solvated ⁇ e.g. , hydrated) and unsolvated forms of the compounds of Formula (I) and salts thereof.
  • the compounds of Formula (I) and salts thereof also are intended to encompass coupling partners in which a compound of Formula (I) or a salt thereof is linked to a coupling partner by, for example, being chemically coupled to the compound or salt or physically associated with it.
  • Examples of coupling partners include a label or reporter molecule, a supporting substrate, a carrier or transport molecule, an effector, a drug, an antibody, or an inhibitor.
  • Coupling partners can be covalently linked to a compound of Formula (I) or salt thereof via an appropriate functional group on the compound, such as an amino group.
  • Other derivatives include formulating a compound of Formula (I) or a salt thereof with liposomes.
  • Mammals include, for example, humans. Mammals also include, for example, companion animals (e.g., dogs, cats, and horses), livestock animals (e.g., cattle and swine); lab animals (e.g., mice and rats); and wild, zoo, and circus animals (e.g., bears, lions, tigers, apes, and monkeys).
  • companion animals e.g., dogs, cats, and horses
  • livestock animals e.g., cattle and swine
  • lab animals e.g., mice and rats
  • wild, zoo, and circus animals e.g., bears, lions, tigers, apes, and monkeys.
  • the compounds and salts of this invention have been observed to modulate, and, in particular, act as antagonist against, the glycine transporter 1 ("GIyTl"). Accordingly, it is believed that the compounds and salts of this invention can be used to modulate the glycine transporter to treat various conditions mediated by (or otherwise associated with) the glycine transporter. In some embodiments, the compounds and salts of this invention exhibit one or more of the following characteristics: desirable potency, desirable efficacy, desirable stability on the shelf, desirable tolerability for a range of patients, and desirable safety.
  • a compound of Formula (I) or a salt thereof is used to modulate (typically antagonize) GIyT 1.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof is used to treat a condition (typically a disorder) associated with GIyTl activity.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof is used to treat a psychosis in a patient in need of such treatment.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof is used to treat a cognitive disorder in a patient in need of such treatment.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof is used to treat a psychotic disorder.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof is used to treat schizophrenia.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof is used to treat a schizoaffective disorder.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof is used to treat a delusional disorder.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof is used to treat a brief psychotic disorder.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof is used to treat a shared psychotic disorder.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof is used to treat a psychotic disorder due to a general medical condition.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof is used to treat a mood disorder.
  • Mood disorders include, for example, a) depressive disorders, including but not limited to major depressive disorders and dysthymic disorders; b) bipolar depression and/or bipolar mania including but not limited to bipolar i, including but not limited to those with manic, depressive or mixed episodes, and bipolar ii; c) cyclothymiac's disorders; and d) mood disorders due to a general medical condition.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof is used to treat a bipolar disorder.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof is used to treat a cognitive disorder selected from mania and manic depression disorders.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof is used to treat an anxiety disorder.
  • the anxiety disorder comprises a disorder selected from a panic disorder without agoraphobia, panic disorder with agoraphobia, agoraphobia without history of any panic disorder, specific phobia, social phobia, an obsessive-compulsive disorder, a stress related disorder, a posttraumatic stress disorder, an acute stress disorder, a generalized anxiety disorder, and a generalized anxiety disorder due to a general medical condition.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof is used to treat a post-traumatic stress disorder.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof is used to treat dementia.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof is used to treat a sleep disorder.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof is used to treat a disorder that is often first diagnosed in infancy, childhood, or adolescence.
  • disorders generally include, for example, mental retardation, downs syndrome, learning disorders, motor skills disorders, communication disorders, pervasive developmental disorders, attention-deficit and disruptive behavior disorders, feeding and eating disorders of infancy or early childhood, tic disorders, and elimination disorders.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof is used to treat a substance-related disorder.
  • disorders include, for example, substance dependence; substance abuse; substance intoxication; substance withdrawal; alcohol-related disorders; amphetamines (or amphetamine-like)-related disorders; caffeine-related disorders; cannabis-related disorders; cocaine-related disorders; hallucinogen- related disorders; inhalant-related disorders; nicotine-related disorders; opioid-related disorders; phencyclidine (or phencyclidine-like)-related disorders; and sedative-, hypnotic- or anxiolytic-related disorders .
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof is used to treat an attention-deficit and disruptive behavior disorder.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof is used to treat an eating disorder.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof is used to treat a personality disorder.
  • Such disorders include, for example, obsessive-compulsive personality disorders.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof is used to treat an impulse-control disorder.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof is used to treat a tic disorder.
  • Such disorders include, for example, Tourette's disorder, chronic motor or vocal tic disorder; and transient tic disorder.
  • a compound or salt of this invention may be used to treat pain.
  • pain may be, for example, chronic pain, neuropathic pain, acute pain, back pain, cancer pain, pain caused by rheumatoid arthritis, migraine, or visceral pain.
  • a compound of Formula I or a pharmaceutically acceptable salt thereof may be administered orally, buccally, vaginally, rectally, via inhalation, via insufflation, intranasally, sublingually, topically, or parenterally (e.g., intramuscularly, subcutaneously, intraperitoneally, intrathoracially, intravenously, epidurally, intrathecally, intracerebroventricularly, or by injection into the joints).
  • parenterally e.g., intramuscularly, subcutaneously, intraperitoneally, intrathoracially, intravenously, epidurally, intrathecally, intracerebroventricularly, or by injection into the joints.
  • a compound or salt of this invention is administered orally.
  • a compound or salt of this invention is administered intravenously.
  • a compound or salt of this invention is administered intramuscularly.
  • a compound or salt of this invention is used to make a medicament (i.e., a pharmaceutical composition).
  • the pharmaceutical composition comprises a therapeutically effective amount of the compound or salt.
  • Pharmaceutical compositions comprising a compound or salt of this invention can vary widely. Although it is contemplated that a compound or salt of this invention could be administered by itself (i.e., without any other active or inactive ingredient), the pharmaceutical composition normally will instead comprise one or more additional active ingredients and/or inert ingredients.
  • carriers and diluents The inert ingredients present in the pharmaceutical compositions of this invention are sometimes collectively referred to as "carriers and diluents.”
  • Methods for making pharmaceutical compositions and the use of carriers and diluents are well known in the art. See, e.g., for example, Remington 's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, 15th Edition, 1975.
  • compositions comprising a compound of Formula I or pharmaceutically acceptable salt thereof can vary widely.
  • the compositions may be formulated for a variety of suitable routes and means of administration, including oral, rectal, nasal, topical, buccal, sublingual, vaginal, inhalation, insufflation, or parenteral administration. It is contemplated that such compositions may, for example, be in the form of solids, aqueous or oily solutions, suspensions, emulsions, creams, ointments, mists, gels, nasal sprays, suppositories, finely divided powders, and aerosols or nebulisers for inhalation.
  • the composition comprises a solid or liquid dosage form that may be administered orally.
  • Solid form compositions may include, for example, powders, tablets, dispersible granules, capsules, cachets, and suppositories.
  • a solid carrier may comprise one or more substances. Such substances are generally inert.
  • a carrier also may act as, for example, a diluent, flavoring agent, solubilizer, lubricant, preservative, stabilizer, suspending agent, binder, or disintegrating agent. It also may act as, for example, an encapsulating material.
  • Examples of often suitable carriers include pharmaceutical grade mannitol, lactose, magnesium carbonate, magnesium stearate, talc, lactose, sugar (e.g. , glucose and sucrose), pectin, dextrin, starch, tragacanth, cellulose, cellulose derivatives (e.g., methyl cellulose and sodium carboxymethyl cellulose), sodium saccharin, low-melting wax, and cocoa butter.
  • the carrier is typically a finely divided solid, which is in a mixture with the finely divided active component.
  • the active component is typically mixed with the carrier having the desirable binding properties in suitable proportions and compacted into the desired shape and size.
  • a low-melting wax e.g., a mixture of fatty acid glycerides and cocoa butter
  • a low-melting wax e.g., a mixture of fatty acid glycerides and cocoa butter
  • the molten homogeneous mixture is then poured into convenient-sized molds and allowed to cool and solidify.
  • non-irritating excipients include, for example, cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol.
  • Liquid compositions can be prepared by, for example, dissolving or dispersing the compound or a salt of this invention in a carrier, such as, for example, water, water/propylene glycol solutions, saline aqueous dextrose, glycerol, or ethanol.
  • aqueous solutions for oral administration can be prepared by dissolving a compound or salt of this invention in water with a solubilizer (e.g., a polyethylene glycol).
  • a solubilizer e.g., a polyethylene glycol
  • aqueous suspensions for oral use can be made by dispersing the compound or salt of this invention in a finely divided form in water, together with a viscous material, such as, for example, one or more natural synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, or other suspending agents.
  • a viscous material such as, for example, one or more natural synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, or other suspending agents.
  • the liquid composition also may contain other non-toxic auxiliary inert ingredients, such as, for example, wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, sorbitan monolaurate, triethanolamine oleate, etc.
  • Such compositions also may contain other ingredients, such as, for example, one or more pharmaceutical adjuvants.
  • the pharmaceutical composition comprises from about
  • the pharmaceutical composition comprises from about 0.10% to about 50% (by weight) of a compound or salt of this invention.
  • a "therapeutically effective amount” is an amount sufficient to reduce or completely alleviate symptoms or other detrimental effects of the condition; cure the condition; reverse, completely stop, or slow the progress of the condition; reduce the risk of the condition getting worse; or delay or reduce the risk of onset of the condition.
  • the optimum dosage and frequency of administration will depend on the particular condition being treated and its severity; the species of the patient; the age, size and weight, diet, and general physical condition of the particular patient; brain/body weight ratio; other medication the patient may be taking; the route of administration; the formulation; and various other factors known to physicians (in the context of human patients), veterinarians (in the context of non-human patients), and others skilled in the art.
  • the optimum amount of a compound or salt of this invention is greater than about 10 pg/kg of body weight per day. In some embodiments, the optimum amount of a compound or salt of this invention is at least about 0.1 mg/kg of body weight per day. In some embodiments, the optimum amount is no greater than about 20 mg/kg of body weight per day. In some embodiments, the optimum amount is from about 0.1 mg/kg to about 20 mg/kg of body weight per day. [175] It is contemplated that the pharmaceutical compositions can be in one or more unit dosage forms. Accordingly, the composition may be divided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be, for example, a capsule, cachet, or tablet itself, or it can be the appropriate number of any of these in packaged forms.
  • the unit dosage form alternatively can be a packaged preparation in which the package contains discrete quantities of the composition, such as, for example, packeted tablets, capsules, or powders in vials or ampoules.
  • Unit dosage forms may be prepared by, for example, various methods well known in the art of pharmacy.
  • a dosage can be given once daily or in divided doses, such as, for example, from 2 to 4 times per day.
  • a compound of Formula (I) or a salt thereof may be administered concurrently, simultaneously, sequentially, or separately with one or more other pharmaceutically active compounds. It is contemplated that, in some such embodiments, the other pharmaceutically active compound(s) may be one or more other compounds of Formula (I) and/or pharmaceutically acceptable salts thereof.
  • the other pharmaceutically active compound(s) may be selected from one or more of the following: antidepressants; antipsychotics; anxiolytics; anticonvulsants; Alzheimer's therapies; Parkinson's therapies; agents for treating extrapyramidal symtpoms; migraine therapies; stroke therapies; neuropathic pain therapies; nociceptive pain therapies; insomnia therapies; mood stabilizers; agents for treating ADHD; agents used to treat substance abuse disorders, dependence, and withdrawal; a cognitive enhancing agent; a memory enhancing agent; an anti-inflammatory agent; and a selective serotonin reuptake inhibitor (or "serotonin-specific reuptake inhibitor" or SSRI").
  • a compound of Formula (I) or salt thereof may be administered as part of a combination therapy with radiotherapy.
  • a compound of Formula (I) or salt thereof may be administered as a combination therapy with chemotherapy.
  • the chemotherapy includes one or more of the following categories of antitumor agents: antiproliferative/antineoplastic drugs, cytostatic agents, anti-invasion agents, inhibitors of growth factor function, antiangiogenic agents, vascular damaging agents, endothelin receptor antagonists, antisense therapies, gene therapy approaches, and immunotherapy approaches.
  • a compound of Formula (I) or salt thereof may be useful as an analgesic agent for use during general anesthesia or monitored anesthesia care.
  • Combinations of agents with different properties are often used to achieve a balance of effects needed to maintain the anesthetic state (e.g. , amnesia, analgesia, muscle relaxation, and sedation).
  • Such a combination may include, for example, one or more inhaled anesthetics, hypnotics, anxiolytics, neuromuscular blockers, and/or opioids.
  • the amount of a compound of Formula (I) or a salt thereof and the amount of the other pharmaceutically active agent(s) are, when combined, therapeutically effective to treat a targeted disorder in the animal patient.
  • the combined amounts are "therapeutically effective amount” if they are, when combined, sufficient to reduce or completely alleviate symptoms or other detrimental effects of the disorder; cure the disorder; reverse, completely stop, or slow the progress of the disorder; reduce the risk of the disorder getting worse; or delay or reduce the risk of onset of the disorder.
  • such amounts may be determined by one skilled in the art by, for example, starting with the dosage range described in this patent for a compound of Formula (I) or a salt thereof and an approved or otherwise published dosage range(s) of the other pharmaceutically active compound(s).
  • a compound of Formula (I) or a salt thereof and the other active ingredients may be administered in a single composition, completely separate compositions, or a combination thereof. It also is contemplated that the active ingredients may be administered concurrently, simultaneously, sequentially, or separately.
  • the particular composition(s) and dosing frequency(ies) of the combination therapy will depend on a variety of factors, including, for example, the route of administration, the condition being treated, the species of the patient, any potential interactions between the active ingredients when combined into a single composition, any interactions between the active ingredients when they are administered to the animal patient, and various other factors known to physicians (in the context of human patients), veterinarians (in the context of non-human patients), and others skilled in the art.
  • kits comprising a compound of Formula (I) or a salt thereof.
  • the kit further comprises one or more additional components, such as, for example: (a) an apparatus for administering the compound of Formula (I) or salt thereof; (b) instructions for administering the compound of Formula (I) or salt thereof; (c) a carrier, diluent, or excipient (e.g., a re-suspending agent); and (d) an additional active ingredient, which may be in the same and/or different dosage forms as the compound of Formula (I) or salt thereof.
  • the salt is a pharmaceutically acceptable salt.
  • GIyTIb-CHO cells Preparation of recombinant human GIyTIb-CHO cells (hGlyT Ib-CHO).
  • the human GIyTIb CDS (GC002087, NM 006934) was cloned downstream of a CMV promoter in a bicistronic expression vector containing a hygromycin B resistance gene.
  • CHO-Kl cells ATCC were transfected with the recombinant vector containing GIyTIb using Lipofectamine 2000 (Invitrogen) and cultured in Ham's/F12 media supplemented with 10% fetal bovine serum, 2 mM L-glutamine at 37 0 C, 5% CO 2 , 90% humidity.
  • cell culture medium Ham's/F12 (Modified) (Mediatech, 10-080-CM), containing 10% FBS, 2 mM L-glutamine (Invitrogen 25030-149) and 0.5 mg/mL hygromycin B (Invitrogen, 10687-010)) in 175 cm flasks until near confluence before use in the assay.
  • Cell suspension Cell medium in a cell culture flask containing near confluent cells was removed and 5 mL of cell stripper was added to submerge all cells on the surface of the culture flask. Cell stripper was removed immediately and the flask incubated in a 37 0 C incubator for ⁇ 5 min. Cells were shaken loose and suspended in 5 mL of PBS. After splitting cells to initiate a new flask(s), the cells remaining were collected by centrifugation, counted, and resuspended in assay buffer to a density of ⁇ 2 million/mL. The cell suspension was kept at room temperature before use.
  • the assays buffer was 10 mM HEPES, pH 7.4, containing 150 mM NaCl, 5 mM KCl, 1.5 mM CaCl 2 , 1.5 mM MgCl 2 , 0.45 mg/mL L-alanine (added fresh), and 1.8 mg/mL D-glucose (added fresh).
  • SPA and isotope mixture WGA PTV beads were suspended in assay buffer (2 mg/ml) containing 60 nM [ 3 H]Glycine (PerkinElmer (NET-004, [2- 3 H]Glycine, 53.3 Ci/mmol, 1 mCi/mL)) and 20 ⁇ M unlabeled glycine and the suspension was kept at room temperature before assay.
  • assay buffer 2 mg/ml
  • NET-004 [2- 3 H]Glycine, 53.3 Ci/mmol, 1 mCi/mL
  • Electrospray Column Acquity UPLC BEH C18 2.1x50mm x 1.7um
  • Mass spectroscopy method MS3 Instrumentation: Waters ZMD fronted by an Agilent 1100 LC
  • Mobile Phase B Water :Acetonitrile: Formic acid (2:98:0.05 v/v) Gradient: Time (%B): 0(5); 3.0(90); 4.0(90); 4.5(5).
  • Method 1 depicts a generalized scheme suitable for racemic synthesis of compounds of Formula I.
  • Those skilled in the art will readily recognize various reagents and intermediates or changes in moieties that could be used to make additional compounds of Formula I.
  • Step A Preparation of methyl 2-methyl-3-oxo-2-azabicyclo[2.2.2]octane-l- carboxylate from methyl 3-oxo-2-azabicyclo[2.2.2]octane-l-carboxylate.
  • Step B Preparation of (2-methyl-2-azabicyclo[2.2.2]octan-l-yl)methanol from methyl 2-methyl-3-oxo-2-azabicyclo [2.2.2] octane-1-carboxylate.
  • Step C Preparation of 2-methyl-2-azabicyclo [2.2.2] octane-1-carbaldehyde from (2-methyl-2-azabicyclo[2.2.2]octan-l-yl)methanol.
  • Step D Preparation of 2-methyl-N-((2-methyl-2-azabicyclo[2.2.2]octan-l- yl)methylene)propane-2-sulfinamide from 2-methyl-2-azabicyclo[2.2.2]octane-l- carbaldehyde.
  • Step E Preparation of 2-methyl-N-((2-methyl-2-azabicyclo[2.2.2]octan-l- yl)(phenyl)methyl)propane-2-sulfinamide from 2-methyl-N-((2-methyl-2- azabicyclo[2.2.2]octan-l-yl)methylene)propane-2-sulfinamide.
  • the aqueous layer was made basic with concentrated aqueous ammonium hydroxide and extracted with dichloromethane (x2). The aqueous layer was then saturated with sodium chloride and further extracted with dichloromethane. The combined organic layers following basif ⁇ cation were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated. The resulting oil was vacuum dried at ambient temperature for 30 min to afford (2-methyl-2- azabicyclo[2.2.2]octan-l-yl)(phenyl)methanamine (0.263g, 98%) as a solid.
  • Step G Preparation of 3,5-dichloro-N-((2-methyl-2- azabicyclo[2.2.2]octan-l-yl)(phenyl)methyl)isonicotinamide from (2-methyl-2- azabicyclo[2.2.2]octan-l-yl)(phenyl)methanamine.
  • Step F N-((2-methyl-2-azabicyclo[2.2.2]octan- 1 -yl)(phenyl)methyl)-2-(methylthio)nicotinamide was prepared according to the procedures of Example 1 , Steps A-G, with the following modifications:
  • Step F no workup was performed and (2-methyl-2-azabicyclo[2.2.2]octan- l-yl)(phenyl)methanamine dihydrochloride was obtained via concentration of the reaction mixture; this material was carried on to Step G without further purification.
  • Step G 2- (methylthio)nicotinic acid was substituted for 3,5-dichloroisonicotinic acid.
  • Step G purification of the final product was conducted via preparative HPLC (C 18, 65%-93% acetonitrle in water containing ammonium carbonate, pH 10) and subsequent drying of fractions using a Genevac afforded N-((2-methyl-2-azabicyclo[2.2.2]octan-l- yl)(phenyl)methyl)-2-(methylthio)nicotinamide as a white solid.
  • IH NMR 500 MHz, DMSO-d ⁇ ) ⁇ ppm 1.20 - 1.60 (m, 7 H), 1.77 - 1.87 (m, 1 H), 1.98 - 2.09 (m, 1 H), 2.33 (br.
  • Method 2 depicts a generalized scheme suitable for preparation of compounds of Formula I by chiral resolution of an intermediate.
  • Those of skill in the art will readily recognize various reagents and intermediates or changes in moieties that could be used to make additional compounds of Formula I.
  • Step A Preparation of tert-butyl ⁇ -methyl ⁇ -azabicyclo ⁇ j ⁇ octan-l- yl)(phenyl)methylcarbamate from (2-methyl-l-azabicyclo [2.2.2] octan-1- yl)(phenyl)methanamine.
  • Step B Preparation of (S)-tert-butyl (2-methyl-2-azabicyclo [2.2.2] octan-1- yl)(phenyl)methylcarbamate and (R)-tert-butyl (2-methyl-2-azabicyclo [2.2.2] octan-1- yl)(phenyl)methylcarbamate from tert-butyl (2-methyl-2-azabicyclo [2.2.2] octan-1- yl)(phenyl)methylcarbamate
  • Chiral analytical supercritical fluid (CO 2 ) chromatography was carried out using a 4.6 x 250 mm ChiralPak IA column with a modifier composed of methanol containing 0.3% isopropyl amine.
  • the flow rate was 2.37 mL/min with the following gradient: isocratic hold at 5% modifier for 1 min, then ramping at 5% per minute to 50% modifier, then holding at this mixture for 5 minutes.
  • Step C Preparation of (S)-(2-methyl-2-azabicyclo[2.2.2]octan-l- yl)(phenyl)methanamine and (R)-(2-methyl-2-azabicyclo[2.2.2]octan-l- yl)(phenyl)methanamine from (S)-tert-butyl (2-methyl-2-azabicyclo [2.2.2] octan-1- yl)(phenyl)methylcarbamate and (R)-tert-butyl (2-methyl-2-azabicyclo [2.2.2] octan-1- yl)(phenyl)methylcarbamate.
  • the resulting residues were reconcentrated from methanol (x2; water bath temp: 45-50 0 C) and then partitioned between water and dichloromethane. The layers were separated, and the organic layer was discarded. The aqueous layer was basif ⁇ ed with concentrated aqueous ammonium hydroxide and then extracted with dichloromethane (x2). The aqueous layer was saturated with sodium chloride and further extracted with dichloromethane. The combined organic layers were washed with saturated aqueous sodium chloride, dried over magnesium sulfate, filtered, and concentrated.
  • This compound was prepared by reacting presumed (S)-(2-methyl-2-azabicyclo[2.2.2]octan- l-yl)(phenyl)methanamine with excess ((lS,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-l- yl)methanesulfonyl chloride and triethyl amine in dichloromethane for 16 h.
  • the desired compound was prepared according to the procedure of Example 1, Step G, with the following modifications:
  • the acid 2-(methylthio)nicotinic acid was substituted for 3,5- dichloroisonicotinic acid and (R)-(2-methyl-2-azabicyclo[2.2.2]octan-l- yl)(phenyl)methanamine was substituted for (2-methyl-2-azabicyclo[2.2.2]octan-l- yl)(phenyl)methanamine.
  • the oil obtained from flash column chromatography was dissolved in acetonitrile and treated with one equivalent of citric acid monohydrate in water.
  • Method 3 depicts a generalized scheme suitable for enantioselective synthesis of compounds of Formula I.
  • R and n can be selected as described elsewhere herein.
  • Step A Preparation of 2-methyl-3-oxo-2-azabicyclo[2.2.2]octane-l- carbaldehyde from methyl 2-methyl-3-oxo-2-azabicyclo[2.2.2]octane-l-carboxylate.
  • Step B Preparation of (R)-2-methyl-N-((2-methyl-3-oxo-2- azabicyclo[2.2.2]octan-l-yl)methylene)propane-2-sulfinamide from crude 2-methyl-3- oxo-2-azabicyclo [2.2.2] octane-1-carbaldehyde.
  • Step C Preparation of (R)-2-methyl-N-((R)-(2-methyl-3-oxo-2- azabicyclo[2.2.2]octan-l-yl)(phenyl)methyl)propane-2-sulfinamide from (R)-2-methyl-N- ((2-methyl-3-oxo-2-azabicyclo[2.2.2]octan-l-yl)methylene)propane-2-sulfinamide.
  • Phenyllithium (1.8 M in di-n-butyl ether, 0.230 mL, 0.41 mmol) was added dropwise over 5 minutes. After 45 min, the reaction mixture was quenched with 1 : 1 concentrated aqueous ammonium hydroxide and saturated aqueous ammonium chloride. The cooling bath was removed, and the mixture was warmed to ambient temperature. The mixture was then extracted with ethyl acetate (x2), and the combined organic layers were washed with water and saturated aqueous sodium chloride, dried over magnesium sulfate, filtered, and concentrated.
  • Step D Preparation of (R)-2-methyl-N-((R)-(2-methyl-2- azabicyclo[2.2.2]octan-l-yl)(phenyl)methyl)propane-2-sulfinamide from (R)-2-methyl-N-
  • Step E Preparation of (R)-(2-methyl-2-azabicyclo[2.2.2]octan-l- yl)(phenyl)methanamine from (R)-2-methyl-N-((R)-(2-methyl-2-azabicyclo [2.2.2] octan- l-yl)(phenyl)methyl)propane-2-sulfinamide.
  • Step F Preparation of (R)-3-bromo-N-((2-methyl-2- azabicyclo[2.2.2]octan-l-yl)(phenyl)methyl)isonicotinamide from (R)-(2-methyl-2- azabicyclo[2.2.2]octan-l-yl)(phenyl)methanamine.
  • the desired compound was prepared according to the procedure of Example 1, Step G, with the following modifications:
  • the acid 3-bromoisonicotinic acid was substituted for 3,5- dichloroisonicotinic acid and (R)-(2-methyl-2-azabicyclo[2.2.2]octan-l- yl)(phenyl)methanamine was substituted for (2-methyl-2-azabicyclo[2.2.2]octan-l- yl)(phenyl)methanamine.
  • no workup was performed.
  • the crude reaction mixture was filtered, diluted with methanol and purified directly via preparative HPLC (C 18, acetonitrile in water containing ammonium carbonate, pH 10) to afford the desired product as a white foam solid upon concentration.
  • Method 4 depicts a generalized scheme suitable for the stereoselective synthesis of sulfonamides of Formula I.
  • Those skilled in the art will readily recognize various reagents and intermediates or changes in moieties that could be used to make additional aryl sulfonamides, either stereoselectively or in racemic form.
  • Step A Preparation of 4-bromo-N,N-dimethylbenzenesulfonamide from 4- bromobenzene-1-sulfonyl chloride.
  • Step C Preparation of 4-((R*)-((R)-l,l-dimethylethylsulfinamido)(2- methyl-2-azabicyclo [2.2.2] octan-l-yl)methyl)-N,N-dimethylbenzenesulfonamide from 4- ((R*)-((R)-l,l-dimethylethylsulfinamido)(2-methyl-3-oxo-2-azabicyclo[2.2.2]octan-l- yl)methyl)-N,N-dimethylbenzenesulfonamide.
  • Step D Preparation of (R*)-N-((4-(N,N-dimethylsulfamoyl)phenyl)(2- methyl-2-azabicyclo [2.2.2] octan-l-yl)methyl)-2,6-dimethylbenzamide from 4-((R*)-((R)- l,l-dimethylethylsulfinamido)(2-methyl-2-azabicyclo[2.2.2]octan-l-yl)methyl)-N,N- dimethylbenzenesulfonamide.
  • Step B Preparation of (R)-N-((R*)-(4-(cyclopropylmethylthio)phenyl)(2- methyl-3-oxo-2-azabicyclo[2.2.2]octan-l-yl)methyl)-2-methylpropane-2-sulfinamide from (R)-2-methyl-N-((2-methyl-3-oxo-2-azabicyclo [2.2.2] octan-1- yl)methylene)propane-2-sulfinamide.
  • Method 6 depicts a generalized scheme suitable for the racemic synthesis of sulfones of Formula I.
  • Those skilled in the art will readily recognize various reagents and intermediates or changes in moieties that could be used to make additional aryl sulfones, either stereoselectively or in racemic form.
  • Example 8 Preparation of 2-chloro-N-((2-methyl-2- azabicyclo[2.2.2]octan-l-yl)(4-(propylsulfonyl)phenyl)methyl)-3- (trifluoromethyl)benzamide.
  • Step A Preparation of (4-bromophenyl)(propyl)sulfane from 4- bromobenzenethiol.
  • Step B Preparation of l-(hydroxymethyl)-2-methyl-2- azabicyclo [2.2.2] octan-3-one from methyl 2-methyl-3-oxo-2-azabicyclo[2.2.2]octane-l- carboxylate.
  • Step C Preparation of 2-methyl-3-oxo-2-azabicyclo[2.2.2]octane-l- carbaldehyde from l-(hydroxymethyl)-2-methyl-2-azabicyclo [2.2.2] octan-3-one.
  • Step E Preparation of tert-butyl (2-methyl-3-oxo-2- azabicyclo[2.2.2]octan-l-yl)(4-(propylsulfonyl)phenyl)methylcarbamate from tert-butyl (2-methyl-3-oxo-2-azabicyclo[2.2.2]octan-l-yl)(4-(propylthio)phenyl)methylcarbamate.
  • Step G Preparation of 2-chloro-N-((2-methyl-2-azabicyclo [2.2.2] octan-1- yl)(4-(propylsulfonyl)phenyl)methyl)-3-(trifluoromethyl)benzamide from tert-butyl (2- methyl-2-azabicyclo[2.2.2]octan-l-yl)(4-(propylsulfonyl)phenyl)methylcarbamate.
  • Method 7 depicts a generalized scheme suitable for the racemic synthesis of substituted compounds of Formula I.
  • Those skilled in the art will readily recognize various reagents and intermediates or changes in moieties that could be used to make additional compounds, either stereoselectively or in racemic form.
  • Example 9 substituting 0.5 M (3-chlorophenyl)magnesium bromide in tetrahydrofuran for 1.0 M (3-methoxyphenyl)magnesium bromide in tetrahydrofuran. Additionally, the final product was purified first by preparative LCMS (C 18, acetonitrile in water containing ammonium carbonate, pH 10), then preparative HPLC (C 18, acetonitrile in water containing ammonium carbonate, pH 10), and finally flash column chromatography (SiO 2 , 0-100% ethyl acetate in hexanes) in order to remove all impurities.
  • preparative LCMS C 18, acetonitrile in water containing ammonium carbonate, pH 10
  • HPLC C 18, acetonitrile in water containing ammonium carbonate, pH 10
  • flash column chromatography SiO 2 , 0-100% ethyl acetate in hexanes
  • Method 8 depicts a generalized scheme suitable for the racemic synthesis of furans of Formula I.
  • Those skilled in the art will readily recognize various reagents and intermediates or changes in moieties that could be used to make additional compounds, either stereoselectively or in racemic form.
  • Method 9 depicts a generalized scheme suitable for the racemic synthesis of substituted furans of Formula I.
  • Those skilled in the art will readily recognize various reagents and intermediates or changes in moieties that could be used to make additional compounds, either stereoselectively or in racemic form.
  • Step A Preparation of tert-butyl (2-methyl-2-azabicyclo[2.2.2]octan-l- yl)(5-methylfuran-2-yl)methylcarbamate from 2-methyl-N-((2-methyl-2- azabicyclo[2.2.2]octan-l-yl)methylene)propane-2-sulfinamide.
  • Step B Preparation of 2-chloro-N-((2-methyl-2-azabicyclo[2.2.2]octan-l- yl)(5-methylfuran-2-yl)methyl)-3-(trifluoromethyl)benzamide from tert-butyl (2-methyl- 2-azabicyclo[2.2.2]octan-l-yl)(5-methylfuran-2-yl)methylcarbamate.
  • Method 10 depicts a generalized scheme suitable for the chiral synthesis of substituted furans of Formula I via resolution of a final product.
  • Those skilled in the art will readily recognize various reagents and intermediates or changes in moieties that could be used to make additional compounds, either stereoselectively or in racemic form.
  • Method 11 depicts a generalized scheme suitable for the stereoselective synthesis of isoquinuclidine N-Me sulfones of Formula I.
  • Those skilled in the art will readily recognize various reagents and intermediates or changes in moieties that could be used to make additional aryl sulfones, either stereoselectively or in racemic form.
  • Step A Preparation of (R)-2-methyl-N-((S*)-(2-methyl-3-oxo-2- azabicyclo[2.2.2]octan-l-yl)(4-(propylthio)phenyl)methyl)propane-2-sulfinamide from (R)-2-methyl-N-((2-methyl-3-oxo-2-azabicyclo[2.2.2]octan-l-yl)methylene)propane-2- sulfinamide.
  • Step B Preparation of (S*)-tert-butyl (2-methyl-3-oxo-2- azabicyclo[2.2.2]octan-l-yl)(4-(propylthio)phenyl)methylcarbamate from (R)-2-methyl- N-((S*)-(2-methyl-3-oxo-2-azabicyclo[2.2.2]octan-l-yl)(4- (propylthio)phenyl)methyl)propane-2-sulfinamide.
  • Method 12 depicts a generalized scheme suitable for the stereoselective synthesis of isoquinuclidine N-H sulfones of Formula I.
  • Those skilled in the art will readily recognize various reagents and intermediates or changes in moieties that could be used to make additional aryl sulfones, either stereoselectively or in racemic form.
  • Example 17 Preparation of (R*)-N-(2-azabicyclo[2.2.2]octan-l-yl(4- (propylsulfonyl)phenyl)methyl)-2,6-dimethylbenzamide.
  • Step A Preparation of (4-bromophenyl)(propyl)sulfane from 4- bromobenzenethiol.
  • Step B Preparation of (R)-N-((2-allyl-3-oxo-2-azabicyclo [2.2.2] octan-1- yl)methylene)-2-methylpropane-2-sulfinamide from methyl 3-oxo-2- azabicyclo[2.2.2]octane-l-carboxylate
  • Step C Preparation of (R)-N-((R*)-(2-allyl-3-oxo-2-azabicyclo [2.2.2] octan- l-yl)(4-(propylthio)phenyl)methyl)-2-methylpropane-2-sulf ⁇ namide and (R)-N-((S*)-(2- allyl-3-oxo-2-azabicyclo[2.2.2]octan-l-yl)(4-(propylthio)phenyl)methyl)-2- methylpropane-2-sulfinamide from (R)-N-((2-allyl-3-oxo-2-azabicyclo [2.2.2] octan-1- yl)methylene)-2-methylpropane-2-sulfinamide.
  • reaction became yellow-orange in color and was stirred at room temperature for 2 h before being quenched with a 1 : 1 mixture of saturated aqueous ammonium chloride and concentrated aqueous ammonium hydroxide. This mixture was diluted with ethyl acetate and the layers were separated. The aqueous layer was extracted with ethyl acetate (x2) and the combined organic layers were stored at O 0 C.
  • Step D Preparation of (R*)-tert-butyl (2-allyl-3-oxo-2- azabicyclo[2.2.2]octan-l-yl)(4-(propylthio)phenyl)methylcarbamate from (R)-N-((R*)-
  • Step E (R*)-tert-butyl ⁇ -allyl-S-oxo ⁇ -azabicyclo [2.2.2] octan-l-yl)(4- (propylsulfonyl)phenyl)methylcarbamate from (R*)-tert-butyl (2-allyl-3-oxo-2- azabicyclo[2.2.2]octan-l-yl)(4-(propylthio)phenyl)methylcarbamate.
  • Step G Preparation of (R*)-N-((2-allyl-2-azabicyclo[2.2.2]octan-l-yl)(4- (propylsulfonyl)phenyl)methyl)-2,6-dimethylbenzamide from (R*)-tert-butyl (2-allyl-2- azabicyclo[2.2.2]octan-l-yl)(4-(propylsulfonyl)phenyl)-methylcarbamate.
  • Step H Preparation of (R*)-N-(2-azabicyclo[2.2.2]octan-l-yl(4- (propylsulfonyl)phenyl)methyl)-2,6-dimethylbenzamide from (R*)-N-((2-allyl-2- azabicyclo[2.2.2]octan-l-yl)(4-(propylsulfonyl)phenyl)methyl)-2,6-dimethylbenzamide.
  • Method 13 depicts a generalized scheme suitable for the stereoselective synthesis of quinuclidine N-propyl sulfones of Formula I.
  • Those skilled in the art will readily recognize various reagents and intermediates or changes in moieties that could be used to make additional N-alkyl aryl sulfones, either stereoselectively or in racemic form.
  • Step A Preparation of (R)-N-((R*)-(2-allyl-3-oxo-2-azabicyclo [2.2.2] octan- l-yl)(phenyl)methyl)-2-methylpropane-2-sulfinamide from (R)-N-((2-allyl-3-oxo-2- azabicyclo[2.2.2]octan-l-yl)methylene)-2-methylpropane-2-sulfinamide.
  • Step B Preparation of (R*)-tert-butyl (2-allyl-3-oxo-2- azabicyclo[2.2.2]octan-l-yl)(phenyl)methylcarbamate from (R)-N-((R*)-(2-allyl-3-oxo-2- azabicyclo[2.2.2]octan-l-yl)(phenyl)methyl)-2-methylpropane-2-sulfinamide.
  • This material was further purified using an ADH column and supercritical fluid chromatography conditions (liquid CO 2 ) employing isocratic 15% methanol containing 0.5% dimethylethylamine to remove undesired minor diastereomer (S*)-tert-butyl (2-allyl-3-oxo-2-azabicyclo[2.2.2]octan-l-yl)(phenyl)methylcarbamate, present in ⁇ 1%. This afforded (R*)-tert-butyl (2-allyl-3-oxo-2-azabicyclo[2.2.2]octan-l- yl)(phenyl)methylcarbamate (0.571 g, 88%) as a white foam solid.
  • Step C Preparation of (R*)-N-((2-allyl-2-azabicyclo[2.2.2]octan-l- yl)(phenyl)methyl)-2,6-dimethylbenzamide from (R*)-tert-butyl (2-allyl-2- azabicyclo[2.2.2]octan-l-yl)(phenyl)methylcarbamate.
  • Step D Preparation of (R*)-2,6-dimethyl-N-(phenyl(2-propyl-2- azabicyclo[2.2.2]octan-l-yl)methyl)benzamide from (R*)-N-((2-allyl-2- azabicyclo[2.2.2]octan-l-yl)(phenyl)methyl)-2,6-dimethylbenzamide.
  • Method 14 depicts a generalized scheme suitable for racemic synthesis of 3-pyridyl compounds of Formula I.
  • Those of skill in the art will readily recognize various reagents and intermediates or changes in moieties that could be used to make additional compounds of Formula I as either racemates or single enantiomers.
  • Step A Preparation of 2-methyl-N-((2-methyl-3-oxo-2- azabicyclo[2.2.2]octan-l-yl)(pyridin-3-yl)methyl)propane-2-sulfinamide from 2-methyl- N-((2-methyl-3-oxo-2-azabicyclo [2.2.2] octan- l-yl)methylene)propane-2-sulfinamide.
  • Step C Preparation of 2-chloro-N-((2-methyl-3-oxo-2- azabicyclo[2.2.2]octan-l-yl)(pyridin-3-yl)methyl)-3-(trifluoromethyl)-benzamide from 1- (amino(pyridin-3-yl)methyl)-2-methyl-2-azabicyclo[2.2.2] octan-3-one.
  • Step D Preparation of 2-chloro-N-((2-methyl-2-azabicyclo [2.2.2] octan-1- yl)(pyridin-3-yl)methyl)-3-(trifluoromethyl)benzamide from 2-chloro-N-((2-methyl-3- oxo-2-azabicyclo[2.2.2]octan-l-yl)(pyridin-3-yl)methyl)-3-(trifluoromethyl)benzamide.
  • Method 15 depicts a generalized scheme suitable for stereoselective synthesis of 4-pyridyl compounds of Formula I.
  • Those of skill in the art will readily recognize various reagents and intermediates or changes in moieties that could be used to make additional compounds of Formula I as either racemates or single enantiomers.
  • Example 20 Preparation of (R)-2-chloro-N-((2-methyl-2- azabicyclo[2.2.2]octan-l-yl)(pyridin-4-yl)methyl)-3-(trifluoromethyl)benzamide
  • Step A Preparation of from (R)-2-methyl-N-((R*)-(2-methyl-3-oxo-2- azabicyclo[2.2.2]octan-l-yl)methylene)propane-2-sulfinamide from (R)-2-methyl-N-((2- methyl-3-oxo-2-azabicyclo[2.2.2]octan-l-yl)methylene)propane-2-sulfinamide.
  • Step B Preparation of (R*)-2-chloro-N-((2-methyl-3-oxo-2- azabicyclo[2.2.2]octan-l-yl)(pyridin-4-yl)methyl)-3-(trifluoromethyl)benzamide from (R)-2-methyl-N-((R*)-(2-methyl-3-oxo-2-azabicyclo[2.2.2]octan-l-yl)(pyridin-4- yl)methyl)propane-2-sulfinamide.
  • Step C Preparation of (R*)-2-chloro-N-((2-methyl-2- azabicyclo[2.2.2]octan-l-yl)(pyridin-4-yl)methyl)-3-(trifluoromethyl)benzamide from (R*)-2-chloro-N-((2-methyl-3-oxo-2-azabicyclo[2.2.2]octan-l-yl)(pyridin-4-yl)methyl)-3- (trifluoromethyl)benzamide.
  • Method 16 depicts a generalized scheme suitable for stereoselective synthesis of 3-pyrazole compounds of Formula I.
  • Those of skill in the art will readily recognize various reagents and intermediates or changes in moieties that could be used to make additional compounds of Formula I as either racemates or single enantiomers.
  • R and n can be selected as described elsewhere herein.
  • Example 21 Preparation of (S*)-N-(2-azabicyclo [2.2.2] octan-l-yl(3-(l- methyl-lH-pyrazol-4-yl)phenyl)methyl)-2-chloro-3-(trifluoromethyl)benzamide
  • Step A Preparation of (S)-N-((S*)-(2-allyl-2-azabicyclo[2.2.2]octan-l- yl)(3-bromophenyl)methyl)-2-methylpropane-2-sulfinamide from (S)-N-((2-allyl-2- azabicyclo[2.2.2]octan-l-yl)methylene)-2-methylpropane-2-sulfinamide.
  • Step B Preparation of (S)-N-((S*)-(2-allyl-2-azabicyclo[2.2.2]octan-l- yl)(3-(l-methyl-lH-pyrazol-4-yl)phenyl)methyl)-2-methylpropane-2-sulfinamide from (S)-N-((S*)-(2-allyl-2-azabicyclo [2.2.2] octan-l-yl)(3-bromophenyl)methyl)-2- methylpropane-2-sulfinamide.
  • Step C Preparation of (S*)-N-((2-allyl-2-azabicyclo[2.2.2]octan-l-yl)(3-(l- methyl-lH-pyrazol-4-yl)phenyl)methyl)-2-chloro-3-(trifluoromethyl)benzamide from (S)-N-((S*)-(2-allyl-2-azabicyclo[2.2.2]octan-l-yl)(3-(l-methyl-lH-pyrazol-4- yl)phenyl)methyl)-2-methylpropane-2-sulfinamide.
  • Step D Preparation of (S*)-N-(2-azabicyclo[2.2.2]octan-l-yl(3-(l-methyl- lH-pyrazol-4-yl)phenyl)methyl)-2-chloro-3-(trifluoromethyl)benzamide from (S*)-N-((2- allyl-2-azabicyclo[2.2.2]octan-l-yl)(3-(l-methyl-lH-pyrazol-4-yl)phenyl)methyl)-2- chloro-3-(trifluoromethyl)benzamide.
  • Method 17 depicts a generalized scheme suitable for racemic synthesis of 3-pyrazole compounds of Formula I.
  • Those of skill in the art will readily recognize various reagents and intermediates or changes in moieties that could be used to make additional compounds of Formula I as either racemates or single enantiomers.
  • Step A Preparation of N-((3-bromophenyl)(2-methyl-2- azabicyclo[2.2.2]octan-l-yl)methyl)-2-methylpropane-2-sulfinamide from 2-methyl-N- ((2-methyl-2-azabicyclo[2.2.2]octan-l-yl)methylene)propane-2-sulfinamide
  • Step B Preparation of N-((3-bromophenyl)(2-methyl-2- azabicyclo[2.2.2]octan-l-yl)methyl)-2-chloro-3-(trifluoromethyl)benzamide from N-((3- bromophenyl)(2-methyl-2-azabicyclo[2.2.2]octan-l-yl)methyl)-2-methylpropane-2- sulfinamide
  • Method 18 depicts a generalized scheme suitable for racemic synthesis of 3-pyrazole compounds of Formula I.
  • Those of skill in the art will readily recognize various reagents and intermediates or changes in moieties that could be used to make additional compounds of Formula I as either racemates or single enantiomers.
  • Step A Preparation of 2-methyl-N-((3-(l-methyl-lH-pyrazol-4- yl)phenyl)(2-methyl-2-azabicyclo [2.2.2] octan-l-yl)methyl)propane-2-sulfinamide from N-((3-bromophenyl)(2-methyl-2-azabicyclo[2.2.2]octan-l-yl)methyl)-2-methylpropane-2- sulfinamide
  • Step B Preparation of 2-chloro-N-((3-(l-methyl-lH-pyrazol-4- yl)phenyl)(2-methyl-2-azabicyclo[2.2.2]octan-l-yl)methyl)-3-(trifluoromethyl)benzamide from 2-methyl-N-((3-(l-methyl-lH-pyrazol-4-yl)phenyl)(2-methyl-2- azabicyclo[2.2.2]octan-l-yl)methyl)propane-2-sulfinamide.
  • the activity and usefulness of the compounds can be assessed in assays known to those skilled in the art.
  • Some compounds of the invention have potency equal to or better than l ⁇ M (i.e., IC 50 ⁇ l ⁇ M).
  • Some compounds in accordance with the invention have potency equal to or better than 0.5 ⁇ M (i.e., IC50 ⁇ 0.5 ⁇ M).
  • Some compounds in accordance with the invention have potency equal to or better than 0.1 ⁇ M (i. e. , IC 50 ⁇ 0.1 ⁇ M).
  • Still further compounds in accordance with the invention have potency equal to or better than 0.05 ⁇ M (i.e., IC50 ⁇ 0.05 ⁇ M). Potency was measured in the [3H]Glycine Uptake Assay substantially as described herein.
  • Additional compounds and isomer mixtures made in accordance with the above-described methods include those shown below in Tables 2-4.
  • the isomer mixtures in Table 2 exhibited an IC50 of less than 0.250 ⁇ M.
  • the compounds in Table 3 exhibited an IC50 of from 0.250 to 13 ⁇ M.
  • the compounds in Table 4 exhibited an IC50 of greater than 13 ⁇ M (i.e., the compounds in Table 4 have relatively less or no activity for the tested target).
  • C m _C n means that the modified group contains from m to n carbon atoms.
  • Ci_C 6 -alkyl means an alkyl group containing from 1 to 6 carbon atoms.
  • C 3 -C 6 -alkenyl means an alkenyl having from 3 to 6 carbon atoms, with at least one double bond.
  • hydrocarbon means a chemical structure comprising only carbon and hydrogen atoms.
  • alkyl means a fully saturated straight or branched hydrocarbon group. In some embodiments, the alkyl comprises from 1 to 12 carbon atoms. In some embodiments, the alkyl comprises from 1 to 6 carbon atoms. And in some embodiments, the alkyl comprises from 1 to 3 carbon atoms.
  • alkyl groups include, for example, methyl; ethyl; propyl; isopropyl; 1-methylpropyl; 2-methylpropyl; n-butyl, t-butyl; isobutyl; 3-methylbutyl; pentyl; hexyl; isohexyl; heptyl; 4,4-dimethylpentyl; diethylpentyl; octyl; 2,2,4-trimethylpentyl; nonyl; decyl; undecyl; and dodecyl.
  • An alkyl may be optionally substituted.
  • alkenyl is a straight or branched hydrocarbon comprising from 1 to 3 carbon-carbon double bonds.
  • the chain comprises up to 20 carbon atoms.
  • the chain comprises up to 10 carbon atoms.
  • the chain comprises from 3 to 8 carbon atoms.
  • the chain comprises from 3 to 6 carbon atoms.
  • An alkenyl may be optionally substituted.
  • Alkynyl refers to a straight or branched hydrocarbon comprising from 1 to 3 carbon-carbon triple bonds.
  • the hydrocarbon comprises up to 20 carbon atoms.
  • the hydrocarbon comprises up to 10 carbon atoms.
  • the hydrocarbon comprises from 2 to 8 carbon atoms.
  • the hydrocarbon comprises from 2 to 6 carbon atoms.
  • alkoxy means -O-alkyl. Examples of alkoxys include methoxy, ethoxy, propoxy, and butoxy. An alkoxy may be optionally substituted.
  • cycloalkyl means a fully saturated cyclic hydrocarbon group.
  • the cycloalkyl may comprise one or more rings. In some embodiments, the cycloalkyl comprises a single ring. In some embodiments, the cycloalkyl comprises from 3 to 10 carbons. In other embodiments, the cycloalkyl comprises from 3 to 6 carbons.
  • cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • a cycloalkyl may be optionally substituted.
  • cycloalkylalkyl means an alkyl group substituted at its terminal carbon with a cycloalkyl.
  • An example of a cycloalkylalkyl is cyclopropylethyl, which corresponds to:
  • heterocyclyl means an unsaturated, partially saturated, or fully saturated ring system wherein 1, 2, or 3 of the ring atoms is/are heteroatoms independently selected from N, O, and S, with the remaining ring atoms being carbon.
  • the heterocyclyl has from 3 to 10 ring atoms.
  • the heterocyclyl has from 4 to 9 ring atoms.
  • the heterocyclyl has from 3 to 8 ring atoms. In some embodiments, the heterocyclyl has from 3 to 6 ring atoms. In some embodiments, the heterocyclyl has 5 rings atoms, i.e., it is a 5-membered ring. In some embodiments, the heterocyclyl has 6 rings atoms, i.e., it is a 6-membered ring.
  • a heterocyclyl may be monocyclic or poly eye lie. A heterocyclyl also may be optionally substituted.
  • single-ring heterocyclyls examples include furanyl, thienyl (also known as “thiophenyl” and “thiofuranyl”), oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiodiazolyl, oxadiazolyl
  • 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl also known as "azoximyl", 1,2,5-oxadiazolyl (also known as “furazanyl”), and 1,3,4-oxadiazolyl
  • pyrrolyl pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxathiazolyl, oxatriazolyl (including 1,2,3,4-oxatriazolyl and 1, 2,3, 5-oxatriazo IyI)
  • pyridinyl diazinyl (including pyridazinyl (also known as "1,2-diazinyl”), pyrimidinyl (also known as "1,3-diazinyl”), and pyrazinyl (also known as "1,4-diazinyl”))
  • triazinyl including s-triazinyl (also known as "1,3,5-triaziny
  • pentoxazolyl 1,2,6-oxazinyl, and 1 ,4-oxazinyl
  • isoxazinyl including o-isoxazinyl and p- isoxazinyl
  • oxadiazinyl including 1,4,2-oxadiazinyl and 1,3,5,2-oxadiazinyl
  • morpholinyl azepinyl, and diazepinyl.
  • a heterocyclyl alternatively may be 2 or 3 rings fused together, such as, for example, indolizinyl, pyranopyrrolyl, purinyl, imidazopyrazinyl, imidazolopyridazyl, pyridopyridinyl (including pyrido [3, 4-b] -pyridinyl, pyrido [3, 2-b] - pyridinyl, pyrido [4, 3 -b]- pyridinyl, and naphthyridinyl), pteridinyl, pyridazinotetrazinyl, pyrazinotetrazinyl, pyrimidinotetrazinyl, pyrindinyl, pyrazolopyrimidinyl, pyrazolopyrazinyl, pyrazolopyridazyl, or 4H-quinolizinyl.
  • indolizinyl pyranopyrrolyl
  • purinyl imid
  • the multi-ring heterocyclyls are selected from indolizinyl, pyranopyrrolyl, purinyl, pyridopyridinyl, pyrindinyl, and 4H- quinolizinyl.
  • fused-ring heterocyclyls include benzo-fused heterocyclyls, such as, for example, benzofuranyl (also known as “coumaronyl”), isobenzofuranyl, benzoxazolyl, benzoisoxazolyl (also known as “indoxazinyl”), anthranilyl, benzothienyl (also known as “benzothiophenyl”, “thionaphthenyl”, and “benzothiofuranyl”), isobenzothienyl (also known as “isobenzothiophenyl”, “isothionaphthenyl", and “isobenzothiofuranyl”), benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, benzoxadiazolyl, indolyl, isoindazolyl (also known as “benzpyrazolyl”), benzoimidazolyl, benzotriazolyl, benzazin
  • the benzo-fused heterocyclyls are benzofuranyl, isobenzofuranyl, benzoxazolyl, benzoisoxazolyl, anthranilyl, benzothienyl, isobenzothienyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, indolyl, isoindazolyl, benzoimidazolyl, benzotriazolyl, benzazinyl, phthalazinyl, quinoxalinyl, benzodiazinyl, carbazolyl, acridinyl, isoindolyl, indoleninyl, benzodioxolyl, chromanyl, isochromanyl, thiochromanyl, benzodioxanyl, tetrahydroisoquinolinyl, benzoxazinyl, benzoisoxazinyl, and xantheny
  • heterocyclyl means a saturated, non- aromatic partially-saturated, or heteroaryl containing two fused rings.
  • Such heterocyclyls include, for example, benzofuranyl, isobenzofuranyl, benzoxazolyl, benzoisoxazolyl, anthranilyl, benzothienyl, isobenzothienyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolizinyl, pyranopyrrolyl, benzoxadiazolyl, indolyl, isoindazolyl, benzoimidazolyl, benzotriazolyl, purinyl, imidazopyrazinyl, imidazolopyridazyl, quinolinyl, isoquinolinyl, pyridopyridinyl, phthalazinyl, quinoxalinyl, benzodiazinyl, pteridinyl
  • the 2-fused-ring heterocyclyls is selected from benzofuranyl, isobenzofuranyl, benzoxazolyl, benzoisoxazolyl, anthranilyl, benzothienyl, isobenzothienyl, benzothiazolyl, benzothiadiazolyl, indolizinyl, pyranopyrrolyl, benzoxadiazolyl, indolyl, isoindazolyl, benzoimidazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, pyridopyridinyl, phthalazinyl, quinoxalinyl, benzodiazinyl, pteridinyl, pyrindinyl, isoindolyl, indoleninyl, benzodioxolyl, benzodioxanyl, tetrahydroisoquinolinyl, 4
  • heterocycloalkyl means a fully saturated heterocyclyl.
  • a heterocycloalkyl may be monocyclic or polycyclic. In some embodiments, the heterocycloalkyl has from 3 to 10 ring atoms. In some embodiments, the heterocycloalkyl has from 4 to 9 ring atoms. In some embodiments, the heterocycloalkyl has from 3 to 8 ring atoms. In some embodiments, the heterocycloalkyl has from 3 to 6 ring atoms. In some embodiments, the heterocycloalkyl is a 5-membered ring. In some embodiments, for example, the heterocycloalkyl is a pyrrolidinyl.
  • the heterocycloalkyl is a 6-membered ring.
  • a heterocycloalkyl may be optionally substituted.
  • the term "heterocycloalkenyl” means a non-aromatic, partially-saturated saturated heterocyclyl.
  • a heterocycloalkenyl may be monocyclic or polycyclic.
  • the heterocycloalkenyl has from 4 to 10 ring atoms.
  • the heterocycloalkenyl has from 4 to 8 ring atoms.
  • the heterocycloalkenyl is a 5-membered ring.
  • the heterocycloalkenyl is a 6-membered ring.
  • a heterocycloalkenyl may be optionally substituted.
  • aryl means an aromatic hydrocarbon ring structure.
  • the aryl may be monocyclic or polycyclic.
  • Aryls include phenyl and naphthyl. In some embodiments, aryl has 6-10 ring atoms. An aryl may be optionally substituted.
  • arylalkyl means an alkyl group substituted at its terminal carbon with an aryl.
  • An example of a arylalkyl is phenylethyl, which corresponds to:
  • heteroaryl means an aromatic heterocyclyl.
  • a heteroaryl may be monocyclic or polycyclic.
  • a heteroaryl also may be optionally substituted.
  • the heteroaryl is a 5-membered ring.
  • the heteroaryl is a 6-membered ring.
  • the heteroaryl is an 8-membered bicyclic ring.
  • the heteroaryl is a 9-membered bicyclic ring.
  • the heteroaryl is a 10-membered bicyclic ring.
  • Examples of 5-membered heteroaryls include furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiodiazolyl, oxadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxathiazolyl, and oxatriazolyl.
  • Examples of 6-membered heteroaryls include pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, and oxathiazinyl.
  • Examples of 7-membered heteroaryls include oxepinyl and thiepinyl.
  • 9-membered heteroaryls include fused-ring systems, such as, for example benzofuranyl, isobenzofuranyl, benzoxazolyl, benzoisoxazolyl, anthranilyl, benzothienyl, isobenzothienyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolizinyl, pyranopyrrolyl, benzoxadiazolyl, indolyl, isoindazolyl, benzoimidazolyl, benzotriazolyl, purinyl, imidazopyrazinyl, imidazopyridinyl, and imidazolopyridazyl.
  • 10- membered heteroaryls include fused-ring systems such as, for example, quinolinyl, isoquinolinyl, pyridopyridinyl, phthalazinyl, quinoxalinyl, benzodiazinyl, pteridinyl, pyridazinotetrazinyl, pyrazinotetrazinyl, pyrimidinotetrazinyl, benzoimidazothiazolyl, carbazolyl, and acridinyl.
  • fused-ring systems such as, for example, quinolinyl, isoquinolinyl, pyridopyridinyl, phthalazinyl, quinoxalinyl, benzodiazinyl, pteridinyl, pyridazinotetrazinyl, pyrazinotetrazinyl, pyrimidinotetrazinyl, benzoimidazothiazolyl, carbazolyl, and acridinyl.
  • the heteroaryl is selected from furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, pyrazolyl, and imidazolyl. In some such embodiments, the heteroaryl is selected from oxazolyl, isoxazolyl, thiazolyl, imidazolyl, and furanyl. In some embodiments, the heteroaryl is selected from pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl. In some such embodiments, the heteroaryl is pyridinyl.
  • the heteroaryl is selected from benzoxazolyl, benzoisoxazolyl, anthranilyl, benzothienyl, isobenzothienyl, and purinyl. And, in some embodiments, the heteroaryl is selected from quinolinyl, isoquinolinyl, and benzodiazinyl. And in some embodiments, the heteroaryl is imidazopyridinyl, such as, for example:
  • heteroaryl is benzoimidazolyl, such as, for example:
  • halogen and "halo” means chlorine, bromine, fluorine, or iodine.
  • the halogen atoms in a molecule are selected from the group consisting of chlorine or fluorine.
  • the halogen atoms in a molecule are chlorine.
  • the halogen atoms in a molecule are fluorine.
  • halo-Ci-C ⁇ -alkyl means a Ci-C ⁇ -alkyl substituted by one or more independently selected halogens. Examples of halo-Ci-C ⁇ -alkyl include -CHCl 2 , -CHF 2 , and -CF 3 ..
  • a pharmaceutically acceptable moiety e.g., a salt, dosage form, carrier, or diluent
  • a pharmaceutically acceptable moiety has one or more benefits that outweigh any deleterious effect that the moiety may have. Deleterious effects may include, for example, excessive toxicity, irritation, allergic response, and other problems and complications.
  • boc means tert-butoxy carbonyl.
  • CO 2 means carbon dioxide.
  • DIPEA N,N-diisopropylethylamine
  • DMF N,N-dimethylformamide
  • DMSO dimethyl sulfoxide
  • DMSO-56 means deuterated dimethyl sulfoxide.
  • EtOAc means ethyl acetate.
  • IH NMR means proton nuclear magnetic resonance.
  • HOBT 1-hydroxybenzotriazole hydrate
  • HPLC high performance liquid chromatography
  • h and hr means hour or hours.
  • LCMS means liquid chromatography mass spectral detection.
  • m-CPBA means meta-chloroperbenzoic acid.
  • NMR nuclear magnetic resonance
  • SFC supercritical fluid chromatography
  • TBTU O-(benzotriazol-l-yl)-N,N,N',N'- tetramethy luronium tetrafluoroborate .
  • tR retention time.

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Abstract

Cette invention porte sur des composés 2-aza-bicyclo[2.2.2]octane (et leurs sels), sur le procédé de fabrication d'un tel composé et sur des compositions pharmaceutiques comprenant un tel composé. L'invention porte également sur l'utilisation des composés pour moduler le transporteur de glycine 1 (GlyT1) et pour le traitement d'une psychose, de troubles cognitifs, de troubles bipolaires, de troubles dépressifs, de troubles de l'anxiété, de troubles de stress post-traumatique et de la douleur.
PCT/SE2010/050070 2009-01-28 2010-01-27 Composés 2-aza-bicyclo[2.2.2]octane et leurs utilisations Ceased WO2010087761A1 (fr)

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Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003089411A1 (fr) * 2002-04-19 2003-10-30 Sanofi-Aventis Derives de n-[phenyl(piperidin-2-yl)methyl] benzamide, leur preparation et leur application en therapeutique
FR2842805A1 (fr) * 2002-07-29 2004-01-30 Sanofi Synthelabo Derives de n-[phenyl(piperidin-2-yl)methyl]benzamide,leur preparation et leur application et therapeutique
FR2842804A1 (fr) * 2002-07-29 2004-01-30 Sanofi Synthelabo Derives de n-[phenyl(piperidin-2-yl)methyl]benzamide, leur preparation et leur application en therapeutique
FR2861076A1 (fr) * 2003-10-17 2005-04-22 Sanofi Synthelabo Derives de n-heterocyclymethylbenzamide, leur preparation et leur application en therapeutique
FR2861074A1 (fr) * 2003-10-17 2005-04-22 Sanofi Synthelabo Derives de n-[phenyl(piperidin-2-yl)methyl]benzamide, leur preparation et leur application en therapeutique
FR2861073A1 (fr) * 2003-10-17 2005-04-22 Sanofi Synthelabo Derives de n-[heteroaryl(piperidin-2-yl)methyl]benzamide, leur preparation et leur application en therapeutique
FR2861071A1 (fr) * 2003-10-17 2005-04-22 Sanofi Synthelabo Derives de n-[phenyl(alkylpiperidin-2-yl) methyl]benzamide, leur prepartation et leur application en therapeutique
WO2006067414A2 (fr) * 2004-12-23 2006-06-29 Glaxo Group Limited Composes
WO2008018639A2 (fr) * 2006-08-11 2008-02-14 Taisho Pharmaceutical Co., Ltd. Inhibiteur de transporteurs de glycine
FR2906251A1 (fr) * 2006-09-22 2008-03-28 Sanofi Aventis Sa Derives de pyrrolizine, indolizine et quinolizine, leur preparation et leur application en therapeutique
US20090030033A1 (en) * 2007-07-23 2009-01-29 Astrazeneca Ab Novel Compounds 894

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003089411A1 (fr) * 2002-04-19 2003-10-30 Sanofi-Aventis Derives de n-[phenyl(piperidin-2-yl)methyl] benzamide, leur preparation et leur application en therapeutique
FR2842805A1 (fr) * 2002-07-29 2004-01-30 Sanofi Synthelabo Derives de n-[phenyl(piperidin-2-yl)methyl]benzamide,leur preparation et leur application et therapeutique
FR2842804A1 (fr) * 2002-07-29 2004-01-30 Sanofi Synthelabo Derives de n-[phenyl(piperidin-2-yl)methyl]benzamide, leur preparation et leur application en therapeutique
FR2861076A1 (fr) * 2003-10-17 2005-04-22 Sanofi Synthelabo Derives de n-heterocyclymethylbenzamide, leur preparation et leur application en therapeutique
FR2861074A1 (fr) * 2003-10-17 2005-04-22 Sanofi Synthelabo Derives de n-[phenyl(piperidin-2-yl)methyl]benzamide, leur preparation et leur application en therapeutique
FR2861073A1 (fr) * 2003-10-17 2005-04-22 Sanofi Synthelabo Derives de n-[heteroaryl(piperidin-2-yl)methyl]benzamide, leur preparation et leur application en therapeutique
FR2861071A1 (fr) * 2003-10-17 2005-04-22 Sanofi Synthelabo Derives de n-[phenyl(alkylpiperidin-2-yl) methyl]benzamide, leur prepartation et leur application en therapeutique
WO2006067414A2 (fr) * 2004-12-23 2006-06-29 Glaxo Group Limited Composes
WO2008018639A2 (fr) * 2006-08-11 2008-02-14 Taisho Pharmaceutical Co., Ltd. Inhibiteur de transporteurs de glycine
FR2906251A1 (fr) * 2006-09-22 2008-03-28 Sanofi Aventis Sa Derives de pyrrolizine, indolizine et quinolizine, leur preparation et leur application en therapeutique
US20090030033A1 (en) * 2007-07-23 2009-01-29 Astrazeneca Ab Novel Compounds 894

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