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WO2008113795A1 - Compounds which potentiate ampa receptor and uses thereof in medicine - Google Patents

Compounds which potentiate ampa receptor and uses thereof in medicine Download PDF

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Publication number
WO2008113795A1
WO2008113795A1 PCT/EP2008/053194 EP2008053194W WO2008113795A1 WO 2008113795 A1 WO2008113795 A1 WO 2008113795A1 EP 2008053194 W EP2008053194 W EP 2008053194W WO 2008113795 A1 WO2008113795 A1 WO 2008113795A1
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Prior art keywords
dihydro
inden
trifluoromethyl
pyrazol
tetrahydro
Prior art date
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PCT/EP2008/053194
Other languages
French (fr)
Inventor
Nicolas Bertheleme
Daniel Marcus Bradley
Francesca Cardullo
Giancarlo Merlo
Alfonso Pozzan
Jaqueline Sandra Scott
Kevin Michael Thewlis
Simon Edward Ward
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Glaxo Group Limited
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Filing date
Publication date
Priority claimed from GB0705330A external-priority patent/GB0705330D0/en
Priority claimed from GB0710874A external-priority patent/GB0710874D0/en
Priority claimed from GB0718199A external-priority patent/GB0718199D0/en
Priority claimed from GB0719000A external-priority patent/GB0719000D0/en
Application filed by Glaxo Group Limited filed Critical Glaxo Group Limited
Publication of WO2008113795A1 publication Critical patent/WO2008113795A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems

Definitions

  • This invention relates to novel compounds which potentiate the AMPA receptor.
  • the invention also relates to the use of the compounds in treating diseases and conditions wherein the potentiation of the AMPA receptor would be beneficial, compositions containing the derivatives and processes for their preparation.
  • Glutamate receptors which mediate the majority of fast excitatory neurotransmission in the mammalian central nervous system (CNS), are activated by the excitatory amino acid, L-glutamate (for review see Watkins JC, Krogsgaard-Larsen P, Honore T (1990) Trends Pharmacol Sci 11 : 25-33).
  • Glutamate receptors can be divided into two distinct families.
  • the G-protein or second messenger-linked "metabotropic" glutamate receptor family which can be subdivided into three groups (Group I, mGlui and mGlu5; Group II, mGlu2 and mGlu3; Group III, mGlu4, mGlu ⁇ , mGlu7, mGlu ⁇ ) based on sequence homology and intracellular transduction mechanisms (for review see Conn PJ and Pinn JP (1997) Ann Rev Pharmacol Toxicol 37: 205-237).
  • the "ionotropic" glutamate receptor family which directly couple to ligand-gated cation channels, can be subdivided into at least three subtypes based on depolarizing activation by selective agonists, N-methyl-D-aspartate (NMDA), ⁇ -amino-3-hydroxy-5- methylisoxazole-4-propionic acid (AMPA) and kainic acid (KA) (for review see Dingledine R, Borges K, Bowie, Traynelis S (1999) 51 : 7-61 ).
  • NMDA N-methyl-D-aspartate
  • AMPA ⁇ -amino-3-hydroxy-5- methylisoxazole-4-propionic acid
  • KA kainic acid
  • AMPAR Native AMPA receptors
  • GIuRI -4 Native AMPA receptors
  • Receptor subunit diversity is increased further as each subunit can undergo alternative splicing of a 38 amino acid sequence in the extracellular region just before the fourth membrane spanning domain M4.
  • GluR2 mRNA changes a neutral glutamine to a positively charged arginine within M2.
  • GluR2 is edited in this way.
  • AMPAR containing such edited GluR2 subunit exhibit low calcium permeability (Burnachev N, Monyer H, Seeburg PH, Sakmann B (1992) Neuron 8: 189-198).
  • the number of AMPAR with high calcium permeability is elevated in certain disease-associated conditions (Weiss JH, and Sensi SL (2000) Trends in Neurosci 23: 365-371 ).
  • LTP Long Term Potentiation
  • AMPAR positive allosteric modulators do not activate the receptor directly.
  • AMPAR modulators increase receptor activity.
  • AMPA receptor modulators enhance synaptic function when glutamate is released and is able to bind at post-synaptic receptor sites.
  • Such compounds also enhance the learning and performance of various cognitive tasks in rodent (Zivkovic I, Thompson DM, Bertolino M, Uzunov D, DiBeIIa M, Costa E, Guidotti A (1995) JPET 272: 300-309, Lebrun C, Pilliere E, Lestage P (2000) Eu J Pharmacol 401 : 205-212), sub-human primate (Thompson DM, Guidotti A, DiBeIIa M, Costa E (1995) Proc Natl Acad Sci 92: 7667-7671 ) and man (Ingvar M, Ambros-lngerson J, Davis M, Granger R, Kessler M, Rogers GA, Schehr RS, Lynch G (1997) Exp Neurol 146: 553-559).
  • the present invention provides a compound of formula (I) or a salt thereof:
  • A is selected from CF 3 and CHF 2 ;
  • R 1 is selected from cyclopropyl and pyridyl and R 2 is hydrogen; or R 1 and R 2 join together to form a 5- or 6-membered non-aromatic ring, wherein one of the carbon atoms in the ring is optionally replaced by an oxygen atom, NH or NCH 3 ;
  • R is selected from the group consisting of:
  • R 3 is selected from hydrogen and C 1-4 alkyl
  • R 4 is selected from C 1-6 alkyl, haloC 1-6 alkyl, C 3-6 cycloalkyl, haloC 3-6 cycloalkyl, - (CH 2 )pZ (where p is 1 , 2 or 3 and Z is a phenyl or a 5- or 6-membered aromatic or non-aromatic heterocyclic ring, the phenyl or the heterocyclic ring being optionally substituted with one or more groups selected from halo and Ci -4 alkyl) and -(CH 2 )qNR 5 R 6 (wherein q is 0, 1 or 2 and R 5 and R 6 are independently C 1-6 alkyl); or
  • R 3 and R 4 together with the NC(O) or NSO 2 group to which they are attached, form a 5- or 6-membered non-aromatic heterocyclic ring, either of which may include one or more further heteroatoms selected from N, O or S, and may be substituted with one or more groups selected from C 1-4 alkyl, C(O)C 1-4 alkyl, halo, hydroxy and oxo.
  • halo refers to fluoro, chloro, bromo or iodo.
  • C 1-6 alkyl refers to an alkyl group having from one to six carbon atoms; and the term “C 1-4 alkyl” refers to an alkyl group having from one to four carbon atoms.
  • Ci -4 alkyl or Ci -6 alkyl may be a straight chain or branched alkyl group.
  • a C 1-4 alkyl group may be selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or t-butyl.
  • a C 1-6 alkyl group may be selected from the group consisting of a Ci -4 alkyl group, sec-pentyl, n-pentyl, isopentyl, tert-pentyl and hexyl.
  • C 1-4 alkyl is methyl.
  • Me means methyl.
  • Et means ethyl.
  • C 1-4 alkoxy refers to the group wherein is as defined above.
  • Cs- ⁇ cycloalkyl refers to a cycloalkyl group consisting of from 3 to 6 carbon atoms, ie cyclopropanyl, cyclobutanyl, cyclopentanyl and cyclohexanyl.
  • haloalkyl refers to an alkyl group as defined above which is substituted with any number of fluorine, chlorine, bromine, or iodine atoms, including with mixtures of those atoms.
  • a haloalkyl group may, for example contain 1 , 2 or 3 halogen atoms.
  • a haloalkyl group may have all hydrogen atoms replaced with halogen atoms.
  • Examples of haloC 1-4 alkyl groups include fluoromethyl, difluoromethyl and trifluoromethyl.
  • haloCs- ⁇ cycloalkyl refers to a cycloalkyl group as defined above which is substituted with any number of fluorine, chlorine, bromine, or iodine atoms, including with mixtures of those atoms.
  • a haloC 3-6 cycloalkyl group may, for example contain 1 , 2 or 3 halogen atoms.
  • a haloCs- ⁇ cycloalkyl group may have all hydrogen atoms replaced with halogen atoms.
  • Examples of haloCs-ecycloalkyl groups include fluorocyclopropyl.
  • 5- or 6-membered aromatic heterocyclic ring refers to a monocyclic 5- or 6-membered aromatic carbocyclic group, containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen and sulphur.
  • Examples include furyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrazinyl, tetrazolyl, triazinyl, oxazepinyl, thiazepinyl, and diazepinyl.
  • nitrogen- containing monocyclic aromatic heterocyclyl groups are pyrrolyl, imidazolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrazinyl, tetrazolyl, triazinyl, oxazepinyl, thiazepinyl, and diazepinyl.
  • 5- or 6-membered non-aromatic heterocyclic ring refers to a monocyclic 5- or 6-membered non-aromatic carbocyclic group, containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen and sulphur.
  • Examples of monocyclic non-aromatic heterocyclyl groups include 2H-pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, dioxolanyl, 1 ,2oxathiolanyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, 3- pyrazolinyl, pyrazolidinyl, 2H-pyranyl, 4H-pyranyl, piperidinyl, 1 ,4diozanyl, morpholinyl, 1 ,4dithianyl, 1 ,4 oxathianyl, thiomorpholinyl, piperazinyl, 6H-1 ,2,5thiadiazinyl and 2H,6H-
  • nitrogen-containing monocyclic non-aromatic heterocyclyl groups include 2H-pyrrole, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, 3-pyrazolinyl, pyrazolidinyl, 2H-pyranyl, 4H-pyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, 6H-1 ,2,5thiadiazinyl and 2H,6H- 1 ,5,2-dithiazinyl.
  • substituted means substituted by one or more defined groups.
  • groups may be selected from a number of alternative groups, the selected groups may be the same or different.
  • the term independently means that where more than one substituent is selected from a number of possible substituents, those substituents may be the same or different.
  • A is CF 3 . In another embodiment, A is CHF 2 .
  • R 1 is selected from cyclopropyl and pyridyl, and R 2 is hydrogen.
  • R 1 and R 2 join together to form a 5- or 6-membered non-aromatic ring, wherein one of the carbon atoms in the ring is optionally replaced by an oxygen atom, NH or NCH 3 .
  • R 1 and R 2 join together to form a 5- or 6-membered non-aromatic ring, wherein one of the carbon atoms in the ring is optionally replaced by an oxygen atom Or NCH 3 .
  • R 1 and R 2 join together to form a 6-membered non-aromatic ring, wherein one of the carbon atoms in the ring is optionally replaced by an oxygen atom or NCH 3 .
  • R 1 and R 2 join together to form the following group:
  • R is a 5- or 6-membered aromatic or non-aromatic heterocyclic ring, optionally substituted with one or more groups selected from C 1-4 alkyl, C(O)C 1-4 alkyl, haloCi -4 alkyl, halo, hydroxy and oxo.
  • the heterocyclic ring is non- aromatic. In one embodiment, it is 5-membered. In one embodiment, it is selected from morpholine, pyrrolidine and piperidine.
  • the 5- or 6-membered aromatic or non-aromatic heterocyclic ring is attached to the remainder of the molecule through a carbon atom (ie C-linked) or a nitrogen atom (ie N-linked).
  • the ring is substituted with one or more groups selected from Ci -4 alkyl, C(O)Ci -4 alkyl, haloCi -4 alkyl, halo, hydroxy and oxo.
  • the substituent is selected from C 1-4 alkyl, haloC 1-4 alkyl and oxo, for example oxo.
  • R is NH 2 .
  • R is selected from NR 3 SO 2 R 4 , NR 3 C(O)R 4 and OR 4 where R 3 and R 4 are as defined for formula (I).
  • R is selected from NH 2 , NR 3 SO 2 R 4 and NR 3 C(O)R 4 where R 3 and R 4 are as defined for formula (I).
  • R is selected from NR 3 SO 2 R 4 , NR 3 C(O)R 4 and OR 4 wherein:
  • R 3 is selected from hydrogen and C 1-4 alkyl
  • R 4 is selected from Ci -6 alkyl, haloCi -6 alkyl, C 3-6 cycloalkyl, haloC 3-6 cycloalkyl and (CH 2 )qNR 5 R 6 wherein q is O, 1 or 2 and R 5 and R 6 are independently Ci -6 alkyl.
  • R 3 is hydrogen.
  • R 4 is selected from and haloC-i- ⁇ alkyl.
  • R 4 is selected from Ci -4 alkyl and haloC 1-4 alkyl.
  • R is selected from NR 3 SO 2 R 4 and NR 3 C(O)R 4 wherein R 3 and R 4 , together with the NC(O) or NSO 2 group to which they are attached, form a 5-membered or a 6-membered non-aromatic heterocyclic ring, either of which may include one or more further heteroatoms selected from N, O or S, and may be substituted with one or more groups selected from C 1-4 alkyl, C(O)C 1-4 alkyl, halo, haloC 1-4 alkyl, hydroxy and oxo.
  • R 3 is selected from hydrogen and • R 4 is selected from C 1-6 alkyl, haloC 1-6 alkyl, C 3-6 cycloalkyl, haloC 3-6 cycloalkyl, -(CH 2 )pZ (where p is 1 , 2 or 3 and Z is a phenyl or a 5- or 6-membered heterocyclic ring, the phenyl or the heterocyclic ring being optionally substituted with one or more groups selected from halo and C 1-4 alkyl) and -(CH 2 )qNR 5 R 6 wherein q is O, 1 or 2 and R 5 and R 6 are independently Ci -6 alkyl; or • R 3 and R 4 , together with the NC(O) group to which they are attached, form a 5- membered or a 6-membered non-aromatic heterocyclic ring, either of which may include one or more further heteroatoms selected from N, O or S, and may be substituted with one or more groups selected from Ci -4 al
  • R 3 is C 1-4 alkyl
  • R 4 is selected from Ci -6 alkyl, haloCi -6 haloalkyl, C 3-6 cycloalkyl and haloC 3-6 cycloalkyl; or • R 3 and R 4 , together with the N(CO) group to which they are attached, form a 5- membered or a 6-membered non-aromatic heterocyclic ring, either of which may include one or more further heteroatoms selected from N, O or S, and may be substituted with one or more groups selected from C(O)C 1-4 alkyl, C 1-4 alkyl, halo, haloCi_ 4 alkyl, hydroxy and oxo.
  • NR 3 C(O)R 4 forms a 5-membered non-aromatic heterocyclic ring.
  • NR 3 C(O)R 4 forms a ring selected from pyrrolidinone and piperidinone.
  • NR 3 C(O)R 4 forms a 5-membered or a 6-membered non-aromatic heterocyclic ring that is substituted with one or more groups selected from C 1-4 alkyl, C(O)Ci -4 alkyl, halo, hydroxy and oxo.
  • the substituent is selected from C- ⁇ alkyl, haloCi -4 alkyl and oxo.
  • the present invention also provides a compound of formula (Ib) or a salt thereof:
  • R 1 is cyclopropyl and R 2 is hydrogen, or R 1 and R 2 join together to form a 6-membered non-aromatic ring, wherein one of the carbon atoms in the ring is optionally replaced by an oxygen atom;
  • R is selected from the group consisting of:
  • R 3 is selected from hydrogen and C 1-4 alkyl
  • R 4 is selected from C 1-6 alkyl, haloC 1-6 alkyl, C 3-6 cycloalkyl, haloC 3-6 cycloalkyl, - (CH 2 )pZ (where p is 1 , 2 or 3 and Z is a phenyl or a 5- or 6-membered heterocyclic ring, the phenyl or the heterocyclic ring being optionally substituted with one or more groups selected from halo and C 1-4 alkyl) and (CH 2 )qNR 5 R 6 (wherein q is 0, 1 or 2 and R 5 and R 6 are independently Ci -6 alkyl); or
  • R 3 and R 4 together with the NC(O) or NSO 2 group to which they are attached, form a 5-membered or a 6-membered non-aromatic heterocyclic ring, either of which may include one or more further heteroatoms selected from N, O or S, and may be substituted with one or more groups selected from C 1-4 alkyl, C(O)C 1-4 alkyl, halo, haloC 1-4 alkyl, hydroxy and oxo.
  • the present invention also provides a compound of formula (Ic) or a salt thereof:
  • A is selected from CF 3 and CHF 2 ;
  • R 1 is selected from cyclopropyl and pyridyl and R 2 is hydrogen; or R 1 and R 2 join together to form a 5- or 6-membered non-aromatic ring, wherein one of the carbon atoms in the ring is optionally replaced by an oxygen atom, NH or NCH 3 ;
  • R is selected from the group consisting of:
  • R 3 is selected from hydrogen and Ci -4 alkyl
  • R 4 is selected from C 1-6 alkyl, haloC 1-6 alkyl, C 3-6 cycloalkyl, haloC 3-6 cycloalkyl and -(CH 2 )qNR 5 R 6 (wherein q is 0, 1 or 2 and R 5 and R 6 are independently C 1- 6 alkyl); or
  • R 3 and R 4 together with the NC(O) or NSO 2 group to which they are attached, form a 5- or 6-membered non-aromatic heterocyclic ring, either of which may include one or more further heteroatoms selected from N, O or S, and may be substituted with one or more groups selected from C 1-4 alkyl, C(O)C 1-4 alkyl, halo, haloC 1-4 alkyl, hydroxy and oxo.
  • A is selected from CF 3 and CHF 2 ;
  • R 1 is selected from cyclopropyl and pyridyl and R 2 is hydrogen; or R 1 and R 2 join together to form a 5- or 6-membered non-aromatic ring, wherein one of the carbon atoms in the ring is optionally replaced by an oxygen atom, NH or NCH 3 ;
  • R is selected from the group consisting of: (a) a 5- or 6-membered N-linked aromatic or non-aromatic heterocyclic ring, optionally substituted with one, two or three groups selected from Ci -4 alkyl, C(O)Ci -4 alkyl, halo, hydroxy and oxo; and (b) NH 2 , NR 3 SO 2 R 4 and NR 3 C(O)R 4 in which
  • R 3 is selected from hydrogen and Ci -4 alkyl; • R 4 is selected from Ci -6 alkyl, haloCi -6 alkyl, C 3-6 cycloalkyl, haloCs- ⁇ cycloalkyl, -
  • (CH 2 )pZ (where p is 1 , 2 or 3 and Z is a phenyl or a 5- or 6-membered aromatic or non-aromatic heterocyclic ring, the phenyl or the heterocyclic ring being optionally substituted with one or more groups selected from halo and C 1-4 alkyl) and -(CH 2 )qNR 5 R 6 (wherein q is 0, 1 or 2 and R 5 and R 6 are independently Ci -6 alkyl); or
  • R 3 and R 4 together with the NC(O) or NSO 2 group to which they are attached, form a 5- or 6-membered non-aromatic heterocyclic ring, either of which may include one or more further heteroatoms selected from N, O or S, and may be substituted with one or more groups selected from Ci -4 alkyl, C(O)Ci -4 alkyl, halo, haloC 1-4 alkyl, hydroxy and oxo.
  • the compounds of the invention may exist in the form of optical isomers, e.g. diastereoisomers and mixtures of isomers in all ratios, e.g. racemic mixtures.
  • the invention includes all such forms, in particular the pure isomeric forms.
  • the different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses.
  • the level of biological activity may vary between the individual stereoisomers of a given molecule. It is intended that the scope of the invention includes all individual stereoisomers (diastereoisomers and enantiomers) and all mixtures thereof, including but not limited to racemic mixtures, which demonstrate appropriate biological activity with reference to the procedures described herein.
  • enrichment in a particular in configuration correspond to at least 90% enantiomeric excess.
  • the isomers correspond to at least 95% enantiomeric excess.
  • the isomers correspond to at least 99% enantiomeric excess.
  • Examples of compounds of formula (I) include:
  • the salt of the compound of formula (I) is a pharmaceutically acceptable salt.
  • the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • salt refers to any salt of a compound according to the present invention prepared from an inorganic or organic acid or base, quaternary ammonium salts and internally formed salts.
  • Pharmaceutically acceptable salts are particularly suitable for medical applications because of their greater aqueous solubility relative to the parent compounds. Such salts must clearly have a pharmaceutically acceptable anion or cation.
  • Suitably pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, hydroiodic, phosphoric, metaphosphoric, nitric and sulfuric acids, and with organic acids, such as tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, formic, propionic, glycolic, gluconic, maleic, succinic, (1 R)-(-)-10-camphorsulphonic, (1 S)-(+)-10- camphorsulphonic, isothionic, mucic, gentisic, isonicotinic, saccharic, glucuronic, furoic, glutamic, ascorbic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic, stearic, sulfinilic, alg
  • Salts having a non- pharmaceutically acceptable anion or cation are within the scope of the invention as useful intermediates for the preparation of pharmaceutically acceptable salts and/or for use in non-therapeutic, for example, in vitro, situations.
  • the salts may have any suitable stoichiometry.
  • a salt may have 1 :1 or 2:1 stoichiometry.
  • Non-integral stoichiometry ratios are also possible.
  • Solvates of the compounds of formula (I) and solvates of the salts of the compounds of formula (I) are included within the scope of the present invention.
  • solvate refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of formula (I) or a salt thereof) and a solvent.
  • solvents include, but are not limited to, water, methanol, ethanol and acetic acid.
  • suitable solvents include, but are not limited to, water, methanol, ethanol and acetic acid.
  • the solvent used is a pharmaceutically acceptable solvent.
  • suitable pharmaceutically acceptable solvents include, without limitation, water, ethanol and acetic acid.
  • the solvent used is water. Where the solvent used is water such a solvate may then also be referred to as a hydrate.
  • crystalline forms of the compounds of structure (I) may exist as polymorphs, which are included in the present invention.
  • prodrugs for certain compounds of the invention include : esters, carbonate esters, hemi-esters, phosphate esters, nitro esters, sulfate esters, sulfoxides, amides, carbamates, azo-compounds, phosphamides, glycosides, ethers, acetals and ketals.
  • the invention also includes all suitable isotopic variations of a compound of the invention.
  • An isotopic variation of a compound of the invention is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature.
  • isotopes examples include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine such as 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F and 36 CI, respectively.
  • Certain isotopic variations of the invention for example, those in which a radioactive isotope such as 3 H or 14 C is incorporated, are useful in drug and/or substrate tissue distribution studies. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
  • isotopic variations of the compounds of the invention can generally be prepared by conventional procedures such as by the illustrative methods or by the preparations described in the Examples hereafter using appropriate isotopic variations of suitable reagents.
  • a compound of formula (I) may be prepared by coupling a compound of formula (II) where X is a leaving group such as a halogen (for example bromine or iodine) with a heterocyclic derivative of formula (III) according to reaction scheme 1.
  • X is a leaving group such as a halogen (for example bromine or iodine)
  • a heterocyclic derivative of formula (III) according to reaction scheme 1.
  • the present invention also provides a process for preparing a compound of the present invention, the process comprising coupling a compound of formula (II):
  • R 1 , R 2 and A are as defined above; and thereafter optionally: a) forming a salt; and/or b) converting a compound of the present invention into another compound of the present invention.
  • Typical coupling conditions comprise heating together for the appropriate time a compound of formula (II), a compound of formula (III), a base (such as potassium carbonate or cesium carbonate), a copper (I) reagent (such as copper (I) iodide or copper (I) oxide) with a ligand (such as N,N-dimethylglycine or frans-1 ,2-diaminocyclohexane) in a suitable solvent such as dimethyl sulfoxide or 1 ,4-dioxane at a suitable temperature such as 180 degC in a microwave reactor or 130 degC by conventional heating.
  • a suitable solvent such as dimethyl sulfoxide or 1 ,4-dioxane
  • R is a secondary or tertiary amide or sulphonamide, or a tertiary amine.
  • R 1 and R 2 are joined together to form a 6-membered non- aromatic ring, wherein one of the carbon atoms in the ring is optionally replaced by an oxygen atom or NMe.
  • Compounds of formula (II) and (III) are commercially available, described in the literature or may be prepared according to standard synthetic methods.
  • Typical conditions comprise treatment of a compound of formula (V) (or salt thereof) with a compound of formula (XVII) in dimethylformamide in the presence of a suitable base such as diisopropylethylamine or triethylamine, followed by addition of a strong base such as sodium hydride (available as a 60% suspension in mineral oil) to effect cyclisation.
  • Scheme 2 is suitable for enantiomerically pure material or racemates.
  • X is bromine or iodine
  • Y is carbonyl or sulphonyl
  • n is 1 or 2.
  • Compounds of formula (XVII) are commercially available, except when Y is sulphonyl and n is 2.
  • Typical conditions comprise addition of reagent (VII) to a cooled solution of (V) (or salt thereof) in dichloromethane in the presence of a suitable base such as triethylamine or 1 ,8-diazabicyclo[5.4.0]undec-7-ene.
  • a suitable base such as triethylamine or 1 ,8-diazabicyclo[5.4.0]undec-7-ene.
  • X is bromine or iodine
  • Y is a carbonyl or sulphonyl
  • R1 is aliphatic.
  • Compounds of formula (VII) are commercially available.
  • Typical conditions comprise addition of reagent (VIII) to a vigorously stirring suspension of the compound of formula (V) (or salt thereof) and base (such as potassium carbonate) in acetonitrile and subsequent heating at reflux for 16 hours.
  • X is bromine or iodine.
  • the compound of formula (VIII) is commercially available.
  • a compound of formula (X) can be prepared from a compound of formula (Xl) by enolate addition to ethyl trifluoroacetate according to reaction scheme 5.
  • Typical conditions comprise treatment of a compound of formula (Xl) with a strong base (such as lithium diisopropylamide (LDA)) under argon in tetrahydrofuran at the appropriate temperature (such as -70 degC) followed by the addition of ethyl trifluoroacetate, mixing for the appropriate time then warming to room temperature.
  • a strong base such as lithium diisopropylamide (LDA)
  • LDA lithium diisopropylamide
  • the appropriate temperature such as -70 degC
  • a compound of formula (XII) can be prepared by condensation of a compound of formula (X) with hydrazine hydrate according to reaction scheme 6. Typical conditions comprise treatment of a compound of formula (X) in ethanol with hydrazine hydrate and heating at the appropriate temperature (such as 70 degC) for the appropriate time (such as 9 hours).
  • Compounds of formula (X) wherein A is CHF 2 are commercially available, described in the literature or may be prepared according to standard synthetic methods.
  • a compound of formula (XIII) can be prepared from a compound of formula (XIV) [prepared according to Liebigs Annalen Der Chemie 1984, 1 1 , 1759-1882;] by enolate addition to ethyl trifluoroacetate followed by condensation with hydrazine hydrate according to reaction scheme 7.
  • Typical conditions comprise treatment of a compound of formula (XIV) with a strong base (such as methyllithium) in tetrahydrofuran at room temperature under argon followed by the addition of ethyl trifluoroacetate at -78 degC, mixing for the appropriate time then warming to room temperature..
  • the isolated product is dissolved in ethanol and treated with hydrazine hydrate and heated at reflux for 6 hours.
  • a compound of formula (XVI) can be prepared by the reduction of a compound of formula (XV) using lithium aluminium hydride according to reaction scheme 8.
  • Typical reduction conditions comprise the addition of lithium aluminium hydride to a cooled solution of a compound of formula (XV) in tetrahydrofuran (THF) followed by heating.
  • Compounds of formula (XV) can be prepared in a manner similar to that described for compounds of formula (XII) in scheme 6.
  • the compounds of the invention may be prepared singly or as compound libraries comprising at least 2, for example 5 to 1 ,000 compounds, for example 10 to 100 compounds.
  • Libraries of compounds of the invention may be prepared by a combinatorial 'split and mix' approach or by multiple parallel synthesis using either solution phase or solid phase chemistry, by procedures known to those skilled in the art.
  • a compound library comprising at least 2 compounds of the invention.
  • the compounds of the present invention potentiate the AMPA receptor.
  • Compounds which potentiate the AMPA receptor may be useful for treating diseases and conditions which are mediated by or caused by a reduction or imbalance in glutamate receptor function, and which therefore benefit from the potentiation of the AMPA receptor.
  • the present invention provides a compound of formula (I) or a salt thereof for use as a medicament. It will be appreciated that the invention includes the following further aspects. The embodiments described in respect of the first aspect apply equally to each of these further aspects:
  • a compound of the invention in the manufacture of a medicament for treating a disease or condition mediated by a reduction or imbalance in glutamate receptor function in a mammal; ii) a compound of the invention for use in treating a disease or condition mediated by a reduction or imbalance in glutamate receptor function in a mammal; iii) a method of treatment of a disease or condition mediated by a reduction or imbalance in glutamate receptor function in a mammal comprising administering an effective amount of a compound of the invention; iv) a combination product of a compound of formulathe invention with an antipsychotic; v) a pharmaceutical composition comprising a combination product as defined in iv) above and at least one carrier, diluent or excipient; vi) the use of a combination product as defined in iv) above in the manufacture of a medicament for treating a disease or condition mediated by a reduction or imbalance in glutamate receptor function in a mammal; vii) a combination
  • relevant diseases or conditions are: psychosis and psychotic disorders (including schizophrenia, schizo-affective disorder, schizophreniform diseases, brief reactive psychosis, child onset schizophrenia,
  • Schizophrenia-spectrum disorders such as schizoid or schizotypal personality disorders, acute psychosis, alcohol psychosis, drug-induced psychosis, autism, delerium, mania
  • neurodegenerative diseases including acute mania, manic depressive psychosis, hallucination, endogenous psychosis, organic psychosyndrome, paranoid and delusional disorders, puerperal psychosis, and psychosis associated with neurodegenerative diseases such as
  • Alzheimer's disease substance related disorders (including alcohol-related disorders and nicotine-related disorders); cognitive impairment (e.g. the treatment of impairment of cognitive functions including attention, orientation, memory (i.e. memory disorders, amnesia, amnesic disorders and age-associated memory impairment) and language function, and including cognitive impairment as a result of stroke, Alzheimer's disease,
  • Aids-related dementia or other dementia states as well as other acute or sub-acute conditions that may cause cognitive decline such as delirium or depression (pseudodementia states) trauma, aging, stroke, neurodegeneration, drug-induced states, neurotoxic agents), mild cognitive impairment, age related cognitive impairment, autism related cognitive impairment, Down's syndrome, cognitive deficit related to psychosis, post-electroconvulsive treatment related cognitive disorders; anxiety disorders (including generalised anxiety disorder, social anxiety disorder, agitation, tension, social or emotional withdrawal in psychotic patients, panic disorder, and obsessive compulsive disorder); neurodegenerative diseases (such as Alzheimer's disease, amyotrophic lateral sclerosis, motor neurone disease and other motor disorders such as Parkinson's disease (including relief from locomotor deficits and/or motor disability, including slowly increasing disability in purposeful movement, tremors, bradykinesia, hyperkinesia (moderate and severe), akinesia, rigidity, disturbance of balance and co-ordination, and
  • psychotic disorder includes :-
  • Schizophrenia including the subtypes Paranoid Type (295.30), Disorganised Type (295.10), Catatonic Type (295.20), Undifferentiated Type (295.90) and Residual Type (295.60); Schizophreniform Disorder (295.40); Schizoaffective Disorder (295.70) including the subtypes Bipolar Type and Depressive Type; Delusional Disorder (297.1 ) including the subtypes Erotomanic Type, Grandiose Type, Jealous Type, Persecutory Type, Somatic Type, Mixed Type and Unspecified Type; Brief Psychotic Disorder (298.8); Shared Psychotic Disorder (297.3); Psychotic Disorder Due to a General Medical Condition including the subtypes With Delusions and With Hallucinations; Substance- Induced Psychotic Disorder including the subtypes With Delusions (293.81 ) and With Hallucinations (293.82); and Psychotic Disorder Not Otherwise Specified (298.9).
  • Compounds of the invention may also be of use in the treatment of the following disorders:-
  • Depression and mood disorders including Major Depressive Episode, Manic Episode, Mixed Episode and Hypomanic Episode; Depressive Disorders including Major Depressive Disorder, Dysthymic Disorder (300.4), Depressive Disorder Not Otherwise Specified (311 ); Bipolar Disorders including Bipolar I Disorder, Bipolar Il Disorder (Recurrent Major Depressive Episodes with Hypomanic Episodes) (296.89), Cyclothymic Disorder (301.13) and Bipolar Disorder Not Otherwise Specified (296.80); Other Mood Disorders including Mood Disorder Due to a General Medical Condition (293.83) which includes the subtypes With Depressive Features, With Major Depressive-like Episode, With Manic Features and With Mixed Features), Substance-Induced Mood Disorder (including the subtypes With Depressive Features, With Manic Features and With Mixed Features) and Mood Disorder Not Otherwise Specified (296.90):
  • Substance-related disorders including Substance Use Disorders such as Substance Dependence, Substance Craving and Substance Abuse; Substance-Induced Disorders such as Substance Intoxication, Substance Withdrawal, Substance-Induced Delirium, Substance-Induced Persisting Dementia, Substance-Induced Persisting Amnestic Disorder, Substance-Induced Psychotic Disorder, Substance-Induced Mood Disorder, Substance-Induced Anxiety Disorder, Substance-Induced sexual Dysfunction, Substance- Induced Sleep Disorder and Hallucinogen Persisting Perception Disorder (Flashbacks); Alcohol-Related Disorders such as Alcohol Dependence (303.90), Alcohol Abuse (305.00), Alcohol Intoxication (303.00), Alcohol Withdrawal (291.81 ), Alcohol Intoxication Delirium, Alcohol Withdrawal Delirium, Alcohol-Induced Persisting Dementia, Alcohol- Induced Persisting Amnestic Disorder, Alcohol-Induced Psychotic Disorder,
  • Sleep disorders including primary sleep disorders such as Dyssomnias such as Primary Insomnia (307.42), Primary Hypersomnia (307.44), Narcolepsy (347), Breathing-Related Sleep Disorders (780.59), Circadian Rhythm Sleep Disorder (307.45) and Dyssomnia Not Otherwise Specified (307.47); primary sleep disorders such as Parasomnias such as Nightmare Disorder (307.47), Sleep Terror Disorder (307.46), Sleepwalking Disorder (307.46) and Parasomnia Not Otherwise Specified (307.47); Sleep Disorders Related to Another Mental Disorder such as Insomnia Related to Another Mental Disorder (307.42) and Hypersomnia Related to Another Mental Disorder (307.44); Sleep Disorder Due to a General Medical Condition, in particular sleep disturbances associated with such diseases as neurological disorders, neuropathic pain, restless leg syndrome, heart and lung diseases; and Substance-Induced Sleep Disorder including the subtypes Insomnia Type, Hypersomnia Type, Parasomnia Type and Mixed Type; sleep apnea and jet-lag
  • Autism Spectrum Disorders including Autistic Disorder (299.00), Asperger's Disorder (299.80), Rett's Disorder (299.80), Childhood Disintegrative Disorder (299.10) and Pervasive Disorder Not Otherwise Specified (299.80, including Atypical Autism).
  • Attention-Deficit/Hyperactivity Disorder including the subtypes Attention-Deficit /Hyperactivity Disorder Combined Type (314.01 ), Attention-Deficit /Hyperactivity Disorder
  • Hyperactive-Impulse Type (314.01 ) and Attention-Deficit /Hyperactivity Disorder Not
  • Tic Disorders such as Tourette's Disorder (307.23): Personality Disorders including the subtypes Paranoid Personality Disorder (301.0), Schizoid Personality Disorder (301.20), Schizotypal Personality Disorder (301 ,22), Antisocial Personality Disorder (301.7), Borderline Personality Disorder (301 ,83), Histrionic Personality Disorder (301.50), Narcissistic Personality Disorder (301 ,81 ), Avoidant Personality Disorder (301.82), Dependent Personality Disorder (301.6), Obsessive-Compulsive Personality Disorder (301.4) and Personality Disorder Not Otherwise Specified (301.9):
  • Enhancement of cognition including the treatment of cognition impairment in other diseases such as schizophrenia, bipolar disorder, depression, other psychiatric disorders and psychotic conditions associated with cognitive impairment, e.g. Alzheimer's disease: and
  • Sexual dysfunctions including sexual Desire Disorders such as Hypoactive Sexual Desire Disorder (302.71 ), and sexual Aversion Disorder (302.79); sexual arousal disorders such as Female sexual Arousal Disorder (302.72) and Male Erectile Disorder (302.72); orgasmic disorders such as Female Orgasmic Disorder (302.73), Male Orgasmic Disorder (302.74) and Premature Ejaculation (302.75); sexual pain disorder such as Dyspareunia (302.76) and Vaginismus (306.51 ); Sexual Dysfunction Not Otherwise Specified (302.70); paraphilias such as Exhibitionism (302.4), Fetishism (302.81 ), Frotteurism (302.89), Pedophilia (302.2), Sexual Masochism (302.83), sexual Sadism (302.84), Transvestic Fetishism (302.3), Voyeurism (302.82) and Paraphilia Not Otherwise Specified (302.9); gender identity disorders such as Gender Identity Disorder in Children (302.6) and Gender Identity Disorder in Adolescents or Adults (302.85); and
  • cognitive impairment includes for example the treatment of impairment of cognitive functions including attention, orientation, learning disorders, memory (i.e. memory disorders, amnesia, amnesic disorders, transient global amnesia syndrome and age-associated memory impairment) and language function; cognitive impairment as a result of stroke, Alzheimer's disease, Huntington's disease, Pick disease, Aids-related dementia or other dementia states such as Multiinfarct dementia, alcoholic dementia, hypotiroidism-related dementia, and dementia associated to other degenerative disorders such as cerebellar atrophy and amyotropic lateral sclerosis; other acute or sub-acute conditions that may cause cognitive decline such as delirium or depression (pseudodementia states) trauma, head trauma, age related cognitive decline, stroke, neurodegeneration, drug-induced states, neurotoxic agents, mild cognitive impairment, age related cognitive impairment, autism related cognitive impairment, Down's syndrome, cognitive deficit related to psychosis, and post- electroconvulsive treatment related cognitive disorders; and dyskinetic disorders
  • the present invention provides a use of a compound of the invention in the manufacture of a medicament for treating schizophrenia or impairment of cognition.
  • the present invention provides a method of treatment of schizophrenia or impairment of cognition, comprising administering an effective amount of a compound of the invention.
  • treatment includes prophylaxis as well as alleviation of established symptoms.
  • the mammal to be treated is a human.
  • the compounds of the invention may be used in combination with one or more of the following agents to treat psychotic disorders: i) antipsychotics (such as olanzapine, risperidone, clozapine, ziprazidone, talnetant); ii) drugs for extrapyramidal side effects, for example anticholinergics (such as benztropine, biperiden, procyclidine, trihexyphenidyl), antihistamines (such as diphenhydramine), dopaminergics (such as amantadine); iii) antidepressants; iv) anxiolytics; v) cognitive enhancers for example cholinesterase inhibitors (such as tacrine, donepezil, rivastigmine,galantamine).
  • antipsychotics such as olanzapine, risperidone, clozapine, ziprazidone, talnetant
  • drugs for extrapyramidal side effects for example anticholinergics
  • the compounds of the invention may be used in combination with antidepressants to treat depression and mood disorders.
  • the compounds of the invention may be used in combination with one or more of the following agents to treat bipolar disease: i) mood stabilisers; ii) antipsychotics; iii) antidepressants.
  • the compounds of the invention may be used in combination with one or more of the following agents to treat anxiety disorders: i) anxiolytics; ii) antidepressants.
  • the compounds of the invention may be used in combination with one or more of the following agents to improve nicotine withdrawal and reduce nicotine craving: i) nicotine replacement therapy, for example a sublingual formulation of nicotine beta-cyclodextrin and nicotine patches; ii) drugs for treating nicotine addition, for example bupropion.
  • nicotine replacement therapy for example a sublingual formulation of nicotine beta-cyclodextrin and nicotine patches
  • drugs for treating nicotine addition for example bupropion.
  • the compounds of the invention may be used in combination with one or more of the following agents to improve alcohol withdrawal and reduce alcohol craving: i) NMDA receptor antagonists for example acamprosate; ii) GABA receptor agonists for example tetrabamate; iii) Opioid receptor antagonists for example naltrexone.
  • the compounds of the invention may be used in combination with one or more of the following agents to improve opiate withdrawal and reduce opiate craving: i) opioid mu receptor agonist/opioid kappa receptor antagonist for example buprenorphine; ii) opioid receptor antagonists for example naltrexone; iii) vasodilatory antihypertensives for example lofexidine.
  • the compounds of the invention may be used in combination with one or more of the following agents to treat sleeping disorders: i) benzodiazepines for example temazepam, lormetazepam, estazolam, triazolam; ii) non-benzodiazepine hypnotics for example Zolpidem, zopiclone, zaleplon, indiplon; iii) barbiturates for example aprobarbital, butabarbital, pentobarbital, secobarbita, phenobarbital; iv) antidepressants; v) other sedative-hypnotics for example chloral hydrate, chlormethiazole.
  • benzodiazepines for example temazepam, lormetazepam, estazolam, triazolam
  • non-benzodiazepine hypnotics for example Zolpidem, zopiclone, zaleplon, indiplon
  • barbiturates for
  • the compounds of the invention may be used in combination with one or more of the following agents to treat anorexia: i) appetite stimulants for example cyproheptidine; ii) antidepressants; iii) antipsychotics; iv) zinc; v) premenstrual agents for example pyridoxine and progesterones.
  • the compounds of the invention may be used in combination with one or more of the following agents to treat bulimia: i) antidepressants; ii) opioid receptor antagonists; iii) antiemetics for example ondansetron; iv) testosterone receptor antagonists for example flutamide; v) mood stabilisers; vi) zinc; vii) premenstrual agents.
  • the compounds of the invention may be used in combination with one or more of the following agents to treat autism: i) antipsychotics; ii) antidepressants; iii) anxiolytics; iv) stimulants for example methylphenidate, amphetamine formulations, pemoline.
  • the compounds of the invention may be used in combination with one or more of the following agents to treat Attention Deficit Hyperactivity Disorder: i) stimulants for example methylphenidate, amphetamine formulations, pemoline; ii) non-stimulants for example norepinephrine reuptake inhibitors (such as atomoxetine), alpha 2 adrenoceptor agonists (such as clonidine), antidepressants, modafinil, cholinesterase inhibitors (such as galantamine and donezepil).
  • stimulants for example methylphenidate, amphetamine formulations, pemoline
  • non-stimulants for example norepinephrine reuptake inhibitors (such as atomoxetine), alpha 2 adrenoceptor agonists (such as clonidine), antidepressants, modafinil, cholinesterase inhibitors (such as galantamine and donezepil).
  • the compounds of the invention may be used in combination with one or more of the following agents to treat personality disorders: i) antipsychotics; ii) antidepressants; iii) mood stabilisers; iv) anxiolytics.
  • the compounds of the invention may be used in combination with one or more of the following agents to treat male sexual dysfunction: i) phosphodiesterase V inhibitors, for example vardenafil, sildenafil; ii) dopamine agonists/dopamine transport inhibitors for example apomorphine, buproprion; iii) alpha adrenoceptor antagonists for example phentolamine; iv) prostaglandin agonists for example alprostadil; v) testosterone agonists such as testosterone; vi) serotonin transport inhibitors for example serotonin reuptake inhibitors; v) noradrenaline transport inhibitors for example reboxetine; vii) 5-HT1A agonists, for example flibanserine.
  • phosphodiesterase V inhibitors for example vardenafil, sildenafil
  • dopamine agonists/dopamine transport inhibitors for example apomorphine, buproprion
  • the compounds of the invention may be used in combination with one or more of the following agents to treat female sexual dysfunction: i) the same agents specified for male sexual dysfunction, ii) an estrogen agonist such as estradiol.
  • Antipsychotic drugs include Typical Antipsychotics (for example chlorpromazine, thioridazine, mesoridazine, fluphenazine, perphenazine, prochlorperazine, trifluoperazine, thiothixine, haloperidol, molindone and loxapine); and Atypical Antipsychotics (for example clozapine, olanzapine, risperidone, quetiapine, aripirazole, ziprasidone, amisulpride, ziprazidone and talnetant).
  • Typical Antipsychotics for example chlorpromazine, thioridazine, mesoridazine, fluphenazine, perphenazine, prochlorperazine, trifluoperazine, thiothixine, haloperidol, molindone and loxapine
  • Atypical Antipsychotics for example clozapine, olanzapine, risperi
  • Antidepressant drugs include serotonin reuptake inhibitors (such as citalopram, escitalopram, fluoxetine, paroxetine and sertraline); dual serotonin/noradrenaline reuptake inhibitors (such as venlafaxine, duloxetine and milnacipran); Noradrenaline reuptake inhibitors (such as reboxetine); tricyclic antidepressants (such as amitriptyline, clomipramine, imipramine, maprotiline, nortriptyline and trimipramine); monoamine oxidase inhibitors (such as isocarboxazide, moclobemide, phenelzine and tranylcypromine); and others (such as bupropion, mianserin, mirtazapine, nefazodone and trazodone).
  • serotonin reuptake inhibitors such as citalopram, escitalopram, fluoxetine, parox
  • Mood stabiliser drugs include lithium, sodium valproate/valproic acid/divalproex, carbamazepine, lamotrigine, gabapentin, topiramate and tiagabine.
  • Anxiolytics include benzodiazepines such as alprazolam and lorazepam.
  • the compounds of the invention may be administered in conventional dosage forms prepared by combining a compound of the invention with standard pharmaceutical carriers or diluents according to conventional procedures well known in the art. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
  • compositions of the invention may be formulated for administration to mammals including humans.
  • the compositions may be formulated for administration by any route.
  • the compositions may be formulated for oral, topical, or parenteral administration, and may be in the form of tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
  • the topical formulations of the present invention may be presented as, for instance, ointments, creams or lotions, eye ointments and eye or ear drops, impregnated dressings and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams.
  • the formulations may also contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions.
  • suitable conventional carriers such as cream or ointment bases and ethanol or oleyl alcohol for lotions.
  • Such carriers may be present as from about 1% up to about 98% of the formulation. More usually they will form up to about 80% of the formulation.
  • Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents.
  • suspending agents for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or
  • Suppositories will contain conventional suppository bases, e.g. cocoa-butter or other glyceride.
  • fluid unit dosage forms are prepared utilising the compound and a sterile vehicle, for example water.
  • a sterile vehicle for example water.
  • the compound depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.
  • the compound can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
  • Agents such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • the dry lyophilised powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use.
  • Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilisation cannot be accomplished by filtration.
  • the compound can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent may be included in the composition to facilitate uniform distribution of the compound.
  • the optimal quantity and spacing of individual dosages of a compound of the invention will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular mammal being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e. the number of doses of a compound of the invention given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests.
  • Flash chromatography was carried out using pre-packed lsolute FlashTM or BiotageTM silica-gel columns as the stationary phase and analytical grade solvents as the eluent.
  • NMR spectra were obtained at 298K, at the frequency stated using either a BrukerTM DPX400 or an Oxford InstrumentsTM 250 MHz machine and run as a dilute solution of CDCI3 unless otherwise stated. All NMR spectra were reference to tetramethylsilane (TMS ⁇ H 0, ⁇ c 0). All coupling constants are reported in hertz (Hz), and multiplicities are labelled s (singlet), bs, (broad singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), dt (doublet of triplets) and m (multiplet).
  • 2-Aminoindan hydrochloride (5.16 g, 30 mmol, Sigma-Aldrich Company Ltd) was suspended in dry dichloromethane (100 ml), and cooled with stirring under argon to 0 0 C. To the suspension was added 1 ,8-diazabicyclo[5.4.0]undec-7-ene (3 eq., about 14ml, about 90 mmol) followed by the dropwise addition of isopropylsulfonyl chloride (6.8ml, 60 mmol). The cooling bath was removed and the mixture stirred at room temperature for 1 h. The reaction mixture was washed with 1 M hydrochloric acid (2 x 50 ml).
  • the title compound was prepared from 5-bromo-2-aminoindane hydrobromide (Prashad et al, Adv. Synth. Catal. 2001 , 343, No. 5, pp 461-472) using a similar process to that used for description 1.
  • UV WL range 200-400 nm Analysis time 17 min
  • the title compound was prepared from (S)-5-bromo-2-aminoindan (1 R)-(- )-10- camphorsulfonate salt using a similar process to that used for description 7, but using triethylamine as the base instead of diisopropylethylamine. Crude product was purified by flash chromatography on a 5g pre-packed silica column eluting from 20-100% ethyl acetate in petroleum ether.
  • This intermediate (32.7g, 167mmol) was dissolved in ethanol (570ml) and to the solution hydrazine hydrate (16.7g, 16.6ml, 334mmol) was added at room temperature. The resulting mixture was stirred at reflux temperature for 6 hours, then it was allowed to cool down to room temperature and the solvent was removed by rotary evaporation. The residue was partitioned between dichloromethane (400ml) and water (200ml). The aqueous layer was extracted twice with dichloromethane (each with 150ml). The combined organic layers were washed with water (200ml), brine (150ml) and dried over sodium sulphate. The solvent was removed by rotary evaporation to obtain 20.47g of a yellow solid.
  • Coloumn Acquity UPLC BEH C18, 2.1 x 50 mm, 1.7 urn.
  • Mobile phase A: Water + 0.1 % formic acid, B: CH 3 CN + 0.06 % formic acid Gradient: 3% to 6% (B) in 0.1 min., 6% to 70% (B) in 0.5 min., 70% (B) to 99% (B) in
  • UV range 210-350 nm
  • Example 1 ⁇ /- ⁇ (2S)-5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]-2,3- dihydro-1H-inden-2-yl ⁇ -2-propanesulfonamide
  • reaction mix was cooled and added to a 5g pre-packed silica column which was then eluted from 50% ethyl acetate in petroleum ether to give a dark oil which was further purified by mass directed auto-prep to give a pure crop of the title compound as a yellow oil (103mg, 48%).
  • Example 2 1 - ⁇ (2/?S)-5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1 -yl]-2,3- dihydro-1H-inden-2-yl ⁇ -2-pyrrolidinone
  • Example 3 1 - ⁇ (2S)-5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1 -yl]-2,3- dihydro-1H-inden-2-yl ⁇ -2 -pyrrolidinone
  • the title compound was prepared from 1-[(2S)-5-bromo-2,3-dihydro-1H-inden-2-yl]-2- pyrrolidinone and 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazole using a similar process to that used for Example 2, except the reaction was heated at 19O 0 C in a microwave reactor for 1 h.
  • Example 4 1 - ⁇ (2/?)-5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1 -yl]-2,3- dihydro-1H-inden-2-yl ⁇ -2 -pyrrolidinone
  • the title compound was prepared from 1-[(2/?)-5-bromo-2,3-dihydro-1 H-inden-2-yl]-2- pyrrolidinone and 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazole using a similar process to that used for Example 2, except the reaction was heated at 19O 0 C in a microwave reactor for 1 h.
  • Typical procedure The title compounds reported in table 1 were prepared by parallel synthesis. 0.12M DMSO solutions of each 5-bromoindane scaffold (YY) and of each pyrazole scaffold (WW) were prepared. Then the necessary scaffold solutions (1.5ml, 0.18mmol) and pyrazole solutions (1.5ml, 0.18mmol) were dispensed into 5ml microwave tubes. To the resulting DMSO mixtures, N,N-dimethylglycine (0.021 g, 0.207mmol), potassium carbonate (0.05Og, 0.360mmol) and copper (I) iodide (0.038g, 0.198mmol) were added.
  • the resulting suspensions were heated at 190 0 C in a microwave reactor for 30 min, then they were filtered and the solvent removed by vacuum centrifuge overnight.
  • the obtained crude products were partitioned between dichloromethane (3ml) and aqueous saturated ammonium chloride (2ml), then the organic layers were separated and the solvent removed by blowing down in air.
  • the obtained crude products were purified by preparative HPLC/MS to give the title compounds (YW) as reported in table 1.
  • Example 8 ⁇ /- ⁇ (2S)-5-[3-(trifluoromethyl)-4,7-dihydropyrano[3,4-c]pyrazol- 1(5H)-yl]-2,3-dihydro-1H-inden-2-yl ⁇ -2-propanesulfonamide
  • Example 23 i- ⁇ PJ-S-IS-cyclopropyl-S-ttrifluoromethylJ-IH-pyrazol-i-yll ⁇ .S- dihydro-1H-inden-2-yl ⁇ -2-pyrrolidinone
  • Example 27 W 2 ,W 2 -c//mefA?y/-yV 7 - ⁇ 2/?S)-5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H- indazol-1 -yl]-2,3-dihydro-1H-inden-2-yl ⁇ glycinamide formic acid salt
  • Example 27 ⁇ / 2 , ⁇ / 2 -dimethyl- ⁇ / 1 - ⁇ 5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1 -yl]- 2,3-dihydro-1 H-inden-2-yl ⁇ glycinamide formic acid salt LC/MS (ES): Found 407 (ES+), retention time 2.10 mins C 2 i H 2 SF 3 N 4 O requires 406.
  • Example 28 ⁇ /- ⁇ (2/?)-5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1 -yl]-2,3- dihydro-1H-inden-2-yl ⁇ -2-propanesulfonamide
  • Example 29 1-[(2/?S)-2-(1,1-dioxido-2-isothiazolidinyl)-2,3-dihydro-1H-inden-5-yl]-3- (trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole And Description 22: 2-[(2/?S)-5-bromo-2,3-dihydro-1H-inden-2-yl]isothiazolidine 1 ,1- dioxide
  • 3-Chloro-1-propanesulfonyl chloride (40 ⁇ l, 0.33mmol) was added in one portion to a stirring solution of diisopropylethylamine (50 ⁇ l, 0.29mmol), and a mixture of 5-[3- (trifluoromethyl)-4, 5, 6, 7-tetrahydro-1 H-indazol-1 -yl]-2,3-dihydro-1 H-inden-2-amine and 5- bromo-2-aminoindane (48.2mg - combined mass of both indane amines) in DMF (1 ml).
  • Example 30 ⁇ /- ⁇ (2/?S)-5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1 -yl]-2,3- dihydro-1H-inden-2-yl ⁇ acetamide
  • Description 23 ⁇ /-[(2/?S)-5-bromo-2,3-dihydro-1H-inden-2-yl]acetamide
  • Acetyl chloride (50 ⁇ l, 0.70mmol) was added in one portion to a room temperature stirring mixture of DBU (1 ,8-diazabicyclo[5.4.0]undec-7-ene) (80 ⁇ l, 0.53mmol), and a mixture of 5-[3-(trifluoromethyl)-4, 5, 6, 7-tetrahydro-1 H-indazol-1 -yl]-2,3-dihydro-1 H-inden-2-amine and 5-bromo-2-aminoindane (77.0mg - combined mass of both indane amines) in DCM (1.5ml).
  • Example 33 1 -[(2/?S)-2-(1 -piperidinyl)-2,3-dihydro-1 H-inden-5-yl]-3-(trifluoromethyl)- 4,5,6,7-tetrahydro-1H-indazole formic acid salt
  • Example 35 ⁇ /- ⁇ (2/?S)-5-[3-(trifluoromethyl)-6,7-dihydropyrano[4,3-c]pyrazol-1(4H)- yl]-2,3-dihydro-1H-inden-2-yl ⁇ acetamide
  • Example 36 The following compounds were synthesised from ⁇ /-[(2/?S)-5-bromo-2,3-dihydro-1 H- inden-2-yl]methanesulfonamide (Example 36) and 2-[(2/?S)-5-bromo-2,3-dihydro-1 H- inden-2-yl]isothiazolidine 1 ,1-dioxide (Example 37) in a manner similar to that described for Example 35.
  • Example 40 1 - ⁇ (2R)-5-[6-methyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H- pyrazolo[3,4-c]pyridin-1-yl]-2,3-dihydro-1 H-inden-2-yl ⁇ -2-pyrrolidinone
  • the resulting suspensions were heated at 190 0 C in a microwave reactor for 30 min, then they were filtered and the solvent removed by vacuum centrifuge overnight.
  • the obtained crude products were dissolved in MeOH (3ml) and eluted through a 2g SCX cartridge (MeOH then 2M solution of NHg in MeOH as eluent). The solvent was then removed by blow down.
  • Example 46 4- ⁇ 5-[5-cyclopropyl-3-(difluoromethyl)-1H-pyrazol-1 -yl]-2,3-dihydro-1H- inden-2-yl ⁇ morpholine
  • Example 48 4- ⁇ (2/?)-5-[5-(3-pyridinyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl]-2,3- dihydro-1H-inden-2-yl ⁇ morpholine, hydrochloride salt
  • the reaction mixture was diluted with ethylacetate then filtered through a pad of kieselguhr to remove the catalyst.
  • the organic solution was washed with water, dried with sodium sulphate and evaporated.
  • the resultant material was purified by MDAP.
  • the resulting material was dissolved in methanol and treated with ethereal hydrochloride. Solvent was removed to give the title compound as a HCI salt (35mg).
  • Example 50 4- ⁇ (2/?)-5-[5-(2-pyridinyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl]-2,3- dihydro-1H-inden-2-yl ⁇ morpholine, hydrochloride salt
  • Example 51 4- ⁇ (2S)-5-[5-(2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazol-1 -yl]-2,3- dihydro-1H-inden-2-yl ⁇ morpholine, hydrochloride salt
  • Example 52 4- ⁇ (2S)-5-[5-(6-methyl-3-pyridinyl)-3-(trifluoromethyl)-1H-pyrazol-1 -yl]- 2,3-dihydro-1H-inden-2-yl ⁇ morpholine, formate salt
  • reaction mixture was partitionned between water (20ml) and DCM (40ml). The aqueous was further extracted with DCM (40ml). The organics were combined, washed with water (20ml), dried over MgSO 4 and concentrated to give a black oil which was purified by reverse phase chromatography using the MDAP to afford 20mg of a brown oil which was purified again using the MDAP. Relevant fractions were combined and concentrated to afford 4mg of the title compound as a clear oil and as the formate salt.
  • Example 54 ⁇ /- ⁇ (2S)-5-[5-(2-pyridinyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl]-2,3- dihydro-1H-inden-2-yl ⁇ -2-propanesulfonamide, hydrochloride salt
  • Example 55 1 - ⁇ (2/?)-5-[5-(6-methyl-3-pyridinyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl]- 2,3-dihydro-1H-inden-2-yl ⁇ -2-pyrrolidinone
  • Example 56 1 - ⁇ (2/?)-5-[5-(4-pyridinyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl]-2,3- dihydro-1H-inden-2-yl ⁇ -2 -pyrrolidinone, hydrochloride salt
  • Example 57 1 - ⁇ (2/?)-5-[5-(3-pyridinyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl]-2,3- dihydro-1H-inden-2-yl ⁇ -2 -pyrrolidinone, hydrochloride salt
  • Coloumn Acquity UPLC BEH C18, 2.1 x 50 mm, 1.7 urn.
  • Mobile phase A: Water + 0.1 % formic acid, B: CH 3 CN + 0.06 % formic acid
  • the generic method used has a 2 minute runtime.
  • UV range 210-350 nm
  • the UV detection was an averaged signal from wavelength of 210nm to 350nm and mass spectra were recorded on a mass spectrometer using alternate-scan positive and negative mode electrospray ionization.
  • HPLC analysis was conducted on a Sunfire C18 column (30mm x 4.6mm i.d. 3.5 ⁇ m packing diameter) at 30 degrees centigrade.
  • the UV detection was an averaged signal from wavelength of 210nm to 350nm and mass spectra were recorded on a mass spectrometer using alternate-scan positive and negative mode electrospray ionization.
  • UV range 210-350 nm
  • UV range 210-350 nm
  • the column used is Waters X-bridge, the dimensions of which are 30mm x
  • the stationary phase particle size is 5 ⁇ m.
  • Aqueous solvent 1OmM Ammonium Bicarbonate solution adjusted to pH 10 with ammonia solution.
  • the ability of the compounds of the invention to potentiate AMPA receptor-mediated response may be determined by using fluorescent calcium-indicator dyes such as FLUO4.
  • fluorescent calcium-indicator dyes such as FLUO4.
  • the compounds of the present invention were not necessarily from the same batch described above. A test compound from one batch may have been combined with other batch(es) for the assay(s).
  • 384 well plates are prepared containing confluent monolayer of HEK 293 cells either stably expressing or transiently transfected with human GluR2 flip (unedited) AMPA receptor subunit. These cells form functional homotetrameric AMPA receptors.
  • tissue culture medium in the wells are discarded and the wells are each washed three times with standard buffer (80 ⁇ l_) for the stable cell line (145 mM NaCI, 5 mM KCI, 1 mM MgCI 2 , 2 mM CaCI 2 , 20 mM N-[2-hydroxyethyl]-piperazine-N-[2-ethanesulfonic acid (HEPES), 5.5 mM glucose, pH 7.3) or with a Na-free buffer for the transient transfected cells (145 mM N-methyl-glucamine instead of NaCI).
  • standard buffer 80 ⁇ l_
  • the plates are then incubated for 60 minutes in the dark with 2 ⁇ M FLUO4-AM dye (20 ⁇ l_) (Molecular Probes, Netherlands) at room temperature to allow cell uptake of the FLUO-4AM, which is then converted to FLUO-4 by intracellular esterases which is unable to leave the cell. After incubation each well is washed three times with buffer (80 ⁇ l_) (30 ⁇ l_ of buffer remained in each well after washing).
  • DMSO dimethylsulfoxide
  • DMSO dimethylsulfoxide
  • a Biomek FX Beckman Coulter
  • Each dilution (1 ⁇ l_) is transferred to another compound plate and buffer (50 ⁇ l_) is added.
  • An agonist stimulus (glutamate) plate is prepared by dissolving sodium glutamate in water to give a concentration of 100 mM.
  • This solution is diluted with buffer to give a final concentration of 500 ⁇ M and dispensed into another 384-well plate (50 ⁇ l_/well) using a Multidrop (Thermolabsystems).
  • the cell plate is then transferred into a fluorescence imaging plate based reader [such as the FLIPR384 (Molecular Devices)].
  • a baseline fluorescence reading is taken over a 10 to 240 second period, and then 10 ⁇ L from each plate containing a compound of the invention made up in standard buffer solution (in a concentration range from 100 ⁇ M to 10 pM) is added (to give a final concentration in the range 30 ⁇ M to 3 pM).
  • the fluorescence is read over 5 minute period.
  • 500 ⁇ M glutamate solution (10 ⁇ l_) is added (to give a final concentration of 100 ⁇ M).
  • the fluorescence is then read over a 4 minute period.
  • the activities of the compounds of the invention and reference compounds are determined by measuring peak fluorescence after the last addition. The activity is also expressed relative to the fluorescence increase induced by cyclothiazide at their maximum response (i.e. greater than 30 ⁇ M).
  • 384 well plates are prepared containing confluent monolayer of HEK 293 cells stably expressing human GluR2 flip (unedited) AMPA receptor subunit.
  • culture medium are discarded and the cells washed three times with standard buffer (145 mM NaCI, 5 mM KCI, 1 mM MgCI2, 2 mM CaCI2, 20 mM N-[2-hydroxyethyl]-piperazine-N-[2-ethanesulfonic acid (HEPES), 5.5 mM glucose, pH 7.3) and 20 ⁇ l_ of buffer remained in each well after washing.
  • standard buffer 145 mM NaCI, 5 mM KCI, 1 mM MgCI2, 2 mM CaCI2, 20 mM N-[2-hydroxyethyl]-piperazine-N-[2-ethanesulfonic acid (HEPES), 5.5 mM glucose, pH 7.3
  • the plates are then incubated at room temperature for 60 minutes in the dark with 2 ⁇ M FLUO-4AM dye to allow cell uptake of the FLUO-4AM, which is then converted to FLUO-4 by intracellular esterases which is unable to leave the cells. After incubation cells are washed three times with buffer and 30 ⁇ l_ of buffer remained in each well after washing. Compounds of the invention are tested in a final assay concentration range from 100 ⁇ M to 1 nM.
  • DMSO dimethylsulfoxide
  • the cell plate is then transferred into a fluorescence imaging plate based reader (such as the FLIPR384 - Molecular Devices).
  • a fluorescence imaging plate based reader such as the FLIPR384 - Molecular Devices.
  • a baseline fluorescence reading is taken over a 5 to 10 second period, and then 10 ⁇ L of 500 ⁇ M glutamate solution is added (to give a final concentration of 100 ⁇ M).
  • the fluorescence is then read over a 4-5 minute period.
  • the activities of the compounds of the invention and reference compounds are determined by measuring peak fluorescence after the last addition. The activity is also expressed relative to the fluorescence increase induced by 150 ⁇ M cyclothiazide at their maximum response.
  • the assay described above is believed to have an effective limit of detection of a pEC 50 in the region of 3.5-4.0 due to the limitations of compound solubility.
  • the pEC 5 o result is generally considered to be accurate +/- 0.3.
  • Example compounds were screened using at least one of the assays described above and gave an average pEC 50 equal to or greater than 3.5 and/or demonstrated an activity of on average at least 20% that of the reference compound (at its maximal response).

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Abstract

Compound of formula (I) and salts thereof are provided: wherein A, R1, R, R2 are as defined in the specification. Processes for preparation, pharmaceutical compositions, and uses thereof as a medicament, for example in the treatment of a disease or condition mediated by a reduction or imbalance in glutamate receptor function, such as schizophrenia or cognition impairment, are also disclosed.

Description

Compounds which potentiate AMPA receptor and uses thereof in medicine
This invention relates to novel compounds which potentiate the AMPA receptor. The invention also relates to the use of the compounds in treating diseases and conditions wherein the potentiation of the AMPA receptor would be beneficial, compositions containing the derivatives and processes for their preparation.
Glutamate receptors, which mediate the majority of fast excitatory neurotransmission in the mammalian central nervous system (CNS), are activated by the excitatory amino acid, L-glutamate (for review see Watkins JC, Krogsgaard-Larsen P, Honore T (1990) Trends Pharmacol Sci 11 : 25-33).
Glutamate receptors can be divided into two distinct families. The G-protein or second messenger-linked "metabotropic" glutamate receptor family which can be subdivided into three groups (Group I, mGlui and mGlu5; Group II, mGlu2 and mGlu3; Group III, mGlu4, mGluθ, mGlu7, mGluδ) based on sequence homology and intracellular transduction mechanisms (for review see Conn PJ and Pinn JP (1997) Ann Rev Pharmacol Toxicol 37: 205-237). The "ionotropic" glutamate receptor family, which directly couple to ligand-gated cation channels, can be subdivided into at least three subtypes based on depolarizing activation by selective agonists, N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5- methylisoxazole-4-propionic acid (AMPA) and kainic acid (KA) (for review see Dingledine R, Borges K, Bowie, Traynelis S (1999) 51 : 7-61 ).
Native AMPA receptors (AMPAR) exist as heterotetramers consisting of combinations of four different protein subunits (GIuRI -4) (for review see Bettler B and Muller C (1995) 34: 123-139.). Receptor subunit diversity is increased further as each subunit can undergo alternative splicing of a 38 amino acid sequence in the extracellular region just before the fourth membrane spanning domain M4. Such editing results in so-called 'flip' and 'flop' receptor isoforms which differ in kinetic and pharmacological properties (Sommer B, Keinanen K, Verdoon TA, Wisden W, Burnashev N, Herb A, Kohler M, Takagi T, Sakmann B, Seeburg PH (1990) Science 249: 1580-1585).
Additionally, post-transcriptional editing of GluR2 mRNA changes a neutral glutamine to a positively charged arginine within M2. In normal humans >99% GluR2 is edited in this way. AMPAR containing such edited GluR2 subunit exhibit low calcium permeability (Burnachev N, Monyer H, Seeburg PH, Sakmann B (1992) Neuron 8: 189-198). There is a suggestion, however, that the number of AMPAR with high calcium permeability is elevated in certain disease-associated conditions (Weiss JH, and Sensi SL (2000) Trends in Neurosci 23: 365-371 ).
AMPAR depolarization removes voltage dependent Mg 2+ block of NMDA receptors which in turn leads to NMDA receptor activation, an integral stage in the induction of Long Term Potentiation ("LTP") (Bliss TVP, Collingridge GL (1993) Nature 361 : 31-9). LTP is a physiological measure of increased synaptic strength following a repetitive stimulus or activity, such as occurs during learning.
It has been reported that direct activation of glutamate receptors by agonists, in conditions where glutamate receptor function is reduced, increases the risk of excitotoxicity and additional neuronal damage. AMPAR positive allosteric modulators do not activate the receptor directly. However, when the ligand (L-glutamate or AMPA) is present AMPAR modulators increase receptor activity. Thus, AMPA receptor modulators enhance synaptic function when glutamate is released and is able to bind at post-synaptic receptor sites.
Compounds which act as AMPAR positive allosteric modulators have been shown to increase ligand affinity for the receptor (Arai A, Guidotti A, Costa E, Lynch G (1996) Neuroreport. 7: 221 1-5.); reduce receptor desensitization and reduce receptor deactivation (Arai AC, Kessler M, Rogers G, Lynch G (2000) 58: 802-813) and facilitate the induction of LTP both in vitro (Arai A, Guidotti A, Costa E, Lynch G (1996) 7: 2211-5.) and in vivo (Staubli U, Perez Y, Xu F, Rogers G, Ingvar M, Stone-Elander S, Lynch G (1994) Proc Natl Acad Sci 91 : 1 1158-1 1162). Such compounds also enhance the learning and performance of various cognitive tasks in rodent (Zivkovic I, Thompson DM, Bertolino M, Uzunov D, DiBeIIa M, Costa E, Guidotti A (1995) JPET 272: 300-309, Lebrun C, Pilliere E, Lestage P (2000) Eu J Pharmacol 401 : 205-212), sub-human primate (Thompson DM, Guidotti A, DiBeIIa M, Costa E (1995) Proc Natl Acad Sci 92: 7667-7671 ) and man (Ingvar M, Ambros-lngerson J, Davis M, Granger R, Kessler M, Rogers GA, Schehr RS, Lynch G (1997) Exp Neurol 146: 553-559). The efficacy of various AMPAR positive allosteric modulators in pre-clinical and clinical models of psychiatric disorders, such as schizophrenia, have been investigated (Morrow J A, Maclean J KF, Jamieson C (2006) Current Opinion in Drug Discovery and Development 9(5) 571-579)
Compounds which act as AMPAR positive allosteric modulators are known, for example in international patent application WO/2007/107539. We have discovered novel compounds which potentiate the AMPA receptor.
In the first aspect, the present invention provides a compound of formula (I) or a salt thereof:
Figure imgf000004_0001
(I) wherein:
• A is selected from CF3 and CHF2;
• R1 is selected from cyclopropyl and pyridyl and R2 is hydrogen; or R1 and R2 join together to form a 5- or 6-membered non-aromatic ring, wherein one of the carbon atoms in the ring is optionally replaced by an oxygen atom, NH or NCH3 ;
• R is selected from the group consisting of:
(a) a 5- or 6-membered aromatic or non-aromatic heterocyclic ring, optionally substituted with one, two or three groups selected from C1-4alkyl, C(O)C1-4alkyl, haloC1-4alkyl, halo, hydroxy and oxo; and
(b) NH2, NR3SO2R4, NR3C(O)R4 and OR4 in which
• R3 is selected from hydrogen and C1-4alkyl;
• R4 is selected from C1-6alkyl, haloC1-6alkyl, C3-6cycloalkyl, haloC3-6cycloalkyl, - (CH2)pZ (where p is 1 , 2 or 3 and Z is a phenyl or a 5- or 6-membered aromatic or non-aromatic heterocyclic ring, the phenyl or the heterocyclic ring being optionally substituted with one or more groups selected from halo and Ci-4alkyl) and -(CH2)qNR5R6 (wherein q is 0, 1 or 2 and R5 and R6 are independently C1-6alkyl); or
• R3 and R4, together with the NC(O) or NSO2 group to which they are attached, form a 5- or 6-membered non-aromatic heterocyclic ring, either of which may include one or more further heteroatoms selected from N, O or S, and may be substituted with one or more groups selected from C1-4alkyl, C(O)C1-4alkyl, halo,
Figure imgf000004_0002
hydroxy and oxo.
The term "halo" refers to fluoro, chloro, bromo or iodo.
The term "C1-6alkyl" refers to an alkyl group having from one to six carbon atoms; and the term "C1-4alkyl" refers to an alkyl group having from one to four carbon atoms. Unless otherwise indicated, Ci-4alkyl or Ci-6alkyl may be a straight chain or branched alkyl group. For example, a C1-4alkyl group may be selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or t-butyl. A C1-6alkyl group may be selected from the group consisting of a Ci-4alkyl group, sec-pentyl, n-pentyl, isopentyl, tert-pentyl and hexyl. For example, C1-4alkyl is methyl. "Me" means methyl. "Et" means ethyl. The term "C1-4alkoxy" refers to the group
Figure imgf000005_0001
wherein
Figure imgf000005_0002
is as defined above.
"CO" and "C(=O)" are interchangeable and represent a carbonyl group. The term "oxo" refers to the group "=O".
The term "Cs-βcycloalkyl" refers to a cycloalkyl group consisting of from 3 to 6 carbon atoms, ie cyclopropanyl, cyclobutanyl, cyclopentanyl and cyclohexanyl.
The term "haloalkyl" refers to an alkyl group as defined above which is substituted with any number of fluorine, chlorine, bromine, or iodine atoms, including with mixtures of those atoms. A haloalkyl group may, for example contain 1 , 2 or 3 halogen atoms. For example, a haloalkyl group may have all hydrogen atoms replaced with halogen atoms. Examples of haloC1-4alkyl groups include fluoromethyl, difluoromethyl and trifluoromethyl.
The term "haloCs-βcycloalkyl" refers to a cycloalkyl group as defined above which is substituted with any number of fluorine, chlorine, bromine, or iodine atoms, including with mixtures of those atoms. A haloC3-6cycloalkyl group may, for example contain 1 , 2 or 3 halogen atoms. For example, a haloCs-βcycloalkyl group may have all hydrogen atoms replaced with halogen atoms. Examples of haloCs-ecycloalkyl groups include fluorocyclopropyl.
The term "5- or 6-membered aromatic heterocyclic ring" as used herein refers to a monocyclic 5- or 6-membered aromatic carbocyclic group, containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen and sulphur. Examples include furyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrazinyl, tetrazolyl, triazinyl, oxazepinyl, thiazepinyl, and diazepinyl. Examples of nitrogen- containing monocyclic aromatic heterocyclyl groups are pyrrolyl, imidazolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrazinyl, tetrazolyl, triazinyl, oxazepinyl, thiazepinyl, and diazepinyl.
The term "5- or 6-membered non-aromatic heterocyclic ring" as used herein refers to a monocyclic 5- or 6-membered non-aromatic carbocyclic group, containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen and sulphur. Examples of monocyclic non-aromatic heterocyclyl groups include 2H-pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, dioxolanyl, 1 ,2oxathiolanyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, 3- pyrazolinyl, pyrazolidinyl, 2H-pyranyl, 4H-pyranyl, piperidinyl, 1 ,4diozanyl, morpholinyl, 1 ,4dithianyl, 1 ,4 oxathianyl, thiomorpholinyl, piperazinyl, 6H-1 ,2,5thiadiazinyl and 2H,6H-
1 ,5,2-dithiazinyl. Examples of nitrogen-containing monocyclic non-aromatic heterocyclyl groups include 2H-pyrrole, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, 3-pyrazolinyl, pyrazolidinyl, 2H-pyranyl, 4H-pyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, 6H-1 ,2,5thiadiazinyl and 2H,6H- 1 ,5,2-dithiazinyl.
For the avoidance of doubt, unless otherwise indicated, the term substituted means substituted by one or more defined groups. In the case where groups may be selected from a number of alternative groups, the selected groups may be the same or different. For the avoidance of doubt, the term independently means that where more than one substituent is selected from a number of possible substituents, those substituents may be the same or different.
In one embodiment, A is CF3. In another embodiment, A is CHF2.
In one embodiment, R1 is selected from cyclopropyl and pyridyl, and R2 is hydrogen.
In one embodiment, R1 and R2 join together to form a 5- or 6-membered non-aromatic ring, wherein one of the carbon atoms in the ring is optionally replaced by an oxygen atom, NH or NCH3.
In one embodiment, R1 and R2 join together to form a 5- or 6-membered non-aromatic ring, wherein one of the carbon atoms in the ring is optionally replaced by an oxygen atom Or NCH3.
In one embodiment, R1 and R2 join together to form a 6-membered non-aromatic ring, wherein one of the carbon atoms in the ring is optionally replaced by an oxygen atom or NCH3.
In one embodiment, R1 and R2 join together to form the following group:
Figure imgf000006_0001
(I)
wherein X1 and X2 are both CH2, or one of X1 and X2 is oxygen and the other one is CH2 In an embodiment, R is a 5- or 6-membered aromatic or non-aromatic heterocyclic ring, optionally substituted with one or more groups selected from C1-4alkyl, C(O)C1-4alkyl, haloCi-4alkyl, halo, hydroxy and oxo. In one embodiment, the heterocyclic ring is non- aromatic. In one embodiment, it is 5-membered. In one embodiment, it is selected from morpholine, pyrrolidine and piperidine.
In one embodiment, the 5- or 6-membered aromatic or non-aromatic heterocyclic ring is attached to the remainder of the molecule through a carbon atom (ie C-linked) or a nitrogen atom (ie N-linked). In an embodiment, the ring is substituted with one or more groups selected from Ci-4alkyl, C(O)Ci-4alkyl, haloCi-4alkyl, halo, hydroxy and oxo. In an embodiment, the substituent is selected from C1-4alkyl, haloC1-4alkyl and oxo, for example oxo.
In one embodiment, R is NH2.
In one embodiment, R is selected from NR3SO2R4, NR3C(O)R4 and OR4 where R3 and R4 are as defined for formula (I).
In one embodiment, R is selected from NH2, NR3SO2R4 and NR3C(O)R4 where R3 and R4 are as defined for formula (I).
In one embodiment, R is selected from NR3SO2R4, NR3C(O)R4 and OR4 wherein:
• R3 is selected from hydrogen and C1-4 alkyl and
• R4 is selected from Ci-6alkyl, haloCi-6alkyl, C3-6cycloalkyl, haloC3-6cycloalkyl and (CH2)qNR5R6 wherein q is O, 1 or 2 and R5 and R6 are independently Ci-6alkyl.
When R is NR3SO2R4, in one embodiment, R3 is hydrogen. In a further embodiment, R4 is selected from
Figure imgf000007_0001
and haloC-i-βalkyl. For example R4 is selected from Ci-4alkyl and haloC1-4alkyl.
In one embodiment, R is selected from NR3SO2R4 and NR3C(O)R4 wherein R3 and R4, together with the NC(O) or NSO2 group to which they are attached, form a 5-membered or a 6-membered non-aromatic heterocyclic ring, either of which may include one or more further heteroatoms selected from N, O or S, and may be substituted with one or more groups selected from C1-4alkyl, C(O)C1-4alkyl, halo, haloC1-4alkyl, hydroxy and oxo.
In one embodiment, there is provided a compound of formula (Ia):
Figure imgf000008_0001
(Ia)
wherein
• R3 is selected from hydrogen and
Figure imgf000008_0002
• R4 is selected from C1-6alkyl, haloC1-6alkyl, C3-6cycloalkyl, haloC3-6 cycloalkyl, -(CH2)pZ (where p is 1 , 2 or 3 and Z is a phenyl or a 5- or 6-membered heterocyclic ring, the phenyl or the heterocyclic ring being optionally substituted with one or more groups selected from halo and C1-4alkyl) and -(CH2)qNR5R6 wherein q is O, 1 or 2 and R5 and R6 are independently Ci-6alkyl; or • R3 and R4, together with the NC(O) group to which they are attached, form a 5- membered or a 6-membered non-aromatic heterocyclic ring, either of which may include one or more further heteroatoms selected from N, O or S, and may be substituted with one or more groups selected from Ci-4alkyl, C(O)Ci-4alkyl, halo, haloC1-4alkyl, hydroxy and oxo.
In an embodiment of compounds of formula (Ia):
• R3 is C1-4 alkyl;
• R4 is selected from Ci-6alkyl, haloCi-6haloalkyl, C3-6cycloalkyl and haloC3-6 cycloalkyl; or • R3 and R4, together with the N(CO) group to which they are attached, form a 5- membered or a 6-membered non-aromatic heterocyclic ring, either of which may include one or more further heteroatoms selected from N, O or S, and may be substituted with one or more groups selected from C(O)C1-4alkyl, C1-4alkyl, halo, haloCi_4alkyl, hydroxy and oxo.
In one embodiment, NR3C(O)R4 forms a 5-membered non-aromatic heterocyclic ring.
In one embodiment, NR3C(O)R4 forms a ring selected from pyrrolidinone and piperidinone.
In an embodiment, NR3C(O)R4 forms a 5-membered or a 6-membered non-aromatic heterocyclic ring that is substituted with one or more groups selected from C1-4alkyl, C(O)Ci-4alkyl,
Figure imgf000008_0003
halo, hydroxy and oxo. In an embodiment, the substituent is selected from C-^alkyl, haloCi-4alkyl and oxo. The present invention also provides a compound of formula (Ib) or a salt thereof:
Figure imgf000009_0001
(Ib) wherein: R1 is cyclopropyl and R2 is hydrogen, or R1 and R2 join together to form a 6-membered non-aromatic ring, wherein one of the carbon atoms in the ring is optionally replaced by an oxygen atom; R is selected from the group consisting of:
- a 5- or 6-membered aromatic or non-aromatic heterocyclic ring, optionally substituted with one, two or three groups selected from C1-4alkyl, C(O)C1-4alkyl, haloC1-4alkyl, halo, hydroxy and oxo; and
- NR3SO2R4 , NR3C(O)R4 and OR4 in which
• R3 is selected from hydrogen and C1-4alkyl;
• R4 is selected from C1-6alkyl, haloC1-6alkyl, C3-6cycloalkyl, haloC3-6 cycloalkyl, - (CH2)pZ (where p is 1 , 2 or 3 and Z is a phenyl or a 5- or 6-membered heterocyclic ring, the phenyl or the heterocyclic ring being optionally substituted with one or more groups selected from halo and C1-4alkyl) and (CH2)qNR5R6 (wherein q is 0, 1 or 2 and R5 and R6 are independently Ci-6alkyl); or
• R3 and R4, together with the NC(O) or NSO2 group to which they are attached, form a 5-membered or a 6-membered non-aromatic heterocyclic ring, either of which may include one or more further heteroatoms selected from N, O or S, and may be substituted with one or more groups selected from C1-4alkyl, C(O)C1-4alkyl, halo, haloC1-4alkyl, hydroxy and oxo.
The present invention also provides a compound of formula (Ic) or a salt thereof:
Figure imgf000010_0001
(Ic) wherein:
• A is selected from CF3 and CHF2;
• R1 is selected from cyclopropyl and pyridyl and R2 is hydrogen; or R1 and R2 join together to form a 5- or 6-membered non-aromatic ring, wherein one of the carbon atoms in the ring is optionally replaced by an oxygen atom, NH or NCH3 ;
• R is selected from the group consisting of:
(a) a 5- or 6-membered aromatic or non-aromatic heterocyclic ring, optionally substituted with one, two or three groups selected from Ci-4alkyl, C(O)Ci-4alkyl, haloC1-4alkyl, halo, hydroxy and oxo; and
(b) NH2, NR3SO2R4, NR3C(O)R4 and OR4 in which
• R3 is selected from hydrogen and Ci-4alkyl;
• R4 is selected from C1-6alkyl, haloC1-6alkyl, C3-6cycloalkyl, haloC3-6cycloalkyl and -(CH2)qNR5R6 (wherein q is 0, 1 or 2 and R5 and R6 are independently C1- 6alkyl); or
• R3 and R4, together with the NC(O) or NSO2 group to which they are attached, form a 5- or 6-membered non-aromatic heterocyclic ring, either of which may include one or more further heteroatoms selected from N, O or S, and may be substituted with one or more groups selected from C1-4alkyl, C(O)C1-4alkyl, halo, haloC1-4alkyl, hydroxy and oxo.
In one embodiment, there is provided a compound of formula (Id) or a salt thereof:
Figure imgf000010_0002
(Id) wherein:
• A is selected from CF3 and CHF2; • R1 is selected from cyclopropyl and pyridyl and R2 is hydrogen; or R1 and R2 join together to form a 5- or 6-membered non-aromatic ring, wherein one of the carbon atoms in the ring is optionally replaced by an oxygen atom, NH or NCH3 ;
• R is selected from the group consisting of: (a) a 5- or 6-membered N-linked aromatic or non-aromatic heterocyclic ring, optionally substituted with one, two or three groups selected from Ci-4alkyl, C(O)Ci-4alkyl,
Figure imgf000011_0001
halo, hydroxy and oxo; and (b) NH2, NR3SO2R4 and NR3C(O)R4 in which
• R3 is selected from hydrogen and Ci-4alkyl; • R4 is selected from Ci-6alkyl, haloCi-6alkyl, C3-6cycloalkyl, haloCs-βcycloalkyl, -
(CH2)pZ (where p is 1 , 2 or 3 and Z is a phenyl or a 5- or 6-membered aromatic or non-aromatic heterocyclic ring, the phenyl or the heterocyclic ring being optionally substituted with one or more groups selected from halo and C1-4alkyl) and -(CH2)qNR5R6 (wherein q is 0, 1 or 2 and R5 and R6 are independently Ci-6alkyl); or
• R3 and R4, together with the NC(O) or NSO2 group to which they are attached, form a 5- or 6-membered non-aromatic heterocyclic ring, either of which may include one or more further heteroatoms selected from N, O or S, and may be substituted with one or more groups selected from Ci-4alkyl, C(O)Ci-4alkyl, halo, haloC1-4alkyl, hydroxy and oxo.
It will be appreciated that the present invention is intended to include compounds having any combination of the groups listed hereinbefore.
Due to the presence of at least one chiral centre, the compounds of the invention may exist in the form of optical isomers, e.g. diastereoisomers and mixtures of isomers in all ratios, e.g. racemic mixtures. The invention includes all such forms, in particular the pure isomeric forms. The different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses. It will also be appreciated, in common with most biologically active molecules that the level of biological activity may vary between the individual stereoisomers of a given molecule. It is intended that the scope of the invention includes all individual stereoisomers (diastereoisomers and enantiomers) and all mixtures thereof, including but not limited to racemic mixtures, which demonstrate appropriate biological activity with reference to the procedures described herein.
For certain Example compounds of the present invention shown below, the chiral intermediates, (2R)-5-bromo-2-aminoindan and (2S)-5-bromo-2-aminoindan were first prepared:
Figure imgf000011_0002
using (1 S)-(+)-camphorsulfonic acid or (1 R)-(- )-10-camphorsulphonic acid as the resolving agent as appropriate, as disclosed in Prashad et al, Adv. Synth. Catal. 2001 , 343, No. 5, pp 461-472. The absolute configuration of (2S)-5-bromo-2-aminoindane (1 /?)-(-)-10- camphorsulphonic acid salt so obtained was confirmed by single crystal X-ray analysis.
In one embodiment, there is provided a compound of formula (I) or a salt thereof enriched in configuration S.
In another embodiment, there is provided a compound of formula (I) or a salt thereof enriched in configuration R.
It is intended in the context of the present invention that enrichment in a particular in configuration correspond to at least 90% enantiomeric excess. In another embodiment the isomers correspond to at least 95% enantiomeric excess. In another embodiment the isomers correspond to at least 99% enantiomeric excess.
Examples of compounds of formula (I) include:
Λ/-{(2S)-5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1-yl]-2,3-dihydro-1 H-inden-2- yl}-2-propanesulfonamide
Racemic 1 -{5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1 -yl]-2,3-dihydro-1 H- inden-2-yl}-2-pyrrolidinone
1-{(2S)-5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1 -yl]-2,3-dihydro-1 H-inden-2- yl}-2-pyrrolidinone 1-{(2R)-5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1 -yl]-2,3-dihydro-1 H-inden-2- yl}-2-pyrrolidinone
1-[(2R)-2-(4-morpholinyl)-2,3-dihydro-1 H-inden-5-yl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-
1 H-indazole
1-[(2S)-2-(4-morpholinyl)-2,3-dihydro-1 H-inden-5-yl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro- 1 H-indazole
N-{(2R)-5-[3-(trifluoromethyl)-4,7-dihydropyrano[3,4-c]pyrazol-1 (5H)-yl]-2,3-dihydro-1 H- inden-2-yl}-2-propanesulfonamide
N-{(2S)-5-[3-(trifluoromethyl)-4,7-dihydropyrano[3,4-c]pyrazol-1 (5H)-yl]-2,3-dihydro-1 H- inden-2-yl}-2-propanesulfonamide 1-[(2R)-2-(4-morpholinyl)-2,3-dihydro-1 H-inden-5-yl]-3-(trifluoromethyl)-1 ,4,5,7- tetrahydropyrano[3,4-c]pyrazole
1-[(2S)-2-(4-morpholinyl)-2,3-dihydro-1 H-inden-5-yl]-3-(trifluoromethyl)-1 ,4,5,7- tetrahydropyrano[3,4-c]pyrazole
1-{(2R)-5-[3-(trifluoromethyl)-4,7-dihydropyrano[3,4-c]pyrazol-1 (5H)-yl]-2,3-dihydro-1 H- inden-2-yl}-2-pyrrolidinone
1-{(2S)-5-[3-(trifluoromethyl)-4,7-dihydropyrano[3,4-c]pyrazol-1 (5H)-yl]-2,3-dihydro-1 H- inden-2-yl}-2-pyrrolidinone N-{(2R)-5-[3-(trifluoromethyl)-6!7-dihydropyrano[4!3-c]pyrazol-1 (4H)-yl]-2!3-dihydro-1 H- inden-2-yl}-2-propanesulfonamide
N-{(2S)-5-[3-(trifluoromethyl)-6!7-dihydropyrano[4!3-c]pyrazol-1 (4H)-yl]-2,3-dihydro-1 H- inden-2-yl}-2-propanesulfonamide 1-[(2R)-2-(4-morpholinyl)-2,3-dihydro-1 H-inden-5-yl]-3-(trifluoromethyl)-1 ,4,6,7- tetrahydropyrano[4,3-c]pyrazole
1 -[(2S)-2-(4-morpholinyl)-2,3-dihydro-1 H-inden-5-yl]-3-(trifluoromethyl)-1 ,4,6,7- tetrahydropyrano[4,3-c]pyrazole
1 -{(2R)-5-[3-(trifluoromethyl)-6,7-dihydropyrano[4,3-c]pyrazol-1 (4H)-yl]-2,3-dihydro-1 H- inden-2-yl}-2-pyrrolidinone
1 -{(2S)-5-[3-(trifluoromethyl)-6,7-dihydropyrano[4,3-c]pyrazol-1 (4H)-yl]-2,3-dihydro-1 H- inden-2-yl}-2-pyrrolidinone
N-{(2R)-5-[5-cyclopropyl-3-(trifluoromethyl)-1 H-pyrazol-1 -yl]-2,3-dihydro-1 H-inden-2-yl}-2- propanesulfonamide N-{(2S)-5-[5-cyclopropyl-3-(trifluoromethyl)-1 H-pyrazol-1 -yl]-2,3-dihydro-1 H-inden-2-yl}-2- propanesulfonamide
4-{(2R)-5-[5-cyclopropyl-3-(trifluoromethyl)-1 H-pyrazol-1 -yl]-2,3-dihydro-1 H-inden-2- yl}morpholine
4-{(2S)-5-[5-cyclopropyl-3-(trifluoromethyl)-1 H-pyrazol-1 -yl]-2,3-dihydro-1 H-inden-2- yljmorpholine
1 -{(2R)-5-[5-cyclopropyl-3-(trifluoromethyl)-1 H-pyrazol-1 -yl]-2,3-dihydro-1 H-inden-2-yl}-2- pyrrolidinone
1-{(2S)-5-[5-cyclopropyl-3-(trifluoromethyl)-1 H-pyrazol-1 -yl]-2,3-dihydro-1 H-inden-2-yl}-2- pyrrolidinone and salts thereof.
Further examples include
2R)-5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1 -yl]-2,3-dihydro-1 H-inden-2- amine (2RS)-5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1 -yl]-2,3-dihydro-1 H-inden-2- amine
N2,N2-dimethyl-N1-{(2RS)-5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1-yl]-2,3- dihydro-1 H-inden-2-yl}glycinamide
N-{(2R)-5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1 -yl]-2,3-dihydro-1 H-inden-2- yl}-2-propanesulfonamide
1-[(2RS)-2-(1 ,1-dioxido-2-isothiazolidinyl)-2,3-dihydro-1 H-inden-5-yl]-3-(trifluoromethyl)-
4,5,6,7-tetrahydro-1 H-indazole
N-{(2RS)-5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1 -yl]-2,3-dihydro-1 H-inden-2- yl}acetamide N-{(2RS)-5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1 -yl]-2,3-dihydro-1 H-inden-2- yl}methanesulfonamide
N,N-dimethyl-N'-{(2-RS)-5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1-yl]-2,3- dihydro-1 H-inden-2-yl}urea
1-[(2RS)-2-(1-piperidinyl)-2!3-dihydro-1 H-inden-5-yl]-3-(trifluoromethyl)-4!5!6,7-tetrahydro-
1 H-indazole
1-[(2RS)-2-(4-morpholinyl)-2!3-dihydro-1 H-inden-5-yl]-3-(trifluoromethyl)-4!5!6,7- tetrahydro-1 H-indazole
N-{(2RS)-5-[3-(trifluoromethyl)-6!7-dihydropyrano[4!3-c]pyrazol-1 (4H)-yl]-2,3-dihydro-1 H- inden-2-yl}acetamide
N-{(2RS)-5-[3-(trifluoromethyl)-6!7-dihydropyrano[4!3-c]pyrazol-1 (4H)-yl]-2,3-dihydro-1 H- inden-2-yl}methanesulfonamide 1-[(2RS)-2-(1 !1-dioxido-2-isothiazolidinyl)-2,3-dihydro-1 H-inden-5-yl]-3-(trifluoromethyl)-
1 ,4,6,7-tetrahydropyrano[4,3-c]pyrazole
1-[(2R)-2-(1 J-dioxido-2-isothiazolidinyl)-2,3-dihydro-1 H-inden-5-yl]-3-(trifluoromethyl)-
4,5,6,7-tetrahydro-1 H-indazole and salts thereof.
Further examples include:
1-{(2R)-5-[6-methyl-3-(trifluoromethyl)-4!5!6!7-tetrahydro-1 H-pyrazolo[3,4-c]pyridin-1-yl]-
2,3-dihydro-1 H-inden-2-yl}-2-pyrrolidinone
1-[(2S)-2-(1 !1-dioxido-2-isothiazolidinyl)-2,3-dihydro-1 H-inden-5-yl]-3-(trifluoromethyl)- 4,5,6,7-tetrahydro-1 H-indazole
4-{5-[5-(2-pyridinyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl]-2,3-dihydro-1 H-inden-2- yl}morpholine
1-[(2S)-2-(4-morpholinyl)-2!3-dihydro-1 H-inden-5-yl]-3-(trifluoromethyl)-4!5!6,7-tetrahydro-
1 H-indazole 3-(difluoromethyl)-1 -[2-(4-morpholinyl)-2,3-dihydro-1 H-inden-5-yl]-4,5,6,7-tetrahydro-1 H- indazole and salts thereof.
Further examples include 1-[(2S)-2-(1 ,1-dioxido-2-isothiazolidinyl)-2,3-dihydro-1 H-inden-5-yl]-3-(trifluoromethyl)-
1 ,4,6,7-tetrahydropyrano[4,3-c]pyrazole
4-{5-[5-cyclopropyl-3-(difluoromethyl)-1 H-pyrazol-1 -yl]-2,3-dihydro-1 H-inden-2- yl}morpholine
1-{(2R)-5-[5-(2-pyridinyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl]-2,3-dihydro-1 H-inden-2-yl}-2- pyrrolidinone
4-{(2R)-5-[5-(3-pyridinyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl]-2,3-dihydro-1 H-inden-2- yl}morpholine
4-{(2R)-5-[5-(4-pyridinyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl]-2,3-dihydro-1 H-inden-2- yl}morpholine 4-{(2R)-5-[5-(2-pyridinyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl]-2,3-dihydro-1 H-inden-2- yl}morpholine 4-{(2S)-5-[5-(2-pyridinyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl]-2,3-dihydro-1 H-inden-2- yl}morpholine
4-{(2S)-5-[5-(6-methyl-3-pyridinyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl]-2,3-dihydro-1 H- inden-2-yl}morpholine N-{(2R)-5-[5-(2-pyridinyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl]-2,3-dihydro-1 H-inden-2-yl}-2- propanesulfonamide
N-{(2S)-5-[5-(2-pyridinyl)-3-(trifluoromethyl)-1 H-pyrazol-1-yl]-2,3-dihydro-1 H-inden-2-yl}-2- propanesulfonamide
1 -{(2R)-5-[5-(6-methyl-3-pyridinyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl]-2,3-dihydro-1 H- inden-2-yl}-2-pyrrolidinone
1-{(2R)-5-[5-(4-pyridinyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl]-2,3-dihydro-1 H-inden-2-yl}-2- pyrrolidinone
1-{(2R)-5-[5-(3-pyridinyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl]-2,3-dihydro-1 H-inden-2-yl}-2- pyrrolidinone and salts thereof.
In one embodiment the salt of the compound of formula (I) is a pharmaceutically acceptable salt. In one embodiment, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof.
As used herein, the term "salt" refers to any salt of a compound according to the present invention prepared from an inorganic or organic acid or base, quaternary ammonium salts and internally formed salts. Pharmaceutically acceptable salts are particularly suitable for medical applications because of their greater aqueous solubility relative to the parent compounds. Such salts must clearly have a pharmaceutically acceptable anion or cation. Suitably pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, hydroiodic, phosphoric, metaphosphoric, nitric and sulfuric acids, and with organic acids, such as tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, formic, propionic, glycolic, gluconic, maleic, succinic, (1 R)-(-)-10-camphorsulphonic, (1 S)-(+)-10- camphorsulphonic, isothionic, mucic, gentisic, isonicotinic, saccharic, glucuronic, furoic, glutamic, ascorbic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic, stearic, sulfinilic, alginic, galacturonic and arylsulfonic, for example naphthalene-1 ,5-disulphonic, naphthalene-1 ,3-disulphonic, benzenesulfonic, and p-toluenesulfonic, acids; base addition salts formed with alkali metals and alkaline earth metals; and internally formed salts. Salts having a non- pharmaceutically acceptable anion or cation are within the scope of the invention as useful intermediates for the preparation of pharmaceutically acceptable salts and/or for use in non-therapeutic, for example, in vitro, situations. The salts may have any suitable stoichiometry. For example, a salt may have 1 :1 or 2:1 stoichiometry. Non-integral stoichiometry ratios are also possible. Solvates of the compounds of formula (I) and solvates of the salts of the compounds of formula (I) are included within the scope of the present invention. As used herein, the term "solvate" refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of formula (I) or a salt thereof) and a solvent. Those skilled in the art of organic chemistry will appreciate that many organic compounds can form such complexes with solvents in which they are reacted or from which they are precipitated or crystallized. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, methanol, ethanol and acetic acid. Preferably the solvent used is a pharmaceutically acceptable solvent. Examples of suitable pharmaceutically acceptable solvents include, without limitation, water, ethanol and acetic acid. Most preferably the solvent used is water. Where the solvent used is water such a solvate may then also be referred to as a hydrate.
Furthermore, some of the crystalline forms of the compounds of structure (I) may exist as polymorphs, which are included in the present invention.
Hereinafter, compounds of formula (I) (whether in solvated or unsolvated form) or their pharmaceutically acceptable salts (whether in solvated or unsolvated form) or prodrugs thereof defined in any aspect of the invention (except intermediate compounds in chemical processes) are referred to as "compounds of the invention".
It will be appreciated by those skilled in the art that certain protected derivatives of compounds of formula (I), which may be made prior to a final deprotection stage, may not possess pharmacological activity as such, but may, in certain instances, be administered orally or parenterally and thereafter metabolised in the body to form compounds of the invention which are pharmacologically active. Such derivatives may therefore be described as "prodrugs". Further, certain compounds of the invention may be administered as prodrugs. Examples of pro-drug forms for certain compounds of the present invention are described in Drugs of Today, Volume 19, Number 9, 1983, pp 499 - 538 and in Topics in Chemistry, Chapter 31 , pp 306 - 316 and in "Design of Prodrugs" by H. Bundgaard, Elsevier, 1985, Chapter 1 (the disclosures in which documents are incorporated herein by reference). It will further be appreciated by those skilled in the art, that certain moieties, known to those skilled in the art as "pro-moieties", for example as described by H. Bundgaard in "Design of Prodrugs" (the disclosure in which document is incorporated herein by reference) may be placed on appropriate functionalities when such functionalities are present within compounds of the invention. Examples of prodrugs for certain compounds of the invention include : esters, carbonate esters, hemi-esters, phosphate esters, nitro esters, sulfate esters, sulfoxides, amides, carbamates, azo-compounds, phosphamides, glycosides, ethers, acetals and ketals. The invention also includes all suitable isotopic variations of a compound of the invention. An isotopic variation of a compound of the invention is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine such as 2H, 3H, 13C, 14C, 15N, 17O, 18O, 31P, 32P, 35S, 18F and 36CI, respectively. Certain isotopic variations of the invention, for example, those in which a radioactive isotope such as 3H or 14C is incorporated, are useful in drug and/or substrate tissue distribution studies. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium, i.e., 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances. Isotopic variations of the compounds of the invention can generally be prepared by conventional procedures such as by the illustrative methods or by the preparations described in the Examples hereafter using appropriate isotopic variations of suitable reagents.
Compounds of the invention may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthesis schemes. In the following schemes, unless otherwise stated, the substituents in the compounds shown have the same definition as for formula (I). It is also recognised that in all of the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles of chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W.
Greene and P. G. M. Wuts (1991 ) Protecting Groups in Organic Synthesis, John Wiley &
Sons). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection of processes as well as the reaction conditions and order of their execution shall be consistent with the preparation of compounds of the invention.
A compound of formula (I) may be prepared by coupling a compound of formula (II) where X is a leaving group such as a halogen (for example bromine or iodine) with a heterocyclic derivative of formula (III) according to reaction scheme 1.
Scheme 1
Figure imgf000018_0001
Thus the present invention also provides a process for preparing a compound of the present invention, the process comprising coupling a compound of formula (II):
Figure imgf000018_0002
(N)
wherein R is as defined above and X is a leaving group, with a compound of formula
Figure imgf000018_0003
wherein R1, R2 and A are as defined above; and thereafter optionally: a) forming a salt; and/or b) converting a compound of the present invention into another compound of the present invention.
Typical coupling conditions comprise heating together for the appropriate time a compound of formula (II), a compound of formula (III), a base (such as potassium carbonate or cesium carbonate), a copper (I) reagent (such as copper (I) iodide or copper (I) oxide) with a ligand (such as N,N-dimethylglycine or frans-1 ,2-diaminocyclohexane) in a suitable solvent such as dimethyl sulfoxide or 1 ,4-dioxane at a suitable temperature such as 180 degC in a microwave reactor or 130 degC by conventional heating. In one embodiment, R is a secondary or tertiary amide or sulphonamide, or a tertiary amine. In one embodiment, in Scheme 1 , R1 and R2 are joined together to form a 6-membered non- aromatic ring, wherein one of the carbon atoms in the ring is optionally replaced by an oxygen atom or NMe. Compounds of formula (II) and (III) are commercially available, described in the literature or may be prepared according to standard synthetic methods.
A compound of formula (IV) may be prepared from a compound of formula (V) (where X=Br or a compound of formula (III)) [for X=Br, see Prashad et al, Adv. Synth. Catal. 2001 , 343, No. 5, pp 461-472] by acylation followed by in situ alkylation according to reaction scheme 2. Typical conditions comprise treatment of a compound of formula (V) (or salt thereof) with a compound of formula (XVII) in dimethylformamide in the presence of a suitable base such as diisopropylethylamine or triethylamine, followed by addition of a strong base such as sodium hydride (available as a 60% suspension in mineral oil) to effect cyclisation. The method of Scheme 2 is suitable for enantiomerically pure material or racemates. In one embodiment, in Scheme 2, X is bromine or iodine, Y is carbonyl or sulphonyl and n is 1 or 2. Compounds of formula (XVII) are commercially available, except when Y is sulphonyl and n is 2.
Scheme 2
Figure imgf000019_0001
(V) (IV)
A compound of formula (Vl) can be prepared from a compound of formula (V) (where X=Br or a compound of formula (III)) [for X=Br, see Prashad et al, Adv. Synth. Catal.
2001 , 343, No. 5, pp 461-472] by acylation or sulphonylation using a reagent of formula
(VII) according to reaction scheme 3. Typical conditions comprise addition of reagent (VII) to a cooled solution of (V) (or salt thereof) in dichloromethane in the presence of a suitable base such as triethylamine or 1 ,8-diazabicyclo[5.4.0]undec-7-ene. In one embodiment, in Scheme 3, X is bromine or iodine, Y is a carbonyl or sulphonyl and R1 is aliphatic. Compounds of formula (VII) are commercially available.
Scheme 3
Figure imgf000019_0002
An intermediate compound of formula (IX) can be prepared from a compound of formula (V) (where X=Br or a compound of formula (III)) [for X=Br, see Prashad et al, Adv. Synth. Catal. 2001 , 343, No. 5, pp 461-472] by alkylation using a reagent of formula (VIII), wherein G is oxygen or CH2, according to reaction scheme 4. Typical conditions comprise addition of reagent (VIII) to a vigorously stirring suspension of the compound of formula (V) (or salt thereof) and base (such as potassium carbonate) in acetonitrile and subsequent heating at reflux for 16 hours. In one embodiment, in Scheme 4, X is bromine or iodine. The compound of formula (VIII) is commercially available. Scheme 4
Figure imgf000020_0001
(V) (V| | |) (IX) A compound of formula (X) can be prepared from a compound of formula (Xl) by enolate addition to ethyl trifluoroacetate according to reaction scheme 5. Typical conditions comprise treatment of a compound of formula (Xl) with a strong base (such as lithium diisopropylamide (LDA)) under argon in tetrahydrofuran at the appropriate temperature (such as -70 degC) followed by the addition of ethyl trifluoroacetate, mixing for the appropriate time then warming to room temperature. The compound of formula (Xl) is commercially available, described in the literature or may be prepared according to standard synthetic methods.
Scheme 5
Figure imgf000020_0002
A compound of formula (XII) can be prepared by condensation of a compound of formula (X) with hydrazine hydrate according to reaction scheme 6. Typical conditions comprise treatment of a compound of formula (X) in ethanol with hydrazine hydrate and heating at the appropriate temperature (such as 70 degC) for the appropriate time (such as 9 hours). Compounds of formula (X) wherein A is CHF2 are commercially available, described in the literature or may be prepared according to standard synthetic methods.
Scheme 6
Figure imgf000020_0003
A compound of formula (XIII) can be prepared from a compound of formula (XIV) [prepared according to Liebigs Annalen Der Chemie 1984, 1 1 , 1759-1882;] by enolate addition to ethyl trifluoroacetate followed by condensation with hydrazine hydrate according to reaction scheme 7. Typical conditions comprise treatment of a compound of formula (XIV) with a strong base (such as methyllithium) in tetrahydrofuran at room temperature under argon followed by the addition of ethyl trifluoroacetate at -78 degC, mixing for the appropriate time then warming to room temperature.. The isolated product is dissolved in ethanol and treated with hydrazine hydrate and heated at reflux for 6 hours.
Scheme 7
Figure imgf000021_0001
A compound of formula (XVI) can be prepared by the reduction of a compound of formula (XV) using lithium aluminium hydride according to reaction scheme 8. Typical reduction conditions comprise the addition of lithium aluminium hydride to a cooled solution of a compound of formula (XV) in tetrahydrofuran (THF) followed by heating. Compounds of formula (XV) can be prepared in a manner similar to that described for compounds of formula (XII) in scheme 6.
Scheme 8
LiAlH4 / THF
Figure imgf000021_0002
Figure imgf000021_0003
(XV) (XVI)
Further details for the preparation of compounds of formula (I) are found in the Examples section hereinafter.
The compounds of the invention may be prepared singly or as compound libraries comprising at least 2, for example 5 to 1 ,000 compounds, for example 10 to 100 compounds. Libraries of compounds of the invention may be prepared by a combinatorial 'split and mix' approach or by multiple parallel synthesis using either solution phase or solid phase chemistry, by procedures known to those skilled in the art. Thus according to a further aspect there is provided a compound library comprising at least 2 compounds of the invention.
The compounds of the present invention potentiate the AMPA receptor. Compounds which potentiate the AMPA receptor may be useful for treating diseases and conditions which are mediated by or caused by a reduction or imbalance in glutamate receptor function, and which therefore benefit from the potentiation of the AMPA receptor.
Thus the present invention provides a compound of formula (I) or a salt thereof for use as a medicament. It will be appreciated that the invention includes the following further aspects. The embodiments described in respect of the first aspect apply equally to each of these further aspects:
i) the use of a compound of the invention in the manufacture of a medicament for treating a disease or condition mediated by a reduction or imbalance in glutamate receptor function in a mammal; ii) a compound of the invention for use in treating a disease or condition mediated by a reduction or imbalance in glutamate receptor function in a mammal; iii) a method of treatment of a disease or condition mediated by a reduction or imbalance in glutamate receptor function in a mammal comprising administering an effective amount of a compound of the invention; iv) a combination product of a compound of formulathe invention with an antipsychotic; v) a pharmaceutical composition comprising a combination product as defined in iv) above and at least one carrier, diluent or excipient; vi) the use of a combination product as defined in iv) above in the manufacture of a medicament for treating a disease or condition mediated by a reduction or imbalance in glutamate receptor function in a mammal; vii) a combination product as defined in iv) above for use in treating a disease or condition mediated by a reduction or imbalance in glutamate receptor function in a mammal; viii) a combination product as defined in iv) above for use as a medicament; ix) a method of treatment of a disease or condition mediated by a reduction or imbalance in glutamate receptor function in a mammal comprising administering an effective amount of a combination product as defined in iv) above.
In the case of aspects i), ii), iii), vi), vii), viii) and ix), relevant diseases or conditions are: psychosis and psychotic disorders (including schizophrenia, schizo-affective disorder, schizophreniform diseases, brief reactive psychosis, child onset schizophrenia,
"schizophrenia-spectrum" disorders such as schizoid or schizotypal personality disorders, acute psychosis, alcohol psychosis, drug-induced psychosis, autism, delerium, mania
(including acute mania), manic depressive psychosis, hallucination, endogenous psychosis, organic psychosyndrome, paranoid and delusional disorders, puerperal psychosis, and psychosis associated with neurodegenerative diseases such as
Alzheimer's disease); substance related disorders (including alcohol-related disorders and nicotine-related disorders); cognitive impairment (e.g. the treatment of impairment of cognitive functions including attention, orientation, memory (i.e. memory disorders, amnesia, amnesic disorders and age-associated memory impairment) and language function, and including cognitive impairment as a result of stroke, Alzheimer's disease,
Aids-related dementia or other dementia states, as well as other acute or sub-acute conditions that may cause cognitive decline such as delirium or depression (pseudodementia states) trauma, aging, stroke, neurodegeneration, drug-induced states, neurotoxic agents), mild cognitive impairment, age related cognitive impairment, autism related cognitive impairment, Down's syndrome, cognitive deficit related to psychosis, post-electroconvulsive treatment related cognitive disorders; anxiety disorders (including generalised anxiety disorder, social anxiety disorder, agitation, tension, social or emotional withdrawal in psychotic patients, panic disorder, and obsessive compulsive disorder); neurodegenerative diseases (such as Alzheimer's disease, amyotrophic lateral sclerosis, motor neurone disease and other motor disorders such as Parkinson's disease (including relief from locomotor deficits and/or motor disability, including slowly increasing disability in purposeful movement, tremors, bradykinesia, hyperkinesia (moderate and severe), akinesia, rigidity, disturbance of balance and co-ordination, and a disturbance of posture), dementia in Parkinson's disease, dementia in Huntington's disease, neuroleptic- induced Parkinsonism and tardive dyskinesias, neurodegeneration following stroke, cardiac arrest, pulmonary bypass, traumatic brain injury, spinal cord injury or the like, and demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis); depression (which term includes bipolar (manic) depression (including type I and type II), unipolar depression, single or recurrent major depressive episodes with or without psychotic features, catatonic features, melancholic features, atypical features (e.g. lethargy, over-eating/obesity, hypersomnia) or postpartum onset, seasonal affective disorder and dysthymia, depression-related anxiety, psychotic depression, and depressive disorders resulting from a general medical condition including, but not limited to, myocardial infarction, diabetes, miscarriage or abortion); post-traumatic stress syndrome; attention deficit disorder; attention deficit hyperactivity disorder; drug-induced (phencyclidine, ketamine and other dissociative anaesthetics, amphetamine and other psychostimulants and cocaine) disorders; Huntingdon's chorea; tardive dyskinesia; dystonia; myoclonus; spasticity; obesity; stroke; sexual dysfunction; sleep disorders and some forms of epilepsy.
Within the context of the present invention, the terms describing the indications used herein are classified in the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, published by the American Psychiatric Association (DSM-IV) and/or the International Classification of Diseases, 10th Edition (ICD-10). Treatment of the various subtypes of the disorders mentioned herein are contemplated as part of the present invention. Numbers in brackets after the listed diseases below refer to the classification code in DSM-IV.
Within the context of the present invention, the term "psychotic disorder" includes :-
Schizophrenia including the subtypes Paranoid Type (295.30), Disorganised Type (295.10), Catatonic Type (295.20), Undifferentiated Type (295.90) and Residual Type (295.60); Schizophreniform Disorder (295.40); Schizoaffective Disorder (295.70) including the subtypes Bipolar Type and Depressive Type; Delusional Disorder (297.1 ) including the subtypes Erotomanic Type, Grandiose Type, Jealous Type, Persecutory Type, Somatic Type, Mixed Type and Unspecified Type; Brief Psychotic Disorder (298.8); Shared Psychotic Disorder (297.3); Psychotic Disorder Due to a General Medical Condition including the subtypes With Delusions and With Hallucinations; Substance- Induced Psychotic Disorder including the subtypes With Delusions (293.81 ) and With Hallucinations (293.82); and Psychotic Disorder Not Otherwise Specified (298.9).
Compounds of the invention may also be of use in the treatment of the following disorders:-
Depression and mood disorders including Major Depressive Episode, Manic Episode, Mixed Episode and Hypomanic Episode; Depressive Disorders including Major Depressive Disorder, Dysthymic Disorder (300.4), Depressive Disorder Not Otherwise Specified (311 ); Bipolar Disorders including Bipolar I Disorder, Bipolar Il Disorder (Recurrent Major Depressive Episodes with Hypomanic Episodes) (296.89), Cyclothymic Disorder (301.13) and Bipolar Disorder Not Otherwise Specified (296.80); Other Mood Disorders including Mood Disorder Due to a General Medical Condition (293.83) which includes the subtypes With Depressive Features, With Major Depressive-like Episode, With Manic Features and With Mixed Features), Substance-Induced Mood Disorder (including the subtypes With Depressive Features, With Manic Features and With Mixed Features) and Mood Disorder Not Otherwise Specified (296.90):
Anxiety disorders including Panic Attack; Panic Disorder including Panic Disorder without Agoraphobia (300.01 ) and Panic Disorder with Agoraphobia (300.21 ); Agoraphobia; Agoraphobia Without History of Panic Disorder (300.22), Specific Phobia (300.29, formerly Simple Phobia) including the subtypes Animal Type, Natural Environment Type, Blood-lnjection-lnjury Type, Situational Type and Other Type), Social Phobia (Social Anxiety Disorder, 300.23), Obsessive-Compulsive Disorder (300.3), Posttraumatic Stress Disorder (309.81 ), Acute Stress Disorder (308.3), Generalized Anxiety Disorder (300.02), Anxiety Disorder Due to a General Medical Condition (293.84), Substance-Induced Anxiety Disorder, Separation Anxiety Disorder (309.21 ), Adjustment Disorders with Anxiety (309.24) and Anxiety Disorder Not Otherwise Specified (300.00):
Substance-related disorders including Substance Use Disorders such as Substance Dependence, Substance Craving and Substance Abuse; Substance-Induced Disorders such as Substance Intoxication, Substance Withdrawal, Substance-Induced Delirium, Substance-Induced Persisting Dementia, Substance-Induced Persisting Amnestic Disorder, Substance-Induced Psychotic Disorder, Substance-Induced Mood Disorder, Substance-Induced Anxiety Disorder, Substance-Induced Sexual Dysfunction, Substance- Induced Sleep Disorder and Hallucinogen Persisting Perception Disorder (Flashbacks); Alcohol-Related Disorders such as Alcohol Dependence (303.90), Alcohol Abuse (305.00), Alcohol Intoxication (303.00), Alcohol Withdrawal (291.81 ), Alcohol Intoxication Delirium, Alcohol Withdrawal Delirium, Alcohol-Induced Persisting Dementia, Alcohol- Induced Persisting Amnestic Disorder, Alcohol-Induced Psychotic Disorder, Alcohol- Induced Mood Disorder, Alcohol-Induced Anxiety Disorder, Alcohol-Induced Sexual Dysfunction, Alcohol-Induced Sleep Disorder and Alcohol-Related Disorder Not Otherwise Specified (291.9); Amphetamine (or Amphetamine-I_ike)-Related Disorders such as Amphetamine Dependence (304.40), Amphetamine Abuse (305.70), Amphetamine Intoxication (292.89), Amphetamine Withdrawal (292.0), Amphetamine Intoxication Delirium, Amphetamine Induced Psychotic Disorder, Amphetamine-Induced Mood Disorder, Amphetamine-Induced Anxiety Disorder, Amphetamine-Induced Sexual Dysfunction, Amphetamine-Induced Sleep Disorder and Amphetamine-Related Disorder Not Otherwise Specified (292.9); Caffeine Related Disorders such as Caffeine Intoxication (305.90), Caffeine-Induced Anxiety Disorder, Caffeine-Induced Sleep Disorder and Caffeine-Related Disorder Not Otherwise Specified (292.9); Cannabis-Related Disorders such as Cannabis Dependence (304.30), Cannabis Abuse (305.20), Cannabis Intoxication (292.89), Cannabis Intoxication Delirium, Cannabis-lnduced Psychotic Disorder, Cannabis-lnduced Anxiety Disorder and Cannabis-Related Disorder Not Otherwise Specified (292.9); Cocaine-Related Disorders such as Cocaine Dependence (304.20), Cocaine Abuse (305.60), Cocaine Intoxication (292.89), Cocaine Withdrawal (292.0), Cocaine Intoxication Delirium, Cocaine-Induced Psychotic Disorder, Cocaine- Induced Mood Disorder, Cocaine-Induced Anxiety Disorder, Cocaine-Induced Sexual Dysfunction, Cocaine-Induced Sleep Disorder and Cocaine-Related Disorder Not Otherwise Specified (292.9); Hallucinogen-Related Disorders such as Hallucinogen Dependence (304.50), Hallucinogen Abuse (305.30), Hallucinogen Intoxication (292.89), Hallucinogen Persisting Perception Disorder (Flashbacks) (292.89), Hallucinogen Intoxication Delirium, Hallucinogen-Induced Psychotic Disorder, Hallucinogen-Induced Mood Disorder, Hallucinogen-Induced Anxiety Disorder and Hallucinogen-Related Disorder Not Otherwise Specified (292.9); Inhalant-Related Disorders such as Inhalant Dependence (304.60), Inhalant Abuse (305.90), Inhalant Intoxication (292.89), Inhalant Intoxication Delirium, Inhalant-Induced Persisting Dementia, Inhalant-Induced Psychotic Disorder, Inhalant-Induced Mood Disorder, Inhalant-Induced Anxiety Disorder and Inhalant-Related Disorder Not Otherwise Specified (292.9); Nicotine-Related Disorders such as Nicotine Dependence (305.1 ), Nicotine Withdrawal (292.0) and Nicotine-Related Disorder Not Otherwise Specified (292.9); Opioid-Related Disorders such as Opioid Dependence (304.00), Opioid Abuse (305.50), Opioid Intoxication (292.89), Opioid Withdrawal (292.0), Opioid Intoxication Delirium, Opioid-lnduced Psychotic Disorder, Opioid-lnduced Mood Disorder, Opioid-lnduced Sexual Dysfunction, Opioid-lnduced Sleep Disorder and Opioid-Related Disorder Not Otherwise Specified (292.9); Phencyclidine (or Phencyclidine-Like)-Related Disorders such as Phencyclidine Dependence (304.60), Phencyclidine Abuse (305.90), Phencyclidine Intoxication (292.89), Phencyclidine Intoxication Delirium, Phencyclidine-lnduced Psychotic Disorder, Phencyclidine-lnduced Mood Disorder, Phencyclidine-lnduced Anxiety Disorder and Phencyclidine-Related Disorder Not Otherwise Specified (292.9); Sedative-, Hypnotic-, or Anxiolytic-Related Disorders such as Sedative, Hypnotic, or Anxiolytic Dependence (304.10), Sedative, Hypnotic, or Anxiolytic Abuse (305.40), Sedative, Hypnotic, or Anxiolytic Intoxication (292.89), Sedative, Hypnotic, or Anxiolytic Withdrawal (292.0), Sedative, Hypnotic, or Anxiolytic Intoxication Delirium, Sedative, Hypnotic, or Anxiolytic Withdrawal Delirium, Sedative-, Hypnotic-, or Anxiolytic-Persisting Dementia, Sedative-, Hypnotic-, or Anxiolytic- Persisting Amnestic Disorder, Sedative-, Hypnotic-, or Anxiolytic- lnduced Psychotic Disorder, Sedative-, Hypnotic-, or Anxiolytic-lnduced Mood Disorder, Sedative-, Hypnotic-, or Anxiolytic-lnduced Anxiety Disorder Sedative-, Hypnotic-, or Anxiolytic-lnduced Sexual Dysfunction, Sedative-, Hypnotic-, or Anxiolytic-lnduced Sleep Disorder and Sedative-, Hypnotic-, or Anxiolytic-Related Disorder Not Otherwise Specified (292.9); Polysubstance-Related Disorder such as Polysubstance Dependence (304.80); and Other (or Unknown) Substance-Related Disorders such as Anabolic Steroids, Nitrate Inhalants and Nitrous Oxide:
Sleep disorders including primary sleep disorders such as Dyssomnias such as Primary Insomnia (307.42), Primary Hypersomnia (307.44), Narcolepsy (347), Breathing-Related Sleep Disorders (780.59), Circadian Rhythm Sleep Disorder (307.45) and Dyssomnia Not Otherwise Specified (307.47); primary sleep disorders such as Parasomnias such as Nightmare Disorder (307.47), Sleep Terror Disorder (307.46), Sleepwalking Disorder (307.46) and Parasomnia Not Otherwise Specified (307.47); Sleep Disorders Related to Another Mental Disorder such as Insomnia Related to Another Mental Disorder (307.42) and Hypersomnia Related to Another Mental Disorder (307.44); Sleep Disorder Due to a General Medical Condition, in particular sleep disturbances associated with such diseases as neurological disorders, neuropathic pain, restless leg syndrome, heart and lung diseases; and Substance-Induced Sleep Disorder including the subtypes Insomnia Type, Hypersomnia Type, Parasomnia Type and Mixed Type; sleep apnea and jet-lag syndrome:
Autism Spectrum Disorders including Autistic Disorder (299.00), Asperger's Disorder (299.80), Rett's Disorder (299.80), Childhood Disintegrative Disorder (299.10) and Pervasive Disorder Not Otherwise Specified (299.80, including Atypical Autism).
Attention-Deficit/Hyperactivity Disorder including the subtypes Attention-Deficit /Hyperactivity Disorder Combined Type (314.01 ), Attention-Deficit /Hyperactivity Disorder
Predominantly Inattentive Type (314.00), Attention-Deficit /Hyperactivity Disorder
Hyperactive-Impulse Type (314.01 ) and Attention-Deficit /Hyperactivity Disorder Not
Otherwise Specified (314.9); Hyperkinetic Disorder; Disruptive Behaviour Disorders such as Conduct Disorder including the subtypes childhood-onset type (321.81 ), Adolescent- Onset Type (312.82) and Unspecified Onset (312.89), Oppositional Defiant Disorder
(313.81 ) and Disruptive Behaviour Disorder Not Otherwise Specified; and Tic Disorders such as Tourette's Disorder (307.23): Personality Disorders including the subtypes Paranoid Personality Disorder (301.0), Schizoid Personality Disorder (301.20), Schizotypal Personality Disorder (301 ,22), Antisocial Personality Disorder (301.7), Borderline Personality Disorder (301 ,83), Histrionic Personality Disorder (301.50), Narcissistic Personality Disorder (301 ,81 ), Avoidant Personality Disorder (301.82), Dependent Personality Disorder (301.6), Obsessive-Compulsive Personality Disorder (301.4) and Personality Disorder Not Otherwise Specified (301.9):
Enhancement of cognition including the treatment of cognition impairment in other diseases such as schizophrenia, bipolar disorder, depression, other psychiatric disorders and psychotic conditions associated with cognitive impairment, e.g. Alzheimer's disease: and
Sexual dysfunctions including Sexual Desire Disorders such as Hypoactive Sexual Desire Disorder (302.71 ), and Sexual Aversion Disorder (302.79); sexual arousal disorders such as Female Sexual Arousal Disorder (302.72) and Male Erectile Disorder (302.72); orgasmic disorders such as Female Orgasmic Disorder (302.73), Male Orgasmic Disorder (302.74) and Premature Ejaculation (302.75); sexual pain disorder such as Dyspareunia (302.76) and Vaginismus (306.51 ); Sexual Dysfunction Not Otherwise Specified (302.70); paraphilias such as Exhibitionism (302.4), Fetishism (302.81 ), Frotteurism (302.89), Pedophilia (302.2), Sexual Masochism (302.83), Sexual Sadism (302.84), Transvestic Fetishism (302.3), Voyeurism (302.82) and Paraphilia Not Otherwise Specified (302.9); gender identity disorders such as Gender Identity Disorder in Children (302.6) and Gender Identity Disorder in Adolescents or Adults (302.85); and Sexual Disorder Not Otherwise Specified (302.9).
Within the context of the present invention, the term "cognitive impairment" includes for example the treatment of impairment of cognitive functions including attention, orientation, learning disorders, memory (i.e. memory disorders, amnesia, amnesic disorders, transient global amnesia syndrome and age-associated memory impairment) and language function; cognitive impairment as a result of stroke, Alzheimer's disease, Huntington's disease, Pick disease, Aids-related dementia or other dementia states such as Multiinfarct dementia, alcoholic dementia, hypotiroidism-related dementia, and dementia associated to other degenerative disorders such as cerebellar atrophy and amyotropic lateral sclerosis; other acute or sub-acute conditions that may cause cognitive decline such as delirium or depression (pseudodementia states) trauma, head trauma, age related cognitive decline, stroke, neurodegeneration, drug-induced states, neurotoxic agents, mild cognitive impairment, age related cognitive impairment, autism related cognitive impairment, Down's syndrome, cognitive deficit related to psychosis, and post- electroconvulsive treatment related cognitive disorders; and dyskinetic disorders such as Parkinson's disease, neuroleptic-induced parkinsonism, and tardive dyskinesias. In one embodiment, the present invention provides a compound of the invention for use in treating schizophrenia or impairment of cognition.
In one embodiment, the present invention provides a use of a compound of the invention in the manufacture of a medicament for treating schizophrenia or impairment of cognition.
In one embodiment, the present invention provides a method of treatment of schizophrenia or impairment of cognition, comprising administering an effective amount of a compound of the invention.
It is to be understood that "treatment" as used herein includes prophylaxis as well as alleviation of established symptoms. In one embodiment, the mammal to be treated is a human.
The compounds of the invention may be used in combination with one or more of the following agents to treat psychotic disorders: i) antipsychotics (such as olanzapine, risperidone, clozapine, ziprazidone, talnetant); ii) drugs for extrapyramidal side effects, for example anticholinergics (such as benztropine, biperiden, procyclidine, trihexyphenidyl), antihistamines (such as diphenhydramine), dopaminergics (such as amantadine); iii) antidepressants; iv) anxiolytics; v) cognitive enhancers for example cholinesterase inhibitors (such as tacrine, donepezil, rivastigmine,galantamine).
The compounds of the invention may be used in combination with antidepressants to treat depression and mood disorders.
The compounds of the invention may be used in combination with one or more of the following agents to treat bipolar disease: i) mood stabilisers; ii) antipsychotics; iii) antidepressants.
The compounds of the invention may be used in combination with one or more of the following agents to treat anxiety disorders: i) anxiolytics; ii) antidepressants.
The compounds of the invention may be used in combination with one or more of the following agents to improve nicotine withdrawal and reduce nicotine craving: i) nicotine replacement therapy, for example a sublingual formulation of nicotine beta-cyclodextrin and nicotine patches; ii) drugs for treating nicotine addition, for example bupropion.
The compounds of the invention may be used in combination with one or more of the following agents to improve alcohol withdrawal and reduce alcohol craving: i) NMDA receptor antagonists for example acamprosate; ii) GABA receptor agonists for example tetrabamate; iii) Opioid receptor antagonists for example naltrexone. The compounds of the invention may be used in combination with one or more of the following agents to improve opiate withdrawal and reduce opiate craving: i) opioid mu receptor agonist/opioid kappa receptor antagonist for example buprenorphine; ii) opioid receptor antagonists for example naltrexone; iii) vasodilatory antihypertensives for example lofexidine.
The compounds of the invention may be used in combination with one or more of the following agents to treat sleeping disorders: i) benzodiazepines for example temazepam, lormetazepam, estazolam, triazolam; ii) non-benzodiazepine hypnotics for example Zolpidem, zopiclone, zaleplon, indiplon; iii) barbiturates for example aprobarbital, butabarbital, pentobarbital, secobarbita, phenobarbital; iv) antidepressants; v) other sedative-hypnotics for example chloral hydrate, chlormethiazole.
The compounds of the invention may be used in combination with one or more of the following agents to treat anorexia: i) appetite stimulants for example cyproheptidine; ii) antidepressants; iii) antipsychotics; iv) zinc; v) premenstrual agents for example pyridoxine and progesterones.
The compounds of the invention may be used in combination with one or more of the following agents to treat bulimia: i) antidepressants; ii) opioid receptor antagonists; iii) antiemetics for example ondansetron; iv) testosterone receptor antagonists for example flutamide; v) mood stabilisers; vi) zinc; vii) premenstrual agents.
The compounds of the invention may be used in combination with one or more of the following agents to treat autism: i) antipsychotics; ii) antidepressants; iii) anxiolytics; iv) stimulants for example methylphenidate, amphetamine formulations, pemoline.
The compounds of the invention may be used in combination with one or more of the following agents to treat Attention Deficit Hyperactivity Disorder: i) stimulants for example methylphenidate, amphetamine formulations, pemoline; ii) non-stimulants for example norepinephrine reuptake inhibitors (such as atomoxetine), alpha 2 adrenoceptor agonists (such as clonidine), antidepressants, modafinil, cholinesterase inhibitors (such as galantamine and donezepil).
The compounds of the invention may be used in combination with one or more of the following agents to treat personality disorders: i) antipsychotics; ii) antidepressants; iii) mood stabilisers; iv) anxiolytics.
The compounds of the invention may be used in combination with one or more of the following agents to treat male sexual dysfunction: i) phosphodiesterase V inhibitors, for example vardenafil, sildenafil; ii) dopamine agonists/dopamine transport inhibitors for example apomorphine, buproprion; iii) alpha adrenoceptor antagonists for example phentolamine; iv) prostaglandin agonists for example alprostadil; v) testosterone agonists such as testosterone; vi) serotonin transport inhibitors for example serotonin reuptake inhibitors; v) noradrenaline transport inhibitors for example reboxetine; vii) 5-HT1A agonists, for example flibanserine.
The compounds of the invention may be used in combination with one or more of the following agents to treat female sexual dysfunction: i) the same agents specified for male sexual dysfunction, ii) an estrogen agonist such as estradiol.
Antipsychotic drugs include Typical Antipsychotics (for example chlorpromazine, thioridazine, mesoridazine, fluphenazine, perphenazine, prochlorperazine, trifluoperazine, thiothixine, haloperidol, molindone and loxapine); and Atypical Antipsychotics (for example clozapine, olanzapine, risperidone, quetiapine, aripirazole, ziprasidone, amisulpride, ziprazidone and talnetant).
Antidepressant drugs include serotonin reuptake inhibitors (such as citalopram, escitalopram, fluoxetine, paroxetine and sertraline); dual serotonin/noradrenaline reuptake inhibitors (such as venlafaxine, duloxetine and milnacipran); Noradrenaline reuptake inhibitors (such as reboxetine); tricyclic antidepressants (such as amitriptyline, clomipramine, imipramine, maprotiline, nortriptyline and trimipramine); monoamine oxidase inhibitors (such as isocarboxazide, moclobemide, phenelzine and tranylcypromine); and others (such as bupropion, mianserin, mirtazapine, nefazodone and trazodone).
Mood stabiliser drugs include lithium, sodium valproate/valproic acid/divalproex, carbamazepine, lamotrigine, gabapentin, topiramate and tiagabine.
Anxiolytics include benzodiazepines such as alprazolam and lorazepam.
The compounds of the invention may be administered in conventional dosage forms prepared by combining a compound of the invention with standard pharmaceutical carriers or diluents according to conventional procedures well known in the art. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
The pharmaceutical compositions of the invention may be formulated for administration to mammals including humans. The compositions may be formulated for administration by any route. The compositions may be formulated for oral, topical, or parenteral administration, and may be in the form of tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions. The topical formulations of the present invention may be presented as, for instance, ointments, creams or lotions, eye ointments and eye or ear drops, impregnated dressings and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams.
The formulations may also contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions. Such carriers may be present as from about 1% up to about 98% of the formulation. More usually they will form up to about 80% of the formulation.
Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents.
Suppositories will contain conventional suppository bases, e.g. cocoa-butter or other glyceride.
For parenteral administration, fluid unit dosage forms are prepared utilising the compound and a sterile vehicle, for example water. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
Agents such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. The dry lyophilised powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use. Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilisation cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle. A surfactant or wetting agent may be included in the composition to facilitate uniform distribution of the compound.
It will be recognised by one of skill in the art that the optimal quantity and spacing of individual dosages of a compound of the invention will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular mammal being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e. the number of doses of a compound of the invention given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests.
The invention is illustrated by the Examples described below.
Starting materials, reagents and solvents were obtained from commercial suppliers and used without further purification unless otherwise stated. Flash chromatography was carried out using pre-packed lsolute Flash™ or Biotage™ silica-gel columns as the stationary phase and analytical grade solvents as the eluent.
NMR spectra were obtained at 298K, at the frequency stated using either a Bruker™ DPX400 or an Oxford Instruments™ 250 MHz machine and run as a dilute solution of CDCI3 unless otherwise stated. All NMR spectra were reference to tetramethylsilane (TMS δH 0, δc 0). All coupling constants are reported in hertz (Hz), and multiplicities are labelled s (singlet), bs, (broad singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), dt (doublet of triplets) and m (multiplet).
Total ion current traces were obtained for electrospray positive and negative ionisation (ES+ / ES-) and atmospheric pressure chemical positive and negative ionisation (AP+ / AP-).
All quoted retention times are as measured using LC/MS (Liquid Chromatography / Mass Spectrometry). Unless otherwise stated, all LC/MS runs are 5 minutes. Where appropriate, these retention times were used as a guide for purification using mass- directed auto-preparation (MDAP), which refers to purification by HPLC, wherein fraction collection is triggered by detection of the programmed mass ion for the compound of interest.
Where reactions are described as having been carried out in a similar manner to earlier, more completely described reactions, the general reaction conditions used were essentially the same. Work up conditions used were of the types standard in the art, but may have been adapted from one reaction to another. The starting material may not necessarily have been prepared from the batch referred to. Unless otherwise stated, all compounds with chiral centre(s) are racemic. All reactions were either carried out under argon or may be carried out under argon, unless otherwise stated. Compounds synthesised may have various purities ranging from for example 85% to 98%. However, calculations of number of moles and yield are generally not adjusted for this. In the assays used and described herein, the compounds of the present invention were not necessarily from the same batch described above. A test compound from one batch may have been combined with other batch(es) for the assay(s).
Abbreviations
TEA Triethylamine
TMS-CI Trimethylsilyl chloride
DME Dimethyl ether ss saturated solution
TFA Trifluoroacetic acid
DAD Diode Array Detector
CD Circular dichroism a/a% percentage by area under the curve
LC/MS Liquid Chromatography / Mass Spectrometry
NMR Nuclear Magnetic Resonance
SCX strong cationic exchange
THF Tetrahydrofuran
DMSO Dimethyl sulfoxide
DMF Dimethylformamide
DCM / MDC Dichloromethane / Methylene dichloride
CDI 1 ,1 '-Carbonyldiimidazole
LDA Lithium diisopropylamide
EDC 1-ethyl-3-(dimethylaminopropyl)carbodiimide
MsCI Methanesulfonyl chloride
AcOH Acetic acid
HOAt 1 -hydroxy-7-azabenzotriazole
HOBt 1 -hydroxybenzotriazole
Pd on C Palladium on Charcoal
MeCN Acetonitrile
MDAP Mass-directed auto-preparation
DBU 1 ,8-diazabicyclo[5.4.0]undec-7-ene
Cy Cyclohexane
EtOAc Ethyl acetate
ES Electrospray min(s) Minute(s) degC Degrees Celsius
LDA Lithium diisopropylamide
MeOH Methanol
HPLC/MS High performance liquid chromatography / mass spectrometry
UPLC/MS Ultra performance liquid chromatography / mass spectrometry
Intermediates
Description 1 : N-(2,3-dihydro-1 H-inden-2-yl)-2-propanesulfonamide
Figure imgf000034_0001
2-Aminoindan hydrochloride (5.16 g, 30 mmol, Sigma-Aldrich Company Ltd) was suspended in dry dichloromethane (100 ml), and cooled with stirring under argon to 0 0C. To the suspension was added 1 ,8-diazabicyclo[5.4.0]undec-7-ene (3 eq., about 14ml, about 90 mmol) followed by the dropwise addition of isopropylsulfonyl chloride (6.8ml, 60 mmol). The cooling bath was removed and the mixture stirred at room temperature for 1 h. The reaction mixture was washed with 1 M hydrochloric acid (2 x 50 ml). The organic layer was separated, dried over sodium sulphate and evaporated in vacuo (ie under reduced pressure) to give a yellow oil (1 1.8 g). The crude product was purified by chromatography on a 5Og Isolute™ Flash silica-gel column eluting from 20-50% ethyl acetate in petroleum ether to give the title compound as a colourless solid (6.88 g, 96 %).
1H-NMR (400MHz, CDCI3): 1.39 (6H, d, J = 7 Hz), 2.91 (2H, m), 3.18 (1 H, m), 3.31 (2H, m), 4.31 (2H, m), 7.21 (4H, m).
Description 2: Λ/-[(2/?S)-5-bromo-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide
Figure imgf000034_0002
The title compound was prepared from 5-bromo-2-aminoindane hydrobromide (Prashad et al, Adv. Synth. Catal. 2001 , 343, No. 5, pp 461-472) using a similar process to that used for description 1.
Mass spectrum (ES"): Found 316 (MH"). Ci2H16 79BrNO2S requires 317.
1H-NMR (400MHz, CDCI3): 1.39 (6H, m), 2.88 (2H, m), 3.18 (1 H, m), 3.28 (2H, m), 4.30
(2H, m), 7.08 (1 H, d, J = 8 Hz), 7.31 (1 H, m), 7.35 (1 H, m).
Description 3: (S)-5-bromo-2-aminoindan (1/?)-(-)-10-camphorsulfonate salt
Figure imgf000034_0003
The title compound was prepared using a similar method to that described in Prashad et al, Adv. Synth. Catal. 2001 , 343, No. 5, pp 461-472: ie by resolution of the free base form of racemic 5-bromo-2-aminoindan using (1 /?)-(-)-10-camphorsulphonic acid to obtain (S)-
5-bromo-2-aminoindan (1 R)-(- )-10-camphorsulfonate salt.
The absolute configuration of (S)-5-bromo-2-aminoindan (1 /?)-(-)-10-camphorsulfonate salt was confirmed by X-ray crystallography. Furthermore, the enantiomeric purity of (S)-
5-bromo-2-aminoindan (1 R)-(- )-10-camphorsulfonate salt was checked by HPLC using the following conditions: Column: chiralpak AD-H 5 urn, 250 x 4.6 mm
Mobile phase: A: n-Hexane; B: Ethanol + 0.1% isopropyl amine
Gradient: isocratic 8% B
Flow rate: 0.8 ml/min
UV WL range: 200-400 nm Analysis time 17 min
Enantiomer 1 was recovered as 0.84% a/a from the racemate. Rt. = 1 1.9 min.
Enantiomer 2 was recovered as 99.16% a/a from the racemate. Rt. = 12.8 min.
Description 4: (/?)-5-bromo-2-aminoindan (1 S)-(+)-10-camphorsulfonate salt
Figure imgf000035_0001
The title compound was prepared using a similar method to that described in Prashad et al, Adv. Synth. Catal. 2001 , 343, No. 5, pp 461-472: ie by resolution of the free base form of racemic 5-bromo-2-aminoindan using (1 S)-(+)-10-camphorsulphonic acid to obtain (R)- 5-bromo-2-aminoindan (1 S)-(+)-10-camphorsulfonate salt. The enantiomeric purity of (R)- 5-bromo-2-aminoindan (1 S)-(+)-10-camphorsulfonate salt was checked by HPLC using the following conditions:
Column: chiralpak AD-H 5 urn, 250 x 4.6 mm
Mobile phase: A: n-Hexane; B: Ethanol + 0.1% ipa Gradient: isocratic 8% B Flow rate: 0.8 ml/min UV wavelength range: 200-400 nm
Analysis time 20 min
Enantiomer 1 was recovered as 98.6% a/a from the racemate. Rt. = 1 1.9 min. Enantiomer 2 was recovered as 1.4% a/a from the racemate. Rt. = 12.9 min.
Description 5: Λ/-[(2S)-5-bromo-2,3-dihydro-1 H-inden-2-yl]-2-propanesulfonamide
Figure imgf000036_0001
In order to obtain the free base form of Description 3, it was treated with NaOH (1 M solution in water, at least 1 eq to reach pH=10) in isopropyl acetate as solvent. This free base form was converted to Λ/-[(2S)-5-bromo-2,3-dihydro-1 H-inden-2-yl]-2- propanesulfonamide by a similar process to that of description 1 , using diazabicyclo[5.4.0]undec-7-ene and isopropylsulfonyl chloride. Refer to description 2 for a comparison of the Mass spec and 1H-NMR data.
Description 6: Λ/-[(2/?)-5-bromo-2,3-dihydro-1 H-inden-2-yl]-2-propanesulfonamide
Figure imgf000036_0002
(R)-5-bromo-2-aminoindan (1 S)-(+)-10-camphorsulfonate salt (6.7g) was suspended in ethyl acetate (70ml) and treated with NaOH (1 M) which was added dropwise under stirring. The water was extracted with ethyl acetate (twice) and dried over sodium sulphate and evaporated to give the free base (3.2g, 15.09mmol) which was dissolved in dry dichloromethane (35ml), and cooled with stirring under nitrogen to O0C. To the solution was added 1 ,8-diazabicyclo[5.4.0]undec-7-ene (2eq., 4.25ml, 30.18mmol) followed by the dropwise addition of isopropylsulfonyl chloride (2eq, 3.4ml, 30.18mmol) over 15 minutes. After a further 15 minutes the mixture was warmed to room temperature. The reaction mixture was diluted with 2 volumes (6.4ml) of water, the phases were separated and the aqueous one extracted with dichloromethane (2 volumes; 2 x 6.4ml). The combined organic layers were dried over sodium sulphate and evaporated in vacuo (ie under reduced pressure) to give crude product that was purified by chromatography on a Biotage™ 65M Flash silica-gel column eluting with 20% ethyl acetate in cyclohexane to give the title compound as a white solid (3.98g).
1H-NMR (400MHz, CDCI3): 1.39 (6H, m), 2.88 (2H, m), 3.18 (1 H, m), 3.28 (2H, m), 4.30 (2H, m), 7.08 (1 H, d, J = 8 Hz), 7.31 (1 H, m), 7.35 (1 H, m).
Description 7: 1-[(2/?S)-5-bromo-2,3-dihydro-1H-inden-2-yl]-2-pyrrolidinone
Figure imgf000036_0003
A suspension of 5-bromo-2-aminoindane hydrobromide (Prashad et al, Adv. Synth. Catal. 2001 , 343, No. 5, pp 461-472) (580mg, 2.0mmol) in anhydrous dimethylformamide (15ml) was treated with diisopropylethylamine (1 ml, 742mg, 5.75mmol) dropwise with stirring under argon. The reaction mixture was then cooled in an ice/methanol bath and treated with 4-chlorobutyryl chloride (211 mg, 1.5mmol) dropwise over 5 minutes. The whole mix was then stirred under argon with cooling for 30 minutes. Then a 60% suspension of sodium hydride in mineral oil (280mg, 7mmol) was added portionwise and the cooling bath removed and stirring continued for a further 2 hours. The reaction mixture was quenched with water (2ml), and then partitioned between dichloromethane (20ml) and water (20ml). The organic layer was dried over sodium sulphate and evaporated under reduced pressure to give the title compound as a yellow liquid (478mg).
LC/MS (ES): Found 280 (ES+), retention time 2.63 mins. Ci3H14 79BrNO requires 279. 1 H-NMR (400MHz, CDCI3): 1.97 (2H, m), 2.39 (2H, m), 2.85 (2H, m), 3.16 (4H, m), 5.09 (1 H, m), 7.09 (1 H, d, J=8Hz), 7.30 (1 H, m), 7.36 (1 H, s).
Description 8: 1 -[(2S)-5-bromo-2,3-dihydro-1 H-inden-2-yl]-2-pyrrolidinone
Figure imgf000037_0001
The title compound was prepared from (S)-5-bromo-2-aminoindan (1 R)-(- )-10- camphorsulfonate salt using a similar process to that used for description 7, but using triethylamine as the base instead of diisopropylethylamine. Crude product was purified by flash chromatography on a 5g pre-packed silica column eluting from 20-100% ethyl acetate in petroleum ether.
LC/MS (ES): Found 280 (ES+), retention time 2.74 mins. C13H14 79BrNO requires 279. 1 H-NMR (400MHz, CDCI3): 1.97 (2H, m), 2.39 (2H, m), 2.85 (2H, m), 3.16 (4H, m), 5.09 (1 H, m), 7.09 (1 H, d, J=8Hz), 7.30 (1 H, m), 7.36 (1 H, s).
Description 9: 1 -[(2/?)-5-bromo-2,3-dihydro-1 H-inden-2-yl]-2-pyrrolidinone
Figure imgf000037_0002
The title compound was prepared from (R)-5-bromo-2-aminoindan (1 S)-(-)-10- camphorsulfonate salt using a similar process to that used for description 7, but using triethylamine as the base instead of diisopropylethylamine. Crude product was purified by flash chromatography on a 5g pre-packed silica column eluting from 20-100% ethyl acetate in petroleum ether.
LC/MS (ES): Found 280 (ES+), retention time 2.65 mins. C13H14 79BrNO requires 279. 1 H-NMR (400MHz, CDCI3): 1.97 (2H, quintet, J=8Hz), 2.39 (2H, m), 2.85 (2H, m), 3.16 (4H, m), 5.09 (1 H, m), 7.09 (1 H, d, J=8Hz), 7.30 (1 H, dd, J=8Hz & 2Hz), 7.36 (1 H, s).
Description 10: 4-[(2S)-5-bromo-2,3-dihydro-1H-inden-2-yl]morpholine
Figure imgf000037_0003
(S)-5-bromo-2-aminoindan (1 R)-(- )-10-camphorsulfonate salt (2g, 4.50mmol) was suspended in acetonitrile (60ml) and potassium carbonate (2.193g, 15.75mmol) was added. The suspension was vigorously stirred at room temperature for 5 min then commercially available bis(2-bromoethyl) ether (0.849ml, 6.75mmol) was added at room temperature. The suspension was then heated at reflux for 16h. The solvent was then removed in vacuo, and the obtained solid was dissolved in a mixture dichloromethane/water. The organic phase was then washed with brine, dried over anhydrous Na2SO4 and the solvent removed under vacuum. The crude product was purified by flash chromatography on silica (from EtOAc/Cy 90%/10% to 100% EtOAc as eluant) to afford, after solvent evaporation, the title compound as a beige solid (1.155g, 91%).
LC/MS (ES): Found 282 & 284 (ES+), retention time 0.46 mins. Ci3H16BrNO requires 281 and 283. 1H-NMR (400MHz, DMSO-d6): 2.42 (4H, br. s), 2.68-2.81 (2H, m,), 2.95-3.14 (3H, m), 3.59 (4H, m), 7.16 (1 H, d, J=8Hz), 7.30 (1 H, d, J=8Hz), 7.39 (1 H, s).
Description 11 : 4-[(2/?)-5-bromo-2,3-dihydro-1 H-inden-2-yl]morpholine
Br" f/?)-5-bromo-2-aminoindan(1 S)-(+)-10-camphorsulfonate salt (2g, 4.50mmol) was suspended in acetonitrile (5ml) and potassium carbonate (2.194g, 15.76mmol) was added. The suspension was vigorously stirred at room temperature for 5 min then commercially available bis(2-bromoethyl)ether (0.849ml, 6.75mmol) was added at room temperature. The suspension was then heated at reflux for 16h. The solvent was removed in vacuo, and the obtained solid was dissolved in a mixture dichloromethane/water. The organic phase was washed with brine, dried over anhydrous Na2SO4 and the solvent removed under vacuum. The crude product was triturated in diethyl ether and filtered to afford, after drying, the title compound (0.97g, 76%).
LC/MS (ES): Found 282 & 284 (ES+), retention time 0.46 mins. Ci3H16BrNO requires 281 and 283.
1H-NMR (400MHz, DMSO-d6): 2.41 (4H, br. s), 2.67-2.80 (2H, m), 2.94-3.11 (3H, m), 3.59 (4H, m), 7.16 (1 H, d, J=8Hz), 7.29 (1 H, d, J=8Hz), 7.38 (1 H, s),
Description 12: 3-(trifluoroacetyl)tetrahydro-4H-pyran-4-one
Figure imgf000038_0001
A solution of tetrahydro-4H-pyran-4-one (5.Og, 50mmol) in tetrahydrofuran (100ml) was cooled to -7O0C with stirring under argon. The solution was then treated with a 2M solution of lithium diisopropylamide in tetrahydrofuran (25ml) dropwise over 30 minutes. The mix was then stirred at -7O0C for 30 minutes, then treated dropwise with ethyl trifluoroacetate (7.1g, 5.9ml, 50mmol)with stirring under argon. The mix was then allowed to warm slowly up to 2O0C and stirred for 16 hours under argon. The reaction mix was then partitioned between ethyl acetate (50ml) and water (100ml). The organic layer was dried over sodium sulphate and the solvent removed by rotary evaporation to give the title compound as a foamy yellow solid (10.34g, quantitative).
LC/MS (ES): Found 195 (ES-), retention time 2.35 mins. C7H7F3O3 requires 196. 1 H-NMR (400MHz, CD3OD): 2.34 (2H, m), 3.22 (1 H, m), 3.87 (2H, m), 4.50 (2H, m).
Description 13: 3-(trifluoromethyl)-1 ,4,6,7-tetrahydropyrano[4,3-c]pyrazole
Figure imgf000039_0001
A mixture of 3-(trifluoroacetyl)tetrahydro-4H-pyran-4-one (5.42g, 27.7mmol), and hydrazine hydrate (1.38g, 1.4ml, 27.6 mmol) in ethanol (120ml) was stirred at 6O0C under argon for 6 hours. A further 0.7ml (14mmol) of hydrazine hydrate was added and the reaction stirred at 7O0C for 3 hours. The reaction mix was allowed to cool and the solvent removed by rotary evaporation. The residue was partitioned between dichloromethane and water. The organic layer was separated, dried over sodium sulphate, and solvent removed by rotary evaporation. The aqueous layer was neutralised with 2N HCI and re- extracted with dichloromethane. The organic layer was separated, dried over sodium sulphate, and the solvent removed by rotary evaporation. The 2 extracts were combined to give the title compound as a yellow solid (3.64g, 68%).
LC/MS (ES): Found 191 (ES-), retention time 1.92 mins. C7H7F3N2O requires 192.
1 H-NMR (400MHz, CDCI3): 2.83 (2H, m), 3.95 (2H, m), 4.76 (2H, s), 1 1.32 (1 H, br s).
Description 14: 3-(trifluoromethyl)-1 ,4,5,7-tetrahydropyrano[3,4-c]pyrazole (D5)
Figure imgf000039_0002
To a solution of (5,6-dihydro-2H-pyran-3-yloxy)(trimethyl)silane (prepared according to Liebigs Annalen Der Chemie 1984, 11 , 1759-1882; - 28.7g, 167mmol) in dry THF (570ml), a solution of Methyllithium 1.6M in diethyl ether ( 104ml, 167mmol) was added dropwise under argon at room temperature. After 2.5 hours the mixture was cooled to -78°C, and then treated dropwise at this temperature with a solution of ethyl trifluoroacetate (23.7g, 19.9ml, 167mmol) in dry THF (20 ml). The mixture was allowed to slowly warm up to room temperature, stirred for 2 hours then quenched with sat. NH4CI solution (250ml), keeping the internal temperature below 100C. The two layers were separated and the aqueous extracted twice with ethyl acetate (each with 250ml). The resulting combined organic phase was finally dried over sodium sulphate and the solvent removed by rotary evaporation to give the intermediate 4-(trifluoroacetyl)dihydro-2H-pyran-3(4H)-one as a foamy yellow solid (32.7g, quantitative).
This intermediate (32.7g, 167mmol) was dissolved in ethanol (570ml) and to the solution hydrazine hydrate (16.7g, 16.6ml, 334mmol) was added at room temperature. The resulting mixture was stirred at reflux temperature for 6 hours, then it was allowed to cool down to room temperature and the solvent was removed by rotary evaporation. The residue was partitioned between dichloromethane (400ml) and water (200ml). The aqueous layer was extracted twice with dichloromethane (each with 150ml). The combined organic layers were washed with water (200ml), brine (150ml) and dried over sodium sulphate. The solvent was removed by rotary evaporation to obtain 20.47g of a yellow solid.
Another two batches of the same compound were prepared from the same procedure (the first of 5.6g was obtained starting from 8.2g of (5,6-dihydro-2H-pyran-3- yloxy)(trimethyl)silane and the second of 1g was obtained starting from 2g of (5,6-dihydro- 2H-pyran-3-yloxy)(trimethyl)silane. The three combined residues were purified by SiO2 flash chromatography eluting with cyclohexane / ethyl acetate from 7/3 to 1/1. The desired product was isolated as a white solid (17.2g, 40%).
UPLC/MS (ES): Found 191 (ES-), retention time 0.58 mins. C7H7F3N2O requires 192. 1 H-NMR (400MHz, CDCI3): 2.61 (2H, m), 3.80 (2H, m), 4.68 (2H, s), 13.28 (1 H, br s),
Description 15: 2-[(2/?)-5-bromo-2,3-dihydro-1H-inden-2-yl]isothiazolidine 1,1- dioxide
Figure imgf000040_0001
Under an inert atmosphere of argon, chloropropylsulfonylchloride (200μl, 1.64mmol) was added in one portion to a stirring solution of (/?)-5-bromo-2-aminoindan-(1 S)-(+)-10- camphorsulfonate salt (500mg, 1.12mmol) and diisopropylethylamine (600μl; 3.53mmol) in anhydrous DMF (5ml). After stirring at room temperature for 30 minutes, the reaction was cooled to O0C and NaH (60 wt% in mineral oil, 231 mg, 5.78mmol) was added in one portion, the mixture warmed to room temperature and stirred for a further 2 hours. The reaction was quenched with methanol, and stirred for a further 20 minutes. The resulting mixture was partitioned between DCM (50ml) and water (50ml). The separated aqueous phase was extracted with DCM (100ml), and the combined organic phase dried (MgSO4). Concentration in vacuo gave a brown oil, which was diluted with DCM (110ml), washed with aqueous hydrochloric acid (2N, 100ml), dried (MgSO4), and concentrated in vacuo. The resulting brown oil (576mg) was purified by column chromatography, giving the title compound as a brown solid (295mg, 0.93mmol).
LC/MS -2 minute run (ES): Found 316, retention time 1.08 mins. Ci2H14 79BrNO2S requires 315. 1HNMR (400MHz, CDCI3): 2.28-2.37 (2H, m), 2.99-3.28 (8H, m), 4.30-4.39 (1 H, m), 7.06- 7.11 (1 H, m), 7.28-7.32 (1 H, m), 7.34-7.37 (1 H, m).
Description 16: 3-(difluoromethyl)-4, dro-1H-indazole
Figure imgf000041_0001
A mixture of 2-(difluoroacetyl)cyclohexanone (5.Og, 28.3mmol) and hydrazine monohydrate (1.93ml, 39.7mmol) in ethanol (100ml) was heated at 6O0C under argon for 16hr. The reaction mixture was cooled to room temperature, and the solvent evaporated off under reduced pressure. The resulting mixture was partitioned between ethyl acetate and brine. The organic layer was separated and washed with brine (4 x 30ml), then dried over sodium sulphate. The solvent was removed by rotary evaporation and the sample was recrystallised from ethyl acetate / n-pentane to give the title compound as a pale brown solid (3.305g, 68%).
LC/MS (ES): Found 173 (ES+) retention time 2.34 mins. C8H10F2N2 requires 172. 1 H-NMR (400MHz, DMSOd6): 1.65 (4H, m), 2.44-2.60 (4H, m), 6.83 (1 H, t, J=54Hz), 12.71 (1 H, br s).
Description 17: 2-[(2S)-5-bromo-2,3-dihydro-1H-inden-2-yl]isothiazolidine 1 ,1- dioxide
Figure imgf000041_0002
The title compound was synthesised in the same manner as 2-[(2/?)-5-bromo-2,3-dihydro-
1H-inden-2-yl]isothiazolidine 1 ,1-dioxide (description 15) from 1.01g of (S)-5-bromo-2- aminoindan-(1 R)-(- )-10-camphorsulfonate salt (Description 3) using the same reaction stoichiometry.
LC/MS (ES): Found 316 (ES+), retention time 1.07 mins (2 minute run). C12H14 79BrNO2S requires 315.
1 H-NMR (400MHz, CDCI3): 2.27-2.37 (2H, m), 2.98-3.28 (8H, m), 4.28-4.37 (1 H, m),
7.06-7.10 (1 H, m), 7.26-7.31 (1 H, m), 7.33-7.36 (1 H, m).
Description 18: 4-(5-bromo-2,3-dihydro-1H-inden-2-yl)morpholine
Figure imgf000042_0001
(5-bromo-2,3-dihydro-1 H-inden-2-yl)amine hydrobromide salt (8g, 27.3mmol) was suspended in acetonitrile (100ml) and potassium carbonate (12.16g, 87mmol) was added. The suspension was vigorously stirred at r.t. for 5 min then bis(2-bromoethyl) ether (4.12ml, 32.8mmol) was added and the resulting suspension was heated at reflux for 16h. The reaction mixture was filtered and the solvent removed in vacuo to obtain a solid which was dissolved in DCM (120ml), and washed with brine (100ml). Drying over Na2SC>4 and removal of the solvent in vacuo afforded a crude solid which was triturated in diethyl ether (40ml). The operation was repeated three times filtering the product, evaporating the mother liquors to afford a crude solid which was suspended again in diethyl ether (25ml the second time, 10ml the third one). The solids which came from each trituration were combined. After drying, 5.65g of beige solid were obtained (recovery 73.3%).
LC/MS (ES): Found 282 and 284 (ES+), retention time 0.48 mins. C13H16 79BrNO requires 281.
1H-NMR (400MHz, DMSOd6): 2.41 (4H, br. s,), 2.67-2.80 (2H, m), 2.94-3.13 (3H, m), 3.59 (4H, m), 7.15 (1 H, m), 7.29 (1 H, m), 7.38 (1 H, bs).
Analytical chromatographic conditions for Description 18
Coloumn: Acquity UPLC BEH C18, 2.1 x 50 mm, 1.7 urn.
Mobile phase : A: Water + 0.1 % formic acid, B: CH3CN + 0.06 % formic acid Gradient: 3% to 6% (B) in 0.1 min., 6% to 70% (B) in 0.5 min., 70% (B) to 99% (B) in
0.5 min, 99% to 3% (B) in 0.35min.
Flow rate: 1 ml/min
UV range: 210-350 nm
Ionization: ES+ Mass range: 100-900 amu
Description 19: 1-tert-butoxycarbo cetyl)-3-piperidinone
Figure imgf000042_0002
A solution of lithium diisopropylamide in THF (40.2ml, 2M) was cooled to -780C with stirring under argon. To this was added a solution of the 1 -tert-butoxycarbonyl-3- piperidinone (16g, 80.4mmol) in THF (100ml) with stirring under argon. The mixture was stirred at -780C for 20mins before being treated dropwise with ethyl trifluoroacetate (9.56ml, 80.4mmol). The reaction mixture was allowed to warm up to room temperature and stirred for 2h. The reaction mixture was quenched with water and neutralized with dilute aqueous hydrochloric acid. The reaction mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulphate and evaporated under reduced pressure to give the title compound as an orange foamy solid (23.6g, crude material).
LC/MS (ES): Found 294 (ES-), retention time 3.31 mins. Ci2H16F3NO4 requires 295.
Description 20: 6-tert-butoxycarbonyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H- pyrazolo[3,4-c]pyridine
Figure imgf000043_0001
A solution of 1-tert-butoxycarbonyl-4-(trifluoroacetyl)-3-piperidinone (23.6g, O.Oδmol) in ethanol (250ml) was treated with hydrazine monohydrate (4.16ml, 0.086mol). The mixture was allowed to stir at 5O0C for 24h. The reaction mixture was cooled to room temperature and then evaporated under reduced pressure. The resulting mixture was partitioned between ethyl acetate and brine. The organic layer was separated and dried over sodium sulphate and evaporated under reduced pressure. Residual material was recrystallised from ethyl acetate / n-pentane to give the title compound as a pale yellow solid (6.5g, 28%).
LC/MS (ES): Found 290 (ES-), retention time 2.90 mins. Ci2H16F3N3O2 requires 291.
1 H-NMR (400MHz, CDCI3): 1.48 (9H, s), 2.70 (2H, m), 3.66 (2H, m), 4.40 (2H, m), 11.13 (1 H, br s),
Description 21 : 6-methyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4- c] pyridine
Figure imgf000043_0002
Under an inert atmosphere of argon, LiAIH4 (2.3 M in THF; 7.5ml; 17.3mmol) was added dropwise over 2 minutes to a cool (O0C) stirring solution of 6-tert-butoxycarbonyl-3- (trifluoromethyl)-4,5,6,7-tetrahydro-1 H-pyrazolo[3,4-c]pyridine (2.0Og; 8.45mmol) in anhydrous THF (42ml). The resulting mixture was stirred in an oil bath at 580C for 17 hours, cooled to O0C, and quenched by the careful addition of an aqueous solution of sodium potassium tartrate (1 M; 50ml). After stirring at room temperature for 1 hour, the mixture was diluted with diethyl ether (50ml) and more aqueous sodium potassium tartrate (1 M; 50ml). After stirring at this temperature for a further 1 hour, the mixture was partitioned between water (100ml) and diethyl ether (200ml). The separated aqueous phase was extracted with ethyl acetate (200ml), and the combined organic phase was dried (MgSO4) and concentrated in vacuo. The resulting off-white solid (1.39g) was purified using an SCX column giving the title compound as a yellow solid (1.23g; 6.01 mmol)
LC/MS (ES): Found 206 (ES+), retention time 1.81 mins. C8H10F3N3 requires 205.
1 H-NMR (400MHz, CDCI3): 2.48 (3H, app s), 2.74 (4H, app s), 3.58 (2H, app s), 5.01
(1 H, br s)
Description 25: 4,4,4-trifluoro-1 -(6-methyl-3-pyridinyl)-1 ,3-butanedione
Figure imgf000044_0001
A solution of 5-acetyl-2-methylpyridine (1 g, 7.40 mmol) in tetrahydrofuran (THF) (40 ml) was cooled to -70 0C with stirring under argon. The solution was then treated with LDA (7.40 ml, 14.80 mmol) dropwise over 15 minutes. The mixture was then stirred at -70 0C for 30 minutes, and then treated dropwise with methyl trifluoroacetate (1.116 ml, 1 1.10 mmol) with stirring under argon. The reaction mixture was then allowed to warm slowly up to 20 0C. Further methyl trifluoroacetate (0.6ml, 3.68 mmol) was added and the reaction mixture was stirred at room temperature for another hour. The reaction mixture was partitioned between water (50ml) and EtOAc (100 ml). The aqueous phase was further extracted with EtOAc (100ml). The organics were combined, dried over MgSO4 and concentrated to give a bright yellow oil. This residue was purified by reverse phase column chromatography using C-18 type cartridge, eluting from 100% of 0.1% of formic acid in water to 100% of 0.1 % formic acid in acetonitrile. Relevant fractions were combined and concentrated to give a yellow solid which was dried in the vacuum oven to give the title compound (670mg).
LC/MS (ES): Found 230 (ES-), retention time 0.49 mins (2 minute method). C10H8F3NO2 requires 231. -methyl-5-[3-(trifluoromethyl)-1 H-pyrazol-5-yl]pyridine
Figure imgf000044_0002
A solution of 4, 4, 4-trifluoro-1-(6-methyl-3-pyridinyl)-1 ,3-butanedione (Description 25,
670mg, 2.90 mmol) in ethanol (16 ml) was treated with hydrazine hydrate (0.141 ml, 2.90 mmol) and the reaction mixture was stirred at 78 0C under argon for 2 days. A few drops of a 2M HCI solution in water were added and the reaction mixture was stirred at 78 0C for another hour. The reaction mixture was cooled down to room temperature and partitioned between water (30ml) and EtOAc (50ml). The aqueous phase was further extracted with EtOAc (50ml). The organics were combined, dried over MgSO4 and concentrated to give the title compound (500mg).
LC/MS (ES): Found 228 (ES+), retention time 0.62 mins (2 minute method). Ci0H8F3N3 requires 227.
Example 1 : Λ/-{(2S)-5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]-2,3- dihydro-1H-inden-2-yl}-2-propanesulfonamide
Figure imgf000045_0001
A mixture of Λ/-[(2S)-5-bromo-2,3-dihydro-1 H-inden-2-yl]-2-propanesulfonamide (159mg, 0.5mmol), 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole (95mg, 0.5mmol), copper(l) iodide (10mol%, 10mg, 0.05mmol), frans-1 ,2-diaminocyclohexane (20mol%, 11 mg, 0.01 mmol) and potassium carbonate (145mg, 1.05mmol) in 1 ,4-dioxane (1.5ml) was stirred at 18O0C in a microwave reactor for 1.5h. The reaction mix was cooled and added to a 5g pre-packed silica column which was then eluted from 50% ethyl acetate in petroleum ether to give a dark oil which was further purified by mass directed auto-prep to give a pure crop of the title compound as a yellow oil (103mg, 48%).
LC/MS (ES): Found 428 (ES+), retention time 3.51 mins. C20H24F3N3O2S requires 427. 1 H-NMR (400MHz, CDCI3): 1.40 (6H, d, J=7Hz), 1.82 (4H, m), 2.67 (4H, m), 2.96 (2H, m), 3.19 (1 H, sept, J=7Hz), 3.35 (2H, m), 4.34 (1 H, m), 4.46 (1 H, m), 7.27 (2H, m), 7.36 (1 H, m).
Example 2: 1 -{(2/?S)-5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1 -yl]-2,3- dihydro-1H-inden-2-yl}-2-pyrrolidinone
Figure imgf000045_0002
A mixture 1-(5-bromo-2,3-dihydro-1 H-inden-2-yl)-2-pyrrolidinone (140mg, O.δmmol), 3- (trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazole (95mg, O.δmmol), copper(l) iodide (10mol%, 10mg, O.Oδmmol), N,N-dimethylglycine (20mol%, 10mg, O.i mmol) and potassium carbonate (138mg, I .Ommol) in dimethylsulfoxide (3ml) was stirred at 19O0C in a microwave reactor for 0.5h. The reaction mix was partitioned between dichloromethane and water. The organic layer was added to a 5g pre-packed silica column and eluted with ethyl acetate. The solvent was removed by evaporation under reduced pressure and the sample further purified by mass directed auto prep to give a pure crop of the title compound as a brown oil (49mg, 25%). LC/MS (ES): Found 390 (ES+), retention time 3.28 mins. C2IH22F3N3O requires 389. 1 H-NMR (400MHz, CDCI3): 1.83 (4H, m), 1.98 (2H, m), 2.41 (2H, m), 2.68 (4H, m), 2.91 (1 H, m), 2.95 (1 H, m), 3.16 (2H, m), 3.25 (2H, m), 5.14 (1 H, m), 7.28 (2H, m), 7.36 (1 H, s).
Example 3: 1 -{(2S)-5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1 -yl]-2,3- dihydro-1H-inden-2-yl}-2 -pyrrolidinone
Figure imgf000046_0001
The title compound was prepared from 1-[(2S)-5-bromo-2,3-dihydro-1H-inden-2-yl]-2- pyrrolidinone and 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazole using a similar process to that used for Example 2, except the reaction was heated at 19O0C in a microwave reactor for 1 h.
LC/MS (ES): Found 390 (ES+), retention time 3.38 mins. C2i H22F3N3O requires 389. 1 H-NMR (400MHz, CDCI3): 1.82 (4H, m), 1.97 (2H, m), 2.40 (2H, t, J=8Hz), 2.68 (4H, m), 2.91 (1 H, m), 2.95 (1 H, m), 3.16 (2H, t, J=7Hz), 3.24 (2H, m), 5.14 (1 H, m), 7.28 (2H, m), 7.37 (1 H, s).
Example 4: 1 -{(2/?)-5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1 -yl]-2,3- dihydro-1H-inden-2-yl}-2 -pyrrolidinone
Figure imgf000046_0002
The title compound was prepared from 1-[(2/?)-5-bromo-2,3-dihydro-1 H-inden-2-yl]-2- pyrrolidinone and 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazole using a similar process to that used for Example 2, except the reaction was heated at 19O0C in a microwave reactor for 1 h.
LC/MS (ES): Found 390 (ES+), retention time 3.28 mins. C2i H22F3N3O requires 389. 1 H-NMR (400MHz, CDCI3): 1.82 (4H, m), 1.97 (2H, quintet, J=8Hz), 2.41 (2H, m), 2.68 (4H, m), 2.91 (1 H, m), 2.95 (1 H, m), 3.16 (2H, m), 3.24 (2H, m), 5.14 (1 H, m), 7.28 (2H, m), 7.36 (1 H, s).
Examples 5-24:
Figure imgf000046_0003
Typical procedure: The title compounds reported in table 1 were prepared by parallel synthesis. 0.12M DMSO solutions of each 5-bromoindane scaffold (YY) and of each pyrazole scaffold (WW) were prepared. Then the necessary scaffold solutions (1.5ml, 0.18mmol) and pyrazole solutions (1.5ml, 0.18mmol) were dispensed into 5ml microwave tubes. To the resulting DMSO mixtures, N,N-dimethylglycine (0.021 g, 0.207mmol), potassium carbonate (0.05Og, 0.360mmol) and copper (I) iodide (0.038g, 0.198mmol) were added. The resulting suspensions were heated at 1900C in a microwave reactor for 30 min, then they were filtered and the solvent removed by vacuum centrifuge overnight. The obtained crude products were partitioned between dichloromethane (3ml) and aqueous saturated ammonium chloride (2ml), then the organic layers were separated and the solvent removed by blowing down in air. The obtained crude products were purified by preparative HPLC/MS to give the title compounds (YW) as reported in table 1.
Preparative conditions for examples reported in table 1
Column: Gemini C18 AXIA, 50 x 21 mm, 5 μm Mobile phase: A: NH4HCO3 sol. 10 mM, pH10; B: CH3CN Gradient: 30% to 35% (B) in 1 min, 35% to 65% (B) in 7 min, 65% to 100% (B) in
1 min, 100% (B) for 2.5 min
Flow rate: 17 ml/min UV range: 210-350 nm Ionization: ES+ Mass range: 100-900 amu
Table 1
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
22 4-{(2S)-5-[5- C20H22F3N3O 378 (2.92) cyclopropyl-3-
(trifluoromethyl)-
Figure imgf000051_0001
1H-pyrazol-1-yl]-
2,3-dihydro-I H- inden-2- yl}morpholine
23 1-{(2R)-5-[5- C20H20F3N3O 376 (2.80) cyclopropyl-3-
(trifluoromethyl)-
Figure imgf000051_0002
1H-pyrazol-1-yl]-
2,3-dihydro-1 H- inden-2-yl}-2- pyrrolidinone
24 1-{(2S)-5-[5- C20H20F3N3O 376 (2.79) cyclopropyl-3-
(trifluoromethyl)-
Figure imgf000051_0003
1H-pyrazol-1-yl]-
2,3-dihydro-1 H- inden-2-yl}-2- pyrrolidinone H-NMR spectra of selected examples reported in table 1 :
Example 8: Λ/-{(2S)-5-[3-(trifluoromethyl)-4,7-dihydropyrano[3,4-c]pyrazol- 1(5H)-yl]-2,3-dihydro-1H-inden-2-yl}-2-propanesulfonamide
1H-NMR (400MHz, DMSO-d6): 1.22 (6H, d, J=7Hz), 2.69 (2H, m), 2.87 (2H, m), 3.21 (3H, m), 3.83 (2H, t, J=7Hz), 4.12 (1 H, m), 4.78 (2H, s), 7.30 (3H, m), 7.45 (1 H, br s).
Example 16: 1 -[(2S)-2-(4-morpholinyl)-2,3-dihydro-1H-inden-5-yl]-3-
(trifluoromethyl)-1,4,6,7-tetrahydropyrano[4,3-c]pyrazole
1H-NMR (600MHz, DMSO-d6): 2.44 (4H, m), 2.81 (2H, m), 2.85 (2H, t, J=7Hz),
3.10 (3H, m), 3.59 (4H, t, J=7Hz), 3.82 (2H, t, J=7Hz), 4.70 (2H, s), 7.34 (2H, m),
7.43 (1 H, s).
Example 23: i-^PJ-S-IS-cyclopropyl-S-ttrifluoromethylJ-IH-pyrazol-i-yll^.S- dihydro-1H-inden-2-yl}-2-pyrrolidinone
1H-NMR (400MHz, DMSO-d6): 0.78 (2H, m), 0.92 (2H, m), 1.81 (3H, m), 2.20 (2H, t, J=7Hz), 2.95 (2H, m), 3.12 (4H, m, J=7Hz), 4.86 (1 H, m), 6.56 (1 H, s), 7.38 (2H, m), 7.44 (1 H, s). Example 25: (2/?)-5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1 -yl]-2,3- dihydro-1H-inden-2-amine
Figure imgf000052_0001
Copper (I) iodide (22.8mg, 0.12mmol) was added in one portion to a stirring mixture of (R)-5-bromo-2-aminoindan-(1 S)-(+)-10-camphorsulfonate salt (439mg, 0.99mmol), 3-
(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazole (180mg, 0.95mmol) , K2CO3 (292mg,
2.11 mmol), and Λ/,Λ/-dimethylglycine (31.2mg, 0.24mmol) in DMSO (4ml). The mixture was stirred at 13O0C for 1 15 hours, cooled to room temperature and partitioned between
DCM (25ml) and water (35ml). The separated aqueous phase was further extracted with DCM (25m, then 35ml), and the combined organic phase purified by SCX column chromatography, giving a brown oil (166mg). This was further purified by column chromatography, giving the title compound as a light brown oil (110mg; 0.34mmol).
LC/MS (ES): Found 322 (ES+), retention time 2.15 mins. Ci7H18F3N3 requires 321 1HNMR (400MHz, CDCI3): 1.75-1.90 (4H, m), 2.61-2.80 (6H, m), 3.18-3.25 (2H, m), 3.85- 3.94 (1 H, m), 7.19-7.23 (1 H, m), 7.24-7.30 (1 H, m), 7.33 (1 H, d, J=I Hz).
Example 26: (2/?S)-5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1 -yl]-2,3- dihydro-1H-inden-2 -amine formic acid salt And
Example 27: W2,W2-c//mefA?y/-yV7-^2/?S)-5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H- indazol-1 -yl]-2,3-dihydro-1H-inden-2-yl}glycinamide formic acid salt
Figure imgf000052_0002
A stirring mixture of 5-bromo-2-aminoindane hydrobromide (Prashad et al, Adv. Synth. Catal. 2001 , 343, No. 5, pp 461-472) (99mg, 0.35mmol), 3-(trifluoromethyl)-4,5,6,7- tetrahydro-1 H-indazole (71.7mg, 0.38mmol), Λ/,Λ/-dimethylglycine (56.8mg, 0.44mmol), and Copper (I) iodide (74.0mg, 0.39mmol) in anhydrous DMSO was heated under microwave conditions at 19O0C for 30 minutes. The mixture was partitioned between DCM (50ml) and water (25ml). The organic phase was purified by SCX column chromatography giving a brown oil (114mg), this was further purified by MDAP, giving separately 5-[3- (trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1 -yl]-2,3-dihydro-1 H-inden-2-amine formic acid salt (Example 26; 36.6mg, 99.6μmol), and Λ/2,Λ/2-dimethyl-Λ/1-{5-[3-(trifluoromethyl)- 4, 5, 6, 7-tetrahydro-1 H-indazol-1 -yl]-2,3-dihydro-1 H-inden-2-yl}glycinamide formic acid salt (Example 27; 4.76mg, 11.7μmol). Example 26: 5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1-yl]-2,3-dihydro-1 H- inden-2-amine formic acid salt LC/MS (ES): Found 322 (ES+), retention time 2.05 mins. Ci7H18F3N3 requires 321.
1HNMR (400MHz, CDCI3): 1.70-1.88 (4H, m), 2.57-2.71 (4H, m), 3.01-3.18 (2H, m), 3.21- 3.38 (2H, m), 4.03-4.17 (1 H, m), 6.76 (3H, br s), 7.17-7.33 (3H, m), 8.1 1 (1 H, br s).
Example 27: Λ/2,Λ/2-dimethyl-Λ/1-{5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1 -yl]- 2,3-dihydro-1 H-inden-2-yl}glycinamide formic acid salt LC/MS (ES): Found 407 (ES+), retention time 2.10 mins C2i H2SF3N4O requires 406.
Example 28: Λ/-{(2/?)-5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1 -yl]-2,3- dihydro-1H-inden-2-yl}-2-propanesulfonamide
Figure imgf000053_0001
lsopropylsulfonyl chloride (50μl, 0.45mmol) was added dropwise over 1 minute to a cool (O0C) stirring solution of (2R)-5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1 -yl]-2,3- dihydro-1 H-inden-2-amine (58.0mg, 0.18mmol; Example 19) and DBU (80μl, 0.53mmol) in
DCM (1 ml). The mixture was stirred at room temperature for 18.5 hours and partitioned between water (1 ml) and DCM (5ml). The separated organic phase was dried (MgSO4), and concentrated in vacuo, giving a brown oil. This was purified by MDAP, giving the title compound as a colourless oil (41.3mg; 96.6μmol).
LC/MS (ES): Found 428 (ES+), retention time 3.45 mins. C20H24F3N3O2S requires 427. 1HNMR (400MHz, CDCI3): 1.40 (6H, d, J=7Hz), 1.74-1.88 (4H, m), 2.60-2.73 (4H, m), 2.9- 3.0 (2H, m), 3.19 (1 H, septet, J=7Hz), 3.30-3.40 (2H, m), 4.28-4.42 (2H, m), 7.22-7.31 (2H, m), 7.36 (1 H, app s).
Example 29: 1-[(2/?S)-2-(1,1-dioxido-2-isothiazolidinyl)-2,3-dihydro-1H-inden-5-yl]-3- (trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole And Description 22: 2-[(2/?S)-5-bromo-2,3-dihydro-1H-inden-2-yl]isothiazolidine 1 ,1- dioxide
Figure imgf000053_0002
3-Chloro-1-propanesulfonyl chloride (40μl, 0.33mmol) was added in one portion to a stirring solution of diisopropylethylamine (50μl, 0.29mmol), and a mixture of 5-[3- (trifluoromethyl)-4, 5, 6, 7-tetrahydro-1 H-indazol-1 -yl]-2,3-dihydro-1 H-inden-2-amine and 5- bromo-2-aminoindane (48.2mg - combined mass of both indane amines) in DMF (1 ml). After stirring at room temperature for 24 minutes, NaH (60 wt% in mineral oil, 38.6mg, 0.97mmol) was added in one portion, and the mixture stirred at this temperature for a further 16 hours. The reaction was quenched with methanol (2ml), stirred for 40 minutes, and concentrated in vacuo. The crude mixture was partitioned between DCM (25ml), and water (15ml). The organic phase was concentrated in vacuo and purified by MDAP, giving separately 1-[2-(1 ,1-dioxido-2-isothiazolidinyl)-2,3-dihydro-1 H-inden-5-yl]-3-
(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazole (Example 29; 6.28mg, 14.8μmol) and 2- (5-bromo-2,3-dihydro-1 H-inden-2-yl)isothiazolidine 1 ,1 -dioxide (Description 22; 38.7mg, 0.12mmol).
Example 29: 1-[2-(1 ,1-dioxido-2-isothiazolidinyl)-2,3-dihydro-1 H-inden-5-yl]-3-
(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazole LC/MS (ES): Found 426 (ES+), retention time 3.40 mins. C20H22F3N3O2S requires 425. 1HNMR (400MHz, CDCI3): 1.78-1.87 (4H, m), 2.29-2.38 (2H, m), 2.62-2.72 (4H, m), 3.09- 3.21 (6H, m), 3.27-3.35 (2H, m), 4.37-4.45 (1 H, m), 7.24-7.31 (2H, m), 7.35 (1 H, app s).
Description 22: 2-(5-bromo-2,3-dihydro-1 H-inden-2-yl)isothiazolidine 1 ,1 -dioxide LC/MS (ES): Found 316 (ES+), retention time 2.83 mins. Ci2H14 79BrNO2S requires 315. 1HNMR (400MHz, CDCI3): 2.26-2.38 (2H, m), 3.0-3.3 (8H, m), 4.4-4.5 (1 H, m), 7.09 (1 H, d, J=8Hz), 7.28-7.32 (1 H, m), 7.35 (1 H, app s).
Example 30: Λ/-{(2/?S)-5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1 -yl]-2,3- dihydro-1H-inden-2-yl}acetamide And Description 23: Λ/-[(2/?S)-5-bromo-2,3-dihydro-1H-inden-2-yl]acetamide
Figure imgf000054_0001
Acetyl chloride (50μl, 0.70mmol) was added in one portion to a room temperature stirring mixture of DBU (1 ,8-diazabicyclo[5.4.0]undec-7-ene) (80μl, 0.53mmol), and a mixture of 5-[3-(trifluoromethyl)-4, 5, 6, 7-tetrahydro-1 H-indazol-1 -yl]-2,3-dihydro-1 H-inden-2-amine and 5-bromo-2-aminoindane (77.0mg - combined mass of both indane amines) in DCM (1.5ml). After stirring at this temperature for 23 hours, the reaction was quenched with methanol (1 ml), followed by water (3ml), and stirred for a further 2 minutes. The mixture was diluted with DCM (6.5ml), and the separated organic phase concentrated in vacuo giving a brown oil (96.9mg). This was purified by MDAP giving separately Λ/-{5-[3- (trifluoromethyl)-4, 5, 6, 7-tetrahydro-1 H-indazol-1 -yl]-2,3-dihydro-1 H-inden-2-yl}acetamide (Example 30; 8.5mg, 23.4μmol) and Λ/-(5-bromo-2,3-dihydro-1 H-inden-2-yl)acetamide (Description 23; 58.0mg, 0.23mmol). Example 30: Λ/-{5-[3-(trif luoromethyl)-4.5,6,7-tetrahydro-1 H-indazol-1 -yl]-2,3-dihydro-1 H- inden-2-yl}acetamide LC/MS (ES): Found 364 (ES+), retention time 3.1 1 mins. C-I9H20F3N3O requires 363.
1HNMR (400MHz, CDCI3): 1.7-1.9 (4H, m), 1.96 (3H, s), 2.60-2.77 (4H, m), 2.79-2.90 (2H, m), 3.28-3.40 (2H, m), 4.73-4.83 (1 H, m), 5.71 (1 H, br d, J=6Hz), 7.23-7.33 (2H, m), 7.36 (1 H, s).
Description 23: Λ/-(5-bromo-2,3-dihydro-1 H-inden-2-yl)acetamide LC/MS (ES): Found 254 (ES+), retention time 2.47 mins. Cn H12 79BrNO requires 253. 1HNMR (400MHz, CDCI3): 1 .94 (3H, s), 2.68-2.83 (2H, m), 3.17-3.33 (2H, m), 4.66-4.77 (1 H, m), 5.76 (1 H, app s), 7.09 (1 H, d, J=8Hz), 7.30 (1 H, d, J=8Hz), 7.36 (1 H, s).
Examples 31 and 32 and Description 18
The following compounds were synthesised in a similar manner to that described for Example 30 and Description 23.
Table 2
Figure imgf000055_0001
Figure imgf000056_0003
Example 33: 1 -[(2/?S)-2-(1 -piperidinyl)-2,3-dihydro-1 H-inden-5-yl]-3-(trifluoromethyl)- 4,5,6,7-tetrahydro-1H-indazole formic acid salt
Figure imgf000056_0001
In a sealed tube, a mixture of 5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1-yl]-2,3- dihydro-1 H-inden-2-amine (56.3mg, 0.18mmol), 1 ,5-diiodopentane (30μl, 0.20mmol), and K2CO3 (23.5mg, 0.17mmol) in anhydrous acetonitrile was stirred at 250C for 1% hours, then at 8O0C for 24 hours. The reaction was quenched with methanol, stirred for 2 hours, quenched with aqueous 2N hydrochloric acid, and purified by successive SCX column chromatography and MDAP, giving the title compound (16mg, 36.7μmol).
LC/MS (ES): Found 390 (ES+), retention time 2.35 mins. C22H26F3N3 requires 389.
Example 34:
The following compound was synthesised from 5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro- 1 H-indazol-1-yl]-2,3-dihydro-1 H-inden-2-amine in a similar manner as that described for Example 33.
Figure imgf000056_0004
Example 35: Λ/-{(2/?S)-5-[3-(trifluoromethyl)-6,7-dihydropyrano[4,3-c]pyrazol-1(4H)- yl]-2,3-dihydro-1H-inden-2-yl}acetamide
Figure imgf000056_0002
A mixture of /V-(5-bromo-2,3-dihydro-1 H-inden-2-yl)acetamide (53.0mg, 0.17mmol), 3- (trifluoromethyl)-1 ,4,6,7-tetrahydropyrano[4,3-c]pyrazole (85.0mg, 0.44mmol), K2CO3 (102mg, 0.74mmol), Λ/,Λ/-dimethylglycine (44.0mg, 0.34mmol), and copper (I) iodide (48.0mg, 0.25mmol) in anhydrous DMSO (1.3ml) was stirred at 19O0C under microwave heating for 30 minutes. The mixture was partitioned between DCM (2 x 20ml) and water (10ml). The separated organic phases were combined, concentrated in vacuo, and purified by MDAP, giving the title compound (31.7mg, 86.7μmol).
LC/MS (ES): Found 366 (ES+), retention time 2.65 mins. Ci8H18F3N3O2 requires 365. 1HNMR (400MHz, CDCI3): 1.96 (3H, s), 2.78-2.93 (4H, m), 3.31-3.39 (2H, m), 3.87-3.99 (2H, m), 4.74-4.86 (3H, m), 5.72 (1 H, d, J=7Hz), 7.25-7.34 (2H, m), 7.38-7.41 (1 H, m).
Examples 36 and 37:
The following compounds were synthesised from Λ/-[(2/?S)-5-bromo-2,3-dihydro-1 H- inden-2-yl]methanesulfonamide (Example 36) and 2-[(2/?S)-5-bromo-2,3-dihydro-1 H- inden-2-yl]isothiazolidine 1 ,1-dioxide (Example 37) in a manner similar to that described for Example 35.
Table 3
Ex Name Structure MF LC/MS
36 Λ/-{(2/?S)-5-[3- C17H18F3N 3O3S Found 402
(trifluoromethyl)-6,7- Requires 401 (ES+), dihydropyrano[4,3- retention time c]pyrazol-1(4H)-yl]-2,3-
Figure imgf000057_0001
2.82 mins. dihydro-1H-inden-2- yl}methanesulfonamide
37 1-[(2/?S)-2-(1,1-dioxido- C-IgH20F3N 3O3S Found 428
2-isothiazolidinyl)-2,3- Requires 427 (ES+), dihydro-1H-inden-5-yl]- retention time
3-(trifluoromethyl)- I
F3C 2.99 mins.
1,4,6,7- tetrahydropyrano[4,3- c]pyrazole
Example 38 and 39:
The following compounds were synthesised each from 2-[(2/?)-5-bromo-2,3-dihydro-1 H- inden-2-yl]isothiazolidine 1 ,1-dioxide (148 mg; 0.47 mmol) and either 3-(trifluoromethyl)- 1 ,4,6,7-tetrahydropyrano[4,3-c]pyrazole 92.4 mg; 0.48 mmol) or 3-(trifluoromethyl)- 4,5,6,7-tetrahydro-1H-indazole (92.8 mg; 0.49 mmol) in a similar manner (with Cs2CO3 replacing K2CO3) and using the same stoichiometry as for Example 35. The reactions were quenched with aqueous hydrochloric acid (2N, 2ml), prior to work up and purified in a similar fashion to Example 35.
Table 4
Figure imgf000058_0002
Example 40: 1 -{(2R)-5-[6-methyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H- pyrazolo[3,4-c]pyridin-1-yl]-2,3-dihydro-1 H-inden-2-yl}-2-pyrrolidinone
Figure imgf000058_0001
A mixture of 1-[(2R)-5-bromo-2,3-dihydro-1 H-inden-2-yl]-2-pyrrolidinone (108mg, 0.39mmol), 6-methyl-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-pyrazolo[3,4-c]pyridine
(202mg, 0.55mmol), Λ/,Λ/-dimethylglycine (53.8mg, 0.52mmol), Cs2CO3 (251 mg, 0.77mmol), and copper (I) oxide (58.3mg, 0.41 mmol) in anhydrous DMSO was heated under microwave conditions at 19O0C for 30 minutes. This was quenched with aqueous HCI (2N, 1 ml), stirred for 30 minutes, and purified by SCX column chromatography giving a brown oil (233mg). This was purified by MDAP followed by SCX, giving the title compound as a brown oily solid (62.5mg, 0.15mmol).
LC/MS (ES): Found 405 (ES+), retention time 0.67 mins (2 minute run). C2IH23F3N4O requires 404. Example 41 : 1-[(2S)-2-(1,1-dioxido-2-isothiazolidinyl)-2,3-dihydro-1H-inden-5-yl]-3- (trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole
Figure imgf000059_0001
Under an inert atmosphere of argon, a mixture of 2-[(2S)-5-bromo-2,3-dihydro-1 H-inden- 2-yl]isothiazolidine 1 ,1 -dioxide (155mg; 0.49mmol), 3-(trifluoromethyl)-4,5,6,7-tetrahydro- 1 H-indazole (94.0mg; 0.49mmol), Λ/,Λ/-dimethyl glycine (60.7mg; 0.59mmol), Cs2CO3 (290mg; 0.89mmol), and Cu2O (76.4mg; 0.53mmol) in anhydrous DMSO (2ml) was stirred under microwave heating at 19O0C for 30 minutes. The reaction was quenched with aqueous HCI (2N, 1 ml), diluted with DCM (1 ml), and stirred for 30 minutes. This was partitioned between DCM (35ml) and water (15ml), and the separated aqueous phase further extracted with DCM (2 x 30ml). The combined organic phase was concentrated in vacuo and purified by column chromatography, giving the title compound as a brown oil (61.2mg; 0.14mmol).
LC/MS (ES): Found 426 (ES+), retention time 1.29 mins (2 minute run). C20H22F3N3O2S requires 425.
1 H-NMR (400MHz, CDCI3): 1.76-1.86 (4H, m), 2.28-2.38 (2H, m), 2.63-2.72 (4H, m),
3.09-3.21 (6H, m), 3.26-3.35 (2H, m), 4.36-4.45 (1 H, m), 7.24-7.31 (2H, m), 7.34-7.36.
(1 H, m).
Examples 42-44:
Figure imgf000059_0002
Typical Procedure: The title compounds reported in table 2 were prepared by parallel synthesis. In 5ml microwave tubes, to 4-(5-bromo-2,3-dihydro-1 H-inden-2-yl)morpholine (60mg, 0.212mmol) in DMSO (2.5ml) the requested monomer (HNR1 R2) (0.254mmol) was added. To the resulting solutions N,N-dimethylglycine (0.021 g, 0.207mmol), potassium carbonate (0.05Og, 0.360mmol) and copper (I) iodide (0.038 g, 0.198 mmol) were added. The resulting suspensions were heated at 1900C in a microwave reactor for 30 min, then they were filtered and the solvent removed by vacuum centrifuge overnight. The obtained crude products were dissolved in MeOH (3ml) and eluted through a 2g SCX cartridge (MeOH then 2M solution of NHg in MeOH as eluent). The solvent was then removed by blow down.
The obtained crude products were purified by preparative HPLC/MS to give the title compounds reported in table 5.
Table 5
Figure imgf000060_0001
Example 45: 1-[(2S)-2-(1,1-dioxido-2-isothiazolidinyl)-2,3-dihydro-1H-inden-5-yl]-3- hydropyrano[4,3-c]pyrazole
Figure imgf000061_0001
Under an inert atmosphere of argon, a mixture of 3-(trifluoromethyl)-1 , 4,6,7- tetrahydropyrano[4,3-c]pyrazole (Description 13, 94.4 mg, 0.49 mmol), 2-[(2S)-5-bromo- 2,3-dihydro-1 H-inden-2-yl]isothiazolidine 1 ,1-dioxide (Description 17, 150.4 mg, 0.48 mmol), Λ/,Λ/-dimethylglycine (59.7 mg, 0.58 mmol), cesium carbonate (305.5 mg, 0.94 mmol) and copper(l) oxide (74.2 mg, 0.52 mmol) in DMSO (2 ml.) was stirred under microwave heating at 190 0C for 30 minutes. The reaction was quenched with aqueous HCI (2N, 1 ml_), diluted with DCM (1 ml_), and stirred for a further 30 minutes. This mixture was partitioned between DCM (35 ml.) and water (15 ml_). The separated aqueous phase was further extracted with DCM (2x30 ml_). The combined organic phase was concentrated in vacuo. Purification by column chromatography gave the desired product (26.8 mg).
LC/MS (ES): Found 428 (ES+), retention time 1.11 mins. (2 minute method) C19H20F3N3O3S requires 427.
Example 46: 4-{5-[5-cyclopropyl-3-(difluoromethyl)-1H-pyrazol-1 -yl]-2,3-dihydro-1H- inden-2-yl}morpholine
Figure imgf000061_0002
4-(5-bromo-2,3-dihydro-1 H-inden-2-yl)morpholine (Description 18, 70 mg, 0.248 mmol) was dissolved in MeCN (3 ml). 5-cyclopropyl-3-(difluoromethyl)-1 H-pyrazole (47.1 mg, 0.298 mmol), N,N-dimethylethylendiamine (0.029 ml, 0.273 mmol), potassium carbonate (69.1 mg, 0.496 mmol) and copper(l) iodide (52.0 mg, 0.273 mmol) were added. The reaction mixture was heated by microwaves at 1900C for 30 minutes. The suspension was directly charged onto a 5g SCX cartridge (pre-conditioned with MeOH) and eluted with MeOH and then 2M solution of NH3 in MeOH. Evaporation of the solvent afforded a crude brown oil (150 mg) which was submitted to preparative HPLC/MS to give the title compound (5.4 mg).
UPLC/MS (ES): Found 360 (ES+), retention time 4.31 mins. C20H23F2N3O requires 359. Example 47: 1 -{(2/?)-5-[5-(2-pyridinyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl]-2,3- dihydro-1H-inden-2-yl}-2-pyrrolidinone
Figure imgf000062_0001
Under an inert atmosphere (Ar), a mixture of 1-[(2R)-5-bromo-2,3-dihydro-1 H-inden-2-yl]- 2-pyrrolidinone (Description 9, 404 mg, 1.443 mmol), 2-[3-(trifluoromethyl)-1 H-pyrazol-5- yl]pyridine (353 mg, 1.657 mmol), N,N-dimethylglycine (200 mg, 1.944 mmol), copper (I) oxide (253 mg, 1.768 mmol) and cesium carbonate (190 mg, 0.584 mmol) in anhydrous DMSO (6 ml) was stirred at 19O0C for 30 minutes under microwave heating conditions. Upon cooling to room temperature, the reaction was quenched with 2N HCI (4 ml_), stirred for 1 hour, and purified by SCX column chromatography. The resultant material was further purified by column chromatography (gradient elution from 100% pentane to 80:20 pentane/EtOAc and then from 100% EtOAc to 80:20 EtOAc/MeOH) giving the title compound (20 mg) as a yellow oil.
LC/MS (ES): Found 413 (ES+), retention time 1.11 mins (2 minute method). C22H19F3N4O requires 412.
Example 48: 4-{(2/?)-5-[5-(3-pyridinyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl]-2,3- dihydro-1H-inden-2-yl}morpholine, hydrochloride salt
Figure imgf000062_0002
A mixture of copper(l) oxide (101 mg, 0.709 mmol), 3-[3-(trifluoromethyl)-1 H-pyrazol-5- yl]pyridine (151 mg, 0.709 mmol), and cesium carbonate (462 mg, 1.418 mmol) in dimethyl sulfoxide (DMSO) (2ml) were stirred for 3 minutes, then 4-[(2R)-5-bromo-2,3- dihydro-1 H-inden-2-yl]morpholine (Description 1 1 , 200mg, 0.709 mmol) and N, N- dimethylglycine (73 mg, 0.709 mmol) were added. The reaction tube was sealed and the contents were heated in an microwave reactor at 18O0C for 40 minutes. The reaction mixture was diluted with ethyl acetate then filtered through a pad of kieselguhr to remove the catalyst. The organic solution was washed with water, dried with sodium sulphate and evaporated. The resultant material was purified by MDAP. The resulting material was dissolved in methanol and treated with ethereal hydrochloride. Solvent was removed to give the title compound as a HCI salt (20mg). LC/MS (ES): Found 415 (ES+), retention time 0.69 mins (2 minute method). C22H2IF3N4O requires 414.
Example 49: 4-{(2/?)-5-[5-(4-pyridinyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl]-2,3- pholine, hydrochloride salt
Figure imgf000063_0001
A mixture of copper(l) oxide (101 mg, 0.709 mmol), 4-[3-(trifluoromethyl)-1 H-pyrazol-5- yl]pyridine (151 mg, 0.709 mmol), and cesium carbonate (462 mg, 1.418 mmol) in dimethyl sulfoxide (DMSO) (2ml) were stirred for 3 minutes then 4-[(2R)-5-bromo-2,3- dihydro-1 H-inden-2-yl]morpholine (Description 1 1 , 200mg, 0.709 mmol) and N, N- dimethylglycine (73 mg, 0.709 mmol) were added. The reaction tube was sealed and the contents were heated in an microwave reactor at 18O0C for 40 minutes. The reaction mixture was diluted with ethylacetate then filtered through a pad of kieselguhr to remove the catalyst. The organic solution was washed with water, dried with sodium sulphate and evaporated. The resultant material was purified by MDAP. The resulting material was dissolved in methanol and treated with ethereal hydrochloride. Solvent was removed to give the title compound as a HCI salt (35mg).
LC/MS (ES): Found 415 (ES+), retention time 0.67 mins (2 minute method). C22H21F3N4O requires 414.
Example 50: 4-{(2/?)-5-[5-(2-pyridinyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl]-2,3- dihydro-1H-inden-2-yl}morpholine, hydrochloride salt
Figure imgf000063_0002
Under an inert atmosphere of argon, a mixture of 4-[(2R)-5-bromo-2,3-dihydro-1 H-inden- 2-yl]morpholine (Description 11 , 202 mg, 0.714 mmol), 2-[3-(trifluoromethyl)-1 H-pyrazol-5- yl]pyridine (160 mg, 0.750 mmol), N,N-dimethylglycine (90 mg, 0.875 mmol), cesium carbonate (86 mg, 0.263 mmol) and copper (I) oxide (115 mg, 0.806 mmol) in anhydrous DMSO (3.4 ml.) were stirred at 19O0C for 30 minutes under microwave heating conditions. Upon cooling to room temperature, the mixture was partitioned between water (20 ml.) and DCM (60 ml.) and the aqueous phase was extracted with DCM (2 x 60 ml_). The combined organic phase was dried and concentrated in vacuo. The resultant material was purified by column chromatography (gradient from 100% EtOAc to 90%/10% EtOAc/MeOH). This material was then purified by high pH MDAP then low pH MDAP. Further purification by SCX chromatography gave the title compound as a free base. Hydrochloric acid in Et2O (1 M) (0.7 ml_, 0.700 mmol) was added in one portion to a solution of this material in DCM (1 ml_). Concentration in vacuo gave the title compound as a HCI salt (38 mg) as a yellow solid.
LC/MS (ES): Found 415 (ES+), retention time 0.79 mins (2 minute method). C22H2IF3N4O requires 414.
Example 51 : 4-{(2S)-5-[5-(2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazol-1 -yl]-2,3- dihydro-1H-inden-2-yl}morpholine, hydrochloride salt
Figure imgf000064_0001
Under an inert atmosphere of argon, a mixture of 4-[(2S)-5-bromo-2,3-dihydro-1 H-inden- 2-yl]morpholine (Description 10, 200 mg, 0.710 mmol), 2-[3-(trifluoromethyl)-1 H-pyrazol-5- yl]pyridine (153 mg, 0.716 mmol), N,N-dimethylglycine (94 mg, 0.914 mmol), cesium carbonate (88 mg, 0.270 mmol) and copper (I) oxide (116 mg, 0.811 mmol) in anhydrous DMSO (3.4 ml.) was stirred at 19O0C for 30 minutes under microwave heating conditions. Upon cooling to room temperature, the mixture was partitioned between water (20 ml.) and DCM (60 ml.) and the aqueous phase was extracted with DCM (2 x 60 ml_). The combined organic phase was dried and concentrated in vacuo. This material was further purified by column chromatography (reverse phase) followed by SCX giving the title compound as a brown oil.
Hydrochloric acid in Et2O (1 M) (0.7 ml_, 0.700 mmol) was added in one portion to a solution of this material in DCM (1 ml_). Concentration in vacuo gave the title compound as a hydrochloride salt (68 mg) as a brown solid.
LC/MS (ES): Found 415 (ES+), retention time 0.80 mins (2 minute method). C22H21F3N4O requires 414.
Example 52: 4-{(2S)-5-[5-(6-methyl-3-pyridinyl)-3-(trifluoromethyl)-1H-pyrazol-1 -yl]- 2,3-dihydro-1H-inden-2-yl}morpholine, formate salt
Figure imgf000064_0002
To a solution of 4-[(2S)-5-bromo-2,3-dihydro-1 H-inden-2-yl]morpholine (Description 10, 200 mg, 0.709 mmol) in dimethyl sulfoxide (DMSO) (5 ml) was added 2-methyl-5-[3- (trifluoromethyl)-1 H-pyrazol-5-yl]pyridine (Description 26, 177 mg, 0.780 mmol), N, N- dimethylglycine (88 mg, 0.851 mmol), cesium carbonate (462 mg, 1.418 mmol) and copper (I) iodide (135 mg, 0.709 mmol). The reaction mixture was heated at 190 0C for 50 minutes in the microwave.
The reaction mixture was partitionned between water (20ml) and DCM (40ml). The aqueous was further extracted with DCM (40ml). The organics were combined, washed with water (20ml), dried over MgSO4 and concentrated to give a black oil which was purified by reverse phase chromatography using the MDAP to afford 20mg of a brown oil which was purified again using the MDAP. Relevant fractions were combined and concentrated to afford 4mg of the title compound as a clear oil and as the formate salt.
LC/MS (ES): Found 429 (ES+), retention time 0.70 mins (2 minute method). C23H23F3N4O requires 428.
Example 53: Λ/-{(2/?)-5-[5-(2-pyridinyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl]-2,3- dihydro-1H-inden-2-yl}-2-propanesulfonamide, hydrochloride salt
Figure imgf000065_0001
Under an inert atmosphere of argon, a mixture of 2-[3-(trifluoromethyl)-1 H-pyrazol-5- yl]pyridine (198 mg, 0.928 mmol), Λ/-[(2R)-5-bromo-2,3-dihydro-1 H-inden-2-yl]-2- propanesulfonamide (Description 6, 31 1 mg, 0.978 mmol), N,N-dimethylglycine (122 mg, 1.187 mmol), cesium carbonate (124 mg, 0.379 mmol) and copper (I) oxide (148 mg, 1.032 mmol) in anhydrous DMSO (4 ml.) was stirred for 30 minutes under microwave conditions. Upon cooling to room temperature, the mixture was partitioned between DCM (45ml_) and water (15 ml.) and the aqueous phase was extracted with DCM (2 x 45ml_). The combined organic phase was dried (Na2SO4) and concentrated in vacuo giving a green oil. The mixture was further purified by SCX followed by MDAP twice giving the title compound as a white solid. HCI in ether (2 ml, 2.000 mmol) was added to this material in DCM (1 ml). Concentration in vacuo gave the title compound as a yellow oil (24 mg).
LC/MS (ES): Found 451 (ES+), retention time 1.12 mins (2 minute method). C2IH21F3N4O2S requires 450.
Example 54: Λ/-{(2S)-5-[5-(2-pyridinyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl]-2,3- dihydro-1H-inden-2-yl}-2-propanesulfonamide, hydrochloride salt
Figure imgf000066_0001
Under an inert atmosphere of argon, a mixture of 2-[3-(trifluoromethyl)-1 H-pyrazol-5- yl]pyridine (205 mg, 0.961 mmol), Λ/-[(2S)-5-bromo-2,3-dihydro-1 H-inden-2-yl]-2- propanesulfonamide (Description 5, 307 mg, 0.966 mmol), N,N-dimethylglycine (125 mg, 1.21 1 mmol), cesium carbonate (128 mg, 0.394 mmol) and copper (I) oxide (154 mg, 1.074 mmol) in anhydrous DMSO (4 ml.) was stirred at 19O0C for 30 minutes under microwave conditions. Upon cooling to room temperature, the mixture was partitioned between DCM (45ml_) and water (15 ml.) and the aqueous phase was extracted with DCM (2 x 45ml_). The combined organic phase was dried (Na2SO4) and concentrated in vacuo giving a green oil. The mixture was purified by reverse phase column chromatography, MDAP and column chromatography on silica giving the title compound as a colourless oil.
HCI in ether (2 ml_, 2.000 mmol) was added to this material in dichloromethane (DCM) (1 ml_). Concentration in vacuo gave the title compound as an HCI salt as a white solid (75 mg).
LC/MS (ES): Found 451 (ES+), retention time 1.12 mins (2 minute method). C21H21 F3N4O2S requires 450.
Example 55: 1 -{(2/?)-5-[5-(6-methyl-3-pyridinyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl]- 2,3-dihydro-1H-inden-2-yl}-2-pyrrolidinone
Figure imgf000066_0002
To a solution of 1-[(2/?)-5-bromo-2,3-dihydro-1 H-inden-2-yl]-2-pyrrolidinone (Description 9, 130 mg, 0.464 mmol) in dimethyl sulfoxide (DMSO) (3 ml) was added 2-methyl-5-[3- (trifluoromethyl)-1 H-pyrazol-5-yl]pyridine (116 mg, 0.510 mmol), N,N-dimethylglycine (57.4 mg, 0.557 mmol), cesium carbonate (302 mg, 0.928 mmol) and copper(l) oxide (66.4 mg, 0.464 mmol). The reaction mixture was heated at 130 0C for 3 days. The reaction mixture was further heated at 150 0C over the weekend. The reaction mixture was partitionned between water (30ml) and DCM (30ml). The aqueous was further extracted with EtOAc (30ml). Organics were combined, dried over MgSO4 and concentrated to give a black oil which was purified by reverse phase chromatography using the MDAP. Relevant fractions were combined and concentrated to afford 2mg of the title compound. LC/MS (ES): Found 427 (ES+), retention time 0.96 mins (2 minute method). C23H2IF3N4O requires 426.
Example 56: 1 -{(2/?)-5-[5-(4-pyridinyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl]-2,3- dihydro-1H-inden-2-yl}-2 -pyrrolidinone, hydrochloride salt
Figure imgf000067_0001
Under an inert atmosphere of argon, a mixture of 4-[3-(trifluoromethyl)-1 H-pyrazol-5- yl]pyridine (201 mg, 0.945 mmol), 1-[(2R)-5-bromo-2,3-dihydro-1 H-inden-2-yl]-2- pyrrolidinone (Description 9, 276 mg, 0.984 mmol), N,N-dimethylglycine (120 mg, 1.166 mmol), cesium carbonate (631 mg, 1.937 mmol) and copper (I) oxide (153 mg, 1.067 mmol) in anhydrous DMSO (4 ml.) was stirred at 130 0C for 19 hours. More 1-[(2R)-5- bromo-2,3-dihydro-1 H-inden-2-yl]-2-pyrrolidinone (Description 9, 264 mg, 0.941 mmol) was added and the mixture stirred for a further 28.5 hours. Upon cooling to room temperature, the mixture was partitioned between DCM (45ml_) and water (15 ml.) and the aqueous phase was extracted with DCM (2x45ml_). The combined organic phase was dried (Na2SO4) and concentrated in vacuo giving a black oil. This was purified by MDAP followed by SCX, high pH MDAP and SCX giving the title compound as a brown oil. HCI in ether (0.2 ml_, 0.200 mmol) was added in one portion to a stirring mixture of this material in DCM (1 ml_). Concentration in vacuo gave the title compound as the hydrochloride salt (19 mg) as a beige solid.
LC/MS (ES): Found 413 (ES+), retention time 0.92 mins (2 minute method). C22H19F3N4O requires 412.
Example 57: 1 -{(2/?)-5-[5-(3-pyridinyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl]-2,3- dihydro-1H-inden-2-yl}-2 -pyrrolidinone, hydrochloride salt
A mixture of 3-[3-(trifluoromethyl)-1 H-pyrazol-5-yl]pyridine (152 mg, 0.714 mmol), copper (I) oxide (102 mg, 0.714 mmol) and Cs2CO3 (465 mg, 1.428 mmol) in anhydrous DMSO (2 ml) was stirred for 5 minutes, then 1-[(2R)-5-bromo-2,3-dihydro-1 H-inden-2-yl]-2- pyrrolidinone (Description 9, 200 mg, 0.714 mmol) and N,N-dimethylglycine (73.6 mg, 0.714 mmol) were added. The resulting mixture was heated at 13O0C for 36 hours with stirring, then the reaction mixture was diluted with ethyl acetate and filtered through kieselguhr to remove the catalyst. The filtrate was washed with water, dried over sodium sulphate, filtered and evaporated. This material was purified by MDAP. The resultant material was partitioned between dichloromethane and aqueous sodium hydrogen carbonate solution. The organic phase was dried over sodium sulphate, filtered and evaporated in vacuo to give the product as a free base. The free base was dissolved in methanol and treated with ethereal hydrochloride. Solvent was removed to give the title compound (121 mg) as a HCI salt.
LC/MS (ES): Found 413 (ES+), retention time 2.39 mins. C22H19F3N4O requires 412.
Analytical chromatographic conditions for Descriptions 10, 11, and 14
Coloumn: Acquity UPLC BEH C18, 2.1 x 50 mm, 1.7 urn. Mobile phase : A: Water + 0.1 % formic acid, B: CH3CN + 0.06 % formic acid
Gradient: 3% to 6% (B) in 0.1 min., 6% to 70% (B) in 0.5 min., 70%
(B) to 99% (B) in 0.5 min, 99% to 3% (B) in 0.35min.
Flow rate: 1 ml/min
UV range: 210-350 nm Ionization: ES+
Mass range: 100-900 amu
Analytical chromatographic conditions for Example compounds in Table 1 and Example 46 Column: Gemini C18, 50 x 4.6 mm, 5 urn
Mobile phase: A: NH4HCO3 sol. 10 mM, pH10; B: CH3CN
Gradient: 35% (B) for 0.5 min, 35% (B) ^ 95% (B) in 4.5 min, 95% (B) for 1.5 min Flow rate: 2 ml/min UV range: 210-350 nm
Ionization: ES+/ES-
Mass range: 100-900 amu
Conditions for Examples 39, 45, 47and Description 15 Column: Waters Acquity BEH UPLC C18, 2.1 mm x 50mm. The stationary phase particle size is 1.7μ m. Solvents: A : Aqueous solvent = Water + 0.05% Formic Acid
B : Organic solvent = Acetonitrile + 0.05% Formic Acid Weak Wash = 1 :1 Methanol : Water Strong Wash = Water
Method: The generic method used has a 2 minute runtime.
Figure imgf000069_0001
Flow rate: 1 ml/min Injection volume: 0.5ul Column temperature: 40 degC UV wavelength range: 220-330 nm
Analytical chromatographic conditions for compounds reported in table 5
Column: Acquity UPLC™ BEH C18, 2.1 x 50 mm, 1.7 μm.
Mobile phase : A: 1OmM NH4HCO3ZNH3, B: CH3CN
Gradient: 3% to 99%(B) in 1.06 min., 99% to 3% (B) in 0.39 min., 99% (B) for 0.05 min
Stop time: 1.50 ml/min
Flow rate: 1 ml/min
Column temperature: 4O0C
UV range: 210-350 nm
ELSD gas Pressure: 35psi
ELSD drift tube temperature: 550C
Ionization: ES+/ES-
Mass Range: 100-1000 amu (ES+), 100-900 amu (ES-)
Formic Acid Generic Analytical UPLC Open Access LC/MS
2 Minute Method (used for Descriptions 25 and 26 and Examples 48-56)
The UPLC analysis was conducted on an Acquity UPLC BEH C18 column (2.1 mm x
50mm i.d. 1.7μm packing diameter) at 40 degrees centigrade.
The solvents employed were:
A = 0.1% v/v solution of Formic Acid in Water.
B = 0.1% v/v solution of Formic Acid in Acetonitrile.
The gradient employed was:
Figure imgf000069_0002
The UV detection was an averaged signal from wavelength of 210nm to 350nm and mass spectra were recorded on a mass spectrometer using alternate-scan positive and negative mode electrospray ionization.
Formic Acid Generic Analytical HPLC Open Access LC/MS 5 Minute Method (used for Example 57)
The HPLC analysis was conducted on a Sunfire C18 column (30mm x 4.6mm i.d. 3.5μm packing diameter) at 30 degrees centigrade.
The solvents employed were:
A = 0.1% v/v solution of Formic Acid in Water.
B = 0.1% v/v solution of Formic Acid in Acetonitrile.
The gradient employed was:
Figure imgf000070_0001
The UV detection was an averaged signal from wavelength of 210nm to 350nm and mass spectra were recorded on a mass spectrometer using alternate-scan positive and negative mode electrospray ionization.
Preparative chromatographic conditions MDAP FractionLynx Autopurification System™ for example 42 reported in table 5
Column: Gemini C18 AXIA, 50 x 21 mm, 5 μm
Mobile phase: A: NH4HCO3 sol. 10 mM, pH10; B: CH3CN
Gradient: 30% to 35% (B) in 1 min, 35% to 65% (B) in 7 min, 65% to 100% (B) in 1 min,
100% (B) for 2.5 min
Flow rate: 17 ml/min
UV range: 210-350 nm
Ionization: ES+
Mass range: 100-900 amu
Preparative chromatographic conditions (MDAP FractionLynx Autopurification System™) for example 43 and 44 reported in table 5 Column: Gemini C18 AXIA, 50 x 21 mm, 5 μm Mobile phase: A: NH4HCO3 sol. 10 mM, pH 10; B: CH3CN
Gradient 1 *: 30% to 35% (B) in 1 min, 35% to 65% (B) in 7 min, 65% to 100% (B) in 1 min, 100% (B) for 2 min Gradient 2**:40% to 45% (B) in 1 min, 45% to 80% (B) in 7 min, 80% to 100% (B) in 1 min, 100% (B) for 2 min Flow rate: 17 ml/min UV range: 210-350 nm Ionization: ES+ Mass range: 100-900 amu
* Gradient 1 used for example 43 ** Gradient 2 used for example 44
Preparative chromatographic conditions (MDAP FractionLynx Autopurification System™) for example 46
Column: Gemini C18 AXIA, 50 x 21 mm, 5 μm
Mobile phase: A: NH4HCO3 sol. 10 mM, pH 10; B: CH3CN Gradient: 35% (B) for 1 min, 35% to 50% (B) in 9 min, 50% to 100% (B) in 0.1 min,
100% (B) for 1.9 min
Flow rate: 17 ml/min
UV range: 210-350 nm
Ionization: ES+ Mass range: 100-900 amu
LC/MS conditions for all other intermediates and Examples
Column: Waters Atlantis, 4.6mm x 50mm. The stationary phase particle size is 3um. Solvents: A : Aqueous solvent = Water + 0.05% Formic Acid; B : Organic solvent = Acetonitrile + 0.05% Formic Acid Methods: The generic method used has a 5 minute runtime.
Time / min %B
0 3
0.1 3
4 97
4.8 97
4.9 3 5.0 3
Flow rate: 3ml/min Injection volume: 5ul
Column temperature: 30 degC UV wavelength range: 220-330 nm
MDAP conditions
Typical conditions used are exemplified by:
Column: Waters Atlantis, 19mm x 100mm (small scale) and 30mm x 100mm
(large scale). Stationary phase particle size = 5um. Solvents: A : Aqueous solvent = Water + 0.1% Formic Acid; B : Organic solvent = Acetonitrile + 0.1% Formic Acid. Make up solvent = Methanol : Water 80:20. Needle rinse solvent = Methanol Methods: There are five methods used depending on the analytical retention time of the compound of interest. They have a 13.5-minute runtime, which comprises of a 10-minute gradient followed by a 3.5 minute column flush and re-equilibration step. Large/Small Scale 1.0-1.5 = 5-30% B Large/Small Scale 1.5-2.2 = 15-55% B Large/Small Scale 2.2-2.9 = 30-85% B Large/Small Scale 2.9-3.6 = 50-99% B
Large/Small Scale 3.6-5.0 = 80-99% B (in 6 minutes followed by 7.5 minutes flush and re-equilibration) Flow rate: 20mls/min (Small Scale) or 40mls/min (Large Scale).
High pH - as above, except for
Column
The column used is Waters X-bridge, the dimensions of which are 30mm x
100mm. The stationary phase particle size is 5μm.
Solvents
A : Aqueous solvent = 1OmM Ammonium Bicarbonate solution adjusted to pH 10 with ammonia solution.
B : Organic solvent = Acetonitrile. Make up solvent = Methanol : Water 80:20
Needle rinse solvent = Methanol
The ability of the compounds of the invention to potentiate AMPA receptor-mediated response may be determined by using fluorescent calcium-indicator dyes such as FLUO4. In the assays used and described herein, the compounds of the present invention were not necessarily from the same batch described above. A test compound from one batch may have been combined with other batch(es) for the assay(s). Calcium Influx Fluorescence Assay 1
384 well plates are prepared containing confluent monolayer of HEK 293 cells either stably expressing or transiently transfected with human GluR2 flip (unedited) AMPA receptor subunit. These cells form functional homotetrameric AMPA receptors. The tissue culture medium in the wells are discarded and the wells are each washed three times with standard buffer (80 μl_) for the stable cell line (145 mM NaCI, 5 mM KCI, 1 mM MgCI2, 2 mM CaCI2, 20 mM N-[2-hydroxyethyl]-piperazine-N-[2-ethanesulfonic acid (HEPES), 5.5 mM glucose, pH 7.3) or with a Na-free buffer for the transient transfected cells (145 mM N-methyl-glucamine instead of NaCI). The plates are then incubated for 60 minutes in the dark with 2 μM FLUO4-AM dye (20 μl_) (Molecular Probes, Netherlands) at room temperature to allow cell uptake of the FLUO-4AM, which is then converted to FLUO-4 by intracellular esterases which is unable to leave the cell. After incubation each well is washed three times with buffer (80 μl_) (30 μl_ of buffer remained in each well after washing).
Compounds of the invention (or the reference compound, cyclothiazide) are dissolved in dimethylsulfoxide (DMSO) at a stock concentration of 10 mM. These solutions are further diluted with DMSO using a Biomek FX (Beckman Coulter) in a 384 compound plate. Each dilution (1 μl_) is transferred to another compound plate and buffer (50 μl_) is added. An agonist stimulus (glutamate) plate is prepared by dissolving sodium glutamate in water to give a concentration of 100 mM. This solution is diluted with buffer to give a final concentration of 500 μM and dispensed into another 384-well plate (50μl_/well) using a Multidrop (Thermolabsystems).
The cell plate is then transferred into a fluorescence imaging plate based reader [such as the FLIPR384 (Molecular Devices)]. A baseline fluorescence reading is taken over a 10 to 240 second period, and then 10 μL from each plate containing a compound of the invention made up in standard buffer solution (in a concentration range from 100 μM to 10 pM) is added (to give a final concentration in the range 30 μM to 3 pM). The fluorescence is read over 5 minute period. 500 μM glutamate solution (10μl_) is added (to give a final concentration of 100 μM). The fluorescence is then read over a 4 minute period. The activities of the compounds of the invention and reference compounds are determined by measuring peak fluorescence after the last addition. The activity is also expressed relative to the fluorescence increase induced by cyclothiazide at their maximum response (i.e. greater than 30 μM).
Calcium Influx Fluorescence Assay 2
384 well plates are prepared containing confluent monolayer of HEK 293 cells stably expressing human GluR2 flip (unedited) AMPA receptor subunit. On the day of the experiment, culture medium are discarded and the cells washed three times with standard buffer (145 mM NaCI, 5 mM KCI, 1 mM MgCI2, 2 mM CaCI2, 20 mM N-[2-hydroxyethyl]-piperazine-N-[2-ethanesulfonic acid (HEPES), 5.5 mM glucose, pH 7.3) and 20 μl_ of buffer remained in each well after washing. The plates are then incubated at room temperature for 60 minutes in the dark with 2 μM FLUO-4AM dye to allow cell uptake of the FLUO-4AM, which is then converted to FLUO-4 by intracellular esterases which is unable to leave the cells. After incubation cells are washed three times with buffer and 30 μl_ of buffer remained in each well after washing. Compounds of the invention are tested in a final assay concentration range from 100 μM to 1 nM.
Compounds of the invention (or the reference compound, cyclothiazide) are dissolved in dimethylsulfoxide (DMSO) at a stock concentration of 10 mM. These solutions are further diluted with DMSO in a 384 compound plate and 1 μl_ of each dilution is transferred to another compound plate. Just prior compounds addition to the cells, 50 μl_ buffer is added to the 1 μl_ compound copy plate. An agonist stimulus 384-well plate containing 50μl_/well of 500 μM glutamate is prepared by diluting with buffer a 100 mM sodium glutamate stock solution prepared in water.
10 μL from each plate containing a compound of the invention made up in buffer solution is added and incubated with the loaded cells for 10 minute in the dark at room temperature.
The cell plate is then transferred into a fluorescence imaging plate based reader (such as the FLIPR384 - Molecular Devices). A baseline fluorescence reading is taken over a 5 to 10 second period, and then 10 μL of 500 μM glutamate solution is added (to give a final concentration of 100 μM). The fluorescence is then read over a 4-5 minute period.
The activities of the compounds of the invention and reference compounds are determined by measuring peak fluorescence after the last addition. The activity is also expressed relative to the fluorescence increase induced by 150μM cyclothiazide at their maximum response.
The assay described above is believed to have an effective limit of detection of a pEC50 in the region of 3.5-4.0 due to the limitations of compound solubility. The pEC5o result is generally considered to be accurate +/- 0.3.
Calcium Influx Fluorescence Assay 3
This is carried out in a similar manner as Assay 2 above, except that: a) the compounds of the invention are tested in a final assay concentration range from 50 μM to 50 nM; b) 50 μL pluronic buffer (standard buffer with 0.05% pluronic-F127 acid) is added to the 1 μL compound copy plate; c) an agonist stimulus 384-well plate containing 50μl_/well of 500 μM glutamate is prepared by diluting with pluronic buffer (standard buffer with 0.05% pluronic-F127 acid) a 100 mM sodium glutamate stock solution prepared in water; d) the reference compound is: Λ/-[(2/?)-2-(4'-cyano-4-biphenylyl)propyl]-2- propanesulfonamide.
All the Example compounds were screened using at least one of the assays described above and gave an average pEC50 equal to or greater than 3.5 and/or demonstrated an activity of on average at least 20% that of the reference compound (at its maximal response).

Claims

Claims
1. A compound of formula (I) or a salt thereof:
Figure imgf000076_0001
(I) wherein:
• A is selected from CF3 and CHF2;
• R1 is selected from cyclopropyl and pyridyl and R2 is hydrogen; or R1 and R2 join together to form a 5- or 6-membered non-aromatic ring, wherein one of the carbon atoms in the ring is optionally replaced by an oxygen atom, NH or NCH3 ; • R is selected from the group consisting of:
(a) a 5- or 6-membered aromatic or non-aromatic heterocyclic ring, optionally substituted with one, two or three groups selected from C1-4alkyl, C(O)C1-4alkyl, haloC1-4alkyl, halo, hydroxy and oxo; and
(b) NH2, NR3SO2R4, NR3C(O)R4 and OR4 in which • R3 is selected from hydrogen and C1-4alkyl;
• R4 is selected from C1-6alkyl, haloC1-6alkyl, C3-6cycloalkyl, haloC3-6cycloalkyl, - (CH2)pZ (where p is 1 , 2 or 3 and Z is a phenyl or a 5- or 6-membered aromatic or non-aromatic heterocyclic ring, the phenyl or the heterocyclic ring being optionally substituted with one or more groups selected from halo and Ci-4alkyl) and -(CH2)qNR5R6 (wherein q is 0, 1 or 2 and R5 and R6 are independently C1-6alkyl); or
• R3 and R4, together with the NC(O) or NSO2 group to which they are attached, form a 5- or 6-membered non-aromatic heterocyclic ring, either of which may include one or more further heteroatoms selected from N, O or S, and may be substituted with one or more groups selected from C1-4alkyl, C(O)C1-4alkyl, halo,
Figure imgf000076_0002
hydroxy and oxo.
2. A compound as claimed in claim 1 , which is:
Λ/-{(2S)-5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1-yl]-2,3-dihydro-1 H-inden-2- yl}-2-propanesulfonamide
Racemic 1 -{5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1 -yl]-2,3-dihydro-1 H- inden-2-yl}-2-pyrrolidinone
1-{(2S)-5-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1 H-indazol-1 -yl]-2,3-dihydro-1 H-inden-2- yl}-2-pyrrolidinone 1-{(2R)-5-[3-(trifluoromethyl)-4!5!6!7-tetrahydro-1H-indazol-1-yl]-2,3-dihydro-1 H-inden-2- yl}-2-pyrrolidinone
1-[(2R)-2-(4-morpholinyl)-2!3-dihydro-1 H-inden-5-yl]-3-(trifluoromethyl)-4!5!6,7-tetrahydro-
1 H-indazole 1-[(2S)-2-(4-morpholinyl)-2!3-dihydro-1 H-inden-5-yl]-3-(trifluoromethyl)-4!5!6,7-tetrahydro-
1 H-indazole
N-{(2R)-5-[3-(trifluoromethyl)-4!7-dihydropyrano[3!4-c]pyrazol-1 (5H)-yl]-2,3-dihydro-1 H- inden-2-yl}-2-propanesulfonamide
N-{(2S)-5-[3-(trifluoromethyl)-4!7-dihydropyrano[3!4-c]pyrazol-1 (5H)-yl]-2,3-dihydro-1 H- inden-2-yl}-2-propanesulfonamide
1-[(2R)-2-(4-morpholinyl)-2,3-dihydro-1 H-inden-5-yl]-3-(trifluoromethyl)-1 , 4,5,7- tetrahydropyrano[3,4-c]pyrazole
1-[(2S)-2-(4-morpholinyl)-2,3-dihydro-1 H-inden-5-yl]-3-(trifluoromethyl)-1 ,4,5,7- tetrahydropyrano[3,4-c]pyrazole 1-{(2R)-5-[3-(trifluoromethyl)-4,7-dihydropyrano[3,4-c]pyrazol-1 (5H)-yl]-2,3-dihydro-1 H- inden-2-yl}-2-pyrrolidinone
1-{(2S)-5-[3-(trifluoromethyl)-4,7-dihydropyrano[3,4-c]pyrazol-1 (5H)-yl]-2,3-dihydro-1 H- inden-2-yl}-2-pyrrolidinone
N-{(2R)-5-[3-(trifluoromethyl)-6,7-dihydropyrano[4,3-c]pyrazol-1 (4H)-yl]-2,3-dihydro-1 H- inden-2-yl}-2-propanesulfonamide
N-{(2S)-5-[3-(trifluoromethyl)-6,7-dihydropyrano[4,3-c]pyrazol-1 (4H)-yl]-2,3-dihydro-1 H- inden-2-yl}-2-propanesulfonamide
1-[(2R)-2-(4-morpholinyl)-2,3-dihydro-1 H-inden-5-yl]-3-(trifluoromethyl)-1 , 4,6,7- tetrahydropyrano[4,3-c]pyrazole 1-[(2S)-2-(4-morpholinyl)-2,3-dihydro-1 H-inden-5-yl]-3-(trifluoromethyl)-1 ,4,6,7- tetrahydropyrano[4,3-c]pyrazole
1-{(2R)-5-[3-(trifluoromethyl)-6,7-dihydropyrano[4,3-c]pyrazol-1 (4H)-yl]-2,3-dihydro-1 H- inden-2-yl}-2-pyrrolidinone
1-{(2S)-5-[3-(trifluoromethyl)-6,7-dihydropyrano[4,3-c]pyrazol-1 (4H)-yl]-2,3-dihydro-1 H- inden-2-yl}-2-pyrrolidinone
N-{(2R)-5-[5-cyclopropyl-3-(trifluoromethyl)-1 H-pyrazol-1 -yl]-2,3-dihydro-1 H-inden-2-yl}-2- propanesulfonamide
N-{(2S)-5-[5-cyclopropyl-3-(trifluoromethyl)-1 H-pyrazol-1 -yl]-2,3-dihydro-1 H-inden-2-yl}-2- propanesulfonamide 4-{(2R)-5-[5-cyclopropyl-3-(trifluoromethyl)-1 H-pyrazol-1 -yl]-2,3-dihydro-1 H-inden-2- yl}morpholine
4-{(2S)-5-[5-cyclopropyl-3-(trifluoromethyl)-1 H-pyrazol-1 -yl]-2,3-dihydro-1 H-inden-2- yl}morpholine
1-{(2R)-5-[5-cyclopropyl-3-(trifluoromethyl)-1 H-pyrazol-1 -yl]-2,3-dihydro-1 H-inden-2-yl}-2- pyrrolidinone
1-{(2S)-5-[5-cyclopropyl-3-(trifluoromethyl)-1 H-pyrazol-1 -yl]-2,3-dihydro-1 H-inden-2-yl}-2- pyrrolidinone 2R)-5-[3-(trifluoromethyl)-4!5!6,7-tetrahydro-1 H-indazol-1 -yl]-2,3-dihydro-1 H-inden-2- amine
(2RS)-5-[3-(trifluoromethyl)-4!5!6,7-tetrahydro-1 H-indazol-1 -yl]-2,3-dihydro-1 H-inden-2- amine N2!N2-dimethyl-N1-{(2RS)-5-[3-(trifluoromethyl)-4!5!6,7-tetrahydro-1 H-indazol-1-yl]-2!3- dihydro-1 H-inden-2-yl}glycinamide
N-{(2R)-5-[3-(trifluoromethyl)-4!5!6,7-tetrahydro-1 H-indazol-1 -yl]-2,3-dihydro-1 H-inden-2- yl}-2-propanesulfonamide
1-[(2RS)-2-(1 ,1-dioxido-2-isothiazolidinyl)-2,3-dihydro-1 H-inden-5-yl]-3-(trifluoromethyl)- 4,5,6,7-tetrahydro-1 H-indazole
N-{(2RS)-5-[3-(trifluoromethyl)-4!5!6,7-tetrahydro-1 H-indazol-1 -yl]-2,3-dihydro-1 H-inden-2- yl}acetamide
N-{(2RS)-5-[3-(trifluoromethyl)-4!5!6,7-tetrahydro-1 H-indazol-1 -yl]-2,3-dihydro-1 H-inden-2- yl}methanesulfonamide N!N-dimethyl-N'-{(2-RS)-5-[3-(trifluoromethyl)-4!5!6,7-tetrahydro-1 H-indazol-1-yl]-2!3- dihydro-1 H-inden-2-yl}urea
1-[(2RS)-2-(1-piperidinyl)-2!3-dihydro-1 H-inden-5-yl]-3-(trifluoromethyl)-4!5!6,7-tetrahydro-
1 H-indazole
1-[(2RS)-2-(4-morpholinyl)-2!3-dihydro-1 H-inden-5-yl]-3-(trifluoromethyl)-4!5!6,7- tetrahydro-1 H-indazole
N-{(2RS)-5-[3-(trifluoromethyl)-6!7-dihydropyrano[4!3-c]pyrazol-1 (4H)-yl]-2,3-dihydro-1 H- inden-2-yl}acetamide
N-{(2RS)-5-[3-(trifluoromethyl)-6!7-dihydropyrano[4!3-c]pyrazol-1 (4H)-yl]-2,3-dihydro-1 H- inden-2-yl}methanesulfonamide 1-[(2RS)-2-(1 ,1-dioxido-2-isothiazolidinyl)-2,3-dihydro-1 H-inden-5-yl]-3-(trifluoromethyl)-
1 ,4,6,7-tetrahydropyrano[4,3-c]pyrazole
1-[(2R)-2-(1 ,1-dioxido-2-isothiazolidinyl)-2,3-dihydro-1 H-inden-5-yl]-3-(trifluoromethyl)-
4,5,6,7-tetrahydro-1 H-indazole
1-{(2R)-5-[6-methyl-3-(trifluoromethyl)-4!5!6!7-tetrahydro-1 H-pyrazolo[3,4-c]pyridin-1-yl]- 2,3-dihydro-i H-inden-2-yl}-2-pyrrolidinone
1-[(2S)-2-(1 ,1-dioxido-2-isothiazolidinyl)-2,3-dihydro-1 H-inden-5-yl]-3-(trifluoromethyl)-
4,5,6,7-tetrahydro-1 H-indazole
4-{5-[5-(2-pyridinyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl]-2,3-dihydro-1 H-inden-2- yl}morpholine 1-[(2S)-2-(4-morpholinyl)-2!3-dihydro-1 H-inden-5-yl]-3-(trifluoromethyl)-4,5!6,7-tetrahydro-
1 H-indazole
3-(difluoromethyl)-1 -[2-(4-morpholinyl)-2,3-dihydro-1 H-inden-5-yl]-4,5,6,7-tetrahydro-1 H- indazole
1-[(2S)-2-(1 ,1-dioxido-2-isothiazolidinyl)-2,3-dihydro-1 H-inden-5-yl]-3-(trifluoromethyl)- 1 ,4,6,7-tetrahydropyrano[4,3-c]pyrazole
4-{5-[5-cyclopropyl-3-(difluoromethyl)-1 H-pyrazol-1 -yl]-2,3-dihydro-1 H-inden-2- yl}morpholine 1-{(2R)-5-[5-(2-pyridinyl)-3-(trifluoromethyl)-1 H-pyrazol-1-yl]-2,3-dihydro-1 H-inden-2-yl}-2- pyrrolidinone
4-{(2R)-5-[5-(3-pyridinyl)-3-(trifluoromethyl)-1 H-pyrazol-1-yl]-2!3-dihydro-1 H-inden-2- yl}morpholine 4-{(2R)-5-[5-(4-pyridinyl)-3-(trifluoromethyl)-1 H-pyrazol-1-yl]-2,3-dihydro-1 H-inden-2- yl}morpholine
4-{(2R)-5-[5-(2-pyridinyl)-3-(trifluoromethyl)-1 H-pyrazol-1-yl]-2,3-dihydro-1 H-inden-2- yl}morpholine
4-{(2S)-5-[5-(2-pyridinyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl]-2,3-dihydro-1 H-inden-2- yl}morpholine
4-{(2S)-5-[5-(6-methyl-3-pyridinyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl]-2,3-dihydro-1 H- inden-2-yl}morpholine
N-{(2R)-5-[5-(2-pyridinyl)-3-(trifluoromethyl)-1 H-pyrazol-1-yl]-2,3-dihydro-1 H-inden-2-yl}-2- propanesulfonamide N-{(2S)-5-[5-(2-pyridinyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl]-2,3-dihydro-1 H-inden-2-yl}-2- propanesulfonamide
1 -{(2R)-5-[5-(6-methyl-3-pyridinyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl]-2,3-dihydro-1 H- inden-2-yl}-2-pyrrolidinone
1-{(2R)-5-[5-(4-pyridinyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl]-2,3-dihydro-1 H-inden-2-yl}-2- pyrrolidinone
1-{(2R)-5-[5-(3-pyridinyl)-3-(trifluoromethyl)-1 H-pyrazol-1 -yl]-2,3-dihydro-1 H-inden-2-yl}-2- pyrrolidinone or a salt thereof.
3. A compound as claimed in claim 1 or claim 2 for use in medicine.
4. A compound as claimed in claim 1 or claim 2 for use in treating a disease or condition mediated by a reduction or imbalance in glutamate receptor function in a mammal.
5. A compound as claimed in claim 4, wherein the disease or condition is schizophrenia or impairment of cognition.
6. A pharmaceutical composition comprising a compound as claimed in claim 1 or claim 2 and at least one carrier, diluent or excipient.
7. Use of a compound as claimed in claim 1 or claim 2 in the manufacture of a medicament for treating a disease or condition mediated by a reduction or imbalance in glutamate receptor function in a mammal.
8. The use as claimed in claim 7, wherein the disease or condition is schizophrenia or impairment of cognition.
9. A method of treatment of a disease or condition mediated by a reduction or imbalance in glutamate receptor function in a mammal comprising administering an effective amount of a compound as claimed in claim 1 or claim 2.
10. The method as claimed in claim 9, wherein the disease or condition is schizophrenia or impairment of cognition.
11. A combination product comprising a compound as claimed in claim 1 or claim 2 with an antipsychotic.
PCT/EP2008/053194 2007-03-20 2008-03-18 Compounds which potentiate ampa receptor and uses thereof in medicine WO2008113795A1 (en)

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