WO2007108742A1 - Novel tetralins as 5-ht6 modulators - Google Patents

Novel tetralins as 5-ht6 modulators Download PDF

Info

Publication number
WO2007108742A1
WO2007108742A1 PCT/SE2007/000252 SE2007000252W WO2007108742A1 WO 2007108742 A1 WO2007108742 A1 WO 2007108742A1 SE 2007000252 W SE2007000252 W SE 2007000252W WO 2007108742 A1 WO2007108742 A1 WO 2007108742A1
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
tetrahydronaphthalen
methylpiperazin
alkyl
benzenesulfonamide
Prior art date
Application number
PCT/SE2007/000252
Other languages
French (fr)
Inventor
Lilian Alcaraz
Gunnar Nordvall
Didier Rotticci
Daniel Sohn
Original Assignee
Astrazeneca Ab
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Astrazeneca Ab filed Critical Astrazeneca Ab
Priority to JP2009500324A priority Critical patent/JP2009533325A/en
Priority to US12/293,176 priority patent/US20090054453A1/en
Priority to EP07716065A priority patent/EP1999121A1/en
Publication of WO2007108742A1 publication Critical patent/WO2007108742A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/65—One oxygen atom attached in position 3 or 5
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/12—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/14—Thiadiazoles; Hydrogenated thiadiazoles condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/15—Six-membered rings
    • C07D285/16—Thiadiazines; Hydrogenated thiadiazines
    • C07D285/18—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines
    • C07D285/20—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems
    • C07D285/22—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D285/24—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with oxygen atoms directly attached to the ring sulfur atom
    • C07D285/26—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with oxygen atoms directly attached to the ring sulfur atom substituted in position 6 or 7 by sulfamoyl or substituted sulfamoyl radicals
    • C07D285/28—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with oxygen atoms directly attached to the ring sulfur atom substituted in position 6 or 7 by sulfamoyl or substituted sulfamoyl radicals with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
    • C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D319/18—Ethylenedioxybenzenes, not substituted on the hetero ring
    • 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
    • C07D417/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to new compounds, to pharmaceutical formulations containing said compounds and to the use of said compounds in therapy.
  • the present invention further relates to processes for the preparation of said compounds and to new intermediates useful in the preparation thereof.
  • Serotonin (5-hydroxy-try ⁇ tamine) (5-HT) receptors play an important role in many physiological and pathological functions like anxiety, sleep regulation, aggression, feeding and depression.
  • the 5-HT receptors are distributed throughout the body and can be divided into seven different 5-HT receptor subtypes, i.e. 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5- HT6, and 5-HT7, with different properties.
  • the 5-HT6 receptor is mostly found in the central nervous system (CNS).
  • 5-HT6 antagonists increase levels of glutamate and aspartate in the frontal cortex and dorsal hippocampus as well as acetylcholine in the frontal cortex. These neurochemicals are known to be involved in memory and cognition (Dawson et al., Neuropsychopharmacology., 25(5), p 662-668, 2001) (Gerard et al., Brain Res., 746, p 207-219, 1997) (Riemer et al J Med Chem 46(7), p 1273-1276, 2003).
  • Acetylcholinesterase inhibitors increase the levels of acetylcholine in the CNS and are used in the treatment of cognitive disorders such as Alzheimer's disease. 5-HT6 antagonists may therefore be used in the treatment of cognitive disorders.
  • 5-HT6 antagonist increases the level of dopamine and noradrenaline in the medial prefrontal cortex suggesting a role for 5-HT6 ligands in cognitive aspects of schizophrenia.
  • Several antidepressants and atypical antipsychotics bind to the 5-HT6 receptor and this may be a factor in their profile of activities (Roth et al., J. Pharm. Exp. Therapeut, 268, 1402-1420, 1994; Sleight et al., Exp. Opin. Ther. Patents, 8, 1217-1224, 1998; Kohen et al., J. Neurochem., 66(1), p 47-56, 1996; Sleight et al. Brit. J. Pharmacol., 124, p 556-562, 1998; Bourson et al., Brit. J. Pharmacol., 125, p 1562-1566, 1998).
  • 5-HT6 modulators have described the potential use of 5-HT6 modulators in the treatment of epilepsy.
  • 5-HT6 receptors have also been linked to generalized stress and anxiety states (Yoshioka et al., Life Sciences, 17/18, p 1473-1477, 1998). The use of modulators for this receptor is therefore expected for a wide range of CNS disorders.
  • 5-HT6 receptor modulators may therefore also be useful in the treatment of feeding disorders like anorexia, obesity, bulimia and similar disorders and also type 2 diabetes.
  • the object of the present invention is to provide compounds exhibiting a modulating activity at the 5-hydroxy-tryptamine 6 (5-HT6) receptor.
  • the present invention relates to a compound having the formula I, wherein:
  • Q is selected from C ⁇ -ioarylCo-ealkyl, Cs. ⁇ heteroarylCo-ealkyL C 3-8 cycloalkylCo -6 alkyL C 3- gheterocycloalkylCo- 6 alkyl, C 2-6 alkenyl and C 2-10 alkyl;
  • R 1 is selected from hydrogen, hydroxy, halogen, C 1-1O aIkVl, C 2- ioalkenyl, C 2 -ioalkynyl, C 1- 10 alkoxy, N(R 5 ) 2 , C 6-10 arylC 0 .6alkyl, Cs- ⁇ heteroarylCo- ⁇ alkyl, C 1-6 haloalkyl, R 5 OCo -6 alkyl, cyano, SR 5 , R 6 SO 2 C 0-6 alkyl, SOR 6 , R 5 CON(R 5 )C 0-6 alkyl, N(R 5 )SO 2 R 5 , COR 6 , R 5 CO 2 C 0- ealkyl, R 5 OC(0)Co -6 alkyl, OSO 2 R 5 , C 3-8 cycloalkyl, C ⁇ heterocycloalkyl, (R 5 ) 2 NCOC 0- ealkyl, SO 2 N(R 5 ) 2
  • n O, 1, 2, 3 or 4;
  • R 2 is selected from hydrogen, C 1-6 alkyl, R 7 OC 2-6 alkyl, C ⁇ ghaloalkyl, cyanoCi- ⁇ alkyl, (R 7 ) 2 NCOC 1-6 alkyl and R 7 CON(R 7 )C 1-6 alkyl;
  • R 3 is selected from hydrogen, C 1-6 alkyl, halogen, cyano, R 7 OC 0-6 alkyl, C 1- ⁇ haloalkyl, cyanoC 1-6 alkyI, NO 2 , (R 7 ) 2 NCOC 0-3 alkyl or R 7 CON(R 7 )C 0-3 alkyl;
  • R 4 is seleceted from hydrogen, C 1-6 alkyl, halogen, cyano, R 7 OCo- 6 alkyl, C 1- ehaloalkyl, cyanoC 1-6 alkyl, NO 2 , (R 7 ) 2 NCOC 0-3 alkyl and R 7 CON(R 7 )C 0-3 alkyl;
  • R 5 is selected from hydrogen, C 1-1O aIkVl, C ⁇ haloalkyl, C 3-8 cycloalkylCo- 6 alkyl, C 3 . 8 heterocycloalkylCo -6 alkyl, C 6-1 oarylCo-6alkyl and Cs. f rheteroarylCo-ealkyl;
  • R 6 is selected from C 1-1O aIlCyI, d- ⁇ haloalkyl, Ci- ⁇ alkoxy, C 3-8 cycloalkylCo -3 alkyl, C 3- sheterocycloalkylCo- ⁇ alkyl, C 6-1 oarylCo -3 alkyl and C 5-6 heteroarylCo -3 alkyl; and
  • any aryl, cycloalkyl, heterocycloalkyl or heteroaryl as defined for R 1 , R 5 and R 6 may be substituted by one or more groups independently selected from hydrogen, halogen, hydroxy, C 1-3 haloalkyl, cyano, OR 8 , C 1-6 alkyl, oxo, CON(R 7 ) 2 , N(R 7 )COR 8 , SO 2 R 8 , SOR 8 , N(R 7 ) 2 and COR 7 ;
  • R 7 is hydrogen, C 1-6 alkyl or Q- ⁇ haloalkyl
  • R 8 is C 1-6 alkyl or C 1-6 haloalkyl
  • One embodiment of the present invention relates to a compound of formula I, wherein: Q is selected from C 6 -ioarylC o .6alkyl, Cs- ⁇ heteroarylCo-ealkyl, C 3-8 cycloalkylCo -6 atkyl, C 3- sheterocycloalkylCo- ⁇ alkyl and C 2 -ioalkyl;
  • R 1 is selected from hydrogen, halogen, Cwoalkyl, C 1-10 alkoxy, N(R 5 ) 2 , C 6-1 oarylC o-6 alkyl, Cs- ⁇ heteroarylCo-ealkyl, C 1-6 haloalkyl, R 5 OC 0-6 alkyl, cyano, SR 5 , R 6 SO 2 C 0-6 alkyl, N(R 5 )SO 2 R 5 , COR 6 , R 5 C0 2 Co -6 alkyl, R 5 OC(O)C 0-6 alkyl, OSO 2 R 5 , C 3-8 cycloalkyl, C 3- sheterocycloalkyl, (R 5 ) 2 NCOCo -6 alkyl, SO 2 N(R 5 ) 2 , N(R 5 )CON(R 5 ) 2 , N(R 7 )COR 8 , NO 2 , OR 5 and oxo; n is O, 1, 2, 3 or 4;
  • R 2 is selected from hydrogen, C 1-6 alkyl, R 7 OC 2-6 alkyl and C 1-6 haloalkyl;
  • R 3 is selected from hydrogen, C 1-6 alkyl, halogen cyano and C 1-6 alkoxy;
  • R 4 is selected from hydrogen, C 1-6 alkyl, halogen, cyano, C 1-6 alkoxy, R 7 OC 0-6 alkyl, C 1- ehaloalkyl, cyanoC 1-6 alkyl, NO 2 , (R 7 ) 2 NCOC 0-3 alkyl and R 7 CON(R 7 )C 0-3 alkyl;
  • R 5 is selected from hydrogen, d-ioalkyl, C 1-6 haloalkyl, Cs-scycloalkylCo- ⁇ alkyl, C 3- 8 heterocycloalkylC 0-6 alkyl and C 6-1 oarylCo-6alkyl;
  • R 6 is selected from Ci-ioalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-8 cycloalkylC 0-3 alkyI and C 3- sheterocycloalkylCo- ⁇ alkyl; and wherein any aryl, cycloalkyl, heterocycloalkyl or heteroaryl as defined for R 1 , R 5 and R 6 may be substituted by one or more groups independently selected from hydrogen, halogen, hydroxy, C 1-3 haloalkyl, cyano, OR 8 , C 1-6 alkyl, oxo, CON(R 7 ) 2 , N(R 7 )COR 8 , SO 2 R 8 , SOR
  • R 7 is hydrogen, C ⁇ alkyl or C 1-6 haloalkyl; and R 8 is Q- ⁇ alkyl or C 1-6 haloalkyl; or pharmaceutically acceptable salts, solvates or solvated salts thereof.
  • Another embodiment of the present invention relates to a compound of formula I, wherein:
  • Q is selected from C6-ioarylCo- 6 alkyl, Cs- ⁇ heteroarylCo-ealkyl, Cs-gcycloalkylCo-ealkyl and
  • R 1 is selected from hydrogen, halogen, C 1-1 OaIlCyI, Ci.ioalkoxy, N(R 5 ) 2 , Ce-ioarylCo- ⁇ alkyl, C 5-1 iheteroarylC 0-6 alkyl, C 1-6 haloalkyl 3 R 5 OC 0-6 alkyl, cyano, SR 5 , R 6 SO 2 C 0-6 alkyl,
  • n 0, 1, 2, 3 or 4;
  • R 2 is selected from hydrogen, C 1 ⁇ aIkVl and Ci- ⁇ haloalkyl;
  • R 3 is selected from hydrogen, C ⁇ aUcyl, halogen and Ci- ⁇ alkoxy;
  • R 4 is selected from hydrogen, C 1-6 alkyl, halogen, cyano and C ⁇ alkoxy;
  • R 5 is selected from hydrogen, C 1-1 OaUCyI, Cs-scycloalkylCo-ealkyl, C 3-8 heterocycloalkylCo-
  • R 6 alkyl and C 6-lo arylCo- 6 alkyl;
  • R 6 is selected from C 1-10 alkyI, Ci- ⁇ haloalkyl and C ⁇ aU-oxy,; and wherein any aryl, cycloalkyl, heterocycloalkyl or heteroaryl as defined for R 1 , R 5 and R 6 may be substituted by one or more groups independently selected from hydrogen, halogen, hydroxy.
  • R 7 is hydrogen
  • R 8 is Cj -6 alkyl; or pharmaceutically acceptable salts, solvates or solvated salts thereof.
  • a further embodiment of the present invention of the present invention relates to a The compound of formula I, wherein:
  • Q is selected from C 6-1 oarylCo -6 alkyl, Cs- ⁇ heteroarylCo-galkyl, C 3-8 cycloalkylCo- 6 alkyl and s C 3-8 heterocycloalkylCo -6 alkyl;
  • R 1 is selected from hydrogen, halogen, C 1-10 alkyl, C 1-10 alkoxy, Cs- ⁇ heteroarylCo-ealkyl, C 1- ehaloalkyl, R 5 OC 0-6 alkyl, cyano, SR 5 , R 6 SO 2 C 0-6 alkyl, COR 6 , R 5 CO 2 C 0-6 alkyl, R 5 OC(O)C 0- ealkyl, SO 2 N(R 5 ) 2 , N(R 7 )COR 8 , NO 2 , 0R5 and oxo; n is 0, 1, 2 or 3; I 0 R 2 is hydrogen or C 1-6 alkyl;
  • R 3 is hydrogen, Ci- ⁇ alkyl or C 1-6 alkoxy
  • R 4 is hydrogen, C ⁇ ⁇ alkyl or C 1-6 alkoxy
  • R 5 is selected from hydrogen, and C ⁇ -ioarylCo-ealkyl
  • R s is selected from Ci-ioalkyl, Q-ghaloalkyl and and is wherein any aryl, cycloalkyl, heterocycloalkyl or heteroaryl as defined for R 1 , R 5 and R 6 may be substituted by one or more groups independently selected from hydrogen, halogen, hydroxy, C 1-3 haloalkyl, cyano, OR 8 , C 1-6 alkyl, oxo, CON(R 7 ) 2 , N(R 7 )COR 8 , SO 2 R 8 , SOR 8 ,
  • R 7 is hydrogen; and 2 o R 8 is C 1-6 alkyl; or pharmaceutically acceptable salts, solvates or solvated salts thereof.
  • Q is phenyl
  • R 2 is hydrogen or Ci -3 alkyl
  • R 3 is hydrogen, C 1-3 alkyl or Ci -3 alkoxy
  • R 4 is hydrogen, Ci -3 alkyl or Ci -3 alkoxy.
  • Q is selected from C 6- ⁇ arylCo-salkyl, C 5 _ ⁇ heteroarylC o-3 alkyl 5 C 3- gcycloalkylC 0-3 alkyl or C 2-4 alkenyl and C 2- 30 5 alkyl;
  • R 1 is selected from hydrogen, halogen, Q ⁇ alkyl, C 1-4 alkoxy, Cs- ⁇ heteroarylCo-salkyl, C 1- ehaloalkyl, R 5 OC 0-3 alfcyl, cyano, R 6 SO 2 C 0-3 alkyl, R 5 CON(R 5 )C 0-3 alkyl, R 5 OC(O)C 0-6 alkyl,
  • R 3 is hydrogen, C 1-3 alkyl or C 1-3 alkoxy
  • R 4 is hydrogen
  • R 5 is hydrogen, C ⁇ aUcyl, C 1-3 haloalkyl, C 6-1 oarylCo -3 aIkyl or Cs ⁇ heteroarylCo-salkyl;
  • R 6 is Ci -4 alkyl or C ⁇ - ⁇ arylCo ⁇ alkyl; and wherein any aryl, cycloalkyl, heterocycloalkyl or heteroaryl as defined for R 1 , R 5 and R 6 may be substituted by one or more groups independently selected from hydrogen, halogen, and Ci- 3 haloalkyl; or pharmaceutically acceptable salts, solvates or solvated salts thereof.
  • the sulphonamide-substituent is attached at position 2 or 3 of the tetrahydronaphtalen core of the compound of formula I.
  • n is O, 1, 2 or 3.
  • the present invention also related to compounds selected from:
  • C m-n or "C 1n-1 , group” used alone or as a prefix, refers to any group having m to n carbon atoms.
  • alkyl used alone or as a suffix or prefix, refers to a saturated monovalent straight or branched chain hydrocarbon radical comprising from 1 to about 10 carbon atoms.
  • alkyls include, but are not limited to, C ⁇ alkyl groups, such as methyl, ethyl, propyl, isopropyl, 2-methyl-l -propyl, 2-methyl-2-propyl, 2-methyl-l- butyl, 3 -methyl- 1 -butyl, 2-methy 1-3 -butyl, 2,2-dimethyl-l -propyl, 2-methyl-l -pentyl, 3- methyl-1-pentyl, 4-methyl-l-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2- pentyl, 2,2-dimethyl-l -butyl, 3,3-dimethyl-l-butyl, 2-ethyl-l -butyl,
  • C 0 means a bond or does not exist.
  • arylCoalkyf ' is equivalent with “aryl”
  • C 2 alkylOC 0 alkyl is equivalent with “C 2 alkylO”.
  • alkenyl refers to an unsaturated carbon chain having one or more double carbon-carbon bonds and includes both straight and branched chain alkenyl groups.
  • Example on alkenyl groups includes, but is not limited to, vinyl, allyl, propenyl, butenyl, , pentenyl, or hexenyl, and a butenyl group may for example be buten-2-yl, buten-3-yl or buten-4-yl.
  • alkynyl refers to an unsaturated carbon chain having one or more triple carbon-carbon bonds and includes both straight and branched chain alkynyl groups.
  • Example on alkynyl groups includes, but is not limited to, etynyl, propargyl, pentynyl or hexynyl and a butynyl group may for example be butyn-3-yl or butyn-4-yl.
  • alkoxy refers to radicals of the general formula -O-R, wherein R is selected from a hydrocarbon radical.
  • alkoxy may include, but is not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, isobutoxy, cyclopropylmethoxy, allyloxy or propargyloxy.
  • amine or “amino” refers to radicals of the general formula -NRR', wherein R and R' are selected independently from hydrogen or a hydrocarbon radical.
  • cycloalkyl refers to an optionally substituted, partially or completely saturated monocyclic, bicyclic or bridged hydrocarbon ring system.
  • C 3-8 cycloalkyl may be, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl or norbornyl.
  • heterocycloalkyl refers to an optionally substituted, partially or completely saturated monocyclic, bicyclic or bridged hydrocarbon ring system containing at least one heteroatom selected independently from N, O or S.
  • aryl refers to an optionally substituted monocyclic or bicyclic hydrocarbon ring system with at least one unsaturated aromatic ring.
  • examples of “aryl” may be, but are not limited to phenyl, naphthyl or tetralinyl.
  • heteroaryl refers to an optionally substituted monocyclic or bicyclic hydrocarbon ring system with at least one unsaturated aromatic ring and containing at least one heteroatom selected independently from N, O or S.
  • heteroaryl may be, but are not limited to pyridyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, tbiazolyl, pyrazolyl, benzofuryl, indolyl, isoindolyl, benzimidazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, tetrazolyl, triazolyl, quinazolinyl or isotiazolyl.
  • a Csheteroaryl refers to a 5 membered aromatic ring system containing at least one heteroatom.
  • arylalkyl and “heteroarylalkyl” refer to a substit ⁇ ent that is attached via the alkyl group to an aryl or heteroaryl group.
  • haloalkyl means an alkyl group as defined above, which is substituted with halogen as defined above.
  • C 1- 6 haloalkyl may include, but is not limited to fluoromethyl, difluoromethyl, trifiuoromethyl, fluoroethyl, difluoroethyl or bromopropyl.
  • C 1-6 haloalkylO may include, but is not limited to fluoromethoxy, difluoromethoxy, trifluoromethoxy, fluoroethoxy or difluoroethoxy.
  • the present invention relates to the compounds of formula I as hereinbefore defined as well as to the salts, solvates or solvated salts thereof.
  • Salts for use in pharmaceutical formulations will be pharmaceutically acceptable salts, but other salts may be useful in the production of the compounds of formula I.
  • a suitable pharmaceutically acceptable salt of the compounds of the invention is, for example, an acid-addition salt, for example a salt with an inorganic or organic acid.
  • a suitable pharmaceutically acceptable salt of the compounds of the invention is an alkali metal salt, an alkaline earth metal salt or a salt with an organic base.
  • Other pharmaceutically acceptable salts and methods of preparing these salts may be found in, for example, Remington's Pharmaceutical Sciences (18 th Edition, Mack Publishing Co.).
  • Some compounds of formula I may have chiral centres and/or geometric isomeric centres (E- and Z- isomers), and it is to be understood that the invention encompasses all such optical, diastereoisomeric and geometric isomers.
  • the invention also relates to any and all tautomeric forms of the compounds of formula I.
  • Step l A compound A, wherein R-* and R* are as defined above, and wherein PG is a protection group, such as, but not limited to, tert-butoxycarbonyl, benzyloxycarbonyl, 2,2,2- tricMoromethylcarbonyl, 2,2,2-trifIuoromethylcarbonyl, allyl, benzyl, phenethyl, p- methoxybenzyl, p-nitrobenzyl, diphenylmethyl, may be transformed into a compound B, wherein R 3 and R 4 are as defined above, by bromination using bromine in a solvent such as acetic acid, optionally in the presence of sodium acetate.
  • a solvent such as acetic acid
  • Other solvents that may be used are for example water, dichloromethane or dioxane.
  • the reaction may be performed at temperatures between 0 0 C and the reflux temperature of the solvent.
  • the product may be isolated by precipitation, extraction or column chromatography.
  • Step 2 A compound B, wherein R 3 and R 4 are as defined above and wherein PG is a protection group as defined above, may be transformed into a compound C, wherein R 2 , R 3 and R 4 are as defined above and wherein PG is a protection group (for examples on suitable PG see step 1) as defined above, by the reaction with an appropriate piperazine.
  • the reaction may be performed without solvent (neat), or in a solvent, such as toluene, THF, dioxane, 1,2- dimethoxyethane, o-xylene, or mixtures thereof, in the presence of a catalyst, such as Pd(OAc) 2 , Pd 2 (dba) 3 , a ligand such as BINAP or bis(2-diphenylphosphinophenyl)ether, l,3-bis(diphenylphosphino)propane, tri- ⁇ -butylphosphine, and a base, such as sodium t- butoxide, caesium carbonate, potassium carbonate, potassium phosphate or lithium bis(trimethylsilyl)amide.
  • the reaction may be run at temperatures between 4O 0 C and the reflux temperature of the solvent, preferably under inert atmosphere.
  • the reaction may also be accelerated by the use of microwave irradiation.
  • the product may be isolated by extraction, precipitation or column
  • Step 3 A compound D, wherein R 2 , R 3 and R 4 are as defined above, may be transformed into a compound I by reaction with a compound E, wherein R 1 and Q are as defined above, in a solvent, such as DMF, iV-methylpyrrolidinone, acetonitrile, dioxane, chloroform or dichloromethane, or mixtures thereof, in the presence of a base, such as pyridine, triethylamine, PS-DIEA or DIPEA, at temperatures between O 0 C and the reflux temperature of the solvent.
  • a solvent such as DMF, iV-methylpyrrolidinone, acetonitrile, dioxane, chloroform or dichloromethane, or mixtures thereof
  • a base such as pyridine, triethylamine, PS-DIEA or DIPEA
  • a further embodiment of the invention relates to compounds selected from the group consisting of (2i?)-N ;> N-dibenzyl-5-bromo-8-methoxy-l,2,3,4-tetrahydronaphthalen-2-amine,
  • a pharmaceutical composition comprising as active ingredient a therapeutically effective amount of the compound of formula I, or salts, solvates or solvated salts thereof, in association with one or more pharmaceutically acceptable diluents, excipients and/or inert carriers.
  • the composition may be in a form suitable for oral administration, for example as a tablet, pill, syrup, powder, granule or capsule, for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion) as a sterile solution, suspension or emulsion, for topical administration e.g. as an ointment, patch or cream, for rectal administration, e.g. as a suppository, or for inhalation.
  • parenteral injection including intravenous, subcutaneous, intramuscular, intravascular or infusion
  • a sterile solution e.g. as an ointment, patch or cream
  • rectal administration e.g. as a suppository, or for inhalation.
  • compositions may be prepared in a conventional manner using one or more conventional excipients, pharmaceutical acceptable diluents and/or inert carriers.
  • Suitable daily doses of the compounds of formula I in the treatment of a mammal, including man, are approximately 0.01 to 250 mg/kg bodyweight at peroral administration and about 0.001 to 250 mg/kg bodyweight at parenteral administration.
  • the typical daily dose of the active ingredient varies within a wide range and will depend on various factors such as the relevant indication, severity of the illness being treated, the route of administration, the age, weight and sex of the patient and the particular compound being used, and may be determined by a physician.
  • the compounds according to the present invention are useful in therapy.
  • the compounds the present invention may be used to produce an inhibitory effect of 5- HT6 receptors in mammals, including man.
  • the compounds of the present invention as defined hereinabove are expected to be suitable for the treatment of disorders relating to or affected by the 5-HT6 receptor including cognitive, personality, behaviour, psychiatric and neurodegenerative disorders.
  • Such disorder may be selected from the group comprising of Alzheimer's disease anxiety, depression, convulsive disorders such as epilepsy, personality disorders, obsessive compulsive disorders, migraine, cognitive disorders such as memory dysfunction, sleep disorders, feeding disorders such as anorexia, obesity, bulimia, panic attacks, withdrawal from drug abuse, schizophrenia, attention deficit hyperactive disorder (ADHD), attention deficit disorder (ADD), dementia, memory loss, disorders associated with spinal trauma and/or head injury, stroke, diabetes type 2, binge disorders, bipolar disorders, psychoses, Parkinson's disease, Huntington's disease, neurodegenerative disorders characterized by impaired neuronal growth, and pain.
  • ADHD attention deficit hyperactive disorder
  • ADD attention deficit disorder
  • dementia memory loss
  • disorders associated with spinal trauma and/or head injury stroke
  • diabetes type 2 binge disorders
  • bipolar disorders bipolar disorders
  • psychoses Parkinson's disease
  • Huntington's disease neurodegenerative disorders characterized by impaired neuronal growth, and pain.
  • gastro-intestinal disorders such as gastroesophageal reflux disease (GERD) and irritable bowel syndrome (IBS).
  • GERD gastroesophageal reflux disease
  • IBS irritable bowel syndrome
  • a compound the present invention as defined hereinabove may also be used for treatment of tolerance to 5-HT6 activators.
  • One embodiment of the invention relates to a compound of the present invention as hereinbefore defined, for use in therapy.
  • Another embodiment of the invention relates to a compound of of the present invention as hereinbefore defined, for use in treatment of 5-HT6 mediated disorders.
  • a further embodiment of the invention relates to a compound of of the present invention as hereinbefore defined, for use in treatment of Alzheimer's disease.
  • Another embodiment of the invention relates to the compounds of of the present invention as hereinbefore defined, for use in treatment of cognitive impairment associated with schizophrenia.
  • Yet a further embodiment of the invention relates to a compound of the present invention as hereinbefore defined, for use in treatment of obesity.
  • One embodiment of the invention relates to a compound of the present invention as hereinbefore defined, for use in Parkinson's disease.
  • Another embodiment of the invention relates to the use of a compound of the present invention as hereinbefore defined, in the manufacture of a medicament for treatment of 5- HT6 mediated disorders, Alzheimer's disease, cognitive impairment associated with schizophrenia, obesity and/or Parkinson's disease, and any other disorder mentioned above.
  • a further embodiment of the invention relates to a method of treatment of 5-HT6 mediated disorders, Alzheimer's disease, cognitive impairment associated with schizophrenia, obesity and/or Parkinson's disease, and any other disorder mentioned above, comprising administering to a mammal, including man in need, of such treatment, a therapeutically effective amount of a compound of the present invention, as hereinbefore defined.
  • Yet another embodiment of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention as hereinbefore defined, for use in treatment of 5-HT6 mediated disorders, Alzheimer's disease, cognitive impairment associated with schizophrenia, obesity and/or Parkinson's disease, and any other disorder mentioned above.
  • One embodiment of the invention relates to an agent for the prevention or treatment of 5- HT6 mediated disorders, Alzheimer's disease, cognitive impairment associated with schizophrenia, obesity and/or Parkinson's disease, and any other disorder mentioned above, which comprises as active ingredient a compound of the present invention as hereinbefore defined.
  • the term “therapy” and “treatment” includes prevention and prophylaxis, unless there are specific indications to the contrary.
  • the terms “treat'ytherapeutic” and “therapeutically” should be construed accordingly.
  • inhibitor and “antagonist” mean a compound that by any means, partly or completely, blocks the transduction pathway leading to the production of a response by the agonist.
  • the compounds according to the present invention are modulators of the 5-HT6 receptors, and may be inhibitors, as well as agonists, inverse-agonists or partial-agonist.
  • disorder means any condition and disease associated with 5-HT6 receptor activity.
  • the compounds of formula I, or salts, solvates or solvated salts thereof are also useful as pharmacological tools in the development and standardisation of in vitro and in vivo test systems for the evaluation of the effects of modulators of 5-HT6 related activity in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutics agents.
  • the Diode Array Detector was scanned from 210-300 nm, step and peak width were set to 2 nm and 0.05 min, respectively. A linear gradient was applied, run from 0% to 100% acetonitrile, in 4 min.
  • TLC Thin layer chromatography
  • Merck TLC-plates Silica gel 60 F 254
  • Flash chromatography was preformed on a Combi Flash ® CompanionTM using RediSepTM normal-phase flash columns or on Merck Silica gel 60 (0.040-0.063 mm).
  • Typical solvents used for flash chromatography were mixtures of chloroform/methanol, toluene/ethyl acetate and ethyl acetate/hexanes.
  • the ZQ was equipped with a combined APPI/APCI ion source and scanned in the positive mode between m/z 120-800 with a scan time of 0.3 s.
  • the APPI repeller and the APCI corona were set to 0.86 kV and 0.80 ⁇ A, respectively.
  • the desolvation temperature (300 0 C), desolvation gas (400 L/Hr) and cone gas (5 L/Hr) were constant for both APCI and APPI mode;
  • Agilent 1100 series high throughout system containing: Agilent 1100 series well plate handler, Agilent 1100 series autointerface, Agilent 1100 series well plate autosampler, 2 x 5 Agilent 1100 series binary pumps, Agilent 1100 series thermostatted column compartment, Agilent 1100 series diode array detector, Agilent 1100 series mass spectrometer.
  • the stationary phase used was 4.6 x 20 mm XTerra® MS C 8 IS columns (Waters) analytical reversed-phase column and the mobile phase used was 0.1% 880 ammonia and acetonitrile with UV detection at 220nm, MS detection 0 with APCI ionisation in positive scan mode.
  • melting points are uncorrected and were determined using a Mettler SP62 automatic melting point apparatus or an oil-bath apparatus; melting points for the end-products of the Formula I were determined after crystallisation from an. appropriate organic solvent or solvent mixture;
  • suitable protecting groups such as, but not limited to, ferf-butoxycarbonyl, benzyloxycarbonyl, 2,2,2-trichloromethylcarbonyl, 2,2,2 -trifluoromethylcarbonyl, allyl, benzyl, phenethyl, p-methoxybenzyl, p-nitrobenzyl, diphenylmethyl will be added to, and subsequently removed from, the various reactants and intermediates in a manner that will be readily understood by one skilled in the art of organic synthesis.
  • the specific sequence of reactions depicted is not critical. For many of the compounds described the order of the reaction steps may be varied.
  • the title compound was prepared according to the method described in Example 1 and a dry film (50 mg, 75%) was obtained.
  • Example 8A tert-butyl 4-((6S)-6- ⁇ [(3-chlorophenyl)sulfonyl]amino ⁇ -4-methoxy-5,6, 7,8- tetrahydronaphthalen-l-ytypiperazine-l-carboxylate fert-Butyl 4-[(65)-6-amino-4-methoxy-5,6 5 7,8-tetrahydronaphthalen- 1 -yl]piperazine- 1 - carboxylate (150 mg, 0.41 mmol) and 3-chlorobenzenesulfonyl chloride (122 mg, 0.58 mmol) were dissolved in dichloromethane (8 ml).
  • Example 8B 3-Chloro-N ⁇ [(2S)-8-methoxy-5-piperazin-l-yl-l, 2,3,4- s tetrahydronaphthalen-2-yl]benzenesulfonamide tert-Butyl 4-((6iS)-6- ⁇ [(3-chlorophenyl)suIfonyl]amino ⁇ -4-methoxy-5,6 3 7 3 8- tetrahydronaphmalen-l-yl)piperazine-l-carboxylate 3 obtained from Example 8A was dissolved in dichloromethane (10 ml) and TFA (1 ml) was added. The mixture was stirred at ambient temperature for 6 h.
  • Example 34 l-(3-Chlorophenyl)-iV-[(2i?)-8-piperazin-l-yl-l,2,3,4-tetrahydronaphthalen-2- yl] methanesulfonamide
  • the title compound was prepared according to the method described in Example 32. but no pyridine was added and 2.5 eq of DIPEA was used.
  • the title compound was prepared according to the method described in Example 32 but no pyridine was added and 2.5 eq of DIPEA was used.
  • Examples 62-151 were prepared using the method described in Example 36.
  • Striatal tissue from adult rats (Sprague-Dawley, 320-370 g, B & K Sweden) were dissected 25 out, weighed and homogenized in buffer containing 50 mM Tris-HCl, 4 mM MgC12, 1 mM EDTA, 10 ⁇ M pargyline and protease inhibitor (Complete, Roche Diagnostics) pH 7.4 using an Ultra-Turrax T8 (IKA Labortechnik, Germany).
  • the tissue homogenate was centrifuged at 48 OOOxg for 10 min and the pellet was resuspended and recentrifuged as above.
  • the final membranes were diluted in buffer to a concentration of 60 mg original 30 wet weight (w.w.) per ml and stored in aliquots at -70°C.
  • Radioligand binding assays
  • Typical IC 50 values as measured in the assays described above are 1 ⁇ M or less. In one aspect of the invention the IC 50 is below 500 nM. In another aspect of the invention the IC 5O is below 50 nM. In a further aspect of the invention the IC 50 is below 10 nM.

Abstract

The present invention relates to new compounds of formula I, or salts, solvates or solvated salts thereof, wherein Q, R1, R2, R3, R4 and n are defined as in claim 1, processes for their preparation and to new intermediates used in the preparation thereof, pharmaceutical formulations containing said compounds and to the use of said compounds in therapy.

Description

NOVEL TETRALINS AS 5-HT6 MODULATORS
FIELD OF TFiE INVENTION
The present invention relates to new compounds, to pharmaceutical formulations containing said compounds and to the use of said compounds in therapy. The present invention further relates to processes for the preparation of said compounds and to new intermediates useful in the preparation thereof.
BACKGROUND OF THE INVENTION Serotonin (5-hydroxy-tryρtamine) (5-HT) receptors play an important role in many physiological and pathological functions like anxiety, sleep regulation, aggression, feeding and depression. The 5-HT receptors are distributed throughout the body and can be divided into seven different 5-HT receptor subtypes, i.e. 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5- HT6, and 5-HT7, with different properties. The 5-HT6 receptor is mostly found in the central nervous system (CNS). From in situ hybridization studies it is known that the 5-HT6 receptor in rat brain is localized in areas like striatum, nucleus accumbens, olfactory tubercle and hippocampal formation (Ward et al., Neuroscience, 64, p 1105-1111, 1995).
Scientific research has revealed a potential therapeutic use for modulators of the 5-HT6 receptor, especially with regard to various CNS disorders. Blocking 5-HT6 receptor function has been shown to enhance cholinergic transmission (Bentley et al, Br J Pharmacol 126: 1537-1542).
Studies have shown that 5-HT6 antagonists increase levels of glutamate and aspartate in the frontal cortex and dorsal hippocampus as well as acetylcholine in the frontal cortex. These neurochemicals are known to be involved in memory and cognition (Dawson et al., Neuropsychopharmacology., 25(5), p 662-668, 2001) (Gerard et al., Brain Res., 746, p 207-219, 1997) (Riemer et al J Med Chem 46(7), p 1273-1276, 2003). Acetylcholinesterase inhibitors increase the levels of acetylcholine in the CNS and are used in the treatment of cognitive disorders such as Alzheimer's disease. 5-HT6 antagonists may therefore be used in the treatment of cognitive disorders.
Studies have also shown that 5-HT6 antagonist increases the level of dopamine and noradrenaline in the medial prefrontal cortex suggesting a role for 5-HT6 ligands in cognitive aspects of schizophrenia. Several antidepressants and atypical antipsychotics bind to the 5-HT6 receptor and this may be a factor in their profile of activities (Roth et al., J. Pharm. Exp. Therapeut, 268, 1402-1420, 1994; Sleight et al., Exp. Opin. Ther. Patents, 8, 1217-1224, 1998; Kohen et al., J. Neurochem., 66(1), p 47-56, 1996; Sleight et al. Brit. J. Pharmacol., 124, p 556-562, 1998; Bourson et al., Brit. J. Pharmacol., 125, p 1562-1566, 1998).
Stean et al., (Brit. J. Pharmacol. 127 Proc. Supplement 13 IP, 1999) have described the potential use of 5-HT6 modulators in the treatment of epilepsy. 5-HT6 receptors have also been linked to generalized stress and anxiety states (Yoshioka et al., Life Sciences, 17/18, p 1473-1477, 1998). The use of modulators for this receptor is therefore expected for a wide range of CNS disorders.
Moreover, a reduction in food intake in rats has been reported using 5-HT6 receptor modulators (Bentley et al., Br. J. Pharmacol. Suppl. 126, P66, 1999; Bentley et al. J. Psychopharmacol. Supl. A64, 255, 1997). 5-HT6 receptor modulators may therefore also be useful in the treatment of feeding disorders like anorexia, obesity, bulimia and similar disorders and also type 2 diabetes.
DETAILED DESCRIPTION OF THE INVENTION
The object of the present invention is to provide compounds exhibiting a modulating activity at the 5-hydroxy-tryptamine 6 (5-HT6) receptor.
The present invention relates to a compound having the formula I, wherein:
Figure imgf000004_0001
Q is selected from Cό-ioarylCo-ealkyl, Cs.πheteroarylCo-ealkyL C3-8cycloalkylCo-6alkyL C3- gheterocycloalkylCo-6alkyl, C2-6alkenyl and C2-10alkyl;
R1 is selected from hydrogen, hydroxy, halogen, C1-1OaIkVl, C2-ioalkenyl, C2-ioalkynyl, C1- 10alkoxy, N(R5)2, C6-10arylC0.6alkyl, Cs-πheteroarylCo-όalkyl, C1-6haloalkyl, R5OCo-6alkyl, cyano, SR5, R6SO2C0-6alkyl, SOR6, R5CON(R5)C0-6alkyl, N(R5)SO2R5, COR6, R5CO2C0- ealkyl, R5OC(0)Co-6alkyl, OSO2R5, C3-8cycloalkyl, C^heterocycloalkyl, (R5)2NCOC0- ealkyl, SO2N(R5)2, N(R5)CON(R5)2, N(R7)COR8, NO2, OR5 and oxo;
n is O, 1, 2, 3 or 4;
R2 is selected from hydrogen, C1-6alkyl, R7OC2-6alkyl, Cμghaloalkyl, cyanoCi-βalkyl, (R7)2NCOC1-6alkyl and R7CON(R7)C1-6alkyl;
R3 is selected from hydrogen, C1-6alkyl, halogen, cyano,
Figure imgf000004_0002
R7OC0-6alkyl, C1- δhaloalkyl, cyanoC1-6alkyI, NO2, (R7)2NCOC0-3alkyl or R7CON(R7)C0-3alkyl;
R4 is seleceted from hydrogen, C1-6alkyl, halogen, cyano,
Figure imgf000004_0003
R7OCo-6alkyl, C1- ehaloalkyl, cyanoC1-6alkyl, NO2, (R7)2NCOC0-3alkyl and R7CON(R7)C0-3alkyl; R5 is selected from hydrogen, C1-1OaIkVl, C^haloalkyl, C3-8cycloalkylCo-6alkyl, C3. 8heterocycloalkylCo-6alkyl, C6-1oarylCo-6alkyl and Cs.frheteroarylCo-ealkyl;
R6 is selected from C1-1OaIlCyI, d-όhaloalkyl, Ci-βalkoxy, C3-8cycloalkylCo-3alkyl, C3- sheterocycloalkylCo-δalkyl, C6-1oarylCo-3alkyl and C5-6heteroarylCo-3alkyl; and
wherein any aryl, cycloalkyl, heterocycloalkyl or heteroaryl as defined for R1, R5 and R6 may be substituted by one or more groups independently selected from hydrogen, halogen, hydroxy, C1-3haloalkyl, cyano, OR8, C1-6alkyl, oxo, CON(R7)2, N(R7)COR8, SO2R8, SOR8, N(R7)2 and COR7;
R7 is hydrogen, C1-6alkyl or Q-βhaloalkyl; and
R8 is C1-6alkyl or C1-6haloalkyl;
or pharmaceutically acceptable salts, solvates or solvated salts thereof.
One embodiment of the present invention relates to a compound of formula I, wherein: Q is selected from C6-ioarylCo.6alkyl, Cs-πheteroarylCo-ealkyl, C3-8cycloalkylCo-6atkyl, C3- sheterocycloalkylCo-δalkyl and C2-ioalkyl;
R1 is selected from hydrogen, halogen, Cwoalkyl, C1-10alkoxy, N(R5)2, C6-1oarylCo-6alkyl, Cs-πheteroarylCo-ealkyl, C1-6haloalkyl, R5OC0-6alkyl, cyano, SR5, R6SO2C0-6alkyl, N(R5)SO2R5, COR6, R5C02Co-6alkyl, R5OC(O)C0-6alkyl, OSO2R5, C3-8cycloalkyl, C3- sheterocycloalkyl, (R5)2NCOCo-6alkyl, SO2N(R5)2, N(R5)CON(R5)2, N(R7)COR8, NO2, OR5 and oxo; n is O, 1, 2, 3 or 4;
R2 is selected from hydrogen, C1-6alkyl, R7OC2-6alkyl and C1-6haloalkyl;
R3 is selected from hydrogen, C1-6alkyl, halogen cyano and C1-6alkoxy;
R4 is selected from hydrogen, C1-6alkyl, halogen, cyano, C1-6alkoxy, R7OC0-6alkyl, C1- ehaloalkyl, cyanoC1-6alkyl, NO2, (R7)2NCOC0-3alkyl and R7CON(R7)C0-3alkyl;
R5 is selected from hydrogen, d-ioalkyl, C1-6haloalkyl, Cs-scycloalkylCo-βalkyl, C3- 8heterocycloalkylC0-6alkyl and C6-1oarylCo-6alkyl; R6 is selected from Ci-ioalkyl, C1-6haloalkyl, C1-6alkoxy, C3-8cycloalkylC0-3alkyI and C3- sheterocycloalkylCo-βalkyl; and wherein any aryl, cycloalkyl, heterocycloalkyl or heteroaryl as defined for R1, R5 and R6 may be substituted by one or more groups independently selected from hydrogen, halogen, hydroxy, C1-3haloalkyl, cyano, OR8, C1-6alkyl, oxo, CON(R7)2, N(R7)COR8, SO2R8, SOR8, N(R7)2 and COR7;
R7 is hydrogen, C^alkyl or C1-6haloalkyl; and R8 is Q-βalkyl or C1-6haloalkyl; or pharmaceutically acceptable salts, solvates or solvated salts thereof.
Another embodiment of the present invention relates to a compound of formula I, wherein:
Q is selected from C6-ioarylCo-6alkyl, Cs-πheteroarylCo-ealkyl, Cs-gcycloalkylCo-ealkyl and
Cs-sheterocycloalkylCo-δalkyl;
R1 is selected from hydrogen, halogen, C1-1OaIlCyI, Ci.ioalkoxy, N(R5)2, Ce-ioarylCo-δalkyl, C5-1 iheteroarylC0-6alkyl, C1-6haloalkyl3 R5OC0-6alkyl, cyano, SR5, R6SO2C0-6alkyl,
N(R5)SO2R5, COR6, R5C02Co-6alkyl, R5OC(O)C0-6alkyl, OSO2R5, C3-8cycloalkyl, C3- sheterocycloalkyl, (R5)2NCOC0-6alkyl, SO2N(R5)2, N(R5)CON(R5)2, N(R7)COR8, NO2,
OR5 and oxo; n is 0, 1, 2, 3 or 4; R2 is selected from hydrogen, C1^aIkVl and Ci-δhaloalkyl;
R3 is selected from hydrogen, C^aUcyl, halogen and Ci-βalkoxy;
R4 is selected from hydrogen, C1-6alkyl, halogen, cyano and C^alkoxy;
R5 is selected from hydrogen, C1-1OaUCyI, Cs-scycloalkylCo-ealkyl, C3-8heterocycloalkylCo-
6alkyl and C6-loarylCo-6alkyl; R6 is selected from C1-10alkyI, Ci-βhaloalkyl and C^aU-oxy,; and wherein any aryl, cycloalkyl, heterocycloalkyl or heteroaryl as defined for R1, R5 and R6 may be substituted by one or more groups independently selected from hydrogen, halogen, hydroxy. C1-3haloalkyl, cyano, OR8, C1-6alkyl, oxo, CON(R7)2, N(R7)COR8, SO2R8, SOR8,
N(R7)2 and COR7; R7 is hydrogen; and
R8 is Cj-6alkyl; or pharmaceutically acceptable salts, solvates or solvated salts thereof. A further embodiment of the present invention of the present invention relates to a The compound of formula I, wherein:
Q is selected from C6-1oarylCo-6alkyl, Cs-πheteroarylCo-galkyl, C3-8cycloalkylCo-6alkyl and s C3-8heterocycloalkylCo-6alkyl;
R1 is selected from hydrogen, halogen, C1-10alkyl, C1-10alkoxy, Cs-πheteroarylCo-ealkyl, C1- ehaloalkyl, R5OC0-6alkyl, cyano, SR5, R6SO2C0-6alkyl, COR6, R5CO2C0-6alkyl, R5OC(O)C0- ealkyl, SO2N(R5)2, N(R7)COR8, NO2, 0R5 and oxo; n is 0, 1, 2 or 3; I0 R2 is hydrogen or C1-6alkyl;
R3 is hydrogen, Ci-βalkyl or C1-6alkoxy;
R4 is hydrogen, Cμδalkyl or C1-6alkoxy;
R5 is selected from hydrogen,
Figure imgf000007_0001
and Cβ-ioarylCo-ealkyl;
Rs is selected from Ci-ioalkyl, Q-ghaloalkyl and
Figure imgf000007_0002
and is wherein any aryl, cycloalkyl, heterocycloalkyl or heteroaryl as defined for R1, R5 and R6 may be substituted by one or more groups independently selected from hydrogen, halogen, hydroxy, C1-3haloalkyl, cyano, OR8, C1-6alkyl, oxo, CON(R7)2, N(R7)COR8, SO2R8, SOR8,
N(R7)2 and COR7;
R7 is hydrogen; and 2o R8 is C1-6alkyl; or pharmaceutically acceptable salts, solvates or solvated salts thereof.
According to one embodiment of the present invention, Q is phenyl.
25 According to another embodiment of the present invention, R2 is hydrogen or Ci-3alkyl; R3 is hydrogen, C1-3alkyl or Ci-3alkoxy; and R4 is hydrogen, Ci-3alkyl or Ci-3alkoxy.
According to yet another embodiment of the present invention, Q is selected from C6- ^arylCo-salkyl, C5_πheteroarylCo-3alkyl5 C3-gcycloalkylC0-3alkyl or C2-4alkenyl and C2- 30 5alkyl; R1 is selected from hydrogen, halogen, Q^alkyl, C1-4alkoxy, Cs-πheteroarylCo-salkyl, C1- ehaloalkyl, R5OC0-3alfcyl, cyano, R6SO2C0-3 alkyl, R5CON(R5)C0-3alkyl, R5OC(O)C0-6alkyl,
(R5)2NCOCo-3alkyl, SO2N(R5)2, NO2 and oxo; n is O, 1, 2, 3 or 4; R2 is hydrogen or Chalky!;
R3 is hydrogen, C1-3alkyl or C1-3alkoxy;
R4 is hydrogen;
R5 is hydrogen, C^aUcyl, C1-3haloalkyl, C6-1oarylCo-3aIkyl or Cs^heteroarylCo-salkyl;
R6 is Ci-4alkyl or Cδ-^arylCo^alkyl; and wherein any aryl, cycloalkyl, heterocycloalkyl or heteroaryl as defined for R1, R5 and R6 may be substituted by one or more groups independently selected from hydrogen, halogen, and Ci-3haloalkyl; or pharmaceutically acceptable salts, solvates or solvated salts thereof.
In yet another embodiment of the invention the sulphonamide-substituent is attached at position 2 or 3 of the tetrahydronaphtalen core of the compound of formula I.
In a further embodiment of the present invention, n is O, 1, 2 or 3.
The present invention also related to compounds selected from:
3-chloro-N-[(2i?)-8-methoxy-5-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2- yl]benzenesulfonamide,
4-chloro-N-[(2i?)-8-methoxy-5-(4-methylpiperazin- 1 -yl)- 1 ,2,3,4-tetrahydronaphthalen-2- yl]benzenesulfonamide, 3-chloro-iV-[(25)-5-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthaIen-2- yljbenzenesulfonamide,
3-chloro-4-methyl-N-[(25)-5-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2- yl]benzenesulfonamide,
5-chloro-N-[(25)-5-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2- yl]naphthalene-2-sulfonamide,
3-chloro-4-methyl-N-[(2iS)-5-piperazin-l-yl-l,2,3,4-tetrahydronaphthalen-2- yl]benzenesulfonamide, 3-chloro-N-[(2.S)-5-piperazin-l-yl-l,2,3,4-tetrahydronaphthalen-2-yl]benzenesulfonamide,
3-chloro-N-[(2S)-8-methoxy-5-piperazin-l-yl-l,2,3,4-tetrahydronaphthalen-2- yl]benzenesulfonamide, iV-[(25)-8-methoxy-5-piperazin-l-yl-l,2,3,4-tetrahydronaphthalen-2-yl]-3,5- dimethylisoxazole-4-sulfonamide, l-[3-chloro-5-(trifluoromethyl)pyridin-2-yll-iV'-[(2JS)-8-methoxy-5-piperazin-l-yl-l,2,3,4- tetrahydronaphthalen-2-yl]-lH-pyrrole-2-sulfonamide,
2,3-dichloro-N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2- yl]benzenesulfbnamide, iV-[(2i?)-8-(4-methylpiperazin-l-yI)-l,2,3,4-tetxahydronaphthalen-2-yl]naphthalene-2- sulfonamide,
3-cliloro-4-methyl-N-[(2R)-8-(4-πiethylpiperazm-l-yl)-l,2,3,4-tetrahydronaplithalen-2- yl]benzenesulfonamide,
N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2- yl]naphthalene-2-sulfonamide, l-[3-chloro-5-(Mfluoromethyl)pyridin-2-yl]-N-[(2i-)-5-methyl-8-(4-methylpiperazin-l-yl)-
1 ,2,3,4-tetrahydronaphthalen-2-yl]- 1 H-pyrrole-2-sulfonamide,
5-chloro-iV-[(2i?)-5-methyl-8-piperazin-l-yl-l,2,3,4-tetrahydronaphthalen-2- yl]naphthalene-2-sulfonamide, iV-[(2i?)-5-methyl-8-piperazin-l-yl-l,2,3,4-tetrahydronaphthalen-2-yl]naphthalene-2- sulfonamide,
2,6-dichloro-N-[(2i?)-5-methyl-8-piperazin-l-yl-l,2,3,4-tetraliydronaphthalen-2- yljbenzenesulfonamide,
3,5-dimethyl-iV'-[(2i?)-5-metliyl-8-piperazin-l-yl-l,2,3,4-tetiahydronaplithalen-2- yl]isoxazole-4-sulfonamide,
2-chloro-6-methyl-iV-[(2i?)-5-methyl-8-piperazin-l-yl-l,2,3,4-tetrahydronaphthalen-2- yl]benzenesulfonamide,
2,6-difluoro-N-[(2i?)-5-methyl-8-piperazin-l-yl-l,2,3,4-tetrahydronaphthalen-2- yl]benzenesulfonamide, iV-[(2i?)-5-methyl-8-piperazin-l-yl-l,2,3,4-tetrahydronaplithalen-2-yl]isoquinoline-5- sulfonamide, 5-chloro-l33-dimethyl-N-[(2i?)-5-methyl-8-piperazin-l-yl-l,2,3,4-tetrahydronaphthalen-2- yl]- 1 H-pyrazole-4-sulfonamide,
2,4-dimethyl-N-[(2i?)-5-methyl-8-piperazin-l-yl-l,2,3,4-tetrahydronaphthalen-2-yl]-lJ3- thiazole-5-sulfonamide, l53,5-trimethyl-N-[(2i?)-5-methyl-8-piperazin-l-yl-l,2,3,4-tetrahydronaphthalen-2-yl]-lH- pyrazole-4-sulfonamide,
4-bromo-2,5-dichloro-N-[(2i?)-5-methyl-8-piperazin-l-yl-l,2,3,4-tetrahydronaphthalen-2- yl]thiophene-3 -sulfonamide,
4-bromo-iV-[(2i?)-5-methyl-8-piperazin-l-yl-l,2,374-tetrahydronaphtlialen-2-yl]thiophene- 3 -sulfonamide,
N-[4-methyl-5-({[(2i?)-5-methyl-8-piperazin-l-yl-l:,2,3,4-tetrahydronaphthalen-2- yl]amino}sulfonyl)-l,3-thiazol-2-yl]acetamide,
2,4-dDimemyl-iV:-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-
2-yl]-l,3-thiazole-5-sulfonamide, s iV-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2-yl]-l,3- benzothiazole-6-sulfonamide,
5-chloro-iV-[(2i?)-8-piperazin-l-yl-l,2,3,4-tetrahydronaphthalen-2-yl]naplithalene-2- sulfonamide,
4-chloro-iV-[(2i?)-8-piperazin- 1 -yl- 1 ,2,3 ,4-tetrahydronaphthalen-2-yl]naphthalene- 1 - o sulfonamide,
5-chloro-N-[(2i?)-8-piperazin-l-yl-l,2,3:>4-tetrahydronaphthalen-2-yl]naphthalene-l- sulfonamide, l-(3-cHlorophenyl)-iV-[(2i?)-8-piperazin-l-yl-l,2,3,4-tetrahydronaplithalen-2- yl]methanesulfonamide, 5 2-(4-chloroρhenyl)-N-[(2i?)-8-piperazin-l -yl- 1 ,2,3,4-tetrahydronaphthalen-2- yl] ethanesulfonamide, iV-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3J4-tetrahydronaphthalen-2- yl]benzenesulfonamide,
3-cyano-N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2- o yl]benzenesulfonamide,
5-cliloro-l,3-dimethyl-iV-[(2JR)-5-methyl-8-(4-methylpiρerazin-l-yl)-l,2,334- tetrahydronaphthalen-2-yl]- 1 H-pyrazole-4-sulfonamide, 3 ,5-dimethyl-N-[(2i?)-5-methyl-8-(4-methylpiperazin-l -yl)- 1 ,2,3 ,4-tetrahydronaphthalen-
2-y 1] isoxazole-4-sulfonamide,
2,6-difluoro-iV-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetraliydronaphthalen-2- yl]benzenesulfonamide, 2-chloro-4-fluoro-N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4- tetrahydronaphthalen-2-yl]benzenesulfonamide,
N-[(2i?)-5-methyl-8-(4-methylpiρerazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2-yl]-2-
(trifluoromethyl)benzenesulfonamide,
5-chloro-2-methoxy-N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4- tetrahydronaphthalen-2-yl]benzenesulfonamide,
N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2-yl]-4- nitrobenzenesulfonamide, iV-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2-yl]-l- phenylmethanesulfonamide, 4-fluoro-iV-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2- yl]benzenesulfonamide,
N-[4-({[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2- yl]amiπo}sulfonyl)phenyl]acetamide,
2,5-difluoro-N-[(2i?)-5-me1iiyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2- yljbenzenesulfonamide, methyl 1 -methyl-5-( { [(2i?)-5-methyl-8-(4-methylρiperazin- 1 -yl)-l ,2,3 ,4- tetrahydronaphtb.alen-2-yl] amino } sulfonyl)- 1 H-pyrrole-2-carboxylate,
4-chloro-2-fluoro-iV-[(2i?)-5-metIiyl-8<4-methylpiperazin-l-yl)-l,2,3,4- tetrahydronapb.thalen-2-yl]benzenesulfonamide, 3,5-dimethyl-N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-
2-yl]benzenesulfonamide, iV-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2-yl]pyridine-
3-sulfonamide,
5-bromo-2,4-difluoro-iV-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4- tetrahydronapb.thalen-2-yl]benzenesulfonamide,
5-bromo-6-chloro-iV-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4- tetrahydronaphthalen-2-yl]pyridine-3-sulfonamide, N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetraliydronaphthalen-2-yl]-l- benzothiophene-3 -sulfonamide,
4-bromo-2,5-difluoro-iV-[(2i?)-5-methyl-S-(4-methylpiperazin-l-yl)-l,2,3,4- tetrahydronaphthalen-2-yl]benzenesulfonamide, 2,3,4-trifluoro-N-[(2R)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-
2-yl]benzenesulfonamide,
N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2:,3,4-tetrahydronapb.thalen-2- yl]thiophene-3-sulfonamide,
N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2-yl]-4- (methylsulfonyl)benzenesulfonamide,
2-chloro-4-cyano-iV-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4- tetrahydronaphthalen-2-yl]benzenesulfonamide,
6-cWoro-N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2- yl]imidazo[2,l-b][l,3]thiazole-5-sulfonamide, 4-chloro-iV-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2- yljbenzenesulfonamide,
3-chloro-N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2- yljbenzenesulfonamide, l-(3-chloroρhenyl)-iV-[(2JR)-5-metliyl-8-(4-methylpiperazin-l-yl)-l,2,3,4- tetrahydronaphthalen-2-yl]methanesulfonamide,
N-[4-methyl-5-( { [(2i?)-5-methyl-8-(4-methylpiperazin- 1 -yl)-l ,2,3 ,4-tetrahydronaphthalen-
2-yl]amino}sulfonyl)-l,3-thiazol-2-yl]acetamide,
N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2- yl]thiophene-2-sulfonamide, N-[(2i?)-5-methyl-8-(4-metliylpiperazin- 1 -yl)- 1 ,2,3,4-tetrahydronaphthalen-2-yl]-3 - nitrobenzenesulfonamide,
2,5-dimemoxy-N-[(2i?)-5-memyl-8-(4-methylpiperazm-l-yl)-l,2,3,4-tetrahydronaphthalen-
2-yl]benzenesulfonamide,
5-bromo-2-methoxy-iV-[(2i?)-5-methyl-8-(4-methylpiperazin- 1 -yl)-l ,2,3 ,4- tetrahydronaphthalen-2-yl]benzenesulfonamide,
N-[(2i?)-5-methyl-8-(4-methylpiperazin- 1 -yl)- 1 ,2,3,4-tetrahydronaphthalen-2-yl]-4-
(phenylsulfonyl)thiophene-2-sulfonamide, N-.[(2JR)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2-yl]-5-
(phenylsulfonyl)thiophene-2-sulfonamide,
N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2-yl]-2,l,3- benzothiadiazole-4-sulfonamide, N-[(2i?)-5-methyl-8-(4-methylpiρerazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2-yl]-2,l,3- benzoxadiazole-4-sulfonamide,
5-isoxazol-3-yl-iV-[(2i2)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,354- tetrahydronaphthalen-2-yl]thiophene-2-sulfonamide, .
2-methyl-N-[(2i?)-5-methyl-8-(4-methylpiperazin- 1 -yl)- 1 ,2,3 ,4-tetrahydronaphthalen-2- yl]-5-nitrobenzenesulfonamide;
3-methyl-N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2- yljbenzenesulfonamide,
2-methyl-iV-[(2i?)-5-methyl-8-(4-methylpiperazm-l-yl)-l,2,3,4-tetrahydronaphthalen-2- yl] -4-nitrobenzenesuIfonamide, 3-chloro-4-fluoro-iV-[(2i?)-5-methyl-8-(4-methylpiperazm- 1 -yl)- 1 ,2,3 ,4- tetrahydronaphthalen-2-yl]benzenesulfonamide,
2,4-difIuoro-N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2- yl]benzenesulfonamide,
5-fluoro-2-methyl-iV-[(2i?)-5-metb.yl-8-(4-πiethylpiperazin-l-yl)-l,2,3,4- tetrahydronaphthalen-2-yl]benzenesulfonamide, l-[(i5,^)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-l-yl]-N-[(2i?)-5-methyl-8-(4- metb.ylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2-yl]methanesulfonamide,
2-fluoro-N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3-4-tetrahydronaphtlialen-2- ' yl]benzenesulfonamide, 3,4-dimethoxy-N-[(2i?)-5-methyl-8-(4-methylpiperazin-l -yl)-l ,2,3,4-tetrahydronaphthalen-
2-yl]benzenesulfonamide,
5-chloro-N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetraliydronaphtlialen-2- yl]thiophene-2-sulfonamide,
2-chloro-6-methyl-iV-[(2i?)-5-inethyl-8-(4-methylpiperazin-l-yl)-l,2J3,4- tetrahydronaphthalen-2-yl]benzenesulfonamide,
5-bromo-N-[(2i2)-5-methyl-8-(4-methylpiperazin-l-yl)-l!2,3,4-tetrahydronaplithalen-2- yl]thiophene-2-suIfonamide, 4-chloro-N-[(2i?)-5-methyI-S-(4-methylpiperazin-l-yl)-l,2,334-tetrahydronaphthalen-2-yl]-
3-nitrobenzenesulfonamide,
3-fluoro-N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2- yl]benzenesulfonamide, N-[2-chloro-4-({[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaplithalen-
2-yl]amino} sulfonyl)phenyl]acetamide,
2-methoxy-5-methyl-N-[(2i?)-5-metiiyl-8-(4-methylpiperazin-l-yl)-l,2,334- tetrahydronaplithalen-2-yl]benzenesulfonamide,
N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2-yl]-2- nitrobenzenesulfonamide.,
3,4,5-trimethoxy-iV-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4- tetrahydronaphthalen-2-yl]benzenesulfonamide,
4-bromo-N-[(2i?)-5-me1iιyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphtliaIen-2- yl]benzenesulfonamide, 2-bromo-N-[(2i?)-5-meth.yl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2- yljbenzenesulfonamide, iV-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2-yl]-4-
(trifluoromethyl)benzenesulfonamide,
4-ethyl-N-[(2i?)-5-methyl-8-(4-methylpiperazin- 1 -yl)-l ,2,3 ,4-tetrahydronaphthalen-2- yl]benzenesulfonamide,
N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2-yl]-2-nitro-4-
(trifluoromethyl)benzenesulfonamide,
4-methyl-N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2- yl]-3 -nitrobenzenesulfonamide, N-[(2i?)-5-meihyl-8-(4-methylpiperazin- 1 -yl)-l ,2,3 ,4-tetrahydronaphthalen-2- yl]naphthalene- 1 -sulfonamide,
N-[(2i?)-5-methyl-8-(4-methylpiperazin- 1 -yl)- 1 ,2,3,4-tetrahydronaplithalen-2-yl]-2-oxo- l,2,3,4-tetrahydroquinoline-6-sulfonamide, l-[(2i?^θ)-7,7-dimethyl-2-oxobicyclo[2.2.1]liept-l-yl]-N-[(2i?)-5-methyl-8-(4- methylpiperazin-1 -yl)- 1 ,2,3 ,4-tetrab.ydronaphthalen-2-yl]methanesulfonamide,
3,4-difluoro-N-[(2i?)-5-methyl-8-(4-methylρiρerazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2- yljbenzenesulfonamide, 2-methyl-iV-[(2i?)-5-methyl-8-(4-methylpiperazm-l -yl)- 1 ,2,3,4-tetrahydronaphthalen-2- yl]benzenesulfonamide,
255-dime%l-N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,334-tetrahydronaphthalen-
2-yl]benzenesulfonamide, N"-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2-yl]-4-
(pyridin-3-yloxy)benzenesulfonamide,
4-chloro-2,5-dimethoxy-N-[(2JR)-5-mefhyl-8-(4-methylpiperazin-l-yl)-l,2,3,4- tetrahydronaphthalen-2-yl]benzenesulfonamide,
6-cMoro-N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronapb.thalen-2-yl]- 2H-l,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide, methyl 2-methyl-5-({[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4- tetrahydronaphthalen-2-yl]amino} sulfony l)-3 -furoate,
2-meώoxy-5-({[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2- yl]amino} sulfonyl)benzamide, 3-cyano-4-fluoro-iV-[(2JR)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4- tetrahydronaphthalen-2-yl]benzenesulfonamide,
3 -fluoro-4-methyl-N-[(2i?)-5-methyl-8-(4-meth.ylpiperazin- 1 -yl)- 1 ,2,3,4- tetrahydronaphthalen-2-yl]benzenes\ilfonamide,
4-fluoro-2-methyl-N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,23,4- tetrahydronaphthalen-2-yl]benzenesulfonamide,
2-methoxy-N-[(2i?)-5-me1fayl-8-(4-me1hylpiperaziaQ-l-yl)-l,2,3,4-tetrah.ydronaplithalen-2- yl]-4-nitrobenzenesulfonamide,
2,4,5-trifluoro-N-[(2i?)-5-methyl-8-(4-me%lpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-
2-yl]benzenesulfonamide, methyl 3-[4-({[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaρhthalen-2- yl]amino}sulfonyl)phenyl]propanoate,
N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2-yl]-6- phenoxypyridine-3 -sulfonamide, iV-[(2i2)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaρhthalen-2-yl]-2,3- dihydro- 1 ,4-benzodioxine-6-sulfonamide, iV-[(2i?)-5-methyl-8-(4-methylpiperazin-l -yl)-l ,2,3 ,4-tetrahydronaphthalen-2-yl]- 1 - benzofuran-2-sulfonamide, 4-chloro-iV2-[(2i?)-5-methyl-8-(4-methylpiperazm-l-yl)-l,2,3J4-tetxaliydronaphthalen-2- yl]benzene- 1 ,3-disulfonamide,
4-fluoro-iV-[(2i2)-5-methyl-8-(4-methylpiperazin-l-yI)-l,2,334-tetral]iydronaphthaIen-2- yljnaphthalene- 1 -sulfonamide, 5 3,5-difluoro-N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l52,3,4-tetrahydronaphthalen-2- yl]benzenesulfonamide,
4-fluoro-iV'-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetraliydronaplithalen-2-yl]-
3-(trifiuoromethyl)benzenesulfonamide,
2-chIoro-4,5-difluoro-iV-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4- i o tetrahydronaphthalen-2-yl]benzenesulfonamide,
5-chloro-2,4-difluoro-N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4- tetrahydronaplithalen-2-yl]benzenesulfonamide,
4-chloro-2,5-difluoro-N-[(2i?)-5-methyl-8-(4-methylpiperazm- 1 -yl)- 1 ,2,3 ,4- tetrahydronaphthaIen-2-yl]benzenesulfonamide, is 3-chloro-4-me1iiyl-iV-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4- tetrahydronaphthalen-2-yl]benzenesulfonamide, iV"-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2-yl]-2-
(methylsulfonyl)benzenesulfonamide, l,3,54rimethyl-iV'-[(2i?)-5-methyl-8-(4-methylpiperaziii-l-yl)-l,2,3,4- 20 tetrahydronaphthalen-2-yl]-l H-pyrazole-4-sulfonamide,
N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2-yl]-l-(3- nitrophenyl)methanesulfonamide,
5-methyl-N-[(2i?)-5-me%l-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaplithalen-2- yl]-2,l,3-benzothiadiazole-4-sulfonamide, 25 2,5-dimethoxy-iV'-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-
2-yl]-4-nitrobenzenesuIfonamide,
N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2-yl]-l-oxo- l,2-dihydroisoquinoline-4-sulfonamide, dimethyl 5-( { [(2i?)-5-methyl-8-(4-methylpiperazin- 1 -yl)-l ,2,3,4-tetrahydronaphthalen-2- 30 yl] amino }sulfonyl)isophthalate,
4-me%l-iV'-[(2i?)-5-meihyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaρhthalen-2- yl]benzenesulfonamide, 4-methoxy-N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2- yljbenzenesulfonamide,
2-cHoro-N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2- yljbenzenesulfonamide, N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphtlialen-2-yl]-3-
(trifluoromethyl)benzenesulfonamide,
N-[(2i?)-5-methyl-8-(4-methylpiperazm-l-yl)-l,2,3,4-tetrahydronaphthalen-2-yl]-5- pyridin-2-ylthlophene-2-sulfonamide,
2-cyano-N-[(2iS)-5-methyl-8-(4-methylpiperazin-l-yI)-l,2,3,4-tetrahydronaphthalen-2- yl]benzenesulfonamide,
4-bromo-2-fluoro-N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4- tetrahydronaphtlialen-2-yl]benzenesulfonamide,
N-[3-( { [(2i?)-5-methyl-8-(4-methylpiperazin- 1 -yl)-l ,2,3 ,4-tetrahydronaphthalen-2- yl]amino}sulfonyl)phenyl]acetamide, 3-chloro-2-methyl-N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4- tetrahydronaphthalen-2-yl]benzenesulfonamide,
4-methoxy-N-[(2i?)-5-methyl-8-(4-methylpiperazm-l-yl)-l,2,3,4-tetrahydronaphthalen-2- yl]-2-nitrobenzenesulfonamide,
3-methoxy-N-[(2i?)-5-metliyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2- yljbenzenesulfonamide,
N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrab.ydronaphthalen-2-yl]-2-
(phenylsulfonyl)benzenesulfonamide,
(E)-N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2-yl]-2- phenylethylenesulfonamide, 2-methoxy-4-methyl-iV'-[(2JR)-5-methyl-8-(4-methylpiperazin- 1 -yl)- 1 ,2,3 ,4- tetrahydronaplithalen-2-yl]benzenesulfonamide,
3-(difluoromethoxy)-iV-[(2i?)-5-methyl-8-(4-methylpiperazm-l-yl)-l,2,3,4- tetrahydronaphthalen-2-yl]benzenesulfonamide,
4-bromo-3-fluoro-iV-[(2i?)-5-methyl-8-(4-methylρiρerazin-l-yl)-l,2,3,4- tetrahydronaphthalen-2-yl]benzenesulfonamide,
N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaρlithalen-2-yl]-5-(l,2,3- thiadiazol-4-yl)thiophene-2-sulfonamide, and methyl 2,5-dimethyl-4-( { [(25)-5-methyl-8-(4-methylpiperazin- 1 -yl)-l ,2,3,4- tetrahydronaphthalen-2-yl]amino} sulfonyl)-3 -furoate, or salts, solvates or solvated salts thereof.
For the avoidance of doubt it is to be understood that where in this specification a group is qualified by 'hereinbefore defined', 'defined hereinbefore' or 'defined above' the said group encompasses the first occurring and broadest definition as well as each and all of the other definitions for that group.
For the avoidance of doubt it is to be understood that in this specification 'C1-6' means a carbon group having 1, 2, 3, 4, 5 or 6 carbon atoms.
The term "Cm-n" or "C1n-1, group" used alone or as a prefix, refers to any group having m to n carbon atoms.
The term "alkyl" used alone or as a suffix or prefix, refers to a saturated monovalent straight or branched chain hydrocarbon radical comprising from 1 to about 10 carbon atoms. Illustrative examples of alkyls include, but are not limited to, C^alkyl groups, such as methyl, ethyl, propyl, isopropyl, 2-methyl-l -propyl, 2-methyl-2-propyl, 2-methyl-l- butyl, 3 -methyl- 1 -butyl, 2-methy 1-3 -butyl, 2,2-dimethyl-l -propyl, 2-methyl-l -pentyl, 3- methyl-1-pentyl, 4-methyl-l-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2- pentyl, 2,2-dimethyl-l -butyl, 3,3-dimethyl-l-butyl, 2-ethyl-l -butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, and hexyl, and longer alkyl groups, such as heptyl, and octyl.
The term "C0" means a bond or does not exist. For example "arylCoalkyf ' is equivalent with "aryl" and "C2alkylOC0alkyl" is equivalent with "C2alkylO".
As used herein, "alkenyl" refers to an unsaturated carbon chain having one or more double carbon-carbon bonds and includes both straight and branched chain alkenyl groups. Example on alkenyl groups includes, but is not limited to, vinyl, allyl, propenyl, butenyl, , pentenyl, or hexenyl, and a butenyl group may for example be buten-2-yl, buten-3-yl or buten-4-yl. As used herein, "alkynyl" refers to an unsaturated carbon chain having one or more triple carbon-carbon bonds and includes both straight and branched chain alkynyl groups. Example on alkynyl groups includes, but is not limited to, etynyl, propargyl, pentynyl or hexynyl and a butynyl group may for example be butyn-3-yl or butyn-4-yl.
As used herein, the term "alkoxy", unless stated otherwise, refers to radicals of the general formula -O-R, wherein R is selected from a hydrocarbon radical. The term "alkoxy" may include, but is not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, isobutoxy, cyclopropylmethoxy, allyloxy or propargyloxy.
In this specification, unless stated otherwise, the term "amine" or "amino" refers to radicals of the general formula -NRR', wherein R and R' are selected independently from hydrogen or a hydrocarbon radical.
In this specification, unless stated otherwise, the term "cycloalkyl" refers to an optionally substituted, partially or completely saturated monocyclic, bicyclic or bridged hydrocarbon ring system. The term "C3-8cycloalkyl" may be, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl or norbornyl.
In this specification, unless stated otherwise, the term "heterocycloalkyl" refers to an optionally substituted, partially or completely saturated monocyclic, bicyclic or bridged hydrocarbon ring system containing at least one heteroatom selected independently from N, O or S.
In this specification, unless stated otherwise, the term "aryl" refers to an optionally substituted monocyclic or bicyclic hydrocarbon ring system with at least one unsaturated aromatic ring. Examples of "aryl" may be, but are not limited to phenyl, naphthyl or tetralinyl.
In this specification, unless stated otherwise, the term "heteroaryl" refers to an optionally substituted monocyclic or bicyclic hydrocarbon ring system with at least one unsaturated aromatic ring and containing at least one heteroatom selected independently from N, O or S. Examples of "heteroaryl" may be, but are not limited to pyridyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, tbiazolyl, pyrazolyl, benzofuryl, indolyl, isoindolyl, benzimidazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, tetrazolyl, triazolyl, quinazolinyl or isotiazolyl. For the avoidance of doubt, a Csheteroaryl refers to a 5 membered aromatic ring system containing at least one heteroatom.
In this specification, unless stated otherwise, the terms "arylalkyl" and "heteroarylalkyl" refer to a substitαent that is attached via the alkyl group to an aryl or heteroaryl group.
In this specification, unless stated otherwise, the terms "halo" and "halogen" may be fluoro, iodo, chloro or bromo.
In this specification, unless stated otherwise, the term "haloalkyl" means an alkyl group as defined above, which is substituted with halogen as defined above. The term "C1- 6haloalkyl" may include, but is not limited to fluoromethyl, difluoromethyl, trifiuoromethyl, fluoroethyl, difluoroethyl or bromopropyl. The term "C1-6haloalkylO" may include, but is not limited to fluoromethoxy, difluoromethoxy, trifluoromethoxy, fluoroethoxy or difluoroethoxy.
The present invention relates to the compounds of formula I as hereinbefore defined as well as to the salts, solvates or solvated salts thereof. Salts for use in pharmaceutical formulations will be pharmaceutically acceptable salts, but other salts may be useful in the production of the compounds of formula I.
A suitable pharmaceutically acceptable salt of the compounds of the invention is, for example, an acid-addition salt, for example a salt with an inorganic or organic acid. In addition, a suitable pharmaceutically acceptable salt of the compounds of the invention is an alkali metal salt, an alkaline earth metal salt or a salt with an organic base. Other pharmaceutically acceptable salts and methods of preparing these salts may be found in, for example, Remington's Pharmaceutical Sciences (18th Edition, Mack Publishing Co.). Some compounds of formula I may have chiral centres and/or geometric isomeric centres (E- and Z- isomers), and it is to be understood that the invention encompasses all such optical, diastereoisomeric and geometric isomers.
The invention also relates to any and all tautomeric forms of the compounds of formula I.
Methods of Preparation General procedure Throughout the following description of such processes it is to be understood that, where appropriate, suitable protecting groups will be added to, and subsequently removed from, the various reactants and intermediates in a manner that will be readily understood by one skilled in the art of organic synthesis. The specific sequence of reactions depicted under "General procedure" is not critical. For many of the compounds described the order of the reaction steps may be varied. The reactions are run until judged complete by LC-UV, LC- MS, TLC or NMR.
Figure imgf000021_0001
Step l A compound A, wherein R-* and R* are as defined above, and wherein PG is a protection group, such as, but not limited to, tert-butoxycarbonyl, benzyloxycarbonyl, 2,2,2- tricMoromethylcarbonyl, 2,2,2-trifIuoromethylcarbonyl, allyl, benzyl, phenethyl, p- methoxybenzyl, p-nitrobenzyl, diphenylmethyl, may be transformed into a compound B, wherein R3 and R4 are as defined above, by bromination using bromine in a solvent such as acetic acid, optionally in the presence of sodium acetate. Other solvents that may be used are for example water, dichloromethane or dioxane. The reaction may be performed at temperatures between 00C and the reflux temperature of the solvent. The product may be isolated by precipitation, extraction or column chromatography.
Step 2 A compound B, wherein R3 and R4 are as defined above and wherein PG is a protection group as defined above, may be transformed into a compound C, wherein R2, R3 and R4 are as defined above and wherein PG is a protection group (for examples on suitable PG see step 1) as defined above, by the reaction with an appropriate piperazine. The reaction may be performed without solvent (neat), or in a solvent, such as toluene, THF, dioxane, 1,2- dimethoxyethane, o-xylene, or mixtures thereof, in the presence of a catalyst, such as Pd(OAc)2, Pd2(dba)3, a ligand such as BINAP or bis(2-diphenylphosphinophenyl)ether, l,3-bis(diphenylphosphino)propane, tri-^-butylphosphine, and a base, such as sodium t- butoxide, caesium carbonate, potassium carbonate, potassium phosphate or lithium bis(trimethylsilyl)amide. The reaction may be run at temperatures between 4O0C and the reflux temperature of the solvent, preferably under inert atmosphere. The reaction may also be accelerated by the use of microwave irradiation. The product may be isolated by extraction, precipitation or column chromatography.
Step 3 A compound D, wherein R2, R3 and R4 are as defined above, may be transformed into a compound I by reaction with a compound E, wherein R1 and Q are as defined above, in a solvent, such as DMF, iV-methylpyrrolidinone, acetonitrile, dioxane, chloroform or dichloromethane, or mixtures thereof, in the presence of a base, such as pyridine, triethylamine, PS-DIEA or DIPEA, at temperatures between O0C and the reflux temperature of the solvent. The product may be isolated by precipitation, extraction or column chromatography. Intermediates
A further embodiment of the invention relates to compounds selected from the group consisting of (2i?)-N;>N-dibenzyl-5-bromo-8-methoxy-l,2,3,4-tetrahydronaphthalen-2-amine,
(2i?)-N:jV-dibenzyl-8-methoxy-5-(4-methylpiperazin- 1 -yl)- 1 ,2,3 ,4-tetrahydronaphthalen-2- amine,
(2i?)-8-memoxy-5-(4-methylpiperazm-l-yl)-l,2,3,4-tetiahydronaphthalen-2-amine,
N-[(25)-5-bromo-8-methoxy- 1 ,2,3 ,4-tetrahydronaphthalen-2-yl]-2,2,2-trifluoroacetamide, tert-butyl 4- {(6lS)-4-methoxy-6-[(trifluoroacetyl)amino]-5,6,7,8-tetrahydronaphthalen-l- yl}piperazine-l-carboxylate, and ter^buryl 4-[(6iS)-6-amino-4-methoxy-5,6,7,8-tetrahydronaphthalen-l-yl]piperazine-l- carboxylate, which may be used as intermediates in the preparation of compounds suited for the treatment of 5-HT6 mediated disorders, especially for use as intermediates for the preparation of compounds of formula I.
Pharmaceutical composition
According to one embodiment of the present invention there is provided a pharmaceutical composition comprising as active ingredient a therapeutically effective amount of the compound of formula I, or salts, solvates or solvated salts thereof, in association with one or more pharmaceutically acceptable diluents, excipients and/or inert carriers.
The composition may be in a form suitable for oral administration, for example as a tablet, pill, syrup, powder, granule or capsule, for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion) as a sterile solution, suspension or emulsion, for topical administration e.g. as an ointment, patch or cream, for rectal administration, e.g. as a suppository, or for inhalation.
In general, the above compositions may be prepared in a conventional manner using one or more conventional excipients, pharmaceutical acceptable diluents and/or inert carriers. Suitable daily doses of the compounds of formula I in the treatment of a mammal, including man, are approximately 0.01 to 250 mg/kg bodyweight at peroral administration and about 0.001 to 250 mg/kg bodyweight at parenteral administration.
The typical daily dose of the active ingredient varies within a wide range and will depend on various factors such as the relevant indication, severity of the illness being treated, the route of administration, the age, weight and sex of the patient and the particular compound being used, and may be determined by a physician.
Medical use Interestingly, it has been found that the compounds according to the present invention are useful in therapy. The compounds of the present invention as defined hereinabove, or pharmaceutically acceptable salts, solvates or solvated salts thereof, as well as their corresponding active metabolites, exhibit a high degree of potency and selectivity for 5- hydroxy-tryptamine 6 (5-HT6) receptors. Accordingly, the compounds of the present invention are expected to be useful in the treatment of conditions associated with excessive activation of 5-HT6 receptors.
The compounds the present invention may be used to produce an inhibitory effect of 5- HT6 receptors in mammals, including man.
The compounds of the present invention as defined hereinabove are expected to be suitable for the treatment of disorders relating to or affected by the 5-HT6 receptor including cognitive, personality, behaviour, psychiatric and neurodegenerative disorders.
Examples of such disorder may be selected from the group comprising of Alzheimer's disease anxiety, depression, convulsive disorders such as epilepsy, personality disorders, obsessive compulsive disorders, migraine, cognitive disorders such as memory dysfunction, sleep disorders, feeding disorders such as anorexia, obesity, bulimia, panic attacks, withdrawal from drug abuse, schizophrenia, attention deficit hyperactive disorder (ADHD), attention deficit disorder (ADD), dementia, memory loss, disorders associated with spinal trauma and/or head injury, stroke, diabetes type 2, binge disorders, bipolar disorders, psychoses, Parkinson's disease, Huntington's disease, neurodegenerative disorders characterized by impaired neuronal growth, and pain.
Further relevant disorders may be selected from the group comprising gastro-intestinal disorders such as gastroesophageal reflux disease (GERD) and irritable bowel syndrome (IBS).
A compound the present invention as defined hereinabove may also be used for treatment of tolerance to 5-HT6 activators.
One embodiment of the invention relates to a compound of the present invention as hereinbefore defined, for use in therapy.
Another embodiment of the invention relates to a compound of of the present invention as hereinbefore defined, for use in treatment of 5-HT6 mediated disorders.
A further embodiment of the invention relates to a compound of of the present invention as hereinbefore defined, for use in treatment of Alzheimer's disease.
Another embodiment of the invention relates to the compounds of of the present invention as hereinbefore defined, for use in treatment of cognitive impairment associated with schizophrenia.
Yet a further embodiment of the invention relates to a compound of the present invention as hereinbefore defined, for use in treatment of obesity.
One embodiment of the invention relates to a compound of the present invention as hereinbefore defined, for use in Parkinson's disease.
Another embodiment of the invention relates to the use of a compound of the present invention as hereinbefore defined, in the manufacture of a medicament for treatment of 5- HT6 mediated disorders, Alzheimer's disease, cognitive impairment associated with schizophrenia, obesity and/or Parkinson's disease, and any other disorder mentioned above.
A further embodiment of the invention relates to a method of treatment of 5-HT6 mediated disorders, Alzheimer's disease, cognitive impairment associated with schizophrenia, obesity and/or Parkinson's disease, and any other disorder mentioned above, comprising administering to a mammal, including man in need, of such treatment, a therapeutically effective amount of a compound of the present invention, as hereinbefore defined.
Yet another embodiment of the invention relates to a pharmaceutical composition comprising a compound of the present invention as hereinbefore defined, for use in treatment of 5-HT6 mediated disorders, Alzheimer's disease, cognitive impairment associated with schizophrenia, obesity and/or Parkinson's disease, and any other disorder mentioned above.
One embodiment of the invention relates to an agent for the prevention or treatment of 5- HT6 mediated disorders, Alzheimer's disease, cognitive impairment associated with schizophrenia, obesity and/or Parkinson's disease, and any other disorder mentioned above, which comprises as active ingredient a compound of the present invention as hereinbefore defined.
In the context of the present specification, the term "therapy" and "treatment" includes prevention and prophylaxis, unless there are specific indications to the contrary. The terms "treat'ytherapeutic" and "therapeutically" should be construed accordingly.
In this specification, unless stated otherwise, the terms "inhibitor" and "antagonist" mean a compound that by any means, partly or completely, blocks the transduction pathway leading to the production of a response by the agonist.
The compounds according to the present invention are modulators of the 5-HT6 receptors, and may be inhibitors, as well as agonists, inverse-agonists or partial-agonist. The term "disorder", unless stated otherwise, means any condition and disease associated with 5-HT6 receptor activity.
Non- Medical use
In addition to their use in therapeutic medicine, the compounds of formula I, or salts, solvates or solvated salts thereof, are also useful as pharmacological tools in the development and standardisation of in vitro and in vivo test systems for the evaluation of the effects of modulators of 5-HT6 related activity in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutics agents.
Examples General Methods s The invention will now be illustrated by the following non-limiting Examples in which, generally :
(i) operations were carried out at ambient or room temperature, i.e. in the range 17 to 25°C and under an atmosphere of an inert gas such as argon unless otherwise stated; o (ii) evaporations were carried out by rotary evaporation in vacuo and work-up procedures were carried out after removal of residual solids by filtration; (iii) HPLC analyses were performed on an Agilent HPl 000 system consisting of
G1379A Micro Vacuum Degasser, G1312A Binary Pump, G1367A Wellplate auto- sampler, G1316A Thermostatted Column Compartment and G1315B Diode Array 5 Detector. Column: X-Terra MS, Waters, 4.6 x 50 mm, 3.5 μm. The column temperature was set to 400C and the flow rate to 1.5 ml/min. The Diode Array Detector was scanned from 210-300 nm, step and peak width were set to 2 nm and 0.05 min, respectively. A linear gradient was applied, run from 0% to 100% acetonitrile, in 4 min. Mobile phase: acetonitriIe/10 mM ammonium acetate in 5 % o acetonitrile in MiIIiQ Water.
(iv) Thin layer chromatography (TLC) was performed on Merck TLC-plates (Silica gel 60 F254) and UV visualized the spots. Flash chromatography was preformed on a Combi Flash® Companion™ using RediSep™ normal-phase flash columns or on Merck Silica gel 60 (0.040-0.063 mm). Typical solvents used for flash chromatography were mixtures of chloroform/methanol, toluene/ethyl acetate and ethyl acetate/hexanes. (v) 1H and 13C NMR spectra were recorded at 400 MHz for proton and 100 MHz for carbon- 13 either on a Varian Unity+ 400 NMR Spectrometer equipped with a 5mm BBO probe with Z-gradients, or a Bruker Avance 400 NMR spectrometer equipped with a 60 μl dual inverse flow probe with Z-gradients, or a Bruker DPX400 NMR spectrometer equipped with a 4-nucleus probe equipped with Z-gradients. Unless specifically noted in the examples, spectra were recorded at 400 MHz for proton and 100 MHz for carbon- 13. The following reference signals were used: the middle line of DMSO-de δ 2.50 (1H); the middle line Of CD3OD δ 3.31 (1H); acetone-d6 2.04 (1H); and CDCl3 δ 7.26 (1H) (unless otherwise indicated); (vi) Mass spectra were recorded on a Waters LCMS consisting of an Alliance 2795 (LC) and a ZQ single quadrupole mass spectrometer. The mass spectrometer was equipped with an electrospray ion source (ESI) operated in a positive or negative ion mode. The capillary voltage was 3 kV and the mass spectrometer was scanned from m/z 100-700 with a scan time of 0.3 or 0.8 s. Separations were performed on either Waters X-Terra MS, C8-columns, (3.5 μm, 50 or 100 mm x 2.1mm i.d.), or a ScantecLab's ACE3AQ column (100mmx2.1mm i.d.). The column temperature was set to 40°C. A linear gradient was applied using a neutral or acidic mobile phase system, running at 0% to 100% organic phase in 4-5 minutes, flow rate 0.3 rnl/min. Mobile phase system: acetonitrile /[10 mM NH4OAc (aq.) / MeCN (95:5)], or [1OmMNH4OAc (aq.)/MeCN (1/9)] / [10mMNH4OAc(aq.)/MeCN(9/l,)]. Acidic mobile phase system: [133mMHCOOH(aq.)/MeCN(5/95)] /
[8mMHCOOH(aq.)/MeCN(98/2)];
(vii) Altenatively a LC-MS system (Sample Manager 2777C, 1525μ binary pump, 1500 Column Oven, ZQ, PDA2996 and ELS detector, Sedex 85) from Waters was used. Separation was performed using a Zorbax column (C8, 3.0 x 50 mm, 3 μm). A four minutes linear gradient was used starting at 100 % A (A= 10 mM NH4OAc in 5%
MeOH) and ending at 100% B (MeOH). The ZQ was equipped with a combined APPI/APCI ion source and scanned in the positive mode between m/z 120-800 with a scan time of 0.3 s. The APPI repeller and the APCI corona were set to 0.86 kV and 0.80 μA, respectively. In addition, the desolvation temperature (3000C), desolvation gas (400 L/Hr) and cone gas (5 L/Hr) were constant for both APCI and APPI mode;
(viii) Preparative chromatography was run on a Gilson auto-preparative HPLC with a diode array detector. Column: XTerra MS C8, 19x300mm, 7μm. Gradient with acetonitrile/O.lM ammonium acetate in 5 % acetonitrile in MiUiQ Water, run from 20% to 60% acetonitrile, in 13 min. Flow rate: 20 ml/min. Alternatively, purification was achieved on a semi preparative Shimadzu LC-8A HPLC with a
Shimadzu SPD-IOA UV-vis.-detector equipped with a Waters Symmetry® column (C 18, 5 μm, 100 mm x 19 mm). Gradient with acetonitrile/0.1% trifluoroacetic acid in MiUiQ Water, run from 35% to 60% acetonitrile in 20 min. Flow rate: 10ml/min; (ix) For the compounds in example 36-151 the following eqipment was used: The s structure and purity of all intermediates were assessed by HPLC and NMR analysis.
1H NMR spectra were determined using a 300MHz and/or 400MHz Varian Unity Inova spectrometer with 4-nucleus 5mm probes installed. LC/MS were performed on Agilent 1100 series HPLC equipped with a 4.6x50 3.5micron XTerra® MS C8 analytical reverse-phase column (Waters), using a gradient of acetonitrile and a o solution of 0.2% 880 ammonia in water at 2ml/min. Agilent MSD APCI was used for MS detection; both positive and negative ion data were collected when appropriate. All purities of the final products were analysed using a Agilent 1100 series high throughout system, containing: Agilent 1100 series well plate handler, Agilent 1100 series autointerface, Agilent 1100 series well plate autosampler, 2 x 5 Agilent 1100 series binary pumps, Agilent 1100 series thermostatted column compartment, Agilent 1100 series diode array detector, Agilent 1100 series mass spectrometer. The stationary phase used was 4.6 x 20 mm XTerra® MS C8 IS columns (Waters) analytical reversed-phase column and the mobile phase used was 0.1% 880 ammonia and acetonitrile with UV detection at 220nm, MS detection 0 with APCI ionisation in positive scan mode. The structures of the final products were confirmed by 1H NMR spectroscopy recorded using Varian Unity Inova 500 MHz spectrometer, equipped with a 60 ul triple resonance flow probe ant the samples were transferred to the flow cell by direct injection with a Gilson 215 liquids handler. Samples were prepared in 20 ul h6-DMSO + 170 ul dδ-DMSO to a final concentration of 2.6 mM. hβ-DMSO is used for the push solvent. Proton NMR spectra were acquired with WET solvent suppression on both the DMSO and H2O signals, using Scout-Scan to find the solvent resonances. Spectra were acquired at
25°C;
(x) AU solvents used were analytical grade and commercially available anhydrous solvents for reactions. Reactions were typically run under an inert atmosphere of nitrogen or argon; yields, where present, are not necessarily the maximum attainable;
(xii) intermediates were not necessarily fully purified but their structures and purity were assessed by thin layer chromatographic, HPLC, infra-red (IR), MS and/or NMR analysis;
(xiϋ) melting points are uncorrected and were determined using a Mettler SP62 automatic melting point apparatus or an oil-bath apparatus; melting points for the end-products of the Formula I were determined after crystallisation from an. appropriate organic solvent or solvent mixture;
(xiv) the following abbreviations have been used:
HPLC high performance liquid chromatography
LC liquid chromatography
MS mass spectometry ret. time retention time
TFA trifluroacetic acid
TEA triethylamine
THF tetrahydrofurane
DMF dimethyforrnamide
DIPEA N,N-diisopropylethylamine
DMSO dimethylsulfoxide
NMP 1 -methyl-2-ρyrrolidinone
THF tetrahydrofuran
MeOH methanol
RT room temperature Na2SO4 sodium sulfate
EtOAc Ethyl acetate
H2O water
Throughout the following description of such processes it is to be understood that, where appropriate, suitable protecting groups, such as, but not limited to, ferf-butoxycarbonyl, benzyloxycarbonyl, 2,2,2-trichloromethylcarbonyl, 2,2,2 -trifluoromethylcarbonyl, allyl, benzyl, phenethyl, p-methoxybenzyl, p-nitrobenzyl, diphenylmethyl will be added to, and subsequently removed from, the various reactants and intermediates in a manner that will be readily understood by one skilled in the art of organic synthesis. The specific sequence of reactions depicted is not critical. For many of the compounds described the order of the reaction steps may be varied.
Starting materials s (2i?)-8-methoxy-l>2,3,4-tetrahydronaphthalen-2-amine hydrochloride (WO9734883); (25)- 5-(4-me%lpiperazm-l-yl)-l,2,3,4-tetrahydronaρhthalen-2-amine (WO9734883); (2i?)-5- methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthaIen-2-amine (WO9905134); tert-butyl 4-[(7i?)-7-amino-4-methyl-5,6,7,8-tetrahydronaphthalen-l-yl]piperazine-l- carboxylate (WO9905134); tert-Butyl 4-[(7i?)-7-amino-5,6,7,8-tetrahydronaphthalen-l- o yl]ρiperazine-l-carboxylate (WO9734883)
Other starting materials used were either available from commercial sources or prepared according to literature procedures.
5 Example 1
3-Chloro-iV-[(2J?)-8-metlioxy-5-(4-methylpiperazin-l-yl)-1.2,354- tetrahydronaphtha!en-2-yl]benzenesulfonamide
(2i?)-8-Methoxy-5-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2-amine (41 mg, 0.15 mmol) and TEA (23 μl, 0.16 mmol) were dissolved in dioxane (1 ml) and 3- 0 chlorobenzenesulfonyl chloride (22 μl, 0.16 mmol) was added. The mixture was stirred at ambient temperature for 20 h. Methanol was added and the mixture was purified by preparative HPLC to give the acetate of the title compound as a dry film (53 mg, 79%). 1H NMR (400 MHz3 CDCl3) δ ppm 7.90 (1 H, t) 7.80 (1 H, d) 7.56 (1 H, d) 7.44 - 7.49 (1 H, m) 6.95 (1 H3 d) 6.64 (1 H3 d) 4.86 (1 H3 br. s.) 3.73 (3 H3 s) 3.64 (1 H3 br. s.) 2.75 - 3.03 (10 H3 m) 2.60 - 2.70 (1 H, m) 2.51 (3 H3 s) 2.40 - 2.49 (1 H, m) 1.92 - 2.01 (1 H3 m) 1.67 - 1.78 (1 H3 m); ESI-MS m/z M+H+ 450, 452.
Example 2
4-Chloro-iV-[(2i?)-8-methoxy-5-(4-methyIpiperazin-l-yl)-l,2,S,4- tetrahydronaphthaIen-2-yI]benzenesulfonamide
The title compound was prepared according to the method described in Example 1 and a dry film (50 mg, 75%) was obtained.
1H NMR (600 MHz3 MeOD-^) δ ppm 7.82 - 7.85 (2 H3 m) 7.49 - 7.52 (2 H3 m) 6.89 (1 H3 d) 6.63 (1 H3 d) 3.70 (3 H3 s) 3.41 - 3.47 (1 H, m) 2.58 - 2.99 (10 H3 m) 2.50 - 2.57 (1 H3 m) 2.43 (3 H3 s) 2.33 - 2.39 (1 H3 m) 1.87 - 1.92 (1 H, m) 1.54 - 1.62 (1 H, m); ESI-MS m/z M+H+ 450, 452.
Example 3
3-Chloro-iV-[(2S)-5-(4-methylpiperazin-l-yl)-l,2,354-tetrahydronaphthalen-2- yljbenzenesulfonamide
(21S)-5-(4-Methylpiperazin-l-yl)-l323334-tetrahydronaphthalen-2-amine (24 mg, 0.10 mmol), 3-chlorobenzenesulfonyl chloride (16 μl, 0.11 mmol) and TEA (16 μl, 0.11 mmol) were dissolved in DMF (0.7 ml). The mixture was stirred at ambient temperature for 20 h. Methanol (0.2 ml) was added and the mixture was purified by preparative HPLC. The fractions containing product were pooled, the acetonitrile was removed by evaporation and the remaining aqueous solution was extracted with dichloromethane (3 times). The organic phase was dried (using Na2SO4) and the solvent was evaporated to give a dry film (16 mg, 38%).
1H NMR (400 MHz, MeOD-^) δ ppm 7.90 (1 H31) 7.83 (1 H3 d) 7.62 - 7.67 (1 H3 m) 7.54 - 7.59 (1 H3 m) 7.05 (1 H3 1) 6.90 (1 H, d) 6.71 (1 H3 d) 3.50 - 3.58 (1 H3 m) 2.81 - 3.00 (7 H3 m) 2.55 - 2.78 (5 H3 m) 2.44 (3 H3 s) 1.84 - 1.92 (1 H3 m) 1.56 - 1.67 (1 H3 m), ESI-MS m/z M+H" 420, 422.
Examples 4 3-Chloro-4-methyl-N-[(2S)-5-(4-methylpiperazin-l-yl)-l,2,3j4-tetrahydronaphthaIen- 2-yl]benzenesulfonamide
The title compound was prepared according to the method described in Example 3. The yield (%) was 62.
1HNMR (400 MHz, CDCl3) δ ppm 7.88 (1 H, s) 7.64 - 7.71 (1 H, m) 7.33 - 7.41 (1 H, m) 7.05 - 7.13 (1 H, m) 6.88 - 6.94 (1 H, m) 6.69 - 6.76 (1 H, m) 4.86 (1 H, br. s.) 3.64 (1 H, br. s.) 2.83 - 3.02 (6 H, m) 2.64 (6 H, br. s.) 2.46 (3 H, s) 2.37 - 2.42 (3 H, m) 1.98 - 2.04 (1 H, m) 1.66 - 1.79 (1 H, m) ESI-MS m/z M+H* 434, 436.
Example 5
5-Chloro-iV-[(25)-5-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2- yl]naphthaϊene-2-sulfonamide
The title compound was prepared according to the method described in Example 3. The yield (%) was 57.
1H NMR (400 MHz, CDCl3) δ ppm 8.49 (1 H, d) 8.42 (1 H, d) 7.99 (1 H, dd) 7.90 (1 H, d) 7.75 (1 H, d) 7.54 (1 H, t) 7.06 (1 H, t) 6.90 (1 H, d) 6.70 (1 H, d) 5.16 (1 H, br. s.) 3.69 (1 H, br. s.) 2.54 - 3.03 (12 H, m) 2.48 (3 H, s) 1.91 - 2.00 (1 H, m) 1.69 - 1.80 (1 H, m) ESI- MS m/z M+H1" 470, 472.
Example 6
S-Chloro^-methyl-iV-JC^-^-S-piperazin-l-yl-l^jS^-tetrahydronaphthalen^- yl]benzenesulfonamide
3-Chloro-4-methyl-N-[(2S)-5-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2- yljbenzenesulfonamide (19 mg, 0.043 mmol) was dissolved in dichloroethane (0.6 ml) and chloroethyl chloroformate (15 μl, 0.13 mmol) was added. The mixture was heated at 80°C for 1 h using microwave irradiation. Chloroethyl chloroformate (150 μl, 1.3 mmol) was added and the mixture was heated at 13O0C for 1 h using microwave irradiation. Methanol (1 ml) was added and the mixture was stirred at ambient temperature for 20 h. The solvent was evaporated and the residue was purified by preparative HPLC to give a dry film (6.5 mg, 31%). 1H NMR (400 MHz5 MeOD-^) δ ppm 7.87 (1 H, d) 7.72 (1 H, dd) 7.50 (1 H, d) 7.09 (1 H, t) 6.94 (1 H, d) 6.77 (1 H, d) 3.46 - 3.55 (1 H, m) 3.24 - 3.36 (4 H, m) 2.86 - 3.14 (6 H, m) 2.58 - 2.69 (2 H, m) 2.47 (3 H, s) 1.87 - 1.92 (I H3 m) 1.58 - 1.69 (1 H, m); ESI-MS m/z M+H+ 420, 422.
Example 7
3-ChIoro-iV-[(2S)-5-piperazin-l-yl-l,2,3,4-tetrahydronaphthalen-2- yl]benzenesulfonamide
3-Chloro-N-[(2S)-5-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2- yl]benzenesulfonamide (215 mg, 0.512 mmol) was dissolved in chloroethyl chloroformate (1.66 ml, 15 mmol) and the mixture was heated at 1300C for 2 h using microwave irradiation. Methanol (3 ml) was added and the mixture was stirred at ambient temperature over night. The solvent was evaporated and the residue was purified by preparative HPLC to give a solid (38 mg, 18%). 1H ΝMR (400 MHz, CDCl3) δ ppm 7.90 (1 H, t) 7.80 (1 H, d) 7.56 (1 H, d) 7.44 - 7.50 (1 H, m) 7.10 (1 H51) 6.90 (1 H5 d) 6.77 (1 H, d) 3.60 - 3.67 (1 H, m) 3.20 (4 H, br. s.) 2.85 - 3.08 (7 H, m) 2.56 - 2.72 (2 H5 m) 1.92 - 2.00 (1 H5 m) 1.66 - 1.77 (1 H5 m); ESI-MS m/z M+H+ 406, 408.
Example 8
3-Chloro-iV-[(2S)-8-methoxy-5-piperazm-l-yl-l,2,3,4-tetrahydronaphthalen-2- yljbenzenesulfonamide
Example 8A tert-butyl 4-((6S)-6-{[(3-chlorophenyl)sulfonyl]amino}-4-methoxy-5,6, 7,8- tetrahydronaphthalen-l-ytypiperazine-l-carboxylate fert-Butyl 4-[(65)-6-amino-4-methoxy-5,657,8-tetrahydronaphthalen- 1 -yl]piperazine- 1 - carboxylate (150 mg, 0.41 mmol) and 3-chlorobenzenesulfonyl chloride (122 mg, 0.58 mmol) were dissolved in dichloromethane (8 ml). DIPEA (0.5 ml) was added and the mixture was stirred at ambient temperature for 1O h. Saturated aqueous sodium hydrogen carbonate was added and the phases were separated. The organic phase was dried (using Na2SO4) filtered and the solvent was evaporated. The residue was purified by column chromatography on silica eluting with gradients of EtOAc and heptane to give the intermediate ter^-butyl 4-((6JS)-6-{[(3-chlorόphenyl)sulfonyl]amino}-4-methoxy-5,6,7,8- tetrahydronaphthalen-l-yl)piperazine-l-carboxylate ESI-MS m/z M-HH+ 536, 538.
Example 8B 3-Chloro-N~[(2S)-8-methoxy-5-piperazin-l-yl-l, 2,3,4- s tetrahydronaphthalen-2-yl]benzenesulfonamide tert-Butyl 4-((6iS)-6- {[(3-chlorophenyl)suIfonyl]amino} -4-methoxy-5,63738- tetrahydronaphmalen-l-yl)piperazine-l-carboxylate3 obtained from Example 8A was dissolved in dichloromethane (10 ml) and TFA (1 ml) was added. The mixture was stirred at ambient temperature for 6 h. The solvent was evaporated and the residue was dissolved o in methanol. The solution was loaded on a SCX column and the column was eluted with 0.7 M ammonia in methanol. The solvent was evaporated and the residue was purified by column chromatography on silica eluting with gradients of 3% ammonia in methanol and chloroform to give a solid (54 mg, 30%). 1H NMR (400 MHz, MeOD-J4) δ ppm 7.88 - 7.91 (1 H, m) 7.81 - 7.85 (1 H, m) 7.62 - 7.66 s . (1 H, m) 7.53 - 7.59 (1 H, m) 6.89 (1 H, d) 6.67 (1 H, d) 3.71 (3 H3 s) 3.46 - 3.54 (1 H3 m) 2.88 - 3.00 (5 H3 m) 2.77 - 2.86 (3 H3 m) 2.71 (2 H3 br. s.) 2.53 - 2.63 (1 H, m) 2.32 - 2.41 (.1 H3 m) 1.81 - 1.89 (1 H, m) 1.52 - 1.63 (1 H, m); ESI-MS m/z MH-H+ 436, 438.
Examples 9 0 7V-[(2S)-8-methoxy-5-piperazin-l-yl-l,2,3,4-tetrahydronaphthalen-2-yl]-3,5- dimethylisoxazoIe-4-sulfonamide
The title compound was prepared according to the method described in Example 8. The yield was 30%.
1H NMR (400 MHz3 CDCl3) δ ppm 6.95 (1 H, d) 6.67 (1 H, d) 4.63 (1 H, br. s.) 3.76 (3 H, 25 s) 3.66 (1 H3 br. s.) 2.89 - 3.05 (6 H3 m) 2.68 - 2.86 (5 H3 m) 2.66 (3 H3 s) 2.49 - 2.58 (1 H3 m) 2.38 (3 H3 s) 1.97 - 2.07 (1 H, m) 1.71 - 1.82 (1 H, m) ESI-MS m/z M+H+ 421
Example 10 l-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-N-[(25)-8-methoxy-5-piperazin-l-yI- 30 l,2,3,4-tetrahydronaphthalen-2-yl]-lH-pyrrole-2-sulfonamide
The title compound was prepared according to the method described in Example 8. The yield was 30%. 1H NMR (400 MHz, CDCl3) δ ppm 8.70 (1 H, s) 8.15 (1 H3 d) 8.07 (1 H3 1) 7.55 - 7.58 (1 H, m) 6.92 (1 H3 d) 6.64 - 6.68 (2 H3 m) 4.48 (1 H3 d) 3.75 (3 H, s) 3.68 - 3.74 (1 H, m) 2.94 - 3.06 (6 H3 m) 2.66 - 2.85 (5 H3 m) 2.48 - 2.56 (1 H, m) 2.01 - 2.10 (1 H, m) 1.72 - 1.82 (1 H, m) ESI-MS m/z MH-H+ 570, 572.
Example 11
2,3-Dichloro-7V-[(2JR)-5-methyl-8-(4-methyIpiperazin-l-yl)-l,2,3,4- tetrahydronaphthalen-2-yl]benzenesu!fonamide
(2i?)-5-Methyl-8-(4-methylpiperazin-l-yl)-l323334-tetraliydronaphthalen-2-amine (100 mg, 0.39 mmol) and 2,3-dichlorobenzenesulfonyl chloride (100 mg, 0.41 mmol) were suspended in dichloromethane and DIPEA was added dropwise until a clear solution was obtained. The mixture was stirred for 1 h. MP-Trisamine (400 mg) was added and the mixture was stirred for 3 h. The mixture was filtered and the solvent was evaporated. The residue was purified by column chromatography on silica eluting with gradients of methanol in chloroform to give a solid (130 mg3 71%).
1H NMR (600 MHz3 CDCl3) δ ppm 8.10 (1 H3 dd) 7.72 (1 H3 dd) 7.39 - 7.42 (1 H3 m) 7.02 (1 H3 d) 6.90 (1 H, d) 5.19 (1 H3 d) 3.60 - 3.67 (1 H3 m) 2.88 - 3.14 (7 H3 m) 2.69 - 2.77 (2 H3 m) 2.57 - 2.68 (6 H, m) 2.16 (3 H, s) 1.95 - 2.02 (1 H3 m) 1.76 - 1.84 (1 H3 m); ESI-MS m/z M+H+ 4683 470.
Example 12 iV-[(2JΪ)-8-(4-Methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2-yl]naphthalene-2- sulfonamide
(2i?)-5-Methyl-8-(4-methylpiperazin-l-yl)-l3233,4-tetrahydronaphthalen-2-amine (70 mg, 0.29 mmol) and naphtalene-2-sulfonyl chloride (70 mg3 0.31 mmol) were dissolved in dichloromethane (3 ml) and DIPEA (1 ml) was added. The mixture was stirred at ambient temperature for 20 h. The solvent was evaporated and the residue was dissolved in dichloromethane. The mixture was washed with saturated aqueous ammonium chloride, dried (Na2SO4), filtered and the solvent was evaporated. The residue was purified by column chromatography on silica eluting with gradients of 2% ammonia in methanol and chloroform to give a solid (86 mg, 68%). 1HNMR (400 MHz, DMSCW6) δ ppm 8.48 (1 H, s) 8.15 (2 H, d) 8.05 (1 H, d) 7.95 (1 H, br. s.) 7.91 (1 H, dd) 7.63 - 7.73 (2 H3 m) 7.01 (1 H, t) 6.71 - 6.76 (1 H, m) 3.40 (1 H3 br. s.) 2.59 - 2.84 (6 H3 m) 2.37 - 2.45 (2 H3 m) 2.19 - 2.29 (1 H, m) 2.01 (3 H, s) 1.99 (3 H, br. s.) 1.86 (1 H3 br. s.) 1.55 - 1.67 (1 H, m); ESI-MS m/z MH-H+ 436.
Examples 13
3-chIoro-4-methyl-Λr-[(2i?)-8-(4-methylpiperazin-l-yl)-l,2,374-tetrahydronaphthalen-
2-yI]benzenesuIfonamide
The title compound was prepared according to the method described in Example 12. The yield was 60%.
1H NMR (400 MHz3 DMSO-J6) δ ppm 7.93 (1 H, br. s.) 7.85 (1 H3 d) 7.72 (1 H3 dd) 7.59 (1 H, d) 7.04 (1 H, t) 6.81 (1 H3 d) 6.76 (1 H3 d) 2.70 - 2.85 (5 H3 m) 2.46 - 2.60 (4 H3 m) 2.43 (3 H, s) 2.22 - 2.32 (4 H3 m) 2.21 (3 H3 s) 1.82 - 1.89 (1 H3 m) 1.55 - 1.66 (1 H3 m) ESI-MS m/z MH-H+ 434, 436.
Examples 14 « iV-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2- yl] naphthalene-2-sulfonamide
The title compound was prepared according to the method described in Example 12. The yield was 79%.
1H NMR (500 MHz3 DMSO-J6) δ ppm 8.47 (1 H, s) 8.15 (2 H3 d) 8.06 (1 H3 d) 7.94 (1 H3 d) 7.91 (1 H3 d) 7.72 (1 H, dd) 7.67 (1 H3 dd) 6.89 (1 H3 d) 6.70 (1 H3 d) 3.05-2.98 (1 H, m) 2.95-2.10 (11 H5 m) 2.06 (3 H3 s) 2.02 (3 H3 s) 1.95 - 1.88 (2 H3 m) 1.68-1.57 (1 H, m) ESI-MS m/z MH-H+ 450.
Example 15 l-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-N-[(2i?)-5-methyl-8-(4-methylpiperazin- l-yl)-l,2,3,4-tetrahydronaphthalen-2-yl]-lH-pyrrole-2-sulfonamide
The title compound was prepared according to the method described in Example 12. The yield was 64%.
1H NMR (400 MHz3 CDCl3) δ ppm 8.69 - 8.71 (1 H, m) 8.15 (1 H3 d) 8.08 (1 H3 dd) 7.59 (1 H, dd) 7.01 (1 H3 d) 6.87 (1 H, d) 6.67 (1 H, dd) 4.50 (1 H3 d) 3.70 - 3.79 (1 H3 m) 3.06 (1 H, dd) 2.61 - 2.90 (7 H, m) 2.51 (4 H, br. s.) 2.32 (3 H, s) 2.17 (3 H, s) 2.02 - 2.11 (1 H, m) 1.S2 - 1.93 (1 H, m)ESI-MS m/z MH-ET" 568, 570.
Example 16 5-ChIoro-iV-[(2i?)-5-methyl-8-piperazin-l-yl-l,2,3,4-tetrahydronaphthaϊen-2- yl]naphthalene-2-suIfonamide fert-Butyl 4-[(7i?)-7-amino-4-methyl-5,6,7,8-tetrahydronaphthalen-l-yl]piperazine-l- carboxylate (55 mg, 0.16 mmol) and 5-chloronaphthalene-2-sulfonyI chloride (45 mg, 0.17 mmol) were dissolved in dichloromethane (3 ml) and DIPEA (1 ml) was added. The mixture was stirred at ambient temperature for 20 h. The solvent was evaporated and the residue was dissolved in dichloromethane. The mixture was washed with saturated aqueous ammonium chloride, dried (Na2SO4), filtered and the solvent was evaporated. The residue was purified by column chromatography on silica eluting with gradients of EtOAc and heptane to give a solid. ESI-MS m/z M-HH+ 570, 572. The obtained solid was dissolved in s dichloromethane (3 ml) and TFA (1 ml) was added. The mixture was stirred at ambient temperature for 5 h. The solvent was evaporated and the residue was dissolved in > dichloromethane and washed with saturated aqueous sodium hydrogen carbonate. The organic phase was dried (Na2SO4), filtered and the solvent was evaporated. The residue was purified by column chromatography on silica eluting with gradients of 3% ammonia in o methanol and chloroform to give a solid (36 mg, 48%).
1R NMR (400 MHz, CDCl3) δ ppm 8.49 (1 H, s) 8.43 (1 H, d) 7.99 (1 H, dd) 7.90 (I H, d) 7.75 (1 H, d) 7.54 (1 H, t) 6.98 (1 H, d) 6.79 (1 H, d) 3.69 - 3.78 (1 H, m) 2.43 - 2.93 (12 H, m) 2.14 (3 H, s) 1.97 - 2.07 (1 H, m) 1.74 - 1.86 (1 H, m); ESI-MS m/z M-HH+ 470, 472.
5 Example 17 iV-[(2R)-5-Methyl-8-piperazm-l-yl-l,2,3,4-tetrahydronaphthalen-2-yl]naphthalene-2- sulfonamide
N-[(2i?)-5-Methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2- yl]naphthalene-2-sulfonamide (200 mg, 0.44 mmol) and chloroethyl chloroformate (0.20 0 ml, 1.8 mmol) were dissolved in dichloroethane (3 ml). The mixture was heated at 14O0C for 10 min using microwave irradiation. Methanol (5 ml) was added and the mixture was stirred at ambient temperature for 20 h. The solvent was removed and the residue was dissolved in dichloromethane and the mixture was washed with saturated aqueous sodium hydrogen carbonate. The organic phase was dried (Na2SO4), filtered and the solvent was evaporated. The residue was purified by column chromatography on silica eluting with gradients of 3% ammonia in methanol and chloroform to give a solid (105 mg, 55%). 1H NMR (400 MHz, CDCl3) δ ppm 8.48 (1 H, s) 7.93 - 8.02 (3 H, m) 7.88 (1 H, dd) 7.60 - 7.70 (2 H, m) 6.99 (1 H, d) 6.79 (1 H, d) 4.62 (1 H, br. s.) 3.76 (1 H, br. s.) 2.89 (1 H, dd) 2.55 - 2.75 (10 H, m) 2.48 (1 H, dd) 2.15 (3 H, s) 1.96 - 2.05 (1 H, m) 1.75 - 1.86 (1 H, m); ESI-MS m/z M+H* 436.
Example 18
2,6-Dichloro-iV-[(2JR)-5-methyI-8-piperazin-l-yl-l,2,3,4-tetrahydronaphthalen-2- yl]benzenesulfonamide fer?-Bu1yl 4-[(7i?)-7-amino-4-methyl-5,6,7,8-tetrahydronaphthalen-l-yl]piperazine-l- carboxylate (87 mg, 0.25 mmol) was dissolved in dichloromethane (2 ml) and DIPEA (52 μl, 0.30 mmol) and 2,6-dichlorobenzenesulfonyl chloride (68 mg, 0.28 mmol) were added. The mixture was stirred for 4 h. The solvent was evaporated and the residue was dissolved in dichloromethane (2 ml) and TFA (0.24 ml) was added. The mixture was stirred at ambient temperature for 15 h. The mixture was concentrated and EtOAc was added. The mixture was washed with aqueous sodium hydroxide (pH 8-9), dried (Na2SO4), filtered and the solvent was evaporated. The residue was purified by preparative HPLC to give a dry film (6.5 mg, 5%).
1H NMR (400 MHz, MeOD-^) δ ppm 7.58 (2 H, d) 7.48 (1 H, d) 6.97 (1 H, d) 6.81 (1 H, d) 3.53 - 3.61 (1 H, m) 3.01 - 3.17 (5 H, m) 2.91 - 2.98 (2 H, m) 2.74 - 2.88 (3 H, m) 2.54 - 2.63 (2 H, m) 2.14 (3 H, s) 1.96 - 2.04 (1 H, m) 1.74 - 1.85 (1 H, m); ESI-MS m/z M+H1" 454, 456, 458. Examples 19-27 were prepared according to the method described in Example 18.
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Example 28
JV-[4-MethyI-5-({[(2JR)-5-methyI-8-piperazin-l-yl-l^,354-tetrahydronaphthalen-2- yl] amino} sulfonyl)-l ,3-thiazoI-2-yI] acetamide tert-Bxάyl 4-[(7i?)-7-amino-4-methyl-5,6,7,8-tetrahydronaphthalen-l -yl]piperazine-l - carboxylate (87 mg, 0.25 mmol) was dissolved in dichloromethane (2 ml) and DIPEA (0.36 ml, 2.0 mmol) was added followed by 2-(acetylamino)-4-methyl-l,3-thiazole-5- sulfonyl chloride (70 mg, 0.28 mmol). The mixture was stirred at ambient temperature for 1.5 h. Triethylsilyl chloride (0.38 ml, 3.0 mmol) and lithium iodide (400 mg, 3.0 mmol) were stirred for 1.5 h and then added to the reaction mixture. The resulting mixture was stirred an additional 1.5 h at ambient temperature. Methanol (2 ml) and DIPEA (0.6 ml) were added. The solvent was evaporated and the residue was purified by preparative HPLC to give the acetate of the title compound as a solid (28 mg, 21%).
1H NMR (400 MHz, MeOD-^) δ ppm 6.99 (1 H, d) 6.86 (1 H3 d) 3.45 - 3.54 (1 H, m) 3.20 - 3.26 (4 H, m) 3.11 - 3.19 (1 H, m) 2.97 - 3.05 (2 H, m) 2.76 - 2.94 (3 H, m) 2.51 - 2.68 (2 s H, m) 2.48 (3 H, s) 2.23 (3 H, s) 2.16 (3 H, s) 1.99 - 2.07 (1 H, m) 1.71 - 1.82 (1 H, m); ESI-MS m/z M+H+ 464.
Example 29
2,4-Dimethyl-iV-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4- o tetrahydronaphthalen-2-yI]-l,3-thiazole-5-sulfonamide
(2i?)-5-Methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2-amine (50 mg, 0.20 mmol) was dissolved in dichloromethane (3 ml) and DIPEA (105 μl, 0.60 mmol) was added. 2,4-Dimethyl-l,3-thiazole-5-sulfonyl chloride (63 mg, 0.30 mmol) was added slowly and the mixture was stirred at ambient temperature for 40 min. The solvent was 5 evaporated and the residue was purified by column chromatography on silica eluting with ammonia in methanol and chloroform to give a solid (69 mg, 72%). 1H NMR (400 MHz, CDCl3) δ ppm 7.03 (1 H, d) 6.89 (1 H, d) 4.71 (1 H, d) 3.74 - 3.82 (1 H, m) 2.98 (1 H, dd) 2.87 (4 H, br. s.) 2.59 - 2.73 (8 H, m) 2.58 (3 H, s) 2.43 (4 H, br. s.) 2.18 (3 H, s) 1.98 - 2.07 (1 H, m) 1.82 - 1.92 (1 H, m); ESI-MS m/zM+tf 435. 0 Example 30
7V-[(2i?)-5-MethyI-8-(4-methyIpiperazin-l-yl)-l,253,4-tetrahydronaphthalen-2-yl]-l,3- benzothiazole-6-sulfonamide
The title compound was prepared according to the method in example 29. s 1H NMR (400 MHz, CDCl3) δ ppm 9.23 (1 H, s) 8.60 (1 H, d) 8.28 (1 H, d) 8.04 (1 H3 dd) 6.99 (1 H, d) 6.85 (1 H, d) 4.79 (1 H, d) 3.68 - 3.78 (1 H, m) 2.57 - 2.98 (11 H, m) 2.41 - 2.56 (4 H, m) 2.15 (3 H, s) 1.93 - 2.02 (1 H, m) 1.74 - 1.84 (1 H, m); ESI-MS m/z M+H* 457.
o Example 31
5-Chloro-iV-[(2R)-8-piperazin-l-yl-l,2,3,4-tetrahydronaphthalen-2-yl}naphthaIene-2- sulfonamide fer?-Butyl 4-[(7J?)-7-amiπιo-5,6,7,8-tetrahydronaphthalen-l-yl]piperazme-l-carboxylate (250 mg, 0.75 mmol), 5-chloronaphtalene-2-sulfonyl chloride (193 mg, 0.74 mmol) and s pyridine (90 μl, 1.1 mmol) were stirred at ambient temperature in dichloromethane (1 ml) for 22 h. DIPEA (126 μl, 0.74 mmol) was added and the mixture was stirred at ambient temperature for 15 min. The solid formed was collected by filtration and washed with dichloromethane to give a solid (147 mg). The filtrate was washed with aqueous citric acid, water and aqueous saturated sodium hydrogen carbonate. The organic phase was dried o (Na2SO4) and the solvent was evaporated. The residue was recrystallized from EtOAc and hexane to give additional solid (183 mg). The combined solids (325 mg) were dissolved in dichloromethane (1 ml) and TFA (1 ml) was added. The mixture was stirred at ambient temperature for 45 min. The solvents were evaporated and the residue was dissolved in DMF and methanol and piperazine (0.5 mmol) was added. The mixture was purified by 5 preparative HPLC to give the acetate of the title compound as solid (152 mg, 57%).
1R NMR (400 MHz, CDCl3) δ ppm 8.50 (1 H, s) 8.35 - 8.45 (1 H, m) 7.96 - 8.06 (1 H, m) 7.84 - 7.93 (1 H, m) 7.69 - 7.78 (1 H, m) 7.48 - 7.58 (1 H, m) 7.01 - 7.13 (1 H, m) 6.75 - 6.86 (2 H, m) 3.61 (1 H, m) 2.61 - 3.14 (10 H, m) 2.40 - 2.61 (1 H, m) 2.20 - 2.39 (1 H, m) 1.90 - 2.03 (1 H, m) 1.63 - 1.84 (1 H, m); ESI-MS m/z M+H* 456, 458.
30 Example 32
4-Chloro-Λ'-[(2JR)-8-piperazin-l-yl-l,2,3,4-tetrahydronaphthalen-2-ylInaphthalene-l- sulfonamide tert-Butyl 4-[(7i?)-7-amino-5,6,7,8-tetxahydronaphthalen-l -yl]piperazine-l -carboxylate (51 mg, 0.15 mmol), 4-chloronaphtalene- 1 -sulfonyl chloride (40 mg, 0.15 mmol) and pyridine
(18 μl, 0.23 mmol) were stirred at ambient temperature in dichloromethane (1 ml) for 4 h.
DIPEA (26 μl, 0.15 mmol) was added and the mixture was stirred at ambient temperature for 20 h. The solvent was evaporated and the mixture was purified by column chromatography on silica eluting with gradients of EtOAc and heptane to give a solid (77 mg). The solid was dissolved in dichloromethane (1 ml) and TFA (1 ml) was added. The mixture was stirred for 1.5 h. Toluene (1 ml) was added and the solvents were evaporated.
The residue was purified by preparative HPLC to give the acetate of the title compound as a solid (64 mg, 93%).
1R NMR (400 MHz3 DMSO- d6) δ ppm 8.81 (1 H, m) 8.40 (1 H, m) 8.16 (1 H, d) 7.82 - 7.89 (3 H, m) 6.99 (1 H, t) 6.66 - 6.72 (2 H, m) 3.29 (1 H, m) 2.26 - 2.83 (11 H, m) 2.13 (1
H, m) 1.73 - 1.83 (1 H, m) 1.49 - 1.61 (1 H, m); ESI-MS m/z M+H+ 456, 458.
Example 33
5-Chloro-iV-[(2JR)-8-piperazin-l-yl-l,2,354-tetrahydronaphthalen-2-yl]naphthalene-l- sulfonamide
The title compound was prepared according to the method described in Example 32. 1H NMR (400 MHz, CDCl3) δ ppm 8.64 (1 H, d) 8.57 (1 H, d) 8.38 (1 H, d) 7.73 (1 H, d) 7.62 - 7.69 (1 H, m) 7.52 - 7.59 (1 H, m) 7.01 - 7.09 (1 H, m) 6.71 - 6.82 (2 H, m) 3.47 - 3.57 (1 H, m) 2.52 - 3.17 (m, 11 H) 2.41 (1 H, m) 1.74 - 1.86 (1 H, m) 1.49 - 1.64 (1 H, m) ESI-MS m/z M+H* 456, 458.
Example 34 l-(3-Chlorophenyl)-iV-[(2i?)-8-piperazin-l-yl-l,2,3,4-tetrahydronaphthalen-2- yl] methanesulfonamide The title compound was prepared according to the method described in Example 32. but no pyridine was added and 2.5 eq of DIPEA was used. 1B NMR (400 MHz, CDCl3) δ ppm 7.28 - 7.3S (4 H, m) 7.16 (1 H, t) 6.93 (1 H, d) 6.90 (1 H, d) 4.21 - 4.29 (2 H, m) 3.57 - 3.65 (1 H, m) 3.18 - 3.26 (4 H, m) 3.08 (1 H, dd) 2.95 - 3.04 (4 H, m) 2.84 - 2.92 (2 H, m) 2.66 (1 H, dd) 2.02 - 2.10 (1 H, m) 1.71 - 1.83 (1 H3 m) ESI-MS m/z M+H1" 420, 422.
Example 35
2-(4-ChIorophenyl)-iV-[(2i?)-8-piperazin-l-yI-l,2,3,4-tetrahydronaphthalen-2- yl] ethanesulfonamϊde
The title compound was prepared according to the method described in Example 32 but no pyridine was added and 2.5 eq of DIPEA was used.
1H NMR (400 MHz, CDCl3) δ ppm 7.26 - 7.32 (2 H, m) 7.11 - 7.20 (3 H3 m) 6.88 - 6.94 (2 H3 m) 3.77 - 3.86 (1 H3 m) 3.26 - 3.33 (2 H3 m) 3.05 - 3.16 (7 H, m) 2.89 - 2.96 (6 H, m) 2.70 (1 H, dd) 2.05 - 2.14 (1 H, m) 1.77 - 1.88 (1 H3 m) ESI-MS m/z M+H÷ 434, 436.
Example 36 iV-[(2R)-5-Methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2- yl] benzenesulf onamide
To a solution of (2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,233,4-tetrahydronaphthalen-2- amine (25.9 mg, 0.10 mmol) and triethylamine (42 ul, 0.30mmol) in N- methylpyrrolidinone (0.5 ml) was added benzenesulfonyl chloride (0.10 mmol). The reaction was shaken for 18 hours at ambient temperature. The volatiles were removed under vacuum and the crude was dissolved in methanol and purified on Tosic-65 resin conditioned with methanol and the compound was eluted with a IN solution of ammonia in methanol. The solvents were removed under vacuum and the crude material was dissolved in DMSO and purified by reverse phase HPLC to give the title compound.
1H ΝMR (500 MHz3 DMSO-^) δ 7.86 (2 H3 d), 7.81 (1 H, d), 7.67 (1 H, dd), 7.63 (2 H, dd)3 6.93 (1 H3 d), 6.75 (1 H3 d), 3.10-2.90 (1 H3 m), 2.90-2.10 (11 H, m). 2.23 (3 H3 s), 2.07 (1 H, s), 1.90-1.82 (2 H3 m), 1.65-1.55 (1 H3 m); ESI-MS m/z MH-H+ 400. Examples 37-61 were prepared using the method described in Example 36.
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Examples 62-151 were prepared using the method described in Example 36.
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Intermediate 1 (22?)-5-Bromo-8-methoxy-l,2,3,4-tetrahydronaphthalen-2-amine
(2i?)-8-Methoxy-l,2,3,4-tetrahydronaphthalen-2-amine hydrochloride (10 g, 47 mmol) and sodium acetate (11.5 g, 140 mmol) were stirred in acetic acid (450 ml) under nitrogen atmosphere for 30 min. Bromine (2.52 ml, 49 mmol) was added and the mixture was stirred at ambient temperature for 10 min. The mixture was concentrated and EtOAC (700 ml) and aqueous ammonia was added. A solid formed in the aqueous phase. The mixture was stirred for 15 min and EtOAc (100 ml) and water (100 ml) were added. The mixture was shaken and the organic phase was decanted leaving the solids in the aqueous phase. The aqueous phase was diluted with water and the slurry was extracted with ether. The ether phase was dried (MgSO4) and the solvent was evaporated to give a solid (3.1 g). The pH in the remaining aqueous phase was adjusted to 12 by addition of 45% aqueous sodium hydroxide. The solid formed was isolated by filtration (3. 8 g). The solid from the ether extraction was combined with the solid isolated by filtration to give the title compound (6.9 g, 58%). EI-MS (70 eV) m/z M+ 255, 257. Intermediate 2 (2i?)-iVjiV-Dibenzyl-5-bromo-S-methoxy-l,2,3,4-tetrahydronaphthalen-2-amme
(2i?)-5-Bromo-8-methoxy-l,233,4-tetrahydronaphthalen-2-amine (7.0 g, 27 mmol) potassium iodide (100 mg, 0.60 mmol) and potassium carbonate (15 g, 108 mmol) were mixed in anhydrous actonitrile (400 ml) under nitrogen atmosphere. Benzylbromide (7.1 ml, 60 mmol) was added and the mixture was heated at reflux for 14 h. The mixture was filtered and the filtrate was concentrated by evaporation. Diethyl ether was added and the mixture was washed with aqueous ammonia (2M) and brine. The organic phase was dried (MgSO4) and the solvent was evaporated. The residue was purified by column chromatography on silica eluting with dichloromethane: hexane 1 :4 to give an oil that solidified upon storage (10 g, 85 %). m.p.l00-101°C; EI-MS (70 eV) m/z M+ 437, 439.
Intermediate 3
(2/?)-iVyV-Dϊbenzyl-8-methoxy-5-(4-methylpiperazin-l-yl)-l,2,3,4- tetrahydronaphthaIen-2-amine
(2i?)-N^-Dibenzyl-5-bromo-8-methoxy-l,2,3,4-tetrahydronaphthalen-2-amine (570 mg, 1.3 mmol) was dissolved in in toluene (13 ml). The mixture was put under nitrogen atmosphere and N-methylpiperazine (0.16 ml, 1.4 mmol) was added followed by BINAP (97 mg, 0.16 mmol) Pd2(dba)3 (71 mg, 0.08 mmol) and sodium t-butoxide (174 mg, 1.8 mmol). The mixture was heated at 850C under nitrogen atmosphere for 20 h. The mixture was filtered and the filtrate was concentrated. The residue was purified by chromatography on silica eluting with gradients of ammonia in methanol and chloroform to give a solid (0.39 g, 66%). ESI-MS m/z M+H4" 456.
Intermediate 4
(22?)-8-Methoxy-5-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2-amine
(2i?)-Nr/V'-Dibenzyl-8-methoxy-5-(4-methylpiperazin-l-yl)-l32,3,4-tetrahydronaphthalen-2- amine (392 mg, 0.86 mmol) was dissolved in methanol (20 ml) and ammonium formate (1.6 g, 25 mmol) was added. The mixture was put under nitrogen atmosphere and palladium on charcoal (10%, 100 mg) was added. The mixture was heated at 50°C for 6 h. The mixture was filtered and the solids were washed with methanol. The filtrate was concentrated, dichloromethane was added and the mixture was washed with aqueous sodium hydroxide (2M) and brine. The organic phase was dried (Na2SO4) and the solvent was evaporated to give a solid (170 mg, 71%). ESI-MS m/z M+ϊt 276.
Intermediate 5 2,2,2-Trifluoro-N-[(2i$)-8-methoxy-l,2,3,4-tetrahydronaphthaleπ-2-yl]acetamide
(2i?)-8-Methoxy-l,2,3,4-tetrahydronaphthalen-2-amine hydrochloride (23.3 g, 109 mmol) was suspended in dichloromethane (300 ml). DIPEA (44.5 ml, 255 mmol) was added and the reaction flask was placed in a room tempered waterbath. Trifluoroacetic anhydride (17.3 ml, 124 mmol) was added over 10 min and the reaction mixture was stirred for 2 h at o ambient temperature. The mixture was washed with saturated aqueous sodium hydrogen carbonate (χ3) dried (Na2SO4) and the solvent was evaporated to give a solid (21 g, 77%). ESI-MS m/z M+H+ 274.
Intermediate 6 s Ar-[(2iS)-5-Bromo-8-methoxy-l,2,3,4-tetrahydronaphthalen-2-yl]-2,2,2- trifluoroacetamide
2,2,2-Trifluoro-N-[(25)-8-methoxy-l,2,3,4-tetrahydronaphthalen-2-yl]acetamide (8.0 g, 29 mmol) and sodium acetate (7.4 g, 90 mmol) were dissolved in acetic acid (120 ml). Bromine (1.6 ml, 31 mmol) was dissolved in acetic acid (40 ml) and was added to the o reaction mixture over 2 h. The mixture was stirred for 1 h and then poured onto ice. The solid formed was isolated by filtration and washed with water. The solid was dissolved in dichloromethane and was washed with saturated aqueous sodium hydrogen carbonate, dried (Na2SO4) filtered and the solvent was removed to give a solid (8.8 g, 86%). ESI-MS m/z M-H+ 350, 352. 5
Intermediate 7 fer/-Butyl 4-{(6S)-4-methoxy-6-[(trifluoroacetyl)amino]-5,6,7,8-tetrahydronaphthalen- l-yl}piperazine-l-carboxylate iV-[(2<S)-5-Bromo-8-methoxy- 1 ,2,3 ,4-tetrahydronaphthalen-2-yl]-2,2,2-trifluoroacetamide 0 (5.0 g, 14.2 mmol) 4-Boc-piperazine (3.2 g, 17.2 mmol) Pd2(dba)3 (337 mg, 0.37 mmol) bis(2-diphenylphosphinophenyl)ether (398 mg, 0.74 mmol) and sodium 7-butoxide (4.09 g, 42.6 mmol) were suspended in toluene (90 ml). The mixture was heated at 1000C under argon atmosphere for 2 h. EtOAc was added and the mixture was washed with saturated aqueous sodium hydrogen carbonate (x2) dried, filtered and the solvent was evaporated. The residue was purified by column chromatography on silica eluting with gradients of EtOAc and heptane to give a solid (0.5 g, 7%). ESI-MS m/z M+H+ 458.
5
Intermediate 8 tert-Butyl 4-[(6iS)-6-amino-4-methoxy-5,6,7,8-tetrahydronaphthalen-l-yl]piperazine-
1-carboxylate tert-Butyl 4-{(65)-4-methoxy-6-[(trifluoroacetyl)amino]-5,6,7,8-tetrahydronaphthalen-l- io yl}piperazine- 1-carboxylate (490 mg) was dissolved in methanol (20 ml). Aqueous sodium hydroxide (2.5 M, 5 ml) was added and the mixture was stirred at ambient temperature for 4 days. The mixture was concentrated and dichloromethane was added. The organic layer was washed with aqueous sodium hydrogen carbonate, dried (Na2SO4) filtered and the solvent was evaporated to give the title compound (0.35 g). ESI-MS m/z M+ϊt 362.
I5
Pharmacology
Method for [125IJSB258585 binding to rat striatal 5-HT6 receptors Materials
[I25I]SB258585 (1) with specific radioactivity 2000 Ci/mmol was purchased from 2o Amersham Biosciences Europe GmbH, Freiburg, Germany. Other chemicals were purchased from commercial sources and were of analytical grade.
Preparation of membranes
Striatal tissue from adult rats (Sprague-Dawley, 320-370 g, B & K Sweden) were dissected 25 out, weighed and homogenized in buffer containing 50 mM Tris-HCl, 4 mM MgC12, 1 mM EDTA, 10 μM pargyline and protease inhibitor (Complete, Roche Diagnostics) pH 7.4 using an Ultra-Turrax T8 (IKA Labortechnik, Germany). The tissue homogenate was centrifuged at 48 OOOxg for 10 min and the pellet was resuspended and recentrifuged as above. The final membranes were diluted in buffer to a concentration of 60 mg original 30 wet weight (w.w.) per ml and stored in aliquots at -70°C. Radioligand binding assays
Saturation binding studies were carried out in duplicate with 1-3 mg w.w. per tube in 0.5 ml buffer (50 mM Tris, 4 mM MgC12, 100 mM NaCl, 1 mM EDTA, 5 mM ascorbate and 10 μM pargyline at pH 7.4), 0.2 nM [125I]SB258585 and unlabelled SB2585S5 to give a final concentration range of 0.23- 20 nM (12 cone). Non-specific binding was determined in the presence of 10 μM methiothepin. In the competition experiments 0.8-2 mg w.w. per tube and a radioligand concentration of 0.5-1 nM were used with 7 concentrations of the competing drug pre-dissolved in DMSO and diluted in buffer. The assays were incubated for 1-3 hours at room temperature, and terminated by rapid filtration through Whatman GF/B filters pretreated with 0.3% polyethyleneimine using a Brandel cell harvester. The radioactivity was determined in a Packard Tri-Carb 2900TR liquid scintillation counter. Data were analyzed by non-linear regression analyses using PRISM 4.00 (GraphPad Software Inc., San Diego, CA).
More informantion about the asay can be found in Hirst, W.D., Minton, J.A.L., Bromidge, S.M., Moss, S.F., Latter, A., Riley, G., Routledge, C, Middlemiss, D.N. & Price, G.W. (2000). Characterization of [125I]-SB-258585 binding to human recombinant and native 5- HT6 receptors in rat, pig and human brain tissue is described in Br. J. Pharmacol., 130, 1597-1605.
Results
Typical IC50 values as measured in the assays described above are 1 μM or less. In one aspect of the invention the IC50 is below 500 nM. In another aspect of the invention the IC5O is below 50 nM. In a further aspect of the invention the IC50 is below 10 nM.
Specimen results from assay.
Figure imgf000068_0001

Claims

1. A compound having the formula I, wherein:
Figure imgf000069_0001
Q is selected from C6-ioarylCo-6alkyl, Cs-πheteroarylCo-δalkyl, C3-8cycloalkylC0-6alkyl, C3- gheterocycloalkylCo-ealkyl, C2-6alkenyl and C2-ioalkyl;
R1 is selected from hydrogen, hydroxy, halogen, Ci-ioalkyl, C2-1oalkenyl, C2-ioalkynyl, C1- 10alkoxy, N(R5)2, C6-1oaxylCo-6alkyl, Cs-nheteroarylCo-δalkyl, C1-6haloalkyl, R5OCo-6alkyl, cyano, SR5, R6SO2C0-6alkyl, SOR6, R5CON(R5)C0-6alkyl, N(RS)SO2R5, COR6, R5CO2C0- 6alkyl, R5OC(O)C0-6alkyl, OSO2R5, C3-8cycloalkyl, C3^heterocycloalkyl, (R5)2NCOC0- βalkyl, SO2N(R5)2, N(R5)CON(R5)2, N(R7)COR8, NO2, OR5and oxo;
n is 0, 1, 2, 3 or 4;
R2 is selected from hydrogen, Chalky!, R7OC2-6alkyl, C1-6haloalkyl, cyanoCi-βalkyl, (R7)2NCOCi-6alkyl and R7CON(R7)C1-6alkyl;
R3 is selected from hydrogen, C^aUcyl, halogen, cyano, C1-6alkoxy, R7OC0-6alkyl, C1- ehaloalkyl, cyanoC1-6alkyl, NO2, (R7)2NCOC0-3alkyl or R7CON(R7)C0-3alkyl;
R4 is seleceted from hydrogen, C^alkyl, halogen, cyano, C1-6alkoxy, R7OCo-6alkyl, C1- ehaloalkyl, cyanoC1-6alkyl, NO2, (R7)2NCOC0-3alkyl and R7CON(R7)C0-3alkyl;
R5 is selected from hydrogen, C1-loalkyl,
Figure imgf000069_0002
Cs-scycloalkylCo-ealkyl, C3- sheterocycloalkylCo-δalkyl, C6-1oarylCo-6alkyl and Cs^heteroarylCo-ealkyl; R6 is selected from C1-10alkyl, Ci-6haloalkyl, C1-6alkoxy, C3-8cycloalkylC0-3alkyl, C3- sheterocycloalkylCo-ealkyl, Cδ-ioarylCo-salkyl and Cs-eheteroarylCo-salkyl; and
wherein any aryl, cycloalkyl, heterocycloalkyl or heteroaryl as defined for R1, R5 and R6 may be substituted by one or more groups independently selected from hydrogen, halogen, hydroxy, C1-3haloalkyl, cyano, OR8, C1-6atkyl, oxo, CON(R7)2, N(R7)CORS, SO2R8, SOR8, N(R7)2 and COR7;
R7 is hydrogen, C^alkyl or C1-6haloalkyl; and
R8 is C1-6alkyl or C1-6haloalkyl;
or pharmaceutically acceptable salts, solvates or solvated salts thereof.
2. The compound according to claim 1, wherein:
Q is selected from C6-ioaryICo-6alkyl, Cs-uheteroarylCo-galkyl, C^scycloalkylCo-δalkyl, C3-
8heterocycloalkylCo-6alkyl and C2.ioalkyl;
R1 is selected from hydrogen, halogen, Ci-10alkyl, Ci-10alkoxy, N(R5)2, C6-1oarylCo-6alkyl,
Cs-πheteroarylCo-ealkyl, C1-6haloalkyl, R5OC0.6alkyl, cyano, SR5. R6S02Co-6alkyl, N(R5)SO2R5, COR5, R5CO2C0-6alkyl, R5OC(O)C0-6alkyl, OSO2R5, C3-8cycloalkyl, C3- sheterocycloalkyl, (R5)2NCOC0-6alkyl, SO2N(R5)2, N(R5)CON(R5)2, N(R7)COR8, OR5,
NO2 and oxo; n is 0, 1, 2, 3 or 4;
R2 is selected from hydrogen, C^aUcyl, R7OC2-6alkyl and Ci-δhaloalkyl; R3 is selected from hydrogen, Chalky!, halogen cyano and Ci-6alkoxy;
R4 is selected from hydrogen, Chalky!, halogen, cyano, C1-6alkoxy, R7OC0-6alkyl, C1- ehaloalkyl, cyanoC1-6alkyl, NO2, (R7)2NCOC0-3alkyl and R7CON(R7)C0-3alkyl;
R5 is selected from hydrogen, Ci-ioalkyl, C1-6haloalkyl, C3-8cycloalkylCo-6alkyl, C3, sheterocycloalkylCo-όalkyl and C6-10arylCo-6alkyl; R6 is selected from C1-1OaIlCyI, C1-6haloalkyl,
Figure imgf000070_0001
C3-8cycloalkylCo-3atkyl and C3- 8heterocycloalkylCo-6alkyl; and wherein any aryl, cycloalkyl, heterocycloalkyl or heteroaryl as defined for R1, R5 and R6 may be substituted by one or more groups independently selected from hydrogen, halogen, hydroxy, C1-3haloalkyl, cyano, OR8, C1-6alkyl, oxo, CON(R7)2, N(R7)CORS, SO2R8, SOR8, N(R7)2 and COR7; R7 is hydrogen, C1-6alkyl or C1-6haloalkyl; and Rs is C1-6alkyl or Ci-6haloalkyl; or pharmaceutically acceptable salts, solvates or solvated salts thereof.
3. The compound according to claim 1 or claim 2, wherein: Q is selected from Cδ-ioarylCc.ealkyl, Cs-πheteroarylCo-δalkyl, C3-8cycloalkylC0-6alkyl and
C3-8heterocycloalkylCo-6alkyl;
R1 is selected from hydrogen, halogen, Ci-iOalkyl, C1-1OaIkOXy, N(R5)2, C6-loarylCo-6alkyl,
Cs-πheteroarylCo-ealkyl, Ci-6haloalkyl, R5OC0-6alkyl, cyano, SR5, R6SO2C0-6alkyl,
N(R5)SO2R5, COR5, R5CO2C0.6alkyl5 R5OC(O)C0.6alkyl, OSO2R5, C3-8cycloalkyl, C3- 8heterocycloalkyl, (R5)2NCOC0-6alkyl, SO2N(R5)2, N(R5)CON(R5)2, N(R7)COR8, OR5,
NO2 and oxo; ' n is O, 1, 2, 3 or 4;
R2 is selected from hydrogen, Ci^alkyl and Q-βhaloalkyl;
R3 is selected from hydrogen, C1-6alkyl, halogen and C1-6alkoxy; R4 is selected from hydrogen, C1-6alkyl, halogen, cyano and Ci-δalkoxy;
R5 is selected from hydrogen, C1-10alkyl, C3-8cycloalkylCo-6alkyl, C3-sheterocycloalkylCo-
6alkyl and Cg.ioarylCo-ealkyl;
R6 is selected from Q-ioalkyl, Ci-δhaloalkyl and C^alkoxy,; and wherein any aryl, cycloalkyl, heterocycloalkyl or heteroaryl as defined for R1, R5 and R6 may be substituted by one or more groups independently selected from hydrogen, halogen, hydroxy, d-3haloalkyl, cyano, OR8, C1-6alkyl, oxo, CON(R7)2, N(R7)COR8, SO2R8, SOR8,
N(R7)2 and COR7;
R7 is hydrogen; and
R8 is C1-6alkyl; or pharmaceutically acceptable salts, solvates or solvated salts thereof.
4. The compound according to any one of claims 1 to 3, wherein: Q is selected from Cδ-ioarylCo-βalkyl, Cs-πheteroarylCo-δalkyl, C3-8cycloalkylCo-6alkyl and
Cs-sheterocycloalkylCo^alkyl;
R1 is selected from hydrogen, halogen, Ci-10alkyl, C1-1OaIkOXy, Cs-πheteroarylCo-δalkyl, C1- 6haloalkyl, R5OC0-6alkyl, cyano, SR5, R6SO2C0-6alkyl, COR6, R5CO2C0-6alkyl, R5OC(O)C0- s 6alkyl, SO2N(R5)2, N(R7)COR8, OR5, NO2 and oxo; n is O, 1, 2 or 3;
R2 is hydrogen or C1-6alkyl;
R3 is hydrogen, Ci-βalkyl or C1^aIkOXy;
R4 is hydrogen, C1-6alkyl or C1-6alkoxy; o R5 is selected from hydrogen, Q.^alkyl and Cg-ioarylCo^alkyl;
R6 is selected from C1-1OaIlSyI, Ci-δhaloalkyl and C1^aIkOXy; and wherein any aryl, cycloalkyl, heterocycloalkyl or heteroaryl as defined for R1, R5 and R6 may be substituted by one or more groups independently selected from hydrogen, halogen, hydroxy, C1-3haloalkyl, cyano, OR8, C^alkyl, oxo, CON(R7)2, N(R7)COR8, SO2R8, SOR8, s N(R7)2 and COR7;
R7 is hydrogen; and
R8 is C1-6alkyl; or pharmaceutically acceptable salts, solvates or solvated salts thereof.
o
5. A compound according to any one of claims 1 to 4, wherein Q is phenyl.
6. A compound according to any one of claims 1 to 5, wherein
R > 2 is hydrogen or C1-3alkyl;
»3
R is hydrogen, C1-3alkyl or C1-3alkoxy; and 5 R »4 is hydrogen, C^alkyl or Ci-3alkoxy.
7. The compound according to claim 1, wherein:
Q is selected from Cβ-ioarylCo-salkyl, Cs-πheteroarylCo-salkyl, Cs-scycloalkylCo-salkyl or C2-4alkenyl and C2-salkyl;
30 R is selected from hydrogen, halogen, C1-4alkyl, C1-4alkoxy, C5-11heteroarylC0-3alkyl, C1. ehaloalkyl, R5OC0-3alkyl, cyano, R6SO2C0-3alkyl, R5CON(R5)C0-3alkyl, R5OC(O)C0-6alkyl, (R5)2NCOC0-3alkyl, SO2N(R5)2, NO2 and oxo; n is 0, 1, 2, 3 or 4;
R2 is hydrogen or C1-3alkyl;
R3 is hydrogen, C1-3alkyl or C^alkoxy;
R4 is hydrogen; • « R5 is hydrogen, C1-3alkyl, C1-3haloalkyl, C6-loarylCo-3alkyl or Cs-sheteroarylCooalkyl;
R6 is C^alkyl or C6-loarylCo-3alkyl; and wherein any aryl, cycloalkyl, heterocycloalkyl or heteroaryl as defined for R1, R5 and. R6 may be substituted by one or more groups independently selected from hydrogen, halogen, and C1-3haloalkyl; or pharmaceutically acceptable salts, solvates or solvated salts thereof.
8. A compound according to any one of claims 1 to 7, wherein n is 0, 1, 2 or 3.
9. Compounds selected from the group consisting of 3-chloro-N-[(2i?)-8-methoxy-5-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2- yl]benzenesulfonamide,
4-chloro-iV-[(2i?)-8-methoxy-5-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2- yljbenzenesulfonamide,
3-chloro-iV-[(2lS)-5-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2- yl]benzenesulfonamide,
3-chloro-4-methyl-iV-[(25)-5-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2- yl]benzenesulfonamide,
5-chloro-iV-[(25)-5-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2- yl]naphthalene-2-sulfonamide, 3-chloro-4-methyl-N-[(2.S)-5-piperazin-l-yl-l,2,3,4-tetrahydronaphthaIen-2- yl]benzenesulfonamide,
3 -chloro-iV-[(2»S)-5-piperazin- 1 -yl- 1 ,2,3 ,4-tetrahydronaphthalen-2-yl]benzenesulfonamide,
3-chloro-N-[(25)-8-methoxy-5-piperazin-l-yl-l,2,3,4-tetrahydronaphthalen-2- yl]benzenesulfonamide, N-[(25)-8-methoxy-5-piperazin-l-yl-l,2,3,4-tetrahydronaphthalen-2-yl]-3,5- dimethylisoxazole-4-sulfonamide, 1 -[3 -chloro-5-(trifluoromethyl)pyridin-2-yl]-N-[(25}-8-methoxy-5-piperazin- 1 -yl-1 ,2,3,4- tetrahydronaphthalen-2-yl]-lH-pyrrole-2-sulfonamide,
2,3-dichloro-iV-[(2i?)-5-methyl-8-(4-methylpiperazin- 1 -yl)- 1 ,2,3 ,4-tetrahydronaphthalen-2- yl]benzenesulfonamide, N-[(2i?)-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2-yl]naphthalene-2- . sulfonamide,
3-chloro-4-methyl-iV-[(2i?)-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2- yljbenzenesulfonamide,
• N-[(2i?)-5-methyl-8-(4-methylpiperazin-l -yl)- 1 ,2,3,4-tetrahydronaphthalen-2- yl]naphthalene-2-sulfonamide, l-[3-chloro-5-(trifluorome1iιyl)pyridin-2-yl]-N-[(2J^)-5-methyl-8-(4-methylpiperazin-l-yl)- l,2,3,4-tetrahydronaphthalen-2-yl]-lH-pyrrole-2-sulfonamide,
5-cHoro-N-[(2i?)-5-methyl-8-piperazin-l-yl-l,2,3,4-tetrahydronaphthalen-2- yl]naphthalene-2-sulfonamide, N-[(2i?)-5-methyl-8-piperazin-l-yl-l,2,3,4-tetrahydronaphthalen-2-yl]naphthalene-2- sulfonamide,
2,6-dichloro-N-[(2i?)-5-methyl-8-piperazin-l-yl-l,2,3,4-tetrahydronaphthalen-2- yljbenzenesulfonamide,
3,5-dimethyl-iV-[(2i?)-5-methyl-8-piperazin-l-yl-l,2,3,4-tetrahydronaphthalen-2- yl]isoxazole-4-sulfonamide,
2-chloro-6-methyl-iV"-[(2i?)-5-methyl-8-ρiperazin-l-yl-l,2,354-tetrahydronapb.thalen-2- yl]benzenesulfonamide,
2,6-difluoro-iV-[(2i?)-5.-methyl-8-piperazin-l-yl-l,2,3,4-tetrahydronaphthalen-2- yl]benzenesulfonamide, N-[(2i?)-5-methyl-8-piperazin-l-yl-l,2,3,4-tetrahydronaplithalen-2-yl]isoqumoline-5- sulfonamide,
5-chloro-l,3-dimetnyl-iV-[(2i?)-5-methyl-8-piperazin-l-yl-l,2,3,4-tetrahydronaphtlialen-2- yl] - 1 H-pyrazole-4-suIfonamide,
2,4-dimethyl-iV'-[(2i?)-5-methyl-8-piperazin-l-yl-l,2,3,4-tetraliydronaphthalen-2-yl]-l,3- thiazole-5-sulfonamide, l,3,5-trimethyl-iV'-[(2Λ)-5-methyl-8-piperazin-l-yl-l,23,4-te1xahydronaρhthalen-2-yl]-lH- pyrazole-4-sulfonamide, 4-bromo-2,5-dichloro-iV-[(2i2)-5-methyl-8-piperazin-l-yl-l,2,3J4-tetrahydronaphtlialen-2- yl]thiophene-3 -sulfonamide,
4-bromo-iV-[(2i?)-5-methyl-8-piperazm-l-yl-l,2,3,4-tetxahydronaplithalen-2-yl]thiophene-
3-sulfonamide, JV-[4-methyl-5-( {[(2i?)-5-methyl-8-piperazin-l -yl-l ,2,3,4-tetrahydronaphthalen-2- yl]amino} sulfonyl)-l ,3-thiazol-2-yl]acetamide,
2,4-dDime%l-N-[(2i?)-5-me%I-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-
2-yl]-l,3-thiazole-5-sulfonamide,
N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2-yl]-l,3- benzothiazole-6-sulfonamide,
5-chloro-iV-[(2i?)-8-piperazin-l -yl- 1 ,2,3,4-tetrahydronaphthalen-2-yl]naphthalene-2- sulfonamide,
4-chloro-iV-[(2i2)-8-piperazin-l-yl-l,2,3,4-tetrahydronaphtlialen-2-yl]naphthalene-l- sulfonamide, 5-chloro-iV-[(2i?)-8-piperazin- 1 -yl- 1 ,2,3 ,4-tetrahydronaphthalen-2-yl]naphthalene- 1 - sulfonamide, l-(3-chlorophenyl)-N-[(2i?)-8-piperazin-l-yl-l,2,3,4-tetrahydronaphthalen-2- yl]methanesulfonamide,
2-(4-chlorophenyl)-N-[(2i?)-8-piperazin-l-yl-l,2,3,4-tetrahydronaphtlialen-2- yl]ethanesulfonamide,
N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2- yl]benzenesulfonamide,
3-cyano-N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphtlialen-2- yl]benzenesulfonamide, 5-chloro- 1 ,3 -dimethyl-iV-[(2i?)-5-metliyl-8-(4-methylpiperazin- 1 -yl)-l ,2,3 ,4- tetrahydronaphthalen-2-yl]- 1 H-pyrazole-4-sulfonamide,
3,5-dimethyl-N-[(2i?)-5-methyl-8-(4-methylρiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-
2-yl]isoxazole-4-sulfonamide,
2,6-difluoro-N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2-' yl]benzenesulfonamide,
2-cMoro-4-fluoro-iV-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4- tetrahydronaphthalen-2-yl]benzenesulfonamide, N-[(2i?)-5-me%l-8-(4-methylρiperazin-l-yl)-l,2}3,4-tetrahydronaphthalen-2-yl]-2-
(trifluoromethyl)benzenesulfonamide,
5-chloro-2-methoxy-N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3;4- tetrahydronaphthalen-2-yl]benzenesulfonamide, iV-[(2i?)-5-methyl-δ-(4-methylpiperazin- 1 -yl)-l ,2,3,4-tetrahydronaphthalen-2-yl]-4- nitrobenzenesulfonamide, iV-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2-yl]-l- phenylmethanesulfonamide,
4-fluoro-N-[(2i?)-5-metihLyl-8-(4-methylpiperazin-l-yl)-l,2,3J4-tetrahydronaphthalen-2- yljbenzenesulfonamide,
Λr-[4-({[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2- yl]amino}sulfonyl)phenyl]acetamide,
2,5-difluoro-N-[(2i?)-5-methyl-8-(4-methylpiperazm-l-yl)-l,2,3,4-tetraliydronaphthalen-2- yl]benzenesulfonamide, methyl l-methyl-5-({[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4- tetrahydronaphthalen-2-yl]amino} sulfonyl)- 1 H-pyrrole-2-carboxylate,
4-chloro-2-fluoro-N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4- tetrahydronaphthalen-2-yl]benzenesulfonamide,
3,5-dimethyl-N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen- 2-yl]benzenesulfonamide, iV-[(2i?)-5-methyl-8-(4-me1iιylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2-yl]pyridine-
3 -sulfonamide,
5-bromo-2,4-difluoro-N-[(2i?)-5-methyl-8-(4-methylρiρerazin- 1 -yl)- 1 ,2,3 ,4- tetrahydronaphthalen-2-yl]benzenesulfonamide, 5-bromo-6-chloro-N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,334- tetrahydronaphthalen-2-yl]pyridine-3-sulfonamide, iV-[(2i?)-5-methyl-8-(4-methylpiperazin-l -yl)-l ,2,3,4-tetrahydronaphthalen-2-yl]- 1 - benzothiophene-3-sulfonamide,
4-bromo-2,5-difluoro-N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4- tetrahydronaphthalen-2-yl]benzenesulfonamide,
23,4-trifluoro-N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-
2-yl]benzenesulfonamide, Λr-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3J4-tetrahydronaphthalen-2- yl]thiophene-3-sulfonamide, iV-[(2i?)-5-methyl-S-(4-methylpiperazin- 1 -yl)-l ,2,3,4-tetrahydronaphthalen-2-yl]-4-
(methylsulfonyl)benzenesulfonamide, 2-cHoro-4-cyano-7V-[(2JR)-5-methyl-8-(4-methylpiperazin-l -yl)-l ,2,3,4- . tetrahydronaphthalen-2-yl]benzenesulfonamide,
6-cMoro-N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2- yl]imidazo[2, 1-b] [1 ,3]thiazole-5-sulfonamide,
4-chloro-iV-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetxahydronaphthalen-2- yl]benzenesulfonamide,
3-chloro-N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2- yl]benzenesulfonamide, l-(3-chlorophenyl)-N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4- tetrahydronaphthalen-2-yl]meth.anesulfonamide, N-[4-methyl-5-( {[(2i?)-5-methyl-8-(4-methylpiperazin-l -yl)- 1 ,2,3 ,4-tetrahydronaphthalen-
2-yl]amino}sulfonyl)-l,3-thiazol-2-yl]acetamide,
N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2- yl]thiophene-2-sulfonamide,
N-[(2i?)-5-me%l-8-(4-me1liylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2-yl]-3- nitrobenzenesulfonamide,
2,5-dimethoxy-N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-
2-yl]benzenesulfonamide,
5-bromo-2-methoxy-N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4- tetrahydronaphthalen-2-yl]benzenesulfonamide, iV-[(2i?)-5-methyl-8-(4-methylpiperazin- l-yl)-l ,2,3,4-tetrahydronaphthalen-2-yl]-4-
(phenylsulfonyl)thiophene-2-sulfonamide, iV-[(2JR)-5-methyl-8-(4-methylpiperazin- 1 -yl)-l ,2,3,4-tetrahydronaphthaϊen-2-yl]-5-
(phenylsulfonyl)thiophene-2-sulfonamide,
N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2-yl]-2,lJ3- benzothiadiazoIe-4-sulfonamide, iV-[(2JR)-5-methyl-8-(4-methylpiperazin-l -yl)- 1 ,2,3,4-tetrahydronaphthalen-2-yl]-2, 1 ,3- benzoxadiazole-4-sulfonamide, 5-isoxazol-3-yl-iV-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-lJ2,3,4- tetrahydronaphthalen-2-yl]thiophene-2-sulfonamide,
2-methyl-N-[(2i?)-5-methyl-8-(4-methylpiperazin- 1 -yl)- 1 ,2,3 ,4-tetrahydronaphthalen-2- yl]-5-nitrobenzenesulfonamide, '3-methyl-N-[(2i?)-5-meώyl-8-(4-meώylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2- yl]benzenesulfonamide,
2-methyl-N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2- yl]-4-nitrobenzenesulfonamide,
3-ciιloro-4-fluoro-iV-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4- tetrahydronaphthalen-2-yl]benzenesυlfonamide,
2,4-difluoro-N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,253,4-tetrahydronaphthalen-2- yl]benzenesulfonamide,
5-fluoro-2-methyl-N-[(2i?)-5-metb.yl-8-(4-methylpiperazin-l-yl)-l,2,3,4- tetrab.ydronaphthalen-2-yl]benzenesulfonamide, l-[(/5')4i?)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-l-yl]-N-[(2i?)-5-methyl-8-(4- methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2-yl]methanesulfonamide,
2-fluoro-N-[(2i2)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2- yljbenzenesulfonamide,
3 ,4-dimethoxy-N-[(2i?)-5 -methyl-8 -(4-methylpiperazin- 1 -yl)- 1 ,2,3 ,4-tetrahy dronaphthalen- 2-yl]benzenesulfonamide,
5-chloro-N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2- yl]thiophene-2-sulfonamide,
2-chloro-6-methyl-N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4- tetrahydronaphthalen-2-yl]benzenesulfonamide, 5-bromo-N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrah.ydronaphthalen-2- yl]thiophene-2-sulfonamide,
4-chloro-N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2-yl]-
3-nitrobenzenesulfonamide,
3-fluoro-N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2- yl]benzenesulfonamide,
N-[2-chloro-4-({[(2i?)-5-methyl-8-(4-me1liylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-
2-yl]amino}sulfonyl)phenyl]acetamide, 2-methoxy-5-methyl-iV-[(2i?)-5-methyl-8-(4-methylρiperazin-l-yl)-l,2,3,4- tetrahydronaphthalen-2-yl]benzenesulfonamide,
N-[(2i?)-5-methyl-8-(4-methylρiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2-yl]-2- nitrobenzenesulfonamide, 3,4,5-trimethoxy-N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4- tetrahydronaphthalen-2-yl]benzenesulfonamide,
4-bromo-N-[(2i?)-5-metiiyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrab.ydronaplithalen-2- yl]benzenesulfonamide,
2-bromo-N-[(2i?)-5-methyl-8-(4-methylpiperazm-l-yl)-l,2,3>4-tetrahydronaphthalen-2- yljbenzenesulfonamide,
N-[(2JR)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2-yl]-4-
(trifluoromethyl)benzenesulfonamide,
4-ethyl-iV-[(2^)-5-me%l-8-(4-methylpiperazm-l-yl)-l,2,3,4-tetrahydronaphtb.alen-2- yljbenzenesulfonamide, N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetraliydronaphthalen-2-yl]-2-nitro-4-
(trifluoromethyl)benzenesulfonamide,
4-methyl-N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2- yl]-3 -nitrobenzenesulfonamide, iV-[(2i?)-5-methyl-8-(4-niethylpiperazin-l-yl)-l,2,3,4-tetraliydronaphthalen-2- yl]naphthalene-l -sulfonamide,
7V-[(2i?)-5-metliyl-8-(4-methylpiperazin- 1 -yl)- 1 ,2,3 ,4-tetrahydronaphthalen-2-yl]-2-oxo- l,2,3,4-tetrahydroquinoline-6-sulfonamide, l-[(2i?^5)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-l-yl]-iV-[(2i?)-5-methyl-8-(4- methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2-yl]methanesulfonamide, 3,4-difluoro-N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,253'4-tetrahydronaphihalen-2- yl]benzenesulfonamide,
2-methyl-N-[(2i?)-5-me%l-8-(4-methylρiperaziii-l-yl)-l,2,3,4-tetrahydronaρhthalen-2- yljbenzenesulfonamide,
2,5-dimethyl-iV-[(2i?)-5-methyl-8-(4-methylpiperazm4-yl)-l)2,3,4-tetrahydronaphthalen- 2-yl]benzenesulfonamide, iV-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2J3,4-tetrahydronaphthalen-2-yl]-4-
(pyridin-3-yloxy)benzenesulfonamide, 4-chloro-2;5-dimethoxy-iV-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l52,3,4- tetrahydronaphthalen-2-yl]benzenesulfonamide,
6-chloro-iV'-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)4,2,3,4-tetrahydronaphthalen-2-yl]-
2H-1 ,2,4-benzothiadiazine-7-sulfonamide 1 , 1 -dioxide, methyl 2-methyl-5-({[(2i?)-5-methyl-8-(4-methylpiρerazin-l-yl)-l,2,3,4- tetrahydronaphthalen-2-yl]amino} sulfonyl)-3 -furoate,
2-methoxy-5-({[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaplithalen-2- yl]amino} sulfonyl)benzamide ,
3-cyano-4-fluoro-iV-[(2JR)-5-metliyl-8-(4-metliylpiperazin-l-yl)-l,2,3,4- tetrahydronaphthalen-2-yl]benzenesulfonamide,
3-fluoro-4-methyl-N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4- tetrahydronaphthalen-2-yl]benzenesulfonamide,
4-fluoro-2-methyl-N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4- tetrahydronaphthalen-2-yl]benzenesulfonaniideJ 2-methoxy-N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrab.ydronaphthalen-2- yl]-4-nitrobenzenesulfonamide,
2,4,5-trifluoro-N-[(2i?)-5-me1iLyl-8-(4-metliylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-
2-yl]benzenesulfonamide, me%1 3-[4-({[(2i?)-5-me%l-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaρhthalen-2- yl] amino} sulfonyl)phenyl]propanoate, iV"-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2-yl]-6- phenoxypyridine-3-sulfonamide, iV-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l>2,3,4-tetrahydronaphthalen-2-yl]-233- dihydro- 1 ,4-benzodioxine-6-sulfonamide, N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l32,3,4-tetrahydronaphthalen-2-yl]-l- benzofuran-2-sulfonamide,
4-chloro-Ni-[(2i?)-5-metliyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2- yl]benzene-l,3-dis"αlfonamide,
4-fluoro-N-[(2i2)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaplitlialen-2- yl]naphthalene-l -sulfonamide,
3,5-difluoro-iV"-[(2i?)-5-metliyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2- yljbenzenesulfonamide, 4-fluoro-N-[(2i?)-5-methyl-8-(4-methylpiperazin-l--yl)-l,2,3,4-tetrahydronaphtlialen-2-yl]-
3-(trifluoromethyl)benzenesulfonamide,
2-chloro-4,5-difluoro-N-[(2JR)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4- tetrahydronaphthalen-2-yl]benzenesulfonamide, 5-chloro-2,4-difluoro-iV-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4- tetrahydronaphmalen-2-yl]benzenesulfonamide,
4-chloro-2,5-difluoro-N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4- tetrahydronaphthalen-2-yl]benzenesulfonamide,
3-chloro-4-methyl-N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4- tetrahydronaphthalen-2-yl]benzenesulfonamide,
N-[(2^)-5-methyl-8-(4-methyIpiperazm-l-yl)-l,2,3,4-te1xahydronaphthalen-2-yl]-2-
(methylsulfonyl)benzenesulfonamide, l?3,5-trimethyl-iV-[(2i?)-5-methyl-8-(4-methylpiperazm-l-yl)-l,2,3,4- tetrahydronaphthalen-2-yl]- 1 H-pyrazole-4-sulfonamide, N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2-yl]-l-(3- nitrophenyl)metb.anesulfonamide,
5-methyl-iV'-[(2i?)-5-methyl-8-(4-metb.ylpiperazin-l-yl)-l,2,3,4-tetrab.ydronaphthalen-2- yl]-2,l,3-benzothiadiazole-4-sulfonamide,
2,5-dimethoxy-N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen- 2-yl]-4-nitrobenzenesulfonamide, iV"-[(2i?)-5-methyl-8-(4-methylpiperazin- l-yl)-l ,2,3,4-tetrahydronaphthalen-2-yl]-l -oxo- l32-dihydroisoqumoline-4-sulfonamide, dimethyl 5-({[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaplitlialen-2- yl] amino} sulfonyl)isophthalate, 4-methyl-N-[(2i?)-5-me%l-8-(4-metiiylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2- yl]benzenesulfonamide,
4-methoxy-N-[(2i2)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphtlialen-2- yljbenzenesulfonamide,
2-chloro-N-[(2i?)-5-methyl-8-(4-methylpiperazm-l-yl)-l,2,3,4-tetrahydronaphthalen-2- yljbenzenesulfonamide, iV-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaρhthalen-2-yl]-3-
(trifluoromethyl)benzenesulfonamide, N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2-yl]-5- pyridm-2-yltMophene-2-sulfonamide,
2-cyano-iV'-[(2<S)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydxonaphthalen-2- yl]benzenesulfonamide, 4-bromo-2-fluoro-iV-[(2i?)-5-methyl-8-(4-methylρiperazm-l-yl)-l,2,3,4- tetrahydronaphthalen-2-yl]benzenesulfonamide,
N43-({[(2i?)-5-me%l-8-(4-methylpiperazin-l-yl)-l,2,3,4-te1iahydronaphthalen-2- yl]amino}sulfonyl)phenyl]acetamide,
3-chloro-2-methyl-iV-[(2i?)-5-methyl-8-(4-metliylpiperazin-l-yl)-l,2,3,4- tetrahydronaρhthalen-2-yl]benzenesulfonamide,
4-methoxy-iV-[(2i?)-5-methyl-8-(4-metiiylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2- yl] -2-nitrobenzenesulfonamide,
3-methoxy-7V"-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,233,4-tetrahydronaphthalen-2- yljbenzenesulfonamide, N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2-yl]-2-
(phenylsulfonyl)benzenesulfonamide,
(£)-N-[(2i?)-5-me%l-8-(4-methylpiperazin-l-yl)-l,2,3,4-tetrahydronaphthalen-2-yl]-2- phenylethylenesulfonamide,
2-methoxy-4-methyl-N-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4- tetrahydronapb.thalen-2-yl]benzenesulfonaniide,
3-(difluoromethoxy)-iV"-[(2i?)-5-methyl-8-(4-methylpiperazin-l-yl)-l,2,3,4- tetrab.ydronaphthalen-2-yl]benzenesulfonamide,
4-bromo-3-fluoro-iV-[(2i?)-5-methyl-8-(4-metliylpiperazin-l-yl)-l,2,3,4- tetrahydronaphthalen-2-yl]benzenesulfonamide, N-[(2i2)-5-methyl-8-(4-methylpiperazin- 1 -yl)- 1 ,2,3,4-tetrahydronaphthalen-2-yl]-5-(l ,2,3 - thiadiazol-4-yl)thiophene-2-sulfonamide, and methyl 2,5-dimethyl-4-( { [(2S)-5-methyl-8-(4-methylpiperazin- 1 -yl)- 1 ,2,3 ,4- tetrahydronaphthalen-2-yl]amino} sulfonyl)-3-furoate, or pharmaceutically acceptable salts, solvates or solvated salts thereof.
10. A compound according to any one of claims 1 to 9, for use in therapy.
11. Use of a compound according to any one of claims 1 to 9, in the manufacture of a medicament for treatment of 5-HT6 mediated disorders.
12. Use of a compound according to any one of claims 1 to 9, in the manufacture of a medicament for treatment of Alzheimer's disease, cognitive impairment associated with schizophrenia, obesity or Parkinson's disease.
13. A pharmaceutical composition comprising as active ingredient a therapeutically effective amount of a compound according to any one of claims 1 to 8, in association with one or more pharmaceutically acceptable diluents, excipients or inert carriers.
14. The pharmaceutical composition according to claim 13, for use in the treatment of Alzheimer's disease, cognitive impairment associated with schizophrenia, obesity or Parkinson's disease.
15. A method of treatment of Alzheimer's disease, cognitive impairment associated with schizophrenia, obesity or Parkinson's disease, comprising administering to a mammal, including man in need of such treatment, a therapeutically effective amount of a compound, according to any one of claims 1 to 9.
16. An agent for the prevention or treatment of Alzheimer's disease, cognitive impairment associated with schizophrenia, obesity or Parkinson's disease, which comprises as active ingredient a compound, according to any one of claims 1 to 9.
17. Compounds selected from selected from the group consisting of
(2J?)-AζJV"-dibenzyl-5-bromo-8-methoxy-l,2,3,4-tetrahydronaphthalen-2-amine3
(2i?)-ΛζJV"-dibenzyI-8-methoxy-5-(4-methylpiperazin-l-yI)-l,2,3,4-tetrahydronaphthalen-2- amine,
(2i?)-8-methoxy-5-(4-methylpiperazin- 1 -yl)- 1 ,2,3 ,4-tetrahydronaphthalen-2-amine, N-[(2iS)-5-bromo-8-methoxy-l,2,3,4-tetrahydronaphthalen-2-yl]-2,2,2-trifluoroacetamide> tert-butyl 4- {(65)-4-methoxy-6-[(triftuoroacetyl)amino]-5,6,7,8-tetrahydronaphthalen- 1 - yl}piperazine-l-carboxylate, and fert-butyl 4-[(65)-6-amino-4-methoxy-5,6,7,8-tetrahydronaplithalen-l-yl]piperazine-l- carboxylate.
18. Use of a compound according to claim 17, as an intermediate in the preparation of a compound according to claim 1.
PCT/SE2007/000252 2006-03-17 2007-03-15 Novel tetralins as 5-ht6 modulators WO2007108742A1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP2009500324A JP2009533325A (en) 2006-03-17 2007-03-15 Novel tetralins as 5-HT6 modulators
US12/293,176 US20090054453A1 (en) 2006-03-17 2007-03-15 Novel Tetralins as 5-HT6 Modulators
EP07716065A EP1999121A1 (en) 2006-03-17 2007-03-15 Novel tetralins as 5-ht6 modulators

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US78357606P 2006-03-17 2006-03-17
US60/783,576 2006-03-17

Publications (1)

Publication Number Publication Date
WO2007108742A1 true WO2007108742A1 (en) 2007-09-27

Family

ID=38522707

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/SE2007/000252 WO2007108742A1 (en) 2006-03-17 2007-03-15 Novel tetralins as 5-ht6 modulators

Country Status (5)

Country Link
US (1) US20090054453A1 (en)
EP (1) EP1999121A1 (en)
JP (1) JP2009533325A (en)
CN (1) CN101448803A (en)
WO (1) WO2007108742A1 (en)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008061006A1 (en) * 2006-11-10 2008-05-22 Wyeth Substituted indan-2-yl, tetrahydronaphthalen-2-yl, or dihydr0-2h-chr0men-3-yl arylsulfonamides and methods of their use
WO2012120054A1 (en) 2011-03-08 2012-09-13 Sanofi Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120053A1 (en) 2011-03-08 2012-09-13 Sanofi Branched oxathiazine derivatives, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120052A1 (en) 2011-03-08 2012-09-13 Sanofi Oxathiazine derivatives substituted with carbocycles or heterocycles, method for producing same, drugs containing said compounds, and use thereof
WO2012120055A1 (en) 2011-03-08 2012-09-13 Sanofi Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120056A1 (en) 2011-03-08 2012-09-13 Sanofi Tetrasubstituted oxathiazine derivatives, method for producing them, their use as medicine and drug containing said derivatives and the use thereof
JP2012525354A (en) * 2009-04-30 2012-10-22 アボット ゲーエムベーハー ウント カンパニー カーゲー N-phenyl- (piperazinyl or homopiperazinyl) -benzenesulfonamide or benzenesulfonyl-phenyl- (piperazine or homopiperazine) compounds suitable for treating disorders responsive to modulation of serotonin 5-HT6 receptors

Families Citing this family (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8877791B2 (en) * 2006-08-04 2014-11-04 Beth Israel Deaconess Medical Center, Inc. Inhibitors of pyruvate kinase and methods of treating disease
EP2417123A2 (en) 2009-04-06 2012-02-15 Agios Pharmaceuticals, Inc. Therapeutic compositions and related methods of use
ES2619557T3 (en) 2009-05-04 2017-06-26 Agios Pharmaceuticals, Inc. PKM2 activators for use in cancer treatment
NZ622505A (en) 2009-06-29 2015-12-24 Agios Pharmaceuticals Inc Therapeutic compounds and compositions
CA2766873C (en) 2009-06-29 2018-08-21 Agios Pharmaceuticals, Inc. Therapeutic compositions and related methods of use
JP5837091B2 (en) 2010-12-17 2015-12-24 アジオス ファーマシューティカルズ， インコーポレイテッド Novel N- (4- (azetidine-1-carbonyl) phenyl)-(hetero-) arylsulfonamide derivatives as modulators of pyruvate kinase M2 (PKM2)
US9328077B2 (en) 2010-12-21 2016-05-03 Agios Pharmaceuticals, Inc Bicyclic PKM2 activators
TWI549947B (en) 2010-12-29 2016-09-21 阿吉歐斯製藥公司 Therapeutic compounds and compositions
CA3088328A1 (en) 2011-05-03 2012-11-08 Agios Pharmaceuticals, Inc. Pyruvate kinase activators for use in therapy
US9181231B2 (en) 2011-05-03 2015-11-10 Agios Pharmaceuticals, Inc Pyruvate kinase activators for use for increasing lifetime of the red blood cells and treating anemia
WO2014139144A1 (en) 2013-03-15 2014-09-18 Agios Pharmaceuticals, Inc. Therapeutic compounds and compositions
CN105085436B (en) 2014-04-19 2019-08-16 广东东阳光药业有限公司 Sulfonic acid amide derivatives and its application on drug
EP3307271B1 (en) 2015-06-11 2023-09-13 Agios Pharmaceuticals, Inc. Methods of using pyruvate kinase activators

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997034883A1 (en) * 1996-03-22 1997-09-25 Astra Aktiebolag Substituted 1,2,3,4-tetrahydronaphthalene derivatives
WO2002100822A1 (en) * 2001-06-11 2002-12-19 Biovitrum Ab Substituted sulfonamide compounds, process for their use as medicament for the treatment of cns disorders, obesity and type ii diabetes
WO2005021530A1 (en) * 2003-08-29 2005-03-10 Glaxo Group Limited 8- (1-piperazinyl)- quinoline derivatives and their use in the treatment of cns disorders
WO2005056540A1 (en) * 2003-12-08 2005-06-23 Warner-Lambert Company Llc Heterocyclic substituted indane derivatives and related compounds for the treatment of schizophrenia
WO2005058847A1 (en) * 2003-12-09 2005-06-30 F. Hoffmann-La Roche Ag Benzoxazine derivatives and uses thereof

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE9703376D0 (en) * 1997-09-18 1997-09-18 Astra Ab A new combination

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997034883A1 (en) * 1996-03-22 1997-09-25 Astra Aktiebolag Substituted 1,2,3,4-tetrahydronaphthalene derivatives
WO2002100822A1 (en) * 2001-06-11 2002-12-19 Biovitrum Ab Substituted sulfonamide compounds, process for their use as medicament for the treatment of cns disorders, obesity and type ii diabetes
WO2005021530A1 (en) * 2003-08-29 2005-03-10 Glaxo Group Limited 8- (1-piperazinyl)- quinoline derivatives and their use in the treatment of cns disorders
WO2005056540A1 (en) * 2003-12-08 2005-06-23 Warner-Lambert Company Llc Heterocyclic substituted indane derivatives and related compounds for the treatment of schizophrenia
WO2005058847A1 (en) * 2003-12-09 2005-06-30 F. Hoffmann-La Roche Ag Benzoxazine derivatives and uses thereof

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008061006A1 (en) * 2006-11-10 2008-05-22 Wyeth Substituted indan-2-yl, tetrahydronaphthalen-2-yl, or dihydr0-2h-chr0men-3-yl arylsulfonamides and methods of their use
JP2012525354A (en) * 2009-04-30 2012-10-22 アボット ゲーエムベーハー ウント カンパニー カーゲー N-phenyl- (piperazinyl or homopiperazinyl) -benzenesulfonamide or benzenesulfonyl-phenyl- (piperazine or homopiperazine) compounds suitable for treating disorders responsive to modulation of serotonin 5-HT6 receptors
WO2012120054A1 (en) 2011-03-08 2012-09-13 Sanofi Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120053A1 (en) 2011-03-08 2012-09-13 Sanofi Branched oxathiazine derivatives, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120052A1 (en) 2011-03-08 2012-09-13 Sanofi Oxathiazine derivatives substituted with carbocycles or heterocycles, method for producing same, drugs containing said compounds, and use thereof
WO2012120055A1 (en) 2011-03-08 2012-09-13 Sanofi Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120056A1 (en) 2011-03-08 2012-09-13 Sanofi Tetrasubstituted oxathiazine derivatives, method for producing them, their use as medicine and drug containing said derivatives and the use thereof

Also Published As

Publication number Publication date
US20090054453A1 (en) 2009-02-26
CN101448803A (en) 2009-06-03
EP1999121A1 (en) 2008-12-10
JP2009533325A (en) 2009-09-17

Similar Documents

Publication Publication Date Title
WO2007108742A1 (en) Novel tetralins as 5-ht6 modulators
US20100105657A1 (en) Compounds, Process for their Preparation, Intermediates, Pharmaceutical Compositions and their use in the Treatment of 5-HT6 Mediated Disorders such as Alzheimer&#39;s Disease, Cognitive Disorders, Cognitive Impairment Associated with Schizophrenia, Obesity and Parkinson&#39;s Disease
US20090030038A1 (en) Novel 8-Sulfonylamino-3 Aminosubstituted Chroman or Tetrahydronaphtalene Derivatives Modulating the 5Ht6 Receptor
CA3207590A1 (en) Pyridopyrimidinone derivative, preparation method therefor, and use thereof
US20100173890A1 (en) Compounds, Process for their Preparation, Intermediates, Pharmaceutical Compositions and their use in the Treatment of 5-HT6 Mediated Disorders such as Alzheimer&#39;s Disease, Cognitive Disorders, Cognitive Impairment Associated with Schizophrenia, Obesity and Parkinson&#39;s Disease
CA2647278A1 (en) Thiazolyldihydroindazole derivatives as protein kinase inhibitors
WO2018183633A1 (en) Compositions for use in methods of inhibiting protein kinases
KR20140135835A (en) Sulphonamide Derivatives of Benzylamine for the Treatment of CNS Diseases
US6521630B1 (en) Tetrahydroquinazoline-2,4-diones and therapeutic uses thereof
CA2659581A1 (en) Substituted indanyl sulfonamide compounds, their preparation and use as medicaments
Keshari et al. Novel Mannich-bases as potential anticonvulsants: syntheses, characterization and biological evaluation
WO2007108744A2 (en) Novel quinazolines as 5-ht6 modulators
JP2005002114A (en) New benzothiazine and benzothiazine compound, method for producing the same, and pharmaceutical composition containing the same
MX2008012535A (en) Thiazolyl dihydro-indazoles.
WO2007108743A2 (en) Novel quinazolines as 5-ht6 modulators ii
US20090099187A1 (en) Novel 8-Sulfonyl-3 Aminosubstituted Chroman or Tetrahydronaphtalene Derivatives Modulating the 5HT6 Receptor
WO2009135925A1 (en) Substituted n-imidazo[2,1-b]thiazole-5-sulfonamide derivatives as 5-ht6 ligands
Torrens Jover et al. 5-HT 7 receptor antagonists
CN101228119A (en) Novel 8-sulfonylamino-3 aminosubstituted chroman or tetrahydronaphtalene derivatives modulating the 5HT6 receptor
PL219283B1 (en) Benzylamine sulfonamide derivatives for the treatment of central nervous system diseases

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 200780017927.4

Country of ref document: CN

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 07716065

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 7292/DELNP/2008

Country of ref document: IN

WWE Wipo information: entry into national phase

Ref document number: 2009500324

Country of ref document: JP

Ref document number: 12293176

Country of ref document: US

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2007716065

Country of ref document: EP