WO2013050938A1 - 3,7-diazabicyclo[3.3.1]nonane and 9-oxa-3,7-diazabicyclo[3.3.1]nonane derivatives - Google Patents

3,7-diazabicyclo[3.3.1]nonane and 9-oxa-3,7-diazabicyclo[3.3.1]nonane derivatives Download PDF

Info

Publication number
WO2013050938A1
WO2013050938A1 PCT/IB2012/055292 IB2012055292W WO2013050938A1 WO 2013050938 A1 WO2013050938 A1 WO 2013050938A1 IB 2012055292 W IB2012055292 W IB 2012055292W WO 2013050938 A1 WO2013050938 A1 WO 2013050938A1
Authority
WO
WIPO (PCT)
Prior art keywords
diaza
bicyclo
methanone
methyl
quinoxalin
Prior art date
Application number
PCT/IB2012/055292
Other languages
French (fr)
Inventor
Christoph Boss
Christine Brotschi
Bibia Heidmann
Thierry Sifferlen
Jodi T. Williams
Original Assignee
Actelion Pharmaceuticals Ltd
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 Actelion Pharmaceuticals Ltd filed Critical Actelion Pharmaceuticals Ltd
Publication of WO2013050938A1 publication Critical patent/WO2013050938A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/08—Bridged systems

Definitions

  • the present invention relates to novel 3,7-diazabicyclo[3.3.1 ]nonane and 9-oxa-3,7- diazabicyclo[3.3.1 ]nonane derivatives of formula (I) and their use as pharmaceuticals.
  • the invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more compounds of formula (I), and especially their use as orexin receptor antagonists.
  • Orexins are neuropeptides found in 1998 by two research groups, orexin A is a 33 amino acid peptide and orexin B is a 28 amino acid peptide (Sakurai T. et al., Cell, 1998, 92, 573-585). Orexins are produced in discrete neurons of the lateral hypothalamus and bind to the G-protein-coupled receptors (OXi and OX 2 receptors).
  • the orexin-1 receptor (OXi) is selective for OX-A
  • the orexin-2 receptor (OX 2 ) is capable to bind OX-A as well as OX-B.
  • Orexin receptor antagonists are a novel type of nervous system or psychotropic drugs. Their mode of action in animals and humans involves either blockade of both orexin-1 and orexin-2 receptor (dual antagonists), or individual and selective blockade of either the orexin-1 or the orexin-2 receptor (selective antagonists) in the brain. Orexins were initially found to stimulate food consumption in rats suggesting a physiological role for these peptides as mediators in the central feedback mechanism that regulates feeding behaviour (Sakurai T. et al. , Cell, 1998, 92, 573-585).
  • orexin neuropeptides and orexin receptors play an essential and central role in regulating circadian vigilance states.
  • orexin neurons collect sensory input about internal and external states and send short intrahypothalamic axonal projections as well as long projections to many other brain regions.
  • the particular distribution of orexin fibers and receptors in basal forebrain, limbic structures and brainstem regions - areas related to the regulation of waking, sleep and emotional reactivity- suggests that orexins exert essential functions as regulators of behavioral arousal; by activating wake-promoting cell firing, orexins contribute to orchestrate all brain arousal systems that regulate circadian activity, energy balance and emotional reactivity.
  • Human memory is comprised of multiple systems that have different operating principles and different underlying neuronal substrates. The major distinction is between the capacity for conscious, declarative memory and a set of unconscious, non-declarative memory abilities. Declarative memory is further subdivided into semantic and episodic memory. Non- declariative memory is further subdivided into priming and perceptual learning, procedural memory for skills and habits, associative and non-associative learning, and some others. While semantic memory refers to the general knowledge about the world, episodic memory is autobiographical memory of events. Procedural memories refer to the ability to perform skill- based operations, as e.g. motor skills.
  • Long-term memory is established during a multiple stage process through gradual changes involving diverse brain structures, beginning with learning, or memory acquisition, or formation. Subsequently, consolidation of what has been learned may stabilize memories. When long-term memories are retrieved, they may return to a labile state in which original content may be updated, modulated or disrupted. Subsequently, reconsolidation may again stabilize memories. At a late stage, long-term memory may be resistant to disruption. Long-term memory is conceptually and anatomically different from working memory, the latter of which is the capacity to maintain temporarily a limited amount of information in mind. Behavioural research has suggested that the human brain consolidates long-term memory at certain key time intervals.
  • the initial phase of memory consolidation may occur in the first few minutes after we are exposed to a new idea or learning experience.
  • the next, and possibly most important phase may occur over a longer period of time, such as during sleep; in fact, certain consolidation processes have been suggested to be sleep-dependent [R. Stickgold et al., Sleep-dependent memory consolidation; Nature 2005,437, 1272-1278].
  • Learning and memory processes are believed to be fundamentally affected in a variety of neurological and mental disorders, such as e.g. mental retardation, Alzheimer's disease or depression. Indeed, memory loss or impairment of memory acquisition is a significant feature of such diseases, and no effective therapy to prevent this detrimental process has emerged yet.
  • Orexin-1 receptor antagonism also attenuated the expression of amphetamine- and cocaine-induced CPP [Gozzi A et al., PLoS One 2011 , 6(1 ), e16406; Hutcheson DM et al., Behav Pharmacol 2011 , 22(2), 173-181], and reduced the expression or development of locomotor sensitization to amphetamine and cocaine [Borgland SL et al., Neuron 2006, 49(4), 589-601 ; Quarta D et al., "The orexin-1 receptor antagonist SB-334867 reduces amphetamine-evoked dopamine outflow in the shell of the nucleus accumbens and decreases the expression of amphetamine sensitization.” Neurochem Int 2010, 56(1 ), 1 1 -15].
  • hypocretin/orexin contributes to the expression of some but not all forms of stress and arousal [Furlong T M et al., Eur J Neurosci 2009, 30(8), 1603- 1614]. Stress response may lead to dramatic, usually time-limited physiological, psychological and behavioural changes that may affect appetite, metabolism and feeding behavior [Chrousos, GP et al., JAMA 1992, 267(9), 1244-1252].
  • the acute stress response may include behavioural, autonomic and endocrinological changes, such as promoting heightened vigilance, decreased libido, increased heart rate and blood pressure, or a redirection of blood flow to fuel the muscles, heart and the brain [Majzoub, JA et al., European Journal of Endocrinology 2006, 155 (suppM ) S71 -S76].
  • Orexins are also involved in mediating the acute behavioral and autonomous nervous system response to stress [Zhang Wet al., "Multiple components of the defense response depend on orexin: evidence from orexin knockout mice and orexin neuron-ablated mice.” Auton Neurosci 2006, 126-127, 139-145].
  • Mood disorders including all types of depression and bipolar disorder are characterized by disturbed "mood” and feelings, as well as by sleeping problems (insomnia as well as hypersomnia), changes in appetite or weight and reduced pleasure and loss of interest in daily or once enjoyed activities [Liu X et al., Sleep 2007, 30(1 ): 83-90].
  • disturbances in the orexin system may contribute to the symptoms of mood disorders.
  • rodent models of depression orexins were also shown to be involved. Pharmacological induction of a depressive behavioral state in rats, for instance, revealed an association with increased hypothalamic orexin levels [Feng P et al., J Psychopharmacol
  • mice A chronic stress model of depression in mice also demonstrated an association of molecular orexin system disturbances with depressed behavioral states and a reversal of these molecular changes by antidepressant treatment [Nollet et al., NeuroPharm 2011 , 61 (1 -2):336-46].
  • the orexin system is also involved in stress-related appetitive/reward seeking behaviour (Berridge CW et al., Brain Res 2009, 1314, 91 -102).
  • a modulatory effect on stress may be complementary to an effect on appetitive/reward seeking behaviour as such.
  • an OX ⁇ selective orexin receptor antagonist was able to prevent footshock stress induced reinstatement of cocaine seeking behaviour [Boutrel, B et al., Proc Natl Acad Sci 2005, 102(52), 19168-19173].
  • stress is also known to play an integral part in withdrawal which occurs during cessation of drug taking (Koob, GF et al., Curr Opin Investig Drugs 2010, 1 1 (1 ), 63-71 ).
  • Orexins have been found to increase food intake and appetite [Tsujino, N, Sakurai, T, Pharmacol Rev 2009, 61 (2) 162-176]. As an additional environmental factor, stress can contribute to binge eating behaviour, and lead to obesity [Adam, TC et al. Physiol Behav 2007, 91 (4) 449-458]. Animal models that are clinically relevant models of binge eating in humans are described for example in W. Foulds Mathes et al.; Appetite 2009, 52, 545-553.
  • the orexin system interacts with neural networks that regulate emotion, reward and energy homeostasis to maintain proper vigilance states. Dysfunctions in its function may thus relate to many mental health disorders in which vigilance, arousal, wakefulness or attention is disturbed.
  • the compound further attenuated cardiovascular responses to conditioned fear and novelty exposure in rats [Furlong T M et al., Eur J Neurosci 2009, 30(8), 1603-1614]. It is also active in an animal model of conditioned fear: the rat fear-potentiated startle paradigm (WO2009/047723) which relates to emotional states of fear and anxiety diseases such as anxieties including phobias and post traumatic stress disorders (PTSDs).
  • WO2009/047723 relates to emotional states of fear and anxiety diseases such as anxieties including phobias and post traumatic stress disorders (PTSDs).
  • PTSDs post traumatic stress disorders
  • intact declarative and non-declarative learning and memory has been demonstrated in rats treated with this compound [WO2007/105177, H Dietrich, F Jenck, Psychopharmacology 2010, 212, 145-154].
  • Said compound furthermore decreased brain levels of amyloid-beta ( ⁇ ) as well as ⁇ plaque deposition after acute sleep restriction in amyloid precursor protein transgenic mice [JE Kang et al., "Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle.”, Science 2009, 326(5955): 1005-1007].
  • ⁇ amyloid-beta
  • the accumulation of the ⁇ in the brain extracellular space is hypothesized to be a critical event in the pathogenesis of Alzheimer's disease.
  • the so-called and generally known "amyloid cascade hypothesis” links ⁇ to Alzheimer's disease and, thus, to the cognitive dysfunction, expressed as impairment of learning and memory.
  • the compound has also been shown to induce antidepressant-like activity in a mouse model of depression, when administered chronically [Nollet et al., NeuroPharm 2011 , 61 (1-2):336-46]. Moreover, the compound has been shown to attenuate the natural activation induced by orexin A in fasted hungry rats exposed to food odors [MJ Prud'Neill et al., Neuroscience 2009, 162(4), 1287-1298]. The compound also displayed pharmacological activity in a rat model of nicotine self-administration [LeSage MG et al., Psychopharmacology 2010, 209(2), 203-212].
  • N- biphenyl-2-yl-1 - ⁇ [(1 -methyl-1 H-benzimidazol-2-yl)sulfanyl]acetyl ⁇ -L-prolinamide inhibited nicotine-reinstatement for a conditioned reinforcer and reduced behavioral (locomotor sensitization) and molecular (transcriptional responses) changes induced by repeated amphetamine administration in rodents [Winrow et al., Neuropharmacology 2009, 58(1 ), 185- 94].
  • the present invention provides novel 3,7-diazabicyclo[3.3.1]nonane and 9-oxa-3,7- diazabicyclo[3.3.1 ]nonane derivatives, which are non-peptide antagonists of human orexin receptors. These compounds are in particular of potential use in the treatment of disorders relating to orexinergic dysfunctions, comprising especially sleep disorders, anxiety disorders, addiction disorders, cognitive dysfunctions, mood disorders, or appetite disorders. Particular compounds of the present invention may notably be useful to treat disorders relating to orexinergic dysfunctions which are mediated by the orexin 1 receptor.
  • a first aspect of the invention relates to compounds of the formula (I)
  • X represents CH 2 or O
  • Ar 1 represents phenyl or 5- or 6-membered heteroaryl, wherein said phenyl or 5- or 6- membered heteroaryl independently is mono-, di-, or tri-substituted;
  • substituents are attached in orffro-position to the point of attachment of Ar 1 to the rest of the molecule; wherein said substituent is phenyl or 5- or 6- membered heteroaryl; wherein said phenyl or 5- or 6-membered heteroaryl substituent is independently unsubstituted, mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, cyano, (C 1-3 )fluoroalkyl, and (C 1-3 )fluoroalkoxy; or said substituent is a benzo[1 ,3]dioxolyl group;
  • Ar 1 represents phenyl which is mono-, di-, or tri-substituted; wherein the substituents are independently selected from the group consisting of (Ci -4 )alkyl; (C 1-4 )alkoxy; halogen; cyano; (C 1-3 )fluoroalkyl; (C 1-3 )fluoroalkoxy; (C 1-3 )alkoxy- (C 1-4 )alkoxy; and benzoyl;
  • Ar 2 represents 5- to 10-membered heteroaryl which is unsubstituted, or mono-, di-, or tri- substituted; wherein the substituents are independently selected from the group consisting of (Ci -4 )alkyl, (Ci -4 )alkoxy, (C 3-6 )cycloalkyl, halogen, cyano, (Ci -3 )fluoroalkyl, and (C 1-3 )fluoroalkoxy.
  • the compounds of formula (I) contain two stereogenic centers depending on each other (i.e.
  • the compounds of formula (I) may contain one or more stereogenic or asymmetric centers, such as one or more asymmetric carbon atoms.
  • the compounds of formula (I) may thus be present as mixtures of stereoisomers or preferably as pure stereoisomers. Mixtures of stereoisomers may be separated in a manner known to a person skilled in the art.
  • the present invention also includes isotopically labelled, especially 2 H (deuterium) labelled compounds of formula (I), which compounds are identical to the compounds of formula (I) except that one or more atoms have each been replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature.
  • Isotopically labelled, especially 2 H (deuterium) labelled compounds of formula (I) and salts thereof are within the scope of the present invention. Substitution of hydrogen with the heavier isotope 2 H (deuterium) may lead to greater metabolic stability, resulting e.g. in increased in-vivo half-life or reduced dosage requirements, or may lead to reduced inhibition of cytochrome P450 enzymes, resulting e.g. in an improved safety profile.
  • the compounds of formula (I) are not isotopically labelled, or they are labelled only with one or more deuterium atoms. In a sub-embodiment, the compounds of formula (I) are not isotopically labelled at all. Isotopically labelled compounds of formula (I) may be prepared in analogy to the methods described hereinafter, but using the appropriate isotopic variation of suitable reagents or starting materials.
  • a dotted line shows the point of attachment of the radical drawn.
  • any reference to compounds of formula (I) is to be understood as referring also to the salts (and especially the pharmaceutically acceptable salts) of such compounds, as appropriate and expedient.
  • pharmaceutically acceptable salts refers to non-toxic, inorg. or organic acid and/or base addition salts. Reference can be made to "Salt selection for basic drugs", Int. J. Pharm. (1986), 33, 201 -217.
  • halogen refers to fluorine, chlorine, or bromine, preferably fluorine or chlorine.
  • alkyl refers to a saturated straight or branched chain alkyl group containing one to six carbon atoms.
  • (C x-y )alkyl refers to an alkyl group as defined before, containing x to y carbon atoms.
  • a (C 1-4 )alkyl group contains from one to four carbon atoms.
  • alkyl groups are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert.-butyl. Preferred are methyl and ethyl. Most preferred is methyl.
  • cycloalkyl refers to a saturated cyclic alkyl group containing three to six carbon atoms.
  • (C x-y )cycloalkyl refers to a cycloalkyl group as defined before containing x to y carbon atoms.
  • a (C 3-6 )cycloalkyl group contains from three to six carbon atoms.
  • Examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Preferred is cyclopropyl.
  • alkoxy refers to an alkyl-O- group wherein the alkyl group is as defined before.
  • (C x-y )alkoxy (x and y each being an integer) refers to an alkoxy group as defined before containing x to y carbon atoms.
  • a (C 1-4 )alkoxy group means a group of the formula (C 1-4 )alkyl-0- in which the term "(C 1-4 )alkyl” has the previously given significance.
  • alkoxy groups are methoxy, ethoxy, n- propoxy, isopropoxy, n-butoxy, isobutoxy, sec.-butoxy and tert.-butoxy. Preferred are ethoxy and especially methoxy.
  • fluoroalkyl refers to an alkyl group as defined before containing one to three carbon atoms in which one or more (and possibly all) hydrogen atoms have been replaced with fluorine.
  • (C x-y )fluoroalkyl (x and y each being an integer) refers to a fluoroalkyl group as defined before containing x to y carbon atoms.
  • a (C 1-3 )fluoroalkyl group contains from one to three carbon atoms in which one to seven hydrogen atoms have been replaced with fluorine.
  • fluoroalkyl groups include trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl and 2,2,2-trifluoroethyl. Preferred are (C ⁇ fluoroalkyl groups such as trifluoromethyl.
  • fluoroalkoxy refers to an alkoxy group as defined before containing one to three carbon atoms in which one or more (and possibly all) hydrogen atoms have been replaced with fluorine.
  • (C x-y )fluoroalkoxy (x and y each being an integer) refers to a fluoroalkoxy group as defined before containing x to y carbon atoms.
  • a (C 1-3 )fluoroalkoxy group contains from one to three carbon atoms in which one to seven hydrogen atoms have been replaced with fluorine.
  • fluoroalkoxy groups include trifluoromethoxy, difluoromethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy and 2,2,2-trifluoroethoxy. Preferred are (C ⁇ fluoroalkoxy groups such as trifluoromethoxy and difluoromethoxy.
  • Ar 1 representing a phenyl group which is mono-, di-, or tri-substituted; wherein the substituents are independently selected from the group consisting of (Ci -4 )alkyl; (Ci -4 )alkoxy; halogen; cyano; (d -3 )fluoroalkyl; (Ci -3 )fluoroalkoxy; (Ci -3 )alkoxy-(Ci -4 )alkoxy; and benzoyl are 2-bromo-5-methoxy-phenyl, 2-bromo-5-methyl-phenyl, 2,5-dimethyl-phenyl, 2,5-dichloro-phenyl, 3-chloro-6-methoxy-phenyl, 2,5-dimethoxy-phenyl, 2-trifluoromethoxy- phenyl, 3-chloro-6-ethoxy-phenyl, 3-fluoro-2-propoxy-phenyl, 2-ethoxy-phenyl, 2-
  • Ar 1 representing a phenyl group, wherein said phenyl is mono-, di-, or tri-substituted; wherein one of said substituents is attached in orffro-position to the point of attachment of Ar 1 to the rest of the molecule; are such that the other of said substituents, if present, is/are independently selected from the group consisting of (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, cyano, (Ci -3 )fluoroalkyl, and (Ci -3 )fluoroalkoxy. In a sub-embodiment, such groups Ar 1 are are mono- or disubstituted.
  • said other substituents is/are independently selected from the group consisting of (C 1-4 )alkyl, (C 1-4 )alkoxy, and halogen.
  • Particular examples of such phenyl groups which are further substituted in ortho position as used for the group Ar 1 are 1 ,2-phenylene, 4-methyl-1 ,2-phenylene, 5- methyl-1 ,2-phenylene, 6-methyl-1 ,2-phenylene, 5-fluoro-1 ,2-phenylene, 6-fluoro-1 ,2- phenylene, 5-chloro-1 ,2-phenylene, 5-cyano-1 ,2-phenylene, 5-methoxy-1 ,2-phenylene, 4,5- dimethoxy-1 ,2-phenylene, 5-trifluoromethyl-1 ,2-phenylene, 5-trifluoromethoxy-1 ,2-phenylene, 6-fluoro-5-methyl-1 ,2-phenylene, and 6-fluoro-5-methoxy-1 ,2-
  • Examples of the particular phenyl groups which are substituents of the group Ar are especially phenyl groups which are unsubstituted, mono-, or di-substituted, wherein the substituents are independently selected from the group consisting of (Ci -4 )alkyl, (Ci -4 )alkoxy, halogen, cyano, (C 1-3 )fluoroalkyl, and (C 1-3 )fluoroalkoxy [notably from (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, and (C 1-3 )fluoroalkyl].
  • Particular examples are phenyl, 2-methyl-phenyl, 3-methyl- phenyl, 4-methyl-phenyl, 3,4-dimethyl-phenyl, 3-methoxy-phenyl, 2-fluoro-phenyl, 3-fluoro- phenyl, 4-fluoro-phenyl, 3,5-difluoro-phenyl, 4-fluoro-3-methyl-phenyl, 3-fluoro-4-methyl- phenyl, 3-chloro-phenyl, 4-chloro-phenyl, 2,3-dichloro-phenyl, 3,4-dichloro-phenyl, 4-bromo- phenyl, 3-trifluoromethyl-phenyl, 4-trifluoromethyl-phenyl.
  • further particular examples are 4-fluoro-2-methyl-phenyl, 2,3-dimethyl-phenyl, 2-ethyl-phenyl,
  • Ar 1 is a phenyl group
  • such phenyl substituent is unsubstituted phenyl; or 2-fluoro- phenyl, 3-fluoro-phenyl, 2-methyl-phenyl, 3-methyl-phenyl, 4-methyl-phenyl, 4-fluoro-2- methyl-phenyl, 2,3-dimethyl-phenyl, 2-ethyl-phenyl, 3,4-dichloro-phenyl, 2-methoxy-phenyl,
  • heteroaryl if not explicitly stated otherwise, means a 5- to 10-membered monocyclic or bicyclic aromatic ring containing 1 to a maximum of 4 (notably 1 to a maximum of 3) heteroatoms independently selected from oxygen, nitrogen and sulfur.
  • heteroaryl groups are 5-membered monocyclic heteroaryl groups such as furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, and triazolyl; 6-membered monocyclic heteroaryl such as pyridyl, pyrimidyl, pyridazinyl, and pyrazinyl; and 8- to 10-membered bicyclic heteroaryl such as indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzoxazolyl (or benzooxazolyl), benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, be
  • Examples of the particular 5- or 6-membered heteroaryl groups which are further substituted in ortho position as used for the group Ar 1 are notably oxazolyl, isoxazolyl, thienyl, thiazolyl, isothiazolyl, pyridyl, pyrimidyl and pyrazinyl.
  • examples are oxazolyl (in particular 2-methyl-oxazol-4,5-diyl), isoxazolyl (in particular 5-methyl-isoxazol-3,4-diyl), thiazolyl (in particular 2-methyl-thiazol-4,5-diyl, 2-dimethylamino-thiazol-4,5-diyl, 2- cyclopropyl-thiazol-4,5-diyl), pyridyl (in particular pyridin-2,3-diyl, 6-methyl-pyridin-2,3-diyl), pyrimidyl (in particular pyrimidin-4,5-diyl, 2-methyl-pyrimidin-4,5-diyl), and pyrazinyl (in particular pyrazin-2,3-diyl) [especially, examples are thiazolyl and pyridyl].
  • These groups are at least mono-substituted in ortho position, and preferably are carry no further substituent or one further substitutent as explicitly defined.
  • optional further substituent may independently be selected from (C 1-4 )alkyl, (C 1-4 )alkoxy, (C 3-6 )cycloalkyl, halogen, cyano, (C 1-3 )fluoroalkyl, (C 1-3 )fluoroalkoxy, and -NR 4 R 5 , wherein R 4 and R 5 are independently selected from hydrogen and (Ci -4 )alkyl [especially from (Ci -4 )alkyl, (C 3- 6)cycloalkyl, and -NR 4 R 5 , wherein R 4 and R 5 are independently selected from hydrogen and (C 1-4 )alkyl; notably from methyl, cyclopropyl, and dimethylamino].
  • the above groups are preferably attached to the rest of the molecule (i.e. the carbonyl group) in position 4 of oxazolyl, isoxazolyl, or thiazolyl groups, in position 2 of pyridyl or pyrazinyl groups, or in position 5 of pyrimidinyl groups.
  • examples of such groups are 2-methyl-thiazol-4,5-diyl, 2- dimethylamino-thiazol-4,5-diyl, 2-cyclopropyl-thiazol-4,5-diyl, and 6-methyl-pyridin-2,3-diyl.
  • Examples of 5- or 6-membered monocyclic heteroaryl groups as used for the group Ar 2 are notably 6-membered heteroaryl groups.
  • Particular examples are oxazolyl, isoxazolyl, thienyl, thiazolyl, isothiazolyl, pyridyl, pyrimidyl and pyrazinyl groups.
  • particular examples are pyridyl, pyrazinyl, and especially pyrimidyl (notably pyrimidin-2-yl) groups. These groups may be unsubstituted or substituted as explicitly defined.
  • substituents are independently selected from the group consisting of (Ci -4 )alkyl, (Ci -4 )alkoxy, (C 3-6 )cycloalkyl, halogen, cyano, (C 1-3 )fluoroalkyl, and (C 1-3 )fluoroalkoxy.
  • substituents are independently selected from the group consisting of (Ci -4 )alkyl, (Ci -4 )alkoxy, halogen, and (Ci -3 )fluoroalkyl.
  • substituents are independently selected from the group consisting of (Ci -4 )alkyl, (Ci -4 )alkoxy, halogen, and (Ci -3 )fluoroalkyl.
  • substituents are independently selected from the group consisting of (Ci -4 )alkyl, (Ci -4 )alkoxy, halogen, and (Ci -3 )fluoroalkyl.
  • substituents are independently selected from the group consisting of (Ci -4 )alkyl, (Ci -4 )alkoxy, halogen, and (Ci -3 )fluoroalkyl.
  • substituents are independently selected from the group consisting of (Ci -4 )alkyl, (Ci -4 )alkoxy,
  • Examples of 8- to 10-membered bicyclic heteroaryl groups as used for the group Ar 2 are notably 9- or 10-membered bicyclic heteroaryl groups.
  • examples are benzimidazolyl, benzoxazolyl, benzo[d]isoxazolyl, benzothiazolyl, benzo[d]isothiazolyl, thiazolo[5,4-b]pyridin-2-yl, quinolinyl, naphthyridinyl, quinazolinyl, and quinoxalinyl.
  • examples are benzoxazol-2-yl, benzothiazol-2-yl, quinazolin-2-yl, quinoxalin-2- yl, thiazolo[5,4-b]pyridin-2-yl, and [1 ,7]naphthyridin-8-yl.
  • examples are indolyl, benzofuranyl, benzothiophenyl, indazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, quinolinyl, naphthyridinyl, cinnolinyl, quinazolinyl, and quinoxalinyl (especially benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, and quinoxalinyl).
  • benzimidazolyl is benzimidazolyl, benzoxazolyl, benzo[d]isoxazolyl, benzothiazolyl, benzo[d]isothiazolyl, quinolinyl, quinazolinyl, and quinoxalinyl.
  • benzoxazol-2-yl is benzoxazol-2-yl, benzothiazol-2-yl, quinazolin-2-yl, and quinoxalin-2-yl.
  • the above mentioned groups may be unsubstituted or substituted as explicitly defined.
  • substituents are independently selected from the group consisting of (Ci -4 )alkyl, (Ci -4 )alkoxy, (C 3- 6)cycloalkyl, halogen, cyano, (Ci -3 )fluoroalkyl, and (C 1-3 )fluoroalkoxy.
  • substituents are independently selected from the group consisting of (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, and (C 1-3 )fluoroalkyl [especially from (C 1-4 )alkyl, and halogen; or from (C 1-4 )alkoxy and halogen; notably the substituents are halogen].
  • Such groups are benzoxazol-2-yl, 5-fluoro-benzoxazol-2-yl, 6-fluoro-benzoxazol-2-yl, 4-chloro- benzoxazol-2-yl, 5-chloro-benzoxazol-2-yl, 6-chloro-benzoxazol-2-yl, benzo[d]isoxazol-3-yl, 5-methyl-benzo[d]isoxazol-3-yl, 6-methyl-benzo[d]isoxazol-3-yl, 5-fluoro-benzo[d]isoxazol-3- yl, 6-fluoro-benzo[d]isoxazol-3-yl, 5-chloro-benzo[d]isoxazol-3-yl, 6-chloro-benzo[d]isoxazol- 3-yl, benzothiazol-2-yl, 5-fluoro-benzothiazol-2-yl, 6-fluoro-benzo-benz
  • particular examples are benzoxazol-2-yl, 5-chloro-benzoxazol-2-yl, benzothiazol-2-yl, 6-chloro-benzothiazol-2-yl, 6-fluoro-benzothiazol-2-yl, quinazolin-2-yl, quinoxalin-2-yl, 6-chloro-quinoxalin-2-yl, 7-chloro-quinoxalin-2-yl, 6-fluoro-quinoxalin-2-yl, 7- fluoro-quinoxalin-2-yl, 6,7-dichloro-quinoxalin-2-yl, 6,7-difluoro-quinoxalin-2-yl, 6-methyl- quinoxalin-2-yl, 7-methyl-quinoxalin-2-yl, 8-methyl-quinoxalin-2-yl, 6,7-dimethyl-quinoxalin-2- yl, 7-fluoro-6-methyl-
  • heteroaryl groups that may be attached to the rest of the molecule at a ring carbon atom which is in alpha position to one or two ring heteroatom(s) (especially N or O) form a particular sub- embodiment. These groups are preferably attached to the rest of the molecule on a carbon atom next to said heteroatom (notably next to a nitrogen atom).
  • Examples of such groups are the 5-membered heteroaryl groups oxazol-2-yl, thiazol-2-yl, imidazol-2-yl, and pyrazol-3-yl; the 6-membered heteroaryl groups pyridin-2-yl, pyrimid-2-yl, pyrimid-4-yl, pyridazin-3-yl, and pyrazin-2-yl; and the bicyclic heteroaryl groups benzimidazol-2-yl, benzoxazol-2-yl, benzo[d]isothiazol-3-yl, benzothiazol-2-yl, benzo[d]isothiazol-3-yl, quinolin-2-yl, quinazolin-2- yl, and quinoxalin-2-yl; and, in addition, thiazolo[5,4-b]pyridin-2-yl, and [1 ,7]naphthyridin-8-yl.
  • Examples of the particular 5- or 6-membered heteroaryl groups which are substituents of the group Ar 1 are notably oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidyl, and pyrazinyl (especially isoxazolyl, oxadiazolyl, pyrazolyl, triazolyl, pyridyl, and pyrimidyl, notably pyrazol-1 -yl, and [1 ,2,3]triazol-2-yl).
  • the above mentioned groups may be unsubstituted or substituted as explicitly defined. In a sub-embodiment, they are unsubstituted. Particular examples are pyrazol-1 -yl, [1 ,2,3]triazol-2-yl, 6-methoxy-pyridin-3-yl, and 3-methyl-[1 ,2,4]oxadiazol-5-yl [notably pyrazol-1 -yl, and especially [1 ,2,3]triazol-2-yl]. In addition to the above-listed, further particular examples are pyrimidin-2-yl and pyridin-2-yl.
  • a second embodiment relates to compounds according to embodiment 1 ), wherein X represents CH 2 .
  • a third embodiment relates to compounds according to embodiment 1 ), wherein X represents O.
  • Ar 1 represents phenyl or 5- or 6-membered heteroaryl, wherein the phenyl or 5- or 6-membered heteroaryl independently is mono-, di-, or tri-substituted;
  • one of said substituents is attached in orffro-position to the point of attachment of Ar 1 to the rest of the molecule; wherein said orffro-substituent is phenyl or 5- or 6-membered heteroaryl; wherein said phenyl or 5- or 6-membered heteroaryl substituent is independently unsubstituted, mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, cyano, (Ci -3 )fluoroalkyl, and (Ci -3 )fluoroalkoxy;
  • Ar 1 represents 5- or 6-membered heteroaryl, wherein the 5- or 6-membered heteroaryl independently is mono-, di-, or tri-substituted (especially mono- or di-substituted); wherein
  • one of said substituents is attached in orffro-position to the point of attachment of Ar 1 to the rest of the molecule; wherein said orffro-substituent is phenyl or 5- or 6-membered heteroaryl; wherein said phenyl or 5- or 6-membered heteroaryl substituent is independently unsubstituted, mono-, di-, or tri-substituted (especially unsubstituted or mono-substituted), wherein the substituents are independently selected from the group consisting of (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, cyano, (C 1-3 )fluoroalkyl, and (Ci -3 )fluoroalkoxy (especially (Ci -4 )alkyl, (Ci -4 )alkoxy, and halogen);
  • Another embodiment relates to compounds according to any one of embodiments 1 ) to 3), wherein Ar 1 represents phenyl which is mono-, di-, or tri-substituted (especially mono- or di- substituted); wherein
  • one of said substituents is attached in orffro-position to the point of attachment of Ar 1 to the rest of the molecule; wherein said orffro-substituent is phenyl or 5- or 6-membered heteroaryl (especially phenyl or 5-membered heteroaryl); wherein said phenyl or 5- or 6- membered heteroaryl substituent is independently unsubstituted (preferred sub- embodiment), or mono-, di-, or tri-substituted [especially unsubstituted, or mono-, di- substituted], wherein the substituents are independently selected from the group consisting of (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, cyano, (C 1-3 )fluoroalkyl, and (Ci -3 )fluoroalkoxy [notably from (Ci -4 )alkyl, (Ci -4 )alkoxy, halogen, and (Ci -3 )fluoroalkyl];
  • Another embodiment relates to compounds according to any one of embodiments 1 ) to 3), wherein
  • Ar 1 represents 5-membered heteroaryl, wherein the 5-membered heteroaryl is mono- or di- substituted; wherein
  • said orffro-substituent is phenyl which is unsubstituted, mono-, di-, or tri-substituted (especially unsubstituted or mono- substituted), wherein the substituents are independently selected from the group consisting of (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, cyano, (C 1-3 )fluoroalkyl, and (C 1-3 )fluoroalkoxy (especially (C 1-4 )alkyl, (C 1-4 )alkoxy, and halogen);
  • Ar 1 represents 6-membered heteroaryl, wherein the 6-membered heteroaryl is mono-, di-, or tri-substituted (especially di-substituted); wherein
  • said orffro-substituent is unsubstituted 5-membered heteroaryl (preferred sub- embodiment);
  • said orffro-substituent is phenyl which is unsubstituted or mono-substituted, wherein the substituents are independently selected from the group consisting of (C 1-4 )alkyl, (C 1-4 )alkoxy, and halogen;
  • substituents if present, is/are independently selected from the group consisting of (Ci -4 )alkyl, (Ci -4 )alkoxy, (C 3-6 )cycloalkyl, halogen, cyano, (C 1-3 )fluoroalkyl, (C 1-3 )fluoroalkoxy, and -NR 4 R 5 , wherein R 4 and R 5 are independently selected from hydrogen and (C 1-4 )alkyl (especially (C 1-4 )alkyl); or Ar 1 represents phenyl which is mono-, di-, or tri-substituted (especially mono- or di- substituted); wherein
  • substituents are attached in orffro-position to the point of attachment of Ar 1 to the rest of the molecule; wherein said orf/70-substituent is phenyl which is unsubstituted (preferred sub- embodiment), or mono-, or di-substituted; wherein the substituents are independently selected from the group consisting of (Ci -4 )alkyl, (Ci -4 )alkoxy, halogen, cyano, (C 1-3 )fluoroalkyl, and (C 1-3 )fluoroalkoxy [notably from (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, and (C 1-3 )fluoroalkyl];
  • or said orffro-substituent is unsubstituted 5-membered heteroaryl
  • substituents if present, is/are independently selected from the group consisting of (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, cyano, (C 1-3 )fluoroalkyl, and (C 1-3 )fluoroalkoxy [notably (C 1-4 )alkyl, (C 1-4 )alkoxy, and halogen; especially (Ci -4 )alkyl and halogen].
  • Ar 1 represents 5-membered heteroaryl, wherein the 5-membered heteroaryl is mono- or di-substituted;
  • one of said substituents is attached in orffro-position to the point of attachment of Ar 1 to the rest of the molecule; wherein said orffro-substituent is phenyl which is unsubstituted, mono-, di-, or tri-substituted (especially unsubstituted or mono-substituted), wherein the substituents are independently selected from the group consisting of (C 1-4 )alkyl, (Ci -4 )alkoxy, halogen, cyano, (Ci -3 )fluoroalkyl, and (Ci -3 )fluoroalkoxy (especially (C 1-4 )alkyl, (C 1-4 )alkoxy, and halogen);
  • Ar 1 represents 6-membered heteroaryl, wherein the 6-membered heteroaryl is mono-, di-, or tri-substituted (especially di-substituted); wherein
  • said orffro-substituent is unsubstituted 5-membered heteroaryl (preferred sub- embodiment);
  • said orffro-substituent is phenyl which is unsubstituted or mono-substituted, wherein the substituents are independently selected from the group consisting of (Ci -4 )alkyl, (C 1-4 )alkoxy, and halogen; • and the other of said substituents, if present, is/are independently selected from the group consisting of (Ci -4 )alkyl, (Ci -4 )alkoxy, (C 3- 6)cycloalkyl, halogen, cyano, (C 1-3 )fluoroalkyl, (C 1-3 )fluoroalkoxy, and -NR 4 R 5 , wherein R 4 and R 5 are independently selected from hydrogen and (C 1-4 )alkyl (especially (C 1-4 )alkyl).
  • Another embodiment relates to compounds according to any one of embodiments 1 ) to 3), wherein Ar 1 represents phenyl which is mono-, di-, or tri-substituted (especially mono- or di-substituted); wherein
  • said orffro-substituent is phenyl which is unsubstituted (preferred sub-embodiment), or mono-, or di-substituted; wherein the substituents are independently selected from the group consisting of (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, cyano, (C 1-3 )fluoroalkyl, and (C 1-3 )fluoroalkoxy [notably from (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, and (C 1-3 )fluoroalkyl]; or said orffro-substituent is unsubstituted 5-membered heteroaryl (another preferred sub- embodiment);
  • Ar 1 represents a 5-membered heteroaryl group, such group is an oxazolyl, or thiazolyl group (especially a thiazolyl group); and / or
  • Ar 1 represents a 6-membered heteroaryl group, such group is a pyridinyl or pyrimidinyl group (especially a pyridinyl group);
  • Another embodiment relates to compounds according to any one of the embodiments 1) 3) wherein Ar 1 is a group selected from the group consisting of the following groups:
  • Another embodiment relates to compounds according to any one of the embodiments 1 ) to 3) wherein Ar 1 is a group selected from the group consisting of the following groups:
  • each of the groups A) to F) forms a particular sub-embodiment [and wherein groups listed under A), C), D), and E); notably A), D), and E); and especially A) and D); are preferred groups].
  • Another embodiment relates to compounds according to any one of the embodiments 1 ) to 3) wherein Ar 1 is a group selected from the group consisting of:
  • Another embodiment relates to compounds according to any one of the embodiments 1 ) to 3) wherein Ar 1 is a group selected from the group consisting of: ) Another embodiment relates to compounds according to any one of the embodiments 1 ) 3) wherein Ar 1 is a group selected from the group consisting of:
  • Another embodiment relates to compounds according to any one of the embodiments 1 ) 3) wherein Ar 1 is a group selected from the group consisting of:
  • Another embodiment relates to compounds according to any one of embodiments 1 ) to ), wherein
  • Ar 2 represents 8- to 10-membered heteroaryl (notably 9- or 10-membered bicyclic heteroaryl) which is unsubstituted, or mono-, di-, or tri-substituted (especially unsubstituted, or mono-, or di-substituted); wherein the substituents are independently selected from the group consisting of (C 1-4 )alkyl, (C 1-4 )alkoxy, (C 3- 6)cycloalkyl, halogen, cyano, (d -3 )fluoroalkyl, and (Ci -3 )fluoroalkoxy [notably from (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, and (C 1-3 )fluoroalkyl; especially from (C 1-4 )alkyl and halogen; or from (Ci -4 )alkoxy and halogen]; • or Ar 2 represents 5- or 6-membered monocyclic heteroaryl (notably 6-membered
  • Ar 2 represents 8- to 10-membered heteroaryl (notably 9- or 10-membered bicyclic heteroaryl) which is unsubstituted, or mono-, di-, or tri-substituted (especially unsubstituted, or mono-, or di-substituted); wherein the substituents are independently selected from the group consisting of (Ci -4 )alkyl, (Ci -4 )alkoxy, (C 3-6 )cycloalkyl, halogen, cyano, (C 1-3 )fluoroalkyl, and (C 1-3 )fluoroalkoxy [notably from (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, and (C 1-3 )fluoroalkyl; especially from (C 1-4 )alkyl and halogen; or from (C 1-4 )alkoxy and halogen].
  • Ar 2 represents 8- to 10-membered heteroaryl (notably 9- or 10-membere
  • Ar 2 represents 8- to 10-membered heteroaryl (notably 9- or 10-membered bicyclic heteroaryl) which is unsubstituted, or mono-, or di-substituted; wherein the substituents are independently selected from the group consisting of (C 1-4 )alkyl, and halogen.
  • Another embodiment relates to compounds according to any one of embodiments 1 ) to 20), wherein,
  • heteroaryl is a group selected from benzoxazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, thiazolo[5,4- b]pyridinyl, and [1 ,7]naphthyridinyl; which groups independently are unsubstituted, or mono-, or di-substituted; wherein the substituents are independently selected from the group consisting of (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, and (C 1-3 )fluoroalkyl; and / or
  • Ar 2 represents 5- or 6-membered heteroaryl, said heteroaryl is pyrimidinyl, which is unsubstituted, or mono-, or di-substituted; wherein the substituents are independently selected from the group consisting of (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, and (C 1-3 )fluoroalkyl.
  • Another embodiment relates to compounds according to any one of embodiments 1 ) to 20), wherein,
  • heteroaryl is a group selected from benzoxazol-2-yl, benzothiazol-2-yl, quinazolin-2-yl, quinoxalin-2-yl, thiazolo[5,4-b]pyridin-2-yl, and [1 ,7]naphthyridin-8-yl; which groups independently are unsubstituted, or mono-, or di-substituted; wherein the substituents are independently selected from the group consisting of (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, and (C 1-3 )fluoroalkyl; and / or
  • Ar 2 represents 5- or 6-membered heteroaryl, said heteroaryl is pyrimidin-2-yl, which is unsubstituted, or mono-, or di-substituted; wherein the substituents are independently selected from the group consisting of (Ci -4 )alkyl, (Ci -4 )alkoxy, halogen, and (C 1-3 )fluoroalkyl.
  • Another embodiment relates to compounds according to any one of embodiments 1 ) to 20), wherein,
  • heteroaryl is selected from the group consisting of benzoxazol-2-yl, 5-chloro-benzoxazol-2-yl, benzothiazol-2-yl, 6-chloro-benzothiazol-2-yl, 6-fluoro-benzothiazol-2-yl, quinazolin-2-yl, quinoxalin-2-yl, 6-chloro-quinoxalin-2-yl, 7-chloro-quinoxalin-2-yl, 6-fluoro-quinoxalin-2-yl, 7-fluoro- quinoxalin-2-yl, 6,7-dichloro-quinoxalin-2-yl, 6,7-difluoro-quinoxalin-2-yl, 6-methyl- quinoxalin-2-yl, 7-methyl-quinoxalin-2-yl, 8-methyl-quinoxalin-2-yl, 6,7-dimethyl- quinoxalin
  • Ar 2 represents 5-or 6-membered heteroaryl
  • said heteroaryl is selected from the group consisting of 5-bromo-pyrimidin-2-yl, 5-ethyl-pyrimidin-2-yl, 4- trifluoromethyl-pyrimidin-2-yl, 5-trifluoromethyl-pyrimidin-2-yl, 4,6-dimethoxy- pyrimidin-2-yl, and 4,6-dimethyl-pyrimidin-2-yl.
  • Another embodiment relates to compounds according to any one of embodiments 1 ) to 20), wherein, in case Ar 2 represents 8- to 10-membered heteroaryl, said heteroaryl is selected from the group consisting of benzoxazol-2-yl, 5-fluoro-benzoxazol-2-yl, 6-fluoro- benzoxazol-2-yl, 4-chloro-benzoxazol-2-yl, 5-chloro-benzoxazol-2-yl, 6-chloro-benzoxazol-2- yl, benzo[d]isoxazol-3-yl, 5-methyl-benzo[d]isoxazol-3-yl, 6-methyl-benzo[d]isoxazol-3-yl, 5- fluoro-benzo[d]isoxazol-3-yl, 6-fluoro-benzo[d]isoxazol-3-yl, 5-chloro-benzo[d]isoxazol-3-yl, 6-chloro-benzo
  • Another embodiment relates to compounds according to any one of embodiments 1 ) to 20), wherein, in case Ar 2 represents 8- to 10-membered heteroaryl, said heteroaryl is selected from the group consisting of benzoxazol-2-yl, 5-chloro-benzoxazol-2-yl, benzothiazol-2-yl, 6-chloro-benzothiazol-2-yl, 6-fluoro-benzothiazol-2-yl, quinazolin-2-yl, quinoxalin-2-yl, 6-chloro-quinoxalin-2-yl, 7-chloro-quinoxalin-2-yl, 6-fluoro-quinoxalin-2-yl, 7- fluoro-quinoxalin-2-yl, 6,7-dichloro-quinoxalin-2-yl, 6,7-difluoro-quinoxalin-2-yl, 6-methyl- quinoxalin-2-yl, 7-methyl-quinoxalin-2-yl, 8
  • Another embodiment relates to compounds according to any one of embodiments 1 ) to 20), wherein, in case Ar 2 represents 5-or 6-membered heteroaryl, said heteroaryl is selected from the group consisting of 5-bromo-pyrimidin-2-yl, 5-ethyl-pyrimidin-2-yl, 4-trifluoromethyl- pyrimidin-2-yl, 5-trifluoromethyl-pyrimidin-2-yl, 4,6-dimethoxy-pyrimidin-2-yl, and 4,6- dimethyl-pyrimidin-2-yl.
  • Another embodiment relates to compounds according to any one of embodiments 1 ) to 18), wherein, in case Ar 2 represents 5-or 6-membered heteroaryl, said heteroaryl is selected from the group consisting of 5-bromo-pyrimidin-2-yl, 5-ethyl-pyrimidin-2-yl, 4-trifluoromethyl- pyrimidin-2-yl, 5-trifluoromethyl-pyrimidin-2-yl, 4,6-dimethoxy-pyrimidin-2-yl, and 5-bromo- pyrimidin-2-yl.
  • Another embodiment relates to compounds according to embodiment 1 ), wherein X represents CH 2 or O;
  • Ar 1 represents 5-membered heteroaryl, wherein the 5-membered heteroaryl is mono- or di- substituted; wherein
  • said orffro-substituent is phenyl which is unsubstituted, mono-, di-, or tri-substituted (especially unsubstituted or mono- substituted), wherein the substituents are independently selected from the group consisting of (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, cyano, (C 1-3 )fluoroalkyl, and (Ci -3 )fluoroalkoxy (especially (Ci -4 )alkyl, (Ci -4 )alkoxy, and halogen);
  • said orffro-substituent is unsubstituted 5-membered heteroaryl (preferred sub- embodiment; especially said 5-membered heteroaryl is [1 ,2,3]triazol-2-yl or pyrazol-1 -yl);
  • said orffro-substituent is phenyl which is unsubstituted or mono-substituted, wherein the substituents are independently selected from the group consisting of (Ci -4 )alkyl, (Ci -4 )alkoxy, and halogen;
  • substituents if present, is/are independently selected from the group consisting of (Ci -4 )alkyl, (Ci -4 )alkoxy, (C 3- 6)cycloalkyl, halogen, cyano, (C 1-3 )fluoroalkyl, (C 1-3 )fluoroalkoxy, and -NR 4 R 5 , wherein R 4 and R 5 are independently selected from hydrogen and (C 1-4 )alkyl (especially (C 1-4 )alkyl); or Ar 1 represents phenyl which is mono-, di-, or tri-substituted (especially mono- or di- substituted); wherein
  • said orffro-substituent is phenyl which is unsubstituted, or mono-, or di- substituted; wherein the substituents are independently selected from the group consisting of (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, cyano, (C 1-3 )fluoroalkyl, and (C 1-3 )fluoroalkoxy [notably from (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, and (Ci -3 )fluoroalkyl];
  • said orffro-substituent is unsubstituted or mono-substituted 5- or 6-membered heteroaryl wherein the substituent is (C 1-4 )alkyl (wherein especially said 5- or 6- membered heteroaryl is unsubstituted [1 ,2,3]triazol-2-yl or unsubstituted pyrazol- 1 -yl; or unsubstituted pyridin-2-yl or unsubstituted pyrimidin-2-yl);
  • Ar 2 represents 5- to 10-membered heteroaryl which is unsubstituted, or mono-, or di- substituted; wherein the substituents are independently selected from the group consisting of (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, and (C 1-3 )fluoroalkyl; whereinthe characteristics defined in embodiments 2) to 27), may be applied, mutatis mutandis, to the compounds of embodiment 28).
  • Another embodiment relates to compounds of formula (I) according to embodiment 1 ) selected from the group consisting of:
  • further compounds of formula (I) according to embodiment 1 are selected from the group consisting of: [7-(6-Fluoro-quinoxalin-2-yl)- ⁇ xa-3,7-diaza-bic clo[3.3.1 ]non-3-yl]-(5-methyl-2-[1 ,2,3]triazol-2-yl-phenyl)- methanone;
  • a further embodiment relates to compounds of formula (I) according to embodiment 1 ) that are potent antagonists of the orexin 1 receptor, which are especially the compounds of embodiments 29), 30), 31 ), 33), and 34); and the compounds of embodiments 37) and 38).
  • a further embodiment relates to compounds of formula (I) according to embodiment 1 ) that are potent antagonists of both the orexin 1 and the orexin 2 receptor, which are especially the compounds selected from the group consisting of:
  • the invention thus, relates to compounds of the formula (I) as defined in embodiment 1), or further limited under consideration of their respective dependencies by the characteristics of any one of embodiments 2) to 41); to pharmaceutically acceptable salts thereof; and to the use of such compounds as medicaments especially in the treatment of mental health disorders relating to orexinergic dysfunctions, which disorders are especially selected from sleep disorders, anxiety disorders, addiction disorders, cognitive dysfunctions, mood disorders, or appetite disorders (notably from anxiety disorders, addiction disorders and mood disorders).
  • the characteristics defined in embodiments 2) to 27) may be applied mutatis mutandis to the compounds of the formula (I) according to embodiment 28).
  • Especially the following embodiments relating to the compounds of formula (I) according to embodiment 1) are thus possible and intended and herewith specifically disclosed in individualized form:
  • the compounds of formula (I) and their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical compositions for enteral (such especially oral) or parenteral administration (including topical application or inhalation).
  • compositions can be effected in a manner which will be familiar to any person skilled in the art (see for example Remington, The Science and Practice of Pharmacy, 21st Edition (2005), Part 5, "Pharmaceutical Manufacturing” [published by Lippincott Williams &Wilkins]) by bringing the described compounds of formula (I) or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.
  • the present invention also relates to a method for the prevention or treatment of a disease or disorder mentioned herein comprising administering to a subject a pharmaceutically active amount of a compound of formula (I).
  • the administered amount is comprised between 1 mg and 1000 mg per day, particularly between 5 mg and 500 mg per day, more particularly between 25 mg and 400 mg per day, especially between 50 mg and 200 mg per day.
  • the compounds according to formula (I) are useful for the prevention or treatment of disorders relating to orexinergic dysfunctions.
  • disorders relating to orexinergic dysfunctions are diseases or disorders where an antagonist of a human orexin receptor is required, notably mental health diseases or disorders relating to orexinergic dysfunctions.
  • the above mentioned disorders may in particular be defined as comprising sleep disorders, anxiety disorders, addiction disorders, cognitive dysfunctions, mood disorders, or appetite disorders.
  • the above mentioned disorders comprise anxiety disorders, addiction disorders and mood disorders, notably anxiety disorders and addiction disorders.
  • disorders relating to orexinergic dysfunctions are selected from treating, controlling, ameliorating or reducing the risk of epilepsy, including absence epilepsy; treating or controlling pain, including neuropathic pain; treating or controlling Parkinson's disease; treating or controlling psychosis including acute mania and bipolar disorder; treating or controlling stroke, particularly ischemic or haemorrhagic stroke; blocking an emetic response i.e. nausea and vomiting; and treating or controlling agitation, in isolation or co-morbid with another medical condition.
  • Sleep disorders comprise dyssomnias, parasomnias, sleep disorders associated with a general medical condition and substance-induced sleep disorders.
  • dyssomnias include intrinsic sleep disorders (especially insomnias, breathing-related sleep disorders, periodic limb movement disorder, and restless leg syndrome), extrinsic sleep disorders, and circadian-rythm sleep disorders.
  • Dyssomnias notably include insomnia, primary insomnia, idiopathic insomnia, insomnias associated with depression, emotional/mood disorders, aging, Alzheimer's disease or cognitive impairment; REM sleep interruptions; breathing-related sleep disorders; sleep apnea; periodic limb movement disorder (nocturnal myoclonus), restless leg syndrome, circadian rhythm sleep disorder; shift work sleep disorder; and jet-lag syndrome.
  • Parasomnias include arousal disorders and sleep-wake transition disorders; notably parasomnias include nightmare disorder, sleep terror disorder, and sleepwalking disorder.
  • Sleep disorders associated with a general medical condition are in particular sleep disorders associated with diseases such as mental disorders, neurological disorders, neuropathic pain, and heart and lung diseases.
  • Substance-induced sleep disorders include especially the subtypes insomnia type, parasomnia type and mixed type, and notably include conditions due to drugs which cause reductions in REM sleep as a side effect. Sleep disorders especially include all types of insomnias, sleep-related dystonias; restless leg syndrome; sleep apneas; jet-lag syndrome; shift work sleep disorder, delayed or advanced sleep phase syndrome, or insomnias related to psychiatric disorders.
  • sleep disorders further include sleep disorders associated with aging; intermittent treatment of chronic insomnia; situational transient insomnia (new environment, noise) or short-term insomnia due to stress; grief; pain or illness.
  • Anxiety disorders can be distinguished by the primary object or specificity of threat, ranging from rather diffuse as in generalized anxiety disorder, to circumscribed as encountered in phobic anxieties (PHOBs) or post-traumatic stress disorders (PTSDs).
  • Anxiety disorders may, thus, be defined as comprising generalized anxiety disorders (GAD), obsessive compulsive disorders (OCDs), acute stress disorders, posttraumatic stress disorders (PTSDs), panic anxiety disorders (PADs) including panic attacks, phobic anxieties (PHOBs), specific phobia, social phobia (social anxiety disorder), avoidance, somatoform disorders including hypochondriasis, separation anxiety disorder, anxiety disorders due to a general medical condition, and substance induced anxiety disorders.
  • circumscribed threat induced anxiety disorders are phobic anxieties or posttraumatic stress disorders.
  • Anxiety disorders especially include generalized anxiety disorders, post-traumatic stress disorders, obsessive compulsive disorders, panic attacks, phobic anxieties, and avoidance.
  • Addiction disorders may be defined as addictions to one or more rewarding stimuli, notably to one rewarding stimulus.
  • Such rewarding stimuli may be of either natural or synthetic origin.
  • Examples of such rewarding stimuli are substances / drugs ⁇ of either natural or synthetic origin; such as cocaine, amphetamines, opiates [of natural or (semi-)synthetic origin such as morphine or heroin], cannabis, ethanol, mescaline, nicotine, and the like ⁇ , which substances / drugs may be consumed alone or in combination; or other rewarding stimuli ⁇ of either natural origin (such as food, sweet, fat, or sex, and the like), or synthetic origin [such as gambling, or internet/IT (such as immoderate gaming, or inappropriate involvement in online social networking sites or blogging), and the like] ⁇ .
  • natural origin such as food, sweet, fat, or sex, and the like
  • synthetic origin such as gambling, or internet/IT (such as immoderate gaming, or inappropriate involvement in online social networking sites or blogging), and the like
  • addiction disorders relating to psychoactive substance use, abuse, seeking and reinstatement are defined as all types of psychological or physical addictions and their related tolerance and dependence components.
  • Substance-related addiction disorders especially include substance use disorders such as substance dependence, substance craving and substance abuse; substance-induced disorders such as substance intoxication, substance withdrawal, and substance-induced delirium.
  • substance use disorders such as substance dependence, substance craving and substance abuse
  • substance-induced disorders such as substance intoxication, substance withdrawal, and substance-induced delirium.
  • prevention or treatment of addictions i.e.
  • preventive or curative treatment of patients who have been diagnosed as having an addiction, or as being at risk of developing addictions refers to diminishing addictions, notably diminishing the onset of addictions, to weakening their maintenance, to facilitating withdrawal, to facilitating abstinence, or to attenuating, decreasing or preventing the occurrence of reinstatement of addiction (especially to diminishing the onset of addictions, to facilitating withdrawal, or to attenuating, decreasing or preventing the occurrence of reinstatement of addiction).
  • Appetite disorders comprise eating disorders and drinking disorders.
  • Eating disorders may be defined as comprising eating disorders associated with excessive food intake and complications associated therewith; anorexias; compulsive eating disorders; obesity (due to any cause, whether genetic or environmental); obesity-related disorders including overeating and obesity observed in Type 2 (non-insulin-dependent) diabetes patients; bulimias including bulimia nervosa; cachexia; and binge eating disorder.
  • Particular eating disorders comprise metabolic dysfunction; dysregulated appetite control; compulsive obesities; bulimia or anorexia nervosa.
  • eating disorders may be defined as especially comprising anorexia nervosa, bulimia, cachexia, binge eating disorder, or compulsive obesities.
  • Drinking disorders include polydipsias in psychiatric disorders and all other types of excessive fluid intake.
  • Pathologically modified food intake may result from disturbed appetite (attraction or aversion for food); altered energy balance (intake vs. expenditure); disturbed perception of food quality (high fat or carbohydrates, high palatability); disturbed food availability (unrestricted diet or deprivation) or disrupted water balance.
  • Cognitive dysfunctions include deficits in attention, learning and especially memory functions occurring transiently or chronically in psychiatric, neurologic, neurodegenerative, cardiovascular and immune disorders, and also occurring transiently or chronically in the normal, healthy, young, adult, or especially aging population. Cognitive dysfunctions especially relate to the enhancement or maintenance of memory in patients who have been diagnosed as having, or being at risk of developing, diseases or disorders in which diminished memory (notably declarative or procedural) is a symptom [in particular dementias such as frontotemporal dementia, or dementia with Lewy bodies, or (especially) Alzheimer's disease].
  • prevention or treatment of cognitive dysfunctions relates to the enhancement or maintenance of memory in patients who have a clinical manifestation of a cognitive dysfunction, especially expressed as a deficit of declarative memory, linked to dementias such as frontotemporal dementia, or dementia with Lewy bodies, or (especially) Alzheimer's disease. Furthermore, the term “prevention or treatment of cognitive dysfunctions” also relates to improving memory consolidation in any of the above mentioned patient populations.
  • Mood disorders include major depressive episode, manic episode, mixed episode and hypomanic episode; depressive disorders including major depressive disorder, dysthymic disorders; bipolar disorders including bipolar I disorder, bipolar I I disorder (recurrent major depressive episodes with hypomanic episodes), cyclothymic disorder; mood disorders including mood disorder due to a general medical condition (including the subtypes with depressive features, with major depressive-like episode, with manic features, and with mixed features), substance-induced mood disorder (including the subtypes with depressive features, with manic features, and with mixed features).
  • mood disorders are especially major depressive episode, major depressive disorder, mood disorder due to a general medical condition; and substance-induced mood disorder.
  • the present compounds may be particularly useful for the treatment of such environmentally conditioned disorder or disease.
  • the compounds of formula (I) contain two stereogenic centers depending on each other (i.e. the relative configuration with regard to the bridge X in the 3,7-diazabicyclo[3.3.1]nonane, respectively, 9-oxa-3,7-diazabicyclo[3.3.1]nonane moiety is cis or (1 R * ,5S * )) and are therefore present as meso-compounds.
  • the synthesis of the 3,7-diazabicyclo[3.3.1]nonane template 8 starts from N-Boc-piperidone 1 which is reacted in a double Mannich reaction with paraformaldehyde 3 and benzylamine 2 to build up the bicyclic ring scaffold 4. Reduction of the carbonyl group was achieved in a two step procedure, wherein 4 was first transformed into the tosylhydrazone derivative 6 by a condensation with tosylhydrazine 5.
  • Intramolecular cyclization to the 9-oxa-3,7-diazabicyclo[3.3.1]nonane system proceeded in toluene under the activating influence of methanesulfonic acid at elevated temperature to give intermediate 13.
  • Cleavage of the sulphonamide was achieved with 62% HBr in water to result in the secondary amine intermediate 14 which was then Boc-protected under standard conditions to give 15.
  • Debenzylation was facilitated by foregoing hydrochloride salt formation to give 16 which was finally deprotected under hydrogenolytic reaction conditions using Pd-C 10% as the catalyst and MeOH as the solvent to give template 17.
  • Scheme 3 summarizes the first possibility to obtain the final orexin antagonist compounds, wherein X, Ar 1 and Ar 2 are as defined hereinbefore, starting with one of the templates (summarized in Scheme 1 and 2) summarized as 18 and reacting it with an appropriate carboxylic acid 19 under standard peptide coupling conditions in the presence of an activating agent such as TBTU or HBTU and a base such as DIPEA or TEA in a solvent like DCM or THF to give 20.
  • an activating agent such as TBTU or HBTU
  • a base such as DIPEA or TEA
  • Boc-deprotection under water free acidic conditions as for example HCI in dioxane or TFA in DCM resulted in precursor 21 which was reacted with a heteroaryl chloride 22 in a solvent such as xylene in the presence of a base (such as K 2 C0 3 or Cs 2 C0 3 ) at elevated temperature to give the final compounds 23.
  • a base such as K 2 C0 3 or Cs 2 C0 3
  • final compounds 23 can as well be prepared via the opposite sequence, using analogous methods to those described for Scheme 3, starting by reacting 18 with heteroaryl chlorides 22 to give intermediates 24. Boc-deprotection to 25 and reaction with the appropriate carboxylic acid 19 again resulted in the final orexin antagonist compounds 23.
  • heteroaryl may be introduced using well known and generally commerially available building blocks (literature for precursors of heteroaryl-containing groups: see e.g. T. Eicher, S. Hauptmann "The chemistry of Heterocycles: Structure, Reactions, Syntheses, and Applications", 2nd Edition 2003, Wiley, ISBN 978-3-527-30720-3; A. R. Katrizky, C. W. Rees, E. F. V. Scriven (Eds.) "Comprehensive Heterocyclic Chemistry I I” 1996, Elsevier, ISBN 0-08-042072-9).
  • Such heteroaryl moiety may replace a phenyl group in the schemes below as appropriate.
  • Carboxylic acid derivatives of formula Ar 1 -CO-OH are well known in the art and/or commercially available; or they may be synthesized according to methods described in the literature [see for example Scheme 5, wherein R 3 is optionally substituted phenyl or 5- or 6- membered heteroaryl as defined for the compounds of formula (I); Y is CH or N; Z is O or S; and R 4 , R 5 and (R) n correspond to the respective optional substituents as defined for the compounds of formula (I)]. In addition, they may be synthesized in analogy to the methods given in the experimental part.
  • Acids of structure 26 can especially be prepared following the procedures reported in WO2008/069997, WO2008/008517, WO2010/048012, WO2010/072722, WO2010/063662, and WO2010/063663.
  • Acids of structure 27 can be prepared following the procedures reported in WO2010/044054, WO2010/038200, and WO2010/004507.
  • Acids of structure 28a and 28b can be prepared following the procedures reported in WO2010/044054.
  • FCS Foatal calf serum
  • Apparatus Agilent 1 100 series with mass spectroscopy detection (MS : Finnigan single quadrupole).
  • MS Finnigan single quadrupole
  • Column Waters XBridge C18 (5 ⁇ , 4.6 x 50 mm).
  • Conditions MeCN [eluent A]; 13 mmol/l NH 3 in water [eluent B].
  • Gradient 95% B ⁇ 5% B over 1.5 min. (flow: 4.5 ml/min.).
  • Detection UVA/is + MS.
  • Apparatus Agilent 1 100 series with mass spectroscopy detection (MS : Finnigan single quadrupole). Column: Waters XBridge C18 (2.5 ⁇ , 4.6 x 30 mm). Conditions: MeCN [eluent A]; water + 0.04% TFA [eluent B]. Gradient: 95% B ⁇ 5% B over 1.5 min. (flow: 4.5 ml/min.). Detection: UVA/is + MS.
  • LC-MS-conditions Analytical. Pump: Waters Acquity Binary, Solvent Manager, MS: Waters SQ Detector, DAD: Acquity UPLC PDA Detector, ELSD: Acquity UPLC ELSD.
  • Eluents A1 : H 2 0 + 0.05 % FA; B1 : MeCN + 0.05 % FA; A2: H 2 0 + 0.05 % TFA; B2: MeCN + 0.05 % TFA.
  • Method Gradient: 2 % B 98 % B over 1.5 min. Flow: 1.2 mL/ min. Detection: UV 214nm and ELSD, and MS, t R is given in min.
  • Step 1
  • Benzylamine (10.82 g; 100 mmol) was dissolved in MeOH (400 ml) followed by the addition of AcOH (6.0 g; 100 mmol), of 37% aq. HCI (4.18 ml; 50 mmol) and paraformaldehyde (6.32 g; 66.7 mmol).
  • the clear reaction solution was heated to reflux (90°C) and 1 -Boc-4- piperidone (20.12 g; 100 mmol) dissolved in MeOH (120 ml) was added over 20 min. Stirring and heating was continued for 3 h. The solution was cooled to rt and concentrated in vacuo.
  • Step 1
  • Benzenesulfonamide (25 g; 0.159 mol) was dissolved in water (250 ml) followed by the addition of epichlorohydrine (58.9 g; 0.636 mol). The reaction mixture was heated to 40°C. At this temperature a solution of NaOH (13.3 g) in water (28 ml) was carefully added and the reaction temperature was kept below 45°C. Stirring was continued at 40°C for 2 h and at RT for 16 h. The excess epichlorohydrine was evaporated and the remaining aq. layer was extracted with DCM (2 x 150 ml).
  • N,N-bis(oxiran-2-ylmethyl)benzenesulfonamide (86.4 g; 0.321 mol) was dissolved in EtOH (820 ml) followed by the addition of benzylamine (27.8 g; 0.257 mol).
  • the reaction mixture was heated to reflux (80°C) for 3 h, then the mixture was cooled to rt, the solvent was evaporated under reduced pressure to result in a white foam, which was dried at high vacuum to give 1 -benzyl-5-(phenylsulfonyl)-1 ,5-diazoctane-3,7-diol which was used in the following step without further purification.
  • bi-(hetero-)aryl-like structures can be synthesised using well established Suzuki chemistry in analogy to the reactions depicted here:
  • Step 1 Amide bond formation:
  • tert-butyl 7-(5-methyl-2-(2H-1 ,2,3-triazol-2-yl)benzoyl)-3,7-diazabicyclo[3.3.1] nonane-3- carboxylate (370 mg; 0.898 mmol) is dissolved in dioxane (5 ml) followed by the addition of HCI in dioxane (4M; 5 ml; 20 mmol). Stirring is continued for 2 h at rt.
  • Step 1 Nucleophilic Substitution:
  • tert-butyl 3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (1.5 g; 6.63 mmol) and 2-chloro-6,7- difluoroquinoxaline (1.564 g; 6.63 mmol) are dissolved in xylene (30 ml) followed by the addition of K 2 C0 3 (4.58 g; 33.1 mmol). The suspension is heated to reflux for 1 h and cooled again to rt followed by the addition of water (250 ml). The product is extracted with EtOAc (2 x 125 ml). The combined organic layers are dried over MgS0 4 , filtered and the solvent is evaporated under reduced pressure. The residue is dried at HV to give tert-butyl 7-(6,7- difluoroquinoxalin-2-yl)-3,7-diazabicyclo[3.3.1 ] nonane-3-carboxylate.
  • tert-butyl 7-(6,7-difluoroquinoxalin-2-yl)-3,7-diazabicyclo[3.3.1] nonane-3-carboxylate (2.54 g; 6.53 mmol) is dissolved in dioxane (16.8 ml) followed by the addition of HCI in dioxane (4M; 16.8 ml; 65.3 mmol). Stirring at rt is continued for 90 minutes.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to 3,7-diazabicyclo[3.3.1]nonane and 9-oxa-3,7- diazabicyclo[3.3.1 ]nonane derivatives of formula (I) wherein Ar1 and Ar2 are as described in the description, to their preparation, to pharmaceutically acceptable salts thereof, and to their use as pharmaceuticals, to pharmaceutical compositions containing one or more compounds of formula (I), and especially to their use as orexin receptor antagonists.

Description

3,7-Diazabicyclo[3.3.1]nonane and 9-oxa-3,7-diazabicyclo[3.3.1]nonane derivatives
The present invention relates to novel 3,7-diazabicyclo[3.3.1 ]nonane and 9-oxa-3,7- diazabicyclo[3.3.1 ]nonane derivatives of formula (I) and their use as pharmaceuticals. The invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more compounds of formula (I), and especially their use as orexin receptor antagonists.
Orexins (orexin A or OX-A and orexin B or OX-B) are neuropeptides found in 1998 by two research groups, orexin A is a 33 amino acid peptide and orexin B is a 28 amino acid peptide (Sakurai T. et al., Cell, 1998, 92, 573-585). Orexins are produced in discrete neurons of the lateral hypothalamus and bind to the G-protein-coupled receptors (OXi and OX2 receptors). The orexin-1 receptor (OXi) is selective for OX-A, and the orexin-2 receptor (OX2) is capable to bind OX-A as well as OX-B. Orexin receptor antagonists are a novel type of nervous system or psychotropic drugs. Their mode of action in animals and humans involves either blockade of both orexin-1 and orexin-2 receptor (dual antagonists), or individual and selective blockade of either the orexin-1 or the orexin-2 receptor (selective antagonists) in the brain. Orexins were initially found to stimulate food consumption in rats suggesting a physiological role for these peptides as mediators in the central feedback mechanism that regulates feeding behaviour (Sakurai T. et al. , Cell, 1998, 92, 573-585).
On the other hand, orexin neuropeptides and orexin receptors play an essential and central role in regulating circadian vigilance states. In the brain, orexin neurons collect sensory input about internal and external states and send short intrahypothalamic axonal projections as well as long projections to many other brain regions. The particular distribution of orexin fibers and receptors in basal forebrain, limbic structures and brainstem regions - areas related to the regulation of waking, sleep and emotional reactivity- suggests that orexins exert essential functions as regulators of behavioral arousal; by activating wake-promoting cell firing, orexins contribute to orchestrate all brain arousal systems that regulate circadian activity, energy balance and emotional reactivity. This role opens large therapeutic opportunities for medically addressing numerous mental health disorders possibly relating to orexinergic dysfunctions [see for example: Tsujino N and Sakurai T, "Orexin/hypocretin: a neuropeptide at the interface of sleep, energy homeostasis, and reward systems.", Pharmacol Rev. 2009, 61 : 162-176; and Carter ME et al., "The brain hypocretins and their receptors: mediators of allostatic arousal.", Curr Op Pharmacol. 2009, 9: 39-45] that are described in the following sections. It was also observed that orexins regulate states of sleep and wakefulness opening potentially novel therapeutic approaches to insomnia and other sleep disorders (Chemelli R.M. et al., Cell, 1999, 98, 437-451 ).
Human memory is comprised of multiple systems that have different operating principles and different underlying neuronal substrates. The major distinction is between the capacity for conscious, declarative memory and a set of unconscious, non-declarative memory abilities. Declarative memory is further subdivided into semantic and episodic memory. Non- declariative memory is further subdivided into priming and perceptual learning, procedural memory for skills and habits, associative and non-associative learning, and some others. While semantic memory refers to the general knowledge about the world, episodic memory is autobiographical memory of events. Procedural memories refer to the ability to perform skill- based operations, as e.g. motor skills. Long-term memory is established during a multiple stage process through gradual changes involving diverse brain structures, beginning with learning, or memory acquisition, or formation. Subsequently, consolidation of what has been learned may stabilize memories. When long-term memories are retrieved, they may return to a labile state in which original content may be updated, modulated or disrupted. Subsequently, reconsolidation may again stabilize memories. At a late stage, long-term memory may be resistant to disruption. Long-term memory is conceptually and anatomically different from working memory, the latter of which is the capacity to maintain temporarily a limited amount of information in mind. Behavioural research has suggested that the human brain consolidates long-term memory at certain key time intervals. The initial phase of memory consolidation may occur in the first few minutes after we are exposed to a new idea or learning experience. The next, and possibly most important phase, may occur over a longer period of time, such as during sleep; in fact, certain consolidation processes have been suggested to be sleep-dependent [R. Stickgold et al., Sleep-dependent memory consolidation; Nature 2005,437, 1272-1278]. Learning and memory processes are believed to be fundamentally affected in a variety of neurological and mental disorders, such as e.g. mental retardation, Alzheimer's disease or depression. Indeed, memory loss or impairment of memory acquisition is a significant feature of such diseases, and no effective therapy to prevent this detrimental process has emerged yet.
In addition, both anatomical and functional evidence from in vitro and in vivo studies suggest an important positive interaction of the endogenous orexin system with reward pathways of the brain [Aston-Jones G et al., Brain Res 2010, 1314, 74-90; Sharf R et al., Brain Res 2010, 1314, 130-138]. Selective pharmacological OXR-1 blockade reduced cue- and stress- induced reinstatement of cocaine seeking [Boutrel B, et al., "Role for hypocretin in mediating stress-induced reinstatement of cocaine-seeking behavior." Proc Natl Acad Sci 2005, 102(52), 19168-19173; Smith RJ et al., "Orexin/hypocretin signaling at the orexin 1 receptor regulates cue-elicited cocaine-seeking." Eur J Neurosci 2009, 30(3), 493-503; Smith RJ et al., "Orexin/hypocretin is necessary for context-driven cocaine-seeking." Neuropharmacology 2010, 58(1 ), 179-184], cue-induced reinstatement of alcohol seeking [Lawrence AJ et al., Br J Pharmacol 2006, 148(6), 752-759] and nicotine self-administration [Hollander JA et al., Proc Natl Acad Sci 2008, 105(49), 19480-19485; LeSage MG et al., Psychopharmacology 2010, 209(2), 203-212]. Orexin-1 receptor antagonism also attenuated the expression of amphetamine- and cocaine-induced CPP [Gozzi A et al., PLoS One 2011 , 6(1 ), e16406; Hutcheson DM et al., Behav Pharmacol 2011 , 22(2), 173-181], and reduced the expression or development of locomotor sensitization to amphetamine and cocaine [Borgland SL et al., Neuron 2006, 49(4), 589-601 ; Quarta D et al., "The orexin-1 receptor antagonist SB-334867 reduces amphetamine-evoked dopamine outflow in the shell of the nucleus accumbens and decreases the expression of amphetamine sensitization." Neurochem Int 2010, 56(1 ), 1 1 -15].
The effect of a drug to diminish addictions may be modelled in normal or particularly sensitive mammals used as animal models [see for example Spealman et al, Pharmacol. Biochem. Behav. 1999, 64, 327-336; or T.S. Shippenberg, G.F. Koob, "Recent advances in animal models of drug addiction" in Neuropsychopharmacology: The fifth generation of progress; K.L.Davis, D. Charney, J.T.Doyle, C. Nemeroff (eds.) 2002; chapter 97, pages 1381 -1397].
Several converging lines of evidence furthermore demonstrate a direct role of the orexin system as modulator of the acute stress response. For instance, stress (i.e. psychological stress or physical stress) is associated with increased arousal and vigilance which in turn is controlled by orexins [Sutcliffe, JG et al., Nat Rev Neurosci 2002, 3(5), 339-349]. Orexin neurons are likely to be involved in the coordinated regulation of behavioral and physiological responses in stressful environments [Y. Kayaba et al., Am. J. Physiol. Regul. Integr. Comp. Physiol. 2003, 285:R581-593]. Hypocretin/orexin contributes to the expression of some but not all forms of stress and arousal [Furlong T M et al., Eur J Neurosci 2009, 30(8), 1603- 1614]. Stress response may lead to dramatic, usually time-limited physiological, psychological and behavioural changes that may affect appetite, metabolism and feeding behavior [Chrousos, GP et al., JAMA 1992, 267(9), 1244-1252]. The acute stress response may include behavioural, autonomic and endocrinological changes, such as promoting heightened vigilance, decreased libido, increased heart rate and blood pressure, or a redirection of blood flow to fuel the muscles, heart and the brain [Majzoub, JA et al., European Journal of Endocrinology 2006, 155 (suppM ) S71 -S76].
As outlined above the orexin system regulates homeostatic functions such as sleep-wake cycle, energy balance, emotions and reward. Orexins are also involved in mediating the acute behavioral and autonomous nervous system response to stress [Zhang Wet al., "Multiple components of the defense response depend on orexin: evidence from orexin knockout mice and orexin neuron-ablated mice." Auton Neurosci 2006, 126-127, 139-145]. Mood disorders including all types of depression and bipolar disorder are characterized by disturbed "mood" and feelings, as well as by sleeping problems (insomnia as well as hypersomnia), changes in appetite or weight and reduced pleasure and loss of interest in daily or once enjoyed activities [Liu X et al., Sleep 2007, 30(1 ): 83-90]. Thus, there is a strong rationale that disturbances in the orexin system may contribute to the symptoms of mood disorders. Evidence in humans, for instance, exists that depressed patients show blunted diurnal variation in CSF orexin levels [Salomon RM et al., Biol Psychiatry 2003, 54(2), 96-104]. In rodent models of depression, orexins were also shown to be involved. Pharmacological induction of a depressive behavioral state in rats, for instance, revealed an association with increased hypothalamic orexin levels [Feng P et al., J Psychopharmacol
2008, 22(7): 784-791]. A chronic stress model of depression in mice also demonstrated an association of molecular orexin system disturbances with depressed behavioral states and a reversal of these molecular changes by antidepressant treatment [Nollet et al., NeuroPharm 2011 , 61 (1 -2):336-46].
The orexin system is also involved in stress-related appetitive/reward seeking behaviour (Berridge CW et al., Brain Res 2009, 1314, 91 -102). In certain instances, a modulatory effect on stress may be complementary to an effect on appetitive/reward seeking behaviour as such. For instance, an OX^ selective orexin receptor antagonist was able to prevent footshock stress induced reinstatement of cocaine seeking behaviour [Boutrel, B et al., Proc Natl Acad Sci 2005, 102(52), 19168-19173]. In addition, stress is also known to play an integral part in withdrawal which occurs during cessation of drug taking (Koob, GF et al., Curr Opin Investig Drugs 2010, 1 1 (1 ), 63-71 ).
Orexins have been found to increase food intake and appetite [Tsujino, N, Sakurai, T, Pharmacol Rev 2009, 61 (2) 162-176]. As an additional environmental factor, stress can contribute to binge eating behaviour, and lead to obesity [Adam, TC et al. Physiol Behav 2007, 91 (4) 449-458]. Animal models that are clinically relevant models of binge eating in humans are described for example in W. Foulds Mathes et al.; Appetite 2009, 52, 545-553.
A number of recent studies report that orexins may play a role into several other important functions relating to arousal, especially when an organism must respond to unexpected stressors and challenges in the environment [Tsujino N and Sakurai T. Pharmacol Rev.
2009, 61 : 162-176; Carter ME, Borg JS and deLecea L, Curr Op Pharmacol. 2009, 9: 39-45; C Boss, C Brisbare-Roch, F Jenck, Journal of Medicinal Chemistry 2009, 52: 891 -903]. The orexin system interacts with neural networks that regulate emotion, reward and energy homeostasis to maintain proper vigilance states. Dysfunctions in its function may thus relate to many mental health disorders in which vigilance, arousal, wakefulness or attention is disturbed.
The compound (2R)-2-{(1 S)-6,7-dimethoxy-1 -[2-(4-trifluoromethyl-phenyl)-ethyl]-3,4-dihydro- 1 H-isoquinolin-2-yl}-A/-methyl-2-phenyl-acetamide (WO2005/1 18548), a dual orexin receptor antagonist, showed clinical efficacy in humans when tested for the indication primary insomnia. In the rat, the compound has been shown to decrease alertness, characterized by decreases in both active wake and locomotion; and to dose-dependently increase the time spent in both REM and NREM sleep [Brisbare et al., Nature Medicine 2007, 13, 150-155]. The compound further attenuated cardiovascular responses to conditioned fear and novelty exposure in rats [Furlong T M et al., Eur J Neurosci 2009, 30(8), 1603-1614]. It is also active in an animal model of conditioned fear: the rat fear-potentiated startle paradigm (WO2009/047723) which relates to emotional states of fear and anxiety diseases such as anxieties including phobias and post traumatic stress disorders (PTSDs). In addition, intact declarative and non-declarative learning and memory has been demonstrated in rats treated with this compound [WO2007/105177, H Dietrich, F Jenck, Psychopharmacology 2010, 212, 145-154]. Said compound furthermore decreased brain levels of amyloid-beta (Αβ) as well as Αβ plaque deposition after acute sleep restriction in amyloid precursor protein transgenic mice [JE Kang et al., "Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle.", Science 2009, 326(5955): 1005-1007]. The accumulation of the Αβ in the brain extracellular space is hypothesized to be a critical event in the pathogenesis of Alzheimer's disease. The so-called and generally known "amyloid cascade hypothesis" links Αβ to Alzheimer's disease and, thus, to the cognitive dysfunction, expressed as impairment of learning and memory. The compound has also been shown to induce antidepressant-like activity in a mouse model of depression, when administered chronically [Nollet et al., NeuroPharm 2011 , 61 (1-2):336-46]. Moreover, the compound has been shown to attenuate the natural activation induced by orexin A in fasted hungry rats exposed to food odors [MJ Prud'homme et al., Neuroscience 2009, 162(4), 1287-1298]. The compound also displayed pharmacological activity in a rat model of nicotine self-administration [LeSage MG et al., Psychopharmacology 2010, 209(2), 203-212]. Another dual orexin receptor antagonist, N- biphenyl-2-yl-1 -{[(1 -methyl-1 H-benzimidazol-2-yl)sulfanyl]acetyl}-L-prolinamide inhibited nicotine-reinstatement for a conditioned reinforcer and reduced behavioral (locomotor sensitization) and molecular (transcriptional responses) changes induced by repeated amphetamine administration in rodents [Winrow et al., Neuropharmacology 2009, 58(1 ), 185- 94].
The present invention provides novel 3,7-diazabicyclo[3.3.1]nonane and 9-oxa-3,7- diazabicyclo[3.3.1 ]nonane derivatives, which are non-peptide antagonists of human orexin receptors. These compounds are in particular of potential use in the treatment of disorders relating to orexinergic dysfunctions, comprising especially sleep disorders, anxiety disorders, addiction disorders, cognitive dysfunctions, mood disorders, or appetite disorders. Particular compounds of the present invention may notably be useful to treat disorders relating to orexinergic dysfunctions which are mediated by the orexin 1 receptor.
1 ) A first aspect of the invention relates to compounds of the formula (I)
Figure imgf000007_0001
Formula (I)
wherein
X represents CH2 or O;
• Ar1 represents phenyl or 5- or 6-membered heteroaryl, wherein said phenyl or 5- or 6- membered heteroaryl independently is mono-, di-, or tri-substituted; wherein
> one of said substituents is attached in orffro-position to the point of attachment of Ar1 to the rest of the molecule; wherein said substituent is phenyl or 5- or 6- membered heteroaryl; wherein said phenyl or 5- or 6-membered heteroaryl substituent is independently unsubstituted, mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, cyano, (C1-3)fluoroalkyl, and (C1-3)fluoroalkoxy; or said substituent is a benzo[1 ,3]dioxolyl group;
> and the other of said substituents, if present, is/are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, (C3-6)cycloalkyl, halogen, cyano, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, and -NR4R5, wherein R4 and R5 are independently selected from hydrogen and (C1-4)alkyl;
• or Ar1 represents phenyl which is mono-, di-, or tri-substituted; wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl; (C1-4)alkoxy; halogen; cyano; (C1-3)fluoroalkyl; (C1-3)fluoroalkoxy; (C1-3)alkoxy- (C1-4)alkoxy; and benzoyl;
and
Ar2 represents 5- to 10-membered heteroaryl which is unsubstituted, or mono-, di-, or tri- substituted; wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl, (Ci-4)alkoxy, (C3-6)cycloalkyl, halogen, cyano, (Ci-3)fluoroalkyl, and (C1-3)fluoroalkoxy. The compounds of formula (I) contain two stereogenic centers depending on each other (i.e. the relative configuration with regard to the bridge X in the 3,7-diazabicyclo[3.3.1]nonane, respectively, 9-oxa-3,7-diazabicyclo[3.3.1]nonane moiety is cis or (1 R*,5S*)) and are therefore present as meso-compounds.
In addition, the compounds of formula (I) may contain one or more stereogenic or asymmetric centers, such as one or more asymmetric carbon atoms. The compounds of formula (I) may thus be present as mixtures of stereoisomers or preferably as pure stereoisomers. Mixtures of stereoisomers may be separated in a manner known to a person skilled in the art.
The present invention also includes isotopically labelled, especially 2H (deuterium) labelled compounds of formula (I), which compounds are identical to the compounds of formula (I) except that one or more atoms have each been replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Isotopically labelled, especially 2H (deuterium) labelled compounds of formula (I) and salts thereof are within the scope of the present invention. Substitution of hydrogen with the heavier isotope 2H (deuterium) may lead to greater metabolic stability, resulting e.g. in increased in-vivo half-life or reduced dosage requirements, or may lead to reduced inhibition of cytochrome P450 enzymes, resulting e.g. in an improved safety profile. In one embodiment of the invention, the compounds of formula (I) are not isotopically labelled, or they are labelled only with one or more deuterium atoms. In a sub-embodiment, the compounds of formula (I) are not isotopically labelled at all. Isotopically labelled compounds of formula (I) may be prepared in analogy to the methods described hereinafter, but using the appropriate isotopic variation of suitable reagents or starting materials.
In this patent application, a dotted line shows the point of attachment of the radical drawn. For example, the radical drawn below
Figure imgf000008_0001
2-(2-triazolyl)-phenyl group.
Where the plural form is used for compounds, salts, pharmaceutical compositions, diseases and the like, this is intended to mean also a single compound, salt, or the like.
Any reference to compounds of formula (I) is to be understood as referring also to the salts (and especially the pharmaceutically acceptable salts) of such compounds, as appropriate and expedient. The term "pharmaceutically acceptable salts" refers to non-toxic, inorg. or organic acid and/or base addition salts. Reference can be made to "Salt selection for basic drugs", Int. J. Pharm. (1986), 33, 201 -217.
Definitions:
The following definitions are intended to apply uniformly to the compounds of formula (I) according to embodiment 1 ) and, mutatis mutandis, throughout the description and the claims unless an otherwise expressly set out definition provides a broader or narrower definition. It is well understood that a definition, a preferred definition, or listed examples of a certain term defines and may replace the respective term throughout the application [independently of (and in combination with) any definition or preferred definition of any or all other terms as defined herein].
The term "halogen" refers to fluorine, chlorine, or bromine, preferably fluorine or chlorine.
The term "alkyl", used alone or in combination, refers to a saturated straight or branched chain alkyl group containing one to six carbon atoms. The term "(Cx-y)alkyl" (x and y each being an integer), refers to an alkyl group as defined before, containing x to y carbon atoms. For example a (C1-4)alkyl group contains from one to four carbon atoms. Examples of alkyl groups are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert.-butyl. Preferred are methyl and ethyl. Most preferred is methyl.
The term "cycloalkyl", used alone or in combination, refers to a saturated cyclic alkyl group containing three to six carbon atoms. The term "(Cx-y)cycloalkyl" (x and y each being an integer), refers to a cycloalkyl group as defined before containing x to y carbon atoms. For example a (C3-6)cycloalkyl group contains from three to six carbon atoms. Examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Preferred is cyclopropyl.
The term "alkoxy", used alone or in combination, refers to an alkyl-O- group wherein the alkyl group is as defined before. The term "(Cx-y)alkoxy" (x and y each being an integer) refers to an alkoxy group as defined before containing x to y carbon atoms. For example a (C1-4)alkoxy group means a group of the formula (C1-4)alkyl-0- in which the term "(C1-4)alkyl" has the previously given significance. Examples of alkoxy groups are methoxy, ethoxy, n- propoxy, isopropoxy, n-butoxy, isobutoxy, sec.-butoxy and tert.-butoxy. Preferred are ethoxy and especially methoxy.
The term "fluoroalkyl" refers to an alkyl group as defined before containing one to three carbon atoms in which one or more (and possibly all) hydrogen atoms have been replaced with fluorine. The term "(Cx-y)fluoroalkyl" (x and y each being an integer) refers to a fluoroalkyl group as defined before containing x to y carbon atoms. For example a (C1-3)fluoroalkyl group contains from one to three carbon atoms in which one to seven hydrogen atoms have been replaced with fluorine. Representative examples of fluoroalkyl groups include trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl and 2,2,2-trifluoroethyl. Preferred are (C^fluoroalkyl groups such as trifluoromethyl.
The term "fluoroalkoxy" refers to an alkoxy group as defined before containing one to three carbon atoms in which one or more (and possibly all) hydrogen atoms have been replaced with fluorine. The term "(Cx-y)fluoroalkoxy" (x and y each being an integer) refers to a fluoroalkoxy group as defined before containing x to y carbon atoms. For example a (C1-3)fluoroalkoxy group contains from one to three carbon atoms in which one to seven hydrogen atoms have been replaced with fluorine. Representative examples of fluoroalkoxy groups include trifluoromethoxy, difluoromethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy and 2,2,2-trifluoroethoxy. Preferred are (C^fluoroalkoxy groups such as trifluoromethoxy and difluoromethoxy.
Particular examples of Ar1 representing a phenyl group which is mono-, di-, or tri-substituted; wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl; (Ci-4)alkoxy; halogen; cyano; (d-3)fluoroalkyl; (Ci-3)fluoroalkoxy; (Ci-3)alkoxy-(Ci-4)alkoxy; and benzoyl are 2-bromo-5-methoxy-phenyl, 2-bromo-5-methyl-phenyl, 2,5-dimethyl-phenyl, 2,5-dichloro-phenyl, 3-chloro-6-methoxy-phenyl, 2,5-dimethoxy-phenyl, 2-trifluoromethoxy- phenyl, 3-chloro-6-ethoxy-phenyl, 3-fluoro-2-propoxy-phenyl, 2-ethoxy-phenyl, 2-benzoyl- phenyl, 2-(2-methoxy-ethoxy)-phenyl, and 2-(2,2, 1 , 1 -tetrafluoro-ethoxy)-phenyl.
Particular examples of Ar1 representing a phenyl group, wherein said phenyl is mono-, di-, or tri-substituted; wherein one of said substituents is attached in orffro-position to the point of attachment of Ar1 to the rest of the molecule; are such that the other of said substituents, if present, is/are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, cyano, (Ci-3)fluoroalkyl, and (Ci-3)fluoroalkoxy. In a sub-embodiment, such groups Ar1 are are mono- or disubstituted. In a further sub-embodiment, said other substituents, if present, is/are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, and halogen. Particular examples of such phenyl groups which are further substituted in ortho position as used for the group Ar1 are 1 ,2-phenylene, 4-methyl-1 ,2-phenylene, 5- methyl-1 ,2-phenylene, 6-methyl-1 ,2-phenylene, 5-fluoro-1 ,2-phenylene, 6-fluoro-1 ,2- phenylene, 5-chloro-1 ,2-phenylene, 5-cyano-1 ,2-phenylene, 5-methoxy-1 ,2-phenylene, 4,5- dimethoxy-1 ,2-phenylene, 5-trifluoromethyl-1 ,2-phenylene, 5-trifluoromethoxy-1 ,2-phenylene, 6-fluoro-5-methyl-1 ,2-phenylene, and 6-fluoro-5-methoxy-1 ,2-phenylene [notably 1 ,2- phenylene, 5-methyl-1 ,2-phenylene, 6-methyl-1 ,2-phenylene, 6-fluoro-1 ,2-phenylene, 5- chloro-1 ,2-phenylene, and 5-methoxy-1 ,2-phenylene]; wherein in the above groups the carbonyl group is attached in position 1. Examples of the particular phenyl groups which are substituents of the group Ar are especially phenyl groups which are unsubstituted, mono-, or di-substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl, (Ci-4)alkoxy, halogen, cyano, (C1-3)fluoroalkyl, and (C1-3)fluoroalkoxy [notably from (C1-4)alkyl, (C1-4)alkoxy, halogen, and (C1-3)fluoroalkyl]. Particular examples are phenyl, 2-methyl-phenyl, 3-methyl- phenyl, 4-methyl-phenyl, 3,4-dimethyl-phenyl, 3-methoxy-phenyl, 2-fluoro-phenyl, 3-fluoro- phenyl, 4-fluoro-phenyl, 3,5-difluoro-phenyl, 4-fluoro-3-methyl-phenyl, 3-fluoro-4-methyl- phenyl, 3-chloro-phenyl, 4-chloro-phenyl, 2,3-dichloro-phenyl, 3,4-dichloro-phenyl, 4-bromo- phenyl, 3-trifluoromethyl-phenyl, 4-trifluoromethyl-phenyl. In addition to the above-listed, further particular examples are 4-fluoro-2-methyl-phenyl, 2,3-dimethyl-phenyl, 2-ethyl-phenyl,
2- methoxy-phenyl, 4-methoxy-phenyl, 4-ethoxy-phenyl, 3-cyano-phenyl, 4-cyano-phenyl, 3- trifluoromethoxy-phenyl, 3-trifluoromethoxy-phenyl. In one sub-embodiment, in particular when Ar1 is a phenyl group, such phenyl substituent is unsubstituted phenyl; or 2-fluoro- phenyl, 3-fluoro-phenyl, 2-methyl-phenyl, 3-methyl-phenyl, 4-methyl-phenyl, 4-fluoro-2- methyl-phenyl, 2,3-dimethyl-phenyl, 2-ethyl-phenyl, 3,4-dichloro-phenyl, 2-methoxy-phenyl,
3- methoxy-phenyl, 4-methoxy-phenyl, 4-ethoxy-phenyl, 3-cyano-phenyl, 4-cyano-phenyl, 3- trifluoromethyl-phenyl, 3-trifluoromethoxy-phenyl, 3-trifluoromethoxy-phenyl. In another sub- embodiment, in particular when Ar1 is a heteroaryl group, such phenyl substituent is phenyl, 2-methyl-phenyl, 3-methyl-phenyl, 4-methyl-phenyl, 3,4-dimethyl-phenyl, 3-methoxy-phenyl,
4- fluoro-phenyl, 3,5-difluoro-phenyl, 4-fluoro-3-methyl-phenyl, 3-fluoro-4-methyl-phenyl, 4- chloro-phenyl, 2,3-dichloro-phenyl, 3,4-dichloro-phenyl, 4-bromo-phenyl, 3-trifluoromethyl- phenyl, or 4-trifluoromethyl-phenyl; or, in addition, 3-chloro-phenyl.
The term "heteroaryl", if not explicitly stated otherwise, means a 5- to 10-membered monocyclic or bicyclic aromatic ring containing 1 to a maximum of 4 (notably 1 to a maximum of 3) heteroatoms independently selected from oxygen, nitrogen and sulfur. Examples of such heteroaryl groups are 5-membered monocyclic heteroaryl groups such as furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, and triazolyl; 6-membered monocyclic heteroaryl such as pyridyl, pyrimidyl, pyridazinyl, and pyrazinyl; and 8- to 10-membered bicyclic heteroaryl such as indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzoxazolyl (or benzooxazolyl), benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, benzoxadiazolyl, benzothiadiazolyl, quinolinyl, isoquinolinyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyrazolo[1 ,5-a]pyridyl, pyrazolo[1 ,5- a] pyrimidyl, imidazo[1 ,2-a]pyridyl, 1 H-pyrrolo[3,2-b]pyridyl, 1 H-pyrrolo[2,3-b]pyridyl, pyrrolo[3,2-d]pyrimidinyl, pyrrolo[2,3-d]pyrimidinyl, 4H-furo[3,2-b]pyrrolyl, pyrrolo[2,1 - b] thiazolyl, imidazo[2,1 -b]thiazolyl and purinyl; and, in addition to the above-listed groups, thiazolo[5,4-b]pyridyl. Examples of the particular 5- or 6-membered heteroaryl groups which are further substituted in ortho position as used for the group Ar1 are notably oxazolyl, isoxazolyl, thienyl, thiazolyl, isothiazolyl, pyridyl, pyrimidyl and pyrazinyl. In a sub-embodiment, examples are oxazolyl (in particular 2-methyl-oxazol-4,5-diyl), isoxazolyl (in particular 5-methyl-isoxazol-3,4-diyl), thiazolyl (in particular 2-methyl-thiazol-4,5-diyl, 2-dimethylamino-thiazol-4,5-diyl, 2- cyclopropyl-thiazol-4,5-diyl), pyridyl (in particular pyridin-2,3-diyl, 6-methyl-pyridin-2,3-diyl), pyrimidyl (in particular pyrimidin-4,5-diyl, 2-methyl-pyrimidin-4,5-diyl), and pyrazinyl (in particular pyrazin-2,3-diyl) [especially, examples are thiazolyl and pyridyl]. These groups are at least mono-substituted in ortho position, and preferably are carry no further substituent or one further substitutent as explicitly defined. In particular such optional further substituent may independently be selected from (C1-4)alkyl, (C1-4)alkoxy, (C3-6)cycloalkyl, halogen, cyano, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, and -NR4R5, wherein R4 and R5 are independently selected from hydrogen and (Ci-4)alkyl [especially from (Ci-4)alkyl, (C3-6)cycloalkyl, and -NR4R5, wherein R4 and R5 are independently selected from hydrogen and (C1-4)alkyl; notably from methyl, cyclopropyl, and dimethylamino]. The above groups are preferably attached to the rest of the molecule (i.e. the carbonyl group) in position 4 of oxazolyl, isoxazolyl, or thiazolyl groups, in position 2 of pyridyl or pyrazinyl groups, or in position 5 of pyrimidinyl groups. In a sub-embodiment, examples of such groups are 2-methyl-thiazol-4,5-diyl, 2- dimethylamino-thiazol-4,5-diyl, 2-cyclopropyl-thiazol-4,5-diyl, and 6-methyl-pyridin-2,3-diyl.
Examples of 5- or 6-membered monocyclic heteroaryl groups as used for the group Ar2 are notably 6-membered heteroaryl groups. Particular examples are oxazolyl, isoxazolyl, thienyl, thiazolyl, isothiazolyl, pyridyl, pyrimidyl and pyrazinyl groups. In a sub-embodiment, particular examples are pyridyl, pyrazinyl, and especially pyrimidyl (notably pyrimidin-2-yl) groups. These groups may be unsubstituted or substituted as explicitly defined. In particular they may be unsubstituted, or mono-, di-, or tri-substituted; wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl, (Ci-4)alkoxy, (C3-6)cycloalkyl, halogen, cyano, (C1-3)fluoroalkyl, and (C1-3)fluoroalkoxy. Notably they may be unsubstituted, or mono-, or di-substituted; wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl, (Ci-4)alkoxy, halogen, and (Ci-3)fluoroalkyl. In a further sub- embodiment, particular examples of such groups are 5-ethyl-pyrimidin-2-yl, 4-trifluoromethyl- pyrimidin-2-yl, 5-trifluoromethyl-pyrimidin-2-yl, 4,6-dimethoxy-pyrimidin-2-yl, and 5-bromo- pyrimidin-2-yl. In addition to the above-listed, a further particular example is 4,6-dimethyl- pyrimidin-2-yl.
Examples of 8- to 10-membered bicyclic heteroaryl groups as used for the group Ar2 are notably 9- or 10-membered bicyclic heteroaryl groups. In one embodiment, examples are benzimidazolyl, benzoxazolyl, benzo[d]isoxazolyl, benzothiazolyl, benzo[d]isothiazolyl, thiazolo[5,4-b]pyridin-2-yl, quinolinyl, naphthyridinyl, quinazolinyl, and quinoxalinyl. In a sub- embodiment examples are benzoxazol-2-yl, benzothiazol-2-yl, quinazolin-2-yl, quinoxalin-2- yl, thiazolo[5,4-b]pyridin-2-yl, and [1 ,7]naphthyridin-8-yl. In another embodiment, examples are indolyl, benzofuranyl, benzothiophenyl, indazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, quinolinyl, naphthyridinyl, cinnolinyl, quinazolinyl, and quinoxalinyl (especially benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, and quinoxalinyl). In a sub-embodiment examples are benzimidazolyl, benzoxazolyl, benzo[d]isoxazolyl, benzothiazolyl, benzo[d]isothiazolyl, quinolinyl, quinazolinyl, and quinoxalinyl. In a further sub-embodiment examples are benzoxazol-2-yl, benzothiazol-2-yl, quinazolin-2-yl, and quinoxalin-2-yl. The above mentioned groups may be unsubstituted or substituted as explicitly defined. In particular they may be unsubstituted, or mono-, di-, or tri- substituted; wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl, (Ci-4)alkoxy, (C3-6)cycloalkyl, halogen, cyano, (Ci-3)fluoroalkyl, and (C1-3)fluoroalkoxy. Notably they may be unsubstituted, or mono-, or di-substituted; wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, and (C1-3)fluoroalkyl [especially from (C1-4)alkyl, and halogen; or from (C1-4)alkoxy and halogen; notably the substituents are halogen]. Particular examples of such groups are benzoxazol-2-yl, 5-fluoro-benzoxazol-2-yl, 6-fluoro-benzoxazol-2-yl, 4-chloro- benzoxazol-2-yl, 5-chloro-benzoxazol-2-yl, 6-chloro-benzoxazol-2-yl, benzo[d]isoxazol-3-yl, 5-methyl-benzo[d]isoxazol-3-yl, 6-methyl-benzo[d]isoxazol-3-yl, 5-fluoro-benzo[d]isoxazol-3- yl, 6-fluoro-benzo[d]isoxazol-3-yl, 5-chloro-benzo[d]isoxazol-3-yl, 6-chloro-benzo[d]isoxazol- 3-yl, benzothiazol-2-yl, 5-fluoro-benzothiazol-2-yl, 6-fluoro-benzothiazol-2-yl, 5-chloro- benzothiazol-2-yl, 6-chloro-benzothiazol-2-yl, 5-chloro-benzo[d]isothiazol-3-yl, 6-chloro- benzo[d]isothiazol-3-yl, quinazolin-2-yl, quinoxalin-2-yl, 6-fluoro-quinoxalin-2-yl, 7-fluoro- quinoxalin-2-yl, 8-fluoro-quinoxalin-2-yl, 6-chloro-quinoxalin-2-yl, 7-chloro-quinoxalin-2-yl, 8- chloro-quinoxalin-2-yl, 5,6-difluoro-quinoxalin-2-yl, 6,7-difluoro-quinoxalin-2-yl, 7,8-difluoro- quinoxalin-2-yl, 6,7-dichloro-quinoxalin-2-yl, 6-methyl-quinoxalin-2-yl, 7-methyl-quinoxalin-2- yl, 8-methyl-quinoxalin-2-yl, 6,7-dimethyl-quinoxalin-2-yl, 7-fluoro-6-methyl-quinoxalin-2-yl, 6- fluoro-7-methyl-quinoxalin-2-yl, 6-methoxy-quinoxalin-2-yl, 7-methoxy-quinoxalin-2-yl, 7- fluoro-6-methoxy-quinoxalin-2-yl, 6-trifluoromethyl-quinoxalin-2-yl, and 7-trifluoromethyl- quinoxalin-2-yl. In addition to the above-listed, further particular examples are thiazolo[5,4- b]pyridin-2-yl, 6-fluoro-thiazolo[5,4-b]pyridin-2-yl, and 6-methyl-[1 ,7]naphthyridin-8-yl.
In a sub-embodiment, particular examples are benzoxazol-2-yl, 5-chloro-benzoxazol-2-yl, benzothiazol-2-yl, 6-chloro-benzothiazol-2-yl, 6-fluoro-benzothiazol-2-yl, quinazolin-2-yl, quinoxalin-2-yl, 6-chloro-quinoxalin-2-yl, 7-chloro-quinoxalin-2-yl, 6-fluoro-quinoxalin-2-yl, 7- fluoro-quinoxalin-2-yl, 6,7-dichloro-quinoxalin-2-yl, 6,7-difluoro-quinoxalin-2-yl, 6-methyl- quinoxalin-2-yl, 7-methyl-quinoxalin-2-yl, 8-methyl-quinoxalin-2-yl, 6,7-dimethyl-quinoxalin-2- yl, 7-fluoro-6-methyl-quinoxalin-2-yl, 6-fluoro-7-methyl-quinoxalin-2-yl, 6-methoxy-quinoxalin- 2-yl, 7-methoxy-quinoxalin-2-yl, 7-fluoro-6-methoxy-quinoxalin-2-yl, 6-trifluoromethyl- quinoxalin-2-yl, and 7-trifluoromethyl-quinoxalin-2-yl. In addition to the above-listed, further particular examples are thiazolo[5,4-b]pyridin-2-yl, 6-fluoro-thiazolo[5,4-b]pyridin-2-yl, and 6- methyl-[1 ,7]naphthyridin-8-yl.
For the substituent Ar2, among the above-mentioned heteroaryl groups those heteroaryl groups that may be attached to the rest of the molecule at a ring carbon atom which is in alpha position to one or two ring heteroatom(s) (especially N or O) form a particular sub- embodiment. These groups are preferably attached to the rest of the molecule on a carbon atom next to said heteroatom (notably next to a nitrogen atom). Examples of such groups are the 5-membered heteroaryl groups oxazol-2-yl, thiazol-2-yl, imidazol-2-yl, and pyrazol-3-yl; the 6-membered heteroaryl groups pyridin-2-yl, pyrimid-2-yl, pyrimid-4-yl, pyridazin-3-yl, and pyrazin-2-yl; and the bicyclic heteroaryl groups benzimidazol-2-yl, benzoxazol-2-yl, benzo[d]isothiazol-3-yl, benzothiazol-2-yl, benzo[d]isothiazol-3-yl, quinolin-2-yl, quinazolin-2- yl, and quinoxalin-2-yl; and, in addition, thiazolo[5,4-b]pyridin-2-yl, and [1 ,7]naphthyridin-8-yl.
Examples of the particular 5- or 6-membered heteroaryl groups which are substituents of the group Ar1 are notably oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidyl, and pyrazinyl (especially isoxazolyl, oxadiazolyl, pyrazolyl, triazolyl, pyridyl, and pyrimidyl, notably pyrazol-1 -yl, and [1 ,2,3]triazol-2-yl). The above mentioned groups may be unsubstituted or substituted as explicitly defined. In a sub-embodiment, they are unsubstituted. Particular examples are pyrazol-1 -yl, [1 ,2,3]triazol-2-yl, 6-methoxy-pyridin-3-yl, and 3-methyl-[1 ,2,4]oxadiazol-5-yl [notably pyrazol-1 -yl, and especially [1 ,2,3]triazol-2-yl]. In addition to the above-listed, further particular examples are pyrimidin-2-yl and pyridin-2-yl.
Further embodiments of the invention are presented hereinafter:
2) A second embodiment relates to compounds according to embodiment 1 ), wherein X represents CH2.
3) A third embodiment relates to compounds according to embodiment 1 ), wherein X represents O.
4) Another embodiment relates to compounds according to any one of embodiments 1 ) to 3), wherein Ar1 represents phenyl or 5- or 6-membered heteroaryl, wherein the phenyl or 5- or 6-membered heteroaryl independently is mono-, di-, or tri-substituted; wherein
• one of said substituents is attached in orffro-position to the point of attachment of Ar1 to the rest of the molecule; wherein said orffro-substituent is phenyl or 5- or 6-membered heteroaryl; wherein said phenyl or 5- or 6-membered heteroaryl substituent is independently unsubstituted, mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, cyano, (Ci-3)fluoroalkyl, and (Ci-3)fluoroalkoxy;
• and the other of said substituents, if present, is/are independently selected from the group consisting of (d-4)alkyl, (Ci-4)alkoxy, (C3-6)cycloalkyl, halogen, cyano, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, and -NR4R5, wherein R4 and R5 are independently selected from hydrogen and (Ci-4)alkyl.
5) Another embodiment relates to compounds according to any one of embodiments 1 ) to 3), wherein Ar1 represents 5- or 6-membered heteroaryl, wherein the 5- or 6-membered heteroaryl independently is mono-, di-, or tri-substituted (especially mono- or di-substituted); wherein
• one of said substituents is attached in orffro-position to the point of attachment of Ar1 to the rest of the molecule; wherein said orffro-substituent is phenyl or 5- or 6-membered heteroaryl; wherein said phenyl or 5- or 6-membered heteroaryl substituent is independently unsubstituted, mono-, di-, or tri-substituted (especially unsubstituted or mono-substituted), wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, cyano, (C1-3)fluoroalkyl, and (Ci-3)fluoroalkoxy (especially (Ci-4)alkyl, (Ci-4)alkoxy, and halogen);
• and the other of said substituents, if present, is/are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, (C3-6)cycloalkyl, halogen, cyano, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, and -NR4R5, wherein R4 and R5 are independently selected from hydrogen and (Ci-4)alkyl (especially (Ci-4)alkyl), (C3-6)cycloalkyl, and -NR4R5, wherein R4 and R5 are independently selected from hydrogen and (C1-4)alkyl).
6) Another embodiment relates to compounds according to any one of embodiments 1 ) to 3), wherein Ar1 represents phenyl which is mono-, di-, or tri-substituted (especially mono- or di- substituted); wherein
• one of said substituents is attached in orffro-position to the point of attachment of Ar1 to the rest of the molecule; wherein said orffro-substituent is phenyl or 5- or 6-membered heteroaryl (especially phenyl or 5-membered heteroaryl); wherein said phenyl or 5- or 6- membered heteroaryl substituent is independently unsubstituted (preferred sub- embodiment), or mono-, di-, or tri-substituted [especially unsubstituted, or mono-, di- substituted], wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, cyano, (C1-3)fluoroalkyl, and (Ci-3)fluoroalkoxy [notably from (Ci-4)alkyl, (Ci-4)alkoxy, halogen, and (Ci-3)fluoroalkyl]; • and the other of said substituents, if present, is/are independently selected from the group consisting of (Ci-4)alkyl, (Ci-4)alkoxy, halogen, cyano, (Ci-3)fluoroalkyl, and (C1-3)fluoroalkoxy [especially (C1-4)alkyl, (C1-4)alkoxy, and halogen].
7) Another embodiment relates to compounds according to any one of embodiments 1 ) to 3), wherein
Ar1 represents 5-membered heteroaryl, wherein the 5-membered heteroaryl is mono- or di- substituted; wherein
> one of said substituents is attached in orffro-position to the point of attachment of Ar1 to the rest of the molecule; wherein said orffro-substituent is phenyl which is unsubstituted, mono-, di-, or tri-substituted (especially unsubstituted or mono- substituted), wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, cyano, (C1-3)fluoroalkyl, and (C1-3)fluoroalkoxy (especially (C1-4)alkyl, (C1-4)alkoxy, and halogen);
> and the other of said substituents, if present, is/are independently selected from the group consisting of (Ci-4)alkyl, (Ci-4)alkoxy, (C3-6)cycloalkyl, halogen, cyano, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, and -NR4R5, wherein R4 and R5 are independently selected from hydrogen and (C1-4)alkyl [especially (C1-4)alkyl), (C3-6)cycloalkyl, and -NR4R5, wherein R4 and R5 are independently selected from hydrogen and (C1-4)alkyl; notably (C1-4)alkyl)];
or Ar1 represents 6-membered heteroaryl, wherein the 6-membered heteroaryl is mono-, di-, or tri-substituted (especially di-substituted); wherein
> one of said substituents is attached in orffro-position to the point of attachment of Ar1 to the rest of the molecule; wherein
said orffro-substituent is unsubstituted 5-membered heteroaryl (preferred sub- embodiment);
or said orffro-substituent is phenyl which is unsubstituted or mono-substituted, wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, and halogen;
> and the other of said substituents, if present, is/are independently selected from the group consisting of (Ci-4)alkyl, (Ci-4)alkoxy, (C3-6)cycloalkyl, halogen, cyano, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, and -NR4R5, wherein R4 and R5 are independently selected from hydrogen and (C1-4)alkyl (especially (C1-4)alkyl); or Ar1 represents phenyl which is mono-, di-, or tri-substituted (especially mono- or di- substituted); wherein
> one of said substituents is attached in orffro-position to the point of attachment of Ar1 to the rest of the molecule; wherein said orf/70-substituent is phenyl which is unsubstituted (preferred sub- embodiment), or mono-, or di-substituted; wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl, (Ci-4)alkoxy, halogen, cyano, (C1-3)fluoroalkyl, and (C1-3)fluoroalkoxy [notably from (C1-4)alkyl, (C1-4)alkoxy, halogen, and (C1-3)fluoroalkyl];
or said orffro-substituent is unsubstituted 5-membered heteroaryl;
> and the other of said substituents, if present, is/are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, cyano, (C1-3)fluoroalkyl, and (C1-3)fluoroalkoxy [notably (C1-4)alkyl, (C1-4)alkoxy, and halogen; especially (Ci-4)alkyl and halogen].
8) Another embodiment relates to compounds according to any one of embodiments 1 ) to 3), wherein Ar1 represents 5-membered heteroaryl, wherein the 5-membered heteroaryl is mono- or di-substituted; wherein
• one of said substituents is attached in orffro-position to the point of attachment of Ar1 to the rest of the molecule; wherein said orffro-substituent is phenyl which is unsubstituted, mono-, di-, or tri-substituted (especially unsubstituted or mono-substituted), wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (Ci-4)alkoxy, halogen, cyano, (Ci-3)fluoroalkyl, and (Ci-3)fluoroalkoxy (especially (C1-4)alkyl, (C1-4)alkoxy, and halogen);
• and the other of said substituents, if present, is/are independently selected from the group consisting of (Ci-4)alkyl, (Ci-4)alkoxy, (C3-6)cycloalkyl, halogen, cyano, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, and -NR4R5, wherein R4 and R5 are independently selected from hydrogen and (Ci-4)alkyl (especially (Ci-4)alkyl), (C3-6)cycloalkyl, and -NR4R5, wherein R4 and R5 are independently selected from hydrogen and (C1-4)alkyl; notably (C1-4)alkyl)).
9) Another embodiment relates to compounds according to any one of embodiments 1 ) to 3), wherein Ar1 represents 6-membered heteroaryl, wherein the 6-membered heteroaryl is mono-, di-, or tri-substituted (especially di-substituted); wherein
• one of said substituents is attached in orffro-position to the point of attachment of Ar1 to the rest of the molecule; wherein
said orffro-substituent is unsubstituted 5-membered heteroaryl (preferred sub- embodiment);
or said orffro-substituent is phenyl which is unsubstituted or mono-substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl, (C1-4)alkoxy, and halogen; • and the other of said substituents, if present, is/are independently selected from the group consisting of (Ci-4)alkyl, (Ci-4)alkoxy, (C3-6)cycloalkyl, halogen, cyano, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, and -NR4R5, wherein R4 and R5 are independently selected from hydrogen and (C1-4)alkyl (especially (C1-4)alkyl).
10) Another embodiment relates to compounds according to any one of embodiments 1 ) to 3), wherein Ar1 represents phenyl which is mono-, di-, or tri-substituted (especially mono- or di-substituted); wherein
• one of said substituents is attached in orffro-position to the point of attachment of Ar1 to the rest of the molecule; wherein
said orffro-substituent is phenyl which is unsubstituted (preferred sub-embodiment), or mono-, or di-substituted; wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, cyano, (C1-3)fluoroalkyl, and (C1-3)fluoroalkoxy [notably from (C1-4)alkyl, (C1-4)alkoxy, halogen, and (C1-3)fluoroalkyl]; or said orffro-substituent is unsubstituted 5-membered heteroaryl (another preferred sub- embodiment);
• and the other of said substituents, if present, is/are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, cyano, (C1-3)fluoroalkyl, and (Ci-3)fluoroalkoxy [notably (Ci-4)alkyl, (Ci-4)alkoxy, and halogen; especially (Ci-4)alkyl and halogen].
1 1 ) Another embodiment relates to compounds according to any one of embodiments 1 ) to 10), wherein,
• in case Ar1 represents a 5-membered heteroaryl group, such group is an oxazolyl, or thiazolyl group (especially a thiazolyl group); and / or
• in case Ar1 represents a 6-membered heteroaryl group, such group is a pyridinyl or pyrimidinyl group (especially a pyridinyl group);
wherein said groups independently are substituted as explicitly defined.
) Another embodiment relates to compounds according to any one of the embodiments 1) 3) wherein Ar1 is a group selected from the group consisting of the following groups:
Figure imgf000019_0001
Figure imgf000019_0002
Figure imgf000019_0003
Figure imgf000020_0001
13) Another embodiment relates to compounds according to any one of the embodiments 1 ) to 3) wherein Ar1 is a group selected from the group consisting of the following groups:
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000022_0002
wherein each of the groups A) to F) forms a particular sub-embodiment [and wherein groups listed under A), C), D), and E); notably A), D), and E); and especially A) and D); are preferred groups].
14) Another embodiment relates to compounds according to any one of the embodiments 1 ) to 3) wherein Ar1 is a group selected from the group consisting of:
Figure imgf000022_0003
15) Another embodiment relates to compounds according to any one of the embodiments 1 ) to 3) wherein Ar1 is a group selected from the group consisting of:
Figure imgf000023_0001
) Another embodiment relates to compounds according to any one of the embodiments 1 ) 3) wherein Ar1 is a group selected from the group consisting of:
Figure imgf000023_0002
) Another embodiment relates to compounds according to any one of the embodiments 1 ) 3) wherein Ar1 is a group selected from the group consisting of:
Figure imgf000023_0003
) Another embodiment relates to compounds according to any one of embodiments 1 ) to ), wherein
• Ar2 represents 8- to 10-membered heteroaryl (notably 9- or 10-membered bicyclic heteroaryl) which is unsubstituted, or mono-, di-, or tri-substituted (especially unsubstituted, or mono-, or di-substituted); wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, (C3-6)cycloalkyl, halogen, cyano, (d-3)fluoroalkyl, and (Ci-3)fluoroalkoxy [notably from (C1-4)alkyl, (C1-4)alkoxy, halogen, and (C1-3)fluoroalkyl; especially from (C1-4)alkyl and halogen; or from (Ci-4)alkoxy and halogen]; • or Ar2 represents 5- or 6-membered monocyclic heteroaryl (notably 6-membered heteroaryl) which is unsubstituted, or mono-, di-, or tri-substituted (especially unsubstituted, or mono-, or di-substituted); wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, (C3-6)cycloalkyl, halogen, cyano, (d-3)fluoroalkyl, and (Ci-3)fluoroalkoxy [notably from (C1-4)alkyl, (C1-4)alkoxy, halogen, and (C1-3)fluoroalkyl].
19) Another embodiment relates to compounds according to any one of embodiments 1 ) to 17), wherein Ar2 represents 8- to 10-membered heteroaryl (notably 9- or 10-membered bicyclic heteroaryl) which is unsubstituted, or mono-, di-, or tri-substituted (especially unsubstituted, or mono-, or di-substituted); wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl, (Ci-4)alkoxy, (C3-6)cycloalkyl, halogen, cyano, (C1-3)fluoroalkyl, and (C1-3)fluoroalkoxy [notably from (C1-4)alkyl, (C1-4)alkoxy, halogen, and (C1-3)fluoroalkyl; especially from (C1-4)alkyl and halogen; or from (C1-4)alkoxy and halogen].
20) Another embodiment relates to compounds according to any one of embodiments 1 ) to 17), wherein Ar2 represents 8- to 10-membered heteroaryl (notably 9- or 10-membered bicyclic heteroaryl) which is unsubstituted, or mono-, or di-substituted; wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, and halogen.
21 ) Another embodiment relates to compounds according to any one of embodiments 1 ) to 20), wherein,
• in case Ar2 represents 8- to 10-membered heteroaryl, said heteroaryl is a group selected from benzoxazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, thiazolo[5,4- b]pyridinyl, and [1 ,7]naphthyridinyl; which groups independently are unsubstituted, or mono-, or di-substituted; wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, and (C1-3)fluoroalkyl; and / or
• in case Ar2 represents 5- or 6-membered heteroaryl, said heteroaryl is pyrimidinyl, which is unsubstituted, or mono-, or di-substituted; wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, and (C1-3)fluoroalkyl.
22) Another embodiment relates to compounds according to any one of embodiments 1 ) to 20), wherein,
• in case Ar2 represents 8- to 10-membered heteroaryl, said heteroaryl is a group selected from benzoxazol-2-yl, benzothiazol-2-yl, quinazolin-2-yl, quinoxalin-2-yl, thiazolo[5,4-b]pyridin-2-yl, and [1 ,7]naphthyridin-8-yl; which groups independently are unsubstituted, or mono-, or di-substituted; wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, and (C1-3)fluoroalkyl; and / or
• in case Ar2 represents 5- or 6-membered heteroaryl, said heteroaryl is pyrimidin-2-yl, which is unsubstituted, or mono-, or di-substituted; wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl, (Ci-4)alkoxy, halogen, and (C1-3)fluoroalkyl.
23) Another embodiment relates to compounds according to any one of embodiments 1 ) to 20), wherein,
• in case Ar2 represents 8- to 10-membered heteroaryl, said heteroaryl is selected from the group consisting of benzoxazol-2-yl, 5-chloro-benzoxazol-2-yl, benzothiazol-2-yl, 6-chloro-benzothiazol-2-yl, 6-fluoro-benzothiazol-2-yl, quinazolin-2-yl, quinoxalin-2-yl, 6-chloro-quinoxalin-2-yl, 7-chloro-quinoxalin-2-yl, 6-fluoro-quinoxalin-2-yl, 7-fluoro- quinoxalin-2-yl, 6,7-dichloro-quinoxalin-2-yl, 6,7-difluoro-quinoxalin-2-yl, 6-methyl- quinoxalin-2-yl, 7-methyl-quinoxalin-2-yl, 8-methyl-quinoxalin-2-yl, 6,7-dimethyl- quinoxalin-2-yl, 7-fluoro-6-methyl-quinoxalin-2-yl, 6-fluoro-7-methyl-quinoxalin-2-yl, 6- methoxy-quinoxalin-2-yl, 7-methoxy-quinoxalin-2-yl, 7-fluoro-6-methoxy-quinoxalin-2- yl, 6-trifluoromethyl-quinoxalin-2-yl, 7-trifluoromethyl-quinoxalin-2-yl, thiazolo[5,4- b]pyridin-2-yl, 6-fluoro-thiazolo[5,4-b]pyridin-2-yl, and 6-methyl-[1 ,7]naphthyridin-8-yl; and / or
• in case Ar2 represents 5-or 6-membered heteroaryl, said heteroaryl is selected from the group consisting of 5-bromo-pyrimidin-2-yl, 5-ethyl-pyrimidin-2-yl, 4- trifluoromethyl-pyrimidin-2-yl, 5-trifluoromethyl-pyrimidin-2-yl, 4,6-dimethoxy- pyrimidin-2-yl, and 4,6-dimethyl-pyrimidin-2-yl.
24) Another embodiment relates to compounds according to any one of embodiments 1 ) to 20), wherein, in case Ar2 represents 8- to 10-membered heteroaryl, said heteroaryl is selected from the group consisting of benzoxazol-2-yl, 5-fluoro-benzoxazol-2-yl, 6-fluoro- benzoxazol-2-yl, 4-chloro-benzoxazol-2-yl, 5-chloro-benzoxazol-2-yl, 6-chloro-benzoxazol-2- yl, benzo[d]isoxazol-3-yl, 5-methyl-benzo[d]isoxazol-3-yl, 6-methyl-benzo[d]isoxazol-3-yl, 5- fluoro-benzo[d]isoxazol-3-yl, 6-fluoro-benzo[d]isoxazol-3-yl, 5-chloro-benzo[d]isoxazol-3-yl, 6-chloro-benzo[d]isoxazol-3-yl, benzothiazol-2-yl, 5-fluoro-benzothiazol-2-yl, 6-fluoro- benzothiazol-2-yl, 5-chloro-benzothiazol-2-yl, 6-chloro-benzothiazol-2-yl, 5-chloro- benzo[d]isothiazol-3-yl, 6-chloro-benzo[d]isothiazol-3-yl, quinazolin-2-yl, quinoxalin-2-yl, 6- fluoro-quinoxalin-2-yl, 7-fluoro-quinoxalin-2-yl, 8-fluoro-quinoxalin-2-yl, 6-chloro-quinoxalin-2- yl, 7-chloro-quinoxalin-2-yl, 8-chloro-quinoxalin-2-yl, 5,6-difluoro-quinoxalin-2-yl, 6,7-difluoro- quinoxalin-2-yl, 7,8-difluoro-quinoxalin-2-yl, 6,7-dichloro-quinoxalin-2-yl, 6-methyl-quinoxalin- 2-yl, 7-methyl-quinoxalin-2-yl, 8-methyl-quinoxalin-2-yl, 6,7-dimethyl-quinoxalin-2-yl, 7-fluoro- 6-methyl-quinoxalin-2-yl, 6-fluoro-7-methyl-quinoxalin-2-yl, 6-methoxy-quinoxalin-2-yl, 7- methoxy-quinoxalin-2-yl, 7-fluoro-6-methoxy-quinoxalin-2-yl, 6-trifluoromethyl-quinoxalin-2-yl, and 7-trifluoromethyl-quinoxalin-2-yl.
25) Another embodiment relates to compounds according to any one of embodiments 1 ) to 20), wherein, in case Ar2 represents 8- to 10-membered heteroaryl, said heteroaryl is selected from the group consisting of benzoxazol-2-yl, 5-chloro-benzoxazol-2-yl, benzothiazol-2-yl, 6-chloro-benzothiazol-2-yl, 6-fluoro-benzothiazol-2-yl, quinazolin-2-yl, quinoxalin-2-yl, 6-chloro-quinoxalin-2-yl, 7-chloro-quinoxalin-2-yl, 6-fluoro-quinoxalin-2-yl, 7- fluoro-quinoxalin-2-yl, 6,7-dichloro-quinoxalin-2-yl, 6,7-difluoro-quinoxalin-2-yl, 6-methyl- quinoxalin-2-yl, 7-methyl-quinoxalin-2-yl, 8-methyl-quinoxalin-2-yl, 6,7-dimethyl-quinoxalin-2- yl, 7-fluoro-6-methyl-quinoxalin-2-yl, 6-fluoro-7-methyl-quinoxalin-2-yl, 6-methoxy-quinoxalin- 2-yl, 7-methoxy-quinoxalin-2-yl, 7-fluoro-6-methoxy-quinoxalin-2-yl, 6-trifluoromethyl- quinoxalin-2-yl, and 7-trifluoromethyl-quinoxalin-2-yl.
26) Another embodiment relates to compounds according to any one of embodiments 1 ) to 20), wherein, in case Ar2 represents 5-or 6-membered heteroaryl, said heteroaryl is selected from the group consisting of 5-bromo-pyrimidin-2-yl, 5-ethyl-pyrimidin-2-yl, 4-trifluoromethyl- pyrimidin-2-yl, 5-trifluoromethyl-pyrimidin-2-yl, 4,6-dimethoxy-pyrimidin-2-yl, and 4,6- dimethyl-pyrimidin-2-yl.
27) Another embodiment relates to compounds according to any one of embodiments 1 ) to 18), wherein, in case Ar2 represents 5-or 6-membered heteroaryl, said heteroaryl is selected from the group consisting of 5-bromo-pyrimidin-2-yl, 5-ethyl-pyrimidin-2-yl, 4-trifluoromethyl- pyrimidin-2-yl, 5-trifluoromethyl-pyrimidin-2-yl, 4,6-dimethoxy-pyrimidin-2-yl, and 5-bromo- pyrimidin-2-yl.
28) Another embodiment relates to compounds according to embodiment 1 ), wherein X represents CH2 or O;
Ar1 represents 5-membered heteroaryl, wherein the 5-membered heteroaryl is mono- or di- substituted; wherein
> one of said substituents is attached in orffro-position to the point of attachment of Ar1 to the rest of the molecule; wherein said orffro-substituent is phenyl which is unsubstituted, mono-, di-, or tri-substituted (especially unsubstituted or mono- substituted), wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, cyano, (C1-3)fluoroalkyl, and (Ci-3)fluoroalkoxy (especially (Ci-4)alkyl, (Ci-4)alkoxy, and halogen);
> and the other of said substituents, if present, is/are independently selected from the group consisting of (Ci-4)alkyl, (Ci-4)alkoxy, (C3-6)cycloalkyl, halogen, cyano, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, and -NR4R5, wherein R4 and R5 are independently selected from hydrogen and (C1-4)alkyl [especially (C1-4)alkyl), (C3-6)cycloalkyl, and -NR4R5, wherein R4 and R5 are independently selected from hydrogen and (C1-4)alkyl; notably (C1-4)alkyl)]; or Ar1 represents 6-membered heteroaryl (especially pyridyl), wherein the 6-membered heteroaryl is mono-, di-, or tri-substituted (especially di-substituted); wherein
> one of said substituents is attached in orffro-position to the point of attachment of Ar1 to the rest of the molecule; wherein
said orffro-substituent is unsubstituted 5-membered heteroaryl (preferred sub- embodiment; especially said 5-membered heteroaryl is [1 ,2,3]triazol-2-yl or pyrazol-1 -yl);
or said orffro-substituent is phenyl which is unsubstituted or mono-substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl, (Ci-4)alkoxy, and halogen;
> and the other of said substituents, if present, is/are independently selected from the group consisting of (Ci-4)alkyl, (Ci-4)alkoxy, (C3-6)cycloalkyl, halogen, cyano, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, and -NR4R5, wherein R4 and R5 are independently selected from hydrogen and (C1-4)alkyl (especially (C1-4)alkyl); or Ar1 represents phenyl which is mono-, di-, or tri-substituted (especially mono- or di- substituted); wherein
> one of said substituents is attached in orffro-position to the point of attachment of Ar1 to the rest of the molecule; wherein
said orffro-substituent is phenyl which is unsubstituted, or mono-, or di- substituted; wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, cyano, (C1-3)fluoroalkyl, and (C1-3)fluoroalkoxy [notably from (C1-4)alkyl, (C1-4)alkoxy, halogen, and (Ci-3)fluoroalkyl];
or said orffro-substituent is unsubstituted or mono-substituted 5- or 6-membered heteroaryl wherein the substituent is (C1-4)alkyl (wherein especially said 5- or 6- membered heteroaryl is unsubstituted [1 ,2,3]triazol-2-yl or unsubstituted pyrazol- 1 -yl; or unsubstituted pyridin-2-yl or unsubstituted pyrimidin-2-yl);
or said substituent is a benzo[1 ,3]dioxolyl group;
> and the other of said substituents, if present, is/are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, cyano, (C1-3)fluoroalkyl, and (Ci-3)fluoroalkoxy [notably (Ci-4)alkyl, (Ci-4)alkoxy, and halogen; especially (C1-4)alkyl and halogen]. and
Ar2 represents 5- to 10-membered heteroaryl which is unsubstituted, or mono-, or di- substituted; wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, and (C1-3)fluoroalkyl; whereinthe characteristics defined in embodiments 2) to 27), may be applied, mutatis mutandis, to the compounds of embodiment 28).
29) Another embodiment relates to compounds of formula (I) according to embodiment 1 ) selected from the group consisting of:
[7-(5-Chloro-benzooxazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(5-methyl-2-[1 ,2,3]triazol-2-yl-phenyl)- methanone;
[7-(6-Fluoro-benzothiazol-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(5-methyl-2-[1 ,2,3]triazol^
methanone;
[7-(6-Chloro-benzothiazol-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(5-methyl-2-[1 ,2,3]triazo
methanone;
(5-Methyl-2-[1 ,2,3]triazol-2-yl-phenyl)-[7-(4-trifluoromethyl-pyrimidin-2-yl)-3J-di
methanone;
(2-Methyl-5-o-tolyl-thiazol-4-yl)-(7-quinoxalin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone;
[2-Dimethylamino-5-(3-fluoro-4-methyl-phenyl)-thiazol-4-yl]-(7-quinoxalin-2-yl-3,7-diaza-bicyclo[3.^
methanone;
[5-(3-Methoxy-phenyl)-2-methyl-thiazol-4-yl]-(7-quinoxalin-2-yl-3,7-diaza-bicyclo[3.3.1]non-3-yl)-methanone;
[5-(3,5-Difluoro-phenyl)-2-methyl-thiazol-4-yl]-(7-quinoxalin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)
Biphenyl-2-yl-[7-(4-trifluoromethyl-pyrimidin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-m
(4-Methyl-biphenyl-2-yl)-[7-(4-trifluoromethyl-pyrimidin-2-yl)-3J-diaza-bicyclo[3.3.1 ]n
(7-Benzothiazol-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-biphenyl-2-yl-methanone;
[7-(6,7-Difluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(2-fluoro-6-[1 ,2,3]triazol-2-yl-phenyl)-methanone; (2-Fluoro-6-[1 ,2,3]triazol-2-yl-phenyl)-(7-quinoxalin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone;
(2-Fluoro-6-[1 ,2,3]triazol-2-yl-phenyl)-(7-quinazolin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone;
(2-Fluoro-6-[1 ,2,3]triazol-2-yl-phenyl)-[7-(8-methyl-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-methanone;
[7-(7-Chloro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-(2-fluoro-6-[1 ,2,3]triazol-2-yl-phenyl)-methanone;
[7-(6-Chloro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-(2-fluoro-6-[1 ,2,3]triazol-2-yl-phenyl)-methanone;
[7-(6,7-Dichloro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-(2-fluoro-6-[1 ,2,3]tn^^
methanone;
[7-(6-Fluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-(2-fluoro-6-[1 ,2,3]triazol-2-yl-phenyl)-methanone;
[7-(7-Fluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(2-fluoro-6-[1 ,2,3]triazol-2-yl-phenyl)-methanone;
[7-(8-Methyl-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-(2-methyl-6-[1 ,2,3]tri
[7-(7-Chloro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-(2-methyl-6-[1 ,2,3]triazol-2-yl-phenyl)-m [7-(6-Chloro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1]non-3-yl]-(2-methyl-6-[1 ,2 ]triazo
[7-(6J-Dichloro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1]non-3-yl]-(2-methyl-6-[1 ,2,3]tra
methanone;
[7-(6-Fluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(2-methyl-6-[1 ,2,3]triazol-2-yl-phenyl)-methanone;
[7-(7-Fluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(2-methyl-6-[1 ,2,3]triazol-2-yl-phenyl)-methanone; (2-Methyl-6-[1 ,2,3]triazol-2-yl-phenyl)-(7-quinoxalin-2-yl-3 J-diaza-bicyclo[3 .1 ]non-3-yl)-methanone;
[7-(6J-Difluoro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(2-methyl-6-[1 ,2 ]triaz
methanone;
(2-Methyl-6-[1 ,2,3]triazol-2-yl-phenyl)-(7-quinazolin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone;
[7-(8-Methyl-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-(5-methyl-2-[1 ,2,3]triazol-2-yl-phenyl)-methanone;
[7-(7-Chloro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-(5-methyl-2-[1 ,2,3]triazol-2-yl-phenyl)-methanone;
[7-(6-Chloro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-(5-methyl-2-[1 ,2,3]triazol-2-yl-phenyl)-methanone;
[7-(6,7-Dichloro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3 .1]non-3-yl]-(5-methyl-2-[1 ,2,3]tri
methanone;
[7-(6-Fluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(5-methyl-2-[1 ,2,3]triazol-2-yl-phenyl)-methanone;
[7-(7-Fluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(5-methyl-2-[1 ,2,3]triazol-2-yl-phenyl)-methanone; (5-Methyl-2-[1 ,2,3]triazol-2-yl-phenyl)-(7-quinoxalin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone;
[7-(6,7-Difluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3 .1 ]non-3-yl]-(5-methyl-2-[1 ,2 ]triaz
methanone;
(5-Methyl-2-[1 ,2,3]triazol-2-yl-phenyl)-(7-quinazolin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone;
(4-Methyl-biphenyl-2-yl)-[7-(8-methyl-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1]non-3-yl]-methanone;
[7-(6-Chloro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-(4-methyl-biphenyl-2-yl)-methanone;
[7-(6-Fluoro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(4-methyl-biphenyl-2-yl)-methanone;
[7-(7-Fluoro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(4-methyl-biphenyl-2-yl)-methanone;
(4-Methyl-biphenyl-2-yl)-(7-quinoxalin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone;
[7-(6J-Difluoro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(4-methyl-biphenyl-2-yl)-methanone;
(4-Methyl-biphenyl-2-yl)-(7-quinazolin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone;
Biphenyl-2-yl-[7-(8-methyl-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-methanone;
Biphenyl-2-yl-[7-(7-chloro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-methanone;
Biphenyl-2-yl-[7-(6-chloro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-methanone;
Biphenyl-2-yl-[7-(6J-dichloro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-methanone;
Biphenyl-2-yl-[7-(6-fluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-methanone;
Biphenyl-2-yl-[7-(7-fluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-methanone;
Biphenyl-2-yl-(7-quinoxalin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone;
Biphenyl-2-yl-[7-(6,7-difluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-methanone;
Biphenyl-2-yl-(7-quinazolin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone;
[7-(6J-Dichloro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1]non-3-yl]-(4-methyl-biphenyl-2-yl)-methanone; [7-(7-Chloro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3 .1]non-3-yl]-(4-methyl-biphenyl-2-yl)-methanone;
(5-Methyl-2-pyrazol-1 -yl-phenyl)-(7-quinoxalin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone;
[7-(6,7-Difluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3 .1 ]non-3-yl]-(5-methyl-2-pyrazol-1 -yl-phenyl)-m
[7-(7-Chloro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1]non-3-yl]-(5-methyl-2-pyrazol-1 -yl-phen
[7-(6-Chloro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1]non-3-yl]-(5-methyl-2-pyrazol-1 -yl-phenyl)-m
[7-(6J-Dichloro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1]non-3-yl]-(5-methyl-2-pyrazol-1 -yl-phen
[7-(6-Fluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(5-methyl-2-pyrazol-1-yl-phenyl)-methanone;
(5-Methyl-2-pyrazol-1 -yl-phenyl)-(7-quinazolin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone;
[7-(6,7-Difluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3 .1 ]non-3-yl]-(2-pyrazol-1-yl-phenyl)-methanone;
[7-(6,7-Dichloro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-(2-pyrazol-1 -yl-phenyl)-methanone;
[7-(5-Chloro-benzooxazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-[2-dimethylamino-5-(3,4-dimethyl-phe
4-yl]-methanone;
(6-Methyl-3-[1 ,2,3]triazol-2-yl-pyridin-2-yl)-(7-quinoxalin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methan
[7-(6J-Difluoro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(6-methyl-3-[1 ,2 ]tria
methanone;
[7-(7-Chloro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3 .1]non-3-yl]-(6-methyl-3-[1 ,2,3]triazol-^^
methanone;
[7-(6-Chloro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1]non-3-yl]-(6-methyl-3-[1 ,2 ]triazol-2^
methanone;
[7-(6,7-Dichloro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-(6-methyl-3-[1 ,2,3]triaz^
methanone;
[7-(6-Fluoro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(6-methyl-3-[1 ,2 ]triazol-2-yl-pyh^
methanone;
(6-Methyl-3-[1 ,2,3]triazol-2-yl-pyridin-2-yl)-(7-quinazolin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methan
[7-(6,7-Difluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(6-methyl-3-pyrazol-1 -yl-pyridin-2-yl)- methanone;
[7-(7-Chloro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1]non-3-yl]-(6-methyl-3-pyrazol-1 -yl-pyridin-2-yl)-meth
[7-(6,7-Dichloro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-(6-methyl-3-pyrazol-1 -yl-pyridin-2-yl)- methanone;
[7-(7-Fluoro-6-methoxy-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(5-methyl-2-[1 ,2,3]triazol-2-yl-p methanone;
[7-(6-Methoxy-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(5-methyl-2-[1 ,2,3]triazol-2-yl-phenyl)-methanone;
[7-(7-Methoxy-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(5-methyl-2-[1 ,2,3]triazol-2-yl-phenyl)-methanone;
[7-(6-Methyl-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1]non-3-yl]-(5-methyl-2-[1 ,2 ]triazol-2-yl-phenyl)-m
[7-(7-Fluoro-6-methyl-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1]non-3-yl]-(5-methyl-2-[1 ,2 ]triazo^
methanone;
[7-(7-Methyl-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1]non-3-yl]-(5-methyl-2-[1 ,2 ]triazol-2-yl-phenyl)-meth (5-Methyl-2-[1 ,2,3]triazol-2-yl-phenyl)-[7-(7-trifluoromethyl-quinoxalin-2-yl)-3,7-d
methanone;
[7-(6-Fluoro-7-methyl-quinoxalin-2-yl)-3,7-diaza-bicyclo[3 .1]non-3-yl]-(5-meth
methanone;
[7-(6,7-Difluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3 .1 ]non-3-yl]-[5-(3,4-dimethyl-phen
methanone;
[5-(2,3-Dichloro-phenyl)-2-methyl-thiazol-4-yl]-[7-(6J-difluoro-quinoxalin-2-yl)-3J-diaza- methanone;
[7-(6,7-Difluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-[2-dimethylamino-5- yl]-methanone;
[7-(6J-Difluoro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(2-methyl-5-o-tolyl-thiazol -yl)-
[7-(6,7-Difluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-[2-dimethylamino-5- thiazol-4-yl]-methanone;
[7-(6,7-Difluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-[5-(3-methoxy-phenyl)-2-methyl^
methanone;
[7-(6J-Difluoro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(2-methyl-5-p-tolyl-thiazol -yl)-met^
[5-(3,4-Dimethyl-phenyl)-2-methyl-thiazol-4-yl]-(7-quinoxalin-2-yl-3J-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone; and
[5-(2,3-Dichloro-phenyl)-2-methyl-thiazol-4-yl]-(7-quinoxalin-2-yl-3J-diaza-bicyclo[3.3.1 ]non-3-yl)-metha
30) In addition to the above-listed compounds, further compounds of formula (I) according to embodiment 1 ) are selected from the group consisting of:
(7-Benzothiazol-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-(5-methyl-2-[1 ,2,3]triazol-2-yl-phenyl)-methanone; and [7-(6-Chloro-benzothiazol-2-yl)-3,7-diaza-bi
31 ) In addition to the above-listed compounds, further compounds of formula (I) according to embodiment 1 ) are selected from the group consisting of:
[2-Dimethylamino-5-(4-fluoro-phenyl)-thiazol-4-yl]-(7-quinoxalin-2-yl-3,7-diaza-bicyclo[3 .1 ]n
[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-(7-quinoxalin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone;
[5-(4-Chloro-phenyl)-2-methyl-thiazol-4-yl]-(7-quinoxalin-2-yl-3,7-diaza-bicyclo[3.3.1]non-3-yl)-methanone;
[7-(6-Chloro-benzothiazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(2-[1 ,2,3]triazol-2-yl-phenyl)-methanone;
Biphenyl-2-yl-[7-(6-chloro-benzothiazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-methanone;
(2-Methyl-5-p-tolyl-thiazol-4-yl)-(7-quinoxalin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone;
[4-(4-Chloro-phenyl)-2-methyl-thiazol-5-yl]-(7-quinoxalin-2-yl-3,7-diaza-bicyclo[3.3.1]non-3-yl)-methanone;
[7-(6-Chloro-benzothiazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(5-methoxy-2-[1 ,2,3]triazol-2-yl-phenyl)- methanone;
[7-(6-Chloro-benzothiazol-2-yl)-3,7-diaza-b^
methanone;
[7-(5-Chloro-benzooxazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(2-fluoro-6-[1 ,2,3]triazol-2-yl-phenyl)-methanone; [7-(5-Chloro-benzooxazol-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(5-methoxy-2-[1 ,2,3]triazol-2-yl-phenyl)- methanone;
[7-(5-Chloro-benzooxazol-2-yl)-3J-diaza-bicyclo[3.3.^
methanone;
[7-(5-Chloro-benzooxazol-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(4-methyl-biphenyl-2-yl)-methanone;
(2-Fluoro-6-[1 ,2,3]tnazol-2-yl-phenyl)-[7-(4-trifluoromethyl-pynmidin-2-yl)-3,7-d
methanone;
(4-Methyl-2-[1 ,2,3]triazol-2-yl-phenyl)-[7-(4-trifluoromethyl-pyrimidin-2-yl)-3J
methanone;
(2-Methyl-6-[1 ,2,3]triazol-2-yl-phenyl)-[7-(4-trifluoromethyl-pyrimidin-2-yl)-3J-di
methanone;
(7-Benzothiazol-2-yl-3J-diaza-bicyclo[3.3.1 ]non-3-yl)-(2-methyl-6-[1 ,2,3]triazol-2-yl-phenyl)-methanone
(2-Pyrazol-1 -yl-phenyl)-(7-quinoxalin-2-yl-3,7-diaza-bicyclo[3.3.1]non-3-yl)-methanone;
[7-(7-Chloro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1]non-3-yl]-(2-pyrazol-1 -yl-phenyl)-methanone;
[7-(6-Chloro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1]non-3-yl]-(2-pyrazol-1 -yl-phenyl)-methanone;
[7-(6-Fluoro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(2-pyrazol-1 -yl-phenyl)-methanone;
(2-Pyrazol-1 -yl-phenyl)-(7-quinazolin-2-yl-3,7-diaza-bicyclo[3.3.1]non-3-yl)-methanone;
[7-(5-Chloro-benzooxazol-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-[2-cyclopropyl-5-(3-fluoro-4-methyl-phenyl)- thiazol-4-yl]-methanone;
[7-(5-Chloro-benzooxazol-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(2-methyl-5-phenyl-thiazol -yl)-methanone;
(6-Methyl-3-pyrazol-1 -yl-pyridin-2-yl)-(7-quinoxalin-2-yl-3J-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone;
[7-(6-Fluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(6-methyl-3-pyrazol-1-yl-pyridin-2-yl)-methanone;
(6-Methyl-3-pyrazol-1 -yl-pyridin-2-yl)-(7-quinazolin-2-yl-3J-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone;
(2-Cyclopropyl-5-m-tolyl-thiazol^-yl)-[7-(6,7-difluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non
[7-(6J-Difluoro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]- methanone;
[5-(4-Chloro-phenyl)-2-methyl-thiazol-4-yl]-[7-(6,7-difluoro-quinoxalin-2-yl)-3,7-diaza-bi
methanone;
[5-(3,5-Difluoro-phenyl)-2-methyl-thiazol-4-yl]-[7-(6,7-difluoro-quinoxalin-2-yl)-3,7-diaza-b
methanone;
[4-(4-Chloro-phenyl)-2-methyl-thiazol-5-yl]-[7-(6,7-difluoro-quinoxalin-2-yl)-3,7-diaza-bi
methanone; and
(5-Methyl-2-[1 ,2,3]triazol-2-yl-phenyl)-(7-quinoxalin-2-yl-9-oxa-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-m
32) In addition to the above-listed compounds, further compounds of formula (I) according to embodiment 1 ) are selected from the group consisting of:
(7-Benzooxazol-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-(5-methyl-2-[1 ,2,3]triazol-2-yl-phenyl)-methanone; [7-(4,6-Dimethox -pyrimidin-2-yl)-3 ^iaza-bicyclo[3.3.1]non-3-yl]-(5-methyl-2-[1 ,2,3]triazol-2-yl-phenyl)- methanone;
[7-(5-Bromo-pyrimidin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(5-methyl-2-[1 ,2,3]triazol-2-yl-phenyl)-methanone;
[7-(5-Chloro-benzooxazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(2-[1 ,2,3]triazol-2-yl-phenyl)-methanone;
[7-(5-Chloro-benzooxazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(4'-fluoro-3'-methyl-biphenyl-2-yl)-metha
[7-(5-Ethyl-pyrimidin-2-yl)-3^ liaza-bicyclo[3.3.1 ]non-3-ylH5-methyl-2-[1 ,2,3]triazol-2-yl-phenyl)-methanone;
(5-Methyl-2-[1 ,2,3]triazol-2-yl-phenyl)-[7-(5-trifluoromethyl-pyrimid
methanone;
(2-Cyclopropyl-5-m-tolyl-thiazol -yl)-(7-quinoxalin-2-yl-3J-diaza-bicyclo[3.3.1 ]non-3-yl)-m
[5-(6-Methoxy-pyridin-3-yl)-2-methyl-thiazol-4-yl]-(7-quinoxalin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-y
[2-Methyl-5-(3-trifluoromethyl-phenyl)-thiazol-4-yl]-(7-quinoxalin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone;
[7-(6-Chloro-benzothiazol-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-[2-(3-methyl-[1 ,2^]oxadiazo
methanone;
[2-Methyl-5-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-(7-quinoxalin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone;
[7-(6-Chloro-benzothiazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(2-pyrazol-1-yl-phenyl)-methanone;
[7-(6-Chloro-benzothiazol-2-yl)-3,7-diaza-bicyclo[3 .1 ]non-3-yl]-(2-[1 ,2,3]triazol-2-yl-5-trifl^
methanone;
[7-(6-Chloro-benzothiazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(5-chloro-2-[1 ,2,3]triazol-2-yl-phenyl)-methanone; 3-[7-(6-Chloro-benzothiazol-2-yl)-3,7-diaza-bicyclo[3.3.1]nonane-3-carbonyl]-4-[1 ,2,3]triazol-2-yl-benzonitrile;
[7-(6-Chloro-benzothiazol-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(2-fluoro-3-methoxy-6-[1 ,2,3]triazol-2-yl-phenyl)- methanone;
[7-(6-Chloro-benzothiazol-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(2-[1 ,2,3]triazol-2-yl-5-trifluoromethoxy-phenyl)- methanone;
[7-(6-Chloro-benzothiazol-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(2-methyl-6-[1 ,2 ]triazol-2-y^
methanone;
[7-(6-Chloro-benzothiazol-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(4,5-dimethoxy-2-[1 ,2,3]triazol-2-yl- methanone;
[7-(5-Chloro-benzooxazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(5-fluoro-2-[1 ,2,3]triazol-2-yl-phenyl)-methanone;
[7-(5-Chloro-benzooxazol-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(5-chloro-2-[1 ,2,3]triazol-2-yl-phenyl)-methanone;
[7-(5-Chloro-benzooxazol-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(2-[1 ,2,3]triazol-2-yl-5-trifluoromethoxy-phenyl)- methanone;
[7-(5-Chloro-benzooxazol-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(4,5-dimethoxy-2-[1 ,2,3]triazol-2-yl-phenyl)- methanone;
[7-(5-Chloro-benzooxazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(2-[1 ,2,3]triazol-2-yl-5-trifluoromethyl-phenyl)- methanone;
[7-(5-Chloro-benzooxazol-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(2-methyl-6-[1 ,2,3]triazol-2-yl-phenyl)- methanone; Biphenyl-2-yl-[7-(5-chloro-benzooxazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-methanone;
(5-Fluoro-2-[1 ,2,3]triazol-2-yl-phenyl)-[7-(4-trifluoromethyl-pyrimidin-2-yl)-3
methanone;
(5-Chloro-2-[1 ,2,3]triazol-2-yl-phenyl)-[7-(4-trifluoromethyl-pyrimidin-2-yl)^
methanone;
(2-[1 ,2,3]Triazol-2-yl-5-trifluoromethoxy-phenyl)-[7-(4 rifluoromethyl-pyrimidin
yl]-methanone;
(5-Methoxy-2-[1 ,2,3]triazol-2-yl-phenyl)-[7-(4-trifluoromethyl-pyrimidin
methanone;
(4,5-Dimethoxy-2-[1 ,2,3]triazol-2-yl-phenyl)-[7-(4-trifluoromethyl-pyrim
methanone;
(2-[1 ,2,3]Triazol-2-yl-5-trifluoromethyl-phenyl)-[7-(4-trifluoromethyl-pyrimidi
yl]-methanone;
(7-Benzothiazol-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-(5-fluoro-2-[1 ,2,3]triazol-2-yl-phenyl)-methanone;
(7-Benzothiazol-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-(2-fluoro-6-[1 ,2,3]triazol-2-yl-phenyl)-methanone;
(7-Benzothiazol-2-yl-3J-diaza-bicyclo[3.3.1 ]non-3-yl)-(5-chloro-2-[1 ,2,3]triazol-2-yl-phenyl)-methanone;
(7-Benzothiazol-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-(2-[1 ,2,3]triazol-2-yl-5-trifluoromethoxy-phenyl)-methanone; (7-Benzothiazol-2-yl-3J-diaza-bicyclo[3.3.1 ]non-3-yl)-(5-methoxy-2-[1 ,2,3]triazol-2-yl-phenyl)-methanone;
(7-Benzothiazol-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-(4-methyl-2-[1 ,2,3]triazol-2-yl-phenyl)-methanone;
(7-Benzothiazol-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-(4,5-dimethoxy-2-[1 ,2,3]triazol-2-yl-phenyl)-methanone; (7-Benzothiazol-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-(2-[1 ,2,3]triazol-2-yl-5-trifluoromethyl-phenyl)-methanone;
[5-(4-Bromo-phenyl)-2-methyl-thiazol-4-yl]-[7-(5-chloro-benzooxazol-2-yl)-3J-diaza-bicyclo[3.3.1]non-3-yl]- methanone;
[7-(5-Chloro-benzooxazol-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(2-cyclopropyl-5-phenyl-thiazol -yl)-methanone;
[7-(5-Chloro-benzooxazol-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(5-phenyl-thiazol-4-yl)-methanone;
[7-(6-Chloro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3 .1]non-3-yl]-(6-methyl-3-pyrazol-1 -yl-pyri
(5-Methyl-2-[1 ,2,3]triazol-2-yl-phenyl)-[7-(6-trifluoromethyl-quinoxalin-2-yl)-3J-diaza-bi
methanone;
[7-(6J-Difluoro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-[5-(6-methoxy-pyridin-3-yl)-2-methyl-thiazol - yl]-methanone;
[7-(6J-Difluoro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-[2-methyl-5-(3-trifluoromethyl-p
yl]-methanone;
[7-(6J-Difluoro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-[2-methyl-5-(4-trifluoromethyl-phenyl)-thiazol-4- yl]-methanone;
33) In addition to the above-listed compounds, further compounds of formula (I) according to embodiment 1 ) are selected from the group consisting of: [7-(6-Fluoro-quinoxalin-2-yl)-^ xa-3,7-diaza-bic clo[3.3.1 ]non-3-yl]-(5-methyl-2-[1 ,2,3]triazol-2-yl-phenyl)- methanone;
[7-(6J-Difluoro-quinoxalin-2-yl)-9-oxa-3J-diaza-bicyclo[3.3.1]non-3-yl]-(5-methyl^
methanone;
(5-Methyl-2-[1 ,2,3]triazol-2-yl-phenyl)-(7-quinazolin-2-yl-9-oxa-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methanon
[7-(8-Methyl-quinoxalin-2-yl)-9-oxa-37-diaza-bicyclo[3 .1 ]non-3-yl]-(5-methyl-2-[
methanone;
[7-(7-Chloro-quinoxalin-2-yl)-9-oxa-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(5-methyl-2-[1 ,2,3^
methanone;
[7-(67-Dichloro-quinoxalin-2-yl)-9-oxa-37-diaza-bicyclo[3.3.1]non-3-yl]-(5-methyl-2-[1 ,2^
methanone;
[7-(6-Fluoro-quinoxalin-2-yl)-9-oxa-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(4-methyl-biphenyl-2-yl)-methanone;
[7-(6J-Difluoro-quinoxalin-2-yl)-9-oxa-3J-diaza-bicyclo[3.3.1]non-3-yl]-(4-methyl-biphenyl-2-yl)-methanone
(4-Methyl-biphenyl-2-yl)-(7-quinazolin-2-yl-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl)-methanone;
(4-Methyl-biphenyl-2-yl)-[7-(8-methyl-quinoxalin-2-yl)-9-oxa-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-me
[7-(6J-Dichloro-quinoxalin-2-yl)-9-oxa-3J-diaza-bicyclo[3.3.1]non-3-yl]-(4-methyl-biphenyl-2-yl)-methanone;
Biphenyl-2-yl-[7-(8-methyl-quinoxalin-2-yl)-9-oxa-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-methanone;
[7-(6J-Dichloro-quinoxalin-2-yl)-9-oxa-3J-diaza-bicyclo[3.3.1]non-3-yl]-(2-fluoro-6-[1 ,2,3]tra
methanone; and
[7-(8-Methyl-quinoxalin-2-yl)-9-oxa-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(2-methyl-6-[1 ,2,3]tr^
methanone.
34) In addition to the above-listed compounds, further compounds of formula (I) according to embodiment 1 ) are selected from the group consisting of:
(5-Methyl-2-[1 ,2,3]triazol-2-yl-phenyl)-(7-quinoxalin-2-yl-9-oxa-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone;
[7-(6-Chloro-quinoxalin-2-yl)-9-oxa-3,7^
methanone;
(4-Methyl-biphenyl-2-yl)-(7-quinoxalin-2-yl-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl)-methanone;
[7-(7-Chloro-quinoxalin-2-yl)-9-oxa-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(4-methyl-biphenyl-2-yl)-methanone;
[7-(6-Chloro-quinoxalin-2-yl)-9-oxa-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(4-methyl-biphenyl-2-yl)-methanone;
[7-(6,7-Dichloro-quinoxalin-2-yl)-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl]-(6-methyl-3-[1 ,2,3]W
yl)-methanone;
(2-Fluoro-6-[1 ,2,3]triazol-2-yl-phenyl)-[7-(8-methyl-quinoxalin-2-yl)-9-oxa-3,7-diaza-bicyc
methanone; and
[7-(6,7-Dichloro-quinoxalin-2-yl)-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl]-(2-methyl-6-[1 ,2,3]W
methanone.
35) In addition to the above-listed compounds, further compounds of formula (I) according to embodiment 1 ) are selected from the group consisting of: (7-Benzothiazol-2-yl-9-oxa-3J-diaza-bicyclo[3.3.1]non-3-yl)-(4-methyl-biphenyl-2-yl)-methanone;
[7-(6-Fluoro-benzothiazol-2-yl)-9-oxa-3J-diaza-bicyclo[3.3.1]non-3-yl]-(4-methyl-biphenyl-2-yl)-methanone;
[7-(5-Chloro-benzooxazol-2-yl)-9-oxa-3J-diaza-bicyclo[3.3.1]non-3-yl]-(4-methyl-biphenyl-2-yl)-methanone;
Biphenyl-2-yl-(7-quinoxalin-2-yl-9-oxa-3J-diaza-bicyclo[3.3.1]non-3-yl)-methanone;
Biphenyl-2-yl-[7-(6,7-difluoro-quinoxalin-2-yl)-9-oxa-3,7-diaza-bicyclo[3 .1 ]non-3-yl]-methanone;
Biphenyl-2-yl-[7-(7-chloro-quinoxalin-2-yl)-9-oxa-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-methanone;
Biphenyl-2-yl-[7-(6-chloro-quinoxalin-2-yl)-9-oxa-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-methanone;
Biphenyl-2-yl-[7-(6,7-dichloro-quinoxalin-2-yl)-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl]-methanone;
Biphenyl-2-yl-[7-(6-fluoro-quinoxalin-2-yl)-9-oxa-3,7-diaza-bicyclo[3.3 ]non-3-yl]-methanone;
Biphenyl-2-yl-(7-quinazolin-2-yl-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl)-methanone;
(7-Benzothiazol-2-yl-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl)-biphenyl-2-yl-methanone;
Biphenyl-2-yl-[7-(6-fluoro-benzothiazol-2-yl)-9-oxa-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-methanone;
Biphenyl-2-yl-[7-(5-chloro-benzooxazol-2-yl)-9-oxa-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-methanone;
[7-(6J-Dichloro-quinoxalin-2-yl)-9-oxa-3J-diaza-bicyclo[3.3.1]non-3-yl]-(6-methyl-3-pyrazol-1-yl^ methanone;
[7-(6J-Difluoro-quinoxalin-2-yl)-9-oxa-3J-diaza- methanone;
(6-Methyl-3-pyrazol-1 -yl-pyridin-2-yl)-(7-quinoxalin-2-yl-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl)-methanone;
[7-(7-Chloro-quinoxalin-2-yl)-9-oxa-3,7-diaza-bicyclo[3 .1 ]non-3-yl]-(6-methyl-3-pyrazol-1 -yl-pyridin-2-yl)- methanone;
[7-(6-Chloro-quinoxalin-2-yl)-9-oxa-3,7-diaza-bicyclo[3 .1 ]non-3-yl]-(6-methyl-3-pyrazol-1 -yl-pyridin-2-yl)- methanone;
(6-Methyl-3-pyrazol-1 -yl-pyridin-2-yl)-(7-quinazolin-2-yl-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl)-methan
[7-(6J-Dimethyl-quinoxalin-2-yl)-9-oxa-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(6-methyl-3-pyrazol-1 -yl-pyridi methanone;
[7-(67-Difluoro-quinoxalin-2-yl)-9-oxa-3J-diaza-bicyclo[3 .1]non-3-yl]-(6-methyl-3-[1 ,2,3]t
methanone;
(6-Methyl-3-[1 ,2 ]triazol-2-yl-pyridin-2-yl)-(7-quinoxalin-2-yl-9-oxa-3J-diaza-bicyclo[3.3.1^
[7-(7-Chloro-quinoxalin-2-yl)-9-oxa-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(6-methyl-3-[1 ,2 ]triazo
methanone;
[7-(6-Chloro-quinoxalin-2-yl)-9-oxa-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(6-methyl-3-[1 ,2 ]tr^
methanone;
(6-Methyl-3-[1 ,2 ]triazol-2-yl-pyridin-2-yl)-(7-quinazolin-2-yl-9-oxa-3J-diaza-bicyclo[3.3.1^
[7-(6J-Dimethyl-quinoxalin-2-yl)-9-oxa-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(6-methyl-3-[1 ,2,3]triaz
yl)-methanone;
(7-Benzothiazol-2-yl-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl)-(5-methyl-2-[1 ,2,3]triazol-2-yl-phenyl)-methanone; (7-Benzothiazol-2-yl-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl)-(5-chloro-2-[1 ,2,3]triazol-2-yl-phenyl)-methanone; [7-(6-Fluoro-benzothiazol-2-yl)-9-oxa-3J-diaza-bicyclo[3.3.1]non-3-yl]-(5-methyl-2-[1 ,2,3]triazol-2-yl-phen methanone;
[7-(6-Fluoro-benzothiazol-2-yl)-9-oxa-3J-diaza-bicyclo[3.3.1]non-3-yl]-(2-methyl-6-[1 ,2,3]triazol-2-yl-ph methanone;
[7-(6-Fluoro-benzothiazol-2-yl)-9-oxa-3J-diaza-bicyclo[3.3.1]non-3-yl]-(5-methoxy-2-[1 ,2,3]triazol-2-yl-phenyl)- methanone;
[7-(6-Fluoro-benzothiazol-2-yl)-9-oxa-3J-diaza-bicyclo[3.3.1]non-3-yl]-(5-fluoro-2-[1 ,2,3]triazol-2-yl-phenyl)- methanone;
[7-(6-Fluoro-benzothiazol-2-yl)-9-oxa-3J-diaza-bicyclo[3.3.1]non-3-yl]-(2-fluoro-6-[1 ,2,3]triazol-2-yl-phenyl)- methanone;
(5-Chloro-2-[1 ,2,3]triazol-2-yl-phenyl)-[7-(6-fluoro-benzothiazol-2-yl)-9-oxa-3J-diaza-bicyclo[3.3.1 ]non-3-yl]- methanone;
(2-Fluoro-6-[1 ,2,3]triazol-2-yl-phenyl)-(7-quinoxalin-2-yl-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl)-methanone;
[7-(6-Fluoro-quinoxalin-2-yl)-9-oxa-3,7-diaza-bicyclo[3 .1 ]non-3-yl]-(2-fluoro-6-[1 ,2,3]tri
methanone;
[7-(6,7-Difluoro-quinoxalin-2-yl)-9-oxa-3 -diaza-bicyclo[3.3.1]non-3-yl]-(2-fluoro-6-[1 ,2,^
methanone;
[7-(7-Fluoro-quinoxalin-2-yl)-9-oxa-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(2-fluoro-6-[1 ,2,3]triazo^^^
methanone;
(2-Fluoro-6-[1 ,2,3]tnazol-2-yl-phenyl)-(7-quinazolin-2-yl-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl)-methanone;
[7-(7-Chloro-quinoxalin-2-yl)-9-oxa-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(2-fluoro-6-[1 ,2 ]triazo
methanone;
[7-(6-Chloro-quinoxalin-2-yl)-9-oxa-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(2-fluoro-6-[1 ,2,3]t^
methanone;
(2-Methyl-6-[1 ,2,3]triazol-2-yl-phenyl)-(7-quinoxalin-2-yl-9-oxa-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone;
[7-(6-Fluoro-quinoxalin-2-yl)-9-oxa-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(2-methyl-6-[1 ,2 ]triazo
methanone;
[7-(6,7-Difluoro-quinoxalin-2-yl)-9-oxa-3 -diaza-bicyclo[3.3.1]non-3-yl]-(2-methyl-6-[1 ,2,^
methanone;
[7-(7-Fluoro-quinoxalin-2-yl)-9-oxa-3,7-diaza-bicyclo[3 .1 ]non-3-yl]-(2-methyl-6-[1 ,2,3]tri
methanone;
(2-Methyl-6-[1 ,2,3]triazol-2-yl-phenyl)-(7-quinazolin-2-yl-9-oxa-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methan
[7-(7-Chloro-quinoxalin-2-yl)-9-oxa-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(2-methyl-6-[1 ,2 ]triazo
methanone; and
[7-(6-Chloro-quinoxalin-2-yl)-9-oxa-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(2-methyl-6-[1 ,2 ]tr^
methanone; 36) In addition to the above-listed compounds, further compounds of formula (I) according to embodiment 1 ) are selected from the group consisting of:
(2-Bromo-5-methoxy-phenyl)-[7-(6-chloro-
(2-Bromo-5-methyl-phenyl)-[7-(6-chloro-benzothiazol-2-yl)-3J-diaza-bicyclo[3.3.1]non-3-yl]-methanone;
[7-(6-Chloro-benzothiazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(2,5-dimethyl-phenyl)-methanone;
[7-(6-Chloro-benzothiazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(2,5-dichloro-phenyl)-methanone;
[7-(6-Chloro-benzothiazol-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(5-chloro-2-methoxy-phenyl)-methanone;
[7-(6-Chloro-benzothiazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(2,5-dimethoxy-phenyl)-methanone;
[7-(6-Chloro-benzothiazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(2-trifluoromethoxy-phenyl)-methanone;
[7-(6-Chloro-benzothiazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(5-chloro-2-ethoxy-phenyl)-methanone;
[7-(6-Chloro-benzothiazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(3-fluoro-2-propoxy-phenyl)-methanone;
[7-(6-Chloro-benzothiazol-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(2-ethoxy-phenyl)-methanone;
(2-Benzoyl-phenyl)-[7-(6-chloro-benzothiazol-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-methanone;
[7-(6-Chloro-benzothiazol-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-[2-(1 ,1 ,2,2-tetrafluoro^
methanone;
[7-(6-Chloro-benzothiazol-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-[2-(2-methoxy-ethoxy)-phenyl]-methanone
37) In addition to the above-listed compounds, further compounds of formula (I) according to embodiment 1 ) are selected from the group consisting of:
(3'-Methoxy-biphenyl-2-yl)-(7-quinazolin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone;
[7-(6J-Dichloro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1]non-3-yl]-(2-methyl-5-o-tolyl-th
(2'-Fluoro-biphenyl-2-yl)-(7-quinazolin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone;
(2-Benzo[1 ,3]dioxol-5-yl-phenyl)-(7-quinazolin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone;
(3'-Fluoro-biphenyl-2-yl)-(7-quinazolin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone;
(3'-Methyl-biphenyl-2-yl)-(7-quinazolin-2-yl-3J-diaza-bicyclo[3.3.1]non-3-yl)-methanone^
2'-[7-(6,7-Difluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]nonane-3-carbonyl]-4'-methyl-biphenyl-4-carbonitrile;
(4'-Methoxy-biphenyl-2-yl)-(7-quinazolin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone;
[7-(6J-Difluoro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(2'-fluoro -methyl-bip
(4'-Ethoxy-biphenyl-2-yl)-(7-quinazolin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone;
[7-(6,7-Dichloro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3 .1]non-3-yl]-[5-(3,5-difluoro-phenyl)-2-methyl-th methanone;
(2-Benzo[1 ,3]dioxol-5-yl-5-methyl-phenyl)-[7-(6,7-difluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]- methanone;
[7-(6,7-Difluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(3'-methoxy^-methyl-biphenyl-2-yl)-methanone;
[7-(6J-Difluoro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(3'-fluoro -methyl-biphenyl-2-yl)-met^
(7-Benzothiazol-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-(4'-methoxy-4-methyl-biphenyl-2-yl)-methanone;
[7-(6,7-Difluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(4,3'-dimethyl-biphenyl-2-yl)-me
(7-Benzothiazol-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-(3'-methoxy-4-methyl-biphenyl-2-yl)-methanone; (2'-Methyl-biphenyl-2-yl)-(7-quinazolin-2-yl-3,7-diaza-bicyclo[3.3.1]non-3-yl)-methanone;
(2\3'-Dimethyl-biphenyl-2-yl)-(7-quinazolin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone
[7-(6-Chloro-benzothiazol-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(4'-methoxy-4-methyl-biphenyl-2-y
(2'-Methoxy-biphenyl-2-yl)-(7-quinazolin-2-yl-3J-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone;
[7-(6J-Difluoro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(4'-methoxy -methyl-biph
[7-(6J-Dichloro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1]non-3-yl]-[5-(6-methoxy-pyridin-3-yl)-2-methyl-th yl]-methanone;
(7-Benzothiazol-2-yl-3J-diaza-bicyclo[3.3.1 ]non-3-yl)-(2'-fluoro -methyl-biphenyl-2-yl)-m
[7-(6J-Dichloro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1]non-3-yl]-(2-methyl -p-tolyl-thiaz
[7-(6-Chloro-benzothiazol-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(3'-methoxy-4-methyl-biphenyl-2-yl)-meth
[7-(6J-Dichloro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1]non-3-yl]-[5-(4-fluoro-phenyl)-2-m
methanone;
[7-(6,7-Difluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(4,2'-dimethyl-biphenyl-2-yl^
(7-Benzothiazol-2-yl-3J-diaza-bicyclo[3.3.1 ]non-3-yl)-(3'-methoxy-biphenyl-2-yl)-methanone;
[7-(6J-Difluoro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(2'-methoxy -methyl-biph
(2-Benzo[1 ,3]dioxol-5-yl-5-methyl-phenyl)-[7-(6-chloro-benzothiazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]- methanone;
[7-(6J-Difluoro-quinoxalin-2-yl)-3J-diaza-b^
[7-(6,7-Dichloro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3 .1]non-3-yl]-[5-(3,4-dimethyl-phenyl)-2-meth methanone;
[7-(6-Chloro-benzothiazol-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(2'-fluoro -methyl-biphenyl-2-yl)-methanone;
[5-(4-Chloro-phenyl)-2-methyl-thiazol-4-yl]-[7-(6,7-dichloro-quinoxalin-2-yl)-3 -diaza-bicyclo[3.3.^ methanone;
[7-(6-Fluoro-benzothiazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(4-methyl-biphenyl-2-yl)-methanone;
(4'-Methyl-biphenyl-2-yl)-(7-quinazolin-2-yl-3,7-diaza-bicyclo[3.3.1]non-3-yl)-methanone;
[7-(6,7-Difluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(4,4'-dimethyl-biphenyl-2-yl)-m
(2-Cyclopropyl-5-phenyl-thiazol-4-yl)-[7-(6,7-dichloro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]- methanone;
(2-Methyl-6-[1 ,2 ]triazol-2-yl-phenyl)-[7-(7-trifluoromethyl-quinoxalin-2-yl)-3J-diaza-bi
methanone;
[5-(2,3-Dichloro-phenyl)-2-methyl-thiazol-4-yl]-[7-(6,7-dichloro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3^ methanone;
[7-(6,7-Difluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(4,2\3'-trimethyl-biphenyl-2-y
(7-Benzothiazol-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-(4-methyl-biphenyl-2-yl)-methanone;
(7-Benzothiazol-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-(2'-fluoro-biphenyl-2-yl)-methanone;
(2'-Ethyl-biphenyl-2-yl)-(7-quinazolin-2-yl-3,7-diaza-bicyclo[3.3.1]non-3-yl)-methanone;
(7-Benzothiazol-2-yl-3J-diaza-bicyclo[3.3.1 ]non-3-yl)-(3'-fluoro -methyl-biphenyl-2-yl)-methanone; (2-Benzo[1 ,3]dioxol-5-yl-5-methyl-phe^
(2-Benzo[1 ,3]dioxol-5-yl-phenyl)-(7-benzothiazol-2-yl-3,7-diaza-bicyclo[3.3.1]non-3-yl)-methan and
[7-(6,7-Dichloro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-[2-dimethylam
yl]-methanone.
38) In addition to the above-listed compounds, further compounds of formula (I) according to embodiment 1 ) are selected from the group consisting of:
[5-(2,3-Dichloro-phenyl)-2-methyl-thiazol-4-yl]-[7-(4-trifluoromethyl-pyrimidin-2-y
yl]-methanone;
(7-Benzothiazol-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-(4'-methoxy-biphenyl-2-yl)-methanone;
[5-(3,4-Dimethyl-phenyl)-2-methyl-thiazo
yl]-methanone;
2'-[7-(6,7-Difluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]nonane-3-carbonyl]-4'-methyl-biphenyl-3-carbonitrile;
(7-Benzothiazol-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-(4'-ethoxy-4-methyl-biphenyl-2-yl)-methanone;
[7-(6-Chloro-benzothiazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(3'-fluoro^-methyl-biphenyl-2-yl)-methanone;
[7-(6J-Difluoro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(4'-fluoro4-methyl-bi
(7-Benzothiazol-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-(4,2\3'-trimethyl-biphenyl-2-yl)-methanone;
(7-Benzothiazol-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-(3'-methyl-biphenyl-2-yl)-methanone;
(5-Methyl-biphenyl-2-yl)-[7-(4-trifluoromethyl-pyrimidin-2-yl)-3J-diaza
[7-(5-Chloro-benzooxazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(4-methyl-biphenyl-2-yl)-methanone;
[7-(6,7-Difluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3 .1 ]non-3-yl]-(2'-ethyl-4-methyl-biphenyl-2-yl)-meth
(7-Quinazolin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-(3'-trifluoromethyl-biphenyl-2-yl)-methanone;
(2-Methyl-5-o-tolyl-thiazol-4-yl)-[7-(4-trifluoromethyl-pyrimidin-2-yl)-3,7-diaza-bicyclo[
2'-(7-Quinazolin-2-yl-3,7-diaza-bicyclo[3.3.1 ]nonane-3-carbonyl)-biphenyl-4-carbonitrile;
[7-(6-Chloro-benzothiazol-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(5-methyl-2-pyridin-2-yl-p
(7-Quinazolin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-(4'-trifluoromethoxy-biphenyl-2-yl)-methanon
(7-Benzothiazol-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-(3'-fluoro-biphenyl-2-yl)-methanone;
[7-(6-Fluoro-thiazolo[5,4-b]pyridin-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(5-methyl-2^
methanone;
(7-Benzothiazol-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-(4,3'-dimethyl-biphenyl-2-yl)-methanone;
[7-(6,7-Dichloro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3 .1]non-3-yl]-[2-methyl-5-(3-trifluorometh
yl]-methanone;
[7-(6J-Difluoro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(4-methyl-4'-trifluoromethoxy-bi
methanone;
(3',4'-Dichloro-biphenyl-2-yl)-(7-quinazolin-2-yl-3J-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone;
[7-(6-Chloro-benzothiazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(4-methyl-biphenyl-2-yl)-methanone;
[7-(6-Chloro-benzothiazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(4'-ethoxy-4-methyl-biphenyl-2-yl)-methanone; [7-(6-Methyl-[1 ,7]naphthyridin-8-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(5-meth^
methanone;
[5-(3-Methoxy-phenyl)-2-methyl-thiazol^-yl]-[7-(4-trifluoromethyl-pyrimidin
methanone;
[5-(3-Chloro-phenyl)-thiazol-4-yl]-[7-(6,7-dichloro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non
(4 hloro -methyl-biphenyl-2-yl)-[7-(6J-difluoro-quinoxalin-2-yl)-3J-diaza-bicyclo[3
[7-(6-Chloro-benzothiazol-2-yl)-3J-diaza-bicyclo[3.^^
[7-(6-Chloro-benzothiazol-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(4-methyl-biphenyl-2-yl)-meth and 2'-(7-Benzothiazol-2-yl-3J-diaza-bicyclo[3.3.1 ]nonane-3-carbonyl)-4'-methyl-biphenyl -carbonitrile.
39) In addition to the above-listed compounds, further compounds of formula (I) according to embodiment 1 ) are selected from the group consisting of:
[7-(6-Chloro-benzothiazol-2-yl)-3,7-diaza-bicyclo[3 .1 ]non-3-yl]-(4,3'-dimethyl-biphenyl-2-yl)-meth
[7-(6J-Dichloro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1]non-3-yl]-[2-dimethylamino-5-(3-fl
thiazol-4-yl]-methanone;
(7-Quinazolin-2-yl-3,7-diaza-bicyclo[3 .1 ]non-3-yl)-(3'-trifluoromethoxy-biphenyl-2-yl)-methanone;
(2-Cyclopropyl-5-m-tolyl-thiazol -yl)-[7-(6J-dichloro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1]non
methanone;
[7-(6-Fluoro-benzothiazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(5-methyl-2-pyridin-2-yl-phenyl)-methanone;
(5-Methyl-2-[1 ,2,3]triazol-2-yl-phenyl)-(7-thiazolo[5,4-b]pyridin-2-yl-3,7-diaza-bicyclo^
(4'-Fluoro-2'-methyl-biphenyl-2-yl)-(7-quinazolin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone;
(4'-Chloro-biphenyl-2-yl)-(7-quinazolin-2-yl-3,7-diaza-bicyclo[3.3.1]non-3-yl)-methanone;
[7-(6-Chloro-benzothiazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(5-methyl-2-pyrimidin-2-yl-phenyl)-methanone;
(7-Benzothiazol-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-(4'-ethoxy-biphenyl-2-yl)-methanone;
[7-(6-Fluoro-benzothiazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(5-methyl-2-pyrimidin-2-yl-phenyl)-methanone;
[7-(4,6-Dimethyl-pyrimidin-2-yl)-3J-diaza-bicyclo[3.3.1]non-3-yl]-(4-methyl-biphenyl-2-yl)-methanone and
[7-(6,7-Dichloro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3 .1]non-3-yl]-[2-methyl-5-(4-trifluoromethyl-phe
yl]-methanone.
40) A further embodimentrelates to compounds of formula (I) according to embodiment 1 ) that are potent antagonists of the orexin 1 receptor, which are especially the compounds of embodiments 29), 30), 31 ), 33), and 34); and the compounds of embodiments 37) and 38).
41 ) A further embodiment relates to compounds of formula (I) according to embodiment 1 ) that are potent antagonists of both the orexin 1 and the orexin 2 receptor, which are especially the compounds selected from the group consisting of:
(2-Fluoro-6-[1 ,2,3]triazol-2-yl-phenyl)-[7-(8-methyl-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-methanone;
[7-(8-Methyl-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-(2-methyl-6-[1 ,2,3]triazol-2-yl^ [7-(6 -Dffluoro-quinoxalin-2-yl)^ -diaza-bicyclo[3.3.1]non-3-yl]-(2-methyl-6-[1 ,2,3]triazol-2-yl-phenyl)- methanone;
[7-(8-Methyl-quinoxalin-2-yl)-3,7-diaza-bicyclo[3 .1]non-3-yl]-(5-methyl-2-[1 ,2,3]triazol-2-yl-phenyl)-methanone;
[7-(6-Fluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-(5-methyl-2-[1 ,2,3]triazol-2-yl-phenyl)-methanone;
[7-(6 -Dffluoro-quinoxalin-2-yl)^ -diaza-bicyclo[3.3.1]non-3-yl]-(5-methyl-2-[1 ,2,3]triazol-2-yl-phenyl)- methanone;
Biphenyl-2-yl-[7-(8-methyl-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-m and
[7-(6,7-Difluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-(3'-methoxy^-meth
The invention, thus, relates to compounds of the formula (I) as defined in embodiment 1), or further limited under consideration of their respective dependencies by the characteristics of any one of embodiments 2) to 41); to pharmaceutically acceptable salts thereof; and to the use of such compounds as medicaments especially in the treatment of mental health disorders relating to orexinergic dysfunctions, which disorders are especially selected from sleep disorders, anxiety disorders, addiction disorders, cognitive dysfunctions, mood disorders, or appetite disorders (notably from anxiety disorders, addiction disorders and mood disorders). In addition, the characteristics defined in embodiments 2) to 27) may be applied mutatis mutandis to the compounds of the formula (I) according to embodiment 28). Especially the following embodiments relating to the compounds of formula (I) according to embodiment 1) are thus possible and intended and herewith specifically disclosed in individualized form:
2+1, 3+1, 4+1, 4+2+1, 4+3+1, 7+1, 7+2+1, 7+3+1, 11+1, 11+4+1, 11+4+2+1, 11+4+3+1, 11+7+1, 11+7+2+1, 11+7+3+1, 12+1, 12+4+1, 12+4+2+1, 12+4+3+1, 12+7+1, 12+7+2+1, 12+7+3+1, 18+1, 18+2+1, 18+3+1, 18+4+1, 18+4+2+1, 18+4+3+1, 18+7+1, 18+7+2+1, 18+7+3+1, 18+11+1, 18+11+4+1, 18+11+4+2+1, 18+11+4+3+1, 18+11+7+1, 18+11+7+2+1, 18+11+7+3+1, 18+12+1, 18+12+4+1, 18+12+4+2+1, 18+12+4+3+1, 18+12+7+1, 18+12+7+2+1, 18+12+7+3+1, 22+1, 22+2+1, 22+3+1, 22+4+1, 22+4+2+1, 22+4+3+1, 22+7+1, 22+7+2+1, 22+7+3+1, 22+11+1, 22+11+4+1, 22+11+4+2+1, 22+11+4+3+1, 22+11+7+1, 22+11+7+2+1, 22+11+7+3+1, 22+12+1, 22+12+4+1, 22+12+4+2+1, 22+12+4+3+1, 22+12+7+1, 22+12+7+2+1, 22+12+7+3+1, 22+18+1, 22+18+2+1, 22+18+3+1, 22+18+4+1, 22+18+4+2+1, 22+18+4+3+1, 22+18+7+1, 22+18+7+2+1, 22+18+7+3+1, 22+18+11+1, 22+18+11+4+1, 22+18+11+4+2+1, 22+18+11+4+3+1, 22+18+11+7+1, 22+18+11+7+2+1, 22+18+11+7+3+1, 22+18+12+1, 22+18+12+4+1, 22+18+12+4+2+1, 22+18+12+4+3+1, 22+18+12+7+1, 22+18+12+7+2+1, 22+18+12+7+3+1;
13+1, 18+13+1, 25+4+1, 25+7+1, 25+11+1, 25+11+4+1, 25+11+7+1, 25+13+1, 25+18+1, 25+18+4+1, 25+18+7+1, 25+18+11+1, 25+18+11+4+1, 25+18+11+7+1, 25+18+13+1, 27+4+1, 27+7+1, 27+11+1, 27+11+4+1, 27+11+7+1, 27+13+1, 27+18+1, 27+18+4+1, 27+18+7+1, 27+18+11+1, 27+18+11+4+1, 27+18+11+7+1, 27+18+13+1, 27+25+1, 27+25+4+1, 27+25+7+1, 27+25+11+1, 27+25+11+4+1, 27+25+11+7+1, 27+25+13+1, 27+25+18+1, 27+25+18+4+1, 27+25+18+7+1, 27+25+18+11+1, 27+25+18+11+4+1, 27+25+18+11+7+1, 27+25+18+13+1;
28+1, 28+2+1, 28+3+1, 28+11+1, 28+11+2+1, 28+11+3+1, 28+12+1, 28+12+2+1, 28+12+3+1, 28+18+1, 28+18+2+1, 28+18+3+1, 28+18+11+1, 28+18+11+2+1, 28+18+11+3+1, 28+18+12+1, 28+18+12+2+1, 28+18+12+3+1, 28+22+1, 28+22+2+1, 28+22+3+1, 28+22+11+1, 28+22+11+2+1, 28+22+11+3+1, 28+22+12+1, 28+22+12+2+1, 28+22+12+3+1, 28+22+18+1, 28+22+18+2+1, 28+22+18+3+1, 28+22+18+11+1, 28+22+18+11+2+1, 28+22+18+11+3+1, 28+22+18+12+1, 28+22+18+12+2+1, 28+22+18+12+3+1, 28+23+1, 28+23+2+1, 28+23+3+1, 28+23+11+1, 28+23+11+2+1, 28+23+11+3+1, 28+23+12+1, 28+23+12+2+1, 28+23+12+3+1, 28+23+18+1, 28+23+18+2+1, 28+23+18+3+1, 28+23+18+11+1, 28+23+18+11+2+1, 28+23+18+11+3+1, 28+23+18+12+1, 28+23+18+12+2+1, 28+23+18+12+3+1.
In the list above the numbers refer to the embodiments according to their numbering provided hereinabove whereas "+" indicates the dependency from another embodiment. The different individualized embodiments are separated by commas. In other words, "4+3+1" for example refers to embodiment 4) depending on embodiment 3), depending on embodiment 1), i.e. embodiment "4+3+1" corresponds to embodiment 1) further limited by the features of embodiments 3) and 4). Likewise, "28+18+3+1" refers to embodiment 28) depending mutatis mutandis on embodiments 3) and 18), depending on embodiment 1), i.e. embodiment "28+18+3+1" corresponds to embodiment 1) further limited by the features of embodiment 28), further limited by the features of embodiments 18) and 3).
The compounds of formula (I) and their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical compositions for enteral (such especially oral) or parenteral administration (including topical application or inhalation).
The production of the pharmaceutical compositions can be effected in a manner which will be familiar to any person skilled in the art (see for example Remington, The Science and Practice of Pharmacy, 21st Edition (2005), Part 5, "Pharmaceutical Manufacturing" [published by Lippincott Williams &Wilkins]) by bringing the described compounds of formula (I) or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants. The present invention also relates to a method for the prevention or treatment of a disease or disorder mentioned herein comprising administering to a subject a pharmaceutically active amount of a compound of formula (I).
In a preferred embodiment of the invention, the administered amount is comprised between 1 mg and 1000 mg per day, particularly between 5 mg and 500 mg per day, more particularly between 25 mg and 400 mg per day, especially between 50 mg and 200 mg per day.
For avoidance of any doubt, if compounds are described as useful for the prevention or treatment of certain diseases, such compounds are likewise suitable for use in the preparation of a medicament for the prevention or treatment of said diseases.
The compounds according to formula (I) are useful for the prevention or treatment of disorders relating to orexinergic dysfunctions.
Such disorders relating to orexinergic dysfunctions are diseases or disorders where an antagonist of a human orexin receptor is required, notably mental health diseases or disorders relating to orexinergic dysfunctions. The above mentioned disorders may in particular be defined as comprising sleep disorders, anxiety disorders, addiction disorders, cognitive dysfunctions, mood disorders, or appetite disorders. Especially, the above mentioned disorders comprise anxiety disorders, addiction disorders and mood disorders, notably anxiety disorders and addiction disorders.
In addition, further disorders relating to orexinergic dysfunctions are selected from treating, controlling, ameliorating or reducing the risk of epilepsy, including absence epilepsy; treating or controlling pain, including neuropathic pain; treating or controlling Parkinson's disease; treating or controlling psychosis including acute mania and bipolar disorder; treating or controlling stroke, particularly ischemic or haemorrhagic stroke; blocking an emetic response i.e. nausea and vomiting; and treating or controlling agitation, in isolation or co-morbid with another medical condition.
Sleep disorders comprise dyssomnias, parasomnias, sleep disorders associated with a general medical condition and substance-induced sleep disorders. In particular, dyssomnias include intrinsic sleep disorders (especially insomnias, breathing-related sleep disorders, periodic limb movement disorder, and restless leg syndrome), extrinsic sleep disorders, and circadian-rythm sleep disorders. Dyssomnias notably include insomnia, primary insomnia, idiopathic insomnia, insomnias associated with depression, emotional/mood disorders, aging, Alzheimer's disease or cognitive impairment; REM sleep interruptions; breathing-related sleep disorders; sleep apnea; periodic limb movement disorder (nocturnal myoclonus), restless leg syndrome, circadian rhythm sleep disorder; shift work sleep disorder; and jet-lag syndrome. Parasomnias include arousal disorders and sleep-wake transition disorders; notably parasomnias include nightmare disorder, sleep terror disorder, and sleepwalking disorder. Sleep disorders associated with a general medical condition are in particular sleep disorders associated with diseases such as mental disorders, neurological disorders, neuropathic pain, and heart and lung diseases. Substance-induced sleep disorders include especially the subtypes insomnia type, parasomnia type and mixed type, and notably include conditions due to drugs which cause reductions in REM sleep as a side effect. Sleep disorders especially include all types of insomnias, sleep-related dystonias; restless leg syndrome; sleep apneas; jet-lag syndrome; shift work sleep disorder, delayed or advanced sleep phase syndrome, or insomnias related to psychiatric disorders. In addition, sleep disorders further include sleep disorders associated with aging; intermittent treatment of chronic insomnia; situational transient insomnia (new environment, noise) or short-term insomnia due to stress; grief; pain or illness.
Anxiety disorders can be distinguished by the primary object or specificity of threat, ranging from rather diffuse as in generalized anxiety disorder, to circumscribed as encountered in phobic anxieties (PHOBs) or post-traumatic stress disorders (PTSDs). Anxiety disorders may, thus, be defined as comprising generalized anxiety disorders (GAD), obsessive compulsive disorders (OCDs), acute stress disorders, posttraumatic stress disorders (PTSDs), panic anxiety disorders (PADs) including panic attacks, phobic anxieties (PHOBs), specific phobia, social phobia (social anxiety disorder), avoidance, somatoform disorders including hypochondriasis, separation anxiety disorder, anxiety disorders due to a general medical condition, and substance induced anxiety disorders. In a sub-embodiment, particular examples of circumscribed threat induced anxiety disorders are phobic anxieties or posttraumatic stress disorders. Anxiety disorders especially include generalized anxiety disorders, post-traumatic stress disorders, obsessive compulsive disorders, panic attacks, phobic anxieties, and avoidance.
Addiction disorders may be defined as addictions to one or more rewarding stimuli, notably to one rewarding stimulus. Such rewarding stimuli may be of either natural or synthetic origin. Examples of such rewarding stimuli are substances / drugs {of either natural or synthetic origin; such as cocaine, amphetamines, opiates [of natural or (semi-)synthetic origin such as morphine or heroin], cannabis, ethanol, mescaline, nicotine, and the like}, which substances / drugs may be consumed alone or in combination; or other rewarding stimuli {of either natural origin (such as food, sweet, fat, or sex, and the like), or synthetic origin [such as gambling, or internet/IT (such as immoderate gaming, or inappropriate involvement in online social networking sites or blogging), and the like]}. In a sub-embodiment, addiction disorders relating to psychoactive substance use, abuse, seeking and reinstatement are defined as all types of psychological or physical addictions and their related tolerance and dependence components. Substance-related addiction disorders especially include substance use disorders such as substance dependence, substance craving and substance abuse; substance-induced disorders such as substance intoxication, substance withdrawal, and substance-induced delirium. The expression "prevention or treatment of addictions" (i.e. preventive or curative treatment of patients who have been diagnosed as having an addiction, or as being at risk of developing addictions) refers to diminishing addictions, notably diminishing the onset of addictions, to weakening their maintenance, to facilitating withdrawal, to facilitating abstinence, or to attenuating, decreasing or preventing the occurrence of reinstatement of addiction (especially to diminishing the onset of addictions, to facilitating withdrawal, or to attenuating, decreasing or preventing the occurrence of reinstatement of addiction).
Appetite disorders comprise eating disorders and drinking disorders. Eating disorders may be defined as comprising eating disorders associated with excessive food intake and complications associated therewith; anorexias; compulsive eating disorders; obesity (due to any cause, whether genetic or environmental); obesity-related disorders including overeating and obesity observed in Type 2 (non-insulin-dependent) diabetes patients; bulimias including bulimia nervosa; cachexia; and binge eating disorder. Particular eating disorders comprise metabolic dysfunction; dysregulated appetite control; compulsive obesities; bulimia or anorexia nervosa. In a sub-embodiment, eating disorders may be defined as especially comprising anorexia nervosa, bulimia, cachexia, binge eating disorder, or compulsive obesities. Drinking disorders include polydipsias in psychiatric disorders and all other types of excessive fluid intake. Pathologically modified food intake may result from disturbed appetite (attraction or aversion for food); altered energy balance (intake vs. expenditure); disturbed perception of food quality (high fat or carbohydrates, high palatability); disturbed food availability (unrestricted diet or deprivation) or disrupted water balance.
Cognitive dysfunctions include deficits in attention, learning and especially memory functions occurring transiently or chronically in psychiatric, neurologic, neurodegenerative, cardiovascular and immune disorders, and also occurring transiently or chronically in the normal, healthy, young, adult, or especially aging population. Cognitive dysfunctions especially relate to the enhancement or maintenance of memory in patients who have been diagnosed as having, or being at risk of developing, diseases or disorders in which diminished memory (notably declarative or procedural) is a symptom [in particular dementias such as frontotemporal dementia, or dementia with Lewy bodies, or (especially) Alzheimer's disease]. Especially, the term "prevention or treatment of cognitive dysfunctions" relates to the enhancement or maintenance of memory in patients who have a clinical manifestation of a cognitive dysfunction, especially expressed as a deficit of declarative memory, linked to dementias such as frontotemporal dementia, or dementia with Lewy bodies, or (especially) Alzheimer's disease. Furthermore, the term "prevention or treatment of cognitive dysfunctions" also relates to improving memory consolidation in any of the above mentioned patient populations.
Mood disorders include major depressive episode, manic episode, mixed episode and hypomanic episode; depressive disorders including major depressive disorder, dysthymic disorders; bipolar disorders including bipolar I disorder, bipolar I I disorder (recurrent major depressive episodes with hypomanic episodes), cyclothymic disorder; mood disorders including mood disorder due to a general medical condition (including the subtypes with depressive features, with major depressive-like episode, with manic features, and with mixed features), substance-induced mood disorder (including the subtypes with depressive features, with manic features, and with mixed features). Such mood disorders are especially major depressive episode, major depressive disorder, mood disorder due to a general medical condition; and substance-induced mood disorder.
In the context of the present invention, it is to be understood that, in case certain environmental conditions such as stress or fear (wherein stress may be of social origin (e.g. social stress) or of physical origin (e.g. physical stress), including stress caused by fear) facilitate or precipitate any of the disorders or diseases as defined before, the present compounds may be particularly useful for the treatment of such environmentally conditioned disorder or disease.
Preparation of compounds of formula (I):
The compounds of formula (I) contain two stereogenic centers depending on each other (i.e. the relative configuration with regard to the bridge X in the 3,7-diazabicyclo[3.3.1]nonane, respectively, 9-oxa-3,7-diazabicyclo[3.3.1]nonane moiety is cis or (1 R*,5S*)) and are therefore present as meso-compounds.
Compounds of formula (I) can be manufactured by the methods given below, by the methods given in the Examples or by analogous methods. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by a person skilled in the art by routine optimization procedures.
Figure imgf000048_0001
Scheme 1: Synthesis of the 3, 7-diazabicyclo[3.3. 1]nonane-template
The synthesis of the 3,7-diazabicyclo[3.3.1]nonane template 8 starts from N-Boc-piperidone 1 which is reacted in a double Mannich reaction with paraformaldehyde 3 and benzylamine 2 to build up the bicyclic ring scaffold 4. Reduction of the carbonyl group was achieved in a two step procedure, wherein 4 was first transformed into the tosylhydrazone derivative 6 by a condensation with tosylhydrazine 5. Reduction of the hydrazone functionality was achieved by reacting 6 with NaBH4 in THF / H20 = 4 / 1 for 16 h at RT followed by 2 h at 85°C to give 7 which was debenzylated by Pd-catalyzed hydrogenation methodology using EtOH as the solvent to give template 8.
Figure imgf000049_0001
Figure imgf000049_0002
15 16 17
Scheme 2: Synthesis of the 9-Oxa-3, 7-diazabicyclo[3.3. 1]nonane [Steps a) to d) are described in WO2004/035592 and Steps e) to g) are described in US 6,559,143]
The synthesis of the 9-oxa-3,7-diazabicyclo[3.3.1]nonane template 17 started by reacting benzenesulfonamide (9) with an excess of epichlorohydrine (10) in water in the presence of a base such as NaOH to give bis-epoxide derivative 11. Cyclization to the 1 ,4-diazacyclo- octane precursor 12 (4 stereoisomers) was achieved by reaction of 11 with 0.8 eq of 2 in refluxing EtOH. Intramolecular cyclization to the 9-oxa-3,7-diazabicyclo[3.3.1]nonane system proceeded in toluene under the activating influence of methanesulfonic acid at elevated temperature to give intermediate 13. Cleavage of the sulphonamide was achieved with 62% HBr in water to result in the secondary amine intermediate 14 which was then Boc-protected under standard conditions to give 15. Debenzylation was facilitated by foregoing hydrochloride salt formation to give 16 which was finally deprotected under hydrogenolytic reaction conditions using Pd-C 10% as the catalyst and MeOH as the solvent to give template 17.
Figure imgf000050_0001
Scheme 3: Synthesis of final compounds of structure of formula (I):
Scheme 3 summarizes the first possibility to obtain the final orexin antagonist compounds, wherein X, Ar1 and Ar2 are as defined hereinbefore, starting with one of the templates (summarized in Scheme 1 and 2) summarized as 18 and reacting it with an appropriate carboxylic acid 19 under standard peptide coupling conditions in the presence of an activating agent such as TBTU or HBTU and a base such as DIPEA or TEA in a solvent like DCM or THF to give 20. Boc-deprotection under water free acidic conditions as for example HCI in dioxane or TFA in DCM resulted in precursor 21 which was reacted with a heteroaryl chloride 22 in a solvent such as xylene in the presence of a base (such as K2C03 or Cs2C03) at elevated temperature to give the final compounds 23.
Figure imgf000050_0002
18
Scheme 4: Alternative synthesis of final compounds of structure of formula (I):
As depicted in Scheme 4, final compounds 23 can as well be prepared via the opposite sequence, using analogous methods to those described for Scheme 3, starting by reacting 18 with heteroaryl chlorides 22 to give intermediates 24. Boc-deprotection to 25 and reaction with the appropriate carboxylic acid 19 again resulted in the final orexin antagonist compounds 23.
In the following, particular methods for the synthesis of carboxylic acid derivatives of formula Ar1-CO-OH and halogenides of formula Ar2-halogenide (such as for example Ar2-CI, or well known equivalents, e.g. the respective trifluoromethane sulfonates) are described. These starting materials are well known in the art and/or commercially available; or they may be synthesized according to methods described in the literature. In addition, they may be synthesized in analogy to the methods given in the experimental part. In case Ar , Ar , or a substituent thereof is a heteroaryl moiety, such heteroaryl may be introduced using well known and generally commerially available building blocks (literature for precursors of heteroaryl-containing groups: see e.g. T. Eicher, S. Hauptmann "The chemistry of Heterocycles: Structure, Reactions, Syntheses, and Applications", 2nd Edition 2003, Wiley, ISBN 978-3-527-30720-3; A. R. Katrizky, C. W. Rees, E. F. V. Scriven (Eds.) "Comprehensive Heterocyclic Chemistry I I" 1996, Elsevier, ISBN 0-08-042072-9). Such heteroaryl moiety may replace a phenyl group in the schemes below as appropriate.
Preparation of building blocks of formula Ar1-CO-OH:
Carboxylic acid derivatives of formula Ar1-CO-OH are well known in the art and/or commercially available; or they may be synthesized according to methods described in the literature [see for example Scheme 5, wherein R3 is optionally substituted phenyl or 5- or 6- membered heteroaryl as defined for the compounds of formula (I); Y is CH or N; Z is O or S; and R4, R5 and (R)n correspond to the respective optional substituents as defined for the compounds of formula (I)]. In addition, they may be synthesized in analogy to the methods given in the experimental part.
Figure imgf000051_0001
Scheme 5: Preparation of building blocks of formula Ar1-CO-OH; [
Acids of structure 26 can especially be prepared following the procedures reported in WO2008/069997, WO2008/008517, WO2010/048012, WO2010/072722, WO2010/063662, and WO2010/063663. Acids of structure 27 can be prepared following the procedures reported in WO2010/044054, WO2010/038200, and WO2010/004507. Acids of structure 28a and 28b can be prepared following the procedures reported in WO2010/044054.
Preparation of building blocks of formula Ar2-CI:
Building blocks of formula Ar2-CI are well known in the art and/or commercially available, or they may be synthesized according to methods described in the literature. In addition, they may be synthesized in analogy to the methods given in the experimental part.
Figure imgf000052_0001
Figure imgf000052_0002
Figure imgf000052_0003
Scheme 6: a representative but not limiting selection of building blocks Ai^-CI
Experimental Section
Abbrevations (as used herein and in the description above):
Ac Acetyl (such as in OAc = acetate, AcOH = acetic acid) anh. Anhydrous
aq. aqueous
atm Atmosphere
Boc terf-Butoxycarbonyl
Boc20 di-ierf-Butyl dicarbonate
BSA Bovine serum albumine
Bu Butyl such as tBu = feri-butyl = tertiary butyl
n-BuLi n-Butyllithium
CHO Chinese Hamster Ovary
cone. Concentrated DBU 1 ,8-Diazabicyclo[5.4.0]undec-7-ene
DCM Dichloromethane
DIPEA Diisopropylethylamine
DMF A/,A/-Dimethylformamide
DMSO Dimethyl sulfoxide
ELSD Evaporative Light-Scattering Detection
eq Equivalent(s)
ES Electron spray
Et Ethyl
Et20 Diethyl ether
EtOAc Ethyl acetate
EtOH Ethanol
FC Flash Chromatography on silica gel
FCS Foatal calf serum
FLIPR Fluorescent imaging plate reader
h Hour(s)
HBSS Hank's balanced salt solution
HBTU 0-Benzotriazole-N,N,N',N'-tetramethyl-uronium-hexafluoro-phosphate
HEPES 4-(2-Hydroxyethyl)-piperazine-1-ethanesulfonic acid
1H-NMR Nuclear magnetic resonance of the proton
HPLC High performance liquid chromatography
LC-MS Liquid chromatography - Mass Spectroscopy
Lit. Literature
M Exact mass (as used for LC-MS)
Me Methyl
MeCN Acetonitrile
MeOH Methanol
MHz Megahertz
min Minute(s)
MS Mass spectroscopy
N Normality
Pd(OAc)2 Palladium diacetate
Pd(PPh3)4 Tetrakis(triphenylphosphine)palladium(0)
Ph Phenyl
PPh3 Triphenylphosphine
prep. Preparative
2-PrOH Isopropanol RT Room temperature
sat. Saturated
TBTU 0-(Benzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate
TEA Triethylamine
TFA trifluoroacetic acid
Tf Trifluoromethansulfonyl
THF Tetrahydrofuran
TLC Thin Layer Chromatography
tR Retention time
UV Ultra violet
I -Chemistry
All temperatures are stated in °C. The commercially available starting materials were used as received without further purification. Compounds are purified by flash column chromatography on silica gel (FC) or by prep. HPLC. Compounds described in the invention are characterized by LC-MS (retention time tR is given in min.; molecular weight obtained from the mass spectrum is given in g/mol, using the conditions listed below). If the mass is not detectable the compounds are also characterized by 1H-NMR (300 MHz: Varian Oxford; chemical shifts are given in ppm relative to the solvent used; multiplicities: s = singlet, d = doublet, t = triplet; p = pentuplet, hex = hexet, hept = heptet, m = multiplet, br = broad, coupling constants are given in Hz).
LC-MS with basic conditions (conditions A)
Apparatus: Agilent 1 100 series with mass spectroscopy detection (MS : Finnigan single quadrupole). Column: Waters XBridge C18 (5 μΐη, 4.6 x 50 mm). Conditions: MeCN [eluent A]; 13 mmol/l NH3 in water [eluent B]. Gradient: 95% B→ 5% B over 1.5 min. (flow: 4.5 ml/min.). Detection: UVA/is + MS.
LC-MS with acidic conditions (conditions B)
Apparatus: Agilent 1 100 series with mass spectroscopy detection (MS : Finnigan single quadrupole). Column: Waters XBridge C18 (2.5 μΐη, 4.6 x 30 mm). Conditions: MeCN [eluent A]; water + 0.04% TFA [eluent B]. Gradient: 95% B→ 5% B over 1.5 min. (flow: 4.5 ml/min.). Detection: UVA/is + MS.
Preparative HPLC for purification of compounds (conditions C) Column: Waters XBridge (10 μιτι, 75 x 30 mm). Conditions: MeCN [eluent A]; water + 0.5% NH4OH (25% aq.) [eluent B]; Gradient: 90% B → 5% B over 6.5 min. (flow: 75 ml/min.). Detection: UV + ELSD.
Preparative HPLC for purification of compounds (conditions D)
Column: Waters Atlantis T3 OBD (10 μΐη, 75 x 30 mm). Conditions: MeCN [eluent A]; water + 0.5% HCOOH [eluent B]; Gradient: 90% B → 5% B over 6.4 min. (flow: 75 ml/min.). Detection: UV + ELSD.
LC-MS for final product analysis (conditions E)
LC-MS-conditions: Analytical. Pump: Waters Acquity Binary, Solvent Manager, MS: Waters SQ Detector, DAD: Acquity UPLC PDA Detector, ELSD: Acquity UPLC ELSD. Column: Acquity UPLC BEH C18 1 .7 mm 2.1 x 50 mm from Waters, thermostated in the Acquity UPLC Column Manager at 50 °C. Eluents: A1 : H20 + 0.05 % FA; B1 : MeCN + 0.05 % FA; A2: H20 + 0.05 % TFA; B2: MeCN + 0.05 % TFA. Method: Gradient: 2 % B 98 % B over 1.5 min. Flow: 1.2 mL/ min. Detection: UV 214nm and ELSD, and MS, tR is given in min.
The following examples illustrate the preparation of compounds of the invention but do not at all limit the scope thereof.
Preparation of precursors and intermediates:
A) Synthesis of the templates:
Synthesis of tert-butyl 3,7-diazabicyclo[3.3.1]nonane-3-carboxylate:
Step 1 :
Figure imgf000055_0001
Benzylamine (10.82 g; 100 mmol) was dissolved in MeOH (400 ml) followed by the addition of AcOH (6.0 g; 100 mmol), of 37% aq. HCI (4.18 ml; 50 mmol) and paraformaldehyde (6.32 g; 66.7 mmol). The clear reaction solution was heated to reflux (90°C) and 1 -Boc-4- piperidone (20.12 g; 100 mmol) dissolved in MeOH (120 ml) was added over 20 min. Stirring and heating was continued for 3 h. The solution was cooled to rt and concentrated in vacuo. A solution of 5M ammonia (400 ml) was added to the residue which was extracted with EtOAc (750 ml). The organic layer was separated from the aq. layer, dried over MgS04, filtered and the solvent was evaporated under reduced pressure to give 34.34 g of crude material. Purification was performed via flashmaster chromatography (silicagel; heptane / EtOAc = 7 / 3) to give 27.6 g of tert-butyl 7-benzyl-9-oxo-3,7-diazabicyclo[3.3.1]nonane-3- carboxylate. LC-MS: tR = 0.97 min; [M+H]+ = 331.08. Method (A)
Step 2:
Figure imgf000056_0001
Tert-butyl 7-benzyl-9-oxo-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate 27.5 g; 83.2 mmol) was dissolved in EtOH (715 ml) at RT followed by the addition of p-toluenesulfonyl hydrazine (17.05 g; 91.5 mmol). The reaction mixture was refluxed (95°C) for 60 min, then cooled to rt and concentrated in vacuo followed by high vacuum drying over night to give 41.5 g tert-butyl 7-benzyl-9-(2-tosylhydrazono)-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate. LC-MS: tR = 0.76 min; [M+H]+ = 499.21. Method (A)
Step 3:
Figure imgf000056_0002
Tert-butyl 7-benzyl-9-(2-tosylhydrazono)-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (10.875 g; 21.8 mmol) was dissolved in a 4/1 -mixture of THF / water (150 ml) and cooled to 0°C followed by NaBH4 (8.25 g; 218 mmol) in portions. Stirring was continued over night while at the same time the reaction mixture was allowed to very slowly warm to RT followed by heating to reflux for 2 h. The reaction mixture was cooled again to RT. Water (50 ml) was slowly added to destroy potential excess of NaBH4. Then again water (250 ml) was added and the product was extracted with EtOAc (3 x 250 ml). The combined organic layers were washed with brine (100 ml), dried over MgS04, filtered and the solvent was evaporated under reduced pressure to give 16.75 g of crude product which was purified by flashmaster chromatography (silicagel; heptane / EtOAc = 4 / 1 ) to give tert-butyl 7-benzyl-3,7- diazabicyclo[3.3.1 ]nonane-3-carboxylate. LC-MS: tR = 1.10 min; [M+H]+ = 317.09. Method (A)
Figure imgf000057_0001
Tert-butyl 7-benzyl-3,7-diazabicyclo[3.3.1 ]nonane-3-carboxylate (7 g; 21 .3 mmol), dissolved in 20 ml EtOH was carefully added to a suspension of Palladium 10% on charcoal 50% water in EtOH (180 ml): The reaction mixture was evacuated and put under hydrogen (1 atm) three times then stirring was continued under a hydrogen pressure (1 atm) at RT for 16 h. The reaction mixture was filtered over celite and the solvent was evaporated under reduced pressure to give tert-butyl 3,7-diazabicyclo[3.3.1]nonane-3-carboxylate. LC-MS: tR = 0.42 min; [M+H]+ = 227.15. Method (B)
Synthesis of tert-butyl 9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate hydrochloride:
Step 1 :
Figure imgf000057_0002
Benzenesulfonamide (25 g; 0.159 mol) was dissolved in water (250 ml) followed by the addition of epichlorohydrine (58.9 g; 0.636 mol). The reaction mixture was heated to 40°C. At this temperature a solution of NaOH (13.3 g) in water (28 ml) was carefully added and the reaction temperature was kept below 45°C. Stirring was continued at 40°C for 2 h and at RT for 16 h. The excess epichlorohydrine was evaporated and the remaining aq. layer was extracted with DCM (2 x 150 ml). The combined organic layers were dried over MgS04, filtered and concentrated under reduced pressure to give crude N,N-bis(oxiran-2- ylmethyl)benzenesulfonamide which was used in the next step without purification. LC-MS: tR = 0.57 min; [M+H]+ = 270.04. Method (B)
Step 2:
Figure imgf000057_0003
N,N-bis(oxiran-2-ylmethyl)benzenesulfonamide (86.4 g; 0.321 mol) was dissolved in EtOH (820 ml) followed by the addition of benzylamine (27.8 g; 0.257 mol). The reaction mixture was heated to reflux (80°C) for 3 h, then the mixture was cooled to rt, the solvent was evaporated under reduced pressure to result in a white foam, which was dried at high vacuum to give 1 -benzyl-5-(phenylsulfonyl)-1 ,5-diazoctane-3,7-diol which was used in the following step without further purification. LC-MS: tR = 0.48 min; [M+H]+ = 377.20. Method (B)
Step 3:
Figure imgf000058_0001
1 -Benzyl-5-(phenylsulfonyl)-1 ,5-diazoctane-3,7-diol (1 1 1 g; 0.236 mol) was dissolved in toluene (900 ml) followed by the addition of methanesulfonic acid (31 ml; 0.47 mol). Stirring was continued at RT for 5 min followed by the addition of another portion of methanesulfonic acid (147 ml; 2.27 mol). The reaction mixture was heated to 1 10°C for 16 h and cooled again to RT. The toluene was evaporated and to the residue was added water (300 ml) and DCM (300 ml). This mixture was cooled to 0°C followed by careful addition of aq. 32 % NaOH solution (260 ml) until the pH reached 14. The aq. and the organic layer were separated. The organic layer was dried over MgS04, filtered and concentrated under reduced pressure to give a white foam containing ca 30% of product 3-benzyl-7-(phenylsulfonyl)-9-oxa-3,7- diazabicyclo[3.3.1 ]nonane and ca 70% of starting material 1 -Benzyl-5-(phenylsulfonyl)-1 ,5- diazoctane-3,7-diol. The exact same procedure with the product / starting material mixture was repeated and after that again repeated to result in 63.5 g of crude material. Purification was performed with a flashmaster chromatography (Silicagel; DCM) to give 3-benzyl-7- (phenylsulfonyl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane as a beige solid. LC-MS: tR = 0.53 min; [M+H]+ = 359.17. Method (B)
Step 4:
Figure imgf000058_0002
In an inert nitrogen atmosphere 3-benzyl-7-(phenylsulfonyl)-9-oxa-3,7- diazabicyclo[3.3.1 ]nonane (7.2 g; 18.1 mmol) was dissolved in an aq. 62% HBr solution (75 ml) and heated to 105°C for 12 h. Another portion of aq. 62% HBr solution (70 ml) was added and stirring at 105°C was continued for another 20 h. The reaction mixture was cooled to RT and extracted with toluene (100 ml). The toluene layer was discarded. The aq. layer was adjusted to pH 14 by the addition of aq. NaOH solution (120 ml; 32%) and extracted with toluene (2x 100 ml). To the combined toluene layers was added HCI in dioxane solution (25 ml; 4M) and stirring was continued for 1 h followed by removal of the solvent under reduced pressure. The residue was suspended in EtOH (50 ml). The solid was filtered off and dried at high vacuum to give 3-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane as a white solid. LC-MS: tR = 0.73 min; [M+H]+ = 219.12. Method (A)
Step 5:
Figure imgf000059_0001
x 2HCf
3-Benzyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane (4.15 g; 14.3 mmol) were dissolved in a mixture of water (40 ml) and DCM (40 ml) followed by the addition of NaHC03 (4.84 g; 57 mmol). Stirring was continued for 10 min followed by the addition of Boc20 (3.38 g; 15.7 mmol) in portions. Stirring at RT continued for 90 min. The organic layer was separated from the aq. layer, which was re-extracted with DCM (20 ml). The combined organic layers were dried with MgS04, filtered and the solvent was evaporated under reduced pressure to give tert-butyl 7-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate as a white solid. LC- MS: tR = 0.97 min; [M+H]+ = 319.15. Method (A) tep 6:
Figure imgf000059_0002
Tert-butyl 7-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (4.48 g; 14.1 mmol) was dissolved in dry EtOAc (25 ml) in an inert atmosphere and cooled to -10°C followed by slow addition over 10 min of a HCI solution in Et20 (2M; 10 ml). Stirring at -10°C was continued for another 60 min. The product was filtered off and dried under high vacuum to give tert-butyl 7-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate hydrochloride salt as a white solid.
Step 7 tert-butyl 9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate hydrochloride:
Figure imgf000059_0003
Tert-butyl 7-benzyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate hydro- chloride salt (4.8 g; 13.5 mmol) was dissolved in MeOH (10 ml) and added to a suspension of 10% palladium on charcoal (480 mg) in MeOH (40 ml) in an inert atmosphere. The reaction mixture was then put under hydrogen pressure (1 atm) for 16 h. The mixture was filtered over celite and the filtrate was concentrated under reduced pressure to give tert-butyl 9-oxa-3,7- diazabicyclo[3.3.1 ]nonane-3-carboxylate hydrochloride salt as a slightly yellow solid. LC-MS: tR = 0.63 min; [M+H]+ = 229.14. Method (B)
B) Synthesis of the substituents:
Generally, bi-(hetero-)aryl-like structures can be synthesised using well established Suzuki chemistry in analogy to the reactions depicted here:
Figure imgf000060_0001
Synthesis of bi-(hetero-)aryl like structures; X is Br, I
Reaction of commercially available (hetero-)aryl-boronic acid derivatives (e.g. carboxylic acids or esters thereof) with commercially available (hetero-)aryl-bromides or (hetero-)aryl- iodides (or analogues thereof, such as chlorides, trifluoromethanesolfonates) in presence of a metal catalyst catalyst such as Pd(PPh3)4 or equivalent and a base such as Na2C03 under heating in a solvent such as toluene, dioxane, THF provides the corresponding bi-(hetero-)aryl like structures.
B1 Preparation of building blocks of formula Ar1-CO-OH:
In addition to commercially available building blocks, further particular building blocks of formula Ar1-CO-OH are prepared as follows:
B1.1 2-Fluoro-3-methyl-6-(2H-1,2,3-triazol-2-yl)benzoic acid:
2-Fluoro-3-methyl-6-(2 - -1 ,2,3-triazol-2-yl)benzoic acid B1.1 is synthesized in analogy to procedures reported in WO2008/069997.
In a dry Schlenk Tube at RT under nitrogen are successively charged 2-fluoro-6-iodo-3- methyl-benzoic acid (1.786 mmol, 1 eq), Cul (0.089 mmol, 0.05 eq), 1 H-1 ,2,3-triazole (3.571 mmol, 2 eq), Cs2C03 (3.571 mmol, 2 eq) and DMF (2.5 ml_). The resulting blue suspension is stirred at 80°C overnight. The obtained reaction mixture is taken up in 1 M aq. HCI and extracted twice with EtOAc. The combined organic layers are dried over Na2S04, filtered and concentrated under reduced pressure. Purification is achieved by prep. HPLC (conditions D) to give the titled compound as a pale yellow solid. LC-MS (conditions B): tR = 0.55 min, [M + 1]+ = 222.19. B1.2 5-Methoxy-2-(2H-1 ,2,3-triazol-2-yl)benzoic acid:
The title compound is prepared in analogy to compound B1.1 starting from 2-iodo-5- methoxybenzoic acid (1 .798 mmol, 1 eq). B1.2 is obtained as a yellow solid. LC-MS (conditions B): tR = 0.49 min, [M + 1]+ = 220.07.
B1.3 2-Fluoro-3-methoxy-6-(2H-1 ,2,3-triazol-2-yl)benzoic acid:
The title compound is prepared in analogy to compound B1.1 starting from 2-fluoro-6-iodo-3- methoxy-benzoic acid (1.689 mmol, 1 eq). B1.3 is obtained as a pale yellow solid. LC-MS (conditions B): tR = 0.48 min, [M + 1]+ = 238.18.
B1.4 2-(2H-1 ,2,3-Triazol-2-yl)-5-(trifluoromethyl)benzoic acid:
The title compound is prepared in analogy to compound B1.1 starting from 2-iodo-5- trifluorobenzoic acid (1.582 mmol, 1 eq). B1.4 is obtained as a white solid. LC-MS (conditions B): tR = 0.64 min, [M + 1]+ = 257.91.
B1.5 2-(2H-1 ,2,3-Triazol-2-yl)-5-(trifluoromethoxy)benzoic acid:
The title compound is prepared in analogy to compound B1.1 starting from 2-iodo-5- (trifluoromethoxy)benzoic acid (1.506 mmol, 1 eq). B1.5 is obtained as an off-white solid. LC- MS (conditions B): tR = 0.66 min, [M + 1 ]+ = 273.69.
B1.6 5-Cyano-2-(2H-1 ,2,3-triazol-2-yl)benzoic acid:
The title compound is prepared in analogy to compound B1.1 starting from 5-cyano-2- iodobenzoic acid (1 .831 mmol, 1 eq). B1.6 is obtained as a grey solid. LC-MS (conditions B): tR = 0.46 min, [M + 1]+ = not detectable. 1 H NMR (D6-DMSO): 13.49 (m, 1 H), 8.21 (m, 1 H), 8.18 (m, 2 H), 8.15 (m, 1 H), 8.03 (m, 1 H).
B1.7 5-Methyl-2-(pyridin-2-yl)benzoic acid:
a) In a dry Schlenk Tube at RT under nitrogen are successively charged 2-iodo-5- methylbenzoic acid methyl ester (13.765 mmol, 1 eq), Cul (2.753 mmol, 0.2 eq), CsF (27.529 mmol, 2 eq), 2-tributylstannylpyridine (20.647 mmol, 1.5 eq), Pd(PPh3)4 (1.376 mmol, 0.1 eq) and DMF (60 mL). The resulting suspension is stirred at 90°C overnight. The obtained reaction mixture is diluted with EtOAc and filtered through a short pad of Celite®. A solution of sat. aq. NaHC03 is then added to the filtrate and the aq. phase extracted with EtOAc (3 times). The combined organic layers are washed with H20 and brine, dried over Na2S04, filtered and concentrated under reduced pressure. Purification is achieved by FC (EtOAc/Heptane 1 :4 to 3:7) to give methyl 5-methyl-2-(pyridin-2-yl)benzoate as a brown oil. LC-MS (conditions B): tR = 0.67 min, [M + 1]+ = 228.07. b) To a solution of methyl 5-methyl-2-(pyridin-2-yl)benzoate (1 1.617 mmol, 1 eq) in MeOH (15 mL) and THF (17 mL) is added 1 M NaOH (23.233 mL, 2 eq). The resulting mixture is stirred at RT overnight. The volatiles are evaporated under reduced pressure and the remaining aq. phase is acidified with 2 M HCI to pH = 1 -2 and extracted with DCM (3 times). The combined organic layers are dried over Na2S04, filtered and concentrated under reduced pressure to give 5-methyl-2-(pyridin-2-yl)benzoic acid B1.7 as a pale brown foam. LC-MS (conditions B): tR = 0.39 min, [M + 1]+ = 214.25.
B1.8 5-Methyl-2-(2H-1 ,2,3-triazol-2-yl)benzoic acid:
The title compound is prepared in analogy to compound B1.1 starting from 2-iodo-5- methylbenzoic acid. B1.8 is obtained as an off-white solid. LC-MS (conditions B): tR = 0.76 min, [M + 1]+ = 204.56.
B1.9 2-(2H-1 ,2,3-triazol-2-yl)benzoic acid:
The title compound is prepared in analogy to compound B1.1 starting from 2-iodo-benzoic acid. B1.9 is obtained as an off-white solid. LC-MS (conditions B): tR = 0.55 min, [M + 1 ]+ = 190.3.
B1.10 5-Fluoro-2-(2H-1 ,2,3-triazol-2-yl)benzoic acid:
The title compound is prepared in analogy to compound B1.1 starting from 2-iodo-5- fluorobenzoic acid. B1.10 is obtained as an off-white solid. LC-MS (conditions B): tR = 0.71 min, [M + 1]+ = 208.35.
B1.11 6-Fluoro-2-(2H-1 ,2,3-triazol-2-yl)benzoic acid:
The title compound is prepared in analogy to compound B1.1 starting from 2-iodo-6- fluorobenzoic acid. B1.11 is obtained as an off-white solid. LC-MS (conditions B): tR = 0.70 min, [M + 1]+ = 208.59.
B1.12 5-Chloro-2-(2H-1 ,2,3-triazol-2-yl)benzoic acid:
The title compound is prepared in analogy to compound B1.1 starting from 2-iodo-5- chlorobenzoic acid. B1.12 is obtained as an off-white solid. LC-MS (conditions B): tR = 0.66 min, [M + 1]+ = 224.3.
B1.13 4,5-Dimethoxy-2-(2H-1 ,2,3-triazol-2-yl)benzoic acid:
The title compound is prepared in analogy to compound B1.1 starting from 2-iodo-4,5- dimethoxybenzoic acid. B1.13 is obtained as an off-white solid. LC-MS (conditions B): tR = 0.46 min, [M + 1]+ = 250.03.
B1.14 4,5-Dimethyl-2-(2H-1 ,2,3-triazol-2-yl)benzoic acid:
The title compound is prepared in analogy to compound B1.1 starting from 2-iodo-4,5- dimethylbenzoic acid. B1.14 is obtained as an off-white solid. LC-MS (conditions B): tR = 0.59 min, [M + 1]+ = 218.19. B1.15 4-Methyl-5-methoxy-2-(2H-1 ,2,3-triazol-2-yl)benzoic acid:
The title compound is prepared in analogy to compound B1.1 starting from 2-iodo-4-methyl- 5-methoxybenzoic acid. B1.15 is obtained as an off-white solid. LC-MS (conditions B): tR = 0.68 min, [M + 1]+ = 234.55
B1.16 6-Methyl-2-(2H-1 ,2,3-triazol-2-yl)benzoic acid:
The title compound is prepared in analogy to compound B1.1 starting from 2-iodo-6- methylbenzoic acid. B1.16 is obtained as an off-white solid. LC-MS (conditions B): tR = 0.51 min, [M + 1]+ = 204.22
B1.17 4-Methyl-2-(2H-1 ,2,3-triazol-2-yl)benzoic acid:
The title compound is prepared in analogy to compound B1.1 starting from 2-iodo-4- methylbenzoic acid. B1.17 is obtained as an off-white solid. LC-MS (conditions B): tR = 0.63 min, [M + 1]+ = 204.22
B1.18 3-(2H-1 ,2,3-triazol-2-yl)picolinic acid:
The title compound is prepared in analogy to compound B1.1 starting from 3-iodopicolinic acid. B1.18 is obtained as an off-white solid. LC-MS (conditions B): tR = 0.25 min, [M + 1]+ = 191.24
B1.19 6-methyl-3-(2H-1 ,2,3-triazol-2-yl)picolinic acid:
The title compound is prepared in analogy to compound B1.1 starting from 3-iodo-6- methylpicolinic acid. B1.19 is obtained as an off-white solid. LC-MS (conditions B): tR = 0.29 min, [M + 1]+ = 205.06
B1.20 2-(1 H-pyrazol-1 -yl) benzoic acid:
The title compound is prepared in analogy to compound B1.1 starting from 2-iodobenzoic acid and using pyrazole instead of triazole in the reaction. B1.20 is obtained as an off-white solid. LC-MS (conditions B): tR = 0.45 min, [M + 1]+ = 189.23
B1.21 5-Metyhl-2-(1 H-pyrazol-1 -yl)benzoic acid:
The title compound is prepared in analogy to compound B1.1 starting from 5-methyl-2-iodo- benzoic acid and using pyrazole instead of triazole in the reaction. B1.21 is obtained as an off-white solid. LC-MS (conditions B): tR = 0.53 min, [M + 1 ]+ = 203.22
B1.22 6-methyl-3-(1 H-pyrazol-1 -yl)picolinic acid:
The title compound is prepared in analogy to compound B1.1 starting from 3-iodo-6- methylpicolinic acid and using pyrazole instead of triazole in the reaction. B1.22 is obtained as an off-white solid. LC-MS (conditions B): tR = 0.26 min, [M + 1]+ = 201.12
The additionally substituted 5-(hetero)arylthiazole-4-carboxylic acid derivatives depicted below are prepared according to methods described in WO2010/044054, WO2010/038200, WO2009/104155, WO2008/081399.
Figure imgf000064_0001
Figure imgf000064_0002
Figure imgf000064_0003
Further carboxylic acids used in the experimental part which are not described previous section are either commercially available or fully described in the literature.
C Preparation of the 2-chloro-quinoxalines:
2-chloro-6,7-difluoroquinoxaline (commercially available) 2-chloro-7-fluoroquinoxaline (WO2010/084152A1 )
2-chloro-6-fluoroquinoxaline (commercially available)
2.6- dichloroquinoxaline (commercially available)
2,6,7-trichloroquinoxaline (commercially available)
2.7- dichloroquinoxaline (commercially available)
D Preparation of precursors:
General Method A: Nucleophilic substitution
To a solution of 1 mmol of secondary amine 18 or 21 (Schemes 3 + 4) in xylene (5-7 mL) are successively added K2C03 (2.5 mmol for the free amine; 3.5 mmol when HCI salt is present) and Ar2-CI (1 .05 mmol). The resulting suspension is stirred at reflux for 30 minutes. Upon completion H20 is added and the aq. phase is extracted with EtOAc (3 times). The combined organic phases are washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure. The residue is purified by column chromatography or by prep. HPLC (conditions C) or by re-crystallization from EtOAc / Et20 = 1 / 1.
General Method B: Nucleophilic substitution
To a solution of 1 mmol of secondary amine 18 or 21 (Schemes 3 + 4) in pyridine (5.5 mL) are successively added DBU (2.5 mmol for the free amine; 3.5 mmol when HCI salt is present) and Ar2-CI (1.2 mmol). The resulting suspension is stirred at 1 10 °C overnight. Upon completion H20 is added and the aq. phase is extracted with EtOAc (3 times). The combined organic phases are washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure. The residue is purified by column chromatography or by prep. HPLC (conditions C).
General Method C: Boc-deprotection
To a solution of 1 mmol of Boc-protected amine 20 or 24 (Schemes 3 + 4) in dioxane (5 mL) is added HCI 4 M in dioxane (5 mL). The resulting reaction mixture is stirred at RT for 2 h and concentrated under reduced pressure. The residue is taken up in MeOH, sonicated and concentrated in vacuum. This operation is repeated 3 times to get rid of all HCI gas. The compound is obtained as foam or solid and is used in the next step without further purification.
General Method D: Boc-deprotection
To a solution of 1 mmol of Boc-protected amine 20 or 24 (Schemes 3 + 4) in Et20 (2.5 mL) at 0°C is added HCI 2 M in Et20 (2.5 mL). The resulting white suspension is stirred at RT for 2 h, cooled down to 0°C diluted with Et20 (1.25 mL) and treated again with HCI 2 M in Et20 (1.25 mL). The resulting reaction mixture is further stirred at RT for an additional 2 h, diluted with cold EtOAc (3 mL) and filtered. The HCI salt is washed with EtOAc and pentane. The compound is obtained as a solid, which is used in the next step without further purification. General Method E: Amide coupling
To a mixture of Ar1-CO-OH (19) (1 mmol) and TBTU (1.05 mmol) in MeCN (5.5 mL) at RT is added DIPEA (5 mmol). The resulting solution is stirred at RT for 15 minutes before addition of a solution of 1 mmol of secondary amine 18 or 25 (Schemes 3 + 4) in MeCN (2 mL). The resulting reaction mixture is stirred at RT overnight. Upon completion aq. sat. NaHC03 is added and the aq. phase is extracted with EtOAc (3 times). The combined organic phases are washed with H20 and brine, dried over Na2S04, filtered and concentrated under reduced pressure. The residue is purified by FC or by prep. HPLC (conditions C).
E Examples:
Synthesis of Example 1 :
The procedure is representative. All other examples can in general be prepared according to the procedure described for the preparation of Example 1 by choosing the appropriate starting materials described herein before. This preparation follows the approach outlined in Scheme 3 above.
Step 1 : Amide bond formation:
Figure imgf000066_0001
5-Methyl-2-(2H-1 ,2,3-triazol-2-yl)benzoic acid (320 mg; 1.73 mmol) is dissolved in MeCN (10 mL) followed by the addition of TBTU (555 mg; 1.73 mmol) and DIPEA (508 mg; 3.93 mmol). Stirring is continued for 15 minutes followed by the addition of tert-butyl 3,7- diazabicyclo[3.3.1 ]nonane-3-carboxylate (356 mg; 1.57 mmol). Stirring is continued at rt. for an additional 1 h. Brine (50) is added to the reaction mixture and the product is extracted with DCM (2 * 50 ml). The combined organic layers are dried over MgS04, filtered and concentrated under reduced pressure. The product is purified by FC (EtOAc / heptanes = 1 / 1 ) to give tert-butyl 7-(5-methyl-2-(2H-1 ,2,3-triazol-2-yl)benzoyl)-3,7-diazabicyclo [3.3.1]nonane-3-carboxylate as a colorless solid.
Step 2: Boc-deprotection:
Figure imgf000066_0002
tert-butyl 7-(5-methyl-2-(2H-1 ,2,3-triazol-2-yl)benzoyl)-3,7-diazabicyclo[3.3.1] nonane-3- carboxylate (370 mg; 0.898 mmol) is dissolved in dioxane (5 ml) followed by the addition of HCI in dioxane (4M; 5 ml; 20 mmol). Stirring is continued for 2 h at rt. The reaction mixture is concentrated under reduced pressure and the product is dried at HV to give 3,7- diazabicyclo[3.3.1 ]nonan-3-yl(5-methyl-2-(2H-1 ,2,3-triazol-2-yl)phenyl)-methanone hydrochloride as a white solid.
Step 3: Nucleophilic Substitution:
Figure imgf000067_0001
3,7-diazabicyclo[3.3.1]nonan-3-yl(5-methyl-2-(2H-1 ,2,3-triazol-2-yl)phenyl)-methanone hydrochloride (291 mg; 0.757 mmol) is dissolved in o-xylene (3 ml) followed by the addition of K2C03 (366 mg; 2.65 mmol) and 2,5-dichloro-benzoxazole (190 mg; 0.757 mmol). The reaction mixture is heated to reflux for 30 min. The mixture is cooled to rt and water (50 ml) and EtOAc (50 ml) is added. A precipitate is formed, filtered off and which upon analysis is identified as the product. The aq. and the organic layer of the filtrate are separated. The organic layer is concentrated under reduced pressure. A precipitate is formed and re- crystallized from a misture of EtOAc / Et20 = 1 / 1. The precipitate and the recrystallized fraction are combined to give (7-(5-chlorobenzo[d]oxazol-2-yl)-3,7-diazabicyclo[3.3.1]nonan- 3-yl)(5-methyl-2-(2H-1 ,2,3-triazol-2-yl)phenyl)methanone as a white solid.
Synthesis of Example 237:
The procedure is representative. All other examples can in general be prepared according to the procedure described for the preparation of Example 237 by choosing the appropriate starting materials described herein before. This preparation follows the approach outlined in Scheme 4 above.
Step 1 : Nucleophilic Substitution:
Figure imgf000067_0002
tert-butyl 3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (1.5 g; 6.63 mmol) and 2-chloro-6,7- difluoroquinoxaline (1.564 g; 6.63 mmol) are dissolved in xylene (30 ml) followed by the addition of K2C03 (4.58 g; 33.1 mmol). The suspension is heated to reflux for 1 h and cooled again to rt followed by the addition of water (250 ml). The product is extracted with EtOAc (2 x 125 ml). The combined organic layers are dried over MgS04, filtered and the solvent is evaporated under reduced pressure. The residue is dried at HV to give tert-butyl 7-(6,7- difluoroquinoxalin-2-yl)-3,7-diazabicyclo[3.3.1 ] nonane-3-carboxylate.
-deprotection:
Figure imgf000068_0001
tert-butyl 7-(6,7-difluoroquinoxalin-2-yl)-3,7-diazabicyclo[3.3.1] nonane-3-carboxylate (2.54 g; 6.53 mmol) is dissolved in dioxane (16.8 ml) followed by the addition of HCI in dioxane (4M; 16.8 ml; 65.3 mmol). Stirring at rt is continued for 90 minutes. Et20 (150 ml) is added to the reaction mixture and the precipitated product is filtered off, washed with cold Et20 (50 ml) and dried at HV to give 2-(3,7-diazabicyclo[3.3.1]nonan-3-yl)-6,7-difluoroquinoxaline hydrochloride as a slightly green solid.
Step 3: Amide bond formation:
Figure imgf000068_0002
5-(4-fluorophenyl)-2-methylthiazole-4-carboxylic acid (31 mg; 0.129 mmol) is dissolved in DMF (1 ml) and TBTU (41.2 mg; 0.128 mmol) and DIPEA (83 mg; 0.642 mmol) are added. The resulting mixture is stirred at rt for 15 min followed by the addition of 2-(3,7- diazabicyclo[3.3.1 ]nonan-3-yl)-6,7-difluoroquinoxaline hydrochloride (42 mg; 0.129 mmol). Stirring at rt is continued for 20 h followed by direct purification of the product by prep. HPLC to give (7-(6,7-difluoroquinoxalin-2-yl)-3,7-diazabicyclo[3.3.1]nonan-3-yl)(5-(4-fluorophenyl)- 2-methylthiazol-4-yl)methanone as a white solid. g to either of the procedures given above and by using the appropriate starting ; described herein before, the example compounds given in the list below are I; LC-MS data given are acquired with Method E:
Chemical name; LC-MS data
[7-(5-Chloro-benzooxazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(5-methyl-2-[1 ,2,3]triazol-2-yl- phenyl)-methanone; LC-MS: tR = 1 .00; [M+H]+ = 463.3
(7-Benzooxazol-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-(5-methyl-2-[1 ,2,3]triazol-2-yl-phenyl)- methanone; LC-MS: tR = 0.84; [M+H]+ = 429.4
(7-Benzothiazol-2-yl-3J-diaza-bicyclo[3.3.1 ]non-3-yl)-(5-methyl-2-[1 ,2,3]triazol-2-yl-ph
methanone; LC-MS: tR = 0.80; [M+H]+ = 445.3
[7-(4,6-Dimethoxy-pyrimidin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-(5-methyl-2-[1 ,2,3]tria phenyl)-methanone; LC-MS: tR = 1 .06; [M+H]+ = 450.1
[7-(6-Fluoro-benzothiazol-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(5-methyl-2-[1 ,2,3]triazo phenyl)-methanone; LC-MS: tR = 0.92; [M+H]+ = 463.3
[7-(6-Chloro-benzothiazol-2-yl)-3,7^
phenyl)-methanone; LC-MS: tR = 1 .02; [M+H]+ = 479.4
[7-(5-Bromo-pyrimidin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-(5-methyl-2-[1 ,2,3]triaz^
methanone; LC-MS: tR = 1.04; [M+H]+ = 468.3
[7-(5-Chloro-benzooxazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(2-[1 ,2,3]triazol-2-yl-phenyl)- methanone; LC-MS: tR = 0.95; [M+H]+ = 449.3
[7-(5-Chloro-benzooxazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(4'-fluoro-3'-methyl-biphenyl-2-yl)- methanone; LC-MS: tR = 1.17; [M+H]+ = 490.4
[7-(5-Ethyl-pyrimidin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(5-methyl-2-[1 ,2,3]triazol-2-yl-phenyl)- methanone; LC-MS: tR = 0.96; [M+H]+ = 418.1
(5-Methyl-2-[1 ,2,3]triazol-2-yl-phenyl)-[7-(4-trifluoromethyl-pyrimidin-2-yl)-3J-diaza-bi
3-yl]-methanone; LC-MS: tR = 1 .09; [M+H]+ = 458.3
(5-Methyl-2-[1 ,2,3]triazol-2-yl-phenyl)-[7-(5-trifluoromethyl-pyrimidin-2-yl)-3J-diaza-bicyc
3-yl]-methanone; LC-MS: tR = 1 .06; [M+H]+ = 458.3
(2-Cyclopropyl-5-m-tolyl-thiazol-4-yl)-(7-quinoxalin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone; LC-MS: tR = 1 .03; [M+H]+ = 496.4
[2-Dimethylamino-5-(4-fluoro-phenyl)-thiazol-4-yl]-(7-quinoxalin-2-yl-3,7-diaza-bicyclo[3.3.1 ]no methanone; LC-MS: tR = 0.79; [M+H]+ = 503.3
[5-(6-Methoxy-pyridin-3-yl)-2-methyl-thiazol-4-yl]-(7-quinoxalin-2-yl-3J-diaza-bicyclo[3.3.1 ]non-3-yl)- methanone; LC-MS: tR = 0.78; [M+H]+ = 487.3 [5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-(7-quinoxalin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-y methanone; LC-MS: tR = 0.86; [M+H]+ = 474.3
(2-Methyl-5-o-tolyl-thiazol-4-yl)-(7-quinoxalin-2-yl-3 -diaza-bicyclo[3.3.1 ]non-3-yl)-methanone; LC- MS: tR = 0.87; [M+H]+ = 470.3
[2-Dimethylamino-5-(4-fluoro-3-methyl-phenyl)-thiazol-4-yl]-(7-quinoxalin-2-yl-3,7-diaza- bicyclo[3.3.1 ]non-3-yl)-methanone; LC-MS: tR = 0.85; [M+H]+ = 517.3
[5-(4-Chloro-phenyl)-2-methyl-thiazol-4-yl]-(7-quinoxalin-2-yl-3,7-diaza-bicyclo[3.3.1]non-3-yl)- methanone; LC-MS: tR = 0.94; [M+H]+ = 490.3
[7-(6-Chloro-benzothiazol-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(2-[1 ,2,3]triazol-2-yl-phen methanone; LC-MS: tR = 0.97; [M+H]+ = 465.3
[7-(6-Chloro-benzothiazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(5-fluoro-2-[1 ,2,3]triazol-2-yl-phenyl)- methanone; LC-MS: tR = 1.01 ; [M+H]+ = 483.3
[7-(6-Chloro-benzothiazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(2-fluoro-6-[1 ,2,3]triazol-2-yl-phenyl)- methanone; LC-MS: tR = 0.9; [M+H]+ = 483.1
[5-(3-Methoxy-phenyl)-2-methyl-thiazol -yl]-(7-quinoxalin-2-yl-3J-diaza-bicyclo[3.3.1]non-3-yl)- methanone; LC-MS: tR = 0.83; [M+H]+ = 486.3
[2-Methyl-5-(3-trifluoromethyl-phenyl)-thiazol-4-yl]-(7-quinoxalin-2-yl-3J-diaza-bicyclo[3.3.1 ]non-3- yl)-methanone; LC-MS: tR = 0.97; [M+H]+ = 524.3
[7-(6-Chloro-benzothiazol-2-yl)-3J-diaza-bicy^
phenyl]-methanone; LC-MS: tR = 0.98; [M+H]+ = 480.1
[2-Methyl-5-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-(7-quinoxalin-2-yl-3J-diaza-bicyclo[3.3.1 ]non-3- yl)-methanone; LC-MS: tR = 1 .0; [M+H]+ = 524.3
Biphenyl-2-yl-[7-(6-chloro-benzothiazol-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-methanone; LC-MS: tR = 1.1 1 ; [M+H]+ = 474
(2-Methyl-5-p-tolyl-thiazol-4-yl)-(7-quinoxalin-2-yl-3J-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone; LC- MS: tR = 0.98; [M+H]+ = 470.3
[5-(3,5-Difluoro-phenyl)-2-methyl-thiazol-4-yl]-(7-quinoxalin-2-yl-3J-diaza-bicyclo[3.3.1 ]non-3-yl)- methanone; LC-MS: tR = 0.91 ; [M+H]+ = 492.3
[4-(4-Chloro-phenyl)-2-methyl-thiazol-5-yl]-(7-quinoxalin-2-yl-3,7-diaza-bicyclo[3.3.1]non-3-yl)- methanone; LC-MS: tR = 1.04; [M+H]+ = 490.3
[7-(6-Chloro-benzothiazol-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(2-pyrazol-1-yl-phenyl)-methanone; LC-MS: tR = 0.95; [M+H]+ = 464.3
[7-(6-Chloro-benzothiazol-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(2-[1 ,2,3]triazol-2-yl-5- trifluoromethyl-phenyl)-methanone; LC-MS: tR = 1 .09; [M+H]+ = 533.2 [7-(6-Chloro-benzothiazol-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl -(5-chloro-2-[1 ,2,3]triazol-2-yl- phenyl)-methanone; LC-MS: tR = 1 .06; [M+H]+ = 499.2
[7-(6-Chloro-benzothiazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl -(5-methoxy-2-[1 ,2,3]triazol-2-yl- phenyl)-methanone; LC-MS: tR = 0.98; [M+H]+ = 495.2
[7-(6-Chloro-benzothiazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl -(4-methyl-2-[1 ,2,3]triazol-2-yl- phenyl)-methanone; LC-MS: tR = 1 .03; [M+H]+ = 479.3
3-[7-(6-Chloro-benzothiazol-2-yl)-3,7-diaza-bicyclo[3.3.1]nonane-3-carbonyl]-4-[1 ,2,3]triazol-2-yl- benzonitrile: LC-MS: tR = 0.96; [M+H]+ = 490.3
[7-(6-Chloro-benzothiazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl -(2-fluoro-3-methoxy-6-[1 ,2,3]triazol- 2-yl-phenyl)-methanone; LC-MS: tR = 0.94; [M+H]+ = 512.88
[7-(6-Chloro-benzothiazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl (2-[1 ,2,3]triazol-2-yl-5- trifluoromethoxy-phenyl)-methanone; LC-MS: tR = 1 .12; [M+H]+ = 548.9
[7-(6-Chloro-benzothiazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl -(2-methyl-6-[1 ,2,3]triazol-2-yl- phenyl)-methanone; LC-MS: tR = 1 .02; [M+H]+ = 479.3
[7-(6-Chloro-benzothiazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl -(4,5-dimethoxy-2-[1 ,2,3]triazol-2-yl- phenyl)-methanone; LC-MS: tR = 0.95; [M+H]+ = 525.3
[7-(5-Chloro-benzooxazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl -(5-fluoro-2-[1 ,2,3]triazol-2-yl-phenyl)- methanone; LC-MS: tR = 0.99; [M+H]+ = 467.3
[7-(5-Chloro-benzooxazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl -(2-fluoro-6-[1 ,2,3]triazol-2-yl-phenyl)- methanone; LC-MS: tR = 0.92; [M+H]+ = 467.1
[7-(5-Chloro-benzooxazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl -(5-chloro-2-[1 ,2,3]triazol-2-yl- phenyl)-methanone; LC-MS: tR = 1 .04; [M+H]+ = 483.3
[7-(5-Chloro-benzooxazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl -(2-[1 ,2,3]triazol-2-yl-5- trifluoromethoxy-phenyl)-methanone; LC-MS: tR = 1 .1 ; [M+H]+ = 533.3
[7-(5-Chloro-benzooxazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl -(5-methoxy-2-[1 ,2,3]triazol-2-yl- phenyl)-methanone; LC-MS: tR = 0.97; [M+H]+ = 512.88
[7-(5-Chloro-benzooxazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl -(4-methyl-2-[1 ,2,3]triazol-2-yl- phenyl)-methanone; LC-MS: tR = 1 .02; [M+H]+ = 463.3
[7-(5-Chloro-benzooxazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl -(4,5-dimethoxy-2-[1 ,2,3]triazol-2-yl- phenyl)-methanone; LC-MS: tR = 0.94; [M+H]+ = 509.4
[7-(5-Chloro-benzooxazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl -(2-[1 ,2,3]triazol-2-yl-5- trifluoromethyl-phenyl)-methanone; LC-MS: tR = 1 .08; [M+H]+ = 517.3
[7-(5-Chloro-benzooxazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl -(2-methyl-6-[1 ,2,3]triazol-2-yl- phenyl)-methanone; LC-MS: tR = 1 ; [M+H]+ = 463.3 Biphenyl-2-yl-[7-(5-chloro-benzooxazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-methanone; LC-MS: tR = 1.1 1 ; [M+H]+ = 458.3
[7-(5-Chloro-benzooxazol-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(4-methyl-biphenyl-2-yl)-methanone; LC-MS: tR = 1 .16; [M+H]+ = 472.2
(5-Fluoro-2-[1 ,2 ]tnazol-2-yl-phenyl)-[7-(4-trifluoromethyl-pyrimidin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non- 3-yl]-methanone; LC-MS: tR = 1 .05; [M+H]+ = 462.3
(2-Fluoro-6-[1 ,2 ]triazol-2-yl-phenyl)-[7-(4-trifluoromethyl-pynmidin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non- 3-yl]-methanone; LC-MS: tR = 1 .04; [M+H]+ = 462.3
(5-Chloro-2-[1 ,2 ]triazol-2-yl-phenyl)-[7-(4-trifluoromethyl-pyrimidin-2-yl)-3J-d
3-yl]-methanone; LC-MS: U = 1 .11 ; [M+H]+ = 478.3
(2-[1 ,2 ]Triazol-2-yl-5-trifluoromethoxy-phenyl)-[7-(4-trifluoromethyl-pyrimidin-2-yl)-3J-diaza- bicyclo[3.3.1 ]non-3-yl]-methanone; LC-MS: tR = 1 .16; [M+H]+ = 428.3
(5-Methoxy-2-[1 ,2,3]triazol-2-yl-phenyl)-[7-(4-trifluoromethyl-pyrimidin-2-yl)-3J-diaza- bicyclo[3.3.1 ]non-3-yl]-methanone; LC-MS: tR = 1 .04; [M+H]+ = 474.4
(4-Methyl-2-[1 ,2 ]triazol-2-yl-phenyl)-[7-(4-trifluoromethyl-pyrimidin-2-yl)-3
3-yl]-methanone; LC-MS: tR = 1 .11 ; [M+H]+ = 458.4
(4,5-Dimethoxy-2-[1 ,2,3]triazol-2-yl-phenyl)-[7-(4-trifluoromethyl-pyrimidin-2-yl)-3,7-diaza- bicyclo[3.3.1 ]non-3-yl]-methanone; LC-MS: tR = 1 .01 ; [M+H]+ = 504.4
(2-[1 ,2 ]Triazol-2-yl-5-trifluoromethyl-phenyl)-[7-(4-trifluoromethyl-pyrimidin-2-yl)-3J-diaza- bicyclo[3.3.1 ]non-3-yl]-methanone; LC-MS: tR = 1 .15; [M+H]+ = 512.3
(2-Methyl-6-[1 ,2,3]triazol-2-yl-phenyl)-[7-(4-trifluoromethyl-pyrimidin-2-yl)-3
3-yl]-methanone; LC-MS: tR = 1 .08; [M+H]+ = 458.4
Biphenyl-2-yl-[7-(4-trifluoromethyl-pyrimidin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-meth LC- MS: U = 1 .2; [M+H]+ = 453.3
(4-Methyl-biphenyl-2-yl)-[7-(4-trifluorom
methanone; LC-MS: tR = 1.25; [M+H]+ = 467.4
(7-Benzothiazol-2-yl-3J-diaza-bicyclo[3.3.1 ]non-3-yl)-(5-fluoro-2-[1 ,2,3]triazol-2-yl-phen methanone; LC-MS: tR = 0.79; [M+H]+ = 449.3
(7-Benzothiazol-2-yl-3J-diaza-bicyclo[3.3.1 ]non-3-yl)-(2-fluoro-6-[1 ,2,3]triazol-2-yl-phenyl)- methanone; LC-MS: tR = 0.68; [M+H]+ = 449.3
(7-Benzothiazol-2-yl-3J-diaza-bicyclo[3.3.1 ]non-3-yl)-(5-chloro-2-[1 ,2 ]triazol-2-yl-phenyl)- methanone; LC-MS: tR = 0.84; [M+H]+ = 465.3
(7-Benzothiazol-2-yl-3J-diaza-bicyclo[3.3.1 ]non-3-yl)-(2-[1 ,2,3]triazol-2-yl-5-trifluoromethoxy-phenyl)- methanone; LC-MS: tR = 0.92; [M+H]+ = 515.3 7-Benzothiazol-2-yl-3,7-diaza-bic clo[3.3.1 ]non-3-yl)-(5-methoxy-2-[1 ,2,3]triazol-2-yl-phenyl)-
67
methanone; LC-MS: tR = 0.77; [M+H]+ = 461 .3
7-Benzothiazol-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-(4-methyl-2-[1 ,2,3]triazol-2-yl-phenyl)- 68
methanone; LC-MS: tR = 0.81 ; [M+H]+ = 445.4
7-Benzothiazol-2-yl-3J-diaza-bicyclo[3.3.1 ]non-3-yl)-(4,5-dimethoxy-2-[1 ,2,3]triazol-2-^ 69
methanone; LC-MS: tR = 0.75; [M+H]+ = 491 .1
7-Benzothiazol-2-yl-3J-diaza-bicyclo[3.3.^^
70
methanone; LC-MS: tR = 0.88; [M+H]+ = 499.3
7-Benzothiazol-2-yl-3J-diaza-bicyclo[3.3.1 ]non-3-yl)-(2-methyl-6-[1 ,2,3]triazol-2-yl-phenyl)- 71
methanone; LC-MS: tR = 0.8; [M+H]+ = 445.2
7-Benzothiazol-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-biphenyl-2-yl-methanone; LC-MS: tR = 0.89; 72
M+H]+ = 440.3
7-Benzothiazol-2-yl-3J-diaza-bicyclo[3.3.1 ]non-3-yl)-(4-methyl-biphenyl-2-yl)-methanone; LC-MS: tR 73
= 0.95; [M+H]+ = 454.4
7-(6,7-Difluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(2-fluoro-6-[1 ,2,3]triazol-2-yl- 74
phenyl)-methanone; LC-MS: tR = 0.99; [M+H]+ = 480.3
2-Fluoro-6-[1 ,2 ]triazol-2-yl-phenyl)-(7-quinoxalin-2-yl-3J-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone; 75
LC-MS: tR = 0.87; [M+H]+ = 444.4
2-Fluoro-6-[1 ,2 ]triazol-2-yl-phenyl)-(7-quinazolin-2-yl-3J-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone; 76
LC-MS: tR = 0.73; [M+H]+ = 444.4
2-Fluoro-6-[1 ,2 ]triazol-2-yl-phenyl)-[7-(8-methyl-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]- 77
methanone; LC-MS: tR = 1.03; [M+H]+ = 458.4
7-(7-Chloro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-(2-fluoro-6-[1 ,2,3]triazol-2-yl-p
78
methanone; LC-MS: tR = 1.02; [M+H]+ = 478.3
7-(6-Chloro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1]non-3-yl]-(2-fluoro-6-[1 ,2 ]triazol-2^ 79
methanone; LC-MS: tR = 1.01 ; [M+H]+ = 478.4
7-(6,7-Dichloro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-(2-fluoro-6-[1 ,2,3]tr^
80
phenyl)-methanone; LC-MS: tR = 1 .12; [M+H]+ = 512.3
7-(6-Fluoro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(2-fluoro-6-[1 ,2,3]triazol-2-yl-ph
81
methanone; LC-MS: tR = 0.93; [M+H]+ = 462.4
7-(7-Fluoro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1 ]no
82
methanone; LC-MS: tR = 0.93; [M+H]+ = 462.4
7-(8-Methyl-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1]non-3-yl]-(2-methyl-6-[1 ,2,3]triazol-2-yl-phenyl)- 83
methanone; LC-MS: tR = 1.09; [M+H]+ = 454.4 [7-(7-Chloro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-(2-methyl-6-[1 ,2,3]triazol-2-^
84
methanone; LC-MS: tR = 1.09; [M+H]+ = 474.4
[7-(6-Chloro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-(2-methyl-6-[1 ,2,3]tri
85
methanone; LC-MS: tR = 1.08; [M+H]+ = 474.4
[7-(6J-Dichloro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1]non-3-yl]-(2-methyl-6-[1 ,2,3
86
phenyl)-methanone; LC-MS: tR = 1 .19; [M+H]+ = 508.3
[7-(6-Fluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(2-methyl-6-[1 ,2,3]tri
87
methanone; LC-MS: tR = 1 ; [M+H]+ = 458.4
[7-(7-Fluoro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(2-methyl-6-[1 ,2 ]triazol-2-yl-ph
88
methanone; LC-MS: tR = 1 ; [M+H]+ = 458.4
(2-Methyl-6-[1 ,2 ]triazol-2-yl-phenyl)-(7-quinoxalin-2-yl-3J-diaza-bicyclo[3.3.1]non-3-yl)-methanone;
89
LC-MS: tR = 0.95; [M+H]+ = 440.4
[7-(6J-Difluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(2-methyl-6-[1 ,2 ]tri
90
phenyl)-methanone; LC-MS: tR = 1 .05; [M+H]+ = 476.4
(2-Methyl-6-[1 ,2 ]triazol-2-yl-phenyl)-(7-quinazolin-2-yl-3J-diaza-bicyclo[3.3.1]non-3-yl)-methanone;
91
LC-MS: tR = 0.92; [M+H]+ = 440.1
[7-(8-Methyl-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1]non-3-yl]-(5-methyl-2-[1 ,2 ]triazol-2-yl-phenyl)-
92
methanone; LC-MS: tR = 1.09; [M+H]+ = 454.4
[7-(7-Chloro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1]non-3-yl]-(5-methyl-2-[1 ,2 ]triazol-2-yl-phenyl)-
93
methanone; LC-MS: U = 1.1 ; [M+H]+ = 474.3
[7-(6-Chloro-quinoxalin-2-yl)-37-diaza-bicyclo[3.3.1]non-3-yl]-(5-methyl-2-[1 ,2,3]tn
94
methanone; LC-MS: tR = 1.08; [M+H]+ = 474.4
[7-(6J-Dichloro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1]non-3-yl]-(5-methyl-2-[1 ,2,3]tri
95
phenyl)-methanone; LC-MS: tR = 0.96; [M+H]+ = 507.97
[7-(6-Fluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-(5-methyl-2-[1 ,2,3]triazo
96
methanone; LC-MS: tR = 1.0; [M+H]+ = 458.4
[7-(7-Fluoro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(5-methyl-2-[1 ,2 ]triazol-2-yl-phenyl^
97
methanone; LC-MS: tR = 1.01 ; [M+H]+ = 458.4
(5-Methyl-2-[1 ,2 ]triazol-2-yl-phenyl)-(7-quinoxalin-2-yl-3J-diaza-bicyclo[3.3.1]non-3-yl)-methanone;
98
LC-MS: tR = 0.96; [M+H]+ = 440.4
[7-(6J-Difluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(5-methyl-2-[1 ,2 ]tri
99
phenyl)-methanone; LC-MS: tR = 1 .06; [M+H]+ = 476.4
(5-Methyl-2-[1 ,2 ]triazol-2-yl-phenyl)-(7-quinazolin-2-yl-3J-diaza-bicyclo[3.3.1]non-3-yl)-methanone;
100
LC-MS: tR = 0.93; [M+H]+ = 440.1
Figure imgf000075_0001
[7-(7-Chloro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3 .1]non-3-yl]-(4-methyl-biphenyl-2-yl)-methanon
118
LC-MS: tR = 1 .27; [M+H]+ = 483.4
(5-Methyl-2-pyrazol-1 -yl-phenyl)-(7-quinoxalin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone; LC-
119
MS: tR = 0.86; [M+H]+ = 442.4
[7-(6,7-Difluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(5-methyl-2-pyrazol-1 -yl-phenyl)-
120
methanone; LC-MS: tR = 1.03; [M+H]+ = 475.4
[7-(7-Chloro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-(5-methyl-2-pyrazol-1 -yl-phenyl)-
121
methanone; LC-MS: tR = 1.08; [M+H]+ = 473.3
[7-(6-Chloro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-(5-methyl-2-pyrazol-1 -yl-phenyl)-
122
methanone; LC-MS: tR = 1.06; [M+H]+ = 473.3
[7-(6,7-Dichloro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-(5-methyl-2-pyrazol-1 -yl-phenyl)-
123
methanone; LC-MS: tR = 1.17; [M+H]+ = 507.3
[7-(6-Fluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(5-methyl-2-pyrazol-1 -yl-phenyl)-
124
methanone; LC-MS: tR = 0.98; [M+H]+ = 457.4
(5-Methyl-2-pyrazol-1 -yl-phenyl)-(7-quinazolin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone LC-
125
MS: tR = 0.90; [M+H]+ = 439.1
(2-Pyrazol-1 -yl-phenyl)-(7-quinoxalin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone; LC-MS: tR =
126
0.88; [M+H]+ = 425.4
[7-(6J-Difluoro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(2-pyrazol-1-yl-phenyl)-methanone;
127
LC-MS: tR = 0.99; [M+H]+ = 461.3
[7-(7-Chloro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-(2-pyrazol-1 -yl-phenyl)-methanone;
128
LC-MS: tR = 1 .02; [M+H]+ = 459.3
[7-(6-Chloro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-(2-pyrazol-1 -yl-phenyl)-methanone;
129
LC-MS: U = 1 .01 ; [M+H]+ = 459.3
[7-(6J-Dichloro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1]non-3-yl]-(2-pyrazol-1 -yl-phenyl)-methanone;
130
LC-MS: tR = 1 .12; [M+H]+ = 493.3
[7-(6-Fluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(2-pyrazol-1 -yl-phenyl)-methanone; LC-
131
MS: tR = 0.93; [M+H]+ = 443.4
(2-Pyrazol-1 -yl-phenyl)-(7-quinazolin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone; LC-MS: tR =
132
0.84; [M+H]+ = 425.1
[5-(4-Bromo-phenyl)-2-methyl-thiazol-4-yl]-[7-(5-chloro-benzooxazol-2-yl)-3J-diaza-
133
bicyclo[3.3.1 ]non-3-yl]-methanone; LC-MS: tR = 1 .12; [M+H]+ = 557
[7-(5-Chloro-benzooxazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(2-cyclopropyl-5-phenyl-thiazol-4-yl)-
134
methanone; LC-MS: tR = 1.13; [M+H]+ = 505.4 [7-(5-Chloro-benzooxazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-[2-cyclopropyl-5-(3-fluoro-4-methyl-
135
phenyl)-thiazol-4-yl]-methanone; LC-MS: tR = 1 .21 ; [M+H]+ = 537.2
[7-(5-Chloro-benzooxazol-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(5-phenyl-thiazol-4-yl)-methanone;
136
LC-MS: tR = 0.97; [M+H]+ = 465.3
[7-(5-Chloro-benzooxazol-2-yl)-3J-diaza-bicycta^
137
phenyl)-thiazol-4-yl]-methanone; LC-MS: tR = 1 .14; [M+H]+ = 536.5
[7-(5-Chloro-benzooxazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(2-methyl-5-phenyl-thiazol-4-yl)-
138
methanone; LC-MS: tR = 1.03; [M+H]+ = 479.3
(6-Methyl-3-[1 ,2,3]triazol-2-yl-pyridin-2-yl)-(7-quinoxalin-2-yl-3,7-diaza-bicyclo[3.3.1 ]n
139
methanone; LC-MS: tR = 0.84; [M+H]+ = 441 .4
[7-(6,7-Difluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(6-methyl-3-[1 ,2,3]t^^
140
pyridin-2-yl)-methanone; LC-MS: tR = 0.97; [M+H]+ = 477.4
[7-(7-Chloro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-(6-methyl-3-[1 ,2,3]tri
141
yl)-methanone; LC-MS: tR = 1 .01 ; [M+H]+ = 475.3
[7-(6-Chloro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-(6-methyl-3-[1 ,2,3]tn
142
yl)-methanone; LC-MS: tR = 0.99; [M+H]+ = 475.3
[7-(6,7-Dichloro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1]non-3-yl]-(6-methyl-3-[1 ,2,3]
143
pyridin-2-yl)-methanone; LC-MS: tR = 1.1 1 ; [M+H]+ = 509.3
[7-(6-Fluoro-quinoxalin-2-yl)-37-diaza-bicyclo[3.3.1 ]non-3-yl]-(6-methyl-3-[1 ,2,3]triaz
144
yl)-methanone; LC-MS: tR = 0.91 ; [M+H]+ = 459.4
(6-Methyl-3-[1 ,2,3]triazol-2-yl-pyridin-2-yl)-(7-quinazolin-2-yl-3,7-diaza-bicyclo[3.3.1 ]n
145
methanone; LC-MS: tR = 0.69; [M+H]+ = 441 .4
(6-Methyl-3-pyrazol-1 -yl-pyridin-2-yl)-(7-quinoxalin-2-yl-3J-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone;
146
LC-MS: tR = 0.82; [M+H]+ = 440.4
[7-(6,7-Difluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(6-methyl-3-pyrazol-1 -yl-pyridin-2-
147
yl)-methanone; LC-MS: tR = 0.95; [M+H]+ = 476.3
[7-(7-Chloro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-(6-methyl-3-pyrazol-1 -yl-pyridin-2-yl)-
148
methanone; LC-MS: tR = 0.98; [M+H]+ = 474.4
[7-(6-Chloro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-(6-methyl-3-pyrazol-1 -yl-pyridin-2-yl)-
149
methanone; LC-MS: tR = 0.97; [M+H]+ = 474.4
[7-(6,7-Dichloro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-(6-methyl-3-pyrazol-1 -yl-pyridin-2-
150
yl)-methanone; LC-MS: tR = 1 .09; [M+H]+ = 508.3
[7-(6-Fluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(6-methyl-3-pyrazol-1 -yl-pyridin-2-yl)-
151
methanone; LC-MS: tR = 0.89; [M+H]+ = 458.4 (6-Methyl-3-pyrazol-1 -yl-pyridin-2-yl)-(7-quinazolin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone;
152
LC-MS: tR = 0.68; [M+H]+ = 440.4
[7-(7-Fluoro-6-methoxy-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(5-methyl-2-[1 ,^
153
yl-phenyl)-methanone; LC-MS: tR = 1.0; [M+H]+ = 488.4
[7-(6-Methoxy-quinoxalin-2-yl)-37-diaza-bicyclo[3.3.1 ]non-3-yl]-(5-methyl-2-[1 ,2,3]tri
154
phenyl)-methanone; LC-MS: tR = 0.97; [M+H]+ = 470.4
[7-(7-Methoxy-quinoxalin-2-yl)-37-diaza-bicyclo[3.3.1 ]non-3-yl]-(5-methyl-2-[1 ,2 ]triaz^
155
phenyl)-methanone; LC-MS: tR = 0.94; [M+H]+ = 470.4
[7-(6-Methyl-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-(5-methyl-2-[1 ,2,3]tri
156
methanone; LC-MS: tR = 1.01 ; [M+H]+ = 454.3
[7-(7-Fluoro-6-methyl-quinoxalin^
157
phenyl)-methanone; LC-MS: tR = 1 .06; [M+H]+ = 472.4
[7-(7-Methyl-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-(5-methyl-2-[1 ,2,3]triaz^
158
methanone; LC-MS: tR = 1.01 ; [M+H]+ = 454.4
(5-Methyl-2-[1 ,2,3]triazol-2-yl-phenyl)-[7-(7-trifluoromethyl-quinoxalin-2-yl)-3J-diaza-
159
bicyclo[3.3.1 ]non-3-yl]-methanone; LC-MS: tR = 1 .13; [M+H]+ = 508.4
(5-Methyl-2-[1 ,2,3]triazol-2-yl-phenyl)-[7-(6-trifluoromethyl-quinoxalin-2-yl)-3J-diaza-
160
bicyclo[3.3.1 ]non-3-yl]-methanone; LC-MS: tR = 1 .11 ; [M+H]+ = 508.3
[7-(6-Fluoro-7-methyl-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-(5-methyl-2-[1 ,2,^
161
phenyl)-methanone; LC-MS: tR = 1 .06; [M+H]+ = 472.4
[7-(6,7-Difluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-[5-(3^-dimethyl-phen
162
thiazol-4-yl]-methanone; LC-MS: tR = 1 .2; [M+H]+ = 520.3
[5-(2,3-Dichloro-phenyl)-2-methyl-thiazol-4-yl]-[7-(6,7-difluoro-quinoxalin-2-yl)-3,7-diaza-
163
bicyclo[3.3.1 ]non-3-yl]-methanone; LC-MS: tR = 1 .23; [M+H]+ = 560.2
(2-Cyclopropyl-5-m-tolyl-thiazol^-yl)-[7-(6,7-difluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-
164
yl]-methanone; LC-MS: tR = 1 .24; [M+H]+ = 532.3
[7-(6J-Difluoro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-[2-dimethylamino-5-(4-fl^
165
phenyl)-thiazol-4-yl]-methanone; LC-MS: tR = 1 .11 ; [M+H]+ = 539.3
[7-(6,7-Difluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-[5-(6-methoxy-pyridin-3-yl)-2-
166
methyl-thiazol-4-yl]-methanone; LC-MS: tR = 1 .03; [M+H]+ = 523.3
[7-(6,7-Difluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-[5-(4-fluoro-phenyl)-2-methyl-
167
thiazol-4-yl]-methanone; LC-MS: tR = 1 .1 ; [M+H]+ = 510.3
[7-(6,7-Difluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(2-methyl-5-o-tolyl-thiazol-4-yl)-
168
methanone; LC-MS: tR = 1.16; [M+H]+ = 506.4 [7-(6,7-Difluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-[2-dimethylam
169
methyl-phenyl)-thiazol-4-yl]-methanone; LC-MS: tR = 1 .18; [M+H]+ = 553.3
[5-(4-Chloro-phenyl)-2-methyl-thiazol-4-yl]-[7-(6,7-difluoro-quinoxalin-2-yl)-3,7-diaza-
170
bicyclo[3.3.1 ]non-3-yl]-methanone; LC-MS: tR = 1 .16; [M+H]+ = 526.3
[7-(6,7-Difluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-[5-(3-methoxy-phenyl)-2-methyl-
171
thiazol-4-yl]-methanone; LC-MS: tR = 1 .1 ; [M+H]+ = 522.3
[7-(6,7-Difluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3 .1 ]non-3-yl]-[2-methyl-5-(3-trifluoromethyl-
172
phenyl)-thiazol-4-yl]-methanone; LC-MS: tR = 1 .19; [M+H]+ = 560.2
[7-(6,7-Difluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3 .1 ]non-3-yl]-[2-methyl-5-(4-trifluoromethyl-
173
phenyl)-thiazol-4-yl]-methanone; LC-MS: tR = 1 .19; [M+H]+ = 560.2
[7-(6,7-Difluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(2-methyl-5-p-tolyl-thiazol-4-yl)-
174
methanone; LC-MS: tR = 1.12; [M+H]+ = 506.3
[5-(3,5-Difluoro-phenyl)-2-methyl-thiazol-4-yl]-[7-(6,7-difluoro-quinoxalin-2-yl)-3,7-diaza-
175
bicyclo[3.3.1 ]non-3-yl]-methanone; LC-MS: tR = 1 .12; [M+H]+ = 528.3
[4-(4-Chloro-phenyl)-2-methyl-thiazol-5-yl]-[7-(6,7-difluoro-quinoxalin-2-yl)-3,7-diaza-
176
bicyclo[3.3.1 ]non-3-yl]-methanone; LC-MS: tR = 1 .15; [M+H]+ = 526.3
[5-(3,4-Dimethyl-phenyl)-2-methyl-thiazol-4-yl]-(7-quinoxalin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-
177
methanone; LC-MS: tR = 0.96; [M+H]+ = 484.4
[5-(2,3-Dichloro-phenyl)-2-methyl-thiazol-4-yl]-(7-quinoxalin-2-yl-3,7-diaza-bicyclo[3 .1 ]non-3-yl)-
178
methanone; LC-MS: tR = 0.97; [M+H]+ = 524.3
(5-Methyl-2-[1 ,2,3]triazol-2-yl-phenyl)-(7-quinoxalin-2-yl-9-oxa-37-diaza-bicyclo[3.3.1]n^
179
methanone; LC-MS: tR = 0.87; [M+H]+ = 442.40
[7-(6-Fluoro-quinoxalin-2-yl)-9-oxa-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(5-methyl-2-[1 ,2,3]
180
phenyl)-methanone; LC-MS: tR = 0.91 ; [M+H]+ = 460.4
[7-(6,7-Difluoro-quinoxalin-2-yl)-9-oxa-3 -diaza-bicyclo[3 .1 ]non-3-yl]-(5-methyl-2-
181
phenyl)-methanone; LC-MS: tR = 0.96; [M+H]+ = 478.4
(5-Methyl-2-[1 ,2 ]triazol-2-yl-phenyl)-(7-quinazolin-2-yl-9-oxa-3J-diaza-bicyclo[3.3.1]non-3-y
182
methanone; LC-MS: tR = 0.90; [M+H]+ = 442.1
[7-(8-Methyl-quinoxalin-2-yl)-9-oxa-3J-diaza-b^
183
phenyl)-methanone; LC-MS: tR = 0.98; [M+H]+ = 456.4
[7-(7-Chloro-quinoxalin-2-yl)-9-oxa-3J-diaza-b^
184
phenyl)-methanone; LC-MS: tR = 1 .01 ; [M+H]+ = 476.3
[7-(6-Chloro-quinoxalin-2-yl)-9-oxa-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(5-methyl-2-[1 ,2 ]tr^
185
phenyl)-methanone; LC-MS: tR = 0.99; [M+H]+ = 476.3 [7-(6J-Dichloro-quinoxalin-2-yl)-9-oxa-3J-diaza-b^
186
yl-phenyl)-methanone; LC-MS: U = 1.1 ; [M+H]+ = 510.0
(4-Methyl-biphenyl-2-yl)-(7-quinoxalin-2-yl-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl)-methanone; LC-
187
MS: tR = 1 .05; [M+H]+ = 451.4
[7-(6-Fluoro-quinoxalin-2-yl)-9-oxa-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(4-methyl-biphenyl-2-yl)-
188
methanone; LC-MS: tR = 1.08; [M+H]+ = 469.4
[7-(6 -Difluoro-quinoxalin-2-yl)-9-oxa-3 -diaza-bicyclo[3.3.1 ]non-3-yl]-(4-methyl-biphenyl-2-yl)-
189
methanone; LC-MS: tR = 1.12; [M+H]+ = 487.4
(4-Methyl-biphenyl-2-yl)-(7-quinazolin-2-yl-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl)-methanone; LC-
190
MS: U = 1 .07; [M+H]+ = 451.4
(4-Methyl-biphenyl-2-yl)-[7-(8-methyl-quinoxalin-2-yl)-9-oxa-3J-diaza-bicyclo[3.3.1 ]n
191
methanone; LC-MS: tR = 1.15; [M+H]+ = 465.4
(7-Benzothiazol-2-yl-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl)-(4-methyl-biphenyl-2-yl)-methanone; LC-
192
MS: tR = 1 .01 ; [M+H]+ = 456.3
[7-(7-Chloro-quinoxalin-2-yl)-9-oxa-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(4-methyl-biphenyl-2-yl)-
193
methanone; LC-MS: tR = 1.17; [M+H]+ = 485.3
[7-(6-Fluoro-benzothiazol-2-yl)-9-oxa-3J-diaza-bicyclo[3.3.1]non-3-yl]-(4-methyl-biphenyl-2-yl)-
194
methanone; LC-MS: tR = 1.07; [M+H]+ = 474.4
[7-(6-Chloro-quinoxalin-2-yl)-9-oxa-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(4-methyl-biphenyl-2-yl)-
195
methanone; LC-MS: tR = 1.15; [M+H]+ = 485.3
[7-(5-Chloro-benzooxazol-2-yl)-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl]-(4-methyl-biphenyl-2-yl)-
196
methanone; LC-MS: U = 1.1 ; [M+H]+ = 474.3
[7-(6,7-Dichloro-quinoxalin-2-yl)-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl]-(4-methyl-biphenyl-2-yl)-
197
methanone; LC-MS: tR = 1.25; [M+H]+ = 519.2
Biphenyl-2-yl-(7-quinoxalin-2-yl-9-oxa-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone; LC-MS: tR =
198
0.99; [M+H]+ = 437.4
Biphenyl-2-yl-[7-(6J-difluoro-quinoxalin-2-yl)-9-oxa-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-methanone; LC-
199
MS: U = 1 .07; [M+H]+ = 473.3
Biphenyl-2-yl-[7-(8-methyl-quinoxalin-2-yl)-9-oxa-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-methanone; LC-
200
MS: U = 1 .10; [M+H]+ = 451.4
Biphenyl-2-yl-[7-(7-chloro-quinoxalin-2-yl)-9-oxa-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-methanone; LC-
201
MS: U = 1 .11 ; [M+H]+ = 471.3
Biphenyl-2-yl-[7-(6-chloro-quinoxalin-2-yl)-9-oxa-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-methanone; LC-
202
MS: tR = 1 .1 ; [M+H]+ = 471 .3 Biphenyl-2-yl-[7-(6,7-dichloro-quinoxalin-2-yl)-9-oxa-3,7-diaza-bicyclo[3 .1]non-3-yl]-methanon
203
LC-MS: tR = 1 .21 ; [M+H]+ = 505.3
Biphenyl-2-yl-[7-(6-fluoro-quinoxalin-2-yl)-9-oxa-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-methanone; LC-
204
MS: tR = 1 .02; [M+H]+ = 455.4
Biphenyl-2-yl-(7-quinazolin-2-yl-9-oxa-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone; LC-MS: tR =
205
1 .02; [M+H]+ = 437.1
(7-Benzothiazol-2-yl-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl)-biphenyl-2-yl-methanone; LC-MS: tR =
206
0.95; [M+H]+ = 442.3
Biphenyl-2-yl-[7-(6-fluoro-benzothiazol-2-yl)-9-oxa-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-methanone; LC-
207
MS: U = 1 .01 ; [M+H]+ = 460.3
Biphenyl-2-yl-[7-(5-chloro-benzooxazol-2-yl)-9-oxa-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-methanone; LC-
208
MS: U = 1 .05; [M+H]+ = 459.9
[7-(6,7-Dichloro-quinoxalin-2-yl)-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl]-(6-methyl-3-pyrazol-1-yl-
209
pyridin-2-yl)-methanone; LC-MS: tR = 0.99; [M+H]+ = 510.3
[7-(6,7-Difluoro-quinoxalin-2-yl)-9-oxa-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(6-methyl-3-pyrazol-1 -yl-
210
pyridin-2-yl)-methanone; LC-MS: tR = 0.85; [M+H]+ = 478.3
(6-Methyl-3-pyrazol-1 -yl-pyridin-2-yl)-(7-quinoxalin-2-yl-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl)-
211
methanone; LC-MS: tR = 0.75; [M+H]+ = 442.3
[7-(7-Chloro-quinoxalin-2-yl)-9-oxa-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(6-methyl-3-pyrazol-1 -yl-pyridin-
212
2-yl)-methanone; LC-MS: tR = 0.88; [M+H]+ = 476.3
[7-(6-Chloro-quinoxalin-2-yl)-9-oxa-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(6-methyl-3-pyrazol-1 -yl-pyridin-
213
2-yl)-methanone; LC-MS: tR = 0.88; [M+H]+ = 476.3
(6-Methyl-3-pyrazol-1 -yl-pyridin-2-yl)-(7-quinazolin-2-yl-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl)-
214
methanone; LC-MS: tR = 0.72; [M+H]+ = 442.3
[7-(6,7-Dimethyl-quinoxalin-2-yl)-9-oxa-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(6-methyl-3-pyrazol-1 -yl-
215
pyridin-2-yl)-methanone; LC-MS: tR = 0.86; [M+H]+ = 470.4
[7-(6J-Dichloro-quinoxalin-2-yl)-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl]-(6-methyl-3-[1 ,^
216
yl-pyridin-2-yl)-methanone; LC-MS: U = 1.01 ; [M+H]+ = 511 .2
[7-(6,7-Difluoro-quinoxalin-2-yl)-9-oxa-3 -diaza-bicyclo[3.3.1 ]non-3-yl]-(6-methyl-3-[1 ,^
217
pyridin-2-yl)-methanone; LC-MS: tR = 0.87; [M+H]+ = 479.3
(6-Methyl-3-[1 ,2,3]triazol-2-yl-pyridin-2-yl)-(7-quinoxalin-2-yl-9-oxa-3,7-diaza-bicyclo[3^
218
methanone; LC-MS: tR = 0.76; [M+H]+ = 443.3
[7-(7-Chloro-quinoxalin-2-yl)-9-oxa-3J-diaza-b^
219
pyridin-2-yl)-methanone; LC-MS: tR = 0.90; [M+H]+ = 477.3 [7-(6-Chloro-quinoxalin-2-yl)-9-oxa
220
pyridin-2-yl)-methanone; LC-MS: tR = 0.89; [M+H]+ = 477.3
(6-Methyl-3-[1 ,2,3]triazol-2-yl-pyridin-2-yl)-(7-quinazolin-2-yl-9-oxa-3,7-diaza-bicyd
221
methanone; LC-MS: tR = 0.73; [M+H]+ = 443.3
[7-(6J-Dimethyl-quinoxalin-2-yl)-9-oxa-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(6-methyl-3-[1 ^
222
yl-pyridin-2-yl)-methanone; LC-MS: tR = 0.87; [M+H]+ = 471 .4
(7-Benzothiazol-2-yl-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl)-(5-methyl-2-[1 ,2,3]triazol-2-yl-phenyl)-
223
methanone; LC-MS: tR = 0.85; [M+H]+ = 447.3
(7-Benzothiazol-2-yl-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl)-(5-chloro-2-[1 ,2,3]triazol-2-y^
224
methanone; LC-MS: tR = 0.89; [M+H]+ = 467.3
[7-(6-Fluoro-benzothiazol-2-yl)-9-oxa-3J-diaza-bicyclo[3.3.1]non-3-yl]-(5-methyl-2-[1 ,2,3]triazol-2-yl-
225
phenyl)-methanone; LC-MS: tR = 0.91 ; [M+H]+ = 465.3
[7-(6-Fluoro-benzothiazol-2-yl)-9-oxa-3J-diaza-bicyclo[3.3.1]non-3-yl]-(2-methyl-6-[1 ,2,3]triazol-2-yl-
226
phenyl)-methanone; LC-MS: tR = 0.91 ; [M+H]+ = 465.3
[7-(6-Fluoro-benzothiazol-2-yl)-9-oxa-3J-diaza-bicyclo[3.3.1]non-3-yl]-(5-methoxy-2-[1 ,2,3]triazol-2-
227
yl-phenyl)-methanone; LC-MS: tR = 0.88; [M+H]+ = 481 .2
[7-(6-Fluoro-benzothiazol-2-yl)-9-oxa-3J-diaza-bicyclo[3.3.1]non-3-yl]-(5-fluoro-2-[1 ,2,3]triazol-2-yl-
228
phenyl)-methanone; LC-MS: tR = 0.89; [M+H]+ = 469.3
[7-(6-Fluoro-benzothiazol-2-yl)-9-oxa-3J-diaza-bicyclo[3.3.1]non-3-yl]-(2-fluoro-6-[1 ,2,3]triazol-2-yl-
229
phenyl)-methanone; LC-MS: tR = 0.83; [M+H]+ = 469.3
(5-Chloro-2-[1 ,2,3]triazol-2-yl-phenyl)-[7-(6-fluoro-benzothiazol-2-yl)-9-oxa-3,7-diaza-
230
bicyclo[3.3.1 ]non-3-yl]-methanone; LC-MS: tR = 0.95; [M+H]+ = 485.2
(2-Fluoro-6-[1 ,2 ]triazol-2-yl-phenyl)-(7-quinoxalin-2-yl-9-oxa-3J-diaza-bicyclo[3.3.1 ]non-3-yl)-
231
methanone; LC-MS: tR = 0.80; [M+H]+ = 446.3
[7-(6-Fluoro-quinoxalin-2-yl)-9-oxa-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(2-fluoro-6-[1 ,2,3]tria
232
phenyl)-methanone; LC-MS: tR = 0.85; [M+H]+ = 464.3
[7-(6J-Difluoro-quinoxalin-2-yl)-9-oxa^
233
phenyl)-methanone; LC-MS: tR = 0.90; [M+H]+ = 482.3
[7-(7-Fluoro-quinoxalin-2-yl)-9-oxa-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(2-fluoro-6-[1 ,2,3]tn
234
phenyl)-methanone; LC-MS: tR = 0.85; [M+H]+ = 464.3
(2-Fluoro-6-[1 ,2,3]triazol-2-yl-phenyl)-[7-(8-methyl-quinoxalin-2-yl)-9-oxa-3,7-diaza-bicyclo[3.3
235
3-yl]-methanone; LC-MS: tR = 0.92; [M+H]+ = 460.4
(2-Fluoro-6-[1 ,2 ]triazol-2-yl-phenyl)-(7-quinazolin-2-yl-9-oxa-3J-diaza-bicyclo[3.3.1 ]non-3-yl)-
236
methanone; LC-MS: tR = 0.78; [M+H]+ = 446.0 [7-(7-Chloro-quinoxalin-2-yl)-9-oxa-37-diaza-bicyclo[3.3.1 ]non-3-yl]-(2-fluoro-6-[1 ,2,3]tra^
237
phenyl)-methanone; LC-MS: tR = 0.93; [M+H]+ = 480.3
[7-(6-Chloro-quinoxalin-2-yl)-9-oxa-3J-fe
238
phenyl)-methanone; LC-MS: tR = 0.93; [M+H]+ = 480.3
[7-(6J-Dichloro-quinoxalin-2-yl)-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl]-(2-fluoro-6-[1 ,2
239
phenyl)-methanone; LC-MS: tR = 1 .04; [M+H]+ = 514.3
(2-Methyl-6-[1 ,2,3]triazol-2-yl-phenyl)-(7-quinoxalin-2-yl-9-oxa-37-diaza-bicyclo[3.3.1]
240
methanone; LC-MS: tR = 0.86; [M+H]+ = 442.4
[7-(6-Fluoro-quinoxalin-2-yl)-9-oxa-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(2-methyl-6-[1 ,2,3]W
241
phenyl)-methanone; LC-MS: tR = 0.90; [M+H]+ = 460.4
[7-(6J-Difluoro-quinoxalin-2-yl)-9-oxa-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(2-methyl-6-[1 ,2,^
242
phenyl)-methanone; LC-MS: tR = 0.96; [M+H]+ = 478.3
[7-(7-Fluoro-quinoxalin-2-yl)-9-oxa-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(2-methyl-6-[1 ,2,3]tra
243
phenyl)-methanone; LC-MS: tR = 0.91 ; [M+H]+ = 460.4
[7-(8-Methyl-quinoxalin-2-yl)-9-oxa-3J-diaza-b^
244
phenyl)-methanone; LC-MS: tR = 0.98; [M+H]+ = 456.4
(2-Methyl-6-[1 ,2,3]triazol-2-yl-phenyl)-(7-quinazolin-2-yl-9-oxa-37-diaza-bicyclo[3.3.1]n
245
methanone; LC-MS: tR = 0.89; [M+H]+ = 442.0
[7-(7-Chloro-quinoxalin-2-yl)-9-oxa-37-diaza-bicyclo[3.3.1 ]non-3-yl]-(2-methyl-6-[1 ,2,3^
246
phenyl)-methanone; LC-MS: tR = 1 .0; [M+H]+ = 476.0
[7-(6-Chloro-quinoxalin-2-yl)-9-oxa-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(2-methyl-6-[1 ,2 ^
247
phenyl)-methanone; LC-MS: tR = 0.99; [M+H]+ = 476.3
[7-(6J-Dichloro-quinoxalin-2-yl)-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl]-(2-methyl-6-[1 ,^
248
yl-phenyl)-methanone; LC-MS: U = 1.1 ; [M+H]+ = 510.0
(2-Bromo-5-methoxy-phenyl)-[7-(6-chloro-benzothiazol-2-yl)-3J-diaza-bicyclo[3.3.1]non-3-yl]-
249
methanone; LC-MS: tR = 1.04; [M+H]+ = 506
(2-Bromo-5-methyl-phenyl)-[7-(6-chloro-benzothiazol-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-
250
methanone; LC-MS: tR = 1.08; [M+H]+ = 490.2
[7-(6-Chloro-benzothiazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(2,5-dimethyl-phenyl)-methanone;
251
LC-MS: tR = 1 .06; [M+H]+ = 426.3
[7-(6-Chloro-benzothiazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(2,5-dichloro-phenyl)-methanone;
252
LC-MS: tR = 1 .09; [M+H]+ = 466.2
[7-(6-Chloro-benzothiazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(5-chloro-2-methoxy-phenyl)-
253
methanone; LC-MS: tR = 1.02; [M+H]+ = 462.2 [7-(6-Chloro-benzothiazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(2,5-dimethoxy-phenyl)-m
254
LC-MS: tR = 0.95; [M+H]+ = 458.3
[7-(6-Chloro-benzothiazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(2-trifluoromethoxy-phenyl)-
255
methanone; LC-MS: tR = 1.07; [M+H]+ = 482.3
[7-(6-Chloro-benzothiazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(5-chloro-2-ethoxy-phenyl)-
256
methanone; LC-MS: tR = 1.08; [M+H]+ = 476.2
[7-(6-Chloro-benzothiazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(3-fluoro-2-propoxy-phenyl)-
257
methanone; LC-MS: U = 1.11 ; [M+H]+ = 474.3
[7-(6-Chloro-benzothiazol-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(2-ethoxy-phenyl)-methanone; LC-
258
MS: tR = 1 .0; [M+H]+ = 442.3
(2-Benzoyl-phenyl)-[7-(6-chloro-benzothiazol-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-methanone; LC-
259
MS: t« = 1 .03; [M+H]+ = 502.3
[7-(6-Chloro-benzothiazol-2-yl)-3J-dia2a-bicyclo[3.3.1 ]non-3-yl]-[2-(1 , 1 ,2,2-tetnafluoro-ethoxy)-
260
phenyl]-methanone; LC-MS: tR = 1 .08; [M+H]+ = 514.1
[7-(6-Chloro-benzothiazol-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-[2-(2-methoxy-ethoxy)-phenyl]-
261
methanone; LC-MS: tR = 0.95; [M+H]+ = 472.4
[7-(6-Chloro-benzothiazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(4-methyl-biphenyl-2-yl)-methanon
262
LC-MS: tR = 1 .24; [M+H]+ = 488.4
[7-(6-Methyl-[1 J]naphthyridin-8-yl)-3J^
263
phenyl)-methanone hydrochloride; LC-MS: tR = 0.67; [M+H]+ = 454.5
(5-Methyl-2-[1 ,2,3]triazol-2-yl-phenyl)-(7-thiazolo[5^-b]pyndin-2-yl-3,7-diaza-bicyclo[
264
methanone hydrochloride; LC-MS: tR = 0.86; [M+H]+ = 446.4
[7-(6-Fluoro-thiazolo[5^b]pyridin-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(5-methyl-2-[1 ,2,3]W
265
yl-phenyl)-methanone hydrochloride; LC-MS: tR = 0.98; [M+H]+ = 464.4
[7-(6J-Dichloro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1]non-3-yl]-[5-(3,4-dimethyl-phenyl)-2-methyl-
266
thiazol-4-yl]-methanone; LC-MS: tR = 1 .41 ; [M+H]+ = 552.4
[5-(2,3-Dichloro-phenyl)-2-methyl-thiazol-4-yl]-[7-(6,7-dichloro-quinoxalin-2-yl)-3,7-diaza-
267
bicyclo[3.3.1 ]non-3-yl]-methanone; LC-MS: tR = 1 .43; [M+H]+ = 592.2
(2-Cyclopropyl-5-m-tolyl-thiazol -yl)-[7-(6J-dichloro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1]non-3-
268
yl]-methanone; LC-MS: tR = 1 .45; [M+H]+ = 564.3
[7-(6J-Dichloro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1]non-3-yl]-[2-dimethylamino-5-(4-fluoro-
269
phenyl)-thiazol-4-yl]-methanone; LC-MS: tR = 1 .32; [M+H]+ = 571.3
[7-(6,7-Dichloro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-[5-(6-methoxy-pyridin-3-yl)-2-
270
methyl-thiazol-4-yl]-methanone; LC-MS: tR = 1 .25; [M+H]+ = 555.3 [7-(6,7-Dichloro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3 .1]non-3-yl]-[5-(4-fluoro-phenyl)-2-methyl-
271
thiazol-4-yl]-methanone; LC-MS: tR = 1 .31 ; [M+H]+ = 542.3
[7-(6,7-Dichloro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3 .1]non-3-yl]-(2-methyl-5-o-tolyl-thiazol-4-yl)-
272
methanone; LC-MS: tR = 1.36; [M+H]+ = 538.3
[7-(6J-Dichloro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1]non-3-yl]-[2-dimethylamino
273
methyl-phenyl)-thiazol-4-yl]-methanone; LC-MS: tR = 1 .4; [M+H]+ = 585.4
[5-(4-Chloro-phenyl)-2-methyl-thiazol-4-yl]-[7-(6,7-dichloro-quinoxalin-2-yl)-3,7-diaza-
274
bicyclo[3.3.1 ]non-3-yl]-methanone; LC-MS: tR = 1 .36; [M+H]+ = 558.3
(2-Cyclopropyl-5-phenyl-thiazol-4-yl)-[7-(6,7-dichloro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-
275
yl]-methanone; LC-MS: tR = 1 .4; [M+H]+ = 550.3
[7-(6,7-Dichloro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3 .1]non-3-yl]-[2-methyl-5-(3-trifluoromethyl-
276
phenyl)-thiazol-4-yl]-methanone; LC-MS: tR = 1 .38; [M+H]+ = 592.3
[5-(3-Chloro-phenyl) hiazol-4-yl]-[7-(6,7-dichloro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3 ]non-3-yl]-
277
methanone; LC-MS: tR = 1.3; [M+H]+ = 544.3
[7-(6,7-Dichloro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-[2-methyl-5-(4-trifluorometh
278
phenyl)-thiazol-4-yl]-methanone; LC-MS: tR = 1 .38; [M+H]+ = 592.4
[7-(6J-Dichloro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1]non-3-yl]-(2-methyl-4-p-tolyl-thia
279
methanone; LC-MS: tR = 1.33; [M+H]+ = 538.3
[7-(6J-Dichloro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1]non-3-yl]-[5-(3,5-difluoro-phenyl)-2-methyl-
280
thiazol-4-yl]-methanone; LC-MS: tR = 1 .33; [M+H]+ = 560.3
(2-Benzo[1 ,3]dioxol-5-yl-5-methyl-phenyl)-(7-benzothiazol-2-yl-3,7-diaza-bicyclo[3.3.1]non-3-yl)-
281
methanone; LC-MS: tR = 1.00; [M+H]+ = 498.4
(7-Benzothiazol-2-yl-3J-diaza-bicyclo[3.3.1 ]non-3-yl)-(3'-methoxy-4-methyl-biphenyl-2-yl)-
282
methanone; LC-MS: tR = 1.02; [M+H]+ = 484.4
(7-Benzothiazol-2-yl-3J-diaza-bicyclo[3.3.1 ]non-3-yl)-(2'-fluoro -methyl-biphenyl-2-yl)-methanone;
283
LC-MS: tR = 1 .03; [M+H]+ = 472.4
(7-Benzothiazol-2-yl-3J-diaza-bicyclo[3.3.1 ]non-3-yl)-(3'-fluoro -methyl-biphenyl-2-yl)-methanone;
284
LC-MS: tR = 1 .04; [M+H]+ = 472.4
(7-Benzothiazol-2-yl-3J-diaza-bicyclo[3.3.1 ]non-3-yl)-(4'-methoxy-4-methyl-biphenyl-2-yl)-
285
methanone; LC-MS: tR = 1.02; [M+H]+ = 484.4
(7-Benzothiazol-2-yl-3J-diaza-bicyclo[3.3.1 ]non-3-yl)-(4,3'-dimethyl-biphenyl-2-yl)-methanone; LC-
286
MS: U = 1 .07; [M+H]+ = 468.5
2'-(7-Benzothiazol-2-yl-3J-diaza-bicyclo[3.3.1 ]nonane-3-carbonyl)-4'-methyl-biphenyl -carbonitrile;
287
LC-MS: tR = 0.99; [M+H]+ = 479.4 (7-Benzothiazol-2-yl-3J-diaza-bicyclo[3.3.1 ]non-3^ LC-
288
MS: tR = 1 .12; [M+H]+ = 482.5
(7-Benzothiazol-2-yl-3J-diaza-bicyclo[3.3.1 ]non-3-yl)-(4'-ethoxy-4-methyl-biphenyl-2-yl)-methanone;
289
LC-MS: tR = 1 .08; [M+H]+ = 498.5
(4'-Chloro-4-methyl-biphenyl-2-yl)-[7-(6,7-difluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non
290
methanone; LC-MS: tR = 1.34; [M+H]+ = 519.4
(2-Benzo[1 ,3]dioxol-5-yl-5-methyl-phenyl)-[7-(6,7-difluoro-quinoxalin-2-yl)-3,7-diaza-
291
bicyclo[3.3.1 ]non-3-yl]-methanone; LC-MS: tR = 1 .25; [M+H]+ = 529.4
[7-(6J-Difluoro-quinoxalin-2-yl)-3J-diaza-
292
methanone; LC-MS: tR = 1.26; [M+H]+ = 515.5
[7-(6J-Difluoro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(4,2'-dimethyl-biphen
293
methanone; LC-MS: tR = 1.33; [M+H]+ = 499.5
[7-(6J-Difluoro-quinoxalin-2-yl)-3J-diaza-b^
294
methanone; LC-MS: tR = 1.28; [M+H]+ = 515.4
[7-(6J-Difluoro-quinoxalin-2-yl)-3J-diaza^
295
methanone; LC-MS: tR = 1.28; [M+H]+ = 503.4
[7-(6J-Difluoro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(4'-fluoro -methyl-biphenyl-2-yl)-
296
methanone; LC-MS: tR = 1.29; [M+H]+ = 503.4
[7-(6J-Difluoro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(3'-fluoro -methyl-biphenyl-2-yl)-
297
methanone; LC-MS: tR = 1.29; [M+H]+ = 503.4
[7-(6J-Difluoro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(4'-methoxy -methyl-biphenyl-2-yl)-
298
methanone; LC-MS: tR = 1.28; [M+H]+ = 515.4
[7-(6J-Difluoro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(4-methyl-4'-trifluoromethoxy-
299
biphenyl-2-yl)-methanone; LC-MS: tR = 1 .37; [M+H]+ = 569.4
2'-[7-(6,7-Difluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]nonane-3-carbonyl]-4'-methyl-biphenyl-3-
300
carbonitrile; LC-MS: tR = 1 .22; [M+H]+ = 510.4
[7-(6,7-Difluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(4,3'-dimethyl-biph
301
methanone; LC-MS: tR = 1.34; [M+H]+ = 499.4
[7-(6J-Difluoro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(4,4'-dimethyl-biphenyl-2-yl^
302
methanone; LC-MS: tR = 1.34; [M+H]+ = 499.4
2'-[7-(6,7-Difluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]nonane-3-carbonyl]-4'-methyl-biphenyl-4-
303
carbonitrile; LC-MS: tR = 1 .24; [M+H]+ = 510.4
[7-(6J-Difluoro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(2'-ethyl-4-methyl-biphenyl-2-yl)
304
methanone; LC-MS: tR = 1.38; [M+H]+ = 513.5 [7-(6J-Difluoro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(4,2 3'-trimethy^
305
methanone; LC-MS: tR = 1.37; [M+H]+ = 513.5
[7-(6J-Difluoro-quinoxalin-2-yl)-3J-diaza-
306
methanone; LC-MS: tR = 1.33; [M+H]+ = 529.4
(2-Benzo[1 ,3]dioxol-5-yl-5-methyl-phenyl)-[7-(6-chloro-benzothiazol-2-yl)-3,7-diaza-bicyclo[3.3.1]non-
307
3-yl]-methanone, LC-MS: tR = 1 .22; [M+H]+ = 532.3
[7-(6-Chloro-benzothiazol-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(3'-methoxy-4-methyl-biphenyl-2-yl)-
308
methanone; LC-MS: tR = 1.24; [M+H]+ = 518.4
[7-(6-Chloro-benzothiazol-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(2'-fluoro -methyl-biphenyl-2-yl)-
309
methanone; LC-MS: tR = 1.24; [M+H]+ = 506.4
[7-(6-Chloro-benzothiazol-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(3'-fluoro -methyl-biphenyl-2-yl)-
310
methanone; LC-MS: tR = 1.25; [M+H]+ = 506.4
[7-(6-Chloro-benzothiazol-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(4'-methoxy-4-methyl-biphenyl-2-yl)-
311
methanone; LC-MS: tR = 1.23; [M+H]+ = 518.4
[7-(6-Chloro-benzothiazol-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(4,3'-dimethyl-biphenyl-2-yl)-
312
methanone; LC-MS: tR = 1.29; [M+H]+ = 502.4
[7-(6-Chloro-benzothiazol-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(4,4'-dimethyl-biphenyl-2-yl)-
313
methanone; LC-MS: tR = 1.29; [M+H]+ = 502.4
[7-(6-Chloro-benzothiazol-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(4'-ethoxy-4-methyl-biphenyl-2-yl)-
314
methanone; LC-MS: tR = 1.29; [M+H]+ = 532.4
(2-Benzo[1 ,3]dioxol-5-yl-phenyl)-(7-benzothiazol-2-yl-3,7-diaza-bicyclo[3.3.1]non-3-yl)-methanone;
315
LC-MS: tR = 0.94; [M+H]+ = 484..4
(7-Benzothiazol-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-(3'-methoxy-biphenyl-2-yl)-methanone; LC-MS:
316
tR = 0.96; [M+H]+ = 470.4
(7-Benzothiazol-2-yl-3J-diaza-bicyclo[3.3.1 ]non-3-yl)-(2'-fluoro-biphenyl-2-yl)-methanone; LC-MS: tR
317
= 0.96; [M+H]+ = 458.4
(7-Benzothiazol-2-yl-3J-diaza-bicyclo[3.3.1 ]non-3-yl)-(3'-fluoro-biphenyl-2-yl)-methanone; LC-MS: tR
318
= 0.98; [M+H]+ = 458.4
(7-Benzothiazol-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-(4'-methoxy-biphenyl-2-yl)-methanone; LC-MS:
319
tR = 0.96; [M+H]+ = 470.4
(7-Benzothiazol-2-yl-3J-diaza-bicyclo[3.3.1 ]non-3-yl)-(3'-methyl-biphenyl-2-yl)-methanone; LC-MS:
320
tR = 1.01 ; [M+H]+ = 454.4
(7-Benzothiazol-2-yl-3J-diaza-bicyclo[3.3.1 ]non-3-yl)-(4'-ethoxy-biphenyl-2-yl)-methanone; LC-MS:
321
U = 1.02; [M+H]+ = 484.4 (2-Methyl-6-[1 ,2,3]triazol-2-yl-phenyl)-[7-(7-trifluoromethyl-quinoxalin-2-yl)-3J-diaza-
322
bicyclo[3.3.1 ]non-3-yl]-methanone; LC-MS: tR = 1 .19; [M+H]+ = 508.4
(4'-Fluoro-2'-methyl-biphenyl-2-yl)-(7-quinazolin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methanon
323
LC-MS: tR = 1 .2; [M+H]+ = 467.5
(3'-Fluoro-biphenyl-2-yl)-(7-quinazolin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone; LC-MS: tR =
324
1 .14; [M+H]+ = 453.5
(7-Quinazolin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-(3'-trifluoromethoxy-biphenyl-2-yl)-methanon
325
LC-MS: U = 1 .27; [M+H]+ = 519.4
(2'-Methoxy-biphenyl-2-yl)-(7-quinazolin-2-yl-3J-diaza-bicyclo[3.3.1]non-3-yl)-methanone; LC-MS: tR
326
= 1.08; [M+H]+ = 465.5
(2'-Methyl-biphenyl-2-yl)-(7-quinazolin-2-yl-3J-diaza-bicyclo[3.3.1]non-3-yl)-methanone; LC-MS: tR =
327
1 .18; [M+H]+ = 449.5
(7-Quinazolin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-(4'-trifluoromethoxy-biphenyl-2-yl)-methanon
328
LC-MS: tR = 1 .27; [M+H]+ = 519.4
(4 hloro-biphenyl-2-yl)-(7-quinazolin-2-yl-3J-diaza-bicyclo[3.3.1]non-3-yl)-methanone; LC-MS: tR =
329
1 .2; [M+H]+ = 469.4
(3'-Methoxy-biphenyl-2-yl)-(7-quinazolin-2-yl-3J-diaza-bicyclo[3.3.1]non-3-yl)-methanone; LC-MS: tR
330
= 1.12; [M+H]+ = 465.5
(3'-Methyl-biphenyl-2-yl)-(7-quinazolin-2-yl-3J-diaza-bicyclo[3.3.1]non-3-yl)-methanone; LC-MS: tR =
331
1 .19; [M+H]+ = 449.5
(4'-Methoxy-biphenyl-2-yl)-(7-quinazolin-2-yl-3J-diaza-bicyclo[3.3.1]non-3-yl)-methanone; LC-MS: tR
332
= 1.1 ; [M+H]+ = 465.5
(4'-Methyl-biphenyl-2-yl)-(7-quinazolin-2-yl-3J-diaza-bicyclo[3.3.1]non-3-yl)-methanone; LC-MS: tR =
333
1 .19; [M+H]+ = 449.5
2'-(7-Quinazolin-2-yl-3,7-diaza-bicyclo[3.3.1 ]nonane-3-carbonyl)-biphenyl-4-carbonitrile; LC-MS: tR =
334
1 .06; [M+H]+ = 460.5
(3 4'-Dichloro-biphenyl-2-yl)-(7-quinazolin-2-yl-3J-diaza-bicyclo[3.3.1 ]non-3-yl)-methano LC-MS:
335
U = 1.28; [M+H]+ = 503.4
(2'-Fluoro-biphenyl-2-yl)-(7-quinazolin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone; LC-MS: tR =
336
1 .12; [M+H]+ = 453.5
(7-Quinazolin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-(3'-trifluoromethyl-biphenyl-2-yl)-methanone; LC-
337
MS: tR = 1 .24; [M+H]+ = 503.4
(2 3'-Dimethyl-biphenyl-2-yl)-(7-quinazolin-2-yl-3J-diaza-bicyclo[3.3.1 ]non-3-yl)-meth^ LC-MS:
338
tR = 1.24; [M+H]+ = 463.5 (2 -Ethyl-bi phenyl-2-yl)-(7-qu inazolin-2-yl-3, 7-diaza-bic clo[3.3.1] non-3-yl)-methanone; LC-MS: tR = 1 .25; [M+H]+ = 463.5
(2-Benzo[1 ]dioxol-5-yl-phenyl)-(7-quinazolin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methanon; LC- MS: t« = 1 .08; [M+H]+ = 479.4
(4'-Ethoxy-biphenyl-2-yl)-(7-quinazolin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone; LC-MS: tR = 1 .19; [M+H]+ = 479.5
(7-Benzothiazol-2-yl-3J-diaza-bicyclo[3.3.1 ]non-3-yl)-(4-methyl-biphenyl-2-yl)-me LC-MS: tR = 1.02; [M+H]+ = 454.5
[7-(6-Fluoro-benzothiazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(4-methyl-biphenyl-2-yl)-methanone; LC-MS: tR = 1 .14; [M+H]+ = 472.4
[7-(6-Fluoro-benzothiazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(5-methyl-2-pyridin-2-yl-phenyl)- methanone; LC-MS: tR = 0.85; [M+H]+ = 473.4
[7-(6-Chloro-benzothiazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(5-methyl-2-pyridin-2-yl-phenyl)- methanone; LC-MS: tR = 0.94; [M+H]+ = 489.4
[7-(6-Chloro-benzothiazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(4-methyl-biphenyl-2-yl)-methanon LC-MS: tR = 1 .24; [M+H]+ = 488.4
[7-(5-Chloro-benzooxazol-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(4-methyl-biphenyl-2-yl)-methanone; LC-MS: tR = 1 .23; [M+H]+ = 472.4
[7-(6-Fluoro-benzothiazol-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(5-methyl-2-pyrimidin-2-yl- methanone; LC-MS: tR = 0.95; [M+H]+ = 474.4
[7-(6-Chloro-benzothiazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(5-methyl-2-pyrimidin-2-yl-phenyl)^ methanone; LC-MS: tR = 1.06; [M+H]+ = 490.4
(5-Methyl-biphenyl-2-yl)-[7-(4 rifluoromethyl-pyrimidin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-y methanone; LC-MS: tR = 1.32; [M+H]+ = 467.4
(2-Methyl-5-o-tolyl-thiazol-4-yl)-[7-(4-trifluoromethyl-pyrimidin-2-yl)-3J-diaza-bicyclo[3.3.1]non-3-yl]- methanone; LC-MS: tR = 1.27; [M+H]+ = 488.4
[5-(2,3-Dichloro-phenyl)-2-methyl-thiazol-4-yl]-[7-(4-trifluoromethyl-pyrimidin-2-yl)-3J-diaza- bicyclo[3.3.1 ]non-3-yl]-methanone; LC-MS: tR = 1 .35; [M+H]+ = 542.3
[5-(3,4-Dimethyl-phenyl)-2-methyl-thiazol-4-yl]-[7-(4-trifluoromethyl-pyrimidin-2-yl)-3J-diaza- bicyclo[3.3.1 ]non-3-yl]-methanone; LC-MS: tR = 1 .31 ; [M+H]+ = 502.4
[5-(3-Methoxy-phenyl)-2-methyl-thiazol -yl]-[7-(4-trifluoromethyl-pyrimidin-2-yl)-3J-diaza- bicyclo[3.3.1 ]non-3-yl]-methanone; LC-MS: tR = 1 .21 ; [M+H]+ = 504.4
[7-(4,6-Dimethyl-pyrimidin-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(4-methyl-biphenyl-2-yl)-methanone; LC-MS: tR = 1 .12; [M+H]+ = 427.5 II. BIOLOGICAL ASSAYS
Antagonistic activities on both orexin receptors have been measured for each example compound using the following procedure:
In vitro assay: Intracellular calcium measurements:
Chinese hamster ovary (CHO) cells expressing the human orexin-1 receptor and the human orexin-2 receptor, respectively, are grown in culture medium (Ham F-12 with L-Glutamine) containing 300 μg/mL G418, 100 U/mL penicillin, 100 μg/mL streptomycin and 10 % heat inactivated fetal calf serum (FCS). The cells are seeded at 20Ό00 cells / well into 384-well black clear bottom sterile plates (Greiner). The seeded plates are incubated overnight at 37 °C in 5 % C02.
Human orexin-A as an agonist is prepared as 1 mM stock solution in MeOH: water (1 :1 ), diluted in HBSS containing 0.1 % bovine serum albumin (BSA), NaHC03: 0.375g/l and 20 mM HEPES for use in the assay at a final concentration of 3 nM.
Antagonists are prepared as 10 mM stock solution in DMSO, then diluted in 384-well plates using DMSO followed by a transfer of the dilutions into in HBSS containing 0.1 % bovine serum albumin (BSA), NaHC03: 0.375g/l and 20 mM HEPES. On the day of the assay, 50 μΙ of staining buffer (HBSS containing 1 % FCS, 20 mM HEPES, NaHC03: 0.375g/l, 5 mM probenecid (Sigma) and 3 μΜ of the fluorescent calcium indicator fluo-4 AM (1 mM stock solution in DMSO, containing 10 % pluronic) is added to each well. The 384-well cell-plates are incubated for 50 min at 37 °C in 5 % C02 followed by equilibration at RT for 30 min before measurement.
Within the Fluorescent Imaging Plate Reader (FLIPR Tetra, Molecular Devices), antagonists are added to the plate in a volume of 10 μΙ/well, incubated for 120 min and finally 10 μΙ/well of agonist is added. Fluorescence is measured for each well at 1 second intervals, and the height of each fluorescence peak is compared to the height of the fluorescence peak induced by 3 nM orexin-A with vehicle in place of antagonist. The IC50 value (the concentration of compound needed to inhibit 50 % of the agonistic response) is determined and may be normalized using the obtained IC50 value of a on-plate reference compound. Optimized conditions were achieved by adjustment of pipetting speed and cell splitting regime. The calculated IC50 values may fluctuate depending on the daily cellular assay performance. Fluctuations of this kind are known to those skilled in the art. Antagonistic activities of example compounds with respect to the OX1 receptor are displayed in Table 1.
Table 1
IC50 OX1 IC50 OX1 IC50 OX1 IC50 OX1
Example Example Example Example
[nM] [nM] [nM] [nM]
1 8 66 237 131 13 196 106
2 29 67 34 132 16 197 3
3 9 68 68 133 86 198 49
4 26 69 745 134 45 199 57
5 2 70 221 135 13 200 6
6 3 71 19 136 1 13 201 44
7 91 72 9 137 3 202 92
8 95 73 3 138 19 203 28
9 85 74 2 139 4 204 77
10 35 75 4 140 2 205 37
11 8 76 3 141 2 206 413
12 27 77 1 142 7 207 186
13 40 78 3 143 1 208 998
14 10 79 4 144 5 209 43
15 68 80 1 145 2 210 367
16 18 81 3 146 28 211 1001
17 2 82 3 147 7 212 241
18 2 83 1 148 9 213 637
19 20 84 2 149 31 214 600
20 17 85 5 150 2 215 1510
21 135 86 2 151 21 216 9
22 12 87 2 152 18 217 88
23 3 88 3 153 8 218 77
24 45 89 3 154 10 219 51
25 735 90 2 155 2 220 287
26 1 1 1 91 2 156 3 221 105
27 15 92 0.4 157 2 222 241
28 10 93 1 158 2 223 124
29 5 94 1 159 3 224 900
30 19 95 1 160 28 225 38 48 96 0.4 161 1 226 275
240 97 1 162 3 227 145
38 98 1 163 2 228 1270
15 99 0.4 164 19 229 324
25 100 1 165 6 230 328
155 101 1 166 37 231 175
194 102 2 167 16 232 79
132 103 1 168 3 233 48
27 104 2 169 5 234 171
219 105 1 170 16 235 17
135 106 1 171 2 236 94
28 107 0.4 172 64 237 142
42 108 1 173 76 238 150
136 109 6 174 4 239 9
22 110 5 175 12 240 62
27 111 3 176 13 241 50
231 112 1 177 1 242 43
276 113 5 178 1 243 92
28 114 2 179 12 244 8
37 115 1 180 8 245 33
12 116 3 181 8 246 34
42 117 3 182 10 247 107
18 118 3 183 3 248 15
37 119 2 184 6 249 1270
396 120 2 185 1 1 250 539
88 121 1 186 1 251 1790
23 122 2 187 1 1 252 1770
458 123 0.3 188 2 253 1350
345 124 3 189 4 254 1070
13 125 2 190 5 255 1270
3 126 25 191 2 256 784
3 127 7 192 143 257 677
384 128 19 193 13 258 1 17
29 129 24 194 53 259 1480
74 130 1 195 19 260 339
1 120 262 21 263 21 264 27 265 19 266 5 267 7 268 26
269 8 270 4 271 4 272 0.6
273 26 274 6 275 7 276 20
277 22 278 57 279 4 280 1.6
281 8.8 282 2 283 4 284 8
285 4 286 19 287 25 288 14
289 1 1 290 22 291 1.7 292 5
293 4.5 294 2 295 1.4 296 13
297 2 298 3.6 299 20 300 1 1
301 3 302 6 303 1.2 304 16
305 7.5 306 5.4 307 5 308 4
309 5.7 310 12 311 3 312 25
313 20 314 21 315 9 316 4.8
317 8 318 19 319 1 1 320 1 1
321 29 322 7 323 28 324 1
325 23 326 3 327 3 328 19
329 29 330 0.5 331 1 332 1
333 4 334 17 335 17 336 0.6
337 17 338 3 339 6.7 340 1
341 1 342 7 343 6 344 1 1
345 18 346 24 347 15 348 30
349 29 350 14 351 17 352 1 1
353 1 1 354 23 355 35
Antagonistic activities of example compounds with respect to the OX2 receptor are displayed in Table 2.
Table 2
IC50 OX2 IC50 OX2 IC50 OX2 IC50 OX2
Example Example Example Example
[nM] [nM] [nM] [nM]
1 484 66 4670 131 366 196 1500
2 1240 67 3940 132 519 197 >5620
3 782 68 2880 133 5280 198 1050
4 1080 69 >7580 134 533 199 669
5 177 70 1420 135 266 200 124
6 152 71 1280 136 7910 201 1630 1 170 72 938 137 60 202 1070
1400 73 2010 138 410 203 1 130
760 74 33 139 901 204 1220
1 150 75 350 140 93 205 1840
919 76 170 141 699 206 3260
907 77 12 142 378 207 986
1260 78 226 143 297 208 2740
1720 79 1 17 144 668 209 5333
5370 80 85 145 1400 210 >8020
3060 81 57 146 >3673 211 >8020
1350 82 69 147 721 212 >8020
199 83 5 148 >2250 213 >8020
1710 84 120 149 1950 214 >8020
352 85 185 150 794 215 >8020
1710 86 168 151 2830 216 2504
524 87 38 152 >5690 217 2064
386 88 59 153 410 218 >8020
1630 89 137 154 431 219 >8020
>7510 90 15 155 181 220 7590
>10000 91 80 156 63 221 >8020
363 92 15 157 57 222 3770
1280 93 173 158 98 223 >7064
937 94 29 159 368 224 >7064
1350 95 99 160 471 225 3880
1330 96 14 161 26 226 3440
1670 97 97 162 53 227 >7580
333 98 195 163 56 228 >7580
564 99 12 164 269 229 5290
512 100 86 165 334 230 4590
2400 101 37 166 1460 231 5220
12700 102 88 167 1210 232 1840
2830 103 53 168 218 233 879
381 104 167 169 75 234 1670
1 180 105 124 170 456 235 386
3640 106 99 171 92 236 2930
1 140 107 127 172 743 237 4480 1443 108 18 173 984 238 5410
1790 109 534 174 132 239 1450
1756 110 81 175 837 240 4020
1580 111 772 176 301 241 1550
>6870.2 112 35 177 160 242 519
1340 113 65 178 60 243 1860
1083 114 88 179 1 150 244 94
1290 115 29 180 1240 245 2480
1400 116 129 181 425 246 3837
3930 117 >7810 182 1350 247 4520
1282 118 >3150 183 429 248 1670
1633 119 1060 184 914 249 >7510
1410 120 88 185 551 250 3650
5800 121 >7790 186 659 251 3090
2220 122 163 187 833 252 3120
71 10 123 168 188 463 253 1990
1320 124 150 189 188 254 2260
1000 125 91 1 190 993 255 2160
473 126 1210 191 255 256 1380
755 127 194 192 1430 257 1620
>7580 128 1798 193 684 258 975
3220 129 629 194 >5620 259 579
1550 130 336 195 857 260 1289
1950 262 314 263 688 264 1220
944 266 141 267 324 268 765
1 140 270 285 271 638 272 130
159 274 424 275 221 276 382
842 278 1 180 279 346 280 555
690 282 235 283 768 284 697
506 286 1750 287 1800 288 474
1290 290 9090 291 38 292 519
305 294 12 295 46 296 9270
97 298 79 299 3780 300 708
122 302 2020 303 163 304 413
165 306 437 307 1 13 308 49
278 310 105 311 70 312 636 313 269 314 315 315 483 316 1 15
317 242 318 626 319 544 320 303
321 297 322 718 323 579 324 72
325 355 326 472 327 175 328 429
329 5310 330 29.1 331 56 332 429
333 284 334 2150 335 638 336 55
337 302 338 48 339 109 340 61
341 75 342 1 120 343 549 344 1840
345 745 346 440 347 604 348 135
349 862 350 445 351 989 352 100
353 314 354 473 355 836
Measurement of brain and systemic concentration after oral administration:
In order to assess brain penetration, the concentration of the compound is measured in plasma ([P]), and brain ([B]), sampled 3 h (or at different time points) following oral administration (100 mg/kg) to male wistar rats. The compounds are formulated in 100% PEG 400. Samples are collected in the same animal at the same time point (+/- 5 min). Blood is sampled from the vena cava caudalis into containers with EDTA as anticoagulant and centrifuged to yield plasma. Brain is sampled after cardiac perfusion of 10 mL NaCI 0.9% and homogenized into one volume of cold phosphate buffer (pH 7.4). All samples are extracted with MeOH and analyzed by LC-MS/MS. Concentrations are determined with the help of calibration curves.

Claims

Claims
1. A compound of formula (I)
Figure imgf000097_0001
Formula (I)
wherein
X represents CH2 or O;
• Ar1 represents phenyl or 5- or 6-membered heteroaryl, wherein said phenyl or 5- or 6- membered heteroaryl independently is mono-, di-, or tri-substituted; wherein
> one of said substituents is attached in orffro-position to the point of attachment of Ar1 to the rest of the molecule; wherein said substituent is phenyl or 5- or 6- membered heteroaryl; wherein said phenyl or 5- or 6-membered heteroaryl substituent is independently unsubstituted, mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl,
Figure imgf000097_0002
halogen, cyano, (Ci-3)fluoroalkyl, and (C1-3)fluoroalkoxy; or said substituent is a benzo[1 ,3]dioxolyl group;
> and the other of said substituents, if present, is/are independently selected from the group consisting of (d-4)alkyl, (Ci-4)alkoxy, (C3-6)cycloalkyl, halogen, cyano, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, and -NR4R5, wherein R4 and R5 are independently selected from hydrogen and (C1-4)alkyl;
• or Ar1 represents phenyl which is mono-, di-, or tri-substituted; wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl; (Ci-4)alkoxy; halogen; cyano; (Ci-3)fluoroalkyl; (Ci-3)fluoroalkoxy; (Ci-3)alkoxy- (C1-4)alkoxy; and benzoyl;
and
Ar2 represents 5- to 10-membered heteroaryl which is unsubstituted, or mono-, di-, or tri- substituted; wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, (C3-6)cycloalkyl, halogen, cyano, (C1-3)fluoroalkyl, and (C1-3)fluoroalkoxy;
or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 ; wherein
X represents CH2 or O;
Ar1 represents 5-membered heteroaryl, wherein the 5-membered heteroaryl is mono- or di- substituted; wherein
> one of said substituents is attached in orffro-position to the point of attachment of Ar1 to the rest of the molecule; wherein said orffro-substituent is phenyl which is unsubstituted, mono-, di-, or tri-substituted, wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl, (Ci-4)alkoxy, halogen, cyano, (C1-3)fluoroalkyl, and (C1-3)fluoroalkoxy;
> and the other of said substituents, if present, is/are independently selected from the group consisting of (Ci-4)alkyl, (Ci-4)alkoxy, (C3-6)cycloalkyl, halogen, cyano, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, and -NR4R5, wherein R4 and R5 are independently selected from hydrogen and (C1-4)alkyl; or Ar1 represents 6-membered heteroaryl, wherein the 6-membered heteroaryl is mono-, di-, or tri-substituted; wherein
> one of said substituents is attached in orffro-position to the point of attachment of Ar1 to the rest of the molecule; wherein
said orffro-substituent is unsubstituted 5-membered heteroaryl;
or said orffro-substituent is phenyl which is unsubstituted or mono-substituted, wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, and halogen;
> and the other of said substituents, if present, is/are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, (C3-6)cycloalkyl, halogen, cyano, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, and -NR4R5, wherein R4 and R5 are independently selected from hydrogen and (C1-4)alkyl; or Ar1 represents phenyl which is mono-, di-, or tri-substituted; wherein
> one of said substituents is attached in orffro-position to the point of attachment of Ar1 to the rest of the molecule; wherein
said orffro-substituent is phenyl which is unsubstituted, or mono-, or di- substituted; wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl, (Ci-4)alkoxy, halogen, cyano, (Ci-3)fluoroalkyl, and (C1-3)fluoroalkoxy;
or said orffro-substituent is unsubstituted or mono-substituted 5- or 6-membered heteroaryl wherein the substituent is (C1-4)alkyl;
or said substituent is a benzo[1 ,3]dioxolyl group; > and the other of said substituents, if present, is/are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, cyano, (C1-3)fluoroalkyl, and (Ci-3)fluoroalkoxy.
and
Ar2 represents 5- to 10-membered heteroaryl which is unsubstituted, or mono-, or di- substituted; wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, and (C1-3)fluoroalkyl; or a pharmaceutically acceptable salt thereof.
3. A compound according to claims 1 or 2; wherein X represents CH2;
or a pharmaceutically acceptable salt thereof.
4. A compound according to claims 1 or 2; wherein X represents O;
or a pharmaceutically acceptable salt thereof.
5. A compound according to any one of claims 1 to 4; wherein Ar1 is a group selected from the group consisting of the following groups:
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
or a pharmaceutically acceptable salt thereof.
6. A compound according to any one of claims 1 to 5; wherein
• Ar2 represents 8- to 10-membered heteroaryl which is unsubstituted, or mono-, di-, or tri-substituted; wherein the substituents are independently selected from the group consisting of (Ci-4)alkyl, (Ci-4)alkoxy, (C3-6)cycloalkyl, halogen, cyano, (d-3)fluoroalkyl, and (C1-3)fluoroalkoxy;
• or Ar2 represents 5- or 6-membered monocyclic heteroaryl which is unsubstituted, or mono-, di-, or tri-substituted; wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, (C3-6)cycloalkyl, halogen, cyano, (Ci-3)fluoroalkyl, and (Ci-3); or a pharmaceutically acceptable salt thereof.
7. A compound according to any one of claims 1 to 6; wherein
• in case Ar2 represents 8- to 10-membered heteroaryl, said heteroaryl is a group selected from benzoxazolyl, benzothiazolyl, quinazolinyl, quinoxalinyl, thiazolo[5,4- b]pyridinyl, and [1 ,7]naphthyridinyl; which groups independently are unsubstituted, or mono-, or di-substituted; wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, and (C1-3)fluoroalkyl; and / or
• in case Ar2 represents 5- or 6-membered heteroaryl, said heteroaryl is pyrimidinyl, which is unsubstituted, or mono-, or di-substituted; wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, and (Ci-3)fluoroalkyl; or a pharmaceutically acceptable salt thereof.
8. A compound according to any one of claims 1 to 6; wherein,
• in case Ar2 represents 8- to 10-membered heteroaryl, said heteroaryl is selected from the group consisting of benzoxazol-2-yl, 5-chloro-benzoxazol-2-yl, benzothiazol-2-yl, 6-chloro-benzothiazol-2-yl, 6-fluoro-benzothiazol-2-yl, quinazolin-2-yl, quinoxalin-2-yl, 6-chloro-quinoxalin-2-yl, 7-chloro-quinoxalin-2-yl, 6-fluoro-quinoxalin-2-yl, 7-fluoro- quinoxalin-2-yl, 6,7-dichloro-quinoxalin-2-yl, 6,7-difluoro-quinoxalin-2-yl, 6-methyl- quinoxalin-2-yl, 7-methyl-quinoxalin-2-yl, 8-methyl-quinoxalin-2-yl, 6,7-dimethyl- quinoxalin-2-yl, 7-fluoro-6-methyl-quinoxalin-2-yl, 6-fluoro-7-methyl-quinoxalin-2-yl, 6- methoxy-quinoxalin-2-yl, 7-methoxy-quinoxalin-2-yl, 7-fluoro-6-methoxy-quinoxalin-2- yl, 6-trifluoromethyl-quinoxalin-2-yl, 7-trifluoromethyl-quinoxalin-2-yl, thiazolo[5,4- b]pyridin-2-yl, 6-fluoro-thiazolo[5,4-b]pyridin-2-yl, and 6-methyl-[1 ,7]naphthyridin-8-yl; and / or
• in case Ar2 represents 5-or 6-membered heteroaryl, said heteroaryl is selected from the group consisting of 5-bromo-pyrimidin-2-yl, 5-ethyl-pyrimidin-2-yl, 4- trifluoromethyl-pyrimidin-2-yl, 5-trifluoromethyl-pyrimidin-2-yl, 4,6-dimethoxy- pyrimidin-2-yl, and 4,6-dimethyl-pyrimidin-2-yl; or a pharmaceutically acceptable salt thereof.
9. A compound according to claim 1 selected from the group consisting of:
[7-(5-Chloro-benzooxazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(5-methyl-2-[1 ,2,3]triazol-2-yl-phenyl)- methanone;
[7-(6-Fluoro-benzothiazol-2-yl)-W
methanone;
[7-(6-Chloro-benzothiazol-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(5-methyl-2-[1 ,2 ]triazo
methanone;
(5-Methyl-2-[1 ,2,3]triazol-2-yl-phenyl)-[7-( -trifluoromethyl-pyrimi
methanone;
(2-Methyl-5-o-tolyl-thiazol-4-yl)-(7-quinoxalin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone;
[2-Dimethylamino-5-(3-fluoro-4-methyl-phenyl)-thiazol-4-yl]-(7-quinoxalin-2-yl-3,7-diaza-bi
methanone;
[5-(3-Methoxy-phenyl)-2-methyl-thiazol-4-yl]-(7-quinoxalin-2-yl-3,7-diaza-bicyclo[3.3.1]non-3-yl)-methanone;
[5-(3,5-Difluoro-phenyl)-2-methyl-thiazo
Biphenyl-2-yl-[7-(4-trifluoromethyl-pyrimidin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-m
(4-Methyl-biphenyl-2-yl)-[7-(4-trifluoromethyl-pyrimidin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]n
(7-Benzothiazol-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-biphenyl-2-yl-methanone;
[7-(6,7-Difluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-(2-fluoro-6-[1 ,2,3]triazol-2-yl-phenyl)-methanone; (2-Fluoro-6-[1 ,2,3]triazol-2-yl-phenyl)-(7-quinoxalin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone;
(2-Fluoro-6-[1 ,2,3]triazol-2-yl-phenyl)-(7-quinazolin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone;
(2-Fluoro-6-[1 ,2,3]triazol-2-yl-phenyl)-[7-(8-methyl-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-methanone;
[7-(7-Chloro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-(2-fluoro-6-[1 ,2,3]triazol-2-yl-phenyl)-methanone;
[7-(6-Chloro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-(2-fluoro-6-[1 ,2,3]triazol-2-yl-phenyl)-methanone;
[7-(6J-Dichloro-quinoxalin-2-yl)-3J-diaza-b^
methanone;
[7-(6-Fluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(2-fluoro-6-[1 ,2,3]triazol-2-yl-phenyl)-methanone;
[7-(7-Fluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(2-fluoro-6-[1 ,2,3]triazol-2-yl-phenyl)-methanone;
[7-(8-Methyl-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-(2-methyl-6-[1 ,2,3]triazol-2-yl-phenyl)-methanone;
[7-(7-Chloro-quinoxalin-2-yl)-3 -diaza-bicyclo[3.3.1]non-3-yl]-(2-methyl-6-[1 ,2,3]triazol-2-yl-phenyl)-methan [7-(6-Chloro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-(2-methyl-6-[1 ,2,3]triazol-2-yl-phenyl)-methanone;
[7-(6J-Dichloro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1]non-3-yl]-(2-methyl-6-[1 ,2,3]
methanone;
[7-(6-Fluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(2-methyl-6-[1 ,2,3]triazol-2-yl-phenyl)-methanone;
[7-(7-Fluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(2-methyl-6-[1 ,2,3]triazol-2-yl-phenyl)-methanone; (2-Methyl-6-[1 ,2,3]triazol-2-yl-phenyl)-(7-quinoxalin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone;
[7-(6,7-Difluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3 .1 ]non-3-yl]-(2-methyl-6-[1 ,2,3]tri
methanone;
(2-Methyl-6-[1 ,2,3]triazol-2-yl-phenyl)-(7-quinazolin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone;
[7-(8-Methyl-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-(5-methyl-2-[1 ,2,3]triazol-2-yl-phenyl)-methanone;
[7-(7-Chloro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-(5-methyl-2-[1 ,2,3]triazol-2-yl-phenyl)-methanone;
[7-(6-Chloro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-(5-methyl-2-[1 ,2,3]triazol-2-yl-phenyl)-methanone;
[7-(6,7-Dichloro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3 .1]non-3-yl]-(5-methyl-2-[1 ,2,3]tri
methanone;
[7-(6-Fluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-(5-methyl-2-[1 ,2,3]triazol-2-yl-phenyl)-methanone;
[7-(7-Fluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(5-methyl-2-[1 ,2,3]triazol-2-yl-phenyl)-methanone; (5-Methyl-2-[1 ,2,3]triazol-2-yl-phenyl)-(7-quinoxalin-2-yl-3,7-diaza-bicyclo[3.3.1]non-3-yl)-methanone;
[7-(6,7-Difluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3 .1 ]non-3-yl]-(5-methyl-2-[1 ,2,3]triaz
methanone;
(5-Methyl-2-[1 ,2,3]triazol-2-yl-phenyl)-(7-quinazolin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone;
(4-Methyl-biphenyl-2-yl)-[7-(8-methyl-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1]non-3-yl]-methanone;
[7-(6-Chloro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1]non-3-yl]-(4-methyl-biphenyl-2-yl)-methanone;
[7-(6-Fluoro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(4-methyl-biphenyl-2-yl)-methanone;
[7-(7-Fluoro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(4-methyl-biphenyl-2-yl)-methanone;
(4-Methyl-biphenyl-2-yl)-(7-quinoxalin-2-yl-3J-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone;
[7-(6J-Difluoro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(4-methyl-biphenyl-2-yl)-methanone;
(4-Methyl-biphenyl-2-yl)-(7-quinazolin-2-yl-3J-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone;
Biphenyl-2-yl-[7-(8-methyl-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-methanone;
Biphenyl-2-yl-[7-(7-chloro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1]non-3-yl]-methanone;
Biphenyl-2-yl-[7-(6-chloro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1]non-3-yl]-methanone;
Biphenyl-2-yl-[7-(6,7-dichloro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-methanone;
Biphenyl-2-yl-[7-(6-fluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-methanone;
Biphenyl-2-yl-[7-(7-fluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-methanone;
Biphenyl-2-yl-(7-quinoxalin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone;
Biphenyl-2-yl-[7-(6,7-difluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-methanone;
Biphenyl-2-yl-(7-quinazolin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone;
[7-(6J-Dichloro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1]non-3-yl]-(4-methyl-biphenyl-2-yl)-methanone; [7-(7-Chloro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3 .1]non-3-yl]-(4-methyl-biphenyl-2-yl)-methanone;
(5-Methyl-2-pyrazol-1 -yl-phenyl)-(7-quinoxalin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone;
[7-(6,7-Difluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3 .1 ]non-3-yl]-(5-methyl-2-pyrazol-1 -yl-phenyl)-m
[7-(7-Chloro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1]non-3-yl]-(5-methyl-2-pyrazol-1 -yl-phen
[7-(6-Chloro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1]non-3-yl]-(5-methyl-2-pyrazol-1 -yl-phenyl)-m
[7-(6J-Dichloro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1]non-3-yl]-(5-methyl-2-pyrazol-1 -yl-phen
[7-(6-Fluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(5-methyl-2-pyrazol-1-yl-phenyl)-methanone;
(5-Methyl-2-pyrazol-1 -yl-phenyl)-(7-quinazolin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone;
[7-(6,7-Difluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3 .1 ]non-3-yl]-(2-pyrazol-1-yl-phenyl)-methanone;
[7-(6,7-Dichloro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-(2-pyrazol-1 -yl-phenyl)-methanone;
[7-(5-Chloro-benzooxazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-[2-dimethylamino-5-(3,4-dimethyl-phe
4-yl]-methanone;
(6-Methyl-3-[1 ,2,3]triazol-2-yl-pyridin-2-yl)-(7-quinoxalin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methan
[7-(6J-Difluoro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(6-methyl-3-[1 ,2 ]tria
methanone;
[7-(7-Chloro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3 .1]non-3-yl]-(6-methyl-3-[1 ,2,3]triazol-^^
methanone;
[7-(6-Chloro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1]non-3-yl]-(6-methyl-3-[1 ,2 ]triazol-2^
methanone;
[7-(6,7-Dichloro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-(6-methyl-3-[1 ,2,3]triaz^
methanone;
[7-(6-Fluoro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(6-methyl-3-[1 ,2 ]triazol-2-yl-pyh^
methanone;
(6-Methyl-3-[1 ,2,3]triazol-2-yl-pyridin-2-yl)-(7-quinazolin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methan
[7-(6,7-Difluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(6-methyl-3-pyrazol-1 -yl-pyridin-2-yl)- methanone;
[7-(7-Chloro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1]non-3-yl]-(6-methyl-3-pyrazol-1 -yl-pyridin-2-yl)-meth
[7-(6,7-Dichloro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-(6-methyl-3-pyrazol-1 -yl-pyridin-2-yl)- methanone;
[7-(7-Fluoro-6-methoxy-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(5-methyl-2-[1 ,2,3]triazol-2-yl-p methanone;
[7-(6-Methoxy-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(5-methyl-2-[1 ,2,3]triazol-2-yl-phenyl)-methanone;
[7-(7-Methoxy-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(5-methyl-2-[1 ,2,3]triazol-2-yl-phenyl)-methanone;
[7-(6-Methyl-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1]non-3-yl]-(5-methyl-2-[1 ,2 ]triazol-2-yl-phenyl)-m
[7-(7-Fluoro-6-methyl-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1]non-3-yl]-(5-methyl-2-[1 ,2 ]triazo^
methanone;
[7-(7-Methyl-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1]non-3-yl]-(5-methyl-2-[1 ,2 ]triazol-2-yl-phenyl)-metha 5-Methyl-2-[1 ,2 ]triazol-2-yl-phenyl)-[7-(7-trifluoromethyl-quinoxalin-2-yl)-3J-d
methanone;
7-(6-Fluoro-7-methyl-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-(5-methyl-2-[
methanone;
7-(6,7-Difluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3 .1 ]non-3-yl]-[5-(3^-dimethyl-phenyl)-2-met
methanone;
5-(2,3-Dichloro-phenyl)-2-methyl-thiazol-4-yl]-[7-(6,7-difluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3
methanone;
7-(6,7-Difluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3 .1 ]non-3-yl]-[2-dimethylamino-5-(4-fluoro^
yl]-methanone;
7-(6J-Difluoro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(2-methyl-5-o-tolyl-thiazol -yl)-m
7-(6,7-Difluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-[2-dimethylamino-5-(3-fluoro^
hiazol-4-yl]-methanone;
7-(6,7-Difluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-[5-(3-methoxy-phenyl)-2-methyl-^
methanone;
7-(6J-Difluoro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(2-methyl-5-p-tolyl-thiazol -yl)-metha
5-(3,4-Dimethyl-phenyl)-2-methyl-thiazol-4-yl]-(7-quinoxalin-2-yl-3J-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone;
5-(2,3-Dichloro-phenyl)-2-methyl-thiazol-4-yl]-(7-quinoxalin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-m
7-Benzothiazol-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-(5-methyl-2-[1 ,2,3]triazol-2-yl-phenyl)-methanone;
7-(6-Chloro-benzothiazol-2-yl)-3J-diaza-bicyclo[3.^^
2-Dimethylamino-5-(4-fluoro-phenyl)-thiazol-4-yl]-(7-quinoxalin-2-yl-3,7-diaza-bicyclo[3.3.1 ]n
5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-(7-quinoxalin-2-yl-3J-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone;
5-(4-Chloro-phenyl)-2-methyl-thiazol-4-yl]-(7-quinoxalin-2-yl-3J-diaza-bicyclo[3.3.1]non-3-yl)-methanone;
7-(6-Chloro-benzothiazol-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(2-[1 ,2 ]triazol-2-yl-phenyl)-methanone;
Biphenyl-2-yl-[7-(6-chloro-benzothiazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-methanone;
2-Methyl-5-p-tolyl-thiazol-4-yl)-(7-quinoxalin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone;
4-(4-Chloro-phenyl)-2-methyl-thiazol-5-yl]-(7-quinoxalin-2-yl-3J-diaza-bicyclo[3.3.1]non-3-yl)-methanone;
7-(6-Chloro-benzothiazol-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(5-methoxy-2-[1 ,2 ]triazol-2-yl-phenyl)- methanone;
7-(6-Chloro-benzothiazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(4-methyl-2-[1 ,2,3]tr^
methanone;
7-(5-Chloro-benzooxazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(2-fluoro-6-[1 ,2,3]triazol-2-yl-phenyl)-methanone;
7-(5-Chloro-benzooxazol-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(5-methoxy-2-[1 ,2,3]triazol-2-yl-phenyl)- methanone;
7-(5-Chloro-benzooxazol-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(4-methyl-2-[1 ,2 ]triazol-2-yl-phenyl^ methanone;
7-(5-Chloro-benzooxazol-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(4-methyl-biphenyl-2-yl)-methanone; (2-Fluoro-6-[1 ,2,3]tnazol-2-yl-phenyl)-[7-(4-trifluoromethyl-pynmidin-2-yl)-3,7-diaza-bicyc
methanone;
(4-Methyl-2-[1 ,2 ]triazol-2-yl-phenyl)-[7-(4-trifluoromethyl-pyrimidi
methanone;
(2-Methyl-6-[1 ,2 ]triazol-2-yl-phenyl)-[7-(4-trifluoromethyl-pynmidin-2-yl)-3
methanone;
(7-Benzothiazol-2-yl-3J-diaza-bicyclo[3.3.1 ]non-3-yl)-(2-methyl-6-[1 ,2 ]triazol-2-yl-phenyl)-methanone;
(2-Pyrazol-1 -yl-phenyl)-(7-quinoxalin-2-yl-3,7-diaza-bicyclo[3.3.1]non-3-yl)-methanone;
[7-(7-Chloro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-(2-pyrazol-1 -yl-phenyl)-methanone;
[7-(6-Chloro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-(2-pyrazol-1 -yl-phenyl)-methanone;
[7-(6-Fluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(2-pyrazol-1 -yl-phenyl)-methanone;
(2-Pyrazol-1 -yl-phenyl)-(7-quinazolin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone;
[7-(5-Chloro-benzooxazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-[2-cyclopropyl-5-(3-fluoro-4-methyl-phenyl)- thiazol-4-yl]-methanone;
[7-(5-Chloro-benzooxazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(2-methyl-5-phenyl-thiazol -yl)-methanone;
(6-Methyl-3-pyrazol-1 -yl-pyridin-2-yl)-(7-quinoxalin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone;
[7-(6-Fluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(6-methyl-3-pyrazol-1-yl-pyridin-2-yl)-meth
(6-Methyl-3-pyrazol-1 -yl-pyridin-2-yl)-(7-quinazolin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone;
(2-Cyclopropyl-5-iri-tolyl-thiazol-4-yl)-[7-(6,7-difluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-methanone;
[7-(6,7-Difluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]- methanone;
[5-(4-Chloro-phenyl)-2-methyl-thiazol-4-yl]-[7-(6,7-difluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]
methanone;
[5-(3,5-Difluoro-phenyl)-2-methyl-thiazol-4-yl]-[7-(6J-difluoro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3
methanone;
[4-(4-Chloro-phenyl)-2-methyl-thiazol-5-yl]-[7-(6,7-difluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]
methanone;
(5-Methyl-2-[1 ,2,3]triazol-2-yl-phenyl)-(7-quinoxalin-2-yl-9-oxa-3 -diaza-bicyclo[3 .1 ]non-3-yl)-methanone;
[7-(6-Fluoro-quinoxalin-2-yl)-9-oxa-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(5-methyl-2-[1 ,2,3]tri
methanone;
[7-(6J-Difluoro-quinoxalin-2-yl)-9-oxa-^
methanone;
(5-Methyl-2-[1 ,2,3]triazol-2-yl-phenyl)-(7-quinazolin-2-yl-9-oxa-3 -diaza-bicyclo[3 .1 ]non-3-yl)-methanone;
[7-(8-Methyl-quinoxalin-2-yl)-9-oxa-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(5-methyl-2-[1 ,2 ]tr^
methanone;
[7-(7-Chloro-quinoxalin-2-yl)-9-oxa-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(5-methyl-2-[1 ,2 ]triazo
methanone; [7-(6J-Dichloro-quinoxalin-2-yl)-9-oxa-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(5-methyl-2-[1 ,2 ] methanone;
[7-(6-Fluoro-quinoxalin-2-yl)-9-oxa-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(4-methyl-biphenyl-2-yl)-methan
[7-(6,7-Difluoro-quinoxalin-2-yl)-9-oxa-3,7-diaza-bicyclo[3 .1]non-3-yl]-(4-methyl-biphenyl-2-yl)-me
(4-Methyl-biphenyl-2-yl)-(7-quinazolin-2-yl-9-oxa-3,7-diaza-bicyclo[3 .1]non-3-yl)-methanone;
(4-Methyl-biphenyl-2-yl)-[7-(8-methyl-quinoxalin-2-yl)-9-oxa-3J-diaza-bicyclo[3.3.1 ]no
[7-(6,7-Dichloro-quinoxalin-2-yl)-9-oxa-3 -diaza-bicyclo[3.3.1]non-3-yl]-(4-methyl-biphenyl-2-yl)-met^
Biphenyl-2-yl-[7-(8-methyl-quinoxalin-2-yl)-9-oxa-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-methanone;
[7-(67-Dichloro-quinoxalin-2-yl)-9-oxa-37-diaza-bicyclo[3 .1]non-3-yl]-(2-fluoro-6-[1 ,2,3]tri
methanone;
[7-(8-Methyl-quinoxalin-2-yl)-9-oxa-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(2-methyl-6-[1 ,2 ]to
methanone;
(5-Methyl-2-[1 ,2,3]triazol-2-yl-phenyl)-(7-quinoxalin-2-yl-9-oxa-3 -diaza-bicyclo[3 .1 ]non-3-yl)-methanon
[7-(6-Chloro-quinoxalin-2-yl)-9-oxa-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(5-methyl-2-[1 ,2 ]tr^
methanone;
(4-Methyl-biphenyl-2-yl)-(7-quinoxalin-2-yl-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl)-methanone;
[7-(7-Chloro-quinoxalin-2-yl)-9-oxa-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(4-methyl-biphenyl-2-yl)-methanone;
[7-(6-Chloro-quinoxalin-2-yl)-9-oxa-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(4-methyl-biphenyl-2-yl)-methanone;
[7-(67-Dichloro-quinoxalin-2-yl)-9-oxa-37-diaza-bicyclo[3.3.1]non-3-yl]-(6-methyl-3-[1 ,2,3^
yl)-methanone;
(2-Fluoro-6-[1 ,2,3]triazol-2-yl-phenyl)-[7-(8-methyl-quinoxalin-2-yl)-9-oxa-37-diaza-bicyclo[3
methanone;
[7-(6J-Dichloro-quinoxalin-2-yl)-9-oxa-3J-diaza^
methanone;
10. A compound according to claim 1 selected from the group consisting of:
(3'-Methoxy-biphenyl-2-yl)-(7-quinazolin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone;
[7-(6J-Dichloro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1]non-3-yl]-(2-methyl-5-o-tolyl-thiazol-4-yl)-me
(2'-Fluoro-biphenyl-2-yl)-(7-quinazolin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone;
(2-Benzo[1 ,3]dioxol-5-yl-phenyl)-(7-quinazolin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone;
(3'-Fluoro-biphenyl-2-yl)-(7-quinazolin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone;
(3'-Methyl-biphenyl-2-yl)-(7-quinazolin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone;
2'-[7-(6J-Difluoro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1 ]nonane-3-carbonyl]-4'-methyl-biphenyl-4-carboni
(4'-Methoxy-biphenyl-2-yl)-(7-quinazolin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone;
[7-(6J-Difluoro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(2'-fluoro -methyl-biphenyl-2-yl)-m
(4'-Ethoxy-biphenyl-2-yl)-(7-quinazolin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone;
[7-(6,7-Dichloro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]-[5-(3,5-difluoro-phenyl)-2-methyl-^ methanone; (2-Benzo[1 ,3]dioxol-5-yl-5-methyl-phenyl)-[7-(6J-difluoro-quinoxalin-2-yl)-3J-diaza-bi
methanone;
[7-(6J-Difluoro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(3'-methoxy -methyl-biph^
[7-(6J-Difluoro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(3'-fluoro -methyl-biphen
(7-Benzothiazol-2-yl-3J-diaza-bicyclo[3.3.1 ]non-3-yl)-(4'-methoxy-4-methyl-biphenyl-2-yl)-methanone;
[7-(6,7-Difluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(4,3'-dimethyl-biphenyl-2-y
(7-Benzothiazol-2-yl-3J-diaza-bicyclo[3.3.1 ]non-3-yl)-(3'-methoxy-4-methyl-biphenyl-2-yl)-methanone;
(2'-Methyl-biphenyl-2-yl)-(7-quinazolin-2-yl-3,7-diaza-bicyclo[3.3.1]non-3-yl)-methanone;
(2\3'-Dimethyl-biphenyl-2-yl)-(7-quinazolin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone;
[7-(6-Chloro-benzothiazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(4'-methoxy-4-methyl-biphenyl-2-yl)-
(2'-Methoxy-biphenyl-2-yl)-(7-quinazolin-2-yl-3J-diaza-bicyclo[3.3.1 ]non-3-yl)-methanone;
[7-(6J-Difluoro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(4'-methoxy -methyl-biph
[7-(6J-Dichloro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1]non-3-yl]-[5-(6-methoxy-pyridin-3-yl)-2-methyl-th yl]-methanone;
(7-Benzothiazol-2-yl-3J-diaza-bicyclo[3.3.1 ]non-3-yl)-(2'-fluoro -methyl-biphenyl-2-yl)-m
[7-(6J-Dichloro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1]non-3-yl]-(2-methyl -p-tolyl-thiaz
[7-(6-Chloro-benzothiazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(3'-methoxy-4-methyl-biphenyl-2-yl)-m
[7-(6J-Dichloro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1]non-3-yl]-[5-(4-fluoro-phenyl)-2-m
methanone;
[7-(6,7-Difluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(4,2'-dimethyl-biphenyl-2-yl)-m
(7-Benzothiazol-2-yl-3J-diaza-bicyclo[3.3.1 ]non-3-yl)-(3'-methoxy-biphenyl-2-yl)-methanone;
[7-(6J-Difluoro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(2'-methoxy -methyl-biphen
(2-Benzo[1 ,3]dioxol-5-yl-5-methyl-phenyl)-[7-(6-chloro-benzothiazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]- methanone;
[7-(6,7-Difluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(4'-ethoxy^-methyl-biphenyl-2-y^
[7-(6,7-Dichloro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3 .1]non-3-yl]-[5-(3,4-dimethyl-phenyl)-2-meth methanone;
[7-(6-Chloro-benzothiazol-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(2'-fluoro -methyl-biphenyl-2-yl)-methanone;
[5-(4-Chloro-phenyl)-2-methyl-thiazol-4-yl]-[7-(6,7-dichloro-quinoxalin-2-yl)-3 -diaza-bicyclo[3.3.1 ^ methanone;
[7-(6-Fluoro-benzothiazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(4-methyl-biphenyl-2-yl)-methanone;
(4'-Methyl-biphenyl-2-yl)-(7-quinazolin-2-yl-3,7-diaza-bicyclo[3.3.1]non-3-yl)-methanone;
[7-(6,7-Difluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(4,4'-dimethyl-biphenyl-2-yl)-m
(2-Cyclopropyl-5-phenyl-thiazol-4-yl)-[7-(6,7-dichloro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3.3.1]non-3-yl]- methanone;
(2-Methyl-6-[1 ,2 ]triazol-2-yl-phenyl)-[7-(7-trifluoromethyl-quinoxalin-2-yl)-3J-diaza-bi
methanone; [5-(2 -Dichloro-phenyl)-2-methyl-thiazol-4-yl]-[7-(6J-dichloro-quinoxalin-2-yl)-3
methanone;
[7-(6J-Difluoro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(4,2 3'-trimethyl-biph
(7-Benzothiazol-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-(4-methyl-biphenyl-2-yl)-methanone;
(7-Benzothiazol-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-(2'-fluoro-biphenyl-2-yl)-methanone;
(2'-Ethyl-biphenyl-2-yl)-(7-quinazolin-2-yl-3,7-diaza-bicyclo[3.3.1]non-3-yl)-methanone;
(7-Benzothiazol-2-yl-3J-diaza-bicyclo[3.3.1 ]non-3-yl)-(3'-fluoro -methyl-biphenyl-2-yl)-m
(2-Benzo[1 ,3]dioxol-5-yl-5-methyl-phenyl)-(7-benzothiazol-2-yl-3,7-diaza-bicyclo[3.3.1]non-3-yl)-methanone;
(2-Benzo[1 ,3]dioxol-5-yl-phenyl)-(7-benzothiazol-2-yl-3,7-diaza-bicyclo[3.3.1]non-3-yl)-methanone;
[7-(6,7-Dichloro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3 .1]non-3-yl]-[2-dimethylamino-5-(4-fluoro
yl]-methanone;
[5-(2,3-Dichloro-phenyl)-2-methyl-thiazol-4-yl]-[7-(4-trifluoromethyl-pyrimidin-2-yl)-3,7-di
yl]-methanone;
(7-Benzothiazol-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-(4'-methoxy-biphenyl-2-yl)-methanone;
[5-(3^-Dimethyl-phenyl)-2-methyl-thiazol-4-yl]-[7-(4-trifluoromethyl-pyrimidin-2-yl)-3J-di
yl]-methanone;
2'-[7-(6J-Difluoro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1 ]nonane-3-carbonyl]-4'-methyl-biphen
(7-Benzothiazol-2-yl-3J-diaza-bicyclo[3.3.1 ]non-3-yl)-(4'-ethoxy-4-methyl-biphenyl-2-yl)-methanone;
[7-(6-Chloro-benzothiazol-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(3'-fluoro -methyl-biphenyl-2-yl)-methan
[7-(6J-Difluoro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(4'-fluoro -methyl-biph
(7-Benzothiazol-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-(4,2\3'-trimethyl-biphenyl-2-yl)-methanone;
(7-Benzothiazol-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-(3'-methyl-biphenyl-2-yl)-methanone;
(5-Methyl-biphenyl-2-yl)-[7-(4-trifluoromethyl-pynmidin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-methanone;
[7-(5-Chloro-benzooxazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(4-methyl-biphenyl-2-yl)-methanone;
[7-(6J-Difluoro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(2'-ethyl-4-methyl-biph
(7-Quinazolin-2-yl-3,7-diaza-bicyclo[3 .1 ]non-3-yl)-(3'-trifluoromethyl-biphenyl-2-yl)-methanone;
(2-Methyl-5-o-tolyl-thiazol-4-yl)-[7-(4-trifluoromethyl-pyrimidin-2-yl)-3J-diaza-bicyclo[3.3.1]n
2'-(7-Quinazolin-2-yl-3,7-diaza-bicyclo[3.3.1 ]nonane-3-carbonyl)-biphenyl-4-carbonitrile;
[7-(6-Chloro-benzothiazol-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(5-methyl-2-pyridin-2-yl-phe
(7-Quinazolin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-(4'-trifluoromethoxy-biphenyl-2-yl)-methanon
(7-Benzothiazol-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-(3'-fluoro-biphenyl-2-yl)-methanone;
[7-(6-Fluoro-thiazolo[5,4-b]pyndin-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(5-methyl-2-[1 ,2,^
methanone;
(7-Benzothiazol-2-yl-3J-diaza-bicyclo[3.3.1 ]non-3-yl)-(4 '-dimethyl-biphenyl-2-yl)-methanone^
[7-(6J-Dichloro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1]non-3-yl]-[2-methyl-5-(3-trifluorom
yl]-methanone; [7-(6J-Difluoro-quinoxalin-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(4-methyl-4'-trifluoromethoxy-bi methanone;
(3\4'-Dichloro-biphenyl-2-yl)-(7-quinazolin-2-yl-3,7-diaza-bicyclo[3.3.1 ]non-3-yl)-meth
[7-(6-Chloro-benzothiazol-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(4-methyl-biphenyl-2-yl)-m
[7-(6-Chloro-benzothiazol-2-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(4'-ethoxy-4-methyl-biphen
[7-(6-Methyl-[1 ,7]naphthyridin-8-yl)-3,7-diaza-bicyclo[3.3.1 ]non-3-yl]-(5-methyl-2-[1 ,2,3]triazol-2-yl-phenyl)- methanone;
[5-(3-Methoxy-phenyl)-2-methyl-thiazol -yl]-[7-(4-trifluoromethyl-pyrimidin-2-yl)-3J-diaza-b
methanone;
[5-(3-Chloro-phenyl)-thiazol-4-yl]-[7-(6,7-dichloro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3 .1]non-3-^
(4'-Chloro^-methyl-biphenyl-2-yl)-[7-(6,7-difluoro-quinoxalin-2-yl)-3,7-diaza-bicyclo[3 .1]n
[7-(6-Chloro-benzothiazol-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(4,4'-dimethyl-biphenyl-2-y^
[7-(6-Chloro-benzothiazol-2-yl)-3J-diaza-bicyclo[3.3.1 ]non-3-yl]-(4-methyl-biphenyl-2-yl)-meth and 2'-(7-Benzothiazol-2-yl-3J-diaza-bicyclo[3.3.1 ]nonane-3-carbonyl)-4'-methyl-biphenyl -carbonitrile; or a pharmaceutically acceptable salt thereof.
11. A pharmaceutical composition containing, as active principle, one or more compounds according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert excipient.
12. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, for use as a medicament.
13. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, for the prevention or treatment of diseases selected from the group consisting of sleep disorders, anxiety disorders, addiction disorders, cognitive dysfunctions, mood disorders, or appetite disorders.
14. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, for use in the preparation of a medicament for the prevention or treatment of diseases selected from the group consisting of sleep disorders, anxiety disorders, addiction disorders, cognitive dysfunctions, mood disorders, or appetite disorders.
PCT/IB2012/055292 2011-10-04 2012-10-03 3,7-diazabicyclo[3.3.1]nonane and 9-oxa-3,7-diazabicyclo[3.3.1]nonane derivatives WO2013050938A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IBPCT/IB2011/054363 2011-10-04
IB2011054363 2011-10-04

Publications (1)

Publication Number Publication Date
WO2013050938A1 true WO2013050938A1 (en) 2013-04-11

Family

ID=47192032

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2012/055292 WO2013050938A1 (en) 2011-10-04 2012-10-03 3,7-diazabicyclo[3.3.1]nonane and 9-oxa-3,7-diazabicyclo[3.3.1]nonane derivatives

Country Status (1)

Country Link
WO (1) WO2013050938A1 (en)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016088813A1 (en) * 2014-12-03 2016-06-09 持田製薬株式会社 Novel diazabicyclo[2.2.2]octane derivative
US9440982B2 (en) 2012-02-07 2016-09-13 Eolas Therapeutics, Inc. Substituted prolines/piperidines as orexin receptor antagonists
US9499517B2 (en) 2012-02-07 2016-11-22 Eolas Therapeutics, Inc. Substituted prolines / piperidines as orexin receptor antagonists
CN106749269A (en) * 2015-11-23 2017-05-31 广东东阳光药业有限公司 Octahydro pyrrolo- [3,4 c] azole derivatives and application thereof
CN107759620A (en) * 2016-08-16 2018-03-06 广东东阳光药业有限公司 Octahydro pyrrolo- [3,4 c] azole derivatives and its application method and purposes
US9937172B2 (en) 2014-09-30 2018-04-10 Derek Alton Lightner Mixtures of heteropolycycles
US10131653B2 (en) 2015-04-24 2018-11-20 Takeda Pharmaceutical Company Limited Heterocyclic compound
US10196383B2 (en) 2015-07-17 2019-02-05 Sunshine Lake Pharma Co., Ltd. Substituted quinazoline compounds and preparation and uses thereof
US10221170B2 (en) 2014-08-13 2019-03-05 Eolas Therapeutics, Inc. Difluoropyrrolidines as orexin receptor modulators
CN110612291A (en) * 2017-05-03 2019-12-24 爱杜西亚药品有限公司 Preparation of 2- ([1,2,3] triazol-2-yl) -benzoic acid derivatives
US10894789B2 (en) 2016-02-12 2021-01-19 Astrazeneca Ab Halo-substituted piperidines as orexin receptor modulators

Citations (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000044755A1 (en) * 1999-01-29 2000-08-03 Abbott Laboratories Diazabicyclic derivatives as nicotinic acetylcholine receptor ligands
WO2005118548A1 (en) 2004-03-01 2005-12-15 Actelion Pharmaceuticals Ltd Substituted 1,2,3,4-tetrahydroisoquinoline derivatives
WO2007105177A1 (en) 2006-03-15 2007-09-20 Actelion Pharmaceuticals Ltd Tetrahydroisoquinoline derivatives to enhance memory function
WO2008008517A2 (en) 2006-07-14 2008-01-17 Merck & Co., Inc. Bridged diazepan orexin receptor antagonists
WO2008069997A1 (en) 2006-12-01 2008-06-12 Merck & Co., Inc. Substituted diazepan compounds as orexin receptor antagonists
WO2008081399A2 (en) 2006-12-28 2008-07-10 Actelion Pharmaceuticals Ltd 2-aza-bicyclo[3.1.0]hexane derivatives as orexin receptor antagonists
WO2008143856A1 (en) * 2007-05-18 2008-11-27 Merck & Co., Inc. Oxo bridged diazepan orexin receptor antagonists
WO2009047723A2 (en) 2007-10-10 2009-04-16 Actelion Pharmaceuticals Ltd Tetrahydroquinoline derivatives for treating post-traumatic stress disorders
WO2009104155A1 (en) 2008-02-21 2009-08-27 Actelion Pharmaceuticals Ltd 2-aza-bicyclo[2.2.1]heptane derivatives
WO2010004507A1 (en) 2008-07-07 2010-01-14 Actelion Pharmaceuticals Ltd Thiazolidine compounds as orexin receptor antagonists
WO2010038200A1 (en) 2008-10-01 2010-04-08 Actelion Pharmaceuticals Ltd Oxazolidine compounds as orexin receptor antagonists
WO2010044054A1 (en) 2008-10-14 2010-04-22 Actelion Pharmaceuticals Ltd Phenethylamide derivatives and their heterocyclic analogues
WO2010048012A1 (en) 2008-10-21 2010-04-29 Merck Sharp & Dohme Corp. 2,5-disubstituted piperidine orexin receptor antagonists
WO2010063662A1 (en) 2008-12-02 2010-06-10 Glaxo Group Limited N-{[(ir,4s,6r-3-(2-pyridinylcarbonyl)-3-azabicyclo [4.1.0] hept-4-yl] methyl}-2-heteroarylamine derivatives and uses thereof
WO2010063663A1 (en) 2008-12-02 2010-06-10 Glaxo Group Limited N-{[(ir,4s,6r-3-(2-pyridinylcarbonyl)-3-azabicyclo [4.1.0]hept-4-yl] methyl}-2-heteroarylamine derivatives and uses thereof
WO2010072722A1 (en) 2008-12-23 2010-07-01 Glaxo Group Limited Piperidine derivatives useful as orexin antagonists
WO2010084152A1 (en) 2009-01-21 2010-07-29 Basilea Pharmaceutica Ag Novel bicyclic antibiotics
WO2011050200A1 (en) * 2009-10-23 2011-04-28 Janssen Pharmaceutica Nv Fused heterocyclic compounds as orexin receptor modulators

Patent Citations (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000044755A1 (en) * 1999-01-29 2000-08-03 Abbott Laboratories Diazabicyclic derivatives as nicotinic acetylcholine receptor ligands
WO2005118548A1 (en) 2004-03-01 2005-12-15 Actelion Pharmaceuticals Ltd Substituted 1,2,3,4-tetrahydroisoquinoline derivatives
WO2007105177A1 (en) 2006-03-15 2007-09-20 Actelion Pharmaceuticals Ltd Tetrahydroisoquinoline derivatives to enhance memory function
WO2008008517A2 (en) 2006-07-14 2008-01-17 Merck & Co., Inc. Bridged diazepan orexin receptor antagonists
WO2008069997A1 (en) 2006-12-01 2008-06-12 Merck & Co., Inc. Substituted diazepan compounds as orexin receptor antagonists
WO2008081399A2 (en) 2006-12-28 2008-07-10 Actelion Pharmaceuticals Ltd 2-aza-bicyclo[3.1.0]hexane derivatives as orexin receptor antagonists
WO2008143856A1 (en) * 2007-05-18 2008-11-27 Merck & Co., Inc. Oxo bridged diazepan orexin receptor antagonists
WO2009047723A2 (en) 2007-10-10 2009-04-16 Actelion Pharmaceuticals Ltd Tetrahydroquinoline derivatives for treating post-traumatic stress disorders
WO2009104155A1 (en) 2008-02-21 2009-08-27 Actelion Pharmaceuticals Ltd 2-aza-bicyclo[2.2.1]heptane derivatives
WO2010004507A1 (en) 2008-07-07 2010-01-14 Actelion Pharmaceuticals Ltd Thiazolidine compounds as orexin receptor antagonists
WO2010038200A1 (en) 2008-10-01 2010-04-08 Actelion Pharmaceuticals Ltd Oxazolidine compounds as orexin receptor antagonists
WO2010044054A1 (en) 2008-10-14 2010-04-22 Actelion Pharmaceuticals Ltd Phenethylamide derivatives and their heterocyclic analogues
WO2010048012A1 (en) 2008-10-21 2010-04-29 Merck Sharp & Dohme Corp. 2,5-disubstituted piperidine orexin receptor antagonists
WO2010063662A1 (en) 2008-12-02 2010-06-10 Glaxo Group Limited N-{[(ir,4s,6r-3-(2-pyridinylcarbonyl)-3-azabicyclo [4.1.0] hept-4-yl] methyl}-2-heteroarylamine derivatives and uses thereof
WO2010063663A1 (en) 2008-12-02 2010-06-10 Glaxo Group Limited N-{[(ir,4s,6r-3-(2-pyridinylcarbonyl)-3-azabicyclo [4.1.0]hept-4-yl] methyl}-2-heteroarylamine derivatives and uses thereof
WO2010072722A1 (en) 2008-12-23 2010-07-01 Glaxo Group Limited Piperidine derivatives useful as orexin antagonists
WO2010084152A1 (en) 2009-01-21 2010-07-29 Basilea Pharmaceutica Ag Novel bicyclic antibiotics
WO2011050200A1 (en) * 2009-10-23 2011-04-28 Janssen Pharmaceutica Nv Fused heterocyclic compounds as orexin receptor modulators

Non-Patent Citations (48)

* Cited by examiner, † Cited by third party
Title
"Comprehensive Heterocyclic Chemistry", 1996, ELSEVIER
"Salt selection for basic drugs", INT. J. PHARM., vol. 33, 1986, pages 201 - 217
ADAM, TC ET AL., PHYSIOL BEHAV, vol. 91, no. 4, 2007, pages 449 - 458
ASTON-JONES G ET AL., BRAIN RES, vol. 1314, 2010, pages 74 - 90
BERRIDGE CW ET AL., BRAIN RES, vol. 1314, 2009, pages 91 - 102
BORGLAND SL ET AL., NEURON, vol. 49, no. 4, 2006, pages 589 - 601
BOUTREL B ET AL.: "Role for hypocretin in mediating stress-induced reinstatement of cocaine-seeking behavior", PROC NATL ACAD SCI, vol. 102, no. 52, 2005, pages 19168 - 19173
BOUTREL, B ET AL., PROC NATL ACAD SCI, vol. 102, no. 52, 2005, pages 19168 - 19173
BRISBARE ET AL., NATURE MEDICINE, vol. 13, 2007, pages 150 - 155
C BOSS; C BRISBARE-ROCH; F JENCK, JOURNAL OF MEDICINAL CHEMISTRY, vol. 52, 2009, pages 891 - 903
CARTER ME ET AL.: "The brain hypocretins and their receptors: mediators of allostatic arousal", CURR OP PHARMACOL., vol. 9, 2009, pages 39 - 45, XP025916388, DOI: doi:10.1016/j.coph.2008.12.018
CARTER ME; BORG JS; DELECEA L., CURR OP PHARMACOL., vol. 9, 2009, pages 39 - 45
CHEMELLI R.M. ET AL., CELL, vol. 98, 1999, pages 437 - 451
CHROUSOS, GP ET AL., JAMA, vol. 267, no. 9, 1992, pages 1244 - 1252
COLEMAN P J ET AL: "Design and synthesis of conformationally constrained N,N-disubstituted 1,4-diazepanes as potent orexin receptor antagonists", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, PERGAMON, ELSEVIER SCIENCE, GB, vol. 20, no. 7, 1 April 2010 (2010-04-01), pages 2311 - 2315, XP026971068, ISSN: 0960-894X, [retrieved on 20100208] *
FENG P ET AL., J PSYCHOPHARMACOL, vol. 22, no. 7, 2008, pages 784 - 791
FURLONG T M ET AL., EUR J NEUROSCI, vol. 30, no. 8, 2009, pages 1603 - 1614
GOZZI A ET AL., PLOS ONE, vol. 6, no. 1, 2011, pages E16406
H DIETRICH; F JENCK, PSYCHOPHARMACOLOGY, vol. 212, 2010, pages 145 - 154
HOLLANDER JA ET AL., PROC NATL ACAD SCI, vol. 105, no. 49, 2008, pages 19480 - 19485
HUTCHESON DM ET AL., BEHAV PHARMACOL, vol. 22, no. 2, 2011, pages 173 - 181
JE KANG ET AL.: "Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle", SCIENCE, vol. 326, no. 5955, 2009, pages 1005 - 1007
KOOB, GF ET AL., CURR OPIN INVESTIG DRUGS, vol. 11, no. 1, 2010, pages 63 - 71
LAWRENCE AJ ET AL., BR J PHARMACOL, vol. 148, no. 6, 2006, pages 752 - 759
LESAGE MG ET AL., PSYCHOPHARMACOLOGY, vol. 209, no. 2, 2010, pages 203 - 212
LIU X ET AL., SLEEP, vol. 30, no. 1, 2007, pages 83 - 90
MAJZOUB, JA ET AL., EUROPEAN JOURNAL OF ENDOCRINOLOGY, vol. 155, no. 1, 2006, pages S71 - S76
MJ PRUD'HOMME ET AL., NEUROSCIENCE, vol. 162, no. 4, 2009, pages 1287 - 1298
NOLLET ET AL., NEUROPHARM, vol. 61, no. 1-2, 2011, pages 336 - 46
QUARTA D ET AL.: "The orexin-1 receptor antagonist SB-334867 reduces amphetamine-evoked dopamine outflow in the shell of the nucleus accumbens and decreases the expression of amphetamine sensitization", NEUROCHEM INT, vol. 56, no. 1, 2010, pages 11 - 15, XP026906710, DOI: doi:10.1016/j.neuint.2009.08.012
R. STICKGOLD ET AL.: "Sleep-dependent memory consolidation", NATURE, vol. 437, 2005, pages 1272 - 1278
REMINGTON: "The Science and Practice of Pharmacy", 2005, LIPPINCOTT WILLIAMS & WILKINS, article "Pharmaceutical Manufacturing"
SAKURAI T. ET AL., CELL, vol. 92, 1998, pages 573 - 585
SALOMON RM ET AL., BIOL PSYCHIATRY, vol. 54, no. 2, 2003, pages 96 - 104
SHARF R ET AL., BRAIN RES, vol. 1314, 2010, pages 130 - 138
SMITH RJ ET AL.: "Orexin/hypocretin is necessary for context-driven cocaine-seeking", NEUROPHARMACOLOGY, vol. 58, no. 1, 2010, pages 179 - 184, XP026736770, DOI: doi:10.1016/j.neuropharm.2009.06.042
SMITH RJ ET AL.: "Orexin/hypocretin signaling at the orexin 1 receptor regulates cue-elicited cocaine-seeking", EUR J NEUROSCI, vol. 30, no. 3, 2009, pages 493 - 503
SPEALMAN ET AL.: "Pharmacol. Biochem. Behav.", vol. 64, 1999, pages: 327 - 336
SUTCLIFFE, JG ET AL., NAT REV NEUROSCI, vol. 3, no. 5, 2002, pages 339 - 349
T. EICHER; S. HAUPTMANN: "The chemistry of Heterocycles: Structure, Reactions, Syntheses, and Applications", 2003, WILEY
T.S. SHIPPENBERG; G.F. KOOB: "Neuropsychopharmacology: The fifth generation of progress", 2002, article "Recent advances in animal models of drug addiction", pages: 1381 - 1397
TSUJINO N; SAKURAI T, PHARMACOL REV., vol. 61, 2009, pages 162 - 176
TSUJINO N; SAKURAI T: "Orexin/hypocretin: a neuropeptide at the interface of sleep, energy homeostasis, and reward systems", PHARMACOL REV., vol. 61, 2009, pages 162 - 176, XP055180000, DOI: doi:10.1124/pr.109.001321
TSUJINO, N; SAKURAI, T, PHARMACOL REV, vol. 61, no. 2, 2009, pages 162 - 176
W. FOULDS MATHES ET AL., APPETITE, vol. 52, 2009, pages 545 - 553
WINROW ET AL., NEUROPHARMACOLOGY, vol. 58, no. 1, 2009, pages 185 - 94
Y. KAYABA ET AL., AM. J. PHYSIOL. REGUL. INTEGR. COMP. PHYSIOL., vol. 285, 2003, pages R581 - 593
ZHANG W ET AL.: "Multiple components of the defense response depend on orexin: evidence from orexin knockout mice and orexin neuron-ablated mice", AUTON NEUROSCI, vol. 126-127, 2006, pages 139 - 145, XP024972647, DOI: doi:10.1016/j.autneu.2006.02.021

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9440982B2 (en) 2012-02-07 2016-09-13 Eolas Therapeutics, Inc. Substituted prolines/piperidines as orexin receptor antagonists
US9499517B2 (en) 2012-02-07 2016-11-22 Eolas Therapeutics, Inc. Substituted prolines / piperidines as orexin receptor antagonists
US9896452B2 (en) 2012-02-07 2018-02-20 Eolas Therapeutics, Inc. Substituted prolines/piperidines as orexin receptor antagonists
US10221170B2 (en) 2014-08-13 2019-03-05 Eolas Therapeutics, Inc. Difluoropyrrolidines as orexin receptor modulators
US9937172B2 (en) 2014-09-30 2018-04-10 Derek Alton Lightner Mixtures of heteropolycycles
US10231970B2 (en) 2014-09-30 2019-03-19 NV Heterocycles Methods of producing heteropolycycles via bis-epoxidation
WO2016088813A1 (en) * 2014-12-03 2016-06-09 持田製薬株式会社 Novel diazabicyclo[2.2.2]octane derivative
US10131653B2 (en) 2015-04-24 2018-11-20 Takeda Pharmaceutical Company Limited Heterocyclic compound
US10196383B2 (en) 2015-07-17 2019-02-05 Sunshine Lake Pharma Co., Ltd. Substituted quinazoline compounds and preparation and uses thereof
JP2018534338A (en) * 2015-11-23 2018-11-22 サンシャイン・レイク・ファーマ・カンパニー・リミテッドＳｕｎｓｈｉｎｅ Ｌａｋｅ Ｐｈａｒｍａ Ｃｏ．，Ｌｔｄ． Octahydropyrrolo [3,4-c] pyrrole derivatives and uses thereof
CN106749269B (en) * 2015-11-23 2019-01-04 广东东阳光药业有限公司 Octahydro pyrrolo- [3,4-c] azole derivatives and application thereof
WO2017088759A1 (en) * 2015-11-23 2017-06-01 Sunshine Lake Pharma Co., Ltd. OCTAHYDROPYRROLO [3, 4-c] PYRROLE DERIVATIVES AND USES THEREOF
CN106749269A (en) * 2015-11-23 2017-05-31 广东东阳光药业有限公司 Octahydro pyrrolo- [3,4 c] azole derivatives and application thereof
US10370380B2 (en) 2015-11-23 2019-08-06 Sunshine Lake Pharma Co., Ltd. Octahydropyrrolo[3,4-c]pyrrole derivatives and uses thereof
US10894789B2 (en) 2016-02-12 2021-01-19 Astrazeneca Ab Halo-substituted piperidines as orexin receptor modulators
US12084437B2 (en) 2016-02-12 2024-09-10 Astrazeneca Ab Halo-substituted piperidines as orexin receptor modulators
US11434236B2 (en) 2016-02-12 2022-09-06 Astrazeneca Ab Halo-substituted piperidines as orexin receptor modulators
CN107759620A (en) * 2016-08-16 2018-03-06 广东东阳光药业有限公司 Octahydro pyrrolo- [3,4 c] azole derivatives and its application method and purposes
CN107759620B (en) * 2016-08-16 2021-11-12 广东东阳光药业有限公司 Octahydropyrrolo [3,4-c ] pyrrole derivatives, methods of use, and uses thereof
US11124488B2 (en) 2017-05-03 2021-09-21 Idorsia Pharmaceuticals Ltd Preparation of 2-([1,2,3]triazol-2-yl)-benzoic acid derivatives
JP2020518573A (en) * 2017-05-03 2020-06-25 イドーシア ファーマシューティカルズ リミテッドＩｄｏｒｓｉａ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｌｔｄ Preparation of 2-([1,2,3]triazol-2-yl)-benzoic acid derivative
JP7182562B2 (en) 2017-05-03 2022-12-02 イドーシア ファーマシューティカルズ リミテッド Preparation of 2-([1,2,3]triazol-2-yl)-benzoic acid derivatives
CN110612291B (en) * 2017-05-03 2024-02-13 爱杜西亚药品有限公司 Preparation of 2- ([ 1,2,3] triazol-2-yl) -benzoic acid derivatives
CN110612291A (en) * 2017-05-03 2019-12-24 爱杜西亚药品有限公司 Preparation of 2- ([1,2,3] triazol-2-yl) -benzoic acid derivatives

Similar Documents

Publication Publication Date Title
US11040966B2 (en) Benzimidazole-proline derivatives
WO2013050938A1 (en) 3,7-diazabicyclo[3.3.1]nonane and 9-oxa-3,7-diazabicyclo[3.3.1]nonane derivatives
US9440970B2 (en) Pyrazole derivative
KR102151288B1 (en) Orexin receptor antagonists which are [ortho bi (hetero )aryl]-[2-(meta bi (hetero )aryl)-pyrrolidin-1-yl]-methanone derivatives
WO2012085852A1 (en) 3,8-diaza-bicyclo[4.2.0]oct-8-yl amides
AU2014358742B2 (en) Crystalline form of (S)-(2-(6-chloro-7-methyl-1H-benzo[d]imidazol-2-yl)-2-methylpyrrolidin-1 -yl)(5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and its use as orexin receptor antagonists
US9403813B2 (en) Azetidine amide derivatives as orexin receptor antagonists
WO2020007977A1 (en) 7-trifluoromethyl-[1,4]diazepan derivatives
WO2020007964A1 (en) 2-(2-azabicyclo[3.1.0]hexan-1-yl)-1h-benzimidazole derivatives
WO2020099511A1 (en) Benzimidazole-2-methyl-morpholine derivatives
WO2023218023A1 (en) Thiazoloaryl-methyl substituted cyclic hydrazine-n-carboxamide derivatives

Legal Events

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

Ref document number: 12787880

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 12787880

Country of ref document: EP

Kind code of ref document: A1