NZ625896B2

NZ625896B2 - 2-(1,2,3-triazol-2-yl)benzamide and 3-(1,2,3-triazol-2-yl)picolinamide derivatives as orexin receptor antagonists

Info

Publication number: NZ625896B2
Application number: NZ625896A
Authority: NZ
Inventors: Martin Bolli; Christoph Boss; Christine Brotschi; Bibia Heidmann; Thierry Sifferlen; Jodi T Williams
Original assignee: Idorsia Pharmaceuticals Ltd
Filing date: 2012-11-07
Publication date: 2016-08-02

Abstract

Provided are 2-(1,2,3-triazol-2-yl)benzamide and 3-(1,2,3-triazol-2- yl)picolinamide derivative compounds of Formula (I), wherein the variables are as defined in the specification. Examples of the compounds include [(R)-3-(2-Fluoro-5-[1,2,3]triazol-2-yl-benzyl)-morpholin-4-yl]-(5-methyl-2-[1,2,3]triazol-2-yl-phenyl)-methanone and [(R)-3-(4-Methyl-3-pyrimidin-2-yl-benzyl)-morpholin-4-yl]-(2-[1,2,3]triazol-2-yl-phenyl)-methanone. The compounds are orexin receptor antagonists. The compounds may be useful in the treatment of anxiety disorders, addiction disorders, mood disorders, appetite disorders, cognitive dysfunctions and sleep disorders. azol-2-yl-phenyl)-methanone and [(R)-3-(4-Methyl-3-pyrimidin-2-yl-benzyl)-morpholin-4-yl]-(2-[1,2,3]triazol-2-yl-phenyl)-methanone. The compounds are orexin receptor antagonists. The compounds may be useful in the treatment of anxiety disorders, addiction disorders, mood disorders, appetite disorders, cognitive dysfunctions and sleep disorders.

Description

2-(1,2,3-TRIAZOLYL)BENZAMIDE AND 3-(1,2,3-TRIAZOLYL)PICOLINAMIDE DERIVATIVES AS OREXIN RECEPTOR ANTAGONISTS The present invention s to novel 2-(1,2,3-triazolyl)benzamide and 3-(1,2,3-triazol yl)picolinamide derivatives of formula (I) and their use as pharmaceuticals. The ion 5 also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more compounds of formula (I), and their use as orexin receptor antagonists, especially as orexin-1 or antagonists.

Orexins (orexin A or OX-A and orexin B or OX-B) are neuropeptides found in 1998 by two ch groups, orexin A is a 33 amino acid e and orexin B is a 28 amino acid peptide 10 (Sakurai T. et al., Cell, 1998 , 92, 573-585). Orexins are produced in discrete s of the lateral alamus and bind to the G-protein-coupled receptors (OX1 and OX2 receptors).

The orexin-1 receptor (OX1) 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 s and humans involves either 15 blockade of both orexin-1 and orexin-2 receptor (dual antagonists), or individual and selective blockade of either the -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 ck mechanism that regulates feeding behaviour (Sakurai T. et al., Cell, 1998 , 92, 573-585). 20 On the other hand, orexin neuropeptides and orexin ors 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 s. The particular bution of orexin fibers and receptors in basal forebrain, limbic structures and brainstem regions - areas 25 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, s contribute to orchestrate all brain arousal systems that regulate circadian activity, energy e and emotional reactivity. This role opens large eutic opportunities for medically addressing numerous mental health disorders possibly ng to 30 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 2 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 ples and different underlying neuronal substrates. The major distinction is between the capacity for 5 conscious, declarative memory and a set of unconscious, non-declarative memory abilities.

Declarative memory is further subdivided into semantic and episodic memory. Nondeclariative memory is further subdivided into priming and perceptual learning, ural memory for skills and , associative and non-associative learning, and some others.

While ic memory refers to the l knowledge about the world, episodic memory is 10 autobiographical memory of events. Procedural memories refer to the ability to m skillbased ions, as e.g. motor skills. Long-term memory is established during a multiple stage process through gradual changes involving diverse brain ures, beginning with learning, or memory acquisition, or formation. uently, consolidation of what has been learned may stabilize memories. When long-term memories are retrieved, they may return to 15 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 20 brain consolidates long-term memory at n 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. old et al., dependent memory 25 consolidation; Nature 2005, 437, 1272-1278]. Learning and memory processes are believed to be fundamentally affected in a y of neurological and mental disorders, such as e.g. mental retardation, mer’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. 30 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 -Jones G et al., Brain Res 2010 , 1314, 74-90; Sharf R et al., Brain Res 2010 , 1314, 8]. Selective pharmacological OXR-1 blockade reduced cue- and stressinduced reinstatement of cocaine seeking [Boutrel B, et al., "Role for hypocretin in mediating 35 -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 3 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 dministration [Hollander JA et al., 5 Proc Natl Acad Sci 2008 , 105(49), 19480-19485; LeSage MG et al., Psychopharmacology 2010 , 209(2), 203-212]. Orexin-1 receptor nism 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 and SL et al., 10 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 s ens and decreases the expression of amphetamine sensitization." Neurochem Int 2010 , 56(1), 11-15].

The effect of a drug to diminish addictions may be modelled in normal or particularly sensitive mammals used as animal models [see for example an et al, Pharmacol. 15 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; vis, D. Charney, J.T.Doyle, C. Nemeroff (eds.) 2002 ; chapter 97, pages 1381-1397].

Several converging lines of evidence rmore demonstrate a direct role of the orexin 20 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 lled 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. 25 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 ci 2009 , 30(8), 1603- 1614]. Stress response may lead to ic, usually imited physiological, psychological and behavioural changes that may affect appetite, lism and feeding behavior [Chrousos, GP et al., JAMA 1992 , 267(9), 252]. The acute stress response 30 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 _1) S71-S76].

As outlined above the orexin system regulates homeostatic functions such as wake 35 cycle, energy balance, emotions and reward. Orexins are also involved in mediating the 4 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 5 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 10 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 sion in mice also demonstrated an 15 association of molecular orexin system bances with depressed behavioral states and a reversal of these molecular changes by antidepressant ent [Nollet et al., NeuroPharm 2011 , 61(1-2):336-46].

The orexin system is also involved in stress-related appetitive/reward seeking behaviour dge CW et al., Brain Res 2009 , 1314, 91-102). In n instances, a modulatory effect 20 on stress may be complementary to an effect on appetitive/reward seeking behaviour as such. For instance, an OX1 selective orexin receptor antagonist was able to prevent ock stress induced reinstatement of cocaine seeking behaviour [Boutrel, B et al., Proc Natl Acad Sci 2005 , ), 19173]. In addition, stress is also known to play an al part in awal which occurs during cessation of drug taking (Koob, GF et al., Curr 25 Opin Investig Drugs 2010 , 11(1), 63-71).

Orexins have been found to increase food intake and te [Tsujino, N, Sakurai, T, Pharmacol Rev 2009 , 61(2) 162-176]. As an onal environmental factor, stress can contribute to binge eating our, and lead to obesity [Adam, TC et al. Physiol Be hav 2007 , 91(4) 449-458]. Animal models that are clinically relevant models of binge eating in 30 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, ally 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 a L., Curr Op Pharmacol. 2009 , 9: 39-45; 35 C Boss, C Brisbare-Roch, F Jenck, l of Medicinal Chemistry 2009 , 52: 891-903]. The 5 orexin system interacts with neural ks 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. 5 The compound (2R){(1S)-6,7-dimethoxy[2-(4-trifluoromethyl-phenyl)-ethyl]-3,4-dihydro- 1H-isoquinolinyl}-N-methylphenyl-acetamide (WO2005/118548), a dual orexin receptor antagonist, showed clinical cy in humans when tested for the indication primary ia. In the rat, the compound has been shown to decrease alertness, characterized by decreases in both active wake and locomotion; and to dose-dependently se the time 10 spent in both REM and NREM sleep [Brisbare et al., Nature Medicine 2007 , 13 , 150-155].

The compound further ated vascular responses to conditioned fear and y 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 15 anxieties including phobias and post traumatic stress disorders (PTSDs). In addition, intact declarative and clarative learning and memory has been trated 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 (Aβ) as well as Aβ plaque deposition after acute sleep restriction in amyloid precursor protein enic 20 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 Aβ 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 Aβ to Alzheimer's e and, thus, to the cognitive dysfunction, expressed as impairment of 25 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 30 pharmacological activity in a rat model of nicotine self-administration e MG et al., Psychopharmacology 2010 , 209(2), 203-212]. Another dual orexin receptor antagonist, N- ylyl{[(1-methyl-1H-benzimidazolyl)sulfanyl]acetyl}-L-prolinamide inhibited nicotine-reinstatement for a ioned reinforcer and reduced behavioral (locomotor sensitization) and lar (transcriptional responses) changes d by repeated 35 amphetamine administration in rodents [Winrow et al., Neuropharmacology 2009 , 58(1),185- 94]. 6 WO2003/002559 discloses N-aroyl cyclic amine derivatives encompassing morpholine derivatives as orexin receptor antagonists. A particular pyrrolidine derived orexin-1 selective nd within the scope of /002559 is sed in Langmead et. al, Brit. J.

Pharmacol. 2004, 141, 340-346: 1-(5-(2-fluoro-phenyl)methyl-thiazolyl)[(S)(5- 5 phenyl-[1,3,4]oxadiazolylmethyl)-pyrrolidinyl)-methanone. The present compounds are different from the compounds disclosed in WO2003/002559 in view of the particular 2-(1,2,3- triazolyl)benzamide and ,3-triazolyl)picolinamide moiety and notably in view of the present particular benzyl substituent in position 3 of the line moiety.

The present invention provides novel 2-(1,2,3-triazolyl)benzamide and 3-(1,2,3-triazol 10 yl)picolinamide derivatives, which are non-peptide antagonists of human orexin receptors, especially the orexin-1 receptor. These compounds are in particular of potential use in the treatment of disorders relating to orexinergic ctions, comprising especially anxiety disorders, addiction ers, mood disorders, or appetite disorders, as well as cognitive dysfunctions or sleep ers. The compounds of the t invention may notably be 15 useful to treat mental health diseases or disorders relating to dysfunctions of the orexin 1 receptor.

In one aspect, the invention provides a compound of formula (I) Formula (I) 20 wherein Ar1 represents a 5- or 6-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein said heteroaryl is unsubstituted, mono-, or di-substituted, wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, 25 (C1-4)alkoxy, halogen, cyano, (C1-3)fluoroalkyl, and (C1-3)fluoroalkoxy; R1 represents one optional substituent selected from (C1-4)alkyl, (C1-4)alkoxy, hydroxy, and halogen; 7 R2 represents hydrogen, (C1-4)alkyl, (C1-4)alkoxy, halogen, or cyano; R3 represents hydrogen, alkyl, (C1-4)alkoxy, (C1-3)fluoroalkyl, or halogen; R4 represents en, (C1-4)alkyl, (C1-3)fluoroalkyl, or halogen; R5 represents one optional substituent on any ring carbon atom of the line ring, 5 wherein said substituent independently is methyl or ethyl; and Q represents CR6; or, in case R2 is (C1-4)alkyl or (C1-4)alkoxy, Q represents CR6 or N; wherein R6 represents en, fluoro or methyl; or a pharmaceutically acceptable salt thereof.

In another aspect, the invention provides a pharmaceutical composition comprising, as active 10 principle, one or more compounds according to the invention, or a pharmaceutically acceptable salt f, and at least one therapeutically inert excipient.

In another aspect, the invention provides a use of a nd according to the invention, or of a pharmaceutically acceptable salt f, in the preparation of a medicament for the prevention or treatment of a disease selected from the group consisting of y disorders, 15 addiction disorders, mood disorders, and te disorders. 1) Herein described are compounds of the formula (I) Formula (I) wherein 20 Ar1 represents a 5- or 6-membered heteroaryl selected from the group consisting of yl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; n said heteroaryl is unsubstituted, 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; 25 R1 represents one optional substituent selected from (C1-4)alkyl, (C1-4)alkoxy, hydroxy, and halogen; 8 R2 represents hydrogen, (C1-4)alkyl, (C1-4)alkoxy, halogen, or cyano; R3 represents en, (C1-4)alkyl, (C1-4)alkoxy, (C1-3)fluoroalkyl, or halogen; R4 represents en, (C1-4)alkyl, (C1-3)fluoroalkyl, or n; R5 represents one optional substituent on any ring carbon atom of the morpholine ring, 5 wherein said substituent independently is methyl or ethyl; and Q represents CR6; or, in case R2 is (C1-4)alkyl or alkoxy, Q represents CR6 or N; wherein R6 represents hydrogen, fluoro or methyl. 2) A second sure s to nds according to disclosure 1), wherein the morpholine ring of the compounds of formula (I): 10 is a ring selected from the group consisting of: O N , , , , , and ; Ar1 represents a 5- or 6-membered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, 15 and pyridazinyl; wherein said heteroaryl is unsubstituted or mono-substituted with (C1-4)alkyl (especially unsubstituted, or in case said heteroaryl is pyrimidinyl, optionally monosubstituted with methyl); R1 represents one optional substituent selected from methyl, methoxy, hydroxy, and halogen; R2 represents hydrogen, methyl, methoxy, halogen, or cyano; 20 R3 represents hydrogen, methyl, methoxy, trifluoroalkyl, or n; R4 represents hydrogen, methyl, trifluoroalkyl, or halogen; Q represents CR6; or, in case R2 is methyl, Q ents CR6 or N; wherein R6 represents en, fluoro or methyl. 9 3) A further disclosure relates to compounds according to disclosures 1) or 2), wherein the morpholine ring of the compounds of formula (I): is a ring selected from the group consisting of: 5 , , , , and . 4) Another disclosure relates to nds according to disclosures 1) or 2), wherein the morpholine ring of the compounds of formula (I): represents , or . 10 5) A further disclosure relates to compounds according to disclosures 1) or 2), n the morpholine ring of the compounds of a (I): represents . 10 6) A further disclosure relates to nds of formula (I) according to disclosure 1) which are also nds of the formula (II) Formula (II) 5 wherein Ar1 represents a 5- or 6-membered heteroaryl selected from the group consisting of yl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, zolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein said heteroaryl is unsubstituted, mono-, or di-substituted, wherein the substituents are independently selected from the group ting of (C1-4)alkyl, 10 (C1-4)alkoxy, halogen, cyano, (C1-3)fluoroalkyl, and (C1-3)fluoroalkoxy; R1 represents one optional substituent selected from (C1-4)alkyl, (C1-4)alkoxy, and halogen; R2 represents hydrogen, (C1-4)alkyl, (C1-4)alkoxy, halogen, or cyano; R3 represents hydrogen, (C1-4)alkyl, (C1-4)alkoxy, or halogen; R4 represents hydrogen, or n; 15 Q represents CH; or, in case R2 is (C1-4)alkyl or alkoxy, Q ents CH, CF or N. 7) Another disclosure relates to compounds according to any one of disclosures 1) to 6), wherein Ar1 represents pyrrolyl, pyrazolyl, [1,2,3]triazolyl, ]triazolyl, [1,2,4]triazolyl, oxazolyl, thiazolyl, [1,2,4]oxadiazolyl, thiophenyl, pyridinyl, pyridinyl, pyridinyl, pyrimidinyl, nyl, and pyridazinyl, which groups are 20 unsubstituted or mono-substituted with (C1-4)alkyl (especially methyl)). 8) Another disclosure relates to compounds according to any one of disclosures 1) to 6), wherein Ar1 represents pyrrolyl, pyrazolyl, [1,2,3]triazolyl, oxazolyl, thiophenyl, pyridinyl, pyridinyl, pyrimidinyl, nyl, and pyridazinyl, which groups are unsubstituted or mono-substituted, wherein the substituents are independently selected from 25 (C1-4)alkyl. 11 9) Another disclosure relates to compounds according to any one of disclosures 1) to 6), wherein Ar 1 represents a 5- or 6-membered heteroaryl ed from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxadiazolyl, thiophenyl, 2-pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein said heteroaryl is unsubstituted, or in case said heteroaryl is dinyl, 5 optionally mono-substituted with methyl. 10) Another disclosure relates to compounds according to any one of disclosures 1) to 6), wherein Ar 1 represents a 5- or 6-membered heteroaryl selected from the group consisting of lyl, triazolyl, oxadiazolyl, and dinyl; wherein said heteroaryl is unsubstituted, or in case said heteroaryl is pyrimidinyl, optionally ubstituted with . 10 11) Another disclosure relates to compounds according to any one of disclosures 1) to 6), n Ar1 represents pyrrolyl, lyl, [1,2,3]triazolyl, [1,2,4]oxadiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl, which groups are unsubstituted, or in case of pyrimidinyl, optionally mono-substituted with methyl. 12) A preferred disclosure s to compounds according to any one of disclosures 1) to 6), 15 wherein Ar 1 represents pyrazolyl, [1,2,3]triazolyl, ]oxadiazolyl, and pyrimidin yl, which groups are unsubstituted, or in case of pyrimidinyl, optionally mono-substituted with methyl. 13) Another preferred disclosure relates to compounds according to any one of disclosures 1) to 6), wherein Ar 1 represents unsubstituted [1,2,4]oxadiazolyl, or unsubstituted 20 [1,2,3]triazolyl. 14) Another disclosure relates to compounds according to any one of disclosures 1) to 6), wherein Ar 1 represents tituted pyrazolyl, or unsubstituted [1,2,3]triazolyl. 15) Another preferred disclosure relates to compounds according to any one of disclosures 1) to 6), wherein Ar 1 represents unsubstituted ]triazolyl. 25 16) Another disclosure relates to compounds ing to any one of disclosures 1) to 15), wherein R1 is absent, or R1 represents (C1-4)alkoxy (especially methoxy). 17) Another disclosure relates to compounds according to any one of disclosures 1) to 15), wherein R1 is absent, or R1 ents methoxy in position 4 of the phenyl ring (i.e. in para position to the point of attachment of the -CH2- group which links the phenyl ring to the rest of 30 the molecule and ortho to the point of attachment of Ar1). 18) Another disclosure relates to compounds according to any one of disclosures 1) to 15), wherein R1 is absent; or R1 represents n (especially fluoro or chloro) in position 2 or 3 of the phenyl ring; or R1 represents methyl in position 2, 3, or 4 of the phenyl ring; or R1 represents methoxy in position 4 of the phenyl ring [it being understood that the point of 12 attachment of the -CH2- group which links the phenyl ring to the rest of the le is position 1, and the point of attachment of Ar1 is in position 5 of the phenyl ring]. 19) Another disclosure relates to compounds according to any one of disclosures 1) to 15), wherein R1 is absent, or R1 represents halogen (especially fluoro or chloro) in position 2 of 5 the phenyl ring (i.e. in para position to the point of attachment of Ar1). 20) Another disclosure relates to compounds according to any one of sures 1) to 19), wherein R2 represents hydrogen, methyl, methoxy, cyano, fluoro, or chloro; R3 represents hydrogen, methyl, methoxy, or ; R4 represent hydrogen, or ; and Q ents CR6; or, in case R2 is methyl, Q represents CH; or, in case R2 is (C1-4)alkyl or (C1-4)alkoxy, Q 10 represents CH, or N. 21) A preferred sure relates to compounds according to any one of disclosures 1) to 5), or 7) to 19); wherein R2 ents hydrogen, methyl, methoxy, cyano, fluoro, or chloro; R3 represents hydrogen, methyl, trifluoromethyl, fluoro, or chloro; R4 represent hydrogen, methyl, trifluoromethyl, or fluoro; and Q represents CR6; or, in case R2 is methyl, Q 15 represents CR6 or N; wherein R6 ents hydrogen, fluoro or methyl. 22) Another disclosure s to compounds according to any one of disclosures 1) to 19), wherein R2 represents hydrogen, , methoxy, cyano, fluoro, or chloro. 23) Another sure relates to nds according to any one of disclosures 1) to 19) or 21), wherein R2 represents hydrogen, fluoro, or chloro. 20 24) Another sure relates to compounds according to any one of disclosures 1) to 5), 7) to 19), 21) or 23), wherein R3 represents hydrogen, methyl, trifluoromethyl, or chloro. 25) Another disclosure s to compounds according to any one of disclosures 1) to 19), or 22), wherein R3 represents hydrogen, methyl, methoxy, or fluoro. 26) r disclosure relates to compounds according to any one of disclosures 1) to 5), 7) 25 to 19), 21), 23), or 24), wherein R4 represents hydrogen or . 27) Another disclosure relates to compounds according to any one of disclosures 1) to 19), 22) or 25), wherein R4 represents hydrogen, or fluoro. 28) Another disclosure relates to compounds according to any one of disclosures 1) to 19), wherein R2, R3 and R4 represent hydrogen; or R2 represents methyl, and R3 and R4 represent 30 hydrogen; or R2 represents methoxy, and R3 and R4 represent hydrogen; or R2 represents , and R3 and R4 represent hydrogen; or R3 represents methyl, and R2 and R4 represent en; or R2 and R3 represent methyl, and R4 represents hydrogen; or R2 represents methoxy, R3 represents methyl or methoxy, and R4 represents hydrogen. 13 29) Another disclosure relates to compounds according to any one of disclosures 1) to 28), wherein Q represents CH; or, in case R2 is (C1-4)alkyl or (C1-4)alkoxy, Q represents CH, or N. 30) Another disclosure relates to compounds according to any one of disclosures 1) to 28), wherein R2 is methyl and Q represents N. 5 31) Another disclosure relates to compounds according to any one of disclosures 1) to 5), 7) to 19), 21), 23), 24), or 26), wherein Q represents CR6; wherein R6 represents hydrogen, fluoro or . 32) A preferred disclosure relates to compounds according to any one of sures 1) to 28), wherein Q represents CH. 10 33) Another preferred disclosure s to compounds according to any one of sures 1) to 5), or 7) to 19), wherein R2 represents hydrogen or chloro; R3 ents hydrogen, chloro, methyl or trifluoromethyl, R4 represent hydrogen or methyl; and Q represents CH. 34) Another preferred disclosure relates to nds according to any one of the disclosures 1) to 5), or 7) to 19), wherein the group 15 is a group independently selected from the following groups A) to F): A) ; B) 20 ; C) ; D) ; 14 E) ; F) ; 5 wherein each of the above groups A) to F) form a particular sub-disclosure. 35) Another preferred disclosure relates to compounds according to any one of the disclosures 1) to 5), or 7) to 19), wherein the group is a group selected from the group consisting of the following groups A) and B): 10 A) ; B) ; wherein the groups A) and B) each form a particular sub-disclosure. 15 36) Another sure relates to compounds according to any one of the disclosures 1) to 19) wherein the group is a group ed from the group consisting of: 15 . 37) Another disclosure relates to compounds ing to any one of the disclosures 1) to 5), or 20) to 36), wherein the group 5 is a group independently selected from the following groups A) to H): A) ; B) ; 10 C) ; D) ; 16 E) ; F) ; 5 G) ; H) ; wherein the groups A) to F), and especially the groups A) to D), each form a red sub- 10 disclosure. 38) Another disclosure relates to compounds according to any one of the disclosures 1) to 6), or 20) to 36), wherein the group is a group independently selected from the group consisting of any one the following groups 15 A), B) and C): A) ; 17 B) ; C) . 5 39) A preferred disclosure relates to compounds according to any one of the disclosures 1) to 6), or 20) to 36), wherein the group is a group independently selected from the group ting of any one the following groups A), B) and C): 10 A) ; B) ; C) 15 . 40) Another preferred disclosure relates to nds according to any one of the disclosures 1) to 6), or 20) to 36), wherein the group is a group selected from the group consisting of the following groups A) and B): 18 A) ; and B) . 5 41) Herein described are compounds of the formula (I) as d in disclosure 1), compounds of the formula (II) as d in disclosure 6); or to such compounds further d by the characteristics of any one of disclosures 2) to 40), under consideration of their respective dependencies; to pharmaceutically able salts thereof; and to the use of such compounds as medicaments ally in the treatment of mental health disorders 10 relating to orexinergic ctions, which disorders are as d below and which are especially selected from anxiety disorders, addiction disorders, mood disorders, and appetite disorders. For avoidance of any doubt, especially the following embodiments relating to the nds of formula (I) and (II) are thus possible and intended and herewith specifically disclosed in individualized form: 15 2+1, 5+1, 7+1, 7+2+1, 7+5+1, 12+1, 12+2+1, 12+5+1, 13+1, 13+2+1, , 15+1, 15+2+1, 15+5+1, 19+1, , 19+5+1, , 19+7+2+1, 19+7+5+1, 19+12+1, 2+1, 19+12+5+1, 19+13+1, 19+13+2+1, 19+13+5+1, 19+15+1, 19+15+2+1, 19+15+5+1, 21+1, 21+2+1, 21+5+1, 21+7+1, 21+7+2+1, 21+7+5+1, 21+12+1, 21+12+2+1, 21+12+5+1, 21+13+1, 21+13+2+1, 5+1, 21+15+1, 21+15+2+1, 21+15+5+1, 21+19+1, 21+19+2+1, 21+19+5+1, 21+19+7+1, 21+19+7+2+1, 21+19+7+5+1, 21+19+12+1, 21+19+12+2+1, 20 21+19+12+5+1, 21+19+13+1, 21+19+13+2+1, 21+19+13+5+1, 21+19+15+1, 21+19+15+2+1, 21+19+15+5+1, 32+1, 32+2+1, 32+5+1, , 32+7+2+1, 32+7+5+1, 32+12+1, 32+12+2+1, 32+12+5+1, 32+13+1, 32+13+2+1, 32+13+5+1, 32+15+1, 32+15+2+1, 32+15+5+1, 32+19+1, 32+19+2+1, 32+19+5+1, 32+19+7+1, 32+19+7+2+1, 32+19+7+5+1, 32+19+12+1, 32+19+12+2+1, 32+19+12+5+1, 32+19+13+1, 32+19+13+2+1, 13+5+1, 15+1, 32+19+15+2+1, 32+19+15+5+1, 32+21+1, 32+21+2+1, 32+21+5+1, 32+21+7+1, 25 32+21+7+2+1, 32+21+7+5+1, 32+21+12+1, 32+21+12+2+1, 32+21+12+5+1, 32+21+13+1, 32+21+13+2+1, 32+21+13+5+1, 32+21+15+1, 32+21+15+2+1, 32+21+15+5+1, 32+21+19+1, 32+21+19+2+1, 32+21+19+5+1, 32+21+19+7+1, 32+21+19+7+2+1, 32+21+19+7+5+1, 32+21+19+12+1, 32+21+19+12+2+1, 32+21+19+12+5+1, 32+21+19+13+1, 32+21+19+13+2+1, 32+21+19+13+5+1, 32+21+19+15+1, 32+21+19+15+2+1, 32+21+19+15+5+1, 33+1, 33+2+1, 33+5+1, 33+7+1, 33+7+2+1, 33+7+5+1, 33+12+1, 33+12+2+1, 33+12+5+1, 30 33+13+1, 33+13+2+1, 33+13+5+1, 33+15+1, 33+15+2+1, 33+15+5+1, 33+19+1, 33+19+2+1, 5+1, 33+19+7+1, 33+19+7+2+1, 7+5+1, 33+19+12+1, 33+19+12+2+1, 33+19+12+5+1, 13+1, 33+19+13+2+1, 33+19+13+5+1, 33+19+15+1, 33+19+15+2+1, 33+19+15+5+1, 34+1, 34+2+1, 34+5+1, 34+7+1, 19 34+7+2+1, 34+7+5+1, 34+12+1, 34+12+2+1, 34+12+5+1, 34+13+1, 34+13+2+1, 34+13+5+1, 34+15+1, 34+15+2+1, 5+1, 34+19+1, 34+19+2+1, 34+19+5+1, 34+19+7+1, 34+19+7+2+1, 34+19+7+5+1, 34+19+12+1, 34+19+12+2+1, 34+19+12+5+1, 34+19+13+1, 34+19+13+2+1, 13+5+1, 34+19+15+1, 34+19+15+2+1, 34+19+15+5+1, 35+1, 35+2+1, 35+5+1, 35+7+1, 35+7+2+1, 35+7+5+1, 35+12+1, 35+12+2+1, 5 35+12+5+1, 35+13+1, 35+13+2+1, 35+13+5+1, 35+15+1, 35+15+2+1, 35+15+5+1, 35+19+1, 35+19+2+1, 35+19+5+1, 35+19+7+1, 35+19+7+2+1, 35+19+7+5+1, 12+1, 35+19+12+2+1, 35+19+12+5+1, 35+19+13+1, 35+19+13+2+1, 35+19+13+5+1, 35+19+15+1, 35+19+15+2+1, 35+19+15+5+1; 37+1, 37+2+1, 37+5+1, 37+21+1, 37+21+2+1, 37+21+5+1, 1, 37+32+2+1, 37+32+5+1, 37+33+1, 37+33+2+1, 37+33+5+1, 37+34+1, 37+34+2+1, 37+34+5+1, 37+35+1, 2+1, 37+35+5+1, 38+1, 38+2+1, 10 38+5+1, 38+21+1, 38+21+2+1, 38+21+5+1, 38+32+1, 38+32+2+1, 38+32+5+1, 38+33+1, 38+33+2+1, 38+33+5+1, 38+34+1, 2+1, 5+1, 38+35+1, 38+35+2+1, 38+35+5+1, 40+1, 40+2+1, 40+5+1, 40+21+1, 40+21+2+1, 40+21+5+1, 40+32+1, 40+32+2+1, 40+32+5+1, 40+33+1, 40+33+2+1, 40+33+5+1, 40+34+1, 40+34+2+1, 40+34+5+1, 40+35+1, 2+1, 40+35+5+1; 6+1, 7+6+1, 14+6+1, , 20+7+6+1, 6+1, 22+6+1, 22+7+6+1, 22+14+6+1, 25+6+1, 25+7+6+1, 15 25+14+6+1, 25+22+6+1, 25+22+7+6+1, 25+22+14+6+1, 27+6+1, 27+7+6+1, 27+14+6+1, 27+22+6+1, 27+22+7+6+1, 14+6+1, 27+25+6+1, 27+25+7+6+1, 27+25+14+6+1, 27+25+22+6+1, 27+25+22+7+6+1, 27+25+22+14+6+1, 28+6+1, +1, 28+14+6+1, 32+6+1, 32+7+6+1, 6+1, 32+22+6+1, 32+22+7+6+1, 32+22+14+6+1, 32+25+6+1, 32+25+7+6+1, 32+25+14+6+1, 22+6+1, 22+7+6+1, 32+25+22+14+6+1, 32+27+6+1, 32+27+7+6+1, 32+27+14+6+1, 32+27+22+6+1, 32+27+22+7+6+1, 20 32+27+22+14+6+1, 32+27+25+6+1, 32+27+25+7+6+1, 32+27+25+14+6+1, 32+27+25+22+6+1, 32+27+25+22+7+6+1, 25+22+14+6+1, 32+28+6+1, 32+28+7+6+1, 32+28+14+6+1, 36+6+1, 36+7+6+1, 6+1.

In the list above the numbers refer to the disclosures according to their numbering provided hereinabove whereas “+” indicates the dependency from another disclosure. The different 25 individualized disclosures are separated by commas. In other words, +5+1 ” for example refers to embodiment 40) depending on disclosure 35), depending on disclosure 5), depending on disclosure 1), i.e. disclosure “40+35+5+1 ” corresponds to the compounds of disclosure 1) further limited by all the es of the disclosures 5), 35), and 40).

The compounds of formula (I) and (II) contain at least one stereogenic center which is 30 situated in position 3 of the morpholine moiety. It is understood that the absolute configuration of said chiral center is as ed in a (I) and (II), i.e. it is in absolute (R) configuration.

In addition, the compounds of formula (I) (especially compounds of formula (I) in case R5 is other than hydrogen) and (II) may contain one or more stereogenic or asymmetric centers, 35 such as one or more asymmetric carbon atoms. The compounds of formula (I) and (II) may 20 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) and (II), which compounds are identical to the nds of 5 formula (I) and (II) 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 (II) and salts thereof are within the scope of the present invention.

Substitution of hydrogen with the heavier isotope 2H (deuterium) may lead to r 10 metabolic stability, ing e.g. in sed in-vivo ife or reduced dosage requirements, or may lead to d inhibition of cytochrome P450 enzymes, resulting e.g. in an ed safety profile. In one embodiment of the invention, the compounds of a (I) and (II) are not isotopically labelled, or they are labelled only with one or more deuterium atoms. In a sub-embodiment, the compounds of formula (I) and (II) are not isotopically 15 labelled at all. Isotopically labelled compounds of formula (I) and (II) 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 20 represents a 2-([1,2,3]triazolyl)-phenyl group.

Where the plural form is used for nds, 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) or (II) is to be understood as referring also to the 25 salts (and especially the pharmaceutically able salts) of such compounds, as appropriate and expedient.

The term "pharmaceutically acceptable salts" refers to non-toxic, inorg. or c acid and/or base addition salts. Reference can be made to "Salt selection for basic drugs", Int. J. Pharm. (1986), 33, 201-217. 30 The term “comprising” as used in this specification and claims means sting at least in part of”. When interpreting statements in this specification, and claims which include the term “comprising”, it is to be understood that other features that are additional to the features 21 ed by this term in each ent or claim may also be present. Related terms such as “comprise” and “comprised” are to be interpreted in similar manner.

In this ication where reference has been made to patent specifications, other external documents, or other s of information, this is generally for the purpose of providing a 5 context for discussing the features of the invention. Unless specifically stated otherwise, reference to such external documents is not to be construed as an admission that such documents, or such sources of ation, in any jurisdiction, are prior art, or form part of the common l knowledge in the art.

In the description in this ication reference may be made to subject matter that is not 10 within the scope of the claims of the current application. That subject matter should be readily identifiable by a person skilled in the art and may assist in putting into practice the invention as defined in the claims of this application.

Definitions provided herein are ed to apply uniformly to the compounds of formula (I) and (II) as defined in any one of sures 1) to 41), and, mutatis mutandis , throughout the 15 description and the claims unless an otherwise expressly set out definition es a broader or narrower definition. It is well understood that a definition or preferred definition of a term defines and may replace the tive term independently of (and in combination with) any definition or preferred definition of any or all other terms as defined herein.

The term “halogen” means fluorine, chlorine, or bromine, preferably fluorine or chlorine. 20 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 )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. 25 Preferred are methyl and ethyl. Most preferred is methyl.

The term “alkoxy”, used alone or in combination, refers to an alkyl-O- group wherein the alkyl group is as defined before. The term )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 (C 1-4)alkoxy group means a group of the a (C1-4)alkyl-O- in which the term “(C1-4)alkyl” 30 has the previously given significance. es of alkoxy groups are methoxy, ethoxy, npropoxy , 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 22 with fluorine. The term “(Cx-y)fluoroalkyl” (x and y each being an r) 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 5 trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl and 2,2,2-trifluoroethyl. Preferred are (C 1)fluoroalkyl groups such as trifluoromethyl.

The term oalkoxy” refers to an alkoxy group as defined before containing one to three carbon atoms in which one or more (and ly all) hydrogen atoms have been ed with fluorine. The term “(Cx-y)fluoroalkoxy” (x and y each being an integer) refers to a 10 fluoroalkoxy group as defined before containing x to y carbon atoms. For example 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. Representative examples of fluoroalkoxy groups include trifluoromethoxy, difluoromethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy and 2,2,2-trifluoroethoxy. Preferred are (C1)fluoroalkoxy groups such as trifluoromethoxy and 15 difluoromethoxy.

Particular examples of Ar 1 representing a "5- or 6-membered heteroaryl ed from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl, enyl, pyridinyl, pyrimidinyl, nyl, and pyridazinyl; wherein said heteroaryl is unsubstituted, mono-, or di-substituted, wherein the 20 substituents are independently selected from the group consisting of (C1-4)alkyl, (C1-4)alkoxy, halogen, cyano, (C1-3)fluoroalkyl, and (C1-3)fluoroalkoxy" are y pyrrolyl (in particular pyrrolyl), pyrazolyl (in ular pyrazolyl), triazolyl (in particular [1,2,3]triazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl), oxazolyl (in particular oxazolyl), thiazolyl (in particular thiazolyl), oxadiazolyl (in ular [1,2,4]oxadiazol 25 yl), thiophenyl (in particular thiophenyl), pyridinyl (in particular pyridinyl, pyridinyl, nyl), pyrimidinyl (in particular pyrimidinyl), nyl (in particular pyrazinyl), and pyridazinyl (in particular pyridazinyl). In a sub-embodiment, particular examples are pyrrol- 1-yl, pyrazolyl, ]triazolyl, oxazolyl, thiophenyl, pyridinyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl. In a r sub-embodiment, particular 30 examples are pyrazolyl, and especially ]triazolyl. The above mentioned groups may be unsubstituted or substituted as explicitly defined. Notably, they are unsubstituted, mono-, or di-substituted, wherein the substituents are ndently selected from (C 1-4)alkyl.

In a sub-embodiment, the above mentioned groups are unsubstituted or mono-substituted with (C1-4)alkyl (especially methyl). In a further sub-embodiment, the above mentioned 35 groups are unsubstituted, or, in the case of pyrimidinyl groups, unsubstituted or monosubstituted with alkyl (especially methyl). 23 42) A further disclosure relates to particular compounds of formula (I) according to sure 1) which are selected from the following compounds: [(R)(3-[1,2,4]Oxadiazolyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)-methanone; (5-Methyl[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,4]oxadiazolyl-benzyl)-morpholinyl]-methanone; 5 [(R)(4-Methoxypyridinyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)-methanone; [(R)(4-Methoxypyridinyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)-methanone; [(R)(4-Methoxypyrimidinyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)-methanone; [(R)(4-Methoxypyrazinyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)-methanone; [(R)(4-Methoxypyridazinyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)-methanone; 10 [(R)(4-Methoxythiazolyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)-methanone; -(4-Methoxyoxazolyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)-methanone; [(R)(4-Methoxythiophenyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)-methanone; (5-Methyl[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; [(R)(3-[1,2,3]Triazolyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)-methanone; 15 [(S)(3-[1,2,3]Triazolyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)-methanone; [(R)(4-Methoxypyrazolyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)-methanone; (5-Methyl[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; [(R)(3-Pyrazolyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)-methanone; (5-Methyl[1,2,3]triazolyl-phenyl)-[(R)(3-pyrimidinyl-benzyl)-morpholinyl]-methanone; 20 [(R)(3-Pyrimidinyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)-methanone; (5-Methyl[1,2,3]triazolyl-phenyl)-[(R)(3-pyrazolyl-benzyl)-morpholinyl]-methanone; (5-Fluoro[1,2,3]triazolyl-phenyl)-[(R)(3-pyrazolyl-benzyl)-morpholinyl]-methanone; (2-Fluoromethyl[1,2,3]triazolyl-phenyl)-[(R)(3-pyrazolyl-benzyl)-morpholinyl]-methanone; (4-Methyl[1,2,3]triazolyl-phenyl)-[(R)(3-pyrazolyl-benzyl)-morpholinyl]-methanone; 25 (5-Methyl[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,4]triazolyl-benzyl)-morpholinyl]-methanone; (5-Methyl[1,2,3]triazolyl-phenyl)-[(R)(3-pyridinyl-benzyl)-morpholinyl]-methanone; (5-Methyl[1,2,3]triazolyl-phenyl)-[(R)(3-pyridinyl-benzyl)-morpholinyl]-methanone; (5-Fluoro[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; (4-Methyl[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; 30 (5-Methyl[1,2,3]triazolyl-phenyl)-[(R)(3-pyridinyl-benzyl)-morpholinyl]-methanone; oromethyl[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; (5-Chloro[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; ,3]Triazolyl[(R)(3-[1,2,3]triazolyl-benzyl)-morpholinecarbonyl]-benzonitrile; (5-Methoxy[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; 35 (2-Fluoromethoxy[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; (4,5-Dimethoxy[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; 24 (4,5-Dimethyl[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; (4-Fluoro[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; (5-Methoxymethyl[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; (5-Methyl[1,2,3]triazolyl-phenyl)-[(R)(3-pyrrolyl-benzyl)-morpholinyl]-methanone; 5 {(R)[3-(4-Methyl-pyrimidinyl)-benzyl]-morpholinyl}-(5-methyl[1,2,3]triazolyl-phenyl)-methanone; {(R)[3-(4-Methyl-pyrimidinyl)-benzyl]-morpholinyl}-(2-[1,2,3]triazolyl-phenyl)-methanone; (5-Methyl[1,2,3]triazolyl-phenyl)-[(R)(3-pyrazinyl-benzyl)-morpholinyl]-methanone; [(R)(3-Oxazolyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)-methanone; (5-Methyl[1,2,3]triazolyl-phenyl)-[(R)(3-thiazolyl-benzyl)-morpholinyl]-methanone; 10 -(3-Thiazolyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)-methanone; (5-Methyl[1,2,3]triazolyl-phenyl)-[(R)(3-thiophenyl-benzyl)-morpholinyl]-methanone; [(R)(3-Thiophenyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)-methanone; (5-Methyl[1,2,3]triazolyl-phenyl)-[(R)(3-pyridazinyl-benzyl)-morpholinyl]-methanone; [(R)(3-Pyridazinyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)-methanone; 15 (2-Fluoromethyl[1,2,3]triazolyl-phenyl)-[(R)(3-pyrimidinyl-benzyl)-morpholinyl]-methanone; (5-Methoxy[1,2,3]triazolyl-phenyl)-[(R)(3-pyrimidinyl-benzyl)-morpholinyl]-methanone; (5-Chloro[1,2,3]triazolyl-phenyl)-[(R)(3-pyrimidinyl-benzyl)-morpholinyl]-methanone; hyl[1,2,3]triazolyl-pyridinyl)-[(R)(3-pyrazolyl-benzyl)-morpholinyl]-methanone; (6-Methyl[1,2,3]triazolyl-pyridinyl)-[(R)(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; and 20 (3-Fluoro[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-methanone. 43) In addition to the above-listed compounds, further particular compounds of formula (I) according to embodiment 1) are selected from the group consisting of: -(4-Hydroxypyrimidinyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)-methanone; -(2-Fluoro[1,2,3]triazolyl-benzyl)-morpholinyl]-(5-methyl[1,2,3]triazolyl-phenyl)-methanone; 25 [(R)(2-Fluoro[1,2,3]triazolyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)-methanone; [(R)(4-Methoxy[1,2,4]oxadiazolyl-benzyl)-morpholinyl]-(5-methyl[1,2,3]triazolyl-phenyl)- methanone; [(R)(4-Methoxy[1,2,4]oxadiazolyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)-methanone; [(R)(4-Methoxy[1,2,4]oxadiazolyl-benzyl)-morpholinyl]-(4-methyl[1,2,3]triazolyl-phenyl)- 30 methanone; (4-Fluoro[1,2,3]triazolyl-phenyl)-[(R)(4-methoxy[1,2,4]oxadiazolyl-benzyl)-morpholinyl]- methanone; [(R)(2-Fluoro[1,2,3]triazolyl-benzyl)-morpholinyl]-(4-methyl[1,2,3]triazolyl-phenyl)-methanone; [(R)(4-Methoxy[1,2,4]oxadiazolyl-benzyl)-morpholinyl]-(2-methyl[1,2,3]triazolyl-phenyl)- 35 methanone; (3-Methyl[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; 25 [(R)(4-Methyl[1,2,3]triazolyl-benzyl)-morpholinyl]-(5-methyl[1,2,3]triazolyl-phenyl)-methanone; [(R)(4-Methyl[1,2,3]triazolyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)-methanone; [(R)(4-Methyl[1,2,3]triazolyl-benzyl)-morpholinyl]-(4-methyl[1,2,3]triazolyl-phenyl)-methanone; [(3R,5R)Methyl(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)-methanone; 5 [(3R,5R)Methyl(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-(4-methyl[1,2,3]triazolyl-phenyl)- one; [(3R,5R)Methyl(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-(3-methyl[1,2,3]triazolyl-phenyl)- methanone; [(3S,5R)Methyl(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-(4-methyl[1,2,3]triazolyl-phenyl)- 10 methanone; [(3S,5R)Methyl(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-(3-methyl[1,2,3]triazolyl-phenyl)- methanone; [(3S,5R)Methyl(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-(5-methyl[1,2,3]triazolyl-phenyl)- methanone; 15 (4,5-Dimethyl[1,2,3]triazolyl-phenyl)-[(3S,5R)methyl(3-[1,2,3]triazolyl-benzyl)-morpholinyl]- methanone; imethyl[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; [(R)(3-[1,2,3]Triazolyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyltrifluoromethyl-phenyl)-methanone; (4-Chloro[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; 20 (4-Fluoromethoxy[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; (4,5-Dimethyl[1,2,3]triazolyl-phenyl)-[(R)(4-methyl[1,2,4]oxadiazolyl-benzyl)-morpholinyl]- methanone; (4,5-Difluoro[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,4]oxadiazolyl-benzyl)-morpholinyl]-methanone; hyl[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,4]oxadiazolyl-benzyl)-morpholinyl]-methanone; 25 (3-Fluoro[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,4]oxadiazolyl-benzyl)-morpholinyl]-methanone; (3-Methyl[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,4]oxadiazolyl-benzyl)-morpholinyl]-methanone; (5-Chloro[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,4]oxadiazolyl-benzyl)-morpholinyl]-methanone; (4,5-Dimethyl[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,4]oxadiazolyl-benzyl)-morpholinyl]-methanone; (4-Chloro[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,4]oxadiazolyl-benzyl)-morpholinyl]-methanone; 30 [(R)(3-[1,2,4]Oxadiazolyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyltrifluoromethyl-phenyl)-methanone; (5-Fluoro[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,4]oxadiazolyl-benzyl)-morpholinyl]-methanone; (3,5-Dimethyl[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,4]oxadiazolyl-benzyl)-morpholinyl]-methanone; [(R)(4-Chloro[1,2,4]oxadiazolyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)-methanone; (4,5-Difluoro[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; 35 (3,4-Dimethyl[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; (4-Methoxy[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; 26 imethyl[1,2,3]triazolyl-phenyl)-[(R)(2-fluoro[1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; [(R)(2-Fluoro[1,2,3]triazolyl-benzyl)-morpholinyl]-(4-methoxy[1,2,3]triazolyl-phenyl)-methanone; [(2S,5R)Methyl(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-(4-methyl[1,2,3]triazolyl-phenyl)- methanone; 5 R)Methyl(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-(3-methyl[1,2,3]triazolyl-phenyl)- methanone; (4,5-Dimethyl[1,2,3]triazolyl-phenyl)-[(2R,5R)methyl(3-[1,2,3]triazolyl-benzyl)-morpholinyl]- methanone; (3,4-Dimethyl[1,2,3]triazolyl-phenyl)-[(2R,5R)methyl(3-[1,2,3]triazolyl-benzyl)-morpholinyl]- 10 methanone; [(2R,5R)Methyl(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)-methanone; [(2R,5R)Methyl(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-(4-methyl[1,2,3]triazolyl-phenyl)- methanone; [(R)Methyl(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-(5-methyl[1,2,3]triazolyl-phenyl)-methanone; 15 (5-Chloromethyl[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; (4-Chloromethoxy[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; [(R)(3-Chloro[1,2,3]triazolyl-benzyl)-morpholinyl]-(4-methyl[1,2,3]triazolyl-phenyl)-methanone; [(R)(3-Chloro[1,2,3]triazolyl-benzyl)-morpholinyl]-(3-methyl[1,2,3]triazolyl-phenyl)-methanone; (3-Chloro[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; 20 [(2R,5R)Methyl(3-pyrimidinyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)-methanone; [(2R,5R)Methyl(3-pyrimidinyl-benzyl)-morpholinyl]-(5-methyl[1,2,3]triazolyl-phenyl)-methanone; [(2R,5R)Methyl(3-pyrimidinyl-benzyl)-morpholinyl]-(4-methyl[1,2,3]triazolyl-phenyl)-methanone; [(2R,5R)Methyl(3-pyrimidinyl-benzyl)-morpholinyl]-(3-methyl[1,2,3]triazolyl-phenyl)-methanone; (3,4-Dimethyl[1,2,3]triazolyl-phenyl)-[(2R,5R)methyl(3-pyrimidinyl-benzyl)-morpholinyl]- 25 one; (5-Chloro[1,2,3]triazolyl-phenyl)-[(2R,5R)methyl(3-pyrimidinyl-benzyl)-morpholinyl]-methanone; (4-Chloro[1,2,3]triazolyl-phenyl)-[(2R,5R)methyl(3-pyrimidinyl-benzyl)-morpholinyl]-methanone; [(2R,5R)(2-Fluoro[1,2,3]triazolyl-benzyl)methyl-morpholinyl]-(5-methyl[1,2,3]triazolyl-phenyl)- methanone; 30 [(2R,5R)(2-Fluoro[1,2,3]triazolyl-benzyl)methyl-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)- methanone; [(2R,5R)(2-Fluoro[1,2,3]triazolyl-benzyl)methyl-morpholinyl]-(4-methyl[1,2,3]triazolyl-phenyl)- methanone; [(2R,5R)(2-Fluoro[1,2,3]triazolyl-benzyl)methyl-morpholinyl]-(3-methyl[1,2,3]triazolyl-phenyl)- 35 methanone; [(R)(2-Methyl[1,2,3]triazolyl-benzyl)-morpholinyl]-(5-methyl[1,2,3]triazolyl-phenyl)-methanone; 27 [(R)(2-Chloro[1,2,3]triazolyl-benzyl)-morpholinyl]-(4-methyl[1,2,3]triazolyl-phenyl)-methanone; [(R)(2-Methyl[1,2,3]triazolyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)-methanone; -(2-Chloro[1,2,3]triazolyl-benzyl)-morpholinyl]-(3-methyl[1,2,3]triazolyl-phenyl)-methanone; [(R)(2-Methyl[1,2,3]triazolyl-benzyl)-morpholinyl]-(4-methyl[1,2,3]triazolyl-phenyl)-methanone; 5 [(R)(2-Methyl[1,2,3]triazolyl-benzyl)-morpholinyl]-(3-methyl[1,2,3]triazolyl-phenyl)-methanone; [(R)(2-Chloro[1,2,3]triazolyl-benzyl)-morpholinyl]-(5-methyl[1,2,3]triazolyl-phenyl)-methanone; [(R)(2-Chloro[1,2,3]triazolyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)-methanone; [(R)(2-Fluoro[1,2,3]triazolyl-benzyl)-morpholinyl]-(3-methyl[1,2,3]triazolyl-phenyl)-methanone; (4,5-Dimethyl[1,2,3]triazolyl-phenyl)-[(R)(2-fluoro[1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; 10 (5-Chloro[1,2,3]triazolyl-phenyl)-[(R)(2-fluoro[1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; (4-Chloro[1,2,3]triazolyl-phenyl)-[(R)(2-fluoro[1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; [(R)(2-Fluoro[1,2,3]triazolyl-benzyl)-morpholinyl]-(5-methoxy[1,2,3]triazolyl-phenyl)-methanone; (2-Fluoromethyl[1,2,3]triazolyl-phenyl)-[(R)(2-fluoro[1,2,3]triazolyl-benzyl)-morpholinyl]- one; 15 (2-Fluoromethoxy[1,2,3]triazolyl-phenyl)-[(R)(2-fluoro[1,2,3]triazolyl-benzyl)-morpholinyl]- methanone; [(R)(2-Fluoro[1,2,3]triazolyl-benzyl)-morpholinyl]-(5-methoxymethyl[1,2,3]triazolyl-phenyl)- methanone; (3-Chloro[1,2,3]triazolyl-phenyl)-[(R)(2-fluoro[1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; 20 [(R)(2-Fluoro[1,2,3]triazolyl-benzyl)-morpholinyl]-(2-fluoro[1,2,3]triazolyl-phenyl)-methanone; (4,5-Difluoro[1,2,3]triazolyl-phenyl)-[(R)(2-fluoro[1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; -(2-Fluoro[1,2,3]triazolyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyltrifluoromethyl-phenyl)- methanone; (4-Chloromethoxy[1,2,3]triazolyl-phenyl)-[(R)(2-fluoro[1,2,3]triazolyl-benzyl)-morpholinyl]- 25 methanone; [(2R,5R)(2-Fluoro[1,2,3]triazolyl-benzyl)methyl-morpholinyl]-(5-methyl[1,2,3]triazolyl-phenyl)- methanone; [(2R,5R)(2-Fluoro[1,2,3]triazolyl-benzyl)methyl-morpholinyl]-(4-methyl[1,2,3]triazolyl-phenyl)- methanone; 30 [(2R,5R)Ethyl(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-(5-methyl[1,2,3]triazolyl-phenyl)-methanone; [(2R,5R)Ethyl(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)-methanone; [(2R,5R)Ethyl(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-(4-methyl[1,2,3]triazolyl-phenyl)-methanone; [(R)(3-Fluoro[1,2,3]triazolyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)-methanone; [(R)(3-Fluoro[1,2,3]triazolyl-benzyl)-morpholinyl]-(4-methyl[1,2,3]triazolyl-phenyl)-methanone; 35 [(2R,5R)(2-Fluoropyrimidinyl-benzyl)methyl-morpholinyl]-(5-methyl[1,2,3]triazolyl-phenyl)- methanone; 28 [(2R,5R)(2-Fluoropyrimidinyl-benzyl)methyl-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)-methanone; R)(2-Fluoropyrimidinyl-benzyl)methyl-morpholinyl]-(4-methyl[1,2,3]triazolyl-phenyl)- methanone; [(2R,5R)(2-Fluoropyrimidinyl-benzyl)methyl-morpholinyl]-(3-methyl[1,2,3]triazolyl-phenyl)- 5 methanone; (3,4-Dimethyl[1,2,3]triazolyl-phenyl)-[(2R,5R)(2-fluoropyrimidinyl-benzyl)methyl-morpholinyl]- one; (5-Chloro[1,2,3]triazolyl-phenyl)-[(2R,5R)(2-fluoropyrimidinyl-benzyl)methyl-morpholinyl]- methanone; 10 (4-Chloro[1,2,3]triazolyl-phenyl)-[(2R,5R)(2-fluoropyrimidinyl-benzyl)methyl-morpholinyl]- methanone; (3-Chloro[1,2,3]triazolyl-phenyl)-[(2R,5R)(2-fluoropyrimidinyl-benzyl)methyl-morpholinyl]- methanone; [(R)(2-Fluoropyrimidinyl-benzyl)-morpholinyl]-(5-methyl[1,2,3]triazolyl-phenyl)-methanone; 15 [(R)(2-Fluoropyrimidinyl-benzyl)-morpholinyl]-(4-methyl[1,2,3]triazolyl-phenyl)-methanone; [(R)(2-Fluoropyrimidinyl-benzyl)-morpholinyl]-(3-methyl[1,2,3]triazolyl-phenyl)-methanone; (3,4-Dimethyl[1,2,3]triazolyl-phenyl)-[(R)(2-fluoropyrimidinyl-benzyl)-morpholinyl]-methanone; (5-Chloro[1,2,3]triazolyl-phenyl)-[(R)(2-fluoropyrimidinyl-benzyl)-morpholinyl]-methanone; (4-Chloro[1,2,3]triazolyl-phenyl)-[(R)(2-fluoropyrimidinyl-benzyl)-morpholinyl]-methanone; 20 (3-Chloro[1,2,3]triazolyl-phenyl)-[(R)(2-fluoropyrimidinyl-benzyl)-morpholinyl]-methanone; [(2S,3R)Methyl(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-(5-methyl[1,2,3]triazolyl-phenyl)- methanone; [(2S,3R)Methyl(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-(4-methyl[1,2,3]triazolyl-phenyl)- methanone; 25 R)Methyl(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-(3-methyl[1,2,3]triazolyl-phenyl)- methanone; [(2R,5R)(2-Fluoropyridazinyl-benzyl)methyl-morpholinyl]-(4-methyl[1,2,3]triazolyl-phenyl)- methanone; [(R)(2-Fluoropyridazinyl-benzyl)-morpholinyl]-(4-methyl[1,2,3]triazolyl-phenyl)-methanone; 30 [(2R,3R)Methyl(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-(5-methyl[1,2,3]triazolyl-phenyl)- methanone; [(2R,3R)Methyl(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-(4-methyl[1,2,3]triazolyl-phenyl)- methanone; [(R)(2-Chloro[1,2,3]triazolyl-benzyl)-morpholinyl]-(3,4-dimethyl[1,2,3]triazolyl-phenyl)-methanone; 35 [(R)(2-Chloro[1,2,3]triazolyl-benzyl)-morpholinyl]-(4-chloro[1,2,3]triazolyl-phenyl)-methanone; [(R)(2-Chloro[1,2,3]triazolyl-benzyl)-morpholinyl]-(3-chloro[1,2,3]triazolyl-phenyl)-methanone; 29 (3-Chloro[1,2,3]triazolyl-phenyl)-[(2R,5R)methyl(3-[1,2,3]triazolyl-benzyl)-morpholinyl]- methanone; (3-Chloro[1,2,3]triazolyl-phenyl)-[(2R,5R)(2-fluoro[1,2,3]triazolyl-benzyl)methyl-morpholinyl]- methanone; 5 -(2-Fluoro[1,2,4]oxadiazolyl-benzyl)-morpholinyl]-(5-methyl[1,2,3]triazolyl-phenyl)-methanone; [(R)(2-Fluoro[1,2,4]oxadiazolyl-benzyl)-morpholinyl]-(4-methyl[1,2,3]triazolyl-phenyl)-methanone; (5-Chloro[1,2,3]triazolyl-phenyl)-[(R)(2-fluoro[1,2,4]oxadiazolyl-benzyl)-morpholinyl]-methanone; [(R)(2-Fluoro[1,2,4]oxadiazolyl-benzyl)-morpholinyl]-(3-methyl[1,2,3]triazolyl-phenyl)-methanone; (4-Chloro[1,2,3]triazolyl-phenyl)-[(R)(2-fluoro[1,2,4]oxadiazolyl-benzyl)-morpholinyl]-methanone; 10 imethyl[1,2,3]triazolyl-phenyl)-[(R)(2-fluoro[1,2,4]oxadiazolyl-benzyl)-morpholinyl]- methanone; (3-Chloro[1,2,3]triazolyl-phenyl)-[(R)(2-fluoro[1,2,4]oxadiazolyl-benzyl)-morpholinyl]-methanone; (3,4-Dimethyl[1,2,3]triazolyl-phenyl)-[(R)(2-fluoro[1,2,4]oxadiazolyl-benzyl)-morpholinyl]- methanone; 15 [(R)(3-[1,2,3]Triazolyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyltrifluoromethyl-phenyl)-methanone; [(R)(2-Fluoro[1,2,3]triazolyl-benzyl)-morpholinyl]-(4-methyl[1,2,3]triazolyl-phenyl)-methanone; (5-Chloro[1,2,3]triazolyl-phenyl)-[(2R,5R)methyl(3-[1,2,3]triazolyl-benzyl)-morpholinyl]- one; (4-Chloro[1,2,3]triazolyl-phenyl)-[(2R,5R)methyl(3-[1,2,3]triazolyl-benzyl)-morpholinyl]- 20 methanone; (5-Chloro[1,2,3]triazolyl-phenyl)-[(2R,5R)(2-fluoro[1,2,3]triazolyl-benzyl)methyl-morpholinyl]- one; (4-Chloro[1,2,3]triazolyl-phenyl)-[(2R,5R)(2-fluoro[1,2,3]triazolyl-benzyl)methyl-morpholinyl]- methanone; 25 [(R)(2-Methylpyrazolyl-benzyl)-morpholinyl]-(5-methyl[1,2,3]triazolyl-phenyl)-methanone; [(R)(2-Methylpyrazolyl-benzyl)-morpholinyl]-(4-methyl[1,2,3]triazolyl-phenyl)-methanone; [(R)(2-Methylpyrazolyl-benzyl)-morpholinyl]-(3-methyl[1,2,3]triazolyl-phenyl)-methanone; (4-Chloro[1,2,3]triazolyl-phenyl)-[(R)(2-methyl[1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; [(R)(4-Methylpyrimidinyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)-methanone; 30 [(R)(4-Methylthiazolyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)-methanone; and [(R)(4-Chloropyrimidinyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)-methanone. 44) A further embodiment relates to particular compounds of formula (I) according to embodiment 1) are selected from the group consisting of: (4-Chloro[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; 35 (4-Methyl[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; [(R)(3-[1,2,3]Triazolyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyltrifluoromethyl-phenyl)-methanone; 30 oro[1,2,3]triazolyl-phenyl)-[(R)(2-fluoro[1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; (3,4-Dimethyl[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; [(R)(2-Chloro[1,2,3]triazolyl-benzyl)-morpholinyl]-(4-methyl[1,2,3]triazolyl-phenyl)-methanone; [(R)(2-Fluoro[1,2,3]triazolyl-benzyl)-morpholinyl]-(4-methyl[1,2,3]triazolyl-phenyl)-methanone; 5 [(R)(3-[1,2,4]Oxadiazolyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyltrifluoromethyl-phenyl)-methanone; (5-Chloro[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; (3-Methyl[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; (3,4-Dimethyl[1,2,3]triazolyl-phenyl)-[(R)(2-fluoro[1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; [(R)(3-[1,2,3]Triazolyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)-methanone; and 10 [(2R,5R)(2-Fluoro[1,2,3]triazolyl-benzyl)methyl-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)- methanone.

The compounds of a (I) and (II) according to any one of disclosures 1) to 44) and their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of ceutical compositions for enteral (such especially oral) or parenteral administration 15 (including topical application or inhalation).

The production of the ceutical 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 20 (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 als and, if desired, usual pharmaceutical adjuvants.

Also described herein is a method for the prevention or treatment of a disease or disorder 25 mentioned herein comprising administering to a subject a pharmaceutically active amount of a compound of formula (I) and (II) according to any one of disclosures 1) to 44).

In a preferred embodiment, 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. 30 For nce 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 tion or treatment of said diseases.

The nds of formula (I) and (II) according to any one of sures 1) to 44) are useful for the tion or treatment of disorders ng to orexinergic dysfunctions. 31 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, notably of the orexin 1 receptor. The above mentioned disorders may in particular be defined as comprising anxiety disorders, addiction 5 disorders, mood disorders, or appetite disorders, as well as cognitive dysfunctions or sleep disorders. Especially, the above mentioned disorders comprise anxiety disorders, addiction disorders and mood ers, notably anxiety disorders and addiction disorders.

In addition, r disorders relating to orexinergic dysfunctions are selected from treating, controlling, rating or reducing the risk of epilepsy, including absence epilepsy; treating 10 or controlling pain, including neuropathic pain; treating or controlling Parkinson's e; ng or controlling psychosis including acute mania and bipolar disorder; treating or controlling , particularly ischemic or haemorrhagic stroke; blocking an emetic se i.e. nausea and vomiting; and treating or controlling agitation, in ion or co-morbid with another medical condition. 15 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 ers (PTSDs). Anxiety disorders may, thus, be defined as comprising generalized anxiety ers (GAD), obsessive compulsive disorders (OCDs), acute stress disorders, posttraumatic stress disorders 20 (PTSDs), panic anxiety disorders (PADs) including panic attacks, phobic anxieties (PHOBs), specific phobia, social phobia (social anxiety disorder), avoidance, form disorders including hypochondriasis, separation y disorder, anxiety disorders due to a general medical condition, and substance induced anxiety disorders. In a sub-embodiment, particular examples of circumscribed threat d anxiety disorders are phobic anxieties or post- 25 traumatic stress disorders. Anxiety disorders especially include lized anxiety disorders, post-traumatic stress disorders, obsessive sive disorders, panic s, phobic anxieties, and avoidance.

Addiction disorders may be defined as addictions to one or more ing stimuli, notably to one rewarding stimulus. Such rewarding stimuli may be of either natural or synthetic origin. 30 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 tic origin [such as gambling, or 35 et/IT (such as rate gaming, or inappropriate involvement in online social 32 networking sites or blogging), and the like]}. In a sub-embodiment, addiction disorders relating to psychoactive substance use, abuse, seeking and reinstatement are d as all types of psychological or physical addictions and their related tolerance and dependence components. Substance-related ion ers especially include substance use 5 disorders such as substance dependence, substance craving and substance abuse; substance-induced disorders such as substance intoxication, substance withdrawal, and substance-induced um. The expression "prevention or treatment of addictions" (i.e. preventive or curative treatment of ts who have been diagnosed as having an addiction, or as being at risk of developing addictions) refers to diminishing addictions, 10 y diminishing the onset of addictions, to weakening their maintenance, to facilitating awal, to tating abstinence, or to attenuating, decreasing or preventing the occurrence of reinstatement of addiction ially to diminishing the onset of addictions, to facilitating withdrawal, or to attenuating, decreasing or preventing the occurrence of reinstatement of addiction). 15 Mood disorders include major depressive e, manic episode, mixed episode and hypomanic episode; depressive disorders including major depressive disorder, dysthymic disorders; bipolar disorders including bipolar I disorder, bipolar II disorder (recurrent major depressive episodes with hypomanic episodes), cyclothymic disorder; mood ers including mood er due to a general medical condition (including the es with 20 depressive features, with major depressive-like episode, with manic features, and with mixed features), substance-induced mood er (including the subtypes with depressive features, with manic features, and with mixed features). Such mood ers are especially major depressive episode, major depressive disorder, mood disorder due to a general l condition; and substance-induced mood disorder. 25 Appetite disorders comprise eating disorders and drinking ers. 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 30 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 ers include polydipsias in psychiatric disorders and all other types 35 of ive fluid intake. Pathologically modified food intake may result from disturbed te ction or aversion for food); altered energy balance (intake vs. expenditure); 33 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, 5 cardiovascular and immune disorders, and also occurring transiently or chronically in the normal, healthy, young, adult, or especially aging population. Cognitive dysfunctions ally 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 10 such as frontotemporal dementia, or dementia with Lewy bodies, or (especially) mer'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) 15 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 tions.

Sleep disorders comprise nias, parasomnias, sleep disorders associated with a general medical condition and substance-induced sleep disorders. In particular, dyssomnias 20 e intrinsic sleep disorders (especially insomnias, breathing-related sleep disorders, periodic limb nt disorder, and restless leg me), extrinsic sleep disorders, and circadian-rythm sleep disorders. Dyssomnias notably include insomnia, primary insomnia, idiopathic insomnia, insomnias ated with depression, emotional/mood disorders, aging, Alzheimer's e or ive impairment; REM sleep interruptions; ing-related 25 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 l disorders and sleep-wake transition disorders; notably parasomnias e nightmare disorder, sleep terror disorder, and alking disorder. Sleep ers associated with a general medical ion are in particular sleep 30 ers associated with diseases such as mental disorders, neurological disorders, neuropathic pain, and heart and lung es. Substance-induced sleep disorders include especially the subtypes ia 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 e all types of insomnias, sleep-related dystonias; restless leg 35 syndrome; sleep apneas; jet-lag syndrome; shift work sleep disorder, delayed or advanced sleep phase syndrome, or insomnias d to psychiatric disorders. In addition, sleep 34 disorders further include sleep disorders associated with aging; intermittent treatment of chronic insomnia; situational transient insomnia (new environment, noise) or term insomnia due to ; grief; pain or illness.

In the context of the present invention, it is to be understood that, in case certain 5 environmental ions such as stress or fear (wherein stress may be of social origin (e.g. social stress) or of physical origin (e.g. physical ), 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. 10 Also described herein are the compounds of formula (I) and (II), and/or to pharmaceutical itions comprising, as active principle, one or more compounds of formula (I) and / or (II) for use in the ent of the above-mentioned disorders relating to orexinergic dysfunctions, in combination with one or more further pharmaceutically active ingredients.

Preparation of compounds of a (I): 15 The compounds of formula (I) can be ed by the methods given below, by the methods given in the experimental part below 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 optimisation procedures. In some cases the final product may be further modified, for example, by manipulation of substituents to give 20 a new final product. These manipulations may include, but are not limited to, reduction, oxidation, alkylation, acylation, and ysis reactions which are commonly known to those skilled in the art. In some cases the order of carrying out the following reaction schemes, and/or reaction steps, may be varied to facilitate the reaction or to avoid unwanted reaction products. 25 Compounds of formula (I) of the present invention can be prepared according to the l sequence of reactions ed below wherein Q, Ar1, R1, R2, R3, R4 and R5 are as defined for formula (I). 35 Compounds of a (I) are prepared by reaction of an amine of Structure 1, or a salt such as a hydrochloride salt thereof, with an acid of Structure 2 in the ce of an amidecoupling reagent such as TBTU, HATU, EDC, DCC or PyBOP and a base like DIPEA or TEA in a solvent such as MeCN or DMF. Alternatively, coupling can be achieved via the 5 corresponding acid chloride of Structure 2, prepared conventionally using a chlorinating reagent like oxalyl chloride or l chloride.

Compounds of Structure 1 may be prepared by one of the synthetic pathways described below.

OH OH OH OH H NHBoc NH2 NH2 N O O Cl O R1 R1 R1 R1 I A-1 I A-2 I A-3 I A-4 O O O O O NH NH NH R1 R1 R1 I A-5 Ar1 Ar1 A-6 1 10 Reaction Scheme A nds of Structure 1 may be ed in analogy to the procedure described in WO2008047109 and as illustrated in Reaction Scheme A. A Boc-protected iodophenyl alanine derivative A-1, racemic or enantiomerically enriched, either commercially available or prepared following the procedure described by Greenspan et al. in J. Med. Chem. 2001, 44, 15 4524-4534, can be Boc-deprotected by treatment with 4M HCl in dioxane or with TFA to give the corresponding iodophenyl alanine as its HCl or TFA salt A-2. Iodophenyl alanine A-2, racemic or enantiomerically enriched, either commercially available or prepared as described above can be d with borane in a solvent like THF to furnish the corresponding amino alcohol A-3. Acylation of A-3 with chloroacetyl chloride furnishes amide A-4 which upon 20 treatment with a base like sodium hydride or potassium tertbutoxide in a solvent like THF affords morpholinone A-5. Arylation of A-5 can be accomplished under metal catalysed conditions employing for example copper, palladium or zinc catalysts to give ediates of type A-6. Alternatively, conversion of A-5 into it’s ponding boronic acid or ester followed by a Suzuki on gives intermediates of type A-6. Reduction of A-6 with borane 25 in a solvent like THF furnishes compounds of Structure 1. 36 Reaction Scheme B Compounds of Structure 1 may also be prepared as rated in Reaction Scheme B.

Reduction of linone B-1 with borane in a solvent like THF gives the ponding 5 morpholine B-2 which can be boc-protected under standard conditions to furnish intermediates of type B-3. Arylation of B-3 can be achieved by following one of several methods. For example, under metal sed conditions as described above, or alternatively, conversion of B-3 into it’s corresponding boronic l ester by treatment with bis(pinacolato) diboron in a solvent like DMSO followed by a Suzuki reaction. Intermediates 10 of type B-3 can also be converted into their corresponding cyano tives by treatment with zinc cyanide under palladium sed conditions in a solvent like 1,4-dioxane followed by treatment with hydroxylamine and subsequent ring closure in trimethyl orthoformate to give intermediates of type B-4 where Ar1 is a 1,2,4-oxadiazole. Boc-deprotection of B-4 by treatment with 4M HCl in dioxane or with TFA leads to compounds of Structure 1. 15 Reaction Scheme C Compounds of Structure 1 may also be prepared as illustrated in Reaction Scheme C.

Intermediate C-1 can be prepared from p-methoxyphenyl alanine in analogy to the ce of reactions described in Reaction Scheme A. Iodination of morpholinone C-1 with NIS in the 20 presence of an acid like triflic acid in a solvent like DCM or MeCN gives the corresponding morpholinone C-2. Arylation of C-2 can be accomplished under metal sed conditions employing for example copper or palladium catalysts to give intermediates of type C-3.

Alternatively, conversion of C-2 into it’s corresponding boronic pinacol ester by treatment with bis(pinacolato) diboron in a t like DMSO followed by a Suzuki reaction with the 25 appropriate aryl halide furnishes intermediates of type C-3. Reduction of C-3 with borane in a solvent like THF furnishes compounds of Structure 1. 37 Final compounds of the present invention may be ed as illustrated in Reaction Scheme D. For example, ediate D-1 can be prepared from p-methoxyphenyl alanine in y to the sequence of reactions described in Reaction Scheme A. Reduction of morpholinone D-1 with borane in a solvent like THF gives the corresponding morpholine D-2. 5 Reaction of D-2 with an acid of Structure 2 in the presence of an amide-coupling reagent such as TBTU, HATU or EDC, and a base like DIPEA or TEA in a solvent such as MeCN or DMF furnishes ediates of type D-3. Iodination of D-3 in the presence of an acid like triflic acid in a solvent like DCM or MeCN gives intermediates of type D-4. Arylation of D-4 can be accomplished under metal catalysed conditions employing for example copper or 10 palladium catalysts to give final compounds. Alternatively, conversion of D-4 into it’s corresponding boronic pinacol ester by treatment with bis(pinacolato) diboron in a solvent like DMSO followed by a Suzuki reaction with the appropriate aryl halide furnishes final compounds. 15 Reaction Scheme D Reaction Scheme G 38 Compounds of ure 1 may also be prepared as illustrated in Reaction Scheme G.

Reduction of commercially available m-halobenzoic acid (X = Br or I) G-1 with borane in a solvent like THF gives the ponding benzyl alcohol G-2 which can be brominated under rd conditions with phosphorus tribromide in a solvent like DCM to furnish benzyl 5 bromides of type G-3. Subsequent Boc-aminomalonate alkylation chemistry with benzyl bromide G-3 as described by Greenspan et al. in J. Med. Chem. 2001, 44, 4524-4534, furnishes Boc-protected halophenyl alanine derivative G-5. Conversion of G-5 into compounds of Structure 1 can be accomplished by following the sequence of transformations as described in on Scheme A. 10 Reaction Scheme H Compounds of Structure 1 may also be prepared as illustrated in Reaction Scheme H.

Reaction of commercially available α-aminoester H-1 with trimethylacetaldehyde in a solvent like DCM in the presence of a dehydrating agent like MgSO4 gives the corresponding imine 15 H-2. Alkylation of H-2 with benzyl bromides H-3, prepared as described in Reaction Scheme G, in a solvent like toluene gives after imine hydrolysis ediates of type H-4. Conversion of H-4 into compounds of Structure 1 can be lished by ing the sequence of ormations as described in Reaction Scheme A.

O R5 O O O R5 R5 O O O O NH NBoc NHBoc N NH R1 R1 R1 R1 R1 Ar1 I-1 Ar1 Ar1 Ar1 Ar1 I-2 I-3 I-4 1 20 Reaction Scheme I Compounds of Structure 1 may also be prepared as illustrated in Reaction Scheme I.

Intermediate I-1, prepared according to on Schemes A, C or G can be Boc-protected following the procedure described by Terashima et al. in Tetrahedron, 1994, 50, 6221-6238 39 to give Boc-morpholinone I-2. on of I-2 with an appropriate alkyl-metal reagent like alkyl lithium reagents in a solvent like THF at a temperature of -78°C gives the ring-opened ketone I-3. Boc-deprotection of I-3 by treatment with 4M HCl in e or with TFA leads to cyclic imines of type I-4 that can be subsequently reduced with NaBH4 in a solvent like 5 MeOH to furnish compounds of Structure 1.

R5 R5 R5 OH O O OH H R5 O O O NH2 N NH NH NH Cl O R1 R1 R1 R1 R1 X J-1 X J-2 X J-3 Ar1 J-4 Ar1 1 Reaction Scheme J Compounds of ure 1 may also be prepared as illustrated in Reaction Scheme J. In analogy to the procedure desribed by Kazmierski et al. in Bioorg. Med. Chem. Lett. 2006, 16, 10 230, amino alcohol J-1, prepared according to Reaction Scheme A can be acylated with chloroacetyl chloride derivatives to furnish amide J-2 which upon treatment with a base like sodium hydride or ium tertbutoxide in a solvent like THF affords morpholinone J-3 as a single cis-diastereomer. Arylation of J-3 can be lished under metal catalysed conditions employing for example copper, palladium or zinc catalysts to give intermediates of 15 type J-4. Alternatively, conversion of J-3 into it’s corresponding boronic acid or ester followed by a Suzuki reaction gives intermediates of type J-4. Reduction of J-4 with borane in a solvent like THF hes compounds of Structure 1. 40 OH OH O OH NHBoc NHBoc NHBoc NHBoc O H R5 R1 R1 R1 R1 X K-1 X K-2 X K-3 X K-4 O OH OH H O NH2 N NH R5 R5 Cl R5 O R1 R1 R1 X K-5 X K-6 X K-7 O O O NH NH R5 R5 R1 R1 Ar1 K-8 Ar1 1 Reaction Scheme K Compounds of Structure 1 may also be prepared as illustrated in on Scheme K. A Boc-protected halophenyl alanine derivative (X = Br or I) K-1, racemic or enantiomerically 5 enriched, either commercially available or prepared as illustrated in Reaction Scheme G can be d with NaBH4 via its mixed anhydride in a solvent like THF to afford Boc-protected amino alcohol K-2. Dess-Martin oxidation of K-2 gives the corresponding aldehyde K-3 which can be alkylated with an alkyl zinc or magnesium t to give the 2° alcohol K-4.

Boc-deprotection of K-4 by treatment with 4M HCl in dioxane or with TFA leads to the amino 10 alcohol K-5 which can be converted into compounds of Structure 1 by following the sequence of transformations described above in Reaction Scheme A. on Scheme L Final compounds of the present invention may also be prepared as illustrated in Reaction 15 Scheme L. For example, intermediate L-1 (X = Br or I), prepared according to on Scheme B can be coupled with an acid of Structure 2 in the presence of an coupling reagent such as TBTU, HATU or EDC, and a base like DIPEA or TEA in a solvent such as 41 MeCN or DMF to furnish intermediates of type L-2. Arylation of L-2 can be accomplished under metal catalysed conditions employing for example copper or palladium catalysts to give final compounds. Alternatively, conversion of L-2 into it’s corresponding boronic l ester by treatment with bis(pinacolato) diboron in a solvent like DMSO followed by a Suzuki 5 reaction with the appropriate aryl halide furnishes final nds.

Carboxylic acid derivatives of Structure 2 are well known in the art and can be ally prepared following the procedures reported in WO2008069997, WO2008008517, WO2010048012, WO2010063662, WO2010063663, WO2011050198, 050200 and WO2011050202. In addition, they may be ed in analogy to the methods given in the 10 experimental part.

Whenever the nds of formula (I) are obtained in the form of es of enantiomers, the enantiomers can be separated using methods known to one skilled in the art: e.g. by formation and separation of diastereomeric salts or by HPLC over a chiral stationary phase such as a Regis Whelk-O1(R,R) (10 µm) column, a Daicel ChiralCel OD-H (5-10 µm) 15 column, or a Daicel ChiralPak IA (10 µm), IC (5 µm) or AD-H (5 µm) column. Typical conditions of chiral HPLC are an isocratic mixture of eluent A (EtOH, in presence or absence of an amine such as triethylamine or diethylamine) and eluent B (heptane), at a flow rate of 0.8 to 150 mL/min.

The following examples are provided to rate the invention. These examples are 20 illustrative only and should not be construed as limiting the invention in any way.

Experimental Part I. Chemistry All temperatures are stated in °C. Commercially available starting materials were used as received without further purification. Unless otherwise ied, all reactions were carried 25 out in oven-dried glassware under an atmosphere of nitrogen. Compounds were purified by flash column chromatography on silica gel or by preparative HPLC. Compounds described in the invention are characterised by LC-MS data (retention time tR is given in min; molecular weight obtained from the mass spectrum is given in g/mol) using the conditions listed below.

In cases where compounds of the present invention appear as a mixture of conformational 30 isomers, particularly visible in their LC-MS spectra, the retention time of the most abundant conformer is given.

LC-MS with acidic conditions Method A: Agilent 1100 series with mass spectrometry ion (MS: Finnigan single quadrupole). Column: Zorbax SB-aq (3.5 µm, 4.6 x 50 mm). Conditions: MeCN [eluent A]; 42 water + 0.04% TFA [eluent B]. Gradient: 95% B → 5% B over 1.5 min (flow: 4.5 mL/min).

Detection: UV/Vis + MS.

Method B: Agilent 1100 series with mass ometry detection (MS: an single quadrupole). Column: Waters XBridge C18 (2.5 µm, 4.6 x 30 mm). ions: MeCN [eluent 5 A]; water + 0.04% TFA [eluent B]. nt: 95% B → 5% B over 1.5 min (flow: 4.5 mL/min).

Detection: UV/Vis + MS.

LC-MS with basic conditions Method C: Agilent 1100 series with mass spectrometry detection (MS: Finnigan single quadrupole). Column: Zorbax Extend C18 (5 µm, 4.6 x 50 mm). Conditions: MeCN [eluent A]; 10 13 mmol/L NH3 in water [eluent B]. Gradient: 95% B → 5% B over 1.5 min (flow: 4.5 mL/min).

Detection: UV/Vis + MS.

Method D: Agilent 1100 series with mass spectrometry detection (MS: Finnigan single pole). Column: Waters e C18 (5 µm, 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 15 mL/min). Detection: UV/Vis + MS.

Preparative HPLC with acidic conditions Method E: Column: Waters XBridge (10 µm, 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/Vis + MS. 20 Preparative HPLC with basic conditions Method F: Column: Waters XBridge (10 µm, 75 x 30 mm). Conditions: MeCN t A]; water + 0.5% NH4OH (25% aq.) [eluent B]; Gradient: 90% B → 5% B over 6.5 min (flow: 75 mL/min). Detection: UV/Vis + MS.

Preparative HPLC for chiral separations 25 Final compounds that are obtained in racemic form are separated into their enantiomers using the following conditions:column:(R,R)Whelk-01 21x250 mm, 5 µM,15% MeCN in MTBE + 0.1% DEA (flow: 16 mL/min). Detection: UV/Vis.

Abbreviations (as used hereinbefore or hereinafter): acac acetylacetonate 30 aq. aqueous atm atmosphere BSA bovine serum albumin Boc butyloxycarbonyl 43 CDI yl diimidazole d days dba dibenzylidene acetone DCC ohexyl carbodiimide 5 DCM dichloromethane DEA diethylamine DIPEA diisopropyl-ethylamine, Hünig's base, ethyl-diisopropylamine DMAP 4-dimethylaminopyridne DMCDA trans-N,N'-dimethylcyclohexane-1,2-diamine 10 DMF dimethylformamide DMP Dess-Martin periodinane DMSO dimethylsulfoxide dppf 1,1'-bis(diphenylphosphino)ferrocene EDC N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide 15 eq. equivalent(s) Et ethyl Et 2O diethyl ether EtOAc ethyl e Ex. example(s) 20 h hour(s) HBTU O-(benzotriazolyl)-N,N,N',N'-tetramethyluronium hexafluorophosphate HOBt 1-hydroxybenzotriazole HPLC high performance liquid chromatography 25 HV high vacuum conditions iBu yl iPr isopropyl KO tBu potassium tert -butoxide LC-MS liquid chromatography – mass spectrometry 30 Lit. Literature Me methyl MeCN acetonitrile MeOH methanol MeLi methyl lithium 35 MTBE methyl-tert butyl ether min minute(s) 44 NaOAc sodium acetate nBuLi n-butyl-lithium NIS N-iodo succinimide nPr n-propyl 5 OAc acetate Pd(dppf)Cl 2DCM [1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium (II) complex with dichloromethane Ph phenyl PPh 3 triphenyl phosphine 10 prep. Preparative PyBOP benzotriazolyl-oxy-tris-pyrrolidino-phosphoniumhexafluoro-phosphate rac racemic RT room temperature 15 s (s) sat. saturated soln. solution TBTU 2-(1H-benzotriazoleyl)-1,2,3,3-tetramethyluronium tetrafluoroborate TEA triethylamine 20 TFA trifluoroacetic acid TFAA trifluoroacetic anhydride THF tetrahydrofuran TLC thin layer tography TMS trimethylsilyl 25 tR retention time General method A for the synthesis of 3-benzyl lines of Structure 1 (R)Amino(3-iodo-phenyl)-propionic acid hydrochloride (A-7) A solution of Bociodo-D-phenylalanine (5 g, 12.8 mmol, available from Matrix Scientific 30 and 3BSC) in 4M HCl in dioxane (63.9 mL, 256 mmol) under argon was stirred at RT for 15h.

The ing suspension was filtered, washed with Et2O and dried in vacuo to give the title compound as a white solid. LC-MS B: tR = 0.42 min; [M+H]+ = 291.98.

(R)Amino(3-iodo-phenyl)-propanol (A-8) Borane.THF x 1M soln. (197 mL, 0.197 mol) was added dropwise to a 0°C 35 suspension of (R)amino(3-iodo-phenyl)-propionic acid hydrochloride A-7 (21.5 g, 65.8 mmol) in THF (200 mL) under argon and after complete addition the reaction mixture was 45 heated to 70°C for 2h. The reaction mixture was cooled to 0°C and quenched with MeOH and after ng for 5 min the reaction mixture was evaporated in vacuo. The residue was partitioned between 2M aq. HCl and MeOH and stirred for 30 min before being concentrated in vacuo. The remaining aqueous phase was diluted with additional water and ted once 5 with DCM. The layers were separated and the organic phase was re-washed with 2M aq.

HCl before being discarded. The acidic aq. phases were combined and ed with 5M aq.

NaOH and extracted with DCM (3x). The combined organic extracts were dried over Na2SO 4, filtered and evaporated in vacuo to give the title compound as a cream solid that was used further without purification. LC-MS B: tR = 0.45 min; [M+H]+ = 278.03. 10 2-Chloro-N-[( R)hydroxymethyl(3-iodo-phenyl)-ethyl]-acetamide (A-9) Chloroacetylchloride (1.05 mL, 13.1 mmol) was added dropwise to a 0°C solution of (R) amino(3-iodo-phenyl)-propanol A-8 (3.03 g, 10.9 mmol) and Et3N (1.98 mL, 14.2 mmol) in THF (50 mL) under argon and the resulting suspension was warmed to RT and stirred for 30 min. The reaction mixture was cooled back to 0°C before being quenched with water and 15 concentrated in vacuo. The remaining aq. phase was extracted with EtOAc (2x) and the combined organic extracts were washed with brine, dried over Na2SO 4, filtered and evaporated in vacuo to give the title compound as a cream solid that was used further without purification. LC-MS B: tR = 0.71 min; [M(35 Cl)+H] + = 353.75.

(R)(3-Iodo-benzyl)-morpholinone (A-10) 20 NaH 60% Dispersion in mineral oil (0.93 g, 23.2 mmol) was added portionwise to a 0°C solution of 2-chloro-N-[( R)hydroxymethyl(3-iodo-phenyl)-ethyl]-acetamide A-9 (3.72 g, 10.5 mmol) in THF (100 mL) under argon and the resulting suspension was warmed to RT and stirred for 1h. The reaction e was cooled back to 0°C before being ed with water and concentrated in vacuo. The remaining aqueous phase was extracted with DCM 25 (3x) and the combined organic extracts were washed with brine, dried over Na2SO 4, filtered and evaporated in vacuo to give the crude product that was purified by flash chromatography (eluting with a gradient of 50% to 100% EtOAc in hexane) to give the title compound as a white solid. LC-MS B: tR = 0.72 min; eCN]+ = ; 1H NMR (CDCl3) δH: 7.64 (d, J = 7.9 Hz, 1 H), 7.59 (s, 1 H), 7.18 (m, 1 H), 7.10 (t, J = 7.7 Hz, 1 H), 6.25 (s, 1 H), 4.20 (s, 2 30 H), 3.91 (dd, J1 = 11.7 Hz, J2 = 3.7 Hz, 1 H), 3.76 (m, 1 H), 3.60 (dd, J1 = 11.7 Hz, J2 = 6.1 Hz, 1 H), 2.87 (dd, J1 = 13.6 Hz, J2 = 6.0 Hz, 1 H), 2.72 (dd, J1 = 13.6 Hz, J2 = 8.5 Hz, 1 H).

(R)(3-Pyrazolyl-benzyl)-morpholinone (A-11) A mixture of (R)(3-iodo-benzyl)-morpholinone A-10 (1.0 g, 3.15 mmol), le (322 mg, 4.73 mmol), K2CO 3 (872 mg, 6.31 mmol), copper(I) chloride (31 mg, 0.32 mmol) and L- 35 proline (73 mg, 0.63 mmol) in DMF (8 mL) was heated under argon to 110°C for 24h. The 46 reaction mixture was cooled to RT and partitioned between water and DCM before being filtered through a celite plug. The layers were separated and the aqueous phase was reextracted with DCM (2x). The combined organic phases were washed with brine, dried over Na 2SO 4, filtered and evaporated in vacuo to give the crude t that was purified by flash 5 chromatography (eluting with a gradient of 50% to 100% EtOAc in hexane) to give the title compound as a white solid. LC-MS B: tR = 0.51 min; [M+H]+ = 257.86.

(R)(3-Pyrazolyl-benzyl)-morpholine (A-12) Borane.THF complex 1M soln. (5.83 mL, 5.83 mmol) was added dropwise to a 0°C on of (R)(3-pyrazolyl-benzyl)-morpholinone A-11 (500 mg, 1.94 mmol) in THF (7 mL) 10 under argon and after complete addition the reaction mixture was heated to 70°C for 2.5h.

The reaction mixture was cooled to 50°C and quenched with MeOH and 2M aq. HCl before being re-heated to 70°C for a r 1h. The reaction mixture was ated in vacuo and the residue was ioned between 2M aq. HCl and EtOAC. The layers were separated and the organic phase was re-washed with 2M aq. HCl before being discarded. The acidic aq. 15 phases were ed and basified with 5M aq. NaOH and extracted with EtOAC (3x). The combined organic ts were dried over Na2SO 4, filtered and evaporated in vacuo to give the title compound as a colourless oil that was used further t purification. LC-MS B: tR = 0.41 min; [M+H]+ = 244.07.

(R)(3-[1,2,3]Triazolyl-benzyl)-morpholinone (A-13) and (R)(3-[1,2,3]triazol 20 yl-benzyl)-morpholinone (A-14) A mixture of (R)(3-iodo-benzyl)-morpholinone A-10 (3.94 g, 12.4 mmol), 1H-1,2,3- triazole (1.08 mL, 18.6 mmol), K2CO 3 (3.43 g, 24.8 mmol), copper(I) chloride (123 mg, 1.24 mmol) and L-proline (286 mg, 2.48 mmol) in DMF (30 mL) was heated under argon to 110°C for 190h. The reaction mixture was cooled to RT and partitioned between water and DCM 25 before being filtered through a celite plug. The layers were separated and the aqueous phase was re-extracted with DCM (2x). The combined organic phases were washed with brine, dried over Na2SO 4, filtered and evaporated in vacuo to give the crude product that was purified by flash chromatography (eluting with a gradient of 50% to 100% EtOAc in hexane) to give the first title compound as a white solid. LC-MS B: tR = 0.55 min; [M+H]+ = 259.19; 1H 30 NMR (CDCl3) δH: 8.04 (m, 1 H), 7.96 (m, 1 H), 7.85 (s, 2 H), 7.50 (m, 1 H), 7.22 (m, 1 H), 6.19 (s, 1 H), 4.21 (s, 2 H), 3.95 (dd, J1 = 11.7 Hz, J2 = 3.7 Hz, 1 H), 3.86 (m, 1 H), 3.64 (m, 1 H), 3.02 (m, 1 H), 2.89 (m, 1 H). Continued elution with 95:5 DCM:MeOH afforded the second title compound as an orange solid. LC-MS B: tR = 0.43 min; [M+H]+ = 259.20; 1H NMR (CDCl3) δH: 8.04 (s, 1 H), 7.89 (s, 1 H), 7.71 (s, 1 H), 7.65 (m, 1 H), 7.54 (t, J = 7.8 Hz, 35 1 H), 7.31 (d, J = 7.6 Hz, 1 H), 6.12 (s, 1 H), 4.21 (s, 2 H), 3.95 (dd, J1 = 11.7 Hz, J2 = 3.6 Hz, 47 1 H), 3.85 (m, 1 H), 3.66 (dd, J1 = 11.7 Hz, J2 = 5.8 Hz, 1 H), 3.04 (dd, J1 = 13.6 Hz, J2 = 5.7 Hz, 1 H), 2.91 (dd, J1 = 13.6 Hz, J2 = 8.6 Hz, 1 H).

(R)(3-[1,2,3]Triazolyl-benzyl)-morpholine (A-15) The title compound was prepared from A-13 in analogy to the procedure described for A-12 . 5 LC-MS A: tR = 0.52 min; [M+H]+ = 245.18.

(R)(3-[1,2,3]Triazolyl-benzyl)-morpholine (A-16) The title compound was ed from A-14 in y to the procedure described for A-12.

LC-MS A: tR = 0.46 min; [M+H]+ = 245.18.

(R)(3-[1,2,4]Triazolyl-benzyl)-morpholinone (A-17) 10 The title compound was prepared from A-10 and 1H-1,2,4-triazole in analogy to the procedure described for A-13. LC-MS B: tR = 0.42 min; [M+H]+ = 258.96.

(R)(3-[1,2,4]Triazolyl-benzyl)-morpholine (A-18) The title compound was prepared from A-17 in analogy to the procedure bed for A-12.

LC-MS B: tR = 0.34 min; [M+H]+ = 245.08. 15 (R)(3-Pyrrolyl-benzyl)-morpholinone (A-19) The title compound was prepared from A-10 and pyrrole in analogy to the ure described for A-13 . LC-MS B: tR = 0.64 min; [M+H]+ = 257.08. (3-Pyrrolyl-benzyl)-morpholine (A-20) The title compound was prepared from A-19 in analogy to the procedure described for A-12 . 20 LC-MS B: tR = 0.51 min; [M+H]+ = 242.94.

(S)Amino(3-iodo-phenyl)-propionic acid hydrochloride (A-21) The title compound was prepared from Bociodo-L-phenylalanine (Matrix Scientific) in analogy to the procedure described for A-7. LC-MS A: tR = 0.49 min; [M+H+MeCN]+ = 333.88. 25 Amino(3-iodo-phenyl)-propanol (A-22) The title compound was prepared from A-21 in analogy to the procedure described for A-8.

LC-MS A: tR = 0.52 min; [M+H+MeCN]+ = 319.06. 2-Chloro-N-[( S)hydroxymethyl(3-iodo-phenyl)-ethyl]-acetamide (A-23) The title compound was prepared from A-22 in analogy to the procedure described for A-9. 30 LC-MS A: tR = 0.71 min; [M(35 Cl)+H] + = 353.70. 48 (S)(3-Iodo-benzyl)-morpholinone (A-24) The title compound was prepared from A-23 in analogy to the procedure described for A-10.

LC-MS A: tR = 0.72 min; [M+H+MeCN]+ = .

(S)(3-[1,2,3]Triazolyl-benzyl)-morpholinone (A-25) 5 The title compound was prepared from A-24 in analogy to the procedure described for A-13.

LC-MS A: tR = 0.65 min; [M+H]+ = 259.18.

(S)(3-[1,2,3]Triazolyl-benzyl)-morpholine (A-26) The title compound was prepared from A-25 in analogy to the procedure described for A-12.

LC-MS B: tR = 0.42 min; [M+H]+ = 245.19. 10 Listed in Table 1 below are morpholinones of type A-6 prepared from the corresponding Bocprotected halophenyl alanine derivative G-5, in analogy to the ce of ons described for A-13. In most cases the isolated racemic morpholinone was uently ted into its R- and S-enantiomers by prep. chiral HPLC. 15 Table 1 No. Starting Intermediate tR [min] MS-data m/z material LC-MS Method [M+H]+ A-27 G-30 (R)(2-Fluoro[1,2,3]triazol- 0.68 277.08 2-yl-benzyl)-morpholinone A A-28 G-31 (R)(2-Chloro[1,2,3]triazol- 0.72 (35Cl) 293.07 2-yl-benzyl)-morpholinone A A-29 G-32 (R)(2-Methyl[1,2,3]triazol- 0.70 273.13 2-yl-benzyl)-morpholinone A A-30 G-33 (R)(3-Chloro[1,2,3]triazol- 0.64 (35Cl) 293.07 2-yl-benzyl)-morpholinone B A-31 G-34 rac(3-Fluoro[1,2,3]triazol- 0.70 277.12 2-yl-benzyl)-morpholinone A A-32 G-35 rac(2-Fluoro[1,2,3]triazol- 0.50 277.21 2-yl-benzyl)-morpholinone B A-33 G-36 (R)(4-Methyl[1,2,3]triazol- 0.56 273.31 2-yl-benzyl)-morpholinone B 49 Listed in Table 2 below are compounds of Structure 1 ed from the corresponding intermediates of type A-6, in analogy to the ure described for A-12.

Table 2 No. Starting line 1 tR [min] MS-data m/z material LC-MS [M+H]+ Method A-34 A-27 (R)(2-Fluoro[1,2,3]triazol 0.53 263.10 yl-benzyl)-morpholine A A-35 A-28 (R)(2-Chloro[1,2,3]triazol 0.56 (35Cl) 279.10 yl-benzyl)-morpholine A A-36 A-29 (R)(2-Methyl[1,2,3]triazol 0.56 259.18 yl-benzyl)-morpholine A A-37 A-30 (3-Chloro[1,2,3]triazol 0.58 320.09 yl-benzyl)-morpholine A [M(35Cl)+H+MeCN]+ A-38 A-31 rac(3-Fluoro[1,2,3]triazol 0.54 304.13 yl-benzyl)-morpholine A [M+H+MeCN]+ A-39 A-32 rac(2-Fluoro[1,2,3]triazol 0.39 263.22 yl-benzyl)-morpholine B A-40 A-33 (R)(4-Methyl[1,2,3]triazol 0.44 259.02 yl-benzyl)-morpholine B 5 (R)(2-Methylpyrazolyl-benzyl)-morpholinone (A-41) The title compound was prepared from G-32 in analogy to the sequence of reactions described for A-11 followed by prep. chiral HPLC. LC-MS A: tR = 0.68 min; [M+H]+ = 272.14.

(R)(2-Methylpyrazolyl-benzyl)-morpholine (A-42) The title compound was prepared from A-41 in analogy to the procedure described for A-12. 10 LC-MS A: tR = 0.55 min; [M+H]+ = 257.99.

General method B for the synthesis of 3-benzyl morpholines of Structure 1 (R)(3-Iodo-benzyl)-morpholine (B-5) The title compound was prepared from A-10 in analogy to the ure described for A-13.

LC-MS B: tR = 0.50 min; [M+H+MeCN]+ = 345.02. 50 (R)(3-Iodo-benzyl)-morpholinecarboxylic acid tert-butyl ester (B-6) A on of Boc2O (635 mg, 2.91 mmol) in DCM (4 mL) was added dropwise to a RT solution of (R)(3-iodo-benzyl)-morpholine B-5 (864 mg, 2.85 mmol) and Et3N (0.4 mL, 2.99 mmol) in DCM (4 mL) under argon and the resulting mixture was stirred for 3h. The reaction 5 e was quenched with 1M aq. citric acid and stirred for another 10 min. The layers were separated and the aq. layer was re-extracted once with DCM. The combined organic extracts were washed with 1M aq. citric acid and water (2x), dried over Na2SO 4, ed and evaporated in vacuo to give the title compound that was used further without purification. LCMS B: tR = 0.95 min; [M-Me]+ = 388.82. 10 (R)[3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolanyl)-benzyl]-morpholinecarboxylic acid tert-butyl ester (B-7) Bis(pinacolato)diboron (732 mg, 2.88 mmol) followed by ium acetate (772 mg, 7.86 mmol) were added in one portion to a RT solution of (R)(3-iodo-benzyl)-morpholine ylic acid tert-butyl ester B-6 (1.06 g, 2.62 mmol) in DMSO (10 mL) and argon was 15 bubbled through the resulting sion for 1 min. Pd(dppf)Cl2DCM (128 mg, 0.16 mmol) was then added in one portion and the suspension was heated to 80°C for 20 min. The reaction mixture was cooled back to RT, diluted with Et2O and filtered through a celite plug rinsing with Et2O and a little MeOH. The volatiles were removed in vacuo and the residue was dissolved in Et2O and washed with water (2x) and sat. aq. NH4Cl soln. The organic 20 phase was dried over Na2SO 4, filtered through a second celite plug and evaporated in vacuo to give the title compound that was used further without purification. LC-MS B: tR = 1.01 min; [M+H-tBu]+ = 348.18.

(R)(3-Pyrimidinyl-benzyl)-morpholinecarboxylic acid tert-butyl ester (B-8) 2-Bromopyrimidine (43 mg, 0.27 mmol) was added in one portion to a RT solution of (R) 25 [3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolanyl)-benzyl]-morpholinecarboxylic acid tertbutyl ester B-7 (100 mg, 0.25 mmol) in dioxane (0.76 mL) under argon. EtOH (0.38 mL) was then added ed by 2M aq. Na2CO 3 (0.38 mL, 0.74 mmol) and argon was bubbled through the resulting suspension for 1 min. Pd(dppf)Cl2DCM (12 mg, 6 mol%) was added in one portion and the resulting e was heated to 80°C for 2h. The reaction mixture was 30 cooled to RT, ed into water and filtered through a celite plug washing with TBME. The layers were separated and the aqueous phase was extracted with TBME (3x). The combined organic extracts were washed with brine, dried over Na2SO 4, filtered through a second celite plug and evaporated in vacuo to give the crude product that was ed by prep. HPLC (method E) to give the title compound as a yellow oil. LC-MS B: tR = 0.79 min; [M+H]+ = 35 356.05. 51 Listed in Table 3 below are intermediates of type B-4, prepared from (R)[3-(4,4,5,5- tetramethyl-[1,3,2]dioxaborolanyl)-benzyl]-morpholinecarboxylic acid tert-butyl ester B-7 according to the procedure described for B-8.

Table 3 No. Aryl Intermediate tR [min] MS-data m/z halide LC-MS Method [M+H]+ B-9 (R)(3-Pyridinyl-benzyl)- 0.60 355.03 linecarboxylic acid B tert-butyl ester B-10 (3-Pyridinyl-benzyl)- 0.59 355.11 morpholinecarboxylic acid tert-butyl ester B B-11 (R)(3-Pyridinyl-benzyl)- 0.57 355.14 morpholinecarboxylic acid tert-butyl ester B B-12 (R)[3-(4-Methyl-pyrimidin 0.85 369.51 yl)-benzyl]-morpholine carboxylic acid tert-butyl ester B B-13 Cl (R)(3-Pyrazinyl-benzyl)- 0.77 356.03 N morpholinecarboxylic acid N tert-butyl ester B B-14 Br (R)(3-Oxazolyl-benzyl)- 0.79 345.04 N O morpholinecarboxylic acid tert-butyl ester B B-15 Br (R)(3-Thiazolyl-benzyl)- 0.84 361.01 N S morpholinecarboxylic acid tert-butyl ester B B-16 Br (R)(3-Thiophenyl-benzyl)- 0.97 345.00 S morpholinecarboxylic acid tert-butyl ester B [M-Me]+ B-17 (3-Pyridazinyl-benzyl)- 0.68 356.05 morpholinecarboxylic acid tert-butyl ester B 5 52 Listed in Table 4 below are compounds of Structure 1 ed from the corresponding ediates of type B-4, in analogy to the procedure described for A-7.

Table 4 No. Starting Morpholine 1 tR [min] MS-data m/z material LC-MS Method [M+H]+ B-18 B-8 (R)(3-Pyrimidinyl-benzyl)- 0.40 256.18 morpholine hydrochloride B B-19 B-9 (R)(3-Pyridinyl-benzyl)- 0.31 255.08 morpholine hydrochloride B B-20 B-10 (R)(3-Pyridinyl-benzyl)- 0.28 296.11 morpholine hydrochloride B [M+H+MeCN]+ B-21 B-11 (R)(3-Pyridinyl-benzyl)- 0.27 255.16 morpholine hydrochloride B B-22 B-12 (R)[3-(4-Methyl-pyrimidin 0.44 270.08 yl)-benzyl]-morpholine B hydrochloride B-23 B-13 (R)(3-Pyrazinyl-benzyl)- 0.39 256.07 morpholine hydrochloride B B-24 B-14 (R)(3-Oxazolyl-benzyl)- 0.41 245.08 line hydrochloride B B-25 B-15 (R)(3-Thiazolyl-benzyl)- 0.45 261.19 morpholine hydrochloride B B-26 B-16 (R)(3-Thiophenyl-benzyl)- 0.56 301.19 morpholine hydrochloride B [M+H+MeCN]+ B-27 B-17 (R)(3-Pyridazinyl-benzyl)- 0.35 297.23 morpholine hydrochloride B 5 -(3-Iodo-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)-methanone (B-28) A solution of (R)(3-iodo-benzyl)-morpholine B-5 (100 mg, 0.33 mmol) and DIPEA (57 µL, 0.33 mmol) in DMF (1.5 mL) was added to a RT solution of 2-(2H-1,2,3-triazolyl)benzoic acid E-2 (62 mg, 0.33 mmol), TBTU (111 mg, 0.35 mmol) and DIPEA (57 µL, 0.33 mmol) in DMF (1.5 ml) under argon and the resulting mixture was d for 22h. The on mixture 10 was quenched with sat. aq. NaHCO3 and stirred for 10 min before being diluted with water and extracted with DCM (3x). The combined organic extracts were washed with 2M aq.

NaOH (1x), 2M aq. HCl (1x) and brine (1x), dried over Na2SO4, filtered and evaporated in 53 vacuo . The crude t was purified by prep. HPLC (method F) to give the title compound as a white solid. LC-MS D: tR = 0.93 min; [M+H]+ = 474.91. 3-[( R)(2-[1,2,3]Triazolyl-benzoyl)-morpholinylmethyl]-benzonitrile (B-29) Pd 2(dba) 3 (11 mg, 0.01 mmol), dppf (7 mg, 0.01 mmol), H2O (45 µL, 2.49 mmol) and zinc 5 cyanide (73 mg, 0.62 mmol) were added to a RT solution of [(R)(3-iodo-benzyl)-morpholin- 4-yl]-(2-[1,2,3]triazolyl-phenyl)-methanone B-28 (118 mg, 0.25 mmol) in DMF (2.49 mL, ~0.1M soln.) and argon was bubbled through the reaction mixture for 5 min before it was heated to 90°C for 17h. The reaction mixture was cooled to RT and quenched with sat. aq.

NH 4Cl before being extracted with EtOAc (3x). The combined organic extracts were dried 10 over Na2SO 4, filtered and evaporated in vacuo to give the crude product that was purified by flash tography (eluting with a gradient of 25% to 75% EtOAc in ) to give the title compound as a yellow solid. LC-MS D: tR = 0.81 min; [M+H]+ = 374.05.

[( R)(3-Iodo-benzyl)-morpholinyl]-(5-methyl[1,2,3]triazolyl-phenyl)-methanone (B-30) 15 The title compound was ed from B-5 and E-3 in analogy to the procedure described for B-28 . LC-MS D: tR = 0.94 min; [M+H]+ = 488.85. 3-[( R)(5-Methyl[1,2,3]triazolyl-benzoyl)-morpholinylmethyl]-benzonitrile (B- 31) The title nd was prepared from B-30 in analogy to the procedure described for B-29 . 20 LC-MS D: tR = 0.85 min; [M+H]+ = .

(R)(3-Iodomethoxy-benzyl)-morpholine (B-32) The title compound was ed from C-7 in analogy to the procedure described for A-12 .

LC-MS B: tR = 0.48 min; [M+H]+ = 334.06.

(R)(3-Iodomethoxy-benzyl)-morpholinecarboxylic acid tert-butyl ester (B-33) 25 The title compound was prepared from B-32 in analogy to the procedure described for B-6.

LC-MS B: tR = 0.91 min; [M-Me]+ = 418.86.

(R)(3-Cyanomethoxy-benzyl)-morpholinecarboxylic acid tert-butyl ester (B-34) The title compound was prepared from B-33 in analogy to the procedure described for B-29 .

LC-MS B: tR = 0.76 min; [M-Me]+ = 318.13. 30 (R)(4-Methoxy[1,2,4]oxadiazolyl-benzyl)-morpholinecarboxylic acid tert-butyl ester (B-35) The title compound was prepared from B-34 in analogy to the procedure described for Example 1. LC-MS B: tR = 0.72 min; [M+H-tBu]+ = 320.04. 54 (R)(4-Methoxy[1,2,4]oxadiazolyl-benzyl)-morpholine hloride (B-36) The title compound was prepared from B-35 in analogy to the procedure described for A-7.

LC-MS B: tR = 0.37 min; [M+H]+ = 276.11.

(R)(3-Cyano-benzyl)-morpholinecarboxylic acid tert-butyl ester (B-37) 5 The title compound was prepared from B-6 in analogy to the procedure bed for B-29 .

LC-MS B: tR = 0.77 min; [M-Me]+ = 288.18.

(R)(3-[1,2,4]Oxadiazolyl-benzyl)-morpholinecarboxylic acid tert-butyl ester (B- 38) The title compound was prepared from B-37 in analogy to the ure described for 10 Example 1. LC-MS A: tR = 0.88 min; Bu] + = 290.01.

(R)(3-[1,2,4]Oxadiazolyl-benzyl)-morpholine hydrochloride (B-39) The title compound was prepared from B-38 in analogy to the procedure described for A-7.

LC-MS B: tR = 0.37 min; [M+H]+ = 276.11.

(R)(2-Fluoro[1,2,4]oxadiazolyl-benzyl)-morpholine hydrochloride (B-40) 15 The title compound was prepared from (R)amino(5-bromofluorophenyl)propanol (Chiral Quest), in analogy to the sequence of reactions bed for the preparation of B-39.

LC-MS A: tR = 0.51 min; [M+H]+ = 264.13. rac (4-Methyl[1,2,4]oxadiazolyl-benzyl)-morpholine hloride (B-41) The title compound was prepared from G-36 in analogy to the sequence of reactions 20 described for the preparation of B-39 . LC-MS A: tR = 0.54 min; [M+H]+ = 260.21. rac (4-Chloro[1,2,4]oxadiazolyl-benzyl)-morpholine hydrochloride (B-42) The title compound was prepared from G-37 in analogy to the sequence of reactions described for the preparation of B-39 . LC-MS A: tR = 0.53 min; [M(35 Cl)+H] + = 321.13.

(R)(2-Fluoropyrimidinyl-benzyl)-morpholine hydrochloride (B-43) 25 The title compound was prepared from (R)amino(5-bromofluorophenyl)propanol (Chiral Quest) or G-30 , in analogy to the ce of reactions described for the preparation of B-18 . LC-MS A: tR = 0.52 min; [M+H]+ = 273.85.

(R)(2-Fluoro(pyridazinyl)benzyl)morpholine hydrochloride (B-44) The title compound was prepared from (R)amino(5-bromofluorophenyl)propanol 30 (Chiral Quest) or G-30 , in analogy to the ce of reactions bed for the preparation of B-18 , substituting 2-bromopyrimidine for 3-bromopyridazine hydrobromide. LC-MS A: tR = 0.48 min; [M+H+MeCN]+ = 315.22. 55 Example compounds 1 and 2 Example 1: -(3-[1,2,4]Oxadiazolyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolylphenyl )-methanone Step 1: Hydroxylamine ~50% in H2O (72 µL, 1.17 mmol) was added to a RT sion of 5 3-[( R)(2-[1,2,3]triazolyl-benzoyl)-morpholinylmethyl]-benzonitrile B-29 (30 mg, 0.08 mmol) in EtOH (1 mL) and the resulting suspension was heated to 70°C for 45 min. The volatiles were removed in vacuo and the crude hydroxyamidine intermediate was used directly in step 2.

Step 2: p-Toluenesulfonic acid monohydrate (1 mg, 5 mol%) was added to a solution of 10 crude hydroxyamidine from step 1 in hyl orthoformate (1 mL) and the resulting mixture was heated to 100°C for 15 min. The reaction mixture was cooled to RT and filtered through a silica plug (eluting with EtOAc) to give the crude product that was subsequently purified by prep. HPLC (method F) to give the title nd as a white solid. LC-MS D: tR = 0.82 min; [M+H] + = 417.03. 15 Example 2: (5-Methyl[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,4]oxadiazolyl-benzyl)- morpholinyl]-methanone The title compound was prepared from B-31 in analogy to the procedure described for Example 1. LC-MS D: tR = 0.82 min; [M+H]+ = 431.02. 20 General method C for the synthesis of yl morpholines of Structure 1 (R)Amino(4-methoxy-phenyl)-propanol (C-4) The title compound was prepared from p-methoxy-D-phenyl e in analogy to the procedure bed for A-8. LC-MS A: tR = 0.43 min; [M+H]+ = 182.29. 2-Chloro-N-[( R)hydroxymethyl(4-methoxy-phenyl)-ethyl]-acetamide (C-5) 25 The title compound was prepared from C-4 in analogy to the procedure described for A-9.

LC-MS A: tR = 0.61 min; [M(35 Cl)+H] + = 257.88.

(R)(4-Methoxy-benzyl)-morpholinone (C-6) The title nd was prepared from C-5 in analogy to the procedure described for A-10 .

LC-MS A: tR = 0.62 min; [M+H+MeCN]+ = 263.17. 30 (R)(3-Iodomethoxy-benzyl)-morpholinone (C-7) A solution of NIS (559 mg, 2.49 mmol) in DCM (3 mL) was added dropwise to a RT solution of (R)(4-methoxy-benzyl)-morpholinone C-6 (500 mg, 2.26 mmol) and trifluoromethanesulfonic acid (220 µL, 2.49 mmol) in DCM (3 mL) under argon and the resulting mixture was stirred for 40 min. The reaction was quenched with sat. aq. NaHCO3 56 and the layers were separated. The organic layer was washed with water (2x), dried over Na 2SO 4, filtered and evaporated in vacuo to give the crude product that was purified by flash chromatography (eluting with a gradient of 50% to 100% EtOAc in hexane) to give the title compound as a pale yellow solid. LC-MS B: tR = 0.62 min; [M+H+MeCN]+ = 388.95. 5 (R)(4-Methoxypyrazolyl-benzyl)-morpholinone (C-8) A mixture of (R)(3-iodomethoxy-benzyl)-morpholinone C-7 (60 mg, 0.17 mmol), pyrazole (18 mg, 0.30 mmol), K2CO 3 (48 mg, 0.35 mmol), copper(I) chloride (1.7 mg, 0.02 mmol) and ine (4 mg, 0.04 mmol) in DMF (1 mL) was heated under argon to 110°C for 168h. The reaction mixture was cooled to RT and partitioned n water and DCM before 10 being filtered through a celite plug. The layers were separated and the aqueous phase was racted with DCM (2x). The combined organic phases were washed with brine, dried over Na2SO 4, filtered and evaporated in vacuo to give the crude t that was purified by flash chromatography (Biotage SP1, 10g SNAP-cartridge eluting with 95:5 DCM:MeOH) to give the title compound as a brown oil. LC-MS B: tR = 0.53 min; [M+H]+ = 288.16. 15 (R)(4-Methoxypyrazolyl-benzyl)-morpholine (C-9) The title compound was prepared from C-8 in analogy to the procedure described for A-12 .

LC-MS B: tR = 0.44 min; [M+H]+ = 273.91.

General method D for the synthesis of example compounds of formula (I) 20 (R)(4-Methoxy-benzyl)-morpholine (D-5) The title compound was prepared from C-6 in analogy to the procedure bed for A-12 .

LC-MS B: tR = 0.38 min; [M+H]+ = .

[( R)(4-Methoxy-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)-methanone (D-6) The title compound was prepared from D-5 and E-2 in analogy to the procedure described 25 for B-28 . LC-MS B: tR = 0.72 min; [M+H]+ = .

[( R)(3-Iodomethoxy-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)- methanone (D-7) The title compound was prepared from D-6 in analogy to the procedure described for C-7.

LC-MS B: tR = 0.80 min; [M+H]+ = 504.81. 30 {( R)[4-Methoxy(4,4,5,5-tetramethyl-[1,3,2]dioxaborolanyl)-benzyl]-morpholin yl}-(2-[1,2,3]triazolyl-phenyl)-methanone (D-8) The title compound was prepared from D-7 in analogy to the procedure described for B-7.

LC-MS B: tR = 0.81 min; [M+H]+ = 505.02. 57 Example compounds 3 to 10 The aryl halide (0.20 mmol) followed by K2CO3 (82 mg, 0.60 mmol) were added successively in one portion to a RT solution of -[4-methoxy(4,4,5,5-tetramethyl- [1,3,2]dioxaborolanyl)-benzyl]-morpholinyl}-(2-[1,2,3]triazolyl-phenyl)-methanone D-8 5 (100 mg, 0.20 mmol) in dioxane (1.8 mL) and H2O (0.9 mL) under argon. The resulting mixture was degassed with argon for 1 min before Pd(PPh3)4 (12 mg, 0.01 mmol) was added and the reaction mixture was heated to 90°C for 1h. The reaction mixture was cooled to RT and quenched with water. The resulting suspension was passed through a phase tor filter extracting with DCM (2x). The combined organic extracts were filtered through a celite 10 plug and ated in vacuo. The crude product was purified by prep. HPLC (method E) to furnish the desired t.

Listed in Table 5 below are example compounds, prepared from D-8 according to the above Suzuki procedure.

Table 5 Example Aryl Compound of Formula (I) tR [min] MS-data No. halide LC-MS m/z Method [M+H]+ 3 [(R)(4-Methoxypyridinyl-benzyl)- 0.54 455.94 morpholinyl]-(2-[1,2,3]triazolyl- B phenyl)-methanone 4 [(R)(4-Methoxypyridinyl-benzyl)- 0.56 455.95 morpholinyl]-(2-[1,2,3]triazolyl- B phenyl)-methanone 5 Br -(4-Methoxypyrimidinyl-benzyl)- 0.59 456.93 N N morpholinyl]-(2-[1,2,3]triazolyl- B phenyl)-methanone 6 Cl [(R)(4-Methoxypyrazinyl-benzyl)- 0.66 456.93 N morpholinyl]-(2-[1,2,3]triazolyl- B N phenyl)-methanone 7 [(R)(4-Methoxypyridazinyl-benzyl)- 0.61 456.94 morpholinyl]-(2-[1,2,3]triazolyl- B )-methanone 8 Br [(R)(4-Methoxythiazolyl-benzyl)- 0.74 461.90 N S morpholinyl]-(2-[1,2,3]triazolyl- B phenyl)-methanone 58 9 Br [(R)(4-Methoxyoxazolyl-benzyl)- 0.63 445.92 N O morpholinyl]-(2-[1,2,3]triazolyl- B phenyl)-methanone 10 Br [(R)(4-Methoxythiophenyl-benzyl)- 0.85 460.91 S morpholinyl]-(2-[1,2,3]triazolyl- B phenyl)-methanone General method E for the sis of o-triazolocarboxylic acids of Structure 2 2-Fluoromethyl(2H-1,2,3-triazolyl)benzoic acid (E-1) The title compound was prepared in analogy to the procedure described in WO2008/069997. 5 Cs2CO3 (6.98 g, 21.4 mmol) was added portionwise to a RT solution of roiodo methyl-benzoic acid (3.0 g, 10.7 mmol) in DMF (15 mL) under argon followed by 1H-1,2,3- triazole (1.24 mL, 21.4 mmol) and Cu(I)I (103 mg, 0.536 mmol) and the resulting blue suspension was stirred at 80°C overnight. The reaction e was quenched with 2M aq.

HCl and filtered through a celite plug before being extracted with DCM (3x). The combined 10 organic layers were dried over Na2SO4, filtered and evaporated in vacuo to give the crude product that was purified by prep. HPLC (method E) to give the title compound as a pale yellow solid. LC-MS B: tR = 0.55 min; [M+H]+ = .

Listed in Table 6 below are o-triazolocarboxylic acids of Structure 2, unless otherwise stated, prepared from the corresponding commercially ble iodo-carboxylic acid ing to 15 the above procedures.

Table 6 No. Carboxylic Acid 2 tR [min] MS-data LC-MS m/z Method [M+H]+ E-2 2-(2H-1,2,3-Triazolyl)benzoic acid 0.55 190.08 A E-3 5-Methyl(2H-1,2,3-triazolyl)benzoic acid 0.53 204.13 B E-4 4-Methyl(2H-1,2,3-triazolyl)benzoic acid 0.53 204.23 B E-5 5-Chloro(2H-1,2,3-triazolyl)benzoic acid 0.66 (35Cl) 224.3 A E-6 4,5-Dimethyl(2H-1,2,3-triazolyl)benzoic 0.59 218.09 acid B 59 E-7 ro(2H-1,2,3-triazolyl)benzoic acid 0.49 208.32 B E-8# 4-Fluoro(2H-1,2,3-triazolyl)benzoic acid 0.51 208.16 B E-9 2-Fluoromethoxy(2H-1,2,3-triazol 0.48 238.01 yl)benzoic acid B E-10 5-Methoxy(2H-1,2,3-triazolyl)benzoic 0.49 220.19 acid B E-11#ⱡ 5-Methoxymethyl(2H-1,2,3-triazol 0.68 234.05 yl)benzoic acid A E-12 4,5-Dimethoxy(2H-1,2,3-triazol 0.46 250.03 yl)benzoic acid B E-13 5-Cyano(2H-1,2,3-triazolyl)benzoic acid 0.46 No B ionisation E-14 6-Methyl(2H-1,2,3-triazolyl)picolinic acid 0.30 205.35 B E-15# 3-Fluoro(2H-1,2,3-triazolyl)benzoic acid 0.56 208.08 A E-16#ⱡ 3,5-Dimethyl(2H-1,2,3-triazolyl)benzoic 0.66 218.10 acid A E-17 4-Chloro(2H-1,2,3-triazolyl)benzoic acid 0.66 (35Cl) 224.10 A E-18# 4-Methoxy(2H-1,2,3-triazolyl)benzoic 0.60 220.05 acid A E-19#ⱡ 4-Fluoromethoxy(2H-1,2,3-triazol 0.64 238.1 yl)benzoic acid A E-20 3,4-Dimethyl(2H-1,2,3-triazolyl)benzoic 0.65 218.30 acid A E-21# 2-(2H-1,2,3-triazolyl) 0.72 No (trifluoromethyl)benzoic acid A ionisation E-22#ⱡ 4-Chloromethoxy(2H-1,2,3-triazol 0.70 (35Cl) 254.01 yl)benzoic acid A E-23# 3-Chloro(2H-1,2,3-triazolyl)benzoic acid 0.61 (35Cl) 224.09 A E-24# fluoro(2H-1,2,3-triazolyl)benzoic 0.56 No acid B ionisation 60 E-25 2-Methyl(2H-1,2,3-triazolyl)benzoic acid 0.51 204.41 B E-26 ro(2H-1,2,3-triazolyl)benzoic acid 0.46 208.21 B #Prepared from the corresponding o-bromo-carboxylic acid ⱡCorresponding o-bromo-carboxylic acid was ed according to the procedure described below 5 sis of 2-bromo-substituted benzoic acids was performed in analogy to described s (Tetrahedron Letters, 2009, 50, 1267-1269, J. Org. Chem, 2007, 72, 9786-9789). 2-Bromomethoxymethyl-benzoic acid Br2 (0.74 mL, 14.4 mmol) was added to a RT suspension of 3-methoxymethylbenzoic acid (2.0 g, 12 mmol) in acetic acid (15 mL) and water (15 mL) and the resulting mixture was 10 heated to 60°C for 2h. The reaction mixture was cooled to RT and filtered rinsing with cold water (40 mL) to yield 2-bromomethoxymethylbenzoic acid as a white solid that was used further without purification. LC-MS A: tR = 0.76 min, [M+H]+ = No ionisation. 1H NMR (DMSO) δH: 7.49 (s, 1 H), 7.29 (s, 1 H), 3.82 (s, 3 H), 2.17 (s, 3 H). 2-Bromofluoromethoxy-benzoic acid 15 The title compound was prepared from romethoxybenzoic acid in analogy to the above described . LC-MS A: tR = 0.72 min, [M+H]+ = No ionisation. 1H NMR (DMSO) δH: 13.52 (bs, 1 H), 7.77 (dd, 1 H), 7.44 (dd, 1 H), 4.01 (s, 3 H). 2-Bromo-3,5-dimethyl-benzoic acid The title compound was prepared from 3,5-dimethyl-benzoic acid in analogy to the above 20 described method. LC-MS A: tR = 0.75 min, [M+H]+ = No ionisation. 1H NMR (DMSO) δH: 7.56 (s, 1 H), 7.28 (m, 2 H), 2.36 (s, 3 H), 2.27 (s, 3 H). 2-Bromochloromethoxybenzoic acid The title compound was prepared from 4-chloromethoxybenzoic acid in analogy to the above described method. LC-MS A: tR = 0.77 min, [M+H]+ = No ionisation. 1H NMR (DMSO) 25 δH: 13.60 (bs, 1 H), 7.82 (s, 1 H), 7.47 (s, 1 H), 3.91 (s, 3 H). 3-Methyl(2H-1,2,3-triazolyl)benzoic acid (E-27) Step 1: K2CO3 (8.18 g, 59.2 mmol) was added to a RT solution of 2-fluoro methylbenzonitrile (4.0 g, 29.6 mmol) and 1H-1,2,3-triazole (1.72 mL, 29.6 mmol) in DMF (80 mL) and the resulting suspension was heated to 120°C for 4h. The reaction mixture was 30 cooled to RT and quenched with water before being extracted with EtOAc (3x). The combined organic extracts were washed with brine, dried over , filtered and 61 ated in vacuo to give the crude product that was purified by flash chromatography ng with a gradient of 33% to 50% EtOAc in hexane) to give 3-methyl(2 H-1,2,3-triazol- 2-yl)benzonitrile as a white solid. LC-MS B: tR = 0.62 min; [M+H]+ = 185.16.

Step 2: 4M aq. NaOH (10 mL, 40.2 mmol) was added to a RT solution of 3-methyl(2 H- 5 1,2,3-triazolyl)benzonitrile (1.48 g, 8.04 mmol) in MeOH (15 mL) and the resulting mixture was heated to 90°C for 50h. The reaction mixture was cooled to RT and diluted with water before the organic solvent was removed in vacuo. The remaining aqueous phase was acidified with 1M aq. HCl and extracted with EtOAc (3x). The combined organic phases were washed with brine, dried over Na2SO 4, ed and evaporated in vacuo to give the title 10 compound that was used r without purification. LC-MS B: tR = 0.50 min; [M+H]+ = 186.17. 5-Chloromethyl(2 H-1,2,3-triazolyl)benzoic acid (E-28) Cs 2CO 3 (742 mg, 2.28 mmol) was added portionwise to a RT solution of 2-bromochloro methyl-benzoic acid methyl ester (300 mg, 1.14 mmol) in DMF (3 mL) followed by 1H-1,2,3- 15 triazole (0.1 mL, 1.71 mmol), Cu(I)I (13 mg, 0.068 mmol) and DMCDA (40 µL, 0.23 mmol).

The resulting suspension was heated to 120°C for 4h. The reaction mixture was cooled to RT, ed with 2M aq. HCl and extracted with EtOAc (3x). The combined organic layers were dried over Na2SO 4, filtered and evaporated in vacuo to give the crude product that was purified by prep. HPLC (method E) to give the title compound as a pale yellow solid. LC-MS 20 A: tR = 0.72 min; [M(35 Cl)+H] + = 238.01. 2-(2 H-1,2,3-Triazolyl)(trifluoromethyl)benzoic acid (E-29) The title compound was prepared from 2-iodo(trifluoromethyl)benzonitrile in analogy to the procedure described for E-27. LC-MS A: tR = 0.68 min; [M+H]+ = No ionisation; 1H NMR (DMSO) δH: 12.01 (m, 1 H), 8.20 (m, 2 H), 8.10 (s, 2 H), 7.95 (m, 1 H). 25 General method G for the synthesis of 3-benzyl morpholines of Structure 1 (2-Fluoroiodo-phenyl)-methanol (G-6) Borane.THF complex 1M soln. (94 mL, 94 mmol) was added dropwise to a 0°C suspension of 2-fluoroiodobenzoic acid (10 g, 37.6 mmol) in THF (60 mL) under argon and after te addition the reaction mixture was heated to 70°C for 2h. The reaction mixture was 30 cooled to 0°C and quenched with MeOH and after stirring for 5 min the reaction mixture was evaporated in vacuo. The e was partitioned between 2M aq. HCl and MeOH and stirred for 30 min at 50°C before being concentrated in vacuo. The remaining aqueous phase was d with additional water and extracted with DCM (3x). The combined c extracts were dried (Na2SO 4), filtered and evaporated in vacuo to give the title compound as 35 a yellow solid that was used further without purification. LC-MS B: tR = 0.66 min; [M+H+Na]+ 62 = 275.99; 1H NMR (DMSO) δ H: 7.77 (dd, J1 = 7.0 Hz, J2 = 2.3 Hz, 1 H), 7.64 (m, 1 H), 7.01 (dd, J1 = 10.1 Hz, J2 = 8.6 Hz, 1 H), 5.38 (t, J = 5.8 Hz, 1 H), 4.52 (d, J = 5.8 Hz, 2 H).

Listed in Table 7 below are intermediates of type G-2, prepared from the corresponding 5 commercially available carboxylic acid according to the above procedure.

Table 7 No. Intermediate tR [min] MS-data m/z LC-MS Method [M+H+Na]+ G-7 oroiodo-phenyl)-methanol 0.79 No ionisation A G-8 (5-Iodomethyl-phenyl)-methanol 0.77 272.09 A G-9 (3-Chloroiodo-phenyl)-methanol 0.75 No ionisation B G-10 (3-Bromofluoro-phenyl)-methanol 0.72 No tion A G-11 (2-Fluoroiodo-phenyl)-methanol 0.64 276.04 B G-12 (3-Iodomethyl-phenyl)-methanol 0.70 272.14 B G-13 (4-Chloroiodo-phenyl)-methanol 0.70 (35Cl) 291.83 B 2-Bromomethylfluoroiodo-benzene (G-14) Phosphorus tribromide 1.0 M soln. in DCM (18.9 mL, 18.9 mmol) was added se to a 10 0°C solution of oroiodo-phenyl)-methanol G-6 (9.52 g, 37.8 mmol) in DCM (215 mL) and the resulting mixture was stirred for 1h before being quenched with water. The layers were separated and the aqueous phase was re-extracted with DCM (2x). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and evaporated in vacuo to give the crude product that was purified by flash chromatography (eluting with 5% 15 EtOAc in hexane) to give the title compound as a white solid. LC-MS B: t R = 0.92 min; No ionisation; 1H NMR (DMSO) δ H: 7.93 (dd, J1 = 7.1 Hz, J2 = 2.3 Hz, 1 H), 7.74 (ddd, J1 = 8.6 Hz, J2 = 4.9 Hz, J3 = 2.3 Hz, 1 H), 7.10 (dd, J1 = 10.0 Hz, J2 = 8.7 Hz, 1 H), 4.66 (s, 2 H). 63 Listed in Table 8 below are intermediates of type G-3, prepared from the corresponding benzyl alcohol G-2, according to the above procedure.

Table 8 No. Intermediate tR [min] a m/z LC-MS Method [M+H]+ G-15 2-Bromomethylchloroiodo- 0.96 No ionisation benzene A G-16 2-Bromomethyliodomethyl- 0.96 No ionisation benzene A G-17 1-Bromomethylchloroiodo- 1.01 No ionisation benzene B G-18 1-Bromobromomethylfluoro- 0.92 No ionisation benzene A G-19 omethylfluoroiodo- 0.90 No ionisation benzene B G-20 4-Bromomethyliodomethyl- 0.97 No ionisation benzene B G-21 omethylchloroiodo- 0.94 No ionisation benzene A 5 2-tert-Butoxycarbonylamino(2-fluoroiodo-benzyl)-malonic acid l ester (G- 22) A solution of diethyl(Boc-amino)malonate (6.96 g, 25.3 mmol, either commercially available or ed by conventional Boc-protection of diethylaminomalonate hydrochloride) in DMF (7 mL) was added dropwise to a 0°C suspension of sodium hydride (0.926 g, 23.2 mmol) in 10 DMF (45 mL) under N2 and then a solution of 2-bromomethylfluoroiodo-benzene G-14 (6.62 g, 21.1 mmol) in DMF (30 mL) was added to the suspension. The ing solution was warmed to RT and stirred for 1h. The reaction was quenched by the addition of water and the mixture was extracted with DCM (3x). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and evaporated in vacuo to give the crude product as a 15 white solid that was used further without purification. LC-MS B: tR = 1.05 min; [M+H]+ = 510.02. 64 Listed in Table 9 below are intermediates of type G-4, prepared from the corresponding benzyl bromide G-3, according to the above procedure.

Table 9 No. Intermediate tR [min] MS-data m/z LC-MS Method [M+H]+ G-23 2-tert-Butoxycarbonylamino(2-chloro- 1.07 (35Cl) 526.02 5-iodo-benzyl)-malonic acid l ester A G-24 2-tert-Butoxycarbonylamino(5-iodo 1.07 506.00 methyl-benzyl)-malonic acid diethyl ester A G-25 -Butoxycarbonylamino(3-chloro- 1.12 (35Cl) 526.14 5-iodo-benzyl)-malonic acid diethyl ester B G-26 2-(3-Bromofluoro-benzyl)tert- 1.05 No ionisation butoxycarbonylamino-malonic acid A diethyl ester G-27 2-tert-Butoxycarbonylamino(2-fluoro- 1.03 509.92 3-iodo-benzyl)-malonic acid diethyl ester B G-28 2-tert-Butoxycarbonylamino(3-iodo 1.08 506.04 methyl-benzyl)-malonic acid diethyl ester B G-29 2-tert-Butoxycarbonylamino(4-chloro- 1.06 (35Cl) 469.88 3-iodo-benzyl)-malonic acid diethyl ester A 5 ractert-Butoxycarbonylamino(2-fluoroiodo-phenyl)-propionic acid (G-30) A suspension of 2-tert-butoxycarbonylamino(2-fluoroiodo-benzyl)-malonic acid diethyl ester G-22 in EtOH (113 mL) was heated to 40°C and water (50 mL) was then added giving an easily stirrable emulsion. 1M aq. NaOH (93 mL) was carefully added and reaction e was heated to 100°C for 16h. The reaction mixture was cooled to RT and the volatiles were 10 removed in vacuo. The remaining aqueous phase was extracted once with TBME and this extract was discarded. The aqueous layer was acidified with 25% aq. HCl and extracted with TBME (2x). The combined organic layers were washed with water, dried over , filtered and evaporated in vacuo to give the crude product that was purified by flash chromatography (eluting with a gradient of 25% to 50% EtOAc in ) to give the title 15 compound as a white solid. LC-MS B: tR = 0.80 min; [M-Me]+ = 394.95.

Listed in Table 10 below are ediates of type G-5, prepared from the corresponding malonic acid derivative G-4, according to the above procedure. 65 Table 10 No. Intermediate tR [min] MS-data m/z LC-MS Method [M-Me]+ G-31 ractert-Butoxycarbonylamino(2- 0.88 (35Cl) 410.85 chloroiodo-phenyl)-propionic acid A G-32 tert-Butoxycarbonylamino(5- 0.88 390.91 iodomethyl-phenyl)-propionic acid A G-33 ractert-Butoxycarbonylamino(3- 0.87 (35Cl) 410.80 chloroiodo-phenyl)-propionic acid B G-34 rac(3-Bromofluoro-phenyl)tert- 0.85 (79Br) 347.01 butoxycarbonylamino-propionic acid A G-35 ractert-Butoxycarbonylamino(2- 0.79 394.92 fluoroiodo-phenyl)-propionic acid B G-36 tert-Butoxycarbonylamino(3- 0.84 391.00 iodomethyl-phenyl)-propionic acid B G-37 ractert-Butoxycarbonylamino(4- 0.84 (35Cl) 410.87 chloroiodo-phenyl)-propionic acid B General method H for the synthesis of 3-benzyl morpholines of Structure 1 racAmino(3-iodo-phenyl)methyl-propionic acid ethyl ester (H-5) 5 Step 1: A suspension of DL-alanine ethyl ester hydrochloride (10 g, 65.1 mmol) in DCM (150 mL) was washed with 2M aq. NaOH and the layers were separated. The organic phase was dried over , filtered and the te was cooled to 0°C before MgSO4 hydrate (11.3 g) followed by pivalaldeyde (7.72 g, 89.6 mmol) were added and the resulting mixture was warmed to RT and stirred for 16h. The reaction mixture was filtered and evaporated in vacuo 10 to give rac-ethyl 2-((2,2-dimethylpropylidene)amino)propanoate that was used further without purification.

Step 2: 3-Iodobenzyl bromide (14.4 g, 48.6 mmol) was added to a RT solution of rac-ethyl 2- ((2,2-dimethylpropylidene)amino)propanoate (10 g, 48.6 mmol) from above in e (100 mL) under argon and the resulting mixture was cooled to -10°C before KOtBu (10.9 g, 97.2 15 mmol) was added nwise. The reaction mixture was stirred at 0°C for 4h before being quenched with water. The toluene was evaporated in vacuo and the remaining aqueous phase was extracted with EtOAC (3x). The combined organic extracts were dried over Na2SO4, filtered and evaporated in vacuo. The residue was stirred in 1M aq. HCl overnight 66 after which LCMS showed the desired product. EtOAc was added and the mixture was stirred for 30 min before the layers were separated. The organic phase was discarded and the aqueous phase was basified with 2M aq. NaOH and re-extracted with EtOAc (3x). The combined organic extracts were dried over Na2SO 4, filtered and evaporated in vacuo to give 5 the title compound that was used further without purification. LC-MS D: tR = 0.88 min; [M+H+MeCN]+ = 375.06. rac Amino(3-iodo-phenyl)methyl-propanol (H-6) BH 3.THF Complex 1 M soln. in THF (9 mL, 9 mmol) was added dropwise to a 0°C solution of rac amino(3-iodo-phenyl)methyl-propionic acid ethyl ester H-5 (1.2 g, 3.6 mol) in THF 10 (10 mL) under argon and the resulting mixture was stirred for 5 min at 0°C before being warmed to RT and d overnight. The on mixture was cooled to 0°C and quenched with MeOH before being evaporated in vacuo. The residue was partioned between 2M aq.

HCl and TBME and stirred for 30 min. The phases were separated and the aqueous phase was re-extracted with TBME (2x) and the combined organic extracts were discarded. The 15 aqueous layer was basified with 2M aq. NaOH and re-extracted with DCM (3x). The combined DCM ts were washed with brine, dried over Na2SO 4, filtered and evaporated in vacuo to give the title compound as a white solid. LC-MS D: tR = 0.74 min; [M+H+MeCN]+ = 333.02. rac Chloro-N-[1-hydroxymethyl(3-iodo-phenyl)methyl-ethyl]-acetamide (H-7) 20 NaOH 1M aq. soln. (10 mL) followed by NaOH 32% (270 µL) were added to a 0°C on of rac amino(3-iodo-phenyl)methyl-propanol H-6 (850 mg, 2.92 mmol) in DCM (10 mL). After 10 min a solution of chloroacetyl chloride (261 mL, 3.21 mmol) in DCM (10 mL) was added dropwise to the reaction mixture maintaining the temperature below 5°C. The resulting sion was heated to 35°C for 30 min after which complete formation of 25 product was observed by LCMS. The layers were separated and the aqueous layer ted with DCM (2x). The combined organic extracts were washed with brine, dried over Na2SO 4, filtered and ated in vacuo to give the title compound that was used r without purification. LC-MS A: tR = 0.79 min; [M(35 Cl)+H]+ = 367.91. rac (3-Iodo-benzyl)methyl-morpholinone (H-8) 30 A solution of rac chloro-N-[1-hydroxymethyl(3-iodo-phenyl)methyl-ethyl]-acetamide H- 7 (1.0 g, 2.7 mmol) in THF (13 mL) was added dropwise to a RT on of KOtBu (6.8 mL, 6.8 mmol, 1M soln. in THF) under argon and the reaction mixture was stirred for 20 min. The reaction was quenched with 1M aq. HCl, diluted with water and concentrated in vacuo. The remaining aqueous phase was extracted with DCM (3x) and the combined c extracts 67 were dried over Na2SO 4, ed and evaporated in vacuo to give the title nd that was used further without cation. LC-MS A: tR = 0.75 min; [M+H+MeCN]+ = 373.02. rac Methyl(3-[1,2,3]triazolyl-benzyl)-morpholinone (H-9) DMCDA (85 µL, 0.538 mmol) followed by 1H-1,2,3-triazole (0.31 mL, 5.38 mmol) were added 5 to a mixture of rac (3-iodo-benzyl)methyl-morpholinone H-8 (890 mg, 2.69 mmol), Cs 2CO 3 (1.75 g, 5.38 mmol) and CuI (77 mg, 0.40 mmol) in DMF (5 mL) under argon and the resulting blue suspension was heated to 120°C for 18h. The on mixture was cooled to RT before being quenched with water and filtered over celite rinsing with water and DCM.

The layers were separated and the aqueous phase was re-extracted with DCM (2x). The 10 combined organic extracts were washed with brine, dried over Na2SO 4, ed and evaporated in vacuo. The crude product was purified by flash chromatography (eluting with a gradient of 75% to 100% EtOAc in hexane) to give the title nd as a pale brown solid.

LC-MS A: tR = 0.69 min; [M+H]+ = 273.21. rac Methyl(3-[1,2,3]triazolyl-benzyl)-morpholine (H-10) 15 The title compound was prepared from H-9 in analogy to the procedure described for A-12 .

LC-MS A: tR = 0.55 min; [M+H]+ = 259.07.

General method I for the synthesis of 3-benzyl morpholines of Structure 1 (R)Oxo(3-[1,2,3]triazolyl-benzyl)-morpholinecarboxylic acid tert-butyl ester (I-5) 20 Boc 2O (1.79 g, 8.19 mmol) was added in one portion to a RT solution of (R)(3- [1,2,3]triazolyl-benzyl)-morpholinone A-13 (1.06 g, 4.09 mmol) and DMAP (51 mg, 0.41 mmol) in Et3N:MeCN 3:1 (16 mL) under Argon and the resulting mixture was stirred for 1.5h.

The reaction mixture was diluted with EtOAc, transferred to a separating funnel and washed successively with 3% aq. HCl, sat. aq. NaHCO3 and brine. The organic phase was dried over 25 Na 2SO 4, filtered and evaporated in vacuo to give the title compound that was used further without purification. LC-MS B: tR = 0.81 min; [M+H-Boc]+ = 259.17.

[( R)(2-Oxo-propoxy)(3-[1,2,3]triazolyl-benzyl)-ethyl]-carbamic acid tert-butyl ester (I-6) MeLi 1.6 M in Et2O (3.6 mL, 5.82 mmol) was added dropwise to a -78°C solution of (R) 30 (3-[1,2,3]triazolyl-benzyl)-morpholinecarboxylic acid tert-butyl ester I-5 (1.49 g, 4.16 mmol) in THF (15 mL) and the resulting mixture was stirred at -78°C for 3h. The reaction mixture was quenched with sat. aq. NH4Cl, warmed to RT and the solvent was removed in vacuo. The remaining aqueous layer was extracted with EtOAc (3x) and the combined c ts were washed with brine, dried over Na2SO 4, filtered and 35 evaporated in vacuo. The crude product was purified by flash chromatography (eluting with 68 20% to 50% EtOAc in hexane) to give the title nd as a yellow solid. LC-MS B: tR = 0.81 min; [M+H-Boc]+ = 259.17. (3 R,5 R)Methyl(3-[1,2,3]triazolyl-benzyl)-morpholine (I-7) and (3S,5 R)Methyl- 5-(3-[1,2,3]triazolyl-benzyl)-morpholine (I-8) 5 Step 1: [(R)(2-Oxo-propoxy)(3-[1,2,3]triazolyl-benzyl)-ethyl]-carbamic acid tert-butyl ester (I-6) (500 mg, 1.34 mmol) was ved in TFA (5 mL) at 0°C and stirred for 1h. The reaction e was evaporated in vacuo and used directly in Step 2.

Step 2: The Boc-cleaved intermediate from above was dissolved in MeOH (10 mL) and cooled to 0°C. Sodium borohydride (52 mg, 1.37 mmol) was then added and the resulting 10 mixture was stirred for 1h. The reaction e was ed with water and the solvent was evaporated in vacuo. The remaining s phase was extracted once with DCM and this extract was discarded. The aqueous layer was basified with 5M aq. NaOH and reextracted with DCM (3x). The combined basic organic extracts were washed with brine, dried over Na2SO 4, filtered and evaporated in vacuo to give the crude product that was purified by 15 flash chromatography (eluting with 95:5 DCM:MeOH) to give the first title compound as a colourless oil. LC-MS A: tR = 0.55 min; [M+H]+ = 259.20. Continued elution afforded the second title compound (major product) as a colourless oil. LC-MS A: tR = 0.54 min; [M+H]+ = 259.21.

General method J for the synthesis of 3-benzyl lines of Structure 1 20 (R)-N-[( 3-Iodo-benzyl)hydroxy-ethyl]chloro-propionamide and (S)-N-[( R) (3-Iodo-benzyl)hydroxy-ethyl]chloro-propionamide (J-5) The title compounds were prepared as a mixture of diastereomers from A-8 and rac chloropropanoyl chloride in analogy to the procedure described for H-7. LC-MS A: tR = 0.76 min; [M(35 Cl)+H] + = 367.98. 25 (2 R,5 R)(3-Iodo-benzyl)methyl-morpholinone (J-6) The title compound was prepared as a single cis -stereoisomer from J-5 in analogy to the procedure described for H-8. LC-MS A: tR = 0.76 min; eCN]+ = 373.04. (2 R,5 R)Methyl(3-[1,2,3]triazolyl-benzyl)-morpholinone (J-7) and (2S,5 R) Methyl(3-[1,2,3]triazolyl-benzyl)-morpholinone (J-8) 30 The title compounds were prepared from J-6 in analogy to the procedure described for H-9.

J-7 LC-MS A: tR = 0.69 min; [M+H]+ = 273.11. J-8 (minor product) LC-MS A: tR = 0.70 min; [M+H] + = 273.14. (2 R,5 R)Methyl(3-[1,2,3]triazolyl-benzyl)-morpholine (J-9) The title compound was prepared from J-7 in y to the procedure described for A-12 . 35 LC-MS A: tR = 0.57 min; [M+H]+ = 259.07. 69 (2 S,5 R)Methyl(3-[1,2,3]triazolyl-benzyl)-morpholine (J-10) The title compound was ed from J-8 in analogy to the procedure described for A-12 .

LC-MS A: tR = 0.55 min; [M+H]+ = 259.07. (2 R,5 R)Ethyl(3-[1,2,3]triazolyl-benzyl)-morpholine (J-11) 5 The title compound was prepared from A-8 and rac chlorobutanoyl chloride in analogy to the sequence of reactions described for J-9. LC-MS A: tR = 0.59 min; [M+H]+ = . (2 R,5 R)(2-Fluoro[1,2,3]triazolyl-benzyl)methyl-morpholine (J-12) The title compound was prepared from (R)amino(5-bromofluorophenyl)propanol (Chiral Quest) or G-30 , in analogy to the sequence of reactions described for the preparation 10 of J-9. LC-MS A: tR = 0.57 min; [M+H]+ = 277.11. (2 R,5 R)(2-Fluoro[1,2,3]triazolyl-benzyl)methyl-morpholine (J-13) The title nd was prepared from amino(5-bromofluorophenyl)propanol (Chiral Quest), in analogy to the sequence of reactions described for the preparation of J-9 and A-16 . LC-MS A: tR = 0.50 min; [M+H+MeCN]+ = 318.14. 15 (2 R,5 R)Methyl(3-pyrimidinyl-benzyl)-morpholine hydrochloride (J-14) The title compound was prepared from A-8 and rac chloropropanoyl de, in analogy to the sequence of reactions described for the preparation of B-18 . LC-MS A: tR = 0.53 min; [M+H] + = 270.14. (2 R,5 R)(2-Fluoropyrimidinyl-benzyl)methyl-morpholine hloride (J-15) 20 The title nd was prepared from (R)amino(5-bromofluorophenyl)propanol (Chiral Quest) and rac chloropropanoyl chloride, in analogy to the sequence of ons bed for the preparation of B-18 . LC-MS A: tR = 0.56 min; [M+H]+ = 288.24. (2 R,5 R)(2-Fluoropyridazinyl-benzyl)methyl-morpholine hydrochloride (J-16) The title compound was prepared from (R)amino(5-bromofluorophenyl)propanol 25 (Chiral Quest) and rac chloropropanoyl chloride, in analogy to the sequence of reactions described for the preparation of B-18 substituting 2-bromopyrimidine for 3-bromopyridazine hydrobromide. LC-MS A: tR = 0.52 min; [M+H]+ = 288.25.

General method K for the synthesis of 3-benzyl morpholines of Structure 1 [( R)Hydroxymethyl(3-iodo-phenyl)-ethyl]-carbamic acid tert-butyl ester (K-9) 30 A solution of Bociodo-D-phenylalanine (6.32 g,16.2 mmol) and 4-methyl-morpholine (1.87 ml, 17 mol) in THF (13 mL) was added dropwise to a -15°C solution of isobutyl chloroformate (2.22 mL, 17 mmol) in THF (13 mL) and the resulting suspension was stirred for 1h. The cold reaction mixture was filtered and the filter cake was rinsed with THF. The filtrate was added dropwise to a 0°C solution of NaBH4 (0.92 g, 24.2 mmol) in dimethylacetamide (7 mL) and 70 the ing suspension was warmed to RT and stirred for 1h. The reaction mixture was cooled back to 0°C and quenched with 1M aq. citric acid. Additional water was added and the mixture was concentrated in vacuo. The remaining aqueous phase was acidified with 1M aq. HCl before being filtered. The filter cake was rinsed with water and dried under HV to 5 give the title compound as an orange solid that was used further without purification. LC-MS A: tR = 0.84 min; [M-Me]+ = 362.93.

[( R)Formyl(3-iodo-phenyl)-ethyl]-carbamic acid tert-butyl ester (K-10) A solution of [(R)hydroxymethyl(3-iodo-phenyl)-ethyl]-carbamic acid tert-butyl ester K-9 (5.32 g, 14.1 mmol) in DCM (100 mL) was added dropwise to a RT suspension of DMP (6.78 10 g, 15.5 mmol) in DCM (40 mL) and the resulting mixture was stirred for 1.5h. The reaction was quenched with 20% aq. NaHCO3 and 10% aq. Na2S2O3 and stirred for 1h. The layers were separated and the s layer was extracted with DCM (2x). The combined c extracts were washed with 1M aq. HCl, brine, dried over Na2SO 4, filtered and evaporated in vacuo . The crude product was subsequently triturated with a little DCM to give the title 15 compound as an orange solid. LC-MS A: tR = 0.87 min; [M+H]+ = No ionisation. [(1 R,2 ydroxy(3-iodo-benzyl)-propyl]-carbamic acid tert-butyl ester and [(1 R,2 R)Hydroxy(3-iodo-benzyl)-propyl]-carbamic acid tert-butyl ester (K-11) Methylmagnesium bromide 3.0 M soln. in Et2O (8.4 mL, 25.2 mmol) was added dropwise to a -78°C solution of [(R)formyl(3-iodo-phenyl)-ethyl]-carbamic acid tert-butyl ester K-10 20 (4.72 g, 12.6 mmol) in THF (100 mL) and the resulting mixture was warmed to 0°C and stirred for 15 min. The on was quenched with sat. aq. NH4Cl and the volatiles were removed in vacuo. The remaining aqueous phase was extracted with DCM (3x) and the combined organic extracts were washed with brine, dried over Na2SO 4, ed and evaporated in vacuo. The crude product purified by flash chromatography (eluting with 25% 25 to 50% EtOAc in hexane) to give the title compounds as an ~1:1 e of reomers.

LC-MS A: tR = 0.88 min; [M+H]+ = 376.97. (2 S,3 R)Amino(3-iodo-phenyl)-butanol hydrochloride and (2 R,3 R)Amino(3- iodo-phenyl)-butanol hydrochloride (K-12) The title compounds were prepared from K-11 in analogy to the procedure described for A-7. 30 LC-MS A: tR = 0.55 min; [M+H+MeCN]+ = . 2-Chloro-N-[(1 R,2 S)hydroxy(3-iodo-benzyl)-propyl]-acetamide and ro-N- [(1 R,2 R)hydroxy(3-iodo-benzyl)-propyl]-acetamide (K-13) The title compounds were prepared from K-12 and chloroacetyl chloride in analogy to the procedure described for H-7. LC-MS A: tR = 0.75 min; [M(35 Cl)+H] + = 367.91. 71 (5 R,6 S)(3-Iodo-benzyl)methyl-morpholinone and (5R,6 R)(3-Iodo-benzyl) -morpholinone (K-14) The title compounds were prepared from K-13 in analogy to the procedure bed for H-8.

LC-MS A: tR = 0.76 min; [M+H+MeCN]+ = 372.92. 5 (5 R,6 R)Methyl(3-[1,2,3]triazolyl-benzyl)-morpholinone and (5R,6 S)Methyl- 1,2,3]triazolyl-benzyl)-morpholinone (K-15 & K-16) The title compounds were prepared from K-14 in analogy to the ure described for H-9 and the two diastereomers were subsequently separated by flash chromatography (eluting with a gradient of 50% to 70% EtOAc in hexane). K-15 or K16 LC-MS A: tR = 0.70 min; 10 [M+H] + = 273.18. K-16 or K-15 LC-MS A: tR = 0.69 min; [M+H]+ = 273.27. (2 R,3 R)Methyl(3-[1,2,3]triazolyl-benzyl)-morpholine (K-17) The title compound was prepared from K-15 or K-16 in analogy to the procedure described for A-12 . LC-MS A: tR = 0.55 min; [M+H]+ = 259.21 or tR = 0.56 min; [M+H]+ = . (2 S,3 R)Methyl(3-[1,2,3]triazolyl-benzyl)-morpholine (K-18) 15 The title compound was prepared from K-16 or K-15 in analogy to the procedure described for A-12 . LC-MS A: tR = 0.56 min; [M+H]+ = 259.30 or tR = 0.55 min; [M+H]+ = 259.21.

General method L for the synthesis of example compounds of a (I) rac -{3-[4-Methyl(4,4,5,5-tetramethyl-[1,3,2]dioxaborolanyl)-benzyl]-morpholin yl}-(2-[1,2,3]triazolyl-phenyl)-methanone (L-3) 20 The title compound was prepared from rac tert-butoxycarbonylamino(3-iodomethylphenyl )-propionic acid G-36 , in analogy to the sequence of reactions described for the preparation of D-8. LC-MS B: tR = 0.96 min; [M+H]+ = 489.12. rac -{3-[4-Chloro(4,4,5,5-tetramethyl-[1,3,2]dioxaborolanyl)-benzyl]-morpholin yl}-(2-[1,2,3]triazolyl-phenyl)-methanone (L-4) 25 The title compound was prepared from rac tert-Butoxycarbonylamino(4-chloroiodophenyl )-propionic acid G-37 , in analogy to the sequence of reactions described for the preparation of D-8. LC-MS A: tR = 0.93 min; [M(35 Cl)+H] + = 508.96.

Example compounds 11 to 54 General method F-1 for the sis of example compounds of formula (I) 30 TBTU (34 mg, 0.11 mmol) was added to a RT solution of the ed acid 2 (0.1 mmol) and DIPEA (25 µL, 0.15 mmol) in DMF (0.5 mL) and after ng for 5 min a solution of the required amine 1 as its free base or HCl salt (0.1 mmol) and DIPEA (25 µL, 0.15 mmol) in DMF (0.5 mL) was added. The resulting mixture was stirred for up to 4d before being purified directly by prep. HPLC (method F) to furnish the desired product. 72 General method F-2 for the synthesis of example compounds of formula (I) A freshly prepared on of the corresponding acid chloride of carboxylic acid 2 (0.11 mmol) in MeCN (0.5 mL) was added to a solution of the ed amine 1 as its free base or HCl salt (0.1 mmol) and Et3N (0.2 mmol) in MeCN (0.5 mL) and the resulting mixture was 5 stirred at RT for up to 4d. The reaction e was subsequently purified directly by prep.

HPLC (method F) to furnish the d product. Example compounds prepared according to General Method F-2 include Examples 68 to 74.

Listed in Tables 11 and 12 below are e compounds, prepared according to the abovementioned methods F-1 and F-2, from the corresponding amine 1, prepared as described 10 above and the corresponding carboxylic acid 2, prepared as described above.

Table 11 Example Amine Acid Compound of a (I) No. 1 2 11 A-15 E-3 (5-Methyl[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,3]triazol yl-benzyl)-morpholinyl]-methanone; LC-MS D: tR = 0.85 min; [M+H]+ = 430.05 12 A-15 E-2 [(R)(3-[1,2,3]Triazolyl-benzyl)-morpholinyl]-(2- [1,2,3]triazolyl-phenyl)-methanone; LC-MS B: tR = 0.73 min; [M+H]+ = 416.0 13 A-26 E-2 [(S)(3-[1,2,3]Triazolyl-benzyl)-morpholinyl]-(2- [1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.85 min; [M+H]+ = 416.05 14 C-9 E-2 [(R)(4-Methoxypyrazolyl-benzyl)-morpholinyl]-(2- [1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.82 min; [M+H]+ = 444.99 15 A-16 E-3 (5-Methyl[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,3]triazol yl-benzyl)-morpholinyl]-methanone; LC-MS D: tR = 0.79 min; [M+H]+ = 430.00 16 A-12 E-2 [(R)(3-Pyrazolyl-benzyl)-morpholinyl]-(2-[1,2,3]triazol- 2-yl-phenyl)-methanone; LC-MS D: tR = 0.83 min; [M+H]+ = 415.07 17 B-18 E-3 (5-Methyl[1,2,3]triazolyl-phenyl)-[(R)(3-pyrimidinylbenzyl )-morpholinyl]-methanone; LC-MS D: tR = 0.82 min; [M+H]+ = 441.06 73 18 B-18 E-2 [(R)(3-Pyrimidinyl-benzyl)-morpholinyl]-(2- ]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.82 min; [M+H]+ = 426.96 19 A-12 E-3 (5-Methyl[1,2,3]triazolyl-phenyl)-[(R)(3-pyrazolylbenzyl )-morpholinyl]-methanone; LC-MS D: tR = 0.83 min; [M+H]+ = 429.04 20 A-12 E-7 oro[1,2,3]triazolyl-phenyl)-[(R)(3-pyrazolylbenzyl )-morpholinyl]-methanone; LC-MS D: tR = 0.85 min; [M+H]+ = 433.02 21 A-12 E-1 (2-Fluoromethyl[1,2,3]triazolyl-phenyl)-[(R)(3- pyrazolyl-benzyl)-morpholinyl]-methanone; LC-MS D: tR = 0.90 min; [M+H]+ = 447.02 22 A-12 E-4 (4-Methyl[1,2,3]triazolyl-phenyl)-[(R)(3-pyrazolylbenzyl )-morpholinyl]-methanone; LC-MS D: tR = 0.83 min; [M+H]+ = 429.02 23 A-18 E-3 (5-Methyl[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,4]triazol yl-benzyl)-morpholinyl]-methanone; LC-MS D: tR = 0.78 min; [M+H]+ = 430.03 24 B-19 E-3 (5-Methyl[1,2,3]triazolyl-phenyl)-[(R)(3-pyridinylbenzyl )-morpholinyl]-methanone; LC-MS D: tR = 0.84 min; [M+H]+ = 440.04 25 B-20 E-3 (5-Methyl[1,2,3]triazolyl-phenyl)-[(R)(3-pyridinylbenzyl )-morpholinyl]-methanone; LC-MS D: tR = 0.80 min; [M+H]+ = 440.07 26 A-15 E-7 (5-Fluoro[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,3]triazol yl-benzyl)-morpholinyl]-methanone; LC-MS D: tR = 0.87 min; [M+H]+ = 434.02 27 A-15 E-4 (4-Methyl[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,3]triazol yl-benzyl)-morpholinyl]-methanone; LC-MS D: tR = 0.87 min; [M+H]+ = 430.05 28 B-21 E-3 (5-Methyl[1,2,3]triazolyl-phenyl)-[(R)(3-pyridinylbenzyl )-morpholinyl]-methanone; LC-MS D: tR = 0.79 min; [M+H]+ = 440.06 74 29 A-15 E-1 (2-Fluoromethyl[1,2,3]triazolyl-phenyl)-[(R)(3- ]triazolyl-benzyl)-morpholinyl]-methanone; LC-MS D: tR = 0.93 min; [M+H]+ = 448.05 30 A-15 E-5 (5-Chloro[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,3]triazol yl-benzyl)-morpholinyl]-methanone; LC-MS D: tR = 0.87 min; [M(35Cl)+H]+ = 449.99 31 A-15 E-13 4-[1,2,3]Triazolyl[(R)(3-[1,2,3]triazolyl-benzyl)- morpholinecarbonyl]-benzonitrile; LC-MS D: tR = 0.80 min; [M+H]+ = 441.04 32 A-15 E-10 (5-Methoxy[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,3]triazol- 2-yl-benzyl)-morpholinyl]-methanone; LC-MS D: tR = 0.86 min; [M+H]+ = 446.05 33 A-15 E-9 (2-Fluoromethoxy[1,2,3]triazolyl-phenyl)-[(R)(3- [1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; LC-MS D: tR = 0.86 min; [M+H]+ = 464.07 34 A-15 E-12 imethoxy[1,2,3]triazolyl-phenyl)-[(R)(3- [1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; LC-MS D: tR = 0.81 min; [M+H]+ = 476.09 35 A-15 E-6 (4,5-Dimethyl[1,2,3]triazolyl-phenyl)-[(R)(3- [1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; LC-MS D: tR = 0.88 min; [M+H]+ = 444.09 36 A-15 E-8 (4-Fluoro[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,3]triazol yl-benzyl)-morpholinyl]-methanone; LC-MS D: tR = 0.85 min; [M+H]+ = 434.06 37 A-15 E-11 (5-Methoxymethyl[1,2,3]triazolyl-phenyl)-[(R)(3- [1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; LC-MS D: tR = 0.90 min; [M+H]+ = 460.06 38 A-20 E-3 (5-Methyl[1,2,3]triazolyl-phenyl)-[(R)(3-pyrrolylbenzyl )-morpholinyl]-methanone; LC-MS B: tR = 0.84 min; [M+H]+ = 427.94 39 B-22 E-3 {(R)[3-(4-Methyl-pyrimidinyl)-benzyl]-morpholinyl}-(5- methyl[1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.86 min; [M+H]+ = 455.07 75 40 B-22 E-2 -[3-(4-Methyl-pyrimidinyl)-benzyl]-morpholinyl}-(2- [1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.85 min; [M+H]+ = 441.04 41 B-23 E-3 (5-Methyl[1,2,3]triazolyl-phenyl)-[(R)(3-pyrazinylbenzyl )-morpholinyl]-methanone; LC-MS D: tR = 0.79 min; [M+H]+ = 441.05 42 B-24 E-2 [(R)(3-Oxazolyl-benzyl)-morpholinyl]-(2-[1,2,3]triazol- 2-yl-phenyl)-methanone; LC-MS D: tR = 0.81 min; [M+H]+ = 416.04 43 B-25 E-3 (5-Methyl[1,2,3]triazolyl-phenyl)-[(R)(3-thiazolylbenzyl )-morpholinyl]-methanone; LC-MS D: tR = 0.87 min; [M+H]+ = 445.99 44 B-25 E-2 [(R)(3-Thiazolyl-benzyl)-morpholinyl]-(2-[1,2,3]triazol- 2-yl-phenyl)-methanone; LC-MS D: tR = 0.85 min; [M+H]+ = 432.00 45 B-26 E-3 (5-Methyl[1,2,3]triazolyl-phenyl)-[(R)(3-thiophenylbenzyl )-morpholinyl]-methanone; LC-MS D: tR = 0.97 min; [M+H]+ = 445.01 46 B-26 E-2 [(R)(3-Thiophenyl-benzyl)-morpholinyl]-(2- [1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.94 min; [M+H]+ = 431.00 47 B-27 E-3 (5-Methyl[1,2,3]triazolyl-phenyl)-[(R)(3-pyridazinylbenzyl )-morpholinyl]-methanone; LC-MS D: tR = 0.78 min; [M+H]+ = 441.05 48 B-27 E-2 [(R)(3-Pyridazinyl-benzyl)-morpholinyl]-(2- [1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.75 min; [M+H]+ = 426.92 49 B-18 E-1 (2-Fluoromethyl[1,2,3]triazolyl-phenyl)-[(R)(3- dinyl-benzyl)-morpholinyl]-methanone; LC-MS D: tR = 0.85 min; [M+H]+ = 458.93 50 B-18 E-10 (5-Methoxy[1,2,3]triazolyl-phenyl)-[(R)(3-pyrimidin yl-benzyl)-morpholinyl]-methanone; LC-MS D: tR = 0.83 min; [M+H]+ = 456.96 76 51 B-18 E-5 (5-Chloro[1,2,3]triazolyl-phenyl)-[(R)(3-pyrimidinylbenzyl )-morpholinyl]-methanone; LC-MS D: tR = 0.84 min; [M(35Cl)+H]+ = 460.99 52 A-15 E-14 (6-Methyl[1,2,3]triazolyl-pyridinyl)-[(R)(3- [1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; LC-MS D: tR = 0.82 min; [M+H]+ = 431.06 53 A-12 E-14 (6-Methyl[1,2,3]triazolyl-pyridinyl)-[(R)(3- pyrazolyl-benzyl)-morpholinyl]-methanone; LC-MS D: tR = 0.80 min; [M+H]+ = 430.03 54 A-15 E-15 (3-Fluoro[1,2,3]triazolyl-phenyl)-[(R)(3- [1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; LC-MS D: tR = 0.84 min; [M+H]+ = 434.04 Example compound 55: [(R)(4-Hydroxypyrimidinyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)- methanone 5 Boron tribromide 1M soln. in DCM (0.8 mL, 0.8 mmol) was added to a -78°C solution of [(R)- 3-(4-methoxypyrimidinyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)- methanone Example 5 (72 mg, 0.16 mmol) in DCM (5 mL) and after complete addition the the reaction mixture was warmed to RT and stirred for 6h. The reaction was quenched with sat. aq. NaHCO3 and the layers were separated. The aqueous layer was extracted with DCM 10 (2x) and the combined c extracts were dried over Na2SO4, filtered and evaporated in vacuo. The crude product was purified by prep. HPLC (method F) to give the title compound as a white solid. LC-MS D: tR = 0.80 min; [M+H]+ = 443.03.

Example compounds 56 to 191 Table 12 e Amine Acid Compound of Formula (I) No. 1 2 56 A-34 E-3 [(R)(2-Fluoro[1,2,3]triazolyl-benzyl)-morpholinyl]- (5-methyl[1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.87 min; [M+H]+ = 448.07 57 A-34 E-2 -(2-Fluoro[1,2,3]triazolyl-benzyl)-morpholinyl]- (2-[1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.86 min; [M+H]+ = 434.06 77 58 B-36 E-3 [(R)(4-Methoxy[1,2,4]oxadiazolyl-benzyl)-morpholin yl]-(5-methyl[1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.85 min; [M+H]+ = 416.05 59 B-36 E-2 [(R)(4-Methoxy[1,2,4]oxadiazolyl-benzyl)-morpholin yl]-(2-[1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.78 min; [M+H]+ = 447.04 60 B-36 E-4 [(R)(4-Methoxy[1,2,4]oxadiazolyl-benzyl)-morpholin yl]-(4-methyl[1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.82 min; [M+H]+ = 461.06 61 B-36 E-8 (4-Fluoro[1,2,3]triazolyl-phenyl)-[(R)(4-methoxy ]oxadiazolyl-benzyl)-morpholinyl]-methanone; LC-MS D: tR = 0.81 min; [M+H]+ = 465.04 62 A-34 E-4 [(R)(2-Fluoro[1,2,3]triazolyl-benzyl)-morpholinyl]- (4-methyl[1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.90 min; [M+H]+ = 448.09 63 B-36 E-25 -(4-Methoxy[1,2,4]oxadiazolyl-benzyl)-morpholin yl]-(2-methyl[1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.75 min; [M+H]+ = 461.07 64 A-15 E-27 (3-Methyl[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,3]triazol yl-benzyl)-morpholinyl]-methanone; LC-MS D: tR = 0.86 min; [M+H]+ = 430.09 65 A-40 E-3 [(R)(4-Methyl[1,2,3]triazolyl-benzyl)-morpholinyl]- (5-methyl[1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.87 min; [M+H]+ = 444.06 66 A-40 E-2 [(R)(4-Methyl[1,2,3]triazolyl-benzyl)-morpholinyl]- (2-[1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.86 min; [M+H]+ = 430.04 67 A-40 E-4 [(R)(4-Methyl[1,2,3]triazolyl-benzyl)-morpholinyl]- (4-methyl[1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.88 min; [M+H]+ = 444.10 68 I-7 E-2 [(3R,5R)Methyl(3-[1,2,3]triazolyl-benzyl)-morpholin yl]-(2-[1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.88 min; [M+H]+ = 430.09 78 69 I-7 E-4 [(3R,5R)Methyl(3-[1,2,3]triazolyl-benzyl)-morpholin yl]-(4-methyl[1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.92 min; [M+H]+ = 444.13 70 I-7 E-27 [(3R,5R)Methyl(3-[1,2,3]triazolyl-benzyl)-morpholin yl]-(3-methyl[1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.90 min; [M+H]+ = 444.14 71 I-8 E-4 [(3S,5R)Methyl(3-[1,2,3]triazolyl-benzyl)-morpholin yl]-(4-methyl[1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.92 min; [M+H]+ = 444.08 72 I-8 E-27 [(3S,5R)Methyl(3-[1,2,3]triazolyl-benzyl)-morpholin yl]-(3-methyl[1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.91 min; [M+H]+ = 444.12 73 I-8 E-3 [(3S,5R)Methyl(3-[1,2,3]triazolyl-benzyl)-morpholin yl]-(5-methyl[1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.92 min; [M+H]+ = 444.15 74 I-8 E-6 (4,5-Dimethyl[1,2,3]triazolyl-phenyl)-[(3S,5R)methyl- 1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; LC-MS D: tR = 0.95 min; [M+H]+ = 457.82 75 A-15 E-16 (3,5-Dimethyl[1,2,3]triazolyl-phenyl)-[(R)(3- [1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; LC-MS D: tR = 0.90 min; [M+H]+ = 444.14 76 A-15 E-21 [(R)(3-[1,2,3]Triazolyl-benzyl)-morpholinyl]-(2- ]triazolyltrifluoromethyl-phenyl)-methanone; LC-MS D: tR = 0.92 min; [M+H]+ = 484.13 77 A-15 E-17 (4-Chloro[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,3]triazol yl-benzyl)-morpholinyl]-methanone; LC-MS D: tR = 0.89 min; [M(35Cl)+H]+ = 450.07 78 A-15 E-19 (4-Fluoromethoxy[1,2,3]triazolyl-phenyl)-[(R)(3- [1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; LC-MS D: tR = 0.88 min; [M+H]+ = 464.11 79* B-41 E-6 (4,5-Dimethyl[1,2,3]triazolyl-phenyl)-[(R)(4-methyl [1,2,4]oxadiazolyl-benzyl)-morpholinyl]-methanone; LC-MS A: tR = 0.90 min; [M+H]+ = 459.11 79 80 B-39 E-24 (4,5-Difluoro[1,2,3]triazolyl-phenyl)-[(R)(3- [1,2,4]oxadiazolyl-benzyl)-morpholinyl]-methanone; LC-MS A: tR = 0.85 min; [M+H]+ = 453.07 81 B-39 E-4 (4-Methyl[1,2,3]triazolyl-phenyl)-[(R)(3- [1,2,4]oxadiazolyl-benzyl)-morpholinyl]-methanone; LC-MS A: tR = 0.85 min; [M+H]+ = 431.10 82 B-39 E-15 (3-Fluoro[1,2,3]triazolyl-phenyl)-[(R)(3- [1,2,4]oxadiazolyl-benzyl)-morpholinyl]-methanone; LC-MS A: tR = 0.90 min; [M+H]+ = 460.06 83 B-39 E-27 (3-Methyl[1,2,3]triazolyl-phenyl)-[(R)(3- [1,2,4]oxadiazolyl-benzyl)-morpholinyl]-methanone; LC-MS A: tR = 0.83 min; [M+H]+ = 431.09 84 B-39 E-5 (5-Chloro[1,2,3]triazolyl-phenyl)-[(R)(3- [1,2,4]oxadiazolyl-benzyl)-morpholinyl]-methanone; LC-MS A: tR = 0.87 min; [M(35Cl)+H]+ = 451.04 85 B-39 E-6 (4,5-Dimethyl[1,2,3]triazolyl-phenyl)-[(R)(3- [1,2,4]oxadiazolyl-benzyl)-morpholinyl]-methanone; LC-MS A: tR = 0.87 min; [M+H]+ = 445.13 86 B-39 E-17 oro[1,2,3]triazolyl-phenyl)-[(R)(3- [1,2,4]oxadiazolyl-benzyl)-morpholinyl]-methanone; LC-MS A: tR = 0.87 min; [M(35Cl)+H]+ = 451.09 87 B-39 E-21 [(R)(3-[1,2,4]Oxadiazolyl-benzyl)-morpholinyl]-(2- [1,2,3]triazolyltrifluoromethyl-phenyl)-methanone; LC-MS A: tR = 0.89 min; [M+H]+ = 485.09 88 B-39 E-7 (5-Fluoro[1,2,3]triazolyl-phenyl)-[(R)(3- [1,2,4]oxadiazolyl-benzyl)-morpholinyl]-methanone; LC-MS A: tR = 0.82 min; [M+H]+ = 435.02 89 B-39 E-16 (3,5-Dimethyl[1,2,3]triazolyl-phenyl)-[(R)(3- [1,2,4]oxadiazolyl-benzyl)-morpholinyl]-methanone; LC-MS A: tR = 0.86 min; [M+H]+ = 445.09 90* B-42 E-2 [(R)(4-Chloro[1,2,4]oxadiazolyl-benzyl)-morpholin -[1,2,3]triazolyl-phenyl)-methanone; LC-MS A: tR = 0.84 min; [M(35Cl)+H]+ = 451.04 80 91 A-15 E-24 (4,5-Difluoro[1,2,3]triazolyl-phenyl)-[(R)(3- [1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; LC-MS D: tR = 0.87 min; [M+H]+ = 452.11 92 A-15 E-20 (3,4-Dimethyl[1,2,3]triazolyl-phenyl)-[(R)(3- [1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; LC-MS D: tR = 0.89 min; [M+H]+ = 444.16 93 A-15 E-18 (4-Methoxy[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,3]triazol- enzyl)-morpholinyl]-methanone; LC-MS D: tR = 0.85 min; [M+H]+ = 446.13 94 A-34 E-20 (3,4-Dimethyl[1,2,3]triazolyl-phenyl)-[(R)(2-fluoro [1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; LC-MS D: tR = 0.90 min; [M+H]+ = 462.17 95 A-34 E-18 [(R)(2-Fluoro[1,2,3]triazolyl-benzyl)-morpholinyl]- (4-methoxy[1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.86 min; [M+H]+ = 464.11 96 J-10 E-4 [(2S,5R)Methyl(3-[1,2,3]triazolyl-benzyl)-morpholin yl]-(4-methyl[1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.90 min; [M+H]+ = 444.18 97 J-9 E-27 [(2R,5R)Methyl(3-[1,2,3]triazolyl-benzyl)-morpholin yl]-(3-methyl[1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.91 min; [M+H]+ = 444.13 98 J-9 E-6 (4,5-Dimethyl[1,2,3]triazolyl-phenyl)-[(2R,5R)methyl- 5-(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; LC-MS D: tR = 0.91 min; [M+H]+ = 458.00 99 J-9 E-20 (3,4-Dimethyl[1,2,3]triazolyl-phenyl)-[(2R,5R)methyl- 1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; LC-MS D: tR = 0.94 min; [M+H]+ = 457.91 100 J-9 E-2 [(2R,5R)Methyl(3-[1,2,3]triazolyl-benzyl)-morpholin yl]-(2-[1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.86 min; [M+H]+ = 430.17 101 J-9 E-4 [(2R,5R)Methyl(3-[1,2,3]triazolyl-benzyl)-morpholin yl]-(4-methyl[1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.89 min; [M+H]+ = 444.19 81 102* H-10 E-3 [(R)Methyl(3-[1,2,3]triazolyl-benzyl)-morpholinyl]- (5-methyl[1,2,3]triazolyl-phenyl)-methanone; LC-MS A: tR = 0.94 min; [M+H]+ = 444.11 103 A-15 E-28 oromethyl[1,2,3]triazolyl-phenyl)-[(R)(3- [1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; LC-MS D: tR = 0.90 min; [M(35Cl)+H]+ = 464.18 104 A-15 E-22 (4-Chloromethoxy[1,2,3]triazolyl-phenyl)-[(R)(3- [1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; LC-MS D: tR = 0.92 min; [M(35Cl)+H]+ = 480.16 105 A-37 E-4 -(3-Chloro[1,2,3]triazolyl-benzyl)-morpholinyl]- (4-methyl[1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.95 min; [M(35Cl)+H]+ = 464.16 106 A-37 E-27 [(R)(3-Chloro[1,2,3]triazolyl-benzyl)-morpholinyl]- (3-methyl[1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.94 min; [M(35Cl)+H]+ = 464.17 107 A-15 E-23 (3-Chloro[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,3]triazol yl-benzyl)-morpholinyl]-methanone; LC-MS D: tR = 0.87 min; [M(35Cl)+H]+ = 449.73 108 J-14 E-2 [(2R,5R)Methyl(3-pyrimidinyl-benzyl)-morpholinyl]- (2-[1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.82 min; [M+H]+ = 441.16 109 J-14 E-3 [(2R,5R)Methyl(3-pyrimidinyl-benzyl)-morpholinyl]- (5-methyl[1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.86 min; [M+H]+ = 455.15 110 J-14 E-4 [(2R,5R)Methyl(3-pyrimidinyl-benzyl)-morpholinyl]- (4-methyl[1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.85 min; [M+H]+ = 455.16 111 J-14 E-27 [(2R,5R)Methyl(3-pyrimidinyl-benzyl)-morpholinyl]- (3-methyl[1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.88 min; [M+H]+ = 455.14 112 J-14 E-20 (3,4-Dimethyl[1,2,3]triazolyl-phenyl)-[(2R,5R)methyl- 5-(3-pyrimidinyl-benzyl)-morpholinyl]-methanone; LC-MS D: tR = 0.91 min; [M+H]+ = 469.19 82 113 J-14 E-5 (5-Chloro[1,2,3]triazolyl-phenyl)-[(2R,5R)methyl(3- pyrimidinyl-benzyl)-morpholinyl]-methanone; LC-MS D: tR = 0.87 min; [M(35Cl)+H]+ = 475.13 114 J-14 E-17 (4-Chloro[1,2,3]triazolyl-phenyl)-[(2R,5R)methyl(3- pyrimidinyl-benzyl)-morpholinyl]-methanone; LC-MS D: tR = 0.89 min; [M(35Cl)+H]+ = 475.13 115 J-12 E-3 [(2R,5R)(2-Fluoro[1,2,3]triazolyl-benzyl)methylmorpholinyl ]-(5-methyl[1,2,3]triazolyl-phenyl)- methanone; LC-MS D: tR = 0.90 min; [M+H]+ = 462.15 116 J-12 E-2 [(2R,5R)(2-Fluoro[1,2,3]triazolyl-benzyl)methylmorpholinyl ]-(2-[1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.90 min; [M+H]+ = 448.15 117 J-12 E-4 [(2R,5R)(2-Fluoro[1,2,3]triazolyl-benzyl)methylmorpholinyl ]-(4-methyl[1,2,3]triazolyl-phenyl)- methanone; LC-MS D: tR = 0.90 min; [M+H]+ = 462.18 118 J-12 E-27 [(2R,5R)(2-Fluoro[1,2,3]triazolyl-benzyl)methylmorpholinyl ]-(3-methyl[1,2,3]triazolyl-phenyl)- methanone; LC-MS D: tR = 0.92 min; [M+H]+ = 462.15 119 A-36 E-3 [(R)(2-Methyl[1,2,3]triazolyl-benzyl)-morpholinyl]- (5-methyl[1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.90 min; [M+H]+ = 4444.18 120 A-35 E-4 [(R)(2-Chloro[1,2,3]triazolyl-benzyl)-morpholinyl]- hyl[1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.92 min; [M(35Cl)+H]+ = 464.07 121 A-36 E-2 [(R)(2-Methyl[1,2,3]triazolyl-benzyl)-morpholinyl]- (2-[1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.87 min; [M+H]+ = 430.20 122 A-35 E-27 [(R)(2-Chloro[1,2,3]triazolyl-benzyl)-morpholinyl]- hyl[1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.92 min; [M(35Cl)+H]+ = 464.11 83 123 A-36 E-4 [(R)(2-Methyl[1,2,3]triazolyl-benzyl)-morpholinyl]- (4-methyl[1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.92 min; [M+H]+ = 444.36 124 A-36 E-27 [(R)(2-Methyl[1,2,3]triazolyl-benzyl)-morpholinyl]- (3-methyl[1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.90 min; [M+H]+ = 444.22 125 A-35 E-3 [(R)(2-Chloro[1,2,3]triazolyl-benzyl)-morpholinyl]- (5-methyl[1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.91 min; l)+H]+ = 464.12 126 A-35 E-2 [(R)(2-Chloro[1,2,3]triazolyl-benzyl)-morpholinyl]- (2-[1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.89 min; [M(35Cl)+H]+ = 450.09 127 A-34 E-27 [(R)(2-Fluoro[1,2,3]triazolyl-benzyl)-morpholinyl]- (3-methyl[1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.88 min; [M+H]+ = 448.14 128 A-34 E-6 (4,5-Dimethyl[1,2,3]triazolyl-phenyl)-[(R)(2-fluoro [1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; LC-MS D: tR = 0.90 min; [M+H]+ = 462.14 129 A-34 E-5 (5-Chloro[1,2,3]triazolyl-phenyl)-[(R)(2-fluoro [1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; LC-MS D: tR = 0.89 min; [M(35Cl)+H]+ = 468.10 130 A-34 E-17 (4-Chloro[1,2,3]triazolyl-phenyl)-[(R)(2-fluoro [1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; LC-MS D: tR = 0.90 min; [M(35Cl)+H]+ = 468.09 131 A-34 E-10 -(2-Fluoro[1,2,3]triazolyl-benzyl)-morpholinyl]- (5-methoxy[1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.89 min; [M+H]+ = 464.16 132 A-34 E-1 (2-Fluoromethyl[1,2,3]triazolyl-phenyl)-[(R)(2- fluoro[1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; LC-MS D: tR = 0.89 min; [M+H]+ = 466.15 133 A-34 E-9 (2-Fluoromethoxy[1,2,3]triazolyl-phenyl)-[(R)(2- fluoro[1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; LC-MS D: tR = 0.87 min; [M+H]+ = 482.16 84 134 A-34 E-11 [(R)(2-Fluoro[1,2,3]triazolyl-benzyl)-morpholinyl]- (5-methoxymethyl[1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.92 min; [M+H]+ = 478.17 135 A-34 E-23 (3-Chloro[1,2,3]triazolyl-phenyl)-[(R)(2-fluoro [1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; LC-MS D: tR = 0.88 min; [M(35Cl)+H]+ = 468.10 136 A-34 E-26 [(R)(2-Fluoro[1,2,3]triazolyl-benzyl)-morpholinyl]- (2-fluoro[1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.87 min; [M+H]+ = 452.08 137 A-34 E-24 (4,5-Difluoro[1,2,3]triazolyl-phenyl)-[(R)(2-fluoro [1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; LC-MS D: tR = 0.89 min; [M+H]+ = 470.14 138 A-34 E-21 [(R)(2-Fluoro[1,2,3]triazolyl-benzyl)-morpholinyl]- (2-[1,2,3]triazolyltrifluoromethyl-phenyl)-methanone; LC-MS D: tR = 0.93 min; [M+H]+ = 502.11 139 A-34 E-22 (4-Chloromethoxy[1,2,3]triazolyl-phenyl)-[(R)(2- fluoro[1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; LC-MS D: tR = 0.93 min; [M(35Cl)+H]+ = 498.13 140 J-13 E-3 [(2R,5R)(2-Fluoro[1,2,3]triazolyl-benzyl)methylmorpholinyl ]-(5-methyl[1,2,3]triazolyl-phenyl)- methanone; LC-MS D: tR = 0.80 min; [M+H2O]+ = 479.20 141 J-13 E-4 [(2R,5R)(2-Fluoro[1,2,3]triazolyl-benzyl)methylmorpholinyl ]-(4-methyl[1,2,3]triazolyl-phenyl)- methanone; LC-MS D: tR = 0.81 min; [M+H2O]+ = 479.21 142 J-11 E-3 R)Ethyl(3-[1,2,3]triazolyl-benzyl)-morpholin -methyl[1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.94 min; [M+H]+ = 457.93 143 J-11 E-2 [(2R,5R)Ethyl(3-[1,2,3]triazolyl-benzyl)-morpholin yl]-(2-[1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.91 min; [M+H]+ = 444.14 144 J-11 E-4 [(2R,5R)Ethyl(3-[1,2,3]triazolyl-benzyl)-morpholin yl]-(4-methyl[1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.44 min; [M+H]+ = 457.95 85 145* A-38 E-2 [(R)(3-Fluoro[1,2,3]triazolyl-benzyl)-morpholinyl]- (2-[1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.88 min; [M+H]+ = 434.24 146* A-38 E-4 [(R)(3-Fluoro[1,2,3]triazolyl-benzyl)-morpholinyl]- (4-methyl[1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.90 min; [M+H]+ = 448.27 147 J-15 E-3 [(2R,5R)(2-Fluoropyrimidinyl-benzyl)methylmorpholinyl ]-(5-methyl[1,2,3]triazolyl-phenyl)- methanone; LC-MS D: tR = 0.88 min; [M+H]+ = 473.18 148 J-15 E-2 R)(2-Fluoropyrimidinyl-benzyl)methylmorpholinyl ]-(2-[1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.88 min; [M+H]+ = 459.06 149 J-15 E-4 [(2R,5R)(2-Fluoropyrimidinyl-benzyl)methylmorpholinyl ]-(4-methyl[1,2,3]triazolyl-phenyl)- methanone; LC-MS D: tR = 0.88 min; [M+H]+ = 473.14 150 J-15 E-27 [(2R,5R)(2-Fluoropyrimidinyl-benzyl)methylmorpholinyl ]-(3-methyl[1,2,3]triazolyl-phenyl)- methanone; LC-MS D: tR = 0.90 min; [M+H]+ = 473.13 151 J-15 E-20 (3,4-Dimethyl[1,2,3]triazolyl-phenyl)-[(2R,5R)(2-fluoro- 5-pyrimidinyl-benzyl)methyl-morpholinyl]-methanone; LC-MS D: tR = 0.92 min; [M+H]+ = 487.17 152 J-15 E-5 (5-Chloro[1,2,3]triazolyl-phenyl)-[(2R,5R)(2-fluoro dinyl-benzyl)methyl-morpholinyl]-methanone; LC-MS D: tR = 0.90 min; [M(35Cl)+H]+ = 493.10 153 J-15 E-17 (4-Chloro[1,2,3]triazolyl-phenyl)-[(2R,5R)(2-fluoro pyrimidinyl-benzyl)methyl-morpholinyl]-methanone; LC-MS D: tR = 0.91 min; [M(35Cl)+H]+ = 493.08 154 J-15 E-23 (3-Chloro[1,2,3]triazolyl-phenyl)-[(2R,5R)(2-fluoro pyrimidinyl-benzyl)methyl-morpholinyl]-methanone; LC-MS D: tR = 0.89 min; [M(35Cl)+H]+ = 493.07 86 155 B-43 E-3 [(R)(2-Fluoropyrimidinyl-benzyl)-morpholinyl]-(5- methyl[1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.85 min; [M+H]+ = 458.89 156 B-43 E-4 [(R)(2-Fluoropyrimidinyl-benzyl)-morpholinyl]-(4- [1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.87 min; [M+H]+ = 459.07 157 B-43 E-27 [(R)(2-Fluoropyrimidinyl-benzyl)-morpholinyl]-(3- methyl[1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.85 min; [M+H]+ = 458.81 158 B-43 E-20 (3,4-Dimethyl[1,2,3]triazolyl-phenyl)-[(R)(2-fluoro pyrimidinyl-benzyl)-morpholinyl]-methanone; LC-MS D: tR = 0.88 min; [M+H]+ = 473.17 159 B-43 E-5 (5-Chloro[1,2,3]triazolyl-phenyl)-[(R)(2-fluoro pyrimidinyl-benzyl)-morpholinyl]-methanone; LC-MS D: tR = 0.87 min; l)+H]+ = 479.06 160 B-43 E-17 (4-Chloro[1,2,3]triazolyl-phenyl)-[(R)(2-fluoro pyrimidinyl-benzyl)-morpholinyl]-methanone; LC-MS D: tR = 0.88 min; [M(35Cl)+H]+ = 479.08 161 B-43 E-23 (3-Chloro[1,2,3]triazolyl-phenyl)-[(R)(2-fluoro pyrimidinyl-benzyl)-morpholinyl]-methanone; LC-MS D: tR = 0.86 min; [M(35Cl)+H]+ = 479.11 162 K-18 E-3 [(2S,3R)Methyl(3-[1,2,3]triazolyl-benzyl)-morpholin yl]-(5-methyl[1,2,3]triazolyl-phenyl)-methanone or [(2R,3R)Methyl(3-[1,2,3]triazolyl-benzyl)-morpholin yl]-(5-methyl[1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.90 min; [M+H]+ = 444.15 163 K-18 E-4 [(2S,3R)Methyl(3-[1,2,3]triazolyl-benzyl)-morpholin yl]-(4-methyl[1,2,3]triazolyl-phenyl)-methanone or [(2R,3R)Methyl(3-[1,2,3]triazolyl-benzyl)-morpholin yl]-(4-methyl[1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.91 min; [M+H]+ = 444.13 87 164 K-18 E-27 [(2S,3R)Methyl(3-[1,2,3]triazolyl-benzyl)-morpholin yl]-(3-methyl[1,2,3]triazolyl-phenyl)-methanone or [(2R,3R)Methyl(3-[1,2,3]triazolyl-benzyl)-morpholin yl]-(3-methyl[1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.89 min; [M+H]+ = 444.14 165 J-16 E-4 [(2R,5R)(2-Fluoropyridazinyl-benzyl)methylmorpholinyl ]-(4-methyl[1,2,3]triazolyl-phenyl)- methanone; LC-MS D: tR = 0.79 min; [M+H]+ = 473.16 166 B-44 E-4 -(2-Fluoropyridazinyl-benzyl)-morpholinyl]-(4- methyl[1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.76 min; [M+H]+ = 459.03 167 K-17 E-3 [(2R,3R)Methyl(3-[1,2,3]triazolyl-benzyl)-morpholin yl]-(5-methyl[1,2,3]triazolyl-phenyl)-methanone or [(2S,3R)Methyl(3-[1,2,3]triazolyl-benzyl)-morpholin yl]-(5-methyl[1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.90 min; [M+H]+ = 444.09 168 K-17 E-4 [(2R,3R)Methyl(3-[1,2,3]triazolyl-benzyl)-morpholin yl]-(4-methyl[1,2,3]triazolyl-phenyl)-methanone or [(2S,3R)Methyl(3-[1,2,3]triazolyl-benzyl)-morpholin yl]-(4-methyl[1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.91 min; [M+H]+ = 444.16 169 A-35 E-20 -(2-Chloro[1,2,3]triazolyl-benzyl)-morpholinyl]- (3,4-dimethyl[1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.94 min; [M(35Cl)+H]+ = 478.11 170 A-35 E-17 [(R)(2-Chloro[1,2,3]triazolyl-benzyl)-morpholinyl]- (4-chloro[1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.95 min; [M(35Cl)+H]+ = 484.06 171 A-35 E-23 [(R)(2-Chloro[1,2,3]triazolyl-benzyl)-morpholinyl]- (3-chloro[1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.91 min; [M(35Cl)+H]+ = 484.03 172 J-9 E-23 (3-Chloro[1,2,3]triazolyl-phenyl)-[(2R,5R)methyl(3- [1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; LC-MS D: tR = 0.91 min; [M(35Cl)+H]+ = 464.07 88 173 J-12 E-23 (3-Chloro[1,2,3]triazolyl-phenyl)-[(2R,5R)(2-fluoro [1,2,3]triazolyl-benzyl)methyl-morpholinyl]- methanone; LC-MS D: tR = 0.92 min; [M(35Cl)+H]+ = 482.10 174 B-40 E-3 [(R)(2-Fluoro[1,2,4]oxadiazolyl-benzyl)-morpholin yl]-(5-methyl[1,2,3]triazolyl-phenyl)-methanone; LC-MS A: tR = 0.85 min; [M+H]+ = 449.11 175 B-40 E-4 [(R)(2-Fluoro[1,2,4]oxadiazolyl-benzyl)-morpholin yl]-(4-methyl[1,2,3]triazolyl-phenyl)-methanone; LC-MS A: tR = 0.86 min; [M+H]+ = 449.11 176 B-40 E-5 (5-Chloro[1,2,3]triazolyl-phenyl)-[(R)(2-fluoro [1,2,4]oxadiazolyl-benzyl)-morpholinyl]-methanone; LC-MS A: tR = 0.86 min; [M(35Cl)+H]+ = 469.07 177 B-40 E-27 [(R)(2-Fluoro[1,2,4]oxadiazolyl-benzyl)-morpholin yl]-(3-methyl[1,2,3]triazolyl-phenyl)-methanone; LC-MS A: tR = 0.85 min; [M+H]+ = 449.10 178 B-40 E17 oro[1,2,3]triazolyl-phenyl)-[(R)(2-fluoro [1,2,4]oxadiazolyl-benzyl)-morpholinyl]-methanone; LC-MS A: tR = 0.88 min; [M(35Cl)+H]+ = 469.04 179 B-40 E-6 (4,5-Dimethyl[1,2,3]triazolyl-phenyl)-[(R)(2-fluoro [1,2,4]oxadiazolyl-benzyl)-morpholinyl]-methanone; LC-MS A: tR = 0.88 min; [M+H]+ = 463.11 180 B-40 E-23 (3-Chloro[1,2,3]triazolyl-phenyl)-[(R)(2-fluoro [1,2,4]oxadiazolyl-benzyl)-morpholinyl]-methanone; LC-MS A: tR = 0.86 min; l)+H]+ = 469.04 181 B-40 E-20 (3,4-Dimethyl[1,2,3]triazolyl-phenyl)-[(R)(2-fluoro [1,2,4]oxadiazolyl-benzyl)-morpholinyl]-methanone; LC-MS A: tR = 0.88 min; [M+H]+ = 463.12 182 A-15 E-29 [(R)(3-[1,2,3]Triazolyl-benzyl)-morpholinyl]-(2- [1,2,3]triazolyltrifluoromethyl-phenyl)-methanone; LC-MS D: tR = 0.89 min; [M+H]+ = 484.18 183* A-39 E-4 [(R)(2-Fluoro[1,2,3]triazolyl-benzyl)-morpholinyl]- (4-methyl[1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.82 min; [M+H]+ = 448.14 89 184 J-9 E-5 (5-Chloro[1,2,3]triazolyl-phenyl)-[(2R,5R)methyl(3- [1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; LC-MS D: tR = 0.90 min; [M(35Cl)+H]+ = 464.13 185 J-9 E-17 (4-Chloro[1,2,3]triazolyl-phenyl)-[(2R,5R)methyl(3- [1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; LC-MS D: tR = 0.92 min; [M(35Cl)+H]+ = 464.14 186 J-12 E-5 (5-Chloro[1,2,3]triazolyl-phenyl)-[(2R,5R)(2-fluoro [1,2,3]triazolyl-benzyl)methyl-morpholinyl]- methanone; LC-MS D: tR = 0.92 min; [M(35Cl)+H]+ = 482.13 187 J-12 E-17 oro[1,2,3]triazolyl-phenyl)-[(2R,5R)(2-fluoro [1,2,3]triazolyl-benzyl)methyl-morpholinyl]- methanone; LC-MS D: tR = 0.93 min; [M(35Cl)+H]+ = 482.10 188 A-42 E-3 -(2-Methylpyrazolyl-benzyl)-morpholinyl]-(5- methyl[1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.85 min; [M+H]+ = 443.16 189 A-42 E-4 [(R)(2-Methylpyrazolyl-benzyl)-morpholinyl]-(4- methyl[1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.87 min; [M+H]+ = 443.14 190 A-42 E-27 [(R)(2-Methylpyrazolyl-benzyl)-morpholinyl]-(3- methyl[1,2,3]triazolyl-phenyl)-methanone; LC-MS D: tR = 0.86 min; [M+H]+ = 443.18 191 A-36 E-17 (4-Chloro[1,2,3]triazolyl-phenyl)-[(R)(2-methyl [1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; LC-MS A: tR = 0.94 min; [M(35Cl)+H]+ = 464.11 *Initially prepared as a racemate and isolated following prep. chiral HPLC Example compounds 192 to 194 e 192: [(R)(4-Methylpyrimidinyl-benzyl)-morpholinyl]-(2-[1,2,3]triazol- 2-yl-phenyl)-methanone 5 The title compound was prepared from L-3 in analogy to the procedure described for e 5 and isolated following prep. chiral HPLC. LC-MS A: tR = 0.79 min; [M+H]+ = 441.09. 90 Example 193: [(R)(4-Methylthiazolyl-benzyl)-morpholinyl]-(2-[1,2,3]triazol yl-phenyl)-methanone The title compound was prepared from L-3 in analogy to the ure described for Example 8 and isolated following prep. chiral HPLC. LC-MS A: tR = 0.86 min; [M+H]+ = 5 446.10.

Example 194: [(R)(4-Chloropyrimidinyl-benzyl)-morpholinyl]-(2-[1,2,3]triazol- 2-yl-phenyl)-methanone The title compound was prepared from L-4 in analogy to the procedure described for Example 5 and isolated following prep. chiral HPLC. LC-MS D: tR = 0.81 min; [M+H]+ = 10 461.07.

Reference compounds N O N N N N N N Ref. compound 1 Ref. compound 2 Ref. compound 3 Ref. compound 4 Reference compound 1: [(S)(3-[1,2,3]Triazolyl-benzyl)-pyrrolidinyl]-(2- 15 ]triazolyl-phenyl)-methanone Step 1: (S)-Tetrahydro-pyrrolo[1,2-c][1,2,3]oxathiazole 1,1-dioxide was prepared from cially available L-prolinol following the ure described for Example 2 in US5,130,432. 1H NMR (CDCl 3) δH: 4.58 (dd, J1 = 8.6 Hz, J2 = 6.9 Hz, 1 H), 4.30 (m, 1 H), 4.07 (dd, J1 = 8.7 Hz, J2 = 6.0 Hz, 1 H), 3.72 (m, 1 H), 3.30 (dt, J1 = 11.2 Hz, J2 = 7.1 Hz, 1 20 H), 2.21 (m, 1 H), 1.99 (m, 2 H), 1.85 (m, 1 H).

Step 2: (S)(3-Iodo-benzyl)-pyrrolidine was ed from 1,3-diiodobenzene and (S)- tetrahydro-pyrrolo[1,2-c][1,2,3]oxathiazole 1,1-dioxide in analogy to the procedure described for Example 4 in US5,130,432. LC-MS A: tR = 0.57 min; [M+H]+ = 287.99.

Step 3: (S)(3-Iodo-benzyl)-pyrrolidinecarboxylic acid tert-butyl ester was prepared from 25 (S)(3-iodo-benzyl)-pyrrolidine in analogy to the procedure bed for B-6. LC-MS A: tR = 1.02 min; [M+H]+ = 387.91.

Step 4: (S)(3-[1,2,3]Triazolyl-benzyl)-pyrrolidinecarboxylic acid tert-butyl ester was prepared from (S)(3-iodo-benzyl)-pyrrolidinecarboxylic acid tert-butyl ester and 1H- 91 1,2,3-triazole in analogy to the procedure described for A-13 . LC-MS A: tR = 0.97 min; [M+H- tBu]+ = 273.16.

Step 5: 2-(3-(S)Pyrrolidinylmethyl-phenyl)-2H-[1,2,3]triazole hydrochloride was prepared from (3-[1,2,3]triazolyl-benzyl)-pyrrolidinecarboxylic acid tert-butyl ester 5 in y to the procedure described for A-7. LC-MS A: tR = 0.55 min; [M+H]+ = .

Step 6: The title compound was prepared from 2-(3-(S)pyrrolidinylmethyl-phenyl)-2H- [1,2,3]triazole hydrochloride and 2-(2H-1,2,3-triazolyl)benzoic acid E-2 following the procedure described for B-28 . LC-MS D: tR = 0.92 min; [M+H]+ = 400.19.

Reference compound 2: (5-Methyl[1,2,3]triazolyl-phenyl)-[( S)(3-[1,2,3]triazol 10 yl-benzyl)-pyrrolidinyl]-methanone The title compound was prepared from 2-(3-(S)pyrrolidinylmethyl-phenyl)-2H- [1,2,3]triazole hydrochloride and 5-methyl(2H-1,2,3-triazolyl)benzoic acid E-3 following the procedure described for B-28 . LC-MS D: tR = 0.96 min; [M+H]+ = 414.21.

Reference compound 3: [(S)(3-[1,2,3]Triazolyl-benzyl)-piperidinyl]-(2- 15 [1,2,3]triazolyl-phenyl)-methanone Step 1: (S)Hydroxymethyl-piperidinecarboxylic acid benzyl ester was prepared from commercially available (S)((benzyloxy)carbonyl)piperidinecarboxylic acid following the procedure bed for A-8. LC-MS B: tR = 0.67 min; [M+H]+ = 250.24.

Step 2: (S)Piperidinyl-methanol; A on of (S)hydroxymethyl-piperidine 20 ylic acid benzyl ester (4.33 g, 17 mmol) in MeOH (50 mL) was degased with argon for 5 min before 10% palladium on activated charcoal (185 mg, 1 mol%) was added and the argon atmosphere was then replaced with hydrogen (hydrogen was bubbled through the reaction mixture for 5 min). The reaction e was stirred at RT for 4h after which the mixture was filtered over a pad of celite washing with additional MeOH and the filtrate was 25 evaporated in vacuo. The crude product appeared as a pale yellow oil and was not further purified. LC-MS B: tR = 0.12 min; [M+H]+ = 116.22.

Step 3: (S)-Hexahydro-[1,2,3]oxathiazolo[3,4-a]pyridine oxide was prepared from (S)- 1-piperidinyl-methanol in analogy to the procedure described for e 2 in US5,130,432. 1H NMR (CDCl3) δH: 4.60 (m, 1 H), 4.21 (m, 1 H), 3.62 (m, 1 H), 3.47 (m, 1 H), 30 2.81 (m, 1 H), 1.90 (m, 3 H), 1.67 (m, 1 H), 1.39 (m, 2 H).

Step 4: (S)(3-Iodo-benzyl)-piperidine was prepared from 1,3-diiodobenzene and (S)- hexahydro-[1,2,3]oxathiazolo[3,4-a]pyridine 1,1-dioxide in analogy to the procedure described for e 4 in US5,130,432. LC-MS B: tR = 0.54 min; [M+H]+ = 302.07. 92 Step 5: (S)(3-Iodo-benzyl)-piperidinecarboxylic acid tert-butyl ester was prepared from (S)(3-iodo-benzyl)-piperidine in analogy to the ure described for B-6. LC-MS B: tR = 1.08 min; + = .

Step 6: (S)(3-[1,2,3]Triazolyl-benzyl)-piperidinecarboxylic acid tert-butyl ester was 5 prepared from (S)(3-iodo-benzyl)-piperidinecarboxylic acid tert-butyl ester and 1H- 1,2,3-triazole in analogy to the ure described for A-13 . LC-MS C: tR = 1.05 min; [M+H- tBu] + = 287.08.

Step 7: (S)(3-[1,2,3]Triazolyl-benzyl)-piperidine hydrochloride was prepared from (S) (3-[1,2,3]triazolyl-benzyl)-piperidinecarboxylic acid tert-butyl ester in y to the 10 procedure described for A-7. LC-MS C: tR = 0.90 min; [M+H]+ = 243.17.

Step 8: The title nd was prepared from (S)(3-[1,2,3]triazolyl-benzyl)-piperidine hydrochloride and 2-(2H-1,2,3-triazolyl)benzoic acid E-2 following the procedure described for B-28 . LC-MS D: tR = 0.91 min; [M+H]+ = 414.05.

Reference compound 4: (5-Methyl[1,2,3]triazolyl-phenyl)-[( S)(3-[1,2,3]triazol 15 yl-benzyl)-piperidinyl]-methanone The title compound was prepared from (S)(3-[1,2,3]triazolyl-benzyl)-piperidine hydrochloride and 5-methyl(2H-1,2,3-triazolyl)benzoic acid E-3 following the procedure described for B-28 . LC-MS D: tR = 0.94 min; [M+H]+ = 427.92. 20 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 25 orexin-2 or, respectively, are grown in culture medium (Ham F-12 with L-Glutamine) containing 300 µg/mL G418, 100 U/mL llin, 100 µg/mL streptomycin and 10 % heat inactivated fetal calf serum (FCS). The cells are seeded at 20’000 cells / well into 384-well black clear bottom sterile plates (Greiner). The seeded plates are incubated overnight at 37°C in 5% CO2. 30 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), NaHCO3: 0.375g/L and 20 mM HEPES for use in the assay at a final concentration of 3 nM. 93 Antagonists are prepared as 10 mM stock solution in DMSO, then diluted in 384-well plates using DMSO ed by a transfer of the dilutions into in HBSS containing 0.1 % bovine serum albumin (BSA), NaHCO3: 0.375g/L and 20 mM HEPES. On the day of the assay, 50 µL of staining buffer (HBSS containing 1% FCS, 20 mM HEPES, : /L, 5 mM 5 probenecid (Sigma) and 3 µM 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 ted for 50 min at 37° C in 5% CO2 followed by equilibration at RT for 30 min before measurement.

Within the Fluorescent Imaging Plate Reader (FLIPR Tetra, Molecular Devices), antagonists 10 are added to the plate in a volume of 10 µL/well, ted for 120 min and finally 10 µL/well of agonist is added. scence 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 15 normalized using the obtained IC50 value of an te reference compound. Optimized conditions were achieved by adjustment of pipetting speed and cell splitting regime. The calculated IC50 values may fluctuate ing on the daily cellular assay performance.

Fluctuations of this kind are known to those skilled in the art. In the case where IC50 values have been determined several times for the same compound, the geometric mean has been 20 given. Antagonistic activities of example compounds are shown in Tables 13 and 14.

Table 13 IC50 IC50 IC50 IC50 IC50 IC50 Example OX1 OX2 Example OX1 OX2 Example OX1 OX2 [nM] [nM] [nM] [nM] [nM] [nM] 1 40 803 21 2 1649 41 8 1043 2 7 406 22 3 318 42 34 2009 3 4 3340 23 34 4780 43 0.3 273 4 6 1880 24 3 1030 44 2 457 5 4 2950 25 11 1400 45 0.1 119 6 12 1940 26 21 822 46 0.5 163 7 26 6090 27 2 274 47 13 2380 8 1 335 28 43 2107 48 39 4440 9 2 468 29 4 333 49 3 582 10 0.5 31 30 4 199 50 2 942 94 11 2 196 31 33 360 51 3 229 12 17 1235 32 7 489 52 43 1630 13 966 4439 33 14 1200 53 27 3404 14 3 905 34 5 1230 54 46 1824 15 24 3160 35 1 25 16 30 1822 36 41 889 17 2 396 37 4 209 Ref. 1 4 40 18 22 1892 38 1 131 Ref. 2 0.5 8 19 2 369 39 5 231 Ref. 3 1 12 20 25 1527 40 34 762 Ref. 4 0.3 2 Table 14 IC50 IC50 IC50 IC50 IC50 IC50 Example OX1 OX2 e OX1 OX2 Example OX1 OX2 [nM] [nM] [nM] [nM] [nM] [nM] 55 27 2010 102 25 1508 149 4 263 56 4 837 103 0.7 47 150 9 506 57 48 2736 104 3 117 151 8 818 58 0.7 42 105 2 101 152 4 129 59 1 80 106 3 335 153 3 85 60 0.7 34 107 5 435 154 13 447 61 1 60 108 10 855 155 3 371 62 3 404 109 1 105 156 3 571 63 9 49 110 2 176 157 39 2590 64 6 784 111 7 983 158 3 2260 65 2 261 112 3 839 159 6 490 66 16 992 113 2 110 160 3 268 67 2 274 114 1 83 161 16 655 68 16 1297 115 2 146 162 24 2530 69 0.9 314 116 21 899 163 22 1864 70 5 2610 117 5 107 164 29 4040 71 35 2190 118 10 728 165 14 1296 95 72 8 2460 119 6 593 166 13 1395 73 10 1850 120 3 531 167 19 2382 74 11 355 121 26 1640 168 40 3505 75 3 547 122 6 1610 169 5 2440 76 2 133 123 5 939 170 7 451 77 1 96 124 9 997 171 10 675 78 17 528 125 7 626 172 3 93 79 0.4 13 126 40 1480 173 16 455 80 28 645 127 26 1500 174 8 642 81 2 212 128 0.7 30 175 3 359 82 41 1140 129 12 188 176 11 240 83 7 403 130 3 191 177 25 893 84 5 246 131 4 1131 178 2 165 85 1 21 132 8 1170 179 2 34 86 42 2652 133 22 2600 180 19 830 87 3 227 134 11 336 181 11 1567 88 30 893 135 16 1880 182 7 371 89 7 420 136 37 574 183 15 2130 90 12 475 137 30 202 184 2 96 91 10 612 138 4 159 185 2 39 92 3 2633 139 10 191 186 11 181 93 5 2086 140 27 1110 187 6 58 94 6 3578 141 16 429 188 21 2130 95 11 1199 142 5 287 189 12 1090 96 10 390 143 19 485 190 25 3770 97 3 237 144 5 104 191 12 1040 98 1 24 145 34 1514 192 16 2606 99 5 1223 146 3 282 193 1 238 100 6 289 147 3 171 194 33 2257 101 2 155 148 39 1935 96 CYP3A4 Inhibition assay The CYP3A4 inhibition assay was med using human liver microsomes and testosterone 6β-hydroxylation as a P450 isoform-specific marker. In a total volume of 150 µL, stosterone at a final concentration of 40 µM in a 100 mM ate buffer 5 (pH 7.4) was incubated in a 96-well plate with 0.3 mg/mL of human liver microsomes in an Eppendorf thermomixer at 37 °C and 400 rpm. A 1.0 µL-aliquot of the 150-fold concentrated compound stock solution, prepared in DMSO, was added to yield final inhibitor concentrations of 0, 0.1, 0.5, 1.0, 5.0, 10, 25, and 50 µM. The reaction was initiated by addition of 15 µL of the NADPH-regenerating system containing the glucosephosphate 10 dehydrogenase and terminated after 7 min with a 75 µL-aliquot of methanol. After centrifugation at 465 g and 4 °C for 20 min, a 50 µL-aliquot of the supernatant was submitted to HPLC according to the method described below. The total concentration of DMSO in the assay including controls without inhibitor was 1 %.

Nicardipine was run in el as a reference inhibitor of CYP3A4 activity at final 15 concentrations of 0, 0.1, 0.5, 1.0, 5.0, 10, 25, and 50 µM. Stock solutions thereof were prepared in DMSO.

The chromatographic separation of testosterone and 6β-hydroxytestosterone was achieved on a enex Luna C18(2) column (5 µm, 2.0 x 10 mm) at RT with a flow rate of 0.6 mL/min. Mobile phases consisted of 1 % aqueous formic acid (phase A) and methanol 20 (phase B) using a gradient method with 0.9 min total run time. Using these chromatographic conditions, the 6β-hydroxy metabolite exhibited a retention time of 0.6 min.

The quantification of 6β-hydroxytestosterone was carried out using a quadrupole mass spectrometer ed with an ionspray interface operating in ve ion mode. The parameters of the mass detector were set as follows: capillary voltage 5 kV, auxiliary gas 25 40 psi, ion gas 3 mTorr, and transfer capillary temperature 420°C. The mass transition used for roxytestosterone was 305.1 to 269.3 with a scan time of 30 ms.

Compounds of the present invention were tested in the above CYP3A4 assay and inhibition values for reference compounds and particular example compounds are given in Table 15.

Table 15 CYP3A4 CYP3A4 CYP3A4 CYP3A4 Example Example Example Example IC50 [µM] IC50 [µM] IC50 [µM]] IC50 [µM] 1 >50 51 20 106 14 154 24 2 43 52 >50 107 22 155 30 97 3 21 53 >50 108 46 156 >50 4 1.2 54 >50 109 43 158 40 5 >50 56 33 110 >50 159 17 6 26 57 20 111 40 160 17 7 >50 58 42 112 >50 161 33 8 3.2 59 32 113 26 163 14 9 8.4 60 41 114 35 165 20 11 43 61 42 115 24 166 19 12 30 62 29 116 21 168 8.5 14 >50 64 33 117 23 169 29 15 14 65 22 118 23 170 9.8 16 43 66 36 119 19 171 13 17 33 67 25 120 19 172 23 18 39 68 24 121 18 173 21 19 32 71 14 122 18 174 50 20 25 73 6.8 123 27 175 35 21 20 75 15 124 22 176 22 22 41 76 7.5 125 22 178 24 23 6 77 16 126 17 179 29 24 >50 78 22 127 30 180 36 26 24 81 33 129 26 181 36 27 31 83 25 130 20 182 14 28 0.3 84 21 131 35 183 >50 29 39 85 25 132 19 184 19 30 17 87 15 133 37 185 20 31 >50 90 21 134 19 186 19 32 >50 91 17 135 30 187 14 33 >50 92 44 138 7.4 188 14 34 >50 93 >50 139 13 189 17 35 20 94 30 141 19 190 26 36 36 95 49 142 9.2 191 14 37 17 96 28 143 9.1 192 >50 98 39 18 97 11 144 9.6 193 0.6 42 5.1 98 9.7 145 22 43 1.2 99 9.6 146 40 44 2 100 13 147 28 47 6 101 9.7 149 31 Ref. 1 5.5 48 9.6 102 17 150 32 Ref. 2 3.3 49 21 104 13 152 15 Ref. 3 6.1 50 >50 105 21 153 18 Ref. 4 7.7 Measurement of brain and systemic concentration after oral stration: In order to assess brain penetration, the concentration of the compound is measured in plasma ([P]), and brain ([B]), sampled 1h or 3h (or at different time ) following oral 5 administration (100 mg/kg) to male wistar rats (n=3). The nds are formulated either in 100% PEG 400 or 10% PEG400 / 90% MC0.5%. 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 c perfusion of 10 mL NaCl 0.9% and homogenized into one volume of cold 10 phosphate buffer (pH 7.4). All samples are extracted with MeOH and analyzed by LCMS /MS. Concentrations are ined with the help of calibration curves. Inter-individual variations between the three rats were limited. Particular compounds of the present invention tested as described above gave brain concentrations ([B]) as shown in Table 16 below; wherein the compounds of Examples 11-37 and 94 were formulated in 100% PEG400 and 15 sampled at 3h. All other examples below were formulated in 10% PEG400 / 90% MC0.5% and sampled at 1h.

Table 16 [B] [B] [B] [B] Example Example Example Example [ng/g] [ng/g] [ng/g] [ng/g] 11 46 30 1869 77 1609 120 5133 12 11888 35 59 87 1875 130 5833 16 160 37 881 92 1971 156 613 21 36 62 4423 94 654 27 5500 64 2371 100 529 29 423 76 1376 116 5933 99

Claims

1. A compound of formula (I) Formula (I) 5 wherein Ar1 represents a 5- or ered heteroaryl selected from the group consisting of pyrrolyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; n said aryl is unsubstituted, mono-, or di-substituted, wherein the substituents are independently selected from the group consisting of (C1-4)alkyl, 10 (C1-4)alkoxy, halogen, cyano, (C1-3)fluoroalkyl, and (C1-3)fluoroalkoxy; R1 represents one optional substituent selected from alkyl, (C1-4)alkoxy, hydroxy, and halogen; R2 represents hydrogen, (C1-4)alkyl, (C1-4)alkoxy, halogen, or cyano; R3 represents hydrogen, (C1-4)alkyl, (C1-4)alkoxy, (C1-3)fluoroalkyl, or n; 15 R4 represents en, (C1-4)alkyl, (C1-3)fluoroalkyl, or halogen; R5 represents one optional substituent on any ring carbon atom of the morpholine ring, wherein said substituent independently is methyl or ethyl; and Q represents CR6; or, in case R2 is alkyl or (C1-4)alkoxy, Q represents CR6 or N; wherein R6 represents hydrogen, fluoro or methyl; 20 or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1; wherein the line ring of the compounds of formula (I): is a ring selected from the group consisting of: 100 O N , , , , , and ; Ar1 represents a 5- or 6-membered heteroaryl selected from the group consisting of pyrrolyl, lyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl; wherein said heteroaryl is unsubstituted or mono-substituted with (C1-4)alkyl; 5 R1 represents one optional substituent selected from methyl, methoxy, hydroxy, and halogen; R2 represents en, , methoxy, halogen, or cyano; R3 represents hydrogen, methyl, methoxy, trifluoroalkyl, or halogen; R4 represents hydrogen, methyl, trifluoroalkyl, or halogen; Q represents CR6; or, in case R2 is methyl, Q represents CR6 or N; wherein 10 R6 represents hydrogen, fluoro or methyl; or a pharmaceutically acceptable salt thereof.

3. A nd according to claims 1 or 2; wherein Ar1 represents pyrazolyl, [1,2,3]triazol- 2-yl, ]oxadiazolyl, or pyrimidinyl, which groups are unsubstituted, or in case of dinyl, optionally mono-substituted with methyl; 15 or a pharmaceutically acceptable salt thereof.

4. A compound according to any one of claims 1 to 3; wherein R2 represents hydrogen, methyl, methoxy, cyano, fluoro, or chloro; R3 represents hydrogen, , trifluoromethyl, fluoro, or chloro; R4 represent hydrogen, methyl, trifluoromethyl, or fluoro; and Q represents CR6; or, in case R2 is methyl, Q represents CR6 or N; wherein R6 represents hydrogen, fluoro 20 or methyl; or a pharmaceutically acceptable salt thereof.

5. A compound according to any one of claims 1 to 4; wherein Q represents CH; or a pharmaceutically acceptable salt f.

6. A compound according to any one of claims 1 to 3; wherein R2 represents hydrogen or 25 chloro; R3 represents hydrogen, , methyl or trifluoromethyl, R4 ent hydrogen or methyl; and Q represents CH; or a pharmaceutically able salt thereof. 101

7. A nd according to any one of claims 1 to 3; wherein the group is a group independently selected from the following groups A) to F): A) 5 ; B) ; C) ; 10 D) ; E) ; F) 15 ; or a pharmaceutically acceptable salt thereof. 102

8. A compound according to any one of claims 1 to 3; wherein the group is a group ed from the group consisting of the following groups A) and B): A) 5 ; B) ; or a pharmaceutically acceptable salt thereof.

9. A compound according to any one of claims 1, 2, or 4 to 8; wherein the group 10 is a group independently selected from the following groups A) to H): A) ; B) 15 ; C) ; 103 D) ; E) ; 5 F) ; G) ; H) 10 ; or a pharmaceutically acceptable salt thereof.

10. A compound according to any one of claims 1, 2, or 4 to 8; wherein the group is a group selected from the group ting of the following groups A) and B): 15 A) ; and 104 B) ; or a pharmaceutically acceptable salt thereof.

11. A nd according to claim 1 selected from the group consisting of: 5 [(R)(3-[1,2,4]Oxadiazolyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)- methanone; (5-Methyl[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,4]oxadiazolyl-benzyl)-morpholinyl]- methanone; [(R)(4-Methoxypyridinyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)- 10 methanone; [(R)(4-Methoxypyridinyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)- methanone; [(R)(4-Methoxypyrimidinyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)- methanone; 15 [(R)(4-Methoxypyrazinyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)- methanone; [(R)(4-Methoxypyridazinyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)- one; [(R)(4-Methoxythiazolyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)- 20 methanone; [(R)(4-Methoxyoxazolyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)- methanone; [(R)(4-Methoxythiophenyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)- methanone; 25 (5-Methyl[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,3]triazolyl-benzyl)-morpholinyl]- methanone; [(R)(3-[1,2,3]Triazolyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)-methanone; [(S)(3-[1,2,3]Triazolyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)-methanone; -(4-Methoxypyrazolyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)- 30 methanone; (5-Methyl[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,3]triazolyl-benzyl)-morpholinyl]- methanone; [(R)(3-Pyrazolyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)-methanone; 105 (5-Methyl[1,2,3]triazolyl-phenyl)-[(R)(3-pyrimidinyl-benzyl)-morpholinyl]- methanone; [(R)(3-Pyrimidinyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)-methanone; (5-Methyl[1,2,3]triazolyl-phenyl)-[(R)(3-pyrazolyl-benzyl)-morpholinyl]- 5 methanone; (5-Fluoro[1,2,3]triazolyl-phenyl)-[(R)(3-pyrazolyl-benzyl)-morpholinyl]- methanone; (2-Fluoromethyl[1,2,3]triazolyl-phenyl)-[(R)(3-pyrazolyl-benzyl)-morpholinyl]- methanone; 10 (4-Methyl[1,2,3]triazolyl-phenyl)-[(R)(3-pyrazolyl-benzyl)-morpholinyl]- one; (5-Methyl[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,4]triazolyl-benzyl)-morpholinyl]- methanone; (5-Methyl[1,2,3]triazolyl-phenyl)-[(R)(3-pyridinyl-benzyl)-morpholinyl]- 15 methanone; (5-Methyl[1,2,3]triazolyl-phenyl)-[(R)(3-pyridinyl-benzyl)-morpholinyl]- methanone; (5-Fluoro[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,3]triazolyl-benzyl)-morpholinyl]- methanone; 20 (4-Methyl[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,3]triazolyl-benzyl)-morpholinyl]- methanone; (5-Methyl[1,2,3]triazolyl-phenyl)-[(R)(3-pyridinyl-benzyl)-morpholinyl]- methanone; (2-Fluoromethyl[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,3]triazolyl-benzyl)-morpholin- 25 4-yl]-methanone; (5-Chloro[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,3]triazolyl-benzyl)-morpholinyl]- methanone; ,3]Triazolyl[(R)(3-[1,2,3]triazolyl-benzyl)-morpholinecarbonyl]-benzonitrile; (5-Methoxy[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,3]triazolyl-benzyl)-morpholinyl]- 30 methanone; (2-Fluoromethoxy[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,3]triazolyl-benzyl)- linyl]-methanone; (4,5-Dimethoxy[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,3]triazolyl-benzyl)-morpholin yl]-methanone; 35 (4,5-Dimethyl[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,3]triazolyl-benzyl)-morpholinyl]- methanone; 106 (4-Fluoro[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,3]triazolyl-benzyl)-morpholinyl]- methanone; (5-Methoxymethyl[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,3]triazolyl-benzyl)- morpholinyl]-methanone; 5 (5-Methyl[1,2,3]triazolyl-phenyl)-[(R)(3-pyrrolyl-benzyl)-morpholinyl]- methanone; {(R)[3-(4-Methyl-pyrimidinyl)-benzyl]-morpholinyl}-(5-methyl[1,2,3]triazolylphenyl )-methanone; {(R)[3-(4-Methyl-pyrimidinyl)-benzyl]-morpholinyl}-(2-[1,2,3]triazolyl-phenyl)- 10 methanone; (5-Methyl[1,2,3]triazolyl-phenyl)-[(R)(3-pyrazinyl-benzyl)-morpholinyl]- one; [(R)(3-Oxazolyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)-methanone; (5-Methyl[1,2,3]triazolyl-phenyl)-[(R)(3-thiazolyl-benzyl)-morpholinyl]- 15 one; [(R)(3-Thiazolyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)-methanone; (5-Methyl[1,2,3]triazolyl-phenyl)-[(R)(3-thiophenyl-benzyl)-morpholinyl]- methanone; [(R)(3-Thiophenyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)-methanone; 20 hyl[1,2,3]triazolyl-phenyl)-[(R)(3-pyridazinyl-benzyl)-morpholinyl]- methanone; [(R)(3-Pyridazinyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)-methanone; (2-Fluoromethyl[1,2,3]triazolyl-phenyl)-[(R)(3-pyrimidinyl-benzyl)-morpholin yl]-methanone; 25 (5-Methoxy[1,2,3]triazolyl-phenyl)-[(R)(3-pyrimidinyl-benzyl)-morpholinyl]- methanone; (5-Chloro[1,2,3]triazolyl-phenyl)-[(R)(3-pyrimidinyl-benzyl)-morpholinyl]- methanone; (6-Methyl[1,2,3]triazolyl-pyridinyl)-[(R)(3-pyrazolyl-benzyl)-morpholinyl]- 30 methanone; (6-Methyl[1,2,3]triazolyl-pyridinyl)-[(R)(3-[1,2,3]triazolyl-benzyl)-morpholinyl]- methanone; and (3-Fluoro[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,3]triazolyl-benzyl)-morpholinyl]- methanone; 35 or a pharmaceutically acceptable salt thereof. 107

12. A compound according to claim 1 ed from the group consisting of: [(R)(4-Hydroxypyrimidinyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)-methanone; [(R)(2-Fluoro[1,2,3]triazolyl-benzyl)-morpholinyl]-(5-methyl[1,2,3]triazolyl-phenyl)-methanone; [(R)(2-Fluoro[1,2,3]triazolyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)-methanone; 5 [(R)(4-Methoxy[1,2,4]oxadiazolyl-benzyl)-morpholinyl]-(5-methyl[1,2,3]triazolyl-phenyl)- methanone; [(R)(4-Methoxy[1,2,4]oxadiazolyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)-methanone; [(R)(4-Methoxy[1,2,4]oxadiazolyl-benzyl)-morpholinyl]-(4-methyl[1,2,3]triazolyl-phenyl)- methanone; 10 (4-Fluoro[1,2,3]triazolyl-phenyl)-[(R)(4-methoxy[1,2,4]oxadiazolyl-benzyl)-morpholinyl]- methanone; [(R)(2-Fluoro[1,2,3]triazolyl-benzyl)-morpholinyl]-(4-methyl[1,2,3]triazolyl-phenyl)-methanone; [(R)(4-Methoxy[1,2,4]oxadiazolyl-benzyl)-morpholinyl]-(2-methyl[1,2,3]triazolyl-phenyl)- methanone; 15 (3-Methyl[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; [(R)(4-Methyl[1,2,3]triazolyl-benzyl)-morpholinyl]-(5-methyl[1,2,3]triazolyl-phenyl)-methanone; [(R)(4-Methyl[1,2,3]triazolyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)-methanone; [(R)(4-Methyl[1,2,3]triazolyl-benzyl)-morpholinyl]-(4-methyl[1,2,3]triazolyl-phenyl)-methanone; [(3R,5R)Methyl(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)-methanone; 20 [(3R,5R)Methyl(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-(4-methyl[1,2,3]triazolyl-phenyl)- methanone; [(3R,5R)Methyl(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-(3-methyl[1,2,3]triazolyl-phenyl)- methanone; [(3S,5R)Methyl(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-(4-methyl[1,2,3]triazolyl-phenyl)- 25 methanone; [(3S,5R)Methyl(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-(3-methyl[1,2,3]triazolyl-phenyl)- methanone; [(3S,5R)Methyl(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-(5-methyl[1,2,3]triazolyl-phenyl)- methanone; 30 imethyl[1,2,3]triazolyl-phenyl)-[(3S,5R)methyl(3-[1,2,3]triazolyl-benzyl)-morpholinyl]- methanone; imethyl[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; [(R)(3-[1,2,3]Triazolyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyltrifluoromethyl-phenyl)-methanone; (4-Chloro[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; 35 (4-Fluoromethoxy[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; 108 (4,5-Dimethyl[1,2,3]triazolyl-phenyl)-[(R)(4-methyl[1,2,4]oxadiazolyl-benzyl)-morpholinyl]- methanone; (4,5-Difluoro[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,4]oxadiazolyl-benzyl)-morpholinyl]-methanone; (4-Methyl[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,4]oxadiazolyl-benzyl)-morpholinyl]-methanone; 5 (3-Fluoro[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,4]oxadiazolyl-benzyl)-morpholinyl]-methanone; (3-Methyl[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,4]oxadiazolyl-benzyl)-morpholinyl]-methanone; (5-Chloro[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,4]oxadiazolyl-benzyl)-morpholinyl]-methanone; (4,5-Dimethyl[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,4]oxadiazolyl-benzyl)-morpholinyl]-methanone; (4-Chloro[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,4]oxadiazolyl-benzyl)-morpholinyl]-methanone; 10 [(R)(3-[1,2,4]Oxadiazolyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyltrifluoromethyl-phenyl)-methanone; (5-Fluoro[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,4]oxadiazolyl-benzyl)-morpholinyl]-methanone; (3,5-Dimethyl[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,4]oxadiazolyl-benzyl)-morpholinyl]-methanone; [(R)(4-Chloro[1,2,4]oxadiazolyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)-methanone; (4,5-Difluoro[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; 15 (3,4-Dimethyl[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; (4-Methoxy[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; (3,4-Dimethyl[1,2,3]triazolyl-phenyl)-[(R)(2-fluoro[1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; [(R)(2-Fluoro[1,2,3]triazolyl-benzyl)-morpholinyl]-(4-methoxy[1,2,3]triazolyl-phenyl)-methanone; [(2S,5R)Methyl(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-(4-methyl[1,2,3]triazolyl-phenyl)- 20 one; [(2R,5R)Methyl(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-(3-methyl[1,2,3]triazolyl-phenyl)- methanone; (4,5-Dimethyl[1,2,3]triazolyl-phenyl)-[(2R,5R)methyl(3-[1,2,3]triazolyl-benzyl)-morpholinyl]- methanone; 25 imethyl[1,2,3]triazolyl-phenyl)-[(2R,5R)methyl(3-[1,2,3]triazolyl-benzyl)-morpholinyl]- methanone; [(2R,5R)Methyl(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)-methanone; [(2R,5R)Methyl(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-(4-methyl[1,2,3]triazolyl-phenyl)- methanone; 30 [(R)Methyl(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-(5-methyl[1,2,3]triazolyl-phenyl)-methanone; (5-Chloromethyl[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; (4-Chloromethoxy[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; -(3-Chloro[1,2,3]triazolyl-benzyl)-morpholinyl]-(4-methyl[1,2,3]triazolyl-phenyl)-methanone; [(R)(3-Chloro[1,2,3]triazolyl-benzyl)-morpholinyl]-(3-methyl[1,2,3]triazolyl-phenyl)-methanone; 35 (3-Chloro[1,2,3]triazolyl-phenyl)-[(R)(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; [(2R,5R)Methyl(3-pyrimidinyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)-methanone; 109 [(2R,5R)Methyl(3-pyrimidinyl-benzyl)-morpholinyl]-(5-methyl[1,2,3]triazolyl-phenyl)-methanone; [(2R,5R)Methyl(3-pyrimidinyl-benzyl)-morpholinyl]-(4-methyl[1,2,3]triazolyl-phenyl)-methanone; [(2R,5R)Methyl(3-pyrimidinyl-benzyl)-morpholinyl]-(3-methyl[1,2,3]triazolyl-phenyl)-methanone; (3,4-Dimethyl[1,2,3]triazolyl-phenyl)-[(2R,5R)methyl(3-pyrimidinyl-benzyl)-morpholinyl]- 5 methanone; oro[1,2,3]triazolyl-phenyl)-[(2R,5R)methyl(3-pyrimidinyl-benzyl)-morpholinyl]-methanone; (4-Chloro[1,2,3]triazolyl-phenyl)-[(2R,5R)methyl(3-pyrimidinyl-benzyl)-morpholinyl]-methanone; [(2R,5R)(2-Fluoro[1,2,3]triazolyl-benzyl)methyl-morpholinyl]-(5-methyl[1,2,3]triazolyl-phenyl)- methanone; 10 [(2R,5R)(2-Fluoro[1,2,3]triazolyl-benzyl)methyl-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)- methanone; [(2R,5R)(2-Fluoro[1,2,3]triazolyl-benzyl)methyl-morpholinyl]-(4-methyl[1,2,3]triazolyl-phenyl)- methanone; [(2R,5R)(2-Fluoro[1,2,3]triazolyl-benzyl)methyl-morpholinyl]-(3-methyl[1,2,3]triazolyl-phenyl)- 15 one; [(R)(2-Methyl[1,2,3]triazolyl-benzyl)-morpholinyl]-(5-methyl[1,2,3]triazolyl-phenyl)-methanone; [(R)(2-Chloro[1,2,3]triazolyl-benzyl)-morpholinyl]-(4-methyl[1,2,3]triazolyl-phenyl)-methanone; [(R)(2-Methyl[1,2,3]triazolyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)-methanone; [(R)(2-Chloro[1,2,3]triazolyl-benzyl)-morpholinyl]-(3-methyl[1,2,3]triazolyl-phenyl)-methanone; 20 [(R)(2-Methyl[1,2,3]triazolyl-benzyl)-morpholinyl]-(4-methyl[1,2,3]triazolyl-phenyl)-methanone; [(R)(2-Methyl[1,2,3]triazolyl-benzyl)-morpholinyl]-(3-methyl[1,2,3]triazolyl-phenyl)-methanone; [(R)(2-Chloro[1,2,3]triazolyl-benzyl)-morpholinyl]-(5-methyl[1,2,3]triazolyl-phenyl)-methanone; [(R)(2-Chloro[1,2,3]triazolyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)-methanone; [(R)(2-Fluoro[1,2,3]triazolyl-benzyl)-morpholinyl]-(3-methyl[1,2,3]triazolyl-phenyl)-methanone; 25 (4,5-Dimethyl[1,2,3]triazolyl-phenyl)-[(R)(2-fluoro[1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; (5-Chloro[1,2,3]triazolyl-phenyl)-[(R)(2-fluoro[1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; (4-Chloro[1,2,3]triazolyl-phenyl)-[(R)(2-fluoro[1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; [(R)(2-Fluoro[1,2,3]triazolyl-benzyl)-morpholinyl]-(5-methoxy[1,2,3]triazolyl-phenyl)-methanone; (2-Fluoromethyl[1,2,3]triazolyl-phenyl)-[(R)(2-fluoro[1,2,3]triazolyl-benzyl)-morpholinyl]- 30 methanone; (2-Fluoromethoxy[1,2,3]triazolyl-phenyl)-[(R)(2-fluoro[1,2,3]triazolyl-benzyl)-morpholinyl]- methanone; [(R)(2-Fluoro[1,2,3]triazolyl-benzyl)-morpholinyl]-(5-methoxymethyl[1,2,3]triazolyl-phenyl)- methanone; 35 (3-Chloro[1,2,3]triazolyl-phenyl)-[(R)(2-fluoro[1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; [(R)(2-Fluoro[1,2,3]triazolyl-benzyl)-morpholinyl]-(2-fluoro[1,2,3]triazolyl-phenyl)-methanone; 110 ifluoro[1,2,3]triazolyl-phenyl)-[(R)(2-fluoro[1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; [(R)(2-Fluoro[1,2,3]triazolyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyltrifluoromethyl-phenyl)- methanone; (4-Chloromethoxy[1,2,3]triazolyl-phenyl)-[(R)(2-fluoro[1,2,3]triazolyl-benzyl)-morpholinyl]- 5 methanone; [(2R,5R)(2-Fluoro[1,2,3]triazolyl-benzyl)methyl-morpholinyl]-(5-methyl[1,2,3]triazolyl-phenyl)- methanone; [(2R,5R)(2-Fluoro[1,2,3]triazolyl-benzyl)methyl-morpholinyl]-(4-methyl[1,2,3]triazolyl-phenyl)- one; 10 [(2R,5R)Ethyl(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-(5-methyl[1,2,3]triazolyl-phenyl)-methanone; [(2R,5R)Ethyl(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)-methanone; [(2R,5R)Ethyl(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-(4-methyl[1,2,3]triazolyl-phenyl)-methanone; [(R)(3-Fluoro[1,2,3]triazolyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)-methanone; [(R)(3-Fluoro[1,2,3]triazolyl-benzyl)-morpholinyl]-(4-methyl[1,2,3]triazolyl-phenyl)-methanone; 15 [(2R,5R)(2-Fluoropyrimidinyl-benzyl)methyl-morpholinyl]-(5-methyl[1,2,3]triazolyl-phenyl)- methanone; [(2R,5R)(2-Fluoropyrimidinyl-benzyl)methyl-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)-methanone; [(2R,5R)(2-Fluoropyrimidinyl-benzyl)methyl-morpholinyl]-(4-methyl[1,2,3]triazolyl-phenyl)- methanone; 20 R)(2-Fluoropyrimidinyl-benzyl)methyl-morpholinyl]-(3-methyl[1,2,3]triazolyl-phenyl)- methanone; (3,4-Dimethyl[1,2,3]triazolyl-phenyl)-[(2R,5R)(2-fluoropyrimidinyl-benzyl)methyl-morpholinyl]- methanone; (5-Chloro[1,2,3]triazolyl-phenyl)-[(2R,5R)(2-fluoropyrimidinyl-benzyl)methyl-morpholinyl]- 25 methanone; (4-Chloro[1,2,3]triazolyl-phenyl)-[(2R,5R)(2-fluoropyrimidinyl-benzyl)methyl-morpholinyl]- methanone; (3-Chloro[1,2,3]triazolyl-phenyl)-[(2R,5R)(2-fluoropyrimidinyl-benzyl)methyl-morpholinyl]- methanone; 30 [(R)(2-Fluoropyrimidinyl-benzyl)-morpholinyl]-(5-methyl[1,2,3]triazolyl-phenyl)-methanone; [(R)(2-Fluoropyrimidinyl-benzyl)-morpholinyl]-(4-methyl[1,2,3]triazolyl-phenyl)-methanone; [(R)(2-Fluoropyrimidinyl-benzyl)-morpholinyl]-(3-methyl[1,2,3]triazolyl-phenyl)-methanone; (3,4-Dimethyl[1,2,3]triazolyl-phenyl)-[(R)(2-fluoropyrimidinyl-benzyl)-morpholinyl]-methanone; (5-Chloro[1,2,3]triazolyl-phenyl)-[(R)(2-fluoropyrimidinyl-benzyl)-morpholinyl]-methanone; 35 (4-Chloro[1,2,3]triazolyl-phenyl)-[(R)(2-fluoropyrimidinyl-benzyl)-morpholinyl]-methanone; (3-Chloro[1,2,3]triazolyl-phenyl)-[(R)(2-fluoropyrimidinyl-benzyl)-morpholinyl]-methanone; 111 [(2S,3R)Methyl(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-(5-methyl[1,2,3]triazolyl-phenyl)- methanone; [(2S,3R)Methyl(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-(4-methyl[1,2,3]triazolyl-phenyl)- methanone; 5 [(2S,3R)Methyl(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-(3-methyl[1,2,3]triazolyl-phenyl)- methanone; [(2R,5R)(2-Fluoropyridazinyl-benzyl)methyl-morpholinyl]-(4-methyl[1,2,3]triazolyl-phenyl)- methanone; [(R)(2-Fluoropyridazinyl-benzyl)-morpholinyl]-(4-methyl[1,2,3]triazolyl-phenyl)-methanone; 10 [(2R,3R)Methyl(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-(5-methyl[1,2,3]triazolyl-phenyl)- one; [(2R,3R)Methyl(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-(4-methyl[1,2,3]triazolyl-phenyl)- methanone; [(R)(2-Chloro[1,2,3]triazolyl-benzyl)-morpholinyl]-(3,4-dimethyl[1,2,3]triazolyl-phenyl)-methanone; 15 [(R)(2-Chloro[1,2,3]triazolyl-benzyl)-morpholinyl]-(4-chloro[1,2,3]triazolyl-phenyl)-methanone; [(R)(2-Chloro[1,2,3]triazolyl-benzyl)-morpholinyl]-(3-chloro[1,2,3]triazolyl-phenyl)-methanone; (3-Chloro[1,2,3]triazolyl-phenyl)-[(2R,5R)methyl(3-[1,2,3]triazolyl-benzyl)-morpholinyl]- methanone; (3-Chloro[1,2,3]triazolyl-phenyl)-[(2R,5R)(2-fluoro[1,2,3]triazolyl-benzyl)methyl-morpholinyl]- 20 methanone; -(2-Fluoro[1,2,4]oxadiazolyl-benzyl)-morpholinyl]-(5-methyl[1,2,3]triazolyl-phenyl)-methanone; [(R)(2-Fluoro[1,2,4]oxadiazolyl-benzyl)-morpholinyl]-(4-methyl[1,2,3]triazolyl-phenyl)-methanone; (5-Chloro[1,2,3]triazolyl-phenyl)-[(R)(2-fluoro[1,2,4]oxadiazolyl-benzyl)-morpholinyl]-methanone; [(R)(2-Fluoro[1,2,4]oxadiazolyl-benzyl)-morpholinyl]-(3-methyl[1,2,3]triazolyl-phenyl)-methanone; 25 (4-Chloro[1,2,3]triazolyl-phenyl)-[(R)(2-fluoro[1,2,4]oxadiazolyl-benzyl)-morpholinyl]-methanone; (4,5-Dimethyl[1,2,3]triazolyl-phenyl)-[(R)(2-fluoro[1,2,4]oxadiazolyl-benzyl)-morpholinyl]- one; (3-Chloro[1,2,3]triazolyl-phenyl)-[(R)(2-fluoro[1,2,4]oxadiazolyl-benzyl)-morpholinyl]-methanone; (3,4-Dimethyl[1,2,3]triazolyl-phenyl)-[(R)(2-fluoro[1,2,4]oxadiazolyl-benzyl)-morpholinyl]- 30 methanone; [(R)(3-[1,2,3]Triazolyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyltrifluoromethyl-phenyl)-methanone; [(R)(2-Fluoro[1,2,3]triazolyl-benzyl)-morpholinyl]-(4-methyl[1,2,3]triazolyl-phenyl)-methanone; (5-Chloro[1,2,3]triazolyl-phenyl)-[(2R,5R)methyl(3-[1,2,3]triazolyl-benzyl)-morpholinyl]- methanone; 35 (4-Chloro[1,2,3]triazolyl-phenyl)-[(2R,5R)methyl(3-[1,2,3]triazolyl-benzyl)-morpholinyl]- methanone; 112 (5-Chloro[1,2,3]triazolyl-phenyl)-[(2R,5R)(2-fluoro[1,2,3]triazolyl-benzyl)methyl-morpholinyl]- methanone; (4-Chloro[1,2,3]triazolyl-phenyl)-[(2R,5R)(2-fluoro[1,2,3]triazolyl-benzyl)methyl-morpholinyl]- methanone; 5 [(R)(2-Methylpyrazolyl-benzyl)-morpholinyl]-(5-methyl[1,2,3]triazolyl-phenyl)-methanone; [(R)(2-Methylpyrazolyl-benzyl)-morpholinyl]-(4-methyl[1,2,3]triazolyl-phenyl)-methanone; [(R)(2-Methylpyrazolyl-benzyl)-morpholinyl]-(3-methyl[1,2,3]triazolyl-phenyl)-methanone; oro[1,2,3]triazolyl-phenyl)-[(R)(2-methyl[1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; [(R)(4-Methylpyrimidinyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)-methanone; 10 [(R)(4-Methylthiazolyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)-methanone; and [(R)(4-Chloropyrimidinyl-benzyl)-morpholinyl]-(2-[1,2,3]triazolyl-phenyl)-methanone; or a pharmaceutically acceptable salt thereof.

13. The compound according to claim 1 which is hyl[1,2,3]triazolyl-phenyl)-[(R)- 3-(3-[1,2,3]triazolyl-benzyl)-morpholinyl]-methanone; 15 or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition comprising, as active principle, one or more compounds according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert excipient.

15. A compound according to any one of claims 1 to 13, or a pharmaceutically acceptable 20 salt f, for use as a ment.

16. A compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of a disease selected from the group consisting of anxiety disorders, addiction disorders, mood disorders, and appetite disorders.

17. Use of a compound according to any one of claims 1 to 13, or of a pharmaceutically 25 able salt thereof, in the preparation of a medicament for the prevention or treatment of a disease selected from the group consisting of y disorders, addiction disorders, mood disorders, and appetite ers.

18. A compound of a (I) according to claim 1, substantially as herein described with reference to any example thereof. 30

19. A pharmaceutical composition according to claim 14, substantially as herein described with reference to any example thereof.

20. A use ing to claim 17, substantially as herein described with reference to any example thereof.