WO2020099511A1

WO2020099511A1 - Benzimidazole-2-methyl-morpholine derivatives

Info

Publication number: WO2020099511A1
Application number: PCT/EP2019/081229
Authority: WO
Inventors: Hamed Aissaoui; Christoph Boss
Original assignee: Idorsia Pharmaceuticals Ltd
Priority date: 2018-11-14
Filing date: 2019-11-13
Publication date: 2020-05-22

Abstract

The present invention relates to compounds of the Formula (I) wherein Ar¹, R¹, and (R⁵)ⁿ are as described in the description, to their preparation, to pharmaceutically acceptable salts thereof, and to their use as pharmaceuticals, to pharmaceutical compositions containing one or more compounds of Formula (I), and especially to their use as orexin receptor antagonists.

Description

Benzimidazole-2-methyl-morpholine derivatives

The present invention relates to novel benzimidazole-2-methyl-morpholine derivatives of Formula (I) and their use as pharmaceuticals. The invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more compounds of Formula (I), and their use as orexin receptor antagonists.

Orexins (orexin A or OX-A and orexin B or OX-B) are neuropeptides found in 1998 by two research groups, orexin A is a 33 amino acid peptide and orexin B is a 28 amino acid peptide (Sakurai T. et al., Cell, 1998, 92, 573- 585). Orexins are produced in discrete neurons of the lateral hypothalamus and bind to the G-protein-coupled receptors (OXi and OX2 receptors). The orexin-1 receptor (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 animals and humans involves either blockade of both orexin-1 and orexin-2 receptor (dual antagonists), or individual and selective blockade of either the orexin-1 or the orexin-2 receptor (selective antagonists) in the brain. Orexins were initially found to stimulate food consumption in rats suggesting a physiological role for these peptides as mediators in the central feedback mechanism that regulates feeding behaviour (Sakurai T. et al., Cell, 1998, 92, 573-585).

On the other hand, orexin neuropeptides and orexin receptors play an essential and central role in regulating circadian vigilance states. In the brain, orexin neurons collect sensory input about internal and external states and send short intrahypothalamic axonal projections as well as long projections to many other brain regions. The particular distribution of orexin fibers and receptors in basal forebrain, limbic structures and brainstem regions - areas related to the regulation of waking, sleep and emotional reactivity- suggests that orexins exert essential functions as regulators of behavioral arousal; by activating wake-promoting cell firing, orexins contribute to orchestrate all brain arousal systems that regulate circadian activity, energy balance and emotional reactivity. This role opens large therapeutic opportunities for medically addressing numerous mental health disorders possibly relating to orexinergic dysfunctions [see for example: Tsujino N and Sakurai T, "Orexin/hypocretin: a neuropeptide at the interface of sleep, energy homeostasis, and reward systems.", Pharmacol Rev. 2009, 61 :162- 176; and Carter ME et al., "The brain hypocretins and their receptors: mediators of allostatic arousal.", Curr Op Pharmacol. 2009, 9: 39-45] that are described in the following sections. It was also observed that orexins regulate states of sleep and wakefulness opening potentially novel therapeutic approaches to insomnia and other sleep disorders (Chemelli R.M. et al., Cell, 1999, 98, 437-451).

Human memory is comprised of multiple systems that have different operating principles and different underlying neuronal substrates. The major distinction is between the capacity for conscious, declarative memory and a set of unconscious, non-declarative memory abilities. Declarative memory is further subdivided into semantic and episodic memory. Non-declariative memory is further subdivided into priming and perceptual learning, procedural memory for skills and habits, associative and non-associative learning, and some others. While semantic memory refers to the general knowledge about the world, episodic memory is autobiographical memory of events. Procedural memories refer to the ability to perform skill-based operations, as e.g. motor skills. Long-term memory is established during a multiple stage process through gradual changes involving diverse brain structures, beginning with learning, or memory acquisition, or formation. Subsequently, consolidation of what has been learned may stabilize memories. When long-term memories are retrieved, they may return to a labile state in which original content may be updated, modulated or disrupted. Subsequently, reconsolidation may again stabilize memories. At a late stage, long-term memory may be resistant to disruption. Long-term memory is conceptually and anatomically different from working memory, the latter of which is the capacity to maintain temporarily a limited amount of information in mind. Behavioural research has suggested that the human brain consolidates long-term memory at certain key time intervals. The initial phase of memory consolidation may occur in the first few minutes after we are exposed to a new idea or learning experience. The next, and possibly most important phase, may occur over a longer period of time, such as during sleep; in fact, certain consolidation processes have been suggested to be sleep-dependent [R. Stickgold et al., Sleep-dependent memory consolidation; Nature 2005,437, 1272-1278]. Learning and memory processes are believed to be fundamentally affected in a variety of neurological and mental disorders, such as e.g. mental retardation, Alzheimer’s disease or depression. Indeed, memory loss or impairment of memory acquisition is a significant feature of such diseases, and no effective therapy to prevent this detrimental process has emerged yet.

In addition, both anatomical and functional evidence from in vitro and in vivo studies suggest an important positive interaction of the endogenous orexin system with reward pathways of the brain [Aston-Jones G et al., Brain Res 2010, 1314, 74-90; Sharf R et al., Brain Res 2010, 1314, 130-138]. Selective pharmacological OXR-1 blockade reduced cue- and stress-induced reinstatement of ***e seeking [Boutrel B, et al., "Role for hypocretin in mediating stress-induced reinstatement of ***e-seeking behavior." Proc Natl Acad Sci 2005, 102(52), 19168-19173; Smith RJ et al., "Orexin/hypocretin signaling at the orexin 1 receptor regulates cue-elicited ***e-seeking." Eur J Neurosci 2009, 30(3), 493-503; Smith RJ et al., "Orexin/hypocretin is necessary for context-driven ***e-seeking." Neuropharmacology 2010, 58(1), 179-184], cue-induced reinstatement of alcohol seeking [Lawrence AJ et al., Br J Pharmacol 2006, 148(6), 752-759] and nicotine self-administration [Hollander JA et al., Proc Natl Acad Sci 2008, 105(49), 19480-19485; LeSage MG et al., Psychopharmacology

2010, 209(2), 203-212] Orexin-1 receptor antagonism also attenuated the expression of amphetamine- and ***e-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 ***e [Borgland SL et al., Neuron 2006, 49(4), 589-601; Quarta D et al., "The orexin-1 receptor antagonist SB-334867 reduces amphetamine-evoked dopamine outflow in the shell of the nucleus accumbens and decreases the expression of amphetamine sensitization." Neurochem Int 2010, 56(1), 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 Spealman et al, Pharmacol. Biochem. Behav. 1999, 64 327-336; or T.S. Shippenberg, G.F. Koob, "Recent advances in animal models of drug addiction" in Neuropsychopharmacology: The fifth generation of progress; K.L.Davis, D. Charney, J.T.Doyle, C. Nemeroff (eds.) 2002; chapter 97, pages 1381-1397]

Several converging lines of evidence furthermore demonstrate a direct role of the orexin system as modulator of the acute stress response. For instance, stress (i.e. psychological stress or physical stress) is associated with increased arousal and vigilance which in turn is controlled by orexins [Sutcliffe, JG et al., Nat Rev Neurosci 2002, 3(5), 339-349] Orexin neurons are likely to be involved in the coordinated regulation of behavioral and physiological responses in stressful environments [Y. Kayaba et al., Am. J. Physiol. Regul. Integr. Comp. Physiol. 2003, 285 :R581-593]. Hypocretin/orexin contributes to the expression of some but not all forms of stress and arousal [Furlong T M et al., Eur J Neurosci 2009, 30(8), 1603-1614] Stress response may lead to dramatic, usually time-limited physiological, psychological and behavioural changes that may affect appetite, metabolism and feeding behavior [Chrousos, GP et al., JAMA 1992, 267(9), 1244-1252] The acute stress response may include behavioural, autonomic and endocrinological changes, such as promoting heightened vigilance, decreased libido, increased heart rate and blood pressure, or a redirection of blood flow to fuel the muscles, heart and the brain [Majzoub, JA et al., European Journal of Endocrinology 2006, 155 (supplj) S71-S76].

As outlined above the orexin system regulates homeostatic functions such as sleep-wake cycle, energy balance, emotions and reward. Orexins are also involved in mediating the acute behavioral and autonomous nervous system response to stress [Zhang Wet al., "Multiple components of the defense response depend on orexin: evidence from orexin knockout mice and orexin neuron-ablated mice." Auton Neurosci 2006, 126-127, 139-145]. Mood disorders including all types of depression and bipolar disorder are characterized by disturbed“mood” and feelings, as well as by sleeping problems (insomnia as well as hypersomnia), changes in appetite or weight and reduced pleasure and loss of interest in daily or once enjoyed activities [Liu X et al., Sleep 2007, 30(1): 83-90]. Thus, there is a strong rationale that disturbances in the orexin system may contribute to the symptoms of mood disorders. Evidence in humans, for instance, exists that depressed patients show blunted diurnal variation in CSF orexin levels [Salomon RM et al., Biol Psychiatry 2003, 54(2), 96-104] In rodent models of depression, orexins were also shown to be involved. Pharmacological induction of a depressive behavioral state in rats, for instance, revealed an association with increased hypothalamic orexin levels [Feng P et al., J Psychopharmacol 2008, 22(7): 784-791]. A chronic stress model of depression in mice also demonstrated an association of molecular orexin system disturbances with depressed behavioral states and a reversal of these molecular changes by antidepressant treatment [Nollet et al., NeuroPharm 2011, 61(1-2):336-46].

The orexin system is also involved in stress-related appetitive/reward seeking behaviour (Berridge CW et al., Brain Res 2009, 1314, 91-102). In certain instances, a modulatory effect on stress may be complementary to an effect on appetitive/reward seeking behaviour as such. For instance, an OXi selective orexin receptor antagonist was able to prevent footshock stress induced reinstatement of ***e seeking behaviour [Boutrel, B et al., Proc Natl Acad Sci 2005, 102(52), 19168-19173]. In addition, stress is also known to play an integral part in withdrawal which occurs during cessation of drug taking (Koob, GF et al., Curr Opin Investig Drugs 2010, 11(1), 63-71).

Orexins have been found to increase food intake and appetite [Tsujino, N, Sakurai, T, Pharmacol Rev 2009, 61(2) 162-176]. As an additional environmental factor, stress can contribute to binge eating behaviour, and lead to obesity [Adam, TC et al. Physiol Bebav 2007, 91 (4) 449-458]. Animal models that are clinically relevant models of binge eating in humans are described for example in W. Foulds Mathes et al.; Appetite 2009, 52, 545-553.

A number of recent studies report that orexins may play a role into several other important functions relating to arousal, especially when an organism must respond to unexpected stressors and challenges in the environment [Tsujino N and Sakurai T. Pharmacol Rev. 2009, 61:162-176; Carter ME, Borg JS and deLecea L, Curr Op Pharmacol. 2009, 9: 39-45; C Boss, C Brisbare-Roch, F Jenck, Journal of Medicinal Chemistry 2009, 52: 891- 903]. The orexin system interacts with neural networks that regulate emotion, reward and energy homeostasis to maintain proper vigilance states. Dysfunctions in its function may thus relate to many mental health disorders in which vigilance, arousal, wakefulness or attention is disturbed.

The compound (2R)-2-{(1 S)-6,7-dimethoxy-1-[2-(4-trifluoromethyl-phenyl)-ethyl]-3,4-dihydro-1 H-isoquinolin-2-yl}- A/-methyl-2-phenyl-acetamide (W02005/118548), a dual orexin receptor antagonist, showed clinical efficacy in humans when tested for the indication primary insomnia. In the rat, the compound has been shown to decrease alertness, characterized by decreases in both active wake and locomotion; and to dose-dependently increase the time spent in both REM and NREM sleep [Brisbare-Roch et al., Nature Medicine 2007, 13 150-155]. The compound further attenuated cardiovascular responses to conditioned fear and novelty exposure in rats [Furlong T M et al., Eur J Neurosci 2009, 30(8), 1603-1614] It is also active in an animal model of conditioned fear: the rat fear-potentiated startle paradigm (W02009/047723) which relates to emotional states of fear and anxiety diseases such as anxieties including phobias and post traumatic stress disorders (PTSDs). In addition, intact declarative and non-declarative learning and memory has been demonstrated in rats treated with this compound [W02007/105177, H Dietrich, F Jenck, Psychopharmacology 2010, 212, 145-154] Said compound furthermore decreased brain levels of amyloid-beta (Ab) as well as Ab plaque deposition after acute sleep restriction in amyloid precursor protein transgenic mice [JE Kang et al., "Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle.", Science 2009, 326(5955): 1005-1007] The accumulation of the Ab 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 Ab to Alzheimer's disease and, thus, to the cognitive dysfunction, expressed as impairment of learning and memory. The compound has also been shown to induce antidepressant-like activity in a mouse model of depression, when administered chronically [Nollet et al., NeuroPharm 2011, 61 (1 -2):336-46]. Moreover, the compound has been shown to attenuate the natural activation induced by orexin A in fasted hungry rats exposed to food odors [MJ Prud’homme et al., Neuroscience 2009, 162(4), 1287-1298] The compound also displayed pharmacological activity in a rat model of nicotine selfadministration [LeSage MG et al., Psychopharmacology 2010, 209(2), 203-212] Another dual orexin receptor antagonist, N-biphenyl-2-yl-1-{[(1-methyl-1 H-benzimidazol-2-yl)sulfanyl]acetyl}-L-prolinamide inhibited nicotine- reinstatement for a conditioned reinforcer and reduced behavioral (locomotor sensitization) and molecular (transcriptional responses) changes induced by repeated amphetamine administration in rodents [Winrow et al., Neuropharmacology 2009, 58(1), 185-94]

Orexin receptor antagonists comprising a 2-substituted saturated cyclic amide derivatives (such as 2-substituted pyrrolidine-1 -carboxamides) are known for example from W02008/020405, W02008/038251 , W02008/081399, W02008/087611 , W02008/117241, W02008/139416, W02009/004584, W02009/016560, W02009/016564, W02009/040730, W02009/104155, WO2010/004507, WO2010/038200, WO2001/096302, W02002/044172, W02002/089800, W02002/090355, W02003/002559, W02003/032991 , W02003/041711 , W02003/051368, W02003/051873, W02004/026866, W02004/041791 , W02004/041807, W02004/041816, W02009/003993, W02009/003997, W02009/124956, WO2010/060470, WO2010/060471 , W02010/060472, WO2010/063662, WO2010/063663, WO2010/072722, WO2010/122151 , and W02008/150364 and WO2013/182972. W02003/002559 and discloses N-aroyl cyclic amine derivatives encompassing morpholine derivatives as orexin receptor antagonists. A particular pyrrolidine derived orexin-1 selective compound within the scope of W02003/002559 is disclosed in Langmead et. al, Brit. J. Pharmacol. 2004, 141 , 340-346: 1-(5-(2-fluoro-phenyl)- 2-methyl-thiazol-4-yl)-1 -[(S)-2-(5-phenyl-[1 ,3,4]oxadiazol-2-ylmethyl)-pyrrolidin-1 -yl)-methanone. W02003/002561 discloses certain N-aroyl cyclic amine derivatives, encompassing a benzimidazol-2-yl-methyl substituted morpholine derivative, as orexin receptor antagonists. Despite the great number of prior art compounds and their high structural variability, all compounds share a common structural feature, i.e. in position 2 of the saturated cyclic amide a linker group such as at least a methylene group (or longer groups such as -CH₂-NH-CO-, -CH2-NH-, -CH2-O-, -CH2-S-, etc.) link the cyclic amide to the respective aromatic ring system substituent. WO2013/182972 discloses pyrrolidine derivatives that have a benzimidazole ring directly attached to a pyrrolidine amide in position 2. For W02003/002561 , one compound is wrongly indexed as containing both a morpholine core and a benzimidazole substituent (CAS Reg. No. 1347329-274), however, this compound corresponds to Example 78 which contains a methylenelinker between the morphioline core and the benzimidazole group. It has now surprisingly been found that, despite the substantial conformational changes that may be expected from the removal of a linker between two rigid structural elements, the present compounds, that have a benzimidazole ring directly attached in position 5 to a 2-methyl-morpholine amide may be potent dual orexin receptor antagonists.

The present invention, thus, provides novel benzimidazole-2-methyl-morpholine derivatives, which are nonpeptide antagonists of human orexin receptors. These compounds are in particular of potential use in the treatment of disorders relating to orexinergic dysfunctions, comprising especially sleep disorders, anxiety disorders, addiction disorders, cognitive dysfunctions, mood disorders, or appetite disorders. 1 ) A first aspect of the invention relates to compounds of the Formula (I)

wherein

R¹ represents hydrogen or (Ci-3)alkyl (especially R¹ represents hydrogen);

Ar¹ represents

• phenyl or 5- or 6-membered heteroaryl, wherein said phenyl or 5- or 6-membered heteroaryl independently is mono-, di-, or tri-substituted; wherein

> one of said substituents is attached in ortho-position to the point of attachment of Ar¹ to the rest of the molecule; wherein said substituent independently is phenyl or 5- or 6-membered heteroaryl; wherein said phenyl or 5- or 6-membered heteroaryl substituent is independently unsubstituted, mono-, di-, or tri-substituted, wherein the substituents are independently selected from (Ci_4)alkyl, (Ci )alkoxy (especially methoxy), halogen, cyano, (Ci-3)fluoroalkyl, and (Ci-3)fluoroalkoxy;

> and the other of said substituents, if present, is/are independently selected from (Ci-4)alkyl

(especially methyl); (Ci-4)alkoxy (especially methoxy); (C3-6)cycloalkyl; halogen; cyano; (Ci-3)fluoroalkyl (especially trifluoromethyl); and ( C i -3)f I u oroal koxy ;

(R⁵)_n represents one to three optional substituents (i.e. n represents the integer 0, 1 , 2, or 3) independently selected from (C jalkyl (especially methyl), (Ci-4)alkoxy (especially methoxy), halogen, (Ci^)alkyl-thio- (especially H₃C-S-), (Ci-3)fluoroalkyl (especially trifluoromethyl), (Ci-3)fluoroalkoxy (especially trifluoromethoxy), (Ci-3)fluoroalkyl-thio- (especially F₃C-S-), and cyano.

2) A second aspect of the invention relates to compounds according to embodiment 1), wherein the absolute configuration of the morpholine moiety is as depicted in Formula (II)

Formula (II) i.e. said morpholine is in enantiomerically enriched absolute (5R)-configuration.

In a sub-embodiment, said morpholine is in enantiomerically enriched absolute (5R)-configuration and the configuration in position 2 of said morpholine moiety is either in enantiomerically enriched absolute (2R) or (2S) (preferably in 2S) configuration, wherein said two enantiomerically enriched diastereoisomers are depicted in Formula (lla) and (lib):

Formula (lla) Formula (lib)

The compounds of Formula (I) contain at least two stereogenic centers which are situated in position 2 and 5 of the morpholine moiety. In case said stereogenic centers are in enantiomerically enriched absolute (5 R)- configuration a compound of Formula (II) represents either a compound of Formula (lla), or a compound of Formula (lib), or any mixture thereof.

In addition, the compounds of formulae (I), (II), (lla), and (lib) may contain one or more further stereogenic or asymmetric centers, such as one or more additional asymmetric carbon atoms. The compounds of formulae (I), (II), (lla), and (lib) may thus be present as mixtures of stereoisomers or preferably as pure stereoisomers. Mixtures of stereoisomers may be separated in a manner known to a person skilled in the art.

3) A third aspect of the invention relates to compounds according to embodiment 1), wherein the absolute configuration is as depicted in Formula (lla) (i.e. the morpholine is in enantiomerically enriched absolute (2S,5R)- configuration):

Formula (lla)

In case a particular compound (or generic structure) is designated as (R)- or (S)-enantiomer / as having an absolute (R)- or (S)-configuration, such designation is to be understood as referring to the respective compound (or generic structure) in enriched, especially essentially pure, enantiomeric form. Likewise, in case a specific asymmetric center in a compound is designated as being in (R)- or (S)-configuration or as being in a certain relative configuration, such designation is to be understood as referring to the compound that is in enriched, especially essentially pure, form with regard to the respective configuration of said asymmetric center. In analogy, c/s- or irans-designations (or (R^*,R^*) / (R^*,S^*) designations) are to be understood as referring to the respective stereoisomer of the respective relative configuration in enriched form, especially in essentially pure form.

The relative configuration of stereoisomers is denoted as follows: for example [(2R^*,5S^*)-5-(5-Chloro-4-methyl- 1H-benzoimidazol-2-yl)-2-methyl-morpholin-4-yl]-(2-fluoro-3-methoxy-6-[1 ,2,3]triazol-2-yl-phenyl)-methanone denominates [(2R,5S)-5-(5-Chloro-4-methyl-1H-benzoimidazol-2-yl)-2-methyl-morpholin-4-yl]-(2-fluoro-3- methoxy-6-[1 ,2,3]triazol-2-yl-phenyl)-methanone, [(2S,5R)-5-(5-Chloro-4-methyl-1 H-benzoimidazol-2-yl)-2- methyl-morpholin-4-yl]-(2-fluoro-3-methoxy-6-[1 ,2,3]triazol-2-yl-phenyl)-methanone, or any mixture of these two enantiomers including the racemate.

The term "enriched", when used in the context of stereoisomers, is to be understood in the context of the present invention to mean that the respective stereoisomer is present in a ratio of at least 70:30, especially of at least 90:10 (i.e., in a purity of at least 70% by weight, especially of at least 90% by weight), with regard to the respective other stereoisomer / the entirety of the respective other stereoisomers.

The term“essentially pure”, when used in the context of stereoisomers, is to be understood in the context of the present invention to mean that the respective stereoisomer is present in a purity of at least 95% by weight, especially of at least 99% by weight, with regard to the respective other stereoisomer / the entirety of the respective other stereoisomers.

In addition, it is well understood that the benzimidazole moiety of the present compounds is unsubstituted on the ring nitrogen having a free valency, such benzimidazole moiety represents tautomeric forms. Thus, substituents (R⁵)_n of the benzimidazole moiety may be attached in the position(s) ortho to the bridgehead atoms (i.e. attached in position(s) 4 and/or 7, corresponding to R¹⁴ and/or R¹⁷), and/or in the position(s) meta to the bridgehead atoms, (i.e. attached in position(s) 5 and/or 6, corresponding to R¹⁵ and/or R¹⁶). It is understood that the two ortho , and, respectively, the two meta positions are considered equivalent. For example, the group 4-methyl-1H- benzoimidazol-2-yl is understood to signify the same group as 7-methyl-1 H-benzoimidazol-2-yl and 4-methyl-3H- benzoimidazol-2-yl and 7-methyl-3H-benzoimidazol-2-yl.

The present invention also includes isotopically labelled, especially ²H (deuterium) labelled compounds of Formula (I), which compounds are identical to the compounds of Formula (I), except that one or more atoms have each been replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Isotopically labelled, especially ²H (deuterium) labelled compounds of Formula (I) and salts thereof are within the scope of the present invention. Substitution of hydrogen with the heavier isotope ²H (deuterium) may lead to greater metabolic stability, resulting e.g. in increased in-vivo half-life or reduced dosage requirements, or may lead to reduced inhibition of cytochrome P450 enzymes, resulting e.g. in an improved safety profile. In one embodiment of the invention, the compounds of Formula (I) are not isotopically labelled, or they are labelled only with one or more deuterium atoms. In a sub-embodiment, the compounds of Formula (I) are not isotopically labelled at all. Isotopically labelled compounds of Formula (I) 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

represents a 2-(2-triazolyl)-phenyl group.

Where the plural form is used for compounds, salts, pharmaceutical compositions, diseases and the like, this is intended to mean also a single compound, salt, or the like.

Any reference to compounds of formulae (I), (II), (lla), and (lib) according to any one of embodiments 1) to 18) is to be understood as referring also to the salts (and especially the pharmaceutically acceptable salts) of such compounds, as appropriate and expedient.

The term "pharmaceutically acceptable salts" refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. Such salts include inorganic or organic acid and/or base addition salts depending on the presence of basic and/or acidic groups in the subject compound. For reference see for example "Salt selection for basic drugs", Int. J. Pharm. (1986), 33, 201-217;“Handbook of Phramaceutical Salts. Properties, Selection and Use.”, P. Heinrich Stahl, Camille G. Wermuth (Eds.), Wiley-VCH, 2008; and“Pharmaceutical Salts and Co-crystals”, Johan Wouters and Luc Quere (Eds.), RSC Publishing, 2012.

Definitions provided herein are intended to apply uniformly to the compounds of formulae (I), (II), (lla), and (lib) as defined in any one of embodiments 1) to 16), and, mutatis mutandis , throughout the description and the claims unless an otherwise expressly set out definition provides a broader or narrower definition. It is well understood that a definition or preferred definition of a term defines and may replace the respective 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.

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“(C_x-y)alkyl” (x and y each being an integer), refers to an alkyl group as defined before, containing x to y carbon atoms. For example a (C jalkyl group contains from one to four carbon atoms. Examples of alkyl groups are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec.-butyl and tert.- butyl. Preferred 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“(C_x-y)alkoxy” (x and y each being an integer) refers to an alkoxy group as defined before containing x to y carbon atoms. For example a (Ci-4)alkoxy group means a group of the formula (Ci^)alkyl-O- in which the term“(Ci_4)alkyl” has the previously given significance. Examples of alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec.-butoxy and tert.-butoxy. Preferred is methoxy.

The term“(Ci-4)alkyl-thio-" used alone or in combination, refers to a group of the formula (Ci^)alkyl-S- in which the term“(Ci^)alkyl” has the previously given significance. An example is CH3-S-.

The term "fluoroalkyl” refers to an alkyl group as defined before containing one to three carbon atoms in which one or more (and possibly all) hydrogen atoms have been replaced with fluorine. The term“ ( C_x-y)f I u 0 roa I ky I” (x and y each being an integer) refers to a fluoroalkyl group as defined before containing x to y carbon atoms. For example a (Ci-3)fluoroalkyl group contains from one to three carbon atoms in which one to seven hydrogen atoms have been replaced with fluorine. Representative examples of fluoroalkyl groups include trifluoromethyl, 2- fluoroethyl, 2,2-difluoroethyl and 2,2,2-trifluoroethyl. Preferred are (Ci)fluoroalkyl groups such as trifluoromethyl.

The term "fluoroalkoxy” refers to an alkoxy group as defined before containing one to three carbon atoms in which one or more (and possibly all) hydrogen atoms have been replaced with fluorine. The term“(C_x-y)fluoroalkoxy” (x and y each being an integer) refers to a fluoroalkoxy group as defined before containing x to y carbon atoms. For example a (Ci-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 (Ci)fluoroalkoxy groups such as trifluoromethoxy and difluoromethoxy.

The term "(Ci-3)fluoroalkyl-thio-" refers to (Ci-3)fluoroalkyl group as defined before, which is linked to the rest of the molecule through a sulfur atom. An example is CF₃-S-.

Particular examples of Ar¹ representing a phenyl group, wherein said phenyl is mono-, di-, or tri-substituted; wherein one of said substituents is attached in ortho- position to the point of attachment of Ar¹ to the rest of the molecule; are such that the other of said substituents, if present, is/are independently selected from (Ci-4)alkyl; (Ci )alkoxy; (C3-6)cycloalkyl; halogen; cyano; (Ci-3)fluoroalkyl; (Ci-3)fluoroalkoxy; unsubstituted pyridinyl; and phenyl which is unsubstituted, or mono- or di-substituted, wherein the substituents are independently selected from (C_M)alkyl, (Ci4)alkoxy, cyano, and halogen [notably the other of said substituents, if present, is/are independently selected from (Ci4)alkyl, (Ci4)alkoxy, halogen, cyano, (Ci-3)fluoroalkyl, and (Ci-3)fluoroalkoxy; especially from (Ci4)alkyl, (Ci4)alkoxy, and halogen]. Particular examples of such phenyl groups which are further substituted in ortho position as used for the group Ar¹ are 1 ,2-phenylene, 4-methyl-1 ,2-phenylene, 5- methyl-1 ,2-phenylene, 4, 5-dimethyl-1 ,2-phenylene, 5-fluoro-1 ,2-phenylene, 5-chloro-1 ,2-phenylene, 5-methoxy- 1 ,2-phenylene, 4-trifluoromethyl-1 ,2-phenylene, 6-fluoro-5-methyl-1 ,2-phenylene, and 6-fluoro-5-methoxy-1,2- phenylene.

Examples of the particular phenyl groups which are substituents of the group Ar¹ are especially phenyl groups which are unsubstituted, mono-, or di-substituted, wherein the substituents are independently selected from (Ci4)alkyl, (Ci4)alkoxy, halogen, cyano, (Ci-3)fluoroalkyl, and (Ci-3)fluoroalkoxy [notably from (Ci4)alkyl, (Ci4)alkoxy, halogen, and (Ci-3)fluoroalkyl] Particular examples are phenyl, and 4-fluoro-phenyl. The term“heteroaryl”, if not explicitly stated otherwise, means a 5- to 10-membered monocyclic, or bicyclic, aromatic ring containing 1 to a maximum of 3 heteroatoms independently selected from oxygen, nitrogen and sulfur. Examples of such heteroaryl groups are 5-membered monocyclic heteroaryl groups such as furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, and triazolyl; 6-membered monocyclic heteroaryl such as pyridyl, pyrimidyl, pyridazinyl, and pyrazinyl; and 8- to 10- membered bicyclic heteroaryl such as indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzoxazolyl (or benzooxazolyl), benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, benzoxadiazolyl, benzothiadiazolyl, quinolinyl, isoquinolinyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidyl, imidazo[1,2-a]pyridyl, 1 H-pyrrolo[3,2- b]pyridyl, 1 H-pyrrolo[2,3-b]pyridyl, pyrrolo[3,2-d]pyrimidinyl, pyrrolo[2,3-d]pyrimidinyl, 4H-furo[3,2-b]pyrrolyl, pyrrolo[2,1-b]thiazolyl, imidazo[2,1-b]thiazolyl and purinyl.

Examples of the particular 5- or 6-membered heteroaryl groups which are further substituted in ortho position as used for the group Ar¹ are the above mentioned 5- or 6-membered heteroaryl groups, notably the 5-membered heteroaryl groups oxazolyl, isoxazolyl, thiophenyl, thiazolyl, isothiazolyl; and the 6-membered heteroaryl groups pyridyl, pyrimidyl and pyrazinyl. In a sub-embodiment, examples are thiazolyl (notably 2-methyl-thiazol-4,5-diyl) and pyridyl (notably 6-methyl-pyridin-2,3-diyl). These groups are at least mono-substituted in ortho position, and preferably and independently carry no further substituent or one further substitutent as explicitly defined. In particular such optional further substituent may independently be selected from (Ci-4)alkyl (especially methyl); (C3-6)cycloalkyl (especially cyclopropyl); -NR¹⁰R¹¹, wherein R¹⁰ and R¹¹ independently represent (Ci-4)alkyl (especially methyl), or R¹⁰ and R¹¹ together with the nitrogen to which they are attached to form a pyrrolidine ring; and phenyl which is unsubstituted, or mono- or di-substituted, wherein the substituents are independently selected from (Ci^)alkyl, (Ci4)alkoxy, cyano, and halogen. In a sub-embodiment, such optional further substituent may independently be selected from (Ci4)alkyl, (Ci4)alkoxy, (C3-6)cycloalkyl, halogen, cyano, (Ci-3)fluoroalkyl, (Ci-3)fluoroalkoxy, and -NR¹⁰R¹¹ [wherein especially oxazolyl groups carry no further substituent or one further substitutent selected from (Ci4)alkyl, (C3-6)cycloalkyl, -NR¹⁰R¹¹; thiazolyl groups carry no further substituent or one further substitutent selected from (Ci4)alkyl, (C3-6)cycloalkyl, -NR¹⁰R¹¹, and phenyl which is unsubstituted, or mono- or di-substituted, wherein the substituents are independently selected from (Ci4)alkyl, (Ci4)alkoxy, cyano, and halogen (notably methyl, cyclopropyl, and phenyl which is unsubstituted, or mono- or di-substituted, wherein the substituents are independently selected from (Ci4)alkyl, (Ci4)alkoxy, cyano, and halogen; especially methyl and cyclopropyl); thiophenyl, pyridinyl and pyrimidinyl groups carry no further substituent or one further substitutent selected from (Ci4)alkyl (especially methyl); and pyrazinyl group carry no further substituent]. The above groups are preferably attached to the rest of the molecule (i.e. the carbonyl group) in position 4 of oxazolyl, isoxazolyl, or thiazolyl groups; in position 2 of pyridyl or pyrazinyl groups; in position 2 of thiophenyl groups; and in position 5 of pyrimidinyl groups. In a further sub-embodiment, particular examples of such groups are 2-methyl- thiazol-4,5-diyl, as well as 6-methyl-pyridin-2,3-diyl. Examples of the particular 5- or 6-membered heteroaryl groups which are substituents of the group Ar¹ are the above mentioned 5- or 6-membered heteroaryl groups; notably the 5-membered heteroaryl groups oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, and the 6- membered heteroaryl groups pyridyl, pyrimidyl, pyrazinyl and pyridazinyl. In a sub-embodiment, such groups are especially pyrazolyl, triazolyl, pyridinyl and pyrimidinyl, notably pyrazol-1-yl, pyrimidin-2-yl, and [1,2,3]triazol-2-yl. The above mentioned groups may be unsubstituted or substituted as explicitly defined; wherein pyrazol-1-yl, and [1 ,2,3]triazol-2-yl groups are preferably unsubstituted. Particular examples are pyrazol-1-yl, [1 ,2,3]triazol-2-yl, and pyrimidin-2-yl [notably the 5-membered heteroaryl group [1,2,3]triazol-2-yl; and the 6-membered heteroaryl group pyrimidin-2-yl].

Further embodiments of the invention are presented hereinafter:

4) A second embodiment relates to compounds according to any one of embodiments 1) to 3), wherein R¹ is hydrogen.

5) Another embodiment relates to compounds according to any one of embodiments 1) to 4), wherein (R⁵)_n represents one or two optional substituents (i.e. n represents the integer 0, 1, or 2) (especially (R⁵)_n represents one or two substituents; i.e. n represents the integer 1 or 2) independently selected from (Ci^)alkyl (especially methyl), (Ci-4)alkoxy (especially methoxy), halogen (especially fluorine, chlorine or bromine), (Ci4)alkyl-thio- (especially H₃C-S-), (Ci-3)fluoroalkyl (especially trifluoromethyl), (Ci-3)fluoroalkoxy (especially trifluoromethoxy), (Ci-3)fluoroalkyl-thio- (especially F₃C-S-), and cyano (especially (R⁵)_n represents one or two substituents independently selected from methyl, and halogen).

6) Another embodiment relates to compounds according to any one of embodiments 1) to 5), wherein the fragment

wherein

R¹⁴, R¹⁵, R¹⁶ and R¹⁷ together represent one or two optional substituents (i.e. at least two of R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are hydrogen) [notably R¹⁴, R¹⁵, R¹⁶ and R¹⁷ together represent one or two substituents (i.e. at least two of R¹⁴, R¹⁵, R¹⁶ and R¹⁷are hydrogen and at least one of R¹⁴, R¹⁵, R¹⁶ and R¹⁷ is different from hydrogen)], wherein

• R¹⁴ and R¹⁷ independently represent hydrogen, (Ci-4)alkyl (especially methyl), (Ci-4)alkoxy (especially methoxy), (Ci^)alkyl-thio- (especially H₃C-S-), halogen, (Ci-3)fluoroalkyl (especially trifluoromethyl); and

• R¹⁵ and R¹⁶ independently represent hydrogen, (Ci-4)alkyl, (Ci4)alkoxy (especially methoxy), (Ci4)alkyl- thio- (especially H₃C-S-), halogen, (Ci-3)fluoroalkyl (especially trifluoromethyl), (Ci-3)fluoroalkoxy (especially trifluoromethoxy), (Ci-3)fluoroalkyl-thio- (especially F₃C-S-), or cyano. 7) Another embodiment relates to compounds according to any one of embodiments 1) to 5), wherein the fragment

wherein

R¹⁴, R¹⁵, R¹⁶ and R¹⁷ together represent one or two optional substituents [notably R¹⁴, R¹⁵, R¹⁶ and R¹⁷ together represent one or two substituents (i.e. at least two of R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are hydrogen and at least one of R¹⁴, R¹⁵, R¹⁶ and R¹⁷ is different from hydrogen)], wherein

• R¹⁴ and R¹⁷ independently represent hydrogen, methyl, methoxy, halogen, or trifluoromethyl; and

• R¹⁵ and R¹⁶ independently represent hydrogen, methyl, methoxy, halogen, trifluoromethyl, or trifluoromethoxy.

8) Another embodiment relates to compounds according to any one of embodiments 1) to 5); wherein the fragment

represents a group independently selected from the following groups A or B:

A.

wherein it is understood that the benzimidazolyl moieties of groups A and B may be present in form of tautomers; and wherein the groups A are preferred.

9) Another embodiment relates to compounds according to any one of embodiments 1) to 5); wherein the fragment

represents a group independently selected from:

wherein it is understood that the benzimidazolyl moieties may be present in form of tautomers.

10) Another embodiment relates to compounds according to any one of embodiments 1) to 9), wherein Ar¹ represents phenyl or 5- or 6-membered heteroaryl selected from thiazolyl and pyridinyl, wherein said phenyl or 5- or 6-membered heteroaryl independently is mono-, di-, or tri-substituted; wherein

one of said substituents is attached in ortho-position to the point of attachment of Ar¹ to the rest of the molecule; wherein said substituent independently is phenyl or 5- or 6-membered heteroaryl selected from pyrazolyl, triazolyl, pyridinyl, and pyrimidinyl; wherein said phenyl or 5- or 6-membered heteroaryl substituent is independently unsubstituted, mono-, di-, or tri-substituted (especially unsubstituted, or mono-substituted), wherein the substituents are independently selected from (Ci-4)alkyl, (Ci )alkoxy (especially methoxy), halogen, cyano, (Ci-3)fluoroalkyl, and (Ci-3)fluoroalkoxy;

• and the other of said substituents, if present, is/are independently selected from (Ci^)alkyl (especially methyl); (Ci-4)alkoxy (especially methoxy); (C3-6)cycloalkyl; halogen; cyano; and (Ci-3)fluoroalkyl (especially trifluromethyl); (Ci-3)fluoroalkoxy. 11) Another embodiment relates to compounds according to any one of embodiments 1) to 9) wherein Ar¹ represents phenyl or 5- or 6-membered heteroaryl selected from thiazolyl and pyridinyl, wherein said phenyl or 5- or 6-membered heteroaryl independently is mono-, di-, or tri-substituted; wherein

• one of said substituents is attached in ortho-position to the point of attachment of Ar¹ to the rest of the molecule; wherein said substituent independently is phenyl or 5- or 6-membered heteroaryl selected from pyrazolyl, triazolyl, pyridinyl, and pyrimidinyl; wherein said phenyl or 5- or 6-membered heteroaryl substituent is independently unsubstituted, or mono-substituted, wherein the substituents are independently selected from (Ci-2)alkyl, (Ci-2)alkoxy, halogen, cyano, trifluoromethyl, and trifluoromethoxy;

• and the other of said substituents, if present, is/are independently selected from methyl; methoxy; cyclopropyl; halogen; cyano; trifluoromethyl; and trifluoromethoxy.

12) Another embodiment relates to compounds according to any one of embodiments 1) to 9), wherein

• Ar¹ represents 5-membered heteroaryl (especially thiazolyl), which is mono- or di-substituted (especially di-substituted); wherein

> one of said substituents is attached in ortho-position to the point of attachment of Ar¹ to the rest of the molecule; wherein

o said ortho-substituent is phenyl which is independently unsubstituted, mono-, di-, or tri-substituted (especially mono-substituted), wherein the substituents are independently selected from (Ci-4)alkyl, (Ci4)alkoxy, halogen, cyano, (Ci-3)fluoroalkyl, and (Ci-3)fluoroalkoxy [wherein phenyl is especially mono-substituted with (Ci4)alkyl, (Ci )alkoxy, halogen, (C )fluoroalkyl, or (Ci-3)fluoroalkoxy;

o or said ortho-substituent is 6-membered heteroaryl (especially pyridyl) which is independently unsubstituted, mono-, di-, or tri-substituted (especially mono- substituted), wherein the substituents are independently selected from (C jalkyl, (Ci4)alkoxy (especially methoxy), halogen, cyano, (C )fluoroalkyl, and (Ci-3)fluoroalkoxy [wherein said 6-membered heteroaryl is notably pyridyl which is mono-substituted with (Ci4)alkoxy (especially methoxy)];

> and the other of said substituents, if present, is/are independently selected from (Cujalkyl (especially methyl); (Ci4)alkoxy (especially methoxy); (C3-6)cycloalkyl; halogen; cyano; (Ci-3)fluoroalkyl; or (Ci-3)fluoroalkoxy;

• or Ar¹ represents 6-membered heteroaryl (especially pyridinyl) which is mono-, di-, or tri-substituted (especially di-substituted); wherein

o said ortho-substituent is unsubstituted 5-membered heteroaryl (notably pyrazol-1-yl or

[1 ,2,3]triazol-2-yl); > and the other of said substituents, if present, is/are independently selected from (Cu)alkyl (especially methyl), (Ci-₄)alkoxy, halogen, and (Ci-₃)fluoroalkyl;

• or Ar¹ represents phenyl which is mono-, di-, or tri-substituted; wherein

o said ortho-substituent is phenyl which is unsubstituted, mono-, di-, or tri-substituted (especially unsubstituted), wherein the substituents are independently selected from (Ci-₄)alkyl, (Ci_₄)alkoxy, halogen, cyano, (Ci-₃)fluoroalkyl, and ( C i -₃ )fl uo roal koxy ;

o or said ortho-substituent is 6-membered heteroaryl (especially selected from pyridinyl or pyrimidinyl) which is unsubstituted, mono-, or di-substituted (especially unsubstituted), wherein the substituents are independently selected from (Cu)alkyl, (Ci-₄)alkoxy, halogen, and (Ci-₃)fluoroalkyl (especially mono-substituted with (Ci-₄)alkyl, or (Cu)alkoxy);

o or said ortho-substituent is 5-membered heteroaryl (especially pyrazolyl or triazolyl) which is unsubstituted, mono-, or di-substituted (especially unsubstituted), wherein the substituents are independently selected from (Cu)alkyl, (Cu)alkoxy, halogen, and (Ci-₃)fluoroalkyl (especially (C jalkyl, notably methyl);

> and the other of said substituents, if present, is/are independently selected from (Cujalkyl;

(Ci₄)alkoxy; (C_3-6)cycloalkyl; halogen; cyano; (Ci-₃)fluoroalkyl; ( C ₁ -₃)f I uo roa I koxy .

) Another embodiment relates to compounds according to any one of embodiments 1) to 9), wherein

• Ar¹ represents 5-membered heteroaryl (especially thiazol-4-yl) which is di-substituted; wherein

> one of said substituents is attached in ortho-position to the point of attachment of Ar¹ to the rest of the molecule (i.e. position 5); wherein

o said ortho-substituent is phenyl which is mono-substituted, wherein the substituent is selected from (Cujalkyl, (Cu)alkoxy, halogen, cyano, (C jfluoroalkyl, and (Ci-₃)fluoroalkoxy;

o or said ortho-substituent is 6-membered heteroaryl (especially pyridyl) which is mono- substituted, wherein the substituent is selected from (Cujalkyl, (Cu)alkoxy (especially methoxy), halogen, cyano, (Ci-₃)fluoroalkyl, and (Ci-₃)fluoroalkoxy;

> and the other of said substituents, if present, is/are independently selected from (Cu)alkyl (especially methyl); (C_3-6)cycloalkyl; (Cu)alkoxy, halogen, and (Ci -₃)fl uoroal kyl ;

• or Ar¹ represents 6-membered heteroaryl (especially pyridinyl) which is di-substituted; wherein

o said ortho-substituent is unsubstituted 5-membered heteroaryl (especially pyrazol-1-yl or [1 ,2,3]triazol-2-yl); > and the other of said substituents, if present, is/are independently selected from (Ci )alkyl (especially methyl), (Ci-4)alkoxy, halogen, and (Ci-3)fluoroalkyl;

• or Ar¹ represents phenyl which is mono-, di-, or tri-substituted; wherein

o said ortho-substituent is unsubstituted phenyl;

o or said ortho-substituent is unsubstituted 6-membered heteroaryl (notably pyrimidin-2-yl); o or said ortho-substituent is unsubstituted 5-membered heteroaryl (notably pyrazol-1-yl or

[1 ,2 ,3]triazol-2-y I ) ;

> and the other of said substituents, if present, is/are independently selected from (Ci-4)alkyl;

(Ci-4)alkoxy; (C3-6)cycloalkyl; halogen; cyano; (Ci-3)fluoroalkyl; ( C i -3)f I uo roa I koxy .

14) Another embodiment relates to compounds according to any one of the embodiments 1) to 9) wherein Ar¹ is a group independently selected from the following groups A, B, C, D, E, F, G, H, I, or J:

10

G.

wherein each of the groups A to J forms a particular sub-embodiment; and wherein the groups A are preferred. 15) Another embodiment relates to compounds according to any one of the embodiments 1) to 9) wherein Ar¹ is a group independently selected from the following groups A, B, C, D, E, or F:

A.

especially wherein each of the groups A to F forms a particular sub-embodiment; and wherein the groups A are preferred.

16) The invention, thus, relates to compounds of the Formula (I) as defined in embodiment 1), compounds of the Formula (lla) as defined in embodiments 2) or 3), compounds of the Formula (lib) as defined in embodiment 2); or to such compounds further limited by the characteristics of any one of embodiments 4) to 15), under consideration of their respective dependencies; to pharmaceutically acceptable salts thereof; and to the use of such compounds as medicaments especially in the treatment of mental health disorders relating to orexinergic dysfunctions, which disorders are as defined below and which are especially selected from sleep disorders, anxiety disorders, addiction disorders, cognitive dysfunctions, mood disorders, or appetite disorders. For avoidance of any doubt, especially the following embodiments relating to the compounds of Formula (I), (II), (lla), and (lib) are thus possible and intended and herewith specifically disclosed in individualized form:

1,2+1, 3+1, 4+1, 4+2+1, 4+3+1, 5+1, 5+2+1, 5+3+1, 5+4+1, 5+4 +2+1, 5+4+3+1, 6+1, 6+2+1, 6+3+1, 6+4+1,

6+4 +2+1, 6+4+3+ 1, 6+5+1, 6+5+2+1, 6+5+3+1, 6+5+4+1, 6+5+4+2+1, 6+5+4+3+1, 7+1, 7+2+1, 7+3+1, 7+4+1,

7+4 +2+1, 7 +4+3+1, 7+5+1, 7+5+2+1, 7+5+3+1, 7+5+4+1, 7+5+4+2+1, 7+5+4+3+1, 8+1, 8+2+1, 8+3+1, 8+4+1,

8+4 +2+1, 8+4+3+1, 8+5+1, 8+5+2+1, 8+5+3+1, 8+5+4+1, 8+5+4+2+1, 8+5+4+3+1, 9+1, 9+2+1, 9+3+1, 9+4+1, 9+4 +2+1, 9+4 +3+1, 9+5+1, 9+5+2+1, 9+5+3+1, 9+5+4+1, 9+5+4+2+1, 9+5+4+3+1, 10+1, 10+2+1, 10+3+1 10+4+1, 10+4+2+1, 10+4+3+1, 10+5+1, 10+5+2+1, 10+5+3+1, 10+5+4+1, 10+5+4+2+1, 10+5+4+3+1, 10+6+1 10+6+2+1, 10+6+3+1, 10+6+4+1, 10+6+4+2+1, 10+6+4+3+1, 10+6+5+1, 10+6+5+2+1, 10+6+5+3+1

10+6+5+4+1, 10+6+5+4+2+1, 10+6+5+4+3+1, 10+7+1, 10+7+2+1, 10+7+3+1, 10+7+4+1, 10+7+4+2+1 10+7+4+3+1, 10+7+5+1, 10+7+5+2+1, 10+7+5+3+1, 10+7+5+4+1, 10+7+5+4+2+1, 10+7+5+4+3+1, 10+8+1 10+8+2+1, 10+8+3+1, 10+8+4+1, 10+8+4+2+1, 10+8+4+3+1, 10+8+5+1, 10+8+5+2+1, 10+8+5+3+1

10+8+5+4+1, 10+8+5+4+2+1, 10+8+5+4+3+1, 10+9+1, 10+9+2+1, 10+9+3+1, 10+9+4+1, 10+9+4+2+1 10+9+4+3+1, 10+9+5+1, 10+9+5+2+1, 10+9+5+3+1, 10+9+5+4+1, 10+9+5+4+2+1, 10+9+5+4+3+1, 11+1 11+2+1, 11+3+1, 11+4+1, 11+4+2+1, 11+4+3+1, 11+5+1, 11+5+2+1, 11+5+3+1, 11+5+4+1, 11+5+4+2+1 11+5+4+3+1, 11+6+1, 11+6+2+1, 11+6+3+1, 11+6+4+1, 11+6+4+2+1, 11+6+4+3+1, 11+6+5+1, 11+6+5+2+1 11+6+5+3+1, 11+6+5+4+1, 11+6+5+4+2+1, 11+6+5+4+3+1, 11+7+1, 11+7+2+1, 11+7+3+1, 11+7+4+1 11+7+4+2+1, 11+7+4+3+1, 11+7+5+1, 11+7+5+2+1, 11+7+5+3+1, 11+7+5+4+1, 11+7+5+4+2+1

11+7+5+4+3+1, 11+8+1, 11+8+2+1, 11+8+3+1, 11+8+4+1, 11+8+4+2+1, 11+8+4+3+1, 11+8+5+1, 11+8+5+2+1 11+8+5+3+1, 11+8+5+4+1, 11+8+5+4+2+1, 11+8+5+4+3+1, 11+9+1, 11+9+2+1, 11+9+3+1, 11+9+4+1 11+9+4+2+1, 11+9+4+3+1, 11+9+5+1, 11+9+5+2+1, 11+9+5+3+1, 11+9+5+4+1, 11+9+5+4+2+1

11+9+5+4+3+1, 12+1, 12+2+1, 12+3+1, 12+4+1, 12+4+2+1, 12+4+3+1, 12+5+1, 12+5+2+1, 12+5+3+1 12+5+4+1, 12+5+4+2+1, 12+5+4+3+1, 12+6+1, 12+6+2+1, 12+6+3+1, 12+6+4+1, 12+6+4+2+1, 12+6+4+3+1 12+6+5+1, 12+6+5+2+1, 12+6+5+3+1, 12+6+5+4+1, 12+6+5+4+2+1, 12+6+5+4+3+1, 12+7+1, 12+7+2+1 12+7+3+1, 12+7+4+1, 12+7+4+2+1, 12+7+4+3+1, 12+7+5+1, 12+7+5+2+1, 12+7+5+3+1, 12+7+5+4+1

12+7+5+4+2+1, 12+7+5+4+3+1, 12+8+1, 12+8+2+1, 12+8+3+1, 12+8+4+1, 12+8+4+2+1, 12+8+4+3+1 12+8+5+1, 12+8+5+2+1, 12+8+5+3+1, 12+8+5+4+1, 12+8+5+4+2+1, 12+8+5+4+3+1, 12+9+1, 12+9+2+1 12+9+3+1, 12+9+4+1, 12+9+4+2+1, 12+9+4+3+1, 12+9+5+1, 12+9+5+2+1, 12+9+5+3+1, 12+9+5+4+1

12+9+5+4+2+1, 12+9+5+4+3+1, 13+1, 13+2+1, 13+3+1, 13+4+1, 13+4+2+1, 13+4+3+1, 13+5+1, 13+5+2+1 13+5+3+1, 13+5+4+1, 13+5+4+2+1, 13+5+4+3+1, 13+6+1, 13+6+2+1, 13+6+3+1, 13+6+4+1, 13+6+4+2+1 13+6+4+3+1, 13+6+5+1, 13+6+5+2+1, 13+6+5+3+1, 13+6+5+4+1, 13+6+5+4+2+1, 13+6+5+4+3+1, 13+7+1 13+7+2+1, 13+7+3+1, 13+7+4+1, 13+7+4+2+1, 13+7+4+3+1, 13+7+5+1, 13+7+5+2+1, 13+7+5+3+1

13+7+5+4+1, 13+7+5+4+2+1, 13+7+5+4+3+1, 13+8+1, 13+8+2+1, 13+8+3+1, 13+8+4+1, 13+8+4+2+1 13+8+4+3+1, 13+8+5+1, 13+8+5+2+1, 13+8+5+3+1, 13+8+5+4+1, 13+8+5+4+2+1, 13+8+5+4+3+1, 13+9+1 13+9+2+1, 13+9+3+1, 13+9+4+1, 13+9+4+2+1, 13+9+4+3+1, 13+9+5+1, 13+9+5+2+1, 13+9+5+3+1

13+9+5+4+1, 13+9+5+4+2+1, 13+9+5+4+3+1, 14+1, 14+2+1, 14+3+1, 14+4+1, 14+4+2+1, 14+4+3+1, 14+5+1 14+5+2+1, 14+5+3+1, 14+5+4+1, 14+5+4+2+1, 14+5+4+3+1, 14+6+1, 14+6+2+1, 14+6+3+1, 14+6+4+1 14+6+4+2+1, 14+6+4+3+1, 14+6+5+1, 14+6+5+2+1, 14+6+5+3+1, 14+6+5+4+1, 14+6+5+4+2+1

14+6+5+4+3+1, 14+7+1, 14+7+2+1, 14+7+3+1, 14+7+4+1, 14+7+4+2+1, 14+7+4+3+1, 14+7+5+1, 14+7+5+2+1 14+7+5+3+1, 14+7+5+4+1, 14+7+5+4+2+1, 14+7+5+4+3+1, 14+8+1, 14+8+2+1, 14+8+3+1, 14+8+4+1 14+8+4+2+1, 14+8+4+3+1, 14+8+5+1, 14+8+5+2+1, 14+8+5+3+1, 14+8+5+4+1, 14+8+5+4+2+1

14+8+5+4+3+1, 14+9+1, 14+9+2+1, 14+9+3+1, 14+9+4+1, 14+9+4+2+1, 14+9+4+3+1, 14+9+5+1, 14+9+5+2+1 14+9+5+3+1, 14+9+5+4+1, 14+9+5+4+2+1 , 14+9+5+4+3+1, 15+1 , 15+2+1 , 15+3+1 , 15+4+1 , 15+4+2+1, 15+4+3+1 , 15+5+1 , 15+5+2+1 , 15+5+3+1, 15+5+4+1, 15+5+4+2+1, 15+5+4+3+1 , 15+6+1, 15+6+2+1 , 15+6+3+1 , 15+6+4+1 , 15+6+4+2+1 , 15+6+4+3+1, 15+6+5+1 , 15+6+5+2+1, 15+6+5+3+1, 15+6+5+4+1 , 15+6+5+4+2+1 , 15+6+5+4+3+1 , 15+7+1, 15+7+2+1, 15+7+3+1, 15+7+4+1 , 15+7+4+2+1, 15+7+4+3+1 , 15+7+5+1 , 15+7+5+2+1 , 15+7+5+3+1 , 15+7+5+4+1, 15+7+5+4+2+1 , 15+7+5+4+3+1, 15+8+1 , 15+8+2+1 , 15+8+3+1 , 15+8+4+1 , 15+8+4+2+1 , 15+8+4+3+1, 15+8+5+1 , 15+8+5+2+1, 15+8+5+3+1, 15+8+5+4+1 , 15+8+5+4+2+1 , 15+8+5+4+3+1 , 15+9+1, 15+9+2+1, 15+9+3+1, 15+9+4+1 , 15+9+4+2+1, 15+9+4+3+1 , 15+9+5+1 , 15+9+5+2+1 , 15+9+5+3+1, 15+9+5+4+1 , 15+9+5+4+2+1, 15+9+5+4+3+1.

In the list above the numbers refer to the embodiments according to their numbering provided hereinabove whereas“+” indicates the dependency from another embodiment. The different individualized embodiments are separated by commas. In other words, “13+6+3+1” for example refers to embodiment 13) depending on embodiment 6), depending on embodiment 3), depending on embodiment 1), i.e. embodiment“13+6+3+1” corresponds to the compounds of Formula (I) according to embodiment 1) further limited by all the features of the embodiments 3), 6), and 13).

17) Another embodiment relates to compounds according to embodiment 1) selected from:

[(2R^*,5S^*)-5-(5-Chloro-4-methyl-1 H-benzoimidazol-2-yl)-2-methyl-morpholin-4-yl]-(2-fluoro-3-methoxy-6-

[1,2,3]triazol-2-yl-phenyl)-methanone;

[(2R*,5S*)-5-(5-Chloro-4-methyl-1 H-benzoimidazol-2-yl)-2-methyl-morpholin-4-yl]-(4,5-dimethyl-2-[1,2,3]triazol-2- yl-phenyl)-methanone;

[(2R*,5S*)-5-(5-Chloro-4-methyl-1H-benzoimidazol-2-yl)-2-methyl-morpholin-4-yl]-(5-methoxy-2-[1,2,3]triazol-2-yl- phenyl)-methanone;

[(2R*,5S*)-5-(5-Chloro-4-methyl-1 H-benzoimidazol-2-yl)-2-methyl-morpholin-4-yl]-(5-methyl-2-[1 ,2,3]triazol-2-yl- phenyl)-methanone;

[(2R*,5S*)-5-(5-Chloro-4-methyl-1 H-benzoimidazol-2-yl)-2-methyl-morpholin-4-yl]-(5-chloro-2-[1 ,2,3]triazol-2-yl- phenyl)-methanone;

[(2R*,5S*)-5-(5-Chloro-4-methyl-1 H-benzoimidazol-2-yl)-2-methyl-morpholin-4-yl]-(5-methyl-2-pyrimidin-2-yl- phenyl)-methanone;

[(2R*,5S*)-5-(5-Chloro-4-methyl-1 H-benzoimidazol-2-yl)-2-methyl-morpholin-4-yl]-[5-(6-methoxy-pyridin-3-yl)-2- methyl-thiazol-4-yl]-methanone;

[(2R*,5S*)-5-(6-Chloro-5-trifluoromethyl-1 H-benzoimidazol-2-yl)-2-methyl-morpholin-4-yl]-(4,5-dimethyl-2-

[1,2,3]triazol-2-yl-phenyl)-methanone;

[(2R^*,5S^*)-5-(5-Chloro-4-methyl-1H-benzoimidazol-2-yl)-2-methyl-morpholin-4-yl]-(2-fluoro-3-methyl-6-

[1,2,3]triazol-2-yl-phenyl)-methanone;

[(2R*,5S*)-5-(5-Chloro-4-methyl-1 H-benzoimidazol-2-yl)-2-methyl-morpholin-4-yl]-[5-(4-fluoro-phenyl)-2-methyl- thiazol-4-yl]-methanone; [(2R*,5S*)-5-(5-Chloro-4-methyl-1 H-benzoimidazol-2-yl)-2-methyl-morpholin4-yl]-(4-methyl-2-[1 ,2,3]triazol-2-yl- phenyl)-methanone; and

[(2R^*,5S^*)-5-(5-Chloro-4-methyl-1 H-benzoimidazol-2-yl)-2-methyl-morpholin4-yl]-(6-methyl-3-[1 ,2,3]triazol-2-yl- pyridin-2-yl)-methanone.

18) Another embodiment relates to compounds according to embodiment 1) selected from:

[(2S,5R)-5-(5-Chloro4-methyl-1H-benzoimidazol-2-yl)-2-methyl-morpholin4-yl]-(2-fluoro-3-methoxy-6-

[1,2,3]triazol-2-yl-phenyl)-methanone;

[(2S,5R)-5-(5-Chloro4-methyl-1 H-benzoimidazol-2-yl)-2-methyl-morpholin4-yl]-(4,5-dimethyl-2-[1,2,3]triazol-2-yl- phenyl)-methanone;

[(2S,5R)-5-(5-Chloro4-methyl-1 H-benzoimidazol-2-yl)-2-methyl-morpholin4-yl]-(5-methoxy-2-[1 ,2,3]triazol-2-yl- phenyl)-methanone;

[(2S,5R)-5-(5-Chloro4-methyl-1H-benzoimidazol-2-yl)-2-methyl-morpholin4-yl]-(5-methyl-2-[1,2,3]triazol-2-yl- phenyl)-methanone;

[(2S,5R)-5-(5-Chloro4-methyl-1H-benzoimidazol-2-yl)-2-methyl-morpholin4-yl]-(5-chloro-2-[1,2,3]triazol-2-yl- phenyl)-methanone;

[(2S,5R)-5-(5-Chloro4-methyl-1 H-benzoimidazol-2-yl)-2-methyl-morpholin4-yl]-(5-methyl-2-pyrimidin-2-yl- phenyl)-methanone;

[(2S,5R)-5-(5-Chloro4-methyl-1H-benzoimidazol-2-yl)-2-methyl-morpholin4-yl]-[5-(6-methoxy-pyridin-3-yl)-2- methyl-thiazol4-yl]-methanone;

[(2S,5R)-5-(6-Chloro-5-trifluoromethyl-1 H-benzoimidazol-2-yl)-2-methyl-morpholin4-yl]-(4,5-dimethyl-2-

[1,2,3]triazol-2-yl-phenyl)-methanone;

[(2S,5R)-5-(5-Chloro4-methyl-1 H-benzoimidazol-2-yl)-2-methyl-morpholin4-yl]-(2-fluoro-3-methyl-6-[1 ,2,3]triazol-

2-yl-phenyl)-methanone;

[(2S,5R)-5-(5-Chloro4-methyl-1H-benzoimidazol-2-yl)-2-methyl-morpholin4-yl]-[5-(4-fluoro-phenyl)-2-methyl- thiazol4-yl]-methanone;

[(2S,5R)-5-(5-Chloro4-methyl-1H-benzoimidazol-2-yl)-2-methyl-morpholin4-yl]-(4-methyl-2-[1,2,3]triazol-2-yl- phenyl)-methanone; and

[(2S,5R)-5-(5-Chloro4-methyl-1H-benzoimidazol-2-yl)-2-methyl-morpholin4-yl]-(6-methyl-3-[1,2,3]triazol-2-yl- pyridin-2-yl)-methanone.

The compounds of formulae (I), (II), (lla), and (lib) according to any one of embodiments 1) to 18) and their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical compositions for enteral (such especially oral) or parenteral administration (including topical application or inhalation).

The production of the pharmaceutical compositions can be effected in a manner which will be familiar to any person skilled in the art (see for example Remington, The Science and Practice of Pharmacy, 21st Edition (2005), Part 5,“Pharmaceutical Manufacturing” [published by Lippincott Williams & Wilkins]) by bringing the described compounds of Formula (I) or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.

The present invention also relates to a method for the prevention or treatment of a disease or disorder mentioned herein comprising administering to a subject a pharmaceutically active amount of a compound of formulae (I), (II), (lla), and (lib) according to any one of embodiments 1) to 18).

In a preferred embodiment of the invention, the administered amount of such a compound of formulae (I), (II), (lla), and (lib) according to any one of embodiments 1) to 18) is comprised between 1 mg and 1000 mg per day, particularly between 5 mg and 500 mg per day, more particularly between 25 mg and 400 mg per day, especially between 50 mg and 200 mg per day.

For avoidance of any doubt, if compounds are described as useful for the prevention or treatment of certain diseases, such compounds are likewise suitable for use in the preparation of a medicament for the prevention or treatment of said diseases.

The compounds according to formulae (I), (II), (lla), and (lib) according to any one of embodiments 1) to 18) are useful for the prevention or treatment of disorders relating to orexinergic dysfunctions.

Such disorders relating to orexinergic dysfunctions are diseases or disorders where an antagonist of a human orexin receptor is required, notably mental health disorders relating to orexinergic dysfunctions. The above mentioned disorders may in particular be defined as comprising sleep disorders, anxiety disorders, addiction disorders, cognitive dysfunctions, mood disorders, or appetite disorders. In one sub-embodiment, the above mentioned disorders comprise especially anxiety disorders, addiction disorders and mood disorders, notably anxiety disorders and addiction disorders. In another sub-embodiment, the above mentioned disorders comprise especially sleep disorders.

In addition, further disorders relating to orexinergic dysfunctions are selected from treating, controlling, ameliorating or reducing the risk of epilepsy, including absence epilepsy; treating or controlling pain, including neuropathic pain; treating or controlling Parkinson's disease; treating or controlling psychosis including acute mania and bipolar disorder; treating or controlling stroke, particularly ischemic or haemorrhagic stroke; blocking an emetic response i.e. nausea and vomiting; and treating or controlling agitation, in isolation or co-morbid with another medical condition.

Anxiety disorders can be distinguished by the primary object or specificity of threat, ranging from rather diffuse as in generalized anxiety disorder, to circumscribed as encountered in phobic anxieties (PHOBs) or post-traumatic stress disorders (PTSDs). Anxiety disorders may, thus, be defined as comprising generalized anxiety disorders (GAD), obsessive compulsive disorders (OCDs), acute stress disorders, posttraumatic stress disorders (PTSDs), panic anxiety disorders (PADs) including panic attacks, phobic anxieties (PHOBs), specific phobia, social phobia (social anxiety disorder), avoidance, somatoform disorders including hypochondriasis, separation anxiety disorder, anxiety disorders due to a general medical condition, and substance induced anxiety disorders. In a sub-embodiment, particular examples of circumscribed threat induced anxiety disorders are phobic anxieties or post-traumatic stress disorders. Anxiety disorders especially include post-traumatic stress disorders, obsessive compulsive disorders, panic attacks, phobic anxieties, and avoidance.

Addiction disorders may be defined as addictions to one or more rewarding stimuli, notably to one rewarding stimulus. Such rewarding stimuli may be of either natural or synthetic origin. Examples of such rewarding stimuli are substances / drugs {of either natural or synthetic origin; such as ***e, amphetamines, opiates [of natural or (semi-)synthetic origin such as morphine or heroin], cannabis, ethanol, mescaline, nicotine, and the like}, which substances / drugs may be consumed alone or in combination; or other rewarding stimuli {of either natural origin (such as food, sweet, fat, or sex, and the like), or synthetic origin [such as gambling, or internet/IT (such as immoderate gaming, or inappropriate involvement in online social networking sites or blogging), and the like]}. In a sub-embodiment, addiction disorders relating to psychoactive substance use, abuse, seeking and reinstatement are defined as all types of psychological or physical addictions and their related tolerance and dependence components. Substance-related addiction disorders especially include substance use disorders such as substance dependence, substance craving and substance abuse; substance-induced disorders such as substance intoxication, substance withdrawal, and substance-induced delirium. The expression "prevention or treatment of addictions" (i.e. preventive or curative treatment of patients who have been diagnosed as having an addiction, or as being at risk of developing addictions) refers to diminishing addictions, notably diminishing the onset of addictions, to weakening their maintenance, to facilitating withdrawal, to facilitating abstinence, or to attenuating, decreasing or preventing the occurrence of reinstatement of addiction (especially to diminishing the onset of addictions, to facilitating withdrawal, or to attenuating, decreasing or preventing the occurrence of reinstatement of addiction).

Mood disorders include major depressive episode, manic episode, mixed episode and hypomanic episode; depressive disorders including major depressive disorder, dysthymic disorders; bipolar disorders including bipolar I disorder, bipolar II disorder (recurrent major depressive episodes with hypomanic episodes), cyclothymic disorder; mood disorders including mood disorder due to a general medical condition (including the subtypes with depressive features, with major depressive-like episode, with manic features, and with mixed features), substance-induced mood disorder (including the subtypes with depressive features, with manic features, and with mixed features). Such mood disorders are especially major depressive episode, major depressive disorder, mood disorder due to a general medical condition; and substance-induced mood disorder.

Appetite disorders comprise eating disorders and drinking disorders. Eating disorders may be defined as comprising eating disorders associated with excessive food intake and complications associated therewith; anorexias; compulsive eating disorders; obesity (due to any cause, whether genetic or environmental); obesity- related disorders including overeating and obesity observed in Type 2 (non-insulin-dependent) diabetes patients; bulimias including bulimia nervosa; cachexia; and binge eating disorder. Particular eating disorders comprise metabolic dysfunction; dysregulated appetite control; compulsive obesities; bulimia or anorexia nervosa. In a subembodiment, eating disorders may be defined as especially comprising anorexia nervosa, bulimia, cachexia, binge eating disorder, or compulsive obesities. Drinking disorders include polydipsias in psychiatric disorders and all other types of excessive fluid intake. Pathologically modified food intake may result from disturbed appetite (attraction or aversion for food); altered energy balance (intake vs. expenditure); disturbed perception of food quality (high fat or carbohydrates, high palatability); disturbed food availability (unrestricted diet or deprivation) or disrupted water balance.

Cognitive dysfunctions include deficits in attention, learning and especially memory functions occurring transiently or chronically in psychiatric, neurologic, neurodegenerative, cardiovascular and immune disorders, and also occurring transiently or chronically in the normal, healthy, young, adult, or especially aging population. Cognitive dysfunctions especially relate to the enhancement or maintenance of memory in patients who have been diagnosed as having, or being at risk of developing, diseases or disorders in which diminished memory (notably declarative or procedural) is a symptom [in particular dementias such as frontotemporal dementia, or dementia with Lewy bodies, or (especially) Alzheimer's disease]. Especially, the term "prevention or treatment of cognitive dysfunctions" relates to the enhancement or maintenance of memory in patients who have a clinical manifestation of a cognitive dysfunction, especially expressed as a deficit of declarative memory, linked to dementias such as frontotemporal dementia, or dementia with Lewy bodies, or (especially) Alzheimer's disease. Furthermore, the term "prevention or treatment of cognitive dysfunctions" also relates to improving memory consolidation in any of the above mentioned patient populations.

Sleep disorders comprise dyssomnias, parasomnias, sleep disorders associated with a general medical condition and substance-induced sleep disorders. In particular, dyssomnias include intrinsic sleep disorders (especially insomnias, breathing-related sleep disorders, periodic limb movement disorder, and restless leg syndrome), extrinsic sleep disorders, and circadian-rythm sleep disorders. Dyssomnias notably include insomnia, primary insomnia, idiopathic insomnia, insomnias associated with depression, emotional/mood disorders, aging, Alzheimer's disease or cognitive impairment; REM sleep interruptions; breathing-related sleep disorders; sleep apnea; periodic limb movement disorder (nocturnal myoclonus), restless leg syndrome, circadian rhythm sleep disorder; shift work sleep disorder; and jet-lag syndrome. Parasomnias include arousal disorders and sleep-wake transition disorders; notably parasomnias include nightmare disorder, sleep terror disorder, and sleepwalking disorder. Sleep disorders associated with a general medical condition are in particular sleep disorders associated with diseases such as mental disorders, neurological disorders, neuropathic pain, and heart and lung diseases. Substance-induced sleep disorders include especially the subtypes insomnia type, parasomnia type and mixed type, and notably include conditions due to drugs which cause reductions in REM sleep as a side effect. Sleep disorders especially include all types of insomnias, sleep-related dystonias; restless leg syndrome; sleep apneas; jet-lag syndrome; shift work sleep disorder, delayed or advanced sleep phase syndrome, or insomnias related to psychiatric disorders. In addition, sleep disorders further include sleep disorders associated with aging; intermittent treatment of chronic insomnia; situational transient insomnia (new environment, noise) or short-term insomnia due to stress; grief; pain or illness.

In the context of the present invention, it is to be understood that, in case certain environmental conditions such as stress or fear (wherein stress may be of social origin (e.g. social stress) or of physical origin (e.g. physical stress), including stress caused by fear) facilitate or precipitate any of the disorders or diseases as defined before, the present compounds may be particularly useful for the treatment of such environmentally conditioned disorder or disease.

Preparation of compounds of Formula (I):

The compounds of formulae (I), (II), (lla), and (lib) can be prepared 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 a new final product. These manipulations may include, but are not limited to, reduction, oxidation, alkylation, acylation, and hydrolysis 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.

Compounds of formulae (I), (II), (lla), and (lib) of the present invention can be prepared according to the general sequence of reactions outlined below wherein Ar¹ and (R⁵)_n are as defined for Formula (I).

The synthesis of compounds of Formula (I), starts from (a) which is commercially available.

There are two general synthetic approaches of equal importance towards compounds of Formula (I).

Synthetic approach 1 starts with a Boc-protection of the respective 2-methyl-morpholine derivative a under standard conditions by for example dissolving the 2-methyl-morpholine a in a solvent such as DCM or THF and adding a base to the solution, for example DIPEA, TEA or aqueous Na₂CC>₃ followed by the addition of B0C2O. The reaction is performed at RT and is usually complete within a few hours and results in the Boc-protected 2- methyl-morpholine derivative b which is then coupled with the appropriate phenylene-diamine-derivative in solvents such as THF, DCM or DMF in the presence of a coupling agent such as HBTU or TBTU or the like and a base, for example DIPEA or TEA to give compound c. To obtain the benzimidazole derivative d the precursor c is dissolved in AcOH and heated to 100°C for 1 h. Compound d is Boc-deprotected under acidic conditions such as 4M HCI in dioxane (preferred method) or TFA in DCM to give precursor e which is converted into final compound f by an amide coupling reaction with Ar¹-COOH in a solvent such as THF, DMF or DCM in the presence of a coupling agent such as TBTU, HBTU, HATU, EDC or the like and a base such as DIPEA, TEA or N- methylmorpholine.

Synthetic approach 2 starts with an esterification (usually methyl ester formation) of the 2-methyl-morpholine derivative a by dissolving the starting material in THF and adding 5 equivalents of the respective alcohol (usually MeOH) followed by the addition of EDC and DMAP. The reaction is run at RT and is usually complete within a few hours. The methyl-ester derivative g is acylated with Ar¹-COOH under conditions described above to result in intermediate h. Esterhydrolysis under standard conditions by dissolving the ester derivative h in THF / MeOH = 1 / 1 followed by the addition of 2 equivalents of aq. 1 M NaOH solution. The reaction runs at RT and is usually complete after a few hours to result in the carboxylic acid derivative i. The final compounds f are obtained via precursor j by applying the same conditions as described for the amide-coupling and the cyclization in synthetic approach 1.

Whenever the compounds of Formula (I) are obtained in the form of mixtures of stereoisomers such as especially enantiomers or diastereoisomers, the stereoisomers 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 Daicel ChiralPak AD-H (5 pm) column, a Daicel ChiralCel OD-H (5 pm) column, a Daicel ChiralCel OD (10 pm) column, a Daicel ChiralPak IA (5 miti) column, a Daicel ChiralPak IB (5 miti) column, a Daicel ChiralPak IC (5 miti) column, or a (R,R)-Whelk-01 (5 miti) column. Typical conditions of chiral HPLC are an isocratic mixture of eluent A (EtOH, in presence or absence of a base like TEA and/or diethylamine or of an acid like TFA) and eluent B (heptane, MeCN).

The following examples are provided to illustrate the invention. These examples are 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 specified, all reactions were carried 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 t_R 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 isomers, particularly visible in their LC-MS spectra, the retention time of the most abundant conformer is given. Racemates can be separated into their enantiomers by preparative HPLC (column: ChiralPaK IC 250x4.6 mm, 5 pm, 45% ethanol in heptane).

LC-MS with acidic conditions (conditions A)

Apparatus: Agilent 1100 series with mass spectroscopy detection (MS : Finnigan single quadrupole). Column: Waters XBridge C18 (2.5 pm, 4.6 x 30 mm). Conditions: MeCN [eluent A]; water + 0.04% TFA [eluent B] Gradient: 95% B ® 5% B over 1.5 min. (flow: 4.5 ml/min.). Detection: UV/Vis + MS.

LC-MS with basic conditions (conditions B)

Apparatus: Agilent 1100 series with mass spectroscopy detection (MS : Finnigan single quadrupole). Column: Waters XBridge C18 (5 pm, 4.6 x 50 mm). Conditions: MeCN [eluent A]; 13 mmol/l NH3 in water [eluent B] Gradient: 95% B ® 5% B over 1.5 min. (flow: 4.5 ml/min.). Detection: UV/Vis + MS.

Preparative HPLC for purification of compounds (conditions C)

Column: Waters XBridge (10 pm, 75 x 30 mm). Conditions: MeCN [eluent A]; water + 0.5% NH₄OH (25% aq.) [eluent B]; Gradient: 90% B ® 5% B over 6.5 min. (flow: 75 ml/min.). Detection: UV + ELSD.

Preparative HPLC for purification of compounds (conditions D)

Column: Waters Atlantis T3 OBD (10 pm, 75 x 30 mm). Conditions: MeCN [eluent A]; water + 0.5% HCOOH [eluent B]; Gradient: 90% B ® 5% B over 6.4 min. (flow: 75 ml/min.). Detection: UV + ELSD.

Abbrevations (as used herein and in the description above):

Ac Acetyl (such as in OAc = acetate, AcOH = acetic acid)

aq. aqueous

Boc ferf-Butoxycarbonyl

B0C2O di-ferf-Butyl dicarbonate Bu Butyl such as in tBu = ferf-butyl = tertiary butyl

DCM Dichloromethane

DIPEA Diisopropylethylamine

DMA A/,A/-Dimethylacetamide

DMF A/,/\/-Dimethylformamide

DMSO Dimethyl sulfoxide

ELSD Evaporative Light-Scattering Detection

eq Equivalent(s)

ES Electron spray

Et Ethyl

Et₂0 Diethyl ether

EtOAc Ethyl acetate

EtOH Ethanol

Ex. Example

FC Flash Chromatography on silica gel

FCS Foatal calf serum

h Hour(s)

HATU 1-[Bis(dimethylamino)methylene]-1/-/-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate

HBSS Hank’s balanced salt solution

HBTU L/, L/, L/', L/'-T etramethyl-0-( 1 /-/-benzotriazol-1 -yl)uron i u m hexafluorophosphate

HEPES 4-(2-Hydroxyethyl)-piperazine-1-ethanesulfonic acid

¹H-NMR Nuclear magnetic resonance of the proton

HPLC High performance liquid chromatography

LC-MS Liquid chromatography - Mass Spectroscopy

Lit. Literature

M Exact mass (as used for LC-MS)

Me Methyl

MeCN Acetonitrile

MeOH Methanol

mΐ microliter

min Minute(s)

MS Mass spectroscopy

N Normality

Pd(OAc)₂ Palladium diacetate

Pd(PPh₃) Tetrakis(triphenylphosphine)palladium(0)

Ph Phenyl RT Room temperature

sat. Saturated

TBTU 0-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate

TEA Triethylamine

TFA trifluoroacetic acid

THF Tetrahydrofuran

tR Retention time

UV Ultra violet The following examples illustrate the preparation of compounds of the invention but do not at all limit the scope thereof.

Preparation of precursors and intermediates:

Preparation of building blocks of formula Ar¹-CO-OH:

The preparation of these acids is described in detail for example in the following documents: WO2013/182972, WO 2008/020405; WO 2008/038251 ; WO 2008/081399; WO 2008/139416. All other carboxylic acids used in the experimental part which are not described in the following section are either commercially available or fully described in the literature listed above and in the introduction part.

In addition to commercially available building blocks, further particular building blocks of formula Ar¹-CO-OH may be prepared as decribed in WO2013/182972:

5-Aryl-2-methyl-thiazole-4-carboxylic acids.

These acids were prepared by a three-step sequence depicted in the scheme below, e.g. Darzens condensation of 4-fluoro-benzaldehyde 49 with methyl dichloroacetate to give the methyl keto-ester 50 (Hamamoto H. et al Tetrahedron Asymmetry 2000, 11 , 4485-4497) which is converted to the desired 5-(4-fluoro-phenyl)-2-methyl-4- carboxylic acid 51 by reaction with thioamide (US 3,282,927) followed by ester hydrolysis under basic conditions.

The following compounds can be prepared according to the same sequence:

Preparation of the Examples:

Synthesis of Example 4:

Step 1 :. rac-(3R^*,6R^*)-6-methylmorpholine-3-carboxylic acid hydrochloride (1686 mg; 8.82 mmol) is dissolved in a 1/1 mixture of MeCN / water (34 ml) followed by the addition of TEA (6.14 ml; 44.1 mmol). Stirring is continued for 10 min at rt followed by the dropwise addition of a solution of B0C2O (2139 mg; 9.7 mmol) in MeCN (8 ml) at 0°C. Stirring is continued at rt for 16 h. The reaction mixture is concentrated under reduced pressure followed by careful addition of +M aq sodium hydroxide solution to pH— 11. The solution was extracted twice with diethyl ether and the ether extracts were discarded. The remaining aqueous solution is carefully acidified with 1 M aq HCI to pH ~2 and the product is extracted with EtOAc (3x). The combined organic layers are dried over magnesium sulfate, filtered and the solvent is removed under reduced pressure to give 1.82 g of rac-(3R^*,6R^*)-4-(tert- butoxycarbonyl)-6-methylmorpholine-3-carboxylic acid which is used without further purification. LC-MS (A): t_R = 0.67 min; [M+H]⁺ = 246.2.

Step 2: rac-(3R^*,6R^*)-4-(tert-butoxycarbonyl)-6-methylmorpholine-3-carboxylic acid (222 mg; 0.905 mmol) is suspended in DCM (1.5 ml) and HATU (361 mg; 0.95 mmol) followed by DIPEA (0.395 ml; 0.226 mmol) are added and stirring is continued for 15 min. To this mixture, 6-chloro-2,3-diaminotoluene (157 mg; 0.95 mmol) dissolved in DCM (1.5 ml) is added and stirring at rt is continued for 16 h. The reaction mixture is concentrated under reduced pressure and the residue is dissolved in EtOAc and washed with brine. The organic layer is dried over magnesium sulfate, filtered and the solvent is removed under reduced pressure to give 350 mg of rac-tert- butyl-(2R^*,5R^*)-5-((6-amino-3-chloro-2-methylphenyl)carbamoyl)-2-methylmorpholine-4-carboxylate which is used without further purification in step 3. LC-MS (A): t_R = 0.91 min; [M+H]⁺ = 384.25.

Step 3: rac-tert-butyl-(2R*,5R*)-5-((6-amino-3-chloro-2-methylphenyl)carbamoyl)-2-methylmorpholine-4- carboxylate (350 mg; 0.905 mmol) is dissolved in 100% acetic acid (5 ml; 87.4 mmol) and heated to 100°C for 1 h. The reaction mixture is concentrated under reduced pressure and the residue is dissolved in DCM followed by slow and careful addition of sat. aq. sodium hydrogencarbonate solution until gaz evolution stopped. Phases are separated and the organic layer is washed with brine, dried over magnesium sulfate, filtered and the solvent is removed under reduced pressure. The crude compound is purified by preparative HPLC (Method C) to give 220 mg of rac-tert-butyl (2R^*,5S^*)-5-(5-chloro-4-methyl-1H-benzo[d]imidazol-2-yl)-2-methylmorpholine-4-carboxylate . LC-MS (A): t_R = 0.76 min; [M+H]⁺ = 366.24.

Step 4: rac-tert-butyl (2R^*,5S^*)-5-(6-chloro-7-methyl-1 H-benzo[d]imidazol-2-yl)-2-methylmorpholine-4-carboxylate (220 mg; 0.6 mmol) is dissolved in dioxane (1 ml) followed by the addition of 4M HCI in dioxane (1 ml; 4 mmol) and stirring is continued at rt for 3 h. The reaction mixture is evaporated to dryness to give 175 mg of rac- (2R^*,5S^*)-5-(5-chloro-4-methyl-1 H-benzo[d]imidazol-2-yl)-2-methylmorpholine. LC-MS (A): t_R = 0.6 min; [M+H]⁺ = 266.27.

Step 5: 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid (11.8 mg; 0.058 mmol) and HATU (22.5 mg; 0.059 mmol) are suspended in DMA (0.7 ml) followed by the addition of DIPEA (0.03 ml; 0.17 mmol) and of rac-(2R^*,5S^*)-5-(6- chloro-7-methyl-1 H-benzo[d]imidazol-2-yl)-2-methylmorpholine (15 mg; 0.056 mmol) dissolved in DMA (0.7 ml). Stirring is continued at rt for 16 h. The product is purified by preparative HPLC (Method C) to give 22.7 mg of rac- ((2R*,5S*)-5-(5-Chloro-4-methyl-1H-benzo[d]imidazol-2-yl)-2-methylmorpholino)(5-methyl-2-(2H-1,2,3-triazol-2- yl)phenyl)methanone (Example 4). LC-MS(A): t_R = 0.82 min; [M+H]⁺ = 451.14.

According to the procedures described herein before, the following examples are prepared:

LC-MS conditions used for analysis of the final compounds given in the Table below: Analytical. Pump: Waters Acquity Binary, Solvent Manager, MS: Waters SQ Detector, DAD: Acquity UPLC PDA Detector, ELSD: Acquity UPLC ELSD. Columns: Acquity UPLC CSH C18 1.7 urn, 2.1x50 mm from Waters, thermostated in the Acquity UPLC Column Manager at 60°C. Eluents: A1: H20 + 0.05% FA; B1: AcCN + 0.045% FA. Method: Gradient: 2% B 98% B over 2.0 min. Flow: 1.0 mL/min. Detection: UV 214nm and ELSD, and MS, t_R is given in min.

Two enantiomers of rac-[(2R^*,5S^*)-5-(5-Chloro-4-methyl-1 H-benzoimidazol-2-yl)-2-methyl-morpholin-4-yl]-(4,5- dimethyl-2-[1 ,2,3]triazol-2-yl-phenyl)-methanone (Example 2) have been separated using chiral HPLC to get [(2R,5S)-5-(5-Chloro-4-methyl-1 H-benzoimidazol-2-yl)-2-methyl-morpholin-4-yl]-(4,5-dimethyl-2-[1,2,3]triazol-2-yl- phenyl)-methanone (Example 2a) and [(2S,5R)-5-(5-Chloro-4-methyl-1 H-benzoimidazol-2-yl)-2-methyl- morpholin-4-yl]-(4,5-dimethyl-2-[1,2,3]triazol-2-yl-phenyl)-methanone (Example 2b). Chiral HPLC conditions: ChiralPak AD-H column 30x250 mm, 5pm; eluent A: CO2, temperature: 40°C, eluent B: MeCN/EtOH 1 :1 ; 100 bar; flow: 160 mL/min; (Example 2a) = 1.5 min, (Example 2b) = 2.4 min.

Two enantiomers of rac-[(2R^*,5R^*)-5-(5-Chloro-4-methyl-1 H-benzoimidazol-2-yl)-2-methyl-morpholin-4-yl]-(5- methoxy-2-[1 ,2,3]triazol-2-yl-phenyl)-methanone (Example 22) have been separated using chiral HPLC to get [(2R,5R)-5-(5-Chloro-4-methyl-1H-benzoimidazol-2-yl)-2-methyl-morpholin-4-yl]-(5-methoxy-2-[1 ,2,3]triazol-2-yl- phenyl)-methanone (Example 22a) and [(2S,5S)-5-(5-Chloro-4-methyl-1 H-benzoimidazol-2-yl)-2-methyl- morpholin-4-yl]-(5-methoxy-2-[1 ,2,3]triazol-2-yl-phenyl)-methanone (Example 22b). Chiral HPLC conditions: ChiralPak IH column 250x4.6 mm ID, 5pm; eluent A: 10% TBME, eluent B: 90% MeOH 0.1% DEA; flow: 0.8 mL/min; (Example 22a) = 5.6 min, (Example 22b) = 4.9 min.

Il-Bioloqical assays

Antagonistic activities on both orexin receptors have been measured for each example compound using the following procedure: In vitro assay: Intracellular calcium measurements:

Chinese hamster ovary (CHO) cells expressing the human orexin-1 receptor and the human orexin-2 receptor, respectively, are grown in culture medium (Ham F-12 with L-Glutamine) containing 300 mg/ml G418, 100 U/ml penicillin, 100 mg/ml streptomycin and 10 % heat inactivated fetal calf serum (FCS). The cells are seeded at 20Ό00 cells / well into 384-well black clear bottom sterile plates (Greiner). The seeded plates are incubated overnight at 37°C in 5% CO2.

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), NaHCOs: 0.375g/l and 20 mM HEPES for use in the assay at a final concentration of 3 nM.

Antagonists are prepared as 10 mM stock solution in DMSO, then diluted in 384-well plates using DMSO followed by a transfer of the dilutions into in HBSS containing 0.1 % bovine serum albumin (BSA), NaHCOs: 0.375g/l and 20 mM HEPES. On the day of the assay, 50 mI of staining buffer (HBSS containing 1% FCS, 20 mM HEPES, NaHCOs: 0.375g/l, 5 mM probenecid (Sigma) and 3 mM of the fluorescent calcium indicator fluo-4 AM (1 mM stock solution in DMSO, containing 10% pluronic) is added to each well. The 384-well cell-plates are incubated for 50 min at 37° C in 5% CO2 followed by equilibration at RT for 30 min before measurement.

Within the Fluorescent Imaging Plate Reader (FLIPR Tetra, Molecular Devices), antagonists are added to the plate in a volume of 10 mI/well, incubated for 120 min and finally 10 mI/well of agonist is added. Fluorescence is measured for each well at 1 second intervals, and the height of each fluorescence peak is compared to the height of the fluorescence peak induced by an approximate EC70 (for example 5 nM) of orexin-A with vehicle in place of antagonist. The IC50 value (the concentration of compound needed to inhibit 50 % of the agonistic response) is determined and may be normalized using the obtained IC50 value of a on-plate reference compound. Optimized conditions are achieved by adjustment of pipetting speed and cell splitting regime. The calculated IC50 values may fluctuate depending on the daily cellular assay performance. Fluctuations of this kind are known to those skilled in the art. Average IC50 values from several measurements are given as geometric mean values.

Antagonistic activities of example compounds with respect to the Oxi and the 0x₂ receptor are displayed in Table 1.

Table 1

Compounds of the present invention may be further characterized with regard to their general pharmacokinetic and pharmacological properties using conventional assays well known in the art; for example relating to their bioavailablility in different species (such as rat or dog); or relating to their ability to cross the blood-brain barrier, using for example a human P-glycoprotein 1 (MDR 1) substrate assay, or an in vivo assay to determine drug concentrations in the brain, e.g. in rats after oral dosing; or relating to their functional behavior in different disease related animal models {for example: the sedative effect of the compound using Electroencephalography (EEG) and Electromyography (EMG) signal measurments [F. Jenck et al., Nature Medicine 2007, 13 150-155]; the effect of the compound in the fear-potentiated startle paradigm [Fendt M et al., Neuroscience Biobehav Rev. 1999, 23, 743-760; W02009/0047723]; the effect of the compound on stress-induced hyperthermia [Vinkers CH et al., European J Pharmacol. 2008, 585, 407-425]; the effect of the compound on morphine-induced locomotor sensitization [Vanderschuren LJMJ et al., in Self DW, Staley JK (eds.) "Behavioral Neuroscience of Drug Addiction", Current Topics in Behavioral Neurosciences 3 (2009), 179-195] }; or for their properties with regard to drug safety and/or toxicological properties using conventional assays well known in the art, for example relating to cytochrome P450 enzyme inhibition and time dependent inhibition, pregnane X receptor (PXR) activation, glutathione binding, or phototoxic behavior. Measurement of brain and systemic concentration after oral administration:

In order to assess brain penetration, the concentration of the compound is measured in plasma ([P]), and brain ([B]), sampled 3 h (or at different time points) following oral administration (e.g. 100 mg/kg) to male wistar rats. The compounds are formulated e.g. in 100% PEG 400. Samples are collected in the same animal at the same time point (+/- 5 min). Blood is sampled from the vena cava caudalis into containers with EDTA as anticoagulant and centrifuged to yield plasma. Brain is sampled after cardiac perfusion of 10 mL NaCI 0.9% and homogenized into one volume of cold phosphate buffer (pH 7.4). All samples are extracted with MeOH and analyzed by LC- MS/MS. Concentrations are determined with the help of calibration curves.

Sedative effects: EEG, EMG and behavioural indices of alertness recorded by radiotelemetrv in vivo in Wistar rats.

Electroencephalography (EEG) and Electromyography (EMG) signals are measured by telemetry using TL11 M2- F20-EET miniature radiotelemetric implants (Data Science Int.) with two pairs of differential leads.

Surgical implantation is performed under general anesthesia with Ketamin/Xylazin, for cranial placement of one differential pair of EEG electrodes and one pair of EMG leads inserted in either side of the muscles of the neck. After surgery, rats recover in a thermoregulated chamber and receive analgesic treatment with subcutaneous buprenorphine twice a day for 2 d. They are then housed individually and allowed to recover for a minimum of 2 weeks. Thereafter, rats— in their home cage— are placed in a ventilated sound-attenuating box, on a 12-h light / 12-h dark cycle, for acclimatization before continuous EEG / EMG recordings started. The telemetric technology that we use allows accurate and stress-free acquisition of biosignals in rats placed in their familiar home cage environment, with no recording leads restricting their movements. Variables analyzed include four different stages of vigilance and sleep, spontaneous activity in the home cage and body temperature. Sleep and wake stages are evaluated using a rodent scoring software (Somnologica Science) directly processing electrical biosignals on 10 s contiguous epochs. The scoring is based on frequency estimation for EEG and amplitude discrimination for EMG and locomotor activity. Using these measurements, the software determines the probability that all components within each epoch best represent active waking (AW), quiet waking (QW), non-REM-sleep (NREM) or REM-sleep (REM). The percentage of total time spent in AW, QW, NREM- and REM-sleep is calculated per 12 h light or dark period. The latency to the onset of the first significant NREM- and REM-sleep episodes and the frequency and duration of those episodes are also calculated. AW, QW, NREM- and REM-sleep, home cage activity and body temperature are measured at baseline for at least one total circadian cycle (12 h-night, 12 h-day) before a test compound is administered. If baseline measurements indicate that animals are stable, test compound or vehicle is given in the evening by oral gavage at the end of the baseline 12- h day period, immediately before the nocturnal rise in orexin and activity in rats. All variables are subsequently recorded for 12 h following administration of the orexin receptor antagonist.

Claims

1. A compound of Formula (I)

Formula (I)

wherein

R¹ represents hydrogen or (Ci-₃)alkyl;

Ar¹ represents

> one of said substituents is attached in ortho-position to the point of attachment of Ar¹ to the rest of the molecule; wherein said substituent independently is phenyl or 5- or 6-membered heteroaryl; wherein said phenyl or 5- or 6-membered heteroaryl substituent is independently unsubstituted, mono-, di-, or tri-substituted, wherein the substituents are independently selected from (Ci^)alkyl, (Ci₄)alkoxy, halogen, cyano, (Ci-₃)fluoroalkyl, and ( C i -₃)f I u o roa I koxy ;

> and the other of said substituents, if present, is/are independently selected from (Ci^)alkyl;

(Ci )alkoxy; (C_3-6)cycloalkyl; halogen; cyano; (Ci -₃)fl uoroal ky I ; and (Ci-₃)fluoroalkoxy; and

(R⁵)_n represents one to three optional substituents independently selected from (Ci₄)alkyl, (Ci₄)alkoxy, halogen,

(Ci₄)alkyl-thio-, (Ci-₃)fluoroalkyl, ( C i -₃ )fl uo roal koxy , (Ci-₃)fluoroalkyl-thio-, and cyano;

or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 ; wherein the absolute configuration is as depicted in Formula (lla):

Formula (lla)

or a pharmaceutically acceptable salt thereof.

3. A compound according to claims 1 or 2; wherein R¹ is hydrogen;

or a pharmaceutically acceptable salt thereof.

4. A compound according to any one of claims 1 to 3; wherein the fragment

; wherein

R¹⁴, R¹⁵, R¹⁶ and R¹⁷ together represent one or two optional substituents, wherein

• R¹⁴ and R¹⁷ independently represent hydrogen, (Ci^)alkyl, (Ci-4)alkoxy, (Ci-4)alkyl-thio-, halogen, (Ci-3)fluoroalkyl; and

• R¹⁵ and R¹⁶ independently represent hydrogen, (Ci^)alkyl, (Ci-4)alkoxy, (Ci-4)alkyl-thio-, halogen, (Ci-3)fluoroalkyl, (Ci-3)fluoroalkoxy, (Ci-3)fluoroalkyl-thio-, or cyano;

or a pharmaceutically acceptable salt thereof.

5. A compound according to any one of claims 1 to 3; wherein the fragment

represents a group independently selected from:

or a pharmaceutically acceptable salt thereof.

6. A compound according to any one of claims 1 to 5; wherein Ar¹ represents phenyl or 5- or 6-membered heteroaryl selected from thiazolyl and pyridinyl, wherein said phenyl or 5- or 6-membered heteroaryl independently is mono-, di-, or tri-substituted; wherein

• and the other of said substituents, if present, is/are independently selected from methyl; methoxy; cyclopropyl; halogen; cyano; trifluoromethyl; and trifluoromethoxy;

or a pharmaceutically acceptable salt thereof.

7. A compound according to any one of claims 1 to 5; wherein

• Ar¹ represents 5-membered heteroaryl, which is di-substituted; wherein

o said ortho-substituent is phenyl which is mono-substituted, wherein the substituent is selected from (Ci_₄)alkyl, (Ci-₄)alkoxy, halogen, cyano, (Ci -₃)fl uoroal kyl , and (Ci-₃)fluoroalkoxy;

o or said ortho-substituent is 6-membered heteroaryl which is mono-substituted, wherein the substituent is selected from (Ci_₄)alkyl, (Ci₄)alkoxy, halogen, cyano, (Ci-₃)fluoroalkyl, and (Ci-₃)fluoroalkoxy;

(C_3-6)cycloalkyl; (Ci-₄)alkoxy, halogen, and (Ci-₃)fluoroalkyl;

• or Ar¹ represents 6-membered heteroaryl, which is di-substituted; wherein

o said ortho-substituent is unsubstituted 5-membered heteroaryl;

> and the other of said substituents, if present, is/are independently selected from (Ci₄)alkyl, (Ci )alkoxy, halogen, and (Ci -₃)fl uoroal kyl ;

• or Ar¹ represents phenyl which is mono-, di-, or tri-substituted; wherein

o said ortho-substituent is unsubstituted phenyl;

o or said ortho-substituent is unsubstituted 6-membered heteroaryl;

o or said ortho-substituent is unsubstituted 5-membered heteroaryl;

> and the other of said substituents, if present, is/are independently selected from (Ci₄)alkyl;

(Ci₄)alkoxy; (C_3-6)cycloalkyl; halogen; cyano; (Ci-₃)fluoroalkyl; ( C i -₃)f I uo roa I koxy ;

or a pharmaceutically acceptable salt thereof.

8. A compound according to any one of claims 1 to 5; wherein Ar¹ is a group independently selected from the following groups A, B, C, D, E, or F:

or a pharmaceutically acceptable salt thereof.

9. A compound according to claim 1 ; selected from the group consisting of:

[(2S,5R)-5-(5-Chloro4-methyl-1H-benzoimidazol-2-yl)-2-methyl-morpholin4-yl]-(2-fluoro-3-methoxy-6- [1 ,2,3]triazol-2-yl-phenyl)-methanone;

[(2S,5R)-5-(5-Chloro4-methyl H-benzoimidazol-2-yl)-2-methyl-morpholin4-yl]-(4,5-dimethyl-2-[1,2,3]triazol-2-yl- phenyl)-methanone;

[(2S,5R)-5-(5-Chloro4-methyl H-benzoimidazol-2-yl)-2-methyl-morpholin4-yl]-(5-methoxy-2-[1 ,2,3]triazol-2-yl- phenyl)-methanone;

[(2S,5R)-5-(5-Chloro4-methyl H-benzoimidazol-2-yl)-2-methyl-morpholin4-yl]-(5-methyl-2-[1,2,3]triazol-2-yl- phenyl)-methanone;

[(2S,5R)-5-(5-Chloro4-methyl H-benzoimidazol-2-yl)-2-methyl-morpholin4-yl]-(5-chloro-2-[1,2,3]triazol-2-yl- phenyl)-methanone;

[(2S,5R)-5-(5-Chloro4-methyl H-benzoimidazol-2-yl)-2-methyl-morpholin4-yl]-(5-methyl-2-pyrimidin-2-yl- phenyl)-methanone;

[(2S,5R)-5-(5-Chloro4-methyl H-benzoimidazol-2-yl)-2-methyl-morpholin4-yl]-[5-(6-methoxy-pyridin-3-yl)-2- methyl-thiazol4-yl]-methanone;

[(2S,5R)-5-(6-Chloro-5-trifluoromethyl-1 H-benzoimidazol-2-yl)-2-methyl-morpholin4-yl]-(4,5-dimethyl-2- [1 ,2,3]triazol-2-yl-phenyl)-methanone; [(2S,5R)-5-(5-Chloro-4-methyl-1 H-benzoimidazol-2-yl)-2-methyl-morpholin-4-yl]-(2-fluoro-3-methyl-6-[1 ,2,3]triazol- 2-yl-phenyl)-methanone;

[(2S,5R)-5-(5-Chloro-4-methyl-1 H-benzoimidazol-2-yl)-2-methyl-morpholin-4-yl]-[5-(4-fluoro-phenyl)-2-methyl- thiazol-4-yl]-methanone;

[(2S,5R)-5-(5-Chloro-4-methyl-1 H-benzoimidazol-2-yl)-2-methyl-morpholin-4-yl]-(4-methyl-2-[1 ,2,3]triazol-2-yl- phenyl)-methanone; and

[(2S,5R)-5-(5-Chloro-4-methyl-1 H-benzoimidazol-2-yl)-2-methyl-morpholin-4-yl]-(6-methyl-3-[1 ,2,3]triazol-2-yl- pyridin-2-yl)-methanone;

or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising, as active principle, one or more compounds according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert excipient.

11. A pharmaceutical composition according to claim 10 for use in the prevention or treatment of mental health diseases or disorders relating to orexinergic dysfunctions.

12. A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, for use as a medicament.

13. A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of diseases or disorders selected from sleep disorders, anxiety disorders, addiction disorders, cognitive dysfunctions, mood disorders, and appetite disorders.

14. Use of a compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the prevention or treatment of diseases or disorders selected from sleep disorders, anxiety disorders, addiction disorders, cognitive dysfunctions, mood disorders, and appetite disorders.

15. A method to treat a disease or disorder selected from a sleep disorder, an anxiety disorder, an addiction disorder, a cognitive dysfunction, a mood disorder, or an appetite disorder; comprising administering to a patient in need thereof, the compound of claim 1 or 9 in free or pharmaceutically acceptable salt form.