The present invention relates to novel cyclic hydrazine-N-carboxamide 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 a/., Cell, 1999, 98, 437-451).

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

In addition, both anatomical and functional evidence from in vitro and in vivo studies suggest an important positive interaction of the endogenous orexin system with reward pathways of the brain [Aston-Jones G et al., Brain Res 2010, 1314, 74-90; Sharf R et al., Brain Res 2010, 1314, 130-138], Selective pharmacological OXR-1 blockade reduced cue- and stress-induced reinstatement of cocaine seeking [Boutrel B, et al., "Role for hypocretin in mediating stress-induced reinstatement of cocaine-seeking behavior." Proc Natl Acad Sci 2005, 102(52), 19168- 19173; Smith RJ et al., "Orexin/hypocretin signaling at the orexin 1 receptor regulates cue-elicited cocaine-seeking." Eur J Neurosci 2009, 30(3), 493-503; Smith RJ et al., "Orexin/hypocretin is necessary for context-driven cocaine- seeking." Neuropharmacology 2010, 58(1), 179-184], cue-induced reinstatement of alcohol seeking [Lawrence AJ et al., Br J Pharmacol 2006, 148(6), 752-759] and nicotine self-administration [Hollander JA et al., Proc Natl Acad Sci 2008, 105(49), 19480-19485; LeSage MG et al., Psychopharmacology 2010, 209(2), 203-212], Orexin-1 receptor antagonism also attenuated the expression of amphetamine- and cocaine-induced OPP [Gozzi A et al., PLoS One 2011 , 6(1), e16406; Hutcheson DM et al., Behav Pharmacol 2011 , 22(2), 173-181], and reduced the expression or development of locomotor sensitization to amphetamine and cocaine [Borgland SL et al., Neuron 2006, 49(4), 589-601 ; Quarta D et al., "The orexin-1 receptor antagonist SB-334867 reduces amphetamine-evoked dopamine outflow in the shell of the nucleus accumbens and decreases the expression of amphetamine sensitization." Neurochem Int 2010, 56(1), 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 timelimited 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 (suppl_1) 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 cocaine seeking behaviour [Boutrel, B et al., Proc Natl Acad Sci 2005, 102(52), 19168-19173], In addition, stress is also known to play an integral part in withdrawal which occurs during cessation of drug taking (Koob, GF et al., Curr Opin Investig Drugs 2010, 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 Behav 2007, 91(4) 449-458], Animal models that are clinically relevant models of binge eating in humans are described for example in W. Foulds Mathes et al.; Appetite 2009, 52, 545-553.

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

The compound (2R)-2-{(1 S)-6,7-dimethoxy-1-[2-(4-trifluoromethyl-phenyl)-ethyl]-3,4- dihydro-1 H-isoquinolin-2-yl}- W-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 nondeclarative 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 (Ap) as well as Ap 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 Ap 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 Ap to Alzheimer's disease and, thus, to the cognitive dysfunction, expressed as impairment of learning and memory. The compound has also been shown to induce antidepressant-like activity in a mouse model of depression, when administered chronically [Nollet et al., NeuroPharm 2011 , 61 (1-2): 336-46], Moreover, the compound has been shown to attenuate the natural activation induced by orexin A in fasted hungry rats exposed to food odors [MJ Prud’homme et al., Neuroscience 2009, 162(4), 1287-1298], The compound also displayed pharmacological activity in a rat model of nicotine self-administration [LeSage MG et al., Psychopharmacology 2010, 209(2), 203-212], Another dual orexin receptor antagonist, N-biphenyl-2-yl-1-{[(1- methyl-1 H-benzi midazol-2-yl)sulfany l]acetyl}-L-prol i n amide 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, W02001/096302, 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, WO2010/060472, WO2010/063662, WO2010/063663, WO2010/072722, W02010/122151, 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, such compounds generally share a common structural feature, i.e. they contain central core ring such as a pyrrolidine, piperidine, or morpholine derivative, containing a chiral carbon center in position 2 that is substituted with an aromatic group, generally via a linker group. WO2013/182972 discloses pyrrolidine derivatives that have a benzimidazole ring directly attached to a pyrrolidine amide in position 2. It has now surprisingly been found that, despite the conformational changes that may be expected from the removal of a chiral center in the core ring structure of the compounds known in the art, the present pyrazolidinyl derivatives carrying particular substituents in position 1 and 2, may be potent dual orexin receptor antagonists.

The present invention, thus, provides novel substituted thiazoloaryl-methyl substituted cyclic hydrazine-W- carboxamide derivatives, which are dual non-peptide antagonists of the human orexin-1 and orexin-2 receptors. These compounds are in particular of potential use in the treatment of disorders relating to orexinergic dysfunctions, comprising especially sleep disorders including insomnias, as well as anxiety disorders, addiction disorders, cognitive dysfunctions, mood disorders, appetite disorders or neuropsychiatric symptoms in dementia. These compounds may have particular advantages such as bioavailability, capacity to cross the blood-brain barrier; and/or may have a particular metabolic and pharmacokinetic profile that may be of advantage for certain medical uses where controled periods of exposure to the active ingredient are required. 1) A first aspect of the invention relates to compounds of the Formula (I)

Formula (I) wherein

R ¹ represents (Ci-3)alkyl (especially methyl), halogen (especially chloro or bromo), cyclopropyl, or trifluoromethyl; [especially R ¹ represents methyl];

X ¹ represents S or 0; [especially X ¹ represents S];

X ² represents CH or N; [especially X ² represents CH];

Z represents -CH2-, -CHfCHs)-, or -CH2-CH2-; [especially Z represents -CH2- or -CHfCHs)-]; and in the fragment

• R ² independently represents hydrogen, (Ci-3)alkyl (especially methyl), halogen (especially chloro), or (Ci-3)alkoxy (especially methoxy);

[notably R ² represents methyl or chloro, especially chloro];

• R ³ independently represents hydrogen, or (Ci-3)alkyl (especially methyl) [especially R ³ represents hydrogen]; and

• Y independently represents CH or N;

[especially Y represents CH];

[wherein, in a sub-embodiment of this embodiment 1), said fragment

• Ar ¹ independently represents:

[especially Ar ¹ independently represents:

The compounds of Formula (I) may contain one or more stereogenic or asymmetric centers, such as one or more asymmetric carbon atoms, which may be present in (R)- or (S)-configuration. The compounds of Formula (I) may thus be present as mixtures of stereoisomers or preferably as pure stereoisomers. Mixtures of stereoisomers may be separated in a manner known to a person skilled in the art.

In case a particular compound (or generic structure) is designated as (R)- or (S)-enantiomer, 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 case a particular compound (or generic structure) contains one (or, likewise, more) stereogenic or asymmetric center(s), such as one (or more) asymmetric carbon atom(s), which may be present in (R)- or (S)-configuration, but where said stereogenic or asymmetric center(s) is/are not explicitly designated as (R)- or (S)-, it is understood that said stereogenic or asymmetric center may be in (R)- or (S)- configuration. Such compound name or generic structure is understood to encompass the compound / generic structure where such center is in (R)- or (S)- configuration, or any mixture of epimers with regard to such center including the racemate. Likewise, in case such stereogenic or asymmetric center is designated as being in (RS)- configuration, this means that such stereogenic or asymmetric center in such compound may be present in (R)- configuration, in (S)-configuration, or in any mixture of epimers with regard to such center including the racemate. In case two or more such stereogenic or asymmetric centers (in undesignated or designated (RS)-configuration) are present in one molecule, it is understood that the order of absolute configuration does not indicate any defined relative configuration with regard to the two or more centers.

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.

The present invention also includes isotopical ly labelled, especially ² H (hydrogen-2, deuterium) labelled compounds of Formula (I) according to embodiments 1) to 18), which compounds are identical to the compounds of Formula (I) except that one or more atoms have each been replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Isotopically labelled, especially ² H labelled compounds of Formula (I) and salts thereof are within the scope of the present invention. Substitution of hydrogen with the heavier isotope ² H 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. Typical positions generally considered suitable for introducing ² H atoms, for example to modify metabolic stability, are for example hydrogen atoms attached to a non-aromatic carbon atom that is directly bound to a heteroatom such as oxygen or nitrogen (e.g. a methoxy-da group replacing the methoxy in a methoxyphenyl group). In one embodiment of the invention, the compounds of Formula (I) are not isotopically labelled, or they are labelled only with one or more ² H atoms. In a sub-embodiment, the compounds of formula (I) are not isotopically labelled at all. Isotopically labelled compounds of Formula (I) may be prepared in analogy to the methods described hereinafter, but using the appropriate isotopic variation of suitable reagents or starting materials.

In this patent application, a bond drawn as a dotted line shows the point of attachment of the radical drawn. For example, the radical drawn below is a 3-methyl-phenyl group.

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

Any reference to compounds of Formula (I) according to 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 “Handbook of Pharmaceutical 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 Formula (I), as defined in any one of embodiments 1) to 18), 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.

Whenever a substituent is denoted as optional, it is understood that such substituent may be absent, in which case all positions having a free valency (to which such optional substituent could have been attached to; such as for example in an aromatic ring the ring carbon atoms and / or the ring nitrogen atoms having a free valency) are substituted with hydrogen where appropriate.

The term “halogen” means fluoro/fluorine, chloro/chlorine, bromo/bromine, or iodo/iodine; especially fluoro, chloro, or bromo. For the substituent R ¹ the term especially represents chloro or bromo. For the substituent R ² the term especially represents chloro.

The term “alkyl”, used alone or in combination and if not explicitly defined in a broader or more narrow way, refers to a saturated straight or branched chain hydrocarbon group containing one to four carbon atoms. The term “(Cx-y)alkyl” (x and y each being an integer), refers to an alkyl group as defined before, containing x to y carbon atoms. For example a (Cujalkyl group contains from one to four carbon atoms. Examples of alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert. -butyl. For avoidance of any doubt, in case a group is referred to as e.g. propyl or butyl, it is meant to be n-propyl, respectively n-butyl. Preferred are methyl and ethyl. Most preferred is methyl. The term “alkoxy”, used alone or in combination and if not explicitly defined in a broader or more narrow way, 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 (Cujalkoxy group means a group of the formula (Ci-4)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 are methoxy.

The term "fluoroalkyl”, used alone or in combination and if not explicitly defined in a broader or more narrow way, 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)fluoroalkyl” (x and y each being an integer) refers to a fluoroalkyl group as defined before containing x to y carbon atoms. For example a (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; especially trifluoromethyl. Preferred are (C-i)fluoroalkyl groups such as trifluoromethyl.

The term "cyano" refers to a group -CN.

The term “cycloalkyl”, used alone or in combination and if not explicitly defined in a broader or more narrow way, refers to a saturated monocyclic hydrocarbon ring containing three to eight carbon atoms. The term "(C _x.y )cycloalkyl " (x and y each being an integer), refers to a cycloalkyl containing x to y carbon atoms. For example, a (Cs-ejcycloalkyl group contains from three to six carbon atoms. A preferred example is cyclopropyl.

The term "aryl", used alone or in combination, means phenyl or naphthyl, especially phenyl. The above-mentioned aryl groups are unsubstituted or substituted as explicitly defined.

The term "heteroaryl", used alone or in combination, means a 5- to 10-membered monocyclic or bicyclic aromatic ring containing one to a maximum of four heteroatoms (especially one to a maximum three), each independently selected from N, 0, and S. Examples of such heteroaryl groups are 5-membered heteroaryl groups such as furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, and tetrazolyl; 6-membered heteroaryl groups such as pyridinyl, pyrimidinyl, pyridazinyl, and pyrazinyl; and 8- to 10-membered bicyclic heteroaryl groups such as indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, furopyridinyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, benzoxadiazolyl, benzothiadiazolyl, thienopyridinyl, quinolinyl, isoquinolinyl, naphthyridinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyrrolopyridinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrrolopyrazinyl, imidazopyridinyl, imidazopyridazinyl, and imidazothiazolyl. The above- mentioned heteroaryl groups are unsubstituted or substituted as explicitly defined.

Whenever the word “between” is used to describe a numerical range, it is to be understood that the end points of the indicated range are explicitly included in the range. For example: if a temperature range is described to be between 40 °C and 80 °C, this means that the end points 40 °C and 80 °C are included in the range; or if a variable is defined as being an integer between 1 and 4, this means that the variable is the integer 1, 2, 3, or 4. Unless used regarding temperatures, the term “about” placed before a numerical value “X” refers in the current application to an interval extending from X minus (10% of X) to X plus (10% of X), and preferably to an interval extending from X minus (5% of X) to X plus (5% of X). Likewise, the term “about” placed before a numerical range “X to Y” refers in the current application to an interval extending from X minus (10% of X) to Y plus (10% of Y), and preferably to an interval extending from X minus (5% of X) to Y plus (5% of Y). In the particular case of temperatures, the term “about” placed before a temperature “Y” refers in the current application to an interval extending from the temperature Y minus 10 °C to Y plus 10 °C, and preferably to an interval extending from Y minus 5 °C to Y plus 5 °C. The term “room temperature” as used herein refers to a temperature of about 25°C.

Further embodiments of the invention are presented hereinafter:

2) Another embodiment relates to compounds according to embodiment 1), wherein R ¹ represents methyl, chloro, bromo, cyclopropyl, or trifluoromethyl; [especially R ¹ represents methyl],

3) Another embodiment relates to compounds according to embodiment 1), wherein R ¹ represents methyl.

4) Another embodiment relates to compounds according to any one of embodiments 1) to 3), wherein

X ¹ represents S.

5) Another embodiment relates to compounds according to any one of embodiments 1) to 4), wherein

X ² represents CH.

6) Another embodiment relates to compounds according to any one of embodiments 1) to 5), wherein Z represents -CH ₂ - or -CH(CH ₃ )-.

7) Another embodiment relates to compounds according to any one of embodiments 1) to 6), wherein, in case Z represents -CHJCHs)-, such compound of Formula (I) has the absolute configuration depicted in Formula (IA) below:

Formula (IA);

(i.e. the chiral carbon atom of the pyrazolidinyl ring is in absolute (R)-configuration).

8) Another embodiment relates to compounds according to any one of embodiments 1) to 6), wherein Z represents -CH2-.

9) Another embodiment relates to compounds according to any one of embodiments 1) to 8), wherein in the fragment

• R ² independently represents hydrogen, methyl, chloro, or methoxy;

[notably R ² independently represents methyl or chloro, especially chloro];

• R ³ independently represents hydrogen or methyl

[especially R ³ independently represents hydrogen]; and

• Y independently represents CH or N;

[especially Y represents CH]; wherein each Ar ¹ independently is as defined in embodiment 1).

10) Another embodiment relates to compounds according to any one of embodiments 1) to 8), wherein the fragment wherein each Ar ¹ independently is as defined in embodiment 1).

11) Another embodiment relates to compounds according to any one of embodiments 1) to 10), wherein Ar ¹ independently represents a group selected from the groups A) to D):

A)

12) Another embodiment relates to compounds according to any one of embodiments 1) to 10), wherein Ar ¹ independently represents a group selected from the groups A) or B):

A)

13) Another embodiment relates to compounds according to any one of embodiments 1) to 10), wherein Ar ¹ independently represents:

14) Another embodiment relates to compounds according to any one of embodiments 1 ) to 8), wherein the fragment represents a group selected from the groups A) to F): 15) Another embodiment relates to compounds according to any one of embodiments 1) to 8), wherein the fragment represents a group selected from the groups A) to D):

16) Another embodiment relates to compounds according to any one of embodiments 1) to 8), wherein the fragment represents:

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

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

(5-methyl-2-(2/7-1 ,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)m ethyl)pyrazolidin-1-yl)methanone;

(5-methyl-2-(2/7-1 ,2,3-triazol-2-yl)phenyl)(2-((2-(trifluoromethyl)benzo[d]thi azol-6-yl)methyl)pyrazolidin-1- yl)methanone;

(2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thi azol-6-yl)methyl)pyrazolidin-1-yl)methanone;

(5-methoxy-2-(2/-/-1 ,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)m ethyl)pyrazolidin-1-yl)methanone;

(5-chloro-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2-methylbe nzo[d]thiazol-6-yl)methyl)pyrazolidin-1-yl)methanone;

(4,5-dimethyl-2-(2/7-1 ,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)m ethyl)pyrazolidin-1-yl)methanone;

(3'-methyl-[1 , 1 '-bi pheny l]-2-y I) (2-((2-methy I benzo[d]th i azol-6-yl) methy l)py razol id in- 1 -yl)methanone;

(5-methyl-2-(4-methyl-1 /-/-pyrazol-1-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)me thyl)pyrazolidin-1- yl)methanone;

(5-methyl-2-(3-methyl-1 /-/-pyrazol-1-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)me thyl)pyrazolidin-1- yl)methanone;

[1,1 '-biphenyl]-2-yl(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyr azolidin-1-yl)methanone;

(5-methyl-2-(2-methylthiazol-4-yl)phenyl)(2-((2-methylben zo[d]thiazol-6-yl)methyl)pyrazolidin-1-yl)methanone; (5-methyl-2-(4-methyl-2/7-1 ,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)m ethyl)pyrazolidin-1- yl)methanone;

(5-methyl-2-(thiazol-2-yl)pyridin-3-yl)(2-((2-methylbenzo [d]thiazol-6-yl)methyl)pyrazolidin-1 -yl)methanone;

(5-methyl-2-(1 /-/-pyrazol-1-yl)pyridin-3-yl)(2-((2-methylbenzo[d]thiazol-6 -yl)methyl)pyrazolidin-1-yl)methanone;

(5-chloro-2-(1 /-/-pyrazol-1-yl)pyridin-3-yl)(2-((2-methylbenzo[d]thiazol-6 -yl)methyl)pyrazolidin-1-yl)methanone;

(2-(4-bromo-2H-1 ,2,3-triazol-2-yl)-5-chlorophenyl)(2-((2-methylbenzo[d]thiaz ol-6-yl)methyl)pyrazolidin-1 - yl)methanone;

(2-(4-chloro-1 /-/-pyrazol-1-yl)-5-methylpyridin-3-yl)(2-((2-methylbenzo[d] thiazol-6-yl)methyl)pyrazolidin-1- yl)methanone;

(5-chloro-2-(4-methyl-1 H-pyrazol-1 -yl)pyridin-3-yl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)py razolidin-1 - yl)methanone;

(2-(2/-/-1,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]t hiazol-6-yl)methyl)tetrahydropyridazin-1(2H)-yl)methanone;

(5-chloro-2-(2/7-1 ,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[c/]thiazol-6-yl) methyl)tetrahydropyridazin-1 (2/7)- yl)methanone;

(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2-methylbe nzo[d]thiazol-6-yl)methyl)tetrahydropyridazin-1(2H)- yl)methanone;

(5-chloro-2-(4-methyl-2/7-1 ,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)m ethyl)pyrazolidin-1- yl)methanone;

(5-chloro-2-(4-ethynyl-2/7-1 ,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[c/]thiazol-6-yl) methyl)pyrazolidin-1 - yl)methanone;

(2-((2-bromobenzo[d]thiazol-6-yl)methyl)pyrazolidin-1-yl) (5-chloro-2-(2/7-1 ,2,3-triazol-2-yl)phenyl)methanone;

(5-chloro-2-(2/7-1 ,2,3-triazol-2-yl)phenyl)(2-((2-methylthiazolo[5,4-b]pyridin -5-yl)methyl)pyrazolidin-1- yl)methanone;

(5-chloro-2-(2/7-1 ,2,3-triazol-2-yl)phenyl)(2-((2-chlorobenzo[d]thiazol-6-yl)m ethyl)pyrazolidin-1-yl)methanone;

(5-chloro-2-(2/7-1 ,2,3-triazol-2-yl)phenyl)(2-((2-(trifluoromethyl)benzo[d]thi azol-6-yl)methyl)pyrazolidin-1- yl)methanone;

(5-chloro-2-(2/7-1 ,2,3-triazol-2-yl)phenyl)(2-((2-cyclopropylbenzo[d]thiazol-6 -yl)methyl)pyrazolidin-1 - yl)methanone;

(5-chloro-2-(2/7-1 ,2,3-triazol-2-yl)phenyl)(2-((2-ethylbenzo[d]thiazol-6-yl)me thyl)pyrazolidin-1-yl)methanone;

(/?)-(5-chloro-2-(2H-1,2,3-triazol-2-yl)phenyl)(4-methyl- 2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1- yl)methanone;

(S)-(5-chloro-2-(2/-/-1,2,3-triazol-2-yl)phenyl)(4-methyl -2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1- yl)methanone;

(R)-4-methyl-2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyra zolidin-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2- yl)phenyl)methanone; (S)-4-methyl-2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazol idin-1-yl)(5-methyl-2-(2/-/-1,2,3-triazol-2- yl)phenyl)methanone;

(S)-(2-(4-bromo-2/7-1,2,3-triazol-2-yl)-5-chlorophenyl)(4 -methyl-2-((2-methylbenzo[d]thiazol-6- yl)methyl)pyrazolidin-1-yl)methanone;

(R)-(2-(4-bromo-2H-1 ,2,3-triazol-2-yl)-5-chlorophenyl)(4-methyl-2-((2-methylbenz o[d]thiazol-6- yl)methyl)pyrazolidin-1-yl)methanone;

(5-methyl-2-(2H-1 ,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]oxazol-6-yl)me thyl)pyrazolidin-1-yl)methanone; (2-(2/-/-1,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thia zol-6-yl)methyl)pyrazolidin-1-yl-4,4-d2)methanone;

(5-methyl-2-(2/7-1 ,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)m ethyl)pyrazolidin-1-yl-4,4- cymethanone;

(5-chloro-2-(2/-/-1 ,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)m ethyl)pyrazolidin-1 -yl-4,4- cymethanone;

(5-chloro-2-(2/7-1 ,2,3-triazol-2-yl-d)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl )methyl)pyrazolidin-1-yl)methanone; and

(R)-(5-chloro-2-(2/-/-1 ,2,3-triazol-2-yl-d)phenyl)(4-methyl-2-((2-methylbenzo[d]thi azol-6-yl)methyl)pyrazolidin-1- yl)methanone.

The compounds of Formula (I) 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 Formula (I) according to any one of embodiments 1) to 18).

The terms “subject”, and likewise, “patient” refers to mammals, especially humans. Preferably, the term “subject” refers to the term “patient”.

The term “prevention” as used in the present disclosure may be understood to mean and is therefore interchangeable with the term “prophylaxis”.

For avoidance of any doubt, if compounds are described as useful for the prevention / prophylaxis or treatment of certain diseases, such compounds are likewise suitable for use in the preparation of a medicament for the prevention / prophylaxis or treatment of said diseases. Likewise, such compounds are also suitable in a method for the prevention / prophylaxis or treatment of such diseases, comprising administering to a subject (mammal, especially human) in need thereof, an effective amount of such compound.

The compounds according to Formula (I) 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 especially including insomnias, as well as anxiety disorders, addiction disorders, cognitive dysfunctions, mood disorders, appetite disorders and neuropsychiatric symptoms in dementia. In one sub-embodiment, the above mentioned disorders comprise especially anxiety disorders, addiction disorders, mood disorders and neuropsychiatric symptoms in dementia, notably anxiety disorders and addiction disorders. In another sub-embodiment, the above mentioned disorders comprise especially sleep disorders, in particular insomnias.

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

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.

Neuropsychiatric symptoms (NPS) in dementia (e.g. Alzheimer’s disease (AD), frontotemporal dementia (FTD), dementia with Lewy bodies (DLB), vascular dementia, other dementias, a pre-dementia cognitive impairment syndrome such as mild cognitive impairment or other cognitive disorder; especially a dementia of Alzheimer's type, in particular AD) are defined as circadian syndromes of increased confusion and restlessness in a patient, wherein said patient has some form of dementia (especially a dementia of Alzheimer's type, in particular AD). Such circadian syndromes especially occur late-day, i.e. in the afternoon and / or evening hours. Cardinal clinical signs include increased agitation, general confusion and mood swings; such signs developing typically as natural light begins to fade.

Neuropsychiatric symptoms in dementia (especially in a dementia of Alzheimer's type, in particular in AD) especially refers to agitation and/or aggression associated with such dementia (sometimes equivalently named sundown syndrome).

The term “agitation” is used to describe a wide range of behaviors that include verbal outbursts, physical aggression, intense anxiety and crying, and persistent perambulation and wandering (Kales et al., J Am Geriatr Soc. 2014;62(4):762-9; Phan et al., Drugs in R&D (2019) 19:93-115). The International Psychogeriatric Association (IPA) compiled a syndromic definition of agitation (see for example N. Stocking: excerpted article as reprint from IPA’s newsletter, the IPA Bulletin, Vol 31(4): https://www.ipa-online.org/news-and-issues/defining- agitation):

• The patient meets criteria for a cognitive impairment or dementia syndrome (e.g. Alzheimer’s disease (AD), frontotemporal dementia (FTD), dementia with Lewy bodies (DLB), vascular dementia, other dementias, a pre-dementia cognitive impairment syndrome such as mild cognitive impairment or other cognitive disorder).

• The patient exhibits at least one of the following behaviors that are associated with observed or inferred evidence of emotional distress (e.g. rapid changes in mood, irritability, outbursts). The behavior has been persistent or frequently recurrent for a minimum of two weeks and represents a change from the patient’s usual behavior.

(a) Excessive motor activity (examples include: pacing, rocking, gesturing, pointing fingers, restlessness, performing repetitious mannerisms).

(b) Verbal aggression (e.g. yelling, speaking in an excessively loud voice, using profanity, screaming, shouting).

(c) Physical aggression (e.g. grabbing, shoving, pushing, resisting, hitting others, kicking objects or people, scratching, biting, throwing objects, hitting self, slamming doors, tearing things, and destroying property).

• Behaviors are severe enough to produce excess disability, which in the clinician’s opinion is beyond that due to the cognitive impairment and including at least one of the following:

(a) Significant impairment in interpersonal relationships.

(b) Significant impairment in other aspects of social functioning.

(c) Significant impairment in ability to perform or participate in daily living activities.

• While co-morbid conditions may be present, the agitation is not attributable solely to another psychiatric disorder, suboptimal care conditions, medical condition, or the physiological effects of a substance.

The term "late day" referred to herein relates to the afternoon and evening, notably the time about sunset and later (but not including the night / the sleep time); for example, the time from about 4 pm to about 10 pm, especially from about 4 pm to about 9 pm. In one sub-embodiment, the term relates to the afternoon, especially from about 4 pm to about 7 pm; in another sub-embodiment the term relates to the evening, especially from about 7 pm to about 10 pm, especially from about 7 pm to about 9 pm.

Dementias include notably dementias of Alzheimer's type including: Alzheimer dementia (presenile dementia or senile dementia), subcortical dementia, (diffuse) Lewy body dementia, and frontotemporal dementia. Dementias further include dementias of vascular type such as: vascular dementia, multi-infarct dementia, Binswanger's dementia, boxer's dementia, arteriosclerotic dementia. Remaining types of dementia (9%) are of other etiologies such as paralytic dementia, substance-induced persisting dementia, dialysis dementia, hydrocephalic dementia, and dementias due to tumors, subdural hematoma, normal pressure hydrocephalus, vasculitis, Vitamin deficiency, or endocrine or metabolic disease. In the context of the present invention, the term preferably refers to dementias of Alzheimer's type, especially to Alzheimer dementia. It is understood that the term dementia also includes any combination of the above listed types of dementias.

Appetite disorders comprise eating disorders and drinking disorders. 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 payability); disturbed food availability (unrestricted diet or deprivation) or disrupted water balance. Drinking disorders include polydipsias in psychiatric disorders and all other types of excessive fluid intake. 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 nervosa (bulimia) or anorexia nervosa. The term "eating disorder" in particular refers to Binge-Eating Disorder (BED); Bulimia Nervosa (BN); Anorexia Nervosa (AN) (notably binge-eating/purging type Anorexia Nervosa; especially binge-eating type Anorexia Nervosa); Pica; Other Specified Feeding and Eating Disorders (OSFED) [notably atypical Bulimia Nervosa, Binge-Eating Disorder of low frequency and/or limited duration, Bulimia Nervosa of low frequency and/or limited duration, or Night Eating Syndrome (NES)]; Unspecified Feeding or Eating Disorder (UFED); Eating Disorder Not Otherwise Specified (EDNOS); and Compulsive Overeating (CO); Loss of Control (LOG) Eating; and hyperphagia and/or binge-eating associated with Prader-Willi Syndrome (PWS). Eating disorders refer especially to such eating disorders comprising a compulsive, binge eating behavior. It is understood that the term “eating disorder comprising a compulsive, binge eating behavior” refers to a disorder comprising recurring episodes of binge eating, i.e. recurring episodes when a subject is eating significantly more food in a short period of time than most people would eat under similar circumstances, with episodes marked by feelings of lack of control. Eating disorder comprising a compulsive, binge eating behavior is characterized by eating large amounts of food, by eating quickly (often to the point of discomfort), and by eating even when no longer hungry. The American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders (DSM-5® or herein also referred to as DSM-5) provides diagnostic criteria for certain feeding and eating disorders. Binge-Eating Disorder (BED) is defined as recurring episodes of eating significantly more food in a short period of time than most people would eat under similar circumstances, with episodes marked by feelings of lack of control. Someone with binge eating disorder may eat too quickly, even when they are not hungry. The person may have feelings of guilt, embarrassment, or disgust and may binge eat alone to hide the behaviour. BED is associated with marked distress and significant physical, emotional, and social health risks such as obesity and extreme weight gain and a wide range of associated diseases such as sleep apnea, cancer, heart disease, high blood pressure, type 2 diabetes, arthritis, etc., being among the most common ones.

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 especially dyssomnias and sleep disorders associated with a general medical condition, as well as parasomnias, and substance-induced sleep disorders. Dyssomnias in particular include intrinsic sleep disorders (especially insomnias, breathing-related sleep disorders, periodic limb movement disorder, and restless leg syndrome), extrinsic sleep disorders, and circadian-rhythm sleep disorders. Sleep disorders notably refer to insomnias including primary insomnia and idiopathic insomnia; intermittent treatment of chronic insomnia; situational transient insomnia (e.g. insomnia associated to a new environment or noise); (short-term) insomnia due to stress, grief, pain or illness; and insomnias related to mental or neurologic disorders including insomnias associated with mood disorders (such as depressive disorders), epilepsy, autism spectrum disorders, attention deficit hyperactivity disorder (ADHD), and cerebral degenerative disorders including Alzheimer's disease and other neurodegenerative and/or cognitive impairment diseases or disorders. In addition, sleep disorders notably refer to dyssomnias such as breathing-related sleep disorders including (obstructive or central) sleep apnea syndrome; periodic limb movement disorder (nocturnal myoclonus); restless leg syndrome; circadian rhythm sleep disorders including shift work sleep disorder; and time-zone-change (jet-lag) syndrome. Sleep disorders further refer to REM sleep interruptions. 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 as defined before, as well as sleep-related dystonias; restless leg syndrome; sleep apneas; jet-lag syndrome; shift work sleep disorder and delayed or advanced sleep phase syndrome. In addition, sleep disorders further include sleep disorders associated with aging.

Sleep disorders associated with a general medical condition include sleep disorders (especially insomnias) related to mental or neurologic disorders; notably sleep disorders (especially insomnias) associated with mood disorders (such as depressive disorders), epilepsy, autism spectrum disorders, attention deficit hyperactivity disorder (ADHD), and cerebral (neuro-)degenerative disorders including Alzheimer's disease and other neurodegenerative and/or cognitive impairment diseases or disorders; as well as sleep disorders (especially insomnias) associated with anxiety disorders, addiction disorders, or appetite disorders.

A particular aspect of the invention relates to a compound of Formula (I) according to any one of embodiments 1) to 18) for use in the treatment of disorders relating to orexinergic dysfunctions, especially of sleep disorders as defined herein above (in particular any type of insomnia as defined herein above, breathing-related sleep disorders including sleep apnea syndrome; periodic limb movement disorder; restless leg syndrome; circadian rhythm sleep disorders including shift work sleep disorder; and time-zone-change syndrome); wherein said treatment comprises the administration of a compound of Formula (I) according to any one of embodiments 1) to 18), wherein said compound is (to be) administered during the night, notably less than 7 hours prior to the morning / wake time; especially between about 7 hours to 2 hours prior to the morning / wake time; in particular about 4 hours to 2 hours prior to the morning / wake time.

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

Preparation of compounds of Formula (I):

The compounds of formula (I), 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 the schemes below, the generic groups Ar ¹ , R ¹ , R ² , R ³ , X ¹ , X ² , Y, and Z are as defined for the compounds of formula (I). In some instances the generic groups Ar ¹ , R ¹ , R ² , R ³ , X ¹ , X ² , Y, and Z may be incompatible with the assembly illustrated in the schemes, or will require the use of protecting groups (PG). The use of protecting groups is well known in the art (see for example “Protective Groups in Organic Synthesis", T.W. Greene, P.G.M. Wuts, Wiley-lnterscience, 1999). For the purposes of this discussion, it will be assumed that such protecting groups as necessary are in place. 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. The compounds obtained may also be converted into salts, especially pharmaceutically acceptable salts in a manner known per se.

Compounds of formula (I) of the present invention can be prepared according to the general sequence of reactions outlined below.

General reaction techniques:

General reaction technique 1 (amide bond formation): The carboxylic acid is reacted with the hydroxylamine or amine derivative in the presence of an activating agent such as DCC, EDC, HOBT, n-propylphosphonic cyclic anhydride, HATU or DSC, in a dry aprotic solvent such as DCM, MeCN or DMF between 20°C and 60°C (see G. Benz in Comprehensive Organic Synthesis, B.M. Trost, I. Fleming, Eds; Pergamon Press: New York (1991), vol. 6, p. 381). Alternatively, the carboxylic acid can be activated by conversion into its corresponding acid chloride by reaction with oxalyl chloride or thionyl chloride neat or in a solvent like DCM between 20° and 60°C. Further activating agents can be found in R. C. Larock, Comprehensive Organic Transformations. A guide to Functional Group Preparations, 2nd Edition (1999), section nitriles, carboxylic acids and derivatives, p. 1941-1949 (Wiley VC; New York, Chichester, Weinheim, Brisbane, Singapore, Toronto).

General reaction technique 2 (reductive amination):

The reaction between the amine and the aldehyde or ketone is performed in a solvent system allowing the removal of the formed water through physical or chemical means (e.g. distillation of the solvent-water azeotrope or presence of drying agents such as molecular sieves, MgSO4 or Na2SO4). Such solvent is typically toluene, Hex, THF, DCM or DCE or a mixture of solvents such as DCE/MeOH. The reaction can be catalyzed by traces of acid (usually AcOH). The intermediate imine is reduced with a suitable reducing agent (e.g. NaBH4, NaBHsCN, or NaBH(OAc)3 or through hydrogenation over a noble metal catalyst such as Pd/C. The reaction is carried out between -10°C and 110°C, preferably between 0°C and 60°C. The reaction can also be carried out in one pot. It can also be performed in protic solvents such as MeOH or water in presence of a picoline-borane complex (Tetrahedron (2004), 60, 7899- 7906).

General reaction technique 3: alkylation:

The NH-containing derivative is reacted with an alkylating agent compound of formula G-CH2-LG, wherein G has the same meaning as in Formula (I) and LG represents OMs, OTf, OTs, Cl, Br or I, in presence of an inorganic base such as K2CO3 or an org. base such as TEA in a solvent such as THF, MeCN or DMF between 0°C and +80°C. Iodide salts such as sodium iodide or tetrabutyl ammonium iodide can be added to promote the nucleophilic substitution reaction. Further details can be found in Comprehensive Organic Transformations. A guide to Functional Group Preparations; 2nd Edition, R. C. Larock, Wiley-VC; New York, Chichester, Weinheim, Brisbane, Singapore, Toronto, (1999). Section Amines p.779.

General reaction technique 4 (Suzuki cross-coupling reaction):

The aromatic halide (typically a bromide) is reacted with the required boronic acid derivative or its boronate ester equivalent (e.g. pinacol ester) in the presence of a palladium catalyst and a base such as K2CO3, CS2CO3, K3PO4, tBuONa or tBuOK between 20 and 120°C in a solvent such as toluene, THF, dioxane, DME or DMF, usually in the presence of water (20 to 50%). Examples of typical palladium catalysts are triarylphosphine palladium complexes such as Pd(PPh3)4. These catalysts can also be prepared in situ from a common palladium source such as Pd(OAc)2 or Pd2(dba)3 and a ligand such as trialkylphosphines (e.g. PCys or P(tBu)3), dialkylphosphinobiphenyls (e.g. S- Phos) or ferrocenylphosphines (e.g. Q-phos). Alternatively, one can use a commercially available precatalyst based on palladacycle (e.g. SK-CC01-A) or N heterocyclic carbene complexes (e.g. PEPPSITM-IPr). The reaction can also be performed by using the corresponding aromatic tritiate. Further variations of the reaction are described in Miyaura and Suzuki, Chem. Rev. (1995), 95, 2457-2483, Beilina et al., Synthesis (2004), 2419-2440, Mauger and Mignani, Aldrichimica Acta (2006), 39, 17-24, Kantchev et al., Aldrichimica Acta (2006), 39, 97 111, Fu, Acc. Chem. Res. (2008), 41, 1555-1564, and references cited therein.

Preparation of compounds of Formula (I):

Compounds of general Formula (I) can be prepared reacting carboxylic acids of structure 1-1 with NH-containing intermediates of structure I-2 using one of the carbon- nitrogen bond formation methods reported in general reaction technique 1 (Scheme 1). Scheme 1

Alternatively, compounds of general Formula I can be prepared via a carbon-nitrogen bond formation reaction involving the NH-containing compounds of structure 11-1 and either an aldehyde intermediate of structure 11-2 using general reaction technique 2 or an alkylating agent of structure 11-3 using general reaction technique 3 (Scheme 2). Scheme 2

Compounds of general Formula I can also be prepared via a cross-coupling reaction involving compounds of structure 111-1 with a boron derivative of structure-l 11-2 using general reaction technique 3 (Scheme 3).

111-1

I

In Scheme 3, LG ¹ represents a leaving group selected from -OTf, -I, -Br or -Cl. D ¹ and D ² represent H, methyl or ethyl or D ¹ and D ² together represent CH2C(Me)2CH2 or C(Me)2C(Me)2 Compounds of general Formula I can also be prepared via a cross-coupling reaction involving compounds of structure IV-1 with a boron derivative of structure-IV-2 using general reaction technique 4 (Scheme 4).

Scheme 4

In Scheme 4, D ¹ and D ² represent H, methyl or ethyl or D ¹ and D ² together represent CH2C(Me)2CH2 or C(Me) ₂ C(Me) ₂

Compounds of general Formula I can also be prepared reacting compounds of structure V-1 with a di-bromide of structure V-2 in presence of a base such as K3PO4 in acetonitrile at a temperature ranging between 60°C and 90°C. (Scheme 5).

Preparation of compounds of structure 1-2, 11-1, 111-1, IV-1 and V-1 :

Compounds of structure I-2 can be prepared via a carbon-nitrogen bond formation reaction involving the NH- containing compounds of structure VI-1 and either an aldehyde intermediate of structure 11-2 using general reaction technique 2 or an alkylating agent of structure 11-3 using general reaction technique 3. The resulting intermediates of structure VI-2 can be subsequently transformed to compounds of structure I-2 by cleavage of PGi. Depending on the nature of PGi, any suitable methods reported in Protecting Groups, Kocienski, P.J. Georg Thieme Verlag Stuttgart-New-York (1994) can be used. For instance, when PGi = Boc, treatment with HCI in dioxane, or alternatively TFA in DCM can be used (Scheme 6).

Scheme 6

In Scheme 6, Ar ¹ , PGi is a protecting group such as Boc.

Compounds of structure 11-1 can be prepared reacting the carboxylic acid of structure 1-1 with the NH-containing intermediate of structure VI-1 using one of the carbon- nitrogen bond formation methods reported in general reaction technique 1 . The resulting intermediates of structure VI 1-1 can be subsequently transformed to compounds of structure 11-1 by cleavage of PGi. Depending on the nature of PGi, any suitable methods reported in Protecting Groups, Kocienski, P.J. Georg Thieme Verlag Stuttgart-New-York (1994) can be used. For instance, when PGi = Boc, a treatment with HCI in dioxane, or alternatively TFA in DCM can be used (Scheme 7).

In Scheme 7, PGi is a protecting group such as Boc.

Alternatively, compounds of structure 11-1 can be prepared by reacting compounds of structure VI 11-1 with carboxylic acids of structure 1-1 using one of the carbon- nitrogen bond formation methods reported in general reaction technique 1. The resulting intermediates of structure VIII-2 can be subsequently transformed to compounds of structure VII-1 by reaction with the di-bromide of structure V-2 in presence of a base such as K3PO4 in acetonitrile at a temperature ranging between 60°C and 90°C. Finally, the compounds of structure VII-1 can be transformed to compounds of structure 11-1 using the abovementioned methods. (Scheme 8) Scheme 8

In Scheme 8, PGi is a protecting group such as Boc.

Compounds of structure 111-1 can be prepared as described in Scheme I for the preparation of compounds of general

Formula I, replacing the carboxylic acids of structure 1-1 by carboxylic acids of structure IX- 1 wherein LGi is a leaving group such as OTf, -I, -Br or -Cl. R ² , R ³ and Y have the same meaning as in formula I Compounds of structure IV- 1 can be prepared as described in Scheme 2 for the preparation of compounds of general Formula I, replacing aldehydes of structure II-2 or alkylating agents of structure II-3 by aldehydes of structure X-1 or alkylating agents of structure X-2 respectively, -Br or -Cl. X ¹ and X ² have the same meaning as in formula I

Compounds of structure V-1 can be obtained from compounds of structure VIII-2, first cleaving PGi. Depending on the nature of PGi, any suitable methods reported in Protecting Groups, Kocienski, P.J. Georg Thieme Verlag Stuttgart-New-York (1994) can be used. For instance, when PGi = Boc, a treatment with HCI in dioxane, or alternatively TFA in DCM can be used. The resulting compounds of XI-1 can eventually be transformed to compounds of structure V-1 by reacting it with aldehydes of structure II-2 using general reaction technique 2 (Scheme 9).

Scheme 9

In Scheme 9, PGi is a protecting group such as Boc

Compounds of structures 1-1, II-2, II-3, III-2, IV-2, V-2, VI-1, VI 11-1 , IX-1 , X-1 and X-2 are either commercially available or prepared in analogy to procedures well known in the art or procedures disclosed in the experimental part.

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. Unless otherwise stated, reaction mixtures are quenched with an appropriate aqueous medium and extracted with an appropriate organic solvents. The organic extracts are combined, washed with a minimal volume of brine, dried over sodium sulfate, filtered and concentrated to dryness to afford a so-called evaporation residue Compounds were obtained after purification of the evaporation residue using either flash column chromatography on silica gel or a preparative HPLC method. Compounds described in the invention are characterised by LC-MS data (retention time IR 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).

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

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

Acac acetyl acetonate aq. aqueous

Boc tert-Butoxycarbonyl

BOC2O di-fert-Butyl dicarbonate

Bu Butyl such as in tBu = tert-butyl = tertiary butyl

Carb, acid carboxylic acid comm. commercial

DCM Dichloromethane

DI PEA Diisopropylethylamine

DMA W,W-Dimethylacetamide

DMF W,W-Dimethylformamide

DMSO Dimethyl sulfoxide dppf bis(diphenylphosphino)ferrocene

ELSD Evaporative Light-Scattering Detection eq Equivalent(s)

ES Electron spray

Et Ethyl

Et20 Diethyl ether

EtOAc Ethyl acetate

EtOH Ethanol

Ex. Example / compound of Example

FC Flash Chromatography on silica gel

FCS Foatal calf serum h Hour(s)

HATU 1-[Bis(dimethylamino)methylene]-1/7-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate

HBSS Hank’s balanced salt solution HBTU A/,A/,A/',A/'-Tetramethyl-O-(1 H-benzotriazol-1 -yl)uronium hexafluorophosphate

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

¹ H-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 pil microliter min Minute(s)

MS Mass spectroscopy

N Normality

Pd(OAc)2 Palladium diacetate

Pd(PPh3)4 Tetrakis(triphenylphosphine)palladium(0)

Ph Phenyl prep. preparative r.t. Room temperature sat. Saturated

TBTU O-(Benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium tetrafluoroborate

TEA Triethylamine

TFA trifluoroacetic acid

THF Tetrahydrofuran tR Retention time

UV Ultra violet

Analytical conditions for LC-MS

Unless notified otherwise, the following conditions were used for analytical LC-MS data:

(A)

Apparatus: Agilent 1100 series with mass spectroscopy detection (MS : Finnigan single quadrupole). Column: Zorbax RRHD SB-Aq (1 .8 pm, 2.6 x 50 mm). Conditions: MeCN [eluent A]; water + 0.04% TFA [eluent B], Gradient: 95% B — > 5% B over 1 .5 min. (flow: 4.5 ml/min.). Detection: UVA/is + MS.

(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: UVA/is + MS. (C)

Apparatus: Waters Acquity UPLC with mass spectroscopy detection (MS : Waters SQ Detector or Xevo TQD). Column: Acquity UPLC CSH C18 (1.7 m, 2.1 x 50 mm). Conditions: MeCN+0.045% formic acid [eluent A]; water + 0.05% formic acid [eluent B], Gradient: 98% B — > 2% B over 2 min. (flow: 1 ml/min.). Detection: UV (214nm) + MS.

Preparative HPLC

Reaction mixture can generally be separated by preparative HPLC. A person skilled in the art will find suitable conditions for each separation. Product containing fractions are collected and lyophilized or freeze dried under vacuum.

Automated FC

Classical flash chromatography is often replaced by automated systems. This does not change the separation process perse. A person skilled in the art will be able to replace a classical FC process by an automated one, and wee versa. Typical automated systems can be used, as they are provided by Buchi, Isco (Combiflash), or Biotage for instance.

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 A: 2-methyl-6-(pyrazolidin-1-ylmethyl)benzo[d]thiazole dihydrochloride

A.i. tert-Butyl 2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidine-1-carbo xylate'.

To a solution of tert-butyl 1-pyrazolidinecarboxylate (4.63 g, 26.9 mmol) in DCM (190 mL) are added successively at r.t. 2-methyl-1 ,3-benzothiazole-6-carbaldehyde (5.02 g, 26.9 mmol) and NaBH(OAc)3 (14.78 g, 67.6 mmol). The resulting mixture is stirred for 23h. Sat. aq. NaHCOa (100 mL) and water (100 mL) are added. The two layers are separated and the aq. layer is extracted with DCM (2 x 75 mL). The evaporation residue is purified by FC (heptane- EtOAc with gradient) to afford the title product (7.18 g) as a colourless oil of 86% purity. LC-MS (A): IR = 0.83 min; [M+H] ⁺ = 334.15. ¹ H NMR (DMSO-d6) 5 7.99 (d, J = 1.2 Hz, 1 H), 7.85 (d, J = 8.3 Hz, 1 H), 7.49 (dd, J = 1.6, 8.3 Hz, 1 H), 3.80 (s, 2H), 3.43 (t, J = 6.8 Hz, 2H), 2.85 (t, J = 6.8 Hz, 2 H), 2.79 (s, 3 H), 2.07 (m, 2H), 1 .29 (s, 9H).

A.ii. 2-Methyl-6-(pyrazolidin-1-ylmethyl)benzo[d]thiazole dihydrochloride:

Intermediate A.i (7.19 g, 21.6 mmol) is dissolved in 4N HCI in dioxane (100 mL, 416 mmol) at r.t. The reaction mixture is stirred for 16 h. The reaction mixture is concentrated to dryness and the resulting solid is dried under vacuum to a constant weight to afford the title compound (6.6 g) as a yellowish solid. LC-MS (A): IR = 0.53 min; [M+H] ⁺ = 234.20.

Preparation B: (5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)(pyrazolidin-1-yl) methanone hydrochloride

B.i. tert-Butyl 2-(5-methyl-2-(2H-1 , 2, 3-triazol-2-yl)'benzoyl)pyrazolidine-1-carboxylate:

To a solution of tert-butyl 1-pyrazolidinecarboxylate (1.0 g, 5.8 mmol) and 5-methyl-2-(2/-/-1 ,2,3-triazol-2-yl)benzoic acid (1.18 g, 5.84 mmol) in DMF (20 mL) are added successively DIPEA (2.03 mL, 11.6 mmol) and HATU (2.38 g, 6.13 mmol). The reaction proceeded at r.t. for 16 h. Sat. NaHCOa (60 mL) and DCM (60 mL) are added. The two layers are separated and the aqueous layer is extracted with DCM (2 x 40 mL). The evaporation residue is purifid by FC (heptane/TBME/MeOH with gradient) to afford the title compound (2.2 g) as an off-white solid. LC-MS (A): t _R = 0.90 min; [M+H] ⁺ = 358.41 . ¹ H NMR (DMSO-d6) 5 8.09 (s, 2 H), 7.76 (d, J = 8.3 Hz, 1 H), 7.41 (dd, J = 1.3, 8.3 Hz, 1 H), 7.34 (d, J = 1.3 Hz, 1 H), 4.04-3.96 (m, 2H), 3.59-3.52 (m, 2H), 3.18-3.12 (m, 2H), 3.08 (s, 3H), 1.11 (s, 9H)

B. ii . (5-Methyl-2-(2H-1,2, 3-triazol-2-yl)phenyl) (pyrazolidin-l-yl)methanone hydrochloride:

Starting from intermediate B.i. (2.24 g, 5.33 mmol) and proceeding according to the procedure described in Preparation A, step A.ii, the title compound (1 .75 g) is prepared as an off-white solid of 90% purity. LC-MS (A): t _R = 0.58 min; [M+H] ⁺ = 257.97.

Preparation C: 5-methyl-2-(thiazol-2-yl)nicotinic acid, lithium salt

C.i. Methyl 5-methyl-2-(thiazol-2-yl)nicotinate'.

To a solution of methyl 2-bromo-5-methylnicotinate (0.350 g, 1.48 mmol) in dioxane (2 mL) are added Cui (0.05g, 0.24mmol), Pd(PPh3)4 (0.03g, 0.03mmol) and 2-(tributylstannyl)-1 ,3-thiazole (0.697 g, 1.77 mmol). The reaction proceeded at 100°C for 16h. After cooling to r.t., the reaction mixture is directly purified by FC (heptane-EtOAc with gradient) to afford the title compound (0.310 g) as a yellowish solid. LC-MS (A): t _R = 0.81 min; [M+H] ⁺ = 234.9. ¹ H NMR (DMSO-d6) 5: 8.60 (d, J = 0.8 Hz, 1 H), 7.96 (d, J = 3.1 Hz, 1 H), 7.88 (d, J = 3.1 Hz, 1 H), 7.86 (s, 1 H), 3.81 (s, 3H), 2.39 (s, 3H).

C.ii. 5-Methyl-2-(thiazol-2-yl)nicotinic acid, lithium salt.

Starting for the intermediate C.i (0.310 g, 1.32 mmmol) and proceeding as described in Preparation H, step H.ii, the crude title salt (0.310g) is obtained as a greyish solid. LC-MS (A): t _R = 0.69 min; [M+H] ⁺ = 221.19.

Preparation D: (2-(trifluoromethyl)benzo[d]thiazol-6-yl)methyl methanesulfonate in mixture with 6- (chloromethyl)-2-(trifluoromethyl)benzo[d]thiazole

D.i. (2-(Trifluoromethyl)benzo[d]thiazol-6-yl)methanol:

To a solution of 2-(trifluoromethyl)benzo[d]thiazole-6-carboxylic acid (0.105 g, 0.404 mmol) in THF (2.5 mL), cooled to - 10°C, is slowly added a solution of borane.tetrahydrofuran complex (1.0 M in THF; 0.8 mL, 0.8 mmol). The reaction mixture is warmed to r.t. and stirred for 2 h. MeOH (1.5 mL) is slowly added. After 15 min stirring, the volatiles are removed in vacuo and the residue is co-evaporated twice with MeOH (2 x 5 mL). The evaporation residue is purified by prep. HPLC to afford the title compound (0.013 g) as a yellowish oil. ¹ H NMR (DMSO-d6) S'. 8.29 (d, J = 0.9Hz, 1 H), 8.21 (d, J = 8.5 Hz, 1 H), 7.65 (dd, J = 0.9, 8.5Hz, 1 H), 5.51 (t, J = 5.5Hz, 1 H), 4.71 (d, J = 5.5Hz, 2H).

D.ii. (2-(Trifluoromethyl)benzo[d]thiazol-6-yl)methyl methanesulfonate in mixture with 6-(chloromethyl)-2- (trifluoromethyl)benzo[d]thiazole: To an ice-chilled suspension of intermediate P.1 .i (0.012 g, 0.0515 mmol) and TEA (0.0143 mL, 0.103 mmol) in DCM (0.5 mL) is added methanesulfonyl chloride (0.006 mL, 0.077 mmol). The reaction proceeded at 0°C for 40 min. The reaction mixture is partitioned between DCM (5 mL) and water (5 mL). The aq. layer is extracted once with DCM (5 mLJ.The evaporation residue afforded the crude title compound in a 1-1 mixture with 6-(chloromethyl)- 2-(trifluoromethyl)benzo[d]thiazole (0.016 g, yellowish oil). The mixture is used without further purification. ¹ H NMR (DMSO-c/6) (1-1 mixture)^: 8.46 (m, 0.5H), 8.45 (m, 0.5H), 8.31 (d, J = 8.5Hz, 0.5H), 8.27 (d, J = 8.5Hz, 0.5H), 7.79 (m, 0.5H), 7.77 (m, 0.5H), 5.48 (s, 2 x 0.5H), 4.98 (s, 2 x 0.5H), 3.29 (s, 3 x 0.5H).

Preparation E: 5-methyl-2-(4-methyl-1H-pyrazol-1-yl)benzoic acid

To a solution of 2-iodo-5-methylbenzoic acid (0.798 g, 2.95 mmol), cesium carbonate (1.06 g, 3.25 mmol) and copper iodide (0.112 g, 0.591 mmol) in DMF (18.3 mL) are added trans-N, W'-dimethylcyclohexane-1,2-diamine (0.086 g, 0.591 mmol) and 4-methyl-1 H-pyrazole (0.247 mL, 2.95 mmol). The resulting mixture is heated to 120°C for 15 h. After cooling to r.t., water (20 mL) is added. The two layers are separated and the aq. layer is washed with DCM. The resulting organic layer is discarded. The aqueous layer is acidified to pH 1 using 1 M HCI. The resulting solution is extracted with DCM (2 x 20 mLJ.The evaporation residue is purified by prep. HPLC to afford the title compound (0.255 g) as a white solid. LC-MS (A): t _R = 0.72 min; [M+H] ⁺ = 217.18. ¹ H NMR (DMSO-d6) 5: 12.80 (s, 1 H), 7.83 (m, 1 H), 7.50 (m, 1 H), 7.46 (s, 1 H), 7.41-7.38 (m, 2 H), 2.38 (s, 3H), 2.09 (s, 3H).

Preparation F: 6-methyl-3-(2-methylthiazol-4-yl)picolinic acid

F.i. Methyl 3-(1-ethoxyvinyl)-6-methylpicolinate'.

To a solution of methyl 3-bromo-6-methylpicolinate (0.475 g, 1.96 mmol) and tributyl(1-ethoxyvinyl)tin (0.767 g, 2.06 mmol) in dioxane (8.64 mL) is added bis(triphenylphosphine)palladium(l I) dichloride (0.055 g, 0.0785 mmol). The reaction proceeded at 80°C for 17 hours. The reaction mixture is diluted with EtOAc (20 mL) is washed with water (10 mL) and brine (10 mL). The residue is purified by prep. HPLC to afford the title compound (0.373 g) as a yellow oil. LC-MS (B): t _R = 0.81 min; [M+H] ⁺ = 222.14.

F.ii. Methyl 3-(2-bromoacetyl)-6-methylpicolinate'.

To a solution of the intermediate F.i (0.37 g, 1.67 mmol) in dioxane (4.5 mL) is added dropwise a solution of bromine (0.0865 mL, 1 .67 mmol) in dioxane (4.5 mL) at 0 °C. The reaction mixture is stirred at r.t. for 1 h. Water (10 mL) is added The solvents are evaporated under reduced pressure. The resulting residue is purified by prep. HPLC to afford the title product (0.052 g) as a white solid. LC-MS (A): t _R = 0.70 min; [M+H] ⁺ = 272.07 / 273.80.

F.iii. Methyl 6-methyl-3-(2-methylthiazol-4-yl)picolinate'.

A solution of thioacetamide (0.014 g, 0.184 mmol) in MeCN (0.13 mL) is added dropwise to a mixture of the intermediate F.ii (0.050 g, 0.184 mmol) and 4A molecular sieves (0.017 g) in MeCN (0.3 mL). The reaction mixture is stirred at r.t. for 2 h. The reaction mixture is cooled to 0°C. The solids are removed by filtration and the filter cake is rinsed with MeOH. The latter solid is suspended in MeOH (0.5 mL) and heatedat 50°C for 1 h. The solution is concentrated in vacuo to afford the title compound (0.046 g) as a yellow solid. LC-MS (A): t _R = 0.71 min; [M+H] ⁺ = 249.14. F.iv. 6-Methyl-3-(2-methylthiazol-4-yl)picolinic acid'.

To a solution of the intermediate F.iii. (0.045 g, 0.181 mmol) in EtOH (0.86 mL) is added , 2 N NaOH aq. (0.91 mL). The reaction proceeded at r.t. for 2 h. 2N HCI is added to reach acidic pH <2. The solution is concentrated under reduced pressure to afford the title acid (0.043 g)as a slightly yellow solid. LC-MS (A): IR = 0.40 min; [M+H] ⁺ = 235.01.

Preparation G: 6-methyl-3-(4-methyl-2H-1,2,3-triazol-2-yl)picolinic acid

Starting from 4-methyl-1 H-1 ,2,3-triazole (0.258 g, 2.95 mmol) and-3-bromo-6-methyl-pyridine-2-carboxylic acid (0.658 g, 2.95 mmol) and proceeding as described in Preparation E, the title product (0.27 g) is obtained as a white solid after purification by prep. HPLC. LC-MS (A): tR = 0.48 min; [M+H] ⁺ = 219.16.

Preparation H: 2-(1-methyl-1H-pyrazol-3-yl)benzoic acid, lithium salt

H.i. Ethyl 2-(1-methyl-1H-pyrazol-3-yl)benzoate'.

To a solution of 2-ethoxycarbonylphenylboronic acid (0.231 g, 1.17 mmol) in dioxane (4.7 mL) and EtOH (2.3 mL) are added 3-iodo-1 -methyl-1 H-pyrazole (0.250 g, 1.17 mmol), 2 M aq. Na2CO3 (1.75 mL, 3.5 mmol) and [1,1 - bis(diphenylphosphino)ferrocene]dichloropalladium.DCM (0.057 g, 0.07 mmol), The reaction mixture is partitioned between water (15 mL) and EtOAc (15 mL). The two layers are separated and the aqueous layer is extracted with EtOAc (2 x 15 mL). The evaporation residue is purified by prep. HPLC to afford the title product (0.144 g) as a green oil. LC-MS (A): t _R = 0.48 min; [M+H] ⁺ = 219.16.

H.ii. 2-(1-Methyl-1H-pyrazol-3-yl)benzoic acid, lithium salt.

To a solution of intermediate H.i (0.14 g, 0.608 mmol) in a THF-water mixture (10: 1, 5.5 mL) is added UOH.H2O (0.028 g, 0.669 mmol). The reaction proceeded at r.t. for 25 h. The reaction mixture is concentrated to dryness, and the residue is triturated in MeCN. The solid is recovered by filtration and dried to a constant weight to afford the title product (0.058 g) as a beige solid. LC-MS (A): t _R = 0.80 min; [M+H] ⁺ = 231.17.

Preparation I: ethyl 2-(4-methylpyrimidin-2-yl)benzoate

Starting from 2-chloro-4-methylpyrimidine (0.153 g, 1.17 mmol) and 2-ethoxycarbonylphenylboronic acid (0.231 g,

I .17 mmol) and proceeding as described in Preparation H. step H.i, the title ester (0.126 g) is obtained as a brownish oil after purification by prep. HPLC. LC-MS (A): t _R = 0.76 min; [M+H] ⁺ = 243.11.

Preparation J: 6-methyl-3-(2H-1,2,3-triazol-2-yl)pyrazine-2-carboxylic acid

The compound is prepared as reported in W02019043407.

Preparation K: 6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxylic acid

The compound is prepared as reported in W02019043407.

Preparation L: 6-methyl-3-pyrazol-1-ylpyridine-2-carboxylic acid

The compound is prepared as reported in W02019043407.

Preparation M: 6-methyl-3-(1,3-thiazol-2-yl)pyridine-2-carboxylic acid

The compound is prepared as reported in W02019043407. Preparation N: 5-methyl-2-(1H-pyrazol-1-yl)nicotinic acid

Starting from methyl 2-bromo-5-methylnicotinate (0.180 g, 0.759 mmol) and pyrazole (0.105 g, 1.52 mmol) and proceeding as described in Preparation E, the title acid (0.101 g) is obtained as a yellowish solid after purification by prep. HPLC. LC-MS (A): t _R = 0.58 min; [M+H] ⁺ = 204.29.

Preparation O: 5-methyl-2-(3-methyl-1H-pyrazol-1-yl)benzoic acid and 5-methyl-2-(5-methyl-1H-pyrazol-1- yl)benzoic acid

Starting from methyl 2-iodo-5-methylbenzoic acid (0.800 g, 2.95 mmol) and 3-methylpyrazole (0.250 g, 2.95 mmol) and proceeding as described in Preparation E, the title acids (0.233 g) are obtained as a mixture (yellowish solid) after purification by prep. HPLC. LC-MS (A): t _R = 0.67 and 0.69 min; [M+H] ⁺ = 217.18.

The first-eluting isomer is 5-methyl-2-(5-methyl-1 H-pyrazol-1 -yl)benzoic acid.

Preparation P: 5-methyl-2-(4-methyl-2H-1,2,3-triazol-2-yl)benzoic acid

P. i . 2-(4-Bromo-5-methyl-2H-1 ,2, 3-triazol-2-yl)-5-methylbenzoic acid:

Starting from 5-bromo-4-methyl-1 H-1 , 2, 3-tri azole (0.1 g, 0.599 mmol, 1 eq)and 2-iodo-5-methylbenzoic acid methyl ester (0.104 mL, 0.599 mmol) and proceeding as described in Preparation E, the title acid (0.053 g) is obtained as an off-white solid after purification by prep. HPLC. LC-MS (A): t _R = 0.84 min; [M+H] ⁺ = 298.12 / 296.08.

P. ii . 5-Methyl-2-(4-methyl-2H-1 ,2, 3-triazol-2-yl)benzoic acid:

To a mixture of intermediate P.i (0.040 g, 0.135 mmol) and sodium acetate (0.033 g, 0.405 mmol) in EtOAc (1.8 mL) and EtOH (0.6 mL) is added palladium hydroxide on carbon (20%; 0.014 g). The reaction proceeded under normal hydrogen atmosphere for 72h. The catalyst is removed by filtration and the filtrate is concentrated to dryness to afford the crude title acid as a white solid. LC-MS (A): t _R = 0.69 min; [M+H] ⁺ = 218.06.

Preparation Q: 5-methyl-2-(2-methylthiazol-4-yl)benzoic acid, lithium salt

Starting from 4-bromo-2-methyl-1 ,3-thiazole (0.081 g, 0.456 mmol) and 2-methoxycarbonyl-4-methylphenylboronic acid (0.093 g, 0.456 mmol) and proceeding successively as described in Preparation H, steps H.i and H.ii, the title salt (0.048 g) is obtained as an off-white solid. LC-MS (A): t _R = 0.68 min; [M+H] ⁺ = 234.13.

Preparation R: 2-methyl-5-(m-tolyl)thiazole-4-carboxylic acid

The compound is prepared as reported in WO2008/65626.

Preparation S: 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid

The compound is prepared as reported in WO2018/202689.

Preparation T: 5-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid

The compound is prepared as reported in WO2019/43407.

Preparation U: 5-chloro-2-(2H-1,2,3-triazol-2-yl)benzoic acid

The compound is prepared as reported in WO2019/43407

Preparation V: 4,5-dimethyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid Starting from 2-iodo-4,5-dimethylbenzoic acid (0.5 g, 1.81 mmol) and 1 H-1 ,2,3-triazole (0.25 g, 3.62 mmol) and proceeding as described in Preparation E, the title compound (0.1 g) is obtained as a white solid after purification by prep. HPLC. LC-MS (A): t _R = 0.68 min; [M+H] ⁺ = 218.10.

Preparation W: 5-methoxy-2-(1H-pyrazol-1-yl)benzoic acid

The compound is commercially available and is prepared as described in WO 2014/057435

Preparation X: 5-chloro-2-(1H-pyrazol-1-yl)nicotinic acid

Starting from 2-bromo-5-chloronicotinic acid (0.500 g, 2.07 mmol) and pyrazole (0.173 g, 2.49 mmol) and proceeding as described in Preparation E, the title acid (0.121 g) is obtained as a beige solid after purification by prep. HPLC. LC-MS (A): t _R = 0.63 min; [M+H] ⁺ = 224.14.

Preparation Y: 2-methyl-6-((tetrahydropyridazin-1(2H)-yl)methyl)benzo[d]thi azole hydrochloride

Starting from tert-butyl tetrahydro-1 (2H)-pyrid azine carboxylate (0.2 g, 1 .02 mmol) and 2-methyl-1 ,3-benzothiazole- 6-carbaldehyde (0.191 g, 1.02 mmol) and proceeding successively as described in Preparation A, steps A.i and A.ii, the title compound (0.252 g) is obtained as a yellowish solid. LC-MS (A): t _R = 0.54 min; [M+H] ⁺ = 248.2.14.

Preparation Z: 2-(4-bromo-2H-1,2,3-triazol-2-yl)-5-chlorobenzoic acid

2-Bromo-5-chlorobenzoic acid (0.1 g, 0.416 mmol), Cui (0.004 g, 0.0208 mmol) and K2CO3 (0.129 g, 0.936 mmol) are suspended in dioxane (2.5 mL). 4-Bromo-1 /7-1,2,3-triazole (0.13 g, 0.832 mmol) ) is added and the reaction mixture is heated at reflux for 1 h. Water (0.06 mL) is added and heating is pursued for 1 h. After collong, the volatiles are removed in vacuo and the residue is diluted with water (2 mL) and acidified to pH 2 with aq 20% H2SO4. The resulting mixture is purified by prep HPLC to afford the title compound (0.12 g) as an oil which cristallized on standing. ¹ H NMR (DMSO-cfe) 5: 13.50 (br s, 1 H), 8.33 (s, 1 H), 7.85 (m, 1 H), 7.81 (m, 2H).

Preparation AA: 2-(4-chloro-1H-pyrazol-1-yl)-5-methylnicotinic acid

Starting from 4-chloro-1 H-pyrazole (0.155 g, 1.47 mmol) and methyl 2-bromo-5-methylnicotinate (0..2 g, 0.843 mmol) and proceeding as described in Preparation E, the title acid (0.138 g) is obtained as a beige solid after purification by prep. HPLC. LC-MS (A): t _R = 0.70 min; [M+H] ⁺ = 238.12.

Preparation AB: (5-chloro-2-(2H-1,2,3-triazol-2-yl)phenyl)(pyrazolidin-1-yl) methanone dihydrochloride

AB.i. tert-Butyl 2-(5-chloro-2-(2H-1 , 2, 3-triazol-2-yl)benzoyl)pyrazolidine-1 -carboxylate:

Oxalyl chloride (0.1 mL, 1.16 mmol) is added dropwise at r.t. to a suspension of 5-chloro-2-(2/-/-1,2,3-triazol-2- yl)benzoic acid (0.245 g, 1.1 mmol) in DCM (5mL). DMF (0.02 mL) is then added dropwise. The reaction proceeded solution is stirred for 1 h30. The volatiles are removed under reduced pressure and co-evaporated twice with dry DCM (4mL). The crude residue is taken up in DCM (6.5 mL) and added dropwise to an ice-chilled solution of tertbutyl pyrazolidine-1 -carboxylate (0.171 g, 0.99 mmol) and NEts (0.415 mL, 2.98 mmol) in DCM (3.2mL) is added. The reaction proceeded at r.t. for 2h 15. Sat. aq. NaHCOa (10 mL) and DCM (10 mL) are added. The two layers are separated. The aqueous layer is extracted with DCM (2 x 10 mL). The evaporation residue is purified by FC (heptane-EtOAc) to afford the title compound (0.311 g) as a yellowish oil. LC-MS (A): t _R = 0.95 min; [M+H] ⁺ = 378.15. AB.ii. (5-chloro-2-(2H-1,2,3-triazol-2-yl)phenyl)(pyrazolidin-1-yl) methanone dihydrochloride'.

Starting from the intermediate AB. i (0.299 g, 0.791 mmol) and proceeding as described in Preparation A, step A.ii, the title compound (0.285 g) is obtained as a yellowish solid. LC-MS (A): t _R = 0.64 min; [M+H]+ = 278.18.

Preparation AC: 5-chloro-2-(4-methyl-1H-pyrazol-1-yl)nicotinic acid

Starting from 4-methyl-1 H-pyrazole (0.15 g, 1.79 mmol) and 2-bromo-5-chloronicotinic acid (0.36 g, 1.49 mmol) and proceeding as described in Preparation E, the title acid (0.18 g) is obtained as a beige solid after purification by prep. HPLC. LC-MS (A): t _R = 0.73 min; [M+H] ⁺ = 238.18.

Preparation AD: 5-methyl-2-(4-methyl-1H-pyrazol-1-yl)nicotinic acid

Starting from 4-methyl-1 H-pyrazole (0.15 g, 1.79 mmol) and methyl 2-bromo-5-methylnicotinate (0.36 g, 1.52 mmol) and proceeding as described in Preparation E, the title acid (0.14 g) is obtained as a beige solid after purification by prep. HPLC. LC-MS (A): t _R = 0.67 min; [M+H] ⁺ = 218.27.

Preparation AE: 5-chloro-2-(4-methyl-1H-pyrazol-1-yl)benzoic acid

Starting from 4-methyl-1 H-pyrazole (0.2 g, 2.0 mmol) and methyl 2-bromo-5-chlorobenzoate (0.5 g, 2.0 mmol) and proceeding as described in Preparation E, the title acid (0.344 g) is obtained as a beige solid after purification by prep. HPLC. LC-MS (A): t _R = 0.74 min; [M+H] ⁺ = 237.16.

Preparation AF: 5-methyl-2-(3-methyl-1H-pyrazol-1-yl)nicotinic acid

Starting from 3-methyl-1 H-pyrazole (0.353 g, 4.22 mmol) and methyl 2-bromo-5-methylnicotinate (0.5 g, 2.11 mmol) and proceeding as described in Preparation E, the title acid (0.18 g) is obtained as a greenish solid after purification by prep. HPLC. LC-MS (A): t _R = 0.64 min; [M+H] ⁺ = 218.26.

Preparation AG: 2-bromobenzo[d]thiazole-6-carbaldehyde

AG . i . ( 2-bromobenzo[d]thiazol-6-yl)methanol'.

To a suspension of ethyl 2-bromobenzo[d]thiazole-6-carboxylate (0.3 g, 1.07 mmol) in DCM (5 mL) at -78°C, DIBAL-H in toluene (2.67mL, 2.67mmol) is added dropwise keeping the temperature below -72°C. The reaction proceeded at the same temperature for 2h then is allowed to reach r.t. during 45 min. Water (0.11 mL), 1 M. NaOH (0.11 mL), water (0.26mL) are added. DCM (5mL) is added and filtered. The evaporation residue is purified by FC (heptane-EtOAc) to afford the title compound (0.189 g) as an off-white solid. LC-MS (A): t _R = 0.70 min; [M+H] ⁺ = 244.05-246.03.

AG . ii 2-bromobenzo[d]thiazole-6-carbaldehyde'.

To a solution of the intermediate AG.i (0.189 g, 0.76 mmol) in a mixture of DCM (4 mL) and THF (2 mL) is added MnO2 (0.46 g, 5.3 mmol). The reaction mixture is stirred overnight at r.t. The reaction mixture is filtered over celite and washed with DCM (2 x 10 mL). The filtrate is concentrated to dryness to afford the title compound (0.182g) as a white solid. ¹ H NMR (DMSO-cfe) 5: 10.12 (s, 1 H), 8.74 (dd, J= 1.6 Hz, 1 H), 8.18 (d, J = 8.4 Hz, 1 H), 8.05 (dd, J= 1.6, 8.4 Hz, 1 H).

Preparation AH: (RS)-2-methyl-6-((4-methylpyrazolidin-1-yl)methyl)benzo[d]th iazole hydrochloride AH.i. 1-benzyl 2-(tert-butyl) (RS)-4-methylpyrazolidine-1,2-dicarboxylate'.

To a suspension of 1-benzyl 2-(fert-butyl) 1 ,2-hydrazine dicarboxylate (0.4 g, 1.5 mmol), K3PO4 (0.7 g, 3.3 mmol) in MeCN (4 mL) is added 1,3-dibromo-2-methylpropane (0.376 g, 1.65 mmol). The reaction proceeded at 55°C for 20 h.More K3PO4 (0.16g, 0.75mmol) is added and the reaction proceeded at 60°C for 48h. After cooling water (5 mL) and TBME (5 mL) are added. The two layers are separated and the aq. layer is extracted with TBME (5 mL). The evaporation residue is purified by FC (heptane-EtOAc gradient) to afford the title compound (0.22 g) as a colorless oil which cristallised on standing. LC-MS (A): t _R = 0.99 min; [M+H] ⁺ = 321.16.

AH.ii. tert-butyl (RS)-4-methylpyrazolidine-1-carboxylate'.

To a solution of intermediate AH.i (0.215 g, 0.671 mmol) in MeOH (2mL) is added Pearlman's catalyst (0.011 g, 0.0201 mmol. The reaction proceeded at r.t. for 1 h under normal hydrogen atmosphere. The catalyst is removed by filtration and the filtrate is concentrated to dryness to afford the title compound (0.123g) as a colorless oil. LC- MS (A): t _R = 0.48 min; [M+H] ⁺ = 187.39.

AH.iii. (RS)-2-methyl-6-((4-methylpyrazolidin-1-yl)methyl)benzo[d]th iazole hydrochloride'.

Starting from intermediate AH.ii. (0.12 g, 0.644 mmol) and 2-methyl-1 ,3-benzothiazole-6-carbaldehyde (0.132 g, 0.709 mmol) and proceeding successively as described in Preparation A, steps A.i and A.ii. the title compound (0.12 g) is prepared as a yellowish solid. LC-MS (A): t _R = 0.56 min; [M+H] ⁺ = 248.23.

Preparation Al: 2-methyl-[1,3]thiazolo[5,4-b]pyridine-5-carbaldehyde

The compound is prepared as described in US5472964.

Preparation AJ: 2-chlorobenzo[d]thiazole-6-carbaldehyde:

Starting from methyl 2-chloro-1,3-benzothiazole-6-carboxylate (0.305 g, 1.27 mmol) and proceeding successively as reported in Preparation AG, steps AG.i and AG.ii, the title aldehyde (0.15 g) is obtained as a white solid after purification by FC (heptane-EtOAc). ¹ H NMR (DMSO-cfe) 5: 10.12 (s, 1 H), 8.74 (dd, J= 1.6 Hz, 1 H), 8.15 (d, J = 8.4 Hz, 1 H), 8.08 (dd, J= 1.6, 8.4 Hz, 1 H).

Preparation AK: (S)-2-methyl-6-((4-methylpyrazolidin-1-yl)methyl)benzo[d]thi azole hydrochloride

AK.i. tert-butyl (R)-2-(3-((tert-butyldimethylsilyl)oxy)-2-methylpropyl)hydra zine-1-carboxylate:

To a solution of (S)-3-((tert-butyldimethylsilyl)oxy)-2-methylpropyl 4-methylbenzenesulfonate (prepared as described in J.Org.Chem. 2003, 68, 5568; 1.5 g, 4.18 mmol) in DMF (10 mL) is added tert-butyl carbazate (2.2 g, 16.7 mmol). The reaction proceeded at 80°C for 24h. After cooling, the solvent is removed in vacuo and the residue is purified by FC (heptane-EtOAc) to afford the title compound (0.675 g; 51 % yield) as a colorless oil. ¹ H NMR (CDCI3) 6: 6.10 (br s, 1 H); 3.58-3.51 (m, 2H), 2.89 (dd, J= 6.8, 11.5 Hz, 1 H), 2.73 (dd, J= 6.3, 11.5 Hz, 1 H), 1.84 (m, 1 H), 1 .48 (s, 9H), 0.94 (d, J = 6.8 Hz, 3H), 0.91 (s, 9H), 0.06 (s, 6H). LC-MS (A): t _R = 0.96 min; [M+H] ⁺ = 319.28.

AK.ii. tert-butyl (R)-2-(3-((tert-butyldimethylsilyl)oxy)-2-methylpropyl)-2-(( 2-methylbenzo[d]thiazol-6- yl)methyl)hydrazine-1-carboxylate'.

Starting from intermediate AK.i. (0.65 g, 2.04 mmol) and 2-methyl-1,3-benzothiazole-6-carbaldehyde (0.362 g, 2.04 mmol) and proceeding successively as described in Preparation A, step A.i, the title compound (0.42 g, 43% yield) is prepared as a colorless oil. ¹ H NMR (CDCh) 5: 7.89 (d, J = 8.3 Hz, 1 H), 7.86 (s, 1 H), 7.45 (dd, J= 1.6, 8.3 Hz, 1 H), 5.63 (br s, 1 H), 4.10 (br s, 2H), 3.51-3.63 (m, 2H), 2.86 (overlapped m, 1 H), 2.84 (s, 3H), 2.63 (br s, 1 H), 1.88 (m, 1 H), 1.39 (s, 9H), 0.97 (d, J= 6.7Hz, 3H), 0.88 (s, 9H), 0.05 (s, 6H). LC-MS (A): t _R = 1.28 min; [M+H] ⁺ = 480.27.

AK. Hi. tert-butyl (R)-2-( 3-hydroxy-2-methylpropyl) -2-( ( 2-methylbenzo[d]thiazol-6-yl)methyl)hydrazine-1- carboxylate:

To a solution of intermediate AK.ii (0.42 g, 0.875 mmol) in THF (5 mL) is added TBAF (1 M in THF; 1.5 mL, 1.5mmol). The reaction proceeded at room temperature for 2h. The solvent is removed in vacuo and the residue is purified by FC (heptane-EtOAc) to afford the title compound (0.32 g, 100% yield) as a colorless oil. ¹ H NMR (CDCh) 5: 7.92 (d, J = 8.3 Hz, 1 H), 7.85 (s, 1 H), 7.43 (dd, J= 1.6, 8.3 Hz, 1 H), 5.51 (br s, 1 H), 4.15 (br s, 1 H), 3.94 (m, 1 H), 3.72 (m, 1 H), 3.53 (m, 1 H), 3.51-3.63 (m, 2H), 2.88 (overlapped m, 1 H), 2.85 (s, 3H), 2.74 (m, 1 H), 2.08 (m, 1 H), 1.35 (s, 9H), 0.84 (d, J= 6.9Hz, 3H), 0.88 (s, 9H), 0.05 (s, 6H).

AK. iv. tert-butyl ( R) -2-( 2-methyl-3-(tosyloxy) propyl) -2-( ( 2-methylbenzo[d]thiazol-6-yl)methyl)hydrazine-1- carboxylate:

To a solution of intermediate AK.iii (0.32 g, 0.875 mmol) in DCM (8 mL) are added at room temperature 4-DMAP (0.177 g; 1.45 mmol)), TEA (0.3 mL, 2.16mmol) and pTsCI (0.33 g, 1.75 mmol). The reaction proceeded at room temperature for 2h. The reaction mixture is directly purified by FC (heptane-EtOAc) to afford the title compound (0.39 g, 86% yield) as a colorless oil. LC-MS (A): t _R = 1.11 min; [M+H] ⁺ = 520.18.

AK.v. tert-butyl (R)-4-methyl-2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazol idine-1-carboxylate:

To a solution of intermediate AK.iv (0.39 g, 0.75 mmol) in acetonitrile (5mL) is added potassium phosphate tribasic (0.319g). The reacction proceeded for 16h at 80°C. After cooling, the solids are filtered off, washed with acetonitrile and the filtrate is concentrated to dryness. The residue is chromatographed (heptane-EtOAc) to afford the title compound (0.25 g, 96% yield) as a colorless oil. ¹ H NMR (CDC ) 6: 7.82-7.95 (m, 2 H), 7.45 (d, J = 8.3 Hz, 1 H), 4.06 (m, 1 H), 3.94 (m, 1 H), 3.78 (m, 1 H), 3.03-3.16 (m, 2 H), 2.85 (s, 3 H), 2.52-2.66 (m, 2 H), 1.48 (s, 9 H), 1.08 (d, J = 5.9 Hz, 3 H); LC-MS (A): t _R = 0.89 min; [M+H] ⁺ = 348.18.

AK.vi. (S)-2-methyl-6-((4-methylpyrazolidin-1-yl)methyl)benzo[d]thi azole hydrochloride'.

Starting from intermediate AK.v. (0.25 g, 0.644 mmol) and proceeding as described in Preparation A, step A.ii. the title compound (0.2 g, 99% yield) is prepared as a yellowish solid. LC-MS (A): t _R = 0.56 min; [M+H] ⁺ = 248.23.

Preparation AL: 2-methyl-6-((pyrazolidin-1-yl-4,4-d2)methyl)benzo[d]thiazole dihydrochloride

ALL propane-1, 3-diyl-2,2-d2 bis(4-methylbenzenesulfonate):

To an ice-chilled solution of 1 ,3-propane-2,2-d2-diol (0.5 g, 6.4 mmol) in DCM (20 mL) are added EtsN (2.68 mL, 19.2 mmol), DMAP (0.08 g, 0.63 mmol) and pTsCI (2.71 g, 14.1 mmol). The resulting solution is stirred for 3 h at rt rt during the course of the reaction. Sat. aq. NaHCOa (5 mL) is added and the two layers are separated. The aq. layer is extracted with DCM (5 mL). The combined org. layers are washed with sat. aq. CU2SO (5mL) and brine (5mL).The evaporation residue is purified by FC (Heptane-EtOAc) to afford the title compound (0.72 g, 29% yield) as a white solid. LC-MS (A): t _R = 1.02 min; [M+H] ⁺ = 387.2. ¹ H NMR (500 MHz, DMSO) 5: 7.74 (d, J = 8.3 Hz, 4 H), 7.48 (d, J = 7.9 Hz, 4 H), 4.00 (s, 4 H), 2.43 (s, 6 H).

AL.ii. 2-methyl-6-((pyrazolidin-1-yl-4,4-d2)methyl)benzo[d]thiazole dihydrochloride'.

Starting from the intermediate AL.i. (0.718 g, 1.86 mmol) and 1-benzyl 2-(tert-butyl) 1 ,2-hydrazine dicarboxylate (0.45 g, 1.69 mmol) and proceeding as described in Preparation AH, steps AH. i and AH.ii (except MeOH-d4 and D2 gas are employed) and Preparation A, steps A.i and A.ii, the title compound (0.099g) is obtained as a yellowish solid. LC-MS (A): t _R = 0.51 min; [M+H] ⁺ = 236.1 ¹ H NMR (500 MHz, DMSO) 5: 8.09 (s, 1 H), 7.93 (d, J = 8.3 Hz, 1 H), 7.54 (d, J = 8.2 Hz, 1 H), 4.32 (s, 2 H), 3.28 (br. s, 2 H), 3.03-3.12 (m, 2 H), 2.81 (s, 3 H)

Preparation of Examples

Example 1 : (5-methyl-2-(2H-1 ,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)m ethyl)pyrazolidin- 1-yl)methanone

To a solution of the compound of Preparation B (0.018 g, 0.061 mmol) and 2-methylbenzo[d]thiazole-6- carbaldehyde (0.010 g, 0.061 mmol) in DMF (0.5 mL) is added sodium triacetoxyborohydride (0.034 g, 0.153 mmol). The reaction proceeded at r.t. for 16h. The reaction mixture is dissolved in DMF (1 mL) and 0.5% aq. NH4OH. The resulting solution is purified by prep. HPLC to afford the title compound (0.012 g) as a white solid.

Example 2: (5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2-(trifluorom ethyl)benzo[d]thiazol-6- yl)methyl)pyrazolidin-1-yl)methanone

To a solution of the compound of Preparation D (0.016 g, 0.051 mmol) in MeCN (0.25 mL) are successively added Nal (0.0015 g, 0.01 mmol), K2CO3 (0.014 g, 0.1 mmol) and the compound of Preparation B (0.015 g, 0.05 mmol). The reaction mixture is refluxed for 2 h. After cooling to r.t., the volatiles are removed in vacuo and the residue is purified by prep. HPLC to afford the title compound (0.001 g) as a white solid. LC-MS (C): t _R = 1.239 min; [M+H] ⁺ = 473.3.

Example 3.1: (2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazo l-6-yl)methyl)pyrazolidin-1- yl)methanone

To a solution of the compound of Preparation A (0.020 g, 0.065 mmol) in DMF (0.5 mL) are added 2-(2H-1,2,3- triazol-2-yl)benzoic acid (0.012 g, 0.043 mmol), DIPEA (0.072 mL, 0.41 mmol) and HATU (0.034 g, 0.09 mmol). The reaction proceeds at r.t. for 2h. The reaction mixture is dissolved in DMF (1 mL) and 0.5% aq. NH4OH. The resulting solution is purified by prep. HPLC to afford the title compound (0.0035 g) as a white solid. In analogy to the procedure described herein before, the following examples 3.1 to 3.16 are prepared using the corresponding carboxylic acid:

Example 4.1: [(2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiaz ol-6-yl)methyl)tetrahydropyridazin- 1(2H)-yl)methanone

To a solution of the compound of Preparation Y (0.020 g, 0.07 mmol) in DMF (0.5 mL) are added 2-(2H-1,2,3- triazol-2-yl)benzoic acid (0.013 g, 0.07 mmol), DIPEA (0.072 mL, 0.41 mmol) and HATU (0.034 g, 0.09 mmol). The reaction proceeded at r.t. for 2h. The reaction mixture is dissolved in DMF (1 mL) and 0.5% aq. NH4OH. The resulting solution is purified by prep. HPLC to afford the title compound (0.0048 g) as a white solid.

In analogy to the procedure described herein before, the following examples 4.1 to 4.3 are prepared using the corresponding carboxylic acid: Example 5: (5-chloro-2-(4-methyl-2H-1,2,3-triazol-2-yl)phenyl)(2-((2-me thylbenzo[d]thiazol-6- yl)methyl)pyrazolidin-1-yl)methanone

To a mixture of example 3.14 (0.03 g, 0.06 mmol), K2CO3 (0.02 g, 0.17 mmol), Pd(PPh3)4 (0.01 g, 0.012 mmol), in dioxane (1 mL) is added trimethylboroxine (0.01 mL, 0.08 mmol). The reaction proceeded at 100°C for 2 h. After cooling, the evaporation residue is purified by prep. HPLC to afford the title compound (0.02 g) as a white solid. LC-MS (C): t _R = 1.075 min; [M+H]+ = 453.1.

Example 6: (5-chloro-2-(4-ethynyl-2H-1,2,3-triazol-2-yl)phenyl)(2-((2-m ethylbenzo[d]thiazol-6- yl)methyl)pyrazolidin-1-yl)methanone

6.i. (5-chloro-2-(4-((trimethylsilyl)ethynyl)-2H-1,2,3-triazol-2- yl)phenyl)(2-((2-methylbenzo[d]thiazol-6- yl)methyl)pyrazolidin-1-yl)methanone'.

To a mixture of Cui (0.002 g, 0.01 mmol) and PdCl2(PPhs)2 (0.004 g, 0.01 mmol) are added a solution of example 3.14 (0.030 g, 0.0579 mmol) in THF (0.45mL) and then trimethylsilylacetylene (0.01 mL, 0.07 mmol) and triethylamine (0.02 mL, 0.15 mmol). The reaction proceeded at 50°C for 2h. After cooling the crude mixture is purified by prep HPLC to afford the title compound (0.022 g, 73% yield) as an off-white solid. LC-MS (C): tR = 1.17 min; [M+H]+ = 535.3.

6.ii. (5-chloro-2-(4-ethynyl-2H-1,2,3-triazol-2-yl)phenyl)(2-((2-m ethylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1- yl)methanone'.

To a solution of intermediate 6.i (0.02 g, 0.04 mmol) in MeOH (0.15 mL) is added K2CO3 (0.01 g, 0.07 mmol). The reaction proceeded at r.t. for 2h. The reaction mixture is purified by prep. HPLC to afford the title compound (0.016 g) as a white solid. LC-MS (C): t _R = 1.113 min; [M+H]+ = 463.2.

Example 7.1 : (2-((2-bromobenzo[d]thiazol-6-yl)methyl)pyrazolidin-1-yl)(5- chloro-2-(2H-1,2,3-triazol-2- yl)phenyl)methanone

To a solution of the compound of Preparation AB (0.215 g, 0.684 mmol) and the compound of Preparation AG (0.182 g, 0.753 mmol) in DCM (7 mL) is added sodium triacetoxyborohydride (0.23 g, 1.03 mmol). The reaction proceeded at r.t. for 16h. The reaction mixture is partitioned between DCM (15 mL) and sat. NaHCOs (15 mL). The two layers are separated and the evaporation residue is purified by FC (heptane-EtOAc) to afford the title compound (0.275 g) as a white foam. LC-MS (C): t _R = 1.176 min; [M+H] ⁺ = 505.1.

In analogy to the procedure described herein before, the following reference examples 7.1 to 7. are prepared using the indicated intermediates:

Example 8: (5-chloro-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2-(trifluorom ethyl)benzo[d]thiazol-6- yl)methyl)pyrazolidin-1-yl)methanone

To a solution of Example 7.1 (0.02 g, 0.0496 mmol) in DMF (0.15 mL) are added Cui (0.011 g, 0.0595 mmol), 2,6- lutidine (0.00701 mL, 0.0595 mmol) and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (0.03 g, 0.149 mmol). The reaction proceeded at 80°C for 18 h. After cooling, the reaction mixture is directly is purified by prep. HPLC to afford the title product (0.011 g) as an off-white solid. LC-MS (C): IR = 1 .236 min; [M+H] ⁺ = 493.2.

Example 9.1: (5-chloro-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2-cyclopropyl benzo[d]thiazol-6- yl)methyl)pyrazolidin-1-yl)methanone

To a mixture of Example 7.1 (0.014 g, 0.031 mmol), CS2CO3 (0.027 g, 0.084 mmol), Pd(dppf)Cl2 (0.003 g, 0.004 mmol), 2-cyclopropyl-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (0.0058 mL, 0.031 mmol) in dioxane (0.2mL) is added water (0.002mL). The reaction proceeded at 100°C for 8 h. The reaction mixture is purified by prep. HPLC to afford the title compound (0.002g) as a beige solid. LC-MS (C): IR = 1.130 min; [M+H] ⁺ = 465.2.

Example 9.2: (5-chloro-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2-ethylbenzo[ d]thiazol-6-yl)methyl)pyrazolidin-1- yl)methanone

Starting from Example 7.1 (0.025 g, 0.049 mmol) and triethyl-1 ,3,5,2,4,6-trioxatriborinane (0.026 g, 0.149 mmol) and proceeding as described in Example 9.1, the title compound (0.011 g) is prepared as a white solid after purification by prep. HPLC. LC-MS (C): IR = 1.103 min; [M+H] ⁺ = 453.2.

Example 10.1 : (RS)-(4-methyl-2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyraz olidin-1-yl)(5-methyl-2-(2H- 1,2,3-triazol-2-yl)phenyl)methanone

Starting from the compound of Preparation AH (0.040 g, 0141 mmol) and 5-methyl-2-(2/-/-1 ,2,3-triazol-2-yl)benzoic acid (0.031 g, 0.155 mmol) and proceeding according to the procedure of Example 3.1 , the title compound (0.022 g) is prepared as a white solid, after purification by prep. HPLC.

In analogy to the procedure described herein before, the following examples 10.1 to 10.3 are prepared using the corresponding carboxylic acid:

Example 10.4: (R)-(5-chloro-2-(2H-1,2,3-triazol-2-yl)phenyl)(4-methyl-2-(( 2-methylbenzo[d]thiazol-6- yl)methyl)pyrazolidin-1-yl)methanone and

Example 10.5: (S)-(5-chloro-2-(2H-1,2,3-triazol-2-yl)phenyl)(4-methyl-2-(( 2-methylbenzo[d]thiazol-6- yl)methyl)pyrazolidin-1-yl)methanone

Two enantiomers of (RS)-(5-chloro-2-[1 ,2,3]triazol-2-yl-phenyl)-[4-methyl-2-(2-methyl-benzothiazol -6-ylmethyl)- pyrazolidin-1 -yl]-methanone are separated using chiral HPLC to get first (R)-(5-chloro-2-(2H-1 ,2,3-triazol-2- yl) phenyl) (4-methy l-2-((2-methyl benzo[d]th iazol-6-y I) methyl) pyrazolid i n- 1 -yl)methanone and then (S)-(5-chloro-2- (2H-1 ,2,3-triazol-2-yl)phenyl)(4-methyl-2-((2-methylbenzo[d]thiaz ol-6-yl)methyl)pyrazolidin-1-yl)methanone.

Preparative chiral HPLC conditions: ChiralPak IH column 30x250 mm, 5pm; eluent A: CO2, temperature: 40°C, eluent B: MeCN/2-propanol 1 :1; 10Obar; flow: 160 mL/min; tR (S-configurated enantiomer, Example 10.5) = 2.9 min, tR (R-configurated enantiomer, Example 10.4) = 3.5 min. Analytical chiral HPLC conditions: ChiralPak IH column 4.6x250 mm, 5pm; eluent A: CO2, temperature: 40°C, eluent B: MeCN/2-propanol 1 :1 (isocratic, 35%B); 150bar; flow: 4 mL/min; t (S-configurated enantiomer, Example 10.5) = 2.5 min, t (R-configurated enantiomer, Example 10.4) = 2.9 min

The absolute configuration and retention time of (R)-(5-chloro-2-(2H-1 ,2,3-triazol-2-yl)phenyl)(4-methyl-2-((2- methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1 -yl)methanone is determined by synthesizing an authentic sample as follows:

Starting from the compound of Preparation AK (0.2 g, 0.719 mmol) and 5-chloro-2-(2H-1,2,3-triazol-2-yl)benzoic acid (0.169 g, 0.755 mmol) and proceeding according to the procedure of Example 3.1 , Example 10.4 (0.26 g, 80% yield) is prepared as a white solid, after purification by FC (Heptane-EtOAc). LC-MS (C): tR = 1.103 min; [M+H] ⁺ = 453.2. Analytical chiral HPLC conditions: ChiralPak IH column 4.6x250 mm, 5pm; eluent A: CO2, temperature: 40°C, eluent B: MeCN/2-propanol 1 :1 (isocratic, 35%B); 150bar; flow: 4 mL/min tR (R-configured enantiomer, Example 10.4) = 2.9 min Example 10.6: (R)-4-methyl-2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazol idin-1-yl)(5-methyl-2-(2H-1,2,3- triazol-2-yl)phenyl)methanone and

Example 10.7: (S)-4-methyl-2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazol idin-1-yl)(5-methyl-2-(2H-1,2,3- triazol-2-yl)phenyl)methanone

Two enantiomers of (RS)-4-methyl-2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazo lidin-1-yl)(5-methyl-2-(2/-/-1,2,3- triazol-2-yl)phenyl)methanone are separated using chiral HPLC to get (R)-4-methyl-2-((2-methylbenzo[d]thiazol-6- yl) methyl) pyrazol idi n- 1 -yl)(5-methy l-2-(2/7- 1 ,2,3-triazol-2-yl)phenyl)methanone and (S)-4-methyl-2-((2- methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1-yl)(5-methyl -2-(2/-/-1 ,2,3-triazol-2-yl)phenyl)methanone. Chiral HPLC conditions: ChiralPak OZ-H column 30x250 mm, 5pm; eluent A: CO2, temperature: 40°C, eluent B: MeCN/EtOH1 :1 ; 10Obar; flow: 160 mL/min; t _R = 2.3 and 3.3 min.

The absolution configuration of each enantiomer is not assigned.

Example 10.8: (S)-(2-(4-bromo-2H-1,2,3-triazol-2-yl)-5-chlorophenyl)(4-met hyl-2-((2-methylbenzo[d]thiazol- 6-yl)methyl)pyrazolidin-1-yl)methanone and

Example 10.9: (R)-(2-(4-bromo-2H-1,2,3-triazol-2-yl)-5-chlorophenyl)(4-met hyl-2-((2-methylbenzo[d]thiazol- 6-yl)methyl)pyrazolidin-1-yl)methanone

Two enantiomers of (RS)-(2-(4-bromo-2H-1, 2, 3-triazol-2-yl)-5-chlorophenyl)(4-methyl-2-((2-methylbenzo[d ]thiazol- 6-yl)methyl)pyrazolidin-1-yl)methanone are separated using chiral HPLC to get first (S)-(2-(4-bromo-2H-1,2,3- triazol-2-yl)-5-chlorophenyl)(4-methyl-2-((2-methylbenzo[d]t hiazol-6-yl)methyl)pyrazolidin-1-yl)methanone and (/?)- (2-(4-bromo-2H-1 ,2,3-triazol-2-yl)-5-chlorophenyl)(4-methyl-2-((2-methylbenz o[d]thiazol-6-yl)methyl)pyrazolidin-1- yl)methanone. Chiral HPLC conditions: ChiralCel OJ-H column 30x250 mm, 5pm; eluent A: CO2, temperature: 40°C, eluent B: MeCN/EtOH1 :1 (15%); 100bar; flow: 160 mL/min; t _R = 3.2 and 3.99 min.

The absolute configuration and retention time of (S)-(2-(4-bromo-2/7-1 ,2,3-triazol-2-yl)-5-chlorophenyl)(4-methyl-2- ((2-methylbenzo[e/]thiazol-6-yl)methyl)pyrazolidin-1 -yl)methanone is assigned as follows:

To a solution Example 10.8 (first eluting enantiomer of Example 10.3) (0.07 g, 0.13 mmol) in MeOH (2.4 mL) and EtsN (0.06 mL, 0.4 mmol) is added under nitrogen atmosphere Pd(OH)2, 20 wt. % (0.02g). The reaction proceeded 2h under hydrogen atmosphere. The catalyst is removed by filtration and the evaporation residue is purified by prep-HPLC to yield Example 10.5 (0.04 g, 75% yield) as a white freeze dried solid. LC-MS (A): t _R = 0.98 min; [M+H] ⁺ = 453.2. Analytical chiral HPLC conditions: ChiralPak IH column 4.6x250 mm, 5pm; eluent A: CO2, temperature: 40°C, eluent B: MeCN/2-propanol 1 :1 (isocratic, 35%B); 150bar; flow: 4 mL/min t _R (S-configured enantiomer, Example 10.5) = 2.5 min. Example 11 : (5-methyl-2-(2H-1 ,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]oxazol-6-yl)me thyl)pyrazolidin- 1-yl)methanone

Starting from the compound of Preparation B (0.018 g, 0.061 mmol) and 2-methyl-benzo[d]oxazole-6-carbaldehyde (0.006g, 0.061 mmol) and proceeding as described in Example 1.1 , the title compound (0.010 g) is prepared as a white solid after purification by prep. HPLC. LC-MS (C): IR = 0.930 min; [M+H] ⁺ = 403.3.

Example 12.1: (2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazo l-6-yl)methyl)pyrazolidin-1-yl-4,4- d2)methanone

To a solution of the compound of Preparation AL (0.025 g, 0.092 mmol) in DMF (0.5 mL) are added 2-(2H-1,2,3- triazol-2-yl)benzoic acid (0.017 g, 0.092 mmol), DIPEA (0.047 mL, 0.27 mmol) and HATU (0.042 g, 0.11 mmol). The reaction proceeded at r.t. for 16h. The reaction mixture is dissolved in DMF (1 mL) and 0.5% aq. NH4OH. The resulting solution is purified by prep. HPLC to afford the title compound (0.0027 g) as a white solid.

In analogy to the procedure described herein before, the following examples 12.1 to 12.3 are prepared using the corresponding carboxylic acid:

Example 12.4: (5-chloro-2-(2H-1,2,3-triazol-2-yl-d)phenyl)(2-((2-methylben zo[d]thiazol-6- yl)methyl)pyrazolidin-1-yl)methanone

To a solution of Example 3.14 (0.053 g, 0.10 mmol) in MeOH-c (2.4mL) under N2 is added Pd(OH)2/C (20wt%, 0.012 g). The reaction proceeded under D2 atmosphere for 1 hi 5. The catalyst is removed by filtration and the evaporation residue is purified by prep-HPLC to yield the title compound (0.039g, 87% yield)as a white solid. LC- MS (C): t _R = 1.015 min; [M+H] ⁺ = 440.3. ¹ H NMR (500 MHz, DMSO-cfe) 5: 8.07 (s, 1 H), 7.88 (d, J = 8.7 Hz, 1 H), 7.69 (d, J = 8.3 Hz, 1 H), 7.58 (dd, J = 2.4, 8.7 Hz, 1 H), 7.43 (d, J = 1.3 Hz, 1 H), 7.00 (s, 1 H), 6.87 (dd, J = 1.6, 8.3 Hz, 1 H), 3.64 (s, 2 H), 3.77-3.50 (overlapped m, 2 H), 2.77 (s, 3 H), 2.64-2.49 (overlapped m, 1 H), 2.26-1.79 (m, 3 H). Example 12.5: (R)-(5-chloro-2-(2H-1,2,3-triazol-2-yl-d)phenyl)(4-methyl-2- ((2-methylbenzo[d]thiazol-6- yl)methyl)pyrazolidin-1-yl)methanone

Starting from Example 10.9 (0.03 g, 0.056 mmol) and proceeded as described in Example 12.4, the title compound (0.021 g) is obtained as a white solid after purification by prep-HPLC. LC-MS (C): IR = 1.091 min; [M+H] ⁺ = 454.3.

Reference Examples

Reference Example RE1.1: (2-(benzo[d]thiazol-6-ylmethyl)pyrazolidin-1-yl)(5-chloro-2- (2H-1,2,3-triazol-2- yl)phenyl)methanone

To a solution of the compound of Preparation AB (0.02 g, 0.057 mmol) and 6-benzo[d]thiazolecarbaldehyde (0.010 g, 0.061 mmol) in DCM (0.5 mL) is added sodium triacetoxyborohydride (0.019 g, 0.089 mmol). The reaction proceeded at r.t. for 16h. The reaction mixture is partitioned between (DCM (5 mL) and sat. NaHCOa (5 mL). The two layers are separated and the evaporation residue is purified by prep. HPLC to afford the title compound (0.013 g) as a white solid.

In analogy to the procedure described herein before, the following reference examples RE1.1 and RE1.2 are prepared using commercially available aldehydes and the indicated intermediates:

Reference Example RE1.3: (5-chloro-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo [d]thiazol-5- yl)methyl)pyrazolidin-1-yl)methanone

RE 1.3. i . 2-methyl-5-(pyrazolidin-1-ylmethyl)benzo[d]thiazole hydrochloride'.

Starting from tert-butyl 1-pyrazolidinecarboxylate (0.250 g, 1.45 mmol) and 2-methyl-benzothiazole-5- carbaldehyde (0.271 g, 1 .47 mmol) and proceeding successively as described in Preparation A, steps A.i and A.ii, the title compound (0.103 g) is obtained as an orange solid. LC-MS (A): IR = 0.50 min; [M+H] ⁺ = 234.17.

RE1.3.ii. (5-chloro-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo [d]thiazol-5-yl)methyl)pyrazolidin-1- yl)methanone'.

Starting form the intermediate RE.1.3J (0.020 g, 0.0741 mmol) and 5-chloro-2-(2/-/-1 ,2,3-triazol-2-yl)benzoic acid (0.0188 g, 0.0815 mmol) and proceeding as described in Example 3.1, the title compound (0.016 g) is obtained as a white solid after purification by prep. HPLC. LC-MS (C): IR = 1 .041 min; [M+H] ⁺ = 439.2. Reference Example RE1.4: (5-chloro-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2-methyl-1H-b enzo[d]imidazol-6- yl)methyl)pyrazolidin-1-yl)methanone

Starting from the compound of Preparation AB (0.03 g, 0.0955 mmol) and 2-methyl-1 H-1 ,3-benzodiazole-5- carbaldehyde (0.02g, O.H mmol) and proceeding as described in Example 7.1, the title compound (0.015 g) is prepared as a white solid after purification by prep. HPLC. LC-MS (C): IR = 0.476 min; [M+H] ⁺ = 422.3.

Reference Example RE1.5: (2-((2-methyl-1H-benzo[d]imidazol-6-yl)methyl)pyrazolidin-1- yl)(5-methyl-2-(2H- 1,2,3-triazol-2-yl)phenyl)methanone

Starting from the compound of Preparation B (0.025 g, 0.0955 mmol) and 2-methyl-1 H-1 ,3-benzodiazole-5- carbaldehyde (0.016g, 0.093mmol) and proceeding as described in Example 7.1 , the title compound (0.016 g) is prepared as a white solid after purification by prep. HPLC. LC-MS (C): IR = 0.476 min; [M+H] ⁺ = 402.3.

Physical characterization

Solubility is determined by the miniaturized saturation shake flask method (screening mode). The compound form is an amorphous film, from DMSO evaporation of a 10 mM stock solution, on which FaSSIF (Fasted State Simulated Intestinal Fluid) medium is added. After 24h of equilibration at 25°C, phases are separated by filtration and aqueous phase compound concentration in aqueous phase is determined by UV-HPLC.

Results: Solubility of the compound of example 3.3: 497 pg/mL; compound of example 10.4: > 770 pg/mL.

Biological assays

Antagonistic activities on both orexin receptors have been measured for each example compound using the following procedure:

In vitro assay: Intracellular calcium measurements:

Chinese hamster ovary (CHO) cells expressing the human orexin-1 receptor and the human orexin-2 receptor, respectively, are grown in culture medium (Ham F-12 with L-Glutamine) containing 300 pg/ml G418, 100 U/ml penicillin, 100 pg/ml streptomycin and 10 % heat inactivated fetal bovine serum (FBS). The cells are seeded at 20’000 cells / well into 384-well black clear bottom sterile plates (Greiner). The seeded plates are incubated overnight at 37°C in 5% CO2.

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), NaHCOa 0.375g/l and 20 mM HEPES for use in the assay at a final concentration of 2 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), NaHCOa: 0.375g/l and 20 mM HEPES. On the day of the assay, cells are washed twice with 100 l assay buffer (HBSS containing NaHCCh: 0.375g/l, 20 mM HEPES and 5 mM Probenecid) using a BioTek EL406 cell washer, 25 pl assay buffer is left on the cells after the washes. 25 pL dye solution (HBSS containing 2 % FBS, 20 mM HEPES, NaHCCh: 0.375g/l, 5 mM probenecid (Sigma) and 4 pM of the fluorescent calcium indicator Fluo-8 AM (2 mM stock solution in DMSO)) is added to each well. The 384-wel I cell-plates are incubated for 60min at 37° C in 5% CO2 followed by equilibration at RT for 15min before measurement.

Within the Fluorescent Imaging Plate Reader (FLIPR Tetra, Molecular Devices), antagonists are added to the plate in a volume of 10 pl/well, incubated for 120 min and finally 10 pl/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 ECso (for example 2 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 . Reference compounds are added on each plate. 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 0x1 and 0x2 receptor are displayed in 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.

Physiologically Based Pharmacokinetic - Pharmacodynamic (PBPK-PD) models are employed to support preclinical development by prioritizing candidate compounds with desirable pharmacokinetic and pharmacodynamic properties/profiles. The models are developed by combining in vitro measured parameters and in silico predicted values, while taking into account the physiology of the respective species.

Measurements of metabolic stability in human liver microsomes and permeability in MDCK-MDR1 cells Microsomal stability assay

Liver microsomes are subcellular fractions, which can be used to measure the intrinsic clearance of a compound and are useful in vitro models of e.g., the hepatic clearance as they contain many of the drug metabolizing enzymes found in the liver. Usually, the microsomes are incubated with the test compound at 37°C in the presence of NADPH (co-factor which initiates the reaction). The disappearance of the compound is monitored over a specific time period (e.g. 45 minutes).

MDCK-MDR1

MDCK-MDR1 cells are Madin Darby canine kidney (MDCK) cells transfected with the MDR1 gene (ABCB1), the gene encoding for the efflux protein, P-glycoprotein (P-gp).When measuring drug transport in both directions (apical to basolateral (A-B) and basolateral to apical (B-A)) across the cell monolayer, an efflux ratio can be determined, which can indicate whether a compound is actively being transported by P-gp, i.e., if a compound is a substrate of P-gp transporter, P-gp will efflux the drug from the inside to the cell to the apical side, preventing its permeation. MDCK-MDR1 helps to gain an understanding of the mechanism of drug efflux, and highlights early potential issues with drug permeability.ln addition to intestinal permeability, MDCK-MDR1 permeability has also been found to be a useful predictor of blood brain barrier permeability.

In this particular assay, MDR1-MDCK cell monolayers are grown to confluence on collagen-coated, microporous membranes in 12-well assay plates. The permeability assay buffer is Hanks’ balanced salt solution containing 10 mM HEPES and 15 mM glucose at a pH of 7.4. The buffer in the receiver chamber also contains 1% bovine serum albumin (BSA). The dosing solution concentration is 1 pM of test article in the assay buffer. Cell monolayers are dosed on the apical side (A-to-B) or basolateral side (B-to-A) and incubated at 37°C with 5% CO2 in a humidified incubator. Samples are taken from the donor and receiver chambers at 120 minutes. Each determination is performed in duplicate. The flux of lucifer yellow is also measured post-experimentally for each monolayer to ensure no damage is inflicted to the cell monolayers during the flux period. All samples are assayed by LC-MS/MS using electrospray ionization.

For example, compounds show the following permeability coefficients:

Sedative effects: EEG, EMG and behavioural indices of alertness recorded by radiotelemetry in vivo in beagle dogs. Electroencephalography (EEG), Electromyography (EMG), and Electrocardiographic (ECG) signals are measured by telemetry using D70-EEE radiotelemetric implants (Data Science Int.) with three pairs of differential leads.

Surgical implantation is performed under general anesthesia with isoflurane and tracheal intubation, for cranial placement of one pair of EEG electrodes and a reference electrode, placement of one pair of ECG electrodes in the cardiac region, and insertion of one EMG lead in either side of the muscles of the neck. After surgery, dogs recover in a recovery room under obseravation and receive analgesic treatment with parecoxib for 5 d and cerfradine for 7d. All dogs are allowed 4 weeks of recovery before start of the experiment. For accurate and stress- free acquisition of biosignals during a experiment using the telemetric technology, the dogs are kept in an observastion station, on a 12-h light / 12-h dark cycle, with no recording leads restricting their movements. Variables analyzed include four different stages of vigilance and sleep and spontaneous activity. Sleep and wake stages are evaluated using a scoring software (Neuroscore; Data Science Int) 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 time spent in AW, QW, NREM- and REM-sleep, total sleep and toal wake time is calculated per 12 h light or dark period and shorter time intervals. Recording is started immediately before test compound or vehicle is given at 10 am. Test compound or vehicle is given orally in gelatine capsules. Food is provided for 30 min 3 h posttreatment (1 :00 pm), and a toy is provided in the animal cages/observation station 6-h post-treatment (4:00 pm), to elicit gently stimulating anticipation in the dogs in the post-prandial phase. Lights are turned off at 7:30 pm and turned on again at 7:00 am. Night-time and daytime recordings are performed under constant infrared illumination and automatic filtering by the cameras.

Total sleep time over 3h was 80 ± 14 min and 92 ± 12 min after 30 mg and 90 mg of the compound of example 3.3 as compared to placebo (46 ± 13 min) with 78 ± 14 min, 90 ± 11 min, and 46 ± 13 min (30 mg, 90 mg, placebo) spent in non-REM sleep. Total wake time was 99 ± 14 min, 87 ± 12 min and 133 ± 14 min over 3h after 30 mg and 90 mg of the compound of example 3.3 and placebo.

Total sleep time over 3h was 64 ± 9 min and 64 ± 9 min after 30 mg and 90 mg of the compound of example 10.4 as compared to placebo (36 ± 9 min) with 60 ± 8 min, 60 ± 9 min, and 35 ± 9 min (30 mg, 90 mg, placebo) spent in non-REM sleep. Total wake time was 125 ± 11 min, 115 ± 9 min and 132 ± 11 min over 3h after 30 mg and 90 mg of the compound of example 10.4 and placebo.