TW202400149A - Thiazoloaryl-methyl substituted cyclic hydrazine-n-carboxamide derivatives - Google Patents

Abstract

The present invention relates to compounds of the formula (I) wherein Ar1, R1, R2, R3, X1, X2, Y, and Z are as described in the description, to their preparation, to pharmaceutically acceptable salts thereof, and to their use as pharmaceuticals, to pharmaceutical compositions containing one or more compounds of formula (I), and especially to their use as orexin receptor antagonists.

Description

Cyclic hydrazine-N-formamide derivatives substituted by thiazoloaryl-methyl

The present invention relates to novel cyclic hydrazine-N-methamide derivatives of formula (I) and their use as pharmaceuticals. The present invention also relates to related aspects including processes for preparing the compounds, pharmaceutical compositions containing one or more compounds of formula (I), and their use as orexin receptor antagonists.

Orexin hormones (orexin A or OX-A and orexin B or OX-B) are neuropeptides discovered by two research groups in 1998. Orexin A is a peptide with 33 amino acids and orexin B is a peptide with 28 amino acids. Amino acid peptides (Sakurai T. et al., Cell, 1998, 92, 573-585). Orexin is produced in discrete neurons in the lateral hypothalamus and binds to G protein-coupled receptors (OX ₁ and OX ₂ receptors). The orexin-1 receptor (OX ₁ ) is selective for OX-A, and the orexin-2 receptor (OX ₂ ) is capable of binding OX-A as well as OX-B. Orexin receptor antagonist is a new type of nervous system or psychotropic drug. Its mode of action in animals and humans involves blocking orexin-1 and orexin-2 receptors (dual antagonists), or individually and selectively blocking orexin-1 or orexin-2 receptors in the brain (selective antagonist). Orexigenic hormones were originally discovered in rats to stimulate food consumption, suggesting a physiological role for these peptides as mediators in central feedback mechanisms regulating eating behavior (Sakurai T. et al., Cell, 1998, 92, 573-585).

On the other hand, orexin neuropeptides and orexin receptors play a basic and central role in regulating the circadian alert state. 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 areas. The specific distribution of orexin fibers and receptors in the basal forebrain, limbic structures, and brainstem regions (regions involved in regulating arousal, sleep, and emotional responses) suggests that orexin plays a fundamental function as a modulator of behavioral arousal; by By firing from activated wake-promoting cells, orexigenic hormones help coordinate all brain arousal systems that regulate circadian activity, energy balance, and emotional responses. This action opens up tremendous therapeutic opportunities to medically address numerous mental health disorders that may be associated with orexin-stimulated dysfunction [see, e.g., 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 ], which are described in the following sections. Orexigenic hormones have also been observed to regulate sleep and wakefulness, opening up potential novel treatments for insomnia and other sleep disorders (Chemelli R.M. et al., Cell, 1999, 98, 437-451).

Human memory consists of multiple systems with different operating principles and different underlying neuronal substrates. The main distinction is between conscious, declarative memory abilities and a set of unconscious, non-declarative memory abilities. Declarative memory is further divided into semantic memory and episodic memory. Non-declarative memory is further divided into guided learning and perceptual learning, procedural memory of skills and habits, relevant and irrelevant learning and some other learning. While semantic memory refers to common knowledge about the world, episodic memory is the autobiographical memory of events. Procedural memory refers to the ability to perform skill-based operations, such as motor skills. Long-term memory is established during a multi-stage process that begins with learning or memory acquisition or formation through gradual changes involving different brain structures. Subsequently, consolidating what has been learned stabilizes the memory. When long-term memory is retrieved, it can return to an unstable state where the original content can be updated, adjusted, or destroyed. Subsequently, reconsolidation can stabilize the memory again. At later stages, long-term memory can become resistant to damage. Long-term memory is conceptually and anatomically different from working memory, which is the ability to temporarily retain a limited amount of information. Behavioral research has shown that the human brain consolidates long-term memories at certain critical intervals. The initial stages of memory consolidation can occur within the first few minutes after we are exposed to a new idea or learning experience. The next and probably most important stage can exist over longer periods of time, such as during sleep; indeed, some consolidation processes have been shown 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 psychiatric disorders, such as, for example, mental retardation, Alzheimer's disease or depression. In fact, memory loss or impairment of memory acquisition is a prominent feature of these diseases, and effective treatments to prevent this harmful process have not yet emerged.

In addition, anatomical and functional evidence from in vitro and in vivo studies indicate that the endogenous orexigenic hormone system has important positive interactions with the brain's reward pathways [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 reduces cues and restores stress-induced cocaine seeking [Boutrel B et al., "Role for hypocretin in mediating stress-induced reinstatement of cocaine-seeking behavior." Proc NatI 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], suggesting induced alcohol seeking recovery [Lawrence AJ et al., Br J Pharmacol 2006, 148(6) , 752-759] and nicotine auto-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 attenuates the manifestations of amphetamine- and cocaine-induced CPP [Gozzi A et al., PLoS One 2011, 6(1), e16406; Hutcheson DM et al., Behav Pharmacol 2011, 22 (2), 173-181], and reduce the manifestation or development of motor 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 effects of drugs attenuating addiction disorders can be modeled in normal or specifically sensitive mammals used as animal models [see, e.g., 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", Neuropsychopharmacology: The fifth generation of progress; K.L.Davis, D. Charney, J.T.Doyle, C. Nemeroff (eds.) 2002; Chapter 97, pp. 1381-1397] .

Several converging lines of evidence further support a direct role for the orexigenic system as a modulator of the acute stress response. For example, stress (ie, psychological or physical stress) is associated with increased arousal and alertness, which are controlled by appetite hormones [Sutcliffe, JG et al., Nat Rev Neurosci 2002, 3(5), 339- 349]. Orexin neurons are likely involved in coordinating behavioral and physiological responses in stressful environments [Y. Kayaba et al., Am. J. Physiol. Regul. Integr. Comp. Physiol. 2003, 285: R581-593]. Hypotocretin/orexin contributes to some but not all forms of stress and arousal manifestations [Furlong T M et al., Eur J Neurosci 2009, 30(8), 1603-1614]. The stress response can cause significant, often time-limited, physiological, psychological, and behavioral changes that can affect appetite, metabolism, and eating behavior [Chrousos, GP et al., JAMA 1992, 267(9), 1244-1252]. The acute stress response may include behavioral, autonomic, and endocrinological changes such as increased alertness, decreased libido, increased heart rate and blood pressure, or redirection of blood flow to the muscles, heart, and brain [Majzoub, JA, et al., European Journal of Endocrinology 2006, 155 (Suppl_1) S71-S76].

As outlined above, the orexigenic hormone system regulates homeostatic functions such as sleep-wake cycles, energy balance, mood, and reward. Orexin is also implicated in mediating acute behavioral and autonomic nervous system responses to stress [Zhang W et al., "Multiple components of the defense response depend on orexin: evidence from orexin knockout mice and orexin neuron-ablated mice." Auton Neurosci 2006 , 126-127, 139-145]. Affective disorders, which include all types of depression and bipolar disorders, are characterized by disturbed "emotions" and feelings, as well as sleep problems (insomnia and hypersomnia), changes in appetite or weight, and pleasure in daily or one-time enjoyment of sexual activities Reduction and loss of interest [Liu X et al., 2007, 30(1): 83-90]. Therefore, there is a strong rationale that disruption of the orexigenic hormone system may contribute to symptoms of affective disorders. For example, there are signs in humans that depressed patients show blunted diurnal changes in CSF orexigenic hormone levels [Salomon RM et al., Biol Psychiatry 2003, 54(2), 96-104]. Appetite hormones have also been shown to be involved in rodent models of depression. For example, pharmacologically induced melancholic behavioral states in rats revealed a correlation with increased hypothalamic orexigenic hormone levels [Feng P et al., J Psychopharmacol 2008, 22(7): 784-791]. The long-term stress model of depression in mice also confirmed the correlation between the interference of the molecular appetite hormone system and the behavioral state of depression and the reversal of these molecular changes by antidepressant treatment [Nollet et al., NeuroPharm 2011, 61(1-2): 336- 46].

The orexigenic hormone system is also involved in stress-related appetite/reward seeking behavior (Berridge CW et al., Brain Res 2009, 1314, 91-102). In some cases, modulatory effects on stress may be complementary to effects on such appetitive/reward-seeking behavior. For example, OX _1- selective orexin receptor antagonists prevent reinstatement of cocaine-seeking behavior induced by foot strike stress [Boutrel, B et al., Proc Natl Acad Sci 2005, 102(52), 19168-19173]. In addition, stress is also known to play a component in the withdrawal that occurs during cessation of drug use (Koob, GF et al., Curr Opin Investig Drugs 2010, 11(1), 63-71).

Orexigenic hormones have been found to increase food intake and appetite [Tsujino, N, Sakurai, T, Pharmacol Rev 2009, 61(2) 162-176]. As another environmental factor, stress can contribute to binge eating behavior and contribute 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.

Many recent studies have reported that orexigenic hormones play a role in several other important functions related to arousal, especially when the organism must respond to unexpected stressors and triggers 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 orexigenic hormone system interacts with neural networks that regulate mood, reward, and energy homeostasis to maintain appropriate alertness. Therefore, functional impairments can be associated with many mental health disorders involving disturbances in alertness, arousal, arousal, or attention.

Compound (2R)-2-{(1S)-6,7-dimethoxy-1-[2-(4-trifluoromethyl-phenyl)-ethyl]-3,4-dihydro-1H -Isoquinolin-2-yl}-N-methyl-2-phenyl-acetamide (WO2005/118548), a dual orexigenic hormone receptor antagonist, was found to be effective in humans when tested for indications in primary insomnia showed clinical efficacy. In rats, this compound has been shown to reduce alertness, characterized by reduced active wakefulness and locomotion; and dose-dependently increase time spent in REM and NREM sleep [Brisbare-Roch et al., Nature Medicine 2007, 13, 150-155]. The compound further weakened the cardiovascular response 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 the following animal models of conditioned fear: the rat fear-potentiated startle paradigm (WO 2009/0047723), which is implicated in fear and anxiety disorders such as anxiety disorders, including phobias and post-traumatic stress disorder ( The emotional state of PTSD)). In addition, intact declarative and non-declarative learning and memory have been demonstrated in rats treated with this compound [WO2007/105177, H Dietrich, F Jenck, Psychopharmacology 2010, 212, 145-154]. In addition, the compound reduced amyloid-beta (Aβ) and Aβ plaque deposition in the brain of mice transgenic for amyloid precursor protein after short-term sleep restriction [JE Kang et al., “Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle.", Science 2009, 326(5955): 1005-1007]. It is hypothesized that the accumulation of Aβ in the extracellular space of the brain is a key event in the pathogenesis of Alzheimer's disease. The so-called and generally known "amyloid cascade hypothesis" links Aβ to Alzheimer's disease and thus to cognitive dysfunction manifested by impairments in learning and memory. This compound has also been shown to induce antidepressant-like activity in mouse models of depression when administered chronically [Nollet et al., NeuroPharm 2011, 61(1-2):336-46]. Furthermore, this compound has been shown to attenuate natural activation induced by orexin A in fasted, hungry rats exposed to food odor [MJ Prud'homme et al., Neuroscience 2009, 162(4), 1287-1298]. The compound also showed 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-1H-benzimidazol-2-yl)thio]acetyl}-L-proline Amide inhibits nicotinic reinstatement of conditioned reinforcers and reduces behavioral (motor 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 including 2-substituted saturated cyclic amide derivatives such as 2-substituted pyrrolidine-1-methamide are known from, for example, WO2008/020405, WO2008/038251, WO2008/081399, WO2008/087611, WO2008/117241, WO2008/139416, WO2009/004584, WO2009/016560, WO2009/016564, WO2009/040730, WO2009/104155, WO2010/004507, WO2010/ 038200、WO2001/096302、WO2002/044172、WO2002/ 089800, WO2002/090355, WO2003/002559, WO2003/032991, WO2003/041711, WO2003/051368, WO2003/051873, WO2004/026866, WO2004/041791, WO2004/041807 , WO2004/041816, WO2009/003993, WO2009/003997, WO2009/124956, WO2010/060470, WO2010/060471, WO2010/060472, WO2010/063662, WO2010/063663, WO2010/072722, WO2010/122151 and WO2008/150364 and WO2013/ 182972. WO2003/002559 discloses N-arylyl cyclic amine derivatives, which encompass morpholine derivatives as orexin receptor antagonists. Specific pyrrolidine-derived orexin-1 selective compounds within the scope of WO2003/002559 are disclosed in Langmead et al., Brit. J. Pharmacol. 2004, 141, 340-346: 1-(5-(2-fluorophenyl )-2-methyl-thiazol-4-yl)-1-[(S)-2-(5-phenyl-[1,3,4]oxadiazol-2-ylmethyl)-pyrrolidine- 1-yl)-methanone. WO2003/002561 discloses certain N-arylyl cyclic amine derivatives, including morpholine derivatives substituted by benzimidazol-2-ylmethyl, as orexin receptor antagonists. Despite the large number and high structural variability of prior art compounds, such compounds generally share a common structural feature, namely that they contain a central core ring, such as pyrrolidine, piperidine or morpholine derivatives, with a chiral carbon center in position 2 , the center is generally substituted with an aromatic group via a linking group. WO2013/182972 discloses pyrrolidine derivatives having a benzimidazole ring directly linked to the pyrrolidinamide at position 2. It has now been surprisingly found that, despite the conformational changes expected from the removal of the chiral center in the core ring structure of compounds known in the art, the pyrazoridines of the invention carrying specific substituents in positions 1 and 2 The base derivatives can be potent dual orexigenic hormone receptor antagonists.

Therefore, the present invention provides novel substituted cyclic hydrazine-N-methamide derivatives substituted with thiazoloarylmethyl, which are dual non-peptide antagonists of human orexin-1 and orexin-2 receptors. These compounds particularly have potential use in the treatment of disorders associated with appetite hormone-induced dysfunction, including, inter alia, sleep disorders, including insomnia, as well as anxiety disorders, addiction disorders, cognitive dysfunction, affective disorders, appetite disorders or loss of appetite. Neuropsychiatric symptoms of wisdom. Such compounds may have special advantages, such as bioavailability, the ability to cross the blood-brain barrier; and/or may have specific metabolic and pharmacokinetic characteristics, which may be useful for certain medical uses requiring controlled exposure of the active ingredient. advantageous.

1) The first aspect of the present invention relates to compounds of formula (I) wherein R ¹ represents (C _1-3 ) alkyl (especially methyl), halogen (especially chlorine or bromine), cyclopropyl or trifluoromethyl; [especially R ¹ represents methyl]; X ¹ represents S or O; [especially X ¹ represents S]; X ² represents CH or N; [especially X ² represents CH]; Z represents -CH ₂ -, -CH(CH ₃ )- or -CH ₂ -CH ₂ -; [especially Z represents -CH ₂ - or -CH(CH ₃ )-]; and in the fragment where ● R ² independently represents hydrogen, (C _1-3 ) alkyl (especially methyl), halogen (especially chlorine) or (C _1-3 ) alkoxy (especially methoxy); [worth Note that R ² represents methyl or chlorine, especially chlorine]; ● R ³ independently represents hydrogen or (C _1-3 ) alkyl (especially methyl) [especially R ³ represents hydrogen]; and ● Y independently represents CH or N; [especially Y represents CH]; [wherein, in the sub-embodiments of this embodiment 1), the fragment In particular: and ● Ar ¹ independently means: [In particular Ar ¹ independently means:

Compounds of formula (I) may contain one or more stereogenic or asymmetric centers, such as one or more asymmetric carbon atoms, which may exist in the (R) or (S) configuration. Accordingly, the compounds of formula (I) may exist as mixtures of stereoisomers or preferably as pure stereoisomers. Mixtures of stereoisomers can be separated in a manner known to those skilled in the art.

Where a particular compound (or general structure) is designated as an (R)- or (S)-enantiomer, it is understood that this designation refers to the enriched, especially substantially pure, enantiomer form. individual compounds (or general structures). Likewise, where a particular asymmetric center in a compound is designated as being in the (R) or (S) configuration or in some relative configuration, it should be understood that this designation refers to the respective asymmetric center relative to that asymmetric center. Compounds that are conformationally enriched, especially in substantially pure form. Where a particular compound (or general structure) contains one (or equally, more than one) stereo or asymmetric center (such as one (or more) asymmetric carbon atoms), it may take the form of (R)- or (S) -Configuration exists, but the stereo or asymmetric center is not explicitly designated as (R)- or (S)-, it should be understood that the stereo or asymmetric center can be in the (R)- or (S)-configuration. It should be understood that this compound name or general structure encompasses compounds/general structures in which the center is in the (R)- or (S)-configuration, or any mixture of epimers relative to the center (including racemic things). Likewise, where a stereo or asymmetric center is designated as being in the (RS) configuration, this means that the stereo or asymmetric center in the compound may be in the (R) configuration, the (S) configuration or relative to that center. Any mixture of epimers (including racemates) exists. Where two or more such stereogenic or asymmetric centers are present in a molecule (in unspecified or specified (RS) configurations), it is understood that absolute configuration order does not indicate relative to two or more Any defined relative configuration of the center.

When used in the context of stereoisomers, it will be understood that the term "enriched" in the context of the present invention means the respective stereoisomer relative to each other stereoisomer/respective other stereoisomers as a whole Present in a ratio of at least 70:30, in particular at least 90:10 (i.e. with a purity of at least 70% by weight, in particular at least 90% by weight).

The term "substantially pure" when used in the context of stereoisomers will be understood to mean in the context of the present invention the respective stereoisomer relative to each other stereoisomer/respective other stereoisomers The whole is present in a purity of at least 95% by weight, especially at least 99% by weight.

The present invention also encompasses isotopically labeled, in particular ² H (hydrogen-2, deuterium) labeled compounds of formula (I) according to embodiments 1) to 18), which compounds are the same as compounds of formula (I) but with one or more Atoms that have been replaced by atoms that each have the same atomic number but an atomic mass different from the atomic masses usually found in nature. Isotopically labeled, particularly ² H (deuterium) labeled compounds of formula (I) and their salts are within the scope of the invention. Substitution of hydrogen with the heavier isotope ² H (deuterium) may lead to greater metabolic stability, thereby e.g. extending half-life in vivo or reducing dosage requirements, or may reduce inhibition of cytochrome P450 enzymes, e.g. improving the safety profile. Typical positions generally considered suitable for the introduction of ^H atoms, e.g. to alter metabolic stability, are e.g. attachment to a non-aromatic carbon atom directly bonded to a heteroatom such as oxygen or nitrogen (e.g. methoxy-d ₃ -substituted methoxy The hydrogen atom of the methoxy group in the base-phenyl group. In one embodiment of the invention, the compound of formula (I) is not isotopically labeled, or it is labeled only with one or more ² H atoms. In a sub-embodiment, the compound of formula (I) is not isotopically labeled at all. Isotopically labeled compounds of formula (I) can be prepared analogously to the methods described below, but using appropriate isotopic variants of suitable reagents or starting materials.

In this patent application, bonds drawn with dashed lines show the points of attachment of the drawn groups. For example, the group drawn below Department of 3-methylphenyl. Where the plural form is used for compounds, salts, pharmaceutical compositions, diseases and the like, it is also intended to refer to a single compound, salt or the like.

Where appropriate and advantageous, it is to be understood that any reference to compounds of formula (I) according to Examples 1) to 18) is also a reference to salts (and in particular pharmaceutically acceptable salts) of these compounds.

The term "pharmaceutically acceptable salts" refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesirable 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 Quéré (eds.), RSC Publishing, 2012.

The definitions provided herein are intended to apply uniformly to the compounds of formula (I) as defined in any one of Examples 1) to 18) and (mutatis mutandis) throughout the description and patent claims, unless otherwise expressly stated. Provide a wider or narrower definition. It is fully understood that the definitions or preferred definitions of a term may be defined independently of (and in conjunction with) any definitions or preferred definitions of any or all other terms defined herein and supersede the respective term.

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

The term "halogen" means fluoro/fluorine, chloro/chlorine, bromo/bromine or iodo/iodine; in particular fluorine, chlorine or bromine. For the substituent R ¹ , this term means in particular chlorine or bromine. For the substituent R ² , this term means in particular chlorine.

The term "alkyl" (used alone or in combination and if not specifically defined in a broader or narrower manner) refers to a saturated straight or branched chain hydrocarbon radical containing from one to four carbon atoms. The term "(C _xy )alkyl" (x and y are each an integer) refers to an alkyl group as previously defined containing x to y carbon atoms. For example, (C _1-4 )alkyl contains one to four carbon atoms. Examples of alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl. For the sake of clarity, where a group is called, for example, propyl or butyl, it is n-propyl, n-butyl respectively. Preferred are methyl and ethyl. The best one is methyl.

The term "alkoxy" (used alone or in combination and if not expressly defined in a broader or narrower manner) refers to an alkyl-O- group, where alkyl is as previously defined. The term "(C _xy )alkoxy" (x and y are each an integer) refers to an alkoxy group as previously defined containing x to y carbon atoms. For example, (C _1-4 )alkoxy means a group of the formula (C _1-4 )alkyl-O-, where the term "(C _1-4 )alkyl" has the meaning given previously. Examples of alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, 2nd butoxy and 3rd butoxy. Preferably it is methoxy.

The term "fluoroalkyl" (used alone or in combination and if not expressly defined in a broader or narrower manner) means an alkyl group as previously defined containing one to three carbon atoms, one or more of which (and Possibly all) hydrogen atoms have been replaced by fluorine. The term "(C _xy )fluoroalkyl" (x and y are each an integer) refers to a fluoroalkyl group as previously defined containing x to y carbon atoms. For example, a (C _1-3 )fluoroalkyl group contains one to three carbon atoms in which one to seven hydrogen atoms have been substituted with fluorine. Representative examples of fluoroalkyl groups include trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl and 2,2,2-trifluoroethyl; especially trifluoromethyl. Preferred is (C ₁ )fluoroalkyl such as trifluoromethyl.

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

The term "cycloalkyl" (used alone or in combination and if not specifically defined in a broader or narrower manner) refers to a saturated monocyclic hydrocarbon ring containing from three to eight carbon atoms. The term "(C _xy )cycloalkyl" (x and y are each an integer) refers to a cycloalkyl group containing x to y carbon atoms. For example, (C _3-6 )cycloalkyl contains 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 aryl groups mentioned above are unsubstituted or substituted as expressly defined.

The term "heteroaryl" used alone or in combination means a 5- to 10-membered monocyclic ring containing one to up to four heteroatoms (especially one to up to three) each independently selected from N, O and S. Or bicyclic aromatic ring. Examples of such heteroaryl groups are 5-membered heteroaryl groups such as furyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl , imidazolyl, pyrazolyl, triazolyl and tetrazolyl; 6-membered heteroaryl, such as pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl; and 8- to 10-membered bicyclic heteroaryl such as Indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothienyl, furopyridyl, indazolyl, benzimidazolyl, benzoxazolyl, benzisoxazole base, benzothiazolyl, benzisothiazolyl, benzotriazolyl, benzoxadiazolyl, benzothiadiazolyl, thienopyridyl, quinolyl, isoquinolinyl, naphthyridinyl , zolinyl, quinazolinyl, quinolinyl, phthalazinyl, pyrrolopyridyl, pyrazopyridyl, pyrazopyrimidinyl, pyrrolopyrazinyl, imidazopyridyl, imidazoda Azinyl and imidazothiazolyl. The above heteroaryl groups are unsubstituted or substituted as expressly defined.

Whenever the word "between" is used to describe a numerical range, it should be understood that the endpoints of the indicated range are expressly included in that range. For example: if a temperature range is described as between 40°C and 80°C, this means that the endpoints 40°C and 80°C are included in the range; or if a variable is defined as an integer between 1 and 4, then This means that the variable is an integer 1, 2, 3 or 4.

Unless used with respect to temperature, the term "about" preceding a numerical value "X" in this application shall mean the range extending from X minus (10% of X) to X plus (10% of Best refers to the range extending from X minus (5% of X) to X plus (5% of X). Likewise, the term "about" before a numerical range "X to Y" in this application refers to the range extending from X minus (10% of X) to Y plus (10% of Y), and preferably It refers to the interval expanded from X minus (5% of X) to Y plus (5% of Y). In the specific case of temperature, the term "about" before the temperature "Y" in this application refers to the range extending from the temperature Y minus 10°C to Y plus 10°C, and preferably refers to the range from the temperature Y minus 10°C. Go to 5℃ and expand it to the interval of Y plus 5℃. The term "room temperature" as used herein refers to a temperature of approximately 25°C.

Further embodiments of the invention are presented below: 2) Another embodiment relates to a compound according to embodiment 1), wherein R ¹ represents methyl, chlorine, bromo, cyclopropyl or trifluoromethyl; [especially R ¹ represents methyl].

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

4) Another embodiment relates to a compound according to any one of embodiments 1) to 3), wherein X ¹ represents S.

5) Another embodiment concerns a compound according to any one of embodiments 1) to 4), wherein ^X2 represents CH.

6) Another embodiment relates to a compound according to any one of embodiments 1) to 5), wherein Z represents _-CH2- or -CH( _CH3 )-.

7) Another embodiment relates to the compound according to any one of embodiments 1) to 6), wherein if Z represents -CH( _CH3 )-, the compound of formula (I) has the following formula ( _IA ) The absolute configuration: (That is, the chiral carbon atom of the pyrazolidinyl ring is in an absolute (R) configuration).

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

9) Another embodiment relates to a compound according to any one of embodiments 1) to 8), wherein in the fragment in ● R ² independently represents hydrogen, methyl, chlorine or methoxy; [It should be noted that R ² independently represents methyl or chlorine, especially chlorine]; ● R ³ independently represents hydrogen or methyl [especially is 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 Example 1).

10) Another embodiment relates to a compound according to any one of embodiments 1) to 8), wherein the fragment represents a group selected from group A) or B): where each Ar ¹ is independently as defined in Example 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 groups A) to D):

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

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

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

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

16) Another embodiment relates to a compound according to any one of embodiments 1) to 8), wherein the fragment express:

17) Another embodiment relates to a compound according to any one of embodiments 1) to 8), wherein the fragment express:

18) Another embodiment relates to a compound according to embodiment 1), which is selected from: (5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)(2- ((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazodin-1-yl)methanone; (5-methyl-2-(2H-1,2,3-triazole) -2-yl)phenyl)(2-(((2-(trifluoromethyl)benzo[d]thiazol-6-yl)methyl)pyrazodin-1-yl)methanone; (2-( 2H-1,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazodin-1-yl)methyl Ketone; (5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl) Methyl)pyrazolin-1-yl)methanone; (5-chloro-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzene) And[d]thiazol-6-yl)methyl)pyrazodin-1-yl)methanone; (4,5-dimethyl-2-(2H-1,2,3-triazol-2-yl) )phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazodin-1-yl)methanone; (3'-methyl-[1,1'-Biphenyl]-2-yl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazodin-1-yl)methanone; (5-methyl-2 -(4-methyl-1H-pyrazol-1-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazodin-1-yl) Methyl ketone; (5-methyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl yl)pyrazodin-1-yl)methanone; [1,1'-biphenyl]-2-yl(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyra Azolidin-1-yl)methanone; (5-methyl-2-(2-methylthiazol-4-yl)phenyl)(2-((2-methylbenzo[d]thiazole-6- (yl)methyl)pyrazolin-1-yl)methanone; (5-methyl-2-(4-methyl-2H-1,2,3-triazol-2-yl)phenyl)(2 -((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazodin-1-yl)methanone; (5-methyl-2-(thiazol-2-yl)pyridine-3 -yl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazodin-1-yl)methanone; (5-methyl-2-(1H-pyrazole) -1-yl)pyridin-3-yl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazodin-1-yl)methanone; (5-chloro- 2-(1H-pyrazol-1-yl)pyridin-3-yl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazodin-1-yl)methyl Ketone; (2-(4-bromo-2H-1,2,3-triazol-2-yl)-5-chlorophenyl)(2-((2-methylbenzo[d]thiazole-6- base)methyl)pyrazolin-1-yl)methanone; (2-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)(2-((2 -methylbenzo[d]thiazol-6-yl)methyl)pyrazodin-1-yl)methanone; (5-chloro-2-(4-methyl-1H-pyrazol-1-yl) Pyridin-3-yl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazodin-1-yl)methanone; (2-(2H-1,2, 3-Triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)tetrahydropyridazin-1(2H)-yl)methanone; (5-Chloro-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)tetrazol Hydropyridazin-1(2H)-yl)methanone; (5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2-methyl Benzo[d]thiazol-6-yl)methyl)tetrahydropyridazin-1(2H)-yl)methanone; (5-chloro-2-(4-methyl-2H-1,2,3- Triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazodin-1-yl)methanone; (5-chloro-2 -(4-ethynyl-2H-1,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazole (2-((2-bromobenzo[d]thiazol-6-yl)methyl)pyrazolin-1-yl)(5-chloro-2-(2H-1) ,2,3-triazol-2-yl)phenyl)methanone; (5-chloro-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2 -Methylthiazolo[5,4-b]pyridin-5-yl)methyl)pyrazodin-1-yl)methanone; (5-chloro-2-(2H-1,2,3-triazole) -2-yl)phenyl)(2-((2-chlorobenzo[d]thiazol-6-yl)methyl)pyrazodin-1-yl)methanone; (5-chloro-2-(2H -1,2,3-triazol-2-yl)phenyl)(2-((2-(trifluoromethyl)benzo[d]thiazol-6-yl)methyl)pyrazolidine-1- yl)methanone; (5-chloro-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2-cyclopropylbenzo[d]thiazole-6- yl)methyl)pyrazolin-1-yl)methanone; (5-chloro-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2-ethyl) ylbenzo[d]thiazol-6-yl)methyl)pyrazodin-1-yl)methanone; (R)-(5-chloro-2-(2H-1,2,3-triazole-2) -yl)phenyl)(4-methyl-2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazodin-1-yl)methanone; (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; (R)-4-methyl-2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidin-1 -yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone; (S)-4-methyl-2-((2-methyl Benzo[d]thiazol-6-yl)methyl)pyrazodin-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methyl Ketone; (S)-(2-(4-bromo-2H-1,2,3-triazol-2-yl)-5-chlorophenyl)(4-methyl-2-((2-methyl Benzo[d]thiazol-6-yl)methyl)pyrazodin-1-yl)methanone; (R)-(2-(4-bromo-2H-1,2,3-triazole-2- base)-5-chlorophenyl)(4-methyl-2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazodin-1-yl)methanone; (5 -Methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]oxazol-6-yl)methyl)pyra Azolidin-1-yl)methanone; (2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazole-6- (yl)methyl)pyrazolin-1-yl-4,4-d ₂ )methanone; (5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl) (2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazodin-1-yl-4,4-d ₂ )methanone; (5-chloro-2-(2H -1,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazodin-1-yl-4, 4-d ₂ ) Methone; (5-chloro-2-(2H-1,2,3-triazol-2-yl-d)phenyl) (2-((2-methylbenzo[d] Thiazol-6-yl)methyl)pyrazolin-1-yl)methanone; and (R)-(5-chloro-2-(2H-1,2,3-triazol-2-yl-d) Phenyl)(4-methyl-2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazodin-1-yl)methanone.

The compounds of formula (I) according to any one of embodiments 1) to 18) and their pharmaceutically acceptable salts may be used as medicaments, for example in the form of pharmaceutical compositions for enteral (such as in particular oral) or parenteral Enteral administration (including topical application or inhalation).

Such pharmaceutical compositions may be produced in any manner that will be familiar to those skilled in the art (see, e.g., Remington, The Science and Practice of Pharmacy, 21st ed. (2005), Part 5, "Pharmaceutical Manufacturing" [Lippincott Williams & Wilkins Published]) By combining said compound of formula (I) or its pharmaceutically acceptable salts with other substances of therapeutic value as appropriate and together with suitable non-toxic inert therapeutically compatible solid or liquid carrier materials, And if necessary, it can be administered in a herbal form together with commonly used pharmaceutical adjuvants.

The present invention also relates to a method for preventing or treating the diseases or disorders mentioned herein, the method comprising administering to an individual a pharmaceutically active amount of a compound of formula (I) according to any one of embodiments 1) to 18) ).

The terms "individual" and "patient" also refer to mammals, particularly humans. Preferably, the term "individual" refers to the term "patient".

The term "prevention" used in the present invention is understood to mean the term "prophylaxis" and is therefore interchangeable therewith.

For the avoidance of any doubt, if a compound is described as being useful for the prevention/prevention or treatment of certain diseases, these compounds are also suitable for the preparation of medicaments for the prevention or treatment of such diseases. Likewise, these compounds are also suitable for use in a method for preventing/preventing or treating these diseases, which method includes administering an effective amount of this compound to an individual (mammal, especially human) in need thereof.

The compound of formula (I) according to any one of embodiments 1) to 18) is useful for preventing or treating disorders related to appetite hormone stimulating dysfunction.

These disorders associated with orexin-stimulated dysfunction are diseases or disorders that require human orexin receptor antagonists, particularly mental health disorders associated with orexin-induced dysfunction. The disorders mentioned above may be specifically defined to include sleep disorders, including in particular insomnia, as well as anxiety disorders, addiction disorders, cognitive dysfunction, affective disorders, appetite disorders, and neuropsychiatric symptoms of dementia. In a sub-embodiment, the disorders mentioned above include in particular anxiety disorders, addiction disorders, affective disorders, and neuropsychiatric symptoms of dementia, in particular anxiety disorders and addiction disorders. In another sub-embodiment, the above-mentioned disorders specifically include sleep disorders, in particular insomnia.

In addition, other disorders associated with orexin-stimulated dysfunction are selected from the group consisting of 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 Parkinson's disease; treating or controlling psychosis, including acute manic and bipolar disorders; treating or controlling stroke, especially ischemic or hemorrhagic stroke; blocking the emetic response, also known as nausea and vomiting; and treating or to control agitation, alone or in combination with another medical condition.

Anxiety disorders can be distinguished by the primary target or specificity of the threat, which can range from fairly diffuse (as in generalized anxiety disorder) to localized (as experienced in phobia-anxiety disorder (PHOB) or post-traumatic stress disorder (PTSD) ). Therefore, anxiety disorders can be defined as including generalized anxiety disorder (GAD), obsessive-compulsive disorder (OCD), acute stress disorder, post-traumatic stress disorder (PTSD), panic anxiety disorder (PAD) (including panic attacks), phobia and anxiety disorder ( PHOB), specific phobia, social phobia (social anxiety disorder), avoidance disorder, somatoform disorders (including hypochondriasis), separation anxiety disorder, anxiety disorders caused by general medical conditions, and substance-induced Anxiety disorder. In a sub-embodiment, specific examples of localized threat-induced anxiety disorders are phobic anxiety disorder or post-traumatic stress disorder. Anxiety disorders include, inter alia, post-traumatic stress disorder, obsessive-compulsive disorder, panic attacks, phobias and avoidance disorders.

An addiction disorder can be defined as an addiction to one or more rewarding stimuli, and in particular to one rewarding stimulus. These rewarding stimuli may be of natural or synthetic origin. Examples of such rewarding stimuli are substances/drugs (of natural or synthetic origin; such as cocaine, amphetamines), opiates (of natural or (semi-)synthetic origin, such as morphine or heroin), cannabis, alcohol, wheat Mescaline, nicotine, and the like}, which substances/drugs may be consumed alone or in combination; or other rewarding stimulants {natural sources (such as food, sweets, fats, or sex, and the like), or Synthetic sources [such as gambling or Internet/IT (such as excessive gambling, or inappropriate involvement in online social networking sites or blogs), and the like]}. In one sub-embodiment, addiction disorders related to psychoactive substance use, abuse, seeking and recovery are defined as all types of psychological or physical addiction and their associated tolerance and dependence components. Substance-related addiction disorders include, inter alia, substance use disorders, such as substance dependence, substance addiction, and substance abuse; substance-induced disorders, such as substance intoxication, substance withdrawal, and substance-induced delirium. The expression "prevention or treatment of addiction" (i.e., preventive or curative treatment of patients diagnosed with addiction or at risk of developing addiction) means reducing addiction (in particular reducing episodes of addiction), weakening It maintains, promotes abstinence, promotes abstinence, or attenuates, reduces or prevents the occurrence of recovery from addiction (in particular reduces the onset of addiction, promotes withdrawal, or attenuates, reduces or prevents the occurrence of recovery from addiction).

Affective disorders include major depressive episodes, manic episodes, mixed episodes and mild manic episodes; depression, including major depression and mild depression; bipolar disorder, including bipolar I disorder, bipolar II disorder (with Recurrent severe depressive episodes (hypomania), cyclothymia; affective disorders, including affective disorders caused by general medical conditions (including subtypes with melancholic features, with quasi-severe depressive episodes, with manic features, and with mixed features) ), substance-induced affective disorders (including subtypes with melancholic characteristics, manic characteristics, and mixed characteristics). These affective disorders include, in particular, major depressive episodes, major depression, affective disorders caused by general medical conditions; and substance-induced affective disorders.

Neuropsychiatric symptoms of dementia (NPS) (such as Alzheimer's disease (AD), frontotemporal dementia (FTD), dementia with Lewy bodies (DLB), vascular dementia, other dementias , pre-dementia cognitive impairment syndrome, such as mild cognitive impairment or other cognitive impairment; especially Alzheimer's disease type dementia, specifically AD) is defined as a circadian rhythm syndrome in which patients have increased confusion and restlessness, in which the The patient has some form of dementia (especially Alzheimer's disease type dementia, specifically AD). This circadian rhythm syndrome occurs particularly later in the day, in the afternoon and/or evening. Key clinical symptoms include increased agitation, generalized confusion, and mood swings; these symptoms usually develop when natural light begins to diminish.

Neuropsychiatric symptoms of dementia (particularly Alzheimer's type dementia, specifically in AD) refer specifically to the agitation and/or aggression associated with such dementia (sometimes also named the sundown syndrome).

The term agitation is used to describe a wide range of behavior that includes verbal outbursts, physical aggression, intense anxiety and crying, and persistent walking 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 Association of Geriatric Psychiatry (IPA) prepares a definition of agitation syndrome (see e.g. N. Stocking: Reprinted as an excerpt from the IPA Newsletter, IPA Bulletin, Vol. 31(4): https://www.ipa-online. org/news-and-issues/defining-agitation): ● The patient meets the criteria for cognitive impairment or dementia syndrome (such as Alzheimer's disease (AD), frontotemporal dementia (FTD), dementia with Lewy bodies (DLB), vascular dementia, other dementias, Predementia cognitive impairment syndrome, such as mild cognitive impairment or other cognitive impairment). ● The patient exhibits at least one of the following behaviors that are associated with observed or inferred evidence of emotional distress (eg, rapid mood changes, irritability, outbursts). The behavior has persisted or recurred frequently for at least two weeks and represents a change in the patient's regular behavior. (a) Excessive motor activity (examples include: pacing, rocking, gesturing, pointing, restlessness, engaging in repetitive behaviors). (b) Verbal aggression (e.g. yelling, speaking too loudly, using profanity, screaming, yelling). (c) Physical aggression (such as grabbing, pushing, shoving, resisting, hitting others, kicking objects or people, scratching, biting, throwing objects, hitting oneself, slamming doors, tearing things and destroying property). ● Behaviors deemed by the clinician to be severe enough to cause undue disability beyond cognitive impairment and include at least one of the following: (a) Interpersonal relationships are seriously damaged. (b) Other aspects of social functions are seriously impaired. (c) The ability to perform or participate in activities of daily living is severely impaired. ● Although comorbidities may be present, agitation cannot be attributed solely to other psychiatric disorders, suboptimal care, medical conditions, or physiological effects of substances.

The term "late evening" as used herein refers to the afternoon and evening, especially the time around sunset (but excluding night/sleep times); for example, from about 4 pm to about 10 pm, especially from about 4 pm to about Time of 9 pm. In one sub-embodiment, the term refers to the afternoon, especially from about 4 pm to about 7 pm; in another sub-embodiment, the term refers to the evening, especially from about 7 pm to about 10 pm, especially is from about 7 pm to about 9 pm.

Dementia specifically includes dementia including the following types of Alzheimer's disease: Alzheimer's disease dementia (pregeric dementia or senile dementia), subcortical dementia, (diffuse) Lewy body dementia and frontotemporal dementia. Dementia further includes vascular dementia, such as vascular dementia, multiple infarct dementia, Binswanger's dementia, boxer's dementia, and arteriosclerotic dementia. The remaining types of dementia (9%) have other causes, such as paralytic dementia, substance-induced persistent dementia, dialysis-induced dementia, hydrocephalic dementia, and due to tumors, subdural hematoma, normal pressure hydrocephalus , vasculitis, vitamin deficiency or dementia caused by endocrine or metabolic diseases. In the context of the present invention, the term preferably refers to dementia of the Alzheimer's type, in particular Alzheimer's dementia. It should be understood that the term dementia also includes any combination of the above types of dementia.

Appetite disorders include eating disorders and alcohol use disorders. Pathologically altered food intake can result from disturbances in appetite (likes or dislikes of food); changes in energy balance (intake versus consumption); disturbances in the perception of food quality (high fat or carbohydrate, high palatability); disturbances in food availability (not restricted diet or deprivation) or caused by disruption of water balance. Alcohol use disorders include polydipsia and all other types of excessive fluid intake in psychiatric disorders. Eating disorders may be defined to include eating disorders associated with excessive food intake and associated complications; anorexia; compulsive eating disorders; obesity (from any cause, whether genetic or environmental); obesity-related disorders, including 2 Overeating and obesity observed in patients with type 2 (non-insulin-dependent) diabetes; bulimia, including psychogenic bulimia; cachexia; and binge eating disorders. Specific eating disorders include metabolic dysfunction; disordered appetite control; compulsive obesity; psychogenic bulimia (bulimia) or anorexia nervosa. The term "eating disorder" means, specifically, binge eating disorder (BED); psychogenic bulimia (BN); anorexia nervosa (AN) (specifically, binge-eating/purging anorexia nervosa; especially binge-eating disorder anorexia); pica; other specific feeding and eating disorders (OSFED) [especially atypical psychogenic bulimia, binge eating disorders of low frequency and/or limited duration, psychogenic disorders of low frequency and/or limited duration Bulimia, or Nocturnal Eating Syndrome (NES)]; Unspecified Feeding or Eating Disorder (UFED); Eating Disorder Not Otherwise Specified (EDNOS); and Compulsive Overeating (CO); Loss of Control of Eating (LOC); and Overeating and/or binge eating associated with Prader-Willi Syndrome (PWS). Eating disorders specifically refer to eating disorders that include compulsive overeating behavior. It should be understood that the term "eating disorder including compulsive binge eating behavior" refers to a disorder that includes recurrent episodes of binge eating, which occur when an individual eats significantly more food in a short period of time than most people would eat under similar circumstances. , whose attacks are characterized by a lack of sensory control. Eating disorders that include compulsive binge eating behavior are characterized by eating large amounts of food, eating quickly (often to the point of discomfort), and eating even when no longer hungry. The American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM-5® or also referred to herein as DSM-5) provides diagnostic criteria for certain eating (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 and characterized by a feeling of lack of control. People with bulimia may eat too quickly even if they are not hungry. The person may feel guilt, embarrassment, or disgust and may binge alone to hide the behavior. BED is associated with significant distress and significant physical, emotional, and social health risks, such as obesity and extreme weight gain, and a wide range of related conditions, including sleep apnea, cancer, heart disease, hypertension, type 2 diabetes, arthritis, and more. One of the common diseases.

Cognitive dysfunction encompasses deficits in attention, learning and especially memory functions, which occur short- or long-term in psychiatric, neurological, neurodegenerative, cardiovascular and immunological disorders, and also in normal, healthy, young, adult or especially old age Occurs in groups in the short or long term. Cognitive dysfunction relates specifically to the enhancement or maintenance of memory in patients who have been diagnosed with, or are at risk of developing, a disease or disorder in which memory is impaired (especially declarative or procedural ) is a symptom [specifically of dementia, such as frontotemporal dementia, or dementia with Lewy bodies, or (especially) Alzheimer's disease]. In particular, the term "prevention or treatment of cognitive impairment" refers to patients with clinical manifestations of cognitive dysfunction, particularly declarative memory deficits (associated with dementia such as frontotemporal dementia, or dementia with Lewy bodies, or Enhance or maintain memory in patients (particularly related to Alzheimer's disease). Furthermore, the term "prevention or treatment of cognitive impairment" also relates to improved memory consolidation in any of the above patient groups.

Sleep disorders include in particular sleep abnormalities and sleep disorders related to general medical conditions as well as narcolepsy and substance-induced sleep disorders. Sleep abnormalities specifically include endogenous sleep disorders (especially insomnia, breathing-related sleep disorders, periodic limb movement disorder, and restless legs syndrome), extrinsic sleep disorders, and circadian rhythm sleep disorders. Sleep disorders specifically refer to insomnia, including primary insomnia and idiopathic insomnia; chronic insomnia with intermittent treatment; situational transient insomnia (such as insomnia related to new environments or noise); caused by stress, sadness, pain or illness (short-term) insomnia; and insomnia related to mental or neurological diseases, including emotional disorders (such as depression), epilepsy, autism spectrum disorders, attention deficit hyperactivity disorder (ADHD) and brain degenerative diseases ( Including insomnia related to Alzheimer's disease and other neurodegenerative and/or cognitive impairment diseases or disorders). Furthermore, sleep disorders refer in particular to abnormal sleep, such as breathing-related sleep disorders, including (obstructive or central) sleep apnea syndrome; periodic limb movement disorder (nocturnal myoclonus); restless legs syndrome; circadian rhythm sleep Disorders, including shift work sleep disorder; time zone change (jet lag) syndrome. Sleep disorder further refers to disruption of REM sleep. Narcolepsy includes arousal disorders and sleep-wake transition disorders; it is worth noting that narcolepsy includes nightmares, sleep terrors and sleepwalking. Sleep disorders are associated with medical conditions in general and in particular with conditions such as mental disorders, neurological disorders, neuropathic pain, and heart and lung diseases. Substance-induced sleep disorders include in particular insomnia, narcolepsy, and mixed subtypes, and in particular include conditions caused by drugs that cause a decrease in REM sleep as a side effect. Sleep disorders include in particular all types of insomnia previously defined, as well as sleep-related muscle tone deficits; restless legs syndrome; sleep apnea; jet lag syndrome; shift work sleep disorders and delayed or advanced sleep phase syndrome. In addition, sleep disorders further include aging-related sleep disorders.

Sleep disorders related to general medical conditions include sleep disorders related to mental or neurological disorders (especially insomnia); especially affective disorders (such as depression), epilepsy, autism spectrum disorders, attention deficit hyperactivity disorder Sleep disorders (especially insomnia) related to ADHD (ADHD) and brain (neuro)degenerative diseases (including Alzheimer's disease and other neurodegenerative and/or cognitive impairment diseases or disorders); as well as anxiety disorders, addiction Sleep disorders (especially insomnia) related to symptoms or appetite disorders.

A particular aspect of the invention relates to compounds of formula (I) according to any one of embodiments 1) to 18) for the treatment of disorders associated with orexin-induced dysfunction, in particular as defined above Sleep disorders (especially any type of insomnia and respiratory-related sleep disorders as defined above, including sleep apnea syndrome; periodic limb movement disorder; restless legs syndrome; circadian rhythm sleep disorders, including shift work sleep disorders; time zone Change Syndrome); wherein the treatment comprises administering a compound of formula (I) according to any one of embodiments 1) to 18), wherein the compound (will be) less than 7 hours during the night, in particular in the morning/awakening time hour; specifically between approximately 7 hours and 2 hours before morning/awakening time; specifically approximately 4 hours to 2 hours before morning/awakening time.

In the context of this invention, it will be understood that if certain environmental conditions such as stress or fear (where stress can be of social origin (e.g., social pressure) or physical origin (e.g., physical stress), including stress caused by fear) promote or contribute Any of the disorders or diseases previously defined, the compounds of the invention may be particularly useful in the treatment of such environmentally conditioned disorders or diseases.

Preparation of compounds of formula (I): Compounds of formula (I) can be prepared by the methods given below, by the methods given in the experimental section below, or by similar methods. Optimum reaction conditions may vary depending on the specific reactants or solvents used, but such conditions can be determined by routine optimization procedures by those skilled in the art. In the schemes below, the general 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 cases, ^the general groups Ar ¹ , R ¹ , R ² , R ³ , X ¹ , PG). The use of protecting groups is well known in the art (see, eg, "Protective Groups in Organic Synthesis", TW Greene, PGM Wuts, Wiley-Interscience, 1999). For the purposes of this discussion, it will be assumed that the necessary protecting groups are in the correct position. In some cases, the final product can be further modified, for example, by manipulating substituents to obtain novel final products. Such operations may include, but are not limited to, reduction, oxidation, alkylation, chelation, and hydrolysis reactions commonly known to those skilled in the art. In some cases, the order in which the following reaction schemes and/or reaction steps are performed may be altered to facilitate the reaction or avoid undesirable reaction products. The compounds obtained can also be converted into salts, in particular pharmaceutically acceptable salts, in a manner known per se.

The compounds of formula (I) of the present invention can be prepared according to the general reaction sequence outlined below.

General reaction techniques: General reaction technique 1 (amide bond formation): Carboxylic acids with hydroxylamine or amine derivatives in the presence of an activator (such as DCC, EDC, HOBT, n-propylphosphocyclic anhydride, HATU or DSC) in a dry aprotic solvent (such as DCM) between 20°C and 60°C , MeCN or DMF) (see G. Benz in Comprehensive Organic Synthesis, edited by B.M. Trost, I. Fleming; Pergamon Press: New York (1991), Volume 6, Page 381). Alternatively, carboxylic acids can be activated by reaction with oxalyl chloride or pure thionite chloride or by conversion to their corresponding acid chlorides in a solvent between 20° and 60°C, such as DCM. Further activators can be found in R. C. Larock, Comprehensive Organic Transformations. A guide to Functional Group Preparations, 2nd ed. (1999), section Nitriles, Carboxylic Acids and Derivatives, pp. 1941-1949 (Wiley VC; New York, Chichester, Weinheim, Brisbane, Singapore, Toronto).

General Reaction Technique 2 (Reductive Amination): The reaction between amines and aldehydes or ketones is carried out in a solvent system, allowing the reaction by physical or chemical means (such as distillation of solvent-water azeotropes or desiccants (such as molecular sieves, MgSO ₄ or the presence of Na ₂ SO ₄ )) removes the water formed. This solvent is typically toluene, Hex, THF, DCM or DCE or a mixture of solvents such as DCE/MeOH. The reaction can be catalyzed by trace amounts of acid (usually AcOH). The intermediate imine is reduced with a suitable reducing agent (such as NaBH ₄ , NaBH ₃ CN or NaBH(OAc) ₃ or through hydrogenation through a noble metal catalyst (such as Pd/C). The reaction is preferably between -10°C and 110°C. It is carried out between 0°C and 60°C. The reaction can also be carried out in a pot. It can also be carried out in a protic solvent such as MeOH or water in the presence of picoline-borane complex (Tetrahedron (2004 ), 60, 7899-7906).

General reaction technique 3: alkylation: react NH-containing derivatives with the formula G- _CH2 -LG (where G has the same meaning as in formula (I) and LG represents OMs, OTf, OTs, Cl, Br or I ) The alkylating agent compound is reacted in the presence of an inorganic base (such as K ₂ CO ₃ ) or an organic 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 tetrabutylammonium iodide may be added to promote nucleophilic substitution reactions. More details can be found in Comprehensive Organic Transformations. A guide to Functional Group Preparations; 2nd ed., RC Larock, Wiley-VC; New York, Chichester, Weinheim, Brisbane, Singapore, Toronto, (1999). Amine Section page 779.

General reaction technology 4 (Suzuki cross-coupling reaction): Aromatic halide (usually bromide) and the desired boric acid derivative or its borate ester equivalent (such as pinacol ester) in a palladium catalyst and a solvent (such as toluene, THF, dioxane, DME) in the presence of a base (such as K ₂ CO ₃ , Cs ₂ CO ₃ , K ₃ PO ₄ , tBuONa or tBuOK), usually in the presence of water (20% to 50%) or DMF) between 20 and 120°C. Examples of typical palladium catalysts are triarylphosphine palladium complexes such as Pd(PPh ₃ ) ₄ . These catalysts can also be composed of common palladium sources such as Pd(OAc) ₂ or Pd ₂ (dba) ₃ and ligands such as trialkylphosphine (such as PCy ₃ or P(tBu) ₃ ), dialkylphosphine Biphenyl (e.g. S-Phos) or ferrocene phosphine (e.g. Q-phos) are prepared in situ. Alternatively, compounds based on palladium rings (e.g. SK-CC01-A) or N-heterocyclic carbene complexes (e.g. PEPPSITM -IPr). The reaction can also be carried out by using the corresponding aromatic triflates. Additional variations of this reaction are described by Miyaura and Suzuki, Chem. Rev. (1995), 95, 2457- 2483, Bellina 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 by using one of the carbon-nitrogen bond formation methods reported in General Reaction Technology 1 to prepare the carboxylic acid of structure I-1 and the NH-containing intermediate of structure I-2. reaction (Scheme 1). plan 1

Alternatively, compounds of general formula I can be synthesized via carbon-nitrogen bonds involving an NH-containing compound of structure II-1 and an aldehyde intermediate of structure II-2 using General Reaction Technique 2 or an alkylating agent of Structure II-3 using General Reaction Technique 3 Formation reaction to prepare (Scheme 2). Scenario 2

Compounds of general formula I can also be prepared via cross-coupling reactions involving compounds of structure III-1 and boron derivatives of structure III-2 using general reaction technique 3 (Scheme 3). Option 3 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 CH ₂ C(Me) ₂ CH ₂ or C(Me) ₂ C(Me) ₂ .

Compounds of general formula I can also be prepared via cross-coupling reactions involving compounds of structure IV-1 and boron derivatives of structure IV-2 using general reaction technique 4 (Scheme 4). Option 4 In Scheme 4, D ¹ and D ² represent H, methyl or ethyl or D ¹ and D ² together represent CH ₂ C(Me) ₂ CH ₂ or C(Me) ₂ C(Me) ₂ .

Compounds of general formula I can also be obtained by reacting a compound of structure V-1 with a dibromide of structure V-2 in acetonitrile in the presence of a base such as K ₃ PO ₄ at a temperature range between 60°C and 90°C. Preparation. (Option 5). Option 5

Preparation of compounds of structures I-2, II-1, III-1, IV-1 and V-1: Compounds of structure I-2 can be prepared via aldehyde intermediates involving NH-containing compounds of structure VI-1 and structure II-2 Prepared using a carbon-nitrogen bond forming reaction using General Reaction Technique 2 or an alkylating agent of structure II-3 using General Reaction Technique 3. The resulting intermediates of structure VI-2 can then be converted to compounds of structure I-2 by cleavage of PG ₁ . Depending on the nature of PG ₁ , any suitable method reported in Protecting Groups, Kocienski, PJ Georg Thieme Verlag Stuttgart-New-York (1994) may be used. For example, when PG ₁ =Boc, it can be treated with HCl in dioxane or TFA in DCM (Scheme 6). Option 6 In Scheme 6, Ar ¹ , PG ₁ are protecting groups, such as Boc.

Compounds of structure II-1 can be prepared by reacting a carboxylic acid of structure I-1 with an NH-containing intermediate of structure VI-1 using one of the carbon-nitrogen bond formation methods reported in General Reaction Technology 1. The resulting intermediates of structure VII-1 can then be converted to compounds of structure II-1 by cleavage of PG ₁ . Depending on the nature of PG ₁ , any suitable method reported in Protecting Groups, Kocienski, PJ Georg Thieme Verlag Stuttgart-New-York (1994) may be used. For example, when PG ₁ =Boc, treatment can be performed with HCl in dioxane or TFA in DCM (Scheme 7). Option 7 In Scheme 7, PG ₁ is a protecting group such as Boc.

Alternatively, a compound of structure II-1 may be prepared by reacting a compound of structure VIII-1 with a carboxylic acid of structure I-1 using one of the carbon-nitrogen bond formation methods reported in General Reaction Technology 1. The resulting intermediate of structure VIII-2 can then be prepared by reaction with the dibromide of structure V-2 in _acetonitrile in the presence of a base such as _K3PO4 at a temperature range between 60°C and 90°C. Converted to a compound of structure VII-1. Finally, compounds of structure VII-1 can be converted into compounds of structure II-1 using the methods described above. (Plan 8) Plan 8 In Scheme 8, PG ₁ is a protecting group such as Boc.

Compounds of structure III-1 can be prepared as described in Scheme I for the preparation of compounds of general formula I by replacing the carboxylic acid of structure I-1 with a carboxylic acid of structure I-1, wherein _LG1 is a leaving group, such as OTf , -I, -Br or -Cl. R ² , R ³ and Y have the same meanings 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 by replacing the aldehyde of structure II-2 or the alkylating agent of structure X-2 with an aldehyde of structure X-1 or an alkylating agent of structure X-2, respectively. 3. Alkylating agent, -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 by first cleaving PG ₁ . Depending on the nature of PG ₁ , any suitable method reported in Protecting Groups, Kocienski, PJ Georg Thieme Verlag Stuttgart-New York (1994) may be used. For example, when PG ₁ = Boc, HCl in dioxane or TFA in DCM can be used for treatment. The resulting compound XI-1 can ultimately be converted to a compound of structure V-1 by reaction with an aldehyde of structure II-2 using general reaction technique 2 (Scheme 9). Option 9 In Scheme 9, PG ₁ is a protecting group such as Boc.

Compounds of structures I-1, II-2, II-3, III-2, IV-2, V-2, VI-1, VIII-1, IX-1, X-1 and X-2 are commercially available , or prepared by procedures similar to those well known in the art or disclosed in the Experimental Section.

Experimental part I.Chemistry

All temperatures are in °C. Commercially available starting materials were used as received without further purification. Unless otherwise stated, all reactions were performed in oven-dried glassware under a nitrogen atmosphere. Unless otherwise stated, the reaction mixture was quenched with an appropriate aqueous medium and extracted with an appropriate organic solvent. The organic extracts are combined, washed with a minimum volume of brine, dried over sodium sulfate, filtered and concentrated to dryness to obtain the so-called evaporation residue. The compound is obtained after purifying the evaporation residue using silica flash column chromatography or preparative HPLC methods. The compounds described in the present invention are characterized by LC-MS data (retention time t _R in min; molecular weight obtained from mass spectrometry in g/mol) using the conditions listed below. In cases where the compounds of the invention occur as mixtures of conformational isomers, this is particularly visible in their LC-MS spectra, giving the retention times of the most abundant conformational isomers. The racemate can be separated into its enantiomers by preparative HPLC (column: ChiralPaK IC 250 x 4.6 mm, 5 μm, 45% ethanol in heptane).

Abbreviations (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 Boc ₂ O dicarbonic acid Di-tert-butyl ester Bu butyl such as in tBu = tert-butyl (tert-butyl) = tertiary butyl (tertiary butyl) Carb. acid carboxylic acid comm. Commercial DCM dichloromethane DIPEA diisopropyl ethyl Amine DMA N,N-dimethylacetamide DMF N,N-dimethylformamide DMSO Dimethylsulfoxide dppf Bis(diphenylphosphino)ferrocene ELSD Evaporative light scattering detection eq. Equivalent ES Electrospray Et Ethyl Et ₂ O Diethyl ether EtOAc Ethyl acetate EtOH Ethanol Ex. Example/example compound FC Silica gel flash chromatography FCS Fetal calf serum h hour HATU 1-[bis(dimethylamino)methylene]-1H -1,2,3-Triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HBSS Hank's balanced salt solution HBTU N,N,N',N' -Tetramethyl-O-(1H-benzotriazol-1-yl)urea hexafluorophosphate HEPES 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid ¹ H-NMR Proton Nuclear Magnetic Resonance HPLC High performance liquid chromatography LC-MS Liquid chromatography-mass spectrometry Lit. Literature M Accurate mass (e.g. for LC-MS) Me Methyl MeCN Acetonitrile MeOH Methanol μl μl min min MS Mass spectrometry N Normal concentration Pd (OAc) _2Palladium diacetate Pd(PPh ₃ ) ₄ (triphenylphosphine)palladium(0) Ph phenyl prep. Preparative rt room temperature sat. Saturated TBTU o-(benzotriazol-1-yl)- N,N,N',N'-tetramethylurea tetrafluoroborate TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran t _R retention time UV ultraviolet light

LC-MS analysis conditions Unless otherwise notified, the following conditions are used to analyze LC-MS data: (A) Device: Agilent 1100 series equipped with mass spectrometry detection (MS: Finnigan single-phase quadrupole column). Column: Zorbax RRHD SB-Aq (1.8 µm, 2.6 x 50 mm). Conditions: MeCN [eluent A]; water + 0.04% TFA [eluent B]. Gradient: 95% B → 5% B in 1.5 minutes (flow rate: 4.5 ml/min.). Detection: UV/Vis + MS.

(B) Device: Agilent 1100 series equipped with mass spectrometry detection (MS: Finnigan single-phase quadrupole column). Column: Waters XBridge C18 (5 µm, 4.6 x 50 mm). Conditions: MeCN [eluent A]; 13 mmol/l NH ₃ in water [eluent B]. Gradient: 95% B → 5% B in 1.5 minutes (flow rate: 4.5 ml/min.). Detection: UV/Vis + MS.

(C) Equipment: Waters Acquity UPLC equipped with mass spectrometry detection (MS: Waters SQ detector or Xevo TQD). Column: Acquity UPLC CSH C18 (1.7 µm, 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 in 2 minutes (flow rate: 1 ml/min.). Detection: UV (214 nm) + MS.

Preparative HPLC Reaction mixtures can generally be separated by preparative HPLC. Those familiar with this technology will find suitable conditions for each separation. Fractions containing product are collected and lyophilized or freeze-dried under vacuum.

Auto FC Traditional flash chromatography methods are often replaced by automated systems. This does not change the separation process itself. Those familiar with this technology will be able to replace traditional FC processes with automated processes, and vice versa. Typical automation systems can be used, such as those provided by Büchi, Isco (Combiflash) or Biotage.

The following examples illustrate the preparation of the compounds of the invention but do not limit their scope in any way.

Preparation of precursors and intermediates: Preparation A: 2-methyl-6-(pyrazolin-1-ylmethyl)benzo[d]thiazole dihydrochloride Ai 2-((2-methylbenzo [d]thiazol-6-yl)methyl)pyrazolidine-1-carboxylic acid tert-butyl ester: To 1-pyrazolidinecarboxylic acid tert-butyl ester (4.63 g, 26.9 mmol) was prepared at rt in DCM ( To the solution in 190 mL), 2-methyl-1,3-benzothiazole-6-carbaldehyde (5.02 g, 26.9 mmol) and NaBH(OAc) ₃ (14.78 g, 67.6 mmol) were added in sequence. The resulting mixture was stirred for 23 h. Add saturated _aqueous NaHCO solution (100 mL) and water (100 mL). The two layers were separated and the aqueous layer was extracted with DCM (2 x 75 mL). The evaporation residue was purified by FC (gradient heptane-EtOAc) to give the title product (7.18 g) as a colorless oil with a purity of 86%. LC-MS (A): t _R = 0.83 min; [M+H] ⁺ = 334.15. ¹ H NMR (DMSO- d6 ) δ: 7.99 (d, J = 1.2 Hz, 1H), 7.85 (d, J = 8.3 Hz, 1H), 7.49 (dd, J = 1.6, 8.3 Hz, 1H), 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-(pyrazolin-1-ylmethyl)benzo[d]thiazole dihydrochloride: Intermediate Ai (7.19 g, 21.6 mmol) was dissolved in dihydrochloride at rt. 4N HCl in oxane (100 mL, 416 mmol). The reaction mixture was stirred for 16 h. The reaction mixture was concentrated to dryness and the resulting solid was dried under vacuum to a constant weight to give the title compound (6.6 g) as a pale yellow solid. LC-MS (A): t _R = 0.53 min; [M+H] ⁺ = 234.20.

Preparation B: (5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)(pyrazodin-1-yl)methanone hydrochloride Bi 2-(5- Methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl)pyrazolidine-1-carboxylic acid tert-butyl ester: To 1-pyrazolidinecarboxylic acid tert-butyl ester Ester (1.0 g, 5.8 mmol) and 5-methyl-2-(2 H -1,2,3-triazol-2-yl)benzoic acid (1.18 g, 5.84 mmol) in DCM (20 mL) DIPEA (2.03 mL, 11.6 mmol) and HATU (2.38 g, 6.13 mmol) were added to the solution in sequence. The reaction was carried out at rt for 16 h, and saturated NaHCO ₃ (60 mL) and DCM (60 mL) were added. The two layers were separated and the aqueous layer was extracted with DCM (2 x 40 mL). The evaporation residue was purified by FC (gradient heptane/TBME/MeOH) to give 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 ) δ: 8.09 (s, 2 H), 7.76 (d, J = 8.3 Hz, 1H), 7.41 (dd, J = 1.3, 8.3 Hz, 1H), 7.34 (d, J = 1.3 Hz, 1H), 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)(pyrazodin-1-yl)methanone hydrochloride: from intermediate Bi (2.24 g, 5.33 mmol) and following the procedure described in Preparation A, Step A.ii, the title compound (1.75 g) was prepared as an off-white solid with a purity of 90%. LC-MS (A): t _R = 0.58 min; [M+H] ⁺ = 257.97.

Preparation C: 5-Methyl-2-(thiazol-2-yl)nicotinic acid, lithium salt Ci methyl 5-methyl-2-(thiazol-2-yl)nicotinate: To 2-bromo-5-methyl To a solution of methylnicotinate (0.350 g, 1.48 mmol) in dioxane (2 mL) was added CuI (0.05 g, 0.24 mmol), Pd(PPh ₃ ) ₄ (0.03 g, 0.03 mmol) and 2- (tributylstannyl)-1,3-thiazole (0.697 g, 1.77 mmol). The reaction was carried out at 100°C for 16 h. After cooling to rt, the reaction mixture was purified directly by FC (gradient heptane-EtOAc) to obtain the title compound (0.310 g) as a pale yellow solid. LC-MS (A): t _R = 0.81 min; [M+H] ⁺ = 234.9. ¹ H NMR (DMSO-d6) δ: 8.60 (d, J = 0.8 Hz, 1H), 7.96 (d, J = 3.1 Hz, 1H), 7.88 (d, J = 3.1 Hz, 1H), 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: Start with intermediate Ci (0.310 g, 1.32 mmol) and proceed as described in Preparation H, Step H.ii , the crude title salt (0.310 g) was obtained as a light gray solid. LC-MS (A): t _R = 0.69 min; [M+H] ⁺ = 221.19.

Preparation D: (2-(trifluoromethyl)benzo[d]thiazol-6-yl)methylmethanesulfonate and 6-(chloromethyl)-2-(trifluoromethyl)benzo[d ] Thiazole mixture Di (2-(trifluoromethyl)benzo[d]thiazol-6-yl)methanol: To 2-(trifluoromethyl)benzo[d]thiazole-6-carboxylic acid (0.105 g To a solution of borane.tetrahydrofuran complex (1.0 M in THF; 0.8 mL, 0.8 mmol) in THF (2.5 mL) (cooled to -10 °C) was slowly added. The reaction mixture was warmed to rt and stirred for 2 h. Add MeOH (1.5 mL) slowly. After stirring for 15 min, the volatiles were removed in vacuo and the residue was co-evaporated twice with MeOH (2 x 5 mL). The evaporation residue was purified by preparative HPLC to give the title compound (0.013 g) as a pale yellow oil. ¹ H NMR (DMSO- d6) δ: 8.29 (d, J = 0.9Hz, 1H), 8.21 (d, J = 8.5 Hz, 1H), 7.65 (dd, J = 0.9, 8.5Hz, 1H), 5.51 ( t, J = 5.5Hz, 1H), 4.71 (d, J = 5.5Hz, 2H). D.ii. (2-(Trifluoromethyl)benzo[d]thiazol-6-yl)methylmethanesulfonate and 6-(chloromethyl)-2-(trifluoromethyl)benzo[ d] Mixture of thiazoles: To an ice-cold 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) was added methanesulfonyl chloride (0.006 mL ,0.077 mmol). The reaction was carried out at 0°C for 40 min. The reaction mixture was partitioned between DCM (5 mL) and water (5 mL). Extract the aqueous layer once with DCM (5 mL). The residue was evaporated to give the crude title compound (0.016 g, pale yellow oil) in a 1-1 mixture with 6-(chloromethyl)-2-(trifluoromethyl)benzo[d]thiazole. The mixture was used without further purification. ¹ H NMR (DMSO- d6) (1-1 mixture) δ: 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 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) was added trans-N,N'-dimethylcyclohexane-1,2-diamine (0.086 g , 0.591 mmol) and 4-methyl-1H-pyrazole (0.247 mL, 2.95 mmol). The resulting mixture was heated to 120 °C for 15 h. After cooling to rt, water (20 mL) was added. The two layers were separated and the aqueous layer was washed with DCM. Discard the resulting organic layer. Acidify the aqueous layer to pH 1 using 1M HCl. The resulting solution was extracted with DCM (2 x 20 mL). The evaporation residue was purified by preparative HPLC to give 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 ) δ: 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: Methyl 6-methyl-3-(2-methylthiazol-4-yl)picolinate Fi 3-(1-ethoxyvinyl)-6-methylpicolinate: To 3-bromo- To a solution of methyl 6-picolinecarboxylate (0.475 g, 1.96 mmol) and tributyl(1-ethoxyvinyl)tin (0.767 g, 2.06 mmol) in dioxane (8.64 mL) was added (Triphenylphosphine)palladium(II) dichloride (0.055 g, 0.0785 mmol). The reaction was carried out at 80°C for 17 hours. The reaction mixture was diluted with EtOAc (20 mL), washed with water (10 mL) and brine (10 mL). The residue was purified by preparative HPLC to give 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-bromoethyl)-6-methylpicolinate: To a solution of intermediate Fi (0.37 g, 1.67 mmol) in dioxane (4.5 mL) at 0°C A solution of bromine (0.0865 mL, 1.67 mmol) in dioxane (4.5 mL) was added dropwise. The reaction mixture was stirred at rt for 1 h. Add water (10 mL). The solvent was evaporated under reduced pressure. The resulting residue was purified by preparative HPLC to give 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: Add a solution of thioacetamide (0.014 g, 0.184 mmol) in MeCN (0.13 mL) dropwise. Add to a mixture of intermediate F.ii (0.050 g, 0.184 mmol) and 4A molecular sieve (0.017 g) in MeCN (0.3 mL). The reaction mixture was stirred at rt for 2 h. The reaction mixture was cooled to 0°C. The solids were removed by filtration and the filter cake was rinsed with MeOH. The latter solid was suspended in MeOH (0.5 mL) and heated at 50 °C for 1 h. The solution was concentrated in vacuo to give 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 intermediate F.iii (0.045 g, 0.181 mmol) in EtOH (0.86 mL) was added 2 N Aqueous NaOH solution (0.91 mL). The reaction was carried out for 2 h at rt, and 2N HCl was added to reach an acidic pH <2. The solution was concentrated under reduced pressure to give the title acid (0.043 g) as a yellowish solid. LC-MS (A): t _R = 0.40 min; [M+H] ⁺ = 235.01.

Preparation G: 6-Methyl-3-(4-methyl-2H-1,2,3-triazol-2-yl)picolinic acid from 4-methyl-1H-1,2,3-triazole ( Starting with 0.258 g, 2.95 mmol) and -3-bromo-6-methylpyridine-2-carboxylic acid (0.658 g, 2.95 mmol) and proceeding as described in Preparation E, purification by preparative HPLC afforded a white solid. The title product (0.27 g). LC-MS (A): t _R = 0.48 min; [M+H] ⁺ = 219.16.

Preparation H: 2-(1-Methyl-1H-pyrazol-3-yl)benzoic acid, lithium salt Hi ethyl 2-(1-methyl-1H-pyrazol-3-yl)benzoate: To 2 -Ethoxycarbonylphenylboronic acid (0.231 g, 1.17 mmol) was added to a solution of dioxane (4.7 mL) and EtOH (2.3 mL) 3-iodo-1-methyl-1H-pyrazole (0.250 g, 1.17 mmol ), 2 M Na ₂ CO ₃ aqueous solution (1.75 mL, 3.5 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride.DCM (0.057 g, 0.07 mmol), The reaction mixture was partitioned between water (15 mL) and EtOAc (15 mL). The two layers were separated and the aqueous layer was extracted with EtOAc (2 x 15 mL). The evaporation residue was purified by preparative HPLC to give 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 intermediate Hi (0.14 g, 0.608 mmol) in a THF-water mixture (10:1, 5.5 mL ) was added LiOH.H ₂ O (0.028 g, 0.669 mmol). The reaction was carried out at RT for 25 h. The reaction mixture was concentrated to dryness and the residue was triturated in MeCN. The solid was recovered by filtration and dried to constant weight to give 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: From 2-chloro-4-methylpyrimidine (0.153 g, 1.17 mmol) and 2-ethoxycarbonylphenylboronic acid (0.231 g, Starting from 1.17 mmol) and proceeding as described in Preparation H. Step Hi, the title ester (0.126 g) was obtained after purification by preparative HPLC as a light brown oil. 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 This compound was prepared as reported in WO2019043407.

Preparation K: 6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxylic acid This compound was prepared as reported in WO2019043407.

Preparation L: 6-Methyl-3-pyrazol-1-ylpyridine-2-carboxylic acid This compound was prepared as reported in WO2019043407.

Preparation M: 6-Methyl-3-(1,3-thiazol-2-yl)pyridine-2-carboxylic acid This compound was prepared as reported in WO2019043407.

Preparation N: 5-Methyl-2-(1H-pyrazol-1-yl)nicotinic acid from 2-bromo-5-methylnicotinic acid methyl ester (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) was obtained as a pale yellow solid after purification by preparative 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 with methyl 2-iodo-5-methylbenzoate (0.800 g, 2.95 mmol) and 3-methylpyrazole (0.250 g, 2.95 mmol) and proceeding as described in Preparation E, by Preparation After HPLC purification, the title acid (0.233 g) was obtained as a mixture (light yellow solid). LC-MS (A): t _R = 0.67 and 0.69 min; [M+H] ⁺ = 217.18. The first lytic isomeric system 5-methyl-2-(5-methyl-1H-pyrazol-1-yl)benzoic acid.

Preparation P: 5-methyl-2-(4-methyl-2H-1,2,3-triazol-2-yl)benzoic acid Pi 2-(4-bromo-5-methyl-2H-1, 2,3-Triazol-2-yl)-5-methylbenzoic acid: From 5-bromo-4-methyl-1H-1,2,3-triazole (0.1 g, 0.599 mmol, 1 equiv) and Starting with methyl 2-iodo-5-methylbenzoate (0.104 mL, 0.599 mmol) and proceeding as described in Preparation E, purification by preparative HPLC afforded the title acid (0.053 g) as an off-white solid. 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: Add intermediate Pi (0.040 g, 0.135 mmol) and sodium acetate ( To a mixture of EtOAc (1.8 mL) and EtOH (0.6 mL) was added palladium hydroxide on carbon (20%; 0.014 g). The reaction was carried out under normal hydrogen atmosphere for 72 h. The catalyst was removed by filtration and the filtrate was concentrated to dryness to give 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 from 4-bromo-2-methyl-1,3-thiazole (0.081 g, 0.456 mmol) and 2 Starting with -methoxycarbonyl-4-methylphenylboronic acid (0.093 g, 0.456 mmol) and proceeding as described in Preparation H, Steps Hi and H.ii, the title salt (0.048 g) was 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 This compound was prepared as reported in WO2008/6562.

Preparation S: 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid This compound was prepared as reported in WO2018/202689.

Preparation T: 5-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid This compound was prepared as reported in WO2019/43407.

Preparation U: 5-chloro-2-(2H-1,2,3-triazol-2-yl)benzoic acid This compound was prepared as reported in WO2019/43407.

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

Preparation W: 5-methoxy-2-(1H-pyrazol-1-yl)benzoic acid This compound is commercially available and prepared as described in WO 2014/057435.

Preparation Proceeding as described in Preparation E, the title acid (0.121 g) was obtained as a beige solid after purification by preparative 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]thiazole hydrochloride from tetrahydro-1(2H)-pyridazinecarboxylic acid Starting with tributyl ester (0.2 g, 1.02 mmol) and 2-methyl-1,3-benzothiazole-6-carbaldehyde (0.191 g, 1.02 mmol) and proceeding as described in Preparation A, Steps Ai and A.ii Proceeding to obtain the title compound (0.252 g) as a pale yellow 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. Combine 2-bromo-5-chlorobenzoic acid (0.1 g, 0.416 mmol), CuI (0.004 g, 0.0208 mmol) and K ₂ CO ₃ (0.129 g, 0.936 mmol) were suspended in dioxane (2.5 mL). 4-Bromo-1H-1,2,3-triazole (0.13 g, 0.832 mmol) was added and the reaction mixture was heated at reflux for 1 h. Add water (0.06 mL) and heat for 1 h. After cooling, the volatiles were removed in vacuo, and the residue was diluted with water (2 mL) and acidified to pH 2 with 20% _{aqueous H2SO4} . The resulting mixture was purified by preparative HPLC to afford the title compound as an oil (0.12 g), which crystallized on standing. ¹ H NMR (DMSO- d ₆ ) δ: 13.50 (br s, 1H), 8.33 (s, 1H), 7.85 (m, 1H), 7.81 (m, 2H).

Preparation AA: 2-(4-chloro-1H-pyrazol-1-yl)-5-methylnicotinic acid from 4-bromo-1H-pyrazole (0.155 g, 1.47 mmol) and 2-bromo-5-methyl Starting with methylnicotinate (0..2 g, 0.843 mmol) and proceeding as described in Preparation E, the title acid (0.138 g) was obtained as a beige solid after purification by preparative 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)(pyrazodin-1-yl)methanone dihydrochloride AB.i. 2- (5-Chloro-2-(2H-1,2,3-triazol-2-yl)benzoyl)pyrazolidine-1-carboxylic acid tert-butyl ester: oxalyl chloride (0.1 mL, 1.16 mmol) was added dropwise to a suspension of 5-chloro-2-(2H-1,2,3-triazol-2-yl)benzoic acid (0.245 g, 1.1 mmol) in DCM (5 mL) middle. Then DMF (0.02 mL) was added dropwise. The reaction solution was stirred for 1 h30. Volatiles were removed under reduced pressure and co-evaporated twice with dry DCM (4 mL). The crude residue was dissolved in DCM (6.5 mL) and added dropwise to tert-butylpyrazolidine-1-carboxylate (0.171 g, 0.99 mmol) and NEt ₃ (0.415 mL, 2.98 mmol) in DCM (3.2 mL) in ice-cold solution. The reaction was carried out at rt for 2h15. Add saturated _aqueous NaHCO (10 mL) and DCM (10 mL). Separate the two layers. Extract the aqueous layer with DCM (2 x 10 mL). The evaporation residue was purified by FC (heptane-EtOAc) to give the title compound (0.311 g) as a pale yellow 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)(pyrazodin-1-yl)methanone dihydrochloride: from intermediate AB Starting from .i (0.299 g, 0.791 mmol) and proceeding as described in Preparation A, Step A.ii, the title compound (0.285 g) was obtained as a pale yellow 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 from 4-methyl-1H-pyrazole (0.15 g, 1.79 mmol) and 2-bromo-5- Starting with chloronicotinic acid (0.36 g, 1.49 mmol) and proceeding as described in Preparation E, purification by preparative HPLC afforded the title acid (0.18 g) as a beige solid. 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 from 4-methyl-1H-pyrazole (0.15 g, 1.79 mmol) and 2-bromo-5 Starting with -methylnicotinate (0.36 g, 1.52 mmol) and proceeding as described in Preparation E, the title acid (0.14 g) was obtained after purification by preparative HPLC as a beige solid. 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 from 4-methyl-1H-pyrazole (0.2 g, 2.0 mmol) and 2-bromo-5- Starting with methyl chlorobenzoate (0.5 g, 2.0 mmol) and proceeding as described in Preparation E, purification by preparative HPLC afforded the title acid (0.344 g) as a beige solid. 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 from 3-methyl-1H-pyrazole (0.353 g, 4.22 mmol) and 2-bromo-5 Starting with -methylnicotinate (0.5 g, 2.11 mmol) and proceeding as described in Preparation E, the title acid (0.18 g) was obtained after purification by preparative HPLC as a light green solid. 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 2-bromobenzo[ d] To a suspension of ethyl thiazole-6-carboxylate (0.3 g, 1.07 mmol) in DCM (5 mL), DIBAL-H in toluene (2.67 mL, 2.67 mmol) was added dropwise, keeping the temperature below -72 ℃. The reaction was carried out at the same temperature for 2 h and then reached rt in 45 min. Add water (0.11 mL), 1 M.NaOH (0.11 mL), water (0.26 mL). Add DCM (5 mL) and filter. The evaporation residue was purified by FC (heptane-EtOAc) to give 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 intermediate AG.i (0.189 g, 0.76 mmol) in a mixture of DCM (4 mL) and THF (2 mL) was added MnO ₂ (0.46 g, 5.3 mmol). The reaction mixture was stirred at rt overnight. The reaction mixture was filtered over celite and washed with DCM (2 x 10 mL). The filtrate was concentrated to dryness to give the title compound (0.182 g) as a white solid. ¹ H NMR (DMSO- d ₆ ) δ: 10.12 (s, 1H), 8.74 (dd, J= 1.6 Hz, 1H), 8.18 (d, J = 8.4 Hz, 1H), 8.05 (dd, J= 1.6, 8.4 Hz, 1H).

Preparation AH: (RS)-2-methyl-6-((4-methylpyrazolin-1-yl)methyl)benzo[d]thiazole hydrochloride AH.i. (RS)-4- Methylpyrazolidine-1,2-dicarboxylic acid 1-benzyl ester 2-(tert-butyl ester): To 1,2-hydrazinedicarboxylic acid 1-benzyl ester 2-(tert-butyl ester) (0.4 g , 1.5 mmol), to a suspension of K ₃ PO ₄ (0.7 g, 3.3 mmol) in MeCN (4 mL) was added 1,3-dibromo-2-methylpropane (0.376 g, 1.65 mmol). The reaction was carried out at 55°C for 20 h. More K ₃ PO ₄ (0.16 g, 0.75 mmol) was added and the reaction was carried out at 60 °C for 48 h. After adding cooling water (5 mL) and TBME (5 mL). The two layers were separated and the aqueous layer was extracted with TBME (5 mL). The evaporation residue was purified by FC (heptane-EtOAc gradient) to give the title compound (0.22 g) which crystallized on standing as a colorless oil. LC-MS (A): t _R = 0.99 min; [M+H] ⁺ = 321.16. AH.ii. (RS)-4-Methylpyrazolidine-1-carboxylic acid tert-butyl ester: To a solution of intermediate AH.i (0.215 g, 0.671 mmol) in MeOH (2 mL) was added Peel Man Catalyst (0.011 g, 0.0201 mmol). The reaction was carried out at rt and normal hydrogen atmosphere for 1 h. The catalyst was removed by filtration and the filtrate was concentrated to dryness to give the title compound (0.123 g) as a colorless oil. LC-MS (A): t _R = 0.48 min; [M+H] ⁺ = 187.39. AH.iii. (RS)-2-Methyl-6-((4-methylpyrazolin-1-yl)methyl)benzo[d]thiazole hydrochloride: From intermediate AH.ii. ( Start with 0.12 g, 0.644 mmol) and 2-methyl-1,3-benzothiazole-6-carbaldehyde (0.132 g, 0.709 mmol) and proceed as described in Preparation A, Steps Ai and A.ii. The title compound (0.12 g) was prepared as a pale yellow solid. LC-MS (A): t _R = 0.56 min; [M+H] ⁺ = 248.23.

Preparation AI: 2-methyl-[1,3]thiazole[5,4-b]pyridine-5-carbaldehyde This compound was prepared as described in US5472964.

Preparation AJ: 2-chlorobenzo[d]thiazole-6-carbaldehyde: Start with 2-chloro-1,3-benzothiazole-6-carboxylic acid methyl ester (0.305 g, 1.27 mmol) and proceed as in Preparation AG, Step The procedure reported in AG.i and AG.ii was followed and purification by FC (heptane-EtOAc) afforded the title aldehyde (0.15 g) as a white solid. ¹ H NMR (DMSO- d ₆ ) δ: 10.12 (s, 1H), 8.74 (dd, J= 1.6 Hz, 1H), 8.15 (d, J = 8.4 Hz, 1H), 8.08 (dd, J= 1.6, 8.4 Hz, 1H).

Preparation AK: (S)-2-methyl-6-((4-methylpyrazolin-1-yl)methyl)benzo[d]thiazole hydrochloride AK.i. (R)-2- (3-((tert-Butyldimethylsilyl)oxy)-2-methylpropyl)hydrazine-1-carboxylic acid tert-butyl ester: To (S)-3-((tert-butyl Dimethylsilyloxy)-2-methylpropyl 4-methylbenzenesulfonate (prepared as described in J. Org. Chem. 2003, 68, 5568; 1.5 g, 4.18 mmol) in DMF (10 mL) was added tert-butylcarbazate (2.2 g, 16.7 mmol). The reaction was carried out at 80°C for 24 h. After cooling, the solvent was removed in vacuo and the residue was purified by FC (heptane-EtOAc) to give the title compound as a colorless oil (0.675 g; 51% yield). ¹ H NMR (CDCl ₃ ) δ: 6.10 (br s, 1H); 3.58-3.51 (m, 2H), 2.89 (dd, J= 6.8, 11.5 Hz, 1H), 2.73 (dd, J= 6.3, 11.5 Hz , 1H), 1.84 (m, 1H), 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. (R)-2-(3-((tert-Butyldimethylsilyl)oxy)-2-methylpropyl)-2-((2-methylbenzo[d] Thiazol-6-yl)methyl)hydrazine-1-carboxylic acid tert-butyl ester: From intermediate AK.i (0.65 g, 2.04 mmol) and 2-methyl-1,3-benzothiazole-6-carbaldehyde Starting with (0.362 g, 2.04 mmol) and proceeding as described in Preparation A, Step Ai, the title compound (0.42 g, 43% yield) was prepared as a colorless oil. ¹ H NMR (CDCl ₃ ) δ: 7.89 (d, J = 8.3 Hz, 1H), 7.86 (s, 1H), 7.45 (dd, J= 1.6, 8.3 Hz, 1H), 5.63 (br s, 1H), 4.10 (br s, 2H), 3.51-3.63 (m, 2H), 2.86 (overlap m, 1H), 2.84 (s, 3H), 2.63 (br s, 1H), 1.88 (m, 1H), 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.iii. (R)-2-(3-hydroxy-2-methylpropyl)-2-((2-methylbenzo[d]thiazol-6-yl)methyl)hydrazine-1-carboxy Acid tert-butyl ester: To a solution of intermediate AK.ii (0.42 g, 0.875 mmol) in THF (5 mL) was added TBAF (1M in THF; 1.5 mL, 1.5 mmol). The reaction was carried out at room temperature for 2 h. The solvent was removed in vacuo and the residue was purified by FC (heptane-EtOAc) to give the title compound as a colorless oil (0.32 g, 100% yield). ¹ H NMR (CDCl ₃ ) δ: 7.92 (d, J = 8.3 Hz, 1H), 7.85 (s, 1H), 7.43 (dd, J= 1.6, 8.3 Hz, 1H), 5.51 (br s, 1H), 4.15 (br s, 1H), 3.94 (m, 1H), 3.72 (m, 1H), 3.53 (m, 1H), 3.51-3.63 (m, 2H), 2.88 (overlapping m, 1H), 2.85 (s, 3H), 2.74 (m, 1H), 2.08 (m, 1H), 1.35 (s, 9H), 0.84 (d, J= 6.9Hz, 3H), 0.88 (s, 9H), 0.05 (s, 6H). AK.iv. (R)-2-(2-methyl-3-(p-toluenesulfonyloxy)propyl)-2-((2-methylbenzo[d]thiazol-6-yl)methyl tert-butylhydrazine-1-carboxylate: To a solution of intermediate AK.iii (0.32 g, 0.875 mmol) in DCM (8 mL) was added 4-DMAP (0.177 g; 1.45 mmol) at room temperature. )), TEA (0.3 mL, 2.16 mmol) and pTsCl (0.33 g, 1.75 mmol). The reaction was carried out at room temperature for 2 h. Direct purification of the reaction mixture by FC (heptane-EtOAc) afforded the title compound as a colorless oil (0.39 g, 86% yield). LC-MS (A): t _R = 1.11 min; [M+H] ⁺ = 520.18. AK.v. (R)-4-Methyl-2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidine-1-carboxylic acid tert-butyl ester: toward the middle To a solution of body AK.iv (0.39 g, 0.75 mmol) in acetonitrile (5 mL) was added tripassium phosphate (0.319 g). The reaction was carried out at 80°C for 16 h. After cooling, the solid was filtered, washed with acetonitrile and the filtrate concentrated to dryness. Chromatography of the residue (Heptane-EtOAc) afforded the title compound as a colorless oil (0.25 g, 96% yield). ¹ H NMR (CDCl ₃ ) δ: 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-methylpyrazolin-1-yl)methyl)benzo[d]thiazole hydrochloride: From intermediate AK.v. ( Starting from 0.25 g, 0.644 mmol) and proceeding as described in Preparation A, step A.ii., the title compound (0.2 g, 99% yield) was prepared as a pale yellow solid. LC-MS (A): t _R = 0.56 min; [M+H] ⁺ = 248.23.

Preparation AL: 2-Methyl-6-((pyrazolin-1-yl-4,4-d ₂ )methyl)benzo[d]thiazole dihydrochloride AL.i. Propane-1,3- Diyl-2,2-d _2bis (4-methylbenzenesulfonate): To 1,3-propane-2,2-d ₂ -diol (0.5 g, 6.4 mmol) in DCM (20 mL) Add Et ₃ N (2.68 mL, 19.2 mmol), DMAP (0.08 g, 0.63 mmol) and pTsCl (2.71 g, 14.1 mmol) to the ice-cold solution. The resulting solution was stirred at RT for 3 h during the reaction. Add _saturated aqueous NaHCO solution (5 mL) and separate the two layers. Extract the aqueous layer with DCM (5 mL). Wash the combined organic layer with saturated aqueous Cu ₂ SO solution (5 mL) and brine (5 mL). The evaporation residue was purified by FC (heptane-EtOAc) to give the title compound as a white solid (0.72 g, 29% yield). LC-MS (A): t _R = 1.02 min; [M+H] ⁺ = 387.2. ¹ H NMR (500 MHz, DMSO) δ: 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-((pyrazolin-1-yl-4,4-d ₂ )methyl)benzo[d]thiazole dihydrochloride: From intermediate AL.i (0.718 g, 1.86 mmol) and 1,2-hydrazinedicarboxylic acid 1-benzyl ester 2-(tert-butyl ester) (0.45 g, 1.69 mmol) starting with preparation AH, steps AH.i and AH.ii (except using MeOH-d ₄ and D ₂ gas) and proceed as described in Preparation A, Steps Ai and A.ii to obtain the title compound (0.099 g) as a pale yellow solid. LC-MS (A): t _R = 0.51 min; [M+H] ⁺ = 236.1 ¹ H NMR (500 MHz, DMSO) δ: 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 Example 1 of Examples: (5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazole-6 -Methyl)pyrazolin-1-yl)methanone was added to the compound of preparation B (0.018 g, 0.061 mmol) and 2-methylbenzo[d]thiazole-6-carbaldehyde (0.010 g, 0.061 mmol) To a solution in DMF (0.5 mL) was added sodium triacetyloxyborohydride (0.034 g, 0.153 mmol). The reaction was carried out at RT for 16 h. The reaction mixture was dissolved in DMF (1 mL) and 0.5% aqueous NH ₄ OH solution. The resulting solution was purified by preparative HPLC to afford the title compound (0.012 g) as a white solid. Example Compound name LC-MS data method _tR (min) [M+H] ⁺ 1 (5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl) Pyrazolidin-1-yl)methanone C 0.992 419.4

Example 2: (5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2-(trifluoromethyl)benzo[d]thiazole- 6-yl)methyl)pyrazolin-1-yl)methanone To a solution of the compound from Preparation D (0.016 g, 0.051 mmol) in MeCN (0.25 mL) was added NaI (0.0015 g, 0.01 mmol), K ₂ CO ₃ (0.014 g, 0.1 mmol) and the compound from preparation B (0.015 g, 0.05 mmol). The reaction mixture was refluxed for 2 h. After cooling to rt, the volatiles were removed in vacuo and the residue was purified by preparative HPLC to give the title compound as a white solid (0.001 g). 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]thiazol-6-yl)methyl)pyrazole To a solution of the compound from Preparation A (0.020 g, 0.065 mmol) in DMF (0.5 mL) was added 2-(2H-1,2,3-triazol-2-yl)benzene Formic acid (0.012 g, 0.043 mmol), DIPEA (0.072 mL, 0.41 mmol) and HATU (0.034 g, 0.09 mmol). The reaction was carried out at RT for 2 h. The reaction mixture was dissolved in DMF (1 mL) and 0.5% aqueous NH ₄ OH solution. The resulting solution was purified by preparative HPLC to afford the title compound (0.0035 g) as a white solid. Similar to the procedure described previously, the following Examples 3.1 to 3.16 were prepared using the corresponding carboxylic acids: Example carboxylic acid Compound name LC-MS data method _tR (min) [M+H] ⁺ 3.1 Commercially available Commercially available (2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidine-1 -Methyl ketone C 0.945 405.4 3.2 Prepare S (5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl )Pyrazolidin-1-yl)methanone C 0.941 435.4 3.3 Prepare U (5-Chloro-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyridine Azolidin-1-yl)methanone C 1.026 439.4 3.4 Prepare V (4,5-Dimethyl-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl) Methyl)pyrazodin-1-yl)methanone C 1.040 433.4 3.5 Commercially available (3'-methyl-[1,1'-biphenyl]-2-yl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidine-1- methyl ketone C 1.237 428.4 3.6 Preparation E (5-methyl-2-(4-methyl-1H-pyrazol-1-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyra Azolidin-1-yl)methanone C 1.063 432.2 3.7 Prepare O (5-methyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyra Azolidin-1-yl)methanone C 1.051 432.2 3.8 Commercially available [1,1'-Biphenyl]-2-yl(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazodin-1-yl)methanone C 1.174 414.2 3.9 Prepare Q (5-methyl-2-(2-methylthiazol-4-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidine-1 -Methyl ketone C 1.082 449.2 3.10 Prepare P (5-methyl-2-(4-methyl-2H-1,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazole-6- methyl)pyrazolin-1-yl)methanone C 1.033 433.3 3.11 Preparation C (5-methyl-2-(thiazol-2-yl)pyridin-3-yl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazoridin-1- methyl ketone C 0.945 436.3 3.12 PreparationN (5-methyl-2-(1H-pyrazol-1-yl)pyridin-3-yl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidine -1-yl)methanone C 0.930 419.3 3.13 PreparationX (5-Chloro-2-(1H-pyrazol-1-yl)pyridin-3-yl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidine- 1-yl)methanone C 1.007 439.2 3.14 Prepare Z (2-(4-bromo-2H-1,2,3-triazol-2-yl)-5-chlorophenyl)(2-((2-methylbenzo[d]thiazol-6-yl) Methyl)pyrazodin-1-yl)methanone C 1.151 519.2 3.15 Prepare AA (2-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl )Pyrazolidin-1-yl)methanone C 1.076 453.2 3.16 Prepare AC (5-chloro-2-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl )Pyrazolidin-1-yl)methanone C 1.100 453.1

Example 4.1: [(2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)tetrazol Hydropyridazin-1(2H)-yl)methanone To a solution of the compound from preparation Y (0.020 g, 0.07 mmol) in DMF (0.5 mL) was added 2-(2H-1,2,3-triazole- 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 was carried out at RT for 2 h. The reaction mixture was dissolved in DMF (1 mL) and 0.5% aqueous NH ₄ OH solution. The resulting solution was purified by preparative HPLC to afford the title compound (0.0048 g) as a white solid. Similar to the procedure described previously, the following Examples 4.1 to 4.3 were prepared using the corresponding carboxylic acids: Example carboxylic acid Compound name LC-MS data method _tR (min) [M+H] ⁺ 4.1 Commercially available (2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)tetrahydropyridazine- 1(2H)-yl)methanone C 1.024 419.2 4.2 Prepare U (5-Chloro-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)tetrazol Hydropyridazine-1(2H)-yl)methanone C 1.121 453.1 4.3 Commercially available (5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl) Tetrahydropyridazine-1(2H)-yl)methanone C 1.084 433.2

Example 5: (5-chloro-2-(4-methyl-2H-1,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazole- 6-yl)methyl)pyrazolin-1-yl)methanone was added to Example 3.14 (0.03 g, 0.06 mmol), K ₂ CO ₃ (0.02 g, 0.17 mmol), Pd(PPh ₃ ) ₄ (0.01 g, To a mixture of 0.012 mmol) in dioxane (1 mL) was added trimethylcyclotriboroxane (0.01 mL, 0.08 mmol). The reaction was carried out at 100°C for 2 h. After cooling, the evaporation residue was purified by preparative HPLC to give 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-methylbenzo[d]thiazole- 6-yl)methyl)pyrazolin-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)pyrazodin-1-yl)methanone: To CuI (0.002 g , 0.01 mmol) and PdCl ₂ (PPh ₃ ) ₂ (0.004 g, 0.01 mmol) was added a solution of Example 3.14 (0.030 g, 0.0579 mmol) in THF (0.45 mL), and then trimethylsilylacetylene was added (0.01 mL, 0.07 mmol) and triethylamine (0.02 mL, 0.15 mmol). The reaction was carried out at 50°C for 2 h. After cooling, the crude mixture was purified by preparative HPLC to afford the title compound as an off-white solid (0.022 g, 73% yield). 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-methylbenzo[d]thiazole -6-yl)methyl)pyrazolin-1-yl)methanone: To a solution of intermediate 6.i (0.02 g, 0.04 mmol) in MeOH (0.15 mL) was added K ₂ CO ₃ (0.01 g, 0.07 mmol). The reaction was carried out at RT for 2 h. The reaction mixture was purified by preparative 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)pyrazodin-1-yl)(5-chloro-2-(2H-1,2,3-tri Azol-2-yl)phenyl)methanone To a solution of the compound from AB (0.215 g, 0.684 mmol) and from AG (0.182 g, 0.753 mmol) in DCM (7 mL) was added triacetyloxy Sodium borohydride (0.23 g, 1.03 mmol). The reaction was carried out at RT for 16 h. The reaction mixture was partitioned between DCM (15 mL) and saturated _NaHCO3 (15 mL). The two layers were separated and the evaporation residue was purified by FC (heptane-EtOAc) to give the title compound (0.275 g) as a white foam. LC-MS (C): t _R = 1.176 min; [M+H] ⁺ = 505.1. Similar to the procedure described above, the following reference examples 7.1 to 7. were prepared using the indicated intermediates: Example Intermediates Compound name LC-MS data method _tR (min) [M+H] ⁺ 7.1 Prepare AG (2-((2-bromobenzo[d]thiazol-6-yl)methyl)pyrazodin-1-yl)(5-chloro-2-(2H-1,2,3-triazole-2 -base)phenyl)methanone C 1.176 505.1 7.2 Prepare AI (5-Chloro-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2-methylthiazolo[5,4-b]pyridin-5-yl) Methyl)pyrazodin-1-yl)methanone C 0.883 440.3 7.3 Prepare AJ (5-Chloro-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2-chlorobenzo[d]thiazol-6-yl)methyl)pyrazole Dino-1-yl)methanone C 1.185 459.2

Example 8: (5-chloro-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2-(trifluoromethyl)benzo[d]thiazole-6 -yl)methyl)pyrazodin-1-yl)methanone To a solution of Example 7.1 (0.02 g, 0.0496 mmol) in DMF (0.15 mL) was added CuI (0.011 g, 0.0595 mmol), 2,6-lutidine (0.00701 mL, 0.0595 mmol) and 2.2-difluoro -Methyl 2-(fluorosulfonyl)acetate (0.03 g, 0.149 mmol). The reaction was carried out at 80°C for 18 h. After cooling, the reaction mixture was directly purified by preparative HPLC to give the title product (0.011 g) as an off-white solid. LC-MS (C): tR = 1.236 min; [M+H]+= 493.2.

Example 9.1: (5-chloro-2-(2H-1,2,3-triazol-2-yl)phenyl) (2-((2-cyclopropylbenzo[d]thiazol-6-yl) Methyl)pyrazolin-1-yl)methanone was added to Example 7.1 (0.014 g, 0.031 mmol), Cs ₂ CO ₃ (0.027 g, 0.084 mmol), Pd(dppf)Cl ₂ (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 (0.2 mL) Add water (0.002 mL). The reaction was carried out at 100°C for 8 h. The reaction mixture was purified by preparative HPLC to afford the title compound (0.002 g) as a beige solid. LC-MS (C): t _R = 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 from Example 7.1 (0.025 g, 0.049 mmol) and triethyl-1,3,5,2,4,6-trioxatriborocyclohexane (0.026 g Starting from , 0.149 mmol) and proceeding as described in Example 9.1, the title compound (0.011 g) was prepared as a white solid after purification by preparative HPLC. LC-MS (C): t _R = 1.103 min; [M+H] ⁺ = 453.2.

Example 10.1: (RS)-(4-methyl-2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolin-1-yl)(5-methyl-2 Preparation of -(2H-1,2,3-triazol-2-yl)phenyl)methanone from the compound AH (0.040 g, 0141 mmol) and 5-methyl-2-(2H-1,2,3 Starting with -triazol-2-yl)benzoic acid (0.031 g, 0.155 mmol) and following the procedure of Example 3.1, the title compound (0.022 g) was prepared as a white solid after purification by preparative HPLC. Similar to the procedure described previously, the following Examples 10.1 to 10.3 were prepared using the corresponding carboxylic acids: Example carboxylic acid Compound name LC-MS data method _tR (min) [M+H] ⁺ 10.1 Commercially available (RS)4-methyl-2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazodin-1-yl)(5-methyl-2-(2H-1 ,2,3-triazol-2-yl)phenyl)methanone C 1.053 433.3 10.2 Commercially available (RS)-(5-chloro-2-(2H-1,2,3-triazol-2-yl)phenyl)(4-methyl-2-((2-methylbenzo[d]thiazole) -6-yl)methyl)pyrazodin-1-yl)methanone C 1.083 453.3 10.3 Prepare Z (RS)-(2-(4-bromo-2H-1,2,3-triazol-2-yl)-5-chlorophenyl)(4-methyl-2-((2-methylbenzo [d]thiazol-6-yl)methyl)pyrazodin-1-yl)methanone C 1.227 533.3

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)pyrazodin-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)pyrazodin-1-yl)methanone isolated using chiral HPLC (RS)-(5-chloro-2-[1,2,3]triazol-2-yl -Phenyl)-[4-methyl-2-(2-methyl-benzothiazol-6-ylmethyl)-pyrazodin-1-yl]-methanone Two mirror image isomers, first Obtain (R)-(5-chloro-2-(2H-1,2,3-triazol-2-yl)phenyl)(4-methyl-2-((2-methylbenzo[d] Thiazol-6-yl)methyl)pyrazolin-1-yl)methanone, then (S)-(5-chloro-2-(2H-1,2,3-triazol-2-yl)benzene yl)(4-methyl-2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazodin-1-yl)methanone. Preparative chiral HPLC conditions: ChiraIPak IH column 30x250 mm, 5 μm; eluent A: CO ₂ , temperature: 40°C, eluent B: MeCN/2-propanol 1:1; 100 bar (bar); flow rate : 160 mL/min; t _R (S configuration enantiomer, Example 10.5) = 2.9 min, t _R (R configuration enantiomer, Example 10.4) = 3.5 min. Analytical chiral HPLC conditions: ChiraIPak IH column 4.6x250 mm, 5 μm; eluent A: CO ₂ , temperature: 40°C, eluent B: MeCN/2-propanol 1:1 (isocratic, 35%B) ; 150 bar; flow rate: 4 mL/min; t _R (S enantiomer, Example 10.5) = 2.5 min, t _R (R enantiomer, Example 10.4) = 2.9 min.

(R)-(5-chloro-2-(2H-1,2,3-triazol-2-yl)phenyl)(4-methyl-2-((2-methylbenzo[d]thiazole The absolute configuration and retention time of -6-yl)methyl)pyrazolin-1-yl)methanone were determined by synthesizing real samples as follows: From the compound from which AK was prepared (0.2 g, 0.719 mmol) and 5-chloro- Prepared by starting from 2-(2H-1,2,3-triazol-2-yl)benzoic acid (0.169 g, 0.755 mmol) and following the procedure of Example 3.1, after purification by FC (heptane-EtOAc) Example 10.4 (0.26 g, 80% yield) was a white solid. LC-MS (C): t _R = 1.103 min; [M+H] ⁺ = 453.2. Analytical chiral HPLC conditions: ChiraIPak IH column 4.6x250 mm, 5 μm; eluent A: CO ₂ , temperature: 40°C, eluent B: MeCN/2-propanol 1:1 (isocratic, 35% B) ; 150 bar; flow rate: 4 mL/min t _R (R enantiomer, example 10.4) = 2.9 min.

Example 10.6: (R)-4-methyl-2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolin-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)pyrazolin-1-yl)(5-methyl-2- Separation of (2H-1,2,3-triazol-2-yl)phenyl)methanone using chiral HPLC (RS)-4-methyl-2-((2-methylbenzo[d]thiazole- Two mirror image isomers of 6-yl)methyl)pyrazolin-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone body, obtaining (R)-4-methyl-2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolin-1-yl)(5-methyl-2- (2H-1,2,3-triazol-2-yl)phenyl)methanone and (S)-4-methyl-2-((2-methylbenzo[d]thiazol-6-yl) Methyl)pyrazodin-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone. Chiral HPLC conditions: ChiraIPak OZ-H column 30x250 mm, 5 μm; eluent A: CO ₂ , temperature: 40°C, eluent B: MeCN/EtOH 1:1; 100 bar; flow rate: 160 mL/min; t _R = 2.3 and 3.3 minutes.

Absolute configuration of each unassigned enantiomer.

Example 10.8: (S)-(2-(4-bromo-2H-1,2,3-triazol-2-yl)-5-chlorophenyl)(4-methyl-2-((2-methyl Benzo[d]thiazol-6-yl)methyl)pyrazodin-1-yl)methanone and Example 10.9: (R)-(2-(4-bromo-2H-1,2,3-tri Azol-2-yl)-5-chlorophenyl)(4-methyl-2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazodin-1-yl)methyl Ketones were separated using chiral HPLC (RS)-(2-(4-bromo-2H-1,2,3-triazol-2-yl)-5-chlorophenyl)(4-methyl-2-(( Two enantiomers of 2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolin-1-yl)methanone, firstly obtain (S)-(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 and (R)-(2-(4-bromo-2H-1,2,3-triazol-2-yl)-5-chlorophenyl)(4-methyl -2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazodin-1-yl)methanone. Chiral HPLC conditions: ChiraICel OJ-H column 30x250 mm, 5 μm; eluent A: CO ₂ , temperature: 40°C, eluent B: MeCN/EtOH1:1 (15%); 100 bar; flow rate: 160 mL /min; t _R = 3.2 and 3.99 min.

(S)-(2-(4-bromo-2H-1,2,3-triazol-2-yl)-5-chlorophenyl)(4-methyl-2-((2-methylbenzo The absolute configuration and residence time of [d]thiazol-6-yl)methyl)pyrazolin-1-yl)methanone are assigned as follows: To Example 10.8 (the first eluted enantiomer of Example 10.3 under nitrogen atmosphere ) (0.07 g, 0.13 mmol) in MeOH (2.4 mL) and Et ₃ N (0.06 mL, 0.4 mmol) was added Pd(OH) ₂ , 20 wt. % (0.02 g). The reaction was carried out under hydrogen atmosphere for 2 h. The catalyst was removed by filtration and the evaporation residue was purified by preparative HPLC to afford Example 10.5 as a white freeze-dried solid (0.04 g, 75% yield). LC-MS (A): t _R = 0.98 min; [M+H] ⁺ = 453.2. Analytical chiral HPLC conditions: ChiraIPak IH column 4.6x250 mm, 5 μm; eluent A: CO ₂ , temperature: 40°C, eluent B: MeCN/2-propanol 1:1 (isocratic, 35%B) ; 150 bar; flow: 4 mL/min t _R ( S configuration enantiomer, example 10.5) = 2.5 min.

Example 11: (5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl) (2-((2-methylbenzo[d]thiazol-6-yl) Methyl)pyrazodin-1-yl)methanone was prepared starting from the compound of preparation B (0.018 g, 0.061 mmol) and 2-methylbenzo[d]oxazole-6-carbaldehyde (0.006 g, 0.061 mmol). Proceeding as described in Example 1.1, the title compound (0.010 g) was prepared as a white solid after purification by preparative HPLC. LC-MS (C): t _R = 0.930 min; [M+H] ⁺ = 403.3.

Example 12.1: (2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazole To a solution of the compound from which AL was prepared (0.025 g, 0.092 mmol) in DMF (0.5 mL) was added 2-(2H-1,2,3 _- tris Azol-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 was carried out at RT for 16 h. The reaction mixture was dissolved in DMF (1 mL) and 0.5% aqueous NH ₄ OH solution. The resulting solution was purified by preparative HPLC to afford the title compound (0.0027 g) as a white solid. Similar to the procedure described previously, the following Examples 12.1 to 12.3 were prepared using the corresponding carboxylic acids: Example carboxylic acid Compound name LC-MS data method _tR (min) [M+H] ⁺ 12.1 Commercially available (2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidine-1 -Base-4,4-d ₂ )methanone C 0.943 407.3 12.2 Commercially available (5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl) Pyrazolidin-1-yl-4,4-d ₂ )methanone C 0.989 421.3 12.3 Prepare U (5-Chloro-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyridine Azolidin-1-yl-4,4-d ₂ )methanone C 1.023 441.3

Example 12.4: (5-chloro-2-(2H-1,2,3-triazol-2-yl-d)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl )Methyl)pyrazolin- ₁ -yl)methanone To a solution of Example 3.14 (0.053 g, 0.10 mmol) in MeOH- _d (2.4 mL) was added Pd(OH) ₂ /C ( 20 wt%, 0.012 g). The reaction was carried out under _D2 atmosphere for 1h15. The catalyst was removed by filtration and the evaporation residue was purified by preparative HPLC to give the title compound as a white solid (0.039 g, 87% yield). LC-MS (C): t _R = 1.015 min; [M+H] ⁺ = 440.3. ¹ H NMR (500 Mhz, DMSO- d ₆ ) δ: 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 (overlap m, 2 H), 2.77 (s, 3 H), 2.64-2.49 (overlap 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-methylbenzene) and[d]thiazol-6-yl)methyl)pyrazodin-1-yl)methanone starting from Example 10.9 (0.03 g, 0.056 mmol) and proceeding as described in Example 12.4, after purification by preparative HPLC The title compound was obtained as a white solid (0.021 g). LC-MS (C): t _R = 1.091 min; [M+H] ⁺ = 454.3.

Reference example

Reference Example RE1.1: (2-(benzo[d]thiazol-6-ylmethyl)pyrazodin-1-yl)(5-chloro-2-(2H-1,2,3-triazole- 2-yl)phenyl)methanone To a solution of the compound from preparation AB (0.02 g, 0.057 mmol) and 6-benzo[d]thiazolecarboxaldehyde (0.010 g, 0.061 mmol) in DCM (0.5 mL) was added Sodium acetylborohydride (0.019 g, 0.089 mmol). The reaction was carried out at RT for 16 h. The reaction mixture was partitioned between DCM (5 mL) and saturated _NaHCO3 (5 mL). The two layers were separated and the evaporation residue was purified by preparative HPLC to give the title compound as a white solid (0.013 g). Similar to the procedure described previously, the following reference examples RE1.1 and RE1.2 were prepared using commercially available aldehydes and the indicated intermediates: Example Intermediates Compound name LC-MS data method _tR (min) [M+H] ⁺ RE1.1 Prepare AB (2-(benzo[d]thiazol-6-ylmethyl)pyrazodin-1-yl)(5-chloro-2-(2H-1,2,3-triazol-2-yl)phenyl )methyl ketone C 0.953 425.2 RE1.2 (2-(benzo[d]thiazol-6-ylmethyl)pyrazodin-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)benzene methyl ketone C 0.933 405.4

Reference Example RE1.3: (5-chloro-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazole-5- methyl)pyrazolin-1-yl)methanone RE1.3.i. 2-Methyl-5-(pyrazodin-1-ylmethyl)benzo[d]thiazole hydrochloride: From Starting with tert-butyl 1-pyrazolidinecarboxylate (0.250 g, 1.45 mmol) and 2-benzothiazole-5-carbaldehyde (0.271 g, 1.47 mmol) as described in Preparation A, Steps Ai and A.ii Proceeding sequentially, the title compound (0.103 g) was obtained as an orange solid. LC-MS (A): t _R = 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]thiazole-5- methyl)pyrazolin-1-yl)methanone: From intermediate RE.1.3.i (0.020 g, 0.0741 mmol) and 5-chloro-2-(2H-1,2,3-triazole- Starting with 2-yl)benzoic acid (0.0188 g, 0.0815 mmol) and proceeding as described in Example 3.1, purification by preparative HPLC afforded the title compound (0.016 g) as a white solid. LC-MS (C): t _R = 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-benzo[d]imidazole) -6-yl)methyl)pyrazolidin-1-yl)methanone was prepared from compound AB (0.03 g, 0.0955 mmol) and 2-methyl-1H-1,3-benzodiazole-5-carbaldehyde Starting from (0.02 g, 0.11 mmol) and proceeding as described in Example 7.1, the title compound (0.015 g) was prepared as a white solid after purification by preparative HPLC. LC-MS (C): t _R = 0.476 min; [M+H] ⁺ = 422.3.

Reference Example RE1.5: (2-((2-methyl-1H-benzo[d]imidazol-6-yl)methyl)pyrazolin-1-yl)(5-methyl-2-(2H -1,2,3-Triazol-2-yl)phenyl)methanone From compound B (0.025 g, 0.0955 mmol) and 2-methyl-1H-1,3-benzodiazole-5- Starting with formaldehyde (0.016 g, 0.093 mmol) and proceeding as described in Example 7.1, the title compound (0.016 g) was prepared as a white solid after purification by preparative HPLC. LC-MS (C): t _R = 0.476 min; [M+H] ⁺ = 402.3.

physical representation

Solubility: Solubility was determined by the miniaturized saturated shake flask method (screening mode). The compound form is an amorphous membrane derived from evaporation of DMSO from a 10 mM stock solution to which FaSSIF (fasted state small intestine simulated fluid) medium is added. After equilibration for 24 hours at 25°C, the phases were separated by filtration and the aqueous compound concentration in the aqueous phase was determined by UV-HPLC. Results: The solubility of the compound of Example 3.3: 497 μg/mL; the compound of Example 10.4: >770 μg/mL.

Bioanalysis The following procedures have been used to measure the antagonistic activity of each example compound at two orexin receptors: In vitro analysis: Intracellular calcium measurement: Chinese hamsters expressing human orexin-1 receptor and human orexin-2 receptor respectively Ovarian (CHO) cells were cultured in culture medium containing 300 μg/ml G418, 100 U/ml penicillin, 100 μg/ml streptomycin and 10% heat-inactivated fetal bovine serum (FBS) (Ham containing L-glutamine). F-12). Cells were seeded into 384-well black transparent bottom sterile plates (Greiner) at 20,000 cells/well. Incubate the inoculated plates overnight at 37 °C in 5% _CO2 . Human Orexin-A as an agonist was prepared as a 1 mM stock solution in MeOH:water (1:1), diluted in a solution containing 0.1% bovine serum albumin (BSA), 0.375 g/l NaHCO and ₂₀ mM HEPES was used in this analysis at a final concentration of 2 nM in HBSS. Antagonists were prepared as 10 mM stock solutions in DMSO, diluted in DMSO in 384-well plates, and transferred to a solution containing 0.1% bovine serum albumin (BSA), 0.375 g/l NaHCO, and ₂₀ mM HEPES. in HBSS. On the day of analysis, use a BioTek EL406 cell washer to wash the cells twice with 100 μl analysis buffer (HBSS containing 0.375 g/l NaHCO ₃ , 20 mM HEPES, and 5mM probenecid). After washing, leave 25 μl analysis buffer. on the cells. Add 25 μL of dye solution (containing 2% FBS, 20 mM HEPES, 0.375 g/l NaHCO ₃ , 5 mM probenecid (Sigma), and 4 μM fluorescent calcium indicator Fluo-8AM (2 in DMSO) to each well. mM stock solution) in HBSS). Incubate 384-well cell plates _in 5% CO at 37°C for 60 min, followed by equilibration at RT for 15 min before measurement. Antagonist was added to the plate in a volume of 10 μl/well in a fluorescence imaging plate reader (FLIPR Tetra, Molecular Devices), incubated for 120 min and finally 10 μl/well of agonist was added. Measure the fluorescence of each well at 1 second intervals and compare the height of each fluorescence peak to the fluorescence peak height induced by Orexin-A with a vehicle surrogate antagonist of approximately EC ₈₀ (e.g. 2 nM) . Determine the IC ₅₀ value (the concentration of compound required to inhibit 50% of the agonist response). Reference compounds were added to each plate. Achieve optimal conditions by adjusting pipetting speed and cell division protocol. The calculated _IC50 value may fluctuate depending on daily cell analysis performance. Such fluctuations are known to those skilled in the art. The average _IC50 value from several measurements is given as the geometric mean. The antagonistic activities of example compounds relative to Ox1 and Ox2 receptors are shown in Table 1. Example IC ₅₀ (nM) (hOX1R) IC ₅₀ (nM) (hOX2R) Example IC ₅₀ (nM) (hOX1R) IC ₅₀ (nM) (hOX2R) 1 4 2 7.1 4 9 2 46 19 7.2 8 6 3.1 44 1 7.3 6 8 3.2 twenty four 18 8 9 12 3.3 18 2 9.1 49 17 3.4 1 0.3 9.2 16 4 3.5 10 1 10.1 26 2 3.6 39 8 10.2 33 2 3.7 47 10 10.3 9 1 3.8 57 6 10.4 4 1 3.9 41 3 10.5 26 2 3.10 twenty one 2 10.6 4 1 3.11 29 3 10.7 36 2 3.12 46 14 10.8 46 3 3.13 19 9 10.9 3 1 3.14 34 3 11 36 12 3.15 41 5 12.1 130 10 3.16 34 7 12.2 12 2 4.1 55 6 12.3 8 3 4.2 14 4 12.4 20 2 4.3 9 3 12.5 4 1 5 27 7 6 13 2 Reference example 1.1 231 26 Reference example 1.4 158 60 Reference example 1.2 116 25 Reference example 1.5 56 55 Reference example 1.3 62 twenty two

The general pharmacokinetic and pharmacological properties of the compounds of the invention can be further characterized using conventional analytical methods well known in the art; for example, with respect to their bioavailability in different species, such as rats or dogs; or regarding its ability to cross the blood-brain barrier, using, for example, human P-glycoprotein 1 (MDR 1) substrate assays, or in vivo assays to determine drug concentrations in the brain (eg, in rats after oral administration); or regarding its ability to cross the blood-brain barrier; Its functional behavior in different disease-related animal models {for example: the sedative effect of the compound measured using electroencephalography (EEG) and electromyography (EMG) signals [F. Jenck et al., Nature Medicine 2007, 13, 150-155]; Effects of compounds in the fear-potentiated startle paradigm [Fendt M et al., Neuroscience Biobehav Rev. 1999, 23, 743-760; WO2009/0047723]; Effects of compounds on stress-induced hyperthermia [ Vinkers CH et al., European J Pharmacol. 2008, 585, 407-425]; Effect of compounds on morphine-induced locomotor sensitization [Vanderschuren LJMJ et al., Self DW, Staley JK (eds.) "Behavioral Neuroscience of Drug Addiction", Current Topics in Behavioral Neurosciences 3 (2009), 179-195] }; or for its properties regarding drug safety and/or toxicological properties, using conventional analyzes well known in this field, such as regarding cytochrome P450 enzymes Inhibitory and time-dependent inhibition, pregnane X receptor (PXR) activation, glutathione binding, or phototoxic behavior.

Modeling and simulation technology to support preclinical development Physiology-based pharmacokinetic-pharmacodynamic (PBPK-PD) models by prioritizing candidate compounds with desirable pharmacokinetic and pharmacodynamic properties/characteristics and used to support preclinical development. These models are developed by combining in vitro measured parameters and computer predictions, taking into account the physiology of the individual species.

Measurement of metabolic stability of human liver microsomes and permeability of MDCK-MDR1 cells Microsomal stability analysis of subcellular fractions of the liver microsomal system, which can be used to measure the intrinsic clearance of compounds and useful in in vitro models such as hepatic clearance , because it contains many drug-metabolizing enzymes found in the liver. Typically, microsomes are incubated with test compounds at 37°C in the presence of NADPH, a cofactor that initiates the reaction. The disappearance of the compound is monitored over a specified period of time (eg 45 minutes).

MDCK-MDR1 MDCK-MDR1 cells are Madin Darby canine kidney (MDCK) cells transfected with the MDR1 gene (ABCB1), which encodes the efflux protein P-glycoprotein (P-gp). When drug transport is measured in both directions of a cell monolayer (apical to basolateral (AB) and basolateral to apical (BA)), the efflux rate can be determined, which indicates whether the compound is actively transported via P-gp. , that is, if the compound is the acceptor of the P-gp transport protein, P-gp will excrete the drug from the inside into the cell to the apical side to prevent its penetration. MDCK-MDR1 helps understand the mechanisms of drug efflux and highlights early potential problems with drug permeability. In addition to intestinal permeability, MDCK-MDR1 permeability was also found to be a useful predictor of blood-brain barrier permeability. In this particular assay, MDR1-MDCK cell monolayers were grown to confluence on collagen-coated microporous membranes in 12-well assay plates. The permeability analysis buffer was Hanks' balanced salt solution containing 10 mM HEPES and 15 mM glucose with a pH of 7.4. The buffer in the receiving chamber also contains 1% bovine serum albumin (BSA). Dosing solution concentration is 1 μM of test article in assay buffer. Cell monolayers were loaded apically (A to B) or basolaterally (B to A) and cultured at 37 °C with 5% CO in a humidified _incubator . Samples were removed from the donor and receiving chambers at 120 minutes. Each assay was performed in duplicate. The luciferin flux of each monolayer was also measured after the experiment to ensure that no damage was caused to the cell monolayer during the flux. All samples were analyzed by LC-MS/MS using electrospray ionization. For example, compounds exhibit the following permeability coefficients: Example compounds P _app A-to-B P _app B-to-A efflux rate Reference example 1.1 6 90 15 Reference example 1.4 0.13 32 242 Example 1 7 73 10 Example 3.3 (4 measurements) 17 13 11 10 66 63 79 82 4 5 7 8 Example 5 16 71 4 Example 10.4 (2 measurements) 18 21 60 61 3 3

Sedation effect: EEG , EMG and alert behavior index recorded by radiotelemetry in beagle dogs . Electroencephalography (EEG), electromyography (EMG), and electrocardiography (ECG) signals were measured via telemetry using a D70-EEE radio telemetry implant (Data Science Int.) equipped with three pairs of differential leads.

Surgical implantation is performed under general anesthesia with isoflurane and endotracheal intubation to place a pair of EEG electrodes and a reference electrode in the skull, a pair of ECG electrodes in the heart region, and one inserted into the neck muscles on either side. EMG leads. After surgery, the dogs recovered under observation in the surgical recovery room and received analgesic treatment with parecoxib for 5 days and cerfradine for 7 days. All dogs were allowed to recover for 4 weeks before the start of the experiment. In order to collect biological signals accurately and stress-free during experiments using telemetry technology, the dogs were kept in an observation station with a 12 h light/12 h dark cycle, and the recording wire did not restrict their movement. The variables analyzed included four different stages of alertness and sleep and spontaneous activity. Sleep and wake stages were assessed using scoring software (Neuroscore; Data Science Int) that directly processes electrical biosignals with a continuous presentation time of 10 seconds. Scoring is based on frequency assessment of EEG and amplitude identification of EMG and motor activity. Using these measurements, the software determines that all components at each occurrence time best represent active wakefulness (AW), resting wakefulness (QW), non-REM sleep (NREM), or REM sleep (REM). Probability. Time spent in AW, QW, NREM and REM sleep, total sleep and total wake time were calculated based on 12 h light or dark cycles and shorter time intervals. Recordings were started immediately before test compound or vehicle was administered at 10 am. Test compounds or vehicle are administered orally in gelatin capsules. Food was provided 30 min 3 h (1:00 pm) after handling and toys were provided in the animal cage/observation station 6 h after handling (4:00 pm) to elicit mild stimulus anticipation in dogs during the postprandial phase. Turn the lights off at 7:30 pm and turn them on again at 7:00 am. Night and daytime recordings were performed under constant infrared illumination and automatically filtered by the camera.

Compared with placebo (46±13 min), after 30 mg and 90 mg of the compound of Example 3.3, the total sleep time within 3 hours was 80±14 min and 92±12 min, and the time spent in non-REM sleep was 78± 14 min, 90±11 min and 46±13 min (30 mg, 90 mg, placebo). After 30 mg and 90 mg of the compound of Example 3.3 and placebo, the total awakening time within 3 hours was 99±14 min, 87±12 min and 133±14 min.

Compared with placebo (36±9 min), after 30 mg and 90 mg of the compound of Example 10.4, the total sleep time within 3 hours was 64±9 min and 64±9 min, and 60±9 minutes were spent in non-REM sleep. 8 min, 60±9 min and 35±9 min (30 mg, 90 mg, placebo). After 30 mg and 90 mg of the compound of Example 10.4 and placebo, the total awakening times within 3 hours were 125±11 min, 115±9 min and 132±11 min.

Claims (16)

A compound of formula (I) Wherein R ¹ represents (C _1-3 ) alkyl, halogen, cyclopropyl or trifluoromethyl; X ¹ represents S or O; X ² represents CH or N; Z represents -CH ₂ -, -CH(CH ₃ )-or-CH ₂ -CH ₂ -; and in the fragment wherein R ² independently represents hydrogen, (C _1-3 ) alkyl, halogen or (C _1-3 ) alkoxy; R ³ independently represents hydrogen or (C _1-3 ) alkyl; and Y independently represents CH or N; and Ar ¹ independently represents: or its pharmaceutically acceptable salt. Such as the compound of claim 1; wherein R ¹ represents methyl, chlorine, bromine, cyclopropyl or trifluoromethyl; or a pharmaceutically acceptable salt thereof. Such as the compound of claim 1; wherein R ¹ represents methyl; or a pharmaceutically acceptable salt thereof. Such as the compound of any one of claims 1 to 3; wherein X ¹ represents S; or a pharmaceutically acceptable salt thereof. Such as the compound of any one of claims 1 to 4; wherein X ² represents CH; or a pharmaceutically acceptable salt thereof. Such as the compound of any one of claims 1 to 5; wherein Z represents -CH ₂ - or -CH(CH ₃ )-; or a pharmaceutically acceptable salt thereof. A compound as claimed in any one of claims 1 to 6; wherein the fragment represents a group selected from group A) or B): or its pharmaceutically acceptable salt. A compound as claimed in any one of claims 1 to 7; wherein Ar ¹ independently represents a group selected from groups A) to D): or its pharmaceutically acceptable salt. A compound as claimed in any one of claims 1 to 6; wherein the fragment represents a group selected from groups A) to F): or its pharmaceutically acceptable salt. A compound as claimed in any one of claims 1 to 6; wherein the fragment express: or its pharmaceutically acceptable salt. Such as the compound of claim 1; wherein the compound is (5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[ d]thiazol-6-yl)methyl)pyrazodin-1-yl)methanone; (5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)( 2-((2-(trifluoromethyl)benzo[d]thiazol-6-yl)methyl)pyrazodin-1-yl)methanone; (2-(2H-1,2,3-tri Azol-2-yl)phenyl) (2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazodin-1-yl)methanone; (5-methoxy- 2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidine-1- yl)methanone; (5-chloro-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl )methyl)pyrazolin-1-yl)methanone; (4,5-dimethyl-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-(( 2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolin-1-yl)methanone; (3'-methyl-[1,1'-biphenyl]-2-yl) (2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazodin-1-yl)methanone; (5-methyl-2-(4-methyl-1H- Pyrazol-1-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazodin-1-yl)methanone; (5-methyl- 2-(3-methyl-1H-pyrazol-1-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazodin-1-yl )methanone; [1,1'-biphenyl]-2-yl(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazodin-1-yl)methanone ; (5-methyl-2-(2-methylthiazol-4-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidine- 1-yl)methanone; (5-methyl-2-(4-methyl-2H-1,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo [d]thiazol-6-yl)methyl)pyrazodin-1-yl)methanone; (5-methyl-2-(thiazol-2-yl)pyridin-3-yl)(2-((2 -Methylbenzo[d]thiazol-6-yl)methyl)pyrazodin-1-yl)methanone; (5-methyl-2-(1H-pyrazol-1-yl)pyridine-3- base) (2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazodin-1-yl)methanone; (5-chloro-2-(1H-pyrazole-1) -yl)pyridin-3-yl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazodin-1-yl)methanone; (2-(4-bromo) -2H-1,2,3-triazol-2-yl)-5-chlorophenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidine- 1-yl)methanone; (2-(4-chloro-1H-pyrazol-1-yl)-5-methylpyridin-3-yl)(2-((2-methylbenzo[d]thiazole) -6-yl)methyl)pyrazolin-1-yl)methanone; (5-chloro-2-(4-methyl-1H-pyrazol-1-yl)pyridin-3-yl)(2- ((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazodin-1-yl)methanone; (2-(2H-1,2,3-triazol-2-yl) Phenyl) (2-((2-methylbenzo[d]thiazol-6-yl)methyl)tetrahydropyridazin-1(2H)-yl)methanone; (5-chloro-2-(2H) -1,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)tetrahydropyridazine-1(2H)- yl)methanone; (5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazole-6- (yl)methyl)tetrahydropyridazin-1(2H)-yl)methanone; (5-chloro-2-(4-methyl-2H-1,2,3-triazol-2-yl)phenyl )(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazodin-1-yl)methanone; (5-chloro-2-(4-ethynyl-2H- 1,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazodin-1-yl)methanone; (2-((2-bromobenzo[d]thiazol-6-yl)methyl)pyrazodin-1-yl)(5-chloro-2-(2H-1,2,3-triazole-2 -yl)phenyl)methanone; (5-chloro-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2-methylthiazolo[5,4 -b]pyridin-5-yl)methyl)pyrazolin-1-yl)methanone; (5-chloro-2-(2H-1,2,3-triazol-2-yl)phenyl)( 2-((2-chlorobenzo[d]thiazol-6-yl)methyl)pyrazodin-1-yl)methanone; (5-chloro-2-(2H-1,2,3-triazole) -2-yl)phenyl)(2-((2-(trifluoromethyl)benzo[d]thiazol-6-yl)methyl)pyrazodin-1-yl)methanone; (5-chloro -2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2-cyclopropylbenzo[d]thiazol-6-yl)methyl)pyrazolidine- 1-yl)methanone; (5-chloro-2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2-ethylbenzo[d]thiazole-6 -yl)methyl)pyrazodin-1-yl)methanone; (R)-(5-chloro-2-(2H-1,2,3-triazol-2-yl)phenyl)(4- Methyl-2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazodin-1-yl)methanone; (S)-(5-chloro-2-(2H- 1,2,3-triazol-2-yl)phenyl)(4-methyl-2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidine-1- yl)methanone; (R)-4-methyl-2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazodin-1-yl)(5-methyl- 2-(2H-1,2,3-triazol-2-yl)phenyl)methanone; (S)-4-methyl-2-((2-methylbenzo[d]thiazole-6- yl)methyl)pyrazolidin-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone; (S)-(2- (4-bromo-2H-1,2,3-triazol-2-yl)-5-chlorophenyl)(4-methyl-2-((2-methylbenzo[d]thiazole-6- yl)methyl)pyrazolin-1-yl)methanone; (R)-(2-(4-bromo-2H-1,2,3-triazol-2-yl)-5-chlorophenyl) (4-methyl-2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazodin-1-yl)methanone; (5-methyl-2-(2H- 1,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]oxazol-6-yl)methyl)pyrazodin-1-yl)methanone ; (2-(2H-1,2,3-triazol-2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazolidine- 1-yl-4,4-d ₂ )methanone; (5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl) (2-((2-methyl Benzo[d]thiazol-6-yl)methyl)pyrazodin-1-yl-4,4-d ₂ )methanone; (5-chloro-2-(2H-1,2,3-triazole) -2-yl)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazodin-1-yl-4,4-d ₂ )methanone; ( 5-Chloro-2-(2H-1,2,3-triazol-2-yl-d)phenyl)(2-((2-methylbenzo[d]thiazol-6-yl)methyl) Pyrazolidin-1-yl)methanone; or (R)-(5-chloro-2-(2H-1,2,3-triazol-2-yl-d)phenyl)(4-methyl- 2-((2-methylbenzo[d]thiazol-6-yl)methyl)pyrazodin-1-yl)methanone, or a pharmaceutically acceptable salt thereof. A pharmaceutical composition, which includes as an active ingredient one or more compounds such as any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert excipient. The compound of any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof is used as a medicament. For example, the compound of any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof is used for the prevention or treatment of sleep disorders, anxiety disorders, addiction disorders, cognitive dysfunction, affective disorders, appetite disorders, or dementia. Neuropsychiatric symptoms. The use of a compound as claimed in any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, which is used to prepare for the prevention or treatment of sleep disorders, anxiety disorders, addiction disorders, cognitive dysfunction, emotional disorders, Drugs for appetite disorders or neuropsychiatric symptoms of dementia. A method for preventing or treating sleep disorders, anxiety disorders, addiction disorders, cognitive dysfunction, affective disorders, appetite disorders or neuropsychiatric symptoms of dementia, comprising administering to an individual in need an effective amount of claim 1 A compound of formula (I) according to any one of to 11 or a pharmaceutically acceptable salt thereof.