WO2024115797A2 - Dihydro-quinazoline, -benzothiazine and -benzoxazine derivatives and use thereof as orexin receptors agonists for treating or preventing neurological diseases - Google Patents

Abstract

The present invention is directed to dihydro-quinazoline, -benzothiazine and -benzoxazine derivatives for use in the prevention or treatment of neurological, psychiatric, sleep disorders and diseases, advantageously in which central orexin neurotransmission is compromised or in which central and peripheral orexin receptors are involved. The present invention is also directed to pharmaceutical compositions comprising these compounds for use in the prevention and/or treatment of neurological disorders and diseases. The present invention is also directed to dihydro-quinazoline, -benzothiazine and -benzoxazine derivatives and the use of these compounds as a medicament.

Description

Dihydro-quinazoline, -benzothiazine and -benzoxazine derivatives and use thereof as orexin receptors agonists for treating or preventing neurological diseases

Field of the invention

The present invention is directed to dihydro-quinazoline, -benzothiazine and - benzoxazine derivatives for use in the prevention or treatment of neurological, psychiatric, sleep disorders and diseases, advantageously in which central orexin neurotransmission is compromised or in which central and peripheral orexin receptors are involved. The present invention is also directed to pharmaceutical compositions comprising these compounds for use in the prevention and/or treatment of neurological disorders and diseases. The present invention is also directed to dihydrobenzothiazine and dihydro-benzoxazine derivatives and the use of these compounds as a medicament.

Background of the present invention

Orexin 1 and 2 (0X1 and 0X2, also known as hypocretin 1 and 2 or orexin A and B) are hypothalamic neuropeptides specifically produced in the lateral hypothalamic area (Sakurai et al. 1998). Orexins act on the two G protein-coupled receptors (GPCRs), the orexin 1 receptor (0X1 R) and the orexin 2 receptor (0X2R), participating in a broad range of physiological functions such as sleep/wakefulness (Gao et al. 2021 ; de Lecea et al. 1998; Lin et al. 1999; Ohno et Sakurai 2008), feeding behavior (Sakurai et al. 1998), reward -seeking (Cason et al. 2010; Harris, Wimmer, et Aston -Jones 2005), and stress responses (Johnson et al. 2010). More especially, OX1 R is mainly involved in motivation and reward and the OX2R in the modulation of sleep/wake cycle and energy homeostasis (Perrey et Zhang 2020).

In genetic studies in mice, the lack of orexin function causes narcoleptic symptoms characterized by excessive daytime sleepiness and cataplexy (Lin et al. 1999; Willie et al. 2003), and intracerebroventricular administration of orexins attenuates the narcoleptic symptoms (Mieda 2017). Besides, OX1 R knockout mice exhibit no obvious sleep/wakefulness-related phenotype but OX2R knockout mice show severe narcoleptic phenotype, suggesting that the 0X2R-mediated signaling would be sufficient to prevent the symptoms of narcolepsy/cataplexy (Mieda et al. 2011 ; Saito et al. 2018).

Increasingly for the last decade, a large number of orexin antagonists have been developed as potential drugs for various pathophysiological conditions involving the orexin system (e.g. for the treatment of insomnia) (Heifetz et al. 2013) but far fewer have been the orexin agonists when they have potential for the treatment of various diseases (Nollet et Leman 2013; Song et al. 2015), including obesity, attention-deficit hyperactivity disorder (ADHD) (Baimel et al. 2015; Cortese, Konofal, et Lecendreux 2008; Heifetz et al. 2013), neurodegenerative diseases (e.g. Alzheimer, Parkinson) (Gao et al. 2021 ; Katsuki et Michinaga 2012), and above all narcolepsy type 1 and 2 (Fujimoto et al. 2022; Mezeiova et al. 2020; Yukitake et al. 2019; Zhang et al. 2021 ).

Using orexin antagonists in animal models, the role of 0X1 R on sleep regulation has been studied. SB-334867 (an experimental 0X1 R selective antagonist) has been reported reversing the REM sleep suppression induced by intracerebroventricular injection of orexin-A (Smith et al. 2003) and above all induces effects on REM sleep and induces Non-REM sleep when administered alone (Morairty et al. 2012).

In contrary to 0X1 R antagonists, a potential therapeutic role of 0X1 R agonists in REM sleep behavior disorder (RBD) is hypothesized due to the interaction between o- synuclein and 0X1 R in pathogenesis. 0X1 R dysfunction can induce the occurrence of RBD and is a potent early sign of Parkinson's disease (PD), but whether the pathogenetic mechanism involved in RBD remains unexplored. In contrast, o-synuclein has been verified to form Lewy bodies in orexin neurons, whose activity and function depend on orexin receptor 1 (0X1 R) (Fan et al. 2023).

0X1 R agonists may be a useful strategy to slow or stop the neurodegenerative process of PD and treating RBD.

Loss of orexinergic neurons in the brain is associated with the cause of narcolepsy type 1 (NT1 ) characterized by excessive daytime sleepiness, cataplexy, hypnagogic/hypnopompic hallucinations, sleep paralysis, and disturbed nighttime sleep (Cao et Guilleminault 2017; Siegel 1999; Thorpy 2020).

Cerebrospinal fluid (CSF) orexin-1 levels are predictive for narcolepsy (abnormal levels in 89.5% of the overall patient population and 94.7% of HLA DQBI*0602 positive cases (Kanbayashi et al. 2002; Nishino 2007).

In NT1 , low or absent CSF hypocretin levels serve as a specific biomarker when in narcolepsy type 2 (NT2) or other variants of central of hypersomnolence disorders or hypersomnias (i.e. idiopathic hypersomnia or secondary or recurrent hypersomnia associated with psychiatric diseases), where this specific biomarker is currently absent (Zhang et al. 2018). Since this finding, orexin agonists have attracted attention of potential treatments development for narcolepsy. In 2008, the first OX2R selective agonists classes were filed to be patented, stimulating the discovery of several compounds, but all acting only as OX2R agonists (Bogen et al. 2021 ; Fujimoto et al. 2022; Yanagisawa 2012; Yukitake et al. 2019; Zhang et al. 2021 ).

However, it is considered that these compounds are not satisfactory, for example, in terms of activity, pharmacokinetics, permeability into the brain/central nervous system or safety, and the development of an improved compound having OX2R agonist activity is desired.

Sunti norexton, firazorexton and danavorexton are selective OX2R which are under development by Takeda for the treatment of narcolepsy. TAK-994 and TAK-861 are active compounds and act as a highly selective agonist of the OX2R. TAK-994 is >700- fold selectivity over the OX1 R. Related to danavorexton (TAK-925), it reached phase 2 clinical trials for narcolepsy. However, clinical development was discontinued in 2021 for safety reasons (Dauvilliers et al. 2023; Ishikawa et al. 2023). TAK-994, was the first oral selective OX2R agonist developed.

Recently, cycloalkyl urea compounds targeting OX2R as an agonist action have been reported in W02021107023, but these compounds failed to target both OX1 R and OX2R.

The international patent application W02022140317 relates to substituted piperidino compounds, particularly, substituted piperidino compounds having agonist activity, once again only OX2R are targeted.

Parkinson's Disease (PD) is the second most common chronic neurodegenerative disease characterized by progressive loss of dopaminergic neurons in the substantia nigra pars compacta (Hornykiewicz et Kish 1987). The incidence of PD in the population over 55 years old is about 1% and the cardinal symptoms of PD include resting tremor, bradykinesia, muscle rigidity, postural instability, and usually companied with cognitive impairment, mental disorder, and other nonmotor symptoms (Beitz 2014; Meerwaldt et Hovestadt 1988). The cause of PD is not fully understood, but several factors including gene mutation, oxidative stress, mitochondrial dysfunction, neurotransmitter toxicity, failure of protein homeostasis appear to be associated with the development of PD. The most common treatment for PD is symptom management. The dopamine precursor levodopa is the most widely used clinical drug (Hornykiewicz 1975), which could only attenuate the symptoms, but fails to halt the progressive degeneration of dopaminergic neurons in the substantia nigra. In recent years, many efforts were devoted to find endogenous neuroprotective mediators to stop or reverse the degenerative changes of dopaminergic neurons in the substantia nigra.

Orexinergic receptors are located in many brain structures, such as cortex, hippocampus, amygdala, thalamus, hypothalamus, and basal ganglia (Hervieu et al. 2001 ; Hu et al. 2015). It is known that orexins play important roles in the regulation of sleep, feeding behavior, energy homeostasis, neuroendocrine, and autonomic control and the activity of orexinergic system decreases with aging, which has been implicated in many neurodegenerative disorders (Liu et al. 2018).

In addition, orexinergic systems also play an important role in motor control (Berhe, Gebre, et Assefa 2020; Hu et al. 2015; Song et al. 2015; Wang, Cao, et Wu 2021 ). Most of the central motor control structures are innervated by orexinergic fibers (Hu et al. 2015; Liu et al. 2018). More importantly, all the basal ganglia nuclei, including the globus pallidus, the subthalamic nucleus, the substantia nigra, and the striatum are innervated by orexigenic fibers (Alrouji et al. 2023; Liu et al. 2018).

From approximatively two decades, increasingly numerous studies demonstrated that orexinergic systems are closely correlated with PD (Katsuki et Michinaga 2012; Yasui et al. 2006). It was reported that parkinsonian patients display significant loss of orexinergic neurons in postmortem exams (Fronczek et al. 2007; Thannickal, Lai, et Siegel 2007).

Experiments with 6-hydroxydopamine (6-OHDA)-induced rat model of PD revealed that the number of orexinergic neurons in the lateral hypothalamus decreases significantly (Long-Biao et al. 2010), when the loss of orexinergic neurons in this animal model of PD seems to resemble the process in parkinsonian patients. Furthermore, the orexin levels in plasma and cerebrospinal fluid decrease dramatically in parkinsonian patients (Drouot et al. 2003; Fronczek et al. 2007). These reports implied the important role of orexinergic systems in PD.

Other studies revealed that orexin-A has neuroprotective effects in cellular models of PD. Orexin-A protects SH-SY5Y cells against 6-OHDA (Esmaeili-Mahani et al. 2013; Pasban-Aliabadi, Esmaeili-Mahani, etAbbasnejad 2017) or MPPC (Feng et al. 2014; Liu et al. 2018) induced toxicity.

Finally, the exact role of orexin-A in the animal models of PD, and the protective mechanisms of orexin-A on the nigral dopaminergic neurons seems demonstrated using MPTP parkinsonian mice (Liu et al. 2018). In this animal model, orexin-A exerted neuroprotective effects, which may imply orexin-A as a potential therapeutic target for PD and OX1 R agonists as potential target for treatment of PD.

Another involvement of orexin was also recognized, this in the immune response and neuroinflammation (Duffy et al. 2019; Polito et al. 2018) suggesting that orexin-A may act as an immunomodulatory regulator of microglia reducing hypothalamic neuron death in the condition of inflammation.

Furthermore, orexin-A exerts protective effects by attenuating neuroinflammation in AD and cerebral ischemia (Couvineau et Laburthe 2012; Xiong et al. 2013). Thus, the anti-inflammatory properties may also be involved in the neuroprotective effects of orexin in PD. The potential therapeutic effects of orexins on both motor and non-motor disorders in animal models of PD have also been indicated.

Cerebroventricular administration of orexin-A alleviates sensory motor deficits in a 6- OHDA-treated rat model of PD (Hadadianpour et al. 2017). Similar results were observed in the MPTP-induced mouse model of PD. The application of orexin-A into the cerebral ventricles improves motor performance in both pole and open field tests by attenuating the loss of dopaminergic neurons and fibers (Liu et al. 2018). Intrapallidal administration of both orexin-A and orexin-B could also alleviate motor deficits in MPTP-treated parkinsonian mice (Ying Wang et al. 2019). Furthermore, chemogenetic activation of orexinergic neurons could reverse the abnormal locomotor activity in the pre-clinical stage in A53T mice (Stanojlovic, Pallais, et Kotz 2019). In addition, cognitive impairments, one of the common non-motor disorders in PD, could also be ameliorated by orexins. In addition, cognitive impairments, one of the common non- motor disorders in PD, could also be ameliorated by orexins. The administration of orexin-A into CA1 or chemogenetic activation of orexinergic neurons increases the firing activity of CA1 neurons (Chen, Chen, et Du 2017) and ameliorates hippocampal- dependent memory impairment in the A53T mouse model of PD (Stanojlovic, Pallais, et Kotz 2019).

Furthermore, sociability and social memory impairments observed in A53T parkinsonian mice are also improved by chemogenetic activation of orexinergic neurons (Stanojlovic et al. 2019). Moreover, the reduced anxiety-like behavior observed in the early stage of PD could be restored by chemogenetic activation of orexinergic neurons in five-month-old A53T mice (Stanojlovic, Pallais, et Kotz 2019). The therapeutic effect of orexin on motor disorders in PD is probably associated with the restoration of dopaminergic neurons and the excitatory effects of orexin on pallidal neurons (Liu et al. 2018; Wang et al. 2019). However, the mechanisms of the therapeutic effects of orexins on non-motor disorders have not been well studied thus far.

Summary of the present invention

The first subject-matter of the invention relates to a compound of formula (I):

wherein: - X represents –NH-, –S- or –O-; - Y and R₂, independently of each other represents a hydrogen atom, a halogen atom, –NO₂ or –NH₂; - R₁, R₃, R₄ each represent, independently of each other, a hydrogen atom or a halogen atom; - R₅, R₆, R₇, R₈, R₉ each represent, independently of each other, a hydrogen atom, a halogen atom, –OR₁₀ or a (C₁–C₃₀)alkyl chain, especially (C₁–C₂₀)alkyl, optionally broken up and/or followed and/or preceded by one or more moieties chosen from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclic, –C≡C–, –C(R₁₁)=C(R₁₂)–, -O-, –S–, –NR₁₃–, –C(O)–, –C(S)–, –C=N–, –N=C–, –OC(O)–, – C(O)O–, –SC(O)–, –C(O)S–, –N(R₁₄)C(O)– and –C(O)N(R₁₅)– groups, the aryl, heteroaryl and heterocyclic rings being optionally substituted; - R₁₀ represents a hydrogen atom or a (C₁–C₃₀)alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl group, the aryl, heteroaryl and heterocyclic rings being optionally substituted; - R₁₁ and R₁₂ represent, independently of each other, a hydrogen atom or a (C₁– C₆)alkyl group; and - R₁₃ to R₁₅ represent, independently of each other, a hydrogen atom or a (C₁– C₆)alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl group, and preferably a hydrogen atom or a (C₁–C₆)alkyl or aryl group, and still more preferably a hydrogen atom or a (C₁–C₆)alkyl group, or a pharmaceutically acceptable salt thereof, a tautomer, a stereoisomer or mixture of stereoisomers thereof, for use in the prevention and/or treatment of neurological diseases, preferably associated with psychiatric and/or sleep disorders and diseases, advantageously in which central orexin neurotransmission is compromised or in which central and peripheral orexin receptors are involved. The present invention also relates to a pharmaceutical composition comprising at least one compound of formula (I) as described above and a pharmaceutically acceptable carrier for use in the prevention and/or treatment of neurological diseases, preferably associated with psychiatric and/or sleep disorders and diseases, advantageously in which central orexin neurotransmission is compromised or in which central and peripheral orexin receptors are involved. Detailed description of the present invention The first subject-matter of the invention relates to a compound of formula (I):

wherein: - X represents –NH-, –S- or –O-; - Y and R₂, independently of each other represents a hydrogen atom, a halogen atom, –NO₂ or –NH₂,; - R₁, R₃, R₄ each represent, independently of each other, a hydrogen atom or a halogen atom; - R₅, R₆, R₇, R₈, R₉ each represent, independently of each other, a hydrogen atom, a halogen atom, –OR₁₀ or a (C₁–C₃₀)alkyl chain, especially (C₁–C₂₀)alkyl, optionally broken up and/or followed and/or preceded by one or more moieties chosen from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclic, –C≡C–, –C(R₁₁)=C(R₁₂)–, -O-, –S–, –NR₁₃–, –C(O)–, –C(S)–, –C=N–, –N=C–,–OC(O)–, – C(O)O–, –SC(O)–, –C(O)S–, –N(R₁₄)C(O)– and –C(O)N(R₁₅)– groups, the aryl, heteroaryl and heterocyclic rings being optionally substituted; - R₁₀ represents a hydrogen atom or a (C₁–C₃₀)alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl group, the aryl, heteroaryl and heterocyclic rings being optionally substituted; - R₁₁ and R₁₂ represent, independently of each other, a hydrogen atom or a (C₁– C₆)alkyl group; and - R₁₃ to R₁₅ represent, independently of each other, a hydrogen atom or a (C₁– C₆)alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl group, and preferably a hydrogen atom or a (C₁–C₆)alkyl or aryl group, and still more preferably a hydrogen atom or a (C₁–C₆)alkyl group, or a pharmaceutically acceptable salt thereof, a tautomer, a stereoisomer or mixture of stereoisomers thereof, for use in the prevention and/or treatment of neurological diseases, preferably associated with psychiatric and/or sleep disorders and diseases, such as narcolepsy, advantageously in which central orexin neurotransmission is compromised or in which central and peripheral orexin receptors are involved. Definitions In the present invention “halogen atom” means fluorine, chlorine, bromine and iodine atoms. In the present invention, “alkyl” group means a saturated, linear or branched hydrocarbon chain. In the present invention, “(C₁–C_x)alkyl” means an alkyl group such as defined above, containing 1 to X carbon atoms. For example, “(C₁–C₆)alkyl” means an alkyl group such as defined above, containing 1 to 6 carbon atoms, such as, for example, methyl, ethyl, isopropyl, tert–butyl, pentyl, etc. In the present invention, “aryl” means an aromatic group, especially a hydrocarbon group, especially containing 6 to 20 carbon atoms, preferably 6 to 10 carbon atoms, and comprising one or more fused rings, such as, for example, a phenyl or naphthyl group. Advantageously, it is a phenyl group. In the present invention, “heteroaryl” means an aromatic group comprising one or more fused rings and comprising 5 to 10 cyclic atoms, including one or more heteroatoms, advantageously 1 to 4 and even more advantageously 1 or 2, such as, for example, sulfur, nitrogen, oxygen, phosphorus or selenium atoms, and preferably sulfur, nitrogen or oxygen, the other cyclic atoms being carbon atoms. Examples of heteroaryl groups are furyl, thienyl, pyrrolyl, pyridinyl, pyrimidinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, indyl or selenophenyl. In the present invention, “acyl” group means a group of formula -CO-R in which R represents a (C₁–C₆) alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group, and preferably a (C₁–C₆) alkyl or aryl group, and still more preferably a (C₁–C₆) alkyl group. In the present invention, “cycloalkyl” means a saturated mono– or polycyclic hydrocarbon chain (especially a bicyclic or tricyclic chain). When it is a polycyclic group, the rings can be fused, bridged or joined by a spiro ring junction two by two. Examples include cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl groups. In the present invention, “heterocyclic” group means a non-aromatic, saturated or unsaturated, monocyclic or polycyclic group (comprising fused, bridged or spiro rings) in which one or several atom(s) of the ring(s) carbon atoms each is replaced with heteroatoms, in particular this term means a 5 to 10–membered ring, saturated or unsaturated, but not aromatic, and containing one or more, advantageously 1 to 4, more advantageously 1 or 2 heteroatoms, the heteroatoms being for example, sulfur, nitrogen or oxygen atoms. It can particularly be a pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl group. The aryl, heteroaryl and heterocyclic group, when substituted, can be substituted with one or more groups chosen from the group consisting of a halogen atom, a (C₁–C₆)alkyl group, an aryl group, -NO₂, –CN, –OR₁₉, –SR₂₀, –NR₁₆R₁₇, –B(OH)₂, –SO₃R₁₇, and –COOR₁₈, in particular chosen from the group consisting of a halogen atom, -NO₂, –CN, –OR₁₉, – SR₂₀, –NR₁₆R₁₇, –B(OH)₂, –SO₃R₁₇, with R₁₆ to R₂₀ representing, independently of each other, a hydrogen atom or a (C₁–C₆)alkyl group. In the present invention, “pharmaceutically acceptable” means what is used in the preparation of a pharmaceutical composition, which is generally safe, nontoxic and not biologically or otherwise undesirable and which is acceptable for both veterinary and human pharmaceutical use. “Pharmaceutically–acceptable salts” of a compound mean of salts that are pharmaceutically acceptable, such as defined here, that have the desired pharmacological activity of the parent compound. Such salts include: (1) hydrates and solvates, (2) pharmaceutically–acceptable acid addition salts formed with pharmaceutically– acceptable inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or formed with pharmaceutically–acceptable organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2–hydroxy ethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, muconic acid, 2–naphthalene sulfonic acid, propionic acid, salicylic acid, succinic acid, dibenzoyl–L–tartaric acid, tartaric acid, p–toluenesulfonic acid, trimethylacetic acid, trifluoroacetic acid and the like, or (3) pharmaceutically–acceptable base addition salts formed when an acid proton present in the parent compound is either replaced by a metal ion, for example an alkaline metal ion, an alkaline–earth metal ion or an aluminum ion, or is coordinated with a pharmaceutically–acceptable organic or inorganic base. Acceptable organic bases include diethanolamine, ethanolamine, N–methylglucamine, triethanolamine, tromethamine and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide. Preferably, the compounds according to the invention will be in the form of pharmaceutically–acceptable base addition salts, the base being such as NaOH or KOH, and especially NaOH. An “optically pure compound” means an enantiomer in an enantiomeric excess of more than 95%, preferably of more than 96%, more preferably of more than 97%, even more preferably of more than 98%, particularly preferably of more than 99%. The present invention also includes all pharmaceutically acceptable isotopic variations of a compound of formula I in which one or more atoms is replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Such compounds are identical to those disclosed herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen such as ²H and ³H, carbon such as ¹¹C, ¹³C and ¹⁴C, nitrogen such as ¹³N and ¹⁵N, oxygen such as ¹⁵O, ¹⁷O and ¹⁸O, sulfur such as ³⁵S, fluorine such as ¹⁸F, iodine such as ¹²³I and ¹²⁵I, and chlorine such as ³⁶Cl. Certain isotopically-labelled compounds of formula I, for example those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. A subject administered with a compound of the present invention, or a pharmaceutically acceptable salt thereof, is generally a mammal, such as a human being, male or female. The amount of compound administered to the subject is an amount sufficient to agonize the orexin receptor in the subject. In an embodiment, the amount of compound can be an “effective amount”, wherein the subject compound is administered in an amount that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician. An effective amount does not necessarily include considerations of toxicity and safety related to the administration of the compound. It is recognized that one skilled in the art may affect neurological and psychiatric disorders associated with orexin receptor activation by treating a subject presently afflicted with the disorders, or by prophylactically treating a subject likely to be afflicted with the disorders, with an effective amount of a compound of the present invention. As used herein, the terms "treatment” and “treating” refer to all processes wherein there may be a slowing, interrupting, arresting, controlling, or stopping of the progression of the neurological and psychiatric disorders described herein, but does not necessarily indicate a total elimination of all disorder symptoms, as well as the prophylactic therapy of the mentioned conditions, particularly in a subject that is predisposed to such disease or disorder. The terms “administration of” and or “administering a” compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the subject. The term “composition” as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. Such term is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier, i.e. the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Diseases and disorders The orexin receptors (OX1R, OX2R) have been implicated in a wide range of biological functions. This has suggested a potential role for these receptors in a variety of disease processes in humans or other species. The compounds of the present invention could therefore have utility in treating, preventing, ameliorating, controlling or reducing the risk of a variety of disorders associated with orexin receptors, including one or more of the following conditions or diseases: narcolepsy with or without cataplexy, narcolepsy type 1 (NT1), narcolepsy type 2 (NT2), Gelineau syndrome (Maladie de Gelineau), narcoleptic syndrome, accompanied by narcolepsy-like symptoms, cataplexy in narcolepsy, excessive daytime sleepiness (EDS) in narcolepsy, hypersomnia, idiopathic hypersomnia, recurrent hypersomnia, Kleine-Levin syndrome, hypersomnia associated with a psychiatric disorder, hypersomnia due to a medical disorder, hypersomnia due to a medication or substance, and insufficient sleep syndrome and any conditions in accordance with The International Classification of Sleep Disorders, Third Edition (ICSD-3) classifies eight different Central Disorders of Hypersomnolence (CDH)(American Academy of Sleep Medicine 2014) and/ or marked by pathologic daytime sleepiness and/or unappropriated arousal status caused or nor by sleep apnea, nocturnal myoclonus, Rapid Eye Movement (REM) sleep interruptions, jet-lag, shift working, sleep disturbances, dyssomnias, sleep disorders, sleep disturbances, hypersomnia associated with depression, emotional / mood disorders, Alzheimer's disease or neurodegenerative disorders or cognitive impairment and tauopathies, Parkinson's disease and other synucleinopathies, Guillain-Barre syndrome, chronic fatigue syndrome, Long COVID-19 and medical or health conditions associated with circadian rhythmicity as well as mental and physical disorders associated with travel across time zones and with rotating shift-work schedules, restless legs syndrome, fibromyalgia, cardiac failure, diseases related to bone loss, sepsis, syndromes which are manifested by unrefreshing sleep and muscle pain, sleep apnea which is associated with respiratory disturbances during sleep ; conditions which result from a diminished quality of sleep and other diseases related to general orexin system dysfunction. In the present invention, “neurological, psychiatric, sleep disorders and diseases” refers to psychiatric and/or sleep neurological disorders and diseases, i.e. neurological diseases associated with sleep and/or psychiatric disorders. In particular, the disorders and diseases in which the central orexin neurotransmission is compromised or central and peripheral orexin receptors are involved. Thus, in certain embodiments the present invention may provide methods for treating or controlling: narcolepsy with or without cataplexy, narcolepsy type 1 (NT1), narcolepsy type 2 (NT2), Gelineau syndrome (Maladie de Gélineau), narcoleptic syndrome, accompanied by narcolepsy-like symptoms, cataplexy in narcolepsy, excessive daytime sleepiness (EDS) in narcolepsy, hypersomnia, idiopathic hypersomnia, recurrent hypersomnia, Kleine-Levin syndrome, hypersomnia associated with a psychiatric disorder, hypersomnia due to a medical disorder, hypersomnia due to a medication or substance, and insufficient sleep syndrome and any conditions in accordance with The International Classification of Sleep Disorders, Third Edition (ICSD-3) classifies eight different Central Disorders of Hypersomnolence (CDH)(American Academy of Sleep Medicine 2014) ; pathologic daytime sleepiness and/or unappropriated arousal status caused or nor by sleep apnea, nocturnal myoclonus, REM sleep interruptions, jet-lag, shift working, sleep disturbances, dyssomnias, sleep disorders, sleep disturbances, hypersomnia associated with depression, emotional / mood disorders, Alzheimer's disease or cognitive impairment, Parkinson's disease, dementias, Guillain-Barre syndrome, chronic fatigue syndrome, Long COVID-19 and medical or health conditions associated with circadian rhythmicity as well as mental and physical disorders associated with travel across time zones and with rotating shift-work schedules, restless legs syndrome, fibromyalgia, cardiac failure, diseases related to bone loss, sepsis, syndromes which are manifested by unrefreshing sleep and muscle pain, sleep apnea which is associated with respiratory disturbances during sleep ; conditions which result from a diminished quality of sleep and other diseases related to general orexin system dysfunction ; sleep disturbances associated with diseases such as neurological disorders including neuropathic pain and restless leg syndrome, treating or controlling addiction disorders, treating or controlling psychoactive substance use and abuse, enhancing cognition, increasing memory retention ; diabetes and appetite, taste, eating, or drinking disorders ; insulin resistance syndrome ; hypothalamic diseases ; depression, including major depression and major depression disorder ; ameliorating or reducing the risk of epilepsy, including absence epilepsy, seizures ; pain, including neuropathic pain ; Parkinson's disease, dementia with Lewy’s bodies and synucleinopathies ; Guillain-Barre syndrome ; Long COVID-19 ; Kleine-Levin syndrome ; psychosis, dysthymic, mood, bipolar disorder, psychotic and anxiety disorders ; side effects or complications due to anesthesia and/ or orexin antagonists in a subject which comprises administering to the subject a compound of the present invention. The dihydro-quinazoline, -benzothiazine and benzoxazine derivatives as compounds of the present invention may also potentially have utility in treating, preventing, ameliorating, controlling or reducing the risk of a variety of other disorders associated with orexin receptors, including one or more of the following conditions or diseases including enhancing sleep quality, improving sleep quality, increasing sleep efficiency, consolidating sleep maintenance, improving sleep initiation, decreasing sleep latency or onset, decreasing difficulties in falling asleep, increasing sleep continuity, decreasing the number of awakenings during sleep, decreasing intermittent waking during sleep, decreasing nocturnal arousals, decreasing the time spent awake following the initial onset of sleep, increasing the total amount of sleep, reducing the fragmentation of sleep, altering the timing, frequency or duration of sleep stages, or duration of slow-wave sleep and / or REM sleep, promoting slow wave sleep, enhancing EEG - delta activity during sleep, decreasing nocturnal arousals, especially early morning awakenings, increasing daytime alertness, reducing daytime drowsiness, treating or reducing excessive daytime sleepiness ; increasing satisfaction with the intensity of sleep, increasing sleep maintenance, idiopathic insomnia, sleep problems, insomnia, night terror, insomnias associated with depression, emotional/mood disorders, Alzheimer's disease or neurodegenerative disorders or cognitive impairment, Parkinson's disease, dementias, Guillain-Barre syndrome, chronic fatigue syndrome, Long COVID-19 and medical or health conditions associated with circadian rhythmicity as well as mental and physical disorders associated with travel across time zones and with rotating shift-work schedules, restless legs syndrome, fibromyalgia, cardiac failure, diseases related to bone loss, sepsis, syndromes which are manifested by unrefreshing sleep and muscle pain, sleep apnea which is associated with respiratory disturbances during sleep ; conditions which result from a diminished quality of sleep ; increasing learning ; augmenting memory ; increasing retention of memory ; eating disorders associated with excessive food intake and complications associated therewith, compulsive eating disorders, obesity (due to any cause, whether genetic or environmental), obesity - related disorders overeating, anorexia, bulimia, cachexia, dysregulated appetite control, hypertension, diabetes, elevated plasma insulin concentrations and insulin resistance, dyslipidemias, hyperlipidemia, endometrial, breast, prostate and colon cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstones, heart disease, lung disease, abnormal heart rhythms and arrythmias, myocardial infarction, congestive heart failure, coronary heart disease, acute and congestive heart failure, hypotension, hypertension, angina pectoris, infarction, ischemic or hemorrhagic stroke, subarachnoid hemorrhage, chronic renal failure, renal disease, impaired glucose tolerance, craniopharyngioma, Prader-Willi Syndrome, Frohlich's syndrome, GH - deficient subjects, Turner's syndrome, and other pathological conditions showing reduced metabolic activity or a decrease in resting energy expenditure as a percentage of total fat – free mass, e.g, children with acute lymphoblastic leukemia, metabolic syndrome, also known as syndrome X, insulin resistance syndrome, reproductive hormone abnormalities, sexual and reproductive dysfunction, such as impaired fertility, infertility, hypogonadism in males and hirsutism in females, fetal defects associated with maternal obesity, gastrointestinal motility disorders, intestinal motility dyskinesias, obesity - related gastroesophageal reflux, hypothalamic diseases, hypophysis diseases, respiratory disorders, such as obesity - hypoventilation syndrome (Pickwickian syndrome), Ondine’s syndrome and sleep- related disorders where there is abnormal coupling of activity, particularly through the thalamus ; enhancing cognitive function, including cognitive dysfunctions that comprise deficits in all types of attention, learning and memory functions occurring transiently or chronically in the normal, healthy, young, adult or aging population, and also occurring transiently or chronically in psychiatric, neurologic, cardiovascular and immune disorders ; treating or controlling Guillain-Barre syndrome chronic fatigue syndrome, Long COVID-19 and medical or health conditions associated with circadian rhythmicity ; treating or controlling Kleine-Levin syndrome ; treating or controlling psychosis ; treating or controlling dysthymic, mood, psychotic and anxiety disorders ; treating complications due to anesthesia ; enhancing memory ; increasing memory retention ; increasing immune response ; increasing immune function ; hot flashes ; night sweats ; extending life span ; schizophrenia ; muscle - related disorders that are controlled by the excitation / relaxation rhythms imposed by the neural system such as cardiac rhythm and other disorders of the cardiovascular system ; conditions related to proliferation of cells such as vasodilation or vaso-restriction and blood pressure ; cancer ; cardiac arrhythmia ; hypertension ; congestive heart failure ; conditions of the genital / urinary system ; disorders of sexual function and fertility ; adequacy of renal function ; responsivity to anesthetics ; mood disorders, such as depression or more particularly depressive disorders, for example, single episodic or recurrent major depressive disorders and dysthymic disorders, or bipolar disorders, for example, bipolar I disorder, bipolar II disorder and cyclothymic disorder, mood disorders due to a general medical condition, and substance - induced mood disorders ; affective neurosis, depressive neurosis, anxiety neurosis ; anxiety disorders including acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive - compulsive disorder, panic attack, panic disorder, post - traumatic stress disorder, separation anxiety disorder, social phobia, specific phobia, substance - induced anxiety disorder and anxiety due to a general medical condition ; acute neurological and psychiatric disorders such as cerebral deficits subsequent to cardiac bypass surgery and grafting, stroke, ischemic stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage ; Huntington's Chorea ; Huntington's disease and Tourette syndrome ; Cushing's syndrome / disease ; basophile adenoma ; prolactinoma ; hyperprolactinemia ; hypophysis tumor / adenoma ; hypothalamic diseases ; inflammatory bowel disease ; gastric diskinesia ; gastric ulcers ; Froehlich's syndrome ; adrenohypophysis disease ; hypophysis disease ; adrenohypophysis hypofunction ; adrenohypophysis hyperfunction ; hypothalamic hypogonadism ; Kallman's syndrome (anosmia, hyposmia) ; functional or psychogenic amenorrhea ; hypopituitarism ; hypothalamic hypothyroidism ; hypothalamic - adrenal dysfunction ; idiopathic hyperprolactinemia ; hypothalamic disorders of growth hormone deficiency ; idiopathic growth deficiency ; dwarfism ; gigantism ; acromegaly ; amyotrophic lateral sclerosis ; multiple sclerosis ; ocular damage ; retinopathy ; cognitive disorders ; idiopathic and drug - induced Parkinson's disease ; muscular spasms and disorders associated with muscular spasticity including tremors, epilepsy, convulsions, seizure disorders, absence seizures, complex partial and generalized seizures ; Lennox - Gastaut syndrome ; cognitive disorders including dementia (associated with Alzheimer's disease, ischemia, trauma, vascular problems or stroke, HIV disease, Parkinson's disease, Dementia with Lewy’s Bodies, Huntington's disease, Pick's disease, Creutzfeldt - Jacob disease, perinatal hypoxia, other general medical conditions or substance abuse) ; delirium, amnestic disorders or age related cognitive decline ; schizophrenia or psychosis including schizophrenia (paranoid, disorganized, catatonic or undifferentiated), schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition and substance - induced psychotic disorder ; dissociative disorders including multiple personality syndromes and psychogenic amnesias ; substance - related disorders, substance use, substance abuse, substance seeking, substance reinstatement, all types of psychological and physical addictions and addictive behaviors, reward - related behaviors (including substance – induced delirium, persisting dementia, persisting amnestic disorder, psychotic disorder or anxiety disorder ; tolerance, addictive feeding, addictive feeding behaviors, binge / purge feeding behaviors, dependence, withdrawal or relapse from substances including alcohol, amphetamines, cannabis, cocaine, heroin, morphine, nicotine, opioids, phencyclidine, sedatives, hypnotics or anxiolytics) ; appetite, taste, eating or drinking disorders ; movement disorders, including akinesias and akinetic - rigid syndromes (including Parkinson's disease, drug - induced parkinsonism, postencephalitic parkinsonism, progressive supranuclear palsy, multiple system atrophy, cortico-basal degeneration, parkinsonism - ALS dementia complex and basal ganglia calcification), chronic fatigue syndrome, fatigue, including Parkinson's fatigue, multiple sclerosis fatigue, fatigue caused by a sleep disorder or a circadian rhythm disorder, medication induced parkinsonism (such as neuroleptic - induced parkinsonism, neuroleptic malignant syndrome, neuroleptic - induced acute dystonia, neuroleptic - induced acute akathisia, neuroleptic - induced tardive dyskinesia and medication - induced postural tremor), Gilles de la Tourette's syndrome, epilepsy, and dyskinesias including tremor (such as rest tremor, essential tremor, postural tremor and intention tremor), chorea (such as Sydenham's chorea, Huntington's disease, benign hereditary chorea, neuro- acanthocytosis, symptomatic chorea, drug - induced chorea and hemi-ballism), myoclonus (including generalized myoclonus and focal myoclonus), tics (including simple tics, complex tics and symptomatic tics), restless leg syndrome and dystonia (including generalized dystonia such as idiopathic dystonia, drug - induced dystonia, symptomatic dystonia and paroxymal dystonia, and focal dystonia such as blepharospasm, oromandibular dystonia, spasmodic dysphonia, spasmodic torticollis, axial dystonia, dystonic writer's cramp and hemiplegic dystonia) ; neurodegenerative disorders including nosological entities such as disinhibition - dementia - parkinsonism - amyotrophy complex ; pallido-ponto-nigral degeneration ; epilepsy ; seizure disorders ; attention deficit/hyperactivity disorder (ADHD) ; conduct disorder ; migraine (including migraine headache) ; headache ; hyperalgesia ; pain ; enhanced or exaggerated sensitivity to pain such as hyperalgesia, causalgia, and allodynia ; acute pain ; burn pain ; atypical facial pain ; neuropathic pain ; back pain ; complex regional pain syndrome I and II ; arthritic pain ; sports injury pain ; pain related to infection e.g. HIV, COVID-19, post chemotherapy pain ; post - stroke pain ; post - operative pain ; neuralgia ; emesis, nausea, vomiting ; gastric dyskinesia ; gastric ulcers ; Kallman's syndrome (anosmia) ; asthma ; cancer ; conditions associated with visceral pain such as irritable bowel syndrome, and angina ; eating disorders ; urinary incontinence ; substance tolerance, substance withdrawal (including, substances such as opiates, nicotine, tobacco products, alcohol, benzodiazepines, cocaine, sedatives, hypnotics, orexin antagonists etc.) ; psychosis ; schizophrenia ; anxiety (including generalized anxiety disorder, panic disorder, and obsessive compulsive disorder) ; mood disorders (including depression, mania, bipolar disorders) ; trigeminal neuralgia ; hearing loss ; tinnitus ; neuronal damage including ocular damage ; retinopathy ; macular degeneration of the eye ; emesis ; brain edema ; pain, including acute and chronic pain states, severe pain, intractable pain, inflammatory pain, neuropathic pain, post - traumatic pain, bone and joint pain (osteoarthritis), repetitive motion pain, dental pain, cancer pain, myofascial pain (muscular injury, fibromyalgia), perioperative pain (general surgery, gynecological), chronic pain, neuropathic pain, post-traumatic pain, trigeminal neuralgia, migraine and migraine headache and other diseases related to general orexin system dysfunction. A preferred embodiment of the invention is a compound of formula (I) or a pharmaceutically acceptable salt thereof, a tautomer, a stereoisomer or mixture of stereoisomers thereof, for use in the prevention and/or treatment of narcolepsy type 1 (NT1), narcolepsy type 2 (NT2), hypersomnia, idiopathic hypersomnia, recurrent hypersomnia, Kleine-Levin syndrome, hypersomnia associated with a psychiatric disorder, hypersomnia due to a medical disorder, hypersomnia due to a medication or substance, Parkinson's disease and other synucleinopathies, preferably narcolepsy type 1 (NT1), narcolepsy type 2 (NT2) and Parkinson's disease. A preferred embodiment of the invention is a compound of formula (I) or a pharmaceutically acceptable salt thereof, a tautomer, a stereoisomer or mixture of stereoisomers thereof, for use in the prevention and/or treatment of REM sleep behavior disorder (RBD). In some embodiments, the neurological diseases, preferably the neurological disorders and diseases in which central orexin neurotransmission is compromised or in which central and peripheral orexin receptors are involved, are selected from the group consisting of narcolepsy type 1 (NT1), narcolepsy type 2 (NT2), hypersomnia, idiopathic hypersomnia, recurrent hypersomnia, Kleine-Levin syndrome, hypersomnia associated with a psychiatric disorder, hypersomnia due to a medical disorder, hypersomnia due to a medication or substance, Parkinson's disease and other synucleinopathies, preferably narcolepsy type 1 (NT1), narcolepsy type 2 (NT2) and Parkinson's disease. In some embodiments, the neurological diseases, preferably the neurological disorders and diseases in which central orexin neurotransmission is compromised or in which central and peripheral orexin receptors are involved, are selected from the group consisting of narcolepsy type 1 (NT1), narcolepsy type 2 (NT2), hypersomnia, idiopathic hypersomnia and recurrent hypersomnia. In particular, the neurological disorders targeted are those requiring an agonist of the orexin 1 receptor (OX1R) and/or the orexin 2 receptor (OX2R), preferably both receptors. Compounds of formula (I) In a preferred embodiment, when one of Y or R₂ represents a halogen atom, –NO₂ or – NH₂, preferably –NO₂ or –NH₂, the other represents a hydrogen atom or a halogen atom. In some embodiments, when Y represents a halogen atom, –NO₂ or –NH₂, preferably – NO₂ or –NH₂, R₂ represents a hydrogen atom or a halogen atom. In some embodiments, when R₂ represents a halogen atom, –NO₂ or –NH₂, preferably –NO₂ or –NH₂, Y represents a hydrogen atom or a halogen atom. In a preferred embodiment, when one of Y or R₂ represents a halogen atom, –NO₂ or – NH₂, preferably –NO₂ or –NH₂, the other represents a hydrogen atom. In some embodiments, when Y represents a halogen atom, –NO₂ or –NH₂, preferably –NO₂ or – NH₂, R₂ represents a hydrogen atom. In some embodiments, when R₂ represents a halogen atom, –NO₂ or –NH₂, preferably –NO₂ or –NH₂, Y represents a hydrogen atom. R₄ represents preferably a hydrogen atom. In a preferred embodiment of the invention, R₁, R₂, R₃, R₄ each represent a hydrogen atom or R₁, R₃, R₄, Y each represent a hydrogen atom. In some embodiments, R₁, R₂, R₃, R₄ can each represent a hydrogen atom. In some embodiments, R₁, R₃, R₄, Y each represent a hydrogen atom. R₅, R₆, R₇, R₈, R₉ can each represent, independently of each other, a hydrogen atom, a halogen atom, –OR₁₀ or a (C₁–C₂₀)alkyl, optionally broken up and/or preceded by one or more moieties chosen from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclic, –C≡C–, –C(R₁₁)=C(R₁₂)–,-O-, –S–, –NR₁₃–, –C(O)–,–OC(O)–, –C(O)O–, – N(R₁₄)C(O)– and –C(O)N(R₁₅)– groups, the aryl, heteroaryl and heterocyclic rings being optionally substituted. In another preferred embodiment, R₅, R₆, R₇, R₈, R₉ each represent, independently of each other, a hydrogen atom or –OR₁₀. Preferably, at least four residues out of R₅, R₆, R₇, R₈ and R₉ each represent a hydrogen atom. In a particular embodiment, R₅, R₆, R₇, R₈, R₉, each represent, a hydrogen atom. In another embodiment, R₅ represents –OR₁₀ with R₁₀ representing a hydrogen atom, a (C₁–C₃₀)alkyl or phenyl group, preferably a (C₁–C₂₀)alkyl or a phenyl group. In some embodiments, R₅ represents –OR₁₀ with R₁₀ representing a hydrogen atom, a (C₁– C₃₀)alkyl or phenyl group, preferably a (C₁–C₂₀)alkyl or a phenyl group, and R₆, R₇, R₈, R₉, each represent, a hydrogen atom. In another embodiment, R₆ represents –OR₁₀ with R₁₀ representing a hydrogen atom, a (C₁–C₃₀)alkyl or phenyl group, preferably a (C₁–C₂₀)alkyl or a phenyl group. In some embodiments, R₆ represents –OR₁₀ with R₁₀ representing a hydrogen atom, a (C₁– C₃₀)alkyl or phenyl group, preferably a (C₁–C₂₀)alkyl or a phenyl group, and R₅, R₇, R₈, R₉, each represent, a hydrogen atom. In another embodiment, R₇ represents –OR₁₀ with R₁₀ representing a hydrogen atom, a (C₁–C₃₀)alkyl or phenyl group, preferably a (C₁–C₂₀)alkyl or a phenyl group. In some embodiments, R₇ represents –OR₁₀ with R₁₀ representing a hydrogen atom, a (C₁– C₃₀)alkyl or phenyl group, preferably a (C₁–C₂₀)alkyl or a phenyl group, and R₅, R₆, R₈, R₉, each represent, a hydrogen atom. In some embodiments, one residue out of R₅, R₆, R₇, R₈ and R₉ represents -OR₁₀ with R₁₀ representing a hydrogen atom, a (C₁–C₃₀)alkyl or phenyl group, preferably a (C₁– C₂₀)alkyl or a phenyl group. In some embodiments, X can represent -NH-. In some embodiments, X can represent - S-. In some embodiments, X can represent -O-. Preferably, X represents –NH- or –S-. Advantageously, the compound of formula (I) is selected from the group consisting of:

and mixtures thereof. Preferably, the compound of formula (I) is selected from the group consisting of:

, , and mixtures thereof.

More preferably, the compound of formula (I) is selected from the group consisting of:

, and

mixtures thereof. In a preferred embodiment of the invention, the neurological, psychiatric, sleep disorders and diseases in which central orexin neurotransmission is compromised or in which orexin receptors are involved is selected from the group consisting of narcolepsy type 1, narcolepsy type 2, idiopathic hypersomnia, recurrent hypersomnia, attention- deficit hyperactivity disorder, anxiety and mood disorders, Alzheimer's disease or any other neurodegenerative disorders or cognitive impairment and tauopathies, Parkinson's disease and other synucleinopathies, Guillain-Barre syndrome, chronic fatigue syndrome, long COVID-19 and medical or health conditions associated with circadian rhythmicity as well as mental and physical disorders associated with travel across time zones and with rotating shift-work schedules, restless legs syndrome, fibromyalgia, cardiac failure, diseases related to bone loss, sepsis, syndromes which are manifested by unrefreshing sleep and muscle pain, sleep apnea which is associated with respiratory disturbances during sleep; conditions which result from a diminished quality of sleep. The dosage of active ingredient in the compositions of this invention may be varied, however, it is necessary that the amount of the active ingredient be such that a suitable dosage form is obtained. The active ingredient may be administered to subjects (animals and human) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy. The selected dosage depends upon the desired therapeutic effect, on the route of administration, and on the duration of the treatment. The dose will vary from subject to subject depending upon the nature and severity of disease, the subject's weight, special diets then being followed by a subject, concurrent medication, and other factors which those skilled in the art will recognize. Generally, dosage levels of between 0.0001 to 100 mg/kg of body weight per day are administered to the subject, e.g., humans, adolescent humans and elderly humans, to obtain effective agonism of orexin receptors. Advantageously, a therapeutic dose of a compound of formula (I) comprised between 0.1 mg/kg/day and 100 mg/kg/day is administrated to a patient in need thereof. The present invention also relates to a pharmaceutical composition comprising at least one compound of formula (I) as described above and a pharmaceutically acceptable carrier for use in the prevention and/or treatment of neurological, psychiatric, sleep disorders and diseases in which central orexin neurotransmission is compromised or in which central and peripheral orexin receptors are involved. The dosage range will generally be from 0.5 mg to 10.0 g per subject per day which may be administered in single or multiple doses. In one embodiment, the dosage range will be from 0.5 mg to 500 mg per subject per day, preferably from 0.5 mg to 200 mg per subject per day, and more preferably from 5 mg to 50 mg per subject per day. Pharmaceutical compositions of the present invention may be provided in a solid dosage formulation such as comprising from 0.5 mg to 500 mg of active ingredient, or comprising from 1 mg to 250 mg of active ingredient. The pharmaceutical composition may be provided in a solid dosage formulation comprising 1 mg, 5 mg, 10 mg, 50 mg, 80 mg, 100 mg, 200 mg active ingredient. In a preferred embodiment, the pharmaceutical composition for use according to the invention comprises between 0.5 mg to 800 mg, preferably between 20 mg to 400 mg of the compound of formula (I). For oral administration, the compositions may be provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, such as 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the subject to be treated. The compounds may be administered on a regimen of 1 to 4 times per day, such as once or twice per day. The compounds may be administered once or multiple times during the day. The compounds may be administered upon awakening or otherwise in the morning, or during waking hours. For example, the compounds may be administered 25 mg, 30 mg or 250 mg, 1 hour after awakening, 30 minutes after awakening or immediately after awakening. In a particular embodiment, the pharmaceutical composition according to the invention is suitable for oral or parenteral administration. Preferably, the pharmaceutical composition according to the invention is in the form of a solution, such as an injectable solution, or a tablet or a capsule or a transdermal delivery system. The compounds of the present invention may be used in combination with one or more other drugs in the treatment, prevention, control, amelioration, or reduction of risk of diseases or conditions for which compounds of the present invention or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone. Such other drug(s) may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the present invention. When a compound of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compound of the present invention is contemplated. However, the combination therapy may also include therapies in which the compound of the present invention and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of the present invention. The above combinations include combinations of a compound of the present invention not only with one other active compound, but also with two or more other active compounds. The weight ratio of the compound of the present invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with another agent, the weight ratio of the compound of the present invention to the other agent will generally range from 1000:1 to 1:1000, preferably from 200:1 to 1:200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used. In such combinations the compound of the present invention and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent. The compounds of the present invention may be administered in combination with compounds which are known in the art to be useful for treating or controlling narcolepsy, including e.g., methylphenidate, amphetamine, atomoxetine, reboxetine, viloxazine, phenelzine, protriptyline, gamma–hydroxybutyric acid, sodium oxybate, or other oxybate salts, modafinil, armodafinil, adrafinil, pitolisant, samelisant, nalfurafin, caffeine, and salts thereof, and combinations thereof, and the like. Compounds of formula (II) The present invention also relates to a compound of formula (II):

wherein: - X represents -NH-, –S- or –O-, preferably -NH- or -S-; - Y and R₂, independently of each other represents a hydrogen atom, a halogen atom, –NO₂ or –NH₂,; - R₁, R₃, R₄ each represent, independently of each other, a hydrogen atom or a halogen atom; - R₅, R₆, R₇, R₈, R₉ each represent, independently of each other, a hydrogen atom, a halogen atom, –OR₁₀ or a (C₁–C₃₀)alkyl chain, especially (C₁–C₂₀)alkyl, optionally broken up and/or followed and/or preceded by one or more moieties chosen from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclic, –C≡C–, –C(R₁₁)=C(R₁₂)–, -O-,–S–, –NR₁₃–, –C(O)–, –C(S)–, –C=N–, –N=C–, –OC(O)–, – C(O)O–, –SC(O)–, –C(O)S–, –N(R₁₄)C(O)– and –C(O)N(R₁₅)– groups, the aryl, heteroaryl and heterocyclic rings being optionally substituted; - R₁₀ represents a hydrogen atom or a (C₁–C₃₀)alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl group, the aryl, heteroaryl and heterocyclic rings being optionally substituted; - R₁₁ and R₁₂ represent, independently of each other, a hydrogen atom or a (C₁– C₆)alkyl group; and - R₁₃ to R₁₅ represent, independently of each other, a hydrogen atom or a (C₁– C₆)alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl group, and preferably a hydrogen atom or a (C₁–C₆)alkyl or aryl group, and still more preferably a hydrogen atom or a (C₁–C₆)alkyl group, or a pharmaceutically acceptable salt thereof, a tautomer, a stereoisomer or mixture of stereoisomers thereof. Preferably, the compound of formula (II) is not

(this compound has been described (Cox et al. 2020) as having an inhibitory activity of amyloid aggregation),

(these four compounds has been described as having an inhibitory effect on cell multiplication (Yale et Kalkstein 1967),

(this compound has been described as having an anticancer activity (Chinigo et al. 2008),

(this compound has been described as having an anti-tumour activity (Mordarski et Chylinska 1971),

(this compound has been used for the treatment of PARP-1 related diseases, see WO 2018044136) (Kim et al. 2023), and provided that when X represents O, each of R₁, R₂, R₃ and R₄ represents H, Y represents an halogen atom and four of R₅, R₆, R₇, R₈, and R₉ represent H, then the remaining group of R₅, R₆, R₇, R₈, and R₉ is not a (C₁-C₃₀)alkyl chain preceded by -O- and broken-up by -O- or broken up, followed and/or preceded by –C(R₁₁)=C(R₁₂)–. In some embodiments, when X represents -O-, then R₅, R₆, R₇, R₈, R₉ each represent, independently of each other, a hydrogen atom, a halogen atom, –OR₁₀ or a (C₁–C₃₀)alkyl chain, especially (C₁–C₂₀)alkyl, optionally broken up and/or followed and/or preceded by one or more moieties chosen from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclic, –C≡C–,–S–, –NR₁₃–, –C(O)–, –C(S)–, –C=N–, –N=C–, –OC(O)–, – C(O)O–, –SC(O)–, –C(O)S–, –N(R₁₄)C(O)– and –C(O)N(R₁₅)– groups, the aryl, heteroaryl and heterocyclic rings being optionally substituted. In a preferred embodiment, when X represents -O-, then Y and R₂, independently of each other represents a hydrogen atom, –NO₂ or –NH₂. In a preferred embodiment, when one of Y or R₂ represents a halogen atom, –NO₂ or – NH₂, preferably –NO₂ or –NH₂, the other represents a hydrogen atom or a halogen atom. In some embodiments, when Y represents a halogen atom, –NO₂ or –NH₂, preferably – NO₂ or –NH₂, R₂ represents a hydrogen atom or a halogen atom. In some embodiments, when R₂ represents a halogen atom, –NO₂ or –NH₂, preferably –NO₂ or –NH₂, Y represents a hydrogen atom or a halogen atom. In a preferred embodiment, when one of Y or R₂ represents a halogen atom, –NO₂ or – NH₂, preferably –NO₂ or –NH₂, the other represents a hydrogen atom. In some embodiments, when Y represents a halogen atom, –NO₂ or –NH₂, preferably –NO₂ or – NH₂, R₂ represents a hydrogen atom. In some embodiments, when R₂ represents a halogen atom, –NO₂ or –NH₂, preferably –NO₂ or –NH₂, Y represents a hydrogen atom. R₄ represents preferably a hydrogen atom. In a preferred embodiment of the invention, when X is NH or O, then R₅, R₆ or R₇ represents –OR₁₀ with R₁₀ representing a hydrogen atom, a (C₁–C₃₀)alkyl or a phenyl group. In a preferred embodiment of the invention, R₁, R₂, R₃, R₄ each represent a hydrogen atom or R₁, R₃, R₄, Y each represent a hydrogen atom. In some embodiments, R₁, R₂, R₃, R₄ can each represent a hydrogen atom. In some embodiments, R₁, R₃, R₄, Y each represent a hydrogen atom. R₅, R₆, R₇, R₈, R₉ can each represent, independently of each other, a hydrogen atom, a halogen atom, –OR₁₀ or a (C₁–C₂₀)alkyl, optionally broken up and/or preceded by one or more moieties chosen from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclic, –C≡C–, –C(R₁₁)=C(R₁₂)–,-O-, –S–, –NR₁₃–, –C(O)–, –OC(O)–, –C(O)O–, – N(R₁₄)C(O)– and –C(O)N(R₁₅)– groups, the aryl, heteroaryl and heterocyclic rings being optionally substituted. In another preferred embodiment, R₅, R₆, R₇, R₈, R₉ each represent, independently of each other, a hydrogen atom or –OR₁₀. Preferably, at least four residues out of R₅, R₆, R₇, R₈ and R₉ each represent a hydrogen atom. In a particular embodiment, R₅, R₆, R₇, R₈, R₉, each represent, a hydrogen atom. In another embodiment, R₅ represents –OR₁₀ with R₁₀ representing a hydrogen atom, a (C₁–C₃₀)alkyl or phenyl group, preferably a (C₁–C₂₀)alkyl or a phenyl group. In some embodiments, R₅ represents –OR₁₀ with R₁₀ representing a hydrogen atom, a (C₁– C₃₀)alkyl or phenyl group, preferably a (C₁–C₂₀)alkyl or a phenyl group, and R₆, R₇, R₈, R₉, each represent, a hydrogen atom. In another embodiment, R₆ represents –OR₁₀ with R₁₀ representing a hydrogen atom, a (C₁–C₃₀)alkyl or phenyl group, preferably a (C₁–C₂₀)alkyl or a phenyl group. In some embodiments, R₆ represents –OR₁₀ with R₁₀ representing a hydrogen atom, a (C₁– C₃₀)alkyl or phenyl group, preferably a (C₁–C₂₀)alkyl or a phenyl group, and R₅, R₇, R₈, R₉, each represent, a hydrogen atom. In another embodiment, R₇ represents –OR₁₀ with R₁₀ representing a hydrogen atom, a (C₁–C₃₀)alkyl or phenyl group, preferably a (C₁–C₂₀)alkyl or a phenyl group. In some embodiments, R₇ represents –OR₁₀ with R₁₀ representing a hydrogen atom, a (C₁– C₃₀)alkyl or phenyl group, preferably a (C₁–C₂₀)alkyl or a phenyl group, and R₅, R₆, R₈, R₉, each represent, a hydrogen atom. In some embodiments, one residue out of R₅, R₆, R₇, R₈ and R₉ represents -OR₁₀ with R₁₀ representing a hydrogen atom, a (C₁–C₃₀)alkyl or phenyl group, preferably a (C₁– C₂₀)alkyl or a phenyl group. In some embodiments, X can represent -NH-. In some embodiments, X can represent - S-. In some embodiments, X can represent -O-. Preferably, X represents –S-. Advantageously, the compound of formula (II) is selected from the group consisting of:

and pharmaceutically acceptable salts thereof. In a preferred embodiment of the invention, the compound of formula (II) is selected from the group consisting of compounds 99, 100, 145, 146, 148, 149, 151, 152, 153, 154, 155, 157, 158, 161, 167, 182, 185, 191, 194, 195, 196, 243, 244, 292, 293, 301, 302, 304, 305, 308, 310, 311, and pharmaceutically acceptable salts thereof. More advantageously, the compound of formula (II) is selected from the group consisting of compounds 99, 148, 152, 153, 154, 155, 157, 161, 167, 191, 194, 195, 196, 301, 302, 304, 305, 308, 310, 311, and pharmaceutically acceptable salts thereof. Even more advantageously, the compound of formula (II) is selected from the group consisting of: ,

and pharmaceutically acceptable salts thereof. In a more preferred embodiment, the compound of formula (II) is selected from the group consisting of:

, ,

and pharmaceutically acceptable salts thereof. The present invention also relates to a pharmaceutical composition comprising a compound of formula (II) and a pharmaceutically acceptable carrier. The pharmaceutical composition is as defined above for compound of formula (I). The present invention also relates to a compound of formula (II) as described above for use as a medicament. The present invention also relates to a compound of formula (II) as described above for use in the manufacture of a medicament. In some embodiments, the present invention provides a method for treating a subject in need thereof comprising administering to said subject a compound of formula (II) or a composition comprising a compound of formula (II). The chromatographic separations of may be achieved as known in the art. Their absolute stereochemistry may be determined by the X-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration. If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography. The coupling reaction is often the formation of salts using an enantiomerically pure acid or base. The diastereomeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue. The racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art. Alternatively, any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art. In some embodiments, the present invention provides a method for treating a subject suffering from neurological diseases, preferably neurological, psychiatric, sleep disorders and diseases, such as narcolepsy and Parkinson’s disease, in which central orexin neurotransmission is compromised or in which central and peripheral orexin receptors are involved, comprising administering to said subject a compound of formula (I) or a composition comprising a compound of formula (I). In particular, said disorders and diseases are as defined above. In some embodiments, the present invention provides a method for preventing neurological diseases, preferably neurological, psychiatric, sleep disorders and diseases, such as narcolepsy and Parkinson’s disease, in which central orexin neurotransmission is compromised or in which central and peripheral orexin receptors are involved, comprising administering to a subject an effective amount of a compound of formula (I) or a composition comprising an effective amount of a compound of formula (I). In particular, said disorders and diseases are as defined above. In some embodiments, the methods further comprise administration of a second active compound. In one aspect, the invention is also related to compounds of formula (I) or pharmaceutical compositions comprising at least one compound of formula (I) for their use in the manufacture of a medicament for the treatment of from neurological diseases, preferably neurological, psychiatric, sleep disorders and diseases, such as narcolepsy and Parkinson’s disease, in which central orexin neurotransmission is compromised or in which central and peripheral orexin receptors are involved. In particular, said disorders and diseases are as defined above. The present invention also relates to the following embodiments: Embodiment 1. A compound of formula (I): wherein: - X represents –NH-, –S- or –O-, preferably -NH- or -S-; - Y represents a halogen atom, –NO₂ or –NH₂, preferably –NO₂ or –NH₂; - R₁, R₂, R₃, R₄ each represent, independently of each other, a hydrogen atom or a halogen atom; - R₅, R₆, R₇, R₈, R₉ each represent, independently of each other, a hydrogen atom, a halogen atom, –OR₁₀ or a (C₁–C₃₀)alkyl chain, especially (C₁–C₂₀)alkyl, optionally broken up and/or followed and/or preceded by one or more moieties chosen from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclic, –C≡C–, –C(R₁₁)=C(R₁₂)–,-O-, –S–, –NR₁₃–, –C(O)–, –C(S)–, –C=N–, –N=C–, –C=C–,– OC(O)–, –C(O)O–, –SC(O)–, –C(O)S–, –N(R₁₄)C(O)– and –C(O)N(R₁₅)– groups, the aryl, heteroaryl and heterocyclic rings being optionally substituted; - R₁₀ represents a hydrogen atom or a (C₁–C₃₀)alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl group, the aryl, heteroaryl and heterocyclic rings being optionally substituted; - R₁₁ and R₁₂ represent, independently of each other, a hydrogen atom or a (C₁– C₆)alkyl group; and - R₁₃ to R₁₅ represent, independently of each other, a hydrogen atom or a (C₁– C₆)alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl group, and preferably a hydrogen atom or a (C₁–C₆)alkyl or aryl group, and still more preferably a hydrogen atom or a (C₁–C₆)alkyl group, or a pharmaceutically acceptable salt thereof, a tautomer, a stereoisomer or mixture of stereoisomers thereof, for use in the prevention and/or treatment of neurological, psychiatric, sleep disorders and diseases in which central orexin neurotransmission is compromised or in which central and peripheral orexin receptors are involved. Embodiment 2. The compound of formula (I) for use according to embodiment 1, characterized in that R₁, R₂, R₃, R₄ each represent a hydrogen atom. Embodiment 3. The compound of formula (I) for use according to embodiment 1 or 2, characterized in that R₅, R₆, R₇, R₈, R₉, each represent, independently of each other, a hydrogen atom or –OR₁₀. Embodiment 4. The compound of formula (I) for use according to any one of embodiments 1 to 3, characterized in that at least four residues out of R₅, R₆, R₇, R₈ and R₉ each represent a hydrogen atom. Embodiment 5. The compound of formula (I) for use according to embodiment 4, characterized in that R₅, R₆, R₇, R₈, R₉, each represent, a hydrogen atom. Embodiment 6. The compound of formula (I) for use according to embodiment 4, characterized in that R₅, R₆ or R₇ represents –OR₁₀ with R₁₀ representing a hydrogen atom, a (C₁–C₃₀)alkyl or phenyl group. Embodiment 7. The compound of formula (I) for use according to any one of embodiments 1 to 6, characterized in that it is selected from the group consisting of compounds 69 , 84 , 87 , 90 , 96 , 97 , 98 , 99 , 148 , 152 , 153 , 154 , 155 , 157 , 161 , 167 , 191 , 194 , 195 , 196 , and mixtures thereof, preferably 84 , 99 , 152 , 155 , 194 , and mixtures thereof. Embodiment 8. The compound of formula (I) for use according to any one of embodiments 1 to 7, characterized in that the neurological, psychiatric, sleep disorders and diseases in which central orexin neurotransmission is compromised or in which orexin receptors are involved is selected from the group consisting of narcolepsy type 1, narcolepsy type 2, idiopathic hypersomnia, recurrent hypersomnia, attention- deficit hyperactivity disorder, anxiety and mood disorders, Alzheimer's disease or any other neurodegenerative disorders or cognitive impairment and tauopathies, Parkinson's disease and other synucleinopathies, Guillain-Barre syndrome, chronic fatigue syndrome, long COVID-19 and medical or health conditions associated with circadian rhythmicity as well as mental and physical disorders associated with travel across time zones and with rotating shift-work schedules, restless legs syndrome, fibromyalgia, cardiac failure, diseases related to bone loss, sepsis, syndromes which are manifested by unrefreshing sleep and muscle pain, sleep apnea which is associated with respiratory disturbances during sleep; conditions which result from a diminished quality of sleep. Embodiment 9. A pharmaceutical composition comprising at least one compound of formula (I) as defined in any one of embodiments 1 to 8 and a pharmaceutically acceptable carrier for use in the prevention and/or treatment of neurological, psychiatric, sleep disorders and diseases in which central orexin neurotransmission is compromised or in which central and peripheral orexin receptors are involved. Embodiment 10. The pharmaceutical composition for use according to embodiment 9, comprising between 0.5 mg to 800 mg, preferably between 20 mg to 400 mg of the compound of formula (I). Embodiment 11. The pharmaceutical composition for use according to embodiment 9 or 10, which is suitable for oral or parenteral administration, preferably in the form of a solution, such as an injectable solution, a tablet, a capsule or a transdermal delivery system. Embodiment 12. A compound of formula (II): wherein: - X represents -NH-, –S- or –O-, such as -S- or -O-, preferably -S-; - Y represents a halogen atom, –NO₂ or –NH₂, preferably –NO₂ or –NH₂; - R₁, R₂, R₃, R₄ each represent, independently of each other, a hydrogen atom or a halogen atom; - R₅, R₆, R₇, R₈, R₉ each represent, independently of each other, a hydrogen atom, a halogen atom, –OR₁₀ or a (C₁–C₃₀)alkyl chain, especially (C₁–C₂₀)alkyl, optionally broken up and/or followed and/or preceded by one or more moieties chosen from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclic, –C≡C–, –C(R₁₁)=C(R₁₂)–, -O-, –S–, –NR₁₃–, –C(O)–, –C(S)–, –C=N–, –N=C–, –C=C–,– OC(O)–, –C(O)O–, –SC(O)–, –C(O)S–, –N(R₁₄)C(O)– and –C(O)N(R₁₅)– groups, the aryl, heteroaryl and heterocyclic rings being optionally substituted; - R₁₀ represents a hydrogen atom or a (C₁–C₃₀)alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl group, the aryl, heteroaryl and heterocyclic rings being optionally substituted; - R₁₁ and R₁₂ represent, independently of each other, a hydrogen atom or a (C₁– C₆)alkyl group; and - R₁₃ to R₁₅ represent, independently of each other, a hydrogen atom or a (C₁– C₆)alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl group, and preferably a hydrogen atom or a (C₁–C₆)alkyl or aryl group, and still more preferably a hydrogen atom or a (C₁–C₆)alkyl group, or a pharmaceutically acceptable salt thereof, a tautomer, a stereoisomer or mixture of stereoisomers thereof. Embodiment 13. The compound of formula (II) according to embodiment 12, characterized in that R₁, R₂, R₃, R₄ each represent a hydrogen atom and R₅, R₆, R₇, R₈, R₉ each represent, independently of each other, a hydrogen atom or –OR₁₀. Embodiment 14. The compound of formula (II) according to embodiments 12 or 13, characterized in that at least four residues out of R₅, R₆, R₇, R₈ and R₉ each represent a hydrogen atom. Embodiment 15. The compound of formula (II) according to embodiment 14, characterized in that R₅, R₆, R₇, R₈, R₉, each represent, a hydrogen atom. Embodiment 16. The compound of formula (II) according to embodiment 14, characterized in that R₅, R₆ or R₇ represents –OR₁₀ with R₁₀ representing a hydrogen atom, a (C₁–C₃₀)alkyl or phenyl group. Embodiment 17. The compound of formula (II) according to any one of embodiments 12 to 16, characterized in that it is selected from the group consisting of compounds 99, 148, 152, 153 , 154 , 155, 157, 161 , 167 , 191 , 194, 195 , 196 , and mixtures thereof, preferably 99 , 152 , 155 , 194 , and mixtures thereof. Embodiment 18. A compound of formula (II) according to any of embodiments 12 to 17, for use as a medicament. One or more features of any embodiments disclosed herein may be combined and/or rearranged within the scope of the invention to produce further embodiments that are also within the scope of the invention. Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be within the scope of the present invention. The invention is further described by the following non-limiting Examples. Examples Examples are provided below to facilitate a more complete understanding of the invention. The following examples illustrate the exemplary modes of making and practicing the invention. However, the scope of the invention is not limited to specific embodiments disclosed in these Examples, which are illustrative only, since alternative methods can be utilized to obtain similar results. Example 1. Chemistry of dihydro-quinazoline derivatives Design, synthesis and preparations of 6-nitro-2,3-dihydro-1H-quinazolin-4-one

Polyphosphoric ester preparation (PPE) P2O4 (150 g) was refluxed in diethyl ether (150 mL) and CHCl3 (300 mL) until a clear solution occurred. Then solvents were removed under reduce pressure to give a clear oil. Synthesis of 2-amino-5-nitrobenzamide A mixture of 2-amino-5-nitro-benzonitrile (25.3 mmol, 4 g) and concentrated H2SO4 (24.2 mL) were heated to 65 °C and stirred for 12 hours. The reaction mixture was gradually poured into ice and the pH was brought to 8-9 by 6 M aq. NaOH solution or aq. NH4OH. The precipitate was filtered off and washed with ice cold H2O to give pure benzamide used without further purification. ¹H NMR (400 MHz, DMSO-d₆): δ ppm 8.54 (d, J= 2.7 Hz, 1H), 8.20 (br.s., 1H), 8.01 (dd, J= 9.0 Hz, 2.8 Hz, 1H), 7.87 (bs, 1H), 7.39 (br.s., 1H), 6.78 (d, J= 9.0 Hz, 1H). General procedure for 6-nitro-2,3-dihydro-1H-quinazolin-4-one: A mixture of 2-amino-5-nitrobenzamide (1 mmol) and PPE (1 g) was added to the corresponding aldehyde (1 mmol) and the solution was heated at 80°C for 30 min without condenser. The solution thus obtained was poured into cold water. The precipitate was filtered off, washed with water and crystallized in diethyl ether to give pure corresponding DHQ with excellent yield (80-95%).

Product 50: 6-nitro-2-phenyl-2,3-dihydro-1H-quinazolin-4-one

1H NMR (300 MHz, DMSO-d6) δ ppm 6.01 (s, 1H) 6.83 (d, J=9.08 Hz, 1H) 7.35-7.50 (m, 5H) 8.10 (dd, J=9.08, 2.75 Hz, 1H) 8.43 (d, J=2.66 Hz, 1H) 8.58 (s, 1H) 8.74 (s, 1H). 1³C NMR (75 MHz, DMSO-d₆) δ ppm 66.27 (C-2), 112.63 (C-8), 114.24 (C-10), 124.17 (C- 4), 126.53 (C-2’), 128.65 (C-3’), 128.87 (C-4’), 128.97 (C-7), 137.10 (C-6), 141.10 (C- 1’), 152.13 (C-9), 161.28 (C-4). Chemical Formula: C₁4H11N3O3: m/z: 269.08 Product 51: 6-nitro-2-(4-hydroxyphenyl)-2,3-dihydro-1H-quinazolin-4-one

1H NMR (300 MHz, DMSO-d6) δ ppm 5.90 (s, 1H) 6.73-6.85 (m, 3H) 7.28 (d, J=8.53 Hz, 2H) 8.09 (dd, J=9.26, 2.93 Hz, 1H) 8.43 (d, J=2.57 Hz, 2H) 8.57 (s, 1H). 1³C NMR (75 MHz, DMSO-d₆) δ ppm 66.30 (C-2), 112.63 (C-10), 114.20 (C-8), 115.26 (C- 3’), 124.25 (C-5), 128.05 (C-2’), 128.93 (C-7), 131.25 (C-1’), 137.01 (C-6), 152.30 (C- 9), 158.03 (C-4’), 161.42 (C-4). Chemical Formula: C₁₄H₁₁N₃O₄: m/z: 285.07. Product 54: 6-nitro-2-(4-methoxyphenyl)-2,3-dihydro-1H-quinazolin-4-one

¹H NMR (300 MHz, DMSO-d6) δ pm 3.75 (s, 3H), 5.95 (s, 1H), 6.81 (d, J=9.08 Hz, 1H), 6.97 (m, J=8.80 Hz, 2H), 7.38 (m, J=8.71 Hz, 2H), 8.09 (dd, J=9.08, 2.75 Hz, 1H), 8.42 (s, 1H), 8.48 (s, 1H), 8.65 (s, 1H). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm 55.19 (OCH3), 65.91 (C-2), 112.62 (C-10), 113.90 (C- 2’), 114.20 (C-8), 124.16 (C-5), 127.94 (C-2’), 128.93 (C-7), 132.94 (C-1’), 136.99 (C- 6), 152.19 (C-9), 159.67 (C-4’), 161.36 (C-4). Chemical Formula: C₁5H13N₃O₄: m/z: 299.09. Product 55: 6-nitro-2-(3-methoxyphenyl)-2,3-dihydro-1H-quinazolin-4-one

¹H NMR (300 MHz, DMSO-d₆) δ ppm 3.75 (s, 3H) 5.98 (s, 1H) 6.84 (d, J=9.17 Hz, 1H) 6.90-6.99 (m, 1H) 6.99-7.08 (m, 2H) 7.33 (t, J=8.16 Hz, 1H) 8.05-8.17 (m, 1H) 8.43 (d, J=2.75 Hz, 1H) 8.57 (s, 1H) 8.74 (s, 1H) Chemical Formula: C₁5H13N₃O₄: m/z: 299.09. Product 56: 6-nitro-2-(2-methoxyphenyl)-2,3-dihydro-1H-quinazolin-4-one

¹H NMR (300 MHz, DMSO-d₆) δ ppm 3.91 (s, 3H, OCH3), 5.95 (s, 1H, C-H₂), 6.88 (d, J=9.17 Hz, 1H, C-H8), 7.16-7.09 (m, 2H, C-H3’,5’), 7.46 (dt, 1H, J=7.1 Hz, C-H4’), 8.10 (m, 1H, C-H7), 8.20-8.18 (dd, 1H, J=1.2;7.8 Hz, C-H6’), 8.44 (d, J=2.75 Hz, 1H, C-H5) 8.57 (s, 1H), 8.75 (s, 1H). ¹³C NMR (75 MHz, DMSO-d₆): δ 55.84(OCH3), 65.78 (C-2), 112.12 (C-10), 113.31(C-3'), 114.22 (C-8), 120.68(C-5'), 124.18 (C-5), 128.45 (C-7), 131.11(C-6'), 131.87 (C-1’), 131.99(C-4'), 134.56 (C-6), 151.31 (C-9), 158.32(C-2'), 161.44 (C-4). Chemical Formula: C₁₅H₁₃N₃O₄: m/z: 299.09. Product 60: 6-nitro-2-(4-propoxyphenyl)-2,3-dihydro-1H-quinazolin-4-one

1H NMR (300 MHz, DMSO-d₆) δ ppm 0.96 (t, J=7.38 Hz, 3H), 1.63-1.80 (m, 2H), 3.92 (t, J=6.46 Hz, 2H), 5.95 (s, 1H), 6.82 (d, J=9.08 Hz, 1H), 6.96 (m, J=8.71 Hz, 2H), 7.37 (m, J=8.71 Hz, 2H), 8.10 (dd, J=9.08, 2.75 Hz, 1H), 8.43 (d, J=2.66 Hz, 1H), 8.48 (s, 1H), 8.64 (s, 1H). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm 10.34 (CH₃), 21.95 (CH₂), 65.98 (O-CH₂), 69.06 (C- 2), 112.66 (C-10), 114.24 (C-8), 114.46 (C-3’), 124.20 (C-5), 127.93 (C-2’), 128.95 (C- 7), 132.89 (C-1’), 137.06 (C-6), 152.21 (C-9), 159.13 (C-4’), 161.38 (C-4). Chemical Formula: C₁₇H₁₇N₃O₄: m/z: 327.12. Product 63: 6-nitro-2-(4-butoxyphenyl)-2,3-dihydro-1H-quinazolin-4-one

¹H NMR (300 MHz, DMSO-d6) δ ppm 0.92 (t, J=7.40 Hz, 3H), 1.35-1.48 (m, 2H), 1.62- 1.73 (m, 2H), 3.95 (t, J=6.48 Hz, 2H), 5.95 (s, 1H), 6.82 (d, J=9.08 Hz, 1H), 6.96 (m, J=8.71 Hz, 2H), 7.37 (m, J=8.71 Hz, 2H), 8.10 (dd, J=9.08, 2.75 Hz, 1H), 8.42 (d, J=2.66 Hz, 1H), 8.48 (s, 1H), 8.64 (s, 1H). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm 13.60 (CH3), 18.62 (CH2), 30.59 (CH2), 57.34 (C-2), 67.20 (OCH2), 69.06 (C-2), 112.68 (C-10), 114.22 (C-8), 114.46 (C-3’), 124.21 (C-5), 127.95 (C-2’), 128.90 (C-7), 132.90 (C-1’), 137.08 (C-6), 152.21 (C-9), 159.14 (C-4’), 161.40 (C-4). Chemical Formula: C₁₈H₁₉N₃O₄ :m/z: 341.14. Product 69: 6-nitro-2-[4-(hexyloxy)phenyl]-2,3-dihydro-1H-quinazolin-4-one

¹H NMR (400 MHz, DMSO-d6) δ ppm 0.81-0.94 (m, 3H), 1.30 (d, J=7.34 Hz, 4H), 1.41 (br. s., 2H), 1.69 (d, J=14.79 Hz, 2H), 3.96 (t, J=6.48 Hz, 2H), 5.95 (s, 1H), 6.82 (d, J=9.05 Hz, 1H), 6.96 (m, J=8.80 Hz, 2H), 7.36 (m, J=8.68 Hz, 2H), 8.10 (dd, J=9.11, 2.75 Hz, 1H), 8.43 (d, J=2.81 Hz, 1H), 8.47 (s, 1H), 8.63 (s, 1H). Chemical Formula: C₂₀H₂₃N₃O₄: m/z: 369.17. Product 84: 6-nitro-2-[4-(undecyloxy)phenyl]-2,3-dihydro-1H-quinazolin-4-one

¹H NMR (300 MHz, DMSO-d6) δ ppm 0.84 (t, J=6.56 Hz, 3H), 1.24 (br. s., 14H), 1.32-1.51 (m, 2H), 1.64-1.83 (m, 2H), 4.05 (t, J=6.46 Hz, 2H), 7.06 (m, J=8.89 Hz, 2H), 7.83 (d, J=8.99 Hz, 1H), 8.16-8.32 (m, 2H), 8.50 (dd, J=8.99, 2.75 Hz, 1H), 8.81 (d, J=2.66 Hz, 1H), 12.78 (br. s., 1H, NH). Chemical Formula: C₂₅H₃₁N₃O₄: m/z: 437.23. Product 87: 6-nitro-2-(4-dodecyloxyphenyl)-2,3-dihydro-1H-quinazolin-4-one

¹H NMR (400 MHz, CDCl₃) δ ppm 0.85 (t, J=6.72 Hz, 3H), 1.15-1.34 (m, 16 H), 1.38 (br. s., 2H), 1.61-1.75 (m, 2H), 3.95 (t, J=6.48 Hz, 2H), 5.95 (s, 1H), 6.83 (d, J=9.05 Hz, 1H), 6.95 (m, J=8.68 Hz, 2H), 7.36 (m, J=8.68 Hz, 2 H), 8.04-8.14 (m, 1H), 8.43 (d, J=2.69 Hz, 1H), 8.53 (s, 1H), 8.64 (s, 1H). ¹³C NMR (101 MHz, DMSO-d6) δ ppm 13.89 (CH3), 22.03 (CH2), 25.43 (CH2), 28.56 (CH2), 28.65 (CH2), 28.70 (CH2), 28.94 (3xCH2), 28.97 (CH2), 31.24 (CH2), 65.89 (OCH2), 67.53 (C-2), 112.62 (C-10), 114.21 (C-8), 114.40 (C-3’), 124.15 (C-5), 127.84 (C-2’), 128.86 (C-7), 132.93 (C-1’), 137.01 (C-6), 152.17 (C-9), 159.08 (C-4’), 161.32 (C-4). Chemical Formula: C₂₆H₃₅N₃O₄: m/z: 453.26. Product 90: 6-nitro-2-(4-tridecyloxyphenyl)-2,3-dihydro-1H-quinazolin-4-one

¹H NMR (300 MHz, CDCl3) δ ppm 0.77-0.99 (m, 3H), 1.28 (br. s., 14H), 1.40-1.55 (m, 2H), 1.68-1.92 (m, 2H), 3.96 (s, 2H), 4.71 (br. s., 1H), 5.33 (br. s., 1H), 6.24 (s, 1 H), 6.68 (d, J=8.99 Hz, 1H), 6.93 (m, J=8.71 Hz, 2H), 7.45 (m, J=8.62 Hz, 2H), 8.16 (d, J=11.55 Hz, 1H), 8.77 (d, J=2.57 Hz, 1H). ¹³C NMR (75 MHz, CDCl₃) δ ppm 14.07 (CH3), 22.64 (CH2), 25.98 (CH2), 29.13 (CH2), 29.30 (CH2), 29.36 (CH2), 29.53 (CH2), 29.58 (2xCH2), 31.87 (CH2), 68.11 (OCH2), 68.27 (C-2), 113.84 (C-10), 114.23 (C-8), 115.10 (C-3’), 125.63 (C-5), 128.49 (C-2’), 129.35 (C-7), 129.44 (C-1’), 139.86 (C-6), 151.38 (C-9), 160.76 (C-4’), 162.66 (C-4). Chemical Formula: C₂₅H₃₃N₃O₄: m/z: 439.25. Product 93: 6-nitro-2-(4-tetradecyloxyphenyl)-2,3-dihydro-1H-quinazolin-4-one

¹H NMR (300 MHz, DMSO-d6) δ ppm 0.84 (s, 3H), 1.23 (s, 22H), 1.38 (br. s., 3H), 1.61- 1.75 (m, 2H), 3.94 (t, J=6.51 Hz, 2H), 5.95 (s, 1H), 6.81 (d, J=9.08 Hz, H), 6.94 (d, J=8.71 Hz, 2H), 7.36 (d, J=8.71 Hz, 2 H), 8.09 (d, J=11.83 Hz, 1H), 8.43 (d, J=2.66 Hz, 1H), 8.48 (s, 1H), 8.64 (s, 1H). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm 13.92 (CH3), 22.08 (CH2), 25.47 (CH2), 28.60 (CH2), 28.70 (CH2), 28.74 (CH2), 29.00 (3xCH2), 29.03 (3x CH2), 31.28 (CH2), 65.95 (OCH2), 67.54 (C-2), 112.65 (C-10), 114.22 (C-8), 114.41 (C-3’), 124.19 (C-5), 127.88 (C-2’), 128.91 (C-7), 132.89 (C-1’), 137.04 (C-6), 152.19 (C-9), 159.12 (C-4’), 161.36 (C-4). Chemical Formula: C₂₈H₃₉N₃O₄: m/z: 481.29. Product 96: 6-nitro-2-(4-phenoxyphenyl)-2,3-dihydro-1H-quinazolin-4-one

¹H NMR (300 MHz, DMSO-d₆) δ ppm 6.02 (s, 1H) 6.84 (d, J=9.17 Hz, 1H) 7.05 (d, J=8.62 Hz, 2H) 7.00 (d, J=8.80 Hz, 2H) 7.12-7.21 (m, 1H) 7.35-7.45 (m, 2H) 7.49 (d, J=8.62 Hz, 2H) 8.11 (dd, J=9.08, 2.75 Hz, 1H) 8.44 (d, J=2.75 Hz, 1H) 8.53 (s, 1H) 8.71 (s, 1H) Chemical Formula: C₂₀H₁₅N₃O₄: m/z: 361.11. Product 98: 6-nitro-2-(2-phenoxyphenyl)-2,3-dihydro-1H-quinazolin-4-one

¹H NMR (300 MHz, DMSO-d₆) δ ppm 6.28 (s, 1H), 6.74 (d, J=9.08 Hz, 1H), 6.84 (d, J=7.89 Hz, 1H), 6.97 (d, J=7.70 Hz, 2H), 7.07-7.24 (m, 2H), 7.29-7.43 (m, 3H), 7.54 (d, J=8.99 Hz, 1H), 7.96-8.08 (m, 1H), 8.40 (d, J=2.66 Hz, 1H), 8.47 (s, 1H), 8.63 (s, 1H). ¹³C NMR (75 MHz, DMSO-d6) δ ppm 62.50 (C-2), 112.42 (C-10), 114.00 (C-8), 118.31 (C- 5’), 118.87 (C-8’), 123.59 (C-3’), 123.72 (C-5), 124.05 (C-2’), 128.42 (C-4’), 128.76 (C- 7), 129.90 (C-9’), 130.52 (C-10’), 131.28 (C-1’), 136.85 (C-6), 152.10 (C-9), 154.46 (C- 7’), 156.22 (C-6’), 161.24 (C-4). Chemical Formula: C₂₀H₁₅N₃O₄: m/z: 361.11. General procedure for 7-nitro-2,3-dihydro-1H-quinazolin-4-one:

A mixture of 2-amino-4-nitrobenzamide (CAS: 31930-18-4, 1 mmol) and PPE (1 g) was added to the corresponding aldehyde (1 mmol) and the solution was heated at 80°C for 30 min without condenser. The solution thus obtained was poured into cold water. The precipitate was filtered off, washed with water and crystallized in diethyl ether to give pure corresponding DHQ with excellent yield (80-95%). Product 300: 7-nitro-2-[4-(dodecyloxy)phenyl]-2,3-dihydroquinazolin-4(1H)-one

1H NMR (300 MHz, DMSO-d6) δ ppm : 0.85 (t, J=6.24 Hz, 3H, CH3), 1.24 (br. s., 16 H, CH2), 1.38 (br. s., 2H, CH2), 1.61 - 1.81 (m, 2H, CH2), 3.94 (t, J=6.28 Hz, 2H, OCH2), 5.85 (s, 1H, C-H₂), 6.94 (d, J=8.44 Hz, 2H, C-H_3',5'), 7.35 - 7.46 (m, 3H, C-H_2',6', C-H₆), 7.57 (d, 1H, C-H₈), 7.65 (s, 1H, N-H), 7.83 (d, J=8.53 Hz, 1H, C-H₅), 8.61 (s, 1H, N-H). 1³C NMR (75 MHz, DMSO-d₆) δ ppm: 13.91 (CH₃), 22.06 (CH₂), 25.45 (CH₂), 28.59 (CH₂), 28.67 (CH2), 28.72 (CH2), 28.96 (3xCH2), 29.00 (CH2), 31.26 (CH2), 66.04 (C-2), 67.50 (OCH2), 108.79 (C-8), 110.89 (C-6), 114.29 (C-3',5'), 119.25 (C-10), 128.02 (C-2',6'), 129.07 (C-5), 132.75 (C-1'), 148.24 (C-9), 150.72 (C-7), 159.01 (C-4'), 161.86 (C-4). Chemical Formula: C₂₆H₃₅N₃O₄: m/z: 453,26 Product 313: 7-nitro-2-[4-(tetradecyloxy)phenyl]-2,3-dihydroquinazolin-4(1H)-one

1H NMR (300 MHz, DMSO-d₆) δ ppm: 0.78 - 0.91 (t, 3H, CH₃), 1.23-1.38 (m, 22H), 1.70 (br. s., 2H, CH₂), 3.94 (t, J=6.46 Hz, 2H, OCH₂), 5.84 (s, 1 H, C-H₂), 6.94 (d, J=8.71 Hz, 2H, C-H3',5'), 7.38 (d, J=8.71 Hz, 2H, C-H2',6'), 7.40 - 7.45 (dd, J=2.2, 8.53 Hz,1H, C-H6), 7.57 (d, J=2.20 Hz, 1H, C-H8), 7.68 (s, 1H, NH), 7.83 (d, J=8.53 Hz, 1H, C-H5), 8.61 (s, 1H, NH). ¹³C NMR (DMSO-d₆) δ ppm: 13.91 (CH₃), 22.06 (C-n), 25.46 (C-g), 28.60 (1C), 28.67 (2C), 28.73 (1C), 28.98 (4C), 29.00 (C-b), 31.26 (C-m), 66.03 (C-2), 67.51 (C-a), 108.81 (C- 8), 110.88 (C-6), 114.29 (C-3',5'), 119.26 (C-10), 128.02 (C-2',6'), 129.07 (C-5), 132.78 (C-1'), 148.24 (C-9), 150.73 (C-7), 159.02 (C-4'), 161.87 (C-4). Chemical Formula: C₂₈H₃₉N₃O₄: m/z: 481,29 Example 2. Chemistry of dihydro-benzothiazine derivatives A) Designs, synthesis and preparations of 6-nitro-2H-benzo[e][1,3]thiazin- 4(3H)-one The design, synthesis and preparation of 6-nitro-2-(phenyl)-2H-benzo[e][1,3]thiazin- 4(3H)-one has never been described. The design, synthesis and preparation of 2-aryl- 2,3-dihydro-4H-1,3-benzothiazin-4-one and 2-aryl-2,3-dihydro-4-one derivatives has been multiple times cited (Boudet 1959; Geng et al. 2012; Ingram et McClelland 1947; Moreau et Delacoux 1962). Our synthetic route begins as below to obtain thiobenzamide:

2-chloro-5-nitrobenzamide RMN ¹H (300 MHz, DMSO-d₆) δ ppm 7.78-7.81 (m, 1H, C-H3), 7.86 (br.s., 1H, NH), 8.12 (brs, 1H, NH), 8.23-8.25 (m, 2H, C-H4,6). RMN ¹³C (75 MHz, DMSO-d6) δ ppm 123.61(C-3), 125.41(C-6), 131.51(C-4), 137.01(C-2), 138.17(C-1), 146.17(C-5), 166.25(CONH₂). Chemical Formula: C₇H₅ClN₂O₃: m/z: 200.00. 2-mercapto-5-nitrobenzamide ¹H (300 MHz, DMSO-d₆) δ ppm 7.37-7.40 (d, 1H, J= 8.88 Hz, C-H3), 7.43 (br. s., 1H, NH), 7.50-7.54 (dd, 1H, J= 2.83, 8.88 Hz, C-H4), 8.77 (d, 1H, J= 3.02 Hz, C-H6), 11.41 (brs, 1H, NH). ¹³C (300 MHz, DMSO-d6) δ ppm, 120.61(C-3), 125.92(C-6), 132.14(C-4), 138.22(C-2), 138.47(C-1), 168.12(CONH2), n.o. (C-5). Chemical Formula: C₇H₆N₂O₃S: m/z: 198.01. General procedure A mixture of 2-mercapto-5-nitrobenzamide (1mmol) and PPE (1 g) was added to the corresponding aldehyde (1 mmol) and the solution was heated to 100°C for 60 min without condenser. The solution thus obtained was poured into cold water. The precipitate was filtered off, washed with water and crystalized in diethyl ether to give pure corresponding dihydro-benzothiazine with excellent yield (80-95%).

Product 148: 6-nitro-2-phenyl-2,3-dihydro-1,3-benzothiazin-4-one

1H NMR (300 MHz, DMSO-d₆) δ ppm: 6.31 (d, J=3.76 Hz, 1 H, C-H₂), 7.29 - 7.43 (m, 3 H, C-H_3',4',5'), 7.43 - 7.53 (m, 2 H, C-H_2',6'), 7.63 (d, J=8.71 Hz, 1 H, C-H₈), 8.24 (dd, J=8.67, 2.61 Hz, 1 H, C-H₇), 8.70 (d, J=2.66 Hz, 1 H, C-H₅), 9.43 (d, J=3.67 Hz, 1 H, N-H). 1³C NMR (75 MHz, DMSO-d₆) δ ppm: 57.36 (C-2), 123.80 (C-5), 126.38 (C-8), 126.86 (C- 10), 128.62 (C-2',6'), 128.67 (C-7), 128.70 (C-4'), 128.86 (C-3',5'), 138.04 (C-1'), 144.63 (C-6), 145.32 (C-9), 162.77 (C-4). Product 149: 6-nitro-2-(4-hydroxyphenyl)-2,3-dihydro-1,3-benzothiazin-4-one

1H NMR (400 MHz, DMSO-d₆) δ ppm 6.21 (d, J=3.18 Hz, 1H), 6.76 (m, J=8.68 Hz, 2H), 7.31 (m, J=8.68 Hz, 2H), 7.62 (d, J=8.56 Hz, 1H), 8.18-8.27 (m, 1H), 8.69 (d, J=2.69 Hz, 1H), 9.27 (d, J=3.18 Hz, 1H). 1³C NMR (75 MHz, DMSO-d6) δ ppm 57.71 (C-2), 115.29 (C-3’), 123.85 (C-5), 126.25 (C- 10), 127.39 (C-8), 128.46 (C-2’), 128.50 (C-1’), 128.75 (C-7), 145.21 (C-9), 145.28 (C- 6), 158.01 (C-4’), 162.92 (C-4). Chemical Formula: C₁₄H₁₀N₂O₄S: m/z: 302.04. Product 151: 6-nitro-2-(2-hydroxyphenyl)-2,3-dihydro-1,3-benzothiazin-4-one

¹H NMR (400 MHz, DMSO-d₆) δ ppm 6.25 (d, J=3.91 Hz, 1H), 6.78 (t, J=7.52 Hz, 1H), 6.87 (d, J=7.46 Hz, 1H), 7.17 (t, J=8.50 Hz, 1H), 7.22 (d, J=7.58 Hz, 1H), 7.58 (d, J=8.56 Hz, 1H), 8.22 (dd, J=8.68, 2.69 Hz, 1H), 8.74 (d, J=2.57 Hz, 1H), 9.18 (d, J=3.91 Hz, 1H), 10.16 (s, 1 H, OH). ¹³C NMR (101 MHz, DMSO-d6) δ ppm 52.11 (C-2), 54.85 (C-3’), 115.53 (C-5’), 119.01 (C- 5’), 123.87 (C-5), 124.01 (C-10), 126.28 (C-8), 126.80 (C-6’), 128.43 (C-1’), 128.62 (C- 7), 129.90 (C-4’), 145.11 (C-9), 153.89 (C-2’), 163.01 (C-4). Chemical Formula: C₁₄H₁₀N₂O₄S: m/z: 302.04. Product 152: 6-nitro-2-(4-methoxyphenyl)-2,3-dihydro-1,3-benzothiazin-4-one

¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.75 (s, 3H), 6.27 (d, J=3.55 Hz, 1H), 6.95 (m, J=8.80 Hz, 2H), 7.42 (m, J=8.68 Hz, 2H), 7.64 (d, J=8.68 Hz, 1H), 8.25 (d, J=11.37 Hz, 1H), 8.70 (s, 1 H), 9.36 (br. s., 1H). Chemical Formula: C₁₅H₁₂N₂O₄S: m/z: 316.05. Product 153: 6-nitro-2-(3-methoxyphenyl)-2,3-dihydro-1,3-benzothiazin-4-one

¹H NMR (300 MHz, DMSO-d₆) δ ppm 3.74 (s, 3H), 6.27 (d, J=3.85 Hz, 1H), 6.94 (s, 1H), 7.04 (s, 2H), 7.25-7.36 (m, 1H), 7.64 (d, J=8.71 Hz, 1H), 8.24 (dd, J=8.71, 2.66 Hz, 1H), 8.70 (d, J=2.57 Hz, 1H), 9.42 (d, J=3.85 Hz, 1H). ¹³C NMR (75 MHz, DMSO-d6) δ ppm 55.13 (OCH3), 57.26 (C-2), 112.68 (C-2’), 114.22 (C- 4’), 119.01 (C-6’), 123.77 (C-5), 125.16 (C-10), 126.41 (C-8), 128.67 (C-7), 129.77 (C- 5’), 139.54 (C-1’), 144.65 (C-9), 145.34 (C-6), 159.21 (C-3’), 162.74 (C-4). Chemical Formula: C₁₅H₁₂N₂O₄S: m/z: 316.05. Product 154: 6-nitro-2-(2-methoxyphenyl)-2,3-dihydro-1,3-benzothiazin-4-one

¹H NMR (400 MHz, DMSO-d6) δ ppm 3.85 (s, 3H), 6.27 (d, J=4.16 Hz, 1H), 6.93 (t, J=7.52 Hz, 1H), 7.07 (d, J=7.95 Hz, 1H), 7.28 (d, J=9.05 Hz, 1H), 7.34 (t, J=8.62 Hz, 1H), 7.57 (d, J=8.68 Hz, 1H), 8.16-8.26 (m, 1H), 8.74 (d, J=2.69 Hz, 1H), 9.21 (d, J=4.28 Hz, 1H). ¹³C NMR (101 MHz, DMSO-d6) δ ppm 51.85 (C-2), 55.73 (OCH3), 111.49 (C-3’), 120.37 (C-5’), 123.86 (C-5), 125.79 (C-1’), 126.31 (C-8), 126.70 (C-6’), 128.33 (C-10), 128.62 (C-7), 130.26 (C-4’), 144.77 (C-6), 145.20 (C-9), 155.53 (C-2’), 162.90 (C-4). Chemical Formula: C₁5H12N₂O₄S: m/z: 316.05. Product 155: 6-nitro-2-(4-ethoxyphenyl)-2,3-dihydro-1,3-benzothiazin-4-one

¹H NMR (400 MHz, DMSO-d6) δ ppm 1.30 (t, J=6.97 Hz, 3H), 4.01 (q, J=6.97 Hz, 2H), 6.26 (d, J=3.42 Hz, 1H), 6.93 (d, J=8.68 Hz, 2H), 7.40 (d, J=8.68 Hz, 2H), 7.63 (d, J=8.68 Hz, 1H), 8.24 (dd, J=8.68, 2.69 Hz, 1H), 8.70 (d, J=2.57 Hz, 1H), 9.35 (d, J=3.30 Hz, 1H). Chemical Formula: C₁₆H₁₄N₂O₄S: m/z: 330.07. Product 157: 6-nitro-2-(2-ethoxyphenyl)-2,3-dihydro-1,3-benzothiazin-4-one

¹H NMR (400 MHz, DMSO-d6) δ ppm 1.36 (t, J=6.97 Hz, 3H), 4.07-4.16 (m, 2H), 6.26 (d, J=4.40 Hz, 1H), 6.91 (t, J=7.52 Hz, 1H), 7.06 (d, J=7.83 Hz, 1H), 7.24 (s, 1H), 7.27- 7.36 (m, 1H), 7.57 (d, J=8.68 Hz, 1H), 8.21 (dd, J=8.68, 2.69 Hz, 1H), 8.75 (d, J=2.57 Hz, 1H), 9.20 (d, J=4.28 Hz, 1H). ¹³C NMR (101 MHz, DMSO-d₆) δ ppm 14.52 (CH3), 51.73 (C-2), 63.79 (OCH2), 112.30 (C- 3’), 120.25 (C-5’), 123.87 (C-5), 126.17 (C-1’), 126.36 (C-8), 126.58 (C-6’), 128.21 (C- 10), 128.65 (C-7), 130.16 (C-4’), 144.76 (C-6), 145.19 (C-9), 154.71 (C-2’), 162.86 (C- 4). Chemical Formula: C₁₆H₁₄N₂O₄S: m/z: 330.07. Product 158: 6-nitro-2-(4-propoxyphenyl)-2,3-dihydro-1,3-benzothiazin-4-one

¹H NMR (300 MHz, DMSO-d6) δ ppm 0.95 (t, J=7.38 Hz, 3H), 1.60-1.82 (m, 2H), 3.91 (t, J=6.51 Hz, 2H), 6.26 (d, J=3.48 Hz, 1H), 6.93 (m, J=8.71 Hz, 2H), 7.40 (m, J=8.71 Hz, 2H), 7.63 (d, J=8.71 Hz, 1H), 8.24 (dd, J=8.62, 2.66 Hz, 1H), 8.70 (d, J=2.57 Hz, 1H), 9.34 (d, J=3.48 Hz, 1H). Chemical Formula: C₁₇H₁₆N₂O₄S: m/z: 344.08. Product 161: 6-nitro-2-(4-butoxyphenyl)-2,3-dihydro-1,3-benzothiazin-4-one

¹H NMR (400 MHz, DMSO-d6) δ ppm 0.92 (t, J=7.40 Hz, 3H), 1.35-1.48 (m, 2H), 1.62- 1.73 (m, 2H), 3.95 (t, J=6.48 Hz, 2H), 6.26 (d, J=3.55 Hz, 1H), 6.93 (m, J=8.68 Hz, 2H), 7.40 (m, J=8.56 Hz, 2H), 7.63 (d, J=8.68 Hz, 1H), 8.19-8.28 (m, 1H), 8.70 (d, J=2.57 Hz, 1H), 9.34 (d, J=3.42 Hz, 1H). ¹³C NMR (101 MHz, DMSO-d₆) δ ppm 13.59 (CH3), 18.64 (CH2), 30.61 (CH2), 57.34 (C- 2), 67.19 (OCH2), 114.41 (C-3’), 123.80 (C-5), 126.28 (C-8), 128.33 (C-2’), 128.58 (C- 10), 128.73 (C-7), 129.26 (C-1’), 145.01 (C-6), 145.25 (C-9), 159.07 (C-4’), 162.84 (C- 4). Chemical Formula: C₁₈H₁₈N₂O₄S: m/z: 358.10. Product 167: 6-nitro-2-[4-(hexyloxy)phenyl]-2,3-dihydro-1,3-benzothiazin-4-one

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.80-0.92 (m, 3H), 1.30 (d, J=7.21 Hz, 4H), 1.40 (d, J=6.72 Hz, 2H), 1.62-1.74 (m, 2H), 3.94 (t, J=6.54 Hz, 2H), 6.26 (d, J=3.42 Hz, 1H), 6.93 (m, J=8.68 Hz, 2H), 7.39 (m, J=8.68 Hz, 2H), 7.63 (d, J=8.68 Hz, 1H), 8.24 (dd, J=8.68, 2.69 Hz, 1H), 8.70 (d, J=2.57 Hz, 1H), 9.34 (d, J=3.42 Hz, 1H). ¹³C NMR (101 MHz, DMSO-d6) δ ppm 13.84 (CH3), 22.00 (CH2), 25.11 (CH2), 28.54 (CH2), 30.91 (CH2), 57.35 (C-2), 67.52 (OCH2), 114.43 (C-3’), 123.82 (C-5), 126.31 (C-8), 128.35 (C-2’), 128.60 (C-10), 128.74 (C-7), 129.27 (C-1’), 145.03 (C-6), 145.26 (C-9), 159.08 (C-4’), 162.87 (C-4). Chemical Formula: C₂₀H₂₂N₂O₄S: m/z: 386.13. Product 182: 6-nitro-2-[4-(undecyloxy)phenyl]-2,3-dihydro-1,3-benzothiazin-4-one

¹H NMR (300 MHz, DMSO-d6) δ ppm 0.75-0.98 (m, 3H), 1.24 (s, 14H), 1.38 (br. s., 2H), 1.57-1.80 (m, 2H), 3.93 (t, J=6.46 Hz, 2H), 6.25 (d, J=3.48 Hz, 1H), 6.92 (m, J=8.80 Hz, 2H), 7.39 (m, J=8.71 Hz, 2H), 7.63 (d, J=8.71 Hz, 1H), 8.24 (d, J=11.37 Hz, 1H), 8.69 (d, J=2.66 Hz, 1H), 9.34 (d, J=3.39 Hz, 1H). Chemical Formula: C₂₅H₃₂N₂O₄S: m/z: 456.21. Product 185: 6-nitro-2-(4-dodecyloxyphenyl)-2,3-dihydro-1,3-benzothiazin-4-one

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.85 (t, J=6.72 Hz, 3H), 1.24 (br. s., 16H), 1.38 (br. s., 2H), 1.62-1.75 (m, 2H), 3.94 (t, J=6.48 Hz, 2H), 6.26 (d, J=3.42 Hz, 1H), 6.92 (m, J=8.80 Hz, 2H), 7.39 (m, J=8.80 Hz, 2H), 7.63 (d, J=8.68 Hz, 1H), 8.24 (dd, J=8.68, 2.57 Hz, 1H), 8.70 (s, 1H), 9.34 (d, J=3.30 Hz, 1H). Chemical Formula: C₂₆H₃₄N₂O₄S: m/z: 470.22. Product 191: 6-nitro-2-(4-tetradecyloxyphenyl)-2,3-dihydro-1,3-benzothiazin-4-one

¹H NMR (400 MHz, DMSO-d6) δ ppm 0.85 (t, J=6.72 Hz, 3H), 1.24 (br. s., 16H), 1.38 (br. s., 2H), 1.62-1.75 (m, 2H), 3.94 (t, J=6.48 Hz, 2H), 6.26 (d, J=3.42 Hz, 1H), 6.92 (m, J=8.80 Hz, 2H), 7.39 (m, J=8.80 Hz, 2H), 7.63 (d, J=8.68 Hz, 1H), 8.24 (dd, J=8.68, 2.57 Hz, 1H), 8.70 (s, 1H), 9.34 (d, J=3.30 Hz, 1H). ¹³C NMR (101 MHz, DMSO-d₆) δ ppm 13.81 (CH3), 22.03 (CH2), 25.11 (CH2), 25.43 (CH2), 28.56 (CH2), 28.65 (CH2), 28.70 (2xCH2), 28.94 (3xCH2), 28.97 (CH2), 31.21 (CH2), 57.35 (C-2), 67.52 (OCH2), 114.43 (C-3’), 123.82 (C-5), 126.31 (C-8), 128.35 (C-2’), 128.60 (C-10), 128.74 (C-7), 129.27 (C-1’), 145.03 (C-6), 145.26 (C-9), 159.08 (C-4’), 162.87 (C-4). Chemical Formula: C₂₆H₃₄N₂O₄S: m/z: 470.22. Product 194: 6-nitro-2-(4-phenoxyphenyl)-2,3-dihydro-1,3-benzothiazin-4-one

¹H NMR (400 MHz, DMSO-d₆) δ ppm 6.32 (d, J=3.55 Hz, 1H), 6.96-7.06 (m, 4H), 7.13- 7.23 (m, 1H), 7.35-7.45 (m, 2H), 7.50 (d, J=8.56 Hz, 2H), 7.65 (d, J=8.56 Hz, 1H), 8.26 (d, J=2.69 Hz, 1H), 8.70 (d, J=2.57 Hz, 1H), 9.40 (d, J=3.67 Hz, 1H). ¹³C NMR (101 MHz, DMSO-d6) δ ppm 57.06 (C-2), 118.12 (C-8’), 119.13 (C-3’), 123.85 (C-5), 123.95 (C-10’), 126.37 (C-8), 128.63 (C-1’), 128.66 (C-10), 128.79 (C-9’), 130.12 (C-2’), 132.44 (C-7), 144.74 (C-6), 145.32 (C-9), 155.90 (C-4’), 157.34 (C-7’), 162.74 (C-4). Chemical Formula: C₂₀H₁₄N₂O₄S: m/z: 378.07. Product 195: 6-nitro-2-(3-phenoxyphenyl)-2,3-dihydro-1,3-benzothiazin-4-one

¹H NMR (400 MHz, DMSO-d₆) δ ppm 6.28 (d, J=4.16 Hz, 1H), 6.91-7.01 (m, 3H), 7.01- 7.05 (m, 1H), 7.10-7.18 (m, 1H), 7.22 (d, J=7.83 Hz, 1H), 7.33-7.44 (m, 3H), 7.62 (d, J=8.68 Hz, 1H), 8.24 (d, J=2.69 Hz, 1H), 8.63 (d, J=2.57 Hz, 1H), 9.44 (d, J=4.16 Hz, 1H). Chemical Formula: C₂₀H₁₄N₂O₄S: m/z: 378.07. Product 196: 6-nitro-2-(2-phenoxyphenyl)-2,3-dihydro-1,3-benzothiazin-4-one

¹H NMR (300 MHz, DMSO-d₆) δ ppm 6.42 (d, J=3.85 Hz, 1 H), 6.84 (d, J=8.16 Hz, 1 H), 7.04 (d, J=8.71 Hz, 2 H), 7.16 (q, J=7.67 Hz, 2 H), 7.30-7.45 (m, 3 H), 7.50 (d, J=9.26 Hz, 1 H), 7.59 (d, J=8.71 Hz, 1 H), 8.18-8.25 (m, 1 H), 8.72 (d, J=2.66 Hz, 1 H), 9.34 (d, J=3.85 Hz, 1 H). ¹³C NMR (75 MHz, DMSO-d6) δ ppm 52.19 (C-2), 118.22 (C-3’), 118.93 (C-8’), 123.54 (C- 10’), 123.89 (C-5), 123.98 (C-5’), 126.36 (C-8), 127.86 (C-6’), 128.36 (C-1’), 128.38 (C- 10), 128.61 (C-7), 130.09 (C-9’), 130.57 (C-4’), 144.45 (C-6), 145.27 (C-9), 153.58 (C- 2’), 156.13 (C-7’), 162.88 (C-4). Chemical Formula: C₂₀H₁₄N₂O₄S: m/z: 378.07. General procedure Reduction of nitro group to amino is done in a hydrogenator apparatus. Nitro derivatives (1 mmol) were introduced in the flask with Pd/C (10% in weight) and ethanol (20 ml). The flask was shacked under 50 psi of hydrogen at room temperature until no more starting material appeared in TLC. Then the solution was filtered off and the solvent was removed under reduce pressure. The desired amino derivatives were then crystallized in diethyl ether. Product 96: 6-nitro-2-(4-phenoxyphenyl)-2,3-dihydro-1H-quinazolin-4-one

¹H NMR (300 MHz, DMSO-d6) δ ppm 6.02 (s, 1H) 6.84 (d, J=9.17 Hz, 1H) 7.05 (d, J=8.62 Hz, 2H) 7.00 (d, J=8.80 Hz, 2H) 7.12-7.21 (m, 1H) 7.35-7.45 (m, 2H) 7.49 (d, J=8.62 Hz, 2H) 8.11 (dd, J=9.08, 2.75 Hz, 1H) 8.44 (d, J=2.75 Hz, 1H) 8.53 (s, 1H) 8.71 (s, 1H). 1³C NMR (75 MHz, DMSO-d₆) δ ppm: 66.17 (C-2), 114.40 (C-8), 114.89 (C-10), 118.26 (C-8'',C-12'), 118.71 (C-3',C-5'), 123.61 (C-10'), 124.35 (C-5), 128.30 (C-7), 128.68 (C- 2',C-6'), 130.07 (C-9',C-11'), 136.51 (C-1'), 137.15 (C-6), 147.85 (C-9), 156.45 (C-4'), 156.86 (C-7'), 163.56 (C-4). Chemical Formula: C₂₀H₁₅N₃O₄: m/z: 361.11. Product 97: 6-nitro-2-(3-phenoxyphenyl)-2,3-dihydro-1H-quinazolin-4-one

¹H NMR (300 MHz, DMSO-d₆) δ ppm: 6.01 (br. s., 1 H, C-H₂), 6.82 (t., 1 H, C-H_10'), 6.99 (d, J=7.61 Hz, 3 H, C-H_8,9',11'), 7.07 - 7.19 (m, 2 H, C-H_8',12'), 7.23 (d, J=7.24 Hz, 1 H, C- H_2'), 7.31 - 7.51 (m, 3 H, C-H_4',5',6'), 8.09 (d, J=8.89 Hz, 1 H, C-H₇), 8.41 (br. s., 1 H, C- H5), 8.59 (br. s., 1 H, N-H), 8.78 (br. s., 1 H, N-H). ¹³C NMR (75 MHz, DMSO-d6) δ ppm: 65.73 (C-2), 112.74 (C-10), 114.32 (C-8), 116.46 (C- 2'), 118.67 (C-4'), 118.78 (C-8',12'), 121.32 (C-10'), 123.72 (C-6'), 124.15 (C-5), 128.98 (C-7), 130.06 (C-9',11'), 130.41 (C-5'), 137.23 (C-6), 143.41 (C-1'), 152.05 (C-9), 156.15 (C-3'), 156.88 (C-7'), 161.26 (C-4). Product 98: 6-nitro-2-(2-phenoxyphenyl)-2,3-dihydro-1H-quinazolin-4-one

1H NMR (300 MHz, DMSO-d₆) δ ppm 6.28 (s, 1H), 6.74 (d, J=9.08 Hz, 1H), 6.84 (d, J=7.89 Hz, 1H), 6.97 (d, J=7.70 Hz, 2H), 7.07-7.24 (m, 2H), 7.29-7.43 (m, 3H), 7.54 (d, J=8.99 Hz, 1H), 7.96-8.08 (m, 1H), 8.40 (d, J=2.66 Hz, 1H), 8.47 (s, 1H), 8.63 (s, 1H). 1³C NMR (75 MHz, DMSO-d6) δ ppm 62.50 (C-2), 112.42 (C-10), 114.00 (C-8), 118.31 (C- 5’), 118.87 (C-8’), 123.59 (C-3’), 123.72 (C-5), 124.05 (C-2’), 128.42 (C-4’), 128.76 (C- 7), 129.90 (C-9’), 130.52 (C-10’), 131.28 (C-1’), 136.85 (C-6), 152.10 (C-9), 154.46 (C- 7’), 156.22 (C-6’), 161.24 (C-4). Chemical Formula: C₂₀H₁₅N₃O₄: m/z: 361.11. Product 99: 6-amino-2-phenyl-2,3-dihydro-1,3-benzothiazin-4-one

1H NMR (400 MHz, DMSO-d6) δ ppm 5.28 (br. s, 2H, NH₂), 5.84 (s, 1H, C-H2), 6.61 - 6.69 (m, 1 H), 6.92 (d, J=8.31 Hz, 1H), 7.30 - 7.43 (m, 3 H, C-H3',4',5'), 7.41 - 7.523 (m, 2 H, C-H2',6'), 8.61 (d, J=3.18 Hz, 1H), 9.54 (s, 1H). 1³C NMR (75 MHz, DMSO-d₆) δ ppm 57.85 (C-2), 114.48 (C-5), 114.99 (C-3’), 118.17 (C- 7), 120.03 (C-10), 127.64 (C-8), 128.62 (C-2',6'), 128.70 (C-4'), 128.86 (C-3',5'), 128.59 (C-9), 129.29 (C-1’), 147.11 (C-6), 164.98 (C-4). Product 100: 6-amino-2-(4-hydroxyphenyl)-2,3-dihydro-1,3-benzothiazin-4-one

1H NMR (400 MHz, DMSO-d6) δ ppm 5.28 (br. s, 2H, NH₂), 5.86 (s, 1H), 6.61 - 6.69 (m, 1 H), 6.73 (d, 2H), 6.92 (d, J=8.31 Hz, 1H), 7.21-7.31 (m, 3H), 8.61 (d, J=3.18 Hz, 1H), 9.54 (s, 1H). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm 57.85 (C-2), 114.48 (C-5), 114.99 (C-3’), 118.17 (C- 7), 120.03 (C-10), 127.64 (C-8), 128.34 (C-2’), 128.59 (C-9), 129.29 (C-1’), 147.15 (C- 6), 157.55 (C-4’), 164.98 (C-4). Chemical Formula: C₁4H12N₂O₂S: m/z: 272.06. Product 145: 6-amino-2-(4-phenoxyphenyl)-2,3-dihydro-1,3-benzothiazin-4-one

¹H NMR (400 MHz, DMSO-d6) δ ppm 5.30 (br. s., 2H), 5.96 (d, J=3.55 Hz, 1H), 6.67 (dd, J=8.31, 2.57 Hz, 1H), 6.91-6.99 (m, 3H), 6.99-7.05 (m, 2H), 7.13-7.19 (m, 1H), 7.25 (d, J=2.57 Hz, 1H), 7.36-7.43 (m, 2H), 7.46 (d, J=8.56 Hz, 2H), 8.76 (d, J=3.67 Hz, 1H). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm 57.15 (C-2), 114.44 (C-5), 117.98 (C-6’), 118.22 (C- 7), 118.95 (C-3’), 119.37 (C-10), 123.76 (C-8’), 127.75 (C-8), 128.70 (C-7’), 129.26 (C- 9), 130.09 (C-2’), 133.72 (C-1’), 147.26 (C-6), 156.15 (C-5’), 156.79 (C-4’), 164.79 (C- 4). Chemical Formula: C₂₀H₁₆N₂O₂S: m/z: 348.09. Product 146: 6-amino-2-(3-phenoxyphenyl)-2,3-dihydro-1,3-benzothiazin-4-one

¹H NMR (400 MHz, DMSO-d₆) δ ppm 5.10 (br. s., 2H, NH₂), 6.03 (br. s., 1H), 6.84-6.97 (m, 3H), 7.04-7.14 (m, 2H), 7.18 (d, J=7.58 Hz, 1H), 7.25-7.39 (m, 4H), 7.47 (d, J=7.95 Hz, 1H), 7.99 (s, 1H), 9.13 (br. s., 1H). Chemical Formula: C₂₀H₁₆N₂O₂S: m/z: 348.09. Product 158: 6-nitro-2-(4-propoxyphenyl)-2,3-dihydro-1,3-benzothiazin-4-one

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.95 (t, J=7.38 Hz, 3H), 1.60-1.82 (m, 2H), 3.91 (t, J=6.51 Hz, 2H), 6.26 (d, J=3.48 Hz, 1H), 6.93 (m, J=8.71 Hz, 2H), 7.40 (m, J=8.71 Hz, 2H), 7.63 (d, J=8.71 Hz, 1H), 8.24 (dd, J=8.62, 2.66 Hz, 1H), 8.70 (d, J=2.57 Hz, 1H), 9.34 (d, J=3.48 Hz, 1H). ¹³C NMR (75 MHz, DMSO-d6) δ ppm 10.34 (CH3), 21.95 (CH2), 65.54 (O-CH2), 114.42 (C- 3’), 123.80 (C-5), 126.28 (C-8), 128.33 (C-2’), 128.58 (C-10), 128.73 (C-7), 129.26 (C- 1’), 145.01 (C-6), 145.25 (C-9), 159.10 (C-4’), 162.83 (C-4). Chemical Formula: C₁7H₁₆N₂O₄S: m/z: 344.08. Example 3. Chemistry of dihydro-benzoxazine derivatives General procedure: Using the same method as for benzothiazine:

Product 243: 6-amino-2-(4-phenoxyphenyl)-2,3-dihydro-1,3-benzoxazin-4-one 1H NMR (400 MHz, DMSO-d₆) δ ppm 6.17 (d, 1H, J= 1.33 Hz, C-H₂), 6.75 (m, 2H, C-H_5,7), 6.01-6.04 (d, 4H, J= 8.5 Hz, C-H_3’,6’), 7.17 (dt, 1H, J= 7.55 Hz, C-H_8’), 7.41 (dt, 2H, J= 7.56 Hz, C-H7’), 7.54-7.57 (d, 2H, J= 8.5 Hz, C-H2’), 8.72 (d, 1H, J= 1.3 Hz, N-H3). 1³C NMR (75 MHz, DMSO-d6) δ ppm 84.2(2), 111.44(5), 117.12(8), 118.23(3'), 118.87(4a), 119.28(6'), 120.84(7), 124.11(8'), 129.46(2'), 130.37(7'), 132.31(1'), 143.59(6), 148.32(4'), 156.33(5'), 157.93(8a), 163.37(4). Chemical Formula: C₂₀H₁₆N₂O₃: m/z: 332.12. Product 244: 6-amino-2-(3-phenoxyphenyl)-2,3-dihydro-1,3-benzoxazin-4-one

1H NMR (400 MHz, DMSO-d6) δ ppm 5.30 (bs, 2H, NH2), 6.17 (d, 1H, J= 1.70 Hz, C-H2), 6.73 (m, 2H, C-H5,7), 6.99-7.04 (m, 4H, C-H8’,9’), 7.14-7.16 (m, 2H, C-H10’,8), 7.29-7.31 (d, 1H, J= 7.74 Hz, C-H_6’), 7.36-7.44 (m, 3H, C-H_{2’,4’,5’}), 8.76 (d, 1H, N-H₃). 1³C NMR (75 MHz, DMSO-d6) δ ppm 83.83(2), 111.39(5), 117.1(2'), 117.36(8), 118.88(4a), 118.91(8'), 119.51(7), 120.78(4'), 122.38(6'), 123.79(10'), 130.19(9'), 130.22(5'), 139.72(1'), 143.57(6), 148.02(8a), 156.46(3'), 156.81(7'), 163.08(4). Chemical Formula: C₂₀H₁₆N₂O₃: m/z: 332.12. Product 246: 6-nitro-2-phenyl-2,3-dihydro-1,3-benzoxazin-4-one

¹H NMR (300 MHz, DMSO-d6) δ ppm 6.59 (d, 1H, J= 1.13 Hz, C-H2), 7.29-7.32 (d, 1H, J= 9.07 Hz, C-H8), 7.42-7.48 (m, 3H, C-H3’,4’,5’), 7.58-7.60 (d, 2H, J= 8.68 Hz, C-H2’,6’), 8.34-8.38 (dd, 1H, J= 2.83, 9.07 Hz, C-H7), 8.54 (d, 1H, J= 2.84 Hz, C-H5), 9.41 (bs, 1H, NH). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm 85.56(C-2), 118.61 (C-10), 118.74 (C-8), 123.41 (C- 5), 127.65 (C-2’,6’), 128.89(C-3’,5’), 129.79 (C-4’), 130.27 (C-7), 136.16 (C-1’), 142.37 (C-6), 161.14 (C-9), 161.64 (C-4). Chemical Formula: C₁₄H₁₀N₂O₄ :m/z: 270.06 Product 292: 6-nitro-2-(4-phenoxyphenyl)-2,3-dihydro-1,3-benzoxazin-4-one

¹H NMR (400 MHz, DMSO-d6) δ ppm 6.58 (d, 1H, J= 1.13 Hz, C-H2), 7.03-7.08 (m, 4H, C-H3’,6’), 7.19 (t, 1H, J= 7.55 Hz, C-H8’), 7.29-7.32 (d, 1H, J= 9.07 Hz, C-H8), 7.42 (dt, 2H, J= 7.37 Hz, C-H7’), 7.59-7.62 (d, 2H, J= 8.68 Hz, C-H2’), 8.35-8.39 (dd, 1H, J= 2.83, 9.07 Hz, C-H7), 8.54 (d, 1H, J= 2.84 Hz, C-H5), 9.37 (bs, 1H, NH). ¹³C NMR (75 MHz, DMSO-d₆) δ ppm 85.35(2), 118.27(3'), 118.53(4a), 118.67(8), 119.44(6'), 123.4(5), 124.28(8'), 129.68(2'), 129.74(7), 130.38(7'), 130.73(1'), 142.33(6), 156.05(4'), 158.5(5'), 161.18(8a), 161.68(4). Chemical Formula: C₂₀H₁₄N₂O₅: m/z: 362.09. Product 293: 6-nitro-2-(3-phenoxyphenyl)-2,3-dihydro-1,3-benzoxazin-4-one

¹H NMR (400 MHz, DMSO-d6) δ ppm 6.58 (d, 1H, J= 1.32 Hz, C-H2), 7.00-7.03 (d, 2H, J= 7.75 Hz, C-H8’), 7.07-7.19 (m, 3H, C-H9’,10’), 7.28-7.31 (d, 1H, J= 9.07 Hz, C-H8), 7.33- 7.48 (m, 4H, C-H_{2’,4’,5’,6’}), 8.33-8.37 (dd, 1H, J= 2.83, 9.07 Hz, C-H₇), 8.50-8.51(d, 1H, J= 2.84 Hz, C-H₅), 9.43 (bs, 1H, NH). ¹³C NMR (75 MHz, DMSO-d6) δ ppm 85.05(2), 117.39(2'), 118.59(4ª), 118.77(8), 119.13(8'), 120.16(4'), 122.51(6'), 123.39(5), 124.1(10'), 129.81(7), 130.37(9'), 130.73(5'), 138.33(1'), 142.43(6), 156.33(3'), 157.12(7'), 160.99(8a), 161.48(4). Chemical Formula: C₂₀H₁₄N₂O₅: m/z: 362.09. Example 4. Binding activities 4.1. Binding activities on OX1R and OX2R sites These compounds express an activity on OX1R and/or OX2R as agonist which is determined in accordance with the following general experimental method by Eurofins using Chinese hamster ovary (CHO) cells expressing human OX1R, and human embryonic kidney (HEK), 293 cells expressing human OX2R. Material and methods OX1 (h) (agonist radioligand) human recombinant (CHO cells); Ligand [125I]orexin A; Ligand concentration: 0.1 nM ; Ligand Kd: 0.87 nM; Non-specific: SB 334867 (1 μM); Incubation: 60 min at RT scintillation counting; Control inhibitor: Orexin-A; Test concentration/dose: IC/EC₅₀ calculation are provided if 5 or more concentrations are selected; Test sample requirements: Minimum for 1) Screen: 60 μl of 10 mM stock -OR- 1 mg (pre-weighed) for 10µM final testing. 2) Dose Response: 90 μl of 10 mM stock - OR- 1 mg (pre-weighed) for a top concentration at 10 µM. OX2 (h) (agonist radioligand) human recombinant (HEK-293 cells); Ligands [125I]orexin A; Ligand concentration: 0.04 nM ; Ligand Kd: 0.2 nM; Non-specific: Orexin-B (1 μM); Incubation: 180 min at RT scintillation counting; Control inhibitor: Orexin-B; Test concentration/dose: IC/EC₅₀ calculation are provided if 5 or more concentrations are selected; Test sample requirements: Minimum for 1) Screen: 60 μl of 10 mM stock -OR- 1 mg (pre-weighed) for 10µM final testing. 2) Dose Response: 90 μl of 10 mM stock - OR- 1 mg (pre-weighed) for a top concentration at 10 µM. The compounds recited in Table 1 were tested at 10^-5 M, calculated as a % inhibition of control (IC) specific binding of a radioactively labeled ligand specific for OX1R and/ or OX2R target. This binding profile panel was broadly defined with roughly an equal number of selective, central and peripheral therapeutically relevant targets, including native animal tissues, radioligands and specific enzymes involved in cell cycle regulation in accordance with Eurofins Standard Operating Procedure. For radioligand binding experiments, the half maximal inhibitory concentration (IC₅₀) and the half maximal effective concentration (EC₅₀) values were determined (via computer software) by nonlinear regression analysis of the competition curves using Hill equation curve fitting. The inhibition constants (K_i) were calculated using the Cheng–Prusoff equation (K_i = IC₅₀/(1+ (L/K_D)), where L is the concentration of radioligand in the assay, and K_D is the affinity of the radioligand for the receptor (Cheng et Prusoff 1973). Results The results obtained according to these binding assays are presented in Table 1. Table 1. Binding activity tested at 10^-5 M on OX1R and OX2R as agonist for these selected nitro- or amino-dihydro-quinazoline, nitro- or amino-dihydro-benzothiazine and nitro- or amino-dihydro-benzoxazine derivatives

Results showing an inhibition (or stimulation) between 25% and 50% are indicative of weak to moderate effects. Results showing an inhibition (or stimulation) lower than 25% are not considered significant and mostly attributable to variability of the signal around the control level. Results showing an inhibition (or stimulation for assays run in basal conditions) higher than 50% are considered to represent significant effects of the test compounds. Low to moderate negative values have no real meaning and are attributable to variability of the signal around the control level. High negative values (≥ 50%) that are sometimes obtained with high concentrations of test compounds are generally attributable to nonspecific effects of the test compounds in the assays. On rare occasion they could suggest an allosteric effect of the test compound. Table 2. Pharmacological activity on OX1R and OX2R as agonist for these selected dihydro-quinazoline, dihydro-benzothiazine and dihydro-benzoxazine derivatives

*: Compounds for which the absence of mutagenicity has been demonstrated by the in vitro micronucleus assay according to the OECD guideline N°487 4.2. Binding activities on dopamine and norepinephrine transporters, metabotropic glutamate 2, cathepsin-H and sigma-1 receptors It has been reported for a long time ago that norepinephrine cells of the locus coeruleus (Hagan et al.1999; Horvath et al.1999) and dopaminergic cells of the Ventral tegmental area (Nakamura et al.2000) all show to increase their firing rates by orexins. The firing rates of these monoaminergic neurons are well known to be associated with sleep/wakefulness states. They fire tonically during awake period, less during NREM sleep, and cease firing during REM sleep (Vanni-Mercier, Sakai, et Jouvet 1984), displaying similar firing patterns with orexin neurons. Previous studies have suggested that firing of these wake-active monoaminergic neurons mediated arousal was supported by orexins. More recently, a prominent role of orexin-to-dopamine circuits mediated by OX2R in the regulation of theta oscillations across vigilance states has been reported (Bandarabadi et al. 2022). In addition to orexin ability to regulate firing rate and induce burst firing though activation of receptors on the somato-dendritic compartment, OX2R could act pre- synaptically at the level of both dopaminergic and glutamatergic axons (Bandarabadi et al. 2022). Product 152 at 10^-5 M significantly targets on OX2R as agonist (IC 73%) and on OX1R as agonist (IC 63%) in addition acting on metabotropic glutamate 2 (mGlu2) receptors which target for the treatment of psychiatric disorders including schizophrenia, depression, and anxiety, which are characterized by a glutamatergic dysfunction with a significantly binding effect (IC 54%). Using a sleep–wake electroencephalogram model in rat to study the central functional activity and target engagement following inactivation of the mGluR₂ signaling, it is demonstrated that mGluR₂ antagonism activity is associated with enhanced theta/gamma oscillations and increased transitions from sleep to waking state (Ahnaou, Ver Donck, et Drinkenburg 2014). Product 194 at 10^-5 M significantly targets on OX2R as agonist (IC 84%) and weakly on OX1R as agonist (IC<50%), acting on dopamine transporter (DAT) and norepinephrine transporter (NET) as a catecholaminergic reuptake inhibitor, with a binding effect on DAT (IC 89%) and NET (IC 58%). Therapeutic approaches targeting cathepsins can contribute to prevent or slow down the pathogenesis of neurodegenerative diseases as seen for neuronal ceroid lipofuscinosis, synucleinopathies (Parkinson's disease, Dementia with Lewy Body and Multiple System Atrophy) as well as Alzheimer's and Huntington's disease (Stoka et al. 2023). Cathepsin H (CTSH) is a lysosomal cysteine protease that plays a role in various physiological processes, including the immune response. In the context of neuroinflammation, CTSH has been implicated in modulating immune reactions within the central nervous system (Wang et al. 2023). Neuroinflammation refers to the inflammatory response in the nervous tissue, often involving glial cell activation and the release of pro-inflammatory molecules. CTSH can influence neuroinflammation by participating in the processing and presentation of antigens, which is crucial for the activation of immune cells such as microglia. Previous studies had also suggested a potential involvement of CTSH in the pathogenesis of narcolepsy (Mogavero et al. 2023). Product 96 at 10^-5 M targets on OX1R as agonist (IC 56%) and moreover on CTSH as antagonist (IC 80%), also acting on dopamine transporter (DAT) and norepinephrine transporter (NET) as a catecholaminergic reuptake inhibitor, with a binding effect on DAT (IC 99%) and NET (IC 77%). Sigma-1 receptor (S1R) participating in various physiological and pathological processes, such as neurotransmission, neuroprotection and neuroinflammation is considered as a therapeutic target for a range of neurodegenerative diseases, including amnesia and AD and also various synucleinopathies (Wang et Jia 2023). S1R agonists find to have multiple mechanisms of action that could be beneficial in AD, such as anti-inflammatory and antioxidant effects, modulation of neurotransmitters, and a neuroprotective effect by inhibiting Aβ aggregation and tau hyperphosphorylation is AD (Cummings, Osse, et Kinney 2023; Malar et al. 2023; Shinoda, Nemoto, et Iwamoto 2023). Product 90 at 10^-5 M targets on OX2R as agonist (IC 67%) and on S1R as antagonist (IC 75%).

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Claims

Claims Claim 1. A compound of formula (I):

wherein: - X represents –NH-, –S- or –O-; - Y and R₂, independently of each other represents a hydrogen atom, a halogen atom, –NO₂ or –NH₂; - R₁, R₃, R₄ each represent, independently of each other, a hydrogen atom or a halogen atom; - R₅, R₆, R₇, R₈, R₉ each represent, independently of each other, a hydrogen atom, a halogen atom, –OR₁₀ or a (C₁–C₃₀)alkyl chain, especially (C₁–C₂₀)alkyl, optionally broken up and/or followed and/or preceded by one or more moieties chosen from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclic, –C≡C–, – C(R₁₁)=C(R₁₂)–, -O-, –S–, –NR₁₃–, –C(O)–, –C(S)–, –C=N–, –N=C–, –OC(O)–, –C(O)O–, –SC(O)–, –C(O)S–, –N(R₁₄)C(O)– and –C(O)N(R₁₅)– groups, the aryl, heteroaryl and heterocyclic rings being optionally substituted; - R10 represents a hydrogen atom or a (C₁–C₃₀)alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl group, the aryl, heteroaryl and heterocyclic rings being optionally substituted; - R₁₁ and R₁₂ represent, independently of each other, a hydrogen atom or a (C₁–C₆)alkyl group; and - R₁₃ to R₁₅ represent, independently of each other, a hydrogen atom or a (C₁–C₆)alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl group, and preferably a hydrogen atom or a (C₁–C₆)alkyl or aryl group, and still more preferably a hydrogen atom or a (C₁–C₆)alkyl group, or a pharmaceutically acceptable salt thereof, a tautomer, a stereoisomer or mixture of stereoisomers thereof, for use in the prevention and/or treatment of neurological diseases, preferably associated with psychiatric and/or sleep disorders and diseases, advantageously in which central orexin neurotransmission is compromised or in which central and peripheral orexin receptors are involved.

Claim 2. The compound of formula (I) for use according to claim 1, characterized in that: - Y represents a halogen atom, –NO2 or –NH2, preferably –NO2 or –NH2, and R2 represents a hydrogen atom or a halogen atom, preferably a hydrogen atom, or - R₂ represents a halogen atom, –NO₂ or –NH₂, preferably –NO₂ or –NH₂, and Y represents a hydrogen atom or a halogen atom, preferably a hydrogen atom.

Claim 3. The compound of formula (I) for use according to claim 1 or 2, characterized in that R1, R2, R3, R4 each represent a hydrogen atom or R1, R3, R4, Y each represent a hydrogen atom.

Claim 4. The compound of formula (I) for use according to any one of claims 1 to 3, characterized in that R₅, R₆, R₇, R₈, R₉ each represent, independently of each other, a hydrogen atom, a halogen atom, –OR₁₀ or a (C₁–C₂₀)alkyl, optionally broken up and/or preceded by one or more moieties chosen from the group consisting of aryl, heteroaryl, cycloalkyl, heterocyclic, –C≡C–, –C(R₁₁)=C(R₁₂)–,-O-, –S–, –NR₁₃–, –C(O)–, –OC(O)–, –C(O)O–, – N(R₁₄)C(O)– and –C(O)N(R₁₅)– groups, the aryl, heteroaryl and heterocyclic rings being optionally substituted.

Claim 5. The compound of formula (I) for use according to any one of claims 1 to 4, characterized in that R5, R6, R7, R8, R9, each represent, independently of each other, a hydrogen atom or –OR₁₀.

Claim 6. The compound of formula (I) for use according to any one of claims 1 to 5, characterized in that at least four residues out of R₅, R₆, R₇, R₈ and R₉ each represent a hydrogen atom.

Claim 7. The compound of formula (I) for use according to claim 6, characterized in that R₅, R₆, R₇, R₈, R₉, each represent, a hydrogen atom.

Claim 8. The compound of formula (I) for use according to claim 6, characterized in that R₅, R₆ or R₇ represents –OR₁₀ with R₁₀ representing a hydrogen atom, a (C₁–C₃₀)alkyl or phenyl group, preferably a (C₁–C₂₀)alkyl or a phenyl group.

Claim 9. The compound of formula (I) for use according to any one of claims 1 to 8, characterized in that it is selected from the group consisting of: 5

5

5

and mixtures thereof, ⁵

5

and mixtures thereof. Claim 10. The compound of formula (I) for use according to any one of claims 1 to 9, characterized in that the neurological diseases are selected from the group consisting of narcolepsy type 1, narcolepsy type 2, idiopathic hypersomnia, recurrent hypersomnia,

10 attention-deficit hyperactivity disorder, anxiety and mood disorders, Alzheimer's disease or any other neurodegenerative disorders or cognitive impairment and tauopathies, Parkinson's disease and other synucleinopathies, Guillain-Barre syndrome, chronic fatigue syndrome, long COVID-19 and medical or health conditions associated with circadian rhythmicity as well as mental and physical disorders associated with travel across time zones and with rotating 15 shift-work schedules, restless legs syndrome, fibromyalgia, cardiac failure, diseases related to bone loss, sepsis, syndromes which are manifested by unrefreshing sleep and muscle pain, sleep apnea which is associated with respiratory disturbances during sleep; conditions which result from a diminished quality of sleep.

Claim 11. The compound of formula (I) for use according to any one of claims 1 to 10, characterized in that the neurological diseases are selected from the group consisting of narcolepsy type 1 (NT1 ), narcolepsy type 2 (NT2), hypersomnia, idiopathic hypersomnia, recurrent hypersomnia, Kleine-Levin syndrome, hypersomnia associated with a psychiatric disorder, hypersomnia due to a medical disorder, hypersomnia due to a medication or substance, Parkinson's disease and other synucleinopathies, preferably narcolepsy type 1 (NT1 ), narcolepsy type 2 (NT2) and Parkinson's disease.

Claim 12. A pharmaceutical composition comprising at least one compound of formula (I) as defined in any one of claims 1 to 11 and a pharmaceutically acceptable carrier for use in the prevention and/or treatment of neurological diseases, preferably associated with psychiatric and/or sleep disorders and diseases, advantageously in which central orexin neurotransmission is compromised or in which central and peripheral orexin receptors are involved.

Claim 13. A pharmaceutical composition comprising at least one compound of formula (I) as defined in any one of claims 1 to 11 and a pharmaceutically acceptable carrier for use in the prevention and/or treatment of narcolepsy type 1 (NT1), narcolepsy type 2 (NT2), hypersomnia, idiopathic hypersomnia, recurrent hypersomnia, Kleine-Levin syndrome, hypersomnia associated with a psychiatric disorder, hypersomnia due to a medical disorder, hypersomnia due to a medication or substance, Parkinson's disease and other synucleinopathies, preferably narcolepsy type 1 (NT1), narcolepsy type 2 (NT2) and Parkinson's disease.

Claim 14. The pharmaceutical composition for use according to claim 12 or 13, comprising between 0.5 mg to 800 mg, preferably between 20 mg to 400 mg of the compound of formula (I).

Claim 15. The pharmaceutical composition for use according to any one of claims 12 to 14, which is suitable for oral or parenteral administration, preferably in the form of a solution, such as an injectable solution, a tablet, a capsule or a transdermal delivery system.