Dihydroquinazoline, dihydrobenzothiazine and dihydrobenzoxazine derivatives and their use as orexin receptor agonists for treatment or prophylaxis of nervous system diseases

Abstract

The present invention relates to dihydroquinazoline, dihydrobenzothiazine and dihydrobenzoxazine derivatives for use in the prevention or treatment of neurological, psychiatric, sleep disorders and diseases, advantageously in which central orexin neurotransmission is impaired or in which central and peripheral orexin receptors are involved. The invention also relates to pharmaceutical compositions comprising these compounds, their use for the prevention and / or treatment of nervous system disorders and diseases. The invention also relates to dihydroquinazoline, dihydrobenzothiazine and dihydrobenzoxazine derivatives, and to the use of these compounds as medicaments.

Description

Technical Field

[0001] This invention relates to dihydroquinazoline, dihydrobenzothiazide, and dihydrobenzoxazine derivatives for the prevention or treatment of neurological, psychiatric, and sleep disorders and diseases, advantageously wherein central orexin neurotransmission is impaired or wherein central and peripheral orexin receptors are involved. The invention also relates to pharmaceutical compositions comprising these compounds for the prevention and / or treatment of neurological symptoms and diseases. Furthermore, the invention relates to dihydrobenzothiazide and dihydrobenzoxazine derivatives, and the use of these compounds as pharmaceuticals. Background Technology

[0002] Orexin 1 and 2 (OX1 and OX2, also known as hypothalamic secretins 1 and 2 or orexin A and B) are hypothalamic neuropeptides produced specifically in the lateral hypothalamus (Sakurai et al. 1998). Orexin acts on two G protein-coupled receptors (GPCRs), namely the orexin 1 receptor (OX1R) and the orexin 2 receptor (OX2R), and is involved in a variety of physiological functions, such as sleep / wake cycle (Gao et al. 2021; de Lecea et al. 1998; Lin et al. 1999; Ohno and Sakurai 2008), feeding behavior (Sakurai et al. 1998), reward seeking (Cason et al. 2010; Harris, Wimmer, and Aston-Jones 2005), and stress response (Johnson et al. 2010). More specifically, OX1R is primarily involved in motivation and reward, while OX2R is primarily involved in regulating the sleep / wake cycle and energy homeostasis (Perrey and Zhang 2020).

[0003] In genetic studies of mice, a lack of orexin function leads to narcolepsy symptoms characterized by excessive daytime sleepiness and cataplexy (Lin et al. 1999; Willie et al. 2003), and intraventricular administration of orexin can alleviate narcolepsy symptoms (Mieda 2017). Furthermore, OX1R knockout mice did not exhibit a significant sleep / wake-related phenotype, but OX2R knockout mice exhibited a severe narcolepsy phenotype, suggesting that OX2R-mediated signaling is sufficient to prevent narcolepsy / cataplexy symptoms (Mieda et al. 2011; Saito et al. 2018).

[0004] In the past decade, numerous 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 few orexin agonists have been developed with the potential to treat a variety of diseases (Nollet and Leman 2013; Song et al. 2015), including obesity, attention deficit hyperactivity disorder (ADHD) (Baimel et al. 2015; Cortese, Konofal, and Lecendreux 2008; Heifetz et al. 2013), neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease) (Gao et al. 2021; Katsuki and Michinaga 2012), and most importantly, type 1 and type 2 narcolepsy (Fujimoto et al. 2022; Mezeiova et al. 2020; Yukitake et al. 2019; Zhang et al. 2021).

[0005] The role of OX1Rs in sleep regulation has been investigated in animal models using orexin antagonists. SB-334867 (an experimental selective OX1R antagonist) has been reported to reverse intraventricular injection of orexin-A-induced REM sleep inhibition (Smith et al. 2003), and more importantly, to induce REM sleep and, when administered alone, non-REM sleep (Morairty et al. 2012).

[0006] Unlike OX1R antagonists, OX1R agonists are hypothesized to have a potential therapeutic role in REM sleep behavior disorder (RBD) due to the interaction between α-synuclein and OX1R in pathogenesis. OX1R dysfunction can induce RBD and is an early sign of Parkinson's disease (PD), but the pathogenesis of RBD remains unclear. In contrast, α-synuclein has been shown to form Lewy bodies in orexin neurons, the activity and function of which depend on orexin receptor 1 (OX1R) (Fan et al. 2023).

[0007] OX1R agonists may be an effective strategy to slow down or stop the neurodegenerative process of PD and to treat RBD.

[0008] The loss of orexinergic neurons in the brain is associated with the etiology of type 1 narcolepsy (NT1), which is characterized by excessive daytime sleepiness, cataplexy, hypnagogic / hypnotic hallucinations, sleep paralysis, and nocturnal sleep disturbances (Cao and Guilleminault 2017; Siegel 1999; Thorpy 2020).

[0009] Cerebrospinal fluid (CSF) orexin-1 levels can predict narcolepsy (abnormal levels were found in 89.5% of the overall patient population and 94.7% of HLADQBI*0602 positive cases) (Kanbayashi et al. 2002; Nishino 2007).

[0010] In NT1, low or absent CSF hypocretin levels serve as a specific biomarker for type 2 narcolepsy (NT2) or other central narcolepsy or narcolepsy variants (i.e., idiopathic narcolepsy or secondary or recurrent narcolepsy associated with mental illness) in which such a specific biomarker is currently absent (Zhang et al. 2018).

[0011] Since this discovery, orexin agonists have attracted attention in the development of potential treatments for narcolepsy. In 2008, the first series of selective OX2R agonists were patented, which facilitated the discovery of several compounds, but all of these compounds function only as OX2R agonists (Bogen et al. 2021; Fujimoto et al. 2022; Yanagisawa 2012; Yukitake et al. 2019; Zhang et al. 2021).

[0012] However, these compounds are considered unsatisfactory in terms of, for example, activity, pharmacokinetics, permeability to the brain / central nervous system, or safety, and there is a need to develop improved compounds with OX2R agonist activity.

[0013] Suntinorexton, firazorexton, and danavorexton are selective OX2Rs being developed by Takeda Pharmaceutical for the treatment of narcolepsy. TAK-994 and TAK-861 are active compounds, acting as highly selective OX2R agonists. TAK-994 exhibits >700-fold selectivity for OX1Rs. Similar to danavorexton (TAK-925), it entered a Phase 2 clinical trial for narcolepsy. However, clinical development was halted in 2021 for safety reasons (Dauvilliers et al. 2023; Ishikawa et al. 2023). TAK-994 is the first developed oral selective OX2R agonist.

[0014] Recently, WO2021107023 reported cycloalkylurea compounds that target OX2R as agonists, but these compounds failed to target both OX1R and OX2R simultaneously.

[0015] International patent application WO2022140317 relates to substituted piperidinyl compounds, particularly substituted piperidinyl compounds with agonist activity, again targeting only OX2R.

[0016] Parkinson's disease (PD) is the second most common chronic neurodegenerative disease, characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (Hornykiewicz and Kish 1987). The prevalence of PD in people over 55 years of age is approximately 1%. The main symptoms of PD include resting tremor, bradykinesia, muscle rigidity, and postural instability, and are often accompanied by cognitive impairment, psychiatric disturbances, and other nonmotor symptoms (Beitz 2014; Meerwaldt and Hovestadt 1988). The etiology of PD is not fully understood, but several factors, including gene mutations, oxidative stress, mitochondrial dysfunction, neurotransmitter toxicity, and protein homeostasis imbalance, appear to be involved in its development. The most common treatment for PD is symptomatic therapy.

[0017] Levodopa, a dopamine precursor, is the most widely used drug in clinical practice (Hornykiewicz 1975). However, it can only relieve symptoms and cannot prevent the progressive degeneration of dopaminergic neurons in the substantia nigra. In recent years, much effort has been devoted to finding endogenous neuroprotective mediators to prevent or reverse the degenerative changes in dopaminergic neurons in the substantia nigra.

[0018] Orexin receptors are located in multiple brain structures, such as the cerebral cortex, hippocampus, amygdala, thalamus, hypothalamus, and basal ganglia (Hervieu et al. 2001; Hu et al. 2015). Orexin is known to play important roles in regulating sleep, feeding behavior, energy homeostasis, neuroendocrine function, and autonomic nervous system control, and the activity of the orexin system decreases with age, which is associated with a variety of neurodegenerative diseases (Liu et al. 2018).

[0019] Furthermore, the orexin system plays a crucial role in motor control (Berhe, Gebre, and Assefa 2020; Hu et al. 2015; Song et al. 2015; Q. Wang, Cao, and Wu 2021). Most central motor control structures are innervated by orexin fibers (Hu et al. 2015; Liu et al. 2018). More importantly, all basal ganglia nuclei, including the globus pallidus, subthalamic nucleus, substantia nigra, and striatum, are innervated by orexin fibers (Alrouji et al. 2023; Liu et al. 2018).

[0020] Over the past two decades, increasing research has shown that the orexin system is closely related to Parkinson's disease (PD) (Katsuki and Michinaga 2012; Yasui et al. 2006). There have been reports of significant loss of orexinergic neurons in autopsies of Parkinson's patients (Fronczek et al. 2007; Thannickal, Lai, and Siegel 2007).

[0021] Experiments using a 6-hydroxydopamine (6-OHDA)-induced PD rat model showed a significant reduction in the number of orexinergic neurons in the lateral hypothalamus (Long-Biao et al. 2010), and this loss of orexinergic neurons in this PD animal model appeared similar to the process in Parkinson's disease patients. Furthermore, in Parkinson's disease patients, plasma and cerebrospinal fluid orexin levels are dramatically decreased (Drouot et al. 2003; Fronczek et al. 2007). These reports suggest an important role for the orexin system in PD.

[0022] Other studies have shown that orexin-A has neuroprotective effects in cellular models of PD. Orexin-A protects SH-SY5Y cells from toxicity induced by 6-OHDA (Esmaeili-Mahani et al. 2013; Pasban-Aliabadi, Esmaeili-Mahani, and Abbasnejad 2017) or MPPC (Feng et al. 2014; Liu et al. 2018).

[0023] Finally, the exact role of orexin-A in animal models of PD, and the protective mechanism of orexin-A on dopaminergic neurons in the substantia nigra, appears to have been confirmed using MPTP mice with Parkinson's disease (Liu et al. 2018). In this animal model, orexin-A exerted a neuroprotective effect, which may mean that orexin-A is a potential therapeutic target for PD, and that OX1R agonists are potential therapeutic targets for PD.

[0024] Another role of orexin has also been recognized, namely, its involvement in immune responses and neuroinflammation (Duffy et al. 2019; Polito et al. 2018), suggesting that orexin-A can act as an immunomodulator of microglia and reduce hypothalamic neuronal death in inflammatory states.

[0025] Furthermore, orexin-A exerts a protective effect by reducing neuroinflammation in AD and cerebral ischemia (Couvineau and Laburthe 2012; Xiong et al. 2013). Therefore, the anti-inflammatory properties of orexin may also be related to its neuroprotective effect in PD. It has also been shown that orexin has potential therapeutic effects on both motor and nonmotor disorders in animal models of PD.

[0026] Intraventricular administration of orexin-A improved sensorimotor dysfunction in a 6-OHDA-treated PD rat model (Hadadianpour et al. 2017). Similar results were observed in an MPTP-induced PD mouse model. Orexin-A administration to the ventricles improved motor performance in pole climbing and open field tests by reducing the loss of dopaminergic neurons and fibers (Liu et al. 2018). Intraglottis administration of orexin-A and orexin-B also alleviated motor dysfunction in MPTP-treated Parkinson's disease mice (Ying Wang et al. 2019). Furthermore, chemogenetic activation of orexinergic neurons reversed abnormal motor activity in A53T mice during the preclinical phase (Stanojlovic, Pallais, and Kotz 2019). In addition, cognitive impairment, a common non-motor disorder in PD, can also be improved with orexin. Administering orexin-A to CA1 or chemically activating orexinergic neurons can increase the firing activity of CA1 neurons (Chen, Chen, and Du 2017) and improve hippocampus-dependent memory impairment in an A53T mouse model of PD (Stanojlovic, Pallais, and Kotz 2019).

[0027] Furthermore, chemogenetic activation of orexinergic neurons improved social skills and social memory impairments observed in A53T Parkinson's disease mice (Stanojlovic et al., 2019). Additionally, chemogenetic activation of orexinergic neurons in five-month-old A53T mice restored the reduction in anxiety-like behaviors observed in early PD (Stanojlovic, Pallais, and Kotz, 2019). The therapeutic effect of orexin on motor disorders in PD may be related to the recovery of dopaminergic neurons and the excitatory effect of orexin on globus pallidus neurons (Liu et al., 2018; Wang et al., 2019). However, the therapeutic mechanism of orexin on non-motor disorders is not yet fully understood. Summary of the Invention

[0028] The first subject of this invention relates to a compound of formula (II):

[0029]

[0030] in:

[0031] -X represents -NH-, -S-, or -O-, with -NH- or -S- being preferred;

[0032] -Y and R2 can each independently represent a hydrogen atom, a halogen atom, -NO2, or -NH2;

[0033] -R1, R3, and R4 each independently represent a hydrogen atom or a halogen atom;

[0034] -R5, R6, R7, R8, and R9 each independently represent a hydrogen atom, a halogen atom, and -OR. 10 or (C1-C) 30 )alkyl chains, especially (C1-C 20 An alkyl group, optionally interrupted by one or more moieties and / or followed by one or more moieties and / or preceded by one or more moieties, said moieties being selected from aryl, heteroaryl, cycloalkyl, heterocyclic, -C≡C-, -C(R) 11 )=C(R 12 -, -O-, -S-, -NR 13 -, -C(O)-, -C(S)-, -C=N-, -N=C-, -OC(O)-, -C(O)O-, -SC(O)-, -C(O)S-, -N(R 14 -C(O)- and -C(O)N(R) 15 )-group, wherein the aryl, heteroaryl and heterocyclic rings are optionally substituted;

[0035] -R 10 Represents a hydrogen atom or (C1-C) 30 Alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl, wherein the aryl, heteroaryl and heterocyclic rings are optionally substituted;

[0036] -R 11 and R 12 Each independently represents a hydrogen atom or a (C1-C6) alkyl group; and

[0037] -R 13 To R 15 Each of these groups independently represents a hydrogen atom or a (C1-C6) alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or acyl group, preferably a hydrogen atom or a (C1-C6) alkyl or aryl group, more preferably a hydrogen atom or a (C1-C6) alkyl group.

[0038] Or a pharmaceutically acceptable salt thereof, its tautomers, stereoisomers, or mixtures thereof.

[0039] The condition is that the compound of formula (II) is not

[0040] Furthermore, the condition is that when X represents O, each of R1, R2, R3, and R4 represents H, Y represents a halogen atom, and four of R5, R6, R7, R8, and R9 represent H, then the remaining groups in R5, R6, R7, R8, and R9 are not (C1-C2).30 ) alkyl chain, the (C1-C 30 The alkyl chain is preceded by -O- and broken by -O-, or by -C(R) 11 )=C(R 12 - Interrupt, followed by -C(R) 11 )=C(R 12 - and / or preceded by -C(R) 11 )=C(R 12 )-.

[0041] The present invention also relates to a pharmaceutical composition comprising a compound of formula (II) as described above.

[0042] The present invention also relates to the use of compounds of formula (II) as described above as pharmaceuticals. Detailed Implementation

[0043] The first subject of this invention relates to a compound of formula (I):

[0044]

[0045] in:

[0046] -X represents -NH-, -S-, or -O-;

[0047] -Y and R2 can each independently represent a hydrogen atom, a halogen atom, -NO2, or -NH2;

[0048] -R1, R3, and R4 each independently represent a hydrogen atom or a halogen atom;

[0049] -R5, R6, R7, R8, and R9 each independently represent a hydrogen atom, a halogen atom, and -OR. 10 or (C1-C) 30 )alkyl chains, especially (C1-C 20 An alkyl group, optionally interrupted by one or more moieties and / or followed by one or more moieties and / or preceded by one or more moieties, said moieties being selected from aryl, heteroaryl, cycloalkyl, heterocyclic, -C≡C-, -C(R) 11 )=C(R 12 -, -O-, -S-, -NR 13 -, -C(O)-, -C(S)-, -C=N-, -N=C-, -OC(O)-, -C(O)O-, -SC(O)-, -C(O)S-, -N(R 14 -C(O)- and -C(O)N(R) 15 )-group, wherein the aryl, heteroaryl and heterocyclic rings are optionally substituted;

[0050] -R 10Represents a hydrogen atom or (C1-C) 30 Alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl, wherein the aryl, heteroaryl and heterocyclic rings are optionally substituted;

[0051] -R 11 and R 12 Each independently represents a hydrogen atom or a (C1-C6) alkyl group; and

[0052] -R 13 To R 15 Each of these groups independently represents a hydrogen atom or a (C1-C6) alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or acyl group, preferably a hydrogen atom or a (C1-C6) alkyl or aryl group, more preferably a hydrogen atom or a (C1-C6) alkyl group.

[0053] Or a pharmaceutically acceptable salt thereof, its tautomers, stereoisomers or mixtures thereof, for the prevention and / or treatment of neurological disorders, preferably neurological disorders related to mental illness and / or sleep disorders and diseases (e.g., narcolepsy), advantageously in which central orexin neurotransmission is impaired or in which neurological disorders involve central and peripheral orexin receptors.

[0054] definition

[0055] In this invention, "halogen atom" refers to fluorine, chlorine, bromine and iodine atoms.

[0056] In this invention, "alkyl" refers to a saturated, straight-chain or branched hydrocarbon chain.

[0057] In this invention, "(C1-C x "(C1-C6)alkyl" refers to an alkyl group containing 1 to X carbon atoms as defined above. For example, "(C1-C6)alkyl" refers to an alkyl group containing 1 to 6 carbon atoms as defined above, such as methyl, ethyl, isopropyl, tert-butyl, pentyl, etc.

[0058] In this invention, "aryl" refers to an aromatic group, especially a hydrocarbon group, which contains 6 to 20 carbon atoms, preferably 6 to 10 carbon atoms, and comprises one or more fused rings, such as phenyl or naphthyl. Advantageously, it is phenyl.

[0059] In this invention, "heteroaryl" refers to an aromatic group comprising one or more fused rings and containing 5 to 10 ring atoms, wherein the ring atoms include one or more heteroatoms, advantageously 1 to 4, or even more advantageously 1 or 2, such as sulfur, nitrogen, oxygen, phosphorus, or selenium atoms, preferably sulfur, nitrogen, or oxygen, and the remaining ring atoms are carbon atoms. Examples of heteroaryl groups include furanyl, thiophene, pyrrole, pyridinyl, pyrimidinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, indolyl, or selenylphenyl.

[0060] In this invention, "acyl" refers to a group of the formula -CO-R, wherein R represents (C1-C6) alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, preferably (C1-C6) alkyl or aryl, more preferably (C1-C6) alkyl.

[0061] In this invention, "cycloalkyl" refers to a saturated monocyclic or polycyclic hydrocarbon chain (especially a bicyclic or tricyclic chain). When it is a polycyclic group, the rings can be fused, bridged, or linked two at a time via spirocyclic linkages. Examples include cyclopropyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0062] In this invention, "heterocyclic group" refers to a non-aromatic, saturated or unsaturated, monocyclic or polycyclic group (including fused rings, bridged rings, or spirocyclic rings) in which one or more ring carbon atoms are each substituted by a heteroatom. Specifically, the term refers to a 5- to 10-membered saturated or unsaturated, but non-aromatic ring containing one or more, advantageously 1 to 4, more advantageously 1 or 2 heteroatoms, such as sulfur, nitrogen, or oxygen atoms. It may particularly be pyrrolidinyl, piperidinyl, piperazineyl, or morpholinyl.

[0063] When aryl, heteroaryl, and heterocyclic groups are substituted, they can be replaced by one or more groups selected from halogen atoms, (C1-C6)alkyl, aryl, -NO2, -CN, and -OR. 19 -SR 20 -NR 16 R 17 -B(OH)2, -SO3R 17 and -COOR 18 Specifically selected from halogen atoms, -NO2, -CN, -OR 19 -SR 20 -NR 16 R 17 -B(OH)2, -SO3R 17 , where R 16 To R 20 Each can be used independently to represent a hydrogen atom or a (C1-C6) alkyl group.

[0064] In this invention, "pharmaceutically acceptable" means a substance used to prepare a pharmaceutical composition that is generally safe, non-toxic, and has no biological or other adverse effects, and is acceptable for veterinary and human pharmaceutical use.

[0065] A "pharmacologically acceptable salt" of a compound is a pharmaceutically acceptable salt, as defined herein, that possesses the desired pharmacological activity of the parent compound. Such salts include:

[0066] (1) Hydrates and solvates,

[0067] (2) Pharmaceutically acceptable acid addition salts formed with pharmaceutically acceptable inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.), or pharmaceutically acceptable acid addition salts formed with pharmaceutically acceptable organic acids (e.g., acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheponic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, mesylate, mucoconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, dibenzoyl-L-tartaric acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, trifluoroacetic acid, etc.), or

[0068] (3) Pharmaceutically acceptable base addition salts are formed by replacing the acidic protons in the parent compound with metal ions (e.g., alkali metal ions, alkaline earth metal ions, or aluminum ions) or by coordinating with pharmaceutically acceptable organic or inorganic bases. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucosamine, triethanolamine, tromethamine, etc. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, and sodium hydroxide.

[0069] Preferably, the compound according to the invention will be in the form of a pharmaceutically acceptable base addition salt, said base being, for example, NaOH or KOH, especially NaOH.

[0070] "Optically pure compound" refers to an enantiomeric excess of more than 95%, preferably more than 96%, more preferably more than 97%, even more preferably more than 98%, and particularly preferably more than 99%.

[0071] This invention also includes all pharmaceutically acceptable isotopic variants of Formula I compounds, wherein one or more atoms are replaced by atoms having the same atomic number but with an atomic mass or mass number different from those commonly found in nature. Such compounds are identical to those disclosed herein, but one or more atoms are replaced by atoms with an atomic mass or mass number different from those commonly found in nature. Examples of isotopes suitable for inclusion in compounds of this invention include isotopes of hydrogen, such as… 2 H and 3 H, an isotope of carbon, for example 11 C 13 C and 14 C, an isotope of nitrogen, for example 13 N and 15 N, an isotope of oxygen, for example 15 O、 17 O and 18 O, an isotope of sulfur, for example 35 S, an isotope of fluorine, for example 18 F, an isotope of iodine, for example 123 I and125 I, and isotopes of chlorine, such as 36 Cl. Certain isotopically labeled compounds of formula I, such as those doped with radioactive isotopes, can be used for studies of drug and / or substrate tissue distribution.

[0072] Subjects administering the compounds of the present invention or pharmaceutically acceptable salts thereof are typically mammals, such as humans, whether male or female. The amount of the compound administered to the subject is sufficient to stimulate the subject's orexin receptors. In one embodiment, the amount of the compound may be an "effective amount," wherein the amount of the test compound administered will elicit a biological or medical response in a tissue, system, animal, or human sought by an investigator, veterinarian, physician, or other clinician. An effective amount does not necessarily include toxicity and safety considerations associated with the administration of the compound. Those skilled in the art will recognize that treating subjects currently suffering from a disease, or providing preventative treatment to subjects who may suffer from a disease, with an effective amount of the compounds of the present invention can influence neurological and psychiatric disorders associated with orexin receptor activation. As used herein, the terms "treatment" and "management" refer to all processes that slow, interrupt, prevent, control, or stop the progression of the neurological and psychiatric disorders described herein, but do not necessarily imply the complete elimination of all disease symptoms, nor do they necessarily imply preventative treatment of the mentioned conditions, particularly for subjects susceptible to such diseases or conditions. The terms “administration” and / or “administering” should be understood as referring to the administration of the compound of the present invention to a subject or a prodrug of the compound of the present invention.

[0073] As used herein, the term "composition" is intended to cover products containing specific amounts of specific ingredients, and any products directly or indirectly produced by combining specific ingredients in specific amounts. The term is also intended to cover products containing an active ingredient and an inert ingredient constituting a carrier, and any products directly or indirectly produced by the combination, complexation, or aggregation of any two or more ingredients, or by the dissociation of one or more ingredients, or by other types of reactions or interactions of one or more ingredients.

[0074] Therefore, the compositions of the present invention cover any composition made by mixing the compounds of the present invention with a pharmaceutically acceptable carrier, i.e., the carrier, diluent or excipient must be compatible with other components in the formulation and harmless to its recipients.

[0075] Diseases and symptoms

[0076] Orexin receptors (OX1R and OX2R) are involved in a variety of biological functions. This suggests that these receptors may play a potential role in a variety of diseases in humans and other species. Therefore, the compounds of the present invention can be used to treat, prevent, improve, control, or reduce the risk of various diseases 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, narcolepsy syndrome with narcolepsy-like symptoms, cataplexy in narcolepsy, excessive daytime sleepiness (EDS) in narcolepsy, hypersomnia, idiopathic hypersomnia, recurrent hypersomnia, Kleine-Levin syndrome, hypersomnia associated with mental disorders, hypersomnia due to medical impairment, hypersomnia due to drugs or substances, sleep deprivation syndrome, and any of the eight different types of central hypersomnia (CDH) that meet the criteria of the International Classification of Sleep Disorders, Third Revision (ICSD-3) (American Academy of Sleep Medicine). Conditions of sleep apnea (2014) and / or conditions characterized by pathological daytime sleepiness and / or inappropriate states of wakefulness (whether or not caused by sleep apnea), nocturnal myoclonus, rapid eye movement (REM) sleep disruption, jet lag, shift work, sleep disturbances, insomnia, sleep disorders, sleep disturbances, narcolepsy associated with depression, mood / psychiatric disorders, Alzheimer's disease or neurodegenerative diseases or cognitive impairment and tau protein diseases, Parkinson's disease and other synucleinopathies, Guillain-Barré syndrome, chronic fatigue syndrome, long-term COVID-19 and medical or health conditions related to circadian rhythms and mental and physical illnesses associated with cross-time zone travel and shift work schedules, restless legs syndrome, fibromyalgia, heart failure, conditions associated with osteoporosis, sepsis, syndromes presenting as unrelieved sleep and muscle pain, sleep apnea associated with breathing disturbances during sleep; conditions resulting from decreased sleep quality and other conditions associated with general orexin system dysfunction.

[0077] In this invention, "neurological, mental, and sleep disorders and diseases" refers to mental and / or sleep-related neurological disorders and diseases, that is, neurological diseases related to sleep and / or mental disorders. In particular, it relates to disorders and diseases involving impaired central orexin neurotransmission or involving central and peripheral orexin receptors.

[0078] Therefore, in some embodiments, the present invention may provide a method for treating or controlling the following conditions in a subject: narcolepsy with or without cataplexy, narcolepsy type 1 (NT1), narcolepsy type 2 (NT2), Gelineau syndrome, narcolepsy syndrome with narcolepsy-like symptoms, cataplexy in narcolepsy, excessive daytime sleepiness (EDS) in narcolepsy, hypersomnia, idiopathic hypersomnia, recurrent hypersomnia, Klein-Levin syndrome, hypersomnia associated with mental disorders, hypersomnia due to medical impairment, hypersomnia due to drugs or substances, sleep deprivation syndrome, and any of the eight different types of central hypersomnia (CDH) that meet the criteria of the International Classification of Sleep Disorders, Third Revision (ICSD-3) (American Academy of Sleep Medicine). Conditions (as of 2014); pathological daytime sleepiness and / or inappropriate states of wakefulness (whether or not caused by sleep apnea), nocturnal myoclonus, REM sleep disruption, jet lag, shift work, sleep disturbances, insomnia, sleep disorders, sleep disturbances, narcolepsy associated with depression, mood / psychiatric disorders, Alzheimer's disease or cognitive impairment, Parkinson's disease, dementia, Guillain-Barré syndrome, chronic fatigue syndrome, prolonged COVID-19 and medical or health conditions related to circadian rhythms and mental and physical illnesses associated with cross-time zone travel and shift work schedules, restless legs syndrome, fibromyalgia, heart failure, conditions associated with osteoporosis, sepsis, syndromes presenting as unrelieved sleep and muscle pain, sleep apnea associated with breathing disturbances during sleep; conditions resulting from decreased sleep quality and dysfunction of the general orexin system. Other related diseases; sleep disorders associated with diseases such as neurological disorders (including neuropathic pain and restless legs syndrome), treatment or control of addiction disorders, treatment or control of the use and abuse of psychoactive substances, enhancing cognition, improving memory; diabetes and appetite, taste, eating or drinking disorders; insulin resistance syndrome; hypothalamic diseases; depression, including major depressive disorder and major depressive disorder; improving or reducing the risk of epilepsy, including absence epilepsy, seizures; pain, including neuropathic pain; Parkinson's disease, Lewy body dementia and synucleinopathies; Guillain-Barré syndrome; prolonged COVID-19; Klein-Levin syndrome; psychosis, dysphoric disorder, mood disorders, bipolar disorder, psychosis and anxiety disorders; side effects or complications caused by anesthetics and / or orexin antagonists, including administration of the compounds of the present invention to the subject.

[0079] Dihydroquinazoline, dihydrobenzothiazide, and benzoxazine derivatives, as compounds of the present invention, may also be used to treat, prevent, improve, control, or reduce the risk of various other conditions related to orexin receptors, including one or more of the following conditions or diseases: enhancing sleep quality, improving sleep efficiency, consolidating sleep maintenance, improving sleep initiation, reducing sleep latency or initiation, reducing difficulty falling asleep, increasing sleep continuity, reducing the number of awakenings during sleep, reducing intermittent awakenings during sleep, reducing nighttime awakenings, reducing wakefulness after first sleep onset, increasing total sleep volume, reducing sleep fragmentation, altering the time, frequency, or duration of sleep stages or the duration of slow-wave sleep and / or REM sleep, promoting slow-wave sleep, enhancing EEG-δ activity during sleep, reducing nighttime awakenings, especially early morning awakenings, and improving daytime sleep quality. Alertness; reducing daytime sleepiness; treating or reducing excessive daytime sleepiness; improving satisfaction with sleep intensity; improving sleep maintenance; idiopathic insomnia; sleep problems; insomnia; night terrors; insomnia associated with depression; mood / psychiatric disorders; Alzheimer's disease or neurodegenerative diseases or cognitive impairment; Parkinson's disease; dementia; Guillain-Barré syndrome; chronic fatigue syndrome; long-term COVID-19 and medical or health conditions related to circadian rhythms, as well as mental and physical illnesses associated with cross-time zone travel and shift work schedules; restless legs syndrome; fibromyalgia; heart failure; osteoporosis-related diseases; sepsis; syndromes characterized by unrelieved sleep and muscle pain; sleep apnea associated with breathing disorders during sleep; conditions resulting from decreased sleep quality; improving learning ability; enhancing memory; improving memory retention.Eating disorders associated with overeating and its complications, compulsive eating disorder, obesity (for any cause, whether genetic or environmental), obesity-related diseases such as binge eating, anorexia, bulimia, cachexia, appetite disorders, hypertension, diabetes, elevated plasma insulin levels and insulin resistance, dyslipidemia, hyperlipidemia, endometrial cancer, breast cancer, prostate cancer and colon cancer, osteoarthritis, obstructive sleep apnea, gallstones, heart disease, lung disease, abnormal heart rhythms and arrhythmias, myocardial infarction, congestive heart failure, coronary artery disease, acute and congestive heart failure, hypotension, hypertension, angina pectoris, infarction, ischemic or hemorrhagic stroke, subarachnoid hemorrhage, chronic renal failure. Kidney disease, impaired glucose tolerance, craniopharyngioma, Prader-Willi syndrome, Frohlich's syndrome, GH deficiency, Turner's syndrome, and other pathological conditions characterized by reduced metabolic activity or a reduced percentage of resting energy expenditure to total lipid deficiencies, such as children with acute lymphoblastic leukemia, metabolic syndrome (also known as syndrome X), insulin resistance syndrome, reproductive hormone abnormalities, sexual and reproductive dysfunctions such as impaired fertility, infertility, male hypogonadism and female hirsutism, fetal defects associated with maternal obesity, gastrointestinal motility disorders, intestinal motility disorders, obesity-related gastric... Esophageal reflux, hypothalamic diseases, pituitary diseases, respiratory diseases such as obesity-hypopnea syndrome (Pickwickian syndrome), Ondine's syndrome, and sleep-related disorders, in which there is abnormal coupling of activity, particularly through the thalamus; enhancing cognitive function, including cognitive impairments, which include all types of attention, learning, and memory deficits that are temporary or long-term in normal, healthy, youth, adult, or elderly populations, as well as all types of attention, learning, and memory deficits that are temporary or long-term in mental, neurological, cardiovascular, and immune diseases; treating or controlling Guillain-Barré syndrome, chronic fatigue syndrome, long-term COVID-19, and Medical or health conditions related to circadian rhythms; treatment or control of Klein-Levin syndrome; treatment or control of psychosis; treatment or control of dysphoric, mood, psychotic, and anxiety disorders; treatment of anesthetic complications; memory enhancement; improved memory retention; enhanced immune response; enhanced immune function; hot flashes; night sweats; life extension; schizophrenia; muscle-related disorders controlled by the excitation / relaxation rhythm imposed by the nervous system, such as heart rhythms and other cardiovascular disorders; disorders related to cell proliferation, such as vasodilation or vasoconstriction and blood pressure; cancer; arrhythmias; hypertension; congestive heart failure; reproductive / urinary system disorders; sexual dysfunction and infertility; renal integrity; responsiveness to anesthetics;Mood disorders, such as depression, or more specifically depressive disorders, such as single-episode or recurrent major depressive disorder and dysthymia disorder, or bipolar disorders, such as bipolar I, bipolar II, and cyclothymic disorder; mood disorders due to general medical conditions, 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 attacks, panic disorder, post-traumatic stress disorder, separation anxiety disorder, social phobia, specific phobias, substance-induced anxiety disorder, and anxiety disorder due to general medical conditions; acute neurological and psychiatric disorders, such as Brain dysfunction after coronary artery bypass surgery and transplantation; stroke; ischemic stroke; cerebral ischemia; spinal cord injury; head trauma; perinatal hypoxia; cardiac arrest; hypoglycemic neuronal damage; Huntington's disease; Huntington's disease and Tourette syndrome; Cushing's syndrome / disease; basophilic adenoma; prolactinoma; hyperprolactinemia; pituitary tumor / adenoma; hypothalamic disease; inflammatory bowel disease; gastric motility disorder; gastric ulcer; Froehlich's syndrome; adrenal-pituitary disease; pituitary disease; adrenal-pituitary hypofunction; adrenal-pituitary hyperfunction; hypothalamic hypogonadism; Kallmann syndrome; Man's syndrome (loss of smell, hyposmegma); functional or psychogenic amenorrhea; hypopituitarism; hypothalamic hypothyroidism; hypothalamic-adrenal dysfunction; idiopathic hyperprolactinemia; hypothalamic growth hormone deficiency; idiopathic growth defects; dwarfism; gigantism; acromegaly; amyotrophic lateral sclerosis; multiple sclerosis; eye injury; retinopathy; cognitive impairment; idiopathic and drug-induced Parkinson's disease; muscle spasms and related disorders, including tremor, epilepsy, convulsions, seizures, absence seizures, complex partial and generalized epilepsy; Lennox-Gastaut syndrome; cognitive impairment. This includes dementia (associated with Alzheimer's disease, ischemia, trauma, vascular problems or stroke, HIV, Parkinson's disease, Lewy body dementia, Huntington's disease, Pick's disease, Creutzfeldt-Jacob's disease, perinatal hypoxia, other general illnesses or substance abuse); delirium, amnesia or age-related cognitive decline; schizophrenia or psychosis, including schizophrenia (paranoid, disorganized, catatonic or undifferentiated), schizophrenia-like disorders, schizoaffective disorder, paranoia, transient psychosis, shared psychosis, psychosis due to general illness and substance-induced psychosis; dissociative disorders, including multiple personality syndrome and psychogenic amnesia;Substance-related disorders, substance use, substance abuse, substance seeking, substance relapse, all types of psychological and physical addiction and addictive behaviors, reward-related behaviors (including substance-induced delirium, persistent dementia, persistent amnesia, psychosis or anxiety disorders); tolerance, addictive eating, addictive eating behaviors, binge eating / purging feeding behaviors, substance dependence, substance withdrawal or relapse, the substances mentioned include alcohol, amphetamines, cannabis, cocaine, heroin, morphine, nicotine, opioids, phencyclidine, sedatives, hypnotics or anxiolytics); appetite, taste, eating or drinking disorders; movement disorders, including akinesia and akinesia-rigid syndrome (including Parkinson's disease, Drug-induced Parkinson's disease, post-encephalitis Parkinson's disease, progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration, Parkinson's disease-ALS dementia syndrome, and basal ganglia calcification; chronic fatigue syndrome; fatigue, including Parkinsonian fatigue, multiple sclerosis fatigue, fatigue caused by sleep disorders or circadian rhythm disturbances; drug-induced Parkinson's disease (e.g., antipsychotic drug-induced Parkinson's disease, antipsychotic drug-induced malignant syndrome, antipsychotic drug-induced acute dystonia, antipsychotic drug-induced acute akathisia, antipsychotic drug-induced tardive dyskinesia, and drug-induced postural tremor); Gilles de la Tourette. La Tourette's syndrome, epilepsy, and movement disorders, including tremors (e.g., resting tremor, essential tremor, postural tremor, and intention tremor), chorea (e.g., Seadenham's chorea, Huntington's disease, benign hereditary chorea, neuroacanthosis, symptomatic chorea, drug-induced chorea, and hemispheric throwing disorder), myoclonus (including generalized myoclonus and focal myoclonus), tics (including simple tics, complex tics, and symptomatic tics), restless legs syndrome, and dystonia (including generalized dystonia, such as idiopathic dystonia, drug-induced dystonia, symptomatic dystonia, and paroxysmal dystonia, and focal dystonia, such as blepharospasm, oromandibular dystonia, spasmodic phonation disorder, spasmodic torticollis, and axial dystonia). Disorders, dystonia (writer's cramp and hemiplegic dystonia); neurodegenerative diseases, including disease classification entities such as disinhibition-dementia-Parkinson's disease-amyotrophic lateral sclerosis syndrome; globus pallidus-pons-substantia nigra degeneration; epilepsy; seizure disorders; attention deficit hyperactivity disorder (ADHD); conduct disorder; migraine (including migraine); headache; hyperalgesia; pain; increased or exaggerated sensitivity to pain, such as hyperalgesia, burning pain, and atypical pain; acute pain; burn pain; atypical facial pain; neuropathic pain; back pain; complex regional pain syndromes I and II; arthritis pain; sports injury pain; infection-related pain, such as HIV, COVID-19, post-chemotherapy pain; post-stroke pain; postoperative pain; neuralgia; vomiting, nausea, vomiting; gastric motility disorders; gastric ulcers;Kallman's syndrome (loss of smell); asthma; cancer; conditions associated with visceral pain, such as irritable bowel syndrome and angina; eating disorders; urinary incontinence; substance tolerance and withdrawal (including substances such as opioids, 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, and bipolar disorder); trigeminal neuralgia; hearing loss; Tinnitus; neuronal damage, including eye damage; retinopathy; macular degeneration; vomiting; cerebral edema; pain, including acute and chronic pain states, severe pain, intractable pain, inflammatory pain, neuropathic pain, post-traumatic pain, osteoarthritis, repetitive motion pain, toothache, cancer pain, myofascial pain (muscle injury, fibromyalgia), perioperative pain (general surgery, gynecology), chronic pain, neuropathic pain, post-traumatic pain, trigeminal neuralgia, migraine and migraine, and other conditions associated with systemic orexin system dysfunction.

[0080] A preferred embodiment of the present invention is a compound of formula (I) or a pharmaceutically acceptable salt thereof, its tautomers, stereoisomers or mixtures thereof, for the prevention and / or treatment of narcolepsy type 1 (NT1), narcolepsy type 2 (NT2), hypersomnia, idiopathic hypersomnia, recurrent hypersomnia, Klein-Levin syndrome, hypersomnia associated with mental disorders, hypersomnia due to medical impairment, hypersomnia due to drugs or substances, Parkinson's disease and other synucleinopathies, preferably for the use of narcolepsy type 1 (NT1), narcolepsy type 2 (NT2) and Parkinson's disease.

[0081] A preferred embodiment of the present invention is a compound of formula (I) or a pharmaceutically acceptable salt thereof, its tautomers, stereoisomers or mixtures thereof, for the prevention and / or treatment of REM sleep behavior disorder (RBD).

[0082] In some embodiments, the neurological disease, preferably a neurological disorder or disease involving central orexin neurotransmission or involving central and peripheral orexin receptors, is selected from type 1 narcolepsy (NT1), type 2 narcolepsy (NT2), hypersomnia, idiopathic hypersomnia, recurrent hypersomnia, Klein-Levin syndrome, hypersomnia associated with mental disorders, hypersomnia due to medical impairment, hypersomnia due to drugs or substances, Parkinson's disease, and other synucleinopathies, preferably type 1 narcolepsy (NT1), type 2 narcolepsy (NT2), and Parkinson's disease.

[0083] In some embodiments, the neurological disease, preferably a neurological disorder or disease involving central or peripheral orexin receptors, is selected from narcolepsy type 1 (NT1), narcolepsy type 2 (NT2), hypersomnia, idiopathic hypersomnia, and recurrent hypersomnia.

[0084] Specifically, the targeted neurological diseases are those that require agonists of orexin 1 receptor (OX1R) and / or orexin 2 receptor (OX2R), preferably those requiring agonists of both receptors.

[0085] Compound of formula (I)

[0086] 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.

[0087] 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.

[0088] R4 preferably represents a hydrogen atom.

[0089] In a preferred embodiment of the invention, R1, R2, R3, and R4 each represent a hydrogen atom, or R1, R3, R4, and Y each represent a hydrogen atom. In some embodiments, R1, R2, R3, and R4 may each represent a hydrogen atom. In some embodiments, R1, R3, R4, and Y each represent a hydrogen atom.

[0090] R5, R6, R7, R8, and R9 can each independently represent a hydrogen atom, a halogen atom, or -OR. 10 or (C1-C) 20 alkyl, optionally broken by one or more moieties and / or preceded by one or more moieties, said moieties being selected from aryl, heteroaryl, cycloalkyl, heterocyclic, -C≡C-, -C(R) 11 )=C(R 12 -, -O-, -S-, -NR13 -, -C(O)-, -OC(O)-, -C(O)O-, -N(R 14 -C(O)- and -C(O)N(R) 15 The aryl, heteroaryl, and heterocyclic rings are optionally substituted.

[0091] In another preferred embodiment, R5, R6, R7, R8, and R9 each independently represent a hydrogen atom or -OR. 10 Preferably, at least four residues of R5, R6, R7, R8, and R9 each represent a hydrogen atom.

[0092] In one particular implementation, R5, R6, R7, R8, and R9 each represent a hydrogen atom.

[0093] In another implementation, R5 stands for -OR 10 , where R 10 Represents hydrogen atoms, (C1-C 30 )alkyl or phenyl, preferably (C1-C 20 )alkyl or phenyl. In some embodiments, R5 represents -OR 10 , where R 10 Represents hydrogen atoms, (C1-C 30 )alkyl or phenyl, preferably (C1-C 20 ) alkyl or phenyl, and R6, R7, R8, and R9 each represent a hydrogen atom.

[0094] In another implementation, R6 stands for -OR 10 , where R 10 Represents hydrogen atoms, (C1-C 30 )alkyl or phenyl, preferably (C1-C 20 )alkyl or phenyl. In some embodiments, R6 represents -OR 10 , where R 10 Represents hydrogen atoms, (C1-C 30 )alkyl or phenyl, preferably (C1-C 20 ) alkyl or phenyl, and R5, R7, R8, and R9 each represent a hydrogen atom.

[0095] In another implementation, R7 stands for -OR 10 , where R 10 Represents hydrogen atoms, (C1-C 30 )alkyl or phenyl, preferably (C1-C 20 )alkyl or phenyl. In some embodiments, R7 represents -OR 10 , where R 10 Represents hydrogen atoms, (C1-C 30)alkyl or phenyl, preferably (C1-C 20 ) alkyl or phenyl, and R5, R6, R8, and R9 each represent a hydrogen atom.

[0096] In some implementations, one of the residues R5, R6, R7, R8, and R9 represents -OR. 10 , where R 10 Represents hydrogen atoms, (C1-C 30 )alkyl or phenyl, preferably (C1-C 20 )alkyl or phenyl.

[0097] In some embodiments, X may represent -NH-. In some embodiments, X may represent -S-. In some embodiments, X may represent -O-. Preferably, X represents -NH- or -S-.

[0098] Advantageously, the compounds of formula (I) are selected from:

[0099] 50 51 54

[0100] 55 56

[0101] 60 63

[0102] 69

[0103] 84

[0104] 87

[0105] 90

[0106] 93

[0107] 96 97

[0108] 98 99

[0109] 100 145

[0110] 146 148

[0111] 149 151

[0112] 152 153

[0113] 154 155

[0114] 157 158

[0115] 161 167

[0116] 182

[0117] 185

[0118] 191

[0119] 194 195

[0120] 196 243

[0121] 244 292

[0122] 293

[0123] 300

[0124] 301 302

[0125] 303 304

[0126] 305

[0127] 306

[0128] 307

[0129] 308

[0130] 309 310

[0131] 311

[0132] 312 313 and its mixtures.

[0133] Preferably, the compound of formula (I) is selected from:

[0134] 69

[0135] 84

[0136] 87

[0137] 90

[0138] 96 97

[0139] 98 99

[0140] 148 152

[0141] 153 154

[0142] 155 157

[0143] 161 167

[0144] 191

[0145] 194 195

[0146] 196 300

[0147] 313 and its mixtures.

[0148] More preferably, the compound of formula (I) is selected from:

[0149] 84 99

[0150] 152 155

[0151] 194 196

[0152] 300 313 and its mixtures.

[0153] In a preferred embodiment of the invention, the neurological, mental, and sleep disorders and diseases involving impaired central orexin neurotransmission or orexin receptors are selected from type 1 narcolepsy, type 2 narcolepsy, idiopathic hypersomnia, recurrent hypersomnia, attention deficit hyperactivity disorder, anxiety and mood disorders, Alzheimer's disease or any other neurodegenerative disease or cognitive impairment and tau protein diseases, Parkinson's disease and other synucleinopathies, Guillain-Barré syndrome, chronic fatigue syndrome, long-term COVID-19 and medical or health conditions related to circadian rhythms, as well as mental and physical illnesses related to cross-time zone travel and shift work schedules, restless legs syndrome, fibromyalgia, heart failure, osteoporosis-related diseases, sepsis, syndromes characterized by unrefreshing sleep and muscle pain, sleep apnea associated with breathing disorders during sleep; and conditions resulting from poor sleep quality.

[0154] The dosage of the active ingredient in the compositions of this invention can be varied, but it must be ensured that the amount of the active ingredient is sufficient to form a suitable dosage form. The active ingredient can be administered to the subject (animal and human) requiring treatment at a dosage that provides optimal efficacy. The selected dosage depends on the desired therapeutic effect, route of administration, and duration of treatment. The dosage will vary from subject to subject, depending on the nature and severity of the disease, the subject's weight, any special diet the subject is following at the time, any concurrent medications, and other factors known to those skilled in the art.

[0155] Typically, dose levels of 0.0001 to 100 mg / kg body weight per day are administered to subjects (e.g., humans, adolescents, and the elderly) to effectively stimulate orexin receptors. Advantageously, therapeutic doses of the compound of formula (I) from 0.1 mg / kg / day to 100 mg / kg / day are administered to patients in need.

[0156] 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 the prevention and / or treatment of neurological, psychiatric, sleep disorders and diseases in which central orexin neurotransmission is impaired or in which central and peripheral orexin receptors are involved.

[0157] The dosage range is typically 0.5 mg to 10.0 g per subject per day, and can be administered in single or multiple doses. In one embodiment, the dosage range is 0.5 mg to 500 mg per subject per day, preferably 0.5 mg to 200 mg per subject per day, and more preferably 5 mg to 50 mg per subject per day. The pharmaceutical compositions of the present invention can be provided in solid dosage forms, for example, containing 0.5 mg to 500 mg of active ingredient, or containing 1 mg to 250 mg of active ingredient. The pharmaceutical compositions can be provided in solid dosage forms containing 1 mg, 5 mg, 10 mg, 50 mg, 80 mg, 100 mg, or 200 mg of active ingredient.

[0158] In a preferred embodiment, the pharmaceutical composition for use according to the invention comprises 0.5 mg to 800 mg, preferably 20 mg to 400 mg, of a compound of formula (I).

[0159] For oral administration, the composition may be provided in tablet form containing 1.0 to 1000 mg 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 mg of the active ingredient, to allow for dose adjustment based on the symptoms of the treated subject. The compound may be administered in a regimen of 1 to 4 times daily, such as once or twice daily. The compound may be administered once or multiple times a day. The compound may be administered upon waking, in the morning, or while awake. For example, 25 mg, 30 mg, or 250 mg of the compound may be administered 1 hour after waking, 30 minutes after waking, or immediately after waking.

[0160] In one 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 injection, or in the form of a tablet, capsule, or transdermal delivery system.

[0161] The compounds of the present invention can be used in combination with one or more other pharmaceutical products for the treatment, prevention, control, improvement, or reduction of the risk of a disease or condition to which the compounds of the present invention or other pharmaceutical products may be applicable, wherein the combination of pharmaceutical products is safer or more effective than any single pharmaceutical product alone. Such other pharmaceutical products may be administered simultaneously or sequentially with the compounds of the present invention via the usual route and at the usual dosage. When the compounds of the present invention are used simultaneously with one or more other pharmaceutical products, a unit dosage form pharmaceutical composition comprising such other pharmaceutical products and the compounds of the present invention may be considered. However, combination therapy may also include therapy in which the compounds of the present invention and one or more other pharmaceutical products are administered in different overlapping regimens. It is also conceivable that when used in combination with one or more other active ingredients, the dosage of the compounds of the present invention and other active ingredients may be lower than the dosage when used individually. Therefore, pharmaceutical compositions of the present invention include those pharmaceutical compositions that, in addition to the compounds of the present invention, also contain one or more other active ingredients. The above combinations include not only combinations of the compounds of the present invention with one other active compound, but also combinations of the compounds of the present invention with two or more other active compounds.

[0162] The weight ratio of the compound of the present invention to the second active ingredient can vary, depending on the effective dose of each ingredient. Typically, the effective dose of each ingredient will be used. Therefore, for example, when the compound of the present invention is combined with another drug, the weight ratio of the compound of the present invention to the other drug will typically be 1000:1 to 1:1000, preferably 200:1 to 1:200. Combinations of the compound of the present invention with other active ingredients generally also fall within the above range, but in each case, the effective dose of each active ingredient should be used. In such combinations, the compound of the present invention and other active ingredients can be administered alone or in combination. Furthermore, the administration of one ingredient can be performed before, simultaneously with, or after the administration of another drug.

[0163] The compounds of the present invention can be administered in combination with compounds known in the art for the treatment or control of narcolepsy, including, for example, methylphenidate, amphetamine, atoxetine, reboxetine, veloxacin, phenelzine, protriptyline, gamma-hydroxybutyric acid, sodium hydroxybutyrate or other hydroxybutyrates, modafinil, armodafinil, adralfenib, pitolisant, samelisant, nalfurafen, caffeine, salts thereof, and combinations thereof.

[0164] Compound of formula (II)

[0165] This invention also relates to a compound of formula (II):

[0166]

[0167] in:

[0168] -X represents -NH-, -S-, or -O-, with -NH- or -S- being preferred;

[0169] -Y and R2 can each independently represent a hydrogen atom, a halogen atom, -NO2, or -NH2;

[0170] -R1, R3, and R4 each independently represent a hydrogen atom or a halogen atom;

[0171] -R5, R6, R7, R8, and R9 each independently represent a hydrogen atom, a halogen atom, and -OR. 10 or (C1-C) 30 )alkyl chains, especially (C1-C 20 An alkyl group, optionally interrupted by one or more moieties and / or followed by one or more moieties and / or preceded by one or more moieties, said moieties being selected from aryl, heteroaryl, cycloalkyl, heterocyclic, -C≡C-, -C(R) 11 )=C(R 12 -, -O-, -S-, -NR 13 -, -C(O)-, -C(S)-, -C=N-, -N=C-, -OC(O)-, -C(O)O-, -SC(O)-, -C(O)S-, -N(R 14 -C(O)- and -C(O)N(R) 15 )-group, wherein the aryl, heteroaryl and heterocyclic rings are optionally substituted;

[0172] -R 10 Represents a hydrogen atom or (C1-C) 30 Alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl, wherein the aryl, heteroaryl and heterocyclic rings are optionally substituted;

[0173] -R 11 and R 12 Each independently represents a hydrogen atom or a (C1-C6) alkyl group; and

[0174] -R 13 To R 15 Each of these groups independently represents a hydrogen atom or a (C1-C6) alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or acyl group, preferably a hydrogen atom or a (C1-C6) alkyl or aryl group, more preferably a hydrogen atom or a (C1-C6) alkyl group.

[0175] Or a pharmaceutically acceptable salt thereof, its tautomers, stereoisomers or mixtures thereof.

[0176] Preferably, the compound of formula (II) is not

[0177]

[0178] (This compound has been described as having inhibitory activity against amyloid aggregation (Cox et al. 2020)).

[0179] (These four compounds were described as having inhibitory effects on cell proliferation (Yale and Kalkstein 1967)).

[0180] (This compound has been described as having anticancer activity (Chinigo et al. 2008))

[0181] (This compound has been described as having antitumor activity (Mordarski and Chylinska 1971))

[0182]

[0183] (This compound has been used to treat PARP-1-related diseases, see WO 2018044136)(Kim et al. 2023),

[0184] Furthermore, the condition is that when X represents O, each of R1, R2, R3, and R4 represents H, Y represents a halogen atom, and four of R5, R6, R7, R8, and R9 represent H, then the remaining groups in R5, R6, R7, R8, and R9 are not (C1-C2). 30 ) alkyl chain, the (C1-C 30 The alkyl chain is preceded by -O- and broken by -O-, or by -C(R) 11 )=C(R 12 - Interrupt, followed by -C(R) 11 )=C(R 12 - and / or preceded by -C(R) 11 )=C(R 12 )-.

[0185] In some implementations, when X represents -O-, then R5, R6, R7, R8, and R9 independently represent a hydrogen atom, a halogen atom, and -OR. 10 or (C1-C) 30 )alkyl chains, especially (C1-C 20 An alkyl group, optionally interrupted by one or more moieties and / or followed by one or more moieties and / or preceded by one or more moieties, said moieties being selected from aryl, heteroaryl, cycloalkyl, heterocyclic, -C≡C-, -S-, -NR 13-, -C(O)-, -C(S)-, -C=N-, -N=C-, -OC(O)-, -C(O)O-, -SC(O)-, -C(O)S-, -N(R 14 -C(O)- and -C(O)N(R) 15 The aryl, heteroaryl, and heterocyclic rings are optionally substituted.

[0186] In a preferred embodiment, when X represents -O-, then Y and R2 each independently represent a hydrogen atom, -NO2, or -NH2.

[0187] 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.

[0188] 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.

[0189] R4 preferably represents a hydrogen atom.

[0190] In a preferred embodiment of the invention, when X is NH or O, R5, R6, or R7 represents -OR. 10 , where R 10 Represents hydrogen atoms, (C1-C 30 )alkyl or phenyl.

[0191] In a preferred embodiment of the invention, R1, R2, R3, and R4 each represent a hydrogen atom, or R1, R3, R4, and Y each represent a hydrogen atom. In some embodiments, R1, R2, R3, and R4 may each represent a hydrogen atom. In some embodiments, R1, R3, R4, and Y each represent a hydrogen atom.

[0192] R5, R6, R7, R8, and R9 can each independently represent a hydrogen atom, a halogen atom, or -OR. 10 or (C1-C) 20alkyl, optionally broken by one or more moieties and / or preceded by one or more moieties, said moieties being selected from aryl, heteroaryl, cycloalkyl, heterocyclic, -C≡C-, -C(R) 11 )=C(R 12 -, -O-, -S-, -NR 13 -, -C(O)-, -OC(O)-, -C(O)O-, -N(R 14 -C(O)- and -C(O)N(R) 15 The aryl, heteroaryl, and heterocyclic rings are optionally substituted.

[0193] In another preferred embodiment, R5, R6, R7, R8, and R9 each independently represent a hydrogen atom or -OR. 10 Preferably, at least four residues of R5, R6, R7, R8, and R9 each represent a hydrogen atom.

[0194] In one particular implementation, R5, R6, R7, R8, and R9 each represent a hydrogen atom.

[0195] In another implementation, R5 stands for -OR 10 , where R 10 Represents hydrogen atoms, (C1-C 30 )alkyl or phenyl, preferably (C1-C 20 )alkyl or phenyl. In some embodiments, R5 represents -OR 10 , where R 10 Represents hydrogen atoms, (C1-C 30 )alkyl or phenyl, preferably (C1-C 20 ) alkyl or phenyl, and R6, R7, R8, and R9 each represent a hydrogen atom.

[0196] In another implementation, R6 stands for -OR 10 , where R 10 Represents hydrogen atoms, (C1-C 30 )alkyl or phenyl, preferably (C1-C 20 )alkyl or phenyl. In some embodiments, R6 represents -OR 10 , where R 10 Represents hydrogen atoms, (C1-C 30 )alkyl or phenyl, preferably (C1-C 20 ) alkyl or phenyl, and R5, R7, R8, and R9 each represent a hydrogen atom.

[0197] In another implementation, R7 stands for -OR 10 , where R 10 Represents hydrogen atoms, (C1-C 30)alkyl or phenyl, preferably (C1-C 20 )alkyl or phenyl. In some embodiments, R7 represents -OR 10 , where R 10 Represents hydrogen atoms, (C1-C 30 )alkyl or phenyl, preferably (C1-C 20 ) alkyl or phenyl, and R5, R6, R8, and R9 each represent a hydrogen atom.

[0198] In some implementations, one of the residues R5, R6, R7, R8, and R9 represents -OR. 10 , where R 10 Represents hydrogen atoms, (C1-C 30 )alkyl or phenyl, preferably (C1-C 20 )alkyl or phenyl.

[0199] In some embodiments, X may represent -NH-. In some embodiments, X may represent -S-. In some embodiments, X may represent -O-. Preferably, X represents -S-.

[0200] Advantageously, compounds of formula (II) are selected from:

[0201] 51 54 55

[0202] 56 60

[0203] 63 69

[0204] 84

[0205] 87

[0206] 90

[0207] 93 96

[0208] 97 98

[0209] 99 100

[0210] 145 146

[0211] 148 149

[0212] 151 152

[0213] 153 154

[0214] 155 157

[0215] 158 161

[0216] 167

[0217] 182

[0218] 185

[0219] 191

[0220] 194 195

[0221] 196 243

[0222] 244 292

[0223] 293 300

[0224] 301 302

[0225] 303 304

[0226] 305 306

[0227] 307

[0228] 308 309

[0229] 310 311

[0230] 312 313 And its pharmaceutically acceptable salts.

[0231] In a preferred embodiment of the invention, the compound of formula (II) is selected from 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 their pharmaceutically acceptable salts.

[0232] More advantageously, the compounds of formula (II) are selected from compounds 99, 148, 152, 153, 154, 155, 157, 161, 167, 191, 194, 195, 196, 301, 302, 304, 305, 308, 310, 311 and their pharmaceutically acceptable salts.

[0233] Even more advantageously, compounds of formula (II) are selected from:

[0234] 99 152

[0235] 155 194 And its pharmaceutically acceptable salts.

[0236] In a more preferred embodiment, the compound of formula (II) is selected from:

[0237] 84 99

[0238] 152 155

[0239] 194 196

[0240] 300 313 And its pharmaceutically acceptable salts.

[0241] The present invention also relates to a pharmaceutical composition comprising a compound of formula (II) and a pharmaceutically acceptable carrier. The pharmaceutical composition is defined as described above for compounds of formula (I).

[0242] The present invention also relates to the use of compounds of formula (II) as described above as pharmaceuticals.

[0243] The present invention also relates to the use of compounds of formula (II) as described above for the preparation of pharmaceuticals. In some embodiments, the present invention provides a method for treating a subject in need, comprising administering to said subject a compound of formula (II) or a composition comprising a compound of formula (II).

[0244] Chromatographic separation can be performed using methods known in the art. Its absolute stereochemistry can be determined by X-ray crystallography of the crystalline product or intermediate, which, if necessary, is derivatized using a reagent containing an asymmetric center of known absolute configuration. If desired, racemic mixtures of the compounds can be separated to isolate individual enantiomers. Separation can be performed using methods well known in the art, for example, by coupling a racemic mixture of the compounds with an enantiomerically pure compound to form a diastereomer mixture, followed by separation of individual diastereomers by standard methods (e.g., fractional crystallization or chromatography). The coupling reaction typically uses an enantiomerically pure acid or base to form a salt. The diastereomeric derivative is then converted to a pure enantiomer by cleaving the added chiral residue. Racemic mixtures of the compounds can also be separated directly by chromatography using a chiral stationary phase, a method well known in the art. Alternatively, any enantiomer of the compound can be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configurations, methods well known in the art.

[0245] In some embodiments, the present invention provides a method for treating a subject suffering from a neurological disorder, preferably a neurological, psychiatric, sleep disorder, or disease, such as narcolepsy and Parkinson's disease, wherein central orexin neurotransmission is impaired or involves central and peripheral orexin receptors, comprising administering to the subject a compound of formula (I) or a composition comprising a compound of formula (I). Specifically, the disorder or disease is as defined above.

[0246] In some embodiments, the present invention provides a method for preventing neurological disorders, preferably neurological, psychiatric, sleep disorders and diseases, such as narcolepsy and Parkinson's disease, wherein central orexin neurotransmission is impaired or wherein the disease involves central and peripheral orexin receptors, 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). Specifically, the disorders and diseases are as defined above.

[0247] In some embodiments, the method further includes applying a second active compound.

[0248] In one aspect, the invention also relates to the use of a compound of formula (I) or a pharmaceutical composition comprising at least one compound of formula (I) in the preparation of a medicament for treating neurological disorders, preferably neurological, psychiatric, sleep disorders and diseases, such as narcolepsy and Parkinson's disease, wherein central orexin neurotransmission is impaired or wherein the disease involves central and peripheral orexin receptors. In particular, the disorders and diseases are as defined above.

[0249] The present invention also relates to the following embodiments:

[0250] Implementation Scheme 1. A compound of formula (I):

[0251] in:

[0252] -X represents -NH-, -S-, or -O-, with -NH- or -S- being preferred;

[0253] -Y represents a halogen atom, -NO2 or -NH2, preferably -NO2 or -NH2;

[0254] -R1, R2, R3, and R4 each independently represent a hydrogen atom or a halogen atom;

[0255] -R5, R6, R7, R8, and R9 each independently represent a hydrogen atom, a halogen atom, and -OR. 10 or (C1-C) 30 )alkyl chains, especially (C1-C 20 An alkyl group, optionally interrupted by one or more moieties and / or followed by one or more moieties and / or preceded by one or more moieties, said moieties being selected from aryl, heteroaryl, cycloalkyl, heterocyclic, -C≡C-, -C(R) 11 )=C(R 12 -, -O-, -S-, -NR 13 -, -C(O)-, -C(S)-, -C=N-, -N=C-, -C=C-, -OC(O)-, -C(O)O-, -SC(O)-, -C(O)S-, -N(R 14 -C(O)- and -C(O)N(R) 15 )-group, wherein the aryl, heteroaryl and heterocyclic rings are optionally substituted;

[0256] -R 10 Represents a hydrogen atom or (C1-C) 30 Alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl, wherein the aryl, heteroaryl and heterocyclic rings are optionally substituted;

[0257] -R 11 and R 12 Each independently represents a hydrogen atom or a (C1-C6) alkyl group; and

[0258] -R 13 To R 15 Each of these groups independently represents a hydrogen atom or a (C1-C6) alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or acyl group, preferably a hydrogen atom or a (C1-C6) alkyl or aryl group, more preferably a hydrogen atom or a (C1-C6) alkyl group.

[0259] Its pharmaceutically acceptable salt, tautomer, stereoisomer, or mixture thereof, for the prevention and / or treatment of neurological, psychiatric, sleep disorders and diseases in which central orexin neurotransmission is impaired or in which central and peripheral orexin receptors are involved.

[0260] Implementation Scheme 2. The compound of formula (I) according to the use of implementation scheme 1, characterized in that R1, R2, R3, and R4 each represent a hydrogen atom.

[0261] Implementation Scheme 3. The compound of formula (I) according to the use of implementation scheme 1 or 2, characterized in that R5, R6, R7, R8, and R9 each independently represent a hydrogen atom or -OR 10 .

[0262] Implementation Scheme 4. The compound of formula (I) for use according to any one of Implementation Schemes 1 to 3, characterized in that at least four residues of R5, R6, R7, R8 and R9 each represent a hydrogen atom.

[0263] Implementation Scheme 5. The compound of formula (I) according to the use of Implementation Scheme 4, characterized in that R5, R6, R7, R8, and R9 each represent a hydrogen atom.

[0264] Implementation Scheme 6. The compound of formula (I) according to the use of implementation scheme 4, characterized in that R5, R6 or R7 represents -OR 10 , where R 10 Represents hydrogen atoms, (C1-C 30 )alkyl or phenyl.

[0265] Implementation Scheme 7. The compound of formula (I) for use according to any one of Implementation Schemes 1 to 6, characterized in that it is selected from 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 compounds 84, 99, 152, 155, 194 and mixtures thereof.

[0266] Implementation Scheme 8. A compound of formula (I) for use according to any one of Implementation Schemes 1 to 7, characterized in that the central orexin neurotransmission is impaired or the neurological, mental, sleep disorders and diseases involving orexin receptors are selected from type 1 narcolepsy, type 2 narcolepsy, idiopathic hypersomnia, recurrent hypersomnia, attention deficit hyperactivity disorder, anxiety and mood disorders, Alzheimer's disease or any other neurodegenerative disease or cognitive impairment and tau protein disease, Parkinson's disease and other synucleinic diseases, Guillain-Barré syndrome, chronic fatigue syndrome, long-term COVID-19 and medical or health conditions related to circadian rhythms and mental and physical illnesses related to cross-time zone travel and shift work schedules, restless legs syndrome, fibromyalgia, heart failure, osteoporosis-related diseases, sepsis, syndromes characterized by unrelieved sleep and muscle pain, sleep apnea related to breathing disorders during sleep; and conditions resulting from poor sleep quality.

[0267] Implementation Scheme 9. A pharmaceutical composition comprising at least one compound of formula (I) as defined in any one of Implementation Schemes 1 to 8 and a pharmaceutically acceptable carrier, for the purpose of preventing and / or treating neurological, psychiatric, sleep disorders and diseases in which central orexin neurotransmission is impaired or in which central and peripheral orexin receptors are involved.

[0268] Implementation Scheme 10. A pharmaceutical composition for use according to Implementation Scheme 9, comprising 0.5 mg to 800 mg, preferably 20 mg to 400 mg, of a compound of formula (I).

[0269] Implementation Scheme 11. A pharmaceutical composition for use according to Implementation Scheme 9 or 10, which is suitable for oral or parenteral administration, preferably in the form of a solution such as an injection, tablet, capsule or transdermal delivery system.

[0270] Implementation Scheme 12. A compound of formula (II):

[0271] in:

[0272] -X represents -NH-, -S-, or -O-, for example -S- or -O-, with -S- being preferred;

[0273] -Y represents a halogen atom, -NO2 or -NH2, preferably -NO2 or -NH2;

[0274] -R1, R2, R3, and R4 each independently represent a hydrogen atom or a halogen atom;

[0275] -R5, R6, R7, R8, and R9 each independently represent a hydrogen atom, a halogen atom, and -OR. 10 or (C1-C) 30 )alkyl chains, especially (C1-C20 An alkyl group, optionally interrupted by one or more moieties and / or followed by one or more moieties and / or preceded by one or more moieties, said moieties being selected from aryl, heteroaryl, cycloalkyl, heterocyclic, -C≡C-, -C(R) 11 )=C(R 12 -, -O-, -S-, -NR 13 -, -C(O)-, -C(S)-, -C=N-, -N=C-, -C=C-, -OC(O)-, -C(O)O-, -SC(O)-, -C(O)S-, -N(R 14 -C(O)- and -C(O)N(R) 15 )-group, wherein the aryl, heteroaryl and heterocyclic rings are optionally substituted;

[0276] -R 10 Represents a hydrogen atom or (C1-C) 30 Alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl, wherein the aryl, heteroaryl and heterocyclic rings are optionally substituted;

[0277] -R 11 and R 12 Each independently represents a hydrogen atom or a (C1-C6) alkyl group; and

[0278] -R 13 To R 15 Each of these groups independently represents a hydrogen atom or a (C1-C6) alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or acyl group, preferably a hydrogen atom or a (C1-C6) alkyl or aryl group, more preferably a hydrogen atom or a (C1-C6) alkyl group.

[0279] Or a pharmaceutically acceptable salt thereof, its tautomers, stereoisomers or mixtures thereof.

[0280] Implementation Scheme 13. The compound of formula (II) according to Implementation Scheme 12, characterized in that R1, R2, R3, R4 each represent a hydrogen atom, and R5, R6, R7, R8, R9 each independently represent a hydrogen atom or -OR 10 .

[0281] Implementation Scheme 14. The compound of formula (II) according to Implementation Scheme 12 or 13, characterized in that at least four residues of R5, R6, R7, R8 and R9 each represent a hydrogen atom.

[0282] Implementation Scheme 15. The compound of formula (II) according to Implementation Scheme 14, characterized in that R5, R6, R7, R8, and R9 each represent a hydrogen atom.

[0283] Implementation Scheme 16. The compound of formula (II) according to Implementation Scheme 14, characterized in that R5, R6 or R7 represents -OR 10 , where R 10 Represents hydrogen atoms, (C1-C 30 )alkyl or phenyl.

[0284] Scheme 17. The compound of formula (II) according to any one of schemes 12 to 16, characterized in that it is selected from compounds 99, 148, 152, 153, 154, 155, 157, 161, 167, 191, 194, 195, 196 and mixtures thereof, preferably compounds 99, 152, 155, 194 and mixtures thereof.

[0285] Implementation Scheme 18. The use of a compound of formula (II) according to any one of Implementation Schemes 12 to 17 as a medicine.

[0286] One or more features of any of the embodiments disclosed herein can be combined and / or rearranged within the scope of this invention to produce further embodiments that are also within the scope of this invention. Those skilled in the art can recognize or determine many equivalent embodiments of the specific embodiments of the invention described herein with only routine experimentation. Such equivalent embodiments should all be included within the scope of this invention.

[0287] The invention is further described by way of the following non-limiting embodiments.

[0288] Example

[0289] The following embodiments are provided to aid in a more comprehensive understanding of the invention. These embodiments illustrate exemplary ways of carrying out and applying the invention. However, the scope of the invention is not limited to the specific implementations disclosed in these embodiments; these embodiments are for illustrative purposes only, as similar results can be obtained using alternative methods.

[0290] Example 1. Chemical analysis of dihydroquinazoline derivatives

[0291] Design, synthesis and preparation of 6-nitro-2,3-dihydro-1H-quinazolin-4-one

[0292]

[0293] Preparation of polyphosphates (PPE)

[0294] P2O4 (150 g) was refluxed in diethyl ether (150 mL) and CHCl3 (300 mL) until the solution was clear. Then, the solvent was removed under reduced pressure to obtain a clear oily substance.

[0295] Synthesis of 2-amino-5-nitrobenzamide

[0296] A mixture of 2-amino-5-nitro-benzonitrile (25.3 mmol, 4 g) and concentrated H₂SO₄ (24.2 mL) was heated to 65 °C and stirred for 12 hours. The reaction mixture was slowly poured into ice, and the pH was adjusted to 8 or 9 with 6 M NaOH or NH₄OH aqueous solution. The precipitate was filtered off and washed with ice-cold H₂O to obtain pure benzamide, which could be used without further purification.

[0297] 1 H NMR (400MHz, DMSO-d6): δppm 8.54(d,J=2.7Hz,1H),8.20(br.s.,1H),8.01(dd,J=9.0Hz,2.8Hz,1H),7.87(bs,1H),7.39(br.s.,1H),6.78(d,J=9.0Hz,1H).

[0298] The general steps for 6-nitro-2,3-dihydro-1H-quinazolin-4-one are as follows:

[0299] 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 minutes without a condenser. The resulting solution was poured into cold water. The precipitate was filtered off, washed with water, and crystallized in diethyl ether to give the corresponding pure DHQ in excellent yield (80 to 95%).

[0300]

[0301] Product 50: 6-nitro-2-phenyl-2,3-dihydro-1H-quinazolin-4-one

[0302]

[0303] 1 H NMR(300MHz,DMSO-d6)δppm 6.01(s,1H)6.83(d,J=9.08Hz,1H)7.35-7.50(m,5H)8.10(dd,J=9.08,2.75Hz,1H)8.43(d,J=2.66Hz,1H)8.58(s,1H)8.74(s,1H).

[0304] 13C NMR(75MHz,DMSO-d6)δppm 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).

[0305] Chemical formula: C 14 H 11 N3O3:m / z:269.08

[0306] Product 51: 6-nitro-2-(4-hydroxyphenyl)-2,3-dihydro-1H-quinazolin-4-one

[0307]

[0308] 1 H NMR (300MHz, DMSO-d6) δppm 5.90 (s, 1H) 6.73-6.85 (m, 3H) 7.28 (d, J = 8.53Hz, 2H) 8.09 (dd, J = 9.26, 2.93Hz, 1H) 8.43 (d, J = 2.57Hz, 2H) 8.57 (s, 1H).

[0309] 13 C NMR(75MHz,DMSO-d6)δppm 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).

[0310] Chemical formula: C 14 H 11 N3O4:m / z:285.07.

[0311] Product 54: 6-nitro-2-(4-methoxyphenyl)-2,3-dihydro-1H-quinazolin-4-one

[0312]

[0313] 1H NMR(300MHz,DMSO-d6)δpm 3.75(s,3H),5.95(s,1H),6.81(d,J=9.08Hz,1H),6.97(m,J=8.80Hz,2H),7.38(m,J =8.71Hz, 2H), 8.09 (dd, J = 9.08, 2.75Hz, 1H), 8.42 (s, 1H), 8.48 (s, 1H), 8.65 (s, 1H).

[0314] 13 C NMR(75MHz,DMSO-d6)δppm 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).

[0315] Chemical formula: C 15 H 13 N3O4:m / z:299.09.

[0316] Product 55: 6-nitro-2-(3-methoxyphenyl)-2,3-dihydro-1H-quinazolin-4-one

[0317]

[0318] 1 H NMR(300MHz,DMSO-d6)δppm 3.75(s,3H)5.98(s,1H)6.84(d,J=9.17Hz,1H)6.90-6.99(m,1H)6.99-7.08(m,2H)7. 33(t,J=8.16Hz,1H)8.05-8.17(m,1H)8.43(d,J=2.75Hz,1H)8.57(s,1H)8.74(s,1H)

[0319] Chemical formula: C 15 H 13 N3O4:m / z:299.09.

[0320] Product 56: 6-nitro-2-(2-methoxyphenyl)-2,3-dihydro-1H-quinazolin-4-one

[0321]

[0322] 1H NMR (300MHz, DMSO-d6) δppm 3.91(s,3H,OCH3),5.95(s,1H,C-H2),6.88(d,J=9.17Hz,1H,C-H8),7.16-7.09(m,2H,C-H3' ,5 '),7.46(dt,1H,J=7.1Hz,C-H4'),8.10(m,1H,C-H7),8.20-8.18(dd,1H,J= 1.2;7.8Hz,C-H6'),8.44(d,J=2.75Hz,1H,C-H5)8.57(s,1H),8.75(s,1H).

[0323] 13 C NMR (75MHz, DMSO-d6): δ55.84(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).

[0324] Chemical formula: C 15 H 13 N3O4:m / z:299.09.

[0325] Product 60: 6-nitro-2-(4-propoxyphenyl)-2,3-dihydro-1H-quinazolin-4-one

[0326]

[0327] 1 H NMR(300MHz,DMSO-d6)δppm 0.96(t,J=7.38Hz,3H),1.63-1.80(m,2H),3.92(t,J=6.46Hz,2H),5.95(s,1H),6.82(d,J=9.08Hz,1H),6.96(m,J=8 .71Hz, 2H), 7.37 (m, J = 8.71Hz, 2H), 8.10 (dd, J = 9.08, 2.75Hz, 1H), 8.43 (d, J = 2.66Hz, 1H), 8.48 (s, 1H), 8.64 (s, 1H).

[0328] 13C NMR(75MHz,DMSO-d6)δppm 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).

[0329] Chemical formula: C 17 H 17 N3O4:m / z:327.12.

[0330] Product 63: 6-nitro-2-(4-butoxyphenyl)-2,3-dihydro-1H-quinazolin-4-one

[0331]

[0332] 1 H NMR(300MHz,DMSO-d6)δppm 0.92(t,J=7.40Hz,3H),1.35-1.48(m,2H),1.62-1.73(m,2H),3.95(t,J=6.48Hz,2H),5.95(s,1H),6.82(d,J=9.08Hz,1H),6. 96(m,J=8.71Hz,2H),7.37(m,J=8.71Hz,2H),8.10(dd,J=9.08,2.75Hz,1H),8.42(d,J=2.66Hz,1H),8.48(s,1H),8.64(s,1H).

[0333] 13 C NMR(75MHz,DMSO-d6)δppm 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).

[0334] Chemical formula: C 18 H 19N3O4:m / z:341.14.

[0335] Product 69: 6-nitro-2-[4-(hexyloxy)phenyl]-2,3-dihydro-1H-quinazolin-4-one

[0336]

[0337] 1 H NMR(400MHz,DMSO-d6)δppm 0.81-0.94(m,3H),1.30(d,J=7.34Hz,4H),1.41(br.s.,2H),1.69(d,J=14.79Hz,2H),3.96(t,J=6.48Hz,2H),5.95(s,1H),6.82(d,J=9.0 5Hz, 1H), 6.96 (m, J = 8.80Hz, 2H), 7.36 (m, J = 8.68Hz, 2H), 8.10 (dd, J = 9.11, 2.75Hz, 1H), 8.43 (d, J = 2.81Hz, 1H), 8.47 (s, 1H), 8.63 (s, 1H).

[0338] Chemical formula: C 20 H 23 N3O4:m / z:369.17.

[0339] Product 84: 6-nitro-2-[4-(undecyloxy)phenyl]-2,3-dihydro-1H-quinazolin-4-one

[0340]

[0341] 1 H NMR(300MHz,DMSO-d6)δppm 0.84(t,J=6.56Hz,3H),1.24(br.s.,14H),1.32-1.51(m,2H),1.64-1.83(m,2H),4.05(t,J=6.46Hz,2H),7.06(m,J=8.89Hz, 2H), 7.83 (d, J=8.99Hz, 1H), 8.16-8.32 (m, 2H), 8.50 (dd, J=8.99, 2.75Hz, 1H), 8.81 (d, J=2.66Hz, 1H), 12.78 (br.s., 1H, NH).

[0342] Chemical formula: C 25 H 31 N3O4:m / z:437.23.

[0343] Product 87: 6-nitro-2-(4-dodecyloxyphenyl)-2,3-dihydro-1H-quinazolin-4-one

[0344]

[0345] 1 H NMR (400MHz, CDCl3) δppm 0.85(t,J=6.72Hz,3H),1.15-1.34(m,16H),1.38(br.s.,2H),1.61-1.75(m,2H),3.95(t,J=6.48Hz,2H),5.95(s,1H),6.83(d,J= 9.05Hz, 1H), 6.95 (m, J = 8.68Hz, 2H), 7.36 (m, J = 8.68Hz, 2H), 8.04-8.14 (m, 1H), 8.43 (d, J = 2.69Hz, 1H), 8.53 (s, 1H), 8.64 (s, 1H).

[0346] 13 C NMR (101MHz, DMSO-d6) δppm 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).

[0347] Chemical formula: C 26 H 35 N3O4:m / z:453.26.

[0348] Product 90: 6-nitro-2-(4-tetratekoxyphenyl)-2,3-dihydro-1H-quinazolin-4-one

[0349]

[0350] 1H NMR (300MHz, CDCl3) δppm 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),6.2 4 (s, 1H), 6.68 (d, J = 8.99Hz, 1H), 6.93 (m, J = 8.71Hz, 2H), 7.45 (m, J = 8.62Hz, 2H), 8.16 (d, J = 11.55Hz, 1H), 8.77 (d, J = 2.57Hz, 1H).

[0351] 13 C NMR(75MHz,CDCl3)δppm 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).

[0352] Chemical formula: C 25 H 33 N3O4:m / z:439.25.

[0353] Product 93: 6-nitro-2-(4-tetradecoxyphenyl)-2,3-dihydro-1H-quinazolin-4-one

[0354]

[0355] 1H NMR(300MHz,DMSO-d6)δppm 0.84(s,3H),1.23(s,22H),1.38(br.s.,3H),1.61-1.75(m,2H),3.94(t,J=6.51Hz,2H),5.95(s,1H),6.81(d,J=9.08Hz,H) ,6.94(d,J=8.71Hz,2H),7.36(d,J=8.71Hz,2H),8.09(d,J=11.83Hz,1H),8.43(d,J=2.66Hz,1H),8.48(s,1H),8.64(s,1H).

[0356] 13 C NMR(75MHz,DMSO-d6)δppm 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).

[0357] Chemical formula: C 28 H 39 N3O4:m / z:481.29.

[0358] Product 96: 6-nitro-2-(4-phenoxyphenyl)-2,3-dihydro-1H-quinazolin-4-one

[0359] 1 H NMR(300MHz,DMSO-d6)δppm 6.02(s,1H)6.84(d,J=9.17Hz,1H)7.05(d,J=8.62Hz,2H)7.00(d,J=8.80Hz,2H)7.12-7.21(m,1H)7.35-7.4 5(m,2H)7.49(d,J=8.62Hz,2H)8.11(dd,J=9.08,2.75Hz,1H)8.44(d,J=2.75Hz,1H)8.53(s,1H)8.71(s,1H)

[0360] Chemical formula: C 20 H 15N3O4:m / z:361.11.

[0361] Product 98: 6-nitro-2-(2-phenoxyphenyl)-2,3-dihydro-1H-quinazolin-4-one

[0362]

[0363] 1 H NMR(300MHz,DMSO-d6)δppm 6.28(s,1H),6.74(d,J=9.08Hz,1H),6.84(d,J=7.89Hz,1H),6.97(d,J=7.70Hz,2H),7.07-7.24(m,2H),7.2 9-7.43(m,3H),7.54(d,J=8.99Hz,1H),7.96-8.08(m,1H),8.40(d,J=2.66Hz,1H),8.47(s,1H),8.63(s,1H).

[0364] 13 C NMR(75MHz,DMSO-d6)δppm 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).

[0365] Chemical formula: C 20 H 15 N3O4:m / z:361.11.

[0366] The general steps for 7-nitro-2,3-dihydro-1H-quinazolin-4-one are as follows:

[0367]

[0368] 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 minutes without a condenser. The resulting solution was poured into cold water. The precipitate was filtered off, washed with water, and crystallized in diethyl ether to give the corresponding pure DHQ in excellent yield (80 to 95%).

[0369] Product 300: 7-nitro-2-[4-(dodecyloxy)phenyl]-2,3-dihydroquinazolin-4(1H)-one

[0370]

[0371] 1 H NMR(300MHz,DMSO-d6)δppm:0.85(t,J=6.24Hz,3H,CH3),1.24(br.s.,16H,CH2),1.38(br.s.,2H,CH 2),1.61-1.81(m,2H,CH2),3.94(t,J=6.28Hz,2H,OCH2),5.85(s,1H,C-H2),6.94(d,J=8.44Hz,2H,CH 3',5' ), 7.35-7.46(m,3H,CH) 2',6' ,C-H6),7.57(d,1H,C-H8),7.65(s,1H,NH),7.83(d,J=8.53Hz,1H,C-H5),8.61(s,1H,NH).

[0372] 13 C NMR(75MHz,DMSO-d6)δppm: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'),1 29.07(C-5),132.75(C-1'),148.24(C-9),150.72(C-7),159.01(C-4'),161.86(C-4).

[0373] Chemical formula: C 26 H 35 N3O4:m / z:453.26

[0374] Product 313: 7-nitro-2-[4-(tetradecoxy)phenyl]-2,3-dihydroquinazolin-4(1H)-one

[0375]

[0376] 1H NMR(300MHz,DMSO-d6)δppm:0.78-0.91(t,3H,CH3),1.23-1.38(m,22H),1.70(br.s. ,2H,CH2),3.94(t,J=6.46Hz,2H,OCH2),5.84(s,1H,C-H2),6.94(d,J=8.71Hz,2H,CH 3',5' ), 7.38 (d, J = 8.71 Hz, 2H, CH) 2',6' ),7.40-7.45(dd,J=2.2,8.53Hz,1H,C-H6),7.57(d,J=2.20Hz,1H,C-H8),7.68(s,1H,NH),7.83(d,J=8.53Hz,1H,C-H5),8.61(s,1H,NH).

[0377] 13 C NMR(DMSO-d6)δppm:13.91(CH3),22.06(Cn),25.46(Cg),28.60(1C),28.67(2C), 28.73(1C),28.98(4C),29.00(Cb),31.26(Cm),66.03(C-2),67.51(Ca),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).

[0378] Chemical formula: C 28 H 39 N3O4:m / z:481.29

[0379] Example 2. Chemical analysis of dihydrobenzothiazine derivatives

[0380] A) Design, synthesis and preparation of 6-nitro-2H-benzo[e][1,3]thiazine-4(3H)-one

[0381] The design, synthesis, and preparation of 6-nitro-2-(phenyl)-2H-benzo[e][1,3]thiazin-4(3H)-one have not been reported. 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 have been cited many times (Boudet 1959; Geng et al. 2012; Ingram and McClelland 1947; Moreau and Delacoux 1962).

[0382] Our synthetic route begins as follows to obtain thiobenzamide:

[0383]

[0384] 2-Chloro-5-nitrobenzamide

[0385] RMN 1 H(300MHz,DMSO-d6)δppm 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).

[0386] RMN 13 C(75MHz,DMSO-d6)δppm 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).

[0387] Chemical formula: C7H5ClN2O3: m / z: 200.00.

[0388] 2-Mercapto-5-nitrobenzamide

[0389] 1 H(300MHz,DMSO-d6)δppm 7.37-7.40(d,1H,J=8.88Hz,C-H3),7.43(br.s.,1H,NH),7.50-7.54(dd,1H ,J=2.83,8.88Hz,C-H4),8.77(d,1H,J=3.02Hz,C-H6),11.41(brs,1H,NH).

[0390] 13C (300MHz, DMSO-d6) δppm, 120.61 (C-3), 125.92 (C-6), 132.14 (C-4), 138.22 (C-2), 138.47 (C-1), 168.12 (CONH2), no (C-5).

[0391] Chemical formula: C7H6N2O3 S: m / z: 198.01.

[0392] General steps

[0393] A mixture of 2-mercapto-5-nitrobenzamide (1 mmol) and PPE (1 g) was added to the corresponding aldehyde (1 mmol), and the solution was heated at 100 °C for 60 minutes without a condenser. The resulting solution was poured into cold water. The precipitate was filtered off, washed with water, and crystallized in diethyl ether to give the corresponding pure dihydrobenzothiazide in excellent yield (80 to 95%).

[0394]

[0395] Product 148: 6-nitro-2-phenyl-2,3-dihydro-1,3-benzothiazin-4-one

[0396]

[0397] 1 H NMR (300MHz, DMSO-d6) δppm: 6.31 (d, J=3.76Hz, 1H, C-H2), 7.29-7.43 (m, 3H, CH 3',4',5' ), 7.43-7.53(m,2H,CH) 2',6' ), 7.63 (d, J = 8.71Hz, 1H, C-H8), 8.24 (dd, J = 8.67, 2.61Hz, 1H, C-H7), 8.70 (d, J = 2.66Hz, 1H, C-H5), 9.43 (d, J = 3.67Hz, 1H, NH).

[0398] 13 C NMR(75MHz,DMSO-d6)δppm:57.36(C-2),123.80(C-5),126.38(C-8),126.86(C-10),128.62(C-2',6'),1 28.67(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).

[0399] Product 149: 6-nitro-2-(4-hydroxyphenyl)-2,3-dihydro-1,3-benzothiazine-4-one

[0400]

[0401] 1 H NMR(400MHz,DMSO-d6)δppm 6.21(d,J=3.18Hz,1H),6.76(m,J=8.68Hz,2H),7.31(m,J=8.68Hz,2H),7.62(d,J =8.56Hz, 1H), 8.18-8.27 (m, 1H), 8.69 (d, J = 2.69Hz, 1H), 9.27 (d, J = 3.18Hz, 1H).

[0402] 13 C NMR(75MHz,DMSO-d6)δppm 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).

[0403] Chemical formula: C 14 H 10 N2O4S:m / z:302.04.

[0404] Product 151: 6-nitro-2-(2-hydroxyphenyl)-2,3-dihydro-1,3-benzothiazine-4-one

[0405]

[0406] 1 H NMR(400MHz,DMSO-d6)δppm 6.25(d,J=3.91Hz,1H),6.78(t,J=7.52Hz,1H),6.87(d,J=7.46Hz,1H),7.17(t,J=8.50Hz,1H),7.22(d,J=7.58Hz,1H), 7.58(d,J=8.56Hz,1H),8.22(dd,J=8.68,2.69Hz,1H),8.74(d,J=2.57Hz,1H),9.18(d,J=3.91Hz,1H),10.16(s,1H,OH).

[0407] 13C NMR(101MHz,DMSO-d6)δppm 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),1 26.80(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).

[0408] Chemical formula: C 14 H 10 N2O4S:m / z:302.04.

[0409] Product 152: 6-nitro-2-(4-methoxyphenyl)-2,3-dihydro-1,3-benzothiazin-4-one

[0410]

[0411] 1 H NMR(400MHz,DMSO-d6)δppm 3.75(s,3H),6.27(d,J=3.55Hz,1H),6.95(m,J=8.80Hz,2H),7.42(m,J=8.68Hz,2H ), 7.64 (d, J = 8.68Hz, 1H), 8.25 (d, J = 11.37Hz, 1H), 8.70 (s, 1H), 9.36 (br.s., 1H).

[0412] Chemical formula: C 15 H 12 N2O4S:m / z:316.05.

[0413] Product 153: 6-nitro-2-(3-methoxyphenyl)-2,3-dihydro-1,3-benzothiazin-4-one

[0414]

[0415] 1 H NMR(300MHz,DMSO-d6)δppm 3.74(s,3H),6.27(d,J=3.85Hz,1H),6.94(s,1H),7.04(s,2H),7.25-7.36(m,1H),7.64(d,J =8.71Hz, 1H), 8.24 (dd, J = 8.71, 2.66Hz, 1H), 8.70 (d, J = 2.57Hz, 1H), 9.42 (d, J = 3.85Hz, 1H).

[0416] 13 C NMR(75MHz,DMSO-d6)δppm 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).

[0417] Chemical formula: C 15 H 12 N2O4S:m / z:316.05.

[0418] Product 154: 6-nitro-2-(2-methoxyphenyl)-2,3-dihydro-1,3-benzothiazin-4-one

[0419]

[0420] 1 H NMR(400MHz,DMSO-d6)δppm 3.85(s,3H),6.27(d,J=4.16Hz,1H),6.93(t,J=7.52Hz,1H),7.07(d,J=7.95Hz,1H),7.28(d,J=9.05Hz,1H),7. 34(t,J=8.62Hz,1H),7.57(d,J=8.68Hz,1H),8.16-8.26(m,1H),8.74(d,J=2.69Hz,1H),9.21(d,J=4.28Hz,1H).

[0421] 13 C NMR(101MHz,DMSO-d6)δppm 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).

[0422] Chemical formula: C 15 H 12 N2O4S:m / z:316.05.

[0423] Product 155: 6-nitro-2-(4-ethoxyphenyl)-2,3-dihydro-1,3-benzothiazine-4-one

[0424]

[0425] 1 H NMR(400MHz,DMSO-d6)δppm 1.30(t,J=6.97Hz,3H),4.01(q,J=6.97Hz,2H),6.26(d,J=3.42Hz,1H),6.93(d,J=8.68Hz,2H),7.40(d,J=8.68 Hz, 2H), 7.63 (d, J = 8.68Hz, 1H), 8.24 (dd, J = 8.68, 2.69Hz, 1H), 8.70 (d, J = 2.57Hz, 1H), 9.35 (d, J = 3.30Hz, 1H).

[0426] Chemical formula: C 16 H 14 N2O4S:m / z:330.07.

[0427] Product 157: 6-nitro-2-(2-ethoxyphenyl)-2,3-dihydro-1,3-benzothiazine-4-one

[0428]

[0429] 1 H NMR(400MHz,DMSO-d6)δppm 1.36(t,J=6.97Hz,3H),4.07-4.16(m,2H),6.26(d,J=4.40Hz,1H),6.91(t,J=7.52Hz,1H),7.06(d,J=7.83Hz,1H),7.24(s,1 H), 7.27-7.36 (m, 1H), 7.57 (d, J = 8.68Hz, 1H), 8.21 (dd, J = 8.68, 2.69Hz, 1H), 8.75 (d, J = 2.57Hz, 1H), 9.20 (d, J = 4.28Hz, 1H).

[0430] 13C NMR(101MHz,DMSO-d6)δppm 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),1 26.58(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).

[0431] Chemical formula: C 16 H 14 N2O4S:m / z:330.07.

[0432] Product 158: 6-nitro-2-(4-propoxyphenyl)-2,3-dihydro-1,3-benzothiazine-4-one

[0433]

[0434] 1 H NMR(300MHz,DMSO-d6)δppm 0.95(t,J=7.38Hz,3H),1.60-1.82(m,2H),3.91(t,J=6.51Hz,2H),6.26(d,J=3.48Hz,1H),6.93(m,J=8.71Hz,2H),7.40( m, J=8.71Hz, 2H), 7.63 (d, J=8.71Hz, 1H), 8.24 (dd, J=8.62, 2.66Hz, 1H), 8.70 (d, J=2.57Hz, 1H), 9.34 (d, J=3.48Hz, 1H).

[0435] Chemical formula: C 17 H 16 N2O4S:m / z:344.08.

[0436] Product 161: 6-nitro-2-(4-butoxyphenyl)-2,3-dihydro-1,3-benzothiazine-4-one

[0437]

[0438] 1H NMR(400MHz,DMSO-d6)δppm 0.92(t,J=7.40Hz,3H),1.35-1.48(m,2H),1.62-1.73(m,2H),3.95(t,J=6.48Hz,2H),6.26(d,J=3.55Hz,1H),6.93(m,J=8.6 8Hz, 2H), 7.40 (m, J = 8.56Hz, 2H), 7.63 (d, J = 8.68Hz, 1H), 8.19-8.28 (m, 1H), 8.70 (d, J = 2.57Hz, 1H), 9.34 (d, J = 3.42Hz, 1H).

[0439] 13 C NMR(101MHz,DMSO-d6)δppm 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).

[0440] Chemical formula: C 18 H 18 N2O4S:m / z:358.10.

[0441] Product 167: 6-nitro-2-[4-(hexyloxy)phenyl]-2,3-dihydro-1,3-benzothiazine-4-one

[0442]

[0443] 1 H NMR(400MHz,DMSO-d6)δppm 0.80-0.92(m,3H),1.30(d,J=7.21Hz,4H),1.40(d,J=6.72Hz,2H),1.62-1.74(m,2H),3.94(t,J=6.54Hz,2H),6.26(d,J=3.42Hz,1H),6.93(m, J=8.68Hz,2H),7.39(m,J=8.68Hz,2H),7.63(d,J=8.68Hz,1H),8.24(dd,J=8.68,2.69Hz,1H),8.70(d,J=2.57Hz,1H),9.34(d,J=3.42Hz,1H).

[0444] 13 C NMR(101MHz,DMSO-d6)δppm 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).

[0445] Chemical formula: C 20 H 22 N2O4S:m / z:386.13.

[0446] Product 182: 6-nitro-2-[4-(undecyloxy)phenyl]-2,3-dihydro-1,3-benzothiazin-4-one

[0447]

[0448] 1 H NMR(300MHz,DMSO-d6)δppm 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=6.46Hz,2H),6.25(d,J=3.48Hz,1H),6.92(m,J=8. 80Hz, 2H), 7.39 (m, J = 8.71Hz, 2H), 7.63 (d, J = 8.71Hz, 1H), 8.24 (d, J = 11.37Hz, 1H), 8.69 (d, J = 2.66Hz, 1H), 9.34 (d, J = 3.39Hz, 1H).

[0449] Chemical formula: C 25 H 32 N2O4S:m / z:456.21.

[0450] Product 185: 6-nitro-2-(4-dodecyloxyphenyl)-2,3-dihydro-1,3-benzothiazine-4-one

[0451]

[0452] 1H NMR(400MHz,DMSO-d6)δppm 0.85(t,J=6.72Hz,3H),1.24(br.s.,16H),1.38(br.s.,2H),1.62-1.75(m,2H),3.94(t,J=6.48Hz,2H),6.26(d,J=3.42Hz,1H),6.92( m,J=8.80Hz,2H),7.39(m,J=8.80Hz,2H),7.63(d,J=8.68Hz,1H),8.24(dd,J=8.68,2.57Hz,1H),8.70(s,1H),9.34(d,J=3.30Hz,1H).

[0453] Chemical formula: C 26 H 34 N2O4S:m / z:470.22.

[0454] Product 191: 6-nitro-2-(4-tetradecoxyphenyl)-2,3-dihydro-1,3-benzothiazin-4-one

[0455]

[0456] 1 H NMR(400MHz,DMSO-d6)δppm 0.85(t,J=6.72Hz,3H),1.24(br.s.,16H),1.38(br.s.,2H),1.62-1.75(m,2H),3.94(t,J=6.48Hz,2H),6.26(d,J=3.42Hz,1H),6.92( m,J=8.80Hz,2H),7.39(m,J=8.80Hz,2H),7.63(d,J=8.68Hz,1H),8.24(dd,J=8.68,2.57Hz,1H),8.70(s,1H),9.34(d,J=3.30Hz,1H).

[0457] 13C NMR (101MHz, DMSO-d6) δppm 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),128.7 4(C-7),129.27(C-1'),145.03(C-6),145.26(C-9),159.08(C-4'),162.87(C-4).

[0458] Chemical formula: C 26 H 34 N2O4S:m / z:470.22.

[0459] Product 194: 6-nitro-2-(4-phenoxyphenyl)-2,3-dihydro-1,3-benzothiazine-4-one

[0460]

[0461] 1 H NMR(400MHz,DMSO-d6)δppm 6.32(d,J=3.55Hz,1H),6.96-7.06(m,4H),7.13-7.23(m,1H),7.35-7.45(m,2H),7.50(d,J=8.56Hz, 2H), 7.65 (d, J = 8.56Hz, 1H), 8.26 (d, J = 2.69Hz, 1H), 8.70 (d, J = 2.57Hz, 1H), 9.40 (d, J = 3.67Hz, 1H).

[0462] 13 C NMR(101MHz,DMSO-d6)δppm 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).

[0463] Chemical formula: C 20 H 14 N2O4S:m / z:378.07.

[0464] Product 195: 6-nitro-2-(3-phenoxyphenyl)-2,3-dihydro-1,3-benzothiazine-4-one

[0465]

[0466] 1 H NMR(400MHz,DMSO-d6)δppm 6.28(d,J=4.16Hz,1H),6.91-7.01(m,3H),7.01-7.05(m,1H),7.10-7.18(m,1H),7.22(d,J=7.83Hz,1H),7.33 -7.44(m,3H),7.62(d,J=8.68Hz,1H),8.24(d,J=2.69Hz,1H),8.63(d,J=2.57Hz,1H),9.44(d,J=4.16Hz,1H).

[0467] Chemical formula: C 20 H 14 N2O4S:m / z:378.07.

[0468] Product 196: 6-nitro-2-(2-phenoxyphenyl)-2,3-dihydro-1,3-benzothiazine-4-one

[0469]

[0470] 1 H NMR(300MHz,DMSO-d6)δppm 6.42(d,J=3.85Hz,1H),6.84(d,J=8.16Hz,1H),7.04(d,J=8.71Hz,2H),7.16(q,J=7.67Hz,2H),7.30-7.45(m,3H), 7.50 (d, J = 9.26 Hz, 1H), 7.59 (d, J = 8.71 Hz, 1H), 8.18-8.25 (m, 1H), 8.72 (d, J = 2.66 Hz, 1H), 9.34 (d, J = 3.85 Hz, 1H).

[0471] 13C NMR(75MHz,DMSO-d6)δppm 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).

[0472] Chemical formula: C 20 H 14 N2O4S:m / z:378.07.

[0473] General steps

[0474] The nitro group was reduced to an amino group in a hydrogenation apparatus. The nitro derivative (1 mmol) was added to a flask along with Pd / C (10% by weight) and ethanol (20 mL). The flask was shaken at room temperature under 50 psi hydrogen until TLC no longer showed the presence of the starting material. The solution was then filtered off, and the solvent was removed under reduced pressure. The desired amino derivative was then crystallized in diethyl ether.

[0475] Product 96: 6-nitro-2-(4-phenoxyphenyl)-2,3-dihydro-1H-quinazolin-4-one

[0476]

[0477] 1 H NMR(300MHz,DMSO-d6)δppm 6.02(s,1H)6.84(d,J=9.17Hz,1H)7.05(d,J=8.62Hz,2H)7.00(d,J=8.80Hz,2H)7.12-7.21(m,1H)7.35-7.4 5(m,2H)7.49(d,J=8.62Hz,2H)8.11(dd,J=9.08,2.75Hz,1H)8.44(d,J=2.75Hz,1H)8.53(s,1H)8.71(s,1H).

[0478] 13C NMR(75MHz,DMSO-d6)δppm:66.17(C-2),114.40(C-8),114.89(C-10),11 8.26(C-8”,C-12’),118.71(C-3’,C-5’),123.61(C-10’),124.35(C-5),1 28.30(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).

[0479] Chemical formula: C 20 H 15 N3O4:m / z:361.11.

[0480] Product 97: 6-nitro-2-(3-phenoxyphenyl)-2,3-dihydro-1H-quinazolin-4-one

[0481]

[0482] 1 H NMR(300MHz,DMSO-d6)δppm:6.01(br.s.,1H,C-H2),6.82(t.,1H,CH 10' ), 6.99 (d, J = 7.61 Hz, 3H, CH) 8,9',11' ), 7.07-7.19(m,2H,CH) 8',12' ), 7.23 (d, J = 7.24 Hz, 1H, CH) 2' ), 7.31-7.51(m,3H,CH 4',5',6' ), 8.09 (d, J = 8.89Hz, 1H, C-H7), 8.41 (br.s., 1H, C-H5), 8.59 (br.s., 1H, NH), 8.78 (br.s., 1H, NH).

[0483] 13C NMR(75MHz,DMSO-d6)δppm:65.73(C-2),112.74(C-10),114.32(C-8),116.4 6(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).

[0484] Product 98: 6-nitro-2-(2-phenoxyphenyl)-2,3-dihydro-1H-quinazolin-4-one

[0485]

[0486] 1 H NMR(300MHz,DMSO-d6)δppm 6.28(s,1H),6.74(d,J=9.08Hz,1H),6.84(d,J=7.89Hz,1H),6.97(d,J=7.70Hz,2H),7.07-7.24(m,2H),7.2 9-7.43(m,3H),7.54(d,J=8.99Hz,1H),7.96-8.08(m,1H),8.40(d,J=2.66Hz,1H),8.47(s,1H),8.63(s,1H).

[0487] 13 C NMR(75MHz,DMSO-d6)δppm 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).

[0488] Chemical formula: C 20 H 15 N3O4:m / z:361.11.

[0489] Product 99: 6-Amino-2-phenyl-2,3-dihydro-1,3-benzothiazine-4-one

[0490]

[0491] 1 H NMR (400MHz, DMSO-d6) δppm 5.28 (br.s, 2H, NH2), 5.84 (s, 1H, C-H2), 6.61-6.69 (m, 1H), 6.92 (d, J = 8.31Hz, 1H), 7.30-7.43 (m, 3H, CH 3',4',5' ), 7.41-7.523(m,2H,CH) 2',6' ), 8.61 (d, J = 3.18Hz, 1H), 9.54 (s, 1H).

[0492] 13 C NMR(75MHz,DMSO-d6)δppm 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).

[0493] Product 100: 6-Amino-2-(4-hydroxyphenyl)-2,3-dihydro-1,3-benzothiazine-4-one

[0494]

[0495] 1 H NMR(400MHz,DMSO-d6)δppm 5.28(br.s,2H,NH2),5.86(s,1H),6.61-6.69(m,1H),6.73(d,2H),6.92( d,J=8.31Hz,1H),7.21-7.31(m,3H),8.61(d,J=3.18Hz,1H),9.54(s,1H).

[0496] 13C NMR(75MHz,DMSO-d6)δppm 57.85(C-2),114.48(C-5),114.99(C-3'),118.17(C-7),120.03(C-10),127.64(C-8),1 28.34(C-2'),128.59(C-9),129.29(C-1'),147.15(C-6),157.55(C-4'),164.98(C-4).

[0497] Chemical formula: C 14 H 12 N2O2S:m / z:272.06.

[0498] Product 145: 6-Amino-2-(4-phenoxyphenyl)-2,3-dihydro-1,3-benzothiazine-4-one

[0499]

[0500] 1 H NMR(400MHz,DMSO-d6)δppm 5.30(br.s.,2H),5.96(d,J=3.55Hz,1H),6.67(dd,J=8.31,2.57Hz,1H),6.91-6.99(m,3H),6.99-7.05(m,2H) ,7.13-7.19(m,1H),7.25(d,J=2.57Hz,1H),7.36-7.43(m,2H),7.46(d,J=8.56Hz,2H),8.76(d,J=3.67Hz,1H).

[0501] 13 C NMR(75MHz,DMSO-d6)δppm 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),1 28.70(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).

[0502] Chemical formula: C 20 H 16 N2O2S:m / z:348.09.

[0503] Product 146: 6-amino-2-(3-phenoxyphenyl)-2,3-dihydro-1,3-benzothiazine-4-one

[0504]

[0505] 1 H NMR(400MHz,DMSO-d6)δppm 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 =7.58Hz,1H),7.25-7.39(m,4H),7.47(d,J=7.95Hz,1H),7.99(s,1H),9.13(br.s.,1H).

[0506] Chemical formula: C 20 H 16 N2O2S:m / z:348.09.

[0507] Product 158: 6-nitro-2-(4-propoxyphenyl)-2,3-dihydro-1,3-benzothiazine-4-one

[0508]

[0509] 1 H NMR(300MHz,DMSO-d6)δppm 0.95(t,J=7.38Hz,3H),1.60-1.82(m,2H),3.91(t,J=6.51Hz,2H),6.26(d,J=3.48Hz,1H),6.93(m,J=8.71Hz,2H),7.40( m, J=8.71Hz, 2H), 7.63 (d, J=8.71Hz, 1H), 8.24 (dd, J=8.62, 2.66Hz, 1H), 8.70 (d, J=2.57Hz, 1H), 9.34 (d, J=3.48Hz, 1H).

[0510] 13 C NMR(75MHz,DMSO-d6)δppm 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'),1 28.58(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).

[0511] Chemical formula: C 17 H 16 N2O4S:m / z:344.08.

[0512] Example 3. Chemical analysis of dihydrobenzoxazine derivatives

[0513] General procedure: Use the same method as for benzothiazide:

[0514]

[0515] Product 243: 6-amino-2-(4-phenoxyphenyl)-2,3-dihydro-1,3-benzoxazine-4-one

[0516] 1 H NMR (400MHz, DMSO-d6) δppm 6.17 (d, 1H, J = 1.33Hz, C-H2), 6.75 (m, 2H, CH 5,7 ),6.01-6.04(d,4H,J=8.5Hz,C-H3' ,6 '), 7.17 (dt, 1H, J = 7.55Hz, C-H8'), 7.41 (dt, 2H, J = 7.56Hz, C-H7'), 7.54-7.57 (d, 2H, J = 8.5Hz, C-H2'), 8.72 (d, 1H, J = 1.3Hz, N-H3).

[0517] 13 C NMR(75MHz,DMSO-d6)δppm 84.2(2),111.44(5),117.12(8),118.23(3'),118.87(4a),119.28(6'),120.84(7),124.11(8'),12 9.46(2'),130.37(7'),132.31(1'),143.59(6),148.32(4'),156.33(5'),157.93(8a),163.37(4).

[0518] Chemical formula: C 20 H 16 N2O3:m / z:332.12.

[0519] Product 244: 6-amino-2-(3-phenoxyphenyl)-2,3-dihydro-1,3-benzoxazine-4-one

[0520]

[0521] 1H NMR (400MHz, DMSO-d6) δppm 5.30 (bs, 2H, NH2), 6.17 (d, 1H, J = 1.70Hz, C-H2), 6.73 (m, 2H, CH 5,7 ), 6.99-7.04(m, 4H, CH 8’,9’ ), 7.14-7.16(m,2H,CH) 10’,8 ),7.29-7.31(d,1H,J=7.74Hz,CH 6’ ), 7.36-7.44(m,3H,CH) 2’,4’,5’ ),8.76(d,1H,N-H3).

[0522] 13 C NMR(75MHz,DMSO-d6)δppm 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'),12 3.79(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).

[0523] Chemical formula: C 20 H 16 N2O3:m / z:332.12.

[0524] Product 246: 6-nitro-2-phenyl-2,3-dihydro-1,3-benzoxazine-4-one

[0525]

[0526] 1 H NMR(300MHz,DMSO-d6)δppm 6.59(d,1H,J=1.13Hz,C-H2),7.29-7.32(d,1H,J=9.07Hz,C-H8),7.42-7.48(m,3H,C-H3',4',5'),7.58-7.60(d,2 H, J=8.68Hz, C-H2',6'), 8.34-8.38 (dd, 1H, J=2.83, 9.07Hz, C-H7), 8.54 (d, 1H, J=2.84Hz, C-H5), 9.41 (bs, 1H, NH).

[0527] 13C NMR(75MHz,DMSO-d6)δppm 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).

[0528] Chemical formula: C 14 H 10 N2O4:m / z:270.06

[0529] Product 292: 6-nitro-2-(4-phenoxyphenyl)-2,3-dihydro-1,3-benzoxazine-4-one

[0530]

[0531] 1 H NMR(400MHz,DMSO-d6)δppm 6.58(d,1H,J=1.13Hz,C-H2),7.03-7.08(m,4H,C-H3',6'),7.19(t,1H, J=7.55Hz,C-H8'),7.29-7.32(d,1H,J=9.07Hz,C-H8),7.42(dt,2H,J=7 .37Hz,C-H7'),7.59-7.62(d,2H,J=8.68Hz,C-H2'),8.35-8.39(dd,1H,J=2.83,9.07Hz,C-H7),8.54(d,1H,J=2.84Hz,C-H5),9.37(bs,1H,NH).

[0532] 13 C NMR(75MHz,DMSO-d6)δppm 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).

[0533] Chemical formula: C 20 H 14 N2O5:m / z:362.09.

[0534] Product 293: 6-nitro-2-(3-phenoxyphenyl)-2,3-dihydro-1,3-benzoxazine-4-one

[0535]

[0536] 1 H NMR (400MHz, DMSO-d6) δppm 6.58 (d, 1H, J = 1.32Hz, C-H2), 7.00-7.03 (d, 2H, J = 7.75Hz, CH 8’ ), 7.07-7.19(m,3H,CH 9’,10’ ),7.28-7.31(d,1H,J=9.07Hz,C-H8),7.33-7.48(m,4H,C-H2' ,4 ' ,5 ' ,6 '),8.33-8.37(dd,1H,J=2.83,9.07Hz,C-H7),8.50-8.51(d,1H,J=2.84Hz,C-H5),9.43(bs,1H,NH).

[0537] 13 C NMR(75MHz,DMSO-d6)δppm 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).

[0538] Chemical formula: C 20 H 14 N2O5:m / z:362.09.

[0539] Example 4. Binding activity

[0540] 4.1. Binding activity to OX1R and OX2R sites

[0541] These compounds exhibited activity as agonists against OX1R and / or OX2R, which was determined by Eurofins using Chinese hamster ovary (CHO) cells expressing human OX1R and human embryonic kidney (HEK) 293 cells expressing human OX2R according to the following general experimental methods.

[0542] Materials and methods

[0543] OX1(h) (Agonist radioligand) Human recombinant (CHO cells); Ligand [125I] orexin A; Ligand concentration: 0.1 nM; Ligand Kd: 0.87 nM; Nonspecific: SB 334867 (1 μM); Incubation: 60 min at room temperature, scintillation count; Control inhibitor: orexin-A; Test concentration / dose: IC / EC50 calculation provided if 5 or more concentrations are selected; Test sample requirements: Minimum 1) Screening: 60 μl of 10 mM stock solution - OR - 1 mg (pre-weighed) for the final 10 μM test. 2) Dose response: 90 μl of 10 mM stock solution - OR - 1 mg (pre-weighed) for the highest 10 μM concentration.

[0544] OX2(h) (Agonist radioligand) Human recombinant (HEK-293 cells); Ligand [125I] Orexin A; Ligand concentration: 0.04 nM; Ligand Kd: 0.2 nM; Nonspecific: Orexin-B (1 μM); Incubation: 180 min at room temperature, scintillation count; Control inhibitor: Orexin-B; Test concentration / dose: IC / EC50 calculation provided if 5 or more concentrations are selected; Test sample requirements: Minimum 1) Screening: 60 μl of 10 mM stock solution - OR - 1 mg (pre-weighed) for the final 10 μM test. 2) Dose response: 90 μl of 10 mM stock solution - OR - 1 mg (pre-weighed) for the highest 10 μM concentration.

[0545] The compounds listed in Table 1 are in 10 -5 M was tested and calculated as the control inhibition (IC) of specific binding of radiolabeled ligands to targets OX1R and / or OX2R.

[0546] The definition of this binding profile panel is broad, encompassing approximately equal numbers of selective, centrally and peripherally therapeutically relevant targets, including natural animal tissues, radioligands, and specific enzymes involved in cell cycle regulation, in accordance with Eurofins standard operating procedures.

[0547] For radioligand binding experiments, the Hill equation fitting method was used, and the half-maximal inhibitory concentration (IC50) was determined by nonlinear regression analysis of the competition curves (via computer software). 50 ) and half-maximum effective concentration (EC50) 50 Suppression constant (K) i Using the Cheng-Prusoff equation (K) i =IC 50 / (1+(L / K D ))Calculate, where L is the concentration of the radioactive ligand in the experiment, and KD The affinity of the radioligand for the receptor (Cheng and Prusoff 1973).

[0548] result

[0549] The results obtained from these combined experiments are shown in Table 1.

[0550] Table 1. These selected nitro or amino dihydroquinazoline, nitro or amino dihydrobenzothiazide, and nitro or amino dihydrobenzoxazine derivatives as agonists in 10 -5 Binding activity of OX1R and OX2R during M assay

[0551]

[0552] The results showed that inhibition (or stimulation) between 25% and 50% indicated a weak to moderate effect.

[0553] Results with inhibition (or stimulation) of less than 25% were not considered significant, primarily due to changes in signal near the control level.

[0554] Results showing inhibition (or stimulation in experiments conducted under basal conditions) of more than 50% are considered to represent a significant effect of the tested compound.

[0555] Low to moderate negative values ​​are meaningless and are attributed to changes in signal near the control level. High negative values ​​(≥50%) obtained with high concentrations of the test compound are often attributed to non-specific effects of the test compound in the experiment. In rare cases, they may suggest an allosteric effect of the test compound.

[0556] Table 2. Pharmacological activities of these selected dihydroquinazoline, dihydrobenzothiazide, and dihydrobenzoxazine derivatives as agonists against OX1R and OX2R.

[0557]

[0558] *: According to OECD Guideline No. 487, compounds that have been shown to be non-mutagenic by in vitro micronucleus assays.

[0559] 4.2. Binding activity to dopamine and norepinephrine transporters, metabolized glutamate 2, cathepsin-H and Sigma-1 receptors

[0560] It has long been reported that noradrenergic cells in the locus coeruleus (Hagan et al. 1999; Horvath et al. 1999) and dopaminergic cells in the ventral tegmental area (Nakamura et al. 2000) can increase their firing frequency through orexin. It is well known that the firing frequency of these monoaminergic neurons is correlated with sleep / wake states. They exhibit a firing pattern similar to that of orexin neurons, showing predominantly tetanic firing during wakefulness, less firing during NREM sleep, and ceasing firing during REM sleep (Vanni-Mercier, Sakai, and Jouvet 1984).

[0561] Previous studies have shown that arousal mediated by the firing of these wake-active monoaminergic neurons is supported by orexin.

[0562] Recent reports have indicated that the orexin-to-dopamine circuits mediated by OX2R play an important role in regulating theta oscillations in alert states (Bandarabadi et al. 2022).

[0563] In addition to orexin being able to regulate firing frequency and induce burst firing by activating receptors on somatic dendritic compartments, OX2R can also exert presynaptic effects at the levels of dopaminergic and glutamatergic axons (Bandarabadi et al. 2022).

[0564] Product 152 at 10 -5 M significantly targets OX2R (as an agonist, IC 73%) and OX1R (as an agonist, IC 63%), and also acts on metabolite glutamate 2 (mGlu2) receptors. It is used to treat mental illnesses including schizophrenia, depression, and anxiety disorders, which are characterized by glutamatergic dysfunction, and has a significant binding effect (IC 54%).

[0565] Using a rat sleep-wake EEG model, we studied central functional activity and target involvement after mGluR2 signal inactivation, demonstrating that mGluR2 antagonistic activity is associated with enhanced θ / γ oscillations and increased transition from sleep to wakefulness (Ahnaou, Ver Donck, and Drinkenburg 2014).

[0566] Product 194 at 10 -5It significantly targets OX2R (as an agonist, IC 84%) and weakly targets OX1R (as an agonist, IC < 50%). It acts on the dopamine transporter (DAT) and norepinephrine transporter (NET) as a catecholamine reuptake inhibitor, and has binding activity to DAT (IC 89%) and NET (IC 58%).

[0567] Treatments targeting cathepsins may help prevent or slow the pathogenesis of neurodegenerative diseases, such as neuronal ceroid lipofuscin deposition, synucleinopathies (Parkinson's disease, Lewy body dementia, and multiple system atrophy), as well as Alzheimer's disease and Huntington's disease (Stoka et al. 2023).

[0568] Cathepsin H (CTSH) is a lysosomal cysteine ​​protease that plays a role in a variety of physiological processes, including immune responses. In the context of neuroinflammation, CTSH is thought to be involved in regulating immune responses within the central nervous system (Wang et al. 2023). Neuroinflammation refers to an inflammatory response in neural tissue, typically involving glial cell activation and the release of pro-inflammatory molecules.

[0569] CTSH can influence neuroinflammation by participating in antigen processing and presentation, which is crucial for activating immune cells such as microglia. Previous studies have also suggested that CTSH may be involved in the pathogenesis of narcolepsy (Mogavero et al. 2023).

[0570] Product 96 in 10 -5 M targets OX1R (as an agonist, IC 56%) and CTSH (as an antagonist, IC 80%), and also acts on the dopamine transporter (DAT) and norepinephrine transporter (NET) as a catecholamine reuptake inhibitor, with binding activity to DAT (IC 99%) and NET (IC 77%).

[0571] Sigma-1 receptor (S1R) is involved in various physiological and pathological processes, such as neurotransmission, neuroprotection, and neuroinflammation. It is considered a therapeutic target for a range of neurodegenerative diseases, including amnesia and Alzheimer's disease (AD), as well as various synucleinopathies (Wang and Jia 2023).

[0572] S1R agonists have been found to have multiple potential beneficial mechanisms of action for AD, such as anti-inflammatory and antioxidant effects, regulation of neurotransmitters, and neuroprotective effects by inhibiting Aβ aggregation and tau hyperphosphorylation in AD (Cummings, Osse, and Kinney 2023; Malar et al. 2023; Shinoda, Nemoto, and Iwamoto 2023).

[0573] Product 90 in 10 -5 M-type receptors target OX2R (as an agonist, IC 67%) and S1R (as an antagonist, IC 75%).

[0574] References

[0575] Ahnaou, A., L. Ver Donck, and WHIMDrinkenburg. 2014. "Blockade of the Metabotropic Glutamate(mGluR2) Modulates Arousal through Vigilance StatesTransitions: Evidence from Sleep-Wake EEG in Rodents." Behavioral brainresearch 270:56-67.

[0576] Alrouji, Mohammed et al. 2023. "Orexin pathway in Parkinson's disease: areview". Molecular Biology Reports: 1-14.

[0577] American Academy of Sleep Medicine. 2014. International Classification of Sleep Disorders. Darien, Ill.: American Acad. of Sleep Medicine.

[0578] Baimel, Corey et al. 2015. "Orexin / Hypocretin Role in Reward: Implications for Opioid and Other Addictions". British Journal of Pharmacology 172(2):334-48.

[0579] Bandarabadi, Mojtaba et al. 2022. "Orexin action on the dopaminergic system modulates theta during REM sleep and wakefulness". bioRxiv: 2022.01.30.478401.

[0580] Beitz, Janice M. 2014. "Parkinson’s disease: a review". Front Biosci(ScholEd) 6(1): 65 - 74.

[0581] Berhe, Derbew Fikadu, Abadi Kahsu Gebre, and Brhane Teklebrhan Assefa. 2020. "Orexins role in neurodegenerative diseases: From pathogenesis to treatment". Pharmacology Biochemistry and Behavior 194: 172 - 929.

[0582] Bogen, Stephane L et al. 2021. "5 - alkyl pyrrolidine orexin receptor agonists".

[0583] Boudet, R. 1959. "Sur un nouvel ensemble hétérocyclique du type benzo - meta - thiazine.2.". Bulletin de la Société Chimique de France(11 - 1): 1791 - 93.

[0584] Cao, Michelle T., and Christian Guilleminault. 2017. "Chapter 90 - Narcolepsy: Diagnosis and Management". In Principles and Practice of Sleep Medicine(Sixth Edition), éd. Meir Kryger, Thomas Roth, et William C. Dement. Elsevier, 873 - 882.e5. https: / / www.sciencedirect.com / science / article / pii / B9780323242882000908.

[0585] Cason, Angie M. et al. 2010. 《Role of Orexin / Hypocretin in Reward-Seeking and Addiction: Implications for Obesity.》Physiology & behavior 100(5):419-28.

[0586] Chen, Xin-Yi, Lei Chen, and Yi-Feng Du. 2017. 《Orexin-A increases the firing activity of hippocampal CA1 neurons through orexin-1 receptors》. Journal of Neuroscience Research 95(7):1415-26.

[0587] Cheng, Y., and W.H. Prusoff. 1973. 《Relationship between the Inhibition Constant (K1) and the Concentration of Inhibitor Which Causes 50 per Cent Inhibition (I50) of an Enzymatic Reaction.》Biochemical pharmacology 22(23):3099-3108.

[0588] Chinigo, Gary M. et al. 2008. 《Asymmetric synthesis of 2,3-dihydro-2-arylquinazolin-4-ones: methodology and application to a potent fluorescent tubulin inhibitor with anticancer activity》. Journal of medicinal chemistry 51(15):4620-31.

[0589] Cortese, Samuele, Eric Konofal, and Michel Lecendreux. 2008. "Alertness and Feeding Behaviors in ADHD: Does the Hypocretin / Orexin System Play a Role?" Medical hypotheses 71(5):770 - 75.

[0590] Couvineau, Alain, and Marc Laburthe. 2012. "VPAC Receptors: Structure, Molecular Pharmacology and Interaction with Accessory Proteins". British journal of pharmacology 166(1):42 - 50.

[0591] Cox, Sarah J. et al. 2020. "High - throughput screening at the membrane interface reveals inhibitors of amyloid - β". Biochemistry 59(24):2249 - 58.

[0592] Cummings, Jeffrey L., Amanda M. Leisgang Osse, and Jefferson W. Kinney. 2023. "Alzheimer’s Disease: Novel Targets and Investigational Drugs for Disease Modification". Drugs: 1 - 22.

[0593] Dauvilliers, Yves et al. 2023. "Oral Orexin Receptor 2 Agonist in Narcolepsy Type 1". New England Journal of Medicine 389(4):309 - 21.

[0594] Drouot, X. et al. 2003. "Low levels of ventricular CSF orexin / hypocretin in advanced PD". Neurology 61(4):540 - 43.

[0595] Duffy, C.M., J.J. Hofmeister, J.P. Nixon, and T.A. Butterick. 2019. "High fat diet increases cognitive decline and neuroinflammation in a model of orexin loss". Neurobiology of Learning and Memory 157:41 - 47.

[0596] Esmaeili - Mahani, Saeed et al. 2013. "Protective effect of orexin - A on 6 - hydroxydopamine - induced neurotoxicity in SH - SY5Y human dopaminergic neuroblastoma cells". Neurochemistry International 63(8):719 - 25.

[0597] Fan, Jing Kai et al. 2023. "α - Synuclein Induced the Occurrence of RBD via Interaction with OX1R and Modulated Its Degradation". NeuroMolecular Medicine. https: / / doi.org / 10.1007 / s12017 - 023 - 08735 - 4.

[0598] Feng, Ya et al. 2014. "Neuroprotection by Orexin - A via HIF - 1α induction in a cellular model of Parkinson’s disease". Neuroscience letters 579:35 - 40.

[0599] Fronczek, Rolf et al. 2007. "Hypocretin(orexin) loss in Parkinson’s disease". Brain 130(6):1577 - 85.

[0600] Fujimoto, Tatsuhiko et al. 2022. 《Discovery of TAK-925 as a Potent, Selective, and Brain-Penetrant Orexin 2 Receptor Agonist.》 ACS medicinal chemistry letters 13(3):457-62.

[0601] Gao, Fan, Tao Liu, Miao Tuo, and Song Chi. 2021. 《The role of orexin in Alzheimer disease: From sleep-wake disturbance to therapeutic target》. Neuroscience Letters 765:136247.

[0602] Geng, H.J. et al. 2012. 《Design, synthesis and antifungal activity of 2-aryl-2,3-dihydro-4H-1,3-benzothiazin-4-one derivatives》. Journal of Shenyang Pharmaceutical University 29(11):834-315.

[0603] Hadadianpour, Zahra et al. 2017. 《The effect of orexin-A on motor and cognitive functions in a rat model of Parkinson’s disease》. Neurological Research 39(9):845-51.

[0604] Hagan, J.J. et al. 1999. 《Orexin A Activates Locus Coeruleus Cell Firing and Increases Arousal in the Rat.》 Proceedings of the National Academy of Sciences of the United States of America 96(19):10911-16.

[0605] Harris, Glenda C., Mathieu Wimmer, and Gary Aston-Jones. 2005. 《A Role for Lateral Hypothalamic Orexin Neurons in Reward Seeking.》Nature 437(7058):556 - 59.

[0606] Heifetz, Alexander et al. 2013. 《Toward an Understanding of Agonist Binding to Human Orexin-1 and Orexin-2 Receptors with G-Protein-Coupled Receptor Modeling and Site-Directed Mutagenesis》. Biochemistry 52(46):8246 - 60.

[0607] Hervieu, G.J. et al. 2001. 《Gene expression and protein distribution of the orexin-1 receptor in the rat brain and spinal cord》. Neuroscience 103(3):777 - 97.

[0608] Hornykiewicz, O., and S.J. Kish. 1987. 《Advances in Neurology, Parkinson’s Disease》.

[0609] Hornykiewicz, Oleh. 1975. 《Brain monoamines and parkinsonism》. Natl Inst Drug Abuse Res Monogr Ser 3:13 - 21.

[0610] Horvath, T.L. et al. 1999. 《Hypocretin (Orexin) Activation and Synaptic Innervation of the Locus Coeruleus Noradrenergic System.》The Journal of comparative neurology 415(2):145 - 59.

[0611] Hu, Bo et al. 2015. "Roles of the orexin system in central motor control". Neuroscience & Biobehavioral Reviews 49:43 - 54.

[0612] Ingram, Jack S., and Ernest W. McClelland. 1947. "146. The formation of some benz - 1:3 - thiazine derivatives by the reduction of benz iso thiazolones". Journal of the Chemical Society (Resumed):763 - 64.

[0613] Ishikawa, Takashi et al. 2023. "TAK - 994, a novel orally available brain - penetrant orexin 2 receptor - selective agonist, suppresses fragmentation of wakefulness and cataplexy - like episodes in mouse models of narcolepsy". Journal of Pharmacology and Experimental Therapeutics 385(3):193 - 204.

[0614] Johnson, Philip L et al. 2010. "A key role for orexin in panic anxiety". Nature Medicine 16(1):111 - 15.

[0615] Kanbayashi, Takashi et al. 2002. "CSF hypocretin - 1(orexin - A) concentrations in narcolepsy with and without cataplexy and idiopathic hypersomnia". Journal of sleep research 11(1):91 - 93.

[0616] Katsuki, Hiroshi, and Shotaro Michinaga. 2012. 《Anti-Parkinson Drugs and Orexin Neurons.》 Vitamins and hormones 89:279-90.

[0617] Kim, Eunhee et al. 2023. Isoquinolinone derivatives, method for preparing the same, and pharmaceutical composition for preventing or treating poly(adp-ribose) polymerase-1-related diseases, comprising the same as active ingredient. Google Patents.

[0618] de Lecea, L. et al. 1998. 《The Hypocretins: Hypothalamus-Specific Peptides with Neuroexcitatory Activity》. Proceedings of the National Academy of Sciences of the United States of America 95(1):322-27.

[0619] Lin, L. et al. 1999. 《The Sleep Disorder Canine Narcolepsy Is Caused by a Mutation in the Hypocretin (Orexin) Receptor 2 Gene.》 Cell 98(3):365-76.

[0620] Liu, Mei-Fang et al. 2018. 《Orexin-A exerts neuroprotective effects via OX1R in Parkinson’s disease》. Frontiers in neuroscience 12:835.

[0621] Long-Biao, Cui et al. 2010. Progressive changes in the orexin system in a 6-hydroxydopa-induced rat model of Parkinson's disease. Neuroscience Bulletin 26:381-87.

[0622] Malar,Dicson S. et al. 2023. "Targeting Sigma Receptors for the Treatment of Neurodegenerative and Neurodevelopmental Disorders". CNS drugs:1-42.

[0623] Meerwaldt, JD, and AHovestadt. 1988. "Cognitioin in parkinsonism". Neurology38(11):1814-1814.

[0624] Mezeiova, Eva et al. 2020. "From Orexin Receptor Agonist YNT-185 to NovelAntagonists with Drug-like Properties for the Treatment of Insomnia." Bioorganic chemistry 103:104179.

[0625] Mieda, Michihiro et al. 2011. "Differential Roles of Orexin Receptor-1and-2 in the Regulation of Non-REM and REM Sleep." The Journal of neuroscience: the official journal of the Society for Neuroscience 31(17):6518-26.

[0626] ———.2017. "The Roles of Orexins in Sleep / Wake Regulation." Neuroscience research 118:56-65.

[0627] Mogavero, Maria Paola et al. 2023. "Genetics and epigenetics of rare hypersomnia". Trends in Genetics.

[0628] Morairty, Stephen R. et al. 2012. "Dual Hypocretin Receptor Antagonism Is More Effective for Sleep Promotion than Antagonism of Either Receptor Alone." PloS one 7(7):e39131.

[0629] Mordarski, M., and J.B. Chylinska. 1971. "Antitumor properties of 1,3-oxazine derivatives, derivatives of dihydro-1,3-oxazine condensed with an aromatic ring in position 5,6."

[0630] Moreau, R.C., and E. Delacoux. 1962. "PREPARATION DE QUELQUES ALCOYL-3 ARYL-2 OXO-4 DIHYDROBENZOTHIAZINES-1,3". BULLETIN DE LA SOCIETE CHIMIQUE DE FRANCE(3):502-.

[0631] Nakamura, T. et al. 2000. "Orexin-Induced Hyperlocomotion and Stereotypy Are Mediated by the Dopaminergic System." Brain research 873(1):181-87.

[0632] Nishino, Seiji. 2007. "Clinical and Neurobiological Aspects of Narcolepsy". Sleep Medicine 8(4):373-99.

[0633] Nollet, Mathieu, and Samuel Leman. 2013. "Role of Orexin in the Pathophysiology of Depression: Potential for Pharmacological Intervention." CNS drugs 27(6):411 - 22.

[0634] Ohno, Kousaku, and Takeshi Sakurai. 2008. "Orexin neuronal circuitry: Role in the regulation of sleep and wakefulness." Frontiers in Neuroendocrinology 29(1):70 - 87.

[0635] Pasban - Aliabadi, Hamzeh, Saeed Esmaeili - Mahani, and Mehdi Abbasnejad. 2017. "Orexin - A protects human neuroblastoma SH - SY5Y cells against 6 - hydroxydopamine - induced neurotoxicity: involvement of PKC and PI3K signaling pathways." Rejuvenation Research 20(2):125 - 33.

[0636] Perrey, David A, and Yanan Zhang. 2020. "Therapeutics Development for Addiction: Orexin - 1 Receptor Antagonists." Brain research 1731:145922 - 145922.

[0637] Polito, Rita et al. 2018. "Adiponectin and Orexin - A as a Potential Immunity Link Between Adipose Tissue and Central Nervous System." Frontiers in physiology 9:982.

[0638] Saito, Yuki C. et al. 2018. <<Serotonergic Input to Orexin Neurons Plays a Role in Maintaining Wakefulness and REM Sleep Architecture.>> Frontiers in neuroscience 12:892.

[0639] Sakurai, T. et al. 1998. 《Orexins and Orexin Receptors: A Family of Hypothalamic Neuropeptides and G Protein-Coupled Receptors That Regulate Feeding Behavior》. Cell 92(5):573-75.

[0640] Shinoda, Yasuharu, Takayuki Nemoto, and Takahiro Iwamoto. 2023. 《The Sigma-1 Receptor: Pathophysiological Roles and Therapeutic Potential in Neurodegenerative Diseases》. 福岡大学医学紀要=Medical Bulletin of Fukuoka University 50(1):43-48.

[0641] Siegel, J.M. 1999. 《Narcolepsy: A Key Role for Hypocretins (Orexins).》 Cell 98(4):409-12.

[0642] Smith, M.I., D.C. Piper, M.S. Duxon, and N. Upton. 2003. 《Evidence Implicating a Role for Orexin-1 Receptor Modulation of Paradoxical Sleep in the Rat.》 Neuroscience letters 341(3):256-58.

[0643] Song, Juhyun et al. 2015. "The Role of Orexin in Post-Stroke Inflammation, Cognitive Decline, and Depression." Molecular brain 8:16.

[0644] Stanojlovic, Milos, Jean Pierre Pallais, and Catherine M. Kotz. 2019. "Chemogenetic Modulation of Orexin Neurons Reverses Changes in Anxiety and Locomotor Activity in the A53T Mouse Model of Parkinson’s Disease." Frontiers in neuroscience 13:702.

[0645] Stanojlovic, Milos, Jean Pierre Pallais Yllescas, Aarthi Vijayakumar, and Catherine Kotz. 2019. "Early Sociability and Social Memory Impairment in the A53T Mouse Model of Parkinson’s Disease Are Ameliorated by Chemogenetic Modulation of Orexin Neuron Activity". Molecular Neurobiology 56(12):8435 - 50.

[0646] Stoka, Veronika, Olga Vasiljeva, Hiroshi Nakanishi, and Vito Turk. 2023. "The Role of Cysteine Peptidases Cathepsins B, H, C, and X / Z in Neurodegeneration and Cancer".

[0647] Thannickal, Thomas C., Yuan-Yang Lai, and Jerome M. Siegel. 2007. 《Hypocretin(orexin) cell loss in Parkinson’s disease》. Brain 130(6):1586-95.

[0648] Thorpy, Michael J. 2020. 《Recently Approved and Upcoming Treatments for Narcolepsy》. CNS drugs 34(1):9-27.

[0649] Vanni-Mercier, G., K. Sakai, and M. Jouvet. 1984. 《[Specific neurons for wakefulness in the posterior hypothalamus in the cat].》Comptes rendus de l’Academie des sciences. Serie III, Sciences de la vie 298(7):195-200.

[0650] Wang, Qinqin, Fei Cao, and Yili Wu. 2021. 《Orexinergic system in neurodegenerative diseases》. Frontiers in Aging Neuroscience 13:713201.

[0651] Wang, Tao, and Hongmei Jia. 2023. 《The Sigma Receptors in Alzheimer’s Disease: New Potential Targets for Diagnosis and Therapy》. International Journal of Molecular Sciences 24(15):12025.

[0652] Wang, Yanfeng et al. 2023. 《Cathepsin H: molecular characteristics and clues to function and mechanism》. Biochemical Pharmacology:115585.

[0653] Wang, Ying et al. 2019. "Orexins alleviate motor deficits via increasing firing activity of pallidal neurons in a mouse model of Parkinson’s disease". American Journal of Physiology-Cell Physiology 317(4): C800-812.

[0654] Willie, Jon T. et al. 2003. "Distinct Narcolepsy Syndromes in Orexin Receptor-2 and Orexin Null Mice: Molecular Genetic Dissection of Non-REM and REM Sleep Regulatory Processes". Neuron 38(5): 715-30.

[0655] Xiong, Xiaoxing et al. 2013. "Mitigation of Murine Focal Cerebral Ischemia by the Hypocretin / Orexin System is Associated With Reduced Inflammation". Stroke 44(3): 764-70.

[0656] Yale, Harry L., and Marion Kalkstein. 1967. "Substituted 2,3-dihydro-4(1H)-quinazolinones. A new class of inhibitors of cell multiplication". Journal of medicinal chemistry 10(3): 334-36.

[0657] Yanagisawa, Masashi. 2012. "Small-molecule agonists for type-2 orexin receptor".

[0658] Yasui, Kenichi et al. 2006. "CSF orexin levels of Parkinson’s disease, dementia with Lewy bodies, progressive supranuclear palsy and corticobasal degeneration". Journal of the neurological sciences 250(1-2):120-23.

[0659] Yukitake, Hiroshi et al. 2019. "TAK-925, an orexin 2 receptor-selective agonist, shows robust wake-promoting effects in mice". Pharmacology Biochemistry and Behavior 187:172794.

[0660] Zhang, Dehui et al. 2021. "Discovery of Arylsulfonamides as Dual Orexin Receptor Agonists." Journal of medicinal chemistry 64(12):8806-25.

[0661] Zhang, Zhongxing et al. 2018. "Exploring the Clinical Features of Narcolepsy Type 1 versus Narcolepsy Type 2 from European Narcolepsy Network Database with Machine Learning". Scientific reports 8(1):10628-10628.

Claims

1. A compound of formula (II): in: -X represents -NH-, -S-, or -O-, with -NH- or -S- being preferred; -Y and R2 can each independently represent a hydrogen atom, a halogen atom, -NO2, or -NH2; -R1, R3, and R4 each independently represent a hydrogen atom or a halogen atom; -R5, R6, R7, R8, and R9 each independently represent a hydrogen atom, a halogen atom, and -OR. 10 or (C1-C) 30 )alkyl chains, especially (C1-C 20 An alkyl group, optionally interrupted by one or more moieties and / or followed by one or more moieties and / or preceded by one or more moieties, said moieties being selected from aryl, heteroaryl, cycloalkyl, heterocyclic, -C≡C-, -C(R) 11 )=C(R 12 -, -O-, -S-, -NR 13 -, -C(O)-, -C(S)-, -C=N-, -N=C-, -OC(O)-, -C(O)O-, -SC(O)-, -C(O)S-, -N(R 14 -C(O)- and -C(O)N(R) 15 )-group, wherein the aryl, heteroaryl and heterocyclic rings are optionally substituted; -R 10 Represents a hydrogen atom or (C1-C) 30 Alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl, wherein the aryl, heteroaryl and heterocyclic rings are optionally substituted; -R 11 and R 12 Each independently represents a hydrogen atom or a (C1-C6) alkyl group; and -R 13 To R 15 Each of these groups independently represents a hydrogen atom or a (C1-C6) alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or acyl group, preferably a hydrogen atom or a (C1-C6) alkyl or aryl group, more preferably a hydrogen atom or a (C1-C6) alkyl group. Or a pharmaceutically acceptable salt thereof, its tautomers, stereoisomers, or mixtures thereof. The condition is that the compound of formula (II) is not Furthermore, the condition is that when X represents O, each of R1, R2, R3, and R4 represents H, Y represents a halogen atom, and four of R5, R6, R7, R8, and R9 represent H, then the remaining groups in R5, R6, R7, R8, and R9 are not (C1-C2). 30 ) alkyl chain, the (C1-C 30 The alkyl chain is preceded by -O- and broken by -O-, or by -C(R) 11 )=C(R 12 - Interrupt, followed by -C(R) 11 )=C(R 12 - and / or preceded by -C(R) 11 )=C(R 12 )-.

2. The compound of formula (II) 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.

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

4. The compound of formula (II) according to any one of claims 1 to 3, characterized in that... R5, R6, R7, R8, and R9 each independently represent a hydrogen atom, a halogen atom, and -OR. 10 or (C1-C) 20 alkyl, optionally broken by one or more moieties and / or preceded by one or more moieties, said moieties being selected from aryl, heteroaryl, cycloalkyl, heterocyclic, -C≡C-, -C(R) 11 )=C(R 12 -, -O-, -S-, -NR 13 -, -C(O)-, -OC(O)-, -C(O)O-, -N(R 14 -C(O)- and -C(O)N(R) 15 The aryl, heteroaryl, and heterocyclic rings are optionally substituted.

5. The compound of formula (II) according to any one of claims 1 to 4, characterized in that... R5, R6, R7, R8, and R9 each independently represent a hydrogen atom or -OR 10 .

6. The compound of formula (II) according to any one of claims 1 to 5, characterized in that... When X is NH or O, then R5, R6, or R7 represent -OR. 10 , where R 10 Represents hydrogen atoms, (C1-C 30 )alkyl or phenyl.

7. The compound of formula (II) according to any one of claims 1 to 5, characterized in that... At least four residues of R5, R6, R7, R8, and R9 each represent a hydrogen atom.

8. The compound of formula (II) according to claim 7, characterized in that... R5, R6, R7, R8, and R9 each represent a hydrogen atom.

9. The compound of formula (II) for the use according to claim 7, characterized in that... R5, R6, or R7 represent -OR 10 , where R 10 Represents hydrogen atoms, (C1-C 30 )alkyl or phenyl, preferably (C1-C 20 )alkyl or phenyl.

10. The compound of formula (II) according to any one of claims 1 to 9, characterized in that... It is selected from: and its mixtures.

11. The compound of formula (II) according to any one of claims 1 to 10, characterized in that... X represents S.

12. A pharmaceutical composition comprising a compound of formula (II) as defined in any one of claims 1 to 11 and a pharmaceutically acceptable carrier.

13. The pharmaceutical composition according to claim 12, comprising 0.5 mg to 800 mg, preferably 20 mg to 400 mg, of a compound of formula (II).

14. Use as a medicine of the compound of formula (II) according to any one of claims 1 to 11 or the pharmaceutical composition according to claim 12 or 13.

Images