Dihydro-quinazoline, -benzothiazine and -benzoxazine derivatives and their use as orexin receptor agonists for treating or preventing neurological disorders - Patent Application 20070122993

Abstract

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

Description

[Technical Field]

[0001] The present invention is directed to dihydro-quinazoline, -benzothiazine and -benzoxazine derivatives, advantageously for use in the prevention or treatment of neurological, psychiatric and sleep disorders and diseases in which central orexin neurotransmission is impaired or in which central and peripheral orexin receptors are involved. The present invention is also directed to pharmaceutical compositions comprising these compounds for use in the prevention and / or treatment of neurological disorders and diseases. The present invention is also directed to dihydro-benzothiazine and dihydro-benzoxazine derivatives and the use of these compounds as medicaments. [Background technology]

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

[0003] In mouse genetic studies, loss of orexin function leads to narcoleptic symptoms characterized by excessive daytime sleepiness and cataplexy (Lin et al. 1999; Willie et al. 2003), and intracerebroventricular administration of orexin attenuates narcoleptic symptoms (Mieda 2017). Furthermore, OX1R knockout mice do not exhibit obvious sleep / wake-related phenotypes, whereas OX2R knockout mice exhibit severe narcoleptic phenotypes, suggesting that OX2R-mediated signaling is sufficient to prevent narcoleptic / cataplexy symptoms (Mieda et al. 2011; Saito et al. 2018).

[0004] Over the past decade, numerous orexin antagonists have been increasingly developed as potential drugs for various pathophysiological conditions involving the orexin system (e.g., the treatment of insomnia) (Heifetz et al. 2013). However, far fewer orexin agonists have been developed with potential for a variety of diseases, including obesity, attention-deficit hyperactivity disorder (ADHD) (Baimel et al. 2015; Cortese, Konofal, et al. 2008; Heifetz et al. 2013), and neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease) (Gao et al. 2021; Katsuki et Michinaga 2012), particularly narcolepsy types 1 and 2 (Fujimoto et al. 2022; Mezeiova et al. 2020; Yukitake et al. 2019; Zhang et al. 2021).

[0005] The role of OX1R in sleep regulation has been investigated using orexin antagonists in animal models. SB-334867, an experimental OX1R-selective antagonist, has been reported to reverse REM sleep suppression induced by intracerebroventricular injection of orexin-A (Smith et al. 2003), and notably, has effects on REM sleep and induces non-REM sleep when administered alone (Morairty et al. 2012).

[0006] Contrary to OX1R antagonists, the potential therapeutic role of OX1R agonists in REM sleep behavior disorder (RBD) is believed to be due to the interaction between α-synuclein and OX1R in the pathology. OX1R dysfunction can induce the onset of RBD, which is a potent early sign of Parkinson's disease (PD), but the pathogenic mechanisms involved in RBD remain unclear. Meanwhile, α-synuclein has been confirmed to form Lewy bodies in orexin neurons, and its activity and function are dependent on orexin receptor 1 (OX1R) (Fan et al. 2023).

[0007] OX1R agonists may be a useful strategy to slow or halt the neurodegenerative process in PD and treat RBD.

[0008] Loss of orexinergic neurons in the brain has been linked to the pathogenesis of narcolepsy type 1 (NT1), which is characterized by excessive daytime sleepiness, cataplexy, hypnagogic / hypnagogic hallucinations, sleep paralysis, and nocturnal sleep disturbances (Cao et Guilleminault 2017; Siegel 1999; Thorpy 2020).

[0009] Cerebrospinal fluid (CSF) orexin-1 levels are predictive of narcolepsy (89.5% of the overall patient population, HLA DQBI * 0602) were abnormal in 94.7% of positive cases (Kanbayashi et al. 2002; Nishino 2007).

[0010] In NT1, low or absent CSF hypocretin concentrations serve as a specific biomarker, whereas in narcolepsy type 2 (NT2) or other central hypersomnia disorders or variants of hypersomnia (i.e., idiopathic hypersomnia or secondary or recurrent hypersomnia associated with psychiatric disorders), this specific biomarker currently does not exist (Zhang et al. 2018).

[0011] Since this discovery, orexin agonists have been attracting attention as potential therapeutic agents for the treatment of narcolepsy. In 2008, the first OX2R-selective agonist class was patented, stimulating the discovery of several compounds, all of which act solely 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 to be unsatisfactory in terms of, for example, activity, pharmacokinetics, brain / central nervous system penetration, or safety, and there is a need for the development of improved compounds having OX2R agonist activity.

[0013] Santinorextone, firazolextone, and danavorextone are selective OX2R agonists being developed by Takeda Pharmaceuticals for the treatment of narcolepsy. TAK-994 and TAK-861 are active compounds that act as highly selective OX2R agonists. TAK-994 is over 700-fold more selective than OX1R. Danavorextone (TAK-925) has reached Phase 2 clinical trials for narcolepsy. However, clinical development was discontinued in 2021 due to safety concerns (Dauvilliers et al. 2023; Ishikawa et al. 2023). TAK-994 is the first oral selective OX2R agonist developed.

[0014] Recently, cycloalkylurea compounds that target OX2R as agonists have been reported in WO2021107023, but these compounds were unable to target both OX1R and OX2R.

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

[0016] Parkinson's disease (PD) is the second most common chronic neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (Hornykiewicz et Kish 1987). The prevalence of PD in the population aged 55 years and older is approximately 1%. The primary symptoms of PD include resting tremor, bradycardia, muscle rigidity, and postural instability, usually accompanied by cognitive impairment, psychiatric disturbances, and other non-motor symptoms (Beitz 2014; Meerwaldt et Hovestadt 1988). The cause of PD is not fully understood, but several factors, including genetic mutations, oxidative stress, mitochondrial dysfunction, neurotransmitter toxicity, and impaired protein homeostasis, appear to be associated with the development of PD. The most common treatment for PD is symptom management.

[0017] Although levodopa, a dopamine precursor, is the most widely used clinical drug (Hornykiewicz 1975), it only alleviates symptoms but does not halt the progressive degeneration of dopaminergic neurons in the substantia nigra. In recent years, much effort has been made to find endogenous neuroprotective mediators that can halt or reverse the degenerative changes of dopaminergic neurons in the substantia nigra.

[0018] Orexin receptors are present in many brain structures, such as the cerebral cortex, hippocampus, amygdala, thalamus, hypothalamus, and basal ganglia (Hervieu et al. 2001; Hu et al. 2015). Orexin plays an important role in regulating sleep, feeding behavior, energy homeostasis, neuroendocrine secretion, and autonomic nervous system control. The activity of the orexinergic system declines with age, which is known to be involved in many neurodegenerative diseases (Liu et al. 2018).

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

[0020] For about 20 years, an increasing number of studies have demonstrated that the orexinergic system is closely related to PD (Katsuki et al. 2012; Yasui et al. 2006). It has been reported that patients with Parkinson's disease show a significant loss of orexinergic neurons in postmortem examinations (Fronczek et al. 2007; Thannickal, Lai, et Siegel 2007).

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

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

[0023] Finally, the precise role of orexin-A in PD animal models and its protective mechanism on nigral dopaminergic neurons appear to have been demonstrated using MPTP Parkinson's disease mice (Liu et al. 2018). In this animal model, orexin-A exerted neuroprotective effects, suggesting that orexin-A is a potential therapeutic target for PD and that OX1R agonists are potential targets for PD treatment.

[0024] Another involvement of orexin has also been recognized, that is in immune responses and neuroinflammation (Duffy et al. 2019; Polito et al. 2018). It has been suggested that orexin-A may act as an immunomodulatory regulator of microglia that reduces hypothalamic neuronal death in inflammatory conditions.

[0025] Furthermore, orexin-A exerts protective effects by suppressing neuroinflammation in AD and cerebral ischemia (Couvineau et al. 2012; Xiong et al. 2013). Therefore, the anti-inflammatory properties may also be involved in the neuroprotective effects of orexin in PD. Potential therapeutic effects of orexin on both motor and non-motor disorders in PD animal models have also been suggested.

[0026] Intracerebroventricular administration of orexin A alleviates sensorimotor deficits in a 6-OHDA-treated rat model of PD (Hadadianpour et al. 2017). Similar results were observed in an MPTP-induced mouse model of PD. Intraventricular application of orexin A improved motor performance in both the pole test and the open field test by attenuating the loss of dopaminergic neurons and fibers (Liu et al. 2018). Intracallosal administration of both orexin A and orexin B alleviated motor deficits in MPTP-treated Parkinson's disease mice (Ying Wang et al. 2019). Furthermore, chemogenetic activation of orexinergic neurons reversed abnormal motor activity in preclinical A53T mice (Stanojlovic, Pallais, et al. 2019). Furthermore, cognitive impairment, a common non-motor deficit in PD, may also be improved by orexin. Furthermore, orexin may also improve cognitive impairment, a common non-motor deficit in PD. Administration of orexin-A to the CA1 or chemogenetic activation of orexinergic neurons increases the firing activity of CA1 neurons (Chen, Chen, et al. 2017) and improves hippocampus-dependent memory impairment in the A53T mouse model of PD (Stanojlovic, Pallais, et al. 2019).

[0027] Furthermore, the impairments in sociability and social memory observed in A53T Parkinson's disease mice were also improved by chemogenetic activation of orexinergic neurons (Stanojlovic et al. 2019). Furthermore, the reduction in anxiety-like behavior observed in the early stages of PD could be restored by chemogenetic activation of orexinergic neurons in 5-month-old A53T mice (Stanojlovic, Pallais, et al. 2019). The therapeutic effects of orexin on PD motor deficits are likely related to the recovery of dopaminergic neurons and the excitatory effects of orexin on pallidal neurons (Liu et al. 2018; Wang et al. 2019). However, the mechanisms underlying the therapeutic effects of orexin on non-motor deficits have not been well studied to date. Summary of the Invention

[0028] Summary of the Invention A first subject of the present invention is a compound of formula (II): [ka] [In the formula, X represents -NH-, -S- or -O-, preferably -NH- or -S-; Y and R2 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, or -OR 10 or (C1-C 30 ) alkyl chains, especially (C1-C 20 ) alkyl, and optionally aryl, heteroaryl, cycloalkyl, heterocycle, —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(R14 )C(O)- and -C(O)N(R 15 )-groups, wherein said aryl, heteroaryl, and heterocyclic rings are optionally substituted; R 10 is a hydrogen atom or (C1-C 30 ) represents an alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl group, wherein the aryl, heteroaryl and heterocyclic rings are optionally substituted; R 11 and R 12 are each independently a hydrogen atom or a (C1-C6) alkyl group; R 13 ~R 15 are each independently 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, a tautomer, a stereoisomer or a mixture of stereoisomers thereof, provided that the compound of formula (II) is [ka] Instead of, 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, the remaining groups of R5, R6, R7, R8 and R9 are preceded by -O-, interrupted by -O- or -C(R 11 )=C(R 12 )- is inserted, followed and / or preceded by (C1-C 30 ) is not an alkyl chain.

[0029] The present invention also relates to pharmaceutical compositions comprising compounds of formula (II) as described above.

[0030] The present invention also relates to a compound of formula (II) as described above for use as a medicament.

[0031] Detailed Description of the Invention A first subject of the present invention is the use of compounds of formula (I): for use in the prevention and / or treatment of neurological disorders, preferably related to psychiatric and / or sleep disorders and diseases, such as narcolepsy, advantageously in which central orexin neurotransmission is impaired or in which central and peripheral orexin receptors are involved [ka] [In the formula, X represents -NH-, -S- or -O-; Y and R2 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, or -OR 10 or (C1-C 30 ) alkyl chains, especially (C1-C 20 ) alkyl, and optionally aryl, heteroaryl, cycloalkyl, heterocycle, —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 )-groups, wherein said aryl, heteroaryl, and heterocyclic rings are optionally substituted; R 10 is a hydrogen atom or (C1-C 30 ) represents an alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl group, wherein the aryl, heteroaryl and heterocyclic rings are optionally substituted; R 11 and R 12are each independently a hydrogen atom or a (C1-C6) alkyl group; R 13 ~R 15 are each independently 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, a tautomer, a stereoisomer or a mixture of stereoisomers thereof.

[0032] definition In the present invention, "halogen atom" means fluorine, chlorine, bromine and iodine atoms.

[0033] In the present invention, an "alkyl" group means a saturated, straight or branched hydrocarbon chain.

[0034] In the present invention, "(C1-C x "(C1-C6)alkyl" means an alkyl group as defined above containing 1 to X carbon atoms. For example, "(C1-C6)alkyl" means an alkyl group as defined above containing 1 to 6 carbon atoms, e.g., methyl, ethyl, isopropyl, tert-butyl, pentyl, etc.

[0035] In the present invention, "aryl" refers in particular to an aromatic, especially hydrocarbon, group containing 6 to 20 carbon atoms, preferably 6 to 10 carbon atoms, and containing one or more condensed rings, such as phenyl or naphthyl groups. Advantageously, aryl is a phenyl group.

[0036] In the present invention, "heteroaryl" refers to an aromatic group containing one or more fused rings and containing one or more heteroatoms, advantageously 1 to 4, more advantageously 1 or 2, such as sulfur, nitrogen, oxygen, phosphorus, or selenium atoms, preferably sulfur, nitrogen, or oxygen, and 5 to 10 ring atoms, the other ring atoms being carbon atoms. Examples of heteroaryl groups are furyl, thienyl, pyrrolyl, pyridinyl, pyrimidinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, indyl, or selenophenyl.

[0037] In the present invention, an "acyl" group refers to a group of the formula -CO-R, where R represents a (C1-C6) alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group, preferably a (C1-C6) alkyl or aryl group, more preferably a (C1-C6) alkyl group.

[0038] In the present invention, "cycloalkyl" refers to a saturated monocyclic or polycyclic hydrocarbon chain (especially a bicyclic or tricyclic chain). In the case of polycyclic groups, the rings may be fused, bridged, or joined two by two by spirocyclic junctions. Examples include cyclopropyl, cyclopentyl, cyclohexyl, and cycloheptyl groups.

[0039] In the present invention, a "heterocyclic" group refers to a non-aromatic, saturated or unsaturated, monocyclic or polycyclic group (comprising fused, bridged or spiro rings) in which one or more ring carbon atoms are each replaced by a heteroatom; in particular, this term refers to a non-aromatic 5- to 10-membered ring, saturated or unsaturated, containing one or more, advantageously 1 to 4, more advantageously 1 or 2 heteroatoms, said heteroatoms being, for example, sulfur, nitrogen or oxygen atoms. It may in particular be a pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl group.

[0040] The aryl, heteroaryl and heterocyclic groups, when substituted, may include halogen atoms, (C1-C6) alkyl groups, aryl groups, -NO2, -CN, -OR 19 , -SR 20, -NR 16 R 17 , -B(OH)2, -SO3R 17 , and -COOR 18 In particular, a halogen atom, -NO2, -CN, -OR 19 , -SR 20 , -NR 16 R 17 , -B(OH)2, -SO3R 17 and R 16 ~R 20 are each independently a hydrogen atom or a (C1-C6) alkyl group.

[0041] As used herein, "pharmaceutically acceptable" means that when used in the preparation of pharmaceutical compositions, it is generally safe, non-toxic, not biologically or otherwise undesirable, and acceptable for both veterinary and human pharmaceutical use.

[0042] "Pharmaceutically acceptable salts" of a compound means salts that are pharmaceutically acceptable, as defined herein, and that possess the desired pharmacological activity of the parent compound. Such salts include: (1) Hydrates and solvates, (2) Pharmaceutically acceptable acid addition salts formed with pharmaceutically acceptable inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or with pharmaceutically acceptable organic acids, such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptanoic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, dibenzoyl-L-tartaric acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, trifluoroacetic acid, and the like; or (3) Pharmaceutically acceptable base addition salts formed when an acid proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth metal ion, or an aluminum ion, or when a pharmaceutically acceptable organic or inorganic base is coordinated. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, etc. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, and sodium hydroxide.

[0043] Preferably, the compounds according to the invention are in the form of a pharmaceutically acceptable base addition salt, the base being such as NaOH or KOH, in particular NaOH.

[0044] By "optically pure compound" is meant an enantiomer with an enantiomeric excess of greater than 95%, preferably greater than 96%, more preferably greater than 97%, even more preferably greater than 98%, and especially preferably greater than 99%.

[0045] The present invention also includes all pharmaceutically acceptable isotopic variations of the compounds of Formula I in which one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Such compounds are identical to those disclosed herein except for the replacement of one or more atoms by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes suitable for inclusion in the compounds of the present invention include: 2 H and 3 Isotopes of hydrogen such as H, 11 C. 13 C and 14 Carbon isotopes such as C, 13 N and 15 Nitrogen isotopes such as N, 15 O. 17 O and 18 Oxygen isotopes such as O 35 Sulfur isotopes such as S, 18 Fluorine isotopes such as F, 123 I and125 Iodine isotopes such as I, and 36 Included are isotopes of chlorine, such as Cl. Certain isotopically labeled compounds of Formula I, for example those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies.

[0046] The subject receiving the compound of the present invention, or a pharmaceutically acceptable salt thereof, is generally a mammal, e.g., a human, male or female. The amount of compound administered to the subject is sufficient to agonize the subject's orexin receptor. In one embodiment, the amount of compound can be an "effective amount," where the subject compound is administered in an amount that elicits the biological or medical response in a tissue, system, animal, or human that is desired by a researcher, veterinarian, medical doctor, or other clinician. An effective amount does not necessarily include considerations of toxicity and safety associated with the administration of the compound. Those skilled in the art will recognize that neurological and psychiatric disorders associated with orexin receptor activation can be affected by treating a subject currently suffering from the disorder or by prophylactically treating a subject likely to suffer from the disorder with an effective amount of a compound of the present invention. As used herein, the terms "treatment" and "treating" refer to any process that may slow, interrupt, prevent, control, or halt the progression of the neurological and psychiatric disorders described herein, but do not necessarily indicate complete elimination of all disorder symptoms, nor prophylactic treatment of the described conditions, particularly in subjects with a predisposition to such diseases or disorders. The terms "administration of a compound" and "administering a compound" should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to a subject.

[0047] The term "composition," as used herein, is intended to encompass a product consisting of specified ingredients in specified amounts, as well as any product resulting directly or indirectly from the combination of specified ingredients in specified amounts. Such term is intended to encompass a product comprising an active ingredient and an inactive ingredient that constitutes a carrier, as well as any product resulting directly or indirectly from the combination, complexation, or aggregation of two or more ingredients, or the dissociation of one or more ingredients, or any other type of reaction or interaction of one or more ingredients.

[0048] Accordingly, the compositions of the present invention encompass any composition made by admixing a compound of the present invention with a pharmaceutically acceptable carrier; i.e., the carrier, diluent or excipient must be compatible with the other ingredients in the formulation and not deleterious to the recipient thereof.

[0049] Diseases and Disorders Orexin receptors (OX1R, OX2R) have been associated with a wide range of biological functions, suggesting a potential role for these receptors in various disease processes in humans or other species. Accordingly, the compounds of the present invention may have utility in treating, preventing, ameliorating, controlling, or reducing the risk of various disorders associated with orexin receptors, including one or more of the following conditions or diseases: narcolepsy with or without cataplexy, narcolepsy type 1 (NT1), narcolepsy type 2 (NT2), Gelineau syndrome (Maladie de Gelineau), 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 psychiatric disorders, hypersomnia due to medical disorders, drug- or substance-induced hypersomnia, according to the eight different central hypersomnia disorders (CDH) classified by the International Classification of Sleep Disorders, Third Edition (ICSD-3) (American Academy of Sleep Medicine 2014), and / or sleep apnea, nocturnal myoclonus, rapid eye movement (REM) sleep interruptions, jet lag, shift work, insomnia, sleep disorder, sleep disturbance, depression, affective / mood disorder, Alzheimer's disease or neurodegenerative or cognitive disorders, and hypersomnia associated with tauopathies and tauopathies, Parkinson's disease and other synucleinopathies, Guillain-Barré syndrome, chronic fatigue syndrome, long term COVID-19 and sleep deprivation syndromes and any conditions characterized by pathological daytime sleepiness and / or inappropriate wakefulness due to or not due to a medical or health condition related to circadian rhythm, as well as mental and physical disorders associated with staggered travel and shift work, restless legs syndrome, fibromyalgia, heart failure, diseases associated with bone loss, sepsis, syndromes manifested by unrefreshing sleep and muscle pain, sleep apnea, which involves breathing disorders during sleep; conditions resulting from poor sleep quality and other diseases associated with general orexin system dysfunction.

[0050] In the present invention, "neurological, psychiatric, and sleep disorders and diseases" refers to psychiatric and / or sleep-related neurological disorders and diseases, i.e., neurological diseases associated with sleep and / or psychiatric disorders, particularly disorders and diseases in which central orexin neurotransmission is impaired or in which central and peripheral orexin receptors are involved.

[0051] Thus, in certain embodiments, the present invention provides for the treatment in a subject of narcolepsy with or without cataplexy, narcolepsy type 1 (NT1), narcolepsy type 2 (NT2), Maladie de Gelineau syndrome, narcolepsy syndrome with narcoleptic symptoms, cataplexy in narcolepsy, excessive daytime sleepiness (EDS) in narcolepsy, hypersomnia, idiopathic hypersomnia, recurrent hypersomnia, Kleine-Levin syndrome, hypersomnia associated with psychiatric disorders, hypersomnia due to medical disorders, drug- or substance-induced hypersomnia, and insufficient sleep syndrome according to the eight different Central Disorders of Hypersomnia (CDH) classified by the International Classification of Sleep Disorders, Third Edition (ICSD-3) (American Academy of Sleep Medicine 2014) and any conditions; sleep apnea, nocturnal myoclonus, REM sleep interruptions, jet lag, shift work, sleep disturbances, insomnia, sleep disorders, sleep disruption, depression, affective / mood disorders, hypersomnia associated with Alzheimer's disease or cognitive impairment, Parkinson's disease, dementia, Guillain-Barré syndrome, chronic fatigue syndrome, long term COVID-19 and pathological daytime sleepiness and / or inappropriate wakefulness due to or not due to medical or health conditions related to circadian rhythm and staggered travel and shift work, restless legs syndrome, fibromyalgia, heart failure, diseases related to bone loss, sepsis, syndromes manifested by unrestful sleep and muscle pain, mental and physical disorders associated with sleep apnea with disordered breathing during sleep; conditions due to poor sleep quality and other diseases associated with general orexin system dysfunction; treating or controlling sleep disturbances associated with diseases such as neuropathic pain and neurological disorders including restless legs syndrome, treating or controlling psychoactive substance use and abuse, enhancing memory retention; diabetes and appetite, taste, eating and drinking disorders; insulin resistance syndrome; hypothalamic diseases; treating or controlling depression, including major depression and major depressive disorder; ameliorating or reducing the risk of absence epilepsy, epilepsy, including seizures; pain, including neuropathic pain; Parkinson's disease, dementia with Lewy bodies and synucleinopathies; Guillain-Barré syndrome; long COVID-19; Kleine-Levin syndrome; psychosis, dysthymia, mood disorders, bipolar disorder, psychotic disorders and anxiety disorders;There may be provided a method for treating or controlling side effects or complications caused by anesthesia and / or orexin antagonists, comprising administering to a subject a compound of the invention;

[0052] The dihydro-quinazoline, -benzothiazine and benzoxazine derivatives as compounds of the present invention may also have utility in the treatment, prevention, amelioration, control or reduction of risk of various other disorders associated with orexin receptors, including one or more of the following conditions or diseases: for example, increasing sleep quality, improving sleep quality, increasing sleep efficiency, enhancing sleep maintenance, improving sleep onset, reducing sleep latency or sleep onset time, reducing difficulty falling asleep, enhancing sleep continuity, reducing the number of awakenings during sleep, reducing intermittent awakenings during sleep, reducing nighttime awakenings, reducing wakefulness after sleep onset, increasing total sleep time, reducing sleep fragmentation, altering the timing, frequency or duration of sleep stages, duration of slow wave sleep and / or REM sleep, promoting slow wave sleep, enhancing EEG-delta activity during sleep, reducing nighttime awakenings, especially early morning awakenings. reducing awakenings, increasing daytime alertness, reducing daytime somnolence, sleepiness, treating or reducing excessive daytime sleepiness; increasing satisfaction with sleep intensity, increasing sleep maintenance, idiopathic insomnia, sleep disorders, insomnia, night terrors, depression, affective / mood disorders, insomnia associated with Alzheimer's disease or neurodegenerative or cognitive disorders, Parkinson's disease, dementia, Guillain-Barré syndrome, chronic fatigue syndrome, long-term COVID-19 and circadian rhythm-related medical or health conditions, as well as staggered travel and shift work, restless legs syndrome, fibromyalgia, heart failure, diseases associated with bone loss, sepsis, syndromes manifested by unrestful sleep and muscle pain, and mental and physical disorders associated with sleep apnea, which is a breathing disorder during sleep; conditions resulting from poor sleep quality; enhancing learning; enhancing memory; enhancing memory retention;Eating disorders associated with excessive food intake and associated complications, compulsive eating disorders, obesity (regardless of genetic or environmental cause), obesity-related disorders, overeating, anorexia, bulimia, cachexia, appetite control disorders, hypertension, diabetes, high plasma insulin concentrations and insulin resistance, dyslipidemia, hyperlipidemia, endometrial, breast, prostate and colon cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstones, heart disease, lung disease, abnormal heart rhythms and arrhythmias, myocardial infarction, congestive heart failure, coronary heart disease, acute congestive heart failure, hypotension, hypertension, angina pectoris , infarction, ischemic or hemorrhagic stroke, subarachnoid hemorrhage, chronic renal failure, renal disease, impaired glucose tolerance, craniopharyngioma, Prader-Willi syndrome, Frohlich syndrome, GH deficiency, Turner syndrome, and other pathological conditions manifesting as decreased metabolic activity or decreased resting energy expenditure relative to lean body mass, e.g., children with acute lymphoblastic leukemia, metabolic syndrome (also known as syndrome X), insulin resistance syndrome, reproductive hormone abnormalities, sexual and reproductive dysfunction, e.g., pregnancy disorders, infertility, hypogonadism in men and hirsutism in women, fetal abnormalities associated with maternal obesity, gastrointestinal disorders To treat motility disorders, intestinal motility disorders, obesity-related gastroesophageal reflux, hypothalamic disorders, pituitary disorders, respiratory disorders, e.g., obesity-hypoventilation syndrome (Pickwickian syndrome), Ondine syndrome, and sleep-related disorders, especially those with abnormal thalamic-mediated coupling of activity; to enhance cognitive function, including cognitive impairments, including all types of attention, learning, and memory impairments, occurring transiently or chronically in normal, healthy, young, adult, or elderly individuals, and occurring transiently or chronically in psychiatric, neurological, cardiovascular, and immune disorders; to treat Guillain-Barré syndrome, chronic fatigue syndrome, and other conditions. Treating or controlling labor pains, long COVID-19, and medical or health conditions related to circadian rhythms; Treating or controlling Kleine-Levin syndrome; Treating or controlling psychosis; Treating or controlling dysthymic, mood, psychotic, and anxiety disorders; Treating complications from anesthesia; Enhancing memory; Enhancing memory retention; Enhancing immune response; Enhancing immune function; Hot flashes; Night sweats; Prolonging life; Schizophrenia; Muscle-related disorders controlled by nervous system-imposed excitation / relaxation rhythms, such as cardiac rhythm, and other disorders of the cardiovascular system;conditions related to cell proliferation, such as vasodilation or vasoconstriction and blood pressure; cancer; cardiac arrhythmias; hypertension; congestive heart failure; conditions of the reproductive / urinary system; sexual dysfunction and impaired fertility; adequacy of renal function; response to anaesthetic drugs; mood disorders, such as depression or more particularly depressive disorders, such as single or recurrent major depressive disorder and dysthymic disorder, or bipolar disorders, such as bipolar disorder type I, bipolar disorder type II and cyclothymic disorder, mood disorders due to general medical conditions, and substance-induced mood disorders; affective neuroses, depressive neuroses, anxiety neuroses; acute stress Anxiety disorders including: anxiety disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attacks, panic disorder, post-traumatic stress disorder, separation anxiety disorder, social phobia, specific phobia, substance-induced anxiety disorder, and anxiety due to general health conditions; acute neurological and psychiatric disorders such as brain injury after cardiac bypass and graft surgery, stroke, ischemic stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, and hypoglycemic neuropathies; Huntington's chorea; Huntington's disease and Tourette's syndrome; Cushing's syndrome / disease; basophilic adenoma; prolactin Hyperprolactinemia; Pituitary tumor / adenoma; Hypothalamic disease; Inflammatory bowel disease; Gastric motility disorder; Gastric ulcer; Fröhlich syndrome; Anterior pituitary disease; Pituitary disease; Hypoadrenocorticism; Hyperadrenocorticism; Hypothalamic hypogonadism; Kallmann syndrome (anosmia, hyposmia); Functional or psychogenic amenorrhea; Hypopituitarism; Hypothalamic hypothyroidism; Hypothalamic-adrenal insufficiency; Idiopathic hyperprolactinemia; Hypothalamic disorders due to growth hormone deficiency; Idiopathic growth failure; Dwarfism; Gigantism; Acromegaly; Amyotrophic lateral sclerosis; Multiple sclerosis; Eye disorders retinopathy; cognitive impairment; idiopathic and drug-induced Parkinson's disease; disorders related to muscle spasms and muscle contractions, including tremors, epilepsy, convulsions, seizure disorders, absence seizures, complex partial seizures and generalized seizures; Lennox-Gastaut syndrome; cognitive impairment, including dementia (associated with Alzheimer's disease, ischemia, trauma, vascular disease or stroke, HIV disease, Parkinson's disease, dementia with Lewy bodies, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, perinatal hypoxia, other general health conditions or substance abuse); delirium, amnesic disorders or age-related cognitive decline;Schizophrenia or psychosis, including schizophrenia (paranoid, disorganized, catatonic, undifferentiated), schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to general health conditions, and substance-induced psychotic disorder; dissociative disorders, including multiple personality syndrome and psychogenic amnesia; substance-related disorders, substance use, substance abuse, substance seeking, substance rediscovery, any kind of psychological and physical addiction and addictive behavior, reward-related behavior (including substance-induced delirium, persistent dementia, persistent amnestic disorder, psychotic disorder, or anxiety disorder); Tolerance, addictive eating, addictive eating behavior, binge-eating and purging behavior, dependence, withdrawal, relapse from substances including alcohol, amphetamines, cannabis, cocaine, heroin, morphine, nicotine, opioids, phencyclidine, sedatives, hypnotics, and anxiolytics; appetite, taste, eating, and alcohol use disorders; akinesia and akinesia-rigidity syndromes (including Parkinson's disease, drug-induced parkinsonism, postencephalitic parkinsonism, progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration, Parkinsonism-ALS dementia complex, and basal ganglia calcifications), chronic fatigue syndrome, fatigue (Parkinson's disease, drug-induced parkinsonism, postencephalitic parkinsonism, progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration, Parkinsonism-ALS dementia complex, and basal ganglia calcifications); and drug-induced parkinsonism (such as neuroleptic-induced parkinsonism, neuroleptic malignant syndrome, neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia, neuroleptic-induced tardive dyskinesia and drug-induced postural tremor), Gilles de la Tourette syndrome, epilepsy, and movement disorders, such as tremor (such as rest tremor, essential tremor, postural tremor and intention tremor), chorea (such as Sydenham chorea, Huntington's disease, benign hereditary chorea, neuropathic ... movement disorders including chorea, symptomatic chorea, drug-induced chorea and hemispheric chorea, etc.), myoclonus (including generalized myoclonus and focal myoclonus), tics (including simple tics, complex tics and symptomatic tics), restless legs syndrome and dystonia (including generalized dystonias such as idiopathic dystonia, drug-induced dystonia, symptomatic dystonia and paroxysmal dystonia, and focal dystonias such as blepharospasm, oromandibular dystonia, spasmodic dysphonia, spasmodic torticollis, axial dystonia, dystonic writer's cramp and hemiplegic dystonia);Neurodegenerative diseases (including nosological entities such as inhibitory dysfunction-dementia-parkinsonism-muscle atrophy complex); pallor congenital blepharopathies; epilepsy; seizure disorders; attention-deficit / hyperactivity (ADHD); conduct disorder; migraine (including migrainous headache); headache; hyperalgesia; pain; increased or exaggerated sensitivity to pain such as hyperalgesia, burning pain, and allodynia; acute pain; burn pain; atypical facial pain; neuropathic pain; back pain; complex regional pain syndrome I and II; arthritis pain; sports injury pain; pain associated with infections such as HIV, COVID-19, post-chemotherapy pain; post-stroke pain; post-operative pain; neuralgia; emesis, nausea, vomiting; gastric motility disorders; gastric ulcers; Kallmann syndrome (anosmia); asthma; cancer; irritable bowel syndrome and conditions related to visceral pain such as angina; eating disorders; urinary incontinence; substance tolerance Sexual and substance withdrawal (including substances such as opiates, nicotine, tobacco products, alcohol, benzodiazepines, cocaine, sedatives, hypnotics, and orexin antagonists); 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 injury, including ocular disorders; retinopathy; macular degeneration of the eye; vomiting; cerebral edema; acute and chronic pain conditions, including severe pain, intractable pain, inflammatory pain, neuropathic pain, post-traumatic pain, bone and joint pain (osteoarthritis), pain due to repetitive motion, dental pain, cancer pain, myofascial pain (muscle injury, fibromyalgia), perioperative pain (general surgery, gynecology), chronic pain, neuropathic pain, post-traumatic pain, trigeminal neuralgia, migraine and migraine headaches, and other disorders related to general orexin system dysfunction.

[0053] A preferred embodiment of the present invention is a compound of formula (I) or a pharmaceutically acceptable salt thereof, a tautomer, stereoisomer or a mixture of stereoisomers thereof for use in the prevention and / or treatment of narcolepsy type 1 (NT1), narcolepsy type 2 (NT2), hypersomnia, idiopathic hypersomnia, recurrent hypersomnia, Kleine-Levin syndrome, hypersomnia associated with psychiatric disorders, hypersomnia due to medical disorders, drug or substance induced hypersomnia, Parkinson's disease and other synucleinopathies, preferably narcolepsy type 1 (NT1), narcolepsy type 2 (NT2) and Parkinson's disease.

[0054] A preferred embodiment of the present invention is a compound of formula (I) or a pharmaceutically acceptable salt thereof, a tautomer, stereoisomer or a mixture of stereoisomers thereof for use in the prevention and / or treatment of REM sleep behavior disorder (RBD).

[0055] In some embodiments, the neurological disease, preferably the neurological disorder and disease, in which central orexin neurotransmission is impaired or in which central and peripheral orexin receptors are involved, is selected from the group consisting of narcolepsy type 1 (NT1), narcolepsy type 2 (NT2), hypersomnia, idiopathic hypersomnia, recurrent hypersomnia, Kleine-Levin syndrome, hypersomnia associated with psychiatric disorders, hypersomnia due to medical disorders, drug or substance induced hypersomnia, Parkinson's disease and other synucleinopathies, preferably narcolepsy type 1 (NT1), narcolepsy type 2 (NT2) and Parkinson's disease.

[0056] In some embodiments, the neurological disease, preferably the neurological disorder and disease, in which central orexin neurotransmission is impaired or in which central and peripheral orexin receptors are involved, is selected from the group consisting of narcolepsy type 1 (NT1), narcolepsy type 2 (NT2), hypersomnia, idiopathic hypersomnia, and recurrent hypersomnia.

[0057] In particular, the targeted neurological disorders are those requiring agonists of the orexin 1 receptor (OX1R) and / or the orexin 2 receptor (OX2R), preferably both receptors.

[0058] Compounds of formula (I) In preferred embodiments, 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.

[0059] In preferred embodiments, 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 is a hydrogen atom. In some embodiments, when R2 represents a halogen atom, -NO2 or -NH2, preferably -NO2 or -NH2, Y represents a hydrogen atom.

[0060] R4 preferably represents a hydrogen atom.

[0061] In a preferred embodiment of the present 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.

[0062] R5, R6, R7, R8, and R9 each independently represent a hydrogen atom, a halogen atom, or -OR 10 or (C1-C 20 ) alkyl, and optionally aryl, heteroaryl, cycloalkyl, heterocycle, —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 )-groups, and said aryl, heteroaryl and heterocyclic rings are optionally substituted.

[0063] In another preferred embodiment, R5, R6, R7, R8, and R9 are each independently a hydrogen atom or -OR 10 Preferably, at least four residues R5, R6, R7, R8 and R9 each represent a hydrogen atom.

[0064] In certain embodiments, R5, R6, R7, R8, R9 each represent a hydrogen atom.

[0065] In another embodiment, R5 is -OR 10 represents R 10 is a hydrogen atom, (C1-C 30 ) alkyl or phenyl groups, preferably (C1-C 20 ) alkyl or phenyl group. In some embodiments, R5 is -OR 10 represents R 10 is a hydrogen atom, (C1-C 30 ) alkyl or phenyl groups, preferably (C1-C 20 ) represents an alkyl or phenyl group, and R6, R7, R8, and R9 each represent a hydrogen atom.

[0066] In another embodiment, R6 is -OR 10 represents R 10 is a hydrogen atom, (C1-C 30 ) alkyl or phenyl groups, preferably (C1-C 20 ) alkyl or phenyl group. In some embodiments, R6 is -OR 10 represents R 10 is a hydrogen atom, (C1-C 30 ) alkyl or phenyl groups, preferably (C1-C 20) represents an alkyl or phenyl group, and R5, R7, R8, and R9 each represent a hydrogen atom.

[0067] In another embodiment, R7 is -OR 10 represents R 10 is a hydrogen atom, (C1-C 30 ) alkyl or phenyl groups, preferably (C1-C 20 ) alkyl or phenyl group. In some embodiments, R7 is -OR 10 represents R 10 is a hydrogen atom, (C1-C 30 ) alkyl or phenyl groups, preferably (C1-C 20 ) represents an alkyl or phenyl group, and R5, R6, R8, and R9 each represent a hydrogen atom.

[0068] In some embodiments, one residue among R5, R6, R7, R8, and R9 is -OR 10 represents R 10 is a hydrogen atom, (C1-C 30 ) alkyl or phenyl groups, preferably (C1-C 20 ) represents an alkyl or phenyl group.

[0069] 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-.

[0070] Advantageously, the compound of formula (I) is [ka] JPEG2026501630000005.jpg234143JPEG2026501630000006.jpg237150JPEG2026501630000007.jpg202157 and mixtures thereof.

[0071] Preferably, the compound of formula (I) is [ka] JPEG2026501630000009.jpg180159 and mixtures thereof.

[0072] More preferably, the compound of formula (I) is [ka] and mixtures thereof.

[0073] In a preferred embodiment of the invention, the neurological, psychiatric, sleep disorders and diseases in which central orexin neurotransmission is impaired or in which orexin receptors are involved are selected from the group consisting of narcolepsy type 1, narcolepsy type 2, idiopathic hypersomnia, recurrent hypersomnia, attention deficit hyperactivity disorder, anxiety and mood disorders, Alzheimer's disease or any other neurodegenerative or cognitive disorder and tauopathy, 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 staggered travel and shift work, restless legs syndrome, fibromyalgia, heart failure, diseases related to bone loss, sepsis, syndromes manifested by unrestful sleep and muscle pain, psychiatric and physical disorders associated with sleep apnea, which involves disordered breathing during sleep; and conditions resulting from poor sleep quality.

[0074] The dosage of active ingredient in the composition of the present invention can be varied, but the amount of active ingredient must be such that a suitable dosage form is obtained.The active ingredient can be administered to the subject (animal and human) who needs such treatment at a dosage that provides optimal pharmaceutical effectiveness.The selected dosage varies depending on the desired therapeutic effect, administration route and treatment duration.The dosage varies from subject to subject depending on the nature and severity of the disease, the subject's body weight, the specific diet that the subject follows, concurrent medication and other factors that those skilled in the art will recognize.

[0075] Generally, to achieve effective agonism of orexin receptors, dosage levels of 0.0001 to 100 mg / kg body weight per day are administered to subjects, e.g., humans, adolescents and elderly. Advantageously, therapeutic doses of 0.1 mg / kg / day and 100 mg / kg / day of a compound of formula (I) are administered to patients in need thereof.

[0076] The present invention also relates to pharmaceutical compositions comprising at least one compound of formula (I) as above and a pharmaceutically acceptable carrier for use in the prevention and / or treatment of neurological, psychiatric or sleep disorders and diseases in which central orexin neurotransmission is impaired or in which central and peripheral orexin receptors are involved.

[0077] The dosage range is generally 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, 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 composition of the present invention can be provided in a solid dosage form containing 0.5 mg to 500 mg of the active ingredient, or 1 mg to 250 mg of the active ingredient. The pharmaceutical composition can be provided in a solid dosage form containing 1 mg, 5 mg, 10 mg, 50 mg, 80 mg, 100 mg, or 200 mg of the active ingredient.

[0078] 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).

[0079] For oral administration, the composition can be provided in the form of tablets containing 1.0 to 1000 milligrams of active ingredient, e.g., 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of active ingredient, for symptomatic treatment of the subject being treated. The compound can be administered one to four times daily, e.g., once or twice daily. The compound can be administered one or more times daily. The compound can be administered in the morning upon awakening or throughout the waking hours. For example, the compound can be administered at 25 mg, 30 mg, or 250 mg, one hour after awakening, 30 minutes after awakening, or immediately after awakening.

[0080] In certain embodiments, the pharmaceutical compositions according to the invention are suitable for oral or parenteral administration. Preferably, the pharmaceutical compositions according to the invention are in the form of a solution, such as an injection solution, or a tablet or capsule, or a transdermal delivery system.

[0081] The compounds of the present invention can be used in combination with one or more other drugs in the treatment, prevention, control, amelioration, or reduction of risk of diseases or conditions for which the compounds of the present invention or other drugs may be useful, where the combination of drugs is safer or more effective than either drug alone. Such other drugs can be administered simultaneously or sequentially with the compounds of the present invention, by a commonly used route and in an amount. When the compounds of the present invention are used in combination with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compounds of the present invention is contemplated. However, combination therapy can also include therapy in which the compounds of the present invention and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used alone. Thus, pharmaceutical compositions of the present invention include those containing one or more other active ingredients in addition to the compounds of the present invention. The above combinations include not only combinations of the compounds of the present invention with one other active compound, but also combinations of two or more other active compounds.

[0082] The weight ratio of the compound of the present invention to the second active ingredient can vary and depends on the effective amount of each ingredient. Generally, an effective amount of each is used. Thus, 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 generally be in the range of 1000:1 to 1:1000, preferably 200:1 to 1:200. The combination of the compound of the present invention with the other active ingredient will also generally be within the aforementioned range, but in either case, an effective amount of each active ingredient should be used. In such combinations, the compound of the present invention and the other active ingredient may be administered separately or in combination. Furthermore, the administration of one element may be before, simultaneously with, or after the administration of the other drug.

[0083] The compounds of the invention can be co-administered with compounds known in the art to be useful in treating or controlling narcolepsy, including, for example, methylphenidate, amphetamines, atomoxetine, reboxetine, viloxazine, phenelzine, protriptyline, gamma-hydroxybutyric acid, sodium oxybate or other oxybate salts, modafinil, armodafinil, adrafinil, pitolisant, samelisant, nalfurafine, caffeine, and salts thereof, and combinations thereof.

[0084] Compound of formula (II) The present invention also provides a compound of formula (II): [ka] [In the formula, X represents -NH-, -S- or -O-, preferably -NH- or -S-; Y and R2 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, or -OR 10 or (C1-C 30) alkyl chains, especially (C1-C 20 ) alkyl, and optionally aryl, heteroaryl, cycloalkyl, heterocycle, —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 wherein said aryl, heteroaryl and heterocyclic rings are optionally substituted; R 10 is a hydrogen atom or (C1-C 30 ) represents an alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl group, wherein the aryl, heteroaryl and heterocyclic rings are optionally substituted; R 11 and R 12 are each independently a hydrogen atom or a (C1-C6) alkyl group; R 13 ~R 15 are each independently 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, a tautomer, a stereoisomer or a mixture of stereoisomers thereof.

[0085] Preferably, the compound of formula (II) is [ka] (This compound has been described to have inhibitory activity against amyloid aggregation (Cox et al. 2020)). [ka] (These four compounds have been described to have inhibitory effects on cell proliferation (Yale et Kalkstein 1967)). [ka] (This compound has been described to have anticancer activity (Chinigo et al. 2008)). [ka] (This compound has been described to have antitumor activity (Mordarski et Chylinska 1971)). [ka] (This compound is used to treat PARP-1-related diseases, see WO2018044136) (Kim et al. 2023) (However, if X represents O, R1, R2, R3 and R4 each represent H, Y represents a halogen atom, and four of R5, R6, R7, R8 and R9 represent H, the remaining groups of R5, R6, R7, R8 and R9 are not preceded and interrupted by -O- or -C(R 11 )=C(R 12 )- inserted, followed and / or preceded (C1-C 30 ) not an alkyl chain).

[0086] In some embodiments, when X represents -O-, R5, R6, R7, R8, and R9 are each independently a hydrogen atom, a halogen atom, or -OR 10 or (C1-C 30 ) alkyl chains, especially (C1-C 20 ) alkyl, and optionally aryl, heteroaryl, cycloalkyl, heterocycle, —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(R15 )-groups, and said aryl, heteroaryl and heterocyclic rings are optionally substituted.

[0087] In a preferred embodiment, when X represents -O-, Y and R2 independently of each other represent a hydrogen atom, -NO2 or -NH2.

[0088] In preferred embodiments, 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.

[0089] In preferred embodiments, 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.

[0090] R4 preferably represents a hydrogen atom.

[0091] In a preferred embodiment of the present invention, when X is NH or O, R5, R6 or R7 is -OR 10 R10 represents a hydrogen atom, (C1-C 30 ) represents an alkyl or phenyl group.

[0092] In a preferred embodiment of the present 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.

[0093] R5, R6, R7, R8, and R9 each independently represent a hydrogen atom, a halogen atom, or -OR 10 or (C1-C 20 ) alkyl, and optionally aryl, heteroaryl, cycloalkyl, heterocycle, —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 )-groups, and said aryl, heteroaryl and heterocyclic rings are optionally substituted.

[0094] In another preferred embodiment, R5, R6, R7, R8, and R9 are each independently a hydrogen atom or -OR 10 Preferably, at least four residues R5, R6, R7, R8 and R9 each represent a hydrogen atom.

[0095] In certain embodiments, R5, R6, R7, R8, R9 each represent a hydrogen atom.

[0096] In another embodiment, R5 is -OR 10 represents R 10 is a hydrogen atom, (C1-C 30 ) alkyl or phenyl groups, preferably (C1-C 20 ) alkyl or phenyl group. In some embodiments, R5 is -OR 10 represents R 10 is a hydrogen atom, (C1-C 30) alkyl or phenyl groups, preferably (C1-C 20 ) represents an alkyl or phenyl group, and R6, R7, R8, and R9 each represent a hydrogen atom.

[0097] In another embodiment, R6 is -OR 10 represents R 10 is a hydrogen atom, (C1-C 30 ) alkyl or phenyl groups, preferably (C1-C 20 ) alkyl or phenyl group. In some embodiments, R6 is -OR 10 represents R 10 is a hydrogen atom, (C1-C 30 ) alkyl or phenyl groups, preferably (C1-C 20 ) represents an alkyl or phenyl group, and R5, R7, R8, and R9 each represent a hydrogen atom.

[0098] In another embodiment, R7 is -OR 10 represents R 10 is a hydrogen atom, (C1-C 30 ) alkyl or phenyl groups, preferably (C1-C 20 ) alkyl or phenyl group. In some embodiments, R7 is -OR 10 represents R 10 is a hydrogen atom, (C1-C 30 ) alkyl or phenyl groups, preferably (C1-C 20 ) represents an alkyl or phenyl group, and R5, R6, R8, and R9 each represent a hydrogen atom.

[0099] In some embodiments, one residue among R5, R6, R7, R8, and R9 is -OR 10 represents R 10 is a hydrogen atom, (C1-C 30 ) alkyl or phenyl groups, preferably (C1-C 20 ) represents an alkyl or phenyl group.

[0100] In some embodiments, X may represent -NH-. In some embodiments, X may represent -S-. In some embodiments, X may represent -O-. Preferably, X may represent -S-.

[0101] Advantageously, the compound of formula (II) is [ka] JPEG2026501630000018.jpg233160JPEG2026501630000019.jpg242158JPEG2026501630000020.jpg170158 and pharmaceutically acceptable salts thereof.

[0102] In a preferred embodiment of the present invention, the compound of formula (II) is selected from the group consisting of compounds 99, 100, 145, 146, 148, 149, 151, 152, 153, 154, 155, 157, 158, 161, 167, 182, 185, 191, 194, 195, 196, 243, 244, 292, 293, 301, 302, 304, 305, 308, 310, 311, and pharmaceutically acceptable salts thereof.

[0103] More preferably, the compound of formula (II) is selected from the group consisting of compounds 99, 148, 152, 153, 154, 155, 157, 161, 167, 191, 194, 195, 196, 301, 302, 304, 305, 308, 310, 311, and pharmaceutically acceptable salts thereof.

[0104] Even more advantageously, the compound of formula (II) is [ka] and pharmaceutically acceptable salts thereof.

[0105] In a more preferred embodiment, the compound of formula (II) is [ka] and pharmaceutically acceptable salts thereof.

[0106] The present invention also relates to a pharmaceutical composition comprising a compound of formula (II) and a pharmaceutically acceptable carrier, the pharmaceutical composition being as defined above for the compound of formula (I).

[0107] The present invention also relates to a compound of formula (II) as described above for use as a medicament.

[0108] The present invention also relates to a compound of formula (II) as described above for use in the manufacture of a medicament. In some embodiments, the present invention provides a method for treating a subject in need thereof, comprising administering to the subject a compound of formula (II) or a composition comprising a compound of formula (II).

[0109] Chromatographic separations can be achieved as known in the art. Their absolute stereochemistry can be determined by X-ray crystallography of crystalline products or crystalline intermediates, derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration. Optionally, racemic mixtures of compounds can be separated to isolate individual enantiomers. This separation can be carried out by methods known in the art, such as coupling a racemic mixture of a compound with an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography. The coupling reaction often involves the formation of a salt with an enantiomerically pure acid or base. The diastereomeric derivatives can then be converted to pure enantiomers by cleavage of the added chiral residue. Racemic mixtures of compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, methods well known in the art. Alternatively, any enantiomer of a compound can be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art.

[0110] In some embodiments, the present invention provides a method for treating a subject suffering from a neurological disease in which central orexin neurotransmission is impaired or in which central and peripheral orexin receptors are involved, preferably a neurological, psychiatric, sleep disorder and disease, such as narcolepsy and Parkinson's disease, comprising administering to said subject a compound of formula (I) or a composition comprising a compound of formula (I). In particular, said disorder and disease are as defined above.

[0111] In some embodiments, the present invention provides a method for preventing neurological disorders in which central orexin neurotransmission is impaired or in which central and peripheral orexin receptors are involved, preferably neurological, psychiatric, sleep disorders and diseases, such as narcolepsy and Parkinson's disease, comprising administering to a subject an effective amount of a compound of formula (I) or a composition comprising an effective amount of a compound of formula (I). In particular, said disorders and diseases are as defined above.

[0112] In some embodiments, these methods further comprise administration of a second active compound.

[0113] In one aspect, the present invention also relates to a compound of formula (I) or a pharmaceutical composition comprising at least one compound of formula (I) for use in the manufacture of a medicament for the treatment of neurological disorders in which central orexin neurotransmission is impaired or in which central and peripheral orexin receptors are involved, preferably neurological, psychiatric, sleep disorders and diseases, such as narcolepsy and Parkinson's disease, in particular said disorders and diseases as defined above.

[0114] The present invention also relates to the following embodiments: Embodiment 1. A compound of formula (I) for use in 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: [In the formula, X represents -NH-, -S- or -O-, preferably -NH- or -S-; Y represents a halogen atom, -NO2 or -NH2, preferably -NO2 or -NH2; R1, R2, R3, 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, or -OR 10 or (C1-C 30 ) alkyl chains, especially (C1-C 20) alkyl, and optionally aryl, heteroaryl, cycloalkyl, heterocycle, —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 )-groups, wherein said aryl, heteroaryl, and heterocyclic rings are optionally substituted; R 10 is a hydrogen atom or (C1-C 30 ) represents an alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl group, wherein the aryl, heteroaryl and heterocyclic rings are optionally substituted; R 11 and R 12 are each independently a hydrogen atom or a (C1-C6) alkyl group; R 13 ~R 15 are each independently 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, a tautomer, stereoisomer or mixture of stereoisomers thereof.

[0115] Embodiment 2. A compound of formula (I) for use according to embodiment 1, characterized in that R1, R2, R3, R4 each represent a hydrogen atom.

[0116] Embodiment 3. R5, R6, R7, R8, R9 are independently a hydrogen atom or -OR 10 3. A compound of formula (I) for use according to embodiment 1 or 2, characterized in that it represents:

[0117] Embodiment 4. A compound of formula (I) for use according to any one of embodiments 1 to 3, characterized in that at least four of the residues R5, R6, R7, R8 and R9 each represent a hydrogen atom.

[0118] Embodiment 5. A compound of formula (I) for use according to embodiment 4, characterized in that R5, R6, R7, R8, R9 each represent a hydrogen atom.

[0119] Embodiment 6. R5, R6 or R7 is -OR 10 represents R 10 is a hydrogen atom, (C1-C 30 ) a compound of formula (I) for use according to embodiment 4, characterized in that it represents an alkyl or phenyl group.

[0120] Embodiment 7. A compound of formula (I) for use according to any one of embodiments 1 to 6, characterized in that it is selected from the group consisting of compounds 69, 84, 87, 90, 96, 97, 98, 99, 148, 152, 153, 154, 155, 157, 161, 167, 191, 194, 195, 196 and mixtures thereof, preferably 84, 99, 152, 155, 194 and mixtures thereof.

[0121] Embodiment 8. A compound of formula (I) for use according to any one of embodiments 1 to 7, characterized in that the neurological, psychiatric or sleep disorders and diseases in which central orexin neurotransmission is impaired or in which orexin receptors are involved are selected from the group consisting of narcolepsy type 1, narcolepsy type 2, idiopathic hypersomnia, recurrent hypersomnia, attention deficit hyperactivity disorder, anxiety and mood disorders, Alzheimer's disease or any other neurodegenerative or cognitive disorder and tauopathy, 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 staggered travel and shift work, restless legs syndrome, fibromyalgia, heart failure, diseases related to bone loss, sepsis, syndromes manifested by unrestful sleep and muscle pain, psychiatric and physical disorders associated with sleep apnea, which is characterized by breathing disorders during sleep; conditions resulting from poor sleep quality.

[0122] Embodiment 9. A pharmaceutical composition comprising at least one compound of formula (I) as defined in any one of embodiments 1-8 and a pharmaceutically acceptable carrier for use in the prevention and / or treatment of neurological, psychiatric, or sleep disorders and diseases in which central orexin neurotransmission is impaired or in which central and peripheral orexin receptors are involved.

[0123] Embodiment 10. A pharmaceutical composition for use according to embodiment 9, comprising 0.5 mg to 800 mg, preferably 20 mg to 400 mg, of a compound of formula (I).

[0124] Embodiment 11. A pharmaceutical composition for use according to embodiment 9 or 10, suitable for oral or parenteral administration, preferably in the form of a solution, such as an injection solution, a tablet, a capsule or a transdermal delivery system.

[0125] Embodiment 12. X represents -NH-, -S- or -O-, for example -S- or -O-, preferably -S-; Y represents a halogen atom, -NO2 or -NH2, preferably -NO2 or -NH2; R1, R2, R3, and R4 each independently represent a hydrogen atom or a halogen atom; R5, R6, R7, R8, and R9 are each independently a hydrogen atom, a halogen atom, or -OR 10 or (C1-C 30 ) alkyl chains, especially (C1-C 20 ) alkyl, and optionally aryl, heteroaryl, cycloalkyl, heterocycle, —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 )-groups, wherein said aryl, heteroaryl, and heterocyclic rings are optionally substituted; R 10 is a hydrogen atom or (C1-C 30 ) represents an alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl group, wherein the aryl, heteroaryl and heterocyclic rings are optionally substituted; R 11 and R 12 are each independently a hydrogen atom or a (C1-C6) alkyl group; R 13 ~R 15 are each independently 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, A compound of formula (II), or a pharmaceutically acceptable salt thereof, a tautomer, a stereoisomer or a mixture of stereoisomers thereof:

[0126] Embodiment 13. R1, R2, R3, R4 each represent a hydrogen atom, and R5, R6, R7, R8, R9, independently of one another, represent a hydrogen atom or -OR 1013. The compound of formula (II) according to embodiment 12, wherein

[0127] Embodiment 14. A compound of formula (II) according to embodiment 12 or 13, characterized in that at least four of the residues R5, R6, R7, R8 and R9 represent a hydrogen atom.

[0128] Embodiment 15. A compound of formula (II) as defined in embodiment 14, characterized in that R5, R6, R7, R8, R9 each represent a hydrogen atom.

[0129] Embodiment 16. R5, R6 or R7 is -OR 10 represents R 10 is a hydrogen atom, (C1-C 30 15. Compounds of formula (II) according to embodiment 14, characterized in that: 1) represents an alkyl or phenyl group.

[0130] Embodiment 17. A compound of formula (II) according to any one of embodiments 12 to 16, characterized in that it is selected from the group consisting of compounds 99, 148, 152, 153, 154, 155, 157, 161, 167, 191, 194, 195, 196 and mixtures thereof, preferably 99, 152, 155, 194 and mixtures thereof.

[0131] Embodiment 18. A compound of formula (II) as defined in any one of embodiments 12 to 17 for use as a medicament.

[0132] One or more features of any embodiment disclosed herein can be combined and / or rearranged within the scope of the invention to produce additional embodiments that are also within the scope of the invention. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be within the scope of the invention.

[0133] The present invention is further illustrated by the following non-limiting examples. [Example]

[0134] The following examples are provided to facilitate a more complete understanding of the present invention. The following examples illustrate exemplary modes of making and practicing the invention. However, the scope of the invention is not limited to the specific embodiments disclosed in these examples, which are illustrative only, as alternative methods may be utilized to obtain similar results.

[0135] Example 1. Chemistry of dihydro-quinazoline derivatives Design, synthesis and preparation of 6-nitro-2,3-dihydro-1H-quinazolin-4-one [ka]

[0136] Preparation of polyphosphate esters (PPE) P2O4 (150 g) was refluxed in diethyl ether (150 mL) and CHCl3 (300 mL) until a clear solution was obtained, and then the solvent was removed under reduced pressure to give a clear oil.

[0137] Synthesis of 2-amino-5-nitrobenzamide A mixture of 2-amino-5-nitro-benzonitrile (25.3 mmol, 4 g) and concentrated H2SO4 (24.2 mL) was heated to 65 °C and stirred for 12 h. The reaction mixture was slowly poured onto ice, and the pH was adjusted to 8–9 with 6 M aqueous NaOH or NH4OH. The precipitate was filtered off and washed with ice-cold HO to give the pure benzamide, which was used without further purification. 1 H NMR (400 MHz, DMSO-d6): δ ppm 8.54 (d, J= 2.7 Hz, 1H), 8.20 (br.s., 1H), 8.01 (dd, J= 9.0 Hz, 2.8 Hz, 1H), 7.87 (bs, 1H), 7.39 (br.s., 1H), 6.78 (d, J= 9.0 Hz, 1H).

[0138] General procedure for 6-nitro-2,3-dihydro-1H-quinazolin-4-one: A mixture of 2-amino-5-nitrobenzamide (1 mmol) and PPE (1 g) was added to the corresponding aldehyde (1 mmol), and the solution was heated at 80 °C for 30 min without 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 yields (80–95%). [ka]

[0139] Product 50: 6-nitro-2-phenyl-2,3-dihydro-1H-quinazolin-4-one [ka] 1 H NMR (300 MHz, DMSO-d6) δ ppm 6.01 (s, 1H) 6.83 (d, J=9.08 Hz, 1H) 7.35-7.50 (m, 5H) 8.10 (dd, J=9.08, 2.75 Hz, 1H) 8.43 (d, J=2.66 Hz, 1H) 8.58 (s, 1H) 8.74 (s, 1H). 13 C NMR (75 MHz, DMSO-d6) δ ppm 66.27 (C-2), 112.63 (C-8), 114.24 (C-10), 124.17 (C-4), 126.53 (C-2'), 128.65 (C-3'), 128.87 (C-4'), 128.97 (C-7), 137.10 (C-6), 141.10 (C-1'), 152.13 (C-9), 161.28 (C-4). Chemical formula: C 14 H 11 N3O3: m / z: 269.08

[0140] Product 51: 6-nitro-2-(4-hydroxyphenyl)-2,3-dihydro-1H-quinazolin-4-one [ka] 1 H NMR (300 MHz, DMSO-d6) δ ppm 5.90 (s, 1H) 6.73-6.85 (m, 3H) 7.28 (d, J=8.53 Hz, 2H) 8.09 (dd, J=9.26, 2.93 Hz, 1H) 8.43 (d, J=2.57 Hz, 2H) 8.57 (s, 1H). 13 C NMR (75 MHz, DMSO-d6) δ ppm 66.30 (C-2), 112.63 (C-10), 114.20 (C-8), 115.26 (C-3'), 124.25 (C-5), 128.05 (C-2'), 128.93 (C-7), 131.25 (C-1'), 137.01 (C-6), 152.30 (C-9), 158.03 (C-4'), 161.42 (C-4). Chemical formula: C 14 H 11 N3O4: m / z: 285.07.

[0141] Product 54: 6-ニトロ-2-(4-メトキシフェニル)-2,3-ジヒドロ-1H-キナゾリン-4-オン

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[0142] Product 55: 6-nitro-2-(3-methoxyphenyl)-2,3-dihydro-1H-quinazolin-4-one [ka] 1 H NMR (300 MHz, DMSO-d6) δ ppm 3.75 (s, 3H) 5.98 (s, 1H) 6.84 (d, J=9.17 Hz, 1H) 6.90-6.99 (m, 1H) 6.99-7.08 (m, 2H) 7.33 (t, J=8.16 Hz, 1H) 8.05-8.17 (m, 1H) 8.43 (d, J=2.75 Hz, 1H) 8.57 (s, 1H) 8.74 (s, 1H) Chemical formula: C 15 H 13 N3O4: m / z: 299.09.

[0143] Product 56: 6-nitro-2-(2-methoxyphenyl)-2,3-dihydro-1H-quinazolin-4-one [ka] 1H NMR (300 MHz, DMSO-d6) δ ppm 3.91 (s, 3H, OCH3), 5.95 (s, 1H, C-H2), 6.88 (d, J=9.17 Hz, 1H, C-H8), 7.16-7.09 (m, 2H, CH 3’,5’ ), 7.46 (dt, 1H, J=7.1 Hz, CH 4’ ), 8.10 (m, 1H, C-H7), 8.20-8.18 (dd, 1H, J=1.2;7.8 Hz, CH 6’ ), 8.44 (d, J=2.75 Hz, 1H, C-H5) 8.57 (s, 1H), 8.75 (s, 1H). 13 C NMR (75 MHz, DMSOd6): δ 55.84(OCH3), 65.78 (C-2), 112.12 (C-10), 113.31(C-3'), 114.22 (C-8), 120.68(C-5'), 124.18 (C-5), 128.45 (C-7), 131.11(C-6'), 131.87 (C-1'), 131.99(C-4'), 134.56 (C-6), 151.31 (C-9), 158.32(C-2'), 161.44 (C-4). Chemical formula: C 15 H 13 N3O4: m / z: 299.09.

[0144] Product 60: 6-ニトロ-2-(4-プロポキシフェニル)-2, 3-ジヒドロ-1H-キナゾリン-4-オン

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[0145] Product 63: 6-ニトロ-2-(4-ブトキシフェニル)-2, 3-ジヒドロ-1H-キナゾリン-4-オン

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[0146] Product 69: 6-ニトロ-2-[4-(ヘキシルオキシ)フェニル]-2,3-ジヒドロ-1H-キナゾリン-4-オン

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[0147] Product 84: 6-ニトロ-2-[4-(ウンデシルオキシ)フェニル]-2,3-ジヒドロ-1H-キナゾリン-4-オン

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[0148] Product 87: 6-ニトロ-2-(4-ドデシルオキシフェニル)-2,3-ジヒドロ-1H-キナゾリン-4-オン

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[0149] Product 90: 6-ニトロ-2-(4-トリデシルオキシフェニル)-2,3-ジヒドロ-1H-キナゾリン-4-オン

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[0150] Product 93: 6-ニトロ-2-(4-テトラデシルオキシフェニル)-2,3-ジヒドロ-1H-キナゾリン-4-オン

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[0151] Product 96: 6-ニトロ-2-(4-フェノキシフェニル)-2,3-ジヒドロ-1H-キナゾリン-4-オン

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[0152] Product 98: 6-ニトロ-2-(2-フェノキシフェニル)-2,3-ジヒドロ-1H-キナゾリン-4-オン

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[0153] General procedure for 7-nitro-2,3-dihydro-1H-quinazolin-4-one: [ka] A mixture of 2-amino-4-nitrobenzamide (CAS: 31930-18-4, 1 mmol) and PPE (1 g) was added to the corresponding aldehyde (1 mmol), and the solution was heated at 80 °C for 30 min without 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 yields (80-95%).

[0154] Product 300: 7-nitro-2-[4-(dodecyloxy)phenyl]-2,3-dihydroquinazolin-4(1H)-one [ka] 1H NMR (300 MHz, DMSO-d6) δ ppm : 0.85 (t, J=6.24 Hz, 3H, CH3), 1.24 (br. s., 16 H, CH2), 1.38 (br. s., 2H, CH2), 1.61 - 1.81 (m, 2H, CH2), 3.94 (t, J=6.28 Hz, 2H, OCH2), 5.85 (s, 1H, C-H2), 6.94 (d, J=8.44 Hz, 2H, 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=8.53 Hz, 1H, C-H5), 8.61 (s, 1H, NH). 13 C NMR (75 MHz, DMSO-d6) δ ppm: 13.91 (CH3), 22.06 (CH2), 25.45 (CH2), 28.59 (CH2), 28.67 (CH2), 28.72 (CH2), 28.96 (3xCH2), 29.00 (CH2), 31.26 (CH2), 66.04 (C-2), 67.50 (OCH2), 108.79 (C-8), 110.89 (C-6), 114.29 (C-3',5'), 119.25 (C-10), 128.02 (C-2',6'), 129.07 (C-5), 132.75 (C-1'), 148.24 (C-9), 150.72 (C-7), 159.01 (C-4'), 161.86 (C-4). Chemical formula: C 26 H 35 N3O4: m / z: 453,26

[0155] Product 313: 7-ニトロ-2-[4-(テトラデシルオキシ)フェニル]-2,3-ジヒドロキナゾリン-4(1H)-オン

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[0156] Example 2. Chemistry of dihydro-benzothiazine derivatives A) 6-ニトロ-2H-ベンゾ[e][1,3]チアジン-4(3H)-オンのDesign and synthesize および modulation The design, synthesis, and preparation of 6-nitro-2-(phenyl)-2H-benzo[e][1,3]thiazin-4(3H)-one have never been described. The design, synthesis, and preparation of 2-aryl-2,3-dihydro-4H-1,3-benzothiazin-4-one and 2-aryl-2,3-dihydro-4-one derivatives have been cited several times (Boudet 1959; Geng et al. 2012; Ingram et McClelland 1947; Moreau et Delacoux 1962).

[0157] Our synthetic route begins with obtaining thiobenzamide as follows. [ka]

[0158] 2-chloro-5-nitrobenzamide RMN 1 H (300 MHz, DMSO-d6) δ ppm 7.78-7.81 (m, 1H, C-H3), 7.86 (br.s., 1H, NH), 8.12 (brs, 1H, NH), 8.23-8.25 (m, 2H, C-H4,6). RMN 13 C (75 MHz, DMSO-d6) δ ppm 123.61(C-3), 125.41(C-6), 131.51(C-4), 137.01(C-2), 138.17(C-1), 146.17(C-5), 166.25(CONH2). Chemical formula: C7H5ClN2O3: m / z: 200.00.

[0159] 2-Mercapto-5-nitrobenzamide 1H (300 MHz, DMSO-d6) δ ppm 7.37-7.40 (d, 1H, J= 8.88 Hz, C-H3), 7.43 (br. s., 1H, NH), 7.50-7.54 (dd, 1H, J= 2.83, 8.88 Hz, C-H4), 8.77 (d, 1H, J= 3.02 Hz, C-H6), 11.41 (brs, 1H, NH). 13 C (300 MHz, DMSO-d6) δ ppm, 120.61(C-3), 125.92(C-6), 132.14(C-4), 138.22(C-2), 138.47(C-1), 168.12(CONH2), no (C-5). Chemical formula: C7H6N2O3S: m / z: 198.01.

[0160] General Procedure 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 min 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 dihydrobenzothiazine in excellent yields (80–95%). [ka]

[0161] Product 148: 6-nitro-2-phenyl-2,3-dihydro-1,3-benzothiazin-4-one [ka] 1 H NMR (300 MHz, DMSO-d6) δ ppm: 6.31 (d, J=3.76 Hz, 1 H, C-H2), 7.29 - 7.43 (m, 3 H, CH 3',4',5' ), 7.43 - 7.53 (m, 2 H, CH 2',6'), 7.63 (d, J=8.71 Hz, 1 H, C-H8), 8.24 (dd, J=8.67, 2.61 Hz, 1 H, C-H7), 8.70 (d, J=2.66 Hz, 1 H, C-H5), 9.43 (d, J=3.67 Hz, 1 H, NH). 13 C NMR (75 MHz, DMSO-d6) δ ppm: 57.36 (C-2), 123.80 (C-5), 126.38 (C-8), 126.86 (C-10), 128.62 (C-2',6'), 128.67 (C-7), 128.70 (C-4'), 128.86 (C-3',5'), 138.04 (C-1'), 144.63 (C-6), 145.32 (C-9), 162.77 (C-4).

[0162] Product 149: 6-ニトロ-2-(4-ヒドロキシフェニル)-2,3-ジヒドロ-1,3-ベンゾチアジン-4-オン

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[0163] Product 151: 6-nitro-2-(2-hydroxyphenyl)-2,3-dihydro-1,3-benzothiazin-4-one [ka] 1 H NMR (400 MHz, DMSO-d6) δ ppm 6.25 (d, J=3.91 Hz, 1H), 6.78 (t, J=7.52 Hz, 1H), 6.87 (d, J=7.46 Hz, 1H), 7.17 (t, J=8.50 Hz, 1H), 7.22 (d, J=7.58 Hz, 1H), 7.58 (d, J=8.56 Hz, 1H), 8.22 (dd, J=8.68, 2.69 Hz, 1H), 8.74 (d, J=2.57 Hz, 1H), 9.18 (d, J=3.91 Hz, 1H), 10.16 (s, 1 H, OH). 13 C NMR (101 MHz, DMSO-d6) δ ppm 52.11 (C-2), 54.85 (C-3'), 115.53 (C-5'), 119.01 (C-5'), 123.87 (C-5), 124.01 (C-10), 126.28 (C-8), 126.80 (C-6'), 128.43 (C-1'), 128.62 (C-7), 129.90 (C-4'), 145.11 (C-9), 153.89 (C-2'), 163.01 (C-4). Chemical formula: C 14 H 10 N2O4S: m / z: 302.04.

[0164] Product 152: 6-nitro-2-(4-methoxyphenyl)-2,3-dihydro-1,3-benzothiazin-4-one [ka] 1H NMR (400 MHz, DMSO-d6) δ ppm 3.75 (s, 3H), 6.27 (d, J=3.55 Hz, 1H), 6.95 (m, J=8.80 Hz, 2H), 7.42 (m, J=8.68 Hz, 2H), 7.64 (d, J=8.68 Hz, 1H), 8.25 (d, J=11.37 Hz, 1H), 8.70 (s, 1H), 9.36 (br. s., 1H). Chemical formula: C 15 H 12 N2O4S: m / z: 316.05.

[0165] Product 153: 6-ニトロ-2-(3-メトキシフェニル)-2,3-ジヒドロ-1,3-ベンゾチアジン-4-オン

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[0166] Product 154: 6-nitro-2-(2-methoxyphenyl)-2,3-dihydro-1,3-benzothiazin-4-one [ka] 1 H NMR (400 MHz, DMSO-d6) δ ppm 3.85 (s, 3H), 6.27 (d, J=4.16 Hz, 1H), 6.93 (t, J=7.52 Hz, 1H), 7.07 (d, J=7.95 Hz, 1H), 7.28 (d, J=9.05 Hz, 1H), 7.34 (t, J=8.62 Hz, 1H), 7.57 (d, J=8.68 Hz, 1H), 8.16-8.26 (m, 1H), 8.74 (d, J=2.69 Hz, 1H), 9.21 (d, J=4.28 Hz, 1H). 13 C NMR (101 MHz, DMSO-d6) δ ppm 51.85 (C-2), 55.73 (OCH3), 111.49 (C-3'), 120.37 (C-5'), 123.86 (C-5), 125.79 (C-1'), 126.31 (C-8), 126.70 (C-6'), 128.33 (C-10), 128.62 (C-7), 130.26 (C-4'), 144.77 (C-6), 145.20 (C-9), 155.53 (C-2'), 162.90 (C-4). Chemical formula: C 15 H 12 N2O4S: m / z: 316.05.

[0167] Product 155: 6-nitro-2-(4-ethoxyphenyl)-2,3-dihydro-1,3-benzothiazin-4-one [ka] 1H NMR (400 MHz, DMSO-d6) δ ppm 1.30 (t, J=6.97 Hz, 3H), 4.01 (q, J=6.97 Hz, 2H), 6.26 (d, J=3.42 Hz, 1H), 6.93 (d, J=8.68 Hz, 2H), 7.40 (d, J=8.68 Hz, 2H), 7.63 (d, J=8.68 Hz, 1H), 8.24 (dd, J=8.68, 2.69 Hz, 1H), 8.70 (d, J=2.57 Hz, 1H), 9.35 (d, J=3.30 Hz, 1H). Chemical formula: C 16 H 14 N2O4S: m / z: 330.07.

[0168] Product 157: 6-ニトロ-2-(2-エトキシフェニル)-2,3-ジヒドロ-1,3-ベンゾチアジン-4-オン

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[0169] Product 158: 6-nitro-2-(4-propoxyphenyl)-2,3-dihydro-1,3-benzothiazin-4-one [ka] 1 H NMR (300 MHz, DMSO-d6) δ ppm 0.95 (t, J=7.38 Hz, 3H), 1.60-1.82 (m, 2H), 3.91 (t, J=6.51 Hz, 2H), 6.26 (d, J=3.48 Hz, 1H), 6.93 (m, J=8.71 Hz, 2H), 7.40 (m, J=8.71 Hz, 2H), 7.63 (d, J=8.71 Hz, 1H), 8.24 (dd, J=8.62, 2.66 Hz, 1H), 8.70 (d, J=2.57 Hz, 1H), 9.34 (d, J=3.48 Hz, 1H). Chemical formula: C 17 H 16 N2O4S: m / z: 344.08.

[0170] Product 161: 6-nitro-2-(4-butoxyphenyl)-2,3-dihydro-1,3-benzothiazin-4-one [ka] 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.92 (t, J=7.40 Hz, 3H), 1.35-1.48 (m, 2H), 1.62-1.73 (m, 2H), 3.95 (t, J=6.48 Hz, 2H), 6.26 (d, J=3.55 Hz, 1H), 6.93 (m, J=8.68 Hz, 2H), 7.40 (m, J=8.56 Hz, 2H), 7.63 (d, J=8.68 Hz, 1H), 8.19-8.28 (m, 1H), 8.70 (d, J=2.57 Hz, 1H), 9.34 (d, J=3.42 Hz, 1H). 13 C NMR (101 MHz, DMSO-d6) δ ppm 13.59 (CH3), 18.64 (CH2), 30.61 (CH2), 57.34 (C-2), 67.19 (OCH2), 114.41 (C-3'), 123.80 (C-5), 126.28 (C-8), 128.33 (C-2'), 128.58 (C-10), 128.73 (C-7), 129.26 (C-1'), 145.01 (C-6), 145.25 (C-9), 159.07 (C-4'), 162.84 (C-4). Chemical formula: C 18 H 18 N2O4S: m / z: 358.10.

[0171] Product 167: 6-ニトロ-2-[4-(ヘキシルオキシ)フェニル]-2,3-ジヒドロ-1,3-ベンゾチアジン-4-オン

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[0172] Product 182: 6-ニトロ-2-[4-(ウンデシルオキシ)フェニル]-2,3-ジヒドロ-1,3-ベンゾチアジン-4-オン

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[0173] Product 185: 6-ニトロ-2-(4-ドデシルオキシフェニル)-2,3-ジヒドロ-1,3-ベンゾチアジン-4-オン

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[0174] Product 191: 6-nitro-2-(4-tetradecyloxyphenyl)-2,3-dihydro-1,3-benzothiazin-4-one [ka] 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.85 (t, J=6.72 Hz, 3H), 1.24 (br. s., 16H), 1.38 (br. s., 2H), 1.62-1.75 (m, 2H), 3.94 (t, J=6.48 Hz, 2H), 6.26 (d, J=3.42 Hz, 1H), 6.92 (m, J=8.80 Hz, 2H), 7.39 (m, J=8.80 Hz, 2H), 7.63 (d, J=8.68 Hz, 1H), 8.24 (dd, J=8.68, 2.57 Hz, 1H), 8.70 (s, 1H), 9.34 (d, J=3.30 Hz, 1H). 13 C NMR (101 MHz, DMSO-d6) δ ppm 13.81 (CH3), 22.03 (CH2), 25.11 (CH2), 25.43 (CH2), 28.56 (CH2), 28.65 (CH2), 28.70 (2xCH2), 28.94 (3xCH2), 28.97 (CH2), 31.21 (CH2), 57.35 (C-2), 67.52 (OCH2), 114.43 (C-3'), 123.82 (C-5), 126.31 (C-8), 128.35 (C-2'), 128.60 (C-10), 128.74 (C-7), 129.27 (C-1'), 145.03 (C-6), 145.26 (C-9), 159.08 (C-4'), 162.87 (C-4). Chemical formula: C 26 H 34 N2O4S: m / z: 470.22.

[0175] Product 194: 6-nitro-2-(4-phenoxyphenyl)-2,3-dihydro-1,3-benzothiazin-4-one

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[0176] Product 195: 6-ニトロ-2-(3-フェノキシフェニル)-2,3-ジヒドロ-1,3-ベンゾチアジン-4-オン

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[0177] Product 196: 6-ニトロ-2-(2-フェノキシフェニル)-2,3-ジヒドロ-1,3-ベンゾチアジン-4-オン

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[0178] General Procedure The reduction of the nitro group to an amino group was carried out using a hydrogenation apparatus. The nitro derivative (1 mmol) was introduced into a flask containing Pd / C (10 wt%) and ethanol (20 ml). The flask was shaken under 50 psi of hydrogen at room temperature until no starting material was observed by TLC. The solution was then filtered and the solvent was removed under reduced pressure. The desired amino derivative was crystallized in diethyl ether.

[0179] Product 96: 6-nitro-2-(4-phenoxyphenyl)-2,3-dihydro-1H-quinazolin-4-one [ka] 1H NMR (300 MHz, DMSO-d6) δ ppm 6.02 (s, 1H) 6.84 (d, J=9.17 Hz, 1H) 7.05 (d, J=8.62 Hz, 2H) 7.00 (d, J=8.80 Hz, 2H) 7.12-7.21 (m, 1H) 7.35-7.45 (m, 2H) 7.49 (d, J=8.62 Hz, 2H) 8.11 (dd, J=9.08, 2.75 Hz, 1H) 8.44 (d, J=2.75 Hz, 1H) 8.53 (s, 1H) 8.71 (s, 1H). 13 C NMR (75 MHz, DMSO-d6) δ ppm: 66.17 (C-2), 114.40 (C-8), 114.89 (C-10), 118.26 (C-8'',C-12'), 118.71 (C-3',C-5'), 123.61 (C-10'), 124.35 (C-5), 128.30 (C-7), 128.68 (C-2',C-6'), 130.07 (C-9',C-11'), 136.51 (C-1'), 137.15 (C-6), 147.85 (C-9), 156.45 (C-4'), 156.86 (C-7'), 163.56 (C-4). Chemical formula: C 20 H 15 N3O4: m / z: 361.11.

[0180] Product 97: 6-ニトロ-2-(3-フェノキシフェニル)-2,3-ジヒドロ-1H-キナゾリン-4-オン

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[0181] Product 98: 6-ニトロ-2-(2-フェンオキシフェニル)-2,3-ジヒドロ-1H-キナゾリン-4-オン

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[0182] Product 99: 6-アミノ-2-フェニル-2,3-ジヒドロ-1,3-ベンゾチアジン-4-オン

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[0183] Product 145: 6-amino-2-(4-phenoxyphenyl)-2,3-dihydro-1,3-benzothiazin-4-one [ka] 1 H NMR (400 MHz, DMSO-d6) δ ppm 5.30 (br. s., 2H), 5.96 (d, J=3.55 Hz, 1H), 6.67 (dd, J=8.31, 2.57 Hz, 1H), 6.91-6.99 (m, 3H), 6.99-7.05 (m, 2H), 7.13-7.19 (m, 1H), 7.25 (d, J=2.57 Hz, 1H), 7.36-7.43 (m, 2H), 7.46 (d, J=8.56 Hz, 2H), 8.76 (d, J=3.67 Hz, 1H). 13 C NMR (75 MHz, DMSO-d6) δ ppm 57.15 (C-2), 114.44 (C-5), 117.98 (C-6'), 118.22 (C-7), 118.95 (C-3'), 119.37 (C-10), 123.76 (C-8'), 127.75 (C-8), 128.70 (C-7'), 129.26 (C-9), 130.09 (C-2'), 133.72 (C-1'), 147.26 (C-6), 156.15 (C-5'), 156.79 (C-4'), 164.79 (C-4). Chemical formula: C 20 H 16 N2O2S: m / z: 348.09.

[0184] Product 146: 6-amino-2-(3-phenoxyphenyl)-2,3-dihydro-1,3-benzothiazin-4-one [ka] 1H NMR (400 MHz, DMSO-d6) δ ppm 5.10 (br. s., 2H, NH2), 6.03 (br. s., 1H), 6.84-6.97 (m, 3H), 7.04-7.14 (m, 2H), 7.18 (d, J=7.58 Hz, 1H), 7.25-7.39 (m, 4H), 7.47 (d, J=7.95 Hz, 1H), 7.99 (s, 1H), 9.13 (br. s., 1H). Chemical formula: C 20 H 16 N2O2S: m / z: 348.09.

[0185] Product 158: 6-ニトロ-2-(4-プロポキシフェニル)-2,3-ジヒドロ-1,3-ベンゾチアジン-4-オン

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[0186] Example 3. Chemistry of dihydro-benzoxazine derivatives General Procedure: Use the same method as for benzothiazine: [ka]

[0187] Product 243: 6-amino-2-(4-phenoxyphenyl)-2,3-dihydro-1,3-benzoxazin-4-one 1 H NMR (400 MHz, DMSO-d6) δ ppm 6.17 (d, 1H, J= 1.33 Hz, C-H2), 6.75 (m, 2H, CH 5,7 ), 6.01-6.04 (d, 4H, J= 8.5 Hz, CH 3’,6’ ), 7.17 (dt, 1H, J= 7.55 Hz, CH 8’ ), 7.41 (dt, 2H, J= 7.56 Hz, CH 7’ ), 7.54-7.57 (d, 2H, J= 8.5 Hz, CH 2’ ), 8.72 (d, 1H, J= 1.3 Hz, N-H3). 13 C NMR (75 MHz, DMSO-d6) δ ppm 84.2(2), 111.44(5), 117.12(8), 118.23(3'), 118.87(4a), 119.28(6'), 120.84(7), 124.11(8'), 129.46(2'), 130.37(7'), 132.31(1'), 143.59(6), 148.32(4'), 156.33(5'), 157.93(8a), 163.37(4). Chemical formula: C 20 H 16 N2O3: m / z: 332.12.

[0188] Product 244: 6-amino-2-(3-phenoxyphenyl)-2,3-dihydro-1,3-benzoxazin-4-one [ka] 1 H NMR (400 MHz, DMSO-d6) δ ppm 5.30 (bs, 2H, NH2), 6.17 (d, 1H, J= 1.70 Hz, C-H2), 6.73 (m, 2H, 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= 7.74 Hz, CH 6’ ), 7.36-7.44 (m, 3H, CH 2’,4’,5’ ), 8.76 (d, 1H, N-H3). 13 C NMR (75 MHz, DMSO-d6) δ ppm 83.83(2), 111.39(5), 117.1(2'), 117.36(8), 118.88(4a), 118.91(8'), 119.51(7), 120.78(4'), 122.38(6'), 123.79(10'), 130.19(9'), 130.22(5'), 139.72(1'), 143.57(6), 148.02(8a), 156.46(3'), 156.81(7'), 163.08(4). Chemical formula: C 20 H 16 N2O3: m / z: 332.12.

[0189] Product 246: 6-nitro-2-phenyl-2,3-dihydro-1,3-benzoxazin-4-one [ka] 1H NMR (300 MHz, DMSO-d6) δ ppm 6.59 (d, 1H, J= 1.13 Hz, C-H2), 7.29-7.32 (d, 1H, J= 9.07 Hz, C-H8), 7.42-7.48 (m, 3H, C-H3',4',5'), 7.58-7.60 (d, 2H, J= 8.68 Hz, C-H2',6'), 8.34-8.38 (dd, 1H, J= 2.83, 9.07 Hz, C-H7), 8.54 (d, 1H, J= 2.84 Hz, C-H5), 9.41 (bs, 1H, NH). 13 C NMR (75 MHz, DMSO-d6) δ ppm 85.56(C-2), 118.61 (C-10), 118.74 (C-8), 123.41 (C-5), 127.65 (C-2',6'), 128.89(C-3',5'), 129.79 (C-4'), 130.27 (C-7), 136.16 (C-1'), 142.37 (C-6), 161.14 (C-9), 161.64 (C-4). Chemical formula: C 14 H 10 N2O4:m / z: 270.06

[0190] Product 292: 6-ニトロ-2-(4-フェノキシフェニル)-2,3-ジヒドロ-1,3-ベンゾキサジン-4-オン

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[0191] Product 293: 6-ニトロ-2-(3-フェノキシフェニル)-2,3-ジヒドロ-1,3-ベンゾキサジン-4-オン

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[0192] Example 4. Binding activity 4.1. Binding activity to OX1R and OX2R sites These compounds exhibit agonistic activity against OX1R and / or OX2R, which is determined according to the following general experimental method by Eurofins using Chinese hamster ovary (CHO) cells expressing human OX1R and human embryonic kidney (HEK) 293 cells expressing human OX2R.

[0193] material and method 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 with RT scintillation counting; Control inhibitor: orexin A; Test concentration / dose: If five or more concentrations are selected, IC / EC calculations are provided; Test sample requirements: 1) Minimum volume for screening: For a final test of 10 μM, use 60 μl of 10 mM stock solution or 1 mg (pre-weighed); 2) Dose response: For a highest concentration of 10 μM, use 90 μl of 10 mM stock solution or 1 mg (pre-weighed).

[0194] 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 RT with scintillation counting; Control inhibitor: orexin B; Test concentration / dose: If five or more concentrations are selected, IC / EC calculations are provided; Test sample requirements: 1) Minimum volume for screening: For a final test of 10 μM, use 60 μl of 10 mM stock solution or 1 mg (pre-weighed); 2) Dose response: For a highest concentration of 10 μM, use 90 μl of 10 mM stock solution or 1 mg (pre-weighed).

[0195] The compounds listed in Table 1 are -5 M and calculated as % inhibition of control (IC ) specific binding of radiolabeled ligands specific for OX1R and / or OX2R targets.

[0196] This binding profile panel, following Eurofins standard operating procedures, broadly defined a roughly equal number of selective, central and peripheral therapeutically relevant targets, including native animal tissues, radioligands and specific enzymes involved in cell cycle regulation.

[0197] In radioligand binding experiments, the 50% inhibitory concentration (IC 50 ) and 50% effective concentration (EC 50The values ​​of the inhibition constant (K) were determined by nonlinear regression analysis of the competition curves using Hill equation curve fitting (by computer software). i ) is the Chen-Prusoff equation (K i =IC 50 / (1+(L / K D )) where L is the concentration of radioligand in the assay and K D is the affinity of the radioligand for the receptor (Cheng et Prusoff 1973).

[0198] result The results obtained from these binding assays are shown in Table 1.

[0199] [Table 1]

[0200] Results showing 25% to 50% inhibition (or stimulation) indicate a weak to moderate effect.

[0201] Results showing less than 25% inhibition (or stimulation) were not considered significant and are mostly due to fluctuations in the signal around the control level.

[0202] Results showing greater than 50% inhibition (or stimulation in assays under basal conditions) are considered to represent a significant effect of the test compound.

[0203] Low to moderate negative values ​​are not meaningful and are due to signal fluctuations around the control level. High negative values ​​(≥50%), which can be obtained with high concentrations of test substance, are generally due to nonspecific effects of the test substance in the assay and may, in rare cases, suggest an allosteric effect of the test substance.

[0204] [Table 2]

[0205] 4.2. Binding activity to dopamine and norepinephrine transporters, metabotropic glutamate 2, cathepsin H, and sigma-1 receptors It has long been reported that norepinephrine neurons in the locus coeruleus (Hagan et al. 1999; Horvath et al. 1999) and dopaminergic neurons in the ventral tegmental area (Vanni-Mercier, Sakai, et al. 2000) both increase their firing rates in response to orexin. The firing rates of these monoaminergic neurons are well known to be correlated with sleep / wake states. These neurons fire strongly during wakefulness, less during non-REM sleep, and abolish firing during REM sleep (Vanni-Mercier, Sakai, et al. 1984), a pattern similar to that of orexin neurons.

[0206] Previous studies have suggested that wakefulness mediated by the firing of these wake-active monoaminergic neurons is assisted by orexin.

[0207] More recently, a key role for the orexin-dopamine circuit via OX2R in regulating theta oscillations during wakefulness has been reported (Bandarabadi et al. 2022).

[0208] In addition to orexin's ability to regulate firing rate and induce burst firing via activation of receptors on the somato-dendritic compartment, OX2R may act presynaptically at the level of both dopaminergic and glutamatergic axons ( Bandarabadi et al. 2022 ).

[0209] Product 152 acts on metabotropic glutamate 2 (mGlu2) receptors, a therapeutic target for psychiatric disorders characterized by glutamatergic dysfunction, including schizophrenia, depression, and anxiety, with significant binding activity (IC54%). -5It significantly targets OX2R as an agonist (IC 73%) and OX1R as an agonist (IC 63%) in M.

[0210] Using a rat sleep-wake EEG model to study central functional activity and target engagement after inactivation of mGluR2 signaling, it was shown that mGluR2 antagonist activity was associated with enhanced theta / gamma oscillations and an enhanced transition from sleep to wakefulness (Ahnaou, Ver Donck, et Drinkenburg 2014).

[0211] Product 194 is 10 -5 M, which significantly targets OX2R as an agonist (IC84%), weakly targets OX1R as an agonist (IC<50%), and acts on the dopamine transporter (DAT) and norepinephrine transporter (NET) as a catecholaminergic reuptake inhibitor, with binding effects on the DAT (IC89%) and NET (IC58%).

[0212] Therapeutic approaches targeting cathepsins can contribute to preventing or delaying the onset of neurodegenerative diseases, as seen in neuronal ceroid lipofuscinoses, synucleinopathies (Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy), as well as Alzheimer's disease and Huntington's disease (Stoka et al. 2023).

[0213] Cathepsin H (CTSH) is a lysosomal cysteine ​​protease that plays a role in various physiological processes, including the immune response. In the context of neuroinflammation, CTSH is involved in regulating immune responses within the central nervous system (Wang et al. 2023). Neuroinflammation refers to an inflammatory response in neural tissue, often accompanied by glial cell activation and the release of inflammatory molecules.

[0214] CTSH may influence neuroinflammation by participating in antigen processing and presentation, which is essential for the activation of immune cells such as microglia. Previous studies have also suggested the possible involvement of CTSH in the pathogenesis of narcolepsy (Mogavero et al. 2023).

[0215] Product 96 is 10 -5 M targets OX1R as an agonist (IC56%) and CTSH as an antagonist (IC80%), and acts on the dopamine transporter (DAT) and norepinephrine transporter (NET) as a catecholaminergic reuptake inhibitor, with combined effects on DAT (IC99%) and NET (IC77%).

[0216] Sigma-1 receptors (S1Rs), which are involved in various physiological and pathological processes such as neurotransmission, neuroprotection, and neuroinflammation, are considered therapeutic targets for various neurodegenerative diseases, including amnesia and AD, as well as various synucleinopathies (Wang et al. 2023).

[0217] S1R agonists have been shown to have multiple mechanisms of action that may be beneficial in AD, including anti-inflammatory and antioxidant effects, neurotransmitter regulation, and neuroprotection through inhibiting Aβ aggregation and increased tau phosphorylation in AD (Cummings, Osse, et Kinney 2023; Malar et al. 2023; Shinoda, Nemoto, et Iwamoto 2023).

[0218] The product 90 is 10 -5 M targets OX2R as an agonist (IC67%) and S1R as an antagonist (IC75%).

[0219] JPEG2026501630000076.jpg239156JPEG2026501630000077.jpg246155JPEG2026501630000078.jpg247156JPEG2026501630000079.jpg245157JPEG2026501630000080.jpg246155JPEG2026501630000081.jpg246156JPEG2026501630000082.jpg45156

Claims

1. Compound of formula (II): 【Chemistry 1】 [In the formula, X represents -NH-, -S- or -O-, preferably -NH- or -S-; Y and R ２ are each independently a hydrogen atom, a halogen atom, or —NO ２ or -NH ２ represents; R １ , R ３ , R ４ are each independently a hydrogen atom or a halogen atom; R ５ , R ６ , R ７ , R ８ , R ９ are each independently a hydrogen atom, a halogen atom, or —OR １０ or (C １ -C ３０ ) alkyl chains, especially (C １ -C ２０ ) alkyl, and optionally aryl, heteroaryl, cycloalkyl, heterocycle, —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 )-groups, wherein said aryl, heteroaryl, and heterocyclic rings are optionally substituted; R １０ is a hydrogen atom or (C １ -C ３０ ) represents an alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, or acyl group, wherein said aryl, heteroaryl, and heterocyclic rings are optionally substituted; R １１ and R １２ are each independently a hydrogen atom or (C １ -C ６ ) represents an alkyl group; R １３ ~R １５ are each independently a hydrogen atom or (C １ -C ６ ) alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl or acyl group, preferably a hydrogen atom or (C １ -C ６ ) an alkyl or aryl group, more preferably a hydrogen atom or (C １ -C ６ ) represents an alkyl group] or a pharmaceutically acceptable salt thereof, a tautomer, a stereoisomer or a mixture of stereoisomers thereof (However, the compound of formula (II) is 【Chemistry 2】 Instead, X represents O and R １ , R ２ , R ３ and R ４ each represents H, Y represents a halogen atom, R ５ , R ６ , R ７ , R ８ , and R ９ If four of the ５ , R ６ , R ７ , R ８ , and R ９ The remaining groups are preceded by, interrupted by, or are —C(R １１ ) = C(R １２ ) - inserted, followed and / or preceded (C １ -C ３０ ) not an alkyl chain).

2. Y is a halogen atom, -NO ２ or -NH ２ , preferably —NO ２ or -NH ２ represents R ２ represents a hydrogen atom or a halogen atom, preferably a hydrogen atom, or R ２ is a halogen atom, -NO ２ or -NH ２ , preferably —NO ２ or -NH ２ wherein Y represents a hydrogen atom or a halogen atom, preferably a hydrogen atom; A compound of formula (II) according to claim 1.

3. R １ , R ２ , R ３ , R ４ each represents a hydrogen atom, or R １ , R ３ , R ４ 3. A compound of formula (II) according to claim 1 or 2, wherein Y each represents a hydrogen atom.

4. R ５ , R ６ , R ７ , R ８ , R ９ are each independently a hydrogen atom, a halogen atom, or —OR １０ or (C １ -C ２０ ) alkyl, and optionally aryl, heteroaryl, cycloalkyl, heterocycle, —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 4. The compound of formula (II) according to any one of claims 1 to 3, wherein the aryl, heteroaryl and heterocyclic rings are optionally substituted, and ...

5. R ５ , R ６ , R ７ , R ８ , R ９ are each independently a hydrogen atom or -OR １０ A compound of formula (II) according to any one of claims 1 to 4, wherein

6. When X is NH or O, R ５ , R ６ or R ７ is OR １０ represents R １０ is a hydrogen atom, (C １ -C ３０ 7. Compounds of formula (II) according to any one of claims 1 to 6, wherein R represents an alkyl or phenyl group.

7. R ５ , R ６ , R ７ , R ８ and R ９ A compound of formula (II) according to any one of claims 1 to 5, wherein at least four residues of each represent a hydrogen atom.

8. R ５ , R ６ , R ７ , R ８ , R ９ 8. A compound of formula (II) according to claim 7, wherein each represents a hydrogen atom.

9. R ５ , R ６ or R ７ Ga-OR １０ represents R １０ is a hydrogen atom, (C １ -C ３０ ) alkyl or phenyl groups, preferably (C １ -C ２０ 8. A compound of formula (II) for use according to claim 7, wherein R represents an alkyl or phenyl group. 【Request Item 10】 【Chemistry 3】 【change】 【change】 【change】 The compound of formula (II) according to any one of claims 1 to 9, selected from the group consisting of: and mixtures thereof.

11. A compound of formula (II) according to any one of claims 1 to 10, wherein X represents S.

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

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

14. A compound of formula (II) according to any one of claims 1 to 11 or a pharmaceutical composition according to claim 12 or 13 for use as a medicament.

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