Benzoxazole compound, pharmaceutical composition containing benzoxazole compound and application of benzoxazole compound

Abstract

The invention provides a benzoxazole compound as shown in a formula I, a tautomer or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a deuterated substance thereof, a hydrate thereof, or a solvate thereof, a pharmaceutical composition containing the benzoxazole compound, and application of the benzoxazole compound as an orexin receptor antagonist, or treatment of orexin signaling pathway abnormality related diseases, such as anoretin receptor antagonist, anoretin signaling pathway abnormality related diseases, anoretin signaling pathway abnormality related diseases, anoretin signaling pathway abnormality related diseases, anoretin signaling pathway abnormality related diseases and anoretin signaling pathway abnormality related diseases. Use of a condition or condition. I.

Description

Technical Field

[0001] This disclosure pertains to the field of medicinal chemistry and specifically relates to a benzoxazole compound of Formula I, its tautomers or stereoisomers, its pharmaceutically acceptable salts, its prodrugs, its deuterated derivatives, its hydrates, or its solvates, pharmaceutical compositions comprising them, and their medicinal uses. Background Technology

[0002] Orexin (also known as Hypocretin) is a family of neuropeptides produced by the protease cleavage of the precursor protein prepro-orexin. Its synthesis is mainly limited to specific neurons in the lateral hypothalamus (LH). Two active forms have been identified: orexin A (OX-A) and orexin B (OX-B).

[0003] OX-A and OX-B are expressed via a common precursor gene (HCRT), but after cleavage, they undergo different post-translational modifications to form functionally distinct bioactive peptides. Orexin functions through two seven-transmembrane G protein-coupled receptors: OX1R (HCRTR1) and OX2R (HCRTR2); OX1R specifically couples to Gq protein, activating phospholipase C (PLC)-IP3-Ca. 2+ Signaling pathways mediate increased neuronal excitability. OX2R can simultaneously couple to Gq and Gi / o proteins, triggering both Ca2+ and β2+ signaling pathways. 2+ It can release and inhibit cAMP production, resulting in more diverse signal regulation. OX-A can simultaneously activate OX1R and OX2R, while OX-B preferentially activates OX2R. The distribution of OX1R and OX2R in the brain shows partial overlap and different expression patterns. OX1Rs are selectively expressed in the locus coeruleus (LC) and cingulate cortex, while OX2Rs are selectively expressed in the tuberculous papillary nucleus (TMN), paraventricular nucleus (PVN) of the hypothalamus, and nucleus accumbens (NAc). Both receptors are expressed in the lateral hypothalamus (LH), medial prefrontal cortex (mPFC), hippocampus, central amygdala (CeA), striatal bed nucleus (BNST), dorsal raphe nucleus (DR), ventral midbrain tegmentum (VTA), dorsolateral tegmentum (LDT), and nucleus of the solitary tract (NTS); OX1Rs are specifically expressed in the locus coeruleus (LC) and cingulate cortex; while OX2Rs are specifically expressed in the tuberculous papillary nucleus (TMN), paraventricular nucleus (PVN), and nucleus accumbens (NAc).

[0004] The orexin system and its receptors play a crucial role in regulating various fundamental physiological processes, including the sleep-wake cycle, energy metabolism, functional behavior, reward pathways, and stress responses. Dysfunction of this pathway is closely associated with a wide range of diseases, conditions, and symptoms, such as depression, anxiety disorders, bipolar disorder (manic-depressive disorder), mood disorders, drug addiction, alcohol dependence, gambling addiction, obsessive-compulsive disorder, schizophrenia, mental disorders, dementia (e.g., Alzheimer's disease), severe intellectual disability, motor disorders (e.g., Huntington's disease, Tourette syndrome), Parkinson's disease, epilepsy, anorexia nervosa, bulimia nervosa, binge eating disorder, cachexia, obesity, pathological eating behaviors (e.g., addictive eating, binge-clearing behavior), sexual dysfunction, and psychosexual disorders. Anxiety disorder, obesity-related infertility, Kallmann syndrome (hypothalamic hypogonadism with loss / hyposmegma), functional amenorrhea, Cushing's syndrome (adrenocortical hyperfunction), pituitary adenoma (prolactinoma, growth hormone adenoma, etc. leading to acromegaly / gigantism), hyperprolactinemia, hypopituitarism (panpapillary or partial hypofunction, such as dwarfism due to growth hormone deficiency), hypothalamic hypothyroidism, hypothalamic-adrenal dysfunction, sudden onset of hyperprolactinemia, hypothalamic-associated growth hormone deficiency, diabetes mellitus, impaired glucose tolerance, narcolepsy (hypersomnia). Insomnia, various forms of sleep disorders (such as deep sleep, sleep apnea, sleep problems related to neurological disorders or pain), jet lag, hyperalgesia, atypical pain (such as burning pain, tenderness to touch), acute pain, chronic pain (neuropathic pain such as burning neuralgia, postherpetic neuralgia, post-stroke pain, postoperative pain, phantom limb pain, complex regional pain syndrome I / II), arthritis pain, sports injury pain, migraine, atypical facial pain, back pain, visceral pain (such as irritable bowel syndrome, angina-related pain), and pain associated with infection (such as HIV) or treatment (such as chemotherapy). Pain, taste / appetite disorders, nausea, vomiting, hypertension, hypotension, angina pectoris, acute myocardial infarction, acute and chronic congestive heart failure, arrhythmia, asthma, urinary retention, overactive bladder, urge incontinence, inflammatory bowel disease (such as Crohn's disease, ulcerative colitis), gastric dysfunction, gastric ulcer, benign prostatic hyperplasia, chronic kidney disease / renal failure, osteoporosis, allergic reactions, tolerance and withdrawal symptoms to narcotics / opioids, dementia-Parkinson-White syndrome, and other diseases, symptoms, and conditions associated with dysfunction of the conventional orexin system.

[0005] In this field, the development of highly effective, low-toxicity drugs with rapid onset of action and minimal residual effects holds great promise for clinical applications. Summary of the Invention

[0006] Through research, the inventors have provided an orexin receptor antagonist, which is a compound of Formula I, its isomer, its pharmaceutically acceptable salt, its prodrug, its deuterated derivative, its hydrate, or its solvate, which treats diseases, symptoms, or conditions associated with abnormal orexin signaling pathways by blocking the binding of orexin neuropeptides (orexin A and B) to their receptors.

[0007] In one aspect, this disclosure provides a benzoxazole compound of formula I, its tautomers or stereoisomers, its pharmaceutically acceptable salts, its prodrugs, its deuterated derivatives, its hydrates, or its solvates.

[0008] I

[0009] Where n is 0, 1, 2, 3 or 4;

[0010] R1 can be independently deuterium, tritium, halogen, C1-C10 alkyl, C1-C10 haloalkyl, C3-C10 cycloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, cyano, amino, amide, or hydroxyl in each occurrence.

[0011] Y is either O or S;

[0012] R2 is a C1-C10 alkyl, C1-C10 haloalkyl, C2-C10 alkenyl, or C2-C10 alkynyl;

[0013] m can be 0, 1, 2, or 3;

[0014] R3 can be independently deuterium, tritium, halogen, C1-C10 alkyl, C1-C10 haloalkyl, C3-C10 cycloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, cyano, amino, or hydroxyl in each occurrence.

[0015] Z is C or S, and for , ,or ;

[0016] Ring A is a C6-C10 aryl, a 5-10 heteroaryl containing 1-3 heteroatoms, a C5-C10 cycloalkenyl, or a 5-10 heterocyclic alkenyl containing 1-3 heteroatoms;

[0017] p is 0, 1, 2, 3, 4 or 5;

[0018] R4, each time it appears, is independently C1-C10 alkoxy, C1-C10 haloalkoxy, halogen, C1-C10 alkyl, C1-C10 haloalkyl, C3-C10 cycloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, 5-10 heteroaryl containing 1-3 heteroatoms, C6-C10 aryl, C5-C10 cycloalkenyl, or 5-10 heterocyclic alkenyl containing 1-3 heteroatoms;

[0019] The R4 is optionally substituted with one or more groups selected from the following: halogen, C1-C10 alkyl, C1-C10 haloalkyl, hydroxyl, amino.

[0020] In one aspect, this disclosure provides a pharmaceutical composition comprising a benzoxazole compound of Formula I, a tautomer or stereoisomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a deuterated thereof, a hydrate thereof, or a solvation thereof.

[0021] In one aspect, this disclosure provides the use of a benzoxazole compound of Formula I, its tautomers or stereoisomers, its pharmaceutically acceptable salts, its prodrugs, its deuterated derivatives, its hydrates, or its solvates, or the pharmaceutical composition thereof, in the preparation of a medicament for treating diseases, conditions, or symptoms associated with abnormalities of the orexin signaling pathway. Alternatively, this disclosure provides a benzoxazole compound of Formula I, its tautomers or stereoisomers, its pharmaceutically acceptable salts, its prodrugs, its deuterated derivatives, its hydrates, or its solvates, or the pharmaceutical composition thereof, for treating diseases, conditions, or symptoms associated with abnormalities of the orexin signaling pathway. Alternatively, this disclosure provides a method for treating a disease, condition, or symptom associated with an abnormality in the orexin signaling pathway in a subject in need, comprising administering to the subject a therapeutically effective amount of a benzoxazole compound of Formula I, its tautomer or stereoisomer, its pharmaceutically acceptable salt, its prodrug, its deuterated derivative, its hydrate, its solvate, or the pharmaceutical composition thereof. Alternatively, this disclosure provides the use of a benzoxazole compound of Formula I, its tautomer or stereoisomer, its pharmaceutically acceptable salt, its prodrug, its deuterated derivative, its hydrate, its solvate, or the pharmaceutical composition thereof for treating a disease, condition, or symptom associated with an abnormality in the orexin signaling pathway.

[0022] In one aspect, the present disclosure provides the use of the benzoxazole compounds represented by Formula I, their tautomers or stereoisomers, their pharmaceutically acceptable salts, their prodrugs, their deuterated compounds, their hydrates, or their solvates, or the pharmaceutical composition in the preparation of orexin receptor antagonists. Alternatively, the present disclosure provides the benzoxazole compounds represented by Formula I, their tautomers or stereoisomers, their pharmaceutically acceptable salts, their prodrugs, their deuterated compounds, their hydrates, or their solvates, or the pharmaceutical composition for use as orexin receptor antagonists. Alternatively, the present disclosure provides a method for antagonizing orexin receptors in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the benzoxazole compounds represented by Formula I, their tautomers or stereoisomers, their pharmaceutically acceptable salts, their prodrugs, their deuterated compounds, their hydrates, or their solvates, or the pharmaceutical composition. Alternatively, the present disclosure provides the use of the benzoxazole compounds represented by Formula I, their tautomers or stereoisomers, their pharmaceutically acceptable salts, their prodrugs, their deuterated compounds, their hydrates, or their solvates, or the pharmaceutical composition for antagonizing orexin receptors in a subject in need thereof.

[0023] The compounds or pharmaceutical compositions containing the same according to the present disclosure may exhibit good antagonistic activities against both orexin receptors hOX1R and hOX2R, may have good blood-brain barrier permeability and pharmacokinetic properties, and thus may have good drug-likeness. Moreover, they may have good sleep-promoting effects, including shortening the sleep latency, reducing the wake time, and having a relatively small impact on the NREM / REM sleep ratio in animals, which is beneficial for the treatment of diseases, disorders or conditions involving orexin receptors, especially those associated with abnormal orexin signaling pathways. Detailed Embodiments

[0024] Unless otherwise specified, the terms used in this application have the following meanings. A particular term should not be considered indeterminate or unclear without a specific definition, but should be understood according to its ordinary meaning in the art.

[0025] Cm-Cn herein represents a group having an integer number of carbon atoms within the range defined by m to n (m < n). For example, "C1-C10" means that the group may have 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.

[0026] In this article, the term "each independently" means that when the number of substituents represented by the same symbol on a certain group is more than 1, the substituents may be the same or different each time they appear.

[0027] In this document, the terms “optional” or “optionally” refer to events or situations described below that may or may not occur. “Optionally substituted” includes both unsubstituted and substituted forms; for example, “optionally” substituted R4 covers both unsubstituted and substituted forms of R4. Those skilled in the art will understand that for any group containing one or more substituents, no substitution or substitution pattern that is spatially impossible and / or cannot be synthesized is introduced.

[0028] In this paper, the term "substitution" refers to the independent replacement of one or more hydrogen atoms in a group by a corresponding number of substituents, wherein the substituents are only in their possible chemical positions.

[0029] In this article, the term "halogen" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0030] In this article, the term "hydrocarbon group" refers to a group consisting of only two types of atoms: carbon and hydrogen, including saturated hydrocarbon groups (also known as alkyl groups) and unsaturated hydrocarbon groups (such as alkenyl and ynyl groups).

[0031] In this document, the term "alkyl" refers to a saturated hydrocarbon group consisting of carbon and hydrogen atoms. Alkyl groups can be straight-chain or branched. For example, the term "C1-C10 alkyl" refers to an alkyl group containing 1 to 10 (e.g., 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1, or 2) carbon atoms, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.

[0032] In this document, the term "alkenyl" refers to an unsaturated hydrocarbon group having at least one carbon-carbon double bond, and the alkenyl group can be straight-chain or branched. For example, the term "C2-C10 alkenyl" refers to an alkenyl group containing 1 to 10 (e.g., 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1 or 2) carbon atoms, including but not limited to vinyl, propenyl, butenyl, 1,3-butadienyl, etc.

[0033] In this document, the term "alkynyl" refers to an unsaturated hydrocarbon group containing a carbon-carbon triple bond, which can be straight-chain or branched. For example, the term "C2-C10 alkynyl" refers to an alkynyl group containing 1 to 10 (e.g., 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1 or 2) carbon atoms, including but not limited to ethynyl (-C≡CH), propynyl (-C≡C-CH3), 1-butynyl (-C≡C-CH2-CH3), 2-butynyl, etc.

[0034] In this article, the term "alkoxy" refers to -O-alkyl.

[0035] In this document, the term "haloalkyl" refers to an alkyl group in which at least one hydrogen atom is substituted by a halogen atom (including F, Cl, Br, or I). For example, as used in this application, C1-C10 haloalkyl refers to a straight-chain or branched alkyl group in which at least one hydrogen atom is substituted by a halogen atom and which consists of 1 to 10 (e.g., 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1, or 2) carbon atoms.

[0036] In this document, the term "haloalkoxy" refers to an alkoxy group in which at least one hydrogen atom is substituted by a halogen atom. For example, C1-C10 haloalkoxy as used in this application refers to a straight-chain or branched-chain alkoxy group in which at least one hydrogen atom is substituted by a halogen atom and which consists of 1 to 10 (e.g., 1-8, 1-7, 1-6, 1-5, 1-4, 1-3, 1 or 2) carbon atoms.

[0037] In this document, the term "cycloalkyl" refers to a fully saturated carbon ring that may exist as a monocyclic, bridged, or spirocyclic ring. "Cycloalkyl" in this application may be a C3-C10 cycloalkyl, such as C3-C9 cycloalkyl, C4-C8 cycloalkyl, C5-C8 cycloalkyl, C5-C7 cycloalkyl, C5-C6 cycloalkyl, C6-C8 cycloalkyl, C6-C7 cycloalkyl, C3-C8 cycloalkyl, C3-C6 cycloalkyl, C3-C5 cycloalkyl, C4-C6 cycloalkyl, C3-C4 cycloalkyl, or C4-C5 cycloalkyl. Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, etc.

[0038] In this document, the term "aryl" refers to a monocyclic or fused polycyclic aromatic ring group having a conjugated π-electron system. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, etc. Common aryl groups include, but are not limited to, phenyl, naphthyl, phenanthryl, anthracene, etc. As used in this application, C6-C10 aryl refers to an aromatic ring group consisting of 6 to 10 carbon atoms (e.g., 6, 7, 8, 9, 10, or any range of two of the aforementioned values).

[0039] In this document, the term "heteroaryl" refers to an aromatic ring group formed by replacing a carbon atom in an aryl group with one or more heteroatoms (e.g., 1-3, 1, or 2). For example, "5-10 heteroaryl containing 1-3 heteroatoms" refers to an aromatic ring group containing 1, 2, or 3 heteroatoms and consisting of 5-10 ring atoms (e.g., 5, 6, 7, 8, 9, 10, or any range of two of the aforementioned values), including but not limited to pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, triazolyl, furanyl, thiophene, pyrroleyl, quinoline, isoquinoline, benzimidazolyl, and benzofuranyl.

[0040] In this document, the term "cycloalkenyl" refers to a non-aromatic carbon ring containing one or more carbon-carbon double bonds, which can exist as a monocyclic, bridged, or spirocyclic ring. The term "mn-membered heterocyclic alkenyl" refers to a saturated cyclic group containing a total of mn ring atoms, including carbon atoms and heteroatoms, where n is greater than m and both are integers. For example, C5-C10 cycloalkenyl refers to a cyclic group containing one or more (e.g., 1-2, 1-3, 1-4) carbon-carbon double bonds and consisting of 5-10 carbon atoms (e.g., 5, 6, 7, 8, 9, 10, or any range of two of the aforementioned values). Common cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and norbornyl.

[0041] In this document, the term "heterocyclic alkenyl" refers to a non-aromatic, unsaturated cyclic group formed by replacing a carbon atom in a cyclic alkenyl group with one or more (e.g., 1-3, 1, or 2) heteroatoms. For example, "5-10 membered heterocyclic alkenyl containing 1-3 heteroatoms" refers to an unsaturated cyclic group consisting of 5-10 (e.g., 5, 6, 7, 8, 9, 10, or any range of two of the aforementioned values) ring atoms containing 1, 2, or 3 heteroatoms. Common heterocyclic alkenyl groups include, but are not limited to, tetrahydropyridyl, dihydropyridyl, tetrahydropyrimidinyl, dihydrofuranyl, dihydropyranyl, pyrrolinyl, dihydropyrazolyl, and dihydrothiophenyl.

[0042] In this article, the term "heteroatom" refers to any atom other than a carbon atom that can covalently bond with a carbon atom. Common heteroatoms include, but are not limited to, O, S, N, P, and Si.

[0043] In this document, the term "hydroxyl" refers to the "-OH" group, the term "amino" refers to the "-NH2" group, the term "cyano" refers to the "-CN" group, the term "carboxyl" refers to the "-C(=O)OH" group, and the term "ester" refers to a group having the formula -C(O)OR. a or -OC(O)R bThe chemical structure of R, where R a R b Selected from alkyl, cycloalkyl, and heterocycloalkyl groups, including but not limited to -C(O)OCH3, -C(O)OCH2CH3, -C(O)O(CH2)2CH3, -C(O)OCH(CH3)2, -OC(O)CH3, -OC(O)CH2CH3, -OC(O)(CH2)2CH3, and -OC(O)CH(CH3)2.

[0044] In this document, the term "solvent" refers to a compound comprising formula I or a pharmaceutically acceptable salt thereof and a complex of one or more pharmaceutically acceptable solvent molecules. For example, when the solvent is water, the term "solvent" refers to a hydrate.

[0045] In this article, the term “treatment” means the process of preventing, alleviating, reducing, stopping or delaying the severity or progression of a disease or related symptoms, or curing a disease or related symptoms, including but not limited to preventing a subject from developing a disease or related symptoms, inhibiting the progression of a disease or related symptoms in a subject or causing the disease or related symptoms to subside, improving the quality of life of a subject, eliminating the disease or related symptoms, or preventing the recurrence of the disease or related symptoms in a subject after treatment.

[0046] In this article, the term "therapeutic effective dose" refers to a dose sufficient to prevent, improve, inhibit, delay, or slow the progression of KAT6-mediated disease, condition, or symptom, which can be determined by clinicians based on the severity of the disease, the patient's physical condition, age, sex, weight, family history, etc.

[0047] In this article, the terms “subject” and “patient” are used interchangeably and cover mammals such as humans, non-human primates (such as rhesus monkeys), pigs, cattle, horses, sheep, dogs, rabbits, mice, etc.

[0048] In this article, the term "pharmaceutically acceptable" refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0049] As pharmaceutically acceptable salts, for example, metal salts, ammonium salts, salts formed with organic bases, salts formed with inorganic acids, salts formed with organic acids, and salts formed with basic or acidic amino acids may be mentioned.

[0050] In this document, the term "pharmaceutically acceptable carrier" refers to carriers that do not cause significant irritation to the organism and do not impair the bioactivity and properties of the active compound. Suitable carriers are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0051] In this document, the term “comprise” or “comprise” and its English variants such as comprises or comprising should be understood in an open, non-exclusive sense, meaning “including but not limited to”.

[0052] Unless the context clearly indicates otherwise, singular terms in this document encompass the plural referents, and vice versa. Similarly, unless the context clearly indicates otherwise, the word "or" in this document is intended to include "and".

[0053] Unless otherwise stated, all figures used herein to indicate the amount of components, measurements, or reaction conditions should be understood to be modified by the term "about" in all cases. When used with percentages, the term "about" may mean, for example, ±1%, preferably ±0.5%, more preferably ±0.1%.

[0054] In this document, the term "tautomer" refers to structural isomers of different energies that can interconvert via low-barrier transitions. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerization. A specific example of a proton tautomer is the imidazole moiety, where a proton can migrate between two ring nitrogens. Valence tautomers include interconversions via the recombination of some bonding electrons. Non-limiting examples of tautomers include, but are not limited to, those... or .

[0055] In this article, the term "stereoisomer" refers to isomers that are formed by atoms in a molecule having the same order of interconnection but different spatial arrangements. Stereoisomers include conformational isomers, cis-trans isomers, and chiral isomers, with chiral isomers further divided into enantiomers and diastereomers. The spatial arrangement of atoms in a stereoisomer is usually represented by wedge-shaped covalent bonds (…). or ) indicates that among them Indicates facing outwards from the paper. Indicates facing inwards onto the paper.

[0056] In some embodiments, this disclosure relates to a benzoxazole compound of formula I, its tautomers or stereoisomers, its pharmaceutically acceptable salts, its prodrugs, its deuterated derivatives, its hydrates, or its solvates.

[0057] I

[0058] Where n is 0, 1, 2, 3 or 4;

[0059] R1 can be independently deuterium, tritium, halogen, C1-C10 alkyl, C1-C10 haloalkyl, C3-C10 cycloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, cyano, amino, amide, or hydroxyl in each occurrence.

[0060] Y is either O or S;

[0061] R2 is a C1-C10 alkyl, C1-C10 haloalkyl, C2-C10 alkenyl, or C2-C10 alkynyl;

[0062] m can be 0, 1, 2, or 3;

[0063] R3 can be independently deuterium, tritium, halogen, C1-C10 alkyl, C1-C10 haloalkyl, C3-C10 cycloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, cyano, amino, or hydroxyl in each occurrence.

[0064] Z is C or S, and for , ,or ;

[0065] Ring A is a C6-C10 aryl, a 5-10 heteroaryl containing 1-3 heteroatoms, a C5-C10 cycloalkenyl, or a 5-10 heterocyclic alkenyl containing 1-3 heteroatoms;

[0066] p is 0, 1, 2, 3, 4 or 5;

[0067] R4, each time it appears, is independently C1-C10 alkoxy, C1-C10 haloalkoxy, halogen, C1-C10 alkyl, C1-C10 haloalkyl, C3-C10 cycloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, 5-10 heteroaryl containing 1-3 heteroatoms, C6-C10 aryl, C5-C10 cycloalkenyl, or 5-10 heterocyclic alkenyl containing 1-3 heteroatoms;

[0068] The R4 is optionally substituted with one or more groups selected from the following: halogen, C1-C10 alkyl, C1-C10 haloalkyl, hydroxyl, amino.

[0069] In some implementations, n is 1, 2, or 3. In some implementations, n is 1 or 2. In some implementations, n is 2.

[0070] In some embodiments, R1 is independently deuterium, tritium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cyano, amino, amide, or hydroxyl each time it appears.

[0071] In some embodiments, R1 is independently deuterium, tritium, halogen, C1-C6 alkyl (e.g., C1-C5 alkyl, C1-C4 alkyl, or C1-C3 alkyl), C1-C6 haloalkyl (e.g., C1-C5 haloalkyl, C1-C4 haloalkyl, or C1-C3 haloalkyl), cyano, amino, or hydroxyl each time it appears.

[0072] In some implementations, R1 is independently fluorine, chlorine, bromine, iodine, methyl, ethyl, or propyl each time it appears.

[0073] In some embodiments, n is 1, 2, or 3, and R1 is independently deuterium, tritium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cyano, amino, amide, or hydroxyl each time it appears.

[0074] In some embodiments, n is 1, 2, or 3, and R1 is independently deuterium, tritium, halogen, C1-C6 alkyl (e.g., C1-C5 alkyl, C1-C4 alkyl, or C1-C3 alkyl), C1-C6 haloalkyl (e.g., C1-C5 haloalkyl, C1-C4 haloalkyl, or C1-C3 haloalkyl), cyano, amino, or hydroxyl in each occurrence.

[0075] In some embodiments, n is 1, 2, or 3, and R1 is independently deuterium, tritium, halogen, C1-C6 alkyl (e.g., C1-C5 alkyl, C1-C4 alkyl, or C1-C3 alkyl), or C1-C6 haloalkyl (e.g., C1-C5 haloalkyl, C1-C4 haloalkyl, or C1-C3 haloalkyl) each time it appears.

[0076] In some implementations, n is 1, 2, or 3, and R1 is independently fluorine, chlorine, bromine, iodine, methyl, ethyl, or propyl each time it appears.

[0077] In some embodiments, n is 2, and R1 is independently fluorine, chlorine, bromine, iodine, methyl, ethyl, or propyl each time it appears. In some embodiments, n is 2, one R1 is fluorine, chlorine, bromine, or iodine, and the other R1 is methyl, ethyl, or propyl.

[0078] In some implementations, Y is 0.

[0079] In some embodiments, R2 is a C1-C6 alkyl (e.g., C1-C5 alkyl, C1-C4 alkyl, or C1-C3 alkyl) or a C1-C6 haloalkyl (e.g., C1-C5 haloalkyl, C1-C4 haloalkyl, or C1-C3 haloalkyl).

[0080] In some embodiments, R2 is a C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, or C1-C3 alkyl. In some embodiments, R2 is methyl, ethyl, or propyl. In some embodiments, R2 is methyl.

[0081] In some implementations, m is 0, 1, or 2.

[0082] In some embodiments, R3 is independently deuterium, tritium, halogen, C1-C6 alkyl (e.g., C1-C5 alkyl, C1-C4 alkyl or C1-C3 alkyl), or C1-C6 haloalkyl (e.g., C1-C5 haloalkyl, C1-C4 haloalkyl or C1-C3 haloalkyl) each time it appears.

[0083] In some implementations, R3 is independently deuterium, tritium, fluorine, chlorine, bromine, iodine, methyl, ethyl, or propyl each time it appears.

[0084] In some embodiments, m is 0, 1, or 2, and R3 is independently deuterium, tritium, halogen, C1-C6 alkyl (e.g., C1-C5 alkyl, C1-C4 alkyl, or C1-C3 alkyl), or C1-C6 haloalkyl (e.g., C1-C5 haloalkyl, C1-C4 haloalkyl, or C1-C3 haloalkyl) each time it appears.

[0085] In some implementations, m is 0 or 1, and R3 is independently deuterium, tritium, fluorine, chlorine, bromine, iodine, methyl, ethyl, or propyl each time it appears.

[0086] In some implementations, m is 0.

[0087] In some implementations, Z is C, and for ,or .

[0088] In some embodiments, ring A is a C6-C10 aryl, a 5-10 heteroaryl containing 1-3 heteroatoms selected from N, O, or S, a C5-C10 cycloalkenyl, or a 5-10 heterocyclic alkenyl containing 1-3 heteroatoms selected from N, O, or S.

[0089] In some embodiments, ring A is a C6-C10 aryl group, or a 5-10 heteroaryl group containing 1-3 (e.g., 1-2) heteroatoms selected from N, O, or S.

[0090] In some embodiments, ring A is a phenyl group, or a 5-6 heteroaryl group containing 1-2 heteroatoms selected from N, O, or S.

[0091] In some embodiments, ring A is selected from one or more of phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, isothiazinyl, oxazinyl, isoxazinyl, imidazole, pyrazinyl, thiophene, pyrroleyl, and furanyl.

[0092] In some embodiments, ring A is selected from one or more of phenyl, pyridinyl, thiazolyl, isothiazolyl, oxazolyl, and isoxazolyl. In some embodiments, ring A is phenyl or pyridinyl.

[0093] In some implementations, p is 1, 2, or 3.

[0094] In some embodiments, R4, each time it appears, is independently a C1-C10 alkoxy, C1-C10 haloalkoxy, halogen, C1-C10 alkyl, C1-C10 haloalkyl, C3-C10 cycloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, a 5-10 heteroaryl containing 1-3 heteroatoms selected from N, O, or S, a C6-C10 aryl, a C5-C10 cycloalkenyl, or a 5-10 heterocyclic alkenyl containing 1-3 heteroatoms selected from N, O, or S.

[0095] In some embodiments, R4, each time it appears, is independently a C1-C6 alkoxy (e.g., C1-C5 alkoxy, C1-C4 alkoxy, or C1-C3 alkoxy), a C1-C6 haloalkoxy (e.g., C1-C5 haloalkoxy, C1-C4 haloalkoxy, or C1-C3 haloalkoxy), a halogen, a C1-C6 alkyl (e.g., C1-C5 alkyl, C1-C4 alkyl, or C1-C3 alkyl), or a C1-C6 haloalkyl (e.g., C1-C5 haloalkyl, C1-C4 haloalkyl, or C1-C6 alkyl). -C3 haloalkyl), C3-C6 cycloalkyl (e.g., C3-C5 cycloalkyl or C3-C4 cycloalkyl), C2-C6 alkenyl (e.g., C2-C5 alkenyl or C2-C4 alkenyl), C2-C6 ynyl (e.g., C2-C5 ynyl or C2-C4 ynyl), 5-8 membered heteroaryl containing 1-3 (e.g., 1-2) heteroatoms selected from N, O or S, C6-C10 aryl, C5-C8 cycloalkenyl, or 5-8 membered heterocyclic alkenyl containing 1-3 (e.g., 1-2) heteroatoms selected from N, O or S.

[0096] In some embodiments, R4, each time it appears, is independently a C1-C6 alkoxy (e.g., C1-C5 alkoxy, C1-C4 alkoxy, or C1-C3 alkoxy), a C1-C6 haloalkoxy (e.g., C1-C5 haloalkoxy, C1-C4 haloalkoxy, or C1-C3 haloalkoxy), a halogen, a C1-C6 alkyl (e.g., C1-C5 alkyl, C1-C4 alkyl, or C1-C3 alkyl), a C1-C6 haloalkyl (e.g., C1-C5 haloalkyl, C1-C4 haloalkyl, or C1-C3 haloalkyl), a 5-8 member (e.g., 5-7 or 5-6 member) heteroaryl, phenyl, a C5-C8 cycloalkenyl, or a 5-8 member heterocyclic alkenyl containing 1-3 (e.g., 1-2) N atoms.

[0097] In some embodiments, R4 is independently C1-C6 alkoxy (e.g., C1-C5 alkoxy, C1-C4 alkoxy, or C1-C3 alkoxy), fluorine, chlorine, bromine, iodine, C1-C6 alkyl (e.g., C1-C5 alkyl, C1-C4 alkyl, or C1-C3 alkyl), a 5-8 member (e.g., 5-7 or 5-6 member) heteroaryl group containing 1-3 (e.g., 1-2) N atoms, or a phenyl group.

[0098] In some embodiments, R4 is independently C1-C3 alkoxy, fluorine, chlorine, bromine, iodine, C1-C3 alkyl, 5-6 heteroaryl containing 1-3 (e.g. 1-2) N atoms, or phenyl.

[0099] In some embodiments, R4 is independently methoxy, ethoxy, propoxy, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, triazolyl, pyrazolyl, imidazoleyl, pyrroleyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, or phenyl each time it appears.

[0100] In some embodiments, R4, each time it appears, is independently methoxy, ethoxy, propoxy, fluorine, chlorine, bromine, methyl, ethyl, propyl, triazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, or phenyl. In some embodiments, R4, each time it appears, is independently methyl, ethyl, propyl, triazolyl, pyrazolyl, pyridinyl, pyrimidinyl, or phenyl. In some embodiments, R4, each time it appears, is independently methyl, ethyl, propyl, pyridinyl, pyrazinyl, pyrimidinyl, or phenyl.

[0101] In some embodiments, p is 1, and R4 is a 5-6 membered heteroaryl group or phenyl group containing 1-3 (e.g., 1-2) N atoms. In some embodiments, p is 1, and R4 is triazolyl, pyrazolyl, imidazole, pyrroleyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, or phenyl. In some embodiments, p is 1, and R4 is triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, or phenyl.

[0102] In some embodiments, p is 2, one R4 is a C1-C3 alkoxy, fluorine, chlorine, bromine, iodine, or C1-C3 alkyl, and the other R4 is a 5-6 membered heteroaryl or phenyl containing 1-3 (e.g., 1-2) nitrogen atoms. In some embodiments, p is 2, one R4 is methoxy, ethoxy, propoxy, fluorine, chlorine, bromine, methyl, ethyl, or propyl, and the other R4 is triazolyl, pyrazolyl, imidazolyl, pyrroleyl, pyridinyl, pyrazinyl, pyrimidinyl, or phenyl. In some embodiments, p is 2, one R4 is methoxy, ethoxy, propoxy, fluorine, chlorine, bromine, methyl, ethyl, or propyl, and the other R4 is triazolyl, pyrazolyl, pyridinyl, pyrimidinyl, or phenyl. In some embodiments, p is 2, one R4 is methyl, ethyl, or propyl, and the other R4 is triazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, or phenyl.

[0103] In some embodiments, the R4 is optionally substituted with one or more groups selected from the following: halogen, C1-C10 alkyl, C1-C10 haloalkyl.

[0104] In some embodiments, R4 is optionally substituted with fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, halomethyl, haloethyl, or halopropyl.

[0105] In some embodiments, the R4 is optionally replaced by fluorine, chlorine, bromine or iodine.

[0106] In some embodiments, in the compound represented by Formula I, n is 1, 2, or 3;

[0107] R1 can be independently deuterium, tritium, halogen, C1-C6 alkyl (e.g., C1-C5 alkyl, C1-C4 alkyl or C1-C3 alkyl), or C1-C6 haloalkyl (e.g., C1-C5 haloalkyl, C1-C4 haloalkyl or C1-C3 haloalkyl) each time it appears.

[0108] Y is either O or S;

[0109] R2 is a C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, or C1-C3 alkyl;

[0110] m is 0, 1, or 2;

[0111] R3 can be independently deuterium, tritium, halogen, C1-C6 alkyl (e.g., C1-C5 alkyl, C1-C4 alkyl or C1-C3 alkyl), or C1-C6 haloalkyl (e.g., C1-C5 haloalkyl, C1-C4 haloalkyl or C1-C3 haloalkyl) each time it appears.

[0112] Z is C, and for ,or ;

[0113] Ring A is phenyl, or contains a 5-6 membered heteroaryl group with 1-2 heteroatoms selected from N, O, or S;

[0114] p is 1 or 2;

[0115] R4, each time it appears, is independently a C1-C6 alkoxy (e.g., C1-C5 alkoxy, C1-C4 alkoxy, or C1-C3 alkoxy), fluorine, chlorine, bromine, iodine, C1-C6 alkyl (e.g., C1-C5 alkyl, C1-C4 alkyl, or C1-C3 alkyl), a 5-8 member (e.g., 5-7 or 5-6 member) heteroaryl group containing 1-3 (e.g., 1-2) N atoms, or a phenyl group;

[0116] The R4 may optionally be substituted by one or more groups selected from the following: halogen, C1-C10 alkyl, C1-C10 haloalkyl.

[0117] In some embodiments, the compound represented by Formula I in this application is the compound represented by Formula I-1:

[0118] I-1

[0119] The definitions of n, R1, Y, R2, m, R3, ring A, p, and R4 are as described in this paper, and X is O or S, preferably O.

[0120] In some embodiments, in the compound represented by Formula I-1, n is 0, 1, 2, 3 or 4;

[0121] R1 can be independently deuterium, tritium, halogen, C1-C10 alkyl, C1-C10 haloalkyl, C3-C10 cycloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, cyano, amino, amide, or hydroxyl in each occurrence.

[0122] Y is either O or S;

[0123] R2 is a C1-C10 alkyl, C1-C10 haloalkyl, C2-C10 alkenyl, or C2-C10 alkynyl.

[0124] m can be 0, 1, 2, or 3;

[0125] R3 can be independently deuterium, tritium, halogen, C1-C10 alkyl, C1-C10 haloalkyl, C3-C10 cycloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, cyano, amino, or hydroxyl in each occurrence.

[0126] X is either O or S;

[0127] Ring A is a C6-C10 aryl, a 5-10 heteroaryl containing 1-3 heteroatoms, a C5-C10 cycloalkenyl, or a 5-10 heterocyclic alkenyl containing 1-3 heteroatoms;

[0128] p is 0, 1, 2, 3, 4 or 5;

[0129] R4, each time it appears, is independently C1-C10 alkoxy, C1-C10 haloalkoxy, halogen, C1-C10 alkyl, C1-C10 haloalkyl, C3-C10 cycloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, 5-10 heteroaryl containing 1-3 heteroatoms, C6-C10 aryl, C5-C10 cycloalkenyl, or 5-10 heterocyclic alkenyl containing 1-3 heteroatoms;

[0130] The R4 is optionally substituted with one or more groups selected from the following: halogen, C1-C10 alkyl, C1-C10 haloalkyl, hydroxyl, amino.

[0131] In some embodiments, the compound represented by Formula I in this application is a compound represented by Formula II, Formula III, Formula IV, or Formula V:

[0132] II, III IV, or V

[0133] The definitions of n, R1, Y, R2, X, ring A, p, and R4 are as described in this paper. This indicates a single key or that the key does not exist.

[0134] In some embodiments, the compound represented by Formula I in this application is a compound represented by Formula VI, Formula VII, Formula VIII, or Formula IX:

[0135] VI, VII, VIII, or IX

[0136] The definitions of n, R1, Y, R2, X, ring A, p, and R4 are as described in this paper.

[0137] In some embodiments, the compound represented by Formula I in this application is the compound represented by Formula X:

[0138] X,

[0139] The definitions of R1, p, and R4 are as described in this paper. This indicates a single key or that the key does not exist.

[0140] In some embodiments, the compound represented by Formula I in this application is a compound represented by Formula IV, Formula V, or Formula IX, wherein R1, each time it appears, is independently deuterium, tritium, fluorine, chlorine, bromine, iodine, C1-C6 alkyl (e.g., C1-C5 alkyl, C1-C4 alkyl, or C1-C3 alkyl), or C1-C6 haloalkyl (e.g., C1-C5 haloalkyl, C1-C4 haloalkyl, or C1-C3 haloalkyl); preferably, R1, each time... Each of the following substances, when present, is independently fluorine, chlorine, bromine, iodine, C1-C6 alkyl (e.g., C1-C5 alkyl, C1-C4 alkyl, or C1-C3 alkyl), or C1-C6 haloalkyl (e.g., C1-C5 haloalkyl, C1-C4 haloalkyl, or C1-C3 haloalkyl); more preferably, R1 is independently fluorine, chlorine, bromine, iodine, or C1-C6 alkyl (e.g., C1-C5 alkyl, C1-C4 alkyl, or C1-C3 alkyl) each time it appears.

[0141] R2 is a C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl or C1-C3 alkyl, preferably methyl, ethyl or propyl;

[0142] n can be 1, 2, or 3, with n being 2 being preferred;

[0143] This indicates a single bond or its absence; preferably, Indicates a single key;

[0144] p is 1 or 2, preferably p is 2;

[0145] R4, each time it appears, is independently a C1-C6 alkoxy (e.g., C1-C5 alkoxy, C1-C4 alkoxy, or C1-C3 alkoxy), a C1-C6 alkyl (e.g., C1-C5 alkyl, C1-C4 alkyl, or C1-C3 alkyl), a 5-8 member (e.g., 5-7 member or 5-6 member) heteroaryl group containing 1-3 (e.g., 1-2) heteroatoms selected from N, O, or S, or a phenyl group; preferably, R4, each time it appears, is independently a C1-C6 alkyl (e.g., C1-C5 alkyl, C1-C4 alkyl, or C1-C3 alkyl), a 5-7 member (e.g., 5-6 member) heteroaryl group containing 1-3 (e.g., 1-2) N atoms, or a phenyl group;

[0146] The R4 is optionally substituted by one or more groups selected from the following: halogen, C1-C10 alkyl, C1-C10 haloalkyl; preferably, the R4 is not substituted.

[0147] In some embodiments, the compound represented by Formula I in this application is a compound represented by Formula IV, Formula V, or Formula IX, wherein R1 is independently fluorine, chlorine, bromine, iodine, methyl, ethyl, or propyl each time it appears. Preferably, one R1 is fluorine, chlorine, bromine, or iodine, and the other R1 is methyl, ethyl, or propyl.

[0148] Indicates a single key;

[0149] R2 is a methyl group;

[0150] n is 2;

[0151] p is 2;

[0152] R4 is different each time it appears, and each is independently methyl, ethyl, propyl, pyridyl, pyrazinyl, pyrimidinyl, or phenyl; preferably, one R4 is methyl, ethyl, or propyl, and the other R4 is pyridyl, pyrazinyl, pyrimidinyl, or phenyl.

[0153] In some embodiments, the compound represented by Formula I in this application is a compound represented by Formula X, wherein R1, each time it appears, is independently deuterium, tritium, fluorine, chlorine, bromine, iodine, C1-C6 alkyl (e.g., C1-C5 alkyl, C1-C4 alkyl, or C1-C3 alkyl), or C1-C6 haloalkyl (e.g., C1-C5 haloalkyl, C1-C4 haloalkyl, or C1-C3 haloalkyl); preferably, R1, each time it appears, is... Each of the following is independently fluorine, chlorine, bromine, iodine, C1-C6 alkyl (e.g., C1-C5 alkyl, C1-C4 alkyl, or C1-C3 alkyl), or C1-C6 haloalkyl (e.g., C1-C5 haloalkyl, C1-C4 haloalkyl, or C1-C3 haloalkyl); more preferably, R1 is independently fluorine, chlorine, bromine, iodine, or C1-C6 alkyl (e.g., C1-C5 alkyl, C1-C4 alkyl, or C1-C3 alkyl) each time it appears.

[0154] This indicates a single bond or its absence; preferably, Indicates a single key;

[0155] p is 1 or 2, preferably p is 2;

[0156] R4, each time it appears, is independently a C1-C6 alkoxy (e.g., C1-C5 alkoxy, C1-C4 alkoxy, or C1-C3 alkoxy), a C1-C6 alkyl (e.g., C1-C5 alkyl, C1-C4 alkyl, or C1-C3 alkyl), a 5-8 member (e.g., 5-7 member or 5-6 member) heteroaryl group containing 1-3 (e.g., 1-2) heteroatoms selected from N, O, or S, or a phenyl group; preferably, R4, each time it appears, is independently a C1-C6 alkyl (e.g., C1-C5 alkyl, C1-C4 alkyl, or C1-C3 alkyl), a 5-7 member (e.g., 5-6 member) heteroaryl group containing 1-3 (e.g., 1-2) N atoms, or a phenyl group;

[0157] The R4 is optionally substituted by one or more groups selected from the following: halogen, C1-C10 alkyl, C1-C10 haloalkyl; preferably, the R4 is not substituted.

[0158] In some embodiments, the compound represented by Formula I in this application is the compound represented by Formula X, wherein R1 is independently fluorine, chlorine, bromine, iodine, methyl, ethyl, or propyl each time it appears. Preferably, one R1 is fluorine, chlorine, bromine, or iodine, and the other R1 is methyl, ethyl, or propyl.

[0159] Indicates a single key;

[0160] p is 2;

[0161] R4 is different each time it appears, and each is independently methyl, ethyl, propyl, pyridyl, pyrazinyl, pyrimidinyl, or phenyl; preferably, one R4 is methyl, ethyl, or propyl, and the other R4 is pyridyl, pyrazinyl, pyrimidinyl, or phenyl.

[0162] In some embodiments, this application relates to compounds, their tautomers or stereoisomers, their pharmaceutically acceptable salts, their prodrugs, their deuterated derivatives, their hydrates, or their solvates:

[0163] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,or .

[0164] In some embodiments, this disclosure provides a pharmaceutical composition comprising a benzoxazole compound of Formula I, a tautomer or stereoisomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a deuterated thereof, a hydrate thereof, or a solvation thereof.

[0165] In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient. In this document, the pharmaceutically acceptable carrier may be any carrier known in the art, such as those described in the Handbook of Pharmaceutical Excipients (Shersky et al., translated by Zheng Junmin, 2005, Chemical Industry Press).

[0166] In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a benzoxazole compound of Formula I, its tautomer or stereoisomer, its pharmaceutically acceptable salt, its prodrug, its deuterated form, its hydrate, or its solvate.

[0167] In some embodiments, the therapeutically effective amount refers to an amount sufficient to improve, inhibit, delay, or slow the progression of a disease, condition, or symptom associated with an abnormal orexin signaling pathway. This amount can be determined by a clinician based on the severity of the disease, the patient's physical condition, age, sex, weight, etc., and can be administered via conventional routes of administration in the art.

[0168] The benzoxazole compounds of Formula I described in this application, their tautomers or stereoisomers, their pharmaceutically acceptable salts, their prodrugs, their deuterated derivatives, their hydrates, their solvates, or pharmaceutical compositions comprising them can be formulated into any conventional dosage form known in the art and can be administered via parenteral, oral, intravenous, or intraperitoneal routes.

[0169] In some embodiments, this disclosure provides the use of the benzoxazole compound of Formula I, its tautomers or stereoisomers, its pharmaceutically acceptable salts, its prodrugs, its deuterated derivatives, its hydrates, or its solvates, or the pharmaceutical composition thereof, in the preparation of a medicament for treating diseases, conditions, or symptoms associated with abnormalities of the orexin signaling pathway.

[0170] In some embodiments, the diseases, conditions, or symptoms associated with abnormalities in the orexin signaling pathway are selected from: depression, anxiety disorders, bipolar disorder (manic-depressive disorder), mood disorders, drug addiction, alcohol dependence, gambling addiction, obsessive-compulsive disorder, schizophrenia, mental disorder, dementia (such as Alzheimer's disease), severe intellectual disability, motor disorders (such as Huntington's disease, Tourette syndrome / Tourette syndrome), Parkinson's disease, epilepsy, anorexia nervosa, bulimia nervosa, binge eating disorder, cachexia, obesity, and pathological eating behaviors (such as addictive eating, binge eating-clearing behavior). Sexual dysfunction, psychosexual disorders, gender anxiety disorder, obesity-related infertility, Kallmann syndrome (hypothalamic hypogonadism with loss / hyposmia), functional amenorrhea, Cushing's syndrome (adrenocortical hyperfunction), pituitary adenoma (prolactinoma, growth hormone adenoma, etc. leading to acromegaly / gigantism), hyperprolactinemia, pituitary hypofunction (panprine or partial pituitary dysfunction, such as dwarfism caused by growth hormone deficiency), hypothalamic hypothyroidism, hypothalamic-adrenal dysfunction, sudden onset of hyperprolactinemia, hypothalamic-related growth hormone deficiency, diabetes mellitus. Impaired glucose tolerance, narcolepsy (hypnotics), insomnia, various forms of sleep disorders (such as deep sleep, sleep apnea, sleep problems related to neurological disorders or pain), jet lag, hyperalgesia, atypical pain (such as burning pain, tenderness to touch), acute pain, chronic pain (neuropathic pain such as burning neuralgia, postherpetic neuralgia, post-stroke pain, postoperative pain, phantom limb pain, complex regional pain syndrome I / II), arthritis pain, sports injury pain, migraine, atypical facial pain, back pain, visceral pain (such as irritable bowel syndrome, angina-related pain) And pain associated with infection (such as HIV) or treatment (such as chemotherapy), taste / appetite disorders, nausea, vomiting, hypertension, hypotension, angina pectoris, acute myocardial infarction, acute and chronic congestive heart failure, arrhythmia, asthma, urinary retention, overactive bladder, urge incontinence, inflammatory bowel disease (such as Crohn's disease, ulcerative colitis), gastric dysfunction, gastric ulcer, benign prostatic hyperplasia, chronic kidney disease / renal failure, osteoporosis, allergic reactions, tolerance and withdrawal symptoms to narcotics / opioids, dementia-Parkinson-White syndrome.

[0171] In some embodiments, this disclosure provides the use of the benzoxazole compound of Formula I, its tautomers or stereoisomers, its pharmaceutically acceptable salts, its prodrugs, its deuterated derivatives, its hydrates, or its solvates, or the pharmaceutical composition thereof, in the preparation of an orexin receptor antagonist.

[0172] In some embodiments, this disclosure provides the use of the benzoxazole compound of Formula I, its tautomers or stereoisomers, its pharmaceutically acceptable salts, its prodrugs, its deuterated derivatives, its hydrates, or its solvates, or the pharmaceutical composition thereof, in the preparation of an orexin receptor antagonist.

[0173] For purposes of description and disclosure, all patents, patent applications, and other identified publications are expressly incorporated herein by reference. These publications are provided solely because their publication predates the filing date of this application. All statements regarding the dates of these documents or representations of their contents are based on information available to the applicant and do not constitute any acknowledgment of the accuracy of the dates or contents of these documents. Furthermore, in any country, any reference to these publications herein does not constitute an endorsement that such publication is part of the general knowledge in the art.

[0174] The present application will be described in detail below through embodiments; however, those skilled in the art will understand that the scope of protection of the present application is not limited thereto. Those skilled in the art can make various modifications, changes, combinations, etc., to the implementation methods and embodiments of the present application without departing from the spirit or scope of the present application, and the resulting adjusted solutions also fall within the scope of protection of the present application.

[0175] Example

[0176] The present disclosure will now be described in detail with reference to embodiments. Those skilled in the art will understand that the following embodiments are for illustrative purposes only and should not be construed as limiting the scope of the disclosure. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer are followed. Reagents or instruments whose manufacturers are not specified are all commercially available conventional products.

[0177] The abbreviations used in the following examples represent: LCMS for liquid chromatography-mass spectrometry, BOPCl for bis(2-oxo-3-oxazolidinyl)phosphine chloride, HATU for 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, HPLC for high performance liquid chromatography, DMSO for dimethyl sulfoxide, HS-15 for polyethylene glycol 15-hydroxystearic acid, and MC for methylcellulose.

[0178] Example 1: Synthesis of (S)-(2-(5-chloro-4-methylbenzo[d]oxazol-2-yl)-2-methylpyrrolidone-1-yl)(5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl) ketone (compound 1)

[0179]

[0180] first step:

[0181] 4-Chloro-3-methylphenol (65.0 g, 455.9 mmol) was dissolved in 650 mL of acetone, and ferric nitrate nonahydrate (92.1 g, 227.9 mmol) was added. The mixture was stirred at 25 °C for 12 hours. After the reaction was complete, 4-chloro-3-methyl-2-nitrophenol (44.0 g, yield 51.4%) was purified by reverse-phase Flash column chromatography (LCMS: 186.0 [MH)). - .

[0182] Step Two:

[0183] 4-Chloro-3-methyl-2-nitrophenol (44.0 g, 234.6 mmol) was dissolved in 550 mL of a mixed solvent of ethanol and concentrated hydrochloric acid (4:1). Stannous chloride (35.6 g, 1876.5 mmol) was added, and the reaction mixture was heated to 80 °C and stirred for 12 hours. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the filter cake was washed with 100 mL of a mixed solvent of ethanol and water to obtain 4-chloro-3-methyl-2-aminophenol (58 g, hydrochloride form), LCMS: 158.1 [M+H]. + .

[0184] Step 3:

[0185] (S)-1-(((9H-fluorene-9-yl)methoxy)carbonyl)-2-methylpyrrolidine-2-carboxylic acid (24.1 g, 68.5 mmol) was dissolved in 240 mL of dichloromethane, and BOPCl (29.1 g, 114.2 mmol), N',N-diisopropylethylamine (22.1 g, 171.3 mmol) and 4-chloro-3-methyl-2-aminophenol (9.0 g, 57.1 mmol) were added sequentially. The mixture was stirred at 25 °C for 12 hours. After the reaction was complete, 200 mL of water was added to the reaction solution, and the mixture was stirred for 10 minutes. The liquid was then separated, and the organic phase was washed twice with 100 mL of 5% sodium bicarbonate aqueous solution, followed by two washes with 100 mL of saturated sodium chloride solution. The solution was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by Flash column chromatography to obtain (9H-fluorene-9-yl)methyl-(S)-2-((3-chloro-6-hydroxy-2-methylphenyl)carbamoyl)-2-methylpyrrolidine-1-carboxylate (9.1 g, yield 32.5%), LCMS: 491.2 [M+H]. + .

[0186] Step 4:

[0187] (9H-fluorene-9-yl)methyl-(S)-2-((3-chloro-6-hydroxy-2-methylphenyl)carbamoyl)-2-methylpyrrolidine-1-carboxylate (9.0 g, 18.3 mmol) was dissolved in 90 mL of toluene, and p-toluenesulfonic acid (4.4 g, 25.6 mmol) was added. The reaction mixture was heated to 110 °C and stirred for 2 hours. After the reaction was complete, the mixture was cooled to room temperature and purified by Flash column chromatography to obtain methyl (9H-fluorene-9-yl)-(S)-2-(5-chloro-4-methylbenzo[d]oxazol-2-yl)-2-methylpyrrolidine-1-carboxylate (6.3 g, yield 72.7%), LCMS: 473.2 [M+H]. + .

[0188] Step 5:

[0189] Methyl (9H-fluorene-9-yl)-(S)-2-(5-chloro-4-methylbenzo[d]oxazol-2-yl)-2-methylpyrrolidine-1-carboxylate (6.2 g, 13.1 mmol) was dissolved in 35 mL of dichloromethane, and 7 mL of piperidine was added. The mixture was stirred at 25 °C for 2 hours. After the reaction was complete, the crude product was purified by Flash column chromatography, and then purified by preparative HPLC to obtain (S)-5-chloro-4-methyl-2-(2-methylpyrrolidine-2-yl)benzo[d]oxazole (2.0 g, yield 60.9%), LCMS: 251.1 [M+H]. + .

[0190] Step 6:

[0191] 5-Methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid (104.8 mg, 0.478 mmol), HATU (181.7 mg, 0.478 mmol), and N'N-diisopropylethylamine (154.7 mg, 1.197 mmol) were dissolved in 3 mL of dichloromethane. After stirring at room temperature for 10 minutes, (S)-5-chloro-4-methyl-2-(2-methylpyrrolidone-2-yl)benzo[d]oxazole (100.0 mg, 0.399 mmol) was added, and the mixture was stirred overnight at room temperature. After the reaction was complete, the compound was purified by preparative HPLC to give title compound 1 (40.1 mg, yield 22%). 1H NMR (400 MHz, CDCl3) δ 7.85 - 7.79 (m, 3H), 7.29 - 7.24(m, 2H), 7.05 - 7.00 (m, 2H), 3.89 (s, 3H), 3.55 - 3.08 (m, 2H), 2.62 (s,3H), 2.37 - 2.31 (m, 1H), 2.06 - 1.86 (m, 6H). LCMS:452.1[M+H] + .

[0192] Example 2: Synthesis of (S)-(2-(5-chloro-4-methylbenzo[d]oxazol-2-yl)-2-methylpyrrolidone-1-yl)(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl) ketone (compound 2)

[0193]

[0194] first step:

[0195] 5-Fluoro-2-iodobenzoic acid (1.0 g, 3.76 mmol), cuprous iodide (35.8 mg, 0.188 mmol), and cesium carbonate (2.5 g, 7.67 mmol) were added to 10 mL of N'N-dimethylformamide. The reaction system was then replaced with a nitrogen atmosphere. 1H-1,2,3-triazole (519 mg, 7.52 mmol) and trans-N,N'-dimethylcyclohexane-1,2-diamine (107 mg, 0.75 mmol) were added. The reaction system was heated to 100 °C and stirred for 4 hours. After the reaction was complete, the mixture was cooled to room temperature, and 50 mL of water was added. The mixture was then extracted three times with 20 mL of ethyl acetate. The organic phases were combined, washed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove the solvent, and purified by Flash column chromatography to obtain 5-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid (514 mg, yield 66%). LCMS: 208.0 [M+H] + .

[0196] Step Two:

[0197] Using intermediates 1-6 and 2-3 as starting materials, the title compound 2 (43.9 mg, yield 25%) was prepared under the reaction and purification conditions described in step 6 of Example 1. 1H NMR (400 MHz, CDCl3) δ 7.83 - 7.69 (m, 3H),7.36 - 7.27 (m, 2H), 7.15 - 7.03 (m, 2H), 3.52 - 3.21 (m, 2H), 2.62 (s, 3H),2.53 - 2.47 (m, 1H), 2.35 - 2.10 (m, 6H). LCMS:440.1[M+H] + .

[0198] Example 3: Synthesis of (S)-(2-(5-chloro-4-methylbenzo[d]oxazol-2-yl)-2-methylpyrrolidine-1-yl)(5-methyl-2-(pyridin-4-yl)phenyl) ketone (compound 3)

[0199]

[0200] first step:

[0201] Methyl 2-iodo-5-methylbenzoate (1.0 g, 3.62 mmol) was dissolved in 10 mL of 1,4-dioxane. The reaction system was purged under a nitrogen atmosphere, and 4-tributyltin pyridine (2.7 g, 7.33 mmol) and 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (117 mg, 0.181 mmol) were added. The reaction system was heated to 100 °C and stirred for 12 hours. After the reaction was completed, the mixture was cooled to room temperature and purified by Flash column chromatography to obtain methyl 5-methyl-2-(pyridin-4-yl)benzoate (510 mg, yield 62%). 1 H NMR (400 MHz, CDCl3) δ 8.66 - 8.57 (m, 2H), 7.40 (t, J =5.8 Hz, 2H), 7.36 - 7.20 (m, 5H), 3.62 - 3.51 (m, 1H), 3.38 - 3.27 (m, 1H), 2.63 (s, 3H), 2.44 - 2.38 (m, 4H), 2.12 - 1.93 (m, 6H). LCMS:228.1[M+H] + .

[0202] Step Two:

[0203] Methyl 5-methyl-2-(pyridin-4-yl)benzoate (500 mg, 2.20 mmol) was dissolved in 2 M sodium hydroxide solution (5.5 mL, 11.0 mmol). The reaction mixture was heated to 60 °C and stirred for 8 hours. After the reaction was complete, the mixture was cooled to room temperature, and the pH was adjusted to 1-2 with 6 M hydrochloric acid solution. The mixture was filtered, and the filter cake was washed with water and n-heptane and dried to give 5-methyl-2-(pyridin-4-yl)benzoic acid (352 mg, 75% yield). LCMS: 214.1 [M+H] + .

[0204] Step 3:

[0205] 5-Methyl-2-(pyridin-4-yl)benzoic acid (102 mg, 0.479 mmol) and (S)-5-chloro-4-methyl-2-(2-methylpyrrolidone-2-yl)benzo[d]oxazole (100.0 mg, 0.399 mmol) were dissolved in 3 mL of ethyl acetate. Then, 1-propylphosphoric anhydride (0.28 mL, 0.479 mmol) was added, and the reaction mixture was heated to 50 °C and stirred for 2 hours. After the reaction was complete, the mixture was cooled to room temperature, and the solution was purified by preparative HPLC to give the title compound 3 (62.3 mg, 35% yield). LCMS: 446.2 [M+H] + .

[0206] Following the methods in steps one through five of Example 1, different substituted benzoxazole intermediates can be synthesized using appropriate starting materials; following the methods in step one of Example 2 or steps one through two of Example 3, different substituted arylbenzoic acid intermediates can be synthesized using appropriate starting materials; following the methods in step six of Example 1 or step three of Example 3, different substituted benzoxazole intermediates and substituted arylbenzoic acid intermediates can be condensed to prepare the compounds of Examples 4 through 39, as shown in Table 1 below:

[0207] Table 1. Compounds prepared in Examples 4 to 39 and their characterization data

[0208] Example Compound Nomenclature Compound structural formula Compound characterization 4 (S)-(2-(5-chloro-4-methylbenzo[d]oxazol-2-yl)-2-methylpyrrolidone-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl) ketone <![CDATA[ 1 H NMR (400 MHz, CDCl3) δ 7.83 - 7.80 (m, 3H),7.32 - 7.26 (m, 4H), 3.51 - 3.13 (m, 2H), 2.63(s, 3H), 2.48 - 2.32 (m, 4H), 2.14 - 1.90 (m,6H)。LCMS:436.1[M+H] + 。]]> 5 (S)-(2-(5-chloro-4-methylbenzo[d]oxazol-2-yl)-2-methylpyrrolid-1-yl)(5-chloro-2-(2H-1,2,3-triazol-2-yl)phenyl) methyl ketone <![CDATA[ 1 H NMR (400 MHz, CDCl3) δ 7.84 - 7.72 (m, 3H),7.36 - 7.27 (m, 4H), 3.52 - 3.14 (m, 2H), 2.63(s, 3H), 2.53 - 2.48 (m, 1H), 2.13 - 1.88 (m,6H)。LCMS:456.1[M+H] + 。]]> 6 (S)-(2-(5-chloro-4-methylbenzo[d]oxazol-2-yl)-2-methylpyrrolidone-1-yl)(2-(2H-1,2,3-triazol-2-yl)phenyl) ketone <![CDATA[ 1 H NMR (400 MHz, CDCl3) δ 7.84 - 7.72 (m, 3H),7.51 - 7.26 (m, 5H), 3.50 - 3.12 (m, 2H), 2.51 -2.47 (m, 1H), 2.11 - 1.89 (m, 6H)。LCMS:422.1[M+H] + 。]]> 7 (S)-(2-(5-chloro-4-methylbenzo[d]oxazol-2-yl)-2-methylpyrrolid-1-yl)(4-chloro-2-(2H-1,2,3-triazol-2-yl)phenyl) ketone <![CDATA[ 1 H NMR (400 MHz, CDCl3) δ 7.88 - 7.74 (m, 4H),7.46 - 7.30 (m, 3H), 3.52 - 3.14 (m, 2H), 2.63(s, 3H), 2.52 - 2.48 (m, 1H), 2.12 - 1.88 (m,6H)。LCMS:456.1[M+H] + 。 <!-- 19 -->]]> 8 (S)-(2-(5-chloro-4-methylbenzo[d]oxazol-2-yl)-2-methylpyrrolidone-1-yl)(4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl) ketone <![CDATA[ 1 H NMR (400 MHz, CDCl3) δ 7.88 - 7.70 (m, 3H),7.31 - 7.27 (m, 1H), 7.17 - 7.08 (m, 3H), 3.63 -3.47 (m, 2H), 2.63 (s, 3H), 2.53 - 2.47 (m, 1H),2.22 - 1.99 (m, 6H)。LCMS:440.1[M+H] + 。]]> 9 (S)-(2-(5-chloro-4-methylbenzo[d]oxazol-2-yl)-2-methylpyrrolidone-1-yl)(4-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl) ketone <![CDATA[ 1 H NMR (400 MHz, CDCl3) δ 7.85 - 7.77 (m, 4H),7.38 - 7.26 (m, 3H), 3.50 - 3.14 (m, 2H), 2.63(s, 3H), 2.50 - 2.35 (m, 4H), 2.12 - 1.88 (m,6H)。LCMS:436.1[M+H] + 。]]> 10 (S)-(2-(5-chloro-4-methylbenzo[d]oxazol-2-yl)-2-methylpyrrolidin-1-yl)(5-methyl-2-(1H-pyrazol-1-yl)phenyl) ketone <![CDATA[ 1 H NMR (400 MHz, CDCl3) δ 7.83 - 7.80 (m, 2H),7.32 - 7.12 (m, 5H), 6.51 - 6.47 (m, 1H), 3.48 -3.15 (m, 2H), 2.63 (s, 3H), 2.49 - 2.35 (m, 4H),2.17 - 1.94 (m, 6H)。LCMS:435.2[M+H] + 。]]> 11 (S)-(3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(2-(5-chloro-4-methylbenzo[d]oxazol-2-yl)-2-methylpyrrolidone-1-yl)methyl ketone <![CDATA[ 1 H NMR (400 MHz, CDCl3) δ 8.35 - 8.03 (m, 2H),7.83 - 7.80 (m, 2H), 7.36 - 7.01 (m, 3H), 3.52 -3.20 (m, 2H), 2.63 (s, 3H), 2.51 - 2.42 (m, 1H),2.25 - 1.97 (m, 6H)。LCMS:423.1[M+H] + 。]]> 12 (S)-(2-(5-chloro-4-methylbenzo[d]oxazol-2-yl)-2-methylpyrrolidin-1-yl)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methyl ketone <![CDATA[ 1 H NMR (400 MHz, CDCl3) δ 8.35 - 8.32 (m, 1H),7.84 - 7.81 (m, 2H), 7.34 - 7.12 (m, 3H), 3.56 -3.31 (m, 2H), 2.70 (s, 3H), 2.59 - 2.46 (m, 1H),2.17 - 1.88 (m, 6H)。LCMS:437.1[M+H] + 。]]> 13 (S)-(2-(5-chloro-4-methylbenzo[d]oxazol-2-yl)-2-methylpyrrolidin-1-yl)(6-methyl-3-(1H-pyrazol-1-yl)pyridin-2-yl)methyl ketone <![CDATA[ 1 H NMR (400 MHz, CDCl3) δ 8.29 - 8.25 (m, 1H),7.97 - 7.93 (m, 1H), 7.38 - 7.09 (m, 4H), 6.53 -6.48 (m, 1H), 3.55 - 3.34 (m, 2H), 2.72 (s, 3H),2.60 - 2.46 (m, 1H), 2.19 - 1.90 (m, 6H)。LCMS:436.1[M+H] + 。]]> 14 (S)-(2-(5-chloro-4-methylbenzo[d]oxazol-2-yl)-2-methylpyrrolidin-1-yl)(6-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl) ketone <![CDATA[ 1 H NMR (400 MHz, CDCl3) δ 7.85 - 7.67 (m, 3H),7.50 - 7.43 (m, 1H), 7.31 - 7.26 (m, 2H), 7.19 -7.12 (m, 1H), 3.75 - 3.49 (m, 2H), 2.65 - 2.62(m, 4H), 2.35 - 2.10 (m, 6H)。LCMS:440.1[M+H] + 。]]> 15 (S)-(2-(5-chloro-4-methylbenzo[d]oxazol-2-yl)-2-methylpyrrolid-1-yl)(5-methyl-2-(pyrimidin-2-yl)phenyl) ketone <![CDATA[ 1 H NMR (400 MHz, CDCl3) δ 8.75 (d, J = 4.8 Hz,2H), 8.21 (d, J = 8.0 Hz, 1H), 7.31 - 7.24 (m,4H), 7.17 (t, J = 4.8 Hz, 1H), 3.60 - 3.54 (m,1H), 3.39 - 3.30 (m, 1H), 2.63 (s, 3H), 2.47 -2.39 (m, 4H), 2.13 - 1.94 (m, 6H)。LCMS:447.2[M+H] + 。]]> 16 (S)-(2-(5-chloro-4-methylbenzo[d]oxazol-2-yl)-2-methylpyrrolidone-1-yl)(5-fluoro-2-(pyrimidin-2-yl)phenyl)methyl ketone <![CDATA[ 1 H NMR (400 MHz, CDCl3) δ 8.78 (d, J = 4.8 Hz,2H), 8.23 (d, J = 8.0 Hz, 1H), 7.42 - 7.24 (m,4H), 7.18 (t, J = 4.8 Hz, 1H), 3.61 - 3.58 (m,1H), 3.42 - 3.32 (m, 1H), 2.64 (s, 3H), 2.49 -2.36 (m, 1H), 2.15 - 1.92 (m, 6H)。LCMS:451.1[M+H] + 。]]> 17 (S)-(2-(5-chloro-4-methylbenzo[d]oxazol-2-yl)-2-methylpyrrolidin-1-yl)(5-methyl-2-(pyridin-2-yl)phenyl) ketone <![CDATA[ 1 H NMR (400 MHz, CDCl3) δ 8.53 (d, J = 4.8 Hz,1H), 7.70 - 7.66 (m, 1H), 7.56 - 7.49 (m, 1H),7.41 - 7.31 (m, 2H), 7.30 - 7.10 (m, 4H), 3.57 -3.30 (m, 2H), 2.62 (s, 3H), 2.42 - 2.35 (m, 4H),2.10 - 1.94 (m, 6H)。LCMS:456.2[M+H] + 。]]> 18 (S)-(2-(5-chloro-4-methylbenzo[d]oxazol-2-yl)-2-methylpyrrolidone-1-yl)(5-methyl-2-(pyrazin-2-yl)phenyl) ketone <![CDATA[ 1 H NMR (400 MHz, CDCl3) δ 8.83 - 8.53 (m, 3H),7.65 - 7.56 (m, 2H), 7.40 - 7.12 (m, 3H), 3.58 -3.33 (m, 2H), 2.62 (s, 3H), 2.43 - 2.34 (m, 4H),2.12 - 1.95 (m, 6H)。LCMS:447.2[M+H] + 。 <!-- 20 -->]]> 19 (S)-(2-(5-chloro-4-methylbenzo[d]oxazol-2-yl)-2-methylpyrrolidone-1-yl)(4-methyl-[1,1'-biphenyl]-2-yl)methyl ketone <![CDATA[ 1 H NMR (400 MHz, CDCl3) δ 7.46 - 7.42 (m, 2H),7.31 - 7.16 (m, 6H), 7.12 - 7.02 (m, 2H), 3.52 -3.20 (m, 2H), 2.61 (s, 3H), 2.38 - 2.27 (m, 4H),2.10 - 1.94 (m, 6H)。LCMS:445.2[M+H] + 。]]> 20 (S)-(2-(5-chloro-4-methylbenzo[d]oxazol-2-yl)-2-methylpyrrolidone-1-yl)(4-methoxy-[1,1'-biphenyl]-2-yl)methyl ketone <![CDATA[ 1 H NMR (400 MHz, CDCl3) δ 7.45 - 7.40 (m, 2H),7.37 - 7.21 (m, 6H), 6.99 - 6.85 (m, 2H), 3.84(s, 3H), 3.54 - 3.22 (m, 2H), 2.59 (s, 3H), 2.36- 2.26 (m, 1H), 2.11 - 1.95 (m, 6H)。LCMS:461.2[M+H] + 。]]> 21 (S)-(5-chloro-2-(pyrimidin-2-yl)phenyl)(2-(5-chloro-4-methylbenzo[d]oxazol-2-yl)-2-methylpyrrolidone-1-yl)methyl ketone <![CDATA[ 1 H NMR (400 MHz, CDCl3) δ 8.77 (d, J = 4.8 Hz,2H), 7.95 (d, J = 8.4 Hz, 1H), 7.55 - 7.50 (m,2H), 7.33 - 7.18 (m, 3H), 3.53 - 3.32 (m, 2H),2.60 (s, 3H), 2.34 - 2.26 (m, 1H), 2.14 - 1.96(m, 6H)。LCMS:467.1[M+H] + 。]]> 22 (S)-(2-(5-chloro-4-methylbenzo[d]oxazol-2-yl)-2-methylpyrrolidone-1-yl)(5-methoxy-2-(pyrimidin-2-yl)phenyl) ketone <![CDATA[ 1 H NMR (400 MHz, CDCl3) δ 8.76 (d, J = 4.8 Hz,2H), 8.04 (d, J = 8.4 Hz, 1H), 7.29 - 7.14 (m,4H), 7.07 - 7.03 (m, 1H), 3.87 (s, 3H), 3.56 -3.34 (m, 2H), 2.60 (s, 3H), 2.37 - 2.28 (m, 1H),2.13 - 1.96 (m, 6H).LCMS:463.2[M+H] + ]]> 23 (S)-(2-(5-chloro-4-methylbenzo[d]oxazol-2-yl)-2-methylpyrrolidone-1-yl)(5-(2-fluorophenyl)-2-methylthiazo-4-yl)methyl ketone <![CDATA[ 1 H NMR (400 MHz, CDCl3) δ 7.52 - 7.45 (m, 1H),7.35 - 7.23 (m, 3H), 7.19 - 7.07 (m, 2H), 3.52 -3.38 (m, 2H), 2.73 (s, 3H), 2.61 (s, 3H), 2.35 -2.28 (m, 1H), 2.14 - 1.95 (m, 6H)。LCMS:470.1[M+H] + 。]]> 24 (S)-(2-(5-chloro-4-methylbenzo[d]oxazol-2-yl)-2-methylpyrrolidone-1-yl)(2-methyl-5-phenylthiazo-4-yl)methyl ketone <![CDATA[ 1 H NMR (400 MHz, CDCl3) δ 7.61 - 7.58 (m, 2H),7.46 - 7.26 (m, 5H), 3.52 - 3.38 (m, 2H), 2.72(s, 3H), 2.62 (s, 3H), 2.34 - 2.27 (m, 1H), 2.16- 1.95 (m, 6H)。LCMS:452.1[M+H] + 。]]> 25 (S)-(2-(5-chloro-4-methylbenzo[d]oxazol-2-yl)-2-methylpyrrolidone-1-yl)(5-(4-fluorophenyl)-2-methylthiazo-4-yl)methyl ketone <![CDATA[1H NMR (400 MHz, CDCl3) δ 7.69 - 7.60 (m, 2H),7.33 - 7.25 (m, 2H), 7.16 - 7.09 (m, 2H), 3.50 -3.35 (m, 2H), 2.74 (s, 3H), 2.62 (s, 3H), 2.34 -2.26 (m, 1H), 2.15 - 1.95 (m, 6H)。LCMS:470.1[M+H] + 。]]> 26 (S)-(2-(5-chlorobenzo[d]oxazol-2-yl)-2-methylpyrrolidone-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl) ketone <![CDATA[ 1 H NMR (400 MHz, CDCl3) δ 7.83 - 7.77 (m, 4H),7.37 - 7.28 (m, 4H), 3.51 - 3.14 (m, 2H), 2.63(s, 3H), 2.45 - 2.31 (m, 1H), 2.12 - 1.88 (m,6H)。LCMS:422.1[M+H] + 。]]> 27 (S)-(2-(5-chlorobenzo[d]oxazol-2-yl)-2-methylpyrrolid-1-yl)(5-methyl-2-(pyrimidin-2-yl)phenyl) ketone <![CDATA[ 1 H NMR (400 MHz, CDCl3) δ 8.77 (d, J = 4.8 Hz,2H), 8.23 (d, J = 8.0 Hz, 1H), 7.31 - 7.21 (m,5H), 7.15 (t, J = 4.8 Hz, 1H), 3.61 - 3.55 (m,1H), 3.41 - 3.32 (m, 1H), 2.62 (s, 3H), 2.49-2.40 (m, 1H), 2.15 - 1.96 (m, 6H)。LCMS:433.2[M+H] + 。]]> 28 (S)-(2-(5-chloro-4-fluorobenzo[d]oxazol-2-yl)-2-methylpyrrolidone-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl) ketone <![CDATA[ 1 H NMR (400 MHz, CDCl3) δ 7.89 - 7.81 (m, 3H),7.32 - 7.26 (m, 4H), 3.51 - 3.13 (m, 2H), 2.62(s, 3H), 2.53 - 2.45 (m, 1H), 2.23 - 1.92 (m,6H)。LCMS:440.1[M+H] + 。]]> 29 (S)-(2-(5-chloro-4-fluorobenzo[d]oxazol-2-yl)-2-methylpyrrolidone-1-yl)(5-methyl-2-(pyrimidin-2-yl)phenyl) ketone <![CDATA[ 1 H NMR (400 MHz, CDCl3) δ 8.78 (d, J = 5.0 Hz,2H), 8.22 (d, J = 8.0 Hz, 1H), 7.35 - 7.26 (m,4H), 7.17 (t, J = 4.8 Hz, 1H), 3.62 - 3.56 (m,1H), 3.41 - 3.33 (m, 1H), 2.62 (s, 3H), 2.50-2.42 (m, 1H), 2.11 - 1.92 (m, 6H)。LCMS:451.1[M+H] + 。 <!-- 21 -->]]> 30 (S)-(2-(5-chloro-4-fluorobenzo[d]oxazol-2-yl)-2-methylpyrrolidone-1-yl)(5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl) ketone <![CDATA[ 1 H NMR (400 MHz, CDCl3) δ 7.88 - 7.78 (m, 3H),7.32 - 7.24 (m, 2H), 7.09 - 7.00 (m, 2H), 3.89(s, 3H), 3.57 - 3.08 (m, 2H), 2.36 - 2.30 (m,1H), 2.09 - 1.88 (m, 6H)。LCMS:456.1[M+H] + 。]]> 31 (S)-(2-(5-bromobenzo[d]oxazol-2-yl)-2-methylpyrrolidone-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl) ketone <![CDATA[ 1 H NMR (400 MHz, CDCl3) δ 7.83 - 7.79 (m, 3H),7.39 - 7.28 (m, 5H), 3.51 - 3.14 (m, 2H), 2.62(s, 3H), 2.45 - 2.31 (m, 1H), 2.12 - 1.89 (m,6H)。LCMS:466.1[M+H] + 。]]> 32 (S)-(2-(5-bromobenzo[d]oxazol-2-yl)-2-methylpyrrolidone-1-yl)(5-methyl-2-(pyrimidin-2-yl)phenyl)methyl ketone <![CDATA[ 1 H NMR (400 MHz, CDCl3) δ 8.68 (d, J = 4.8 Hz,2H), 8.15 (d, J = 8.0 Hz, 1H), 7.33 - 7.21 (m,5H), 7.17 (t, J = 4.8 Hz, 1H), 3.60 - 3.55 (m,1H), 3.43 - 3.33 (m, 1H), 2.63 (s, 3H), 2.47-2.40 (m, 1H), 2.18 - 1.99 (m, 6H)。LCMS:433.2[M+H] + 。]]> 33 (S)-(2-(5-bromo-4-methylbenzo[d]oxazol-2-yl)-2-methylpyrrolidone-1-yl)(5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl) ketone <![CDATA[ 1 H NMR (400 MHz, CDCl3) δ 7.87 - 7.80 (m, 3H),7.35 - 7.24 (m, 2H), 7.06 - 7.00 (m, 2H), 3.91(s, 3H), 3.57 - 3.11 (m, 2H), 2.63 (s, 3H), 2.38- 2.31 (m, 1H), 2.07 - 1.88 (m, 6H)。LCMS:496.1[M+H] + 。]]> 34 (S)-(2-(5-bromo-4-methylbenzo[d]oxazol-2-yl)-2-methylpyrrolidone-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl) ketone <![CDATA[ 1 H NMR (400 MHz, CDCl3) δ 7.85 - 7.80 (m, 3H),7.36 - 7.26 (m, 4H), 3.53 - 3.13 (m, 2H), 2.62(s, 3H), 2.49-2.32 (m, 4H), 2.15 - 1.90 (m, 6H)。LCMS:480.1[M+H] + ]]> 35 (S)-(2-(5-bromo-4-methylbenzo[d]oxazol-2-yl)-2-methylpyrrolidone-1-yl)(5-methyl-2-(pyrimidin-2-yl)phenyl)methyl ketone <![CDATA[ 1 H NMR (400 MHz, CDCl3) δ 8.75 (d, J = 4.8 Hz,2H), 8.21 (d, J = 8.0 Hz, 1H), 7.37 - 7.26 (m,4H), 7.17 (t, J = 4.8 Hz, 1H), 3.61 - 3.55 (m,1H), 3.40 - 3.32 (m, 1H), 2.63 (s, 3H), 2.47-2.40 (m, 4H), 2.15 - 1.97 (m, 6H)。LCMS:491.1[M+H] + 。]]> 36 (S)-(2-(5-chloro-4-methylbenzo[d]oxazol-2-yl)-2-methylpyrrolidone-1-yl)(5-methoxy-2-(pyrimidin-2-yl)phenyl) ketone <![CDATA[ 1 H NMR (400 MHz, CDCl3) δ 8.75 (d, J = 4.8 Hz,2H), 8.21 (d, J = 8.0 Hz, 1H), 7.38 - 7.24 (m,4H), 7.17 (t, J = 4.8 Hz, 1H), 3.89 (s, 3H),3.60 - 3.54 (m, 1H), 3.39 - 3.30 (m, 1H), 2.47 -2.39 (m, 4H), 2.13 - 1.94 (m, 6H)。LCMS:463.2[M+H] + 。]]> 37 (S)-(2-(5-chloro-4-methylbenzo[d]oxazol-2-yl)-2-methylpyrrolidone-1-yl)(5-methyl-2-(2-methylthiazo-5-yl)phenyl) ketone <![CDATA[ 1 H NMR (400 MHz, CDCl3) δ 7.93 - 7.79 (m, 3H),7.37 - 7.26 (m, 3H), 3.51 - 3.13 (m, 2H), 2.61(s, 3H), 2.51 - 2.32 (m, 7H), 2.15 - 1.92 (m,6H)。LCMS:466.1[M+H] + 。]]> 38 (S)-(2-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethoxy)phenyl)(2-(5-chloro-4-methylbenzo[d]oxazol-2-yl)-2-methylpyrrolidone-1-yl)methyl ketone <![CDATA[ 1 H NMR (400 MHz, CDCl3) δ 7.85 - 7.78 (m, 3H),7.27 - 7.23 (m, 2H), 7.05 - 6.99 (m, 2H), 3.58 -3.11 (m, 2H), 2.63 (s, 3H), 2.36 - 2.31 (m, 1H),2.06 - 1.86 (m, 6H)。LCMS:506.1[M+H] + 。]]> 39 (S)-(2-(5-chloro-4-methylbenzo[d]oxazol-2-yl)-2-methylpyrrolidone-1-yl)(5-(difluoromethoxy)-2-(2H-1,2,3-triazol-2-yl)phenyl) ketone <![CDATA[ 1 H NMR (400 MHz, CDCl3) δ 7.86 - 7.79 (m, 3H),7.35 - 7.23 (m, 3H), 7.05 - 7.00 (m, 2H), 3.60 -3.13 (m, 2H), 2.61 (s, 3H), 2.37 - 2.31 (m, 1H),2.09- 1.87 (m, 6H)。LCMS:488.1[M+H] + 。]]>

[0209] Example 40: Synthesis of (S)-(2-(6-chloro-7-methylbenzo[d]oxazol-2-yl)-2-methylpyrrolidone-1-yl)(5-methyl-2-(pyrimidin-2-yl)phenyl) ketone (compound 40)

[0210]

[0211] first step:

[0212] 2-Chloro-3-hydroxytoluene (30.0 g, 210.4 mmol) was dissolved in 300 mL of acetone, and ferric nitrate nonahydrate (25.44 g, 105.2 mmol) was added. The mixture was stirred at 25 °C for 6 hours. After the reaction was complete, the product was purified by reverse-phase Flash column chromatography (water / methanol = 100 / 0 ~ 35 / 66) to give 3-chloro-2-methyl-6-nitrophenol (17.3 g, yield 44.0%). 1 HNMR (400 MHz, CDCl3) δ 11.18 (d, J = 0.92 Hz, 1H), 7.94 (d, J = 9.2 Hz, 1H), 7.03 (d, J = 9.2 Hz, 1H), 2.41 (s, 3H).

[0213] Step Two:

[0214] 17.7 g (94.4 mmol) of 3-chloro-2-methyl-6-nitrophenol was dissolved in 300 mL of ethanol, and 134.2 g (710 mmol) of stannous chloride was added. The reaction mixture was heated to 80 °C and stirred for 12 hours. After the reaction was complete, the mixture was cooled to room temperature and purified by Flash column chromatography (dichloromethane / water = 100 / 0 ~ 50 / 50) to give 8.65 g (58% yield) of 6-amino-3-chloro-2-methylphenol. 1 H NMR (400 MHz, CDCl3) δ 6.83 (d, J = 8.0 Hz, 1H), 6.63 (d, J = 8.0 Hz, 1H), 5.21 (s, 1H), 3.52 (s, 2H), 2.30 (s, 3H).

[0215] Step 3:

[0216] (S)-1-(((9H-fluorene-9-yl)methoxy)carbonyl)-2-methylpyrrolidine-2-carboxylic acid (10.4 g, 29.5 mmol) was dissolved in 50 mL of dichloromethane, and BOPCl (12.6 g, 49.1 mmol), N',N-diisopropylethylamine (9.60 g, 73.68 mmol) and 6-amino-3-chloro-2-methylphenol (3.90 g, 24.6 mmol) were added sequentially. The mixture was stirred at 25 °C for 12 hours. After the reaction was complete, 100 mL of water was added to the resulting reaction solution. The mixture was stirred for 10 minutes and then separated. The organic phase was washed twice with 100 mL of 5% sodium bicarbonate aqueous solution, then twice with 100 mL of saturated sodium chloride solution. The solution was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by Flash column chromatography (petroleum ether / water = 100 / 0 ~ 66 / 34) to obtain (9H-fluorene-9-yl)methyl-(S)-2-(6-chloro-7-methylbenzo[d]oxazol-2-yl)-2-methylpyrrolidine-1-carboxylic acid ester (4.0 g, yield 33.0%), LCMS: 491.1 [M+H]. + .

[0217] Step 4:

[0218] (9H-fluorene-9-yl)methyl-(S)-2-(6-chloro-7-methylbenzo[d]oxazol-2-yl)-2-methylpyrrolidine-1-carboxylic acid ester (6.40 g, 13.1 mmol) was dissolved in 90 mL of toluene, and p-toluenesulfonic acid (3.21 g, 18.3 mmol) was added. The reaction system was heated to 110 °C and stirred for 2 hours. After the reaction was complete, the mixture was cooled to room temperature, diluted with 300 mL of water, and then extracted three times with 100 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The solution was then purified by Flash column chromatography (petroleum ether / ethyl acetate = 100 / 0 ~ 75 / 25) to obtain methyl (9H-fluorene-9-yl)-(S)-2-(6-chloro-7-methylbenzo[d]oxazol-2-yl)-2-methylpyrrolidine-1-carboxylate (5.05 g, yield 82.0%), LCMS: 473.2 [M+H]. + .

[0219] Step 5:

[0220] Methyl (9H-fluorene-9-yl)-(S)-2-(6-chloro-7-methylbenzo[d]oxazol-2-yl)-2-methylpyrrolidine-1-carboxylate (6.85 g, 14.5 mmol) was dissolved in 80 mL of dichloromethane, and piperidine (6.17 g, 72.4 mmol) was added. The mixture was stirred at 25 °C for 2 hours. After the reaction was complete, the reaction mixture was diluted with water, extracted three times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, and purified by Flash column chromatography (petroleum ether / ethyl acetate = 100 / 0 ~ 50 / 50) after solvent removal to obtain (S)-5-chloro-4-methyl-2-(2-methylpyrrolidine-2-yl)benzo[d]oxazole (1.90 g, yield 53.0%), LCMS: 251.1 [M+H). + . 1 H NMR (400 MHz, DMSO-d6) δ: 7.53 (d, J = 8.0 Hz, 1H), 7.39 (d, J= 8.0 Hz, 1H), 3.02-2.98 (m, 1H), 2.93-2.87 (m, 1H), 2.51 (s, 3H), 2.42-2.37(m 1H), 1.88 – 1.75 (m, 3H), 1.57 (s, 3H).

[0221] Step 6:

[0222] 2-(2-pyrimidinyl)-5-methylbenzoic acid (102 mg, 0.479 mmol) and (S)-5-chloro-4-methyl-2-(2-methylpyrrolidone-2-yl)benzo[d]oxazole (100.0 mg, 0.399 mmol) were dissolved in 3 mL of ethyl acetate, and then 1-propylphosphoric anhydride (0.28 mL, 0.479 mmol) was added. The reaction mixture was heated to 50 °C and stirred for 2 hours. After the reaction was completed, the mixture was cooled to room temperature and purified by Flash column chromatography (petroleum ether / ethyl acetate = 10 / 90 ~ 50 / 50) to give the title compound 40 (103.8 mg, yield 58.0%). 1H NMR (400 MHz, CDCl3) δ 8.76 (d, J = 4.7 Hz, 2H), 8.23 ​​(d, J = 8.0 Hz, 1H), 7.47 (d, J = 8.5 Hz, 1H), 7.35 - 7.28 (m, 2H), 7.25 -7.15 (m, 2H), 3.61 – 3.53 (m, 1H), 3.37 – 3.28 (m, 1H), 2.58 (s, 3H), 2.48 –2.40 (m, 4H), 2.16 – 1.96 (m, 6H). LCMS:447.2[M+H] + .

[0223] Following the synthetic method in Example 40, different substituted aryl benzoic acids were condensed with corresponding intermediates to prepare the compounds of Examples 41-43, as shown in Table 2 below:

[0224] Table 2. Compounds prepared in Examples 41-43 and their characterization data

[0225] Example Compound Nomenclature Compound structural formula Compound characterization 41 (S)-(2-(6-chloro-7-methylbenzo[d]oxazol-2-yl)-2-methylpyrrolidone-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl) ketone <![CDATA[ 1 H NMR (400 MHz, CDCl3) δ 7.83 - 7.80 (m,3H), 7.34 - 7.26 (m, 4H), 3.51 - 3.13 (m,2H), 2.63 (s, 3H), 2.48 - 2.32 (m, 4H), 2.14- 1.90 (m, 6H)。LCMS:436.1[M+H] + 。]]> 42 (S)-(2-(6-chloro-7-methylbenzo[d]oxazol-2-yl)-2-methylpyrrolidone-1-yl)(5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl) ketone <![CDATA[ 1 H NMR (400 MHz, CDCl3) δ 7.84 - 7.79 (m,3H), 7.28 - 7.24 (m, 2H), 7.05 - 7.00 (m,2H), 3.88 (s, 3H), 3.53 - 3.07 (m, 2H), 2.61(s, 3H), 2.35 - 2.30 (m, 1H), 2.07 - 1.88(m, 6H)。LCMS:452.1[M+H] + 。]]> 43 (S)-(2-(6-chloro-7-methylbenzo[d]oxazol-2-yl)-2-methylpyrrolid-1-yl)(5-methyl-2-(2-methylthiazo-5-yl)phenyl) ketone <![CDATA[ 1 H NMR (400 MHz, CDCl3) δ 7.91 - 7.77 (m,3H), 7.37 - 7.26 (m, 3H), 3.50 - 3.14 (m,2H), 2.62 (s, 3H), 2.50 - 2.31 (m, 7H), 2.13- 1.90 (m, 6H)。LCMS:466.1[M+H] + 。]]>

[0226] Next, the bioactivity of the compounds in the embodiments of this disclosure will be evaluated through the following experiments:

[0227] Biological Experiment Example 1: Test of the antagonistic activity of compounds against hOX1 and hOX2 receptors

[0228] The antagonistic activity of compounds against hOX1 and hOX2 receptors was evaluated by detecting cellular calcium ion flux using a high-throughput real-time fluorescence detection and analysis system (FLIPR).

[0229] Experimental steps:

[0230] 1) CHO cells (purchased from ATCC) cultured in DMEM medium (purchased from Cytiva) were treated with 0.25% trypsin-EDTA (purchased from Gibco), centrifuged, and the medium was removed. Cells were counted and then subjected to a 1.2 × 10⁶ cell line. 4 The plates were laid in 384-well plates with a density of / wells, fresh culture medium was added, and then the plates were incubated at 37°C and 5% CO2 for 16-20 hours.

[0231] 2) According to the FLIPR calcium flow detection kit (FLIPR ® Prepare the test buffer according to the instructions of the Calcium 6 Assay Kit (purchased from Molecular Devices). Freeze-thaw the dye to room temperature and dilute it with the prepared test buffer to obtain 1x working buffer.

[0232] 3) Centrifuge to remove the culture medium, and add 35 μL of 1x working buffer to each well. After centrifugation, incubate the 384-well plate at 37°C in the dark for 2 hours;

[0233] 4) The test compound was serially diluted with DMSO (starting concentration 10 μM, 4-fold dilution, 10 concentrations). 5 μL of the compound solution diluted to 10× with the 1x working buffer was added to the corresponding experimental well. After centrifugation, the solution was incubated at 37°C for 30 minutes. Meanwhile, wells containing only the solvent (obtained by diluting DMSO with the 1x working buffer as described above) were used as blank control wells.

[0234] 5) The prepared agonists (hOX1: final concentration of 9 nM, hOX2: final concentration of 10 nM) were added to the 384-well plate at a rate of 20 μL / well;

[0235] 6) Place the 384-well plate on a FLIPR (Molecular Devices) instrument and acquire data at a wavelength of 515nm - 575nm;

[0236] 7) Plot the signal value and compound concentration curves, and use the nonlinear regression method in GraphPad Prism software to fit the curves and calculate the IC50. 50 The results are shown in the table below.

[0237] Table 3. Results of tests on the antagonistic activity of compounds against hOX1 and hOX2 receptors

[0238] compound <![CDATA[hOX1RIC 50 (nM)]]> <![CDATA[hOX2RIC 50 (nM)]]> compound <![CDATA[hOX1RIC 50 (nM)]]> <![CDATA[hOX2RIC 50 (nM)]]> Example 1 53 61 Example 23 10 15 Example 2 16 23 Example 24 29 36 Example 3 17 22 Example 25 18 22 Example 4 25 24 Example 26 46 489 Example 5 8 10 Example 27 32 268 Example 6 257 366 Example 28 28 78 Example 7 108 125 Example 29 32 69 Example 8 153 162 Example 30 56 136 Example 9 98 95 Example 31 23 98 Example 10 32 28 Example 32 18 79 Example 11 286 253 Example 33 36 29 Example 12 17 65 Example 34 19 17 Example 13 23 136 Example 35 8 9 Example 14 136 141 Example 36 17 19 Example 15 16 22 Example 37 19 49 Example 16 12 26 Example 38 3596 2391 Example 17 25 28 Example 39 986 656 Example 18 57 76 Example 40 10 7 Example 19 28 69 Example 41 18 19 Example 20 26 71 Example 42 38 29 Example 21 10 18 Example 43 15 52 Example 22 36 43

[0239] As shown in the table above, the compounds of this disclosure exhibit good antagonistic activity against both hOX1R and hOX2R. In particular, the IC50 values ​​of some of the compound examples are [not specified]. 50 Values ​​less than 100 nM, especially less than 50 nM.

[0240] Biological Experiment Example 2: In vitro brain permeability assessment of compounds

[0241] The permeability of compounds to the blood-brain barrier was evaluated using a variant (blood-brain barrier) parallel artificial membrane permeation model (PAMPA BBB) and an MDCK-MDR1 cell model.

[0242] PAMPA BBB experimental procedure:

[0243] 1) Prepare a 10 mM working solution of the test compound using DMSO and dilute it with PBS to obtain a 10 μM working solution;

[0244] 2) Ultrasonic treatment of 20 mg / mL porcine brain lipid extract;

[0245] 3) Add 300 μL of working solution to the donor chamber (bottom);

[0246] 4) Add 5 μL of porcine brain lipid extract to the receptor chamber (top), then add 200 μL of PBS over 10 minutes;

[0247] 5) Add 50 μL of the working solution to the sample plate containing 200 μL of methanol;

[0248] 6) Insert the recipient chamber into the donor chamber and incubate at 25°C for 16 hours;

[0249] 7) Take 50 μL of solution from each of the recipient and donor compartments and add it to a sample plate containing 200 μL of methanol;

[0250] 8) Centrifuge the sample plate at 4℃ and 3220g for 40 minutes;

[0251] 9) Add 100 μL of supernatant to an analytical plate containing ultrapure water for LC-MS / MS analysis (instrument: SHIMADZU LC-40AD X3 / AB Sciex Triple Quad 5500+, mobile phase A: 0.1% formic acid-water, mobile phase B: 0.1% formic acid-acetonitrile, chromatographic column: Shim-pack Scepter C18-120, 3 µm, 3.0x50 mm, column temperature: 40℃; ion source: Turbo Spray).

[0252] MDCK-MDR1 Experimental Procedure:

[0253] 1) MDCK-MDR1 cells were cultured at a rate of 2 × 10⁻⁶ 6 10 cells / mL were seeded into 96-well cell plates and cultured at 37°C, 5% CO2, and 95% RH for 3-7 days, with the medium changed every other day using fresh MEM Alpha medium.

[0254] 2) Wash the 96-well cell plate twice with preheated HBSS (10mM HEPES, pH 7.4) and incubate at 37°C for 30 minutes;

[0255] 3) Prepare a 1 mM solution of the test compound using DMSO, and then dilute it with HBSS (10 mM HEPES, pH 7.4) to obtain a 5 μM working solution of the test compound;

[0256] 4) Top to base side: Add 75 μL of the working solution of the analyte to the top side compartment and 235 μL of HBSS (10 mM HEPES, pH 7.4) to the base side compartment.

[0257] 5) Base-side to top-side: Add 235 μL of the working solution of the analyte to the base-side compartment and 75 μL of HBSS (10 mM HEPES, pH 7.4) to the top-side compartment.

[0258] 6) Add 50 μL of the working solution of the test compound to a sample plate containing 200 μL of methanol;

[0259] 7) Incubate the cell plate at 37°C, 5% CO2, and 95% RH for 2 hours;

[0260] 8) Take 50 μL of solution from each of the top and bottom side compartments and add it to a sample plate containing 200 μL of methanol;

[0261] 9) Centrifuge the sample plate at 3220g for 40 minutes;

[0262] 10) Transfer 100 μL of supernatant to an analytical plate containing ultrapure water for LC-MS / MS analysis (instrument: SHIMADZU LC-30AD / AB Sciex Triple Quad 5500+, mobile phase A: 0.1% formic acid-water, mobile phase B: 0.1% formic acid-acetonitrile, column: Shim-pack Scepter C18-120, 3 µm, 3.0×50 mm, column temperature: 40℃; ion source: Turbo Spray).

[0263] 11) Fluorescein transport assay was used to determine MDCK-MDR1 cell permeability, and the results are shown in the table below.

[0264] Table 4: Results of in vitro brain permeability of compounds

[0265]

[0266] In vitro brain permeability experiments showed that the compounds of the present invention have high blood-brain barrier permeability and are not p-gp substrates.

[0267] Biological Experiment Example 3: Pharmacokinetic Evaluation of Compounds in Rats

[0268] 1) Experimental Design

[0269] Six male SD rats, weighing approximately 250 g, were used for each compound and randomly divided into four groups. One group received the compound via intravenous injection (1 MPa), and one group received the positive control drug Daridorexant via injection (1 MPa). One group received the compound via gavage (10 MPa), and one group received the positive control drug Daridorexant via gavage (10 MPa). Rats in the gavage group were fasted for 12–16 hours before administration, but had free access to water. Feeding resumed 4 hours after administration.

[0270] 2) Drug preparation

[0271] Weigh out the compounds from the examples respectively: add solvent 1 (5 vol% DMSO + 5 vol% HS-15 + 90 vol% physiological saline) to prepare a 0.2 mg / mL colorless and clear solution (intravenous injection group); add solvent 2 (99.5 vol% 0.5% MC solution + 0.5 vol% HS-15) and vortex to prepare a 1.0 mg / mL homogeneous suspension (gavage administration group).

[0272] 3) Sample collection

[0273] According to the set blood collection time points (intravenous injection group: 0 min, and 5 min, 15 min, 30 min, 1 h, 4 h, 8 h, 24 h after administration; gavage group: 0 min, and 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 24 h after administration), approximately 0.25 mL of blood was collected from the jugular vein of rats and placed in a blood collection tube containing EDTA-K2 anticoagulant. Whole blood samples were kept at room temperature and centrifuged within 1 h after collection at 3000 g at 4°C for 10 min. After centrifugation, the supernatant plasma was collected and added to cryovials. These were kept at room temperature after collection and temporarily stored at -20°C (-10 to -30°C) or below for 2 h. Once all samples were collected, they were transferred to -80°C (-60 to -90°C) for storage.

[0274] 4) Biological sample analysis

[0275] Using Analyst 1.6.2 or later software, the peak areas of the analyte and internal standard were collected (column: WEC18, 5µm, 50×2.1mm, mobile phase A: 0.1% formic acid-water, mobile phase B: acetonitrile, flow rate: 1.0mL / min). The concentration of the analyte in the calibration standard was linearly regressed using a weighted (W=1 / x²) least squares method with the analyte concentration (x) in the sample as the peak area ratio (y). The resulting regression equation (y=ax+b) is the standard curve. The concentration of the analyte in the blood samples of the test animals was calculated based on the standard curve.

[0276] 5) Calculation and data processing of pharmacokinetic parameters

[0277] Pharmacokinetic parameters (including T) were calculated using the statistical moment method in WinNonlin software. max T 1 / 2 C0 / C max AUC 0-t (Cl / Cl_F, etc.), the results are shown in the table below.

[0278] Table 5: Results of Pharmacokinetic Parameter Measurement

[0279]

[0280] As can be seen from the table above, compared with the positive control drug Daridorexant, the compounds of this embodiment have advantages such as high blood drug concentration, high exposure, low clearance, short time to peak blood drug concentration after gavage administration, and suitable half-life in SD rats, and can have pharmacokinetic advantages.

[0281] Biological Experiment Example 4: Analysis of the Effects of Compounds on Rat Sleep

[0282] Rodents are the most commonly used model organisms for sleep research. This experiment used electroencephalography / electromyography (EEG / EMG) to measure sleep latency, sleep phase diagrams (including the duration of each stage of wake, non-rapid eye movement (NREM) sleep, and rapid eye movement (REM) sleep) in SD rats, thereby evaluating the effects of the disclosed compound on the sleep structure of SD rats.

[0283] Main instruments:

[0284] name brand model Powerlab Physiological Recording System ADInstruments PL15T02 Stereo positioning device Shenzhen Ruiwode 71000-R

[0285] Experimental steps:

[0286] 1) Select 7-8 week old male SD rats with an initial weight of 200-220g. n=3-5 rats / group; a total of 5 groups. After all animals arrive at the animal facility, they enter a one-week acclimatization period: constant temperature 22 ± 2 ℃, humidity 44%-56%, and 12 / 12 h day / night light and dark alternation.

[0287] 2) After weighing the rats, anesthetize them by intraperitoneal injection of 2% sodium pentobarbital. Shave the fur off the animal's head to expose the skin. Disinfect the skin with povidone-iodine. Make a longitudinal incision in the head skin from the midpoint between the eyes to the midpoint between the external auditory canals. Then, use tissue scissors to clean the subcutaneous tissue on both sides of the wound to fully expose the surgical field. Clean the surface of the skull with scissors or forceps to expose the anterior fontanelle. Apply pressure with an alcohol swab to stop bleeding.

[0288] 3) Stereoscopic localization of the animal's brain: Using a sterilized dental drill, holes were drilled in the surface of the skull at the marked locations (in the frontal and parietal lobes of the skull) to implant EEG electrodes. Simultaneously, electromyography (EMG) recording electrodes were implanted in the neck muscles of the animal. The denture base resin was mixed evenly and then applied around the EEG electrodes. After the resin solidified, the animal was placed in a cage for individual rearing for 5-7 days.

[0289] 4) After the animals have fully recovered post-surgery, the adaptation record for each cage of animals was recorded 24 hours before administration. The test drug and the positive control drug (Daridorexant) were dissolved in 100% PEG400, and the same volume of 100% PEG400 was used as the fusion medium control. On the day of administration, the animals were administered the drug by gavage according to their groups starting at 17:00. The EEG / EMG data were recorded 6 hours after administration.

[0290] 5) After analyzing EEG / EMG data using sleep software, manual correction was performed to analyze the sleep latency (NREM, REM) of each animal and the proportion of time occupied by each sleep stage (wakefulness, NREM, REM) within 6 hours. All data are expressed as averages, processed using GraphPad 9.0.0 software, and subjected to one-way ANOVA statistical analysis. The results are shown in the table below.

[0291] Table 6: Sleep analysis results (* p<0.05)

[0292] Grouping Dosage (mpk) Sleep latency (min) Changes in sleep latency compared to the solvent control group The percentage of people who are awake within 6 hours NREM sleep rate within 6 hours REM sleep percentage within 6 hours Solvent comparison / 25.92 / 64.8% 29.6% 5.6% Example 40 10 12.84 -50.5%* 57.2% 35.1% 7.7% Example 40 30 11.55 -55.4%* 53.3%* 41.4% 5.3% Example 40 100 14.75 -43.1%* 50.4%* 40.7% 8.9% Daridorexant 30 17.33 -33.1%* 57.7% 33.5% 8.8%

[0293] As can be seen from the results in the table above, the compounds of this disclosure can significantly shorten the sleep latency of SD rats at low doses, significantly reduce the wakefulness time of SD rats within 6 hours, and have little effect on the ratio of NREM and REM sleep, thus exhibiting a good sleep-promoting effect.

Claims

1. A benzoxazole compound of Formula I, its tautomers or stereoisomers, its pharmaceutically acceptable salts, its prodrugs, its deuterated derivatives, its hydrates, or its solvates. I in, n is 0, 1, 2, 3 or 4; R1 can be independently deuterium, tritium, halogen, C1-C10 alkyl, C1-C10 haloalkyl, C3-C10 cycloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, cyano, amino, amide, or hydroxyl in each occurrence. Y is either O or S; R2 is a C1-C10 alkyl, C1-C10 haloalkyl, C2-C10 alkenyl, or C2-C10 alkynyl; m can be 0, 1, 2, or 3; R3 can be independently deuterium, tritium, halogen, C1-C10 alkyl, C1-C10 haloalkyl, C3-C10 cycloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, cyano, amino, or hydroxyl in each occurrence. Z is C or S, and for , ,or ; Ring A is a C6-C10 aryl, a 5-10 heteroaryl containing 1-3 heteroatoms, a C5-C10 cycloalkenyl, or a 5-10 heterocyclic alkenyl containing 1-3 heteroatoms; p is 0, 1, 2, 3, 4 or 5; R4, each time it appears, is independently C1-C10 alkoxy, C1-C10 haloalkoxy, halogen, C1-C10 alkyl, C1-C10 haloalkyl, C3-C10 cycloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, 5-10 heteroaryl containing 1-3 heteroatoms, C6-C10 aryl, C5-C10 cycloalkenyl, or 5-10 heterocyclic alkenyl containing 1-3 heteroatoms; The R4 is optionally substituted with one or more groups selected from the following: halogen, C1-C10 alkyl, C1-C10 haloalkyl, hydroxyl, amino.

2. The compound of claim 1, its tautomers or stereoisomers, its pharmaceutically acceptable salts, its prodrugs, its deuterated derivatives, its hydrates, or its solvates, wherein, n is 1, 2, or 3; and / or R1 can be independently deuterium, tritium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cyano, amino, amide, or hydroxyl in each occurrence. Preferably, R1 is independently deuterium, tritium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, cyano, amino, or hydroxyl in each occurrence; Preferably, R1 is independently fluorine, chlorine, bromine, iodine, methyl, ethyl, or propyl each time it appears; More preferably, n is 2, and R1 is independently fluorine, chlorine, bromine, iodine, methyl, ethyl, or propyl each time it appears.

3. The compound of claim 1 or 2, its tautomer or stereoisomer, its pharmaceutically acceptable salt, its prodrug, its deuterated derivative, its hydrate, or its solvate, wherein, Y is 0; and / or R2 is a C1-C6 alkyl or a C1-C6 haloalkyl; Preferably, R2 is a C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, or C1-C3 alkyl; More preferably, R2 is methyl, ethyl, or propyl.

4. The compound, tautomer or stereoisomer of any one of claims 1-3, its pharmaceutically acceptable salt, its prodrug, its deuterated derivative, its hydrate, or its solvate, wherein, m is 0, 1, or 2, preferably m is 0; and / or R3 can be independently deuterium, tritium, halogen, C1-C6 alkyl, or C1-C6 haloalkyl each time it appears; Preferably, R3 is independently deuterium, tritium, fluorine, chlorine, bromine, iodine, methyl, ethyl, or propyl each time it appears.

5. The compound, tautomer or stereoisomer of any one of claims 1-4, its pharmaceutically acceptable salt, its prodrug, its deuterated derivative, its hydrate, or its solvate, wherein, Z is C, and for ,or ; and / or Ring A is a C6-C10 aryl, a 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, a C5-C10 cycloalkenyl, or a 5-10 membered heterocyclic alkenyl containing 1-3 heteroatoms selected from N, O or S. Preferably, ring A is a C6-C10 aryl group, or a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O, or S; Preferably, ring A is phenyl, or contains a 5-6 membered heteroaryl group with 1-2 heteroatoms selected from N, O, or S; Preferably, ring A is selected from one or more of phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazole, pyrazolyl, thiophenyl, pyrroleyl, and furanyl; Preferably, ring A is selected from one or more of phenyl, pyridinyl, thiazolyl, isothiazolyl, oxazolyl, and isoxazolyl; More preferably, ring A is phenyl or pyridyl.

6. The compound, tautomer or stereoisomer of any one of claims 1-5, its pharmaceutically acceptable salt, its prodrug, its deuterated derivative, its hydrate, or its solvate, wherein, p is 1, 2, or 3; and / or R4, each time it appears, is independently C1-C10 alkoxy, C1-C10 haloalkoxy, halogen, C1-C10 alkyl, C1-C10 haloalkyl, C3-C10 cycloalkyl, C2-C10 alkenyl, C2-C10 alkynyl, 5-10 heteroaryl containing 1-3 heteroatoms selected from N, O, or S, C6-C10 aryl, C5-C10 cycloalkenyl, or 5-10 heterocyclic alkenyl containing 1-3 heteroatoms selected from N, O, or S; Preferably, R4, each time it appears, is independently a C1-C6 alkoxy, C1-C6 haloalkoxy, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, a 5-8 membered heteroaryl containing 1-3 heteroatoms selected from N, O, or S, a C6-C10 aryl, a C5-C8 cycloalkenyl, or a 5-8 membered heterocyclic alkenyl containing 1-3 heteroatoms selected from N, O, or S; Preferably, R4 is independently C1-C6 alkoxy, C1-C6 haloalkoxy, halogen, C1-C6 alkyl, C1-C6 haloalkyl, 5-8 membered heteroaryl containing 1-3 N atoms, phenyl, C5-C8 cycloalkenyl, or 5-8 membered heterocyclic alkenyl containing 1-3 N atoms each time it appears. Preferably, R4 is independently C1-C6 alkoxy, fluorine, chlorine, bromine, iodine, C1-C6 alkyl, 5-8 heteroaryl containing 1-3 N atoms, or phenyl each time it appears; Preferably, R4 is independently C1-C3 alkoxy, fluorine, chlorine, bromine, iodine, C1-C3 alkyl, 5-6 heteroaryl containing 1-3 N atoms, or phenyl each time it appears; Preferably, R4 is independently methoxy, ethoxy, propoxy, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, triazolyl, pyrazolyl, imidazolyl, pyrroleyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, or phenyl in each occurrence. Preferably, R4 is independently methoxy, ethoxy, propoxy, fluorine, chlorine, bromine, methyl, ethyl, propyl, triazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, or phenyl each time it appears; More preferably, R4 is independently methyl, ethyl, propyl, pyridyl, pyrazinyl, pyrimidinyl, or phenyl each time it appears; and / or The R4 is optionally substituted by one or more groups selected from the following: halogen, C1-C10 alkyl, C1-C10 haloalkyl; Preferably, R4 is optionally substituted with fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, halomethyl, haloethyl or halopropyl; More preferably, the R4 is optionally replaced by fluorine, chlorine, bromine or iodine.

7. The compound, tautomer or stereoisomer of any one of claims 1-6, its pharmaceutically acceptable salt, its prodrug, its deuterated derivative, its hydrate, or its solvate, wherein, p is 1, and R4 is a 5-6 membered heteroaryl or phenyl group containing 1-3 nitrogen atoms; or p is 2, one R4 is a C1-C3 alkoxy, fluorine, chlorine, bromine, iodine, or C1-C3 alkyl, and the other R4 is a 5-6 membered heteroaryl or phenyl containing 1-3 N atoms.

8. The compound, tautomer or stereoisomer of any one of claims 1-7, its pharmaceutically acceptable salt, its prodrug, its deuterated derivative, its hydrate, or its solvate, wherein, The compound is: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,or .

9. A pharmaceutical composition, wherein, The pharmaceutical composition comprises a benzoxazole compound of formula I as described in any one of claims 1-8, its tautomer or stereoisomer, its pharmaceutically acceptable salt, its prodrug, its deuterated derivative, its hydrate, or its solvate. Preferably, the pharmaceutical composition further comprises pharmaceutically acceptable excipients.

10. The use of a benzoxazole compound of Formula I as described in any one of claims 1-8, its tautomer or stereoisomer, its pharmaceutically acceptable salt, its prodrug, its deuterated derivative, its hydrate, or its solvate, or the pharmaceutical composition as described in claim 9, in the preparation of an orexin receptor antagonist or in the preparation of a medicament for treating diseases, conditions, or symptoms associated with abnormalities of the orexin signaling pathway; Preferably, the diseases, conditions, or symptoms associated with abnormal orexin signaling pathways are selected from: depression, anxiety disorders, bipolar disorder, mood disorders, drug addiction, alcohol dependence, gambling addiction, obsessive-compulsive disorder, schizophrenia, mental confusion, dementia, severe intellectual disability, motor disorders, Parkinson's disease, epilepsy, anorexia nervosa, bulimia nervosa, binge eating disorder, cachexia, obesity, pathological eating behavior, sexual dysfunction, sexual psychological disorders, gender anxiety disorder, obesity-related infertility, Kallmann syndrome, functional amenorrhea, Cushing's syndrome, pituitary adenoma, hyperprolactinemia, pituitary hypofunction, hypothalamic hypothyroidism, hypothalamic-adrenal dysfunction, sudden onset of hyperprolactinemia, hypothalamic-associated growth hormone deficiency, and diabetes. Impaired glucose tolerance, narcolepsy, insomnia, various forms of sleep disorders, jet lag, hyperalgesia, atypical pain, acute pain, chronic pain, arthritis pain, sports injury pain, migraine, atypical facial pain, back pain, visceral pain and pain related to infection or treatment, taste / appetite disorders, nausea, vomiting, hypertension, hypotension, angina pectoris, acute myocardial infarction, acute and chronic congestive heart failure, arrhythmia, asthma, urinary retention, overactive bladder, urge incontinence, inflammatory bowel disease, gastric dysfunction, gastric ulcer, benign prostatic hyperplasia, chronic kidney disease / renal failure, osteoporosis, allergic reactions, tolerance and withdrawal symptoms to narcotics / opioids, dementia-Parkinson-White syndrome.

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