Deuterated benzimidazole derivative as well as preparation method and application thereof

Abstract

The invention provides a benzimidazole deuterated derivative as shown in a formula (I) or a tautomer, a stereoisomer or pharmaceutically acceptable salt thereof as well as a preparation method and application of the benzimidazole deuterated derivative. The series of derivatives have good orexin receptor antagonistic activity and excellent pharmacokinetic properties.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to deuterated benzimidazole derivatives and preparation methods and uses thereof. Background Art

[0002] Sleep disorders are caused by a variety of factors (often related to physical diseases), and the normal rhythm of sleep and wakefulness is disturbed, resulting in abnormal sleep quality and quantity and abnormal behavior during sleep. The most common clinical manifestation of sleep disorders is insomnia, which includes many forms, such as difficulty falling asleep, early awakening, poor sleep maintenance, decreased sleep quality, and disordered sleep structure. It is one of the complex series of diseases in neurology. The characteristics of insomnia are that in the appropriate sleep opportunity and environment, it is still difficult to fall asleep and / or sleep maintenance is short; it is difficult to meet the amount of sleep time, which affects the subjective experience of work and social activities the next day. Insomnia has a chronic course, and nearly half of severe insomnia can last for more than 10 years, seriously damaging the patient's physical and mental health. According to statistics from the World Health Organization: 27% of adults in the world have sleep disorders, and about 3,000 people die every day due to sleep disorders. In China, the incidence of insomnia is as high as 38.2%. Insomnia has a great impact on the global economy, environment and human life safety, and sleep issues have attracted the attention of the international community.

[0003] The traditional clinical approach to insomnia is to use sedative hypnotic drugs for treatment, but the sleep induced by these drugs is different from normal sleep, and there are large differences in non-rapid eye movement, rapid eye movement, and dreams. Patients often cannot get enough rest and their fatigue during the day continues to increase. Moreover, these drugs are drugs that control the central nervous system and have been found to be associated with risks such as falls, cognitive impairment, and abnormal behavior at night. Long-term use may lead to tolerance and physiological dependence, and withdrawal symptoms may occur after stopping the drug.

[0004] Orexin, also known as hypocretin, is a type of hormone secreted by the hypothalamus. There are two types of orexin, orexin-A and orexin-B (or hypocretin-1 and hypocretin-2). Studies have shown that the content of orexin is directly related to human hunger and sleep. Activation of the orexin pathway often leads to active central nervous system in the human body and difficulty in falling asleep. Inhibition of this pathway is expected to induce more adequate and effective normal physiological sleep and significantly improve sleep quality. Therefore, dual orexin receptor antagonists are considered to be a new generation of insomnia drugs with great potential, and their research and development field has attracted much attention for many years.

[0005] The dual orexin receptor antagonists currently on the market include: Merck's Belsomra (suvorexant), Eisai's Dayvigo (Lemborexant) and Idorsia's QUVIVIQ (Daridorexant). Compared with traditional sedatives and hypnotics, although dual orexin receptor antagonists improve patients' sleep quality, they all have more serious next-day residual effects and depression. Among them, Belsomra and Dayvigo have caused the FDA to issue safety risk warnings due to the above-mentioned serious side effects. Daridorexant also has related safety risks.

[0006] In recent years, the number of insomnia patients has increased day by day, and there is a great demand for the research and development of new drugs with better efficacy and fewer side effects. The present invention is proposed to overcome the deficiencies in the prior art and meet the growing needs of patients. Summary of the invention

[0007] In the first aspect of the present invention, there is provided a compound represented by the following formula (I), its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, which has the following structure

[0008]

[0009] Among them, R1~R 22 are each independently hydrogen or deuterium, and R1 to R 22 At least one of the atoms is a deuterium atom; preferably 1-13 deuterium atoms, specifically 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 deuterium atoms; more preferably 2, 3, 5, 7, 8, 10, 11 or 13 deuterium atoms; further preferably 2, 3 or 5 deuterium atoms.

[0010] In some embodiments of the present invention, R1 to R2 have 0-2 deuteriums in total, specifically 0, 1 or 2 deuteriums.

[0011] In some embodiments of the present invention, R3 to R5 (such expression means R3, R4 and R5, and the rest of the expressions are similar) have a total of 0-3 deuteriums, specifically 0, 1, 2 or 3 deuteriums; preferably 1-3 deuteriums, specifically 1, 2 or 3 deuteriums; more preferably 0 or 3 deuteriums; more preferably 3 deuteriums.

[0012] In some embodiments of the present invention, R6 to R 11 A total of 0-6 deuteriums, specifically 0, 1, 2, 3, 4, 5 or 6 deuteriums; preferably 0-2 deuteriums; more preferably 0 or 2 deuteriums; more preferably 2 deuteriums.

[0013] In some embodiments of the present invention, R 12 ~R14 A total of 0-3 deuteriums, specifically 0, 1, 2 or 3 deuteriums; preferably 1-3 deuteriums, specifically 1, 2 or 3 deuteriums; more preferably 0 or 3 deuteriums; more preferably 3 deuteriums.

[0014] In some embodiments of the present invention, R 15 , R 19 , R 20 There are 0-3 deuteriums in total, specifically 0, 1, 2 or 3 deuteriums.

[0015] In some embodiments of the present invention, R 16 ~R 18 A total of 0-3 deuteriums, specifically 0, 1, 2 or 3 deuteriums; preferably 1-3 deuteriums, specifically 1, 2 or 3 deuteriums; more preferably 0 or 3 deuteriums; more preferably 3 deuteriums.

[0016] In some embodiments of the present invention, R 21 ~R 22 There are 0-2 deuteriums in total, specifically 0, 1 or 2 deuteriums; more preferably 0 or 2 deuteriums; more preferably 2 deuteriums.

[0017] In some embodiments of the present invention, R 16 ~R 18 There are 3 deuteriums and the other substituents are all hydrogen.

[0018] In some embodiments of the present invention, R 21 ~R 22 There are 2 deuteriums, and the other substituents are all hydrogen.

[0019] In some embodiments of the present invention, R 16 ~R 18 is 3 deuterium, R 21 ~R 22 There are 2 deuteriums, and the other substituents are all hydrogen.

[0020] In some embodiments of the present invention, R1-R2 are 2 deuteriums, and the other substituents are all hydrogen.

[0021] In some embodiments of the present invention, R3 to R5 are 3 deuteriums, and the other substituents are all hydrogen.

[0022] In some embodiments of the present invention, R1 to R5 are 5 deuteriums, and the other substituents are all hydrogen.

[0023] In some embodiments of the present invention, R 12 ~R 14 There are 3 deuteriums and the other substituents are all hydrogen.

[0024] In some embodiments of the present invention, R1 to R5 are 5 deuteriums, R12 ~R 14 There are 3 deuteriums and the other substituents are all hydrogen.

[0025] In some embodiments of the present invention, R1 to R5 are 5 deuteriums, R 16 ~R 18 There are 3 deuteriums and the other substituents are all hydrogen.

[0026] In some embodiments of the present invention, R1 to R5 are 5 deuteriums, R 21 ~R 22 There are 2 deuteriums, and the other substituents are all hydrogen.

[0027] In some embodiments of the present invention, R 12 ~R 14 is 3 deuterium, R 16 ~R 18 There are 3 deuteriums and the other substituents are all hydrogen.

[0028] In some embodiments of the present invention, R 12 ~R 14 is 3 deuterium, R 21 ~R 22 There are 2 deuteriums, and the other substituents are all hydrogen.

[0029] In some embodiments of the present invention, R1 to R5 are 5 deuteriums, R 12 ~R 14 is 3 deuterium, R 16 ~R 18 There are 3 deuteriums and the other substituents are all hydrogen.

[0030] In some embodiments of the present invention, R1 to R5 are 5 deuteriums, R 12 ~R 14 is 3 deuterium, R 21 ~R 22 There are 2 deuteriums, and the other substituents are all hydrogen.

[0031] In some embodiments of the present invention, R1 to R5 are 5 deuteriums, R 16 ~R 18 is 3 deuterium, R 21 ~R 22 There are 2 deuteriums, and the other substituents are all hydrogen.

[0032] In some embodiments of the present invention, R 12 ~R 14 is 3 deuterium, R 16 ~R 18 is 5 deuterium, R 21 ~R 22 There are 2 deuteriums, and the other substituents are all hydrogen.

[0033] In some embodiments of the present invention, R1 to R5 are 5 deuteriums, R 12 ~R 14 is 3 deuterium, R 16 ~R 18 is 3 deuterium, R 21 ~R 22 There are 2 deuteriums, and the other substituents are all hydrogen.

[0034] The following are example structures, including but not limited to compounds of the following structural formulas, their tautomers, stereoisomers, or pharmaceutically acceptable salts thereof:

[0035]

[0036]

[0037] In a second aspect, the present invention provides a pharmaceutical composition comprising a compound represented by formula (I), its tautomers, stereoisomers or pharmaceutically acceptable salts thereof, and optionally, a pharmaceutically acceptable carrier.

[0038] The third aspect of the present invention provides the use of the compound represented by formula (I), its tautomer, stereoisomer or pharmaceutically acceptable salt thereof or the pharmaceutical composition described in the second aspect of the present invention in the preparation of a drug having antagonistic activity against orexin receptors.

[0039] In some embodiments of the present invention, the compound represented by formula (I), its tautomer, stereoisomer or pharmaceutically acceptable salt or the pharmaceutical composition described in the second aspect of the present invention is used in the preparation of a drug for preventing, improving and / or treating diseases or conditions of neurological and psychiatric disorders related to orexin receptors.

[0040] In some embodiments of the present invention, the compound represented by formula (I), its tautomer, stereoisomer or pharmaceutically acceptable salt or the pharmaceutical composition described in the second aspect of the present invention is used in the preparation of a drug for preventing, improving and / or treating a disease or condition such as sleep disorder, anxiety, addiction, cognitive dysfunction, mood disorder or appetite disorder.

[0041] In some embodiments of the present invention, the compound represented by formula (I), its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition described in the second aspect of the present invention is used in the preparation of a medicament for preventing, improving and / or treating sleep disorders; preferably, the sleep disorder is selected from: abnormal sleep, parasomnia, sleep disorders associated with general medical conditions and substance-induced sleep disorders.

[0042] In some embodiments of the present invention, the compound represented by formula (I), its tautomer, stereoisomer or pharmaceutically acceptable salt or the pharmaceutical composition described in the second aspect of the present invention is used in the preparation of a drug for preventing, improving and / or treating insomnia.

[0043] In some embodiments of the present invention, the compound represented by formula (I), its tautomer, stereoisomer or pharmaceutically acceptable salt or the pharmaceutical composition described in the second aspect of the present invention is used in the preparation of a drug for preventing, improving and / or treating related diseases or conditions for which Daridorexant is applicable.

[0044] In a fourth aspect, the present invention provides a method for preventing, ameliorating and / or treating diseases or conditions of neurological and psychiatric disorders associated with orexin receptors, comprising administering to a patient a therapeutically effective dose of a compound of formula (I), its tautomers, stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition of the present invention; preferably, the diseases or conditions of neurological and psychiatric disorders associated with orexin receptors are selected from: sleep disorders, anxiety disorders, addiction disorders, cognitive dysfunction, mood disorders or appetite disorders, etc.

[0045] In some embodiments of the present invention, a method for preventing, improving and / or treating a disease or condition of sleep disorder is provided, comprising administering to a patient a therapeutically effective dose of a compound of formula (I), a tautomer, a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention; preferably, the sleep disorder is selected from: abnormal sleep, parasomnia, sleep disorder associated with a general medical condition, and substance-induced sleep disorder. In some embodiments of the present invention, a method for preventing, improving and / or treating insomnia is provided, comprising administering to a patient a therapeutically effective dose of a compound of formula (I), a tautomer, a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention.

[0046] The treatment of insomnia is to improve sleep quality; enhance sleep maintenance; increase rapid eye movement sleep; increase stage 2 sleep; reduce fragmentation of sleep patterns; treat insomnia; enhance cognition; increase memory; and treat or control depression.

[0047] In some embodiments of the present invention, the compound represented by formula (I) of the present invention or its tautomer, stereoisomer or pharmaceutically acceptable salt may be administered in combination with other related drugs.

[0048] In some embodiments of the present invention, the other related drug is an orexin receptor antagonist.

[0049] In a fifth aspect, the present invention provides a method for preparing a compound represented by formula (I), its tautomers, stereoisomers or pharmaceutically acceptable salts thereof, wherein the compound can be prepared by the following steps:

[0050]

[0051] Among them, R1~R 22 The definition of is as defined above for the compound of formula (I);

[0052] P is a protecting group for amino, selected from the group consisting of tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), trityl (Trt), p-methoxybenzyl (Pmb) and benzyl (Bn), etc.; preferably tert-butyloxycarbonyl (Boc);

[0053] Step 1: Compound (II) and compound (III) undergo condensation reaction to obtain compound (VII);

[0054] Step 2: Compound (VII) is subjected to a cyclization reaction to obtain compound (VIII);

[0055] Step 3: Compound (VIII) is subjected to a deprotection reaction to obtain compound (IX);

[0056] Step 4: Compound (IV) and compound (V) undergo substitution reaction and ester hydrolysis reaction to obtain compound (X);

[0057] Step 5: Compound (X) and compound (VI) undergo substitution reaction to obtain compound (XI);

[0058] Step 6: Compound (IX) and compound (XI) are subjected to condensation reaction to obtain target compound (I);

[0059] in:

[0060] The first step of the condensation reaction uses a single solvent or a mixed solvent with good solubility and stable properties, including but not limited to N, N-dimethylformamide, tetrahydrofuran, acetonitrile, acetone, butanone, dioxane, N, N-dimethylacetamide, dimethyl sulfoxide, ethyl acetate, dichloromethane, chloroform, 1,2-dichloroethane, methanol, ethanol, isopropanol, water, etc., or a mixture of several thereof; the selected condensing agent includes but is not limited to 1-hydroxybenzotriazole, dichloroethylene, etc. Sulfone, phosphorus oxychloride, 2-hydroxypyridine-N-oxide, dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, etc.; the acid binding agent selected for the reaction includes but is not limited to potassium carbonate, sodium carbonate, triethylamine, N,N-diisopropylethylamine, cesium carbonate, etc.; the reaction temperature ranges from 0°C to 60°C, preferably from 15°C to 35°C;

[0061] The second step is to react dehydration and cyclization under acidic conditions, and the acidic substances include but are not limited to p-toluenesulfonic acid or its hydrate, methanesulfonic acid, trifluoromethanesulfonic acid, hydrochloric acid, sulfuric acid, nitric acid, formic acid, acetic acid, propionic acid, trifluoroacetic acid, benzoic acid, phosphoric acid, etc.; the reaction temperature ranges from 10°C to 250°C, preferably 75°C to 125°C;

[0062] The third step is to remove the protecting group under catalytic conditions, the solvent is a single or mixed solvent, including but not limited to dichloromethane, dioxane, water, N,N-dimethylformamide, tetrahydrofuran, N,N-dimethylacetamide, dimethyl sulfoxide, ethyl acetate, acetonitrile, ethanol, methanol, isopropanol, acetone, butanone, etc., or a mixture of several thereof; the selected acid includes but is not limited to hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, periodic acid, hydrobromic acid, acetic acid, formic acid, etc.; the catalyst includes but is not limited to palladium carbon, tetrakis(triphenylphosphine)palladium, palladium hydroxide, nickel tetracarbonyl, tetrabutylammonium fluoride, triethylammonium formate, hydrazine, etc., and the reaction temperature ranges from 5°C to 80°C, preferably from 15°C to 45°C;

[0063] The fourth step is to carry out a substitution reaction under alkaline conditions, the solvent is a single or mixed solvent, including but not limited to one or more of dichloromethane, dioxane, N,N-dimethylformamide, tetrahydrofuran, N,N-dimethylacetamide, dimethyl sulfoxide, ethyl acetate, acetonitrile, acetone, butanone, etc.; the base selected includes but is not limited to potassium carbonate, sodium hydride, lithium hydroxide, sodium hydroxide, cesium carbonate, potassium hydroxide, sodium carbonate, etc.; the reaction temperature is 5°C to 100°C, preferably 25°C to 65°C; then, an ester hydrolysis reaction is carried out under alkaline conditions, the solvent is a single or mixed solvent, including but not limited to one or more of water, methanol, ethanol, isopropanol, N,N-dimethylformamide, tetrahydrofuran, acetonitrile, etc.; the base selected includes but is not limited to lithium hydroxide, sodium hydroxide, potassium carbonate, sodium hydride, cesium carbonate, potassium hydroxide, sodium carbonate, etc.; the reaction temperature is 5°C to 55°C, preferably 15°C to 45°C

[0064] The fifth step is to carry out a substitution reaction under alkaline conditions, wherein the solvent is a single solvent or a mixed solvent, including but not limited to one or a mixture of N,N-dimethylformamide, 1,4-dioxane, N,N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, butanone, etc.; the base selected includes but is not limited to cesium carbonate, potassium carbonate, sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, etc.; the catalyst selected includes but is not limited to copper iodide, copper and iron, etc.; the reaction temperature is 5°C to 125°C, preferably 50°C to 90°C;

[0065] The condensation reaction in the sixth step uses a single solvent or a mixed solvent with good solubility and stable properties, including but not limited to one or a mixture of dichloromethane, N,N-dimethylformamide, tetrahydrofuran, acetonitrile, acetone, butanone, dioxane, N,N-dimethylacetamide, dimethyl sulfoxide, ethyl acetate, chloroform, 1,2-dichloroethane, methanol, ethanol, isopropanol, water, etc.; the condensation agent selected includes but is not limited to 2-(7-azabenzotriazole )-N,N,N',N'-tetramethyluronium hexafluorophosphate, 1-hydroxybenzotriazole, dichlorothionyl, phosphorus oxychloride, 2-hydroxypyridine-N-oxide, dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, etc.; the acid binding agent selected for the reaction includes but is not limited to N,N-diisopropylethylamine, potassium carbonate, sodium carbonate, triethylamine, cesium carbonate, etc.; the reaction temperature is 0°C to 60°C, preferably 15°C to 35°C.

[0066] Preferably, compound (II) is the following compound A1, compound A2, compound A3 or compound E,

[0067]

[0068] Preferably, compound (III) is the following compound B, or compound F, wherein P is as defined in the present invention,

[0069]

[0070] Preferably, compound (V) is the following compound C or compound G,

[0071]

[0072] Preferably, compound (VI) may be the following compound D or compound H,

[0073]

[0074] In a sixth aspect, the present invention provides the intermediates shown below, their tautomers, stereoisomers or pharmaceutically acceptable salts thereof:

[0075]

[0076] in,

[0077] In the compound of formula (II), R1 to R5 are each independently hydrogen or deuterium, and at least one of R1 to R5 is deuterium, or

[0078] In the compound of formula (III), R6 to R 14 are each independently hydrogen or deuterium, and R6 to R 14 At least one of them is deuterium, and P is as defined in the present invention, or

[0079] In the compound of formula (X), R 15 ~R 20 are each independently hydrogen or deuterium, and R 15 ~R 20 At least one of them is deuterium, or

[0080] In the compound of formula (VI), R 21 ~R 22 are each independently hydrogen or deuterium, and R 21 ~R 22 At least one of them is deuterium, or

[0081] In the compound of formula (VII) or formula (VIII), R1 to R 14 are each independently hydrogen or deuterium, and R1 to R 14 At least one of them is deuterium, and P is as defined in the present invention, or

[0082] In the compound of formula (IX), R1 to R 14 are each independently hydrogen or deuterium, and R1 to R 14 At least one of them is deuterium, or

[0083] In the compound of formula (XI), R 15 ~R22 are each independently hydrogen or deuterium, and R 15 ~R 22 At least one of them is deuterium.

[0084] In some embodiments of the present invention, in the compound of formula (II), R1-R2 are 2 deuteriums, and the other substituents are hydrogen.

[0085] In some embodiments of the present invention, in the compound of formula (II), R3 to R5 are 3 deuteriums, and the other substituents are hydrogen.

[0086] In some embodiments of the present invention, in the compound of formula (II), R1 to R5 are 5 deuteriums.

[0087] In some embodiments of the present invention, in the compound of formula (III), R 12 ~R 14 There are 3 deuteriums and the other substituents are all hydrogen.

[0088] In some embodiments of the present invention, in the compound of formula (X), R 16 ~R 18 There are 3 deuteriums and the other substituents are all hydrogen.

[0089] In some embodiments of the present invention, in the compound of formula (VI), R 21 ~R 22 is 2 deuterium.

[0090] In some embodiments of the present invention, in the compound of formula (VII), formula (VIII) or formula (IX), R1 to R2 are 2 deuteriums, and the other substituents are hydrogen.

[0091] In some embodiments of the present invention, in the compound of formula (VII), formula (VIII) or formula (IX), R3 to R5 are 3 deuteriums, and the other substituents are hydrogen.

[0092] In some embodiments of the present invention, in the compound of formula (VII), formula (VIII) or formula (IX), R1 to R5 are 5 deuteriums, and the other substituents are hydrogen.

[0093] In some embodiments of the present invention, in the compounds of formula (VII), (VIII) or (IX), R 12 ~R 14 There are 3 deuteriums and the other substituents are all hydrogen.

[0094] In some embodiments of the present invention, in the compounds of formula (VII), (VIII) or (IX), R1 to R2 are 2 deuteriums, R 12 ~R 14 There are 3 deuteriums and the other substituents are all hydrogen.

[0095] In some embodiments of the present invention, in the compounds of formula (VII), (VIII) or (IX), R3 to R5 are 3 deuteriums, R 12 ~R 14 There are 3 deuteriums and the other substituents are all hydrogen.

[0096] In some embodiments of the present invention, in the compounds of formula (VII), (VIII) or (IX), R1 to R5 are 5 deuteriums, R 12 ~R 14 There are 3 deuteriums and the other substituents are all hydrogen.

[0097] In some embodiments of the present invention, in the compound of formula (XI), R 16 ~R 18 There are 3 deuteriums and the other substituents are all hydrogen.

[0098] In some embodiments of the present invention, in the compound of formula (XI), R 21 ~R 22 There are 2 deuteriums, and the other substituents are all hydrogen.

[0099] In some embodiments of the present invention, in the compound of formula (XI), R 16 ~R 18 is 3 deuterium, R 21 ~R 22 There are 2 deuteriums, and the other substituents are all hydrogen.

[0100] In some embodiments of the present invention, there is provided an intermediate as shown below, its tautomer, stereoisomer or a pharmaceutically acceptable salt thereof:

[0101]

[0102]

[0103] definition

[0104] Unless otherwise specified, D in the present invention represents deuterium ( 2 H).

[0105] Unless otherwise specified, the term "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" refers to salts that are suitable for contact with mammalian, especially human tissues without excessive toxicity, irritation, allergic reaction, etc. and commensurate with a reasonable benefit / risk ratio within the scope of reasonable medical judgment, such as amines, carboxylic acids and other types of medically acceptable salts of compounds are well known in the art. The salt can be prepared in situ during the final isolation and purification of the compounds of the present invention, or separately by reacting the free base or free acid with a suitable reagent. The pharmaceutically acceptable salt is preferably a hydrochloride.

[0106] Unless otherwise specified, pharmaceutically acceptable salts of the compounds of the present invention also include "solvates" thereof. The terms "solvate" and "solvate" mean a physical association of a salt of a compound of the present invention with one or more solvent molecules (whether organic or inorganic). The physical association includes hydrogen bonds. In some cases, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate will be able to be separated. The solvent molecules in the solvate may exist in a regular arrangement and / or a disordered arrangement. The solvate may contain stoichiometric or non-stoichiometric amounts of solvent molecules. "Solvate" encompasses solution phases and separable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

[0107] Unless otherwise specified, pharmaceutically acceptable salts of the compounds of the present invention also include "hydrates" thereof. The term "hydrate" refers to a substance formed in which water molecules are combined with cations or anions in the compound by coordination bonds or covalent bonds, or in which water ions are not directly combined with cations or anions but exist in a certain proportion at a certain position in the solid crystal lattice.

[0108] Unless otherwise specified, the compounds of the present invention also include "prodrugs" thereof, which refers to a drug that is converted into the parent drug in vivo. Prodrugs are generally useful and can improve some certain, undesirable physical or biological properties. Physical properties are generally related to solubility (too high or insufficient lipid or water solubility) or stability, while problematic biological properties include too rapid metabolism or poor bioavailability, which may themselves be related to physicochemical properties. For example, they can be bioavailable by oral administration, while the parent is not. Prodrugs also have improved solubility in pharmaceutical compositions compared to the parent drug. An example of a prodrug, but not limited to this, can be any compound of the present invention, which is administered as an ester ("prodrug") to facilitate transmission across cell membranes, where water solubility is detrimental to mobility, but once inside the cell, water solubility is beneficial, which is then metabolically hydrolyzed to the carboxylic acid, the active entity. Another example of a prodrug can be a short peptide (polyamino acid) bound to an acid group, where the peptide is metabolized to reveal the active moiety.

[0109] Unless otherwise specified, the compounds of the present invention also include their "solvates". The terms "solvate" and "solvate" mean the physical association of the compounds of the present invention with one or more solvent molecules (whether organic or inorganic). The physical association includes hydrogen bonds. In some cases, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate will be able to be separated. The solvent molecules in the solvate may exist in a regular arrangement and / or a disordered arrangement. The solvate may contain stoichiometric or non-stoichiometric solvent molecules. "Solvate" covers solution phases and separable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

[0110] Unless otherwise specified, the compounds of the present invention also include their "hydrates". The term "hydrate" refers to a substance formed by water molecules combining with cations or anions in the compound by coordination bonds or covalent bonds, or by water ions not directly combining with cations or anions but existing in a certain proportion at a certain position in the solid crystal lattice.

[0111] Unless otherwise specified, the term "stereoisomer" refers to compounds with the same chemical constitution but different arrangements of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis / trans) isomers, atropisomers, etc. Any resulting mixture of stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, for example, by chromatography and / or fractional crystallization based on the differences in the physical and chemical properties of the components.

[0112] Unless otherwise specified, the term "geometric isomer (cis / trans) isomer" may contain carbon-carbon double bonds or carbon-nitrogen double bonds in the E or Z configuration, wherein the term "E" represents higher order substituents on opposite sides of the carbon-carbon or carbon-nitrogen double bond, and the term "Z" represents higher order substituents on the same side of the carbon-carbon or carbon-nitrogen double bond (determined using the Cahn-Ingold Prelog priority rules). The compounds of the present invention may also exist as a mixture of "E" and "Z" isomers.

[0113] Unless otherwise specified, the term "tautomer" refers to structural isomers with different energies that can be interconverted through a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions by reorganization of some of the bonding electrons.

[0114] Unless otherwise indicated, the structural formulas described in the present invention include all isomeric forms (such as enantiomers, diastereomers, and geometric isomers (or conformational isomers)): for example, R, S configurations containing asymmetric centers, (Z), (E) isomers of double bonds, and (Z), (E) conformational isomers. Therefore, single stereochemical isomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers, or geometric isomers (or conformational isomers) are all within the scope of the present invention.

[0115] Unless otherwise specified, the term "treatment" encompasses any treatment of a disease, disorder or condition in a patient, including: (a) inhibiting the symptoms of the disease, disorder or condition, i.e., arresting its development; or (b) relieving the symptoms of the disease, disorder or condition, i.e., causing regression of the disease or symptoms; or (c) ameliorating or eliminating the disease, disorder or condition or one or more symptoms associated with the disease.

[0116] The therapeutically effective amount of the present invention refers to an effective dosage considered pharmaceutically, that is, the amount of the active compound is sufficient to significantly improve the condition without causing serious side effects.

[0117] The beneficial effects of the present invention are:

[0118] The present invention provides a benzimidazole deuterated derivative or its tautomer, stereoisomer or pharmaceutically acceptable salt and application thereof. The deuterated derivative has good orexin receptor antagonist activity and / or excellent pharmacokinetic properties. DETAILED DESCRIPTION

[0119] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples that do not specify specific conditions are usually performed under conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise defined, all professional and scientific terms used in the text have the same meanings as those familiar to professionals in the field. In addition, any method and material similar or equivalent to the described content can be applied to the method of the present invention. The preferred implementation methods and materials shown in the text are for demonstration purposes only.

[0120] The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS) and / or liquid chromatography (HPLC).

[0121] The starting materials in the examples of the present invention are known and can be purchased on the market, or can be synthesized by or according to methods known in the art.

[0122] Example 1: Preparation of (S)-(2-(5-chloro-4-methyl-1H-benzo[d]imidazol-2-yl)-2-methylpyrrolidin-1-yl)(5-(methoxy-d3)-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone (Compound TM-03)

[0123]

[0124] The compound TM-03 can be prepared by the following steps:

[0125] (1) Preparation of (S)-5-chloro-4-methyl-2-(2-methylpyrrolidin-2-yl)-1H-benzo[d]imidazole

[0126]

[0127] Compound E (2.29 g, 10 mmol, 1 eq) was dissolved in dichloromethane (20 ml), and compound F (1.56 g, 10 mmol), N,N-diisopropylethylamine (25 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (10 mmol) were added, and stirred at room temperature for 20 h. The solvent was evaporated under reduced pressure, and water (20 mL) was added to the concentrate, and then extracted with ethyl acetate (20 mL*3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered and concentrated.

[0128] The concentrate was dissolved in glacial acetic acid (15 g) without purification, heated to 110°C and stirred for 2 h. The reaction solution was concentrated, the residue was adjusted to pH 7-8 with aqueous sodium bicarbonate solution, and the phases were extracted with ethyl acetate (40 ml*3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered and concentrated.

[0129] The concentrate was dissolved in dioxane (5 ml) without purification, and a hydrogen chloride dioxane solution (4M, 5.2 ml) was added, stirred at room temperature for 4 h, and ether (10 ml) was added, crystallized at room temperature for 2 h, and filtered. The obtained solid was dissolved in water (10 mL), and the pH was adjusted to 7-8 with a saturated sodium bicarbonate aqueous solution. The phases were extracted with ethyl acetate (40 ml*3), the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain 2.27 g of the target compound. LC-MS (ESI) m / z: 249.96 [M+H] + .

[0130] 1H NMR (600MHz, DMSO-d6) δ10.328(s,1H),7.475(d,J=8.6Hz,1H),7.309(d,J=8.6Hz,1H),3.420-3.429(m,2H),2. 612(s,3H),2.560-2.610(m,1H),2.236-2.284(m,1H),2.095-2.145(m,1H),1.861-1.950(m,1H),1.851(s,3H).

[0131] (2) Preparation of 2-iodo-5-(methoxy-d3)benzoic acid

[0132]

[0133] Dissolve 5-hydroxy-2-iodobenzoic acid methyl ester (2.00 g, 7.19 mmol, 1 eq) in N,N-dimethylformamide (20 mL), add deuterated iodomethane (compound C, 21.5 mmol) and potassium carbonate (15.80 mmol), stir at room temperature for 20 hours, filter the reaction solution, concentrate to dryness, add water (50 mL), extract with ethyl acetate (30 mL*3), dry the organic phase with anhydrous magnesium sulfate, and concentrate. Dissolve the concentrate in methanol:tetrahydrofuran = 1:1 (20 mL), add lithium hydroxide aqueous solution (2M, 8 mL), continue to react at room temperature for 20 hours, concentrate the reaction solution, adjust the pH to 3-4 with hydrochloric acid, precipitate solid, and filter to obtain 1.8 g of the target compound. LC-MS (ESI) m / z: 280.01 [MH] - .

[0134] 1 H NMR (600MHz, DMSO-d6) δ 13.057 (s, 1H), 7.831 (d, J = 8.7Hz, 1H), 7.256 (d, J = 2.9Hz, 1H), 6.876 (dd, J = 8.7Hz, 2.9Hz, 1H).

[0135] (3) Preparation of 5-(methoxy-d3)-2-(2H-1,2,3-triazol-2-yl)benzoic acid

[0136]

[0137] Dissolve 2-iodo-5-(methoxy-d3)benzoic acid (1.80 g, 6.4 mmol, 1 eq) in N,N-dimethylformamide (25 mL), then add 1,2,3-2H-triazole (compound H, 12.8 mmol) and cesium carbonate (12.8 mmol). Heat to 40°C, add copper iodide (0.47 mmol), heat to 70°C and continue stirring for 1.5 hours. Evaporate the solvent under reduced pressure, add water (45 ml) and ethyl acetate (25 ml), adjust the pH to 3-4 with hydrochloric acid while stirring, filter, separate the phases, dry the organic phase with anhydrous magnesium sulfate, filter, and concentrate to obtain 1.1 g of the target compound. LC-MS (ESI) m / z: 222.96 [M+H] + .

[0138] 1 H NMR (600MHz, DMSO-d6) δ13.084 (s, 1H), 8.025 (s, 2H), 7.680 (d, J = 8.7Hz, 1H), 7.282 (d, J = 2.9Hz, 1H), 7.262 (dd, J = 8.7Hz, 2.9Hz, 1H).

[0139] (4) Preparation of (S)-(2-(5-chloro-4-methyl-1H-benzo[d]imidazol-2-yl)-2-methylpyrrolidin-1-yl)(5-(methoxy-d3)-2-(2H-1,2,3)triazol-2-yl)phenyl)methanone (Compound TM-03)

[0140]

[0141] (S)-5-chloro-4-methyl-2-(2-methylpyrrolidin-2-yl)-1H-benzo[d]imidazole (1.18 g, 4.74 mmol, 1 eq) was dissolved in dichloromethane (20 mL), and 5-(methoxy-d3)-2-(1,2,3-2H-triazol-2-yl)benzoic acid (4.74 mmol), N,N-diisopropylethylamine (14.24 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (4.74 mmol) were added in turn under ice-cooling, and stirred at room temperature for 20 hours. The solvent was evaporated under reduced pressure, and the concentrate was dissolved in ethyl acetate (20 mL) and washed with water (20 mL). The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated, and then purified by BUCHIPURE Flash rapid preparation (dichloromethane: methanol = 10: 1). The mixture was collected and concentrated to obtain 1.22 g of the target compound, LC-MS (ESI) m / z: 454.20 [M+H] + .

[0142] 1H NMR(600MHz, DMSO-d6)δ8.037(s,2H),7.778(d,J=8.9Hz,1H),7.234-7.390(m,2H),7.148-7.182(m,2H),3.613-3.645(m,1H),3 .305-3.320(m,1H),2.687(s,3H),2.501(s,3H),2.035-2.050(m,1H),1.952-1.969(m,1H),1.911-1.925(m,2H),1.866(s,3H).

[0143] Furthermore, the obtained compound can be prepared into the corresponding salt form, such as the hydrochloride preparation process is as follows:

[0144]

[0145] The TM-03 compound (1.00 g) was dissolved in 10 mL of isopropanol, and then a 4 M hydrogen chloride isopropanol solution (3 mL) was added. The mixture was stirred for 0.5 hours under ice bath to precipitate a solid, which was filtered to obtain 0.95 g of the hydrochloride salt of the TM-03 compound.

[0146] Example 2: Preparation of TM-04

[0147] Referring to the preparation method of Example 1, the deuterated compound TM-04 was prepared using the corresponding compound raw materials.

[0148]

[0149]

[0150] LC-MS (ESI) m / z::453.32 [M+H] +

[0151] 1 H NMR(600MHz,DMSO-d6)δ7.780(d,J=8.9Hz,1H),7.234-7.402(m,2H),7.149-7.182(m,2H),3.894(s,3H),3.610-3.642(m,1H),3 .307-3.322(m,1H),2.689(s,3H),2.501(s,3H),2.032-2.047(m,1H),1.962-1.970(m,1H),1.911-1.924(m,2H),1.868(s,3H).

[0152] Among them, the preparation of 2H-1,2,3-triazole-4,5-d2 (compound D) is as follows:

[0153]

[0154] 4,5-Dibromo-2H-1,2,3-triazole (2.00 g, 8.81 mmol) was dissolved in deuterated methanol-d4 (10 mL), palladium carbon (Pd / C, 10%, 0.10 g) and anhydrous potassium carbonate (4.00 g, 28.94 mmol) were added, nitrogen was replaced 3 times, and then deuterium was replaced 3 times. The reaction was stirred at room temperature under deuterium environment for 4 hours, and the reaction was stopped. After nitrogen replacement, the reaction solution was filtered, and the filter cake was washed with a small amount of methanol. The organic phases were combined and concentrated to obtain compound D (0.55 g), LC-MS (ESI) m / z: 72.04 [M+H] + .

[0155] Example 3: Preparation of TM-10

[0156] Referring to the preparation method of Example 1, the deuterated compound TM-10 was prepared using the corresponding compound raw materials.

[0157]

[0158] LC-MS (ESI) m / z: 456.29 [M+H] +

[0159] 1 H NMR(600MHz,DMSO-d6)δ7.779(d,J=8.9Hz,1H),7.232-7.403(m,2H),7.149-7.183(m,2H),3.612-3.645(m,1H),3.309-3 .326(m,1H),2.689(s,3H),2.501(s,3H),2.033-2.047(m,1H),1.962-1.971(m,1H),1.912-1.925(m,2H),1.866(s,3H).

[0160] Referring to the preparation method of Example 1, the following deuterated compounds were prepared using the corresponding compound raw materials:

[0161]

[0162]

[0163] Biological test evaluation

[0164] The present invention is further described and explained below in conjunction with test examples, but these embodiments are not intended to limit the scope of the present invention.

[0165] Experimental Example 1: Sleep experiment in mice

[0166] 1. Purpose:

[0167] The efficacy of the compounds of the present invention was evaluated in mice.

[0168] 2. Reagents and experimental animals:

[0169] Reagents: dimethyl sulfoxide (DMSO), 2-hydroxypropyl-β-cyclodextrin (HP-β-CD).

[0170] Experimental animals: CD-1 (ICR) mice.

[0171] 3. Animal in vivo sleep experiment method

[0172] (1) Preparation of drug solution:

[0173] 5% DMSO + 30% 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) aqueous solution;

[0174] (2) Dosage regimen:

[0175] Healthy mice (3 animals per group); housed under a 12-h light 12-h dark cycle (LD 12:12) at least 12 h before surgery. All mice were maintained on LD 12:12 throughout the experiment with free access to food and water.

[0176] Electrodes were implanted in mice through surgery, and EEG (electroencephalography) and EMG (electromyography) activities were recorded, and polysomnography was used to quantify sleep determination. Three blank groups were not given medication, and three medication groups were orally administered before turning off the lights at ZT12:00 (zeitgeber time), and the recording of EEG / EMG data was from ZT 12:00 to ZT 20:00. EEG / EMG activity results were recorded by software, and then experienced and treatment-unaware sleep researchers were confirmed by vision to determine wakefulness and sleep. Data represent the alert state time per hour (for time course) or 3 hours (for cumulative analysis) after turning off the lights.

[0177] The results showed that the compounds of the present invention could reduce the wakefulness time of mice.

[0178] Test Example 2: Pharmacokinetics in rats

[0179] 1. Purpose:

[0180] The metabolic stability of the compounds of the present invention and daridorexant in rats was investigated, and the in vivo pharmacokinetics of the exposure after intravenous and oral administration were evaluated.

[0181] 2. Reagents and experimental animals:

[0182] Reagents: dimethyl sulfoxide (DMSO), 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), methylcellulose (MC).

[0183] Experimental animals: Wistar Han rats, male.

[0184] 3. Comparative experimental method of pharmacokinetics in rats

[0185] 1) Drug preparation

[0186] The compound of the present invention and daridorexant stock solutions were prepared in the following manner.

[0187] Intravenous administration: 5% DMSO + 30% 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) aqueous solution, concentration 0.20 mg / mL;

[0188] Oral administration: 0.5% methylcellulose (MC) suspension, concentration 0.30 mg / mL.

[0189] 2) Dosage regimen, blood sample processing and testing

[0190] Healthy adult Wistar Han rats (3 animals per group); after fasting overnight (free access to water), 1.0 mg / kg was injected into the tail vein (iv) and administered by gavage (po.); 0.2 ml of blood was collected from the jugular vein in the iv group at 5 min, 15 min, 0.5 h, 1 h, 2 h, 4 h, 8 h, 12 h, and 24 h after administration, and the blood samples were placed in wet ice after collection, and plasma was separated within 1 h (4 ° C, 3500g, 5 min centrifugation). The plasma was placed in a labeled 1.5 mL EP tube and stored in a -80 ° C ultra-low temperature refrigerator for testing. 0.2 ml of blood was collected from the jugular vein in the po. group before administration and 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, and 24 h after administration, and the treatment method was the same as the intravenous injection group. An LC / MS / MS method was established to determine the concentration of the unchanged drug in plasma, and the plasma concentration-time curve was drawn. The main pharmacokinetic parameters were calculated using WinNonlin7.2 software.

[0191] 4. Pharmacokinetic parameters after oral administration in rats:

[0192]

[0193]

[0194] The experimental results show that the compounds of the present invention have good in vivo pharmacokinetics after oral administration. Compared with daridorexant, the pharmacokinetic parameters of TM-03 and TM-04 are better than daridorexant, especially TM-04, the maximum blood drug concentration and exposure are increased by nearly 150%, and the bioavailability is increased by 128%.

[0195] Experimental Example 3: Cell function experiment

[0196] 1. Purpose:

[0197] The inhibitory ability of the compounds of the present invention on human orexin type I receptor (Orexin receptor 1; OX1R) and orexin type II receptor (Orexin receptor 2; OX2R) was evaluated.

[0198] 2. Instruments:

[0199] Instruments: 384-well cell culture plate (Corning: 3764); plate reader FLIPR Penta.

[0200] 3. Cell culture and reagent preparation

[0201] Cell line: Flp-In-CHO-OX1 / OX2 stable pool

[0202] Complete medium: Ham's F-12K + 10% FBS + 1x Penicillin-Streptomycin (PS) + 600μg / ml Hygromycin B

[0203] Cell seeding medium: Ham's F-12K + 10% FBS

[0204] Assay buffer: 1X HBSS + 20mM HEPES

[0205] 4. Determination of the inhibitory activity of compounds on orexin receptors

[0206] 1) Flp-In-CHO-OX1 / OX2 stable pool cell lines were cultured in complete medium at 37°C, 5% CO 2 To 70% to 90% fusion degree.

[0207] 2) After TrypLE digestion, the cells were resuspended in inoculation medium and inoculated in a 384-well cell culture plate (Corning, 3764), with 7,000 cells per well, at 37°C and 5% CO 2 Incubate overnight.

[0208] 3) Freeze-thaw 2X Component A to room temperature, dilute it with assay buffer to a 2X working concentration containing 5 mM Robenecid, and place at room temperature for use.

[0209] 4) Take out the cell culture plate, invert and centrifuge to remove the culture medium, immediately add 20 μL of experimental buffer, and then add 20 μL of 2X Component A containing 5 mM Probenecid to each experimental well, centrifuge at room temperature (200g) for 3-5 seconds, and incubate at 37°C for 2 hours.

[0210] 5) Prepare the positive control compound and the test compound working solution (5X).

[0211] 6) Use FLIPR Penta to add 10 μL of the working solution prepared in step 5) to each experimental well and collect data.

[0212] 5. Experimental results

[0213] The Kb value of the compound was calculated using the GraphPad nonlinear fitting formula:

[0214]

[0215] Note: Compound Kb value: 5nM<A≤10nM.

[0216] The experimental results show that compared with daridorexant, the compounds of the present invention have comparable inhibitory abilities on human OX1R and OX2R.

Claims

1. A compound represented by the following formula (I), its tautomer, stereoisomer or a pharmaceutically acceptable salt thereof, which has the following structure: in, R1~R 22 are each independently hydrogen or deuterium, and R1 to R 22 1-13 deuteriums, specifically 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 deuteriums; preferably 2, 3, 5, 7, 8, 10, 11 or 13 deuteriums; more preferably 2, 3 or 5 deuteriums.

2. The compound according to claim 1, its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, characterized in that: R1-R2 have 0-2 deuteriums in total, specifically 0, 1 or 2 deuteriums; or R3 to R5 have 0-3 deuteriums in total, specifically 0, 1, 2 or 3 deuteriums; preferably 1-3 deuteriums, specifically 1, 2 or 3 deuteriums; more preferably 0 or 3 deuteriums; more preferably 3 deuteriums; or R6~R 11 has a total of 0-6 deuteriums, specifically 0, 1, 2, 3, 4, 5 or 6 deuteriums; preferably 0-2 deuteriums; more preferably 0 or 2 deuteriums; more preferably 2 deuteriums; or R 12 ~R 14 A total of 0-3 deuteriums, in particular 0, 1, 2 or 3 deuteriums; preferably 1-3 deuteriums, in particular 1, 2 or 3 deuteriums; more preferably 0 or 3 deuteriums; more preferably 3 deuteriums; or R 15 , R 19 , R 20 has 0-3 deuteriums in total, specifically 0, 1, 2 or 3 deuteriums; or R 16 ~R 18 A total of 0-3 deuteriums, in particular 0, 1, 2 or 3 deuteriums; preferably 1-3 deuteriums, in particular 1, 2 or 3 deuteriums; more preferably 0 or 3 deuteriums; more preferably 3 deuteriums; or R 21 ~R 22 There are 0-2 deuteriums in total, specifically 0, 1 or 2 deuteriums; more preferably 0 or 2 deuteriums; more preferably 2 deuteriums.

3. The compound represented by the following structural formula, its tautomer, stereoisomer or pharmaceutically acceptable salt thereof:

4. The compound of formula (I) according to any one of claims 1 to 3, its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, characterized in that: The pharmaceutically acceptable salt is hydrochloride.

5. A pharmaceutical composition comprising a compound of formula (I) as described in any one of claims 1 to 4, its tautomer, stereoisomer or a pharmaceutically acceptable salt thereof, and optionally, further comprising a pharmaceutically acceptable carrier.

6. Use of the compound of formula (I) according to any one of claims 1 to 4, its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 5 in the preparation of a medicament having antagonistic activity against orexin receptors; preferably, the medicament is used for preventing, improving and / or treating diseases or conditions of neurological and psychiatric disorders associated with orexin receptors; Further preferably, the drug is used to prevent, improve and / or treat diseases or conditions such as sleep disorders, anxiety disorders, addiction disorders, cognitive dysfunction, mood disorders or appetite disorders; More preferably, the drug is used to prevent, improve and / or treat sleep disorders; More preferably, the medicament is used for preventing, improving and / or treating insomnia.

7. The intermediates shown below, their tautomers, stereoisomers or pharmaceutically acceptable salts thereof: in, In the compound of formula (II), R1 to R5 are each independently hydrogen or deuterium, and at least one of R1 to R5 is deuterium, or In the compound of formula (III), R6 to R 14 are each independently hydrogen or deuterium, and R6 to R 14 At least one of them is deuterium, P is a protecting group of amino selected from the group consisting of tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), trityl (Trt), p-methoxybenzyl (Pmb) and benzyl (Bn); preferably tert-butyloxycarbonyl (Boc), or In the compound of formula (X), R 15 ~R 20 are each independently hydrogen or deuterium, and R 15 ~R 20 At least one of them is deuterium, or In the compound of formula (VI), R 21 ~R 22 are each independently hydrogen or deuterium, and R 21 ~R 22 At least one of them is deuterium, or In the compound of formula (VII) or formula (VIII), R1 to R 14 are each independently hydrogen or deuterium, and R1 to R 14 At least one of them is deuterium, P is a protecting group of amino selected from the group consisting of tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), trityl (Trt), p-methoxybenzyl (Pmb) and benzyl (Bn); preferably tert-butyloxycarbonyl (Boc), or In the compound of formula (IX), R1 to R 14 are each independently hydrogen or deuterium, and R1 to R 14 At least one of them is a deuterium atom, or In the compound of formula (XI), R 15 ~R 22 are each independently hydrogen or deuterium, and R 15 ~R 22 At least one of them is deuterium.

8. The intermediates shown below, their tautomers, stereoisomers or pharmaceutically acceptable salts thereof:

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