Benzimidazole derivative and use thereof

Abstract

The present invention provides a benzimidazole derivative as shown in formula (I) or a tautomer, a stereoisomer, a deuterated compound or a pharmaceutically acceptable salt thereof, and a use thereof. The derivative has physical properties more conducive to drug development (such as higher solubility) and more excellent pharmacokinetic properties.

Description

Benzimidazole derivatives and their uses

[0001] This application claims priority to two earlier applications filed with the China National Intellectual Property Administration (CNIPA) on July 8, 2024, patent application number 202410904973.1, and on June 24, 2025, patent application number 202510855132.0, both entitled "Benzimazole Derivatives and Uses Thereof". The full text of both applications is incorporated herein by reference. Technical Field

[0002] This invention relates to the field of pharmaceutical technology, and more specifically, to benzimidazole derivatives and their uses. Background Technology

[0003] Sleep disorders are caused by a variety of factors (often related to physical illness), disrupting the normal rhythmic alternation of sleep and wakefulness, resulting in abnormalities in the quality and quantity of sleep, as well as abnormal behaviors during sleep. The most common clinical manifestation of sleep disorders is insomnia, which includes various 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 neurological diseases. Insomnia is characterized by difficulty falling asleep and / or short-lived sleep despite adequate sleep opportunities and environments; difficulty meeting sleep duration requirements, affecting subjective experience in work and social activities the next day. Insomnia has a chronic course; nearly half of severe insomnia cases can last for more than 10 years, seriously damaging the patient's physical and mental health. According to the World Health Organization, 27% of adults worldwide suffer from sleep disorders, and approximately 3,000 people die from sleep disorders every day. In China, the incidence of insomnia is as high as 38.2%. Insomnia has a significant impact on the global economy, environment, and human life, and the issue has attracted international attention.

[0004] Traditional clinical treatment for insomnia involves the use of sedative-hypnotic drugs. However, the sleep induced by these drugs differs from normal sleep, exhibiting significant differences in the non-rapid eye movement (NREM) sleep phase, rapid eye movement (REM) sleep phase, and dream state. Patients often fail to get sufficient rest, and daytime fatigue continues to worsen. Furthermore, these drugs are central nervous system regulators and have been linked to risks such as falls, cognitive impairment, and abnormal nighttime behavior. Long-term use may also lead to tolerance and physiological dependence, resulting in withdrawal symptoms upon discontinuation.

[0005] Orexin, also known as hypothalamic secretin, is a hormone secreted by the hypothalamus. There are two types: orexin-A and orexin-B (or hypothalamic secretin-1 and hypothalamic secretin-2). Studies have shown that orexin levels are directly related to hunger and sleep. Activation of the orexin pathway often leads to increased central nervous system activity and difficulty falling asleep. Inhibition of this pathway is expected to induce more complete and effective normal physiological sleep, significantly improving sleep quality. Therefore, dual orexin receptor antagonists are considered a promising next-generation drug for insomnia, and their development has received considerable attention for many years.

[0006] Currently available dual orexin receptor blockers include: Merck's Belsomra (suvorexant), Eisai's Dayvigo (Lemborexant), and Idorsia's QUVIVIQ (Daridorexant). Compared to traditional sedative-hypnotic drugs, dual orexin receptor blockers improve patients' sleep quality, but all have significant daytime residual effects and depressive effects. Belsomra and Dayvigo, in particular, have received safety risk warnings from the FDA due to these serious side effects. Daridorexant also presents related safety risks.

[0007] In recent years, the number of patients with insomnia has been increasing, and there is a great demand for the research and development of new drugs with better efficacy and fewer side effects. This invention is proposed to overcome the shortcomings of existing technologies and meet the growing needs of patients. Summary of the Invention

[0008] The purpose of this invention is to provide a compound having a benzimidazole structure and its use in treating sleep disorders, especially insomnia.

[0009] In a first aspect, the present invention provides a compound of formula (I), its tautomers, stereoisomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, having the following structure:

[0010] R1 to R5 are each independently hydrogen, deuterium, and halogen;

[0011] R is selected from

[0012] L represents the key, -C 1-3 alkylene-, -C 1-3 Alkylene -O(CO)O-, -C 1-3 Alkylene -O-, -C 1-3 Alkylene-(CO)-, -C 1-3 Alkylene -O(CO)-, -C1-3 Alkylene -(CO)O-, -C 1-3 Alkylene-O(CO)OC 1-3 alkylene-, -C 1-3 Alkylene-OC 1-3 alkylene-, -C 1-3 Alkylene-(CO)-C 1-3 alkylene-, -C 1-3 Alkylene-O(CO)-C 1-3 alkylene-, -C 1-3 Alkylene-(CO)OC 1-3 alkylene-; the C 1-3 Alkylenes are optionally divided by 1 to 2 identical or different deuteriums, C 1-3 Alkyl, hydroxyl, halogen, amino, cyano, mercapto, C 1-3 Alkyloxy group, halogenated C 1-3 Alkyl, C 1-3 Alkylamino substituents;

[0013] R6 is selected from R7,

[0014] R7 is selected from C 1-6 Alkyl, C 3-8 Carbocyclic groups, 3-8 membered heterocyclic groups, -C 1-3 Alkylene-C 3-8 carbonyl group, C 6-10 Aromatic ring group, 5-10 membered heteroaryl group, wherein the heterocyclic group contains 1-3 N, O, C (=O), S or S (=O) heteroatoms or heteroatom groups; the C 1-6 Alkyl, C 3-8 Carbocyclic group, 3-8 membered heterocyclic group, C 6-10 The aryl ring group and the 5-10 membered heteroaryl group are optionally surrounded by 1-6 (e.g., 1, 2, 3, 4, 5, or 6) identical or different deuterium, cyano, amino, hydroxyl, mercapto, C group. 1-6 Alkyl, halogen, C 1-6 Alkyloxy group, halogenated C 1-6 Alkyl, C 1-6 Alkylamino substitution;

[0015] R8 and R9 are each independently selected from hydrogen, Na, K, and Ca (Ca 1 / 2 C 1-6 Alkyl groups, or R8 and R9, together with the atoms they are attached to, form 4-8 membered heterocycles.

[0016] In some embodiments of the present invention, R1 to R5 have a total of 0, 2, 3 or 5 deuterium atoms.

[0017] In some embodiments of the present invention, R1 to R3 have a total of 0 or 3 deuterium atoms.

[0018] In some embodiments of the present invention, R4 to R5 have a total of 0 or 2 deuterium atoms.

[0019] In some embodiments of the present invention, R1 to R5 have a total of 0 or 5 deuterium atoms.

[0020] In some embodiments of the present invention, R1 to R5 have a total of 2 deuterium atoms, wherein R1 to R3 are H atoms and R4 to R5 are deuterium atoms.

[0021] In some embodiments of the present invention, R1 to R5 have a total of 3 deuterium atoms, wherein R1 to R3 are deuterium atoms and R4 to R5 are hydrogen atoms.

[0022] In some embodiments of the present invention, R1 to R5 have a total of 5 deuterium atoms, wherein R1 to R5 are all deuterium atoms.

[0023] In some embodiments of the present invention, R1 to R5 have a total of 0 deuterium atoms, wherein R1 to R5 are all H atoms.

[0024] In some embodiments of the present invention, R4 to R5 are each independently selected from hydrogen or halogens, wherein the halogens are selected from F, Cl or Br, preferably Br.

[0025] In some embodiments of the present invention, R4 to R5 are all Br.

[0026] In some embodiments of the present invention, L is selected from: bond, -CH2-, -CH2-O(CO)O-, -CH2-O-, CH2-(CO)-, -CH2-O(CO)-, -CH2-(CO)O-, -CH2-O(CO)O-CH2-, -CH2-O-CH2-, -CH2-(CO)-CH2-, -CH2-O(CO)-CH2-, -CH2-(CO)O-CH2-; wherein -CH2- is optionally replaced by 1 to 2 identical or different deuterium, methyl, hydroxyl, halogen, amino, cyano, mercapto, methoxy, halomethyl, methylamino.

[0027] In some embodiments of the present invention, L is selected from: -CH2-, -CH2-O(CO)O-, -CH2-O(CO)-, -CH2-O(CO)O-CH2-.

[0028] In some embodiments of the present invention, R7 is selected from C. 1-5 Alkyl, C 3-6 Carbocyclic group, 3-6 membered heterocyclic group, C 6-10Aromatic ring group, 5-10 membered heteroaryl group, wherein the heterocyclic group contains 1-3 N, O, C (=O), S or S (=O) heteroatoms or heteroatom groups; the C 1-5 Alkyl, C 3- 6-carbon cyclic group, 3-6 membered heterocyclic group, C 6-10 The aryl ring group and the 5-10 membered heteroaryl group are optionally surrounded by 1-6 (e.g., 1, 2, 3, 4, 5, or 6) identical or different deuterium, cyano, amino, hydroxyl, C group. 1-4 Alkyl, halogen, C 1-4 Alkyloxy group, halogenated C 1-4 Alkyl or C 1-4 Alkylamino substitution.

[0029] In some embodiments of the present invention, R7 is selected from C. 1-4 Alkyl, C 3-6 Carbocyclic group, 3-6 membered heterocyclic group, C 6-10 Aromatic ring group, 5-10 membered heteroaryl group, wherein the heterocyclic group contains 1-3 N, O, C (=O), S or S (=O) heteroatoms or heteroatom groups; the C 1-4 Alkyl, C 3- 6-carbon cyclic group, 3-6 membered heterocyclic group, C 6-10 The aryl ring group and the 5-10 membered heteroaryl group are optionally surrounded by 1-6 (e.g., 1, 2, 3, 4, 5, or 6) identical or different deuterium, cyano, amino, hydroxyl, C group. 1-4 Alkyl, halogen, C 1-4 Alkyloxy group, halogenated C 1-4 Alkyl or C 1-4 Alkylamino substitution.

[0030] In some embodiments of the present invention, R7 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclopropyl, aziridinepropyl, thiohexylpropyl, oxacyclobutyl, aziridine, thiohexyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydrothiophenyl, piperidinyl, tetrahydrothioranyl, dioxanecycloyl, piperazinyl, hexahydropyrazinyl, morpholinyl, dithiaalkyl, tetramethylpiperidinyl, etc.

[0031] In some embodiments of the present invention, R7 is selected from...

[0032] In some embodiments of the present invention, R7 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0033] In some embodiments of the present invention, R7 is selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclopentyl, ...

[0034] In some embodiments of the present invention Selected from:

[0035] In some embodiments of the present invention, R6 is selected from R7, which is as defined in the present invention.

[0036] In some embodiments of the present invention, R6 is selected from... R8 and R9 are as defined in this invention.

[0037] In some embodiments of the present invention, R is selected from:

[0038] In some embodiments of the present invention, R is selected from:

[0039] In some embodiments of the present invention, R is selected from...

[0040] In some embodiments of the present invention, R is selected from...

[0041] In some embodiments of the present invention, the pharmaceutically acceptable salts of the compounds represented by formula (I) include, but are not limited to, their alkali metal salts or alkaline earth metal salts, such as those selected from their sodium salts, potassium salts, calcium salts, and preferably sodium salts.

[0042] The following are examples of structures, including but not limited to compounds with the following structural formulas, their tautomers, stereoisomers, deuterated derivatives, or pharmaceutically acceptable salts thereof:

[0043] In a second aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I), its tautomers, stereoisomers, deuterated derivatives or pharmaceutically acceptable salts thereof, optionally further comprising a pharmaceutically acceptable carrier.

[0044] In a third aspect, the present invention provides the use of the compound of formula (I), its tautomers, stereoisomers, deuterated derivatives or pharmaceutically acceptable salts thereof, or the pharmaceutical composition of the second aspect of the present invention in the preparation of a medicament having antagonistic activity against orexin receptors.

[0045] In some embodiments of the present invention, the use of the compound of formula (I), its tautomers, stereoisomers, deuterated derivatives or pharmaceutically acceptable salts thereof, or the pharmaceutical composition described in the second aspect of the present invention in the preparation of a medicament for the prevention, improvement and / or treatment of diseases or conditions of neurological and mental disorders related to orexin receptors.

[0046] In some embodiments of the present invention, the use of the compound of formula (I), its tautomers, stereoisomers, deuterated derivatives or pharmaceutically acceptable salts thereof, or the pharmaceutical composition described in the second aspect of the present invention in the preparation of a medicament for the prevention, improvement and / or treatment of diseases or conditions such as sleep disorders, sunset syndrome, Alzheimer's disease, anxiety disorders, addiction, depression, cognitive impairment, mood disorders, neuropathic pain, headache, and appetite disorders.

[0047] In some embodiments of the present invention, the use of the compound represented by formula (I), its tautomers, stereoisomers, deuterated derivatives or pharmaceutically acceptable salts thereof, or the pharmaceutical composition described in the second aspect of the present invention in the preparation of a medicament for the prevention, improvement and / or treatment of sleep disorders; preferably, the sleep disorder is selected from: sleep abnormalities, narcolepsy, sleep disorders related to general medical conditions and substance-induced sleep disorders.

[0048] In some embodiments of the present invention, the use of the compound of formula (I), its tautomers, stereoisomers, deuterated derivatives or pharmaceutically acceptable salts thereof, or the pharmaceutical composition described in the second aspect of the present invention in the preparation of a medicament for the prevention, improvement and / or treatment of insomnia.

[0049] In some embodiments of the present invention, the use of the compound of formula (I), its tautomers, stereoisomers, deuterated derivatives or pharmaceutically acceptable salts thereof, or the pharmaceutical composition described in the second aspect of the present invention in the preparation of a medicament for the prevention, improvement and / or treatment of relevant diseases or conditions to which Daridorexant is applicable.

[0050] In a fourth aspect, the present invention provides a method for preventing, improving, and / or treating diseases or conditions of neurological and mental disorders related to orexin receptors, comprising administering to a patient a therapeutically effective dose of a compound of formula (I), its tautomers, stereoisomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, or the pharmaceutical composition described herein; preferably, the diseases or conditions of neurological and mental disorders related to orexin receptors are selected from: sleep disorders, sunset syndrome, Alzheimer's disease, anxiety disorders, addiction, depression, cognitive impairment, mood disorders, neuropathic pain, headache, appetite disorders, etc.

[0051] In some embodiments of the present invention, a method is provided for preventing, improving and / or treating a disease or condition of sleep disorder, comprising administering to a patient a therapeutically effective dose of a compound of formula (I), its tautomers, stereoisomers, deuterated derivatives or pharmaceutically acceptable salts thereof, or the pharmaceutical composition of the present invention; preferably, the sleep disorder is selected from: sleep abnormalities, narcolepsy, sleep disorders associated with general medical conditions and substance-induced sleep disorders.

[0052] 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), its tautomers, stereoisomers, deuterated derivatives or pharmaceutically acceptable salts thereof, or the pharmaceutical composition of the present invention.

[0053] The treatment for insomnia includes improving sleep quality; enhancing sleep maintenance; increasing REM sleep; increasing stage 2 sleep; reducing sleep pattern fragmentation; treating insomnia; enhancing cognition; increasing memory; and treating or controlling depression.

[0054] In some embodiments of the present invention, a method is provided for preventing, improving and / or treating diseases or conditions to which Daridorexant is applicable, comprising administering to a patient a therapeutically effective dose of a compound of formula (I), its tautomers, stereoisomers, deuterated derivatives or pharmaceutically acceptable salts thereof, or the pharmaceutical composition of the present invention.

[0055] In some embodiments of the present invention, the compound represented by formula (I) of the present invention or its tautomers, stereoisomers, deuterated derivatives or pharmaceutically acceptable salts thereof, or the pharmaceutical composition described in the present invention, may be administered in combination with other related drugs or treatments.

[0056] In some embodiments of the present invention, the other related drugs are orexin receptor antagonists.

[0057] definition

[0058] Unless otherwise specified, D in this invention represents deuterium (2 H).

[0059] Unless otherwise specified, the terms "pharmaceutically acceptable salt" or "medicinal salt" refer to a salt that, within reasonable medical judgment, is suitable for contact with mammalian, particularly human, tissues without excessive toxicity, irritation, allergic reactions, etc., and is proportionate to a reasonable benefit / risk ratio. Medically acceptable salts of amines, carboxylic acids, and other types of compounds are well known in the art. The salts can be prepared in situ during the final isolation and purification of the compounds of this invention, or solely by reacting a free base or free acid with a suitable reagent.

[0060] Unless otherwise specified, pharmaceutically acceptable salts of the compounds of this invention also include their “solvates,” the terms “solvate” and “solvent compound” referring to the physical association of the salt of the compounds of this invention with one or more solvent molecules (organic or inorganic). This physical association includes hydrogen bonding. In some cases, such as when one or more solvent molecules are incorporated into the lattice of a crystalline solid, the solvate can be separated. Solvent molecules in the solvate may be present in a regular and / or disordered arrangement. The solvate may contain stoichiometric or non-stoichiometric solvent molecules. “Solvate” encompasses both solution phases and separable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanol compounds, methanol compounds, and isopropanol compounds. Solvation methods are well known in the art.

[0061] Unless otherwise specified, pharmaceutically acceptable salts of the compounds of this invention also include their “hydrates”. The term “hydrate” refers to a substance in which water molecules are bonded to cations or anions in a compound by coordination or covalent bonds, or in which water ions do not directly bond to cations or anions but exist in a certain proportion at specific positions in a solid crystal lattice.

[0062] Unless otherwise specified, the term "stereoisomer" refers to compounds having the same chemical structure but with different spatial arrangements of atoms or groups. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans) isomers, and inhibited isomers. Any mixture of stereoisomers obtained can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physicochemical properties of the components, for example, by chromatography and / or fractional crystallization.

[0063] Unless otherwise specified, the term "geometric isomer (cis / trans) isomer" may contain an E or Z configuration of a carbon-carbon double bond or a carbon-nitrogen double bond, wherein the term "E" represents a higher-order substituent on the opposite side of the carbon-carbon or carbon-nitrogen double bond, and the term "Z" represents a higher-order substituent on the same side of the carbon-carbon or carbon-nitrogen double bond (determined using the Cahn-Ingold Prelog priority rule). The compounds of the present invention may also exist in the form of a mixture of "E" and "Z" isomers.

[0064] Unless otherwise specified, the term "tautomer" refers to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium can be achieved in the tautomer. For example, proton tautomers (also called proton transfer tautomers) involve interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve interconversions via the rearrangement of some bonding electrons.

[0065] Unless otherwise indicated, the structural formulas described in this invention include all isomers (e.g., enantiomers, diastereomers, and geometric isomers (or conformational isomers)): for example, R and S configurations containing an asymmetric center, (Z) and (E) isomers of double bonds, and (Z) and (E) conformational isomers. Therefore, any single stereochemical isomer of the compounds of this invention, or its enantiomers, diastereomers, or mixtures of geometric isomers (or conformational isomers), is within the scope of this invention.

[0066] Unless otherwise specified, the term "carbocyclic group" refers to a non-aromatic cyclic hydrocarbon group having 3 to 14 ring carbon atoms ("C"). 3-14 The carbocyclic group (“C”) has 3-8 ring carbon atoms (“C”) and does not contain heteroatoms in this non-aromatic ring system. In some embodiments, the carbocyclic group has 3-8 ring carbon atoms (“C”). 3-8 (Carbocyclic group), or 3-6 ring carbon atoms ("C") 3-6 (Carbocyclic group), or 5 to 8 ring carbon atoms ("C") 5-8 Carbocyclic group (“CCR”). In some embodiments, the carbocyclic group has 5 to 6 cyclic carbon atoms (“C”). 5-6 (Carbocyclic group). Example C 3-6 The carbocyclic group includes, but is not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), etc. Example C 5-8 Carbocyclic groups include, but are not limited to, the C mentioned above. 3-6Carbocyclic groups include cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cyclohepttrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), etc. As illustrated in the examples above, in some embodiments, the carbocyclic group is monocyclic (“monocyclic carbocyclic”) or a fused (fused-ring), bridged (bridged-ring), or spiro-fused (spirocyclic) ring system, such as a bicyclic system (“bicyclic carbocyclic”), and may be saturated or may be partially unsaturated. “Carbocyclic” also includes ring systems in which the carbocyclic ring as defined above is fused with one or more aryl or heteroaryl groups, wherein the attachment point is on the carbocyclic ring, and in such cases, the number of carbons in the carbocyclic ring system is the number of carbons in the fused carbocyclic system. In some embodiments, each example of the carbocyclic group is independently optionally substituted, for example, unsubstituted (an "unsubstituted carbocyclic group") or substituted with one or more substituents (a "substituted carbocyclic group"). In some embodiments, the carbocyclic group is an unsubstituted C 5-8 Carbocyclic group. In some embodiments, the carbocyclic group is a substituted C 5-8 Carbon cyclic group.

[0067] Unless otherwise specified, the term "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group, a straight-chain or branched group comprising 1-20 carbon atoms, preferably comprising 1-10 carbon atoms (i.e., C10). 1-10 Alkyl groups, more preferably containing 1-8 carbon atoms (C64- ... 1-8 Alkyl groups, more preferably containing 1-6 carbon atoms (i.e., C64-C ... 1-6 Alkyl groups, 1-5 carbon atoms (i.e., C46) 1-5 Alkyl groups, 1-4 carbon atoms (i.e., C4) 1-4 Alkyl group or 1-3 carbon atoms (i.e., C46) 1-3 Alkyl), for example, "C 1-6 "Alkyl" refers to a group that is alkyl and has 1 to 6 carbon atoms in its carbon chain (specifically, 1, 2, 3, 4, 5, or 6). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl, etc.

[0068] Unless otherwise stated, the definitions of terms in this document also apply to groups containing the term, such as C. 1-6 The definition of alkyl also applies to halogenated C. 1-6 Alkyl groups, etc.

[0069] Unless otherwise specified, the term "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon group having a specific number of carbon atoms, preferably containing 3-12 carbon atoms (i.e., C12-C12). 3-12 cycloalkyl), more preferably containing 3-10 carbon atoms (C 3-10 cycloalkyl groups, more preferably 3-8 carbon atoms (C 3-8 cycloalkyl groups, 3-6 carbon atoms (C 3-6 cycloalkyl groups), 5-6 carbon atoms (C 5-6 (Cycloalkyl). Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, 2-ethyl-cyclopentyl, dimethylcyclobutyl, etc.

[0070] Unless otherwise specified, the term "alkoxy" refers to -O-alkyl, which is defined as above, i.e., containing 1-20 carbon atoms, preferably 1-10 carbon atoms, more preferably 1-8 carbon atoms, and even more preferably 1-6 carbon atoms (specifically 1, 2, 3, 4, 5, or 6). Examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, tert-butoxy, pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, etc.

[0071] Unless otherwise specified, the terms "halogen" or "halogenated" refer to F, Cl, Br, and I. The term "halogenated alkyl" refers to an alkyl group as defined above in which one, two, or more hydrogen atoms, or all hydrogen atoms, are replaced by a halogen. Representative examples of halogenated alkyl groups include CCl3, CF3, CHF2, CH2F, CHCl2, CH2Cl, CH2Br, CH2I, CH2CF3, and CF2CF3.

[0072] Unless otherwise specified, the term "heterocyclic group" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic non-aromatic substituent having a ring carbon atom and 1 to 4 ring heteroatoms, comprising 3 to 20 ring atoms, wherein 1, 2, 3 or more ring atoms are selected from N, O or S, and the remaining ring atoms are C, wherein one or more S ring atoms (if present) and / or one or more N ring atoms (if present) may optionally be oxidized, and wherein one or more carbon ring atoms may optionally be oxidized (i.e., forming an oxo group). For example, the heterocyclic group may contain 1 to 3 (1, 2, 3) N, O, C (=O), S or S (=O) heteroatoms or heteroatom groups. The heterocyclic group preferably comprises 3 to 10 ring atoms (3-10 membered heterocyclic group), more preferably 3 to 8 ring atoms (3-8 membered heterocyclic group), or 3 to 6 ring atoms (3-6 membered heterocyclic group), or 4 to 6 ring atoms (4-6 membered heterocyclic group), 5 to 8 ring atoms (5-8 membered heterocyclic group), or 5 to 6 ring atoms (5-6 membered heterocyclic group). The number of heteroatoms is preferably 1 to 4, more preferably 1 to 3 (i.e., 1, 2, or 3). Examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazoalkyl, tetrahydrofuranyl, dihydropyrrolidinyl, piperidinyl, piperazinyl, pyranyl, etc. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups. A "heterocyclic group" can be a monocyclic ("monocyclic heterocyclic group") or a fused ("fused heterocyclic group" or "heterofused-cyclic group"), bridged ("heterobridged heterocyclic group" or "bridged-ring heterocyclic group") or spiro-fused ("heterospirocyclic group" or "spirocyclic heterocyclic group") ring system, such as a bicyclic system ("bicyclic heterocyclic group"), and can be saturated or partially unsaturated. A heterocyclic bicyclic system can include one or more heteroatoms in one or both rings. "Heterocyclic group" also includes a ring system in which the heterocyclic ring as defined above is fused with one or more carbocyclic groups, wherein the attachment point is on the carbocyclic or heterocyclic ring; or "heterocyclic group" also includes a ring system in which the heterocyclic ring as defined above is fused with one or more aryl or heteroaryl groups, or a ring system in which a cycloalkyl ring as defined above is fused with one or more heteroaryl groups, wherein the attachment point is on the heterocyclic or cycloalkyl ring, and in such cases, the number of members in the heterocyclic ring system is the number of atoms in the fused ring system. In some embodiments, each example of a heterocyclic group is independently optionally substituted, for example, unsubstituted (an "unsubstituted heterocyclic group") or substituted with one or more substituents (a "substituted heterocyclic group"). Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirropropyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirrocyclobutane, oxocyclobutane, and thiocyclobutane.Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrophenylthio, dihydrophenylthio, pyrrolidinyl, dihydropyrrolidinyl, and pyrrolidin-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxolanecyclopentyl, oxathiocyclopentyl, dithiocyclopentyl, and oxazolidinyl-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithiocyclohexyl, and dioxolanecyclohexyl. Exemplary 6-membered heterocyclic groups containing 3 heteroatoms include, but are not limited to, triazacyclohexyl, oxadiazineyl, thiadiaziranyl, oxathiaziranyl, and dioxazinanyl. Exemplary 7-membered heterocyclic groups containing 1 heteroatom include, but are not limited to, azirheptanyl, oxadiazineyl, and thioheptanyl. Exemplary 8-membered heterocyclic groups containing 1 heteroatom include, but are not limited to, azirheptanyl, oxadiazineyl, and thioheptanyl. Exemplary 5-membered heterocyclic groups fused to a C6 aryl ring (also referred to herein as a 5,6-bicyclic heterocycle) include, but are not limited to, dihydroindolyl, isodihydroindolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinone, etc. Exemplary 6-membered heterocyclic groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocycle) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0073] Term "C" 6-10 "Aromatic ring group" should be understood as representing a monocyclic, bicyclic, or tricyclic hydrocarbon ring with 6 to 10 carbon atoms that is monovalent and partially aromatic. 6-10 "Aryl" should preferably be understood to represent a monocyclic or bicyclic hydrocarbon ring with 6, 7, 8, 9, or 10 carbon atoms that is monovalent and aromatic or partially aromatic ("C"). 6-10 Aryl), particularly a ring with 6 carbon atoms (“C6 aryl”), such as phenyl; or biphenyl, or a ring with 9 carbon atoms (“C9 aryl”), such as indenyl or indenyl, or a ring with 10 carbon atoms (“C9 aryl”). 10 Aryl), such as tetrahydronaphthyl, dihydronaphthyl, or naphthyl. When the C 6-10 When the aryl group is substituted, it can be monosubstituted or polysubstituted. Furthermore, there are no restrictions on the substitution site; for example, it can be ortho, para, or meta substituted.

[0074] The term "5-10-membered heteroaryl" should be understood to include monovalent monocyclic or bicyclic aromatic ring systems having 5, 6, 7, 8, 9, or 10 ring atoms, and comprising 1-5, preferably 1-3, heteroatoms independently selected from N, O, and S, and may be benzo-fused. Specifically, the heteroaryl group is selected from thienyl, furanyl, pyrroleyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl, etc., and their benzo-derived derivatives, such as benzofuranyl, benzothienyl, benzooxazolyl, benzoisooxazolyl, benzoimidazolyl, benzotriazolyl, indazole, indolyl, isoindolyl, etc.

[0075] In various parts of this invention, linking substituents (e.g., L) are described. Those skilled in the art will understand that when a linking group is clearly required in the structure of a compound, the Markush variables listed for that group should be understood as linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "*", it should be understood that "alkyl" represents a linked alkylene group. Therefore, when used as a linking group, "alkylene" and "*" have equivalent definitions.

[0076] Unless otherwise specified, the term “treatment” covers any treatment of a patient’s disease, symptom, and condition, including: (a) suppressing the symptoms of the disease, symptom, and condition, i.e., preventing its development; or (b) alleviating the symptoms of the disease, symptom, and condition, i.e., causing the disease or symptoms to subside; or (c) improving or eliminating the disease, symptom, and condition or one or more symptoms associated with said disease.

[0077] The therapeutically effective dose described in this invention refers to a pharmaceutically recognized effective dosage, that is, an amount of active compound sufficient to significantly improve the condition without causing serious side effects.

[0078] The beneficial effects of this invention are as follows:

[0079] This invention provides a benzimidazole derivative or its tautomers, stereoisomers, deuterated derivatives or pharmaceutically acceptable salts thereof and their applications, wherein the derivative has more favorable physical properties for drug formulation (such as higher solubility) and better pharmacokinetic properties. Detailed Implementation

[0080] The structures of the compounds of the present invention were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS) and / or high-performance liquid chromatography (HPLC).

[0081] The raw materials used in this invention are known and commercially available, or can be synthesized using methods known in the art.

[0082] Preparation Example 1: Preparation of [(S)-2-(5-chloro-4-methyl-1H-benzimidazol-2-yl)-2-methyl-pyrrolidine-1-yl]-[5-(methoxy-d3)-2-(1,2,3)triazol-2-yl-phenyl]-methyl ketone (compound TM-03)

[0083] (1) Preparation of (S)-5-chloro-4-methyl-2-(2-methylpyrrolidone-2-yl)-1H-benzimidazole

[0084] 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), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (10 mmol) were added. The mixture was stirred at room temperature for 20 h, the solvent was removed by vacuum evaporation, water (20 mL) was added to the concentrate, and then the concentrate was extracted with ethyl acetate (20 mL * 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated.

[0085] The concentrate was dissolved in glacial acetic acid (15g) without purification. The mixture was heated to 110℃ and stirred for 2 hours. The reaction solution was concentrated. The pH of the residue was adjusted to 7-8 with sodium bicarbonate aqueous solution. The residue was extracted and separated with ethyl acetate (40ml*3). The organic phases were combined, dried with anhydrous magnesium sulfate, filtered, and concentrated.

[0086] The concentrate was readily soluble in dioxane (5 mL) without purification. A 4 M dioxane chloride solution (5.2 mL) was added, and the mixture was stirred at room temperature for 4 h. Diethyl ether (10 mL) was added, and crystallization was carried out at room temperature for 2 h. The crystals were then filtered. The resulting solid was dissolved in water (10 mL), and the pH was adjusted to 7–8 with a saturated sodium bicarbonate solution. The phases were extracted with ethyl acetate (40 mL * 3), and the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated to give 2.27 g of (S)-5-chloro-4-methyl-2-(2-methylpyrrolidone-2-yl)-1H-benzimidazole. LC-MS (ESI) m / z: 250.0 [M+H] + .

[0087] 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).

[0088] (2) Preparation of 5-(methoxy-d3)-2-iodobenzoic acid

[0089] Methyl 5-hydroxy-2-iodobenzoate (2.00 g, 7.19 mmol, 1 eq) was dissolved in N,N-dimethylformamide (20 mL), and deuterated iodomethane (compound C, 21.5 mmol) and potassium carbonate (15.80 mmol) were added. The mixture was stirred at room temperature for 20 hours. The reaction solution was filtered, concentrated to dryness, and water (50 mL) was added. The solution was extracted with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous magnesium sulfate and concentrated. The concentrate was dissolved in methanol:tetrahydrofuran = 1:1 (20 mL), and lithium hydroxide aqueous solution (2 M, 8 mL) was added. The reaction was continued at room temperature for 20 hours. The reaction solution was concentrated, and the pH was adjusted to 3-4 with hydrochloric acid. A solid precipitated and was filtered to give 1.8 g of the intermediate 5-methoxy-d3-2-iodobenzoic acid. LC-MS (ESI) m / z: 280.0 [MH] - .

[0090] 1 H NMR (600MHz, DMSO-d6): δ13.057 (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).

[0091] (3) Preparation of 5-(methoxy-d3)-2-(1,2,3-2H-triazol-2-yl)benzoic acid

[0092] 5-(methoxy-d3)-2-iodobenzoic acid (1.80 g, 6.4 mmol, 1 eq) was dissolved in N,N-dimethylformamide (25 mL), followed by the addition of 1,2,3-2H-triazole (compound H, 12.8 mmol) and cesium carbonate (12.8 mmol). The mixture was heated to 40 °C, and copper iodide (0.47 mmol) was added. The temperature was then raised to 70 °C and stirred continuously for 1.5 hours. The solvent was removed under reduced pressure, and water (45 mL) and ethyl acetate (25 mL) were added. The pH was adjusted to 3–4 with hydrochloric acid while stirring. The mixture was filtered, and the phases were separated. The organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain 1.1 g of 5-(methoxy-d3)-2-(1,2,3-2H-triazol-2-yl)benzoic acid. LC-MS (ESI) m / z: 223.0 [M+H] + .

[0093] 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).

[0094] (4) Preparation of [(S)-2-(5-chloro-4-methyl-1H-benzimidazol-2-yl)-2-methyl-pyrrolidine-1-yl]-[5-(methoxy-d3)-2-(1,2,3)triazol-2-yl-phenyl]-methyl ketone

[0095] (S)-5-chloro-4-methyl-2-(2-methylpyrrolidin-2-yl)-1H-benzimidazole (1.18 g, 4.74 mmol, 1 eq) was dissolved in dichloromethane (20 mL). 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'-tetramethylurea hexafluorophosphate (4.74 mmol) were added sequentially under ice bath conditions. The mixture was stirred at room temperature for 20 hours. The solvent was removed by vacuum distillation, 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, concentrated, and then purified by rapid preparation using a BUCHIPURE Flash method (dichloromethane:methanol = 10:1). The purified phase was collected and concentrated to give 1.22 g of the target compound. LC-MS (ESI) m / z: 454.1 [M+H] + .

[0096] 1H NMR(600MHz,Methanol-d4)δ7.929(s,2H),7.901(m 1H),7.648(q,2H),7.294(s,1H),7.213(m,1H),3.881(t,1H),3.536(s,1H),2.775(s,3H),2.61 0(m,1H),2.415(m,1H),2.319–2.230(m,1H),2.254–2.190(m,1H),2.135(s,3H),1.172(m,1H).

[0097] Preparation Example 2: Preparation of TM-04

[0098] Following the preparation method in Preparation Example 1, the deuterated compound TM-04 was prepared using the corresponding compound reactants.

[0099] LC-MS (ESI) m / z: 453.3 [M+H] +

[0100] 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).

[0101] The preparation of 2H-1,2,3-triazole-4,5-d2 (compound D) is as follows:

[0102] 4,5-Dibromo-2H-1,2,3-triazole (2.00 g, 8.81 mmol) was dissolved in deuterated methanol-d4 (10 mL), and palladium on carbon (Pd / C, 10%, 0.10 g) and anhydrous potassium carbonate (4.00 g, 28.94 mmol) were added. The mixture was purged with nitrogen three times, followed by deuteration three times. The mixture was stirred at room temperature under deuteration for 4 hours, and then the reaction was stopped. After nitrogen purging, 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 give compound D 0.55 g. LC-MS (ESI) m / z: 72.04 [M+H] + .

[0103] Preparation Example 3: Preparation of TM-10

[0104] The deuterated compound TM-10 was prepared using the corresponding compound reactants according to the preparation method in Example 1.

[0105] LC-MS (ESI) m / z: 456.3 [M+H] +

[0106] 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).

[0107] Preparation Example 5: Preparation of TM-16

[0108] Following the preparation method in Preparation Example 1, the brominated compound TM-16 was prepared using the corresponding compound reactants.

[0109] Confirmatory data: LC-MS (ESI) m / z: 609.0 [M+H] +

[0110] 1 H NMR(600MHz,DMSO-d6)δ7.764(m,1H),7.417–7.370(m,1H),7.344–7.286(m,1H),7.214–7.133(m,2H),3.911(m, 3H),3.763–3.690(m,1H),3.379(m,1H),2.561(m,3H),2.264(s,1H),2.082(m,1H),2.014(s,2H),1.888(m,3H).

[0111] Example 1: Preparation of (S)-(5-chloro-2-(1-(5-methoxy-2-)2H-1,2,3-triazol-2-yl)benzoyl)-2-methylpyrrolidone-2-yl)-4-methyl-1H-benzo[d]imidazol-1-yl)methyl carbonate (compound DA-05)

[0112] Daridorexant free base (0.30 g, 0.67 mmol) was dissolved in DMF (5 mL), and sodium hydride (3.35 mmol) was added. The mixture was stirred at room temperature for 0.5 hours. Then, chloromethyl methyl carbonate (0.25 mL, 2.68 mmol) was added dropwise, and the mixture was heated to 50 °C and stirred continuously for 3 hours until the reaction was complete. The solvent was removed by vacuum distillation, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL). The organic phase was dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by BUCHIPURE Flash (n-heptane:ethyl acetate = 3:1). The eluent was concentrated to give 0.18 g of the target compound.

[0113] LC-MS (ESI) m / z: 539.0 [M+H] + .

[0114] 1 H NMR(600MHz,DMSO-d6)δ8.078(s,2H),7.794(d,1H),7.463(d,1H),7.339(d,1H),7.188(m,1H),7.102(s,1H),6.371-6.450(m,2H) ,3.898(s,3H),3.782(s,3H),3.661-3.612(m,1H),3.420(s,1H),2.564(s,3H),2.372(m,1H),1.991-2.082(m,3H),1.928(s,3H).

[0115] Example 2: Preparation of (S)-(5-chloro-2-(1-(5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoyl)-2-methylpyrrolidone-2-yl)-4-methyl-1H-benzo[d]imidazol-1-yl)methyl dihydrogen phosphate (compound DA-14)

[0116] Daridorexant free base (5.00 g, 11.08 mmol) was dissolved in DMF (50 mL), and 60% sodium hydride (55.15 mmol) was added. The mixture was stirred at room temperature for 0.5 hours. Then, di-tert-butylchloromethyl phosphate (44.12 mmol) was added dropwise, and the mixture was heated to 50 °C and stirred continuously for 3 hours until the reaction was complete. The solvent was removed by vacuum distillation, and the reaction was quenched by adding water (250 mL). The mixture was extracted with ethyl acetate (250 mL), dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by BUCHIPURE Flash (n-heptane:ethyl acetate = 3:1). The eluent was concentrated to obtain INT1, which was then directly used for the next step.

[0117] The concentrate was added to concentrated hydrochloric acid (20 mL) and stirred at room temperature for 3 hours until the reaction of the raw materials was complete. After concentration, it was purified by rapid preparation using BUCHIPURE Flash (acetonitrile / water = 25%). The eluent was concentrated to obtain 5.5 g of the target compound.

[0118] LC-MS (ESI) m / z: 561.1 [M+H] + .

[0119] 1 H NMR(600MHz,DMSO-d6)δ8.079(s,2H),7.791(m,1H),7.472(m,1H),7.332(m,1H),7.181(m,1H),7.050(s,1H),6.126 (s,2H),3.897(s,3H),3.667(m,1H),3.451(s,1H),2.568(s,3H),2.412(m,1H),2.070–1.990(m,3H),1.937(s,3H).

[0120] By analyzing the NOE correlation between methylene hydrogen (referring to the methylene hydrogen linked to the benzimidazole group) and the spatially closer benzene ring hydrogen (the para-methyl hydrogen in the benzimidazole group structure) in NOESY NMR spectroscopy, and the absence of the NOE correlation between the methylene hydrogen and the para-methyl hydrogen in the benzimidazole group structure, the substitution positions of the N-substituents on the benzimidazole ring group were determined.

[0121] Example 3: Preparation of (S)-(5-chloro-2-(1-(5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoyl)-2-methylpyrrolidone-2-yl)-4-methyl-1H-benzo[d]imidazol-1-yl)sodium methylphosphate (compound DA-16)

[0122] Compound DA-14 (2.16 g, 3.85 mmol) was dissolved in methanol (20 mL), and 5 mL of an aqueous solution containing sodium hydroxide (19.25 mmol) was added dropwise. The mixture was stirred at room temperature for 1.5 hours. Then, methanol was removed by vacuum evaporation at 25–30 °C, 10 mL of acetone was added, crystals were precipitated, filtered, and dried to obtain 1.34 g of the target compound.

[0123] LC-MS (ESI) m / z: 561.1 [M+H] + .

[0124] 1H NMR(600MHz,CD3OD)δ7.943(s,2H),7.669(m,1H),7.542(m,1H),7.330(m,1H),7.156(m,1H),7.076(m,1H),5.903– 5.780(m,2H),3.871(s,3H),3.767(m,1H),3.052(s,1H),2.545(m,3H),2.288(s,1H),2.022(m,3H),1.845(s,3H).

[0125] Examples 4-7

[0126] Following the preparation method in Example 2, the target compounds DA-32, DA-50, DA-68, and DA-86 were prepared using the corresponding compound reactants.

[0127] Example 8:

[0128] Following the preparation methods of Examples 1-3, and using the corresponding compound reactants, the following compounds were obtained:

[0129] Test Example 1: Solubility Test Evaluation

[0130] 1. Experimental reagents and equipment

[0131] Experimental reagents: purified water, electronic balance.

[0132] Instruments and equipment: water bath constant temperature shaker, high performance liquid chromatograph.

[0133] 2. Experimental methods:

[0134] Test in water at 25°C: Add 5 mL of water to a transparent vial, then add an appropriate amount of the compound until a noticeable solid precipitates. Seal the vial and place it in a water bath with a constant temperature shaker set to 25°C and 200 rpm for 12 hours. Filter the suspension through a 0.22 μm filter membrane and determine the solubility using HPLC according to the external standard method.

[0135] 3. Experimental Results:

[0136] The solubility test results of the exemplary compounds are as follows:

[0137] Notes: A: Solubility > 800, B: 500 < solubility ≤ 800, C: 200 < solubility ≤ 500, D: 1 < solubility ≤ 200, E: 0.5 < solubility ≤ 1, F: Solubility ≤ 0.5.

[0138] Test Example 2: Pharmacokinetic Experiment in Rats

[0139] 1. Purpose:

[0140] The metabolic stability of the compounds of this invention and Daridorexant hydrochloride in rats was investigated, and the in vivo pharmacokinetics of the exposure after oral administration were evaluated.

[0141] 2. Reagents and experimental animals:

[0142] Reagent: Methylcellulose (MC).

[0143] Test animals: Wistar Han rats, male.

[0144] 3. Comparative Experimental Methods for Pharmacokinetics in Rats

[0145] (1) Drug preparation

[0146] The compound of the present invention and the Daridorexant hydrochloride stock solution were prepared using the following configuration methods.

[0147] Oral administration: 0.5% suspension of methylcellulose (MC).

[0148] (2) Dosing regimen

[0149] Healthy adult Wistar Han rats (n=3 per group) were administered the drug via gavage (po.) after overnight fasting (free access to water). Blood samples of 0.25 ml were collected from the orbital or jugular vein before administration and at 15 min, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h after administration. The samples were placed in EDTA-K2 tubes, mixed by inversion, and centrifuged at 2–8 °C (at least 3500 rpm for 10 min) in an ice-water bath for 30 min. The samples were then frozen at –80 °C for analysis. An LC / MS / MS method was established to determine the plasma concentration of the parent drug. Plasma drug concentration-time curves were plotted, and the main pharmacokinetic parameters were calculated using WinNonlin 7.2 software.

[0150] 4. Experimental Results

[0151] The experimental results for the exemplary compounds are as follows:

[0152] Experimental results show that the compounds of this invention exhibit superior in vivo pharmacokinetic performance compared to Daridorexant hydrochloride. The exemplary compound DA-14 has a half-life less than half that of Daridorexant hydrochloride. max It is more than 3 times that of Daridorexant hydrochloride, with an AUC of last It is more than 2.5 times that of Daridorexant hydrochloride.

[0153] Test Example 3: Pharmacokinetic Experiment in Dogs

[0154] 1. Purpose:

[0155] The metabolic stability of the compounds of this invention and Daridorexant hydrochloride in dogs was investigated, and the in vivo pharmacokinetics of the exposure after oral administration were evaluated.

[0156] 2. Reagents and experimental animals:

[0157] Experimental animal: male Beagle dog.

[0158] Capsule shells: gelatin empty capsules (ACG), enteric-coated gelatin empty capsules (Qingdao Yiqing Biotechnology Co., Ltd.).

[0159] 3. Comparative Experimental Methods for Pharmacokinetics in Dogs

[0160] (1) Drug preparation

[0161] Daridorexant hydrochloride was filled into ACG gelatin hollow capsule shells to prepare capsules.

[0162] Capsules are prepared by filling the compounds of the present invention into capsule shells (enteric-coated capsule shells for cationic salts, gastric-coated capsule shells for anionic salts and free compounds).

[0163] (2) Dosing regimen

[0164] Healthy adult Beagle dogs were administered the drug orally (po.) after fasting overnight (with free access to water). Whole blood samples (1-1.5 mL) were collected via the forelimb vein before administration and at 5, 15, 30, and 45 minutes, and at 1, 2, 4, 8, and 24 hours after administration. The samples were placed in vacuum blood collection tubes, inverted to mix, and centrifuged at 2-8°C (at least 3500 rpm for 10 minutes) in an ice-water bath for 30 minutes. The samples were then frozen at -80°C for analysis. An LC / MS / MS method was established to determine the plasma concentration of the parent drug. Plasma drug concentration-time curves were plotted, and the main pharmacokinetic parameters were calculated using WinNonlin 8.3.

[0165] 4. Experimental Results

[0166] The experimental results for the exemplary compounds are as follows:

[0167] Experimental results show that the compounds of this invention exhibit superior in vivo pharmacokinetic performance compared to Daridorexant hydrochloride. The exemplary compound DA-16 has a shorter half-life compared to Daridorexant hydrochloride. max It is more than 5 times that of Daridorexant hydrochloride, with an AUC of last It is more than 3.6 times that of Daridorexant hydrochloride.

[0168] The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A compound of formula (I), its tautomers, stereoisomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, having the following structure in, R1 to R5 are each independently hydrogen, deuterium, and halogen; R is selected from L represents the key, -C 1-3 alkylene-, -C 1-3 Alkylene -O(CO)O-, -C 1-3 Alkylene -O-, -C 1-3 Alkylene-(CO)-, -C 1-3 Alkylene -O(CO)-, -C 1-3 Alkylene -(CO)O-, -C 1-3 Alkylene-O(CO)OC 1-3 alkylene-, -C 1-3 Alkylene-OC 1-3 alkylene-, -C 1-3 Alkylene-(CO)-C 1-3 alkylene-, -C 1-3 Alkylene-O(CO)-C 1-3 alkylene-, -C 1-3 Alkylene-(CO)OC 1-3 alkylene-; the C 1-3 Alkylenes are optionally divided by 1 to 2 identical or different deuteriums, C 1-3 Alkyl, hydroxyl, halogen, amino, cyano, mercapto, C 1-3 Alkyloxy group, halogenated C 1-3 Alkyl, C 1-3 Alkylamino substituents; R6 is selected from R7, R7 is selected from C 1-6 Alkyl, C 3-8 Carbocyclic groups, 3-8 membered heterocyclic groups, -C 1-3 Alkylene-C 3-8 carbonyl group, C 6-10 Aromatic ring group, 5-10 membered heteroaryl group, wherein the heterocyclic group contains 1-3 N, O, C (=O), S or S (=O) heteroatoms or heteroatom groups; the C 1-6 Alkyl, C 3-8 Carbocyclic group, 3-8 membered heterocyclic group, C 6-10 The aromatic ring group and the 5-10 heteroaryl group are optionally coated with 1-6 identical or different deuterium, cyano, amino, hydroxyl, mercapto, C group, etc. 1-6 Alkyl, halogen, C 1-6 Alkyloxy group, halogenated C 1-6 Alkyl, C 1-6 Alkylamino substitution; R 8、 R9 is independently selected from hydrogen, Na, K, Ca, and C. 1-6 Alkyl groups, or R8 and R9, together with the atoms they are attached to, form 4-8 membered heterocycles.

2. The compound of claim 1, its tautomers, stereoisomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, characterized in that, R1 to R5 together contain two deuterium atoms, of which R1 to R3 are H and R4 to R5 are deuterium; or, R1 to R5 contain a total of 3 deuterium atoms, of which R1 to R3 are deuterium and R4 to R5 are hydrogen; or R1 to R5 contain a total of 5 deuteriums, of which R1 to R5 are all deuteriums; or R1 to R5 have a total of 0 deuterium atoms, where all of R1 to R5 are H atoms; or R4 to R5 are each independently selected from hydrogen or halogens, wherein the halogens are selected from F, Cl or Br, preferably Br; more preferably, all of R4 to R5 are Br.

3. The compound, its tautomers, stereoisomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, as described in any one of claims 1-2, characterized in that... L is selected from: bond, -CH2-, -CH2-O(CO)O-, -CH2-O-, CH2-(CO)-, -CH2-O(CO)-, -CH2-(CO)O-, -CH2-O(CO)O-CH2-, -CH2-O-CH2-, -CH2-(CO)-CH2-, -CH2-O(CO)-CH2-, -CH2-(CO)O-CH2-; wherein the -CH2- is optionally replaced by 1 to 2 identical or different deuterium, methyl, hydroxyl, halogen, amino, cyano, mercapto, methoxy, halomethyl, methylamino; or L is selected from: -CH2-, -CH2-O(CO)O-, -CH2-O(CO)-, -CH2-O(CO)O-CH2-.

4. The compound, its tautomers, stereoisomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, as described in any one of claims 1-3, characterized in that... R7 is selected from C 1-5 Alkyl, C 3-6 Carbocyclic group, 3-6 membered heterocyclic group, C 6-10 Aromatic ring group, 5-10 membered heteroaryl group, wherein the heterocyclic group contains 1-3 N, O, C (=O), S or S (=O) heteroatoms or heteroatom groups; the C 1-5 Alkyl, C 3-6 Carbocyclic group, 3-6 membered heterocyclic group, C 6-10 The aromatic ring group and the 5-10 heteroaryl group are optionally coated with 1-6 identical or different deuterium, cyano, amino, hydroxyl, C group. 1-4 Alkyl, halogen, C 1- 4-alkyloxy, halogenated C 1-4 Alkyl or C 1-4 Alkylamino substitution; or R7 is selected from C 1-4 Alkyl, C 3-6 Carbocyclic group, 3-6 membered heterocyclic group, C 6-10 Aromatic ring group, 5-10 membered heteroaryl group, wherein the heterocyclic group contains 1-3 N, O, C (=O), S or S (=O) heteroatoms or heteroatom groups; the C 1-4 Alkyl, C 3-6 Carbocyclic group, 3-6 membered heterocyclic group, C 6-10 The aromatic ring group and the 5-10 heteroaryl group are optionally coated with 1-6 identical or different deuterium, cyano, amino, hydroxyl, C group. 1-4 Alkyl, halogen, C 1-4 Alkyloxy group, halogenated C 1-4 Alkyl or C 1-4 Alkylamino substitution; or R7 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetyl, aziretyl, thiohexetyl, oxetyl, aziretyl, thiohexetyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydrothiophene, piperidinyl, tetrahydrothioranyl, dioxanecycloyl, piperazinyl, hexahydropyrazinyl, morpholinyl, dithiaalkyl, tetramethylpiperidinyl. Or R7 is selected from or R7 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. or R7 is selected from methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclopentyl, ...

5. The compound, its tautomer, stereoisomer, deuterated derivative, or pharmaceutically acceptable salt thereof, as described in any one of claims 1-4, characterized in that... Selected from:

6. The compound, its tautomer, stereoisomer, deuterated derivative, or pharmaceutically acceptable salt thereof, as described in any one of claims 1-5, characterized in that... R is selected from: Or R is selected from Or R is selected from: or R is selected from Or R is selected from 7. The following compounds, their tautomers, stereoisomers, deuterated derivatives, or pharmaceutically acceptable salts:

8. A pharmaceutical composition comprising a compound of formula (I) as claimed in any one of claims 1-7, a tautomer, a stereoisomer, a deuterated form thereof, or a pharmaceutically acceptable salt thereof, optionally further comprising a pharmaceutically acceptable carrier.

9. Use of the compound of formula (I) as claimed in any one of claims 1-7, its tautomers, stereoisomers, deuterated derivatives or pharmaceutically acceptable salts thereof, or the pharmaceutical composition of claim 8 in the preparation of a medicament or as a medicament, wherein the medicament has antagonistic activity against orexin receptors.

10. The use as described in claim 9, characterized in that, The drug is used to prevent, improve and / or treat diseases or conditions involving neurological and psychiatric disorders related to orexin receptors; And / or, the drug is used to prevent, improve and / or treat diseases or conditions such as sleep disorders, sunset syndrome, Alzheimer's disease, anxiety disorders, addiction, depression, cognitive impairment, mood disorders, neuropathic pain, headache, and appetite disorders. And / or, the drug is used to prevent, improve and / or treat sleep disorders; And / or, the drug is used to prevent, improve and / or treat insomnia; And / or, the use of the drug in the prevention, improvement and / or treatment of the relevant diseases or conditions for which Daridorexant is applicable.

11. A method for preventing, improving, and / or treating diseases or conditions of neurological and psychiatric disorders related to orexin receptors, comprising administering to a patient a therapeutically effective dose of a compound of formula (I) as described in any one of claims 1-7, its tautomers, stereoisomers, deuterated derivatives, or pharmaceutically acceptable salts thereof, or the pharmaceutical composition of claim 8; preferably, the diseases or conditions of neurological and psychiatric disorders related to orexin receptors are selected from: sleep disorders, sunset syndrome, Alzheimer's disease, anxiety disorders, addiction, depression, cognitive impairment, mood disorders, neuropathic pain, headache, and appetite disorders; And / or, a method for preventing, improving and / or treating a disease or condition of sleep disorder, comprising administering to a patient a therapeutically effective dose of a compound of formula (I) as claimed in any one of claims 1-7, its tautomers, stereoisomers, deuterated derivatives or pharmaceutically acceptable salts thereof, or the pharmaceutical composition of claim 8. And / or, a method for preventing, improving and / or treating insomnia, comprising administering to a patient a therapeutically effective dose of a compound of formula (I) as described in any one of claims 1-7, a tautomer, stereoisomer, deuterated form thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 8. And / or, a method for preventing, improving and / or treating a disease or condition to which Daridorexant is applicable, comprising administering to a patient a therapeutically effective dose of a compound of formula (I) as described in any one of claims 1-7, a tautomer, stereoisomer, deuterated form thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 8.

12. The use as described in any one of claims 9-10 or the method as described in claim 11, the compound represented by formula (I) as described in any one of claims 1-7 or the tautomer, stereoisomer, deuterated product or pharmaceutically acceptable salt thereof or the pharmaceutical composition as described in claim 8, may be administered in combination with other related drugs or treatments.

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