Tetrahydropyrrolocyclic compound and application thereof

Abstract

A tetrahydropyrrolocyclic compound as represented by formula (I), a pharmaceutically acceptable salt thereof, and an application thereof in preparation of a drug for treating a disease related to a selective orexin-2 (OX-2) receptor antagonist, wherein the related disease is selected from insomnia and depression.

Description

Tetrahydropyrrolocyclic compounds and their applications

[0001] This application claims priority to

[0002] CN2021101461359, application date February 2, 2021;

[0003] CN2021106175620, application date June 2, 2021;

[0004] CN2021109065355, application date August 11, 2021;

[0005] CN2021116252159, application date December 27, 2021. Technical Field

[0006] The present invention relates to a class of tetrahydropyrrolocyclic compounds, in particular to a compound represented by formula (I) and pharmaceutically acceptable salts thereof. Background Art

[0007] Orexin (orexin, hypocretin) signaling is mediated by two receptors and two peptide agonists. Orexin A and orexin B bind to two high-affinity receptors, called the orexin-1 receptor (OX-1 receptor) and the orexin-2 receptor (OX-2 receptor). The OX-1 receptor has a higher affinity for orexin A, while the OX-2 receptor binds to orexin A and orexin B with similar affinity. Orexin-secreting neurons are primarily located in the prefrontal nucleus, dorsal hypothalamus, and lateral hypothalamus (C. Peyron et al., J. Neurosci., 1998, 18(23), 9996-10015). The secreted orexin can affect many areas of the brain and participate in many behavioral and physiological functions, including: eating, drinking, reproduction, arousal system, stress system, reward system, etc. (T. Sakurai, Nature Reviews Neuroscience, 2007, 8 (3), 171-181). Among them, the orexin system has a significant regulatory effect on the sleep-wake process. The awake time of rodents administered orexin intraperitoneally is prolonged (Piper et al., J. Neurosci. 2000, 12, 726-730). On the other hand, mutated or non-functional orexin-2 receptors will cause narcolepsy in dogs (Lin et al., Cell 1999, 98, 365-376) and the cerebrospinal fluid of humans with narcolepsy is deficient in orexin signals (Nishino et al., Lancet 2000. 355, 39-40). This shows that the orexin system promotes human wakefulness, while inhibiting the orexin system is beneficial to promote sleep. Orexin receptor antagonists may therefore be used to treat conditions such as insomnia, depression, anxiety, drug addiction, psychotic disorders, dementia, schizophrenia, Parkinson's disease, Alzheimer's disease, insulin resistance, type 2 diabetes, hyperlipidemia, gallstones, angina, hypertension, dyspnea, tachycardia, infertility, sleep apnea, back and joint pain, varicose veins and osteoarthritis, among others.

[0008] Summary of the Invention

[0009] The present invention provides a compound represented by the following formula or a pharmaceutically acceptable salt thereof, which is selected from:

[0010]

[0011] in,

[0012] Each R1 is independently selected from halogen, cyano, C 1-3 Alkyl and C 1-3 Alkoxy, the C 1-3 Alkyl and C 1-3The alkoxy groups are each independently optionally substituted with 1, 2 or 3 halogen atoms;

[0013] Each R2 is independently selected from halogen, cyano, C 1-3 Alkyl and C 1-3 Alkoxy, the C 1-3 Alkyl and C 1-3 The alkoxy groups are each independently optionally substituted with 1, 2 or 3 halogen atoms;

[0014] R3 is selected from H, C 1-3 Alkyl and C 3-6 Cycloalkyl;

[0015] m and n are independently selected from 0, 1, 2 and 3;

[0016] Ring A is selected from

[0017] Ring B is selected from

[0018] In some embodiments of the present invention, each R1 is independently selected from halogen, cyano, methyl and methoxy, and the methyl and methoxy are independently optionally substituted with 1, 2 or 3 Fs, and other variables are as defined in the present invention.

[0019] In some embodiments of the present invention, each R1 is independently selected from F, Cl, methyl and methoxy, and other variables are as defined in the present invention.

[0020] In some embodiments of the present invention, each R2 is independently selected from halogen, cyano, methyl and methoxy, and the methyl and methoxy are independently optionally substituted with 1, 2 or 3 Fs, and other variables are as defined in the present invention.

[0021] In some embodiments of the present invention, each R2 is independently selected from F, Cl, methyl and methoxy, and other variables are as defined in the present invention.

[0022] In some embodiments of the present invention, the above R3 is selected from H, methyl and cyclopropyl, and other variables are as defined in the present invention.

[0023] In some embodiments of the present invention, the compound is selected from the structures represented by formula (I-1), (I-2) and (I-3):

[0024]

[0025] wherein R1, R2, R3, m and n are as defined in the present invention.

[0026] Some other solutions of the present invention are obtained by arbitrarily combining the above variables.

[0027] The present invention also provides the following compounds or pharmaceutically acceptable salts thereof, wherein the compound is selected from:

[0028]

[0029] In some embodiments of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

[0030]

[0031]

[0032] The present invention also provides the use of the above-mentioned compound or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating diseases related to selective orexin-2 receptor antagonists.

[0033] In some embodiments of the present invention, the selective orexin-2 receptor antagonist-related disease is selected from insomnia and / or depression.

[0034] The present invention also provides the following testing method:

[0035] 1. Determination of Pharmacokinetic Parameters in Rat Plasma

[0036] Four healthy SD rats aged 6-9 weeks were selected and randomly divided into two groups, with 2 rats in each group. One group was given the test compound 2 mg / kg by intravenous injection, and the other group was given the test compound 10 mg / kg by oral gavage. Plasma samples were collected from the animals in the intravenous and oral gavage groups at 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, and 24 hours after administration. Quantitative analysis of all biological samples was performed using LC-MS / MS, and WinNonlin TM Version 6.3 (Pharsight, Mountain View, CA) pharmacokinetic software was used to calculate relevant pharmacokinetic parameters using the non-compartmental linear logarithmic trapezoidal method. 0-last represents the area under the plasma concentration-time curve from time zero to the last detectable concentration time point; po stands for oral administration; iv stands for intravenous injection; T 1 / 2 represents half-life; CL represents clearance; Vd represents apparent volume of distribution; C max represents peak concentration; T max represents the time to peak; F% represents oral bioavailability.

[0037] 2. Determination of Drug Concentration in Rat Brain Tissue

[0038] Four healthy 6-9 week old Sprague-Dawley rats were selected. Another group was administered the test compound at 10 mg / kg via oral gavage. Plasma and brain tissue samples were collected from two animals at 0.5 and 2 hours after administration, respectively. Quantitative analysis of all biological samples was performed using LC-MS / MS.

[0039] Technical Effects

[0040] As an OX-2 receptor antagonist, the compound of the present invention has a selective antagonistic effect on the OX-2 receptor and exhibits good activity in in vitro tests. It can be used to develop drugs for treating insomnia, depression and other mental illnesses related to the Orexin signaling pathway. The compound of the present invention exhibits good pharmacokinetic properties in rats, can penetrate the blood-brain barrier in rats, enter the brain tissue, and achieve high drug concentrations.

[0041] Definition and Description

[0042] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be construed as indefinite or unclear unless specifically defined, but rather should be understood in accordance with its ordinary meaning. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0043] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0044] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, prepared by reacting the compounds of the present invention with relatively nontoxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the compounds with a sufficient amount of base in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts, or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, bisulfate, hydroiodic acid, phosphorous acid, and the like; and organic acid salts such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; and salts of amino acids (such as arginine) and organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups and can be converted into either base or acid addition salts.

[0045] Pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture of the two.

[0046] Unless otherwise specified, the term “C 1-3 "Alkyl" is used to represent a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms. 1-3 Alkyl groups include C 1-2 and C 2-3 Alkyl, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). 1-3 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.

[0047] Unless otherwise specified, the term “C 1-3 "Alkoxy" refers to those alkyl groups containing 1 to 3 carbon atoms which are attached to the rest of the molecule via an oxygen atom. The C 1-3 Alkoxy groups include C 1-2 、C 2-3 , C3 and C2 alkoxy, etc. 1-3Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.

[0048] Unless otherwise specified, “C 3-6 "Cycloalkyl" means a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which is a monocyclic or bicyclic ring system. 3-6 Cycloalkyl groups include C 3-5 、C 4-5 and C 5-6 Cycloalkyl, etc.; it may be monovalent, divalent or polyvalent. 3-6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0049]

[0046] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.

[0050] Unless otherwise indicated, the term "isomer" is intended to include geometric isomers, cis-trans isomers, stereoisomers, enantiomers, optical isomers, diastereomers and tautomers.

[0051] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are encompassed within the scope of the present invention.

[0052] Unless otherwise indicated, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of one another.

[0053] Unless otherwise indicated, the term "cis-trans isomers" or "geometric isomers" arises from the inability to rotate freely about double bonds or single bonds forming ring carbon atoms.

[0054] Unless otherwise indicated, the term "diastereomer" refers to stereoisomers that have two or more chiral centers and that are not mirror images of each other.

[0055] Unless otherwise indicated, "(+)" indicates dextrorotatory, "(-)" indicates levorotatory, and "(±)" indicates racemic.

[0056] Unless otherwise specified, use a solid wedge key. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond and straight dashed bond Indicate the relative configuration of stereocenters with a wavy line Indicates a wedge-shaped solid key or dotted wedge key Or use a wavy line Indicates a straight solid bond or straight dashed key

[0057] Unless otherwise indicated, the terms "enriched in one isomer", "isomerically enriched", "enriched in one enantiomer" or "enantiomerically enriched" mean that the content of one isomer or enantiomer is less than 100%, and the content of that isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.

[0058] Unless otherwise indicated, the term "isomer excess" or "enantiomeric excess" refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (ee value) is 80%.

[0059] Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are resolved by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is typically accomplished by using chromatography, which employs a chiral stationary phase and is optionally combined with a chemical derivatization method (e.g., carbamate formation from an amine).

[0060] The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium ( 3H), iodine-125( 125 I) or C-14( 14 C). For example, deuterated drugs can be formed by replacing hydrogen with heavy hydrogen. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs have advantages such as reduced toxic side effects, increased drug stability, enhanced efficacy, and prolonged drug biological half-life. All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of this invention.

[0061] The terms "optional" or "optionally" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0062] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups.

[0063] The term "optionally substituted" means that the group may be substituted or not substituted, and unless otherwise specified, the type and number of the substituents may be any based on chemical feasibility.

[0064] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, with each occurrence of R being an independent choice. Furthermore, combinations of substituents and / or their variants are permissible only if such combinations result in stable compounds.

[0065] When the number of a linking group is 0, such as -(CRR)0-, it means that the linking group is a single bond.

[0066] When the number of a substituent is 0, it means that the substituent does not exist, for example, -A-(R)0 means that the structure is actually -A.

[0067] When a substituent is vacant, it means that the substituent does not exist. For example, when X in AX is vacant, it means that the structure is actually A.

[0068] When one of the variables is selected from a single bond, it means that the two groups it connects are directly connected. For example, when L in ALZ represents a single bond, it means that the structure is actually AZ.

[0069] When a substituent's bond can cross-link to two or more atoms in a ring, the substituent can be bonded to any atom in the ring, e.g. The substituent R can be substituted at any position on the cyclohexyl group or cyclohexadiene. When the listed substituent does not specify the atom through which it is bonded to the substituted group, the substituent can be bonded through any atom. For example, a pyridyl substituent can be bonded to the substituted group through any carbon atom on the pyridine ring.

[0070] When the linking group is listed without specifying its linking direction, its linking direction is arbitrary, for example, The connecting group L is -MW-, in which case -MW- can connect ring A and ring B in the same direction as the reading order from left to right to form You can also connect ring A and ring B in the opposite direction of reading from left to right to form Combinations of linkers, substituents, and / or variations thereof are permissible only if such combinations result in stable compounds.

[0071] Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the chemical bond connection mode is non-positional and there are H atoms at the connectable sites, when the chemical bond is connected, the number of H atoms at the site will decrease accordingly with the number of connected chemical bonds, and become a group with a corresponding valence. The chemical bond connecting the site to other groups can be a straight solid bond. Straight dotted key or wavy lines For example, the straight solid bond in -OCH3 indicates that it is connected to other groups through the oxygen atom in the group; The straight dashed bond in the group indicates that the two ends of the nitrogen atom in the group are connected to other groups; The wavy line in the phenyl group indicates that it is connected to other groups through the carbon atoms at positions 1 and 2 in the phenyl group; Indicates that any linkable site on the piperidinyl group can be connected to other groups through a chemical bond, including at least In these four connection methods, even if an H atom is drawn on -N-, Still includes For groups connected in this way, when one chemical bond is connected, the H at that site will be reduced by one and become a corresponding monovalent piperidine group.

[0072] Unless otherwise specified, the number of atoms in a ring is generally defined as the number of members of the ring, for example, a "5-7 membered ring" refers to a "ring" having 5-7 atoms arranged around it.

[0073] The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present invention.

[0074] The structures of the compounds of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compounds, the absolute configuration can be confirmed by conventional techniques in the art. For example, single crystal X-ray diffraction (SXRD) is used to collect diffraction intensity data on the cultured single crystal using a Bruker D8 venture diffractometer, using CuKα radiation as the light source and scanning mode: After scanning and collecting relevant data, the crystal structure is further analyzed using the direct method (Shelxs97) to confirm the absolute configuration.

[0075] The present invention uses the following abbreviations: H2O represents water; eq represents equivalent; PE represents petroleum ether; EtOAc represents ethyl acetate; EtOH represents ethanol; MeOH represents methanol; HOAc represents acetic acid; HCl represents hydrochloric acid; HPLC represents high performance liquid chromatography; H2SO4 represents sulfuric acid; HCl / EtOAc represents hydrochloric acid in ethyl acetate; HATU represents O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate; TFA represents trifluoroacetic acid; TEA represents triethylamine; DIEA or DIPEA represents N,N-diisopropylethylamine; mp represents melting point; °C represents degrees Celsius; h represents hours; mL represents milliliters; mM represents millimoles per liter; mmol represents millimoles; μmol represents micromoles; HNMR represents hydrogen nuclear magnetic resonance; MS represents mass spectrometry; min represents minutes; pH represents the negative logarithm of the molar concentration of hydrogen ions; SFC represents supercritical fluid chromatography.

[0076] The solvent used in the present invention is commercially available.

[0077] Compounds were manually or using Software naming, commercially available compounds use supplier catalog names. DETAILED DESCRIPTION

[0078] The present invention is described in detail below by way of examples, but is not intended to limit the present invention in any way. While the present invention has been described in detail herein, and specific embodiments thereof have been disclosed, it will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention.

[0079] Example 1

[0080]

[0081] Synthesis route:

[0082]

[0083] Step 1: Synthesis of compound 1-2

[0084] Compound 1-1 (233 mg), 4-methoxy-o-phenylenediamine (169.99 mg), HATU (584.76 mg), DIPEA (267.88 μL), and DMF (3 mL) were added to a pre-dried flask and stirred at 25°C under nitrogen for 15 h. After completion of the reaction, the mixture was quenched with water (40 mL) and extracted with ethyl acetate (20 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was then purified on a flash silica gel column (petroleum ether:ethyl acetate = 60:40) to afford compound 1-2. 1 H NMR (400MHz, CDCl3) δppm 6.93-7.20 (m, 1H), 6.31 (br d, J=12.30Hz, 2H), 4.43 (s, 1H), 3.80-4.01 (m, 2H), 3.75 (s, 3H), 3.37-3.72 (m, 2H), 1.92 (br s, 1H), 1.62 (br s, 1H), 1.46 (s, 9H), 0.82 (br d, J=6.02Hz, 1H), 0.23 (q, J=4.27Hz, 1H).

[0085] Step 2: Synthesis of Compounds 1-3

[0086] Compound 1-2 (100 mg) and glacial acetic acid (5 mL) were added to a pre-dried flask and stirred at 100°C for 5 h. After completion of the reaction, water (20 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (20 mL) and saturated NaHCO₃ (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford crude compound 1-3, which was used directly in the next step without purification. LCMS m / z = 330.0 [M+H] +

[0087] Step 3: Synthesis of trifluoroacetate salt of compound 1-4

[0088] Compound 1-3 (90 mg) and DCM (2 mL) were added to a pre-dried flask, followed by TFA (2 mL). The mixture was stirred at 25°C under nitrogen for 1 hour. After completion of the reaction, the reaction solution was concentrated to dryness to obtain the crude trifluoroacetate salt of compound 1-4, which was used directly in the next step without purification. LCMS m / z = 230.0 [M+H] +

[0089] Step 4: Synthesis of compound 1

[0090] In a pre-dried flask were added the trifluoroacetate salt of compound 1-4 (60 mg), 2-(2H-1,2,3-triazol-2-yl)benzoic acid (64.36 mg), HATU (149.25 mg), DIPEA (68.37 μL) and solvent DMF (3 mL). The mixture was stirred at 25°C for 15 h. After completion of the reaction, ethyl acetate (10 mL) was added for dilution, and the mixture was extracted with water (20 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was separated by Pre-HPLC (column type: Phenomenex Gemini-NX 80*30mm*3μm; mobile phase: [H2O(10mM NH4HCO3)-ACN]; ACN%: 30%-60%, 9 min) to obtain compound 1. 1 H NMR (400MHz, DMSO-d6) δppm 12.08(br s, 1H), 8.24-8.00 (m, 1H), 7.99-7.70 (m, 2H), 7.68-7.25 (m, 4H), 7.21-6.99 (m, 1H), 6.94-6.72 (m , 1H), 5.35 (s, 0.63H), 4.65 (s, 0.37H), 3.97-3.60 (m, 5H), 1.95-1.52 (m, 2H), 0.91-0.43 (m, 2H). LCMS m / z=401.2[M+H] +

[0091] Example 2

[0092]

[0093] Synthesis route:

[0094]

[0095] Step 1: Synthesis of compound 2-2

[0096] Compound 2-1 (500 mg), HATU (1.25 g), and DMF (10 mL) were added to a pre-dried flask, followed by 4-methoxy-o-phenylenediamine (364.79 mg) and DIPEA (1.15 mL). The mixture was stirred at 15°C for 15 h. After completion of the reaction, the mixture was diluted with ethyl acetate (80 mL) and washed with water (100 mL) and brine (100 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield the crude product, which was then purified on a flash silica gel column (petroleum ether:ethyl acetate = 30:70) to afford compound 2-2. 1 H NMR (400MHz, DMSO-d6) δ9.03 (br s, 1H), 6.73-7.06 (m, 1H), 6.04-6.34 (m, 2H), 4.68-5.01 (m, 2H), 3.96 (br s, 1H), 3.65 (s, 3H), 3.37 (br s, 1H), 2.22-2.39 (m, 1H), 2.06-2.20 (m, 1H), 1.59 (br s, 1H), 1.29-1.47 (m, 9H), 0.72 (td, J=5.55, 8.47Hz, 1H), 0.42 (br s, 1H).

[0097] Step 2: Synthesis of compound 2-3

[0098] Compound 2-2 (500 mg) and glacial acetic acid (10 mL) were added to a pre-dried flask and stirred at 100°C for 1.5 h. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to obtain a crude product. Saturated sodium bicarbonate (80 mL) was added to the crude product and extracted with DCM / MeOH (80 mL×2, 10 / 1). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash silica gel column (petroleum ether: ethyl acetate = 50:50) to obtain compound 2-3. 1 H NMR (400MHz, CDCl3) δ10.41 (br s, 1H), 6.85-7.74 (m, 3H), 4.99 (br s, 1H), 3.84 (s, 3H), 3.24 (br s, 2H), 2.40 (br t, J=10.92Hz, 1H), 1.81 (br s, 1H), 1.50 (br s, 9H), 0.91 (td, J=5.62, 8.60Hz, 1H), 0.50 (br s, 1H).

[0099] Step 3: Synthesis of the hydrochloride salt of compound 2-4

[0100] Compound 2-3 (300 mg) and ethyl acetate (8 mL) were added to a pre-dried flask, followed by HCl / EtOAc (4 M, 8 mL), and stirred at 15° C. for 15 h. After the reaction was complete, the mixture was concentrated and dried to obtain the hydrochloride salt of compound 2-4. 1 H NMR(400MHz, DMSO-d6)δ10.71(br s, 1H), 7.64 (d, J=9.03Hz, 1H), 7.19 (d, J=2.26Hz, 1H), 7.03 (dd, J=2.38, 8.91Hz, 1 H), 4.79-4.93(m, 1H), 3.83(s, 3H), 3.37-3.49(m, 1H), 2.53-2.67(m, 2H), 1.95(br dd, J=4.27, 8.53Hz, 1H), 1.09-1.20 (m, 1H), 0.80-0.92 (m, 1H).

[0101] Step 4: Synthesis of compound 2

[0102] To a pre-dried flask, 2-(2H-1,2,3-triazol-2-yl)benzoic acid (128.14 mg), HATU (372.02 mg), and dichloromethane (10 mL) were added, followed by the hydrochloride salt of compound 2-4 (200 mg) and DIEA (393.27 μL). The mixture was stirred at 15°C for 15 h. After completion of the reaction, the mixture was diluted with dichloromethane (80 mL) and washed with water (80 mL) and brine (80 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield the crude product. The crude product was purified on a flash silica gel column (petroleum ether:ethyl acetate = 30:70) to yield compound 2. 1 H NMR (400MHz, CDCl3) δ8.06 (d, J=8.28Hz, 1H), 7.53-7.64 (m, 4H), 7.44-7.51 (m, 2H), 7.05 (d, J=2.01Hz, 1H), 6.94 (dd, J=2.26, 9.03Hz, 1H), 5.58 (br d, J=5.77Hz, 1H), 3.81 (s, 3H), 2.97-3.09 (m, 2H), 2.44 (dd, J=9.66, 13.18Hz, 1H), 1.89-2.00 (m, 1H), 0.73 (br s, 1H), 0.53 (br s, 1H). LCMS m / z=401.1[M+H] +

[0103] Example 3

[0104]

[0105] Synthesis route:

[0106]

[0107] Step 1: Synthesis of compound 3-2

[0108] To a dry vial, add H2SO4 (50.00 mL), then slowly add HNO3 (2.84 mL, 65% concentration) dropwise at 0°C. Compound 3-1 (5 g) is then slowly added and the reaction is stirred at 15°C for 16 hours. The reaction solution is slowly poured into 100 mL of ice water, and the aqueous phase is extracted with methyl tert-butyl ether (20 mL x 2). The combined organic phases are dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product is homogenized with 50 mL of petroleum ether for 1 hour, then filtered. The filter cake is collected, concentrated, and dried to yield compound 3-2. 1 H NMR (400MHz, CDCl3) δ: 8.06 (d, J=8.8Hz, 1H), 7.70 (d, J=8.8Hz, 1H), 2.43 (s, 3H). MS m / z: 239[M+23] + .

[0109] Step 2: Synthesis of compound 3-3

[0110] In a single-necked flask, compound 3-2 (4.6 g) was dissolved in EtOH (100 mL) and H₂O (50 mL). Fe powder (11.86 g) and NH₄Cl (22.72 g) were added and stirred at 75°C for 16 hours. The reaction solution was diluted with 200 mL of ethanol and filtered. The filter cake was washed with ethanol (200 mL x 2). The filtrate was concentrated and dissolved in 500 mL of ethyl acetate for 30 minutes before filtering and concentrating the filtrate. The crude product was purified by column chromatography (PE:EtOAc = 10:1 to 1:1) to obtain compound 3-3. 1 H NMR (400MHz, CDCl3) δ: 6.74 (d, J=8.4Hz, 1H), 6.55 (d, J=8.4Hz, 1H), 3.41 (br s, 4H), 2.26 (s, 3H). MS m / z: 157[M+H] + .

[0111] Step 3: Synthesis of compound 3-4

[0112] Compound 3-3 (227.42 mg) and compound 1-1 (300 mg) were dissolved in DMF (10 mL) in a dry vial. DIEA (511.83 mg) and tri-n-propyl cyclic phosphoric anhydride ethyl acetate solution (785.10 μL, 50% content) were added under nitrogen at 0°C. The reaction was then stirred at 15°C for 16 hours. The reaction solution was poured into 50 mL of water, and the aqueous phase was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with water (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (PE: EtOAc = 10:1 to 1:1). Compound 3-4 was obtained. MS m / z: 310 [M+H-56] + .

[0113] Step 4: Synthesis of Compound 3-5

[0114] In a dry vial, compound 3-4 (450 mg) was dissolved in DMF (8 mL) and AcOH (703.44 μL) was added. The reaction was stirred at 130°C for 2 hours. The reaction solution was poured into 50 mL of water, and the aqueous phase was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with water (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (PE:EtOAc = 10:1 to 1:1) to obtain compound 3-5. MS m / z: 348 [M+H] + .

[0115] Step 5: Synthesis of the hydrochloride salt of compound 3-6

[0116] Compound 3-5 (310 mg) was dissolved in EtOAc (5 mL) in a dry vial and HCl / EtOAc (4 M, 4.46 mL) was added. The reaction was stirred at 15°C for 16 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product, compound 3-6 hydrochloride, which was used directly in the next step without further purification. MS m / z: 248 [M+H] + .

[0117] Step 6: Synthesis of compound 3

[0118] In a dry vial, the hydrochloride salt of compound 3-6 (100 mg) and 2-(2H-1,2,3-triazol-2-yl)benzoic acid (66.57 mg) were dissolved in THF (5 mL). TEA (146.93 μL) and tri-n-propyl cyclic phosphoric anhydride in ethyl acetate (418.55 μL, 50% purity) were added. The reaction was stirred at 50°C under nitrogen for 16 hours. After completion, the reaction solution was poured into 20 mL of water, and the aqueous phase was extracted with ethyl acetate (10 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by preparative HPLC (Phenomenex Gemini-NX 80*40 mm*3 μm column; mobile phase: [water (containing 10 mM NH4HCO3)-acetonitrile]; acetonitrile percentage: 35%-65%, 8 min) to obtain compound 3. 1 H NMR (400 MHz, DMSO-d 6 )δ: 8.30-7.89 (m, 3H), 7.66-7.63 (m, 1H), 7.58-7.31 (m, 3H), 7.24-7.20 (m, 1H), 5.39 (s, 1H), 4 .15-3.86 (m, 1H), 2.67-2.59 (m, 3H), 2.43-2.32 (m, 1H), 1.82-1.58 (m, 3H), 0.80-0.52 (m, 3H). MS m / z: 419[M+H] + .

[0119] Example 4

[0120]

[0121] Synthesis route:

[0122]

[0123] Step 1: Synthesis of compound 4

[0124] In a dry vial, the trifluoroacetate salt of compound 1-4 (100 mg) and 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid (82.49 mg) were dissolved in THF (5 mL). TEA (157.13 μL) and tri-n-propyl cyclic phosphoric anhydride in ethyl acetate (447.61 μL, 50% content) were added. The reaction was stirred at 50°C under nitrogen for 16 hours. The reaction solution was poured into 20 mL of water, and the aqueous phase was extracted with ethyl acetate (10 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by preparative HPLC (column: Phenomenex Gemini-NX 80*40 mm*3 μm; mobile phase: [water (10 mM NH4HCO3)-acetonitrile]; acetonitrile percentage: 25%-55%, 8 min) to obtain compound 4. 1 H NMR (400MHz, DMSO-d6) δ: 12.17-12.10(m, 1H), 8.09-8.08(m, 2H), 7.77-7.70(m, 1H), 7.49-7.47(m, 1H), 7.41-7.32(m, 1H), 7.20-7.00( m, 2H), 6.93-6.79 (m, 1H), 5.31-4.74 (m, 1H), 3.99-3.76 (m, 6H), 3.07 (m, 1H), 2.51-2.49 (m, 1H), 1.66-1.63 (m, 2H), 0.77-0.54 (m, 2H). MS m / z: 431[M+H] + .

[0125] Example 5

[0126]

[0127] Synthesis route:

[0128]

[0129] The trifluoroacetate salt of compound 1-4 (50 mg), 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid (44.31 mg), and THF (1 mL) were added to a reaction flask. TEA (151.77 μL) and a 50% solution of tri-n-propyl cyclic phosphoric anhydride in ethyl acetate (194.54 μL) were added with stirring, and the mixture was reacted at 50°C for 16 h. The reaction solution was added with water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which was purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30 mm*3 μm; mobile phase: [water (10 mM NH4HCO3)-acetonitrile]; acetonitrile percentage: 25%-45%, 8 min) to obtain compound 5. 1 H NMR (400MHz, DMSO-d6) δ: 10.97-12.91 (m, 1H), 7.81-8.39 (m, 1H), 7.67-7.80 (m, 1H), 7.22-7.65 (m, 3H), 6.87-7.2 1(m, 1H), 6.72-6.86(m, 1H), 6.15-6.58(m, 1H), 4.61-5.38(m, 1H), 3.82-4.02(m, 1H), 3.75-3.81(m, 3H), 2.56(br s, 1H), 2.38-2.44 (m, 2 H), 1.57-1.86 (m, 3H), 0.72-0.80 (m, 1H), 0.51-0.61 (m, 1H). MS m / z: 415[M+H] + .

[0130] Example 6

[0131]

[0132] Synthesis route:

[0133]

[0134] To a reaction flask, the trifluoroacetate salt of compound 1-4 (100 mg), 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid (99.39 mg), and THF (2 mL) were added, stirred, and TEA (303.54 μL) and a 50% solution of tri-n-propyl cyclic phosphoric anhydride in ethyl acetate (389.09 μL) were added. The mixture was reacted at 50°C for 16 h. The reaction solution was added with water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, which was separated and purified by preparative HPLC (column: Phenomenex Gemini-NX C18 75*30 mm*3 μm; mobile phase: [water (10 mM NH4HCO3)-acetonitrile]; acetonitrile percentage: 25%-45%, 8 min) to obtain compound 6. 1 H NMR (400MHz, DMSO-d6) δ: 11.53-12.33 (m, 1H), 8.15-8.26 (m, 1H), 7.74-7.90 (m, 1H), 7.60-7.73 (m, 1H), 7.11-7.60 (m, 3H), 6.52-7. 10 (m, 2H), 4.52-5.50 (m, 1H), 3.90-4.22 (m, 1H), 3.79 (d, J=13.13Hz, 3H), 3.21-3.50 (m, 1H), 1.53-1.94 (m, 2H), 0.33-0.88 (m, 2H). MS m / z: 419[M+H] + .

[0135] Example 7

[0136]

[0137] Synthesis route:

[0138]

[0139] To a reaction flask, the hydrochloride salt of compound 2-4 (100 mg), 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid (97.49 mg), and THF (2 mL) were added, stirred, and TEA (607.08 μL) and a 50% solution of tri-n-propyl cyclic phosphoric anhydride in ethyl acetate (778.18 μL) were added. The mixture was reacted at 15°C for 16 h. After completion of the reaction, water (10 mL) was added, and the mixture was extracted with ethyl acetate (3 × 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [water (10 mM NH4HCO3)-acetonitrile]; acetonitrile percentage: 20%-50%, 8 min) to obtain compound 7. 1 H NMR (400MHz, DMSO-d6) δ: 11.75-12.09 (m, 1H), 7.87-8.16 (m, 2H), 7.63-7.85 (m, 1H), 7.41-7.53(m, 2H), 6.38-7.40(m, 3H), 4.60-5.20(m, 1H), 3.73-3.79(m, 3H), 3.11(br d, J=6.02Hz, 1H), 2.30-2.45 (m, 4H), 1.52-1.81 (m, 2H), 0.46-0.98 (m, 2H). MSm / z:415[M+H] + .

[0140] The chiral purity was determined by chiral SFC (column: Chiralcel OD-3, 50×4.6 mm ID, 3 μm; mobile phase: [supercritical CO2-methanol (containing 0.1% isopropylamine)]; methanol (containing 0.1% isopropylamine) %: 5%-50%, 3 min), retention time = 1.161 min, ee = 100%.

[0141] Example 8

[0142]

[0143] Synthesis route:

[0144]

[0145] To a reaction flask, the hydrochloride salt of compound 2-4 (100 mg), 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid (105.16 mg), and THF (2 mL) were added, stirred, and TEA (607.08 μL) and a 50% solution of tri-n-propyl cyclic phosphoric anhydride in ethyl acetate (778.18 μL) were added. The mixture was allowed to react at 15°C for 16 h. After completion of the reaction, water (10 mL) was added, and the mixture was extracted with ethyl acetate (3 × 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [water (10 mM NH4HCO3)-acetonitrile]; acetonitrile percentage: 20%-95%, 8 min) to obtain compound 8. 1 H NMR (400MHz, DMSO-d6) δ: 11.71 (s, 1H), 7.99-8.15 (m, 1H), 7.81-7.91 (m, 2H), 7.38-7.72 (m, 1H), 7.07-7.36 (m, 2H), 6.44-7.03 (m, 2 H), 4.76-5.18(m, 1H), 3.63-3.91(m, 6H), 3.17-3.20(m, 1H), 2.34-2.38(m, 1H), 1.70-1.85(m, 1H), 1.11(s, 1H), 0.55-0.89(m, 2H). MS m / z: 431[M+H] + Optical rotation: (+) 60.99° ± 0.13° (10.38 mg / mL chloroform solution, length = 50 mm, temperature = 20°C, n = 2). Chiral purity was determined by chiral SFC (column: Chiralpak AS-3, 50 × 4.6 mm ID, 3 μm; mobile phase: [supercritical CO₂-methanol (containing 0.1% isopropylamine)]; methanol (containing 0.1% isopropylamine) %: 5%-50%, 3 min), retention time = 0.980 min, ee = 100%.

[0146] Example 9

[0147]

[0148] Synthesis route:

[0149]

[0150] Step 1: Synthesis of compound 9-2

[0151] Compound 9-1 (4.5 g), 1H-1,2,3-triazole (1.29 g), 1,10-phenanthroline (152.43 mg), cesium carbonate (8.27 g), and 1,4-dioxane (45 mL) were added to a reaction flask. Cuprous iodide (322.18 mg) was added, and the nitrogen atmosphere was replaced three times. The reaction was carried out at 100°C for 16 hours. After the reaction was completed, water (10 mL) was added to the reaction solution, and the pH was adjusted to 1-2 with HCl. The solution was extracted with ethyl acetate (3 × 50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (eluent: DCM: MeOH = 100:1 to 50:1) to obtain compound 9-2. 1 H NMR (400MHz, DMSO-d6) δ: 13.1 (s, 1H), 7.85 (s, 2H), 7.81-7.83 (m, 1H), 7.65-7.68 (m, 1H), 7.46-7.65 (m, 1H). MS m / z: 208[M+H] + .

[0152] Step 2: Synthesis of compound 9

[0153] Compound 9-2 (100.00 mg) and toluene (1 mL) were added to a reaction flask, stirred, and thionyl chloride (38.52 μL) was added. The mixture was reacted at 50°C for 1 hour. The reaction solution was concentrated under reduced pressure and dissolved in 0.5 mL of dichloromethane for later use. Compound 2-4 hydrochloride (100 mg), dichloromethane (1 mL), and triethylamine (261.89 μL) were added to the reaction flask, stirred, cooled to 0°C, and the above dichloromethane solution was added dropwise. The mixture was reacted at 15°C for 16 hours. After the reaction was complete, water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 × 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by HPLC (chromatographic column: Waters Xbridge BEH C18 100*30mm*10μm; mobile phase: [water (10mM NH4HCO3)-acetonitrile]; acetonitrile%: 25%-55%, 8min) to give compound 9. 1H NMR (400MHz, CDCl3) δ: 9.59-11.75 (m, 1H), 7.82 (d, J=2.4, 1H), 7.35-7.69 (m, 4H), 7.04-7.23 (m, 2H), 6.95 (d, J=4, 1H), 5.63 (m, 1H), 3.88 (s, 3H), 3.53 (m, 1H), 2.72-2.83 (m, 1H), 2.30 (m, 1H), 1.92-2.08 (m, 1H), 0.74-0.91 (m, 1H), 0.36-0.62 (m, 1H). MS m / z: 419[M+H] + .

[0154] Example 10

[0155]

[0156] Synthesis route:

[0157]

[0158] Step 1: Synthesis of compound 10-2

[0159] Compound 10-1 (2.8 g), 1H-1,2,3-triazole (811.78 mg), cesium carbonate (5.22 g), 1,10-phenanthroline (96.28 mg), and 1,4-dioxane (28 mL) were added to a reaction flask. Cuprous iodide (203.50 mg) was added and the mixture was reacted at 100°C for 16 hours. After completion of the reaction, water (10 mL) was added to the reaction solution, and the pH was adjusted to 1-2 with HCl. The mixture was extracted with ethyl acetate (3 × 50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (eluent: DCM: MeOH = 100:1 to 50:1) to obtain compound 10-2. 1 H NMR (400MHz, DMSO-d6) δ: 12.9 (s, 1H), 8.06 (s, 2H), 7.67 (d, J=8, 1H), 7.55 (s, 1H), 7.39 (d, J=6.8, 1H), 2.43 (s, 3H). MSm / z:204[M+H] + .

[0160] Step 2: Synthesis of compound 10

[0161] To a reaction flask, the hydrochloride salt of compound 2-4 (100 mg), compound 10-2 (97.49 mg), and tetrahydrofuran (2 mL) were added, stirred, and triethylamine (607.08 μL) and a 50% tri-n-propyl cyclic phosphoric anhydride ethyl acetate solution (778.18 μL, 50% content) were added. The mixture was reacted at 15°C for 16 hours. After completion of the reaction, the reaction solution was added with water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [water (containing 10 mM NH4HCO3)-acetonitrile]; acetonitrile %: 25%-45%, 8 min)-acetonitrile]; acetonitrile %: 45%-75%, 10 min) to obtain compound 10. 1 H NMR (400MHz, DMSO-d6) δ: 11.72-12.20 (m, 1H), 7.87-8.19 (m, 2H), 7.76 (s, 1H), 7.56-7.66 (m, 1H), 6.71-7.47 (m, 4H), 4.53-5.32 ( m, 1H), 3.62-3.81 (m, 3H), 3.30 (s, 1H), 3.02-3.14 (m, 1H), 2.44 (s, 3H), 2.21-2.31 (m, 1H), 1.66-1.80 (m, 1H), 0.49-1.04 (m, 2H). MS m / z: 415[M+H] + .

[0162] Example 11

[0163]

[0164] Synthesis route:

[0165]

[0166] Step 1: Synthesis of compound 11-2

[0167] Compound 11-1 (3 g), 1H-1,2,3-triazole (856.80 mg), cesium carbonate (5.51 g), 1,10-phenanthroline (101.62 mg), and 1,4-dioxane (30 mL) were added to a reaction flask, along with cuprous iodide (214.79 mg). The mixture was reacted at 100°C for 16 hours. After completion of the reaction, water (10 mL) was added to the reaction solution, the pH was adjusted to 1-2 with HCl, and the mixture was extracted with ethyl acetate (3 × 50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (eluent DCM: MeOH = 100: 1 to 50: 1) and the obtained product was further purified by preparative HPLC (chromatographic column: Phenomenex luna C18 (250*70mm, 15μm); mobile phase: [water (containing HCl)-acetonitrile]; acetonitrile%: 8%-38%, 20min) to give compound 11-2. 1 H NMR (400MHz, DMSO-d6) δ: 13.3 (s, 1H), 8.08 (s, 2H), 7.79-7.82 (m, 1H), 7.57-7.63 (m, 2H). MS m / z: 208[M+H] + .

[0168] Step 2: Synthesis of compound 11

[0169] To a reaction flask, the hydrochloride salt of compound 2-4 (50 mg), compound 11-2 (49.69 mg), and N,N-dimethylformamide (1 mL) were added, stirred, and N,N-diisopropylethylamine (113.95 μL) and HATU (165.84 mg) were added. The mixture was reacted at 15°C for 16 hours. After completion of the reaction, the reaction solution was added with water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [water (containing 10 mM NH4HCO3)-acetonitrile]; acetonitrile percentage: 20%-50%, 8 min) to obtain compound 11. 1H NMR (400MHz, DMSO-d6) δ: 11.75-12.21 (m, 1H), 7.80-8.24 (m, 3H), 7.69 (dd, J=8.13, 3.25Hz, 1H), 7.19-7.56 (m, 2H), 6.60-7.14 ( m, 2H), 4.66-5.21 (m, 1H), 3.69-3.81 (m, 3H), 3.31 (s, 1H), 3.19 (s, 1H), 2.34-2.42 (m, 1H), 1.72-1.84 (m, 1H), 0.55-1.03 (m, 2H). MS m / z: 419[M+H] + .

[0170] Example 12

[0171]

[0172] Synthesis route:

[0173]

[0174] Step 1: Synthesis of compound 12-2

[0175] Compound 12-1 (1 g), 1H-1,2,3-triazole (285.60 mg), cesium carbonate (1.84 g), 1,10-phenanthroline (33.87 mg), and 1,4-dioxane (10 mL) were added to a reaction flask. Cuprous iodide (71.60 mg) was added and the mixture was reacted at 100°C for 16 hours. After completion of the reaction, water (10 mL) was added to the reaction solution, and the pH was adjusted to 1-2 with HCl. The mixture was extracted with ethyl acetate (3 × 30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (eluent: DCM: MeOH = 100:1 to 50:1) to obtain compound 12-2. 1 H NMR (400MHz, DMSO-d6) δ: 13.67 (s, 1H), 8.16 (s, 2H), 7.71-7.80 (m, 1H), 7.68-7.70 (m, 1H), 7.44-7.47 (m, 1H).

[0176] Step 2: Synthesis of compound 12

[0177] To a pre-dried single-necked vial, the hydrochloride salt of compound 2-4 (50 mg), compound 12-2 (35.08 mg), and acetonitrile (1 mL) were added and stirred. Subsequently, the reagents N,N-diisopropylethylamine (65.55 μL), N-methylimidazole (52.49 μL), and N,N,N,N-tetramethylchloroformamidine hexafluorophosphate (63.35 mg) were added. The reaction was incubated at 15°C for 16 hours. After completion, the reaction solution was added with water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [water (containing 10 mM NH4HCO3)-acetonitrile]; acetonitrile percentage: 20%-50%, 8 min) to obtain compound 12. 1 H NMR (400MHz, DMSO-d6) δ: 11.34-12.19(m, 1H), 8.10-8.29(m, 1H), 7.63-7.92(m, 2H), 7.39-7.54(m, 2H), 6.59-7.37(m, 3H), 4.52-5.52(m, 1H) ), 3.70-3.87(m, 3H), 3.12-3.31(m, 1H), 2.77-2.99(m, 1H), 2.34-2.63 (m, 1H), 1.74-1.97 (m, 1H), 0.72-1.18 (m, 1.5H), 0.24-0.50 (m, 0.5H). MS m / z: 419[M+H] + .

[0178] Example 13

[0179]

[0180] Synthesis route:

[0181]

[0182] Step 1: Synthesis of compound 13

[0183] To a reaction flask, the hydrochloride salt of compound 2-4 (30 mg), 5-methyl-2-(pyrimidin-2-yl)benzoic acid (25.23 mg), and tetrahydrofuran (1 mL) were added, stirred, and triethylamine (91.06 μL) and a solution of tri-n-propyl cyclic phosphoric anhydride in ethyl acetate (233.45 μL, 50%) were added. The mixture was reacted at 15°C for 16 hours. After completion of the reaction, water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 × 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 1:1 to 0:1). The obtained product was further purified by HPLC (chromatographic column: Waters Xbridge BEH C18 100*30mm*10μm; mobile phase: [water (containing 10mM NH4HCO3)-acetonitrile]; acetonitrile%: 25%-55%, 8min) to obtain compound 13. 1 H NMR (400MHz, CDCl3) δ: 8.18-8.33 (m, 3H), 7.33-7.62 (m, 2H), 7.28 (s, 1H), 7.04-7.19 (m, 1H), 6.89-7.00 (m, 2H), 5.64 (dd, J=8.82, 2.69Hz, 1H), 3.88(s, 3H), 3.57(m, 1H), 2.81-2.93(m, 1H), 2.47(s, 3H), 2.29- 2.41 (m, 1H), 1.94-2.04 (m, 1H), 0.69-0.84 (m, 1H), 0.48-0.61 (m, 1H). MS m / z: 426[M+H] + .

[0184] Example 14

[0185]

[0186] Synthesis route:

[0187]

[0188] Step 1: Synthesis of compound 14-2

[0189] Compound 14-1 (9 g), 1H-1,2,3-triazole (2.42 g), and 1,4-dioxane (90 mL) were added to a reaction flask and stirred. Cesium carbonate (15.57 g), 1,10-phenanthroline (287.10 mg), and cuprous iodide (606.82 mg) were then added. The nitrogen atmosphere was replaced three times and the reaction was carried out at 100°C for 16 hours. After the reaction was completed, water (10 mL) was added to the reaction solution, the pH was adjusted to 1-2 with HCl, and the mixture was extracted with ethyl acetate (3 × 100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (eluent: DCM: MeOH = 100:1 to 50:1) to obtain compound 14-2. 1 H NMR (400MHz, DMSO-d6) δ: 13.46 (s, 1H), 8.1 (s, 2H), 7.77-7.82 (m, 3H). MS m / z: 224[M+H] + .

[0190] Step 2: Synthesis of compound 14

[0191] Acetonitrile (1 mL) was added to the reaction flask. Compound 2-4 hydrochloride (50 mg), compound 14-2 (43.89 mg), N,N-diisopropylethylamine (75.97 μL), N-methylimidazole (60.84 μL), and N,N,N,N-tetramethylchloroformamidine hexafluorophosphate (73.43 mg) were added with stirring at 15°C. The mixture was allowed to react at 15°C for 16 hours. After completion of the reaction, the reaction solution was added with water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [water (containing 10 mM NH4HCO3)-acetonitrile]; acetonitrile percentage: 30%-60%, 8 min) to obtain compound 14. 1 H NMR (400MHz, CDCl3) δ: 8.03 (d, J=8.63Hz, 1H), 7.38-7.62 (m, 5H), 7.06-7.18 (m, 1H), 6.96 (dd, J=8.82, 2.31Hz, 1H), 5.63 (d d, J=8.57, 2.19Hz, 1H), 3.89 (s, 3H), 3.53 (m, 1H), 2.83 (t, 1H), 2.33 (m, 1H), 1.98-2.10 (m, 1H), 0.78-0.91 (m, 1H), 0.54 (br s, 1H).MS m / z: 435[M+H] + .

[0192] Biological testing

[0193] Experimental Example 1: In vitro activity test of OX1 and OX2 receptors

[0194] Purpose of the experiment:

[0195] The changes in intracellular calcium signals were detected by FLIPR, and the IC 50 The values ​​were used as indicators to evaluate the antagonistic effects of the compounds on OX1R and OX2R receptors.

[0196] Experimental Materials:

[0197] Cell lines: HEK293-OX1R and HEK293-OX2R stable cell lines

[0198] HEK293-OX1R cell culture medium (DMEM, Invitrogen #11960-044, 10% serum Gibco #10099141, L-Glutamine 1×, Gibco #25030, sodium pyruvate 1×, Gibco #11360, Geneticin 300 μg / mL, Gibco #10131)

[0199] HEK293-OX2R cell culture medium (DMEM, Invitrogen #11960-044, 10% serum Gibco #10099141, L-Glutamine 1×, Gibco #25030, sodium pyruvate 1×, Gibco #11360, Geneticin 300 μg / mL, Gibco #10131, Blasticin 2 μg / mL, Invitrogen #R21001)

[0200] Table 1. Reagents, instruments, brands and product numbers used

[0201]

[0202] Experimental steps and methods:

[0203] a) Cell seeding (HEK293-OX1R and HEK293-OX2R cells)

[0204] 1) Preheat culture medium, trypsin, and DPBS in a 37°C water bath. Aspirate the culture medium and rinse the cells with 10 mL of DPBS.

[0205] 2) Add preheated trypsin to the culture flask, swirl the flask to evenly cover the flask with trypsin, and place in a 37°C, 5% CO2 incubator for 1-2 minutes.

[0206] 3) Suspend cells in 10-15 mL of culture medium per T150 tube, centrifuge at 800 rpm for 5 minutes, resuspend cells in 10 mL of culture medium, aspirate 1 mL of the cell suspension, and count cells using a Vi-cell.

[0207] 4) Dilute OX1R cells to 5×10 5 / mL, OX2R cells to 4×10 5 / mL, add the diluted cells to a 384 plate (Greiner.781946) using a dispenser (50 μL / well, 25,000 cells / well for OX1R cells, 20,000 cells / well for OX2R cells), and place the cell plate in a 37°C, 5% CO2 incubator overnight.

[0208] b) Compound addition:

[0209] 1) Dilute the compound to 20 mM with DMSO in a 3-fold dilution series of 8 replicates, and add it to the compound plate using an Echo liquid handler. Then, add 20 μL of buffer to ensure a final DMSO concentration of 0.1%.

[0210] c) FLIPR experiment:

[0211] 1) Wash out the cell culture medium in the 384-well plate using a vacuum pump, add 30 μL of Fluo-4 Direct fluorescent dye, incubate in a 37°C, 5% CO2 incubator for 1 hour, and then equilibrate at room temperature for 10 minutes.

[0212] 2)EC 50 Test: Manually dilute OrexinA on ice in a 3-fold dilution series with eight replicates. Prepare a DMSO plate with a DMSO concentration of 0.5%. Place the cell plate, OrexinA plate, and DMSO plate into the FLIPR and read the fluorescence.

[0213] 3) EC through OrexinA 50 value, calculate EC 70 Value, prepare 5×EC 70 The solution was added to the 384 compound plate using a dispenser and stored on ice.

[0214] 4) In FLIPR, place compound plates, 5×EC 70 Plate, cell plate, FLIPR pipette tip, run the program, and read the fluorescence value.

[0215] d) Data analysis: Prism 5.0 was used to analyze the data and calculate the IC of the compounds. 50 value.

[0216] The experimental results are shown in Table 2:

[0217] Table 2. FLIPR Detection IC 50 Test results

[0218] Compound No. hOX1R IC 50 (nM)hOX2R IC 50 (nM) Compound 1 > 1000025 Compound 2 > 1000072 Compound 446264 Compound 533796 Compound 61416299 Compound 787724 Compound 8179442 Compound 9317042 Compound 1071017 Compound 11360233 Compound 12127881 Compound 13244460 Compound 14103630

[0219] Conclusion: The compounds of the present invention have certain antagonistic activity against human orexin receptors and show higher activity against OX2 receptors.

[0220] Experimental Example 2: Determination of pharmacokinetic parameters of the test substance in SD rat plasma

[0221] Four healthy male SD rats aged 6-9 weeks were selected and randomly divided into two groups, with 2 rats in each group. One group was given the test compound 2 mg / kg by intravenous injection, and the other group was given the test compound 10 mg / kg by oral gavage. Plasma samples were collected from the animals in the intravenous and oral gavage groups at 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, and 24 hours after administration. Quantitative analysis of all biological samples was performed using LC-MS / MS, and WinNonlin TM Version 6.3 (Pharsight, Mountain View, CA) pharmacokinetic software was used to calculate relevant pharmacokinetic parameters using the non-compartmental linear logarithmic trapezoidal method. 0-last represents the area under the plasma concentration-time curve from time zero to the last time point with detectable concentration; po stands for oral administration; iv stands for intravenous injection; T 1 / 2 represents half-life; CL represents clearance; Vd represents apparent volume of distribution; C max represents peak concentration; T max represents the time to peak; F% represents the oral bioavailability. The experimental results are shown in Table 3.

[0222] Table 3. Pharmacokinetic properties of the tested compounds

[0223]

[0224] Conclusion: The compounds of the present invention exhibited good pharmacokinetic properties in SD rats.

[0225] Experimental Example 3: Determination of drug concentration of the test substance in SD rat brain tissue

[0226] Four healthy male Sprague-Dawley rats aged 6-9 weeks were administered the test compounds via oral gavage. Two animals were randomly selected for euthanasia at 0.5 and 2 hours after administration, respectively. Plasma and brain tissue samples were collected and quantitatively analyzed using LC-MS / MS. The results are shown in Table 4.

[0227] Table 4. Brain-to-blood ratio of the test compounds in rats

[0228]

[0229] Conclusion: The compounds of the present invention can penetrate the blood-brain barrier and enter the brain tissue in rats.

[0230] Experimental Example 4: Determination of the proportion of free drug in the brain tissue of SD rats

[0231] Brain tissue homogenates from SD rats (i.e., matrix, purchased from BioIVT) were added to a working solution of the test compound in DMSO or a working solution of the control (propranolol) in DMSO, resulting in a final concentration of 2 μM for both the test compound and propranolol in the plasma sample. The samples were then thoroughly mixed. The final DMSO concentration was controlled to 0.5%. 50 μL was pipetted into a sample receiving plate and immediately added with the corresponding volume of blank matrix / buffer, bringing the final volume per well to 100 μL. The matrix:dialysis buffer volume ratio was 1:1. Stop solution was then added to these samples, which served as the T0 sample for recovery and stability determination. The test compound and propranolol samples were added to the dosing port of each dialysis well, and blank dialysis buffer was added to the receiving port of the corresponding dialysis well. The plates were then incubated in a humidified 5% CO2 incubator at 37°C with shaking at 100 rpm for 4 hours. After dialysis, transfer 50 μL of the dialyzed buffer sample and the dialyzed brain tissue homogenate sample to a new sample receiving plate. Add the corresponding volume of blank matrix / buffer to the sample so that the final volume of each sample well is 100 μL and the volume ratio of plasma to dialysis buffer is 1:1. ∶ 1. All samples were subjected to protein precipitation and then analyzed by LC / MS / MS. The unbound rate (% Unbound), bound rate (% Bound), and recovery rate (% Recovery) of the compound were calculated using the following formula:

[0232] %Unbound=100*F C / T C ,

[0233] %Bound=100-%Unbound,

[0234] %Recovery=100*(F C +T C ) / T0.

[0235] Among them F C is the concentration of the compound at the buffer end of the dialysis plate; T C is the concentration of the compound at the matrix end of the dialysis plate; T0 is the concentration of the compound in the plasma sample at time zero. The experimental results are shown in Table 5.

[0236] Table 5. SD rat brain tissue binding rate test results

[0237] Compound No. SD rat brain tissue_Unbound (%) Compound 821.8%

[0238] Conclusion: The proportion of the unbound drug of the compound of the present invention in the brain tissue of SD rats is relatively high.

[0239] Experimental Example 5: Determination of pharmacokinetic parameters of the test substance in beagle dog plasma

[0240] Four healthy male beagle dogs were randomly divided into two groups, with two dogs in each group. One group was given the test compound 1 mg / kg by intravenous injection, and the other group was given the test compound 5 mg / kg by oral gavage. Plasma samples were collected from the animals in the intravenous and oral gavage groups at 0.033, 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, and 24 hours after administration. Quantitative analysis of all biological samples was performed using LC-MS / MS, and WinNonlin TM Version 6.3 (Pharsight, Mountain View, CA) pharmacokinetic software was used to calculate relevant pharmacokinetic parameters using the non-compartmental linear logarithmic trapezoidal method. 0-last represents the area under the plasma concentration-time curve from time zero to the last detectable concentration time point; po stands for oral administration; iv stands for intravenous injection; T 1 / 2 represents half-life; CL represents clearance; Vd represents apparent volume of distribution; C max represents peak concentration; T max represents the time to peak; F% represents the oral bioavailability. The experimental results are shown in Table 6.

[0241] Table 6 Pharmacokinetic properties of the test compounds

[0242]

[0243]

[0244] Conclusion: The compounds of the present invention exhibited good pharmacokinetic properties in beagle dogs.

[0245] Experimental Example 6: Determination of drug concentration of the test substance in the cerebrospinal fluid of beagle dogs

[0246] Two healthy male beagle dogs were orally administered with the test compound at 5 mg / kg. Cerebrospinal fluid samples were collected at 0.5 hours, 2 hours, and 6 hours after administration. Quantitative analysis of all biological samples was performed using LC-MS / MS. WinNonlin TM Version 6.3 (Pharsight, Mountain View, CA) pharmacokinetic software was used to calculate relevant pharmacokinetic parameters using the non-compartmental linear logarithmic trapezoidal method. 0-last represents the area under the plasma concentration-time curve from time zero to the last detectable concentration time point; po stands for oral administration; iv stands for intravenous injection; T 1 / 2 represents half-life; CL represents clearance; Vd represents apparent volume of distribution; C max represents peak concentration; T max represents the time to peak; F% represents the oral bioavailability. The experimental results are shown in Table 7.

[0247] Table 7. Drug concentrations of test compounds in dog cerebrospinal fluid

[0248]

[0249] Conclusion: The compounds of the present invention can be detected in canine CSF, indicating that the compounds can cross the blood-brain barrier and reach the brain.

[0250] Experimental Example 7: Effects of the test substance on spontaneous activity of SD rats

[0251] The purpose of the test is to determine the effect of the test compound on the activity of rats by measuring the distance of spontaneous activity of rats over a period of time.

[0252] Experimental plan: 12 7-week-old male SD rats were acclimated to the environment in the laboratory one day before the start of the test. On the day of the experiment, they were randomly divided into 2 groups according to body weight, with 6 rats in each group, and given blank solvent and 30 mg / kg compound 8 respectively. The animals were placed in the test box 30 minutes after administration, and the distance data of the animal's activities were recorded every 5 minutes using Any-maze software for 60 minutes. By comparing the total distance of the animal's activities during the recording time, it was determined whether the drug had a significant effect on the animal's spontaneous activity. The experimental data are represented by mean ± standard deviation (Mean ± SEM), and the statistical method used was one-way analysis of variance with Dunnett's multiple comparisons. p < 0.05 is represented as *, p < 0.01 is represented as **, and p < 0.001 is represented as ***. The experimental results are shown in Table 8.

[0253] Table 8. Rat spontaneous activity test data

[0254]

[0255] Conclusion: The compound of the present invention can significantly reduce the spontaneous activity distance of SD rats.

[0256] Experimental Example 8: Evaluation of the Effect of the Test Substance on Sleep in SD Rats Using EEG / EMG Telemetry

[0257] Experimental purpose: To evaluate the effects of the test substance on the sleep of SD rats by electroencephalography / electromyography (EEG) technology.

[0258] Experimental Protocol: Thirty-six male Sprague-Dawley rats, aged 5-6 weeks, underwent a 5-15 day acclimation period upon arrival. During this period, the animals were placed in a 12-hour light-dark cycle (lights on: 7:00 PM; lights off: 7:00 AM) to adjust their circadian rhythm, and their health was monitored daily. The animals underwent surgical implantation of EEG and EMG electrodes to enable subsequent telemetry data collection. On the day of surgery, the animals were anesthetized with Zolpidem (20 mg / kg per ip) combined with thiazide (8 mg / kg per ip). After anesthesia, the rats were fixed in a stereotaxic apparatus. After hair clipping and disinfection, the head was cut open and the four corners of the skull were clamped with hemostats to fully expose the skull. The periosteum was then stripped and wiped clean with dry cotton wool until the surface was dry. Holes were drilled according to the implant model, and the electrodes were implanted, contacting the dura mater. Dental cement was used to secure the electrodes to the skull, and any cement dripping onto the tissue and skin was cleaned. Two electromyographic electrodes were inserted into the neck muscles in parallel and fixed at both ends with sutures to prevent their ends from touching each other. The implant was then placed subcutaneously, and the surgical wound was sutured and disinfected. After surgery, the rats were carefully placed in a clean recovery cage in a lateral position to ensure airway patency. They were housed in individual cages in a shielded recovery room with 12-hour automatic light and dark alternation (lights on: 19:00, lights off: 07:00), a temperature of 20-26°C, and a relative humidity of 40-70%. The animals were cared for for 3 days after surgery, the surgical incision was treated with cephaladin powder locally, gentamicin 4-8 mg / kg was administered subcutaneously, and meloxicam 0.1 mL / animal was injected subcutaneously for 3 consecutive days. Experiments were performed after 7-10 days of recovery. The animals were randomly divided into groups based on their body weight the day before the experiment.

[0259] On the day of the experiment, basic EEG and EMG recordings were performed first. After completion, drug administration began. EEG and EMG recordings were maintained during and after drug administration until 24 hours after drug administration. Raw data were collected by DSI system Ponemah software and analyzed by NeuroScore software. Experimental data were expressed as mean ± standard error (Mean ± SEM) and statistically analyzed using the one-way ANOVA method. Compared with the blank solvent group, P < 0.05 indicated a significant difference, indicated by *; P < 0.01 indicated a very significant difference, indicated by **; P < 0.001 indicated an extremely significant difference, indicated by ***. The experimental results are shown in Table 9.

[0260] Table 9. Rat EEG test data

[0261]

[0262] Conclusion: 10 mg / kg and 30 mg / kg of the compound of the present invention significantly shortened sleep latency in SD rats. 30 mg / kg of the compound of the present invention significantly reduced wakefulness and increased sleep time within 7 hours of administration. Therefore, the compound of the present invention has a good sleep-promoting effect.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, selected from: wherein, Each R1 is independently selected from halogen, cyano, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are each independently optionally substituted by 1, 2 or 3 halogen atoms; Each R2 is independently selected from halogen, cyano, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are each independently optionally substituted by 1, 2 or 3 halogen atoms; R3 is selected from H, C 1-3 alkyl, and C 3-6 cycloalkyl; m and n are each independently selected from 0, 1, 2, and 3; Ring A is selected from Ring B is selected from 2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein, Each R1 is independently selected from halogen, cyano, methyl, and methoxy, and the methyl and methoxy are each independently optionally substituted with 1, 2, or 3 F.

3. The compound or a pharmaceutically acceptable salt thereof according to claim 2, wherein, Each R1 is independently selected from F, Cl, methyl, and methoxy.

4. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein, Each R2 is independently selected from halogen, cyano, methyl, and methoxy, and the methyl and methoxy are each independently optionally substituted with 1, 2, or 3 F.

5. The compound or a pharmaceutically acceptable salt thereof according to claim 4, wherein, Each R2 is independently selected from F, Cl, methyl, and methoxy.

6. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein, R3 is selected from H, methyl, and cyclopropyl.

7. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 - 6, wherein, The compound is selected from the structures shown in formula (I-1), (I-2), and (I-3), wherein R1, R2, R3, m, and n are as defined in any one of claims 1 to 6.

8. A compound of the following formula or a pharmaceutically acceptable salt thereof:

9. The compound or a pharmaceutically acceptable salt thereof according to claim 8, wherein, The compound is selected from:

10. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 - 9 in the preparation of a medicament for treating diseases related to selective orexin - 2 receptor antagonists.

11. The use according to claim 10, wherein the diseases related to selective orexin - 2 receptor antagonists are selected from insomnia and / or depression.