Tetrahydropyrrolocyclic compounds and their uses

Abstract

Disclosed is the use of a tetrahydropyrrolo ring compound represented by formula (I), a pharma- ceutically acceptable salt thereof, and the like in the manufacture of a medicament for treating a disease associated with a selective orexin-2 (OX-2) receptor antagonist, selected from insomnia and depression. [Formula 1] JPEG2024504854000064.jpg5592

Description

[Technical field]

[0001] This application claims priority to: CN2021101461359, the filing date is February 2, 2021; CN2021106175620, the filing date is June 2, 2021; CN2021109065355, the filing date is August 11, 2021; CN2021116252159, application date is December 27, 2021.

[0002] The present invention relates to a class of tetrahydropyrrolocyclic compounds, in particular, compounds represented by formula (I) and pharma- ceutically acceptable salts thereof: [Background technology]

[0003] Orexin (Hypocretin) signaling is mediated by two receptors and two peptide agonists. Orexin A and orexin B bind to two high affinity receptors called orexin 1 receptor (OX-1 receptor) and orexin 2 receptor (OX-2 receptor). OX-1 receptor has high affinity for orexin A, whereas OX-2 receptor binds to orexin A and orexin B with the same affinity. Orexin-secreting neurons are mainly distributed in the prefrontal nucleus, dorsal hypothalamus, and lateral hypothalamus (C. Peyron et al., J. Neurosci., 1998, 18(23), 9996- 10015). Secreted orexin affects many areas of the brain and is involved 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, and rodents administered orexin intraperitoneally have a prolonged wakefulness state (Piper et al., J. Neurosci. 2000, 12, 726-730). Meanwhile, mutated or dysfunctional orexin-2 receptors cause narcolepsy in dogs (Lin et al., Cell 1999, 98, 365-376), and orexin signaling is insufficient in the cerebrospinal fluid of humans with narcolepsy (Nishino et al., Lancet 2000, 355, 39-40). All these indicate that the orexin system promotes wakefulness in people, and that inhibiting the orexin system is beneficial for promoting sleep. Thus, orexin receptor antagonists can be used to treat diseases such as insomnia, depression, anxiety, drug addiction, psychosis, dementia, schizophrenia, Parkinson's disease, Alzheimer's disease, insulin resistance, type II diabetes, hyperlipidemia, gallstones, angina pectoris, hypertension, dyspnea, tachycardia, infertility, sleep apnea, back and joint pain, varicose veins and osteoarthritis. Summary of the Invention

[0004] The present invention provides a compound selected from the formula: or a pharma- ceutically acceptable salt thereof.

[0005] [ka]

[0006] however, Each R 1 are each independently halogen, cyano, or C 1-3 Alkyl and C 1-3 alkoxy, 1-3 Alkyl and C 1-3 each alkoxy is optionally substituted with 1, 2 or 3 halogen atoms; Each R 2 are each independently halogen, cyano, or C 1-3 Alkyl and C 1-3 alkoxy, 1-3 Alkyl and C 1-3 each alkoxy is optionally substituted with 1, 2 or 3 halogen atoms; R 3 , 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

[0007] [ka]

[0008] is selected from Ring B is

[0009] [ka]

[0010] is selected from.

[0011] In some embodiments of the present invention, each R 1 are each independently selected from halogen, cyano, methyl and methoxy, wherein said methyl and methoxy are each independently optionally substituted with 1, 2 or 3 F, and the other variables are as defined herein.

[0012] In some embodiments of the present invention, each R 1 are each independently selected from F, Cl, methyl and methoxy, and all other variables are as defined herein.

[0013] In some embodiments of the present invention, each R 2 are each independently selected from halogen, cyano, methyl and methoxy, wherein said methyl and methoxy are each independently optionally substituted with 1, 2 or 3 F, and the other variables are as defined herein.

[0014] In some embodiments of the present invention, each R 2 are each independently selected from F, Cl, methyl and methoxy, and all other variables are as defined herein.

[0015] In some embodiments of the present invention, the R 3 is selected from H, methyl and cyclopropyl, and the other variables are as defined herein.

[0016] In some embodiments of the present invention, the compound is selected from structures represented by formulas (I-1), (I-2) and (I-3).

[0017] [ka]

[0018] However, R 1 , R 2 , R 3 , m and n are as defined herein. Some embodiments of the present invention are further formed by any combination of the variables described above. The present invention further provides a compound selected from the formula: or a pharma- ceutically acceptable salt thereof.

[0019] [ka]

[0020] [ka]

[0021] In some embodiments of the present invention, in the above compound or a pharma- ceutically acceptable salt thereof, the compound is selected from the following formula:

[0022] [ka]

[0023] [ka]

[0024] The present invention further provides the use of the above compound or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for treating a disease associated with a selective orexin-2 receptor antagonist.

[0025] In some embodiments of the present invention, the disease associated with the selective orexin-2 receptor antagonist is selected from insomnia and / or depression.

[0026] The present invention further provides the following test method.

[0027] 1. Measurement of pharmacokinetic parameters in rat plasma Four healthy SD rats aged 6-9 weeks were selected and randomly divided into two groups, two rats in each group. One group was administered 2 mg / kg of the test compound by intravenous injection, and the other group was administered 10 mg / kg of the test compound by intragastric administration. Plasma samples were collected from both the intravenous and intragastric 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 an LC-MS / MS method, and relevant pharmacokinetic parameters were calculated using the non-compartmental model linear logarithmic ladder method using WinNonli™ Version 6.3 (Pharsight, Mountain View, CA) pharmacokinetic software. AUC 0-last represents the area under the plasma concentration-time curve from time 0 to the time of the last detectable concentration; po represents oral administration; iv represents intravenous administration; T 1 / 2 represents the half-life, CL represents the clearance, Vd represents the apparent volume of distribution, and C max represents the peak concentration, and T max represents the peak time and F% represents the oral bioavailability.

[0028] 2. Measurement of drug concentrations in rat brain tissue Four healthy SD rats aged 6-9 weeks were selected, and the other group was administered 10 mg / kg of the test compound via intragastric administration. Two animals were randomly selected at 0.5 and 2 hours after administration, and plasma and brain tissue samples were collected. All biological samples were quantitatively analyzed using LC-MS / MS method. (Effects of the Invention)

[0029] As OX-2 receptor antagonists, the compounds of the present invention have selective antagonistic effects on OX-2 receptors and show excellent activity in in vitro tests, and can be used to develop drugs for treating psychiatric disorders related to the orexin signal pathway, such as insomnia, depression, etc. The compounds of the present invention show excellent pharmacokinetic properties in rats, and can penetrate the fluid-brain barrier and penetrate into brain tissue in rats, thereby reaching higher drug concentrations.

[0030] (Definitions and Explanations) Unless otherwise stated, the following terms and phrases used herein have the following meanings. A particular term or phrase, unless otherwise defined, should be understood as being of ordinary definition, not indefinite or unclear. When a trade name is mentioned in this specification, it refers to the corresponding product or its active ingredient.

[0031] As used herein, "pharmacologically acceptable" refers to those compounds, materials, compositions and / or dosage forms which are within the scope of sound medical judgment, suitable for contact with human and animal tissues, without significant toxicity, irritation, allergic response or other problem or complication, and consistent with a reasonable benefit / risk ratio.

[0032] The term "pharmaceutical acceptable salt" refers to a salt of a compound of the present invention, which is prepared with a relatively non-toxic acid or base with a compound having certain substituents discovered in this invention. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting these compounds with a sufficient amount of base in a separate 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 these compounds with a sufficient amount of acid in a separate solution or in a suitable inert solvent. Examples of pharma- ceutically acceptable acid addition salts include inorganic and organic acid salts, as well as salts of amino acids (such as arginine) and organic acids such as glucuronic acid, such as inorganic acids including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, and the like, and organic acids including, for example, 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, methanesulfonic acid, and the like. Certain compounds of the present invention contain both basic and acidic functional groups and can therefore be converted into any suitable base or acid addition salt.

[0033] The pharma- ceutically acceptable salts of the present invention can be synthesized in a conventional manner from the parent compound which contains an acidic or basic group. Typically, such salts are prepared by reacting the compound in its free acid or base form with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture of both.

[0034] Unless otherwise defined, the term "C 1-3 "Alkyl" refers to a saturated hydrocarbon group consisting of 1 to 3 carbon atoms in a straight or branched chain. 1-3 Alkyl has C 1-2 and C. 2-3Alkyl, which may be monovalent (e.g., methyl), divalent (e.g., methylene) and polyvalent (e.g., methine). 1-3 Examples of alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl).

[0035] Unless otherwise defined, the term "C 1-3 "Alkoxy" refers to an alkyl group containing 1 to 3 carbon atoms linked to the remainder of the molecule via an oxygen atom. 1-3 Alkoxy is C 1-2 , C 2-3 , C 3 and C 2 Alkoxy and the like are included. C 1-3 Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy or isopropoxy), and the like.

[0036] Unless otherwise defined, "C 3-6 "Cycloalkyl" is a saturated hydrocarbon group consisting of 3 to 6 carbon atoms, which represents monocyclic and bicyclic ring systems, and is defined as above. 3-6 Cycloalkyl is C 3-5 , C 4-5 and C 5-6 cycloalkyl, etc.; it may be monovalent, divalent or polyvalent. C 3-6 Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0037] Unless otherwise defined, the terms "halogen" or "halo," by themselves or as part of another substituent, mean a fluorine, chlorine, bromine, or iodine atom.

[0038] Unless otherwise specified, the term "isomer" is intended to include geometric isomers, cis-trans isomers, stereoisomers, enantiomers, optical isomers, enantiomers and tautomers.

[0039] 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 and other mixtures thereof, such as mixtures enriched in enantiomers or non-enantiomers, and all such mixtures are within the scope of the present invention. Other asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers and mixtures thereof are both within the scope of the present invention.

[0040] Unless otherwise stated, the terms "enantiomers" or "optical isomers" are stereoisomers that are mirror images of each other.

[0041] Unless otherwise stated, the terms "cis-trans isomers" or "geometric isomers" refer to the inability to freely rotate about double bonds or single bonds of ring carbon atoms.

[0042] Unless otherwise explained, the term "diastereomer" is a stereoisomer whose molecules have two or more centers of chirality and whose molecules are not mirror-images of each other.

[0043] Unless otherwise specified, "(+)" means dextrorotatory, "(-)" means levorotatory, and "(±)" means racemic.

[0044] [ka]

[0045] Unless otherwise explained, the terms "enriched in one isomer," "isomer-enriched," "enriched in one enantiomer," or "enantiomer-enriched" mean that the amount of one isomer or enantiomer is less than 100% and that the amount of such isomer or enantiomer is 60% or more, or 70% or more, or 80% or more, or 90% or more, or 95% or more, or 96% or more, or 97% or more, or 98% or more, or 99% or more, or 99.5% or more, or 99.6% or more, or 99.7% or more, or 99.8% or more, or 99.9% or more.

[0046] Unless otherwise stated, 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%, then the isomeric or enantiomeric excess (ee value) is 80%.

[0047] Optically active (R)- and (S)-isomers, as well as D- and L-isomers, can be prepared using asymmetric synthesis or chiral reagents or other conventional techniques. One enantiomer of a compound of the invention can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary is decomposed to provide the desired isolated enantiomer. Alternatively, if the molecule contains a basic (e.g., amino) or acidic (e.g., carboxyl) functional group, the diastereomeric salt can be formed with an appropriate optically active acid or base, and the diastereomers can be resolved by conventional methods known in the art, followed by recovery to provide the isolated enantiomers. Separation of enantiomers and diastereomers is also typically accomplished by chromatographic techniques using chiral stationary phases and any chemical derivatization techniques (e.g., carbamate formation from amines).

[0048] The compounds of the present invention may contain unnatural atomic isotopes at one or more atoms constituting the compounds. For example, tritium (3 H), iodine-125( 125 I) or C-14( 14 Compounds can be labeled with radioisotopes such as radioisotopes C). Also, for example, deuterium can be replaced with hydrogen to form deuterated drugs, where the bond formed between deuterium and carbon is stronger than the bond formed between normal hydrogen and carbon, and compared to non-deuterated drugs, deuterated drugs have the advantages of reduced toxic side effects, increased drug stability, improved therapeutic efficacy, and extended biological half-life of the drug. Conversion of the isotopic composition of the compounds of the invention, whether radioactive or not, is within the scope of the invention.

[0049] The terms "optionally" and "optionally" mean that the following event or circumstance is possible but not necessarily occurring, and that the description includes the case where the described event or circumstance does not occur, if that event or circumstance occurs.

[0050] The term "substituted" refers to the replacement of any one or more hydrogen atoms at a particular atom with a substituent, which may include deuterium and hydrogen variants, provided that the particular valence state is correct and the compound is stable after substitution. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. Keto group substitution does not occur on aromatic groups.

[0051] The term "optionally substituted" means that the group may be substituted or unsubstituted, and unless otherwise defined, the type and number of the substituents are optional as long as they are chemically stable and can be realized.

[0052] When any variable (e.g., R) occurs more than once in a composition or structure of a compound, its definition is independent in each occurrence. Thus, for example, if a group is substituted with 0-2 R, then said group is optionally substituted with up to 2 R, and each occurrence of R is independently optional. Also, combinations of substituents and / or variants thereof are permissible only if such combinations result in stable compounds.

[0053] When the number of linking groups is 0, for example, -(CRR) 0 - means that the linking group is a single bond.

[0054] When the number of the substituents is 0, it means that the substituent does not exist, for example, -A-(R) 0 indicates that the structure is actually -A.

[0055] The absence of a substituent represents that the substituent does not exist; for example, the absence of X in AX represents that the structure is actually A.

[0056] When one of the variables is a single bond, the two groups it links are directly linked; for example, when L in ALZ represents a single bond, the structure is actually AZ.

[0057] If the bonds of a substituent can be cross-linked to more than one atom on the ring, the substituent can be bonded through any atom on the ring, e.g., a structural unit

[0058] [ka]

[0059] indicates that the substituent R may be substituted at any position of the cyclohexyl or cyclohexadiene. If the atom through which the substituent is substituted for a given substituent is not specified, then such substituent may be bonded through any atom thereof, e.g., pyridinyl as a substituent may be bonded to the substituent through any carbon atom of the pyridine ring.

[0060] If the listed linking group does not specify another linking direction, then the linking direction is arbitrary, for example:

[0061] [ka]

[0062] In the formula, the linking group L is -MW-, and -MW- is connected between ring A and ring B in the same direction as reading from left to right.

[0063] [ka]

[0064] and you can read ring A and ring B in the reverse order from left to right.

[0065] [ka]

[0066] Combinations of the above linking groups, substituents and / or variables are permissible only if such combinations result in stable compounds.

[0067] Unless otherwise specified, when a group has one or more bondable sites, any one or more sites of the group can be bonded to other groups by chemical bonds. When the bonding mode of the chemical bond is delocalized and there is an H atom at the bondable site, the number of H atoms at the site is reduced to a group with a corresponding valence according to the number of bonded chemical bonds. The chemical bond by which the site is bonded to another group is:

[0068] [ka]

[0069] For example, -OCH 3 A straight solid bond means that the group is bonded to another group via an oxygen atom of the group.

[0070] [ka]

[0071] The dashed-line connection of the straight line in the formula means that both ends of the nitrogen atom in the group are bonded to other groups.

[0072]

Chem.

[0073] The wavy line in the formula means that it is bonded to other groups through the carbon atoms at positions 1 and 2 of the phenyl group.

[0074]

Chem.

[0075] means that any bondable site of the piperidinyl can be bonded to other groups by one chemical bond, and at least

[0076]

Chem.

[0077] includes four bonding forms, and even if an H atom is depicted on -N,

[0078]

Chem.

[0079] although the group in this bonding form is included, when one chemical bond is connected, the H at that site decreases by one to become the corresponding monovalent piperidine.

[0080] Unless otherwise stated, the number of atoms in the ring is generally defined as the number of ring members. For example, "5- to 7-membered ring" refers to a "ring" of 5 to 7 atoms arranged around it.

[0081] The compounds of the present invention can be prepared by a variety of synthetic methods familiar to those skilled in the art, including the specific embodiments given below, embodiments in combination with other chemical synthetic methods, and equivalent alternative methods familiar to those skilled in the art, and preferred embodiments include, but are not limited to, the examples of the present invention.

[0082] The structure of the compound of the present invention can be confirmed by conventional methods known to those skilled in the art, and when the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means of those skilled in the art. For example, single crystal X-ray diffraction (SXRD), the cultured single crystal is collected by Bruker D8 venture diffractometer, the light source is CuKα radiation, the scanning method is φ / ω scanning, after collecting the relevant data, the absolute configuration can be confirmed by direct method (Shelxs97) crystal structure analysis.

[0083] The present invention uses the following abbreviations: 2 O stands for water; eq stands for equivalent; PE stands for petroleum ether; EtOAc stands for ethyl acetate; EtOH stands for ethanol; MeOH stands for methanol; HOAc stands for acetic acid; HCl stands for hydrochloric acid; HPLC stands for high performance liquid chromatography; 2 SO 4 stands for sulfuric acid; HCl / EtOAc stands for hydrochloric acid in ethyl acetate; HATU stands for O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; TFA stands for trifluoroacetic acid; TEA stands for triethylamine; DIEA or DIPEA stands for N,N-diisopropylethylamine; mp stands for melting point; °C stands for degrees Celsius; h stands for hours; mL stands for milliliters; mM stands for millimoles per liter; mmol stands for millimole; μmol stands for micromoles; HNMR stands for hydrogen nuclear magnetic resonance spectroscopy; MS stands for mass spectroscopy; min stands for minutes; pH stands for the negative logarithm of hydrogen ion molar concentration; and SFC stands for supercritical fluid chromatography.

[0084] All solvents used in this invention can be obtained commercially. Compounds were named manually or by ChemDraw® software; commercially available compounds were named from the manufacturer's catalogue. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0085] The present invention will be specifically described below by way of examples, but is not intended to be an adverse restriction of the present invention. The present invention has been described in detail herein, and specific embodiments thereof have been disclosed. It is obvious to those skilled in the art that various changes and modifications can be made in the specific embodiments of the present invention without departing from the spirit and scope of the present invention.

[0086] Example 1

[0087] [ka]

[0088] Synthesis scheme:

[0089] [ka]

[0090] Step 1: Synthesis of Compound 1-2 Compound 1-1 (233 mg), 4-methoxy-o-phenylenediamine (169.99 mg), HATU (584.76 mg), DIPEA (267.88 μL) and solvent DMF (3 mL) were added to a pre-dried flask and stirred for 15 h under nitrogen gas protection at 25 ° C. After completion of the reaction, water (40 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by flash silica gel column (petroleum ether: ethyl acetate = 60: 40) to obtain compound 1-2. 1 H NMR (400 MHz, CDCl 3) δ ppm 6.93 - 7.20 (m, 1 H), 6.31 (br d, J=12.30 Hz, 2 H), 4.43 (s, 1 H), 3.80 - 4.01 (m, 2 H), 3.75 (s, 3 H), 3.37 - 3.72 (m, 2 H), 1.92 (br s, 1 H), 1.62 (br s, 1 H), 1.46 (s, 9 H), 0.82 (br d, J=6.02 Hz, 1 H), 0.23 (q, J=4.27 Hz, 1 H).

[0091] Step 2: Synthesis of compounds 1-3 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 the reaction was completed, it was quenched by adding water (20 mL) and ethyl acetate (20 mL) and saturated NaHCO 3 (30mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product compound 1-3, which was used directly in the next step without purification. LCMS m / z = 330.0 [M+H] +

[0092] Step 3: Synthesis of trifluoroacetate salts of compounds 1-4 Compound 1-3 (90 mg) and solvent DCM (2 mL) were added to a pre-dried flask, followed by TFA (2 mL) and stirring for 1 h at 25° C. under nitrogen gas protection. 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] +

[0093] Step 4: Synthesis of Compound 1 Compound 1-4 trifluoroacetate (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) were added to a pre-dried flask and stirred at 25 °C for 15 h. After the reaction was completed, ethyl acetate (10 mL) was added to dilute the mixture and extracted with water (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude product, which was then purified by Pre-HPLC (column type: Phenomenex Gemini-NX 80 × 30 mm × 3 μm; mobile phase: [H 2 HO (10 mM NH 4 HCO 3 )-ACN]; ACN%: 30% to 60%, 9 min) to obtain compound 1. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 12.08 (br s, 1 H), 8.24 - 8.00 (m, 1 H), 7.99 - 7.70 (m, 2 H), 7.68 - 7.25 (m, 4 H), 7.21 - 6.99 (m, 1 H), 6.94 - 6.72 (m, 1 H), 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] +

[0094] Example 2

[0095] [ka]

[0096] Synthesis scheme:

[0097] [ka]

[0098] Step 1: Synthesis of compound 2-2 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), and 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×2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude product, which was purified by flash silica gel column (petroleum ether:ethyl acetate=30:70) to obtain compound 2-2. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.03 (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, 8.47 Hz, 1H), 0.42 (br s, 1H).

[0099] Step 2: Synthesis of compound 2-3 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 completion of the reaction, the reaction solution was directly concentrated under reduced pressure to obtain the crude product. Saturated sodium bicarbonate (80 mL) was added to the crude product, 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 the 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 (400 MHz, CDCl 3) δ 10.41 (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=10.92 Hz, 1H), 1.81 (br s, 1H), 1.50 (br s, 9H), 0.91 (td, J=5.62, 8.60 Hz, 1H), 0.50 (br s, 1H).

[0100] Step 3: Synthesis of the hydrochloride salt of compound 2-4 Compound 2-3 (300 mg) and solvent ethyl acetate (8 mL) were added to a pre-dried flask, followed by HCl / EtOAc (4M, 8 mL) and stirring for 15 h at 15° C. After completion of the reaction, it was directly concentrated and spun to dryness to give the hydrochloride salt of compound 2-4. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.71 (br s, 1H), 7.64 (d, J=9.03 Hz, 1H), 7.19 (d, J=2.26 Hz, 1H), 7.03 (dd, J=2.38, 8.91 Hz, 1H), 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, 8.53 Hz, 1H), 1.09-1.20 (m, 1H), 0.80-0.92 (m, 1H).

[0101] Step 4: Synthesis of compound 2 2-(2H-1,2,3-triazol-2-yl)benzoic acid (128.14 mg), HATU (372.02 mg) and dichloromethane (10 mL) were added to a pre-dried flask, followed by the hydrochloride salt of compound 2-4 (200 mg) and DIEA (393.27 μL), and 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 obtain the crude product. The crude product was purified by flash silica gel column (petroleum ether: ethyl acetate = 30:70) to obtain compound 2. 1 H NMR (400 MHz, CDCl 3 ) δ 8.06 (d, J=8.28 Hz, 1H), 7.53-7.64 (m, 4H), 7.44-7.51 (m, 2H), 7.05 (d, J=2.01 Hz, 1H), 6.94 (dd, J=2.26, 9.03 Hz, 1H), 5.58 (br d, J=5.77 Hz, 1H), 3.81 (s, 3H), 2.97-3.09 (m, 2H), 2.44 (dd, J=9.66, 13.18 Hz, 1H), 1.89-2.00 (m, 1H), 0.73 (br s, 1H), 0.53 (br s, 1H). LCMS m / z = 401.1[M+H] +

[0102] Example 3

[0103] [ka]

[0104] Synthesis scheme:

[0105] [ka]

[0106] Step 1: Synthesis of compound 3-2 Add H to one dry vial. 2SO 4 (50.00 mL) was then added at 0° C. with HNO 3 (2.84mL, 65% concentration) was slowly added dropwise, then compound 3-1 (5g) was slowly added, and the reaction system was stirred at 15°C for 16h. The reaction solution was slowly poured into 100mL of ice water, then the aqueous phase was extracted with methyl tert-butyl ether (20mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. 50mL of petroleum ether was added to the crude product, homogenized for 1h, filtered, and the cake was collected, concentrated, and dried to give compound 3-2. 1 H NMR (400MHz, CDCl 3 ) δ: 8.06 (d, J=8.8Hz, 1 H), 7.70 (d, J=8.8Hz, 1 H), 2.43 (s, 3 H). MS m / z: 239[M+23] + .

[0107] Step 2: Synthesis of compound 3-3 In a one-neck flask, compound 3-2 (4.6 g) was dissolved in EtOH (100 mL) and H 2 The mixture was dissolved in 50 mL of HO and mixed with Fe powder (11.86 g) and NH 4 Cl (22.72 g) was added and the reaction system was stirred at 75 °C for 16 h. The reaction solution was diluted with 200 mL of ethanol, filtered, the cake was washed with ethanol (200 mL × 2), the filtrate was concentrated, and then 500 mL of ethyl acetate was added to dissolve it, homogenized for 30 minutes, filtered, and the filtrate was concentrated. The crude product was separated and purified by column chromatography (PE: EtOAc = 10: 1 to 1: 1) to obtain compound 3-3. 1 H NMR (400MHz, CDCl 3 ) δ: 6.74 (d, J=8.4Hz, 1 H), 6.55 (d, J=8.4Hz, 1 H), 3.41 (br s, 4H), 2.26 (s, 3 H). MS m / z: 157[M+H] + .

[0108] Step 3: Synthesis of Compound 3-4 In one dried vial, compound 3-3 (227.42 mg) and compound 1-1 (300 mg) were dissolved in DMF (10 mL), and under the protection of nitrogen gas, DIEA (511.83 mg) and tri-n-propylcyclophosphoric anhydride ethyl acetate solution (785.10 μL, 50% content) were added at 0 ° C, and then the reaction system was stirred at 15 ° C for 16 h. The reaction solution was poured into 50 mL of water, the aqueous phase was extracted with ethyl acetate (20 mL × 3), the organic phase was combined and washed with water (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by column chromatography (PE: EtOAc = 10: 1 to 1: 1) to obtain compound 3-4. MS m / z: 310 [M + H-56] + .

[0109] Step 4: Synthesis of compounds 3-5 In one dried vial, compound 3-4 (450 mg) was dissolved in DMF (8 mL), AcOH (703.44 μL) was added, and the reaction system was stirred at 130 °C for 2 h. The reaction solution was poured into 50 mL water, the aqueous phase was extracted with ethyl acetate (20 mL × 3), and the combined organic phase was washed with water (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by column chromatography (PE: EtOAc = 10: 1 to 1: 1) to obtain compound 3-5. MS m / z: 348 [M + H] + .

[0110] Step 5: Synthesis of the hydrochloride salts of compounds 3-6 In one dry vial, compound 3-5 (310 mg) was dissolved in EtOAc (5 mL), HCl / EtOAc (4M, 4.46 mL) was added, and the reaction was stirred at 15° C. for 16 h. The reaction solution was concentrated under reduced pressure to give the crude product compound 3-6 hydrochloride salt, which was used directly in the next step without further purification. MS m / z: 248 [M+H] + .

[0111] Step 6: Synthesis of compound 3 In one dried vial, compound 3-6 hydrochloride (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-propylcyclophosphoric anhydride in ethyl acetate (418.55 μL, 50% purity) were added, and the reaction system was stirred at 50 °C for 16 h under the protection of nitrogen gas. After the reaction was completed, the reaction solution was poured into 20 mL of water, the aqueous phase was extracted with ethyl acetate (10 mL × 2), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by preparative HPLC (chromatography column: Phenomenex Gemini-NX 80 × 40 mm × 3 μm; mobile phase: [water (10 mM NH 4 HCO 3 Compound 3 was obtained by separation and purification using a 20% alcohol-acetonitrile mixture (containing acetonitrile; acetonitrile%: 35% to 65%, 8 min). 1 H NMR (400 MHz, DMSO-d 6 ) δ: 8.30-7.89 (m, 3 H), 7.66-7.63 (m, 1 H), 7.58-7.31 (m, 3 H), 7.24-7.20 (m, 1 H), 5.39 (s, 1 H), 4.15-3.86 (m, 1 H), 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] + .

[0112] Example 4

[0113] [ka]

[0114] Synthesis scheme:

[0115] [ka]

[0116] Step 1: Synthesis of compound 4 In one dried 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-propylcyclophosphoric anhydride in ethyl acetate (447.61 μL, 50% content) were added, and the reaction system was stirred at 50 °C for 16 h under the protection of nitrogen gas. The reaction solution was poured into 20 mL of water, the aqueous phase was extracted with ethyl acetate (10 mL × 2), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by preparative HPLC (chromatographic column: Phenomenex Gemini-NX 80 × 40 mm × 3 μm; mobile phase: [water (10 mM NH 4 HCO 3 )-acetonitrile]; acetonitrile%: 25% to 55%, 8 min) to obtain compound 4. 1 H NMR (400 MHz, DMSO-d 6 )δ:12.17-12.10 (m, 1 H), 8.09-8.08 (m, 2 H), 7.77-7.70 (m, 1 H), 7.49-7.47 (m, 1 H), 7.41-7.32 (m, 1 H), 7.20-7.00 (m, 2 H), 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] + .

[0117] Example 5

[0118] [ka]

[0119] Synthesis scheme:

[0120] [ka]

[0121] Compound 1-4 trifluoroacetate (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, and TEA (151.77 μL) and tri-n-propylcyclophosphoric anhydride ethyl acetate solution (194.54 μL, 50% content) were added under stirring, and the reaction was carried out at 50 ° C for 16 h. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 × 10 mL). The organic phase was combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was then purified by preparative HPLC (chromatography column: Phenomenex Gemini-NX C18 75 × 30 mm × 3 μm; mobile phase: [water (10 mM NH 4 HCO 3 )-acetonitrile]; acetonitrile%: 25% to 45%, 8 min) to obtain compound 5. 1 H NMR (400 MHz, DMSO-d 6 ) δ: 10.97 - 12.91 (m, 1 H), 7.81 - 8.39 (m, 1 H), 7.67 - 7.80 (m, 1 H), 7.22 - 7.65 (m, 3 H), 6.87 - 7.21 (m, 1 H), 6.72 - 6.86 (m, 1 H), 6.15 - 6.58 (m, 1 H), 4.61 - 5.38 (m, 1 H), 3.82 - 4.02 (m, 1 H), 3.75 - 3.81 (m, 3 H), 2.56 (br s, 1 H), 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] + .

[0122] Example 6

[0123] [ka]

[0124] Synthesis scheme:

[0125] [ka]

[0126] 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 to a reaction flask, stirred, TEA (303.54 μL) and an ethyl acetate solution of tri-n-propylcyclophosphoric anhydride (389.09 μL, 50% content) were added, and the reaction was carried out at 50 ° C for 16 h. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 × 10 mL). The organic phase was combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was then purified by preparative HPLC (chromatography column: Phenomenex Gemini-NX C18 75 × 30 mm × 3 μm; mobile phase: [water (10 mM NH 4 HCO 3 )-acetonitrile]; acetonitrile%: 25% to 45%, 8 min) to obtain compound 6. 1 H NMR (400 MHz, DMSO-d 6) δ: 11.53 - 12.33 (m, 1 H), 8.15 - 8.26 (m, 1 H), 7.74 - 7.90 (m, 1 H), 7.60 - 7.73 (m, 1 H), 7.11 - 7.60 (m, 3 H), 6.52 - 7.10 (m, 2 H), 4.52 - 5.50 (m, 1 H), 3.90 - 4.22 (m, 1 H), 3.79 (d, J=13.13 Hz, 3 H), 3.21 - 3.50 (m, 1 H), 1.53 - 1.94 (m, 2 H), 0.33 - 0.88 (m, 2 H). MS m / z: 419 [M+H] + .

[0127] Example 7

[0128] [ka]

[0129] Synthesis scheme:

[0130] [ka]

[0131] Compound 2-4 hydrochloride (100 mg), 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid (97.49 mg), and THF (2 mL) were added to a reaction flask, stirred, TEA (607.08 μL), and tri-n-propylcyclophosphoric anhydride in ethyl acetate (778.18 μL, 50% content) were added, and the reaction was carried out at 15 ° C for 16 h. After the reaction was completed, 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 (chromatography column: Waters Xbridge BEH C18 100 × 30 mm × 10 μm; mobile phase: [water (10 mM NH 4 HCO 3)-acetonitrile]; acetonitrile%: 20% to 50%, 8 min) to obtain compound 7. 1 H NMR (400 MHz, DMSO-d 6 ) δ: 11.75 - 12.09 (m, 1 H), 7.87 - 8.16 (m, 2 H), 7.63 - 7.85 (m, 1 H), 7.41 - 7.53 (m, 2 H), 6.38 - 7.40 (m, 3 H), 4.60 - 5.20 (m, 1 H) , 3.73 - 3.79 (m, 3 H), 3.11 (br d, J=6.02 Hz, 1 H), 2.30 - 2.45 (m, 4 H), 1.52 - 1.81 (m, 2 H), 0.46 - 0.98 (m, 2 H). MS m / z: 415 [M+H] + .

[0132] Chiral purity was determined using Chiral SFC (chromatographic column: Chiralcel OD-3, 50 × 4.6 mm ID, 3 μm; mobile phase: [supercritical CO 2 -methanol (containing 0.1% isopropylamine)]; methanol (containing 0.1% isopropylamine) %: 5% to 50%, 3 min), retention time = 1.161 min, ee = 100%.

[0133] Example 8

[0134] [ka]

[0135] Synthesis scheme:

[0136] [ka]

[0137] Compound 2-4 hydrochloride (100 mg), 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid (105.16 mg), and THF (2 mL) were added to a reaction flask, stirred, TEA (607.08 μL), and tri-n-propylcyclophosphoric anhydride in ethyl acetate (778.18 μL, 50% content) were added, and the reaction was carried out at 15 ° C for 16 h. After the reaction was completed, 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 (chromatography column: Waters Xbridge BEH C18 100 × 30 mm × 10 μm; mobile phase: [water (10 mM NH 4 HCO 3 )-acetonitrile]; acetonitrile%: 20% to 95%, 8 min) to obtain compound 8. 1 H NMR (400 MHz, DMSO-d 6 ) δ : 11.71 (s, 1 H), 7.99 - 8.15 (m, 1 H), 7.81 - 7.91 (m, 2 H), 7.38 - 7.72 (m, 1 H), 7.07 - 7.36 (m, 2 H), 6.44 - 7.03 (m, 2 H), 4.76 - 5.18 (m, 1 H), 3.63 - 3.91 (m, 6 H), 3.17 - 3.20 (m, 1 H), 2.34 - 2.38 (m, 1 H), 1.70 - 1.85 (m, 1 H), 1.11 (s, 1 H), 0.55 - 0.89 (m, 2H). MS m / z: 431 [M+H] + Optical rotation value: (+) 60.99° ± 0.13° (10.38 mg / mL in chloroform, length = 50 mm, temperature = 20 °C, n = 2). Chiral purity was determined by Chiral SFC (chromatographic column: Chiralpak AS-3, 50 × 4.6 mm ID, 3 μm; mobile phase: [supercritical CO 2-methanol (containing 0.1% isopropylamine)]; methanol (containing 0.1% isopropylamine) %: 5% to 50%, 3 min), retention time = 0.980 min, ee = 100%.

[0138] Example 9

[0139] [ka]

[0140] Synthesis scheme:

[0141] [ka]

[0142] Step 1: Synthesis of compound 9-2 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, and cuprous iodide (322.18 mg) was added. The atmosphere was replaced with nitrogen gas three times, and the reaction was carried out at 100 ° C for 16 h. 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 solution was extracted with ethyl acetate (3 x 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 was DCM:MeOH = 100:1-50:1) to obtain compound 9-2. 1 H NMR (400 MHz, DMSO-d 6 )δ:13.1 (s, 1 H), 7.85 (s, 2 H), 7.81-7.83 (m, 1 H), 7.65-7.68 (m, 1 H), 7.46-7.65(m, 1 H). MS m / z: 208 [M+H] + .

[0143] Step 2: Synthesis of compound 9 Compound 9-2 (100.00 mg) and toluene (1 mL) were added to a reaction flask, stirred, thionyl chloride (38.52 μL) was added, and the reaction solution was reacted at 50 ° C for 1 h. The reaction solution was concentrated under reduced pressure and dissolved in 0.5 mL of dichloromethane to prepare the product. Compound 2-4 hydrochloride (100 mg), dichloromethane (1 mL), and triethylamine (261.89 μL) were added to a reaction flask, stirred, cooled to 0 ° C, and the above dichloromethane solution was added dropwise and reacted at 15 ° C for 16 h. After the reaction was completed, water (10 mL) was added to the reaction solution, extracted with ethyl acetate (3 × 10 mL), and the organic phase was combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative HPLC (chromatography column: Waters Xbridge BEH C18 100 × 30 mm × 10 μm; mobile phase: [water (10 mM NH 4 HCO 3 )-acetonitrile]; acetonitrile%: 25% to 55%, 8 min) to obtain compound 9. 1 H NMR (400 MHz, CDCl 3 ) δ: 9.59 - 11.75 (m, 1 H), 7.82 (d, J=2.4, 1 H), 7.35 - 7.69 (m, 4 H), 7.04 - 7.23 (m, 2 H), 6.95 (d, J=4, 1 H), 5.63 (m, 1 H), 3.88(s, 3 H), 3.53 (m, 1 H), 2.72 - 2.83 (m, 1 H), 2.30 (m, 1 H), 1.92 - 2.08 (m, 1 H), 0.74 - 0.91 (m, 1 H), 0.36 - 0.62 (m, 1 H). MS m / z: 419 [M+H] + .

[0144] Example 10

[0145] [ka]

[0146] Synthesis scheme:

[0147] [ka]

[0148] Step 1: Synthesis of compound 10-2 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, and cuprous iodide (203.50 mg) was added and reacted at 100 ° C for 16 h. After the reaction was completed, water (10 mL) was added to the reaction solution, pH was adjusted to 1-2 with HCl, and the solution was extracted with ethyl acetate (3 x 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 was DCM:MeOH = 100:1-50:1) to obtain compound 10-2. 1 H NMR (400 MHz, DMSO-d 6 ) δ: 12.9 (s, 1 H),8.06 (s, 2 H), 7.67 (d, J=8, 1 H), 7.55 (s, 1 H), 7.39 (d, J=6.8, 1 H), 2.43 (s, 3 H). MS m / z: 204 [M+H] + .

[0149] Step 2: Synthesis of compound 10 Compound 2-4 hydrochloride (100 mg), compound 10-2 (97.49 mg), and tetrahydrofuran (2 mL) were added to a reaction flask, stirred, triethylamine (607.08 μL), and tri-n-propylcyclophosphoric anhydride in ethyl acetate (778.18 μL, 50% content) were added, and the reaction was carried out at 15 ° C for 16 h. After the reaction was completed, water (10 mL) was added to the reaction solution, extracted with ethyl acetate (3 × 10 mL), and the organic phase was combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by preparative HPLC (chromatography column: Waters Xbridge BEH C18 100 × 30 mm × 10 μm; mobile phase: [water (10 mM NH 4 HCO 3 Compound 10 was obtained by purifying the mixture by using an aqueous solution of acetonitrile (containing acetonitrile); acetonitrile%: 25% to 45%, 8 min)-acetonitrile; acetonitrile%: 45% to 75%, 10 min). 1 H NMR (400 MHz, DMSO-d 6 ) δ: 11.72 - 12.20 (m, 1 H), 7.87 - 8.19 (m, 2 H), 7.76 (s, 1 H), 7.56 - 7.66 (m, 1 H), 6.71 - 7.47 (m, 4 H), 4.53 - 5.32 (m, 1 H), 3.62 - 3.81 (m, 3 H), 3.30 (s, 1 H), 3.02 - 3.14 (m, 1 H), 2.44 (s, 3 H), 2.21 - 2.31 (m, 1 H), 1.66 - 1.80 (m, 1 H), 0.49 - 1.04 (m, 2 H). MS m / z: 415 [M+H] + .

[0150] Example 11

[0151] [ka]

[0152] Synthesis scheme:

[0153] [ka]

[0154] Step 1: Synthesis of compound 11-2 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, and cuprous iodide (214.79 mg) was added and reacted at 100° C. for 16 h. After the reaction was completed, water (10 mL) was added to the reaction solution, pH was adjusted to 1-2 with HCl, and 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), and the obtained product was further purified by preparative HPLC (chromatography column: Phenomenex luna C18 (250 × 70 mm, 15 μm); mobile phase: [water (containing HCl)-acetonitrile]; acetonitrile%: 8% to 38%, 20 min) to obtain compound 11-2. 1 H NMR (400 MHz, DMSO-d 6 ) δ : 13.3 (s, 1 H), 8.08 (s, 2 H), 7.79-7.82 (m, 1 H), 7.57-7.63 (m, 2 H). MS m / z: 208 [M+H] + .

[0155] Step 2: Synthesis of compound 11 Compound 2-4 hydrochloride (50 mg), compound 11-2 (49.69 mg), and N,N-dimethylformamide (1 mL) were added to a reaction flask, stirred, and N,N-diisopropylethylamine (113.95 μL) and HATU (165.84 mg) were added, and the reaction was allowed to proceed at 15° C. for 16 h. After completion of the reaction, water (10 mL) was added to the reaction solution, which was then 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 (chromatography column: Waters Xbridge BEH C18 100×30 mm×10 μm; mobile phase: [water (10 mM NH 4 HCO 3 The mixture was purified by using a solvent mixture containing acetonitrile (containing acetonitrile); acetonitrile%: 20% to 50%, 8 min) to obtain compound 11. 1 H NMR (400 MHz, DMSO-d 6 ) δ : 11.75 - 12.21 (m, 1 H), 7.80 - 8.24 (m, 3 H), 7.69 (dd, J=8.13, 3.25 Hz, 1 H), 7.19 - 7.56 (m, 2 H), 6.60 - 7.14 (m, 2 H), 4.66 - 5.21 (m, 1 H), 3.69 - 3.81 (m, 3 H), 3.31 (s, 1 H), 3.19 (s, 1 H), 2.34 - 2.42 (m, 1 H), 1.72 - 1.84 (m, 1 H), 0.55 - 1.03 (m, 2 H). MS m / z: 419 [M+H] + .

[0156] Example 12

[0157] [ka]

[0158] Synthesis scheme:

[0159] [ka]

[0160] Step 1: Synthesis of compound 12-2 Compound 12-1 (1g), 1H-1,2,3-triazole (285.60mg), cesium carbonate (1.84g), 1,10-phenanthroline (33.87mg) and 1,4-dioxane (10mL) were added to a reaction flask, and cuprous iodide (71.60mg) was added and reacted at 100℃ for 16h. After the reaction was completed, water (10mL) was added to the reaction solution, pH was adjusted to 1-2 with HCl, and the solution was extracted with ethyl acetate (3×30mL). 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 was DCM:MeOH=100:1-50:1) to obtain compound 12-2. 1 H NMR (400 MHz, DMSO-d 6 ) δ: 13.67 (s, 1 H), 8.16 (s, 2 H), 7.71-7.80 (m, 1 H), 7.68-7.70 (m, 1 H), 7.44-7.47 (m, 1 H).

[0161] Step 2: Synthesis of compound 12 Compound 2-4 hydrochloride (50 mg), compound 12-2 (35.08 mg) and acetonitrile (1 mL) were added to a pre-dried one-neck flask and stirred, then reagents N,N-diisopropylethylamine (65.55 μL), N-methylimidazole (52.49 μL), N,N,N,N-tetramethylchloroformamidine hexafluorophosphate (63.35 mg) were added, and the reaction system was reacted at 15 ° C for 16 h. After the reaction was completed, water (10 mL) was added to the reaction solution, extracted with ethyl acetate (3 × 10 mL), the organic phase was combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (chromatography column: Waters Xbridge BEH C18 100 × 30 mm × 10 μm; mobile phase: [water (10 mM NH 4 HCO 3 The mixture was purified by ethanol (containing acetonitrile); acetonitrile%: 20% to 50%, 8 min) to obtain compound 12. 1H NMR (400 MHz, DMSO-d 6 ) δ: 11.34 - 12.19 (m, 1 H), 8.10 - 8.29 (m, 1 H), 7.63 - 7.92 (m, 2 H), 7.39 - 7.54 (m, 2 H), 6.59 - 7.37 (m, 3 H), 4.52 - 5.52 (m, 1 H), 3.70 - 3.87 (m, 3 H), 3.12 - 3.31 (m, 1 H), 2.77 - 2.99 (m, 1 H), 2.34 - 2.63 (m, 1 H), 1.74 - 1.97 (m, 1 H), 0.72 - 1.18 (m, 1.5 H), 0.24 - 0.50 (m, 0.5 H). MS m / z : 419 [M+H] + .

[0162] Example 13

[0163]

change

[0164] Synthetic スキーム:

[0165]

change

[0166] ステップ1:Synthesis of compound 13 Compound 2-4 hydrochloride (30 mg), 5-methyl-2-(pyrimidin-2-yl)benzoic acid (25.23 mg), and tetrahydrofuran (1 mL) were added to a reaction flask, stirred, triethylamine (91.06 μL), and a solution of tri-n-propylcyclophosphoric anhydride in ethyl acetate (233.45 μL, 50% concentration) were added, and the reaction was carried out for 16 h at 15 ° C. After completion of the reaction, water (10 mL) was added to the reaction solution, extracted with ethyl acetate (3 × 10 mL), and 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: petroleum ether: ethyl acetate = 1:1 to 0:1), and the obtained product was further fractionated by preparative HPLC (chromatography column: Waters Xbridge BEH C18 100 × 30 mm × 10 μm; mobile phase: [water (10 mM NH 4 HCO 3 The mixture was purified by ethanol (containing acetonitrile); acetonitrile%: 25% to 55%, 8 min) to obtain compound 13. 1 H NMR (400 MHz, CDCl 3 ) δ : 8.18 - 8.33 (m, 3 H), 7.33 - 7.62 (m, 2 H), 7.28 (s, 1 H), 7.04 - 7.19 (m, 1 H), 6.89 - 7.00 (m, 2 H), 5.64 (dd, J=8.82, 2.69 Hz, 1 H), 3.88 (s, 3 H), 3.57 (m, 1 H), 2.81 - 2.93 (m, 1 H), 2.47 (s, 3 H), 2.29 - 2.41 (m, 1 H), 1.94 - 2.04 (m, 1 H), 0.69 - 0.84 (m, 1 H), 0.48 - 0.61 (m, 1 H). MS m / z: 426 [M+H] + .

[0167] Example 14

[0168] [ka]

[0169] Synthesis scheme:

[0170] [ka]

[0171] Step 1: Synthesis of compound 14-2 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, stirred, cesium carbonate (15.57 g), 1,10-phenanthroline (287.10 mg), and cuprous iodide (606.82 mg) were added, and the mixture was purged with nitrogen gas three times and reacted at 100 ° C for 16 h. 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 x 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 was DCM:MeOH = 100:1-50:1) to obtain compound 14-2. 1 H NMR (400 MHz, DMSO-d 6 ) δ : 13.46 (s, 1 H), 8.1 (s, 2 H), 7.77 - 7.82 (m, 3 H). MS m / z: 224 [M+H] + .

[0172] Step 2: Synthesis of compound 14 Acetonitrile (1 mL) was added to the reaction flask, and the hydrochloride salt of compound 2-4 (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 under stirring at 15 ° C., and the reaction was carried out for 16 h at 15 ° C. After the reaction was completed, water (10 mL) was added to the reaction solution, extracted with ethyl acetate (3 × 10 mL), and the organic phase was combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative HPLC (chromatography column: Waters Xbridge BEH C18 100 × 30 mm × 10 μm; mobile phase: [water (10 mM NH 4 HCO 3 The mixture was purified by ethanol (containing acetonitrile); acetonitrile%: 30% to 60%, 8 min) to obtain compound 14. 1 H NMR (400 MHz, CDCl 3 ) δ : 8.03 (d, J=8.63 Hz, 1 H), 7.38 - 7.62 (m, 5 H), 7.06 - 7.18 (m, 1 H), 6.96 (dd, J=8.82, 2.31 Hz, 1 H), 5.63 (dd, J=8.57, 2.19 Hz, 1 MS m / z : 435 [M+H] + .

[0173] Biological testing Experimental Example 1: In vitro activity test of OX1 and OX2 receptors Purpose of the Test: Detect changes in intracellular calcium signals with FLIPR and measure the IC of compounds 50 This is to evaluate the antagonistic effect of a compound against OX1R and OX2R receptors using this value as an index.

[0174] Test materials: 1. Cell lines: HEK293-OX1R and HEK293-OX2R stably transfected cell lines HEK293-OX1R cell culture medium (DMEM, Invitrogen#11960-044; 10% serum, Gibco#10099141; L-Glutamine 1x, Gibco#25030; Sodium pyruvate 1x, Gibco#11360; Geneticin 300μg / mL, Gibco#10131) HEK293-OX2R cell culture medium (DMEM, Invitrogen#11960-044; 10% serum, Gibco#10099141; L-Glutamine 1x, Gibco#25030; Sodium Pyruvate 1x, Gibco#11360; Geneticin 300μg / mL, Gibco#10131; Blasticin 2μg / mL, Invitrogen#R21001)

[0175] [Table 1]

[0176] Experimental steps and methods: a) Cell inoculation (HEK293-OX1R and HEK293-OX2R cells) 1) Preheat the medium, trypsin, and DPBS in a water bath at 37°C. Aspirate the cell culture medium and wash with 10 mL of DPBS; 2) Add pre-warmed trypsin to the culture flask, rotate the culture flask so that the trypsin covers the culture flask evenly, and incubate at 37°C, 5% CO 2 incubator for 1-2 min to digest; 3) For each T150, cells were suspended in 10-15 mL of medium, centrifuged at 800 rpm for 5 minutes, resuspended in 10 mL of medium, and 1 mL of cell suspension was aspirated and counted in Vi-cell; 4) 5 × 10 OX1R cells in culture medium 5 Dilute OX2R cells to 4 x 10 / mL. 5The cells were diluted to 1000 / mL and pipetted into a 384-well plate (Greiner.781946) (50 μL / well, OX1R cells: 25,000 cells / well, OX2R cells: 20,000 cells / well). The cell plate was incubated at 37°C, 5% CO 2 The plates were then left overnight in an incubator.

[0177] b) Compound loading: 1) Compounds were diluted to 20 mM in DMSO and diluted 3-fold in eight gradients, in duplicate wells, into the compound plate using an Echo liquid handler. 20 μL of buffer was then added to maintain a final DMSO concentration of 0.1%;

[0178] c) FLIPR experiment: 1) Remove the cell culture medium from the 384-cell plate using a vacuum pump, add 30 μL of Fluo-4 Direct fluorescent dye, and incubate at 37°C, 5% CO 2 The plates were then cultured in an incubator at 37 °C for 1 hour and equilibrated again at room temperature for 10 minutes. 2)EC 50 Test: Dilute Orexin A manually on ice, diluting 3-fold into eight gradients, with two replicate wells. Prepare a DMSO plate again so that the DMSO concentration is 0.5%. Place the cell plate, Orexin A plate, and DMSO plate in the FLIPR respectively, and read the fluorescence value. 3) Orexin A EC 50 EC by value 70 Calculate the value, 5 x EC 70 Solutions were prepared and pipetted into the 384 compound plate and kept on ice. 4) Compound plate in FLIPR, 5xEC 70 The plate, cell plate, and FLIPR chip were added sequentially, and the program was run to read the fluorescence values.

[0179] d) Data analysis: Data were analyzed using Prism 5.0 and the IC 50 values ​​were calculated.

[0180] The experimental results are shown in Table 2.

[0181] [Table 2]

[0182] Conclusion: The compounds of the present invention have certain antagonistic activity against human Orexin receptors and show higher activity against OX2 receptors.

[0183] Experimental Example 2: Measurement of pharmacokinetic parameters of test substances in SD rat plasma Four healthy SD rats aged 6-9 weeks were selected and randomly divided into two groups, two rats in each group. One group was administered 2 mg / kg of the test compound by intravenous injection, and the other group was administered 10 mg / kg of the test compound by intragastric administration. Plasma samples were collected from both the intravenous and intragastric 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 an LC-MS / MS method, and pharmacokinetic parameters were calculated using the non-compartmental model linear logarithmic ladder method using WinNonli™ Version 6.3 (Pharsight, Mountain View, CA) pharmacokinetic software. AUC 0-last represents the area under the plasma concentration-time curve from time 0 to the time of the last detectable concentration; po represents oral administration; iv represents intravenous administration; T 1 / 2 represents the half-life, CL represents the clearance, Vd represents the apparent volume of distribution, and C max represents the peak concentration, and T max represents the peak time, and F% represents the oral bioavailability. The experimental results are shown in Table 3.

[0184] [Table 3]

[0185] Conclusion: The compounds of the present invention showed good pharmacokinetic properties in SD rats.

[0186] Experimental Example 3: Measurement of drug concentration of test substance in brain tissue of SD rats Four healthy male SD rats aged 6 to 9 weeks were selected and the test compound was administered intragastrically. Two animals were randomly selected and euthanized at 0.5 and 2 hours after administration, and plasma and brain tissue samples were collected. All biological samples were quantitatively analyzed using LC-MS / MS method. The experimental results are shown in Table 4.

[0187] [Table 4]

[0188] Conclusion: It was demonstrated that the compound of the present invention can penetrate the blood-brain barrier and penetrate into the brain tissue in rats.

[0189] Experimental Example 4: Measurement of free drug ratio of test substance in brain tissue of SD rats Brain tissue homogenates of SD rats (i.e., matrix, purchased from BioIVT) were collected, and the DMSO working solution of the test compound or the DMSO working solution of the control group (propranolol) was added, so that the final concentrations of the test compound and propranolol in the plasma samples were both 2 μM, and the samples were mixed thoroughly. The final concentration of DMSO was controlled to 0.5%, and 50 μL was pipetted into the sample receiving plate, and the corresponding blank matrix / buffer was immediately added in the corresponding volume so that the final volume of each sample well was 100 μL, and the volume ratio of matrix:dialysis buffer was 1:1, and then the stop solution was added to these samples, and the samples were T 0 The samples were used for recovery and stability measurements. Test compound and propranolol samples were added to the dosing end of each dialysis well, and blank dialysis buffer was added to the corresponding receiving end of the dialysis well. The wells were then incubated in a humidified 5% CO 2The plates were placed in an incubator and incubated at 37°C with shaking at 100 rpm for 4 hours. After dialysis was completed, 50 μL of the dialysis buffer sample and the dialyzed brain tissue homogenate sample were pipetted into a new sample receiving plate. The blank matrix / buffer corresponding to the sample was added in a corresponding volume so that the final volume of each sample well was 100 μL and the volume ratio of plasma:dialysis buffer was 1:1. All samples were analyzed by LC / MS / MS after protein precipitation, and the free rate (%Unbound), bound rate (%Bound), and recovery rate (%Recovery) of the compound were calculated by the following formula.

[0190] %Unbound=100*F C / T C , %Bound=100-%Unbound, %Recovery=100*(F C +T C ) / T 0 .

[0191] where FC represents the concentration of the compound at the buffer end of the dialysis plate, and T C represents the concentration of the compound at the matrix end of the dialysis plate, and T 0 represents the concentration of the compound in the plasma sample at time zero. The experimental results are shown in Table 5.

[0192] [Table 5]

[0193] Conclusion: The compounds of the present invention showed a relatively high proportion of unbound drug in the brain tissue of SD rats.

[0194] Experimental Example 5: Measurement of pharmacokinetic parameters of test substances in beagle plasma Four healthy male beagles were selected and randomly divided into two groups, two in each group. One group was administered 1 mg / kg of the test compound by intravenous injection, and the other group was administered 5 mg / kg of the test compound by intragastric administration. Animals in both the intravenous and intragastric groups were subjected to plasma samples 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 an LC-MS / MS method, and pharmacokinetic parameters were calculated using the non-compartmental model linear logarithmic ladder method using WinNonlin™ Version 6.3 (Pharsight, Mountain View, CA) pharmacokinetic software. AUC 0-last represents the area under the plasma concentration-time curve from time 0 to the time of the last detectable concentration; po represents oral administration; iv represents intravenous administration; T 1 / 2 represents the half-life, CL represents the clearance, Vd represents the apparent volume of distribution, and C max represents the peak concentration, and T max represents the peak time, and F% represents the oral bioavailability. The experimental results are shown in Table 6.

[0195] [Table 6]

[0196] Conclusion: The compounds of the present invention showed good pharmacokinetic properties in beagles.

[0197] Experimental Example 6: Measurement of drug concentrations of test substances in cerebrospinal fluid of beagles Two healthy male beagles were selected and 5 mg / kg of the test compound was administered intragastrically, and cerebrospinal fluid samples were collected at 0.5, 2 and 6 hours after administration. Quantitative analysis of all biological samples was performed using an LC-MS / MS method, and pharmacokinetic parameters were calculated using the non-compartmental model linear logarithmic ladder method using WinNonli™ Version 6.3 (Pharsight, Mountain View, CA) pharmacokinetic software. AUC 0-last represents the area under the plasma concentration-time curve from time 0 to the time of the last detectable concentration; po represents oral administration; iv represents intravenous administration; T 1 / 2 represents the half-life, CL represents the clearance, Vd represents the apparent volume of distribution, and C max represents the peak concentration, and T max represents the peak time, and F% represents the oral bioavailability. The experimental results are shown in Table 7.

[0198] [Table 7]

[0199] Conclusion: The compounds of the present invention could be detected in the CSF of dogs, indicating that the compounds could penetrate the blood-brain barrier and reach the brain.

[0200] Experimental Example 7: Effects of test substances on spontaneous activity in SD rats Test objective: To determine the effect of the test compound on the activity of rats by measuring the spontaneous movement distance of the rats over a certain period of time.

[0201] Test scheme: 12 male SD rats aged 7 weeks were adapted to the environment in the laboratory 1 day before the start of the test. On the day of the experiment, they were randomly divided into two groups, 6 rats per group, according to their body weight, and administered blank solvent and 30 mg / kg of compound 8, respectively. 30 minutes after administration, the animals were placed in the test box, and the Any-maze software recorded the activity distance data of the animals at 5-minute intervals, and the recording continued for 60 minutes. The total movement distance of the animals during the recording time was compared to determine whether the drug had a significant effect on the spontaneous activity of the animals. The experimental data were expressed as mean ± standard deviation (Mean ± SEM), and the statistical method was one-way analysis of variance and Dunnett's multiple comparison, and p<0.05 was represented by *, p<0.01 was represented by **, and p<0.001 was represented by ***. The experimental results are shown in Table 8.

[0202] [Table 8]

[0203] Conclusion: It was shown that the compounds of the present invention can significantly reduce the spontaneous activity distance of SD rats.

[0204] Experimental Example 8: Evaluation of the effects of test substances on sleep in SD rats using EEG / EMG telemetry technology

[0205] Purpose of the study: To evaluate the effects of the test substances on sleep in SD rats by electroencephalogram / electromyogram telemetry technology (EEG).

[0206] Test scheme: Thirty-six male SD rats aged 5 to 6 weeks were required for an adaptation period of 5 to 15 days after arriving at the facility. During this period, the experimental animals were placed in a 12-hour alternating light-dark environment (lights on: 19:00, lights off: 07:00) to regulate the rhythm time, and the health status of the animals was monitored daily. To carry out the subsequent collection of telemetry data, the animals were implanted with EEG and EMG electrodes through surgery. On the day of the surgical experiment, the animals were anesthetized with Zoletil (ip, 20 mg / kg) in combination with Xylazine (ip, 8 mg / kg), and after anesthesia, they were fixed in a stereotaxic apparatus. After the hair on the head was cut and disinfected, the skin on the head was incised and the four corners were fixed with hemostatic forceps so that the skull was completely exposed, the periosteum was peeled off, and the surface was wiped with dry absorbent cotton until it was dry and clean. A hole was drilled according to the implant model, and the electrode was implanted to contact the dura mater, and the electrode was fixed to the skull using dental cement, and at the same time, the cement that fell on the tissue and skin was cleanly removed. Two electromyography electrodes were inserted parallel to the neck muscles, respectively, and fixed with sutures so that both ends did not touch each other. Then, the implant was placed subcutaneously, and the surgical wound was sutured and disinfected. After surgery, the rat was carefully placed in a clean recovery cage and made to lie down so that the airway was not blocked. The rats were kept in single cages and placed in a shielded recovery room with an automatic 12-hour light-dark alternating cycle (lights on: 19:00, lights off: 07:00), with a temperature of 20°C to 26°C and a relative humidity of 40% to 70%. After surgery, the animals were nursed for 3 days, treated with ceprazin powder administered topically at the surgical incision site, subcutaneously administered 4-8 mg / kg gentamicin, and subcutaneously injected with 0.1 mL / animal meloxicam for 3 consecutive days, and then recovered for 7-10 days before the experiment was performed. One day before the experiment, the animals were randomly divided into groups according to their body weight.

[0207] On the day of the experiment, the basic electroencephalogram and electromyogram were recorded first, and administration was started after completion. The electroencephalogram and electromyogram were continuously recorded during the administration period and up to 24 hours after administration. Raw data were collected by DSI system Ponemah software and analyzed by NeuroScore software. The experimental data are expressed as mean ± standard error (Mean ± SEM), and statistical analysis was performed using the single variance method. Compared with the blank vehicle group, P<0.05 indicates significant difference, represented by *; P<0.01 indicates highly significant difference, represented by **; P<0.001 indicates highly significant difference, represented by ***. The experimental results are shown in Table 9.

[0208] [Table 9]

[0209] Conclusion: 10mg / kg and 30mg / kg of the compound of the present invention can significantly shorten the sleep latency of SD rats, and 30mg / kg of the compound of the present invention can significantly reduce the wakefulness time and increase the sleep time within 7 hours after administration. Therefore, the compound of the present invention has excellent sleep-promoting effect.

Claims

1. A compound of formula (I) or a pharma- ceutically acceptable salt thereof selected from the following: 【Chemistry 1】 (however, Each R １ are each independently a halogen, a cyano, or a C １－３ Alkyl and C １－３ alkoxy, １－３ Alkyl and C １－３ each alkoxy is optionally substituted with 1, 2 or 3 halogen atoms; Each R ２ are each independently a halogen, a cyano, or a C １－３ Alkyl and C １－３ alkoxy, １－３ Alkyl and C １－３ each alkoxy is optionally substituted with 1, 2 or 3 halogen atoms; R ３ is H, m and n are each independently selected from 0, 1, 2, and 3; Ring A is 【Chemistry 2】 and Ring B is 【Chemistry 3】 It is.)

2. Each R １ are each independently selected from halogen, cyano, methyl and methoxy, and said methyl and methoxy are each independently optionally substituted by 1, 2 or 3 F, or a pharma- ceutically acceptable salt thereof.

3. Each R １ or a pharma- ceutically acceptable salt thereof.

3. The compound of claim 2, wherein each of R, R and R is independently selected from F, Cl, methyl and methoxy;

4. Each R ２ are each independently selected from halogen, cyano, methyl and methoxy, and said methyl and methoxy are each independently optionally substituted by 1, 2 or 3 F, or a pharma- ceutically acceptable salt thereof.

5. Each R ２ or a pharma- ceutically acceptable salt thereof, according to claim 4, wherein each of R, R and R is independently selected from F, Cl, methyl and methoxy.

6. A compound represented by the following formula or a pharma- ceutically acceptable salt thereof: 【Chemistry 4】

7. 7. The compound of claim 6, wherein the compound is selected from the following formula: or a pharma- ceutically acceptable salt thereof. 【Chemistry 5】

8. 13. Use of a compound according to any one of claims 1 to 7 or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for treating a disease associated with a selective orexin-2 receptor antagonist.

9. The use according to claim 8, wherein the disease associated with the selective orexin-2 receptor antagonist is selected from insomnia and / or depression.

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