Heterocyclic compound as well as pharmaceutical composition and application thereof

Abstract

The invention provides a heterocyclic compound and a pharmaceutical composition and application thereof, and belongs to the technical field of pharmaceutical chemistry. The series of heterocyclic compounds prepared by the invention have efficient sedative, hypnotic and / or anesthetic effects, can control the state of epilepsy, also have an analgesic effect, and have great significance for clinically preparing drugs with the analgesic effect and drugs with anesthetic, sedative, hypnotic and / or capable of controlling the state of epilepsy. The invention provides a new choice for the medicine which has the effects of anesthesia, sedation and hypnosis and / or can control epilepsy persistence and also has an analgesic effect.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemistry, specifically relating to a heterocyclic compound, its pharmaceutical composition, and its uses. Background Technology

[0002] In clinical practice, anesthetic drugs play a crucial role in the induction and maintenance of general anesthesia, as well as in the sedation of critically ill patients in the ICU. Propofol is currently a rapidly acting, short-acting intravenous general anesthetic used clinically. It has advantages such as rapid onset of anesthesia, rapid recovery, and complete functional restoration, with a low incidence of postoperative nausea and vomiting. However, clinically used intravenous general anesthetics, including propofol, etomidate, disodium fosfopropofol, and cyclopropofol, do not have analgesic effects. If a compound possesses sedative, hypnotic, and / or anesthetic effects, capable of controlling status epilepticus, while also exhibiting analgesic properties, it would achieve more comprehensive analgesia, significantly reduce the dosage of opioid analgesics, decrease the adverse reactions of opioid analgesics, and make the sedation, hypnosis, and / or anesthesia process more stable. Simultaneously, it could reduce the dosage of other drugs used in combined anesthesia, accelerate the patient's recovery from sedation, hypnosis, and / or anesthesia, and increase patient safety. Therefore, there is an urgent need to develop a drug that not only has sedative, hypnotic, and / or anesthetic effects, capable of controlling status epilepticus, but also has analgesic effects.

[0003] (±)-5-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole, an α-2-adrenergic receptor agonist of the imidazole class, possesses sedative and analgesic effects. However, the activity of (±)-5-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole requires further improvement. Therefore, there is an urgent need to develop drugs that not only have highly effective sedative, hypnotic, and / or anesthetic effects to control status epilepticus, but also analgesic effects. Summary of the Invention

[0004] The purpose of this invention is to provide a heterocyclic compound and its use in the preparation of a drug having analgesic effects, in the preparation of a drug having anesthetic, sedative, hypnotic effects and / or being able to control status epilepticus, and in the preparation of a drug having both anesthetic, sedative, hypnotic effects and / or being able to control status epilepticus and also having analgesic effects.

[0005] This invention provides a compound, its stereoisomer, its pharmaceutically acceptable salt, its solvate, its prodrug, its metabolite, or its deuterated derivative thereof, the structure of which is shown in Formula I:

[0006]

[0007] in,

[0008] Rx11 Selected from hydrogen, C 1～5 alkyl;

[0009] R n1 Selected from none or

[0010] R x6 R x7 R x8 R x9 R x10 Each is independently selected from hydrogen, halogen, halogenated or unhalogenated C 1～5 alkyl;

[0011] R n2 Selected from hydrogen and halogens;

[0012] R x1 R x2 R x3 R x4 Each is independently selected from hydrogen, halogen, halogenated or unhalogenated C 1～5 alkyl;

[0013] When X is F, R n1 For none, R n2 When it is hydrogen, ring A is R x1 R x2 R x3 R x4 Each is independently selected from hydrogen, halogen, and C. 1～5 Alkyl; or, ring A is R x4 For F, R x1 R x2 R x3 Each is independently selected from hydrogen, halogen, and C. 1～5 Alkyl, and R x1 R x2 R x3 Not both are hydrogen; or, ring A is R x1 R x2 R x3 R x4 Each is independently selected from hydrogen, halogen, and C. 1～5 alkyl;

[0014] When X is not F, R n1 for When the compound is: Rq is selected from halogen or C 1～5 alkyl;

[0015] When X is not F, R n1None; the compound is: Among them, R n2 R is hydrogen or halogen. k1 Selected from C 1～5 Alkyl, R x1 R x2 R x3 R x4 Selected from hydrogen, halogens, C 1～5 Alkyl; R m1 Selected from hydrogen, chlorine, C 1～5 alkyl.

[0016] Furthermore, the structure of the compound is shown in Formula II:

[0017]

[0018] in,

[0019] R x5 Selected from hydrogen and halogens;

[0020] R x6 R x7 R x8 R x9 R x10 Each is independently selected from hydrogen, halogen, halogenated or unhalogenated C 1～5 alkyl;

[0021] R x11 Selected from hydrogen, C 1～5 alkyl;

[0022] The Selected from

[0023] R 12 Selected from hydrogen, F; when R 12 For hydrogen, R x5 For F, R x11 When it is methyl, R x9 R x10 Not both of them are F;

[0024] R 13 Selected from F, Cl, Br, CH3, CF3, CH2F;

[0025] R 14 Selected from F, Cl, Br, CH3, CF3, CH2F;

[0026] R 15 Selected from hydrogen, F, Cl, Br, CH3, CF3, CH2F; when R 15 For hydrogen, R x5 For F, Rx11 When it is methyl, R x9 R x10 Not both of them are F;

[0027] R 16 Selected from CF3 and CH2F;

[0028] R 17 Selected from F, CF3, CH3, CH2F;

[0029] When R 17 Selected from F, CH3, R x5 When selected from hydrogen, R x6 R x7 R x8 R x9 R x10 Each is independently selected from hydrogen, halogen, halogenated or unhalogenated C 1～5 alkyl;

[0030] When R 17 When selected from F and CH3, R x5 When selected from halogens, R x6 R x7 R x8 R x9 R x10 Both are hydrogen; or, when R 17 When selected from F and CH3, R x5 Selected from halogens, R x10 C for halogenation 1～5 When alkyl, R x6 R x7 R x8 R x9 Each is independently selected from hydrogen, halogen, halogenated or unhalogenated C 1～5 Alkyl; or, when R 17 When selected from F and CH3, R x5 Selected from halogens, R x8 R x9 R x10 When both are selected from halogens, R x6 R x7 Each is independently selected from hydrogen, halogen, halogenated or unhalogenated C 1～5 Alkyl; or, when R 17 When selected from F and CH3, R x5 Selected from halogens, R x10 When it is Cl, R x6 R x7 R x8 R x9 Each is independently selected from hydrogen, halogen, halogenated or unhalogenated C 1～5 Alkyl, while R x9It cannot be F.

[0031] Furthermore, the aforementioned Selected from

[0032] R x5 Selected from hydrogen and halogens;

[0033] R x6 R x7 R x8 R x9 R x10 Each is independently selected from hydrogen, halogen, halogenated or unhalogenated C 1～5 alkyl;

[0034] R x11 Selected from hydrogen, C 1～5 alkyl.

[0035] Furthermore, the aforementioned Selected from

[0036] R x5 Selected from hydrogen and halogens;

[0037] R x6 R x7 R x8 R x9 R x10 Each is independently selected from hydrogen, halogen, halogenated or unhalogenated C 1～5 alkyl;

[0038] R x11 Selected from hydrogen, C 1～5 alkyl.

[0039] Furthermore, the structure of the compound is shown in Formula III:

[0040]

[0041] R x1 C selected from halogen, halogenated or non-halogenated 1～5 alkyl;

[0042] R x5 Selected from hydrogen and halogens;

[0043] R x6 R x7 R x8 R x9 R x10 Each is independently selected from hydrogen, halogen, halogenated or unhalogenated C 1～5 alkyl.

[0044] Furthermore, the structure of the compound is shown in Formula IV:

[0045]

[0046] R x1 C selected from halogen, halogenated or non-halogenated 1～5 alkyl;

[0047] R x5 Selected from hydrogen and halogens;

[0048] R x6 R x7 R x8 R x9 R x10 Each is independently selected from hydrogen, halogen, halogenated or unhalogenated C 1～5 alkyl.

[0049] Furthermore, the structure of the compound is shown in Formula V:

[0050]

[0051] in,

[0052] R x5 Selected from hydrogen and halogens;

[0053] R x6 R x7 R x8 R x9 R x10 Each is independently selected from hydrogen, halogen, halogenated or unhalogenated C 1～5 alkyl;

[0054] R x11 Selected from hydrogen, C 1～5 alkyl;

[0055] R x1 R x2 R x3 R x4 Of these, two are F and the other two are hydrogen.

[0056] Or, R x1 R x2 R x3 R x4 In the middle, one is C replaced by F. 1～5 Alkyl group, and the other two have one hydrogen atom;

[0057] Or, R x1 R x2 R x3 R x4 In this composition, one is F, and the other is either hydrogen or C. 1～5Alkyl groups, the other two having one hydrogen atom, and the compound is not:

[0058]

[0059] Furthermore, the aforementioned Selected from

[0060] R x5 Selected from hydrogen and halogens;

[0061] R x6 R x7 R x8 R x9 R x10 Each is independently selected from hydrogen, halogen, halogenated or unhalogenated C 1～5 alkyl;

[0062] R x11 Selected from hydrogen, C 1～5 alkyl.

[0063] The present invention also provides a compound, its stereoisomer, its pharmaceutically acceptable salt, its solvate, its prodrug, its metabolite, or its deuterated derivative thereof, wherein the compound is selected from:

[0064]

[0065]

[0066]

[0067]

[0068]

[0069] Further, the pharmaceutically acceptable salts are citrates, hydrofluoric acid salts, phosphates, propionates, succinates, tartrates, acetates, adipates, aspartates, benzoates, benzenesulfonates, bicarbonates, carbonates, bisulfates, sulfates, borates, camphor sulfonates, citrates, cyclohexanesulfonates, ethanedisulfonates, ethanesulfonates, formates, fumarates, glucohepanoates, glucuronates, glucuronates, hexafluorophosphates, hydrochlorides, hydrobromide, hydroiodates, hydroxyethyl sulfonates, lactates, malates, maleic acid sulfonates, malonates, methanesulfonates, methyl sulfates, naphthates, succinates, nicotinates, nitrates, orotates, oxalates, palmitates, dihydroxynaphthyl salts, phosphates, hydrogen phosphates, dihydrogen phosphates, pyroglutamates, glycosides, stearates, succinates, tannates, tartrates, toluenesulfonates, trifluoroacetates, sine salts, or p-toluenesulfonates.

[0070] The present invention also provides a pharmaceutical composition comprising, wherein the pharmaceutical composition is an active ingredient comprising the above-mentioned compound, its stereoisomer, its pharmaceutically acceptable salt, its solvate, its prodrug, its metabolite or its deuterated derivative thereof, and pharmaceutically acceptable excipients.

[0071] The present invention also provides the use of the above-mentioned compounds, their stereoisomers, their pharmaceutically acceptable salts, their solvates, their prodrugs, their metabolites or their deuterated derivatives in the preparation of medicaments having analgesic effects, and / or having anesthetic, sedative, hypnotic effects and / or being able to control status epilepticus.

[0072] "Use in drugs that have analgesic effects and / or anesthetic, sedative, hypnotic and / or control status epilepticus" includes the following three situations: (1) having analgesic effects; (2) having anesthetic, sedative, hypnotic and / or control status epilepticus; (3) having both anesthetic, sedative, hypnotic and / or control status epilepticus and analgesic effects.

[0073] The phrase "having both anesthetic, sedative, hypnotic effects and / or the ability to control epileptic status while also having analgesic effects" as described in this invention means that when the compounds of this invention produce sedative, hypnotic, and / or anesthetic effects, they do not respond to noxious stimuli or increase the response threshold to noxious stimuli.

[0074] The "drug with sedative effect" described in this invention refers to a drug that effectively helps and improves sleep. That is, it can prevent the serious harm of insomnia to the human body, treat insomnia, and improve sleep quality.

[0075] The "hypnotic drug" described in this invention refers to a drug that can induce drowsiness and promote sleep. Specifically, it has an inhibitory effect on the central nervous system; small doses cause sedation, while excessive doses lead to general anesthesia.

[0076] The "drug with anesthetic effect" described in this invention refers to a reversible functional inhibition of the central and / or peripheral nervous systems produced by the drug, characterized primarily by the loss of sensation, especially pain. Preferably, the anesthesia is general anesthesia.

[0077] The "general anesthesia" mentioned in this invention refers to the temporary inhibition of the central nervous system produced by anesthetic drugs after entering the body. Clinically, it manifests as loss of consciousness, loss of pain sensation throughout the body, amnesia, reflex inhibition, and skeletal muscle relaxation.

[0078] The "status epilepticus" described in this invention refers to a series of epileptic seizures in which consciousness is not fully restored before frequent recurrences, or seizures lasting more than 30 minutes without spontaneous cessation. Prolonged epileptic seizures, if not treated promptly, can lead to irreversible brain damage due to high fever, circulatory failure, or neuronal excitotoxicity, resulting in high rates of disability and mortality. Therefore, status epilepticus is a common medical emergency.

[0079] Regarding the definition of terms used in this invention: Unless otherwise stated, the initial definitions provided for groups or terms herein apply to the groups or terms used throughout this specification; for terms not specifically defined herein, the meanings that a person skilled in the art would give them should be given based on the disclosure and context.

[0080] The minimum and maximum carbon atom content in hydrocarbon groups are indicated by a prefix, for example, the prefix C. a～b Alkyl groups refer to any alkyl group containing one to two carbon atoms ("a" to "b"). For example, C 1～5 Alkyl refers to a straight-chain or branched alkyl group containing 1, 2, 3, 4 or 5 carbon atoms, and so on.

[0081] In this article, "substitution" refers to the replacement of one, two, or more hydrogen atoms in a molecule by other different atoms or molecules, including one, two, or more substitutions on isotopes or ectopic atoms in the molecule.

[0082] In this article, "halogenation" refers to the replacement of one, two, or more hydrogen atoms in a molecule with other different halogens, including one, two, or more substitutions on isotopes or ectopic atoms in the molecule.

[0083] Halogens are fluorine, chlorine, bromine or iodine.

[0084] In this invention, "pharmaceutically acceptable" means that a carrier, delivery substance, diluent, excipient, and / or the salt formed therefrom is generally chemically or physically compatible with other components constituting a drug dosage form and physiologically compatible with the receptor.

[0085] In this invention, "salt" refers to an acidic and / or basic salt formed by a compound or its stereoisomer with an inorganic and / or organic acid and / or base, including zwitterionic salts (internal salts) and quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly during the final separation and purification of the compound. Alternatively, they can be obtained by mixing the compound, or its stereoisomer, with an appropriate amount (e.g., equimolar amounts) of an acid or base. These salts may precipitate in solution and be collected by filtration, or be recovered after solvent evaporation, or be prepared by freeze-drying after reaction in an aqueous medium. The salts described in this invention can be hydrochlorides, sulfates, citrates, benzenesulfonates, hydrobromides, hydrofluoric acids, phosphates, acetates, propionates, succinates, oxalates, malates, succinates, fumarates, maleates, tartrates, or trifluoroacetates of the compound.

[0086] "Solvate" refers to the solvate formed by the compound of the present invention and a solvent, wherein the solvent includes (but is not limited to): water, ethanol, methanol, isopropanol, propylene glycol, tetrahydrofuran, and dichloromethane.

[0087] "Stereoisomerism" refers to compounds with the same molecular formula in which atoms or groups of atoms are connected in the same order, but arranged in different ways in space.

[0088] Sulphate is 2,4-dimethylbenzenesulfonate.

[0089] Compared with the prior art, the compounds of the present invention have the following beneficial effects:

[0090] This invention provides compounds with novel core structures other than imidazole compounds, and for the first time discovers that these compounds have sedative, hypnotic and / or anesthetic effects, and can control status epilepticus, providing a new option for the clinical preparation of drugs with sedative, hypnotic and / or anesthetic effects and for controlling status epilepticus.

[0091] Furthermore, this invention is the first to discover that the compound of this invention not only has highly effective sedative, hypnotic, and / or anesthetic effects, which can control status epilepticus, but also has analgesic effects. In clinical applications, it can reduce or eliminate the need for opioid analgesics such as fentanyl, alfentanyl, sufentanil, or remifentanil, thereby reducing the occurrence of adverse reactions such as circulatory depression, respiratory depression, urinary retention, and skin itching caused by opioid analgesics.

[0092] Obviously, based on the above description of the present invention, and according to common technical knowledge and conventional methods in the field, various other modifications, substitutions or alterations can be made without departing from the basic technical concept of the present invention.

[0093] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following embodiments. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention. Detailed Implementation

[0094] All raw materials and equipment used in this invention are known products, obtained by purchasing commercially available products. In the specific embodiments of this invention, all raw materials and equipment are known products, obtained by purchasing commercially available products.

[0095] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ ohms. -6 The unit (ppm) is given. NMR measurements were performed using a Bruker Avance III 400 NMR spectrometer, with deuterated dimethyl sulfoxide (d6-DMSO) as the solvent and tetramethylsilane (TMS) as the internal standard.

[0096] The LCMS determination was performed using an Agilent LCMS1260-6110 (ESI) column: Waters X-Bridge C18 (50 mm x 4.6 mm x 3.5 μm); column temperature: 40 °C; flow rate: 2.0 mL / min; mobile phase: gradient from 95% [water + 0.05% TFA] and 5% [CH3CN + 0.05% TFA] to 0% [water + 0.05% TFA] and 100% [CH3CN + 0.05% TFA] over 3 minutes, held for 1 minute, then gradient to 95% [water + 0.05% TFA] and 5% [CH3CN + 0.05% TFA] over 0.05 minutes, and held for 0.7 minutes.

[0097] 1) Medicinal materials and reagents

[0098] The silica gel plates used for thin-layer chromatography are HSGF254 silica gel plates from Yantai Xinnuo Chemical Co., Ltd., with a thickness of 1mm.

[0099] Thin-layer chromatography (TLC) was performed using products from Yantai Jiangyou Silica Gel Development Co., Ltd., with a specification of 0.2±0.03 mm.

[0100] Column chromatography typically uses 100-200 mesh or 200-300 mesh silica gel from Rushan Taiyang Desiccant Co., Ltd. (Weihai, Shandong) as the carrier.

[0101] 2) Main instruments

[0102] JA2003N Electronic Balance (Shanghai Youke Instrument Co., Ltd.);

[0103] DF-101S Thermostatic Heating Magnetic Stirrer (Zhengzhou Setelis Biotechnology Co., Ltd.);

[0104] 98-2 Magnetic Stirrer (Shanghai Sile Instruments Co., Ltd.);

[0105] ZF-2 Three-Purpose Ultraviolet Analyzer (Shanghai Anting Electronic Instrument Factory);

[0106] RE-2000B Rotary Evaporator (Zhengzhou Ketai Experimental Equipment Co., Ltd.);

[0107] DLSK-5 / 20 Cryogenic Coolant Circulation Pump (Zhengzhou Kete Experimental Equipment Co., Ltd.);

[0108] W201D constant temperature water bath (Shanghai Shenshun Biotechnology Co., Ltd.);

[0109] SHB-III circulating water vacuum pump (Zhengzhou Huicheng Science & Technology Co., Ltd.);

[0110] SHB-B95 portable water pump (Zhengzhou Huicheng Science & Technology Co., Ltd.);

[0111] Ultraviolet high-pressure mercury lamp (Beijing Tianmai Heng Hui Light Source Electric Co., Ltd.).

[0112] DGJ-10C Vacuum Freeze Dryer (Shanghai Boden Biotechnology Co., Ltd.);

[0113] KQ5200 Ultrasonic Cleaner (Kunshan Ultrasonic Instrument Co., Ltd.);

[0114] 2XZ-2 type rotary vane vacuum pump (Linhai Tanshi Vacuum Equipment Co., Ltd.);

[0115] Biotage Isolera One(Biotage Sweden AB)

[0116] Example 1: Preparation of compound DA-232 of the present invention

[0117]

[0118] At room temperature, 2,4,6-trifluoroacetophenone (20.0 g, 115 mmol), formic acid (15.87 g, 345 mmol), and triethylamine (58.08 g, 575 mmol) were sequentially added to isopropanol (200 mL). The reaction system was purged three times with argon. Then, (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropyltoluene)ruthenium chloride (1.46 g, 2.30 mmol) was added to the reaction system. The mixture was stirred at 60 °C for 4 hours under argon protection. After the reaction was complete under C monitoring, the mixture was cooled to room temperature, filtered, and extracted with EtOAc (3 × 100 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 to 1 / 5). TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5) was used to monitor the reaction. The fraction with Rf = 0.5 to 0.6 was collected to give a light yellow oily compound DA-232.2 (18.93 g, yield 93.5%).

[0119] At room temperature, 5-fluoro-1H-imidazol-4-carboxaldehyde (1.14 g, 10.00 mmol) was dissolved in dry THF (30 mL), and the temperature was lowered to ~-30 °C using a dry ice acetone bath. Then, DA-232.2 (2.64 g, 15.00 mmol) and PBu3 (4.04 g, 20.00 mmol) were added to the reaction system sequentially. DEAD (3.48 g, 20.00 mmol) was slowly added to the reaction system using a syringe, and the mixture was stirred overnight at room temperature. After the reaction was confirmed to be complete by TLC, ice water was added to the reaction system, and the mixture was extracted with EtOAc (3 × 100 mL). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 to 1 / 3). TLC (ethyl acetate / petroleum ether (v / v) = 1 / 3) was used to monitor the reaction, and the fraction with Rf = 0.5–0.6 was collected to give a colorless oily compound DA-232.3 (1.98 g, yield 69.4%). (ESI [M+H]) + =273.1.

[0120] 2,3-Difluorobromobenzene (1.54 g, 8.00 mmol) was dissolved in 20 mL of dry THF under a dry ice-acetone bath at -78 °C. Under nitrogen protection, 2.56 mL of n-butyllithium (2.5 mol / L in 6.4 mmol THF) was added to the reaction system, and the mixture was stirred for 1 hour. A 5 mL THF solution of compound DA-232.3 (1.09 g, 4.00 mmol) was slowly added to the reaction system using a syringe, and the mixture was stirred for 1 hour. After the reaction was complete as monitored by TLC, ice water was added to the reaction system, and the mixture was extracted with EtOAc (3 × 30 mL). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product compound DA-232.4. The crude product was dissolved in 50 mL of dry DCM, and then 6.96 g of manganese dioxide (80 mmol) was added to the reaction system, and the mixture was refluxed and stirred overnight. After the reaction was monitored by TLC until complete, the mixture was filtered and concentrated under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10–1 / 3). TLC (ethyl acetate / petroleum ether (v / v) = 1 / 3) was used to monitor the reaction, and the fraction with Rf = 0.5–0.6 was collected to give the colorless syrup compound DA-232 (455 mg, overall yield of both parts 29.5%). ESI [M+H] + =385.1.

[0121] 1 H NMR(400MHz,DMSO)δ8.44(s,1H),7.73–7.60(m,1H),7.34(td,J=8.0,4.3Hz,1 H),7.24(dd,J=18.4,9.2Hz,3H),6.29(d,J=7.2Hz,1H),1.95(d,J=7.2Hz,3H).

[0122] Example 2: Preparation of compounds DA-234, DA-249, DA-252 to DA-253, DA-261, and DA-264 to DA-265 of the present invention

[0123]

[0124] The preparation of the target compounds DA-234, DA-249, DA-252 to DA-253, DA-261, and DA-264 to DA-265 of this invention is similar to that of compound DA-232.

[0125] Compound DA-234: 1040 mg, colorless syrup, ESI [M+H] + =367.1.

[0126] 1H NMR (400MHz, DMSO) δ8.54(s,1H),7.69–7.61(m,1H),7.57(s,1H),7.36–7.26(m,2H),7.20(s,2H),6.35(q,J=7.1Hz,1H),1.97(d,J=7.2Hz,3H).

[0127] Compound DA-249: 201 mg, colorless syrup, ESI [M+H] + =385.1.

[0128] 1 H NMR(400MHz,DMSO)δ8.37(d,J=1.7Hz,1H),7.67(ddd,J=10.6,7.7,2.3Hz,1H),7.39–7 .28(m,3H),6.96(td,J=8.1,2.3Hz,1H),6.40(d,J=7.1Hz,1H),1.91(d,J=7.1Hz,3H).

[0129] Compound DA-252: 170 mg, colorless syrup, ESI [M+H] + =381.1.

[0130] 1 H NMR (400MHz, DMSO) δ8.32(d,J=1.7Hz,1H),7.49(t,J=6.9Hz,1H),7.34(td,J=9.6,2.0Hz,1H),7.27(t,J=6.5 Hz,1H),7.20(s,1H),6.99–6.90(m,1H),6.41(q,J=7.1Hz,1H),2.26(d,J=1.7Hz,3H),1.90(d,J=7.1Hz,3H).

[0131] Compound DA-253: 67 mg, colorless syrup, ESI [M+H] + =401.1.

[0132] 1 H NMR (400MHz, DMSO) δ8.37(d,J=1.6Hz,1H),7.61–7.55(m,1H),7.51(td,J=8.0,5.2Hz,1H),7.39–7.30(m ,1H),7.28(d,J=7.5Hz,1H),6.96(dd,J=14.2,5.9Hz,1H),6.42(q,J=7.1Hz,1H),1.92(d,J=7.1Hz,3H).

[0133] Compound DA-261: 901 mg, colorless syrup, ESI [M+H] + =385.1.

[0134] 1 H NMR(400MHz,DMSO)δ8.46(s,1H),7.69–7.62(m,1H),7.54–7.43(m,1H),7.33(dd,J=7.9,4.0 Hz,1H),7.30–7.25(m,1H),7.20–7.11(m,1H),6.34(q,J=7.1Hz,1H),1.99(d,J=7.2Hz,3H).

[0135] Compound DA-264: 956 mg, colorless syrup, ESI [M+H] + =381.1.

[0136] 1 H NMR (400MHz, DMSO) δ8.39 (s, 1H), 7.52–7.42 (m, 2H), 7.25–7.11 (m, 3H), 6.35 (q, J = 6.9Hz, 1H), 2.24 (d, J = 1.8Hz, 3H), 1.98 (d, J = 7.2Hz, 3H).

[0137] Compound DA-265: 400 mg, colorless syrup, ESI [M+H] + =401.1.

[0138] 1 ¹H NMR (400MHz, DMSO) δ 8.47 (s, 1H), 7.60–7.54 (m, 1H), 7.54–7.45 (m, 2H), 7.24 (d, J = 7.5Hz, 1H), 7.19–7.11 (m, 1H), 6.36 (q, J = 7.1Hz, 1H), 2.00 (d, J = 7.2Hz, 3H). Example 3: Preparation of compound DA-233 of the present invention.

[0139]

[0140] At room temperature, 2,6-difluoroacetophenone (20.0 g, 128 mmol), formic acid (17.66 g, 384 mmol), and triethylamine (64.64 g, 640 mmol) were added sequentially to isopropanol (200 mL). The reaction system was purged three times with argon. Then, (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropyltoluene)ruthenium chloride (1.63 g, 2.56 mmol) was added to the reaction system. The mixture was stirred at 60 °C for 4 hours under argon protection. The reaction mixture was then analyzed by TLC. After the reaction was monitored to be complete, the mixture was cooled to room temperature, filtered, and extracted with EtOAc (3 × 100 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 to 1 / 5). The fraction with Rf = 0.5 to 0.6 was collected under TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5) to obtain the light yellow oily compound DA-233.2 (19.03 g, yield 94.1%).

[0141] At room temperature, 4-fluoro-N-methoxy-N-methyl-1H-imidazol-5-carboxamide (1.73 g, 10.0 mmol) was dissolved in dry THF (20 mL), and the temperature was lowered to ~-30 °C using a dry ice acetone bath. Then, (S)-1-phenyl-1-ethanol (2.37 g, 15.0 mmol) and PPh3 (5.24 g, 20 mmol) were added to the reaction system sequentially. DEAD (3.48 g, 20 mmol) was slowly added to the reaction system using a syringe, and the mixture was stirred overnight at room temperature. After the reaction was confirmed to be complete by TLC, ice water was added to the reaction system, and the mixture was extracted with EtOAc. The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 5 to 1 / 1). TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1) was used to monitor the reaction, and the fraction with Rf = 0.5 to 0.6 was collected to give 233.3 g (2.03 g, yield 64.7%) of a colorless oily compound. (ESI[M+H]) + =314.1.

[0142] Compound 233.3 (470 mg, 1.50 mmol) was dissolved in 10 mL of dry THF at room temperature. The reaction system was purged three times with nitrogen under nitrogen protection and cooled to 0 °C in an ice-salt bath. A (7.5 mL, 1 mol / L in THF, 7.5 mmol) was slowly added dropwise to the system using a syringe, and the mixture was stirred at room temperature for 4 hours. After the reaction was confirmed to be complete by TLC, the reaction system was poured into ice water. A saturated ammonium chloride aqueous solution (20 mL) was slowly added to the reaction system, and the mixture was extracted with EtOAc (3 × 30 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 to 1 / 3). The fraction with Rf = 0.5 to 0.6 was collected under TLC (ethyl acetate / petroleum ether (v / v) = 1 / 3) to obtain the white solid compound DA-233 (349 mg, yield 65%). ESI[M+H] + =359.1.

[0143] 1 H NMR (400MHz, DMSO) δ8.33 (s, 1H), 7.44–7.35 (m, 1H), 7.26 (d, J = 7.4Hz, 1H), 7.16–7.04 (m, 3H), 6.91(d,J=7.6Hz,1H),6.42(d,J=7.2Hz,1H),2.23(s,3H),1.97(d,J=7.2Hz,3H),1.89(s,3H).

[0144] Example 4. Preparation of compounds of the present invention DA-235, DA-240~DA-244, DA-246~DA-248, DA-250~DA-251, DA-254, DA-260, DA-262~DA-263, DA-266, DA-268 and DA-282~DA-287

[0145]

[0146] The preparation of target compounds DA-235, DA-240~DA-244, DA-246~DA-248, DA-250~DA-251, DA-254, DA-260, DA-262~DA-263, DA-266, DA-268, and DA-282~DA-287 is similar to that of compound DA-21.

[0147] Compound DA-235: 301 mg, white solid, ESI [M+H] + =341.1.

[0148] 1H NMR (400MHz, DMSO) δ8.45(s,1H),7.43–7.34(m,1H),7.28(d,J=7.4Hz,1H),7.17(s,1H),7.14(t,J=7.6Hz,1H ),7.08(s,2H),7.00(d,J=7.7Hz,1H),6.49(q,J=7.2Hz,1H),2.24(s,3H),1.99(d,J=7.2Hz,3H),1.86(s,3H).

[0149] Compound DA-240: 451 mg, colorless syrup, ESI [M+H] + =379.1.

[0150] 1 H NMR (400MHz, DMSO) δ8.30(d,J=1.7Hz,1H),7.58(d,J=7.9Hz,1H),7.35–7.27(m,2H),7.20(d ,J=7.6Hz,1H),7.18–7.07(m,2H),6.45(d,J=7.1Hz,1H),2.09(s,3H),1.90(d,J=7.1Hz,3H).

[0151] Compound DA-241: 363 mg, white solid, ESI [M+H] + =379.1.

[0152] 1 H NMR(400MHz,DMSO)δ8.40(s,1H),7.60–7.53(m,1H),7.41(s,1H),7.30(t,J=7.8Hz,1 H),7.10(t,J=8.6Hz,3H),6.40(d,J=7.2Hz,1H),2.00(s,3H),1.97(d,J=7.2Hz,3H).

[0153] Compound DA-242: 391 mg, colorless syrup, ESI [M+H] + =363.1.

[0154] 1 H NMR (400MHz, DMSO) δ8.39 (s, 1H), 7.41 (s, 1H), 7.30 (dd, J = 8.4, 3.7Hz, 2H), 7.10 (t, J = 8.7Hz ,2H),7.03–6.96(m,1H),6.40(d,J=7.1Hz,1H),1.97(d,J=7.2Hz,3H),1.93(d,J=1.9Hz,3H).

[0155] Compound DA-243: 370 mg, colorless syrup, ESI [M+H] + =381.1.

[0156] 1 H NMR (400MHz, DMSO) δ8.40 (s, 1H), 7.31 (dd, J = 8.2, 3.8Hz, 2H), 7.23 (t, J = 9.2Hz, 2 H),7.05–6.99(m,1H),6.34(d,J=7.1Hz,1H),1.96(s,3H),1.95(d,J=4.4Hz,3H).

[0157] Compound DA-244: 620 mg, white solid, ESI [M+H] + =377.1.

[0158] 1 H NMR (400MHz, DMSO) δ8.32(s,1H),7.28(d,J=7.5Hz,1H),7.21(t,J=9.2Hz,2H),7.14(t,J=7.6Hz,1 H), 6.94 (d, J = 7.6Hz, 1H), 6.37 (q, J = 7.1Hz, 1H), 2.25 (s, 3H), 1.96 (d, J = 7.2Hz, 3H), 1.93 (s, 3H).

[0159] Compound DA-246: 1080 mg, white solid, ESI [M+H] + =397.1.

[0160] 1 H NMR (400MHz, DMSO) δ8.40(s,1H),7.57(d,J=7.4Hz,1H),7.31(t,J=7.8Hz,1H),7.23(t,J=9 .2Hz,2H),7.14(d,J=7.7Hz,1H),6.35(d,J=7.2Hz,1H),2.05(s,3H),1.96(d,J=7.2Hz,3H).

[0161] Compound DA-247: 524 mg, white solid, ESI [M+H] + =395.1.

[0162] 1H NMR (400MHz, DMSO) δ8.34(d,J=1.5Hz,1H),7.57(d,J=7.9Hz,1H),7.45–7.36(m,2H),7.30(t,J=7.8Hz,1 H),7.18(d,J=7.6Hz,1H),6.76–6.68(m,1H),6.47(d,J=7.0Hz,1H),2.06(s,3H),1.88(d,J=7.1Hz,3H).

[0163] Compound DA-248: 183 mg, colorless syrup, ESI [M+H] + =377.1.

[0164] 1 H NMR (400MHz, DMSO) δ8.30(d,J=1.6Hz,1H),7.34(d,J=9.3Hz,1H),7.29(d,J=7.5Hz,1H),7.15(t,J=7.5Hz,1H),7. 02(d,J=7.5Hz,1H),6.92(d,J=8.3Hz,1H),6.47(d,J=7.1Hz,1H),2.26(s,3H),1.97(s,3H),1.91(d,J=7.1Hz,3H).

[0165] Compound DA-250: 104 mg, colorless syrup, ESI [M+H] + =381.1.

[0166] 1 H NMR(400MHz,DMSO)δ8.34(d,J=1.8Hz,1H),7.38–7.28(m,3H),7.10(dd,J=4.6,3.2Hz,1H), 6.94(d,J=8.4Hz,1H), 6.45(d,J=7.1Hz,1H), 2.01(d,J=2.2Hz,3H), 1.91(d,J=7.1Hz,3H).

[0167] Compound DA-251: 210 mg, white solid, ESI [M+H] + =397.1.

[0168] 1H NMR (400MHz, DMSO) δ8.34(d,J=1.7Hz,1H),7.61–7.55(m,1H),7.40–7.28(m,2H),7.22(d,J =7.6Hz,1H),6.99–6.89(m,1H),6.45(q,J=7.1Hz,1H),2.10(s,3H),1.91(d,J=7.1Hz,3H).

[0169] Compound DA-254: 160 mg, white solid, ESI [M+H] + =377.1.

[0170] 1 H NMR (400MHz, DMSO) δ8.37(s,1H),7.49(qd,J=9.3,4.9Hz,1H),7.28(d,J=7.4Hz,1H),7.20–7.11(m, 2H), 6.95 (d, J = 7.6Hz, 1H), 6.41 (d, J = 7.2Hz, 1H), 2.24 (s, 3H), 1.99 (d, J = 7.2Hz, 3H), 1.91 (s, 3H).

[0171] Compound DA-260: 441 mg, colorless syrup, ESI [M+H] + =377.1.

[0172] 1 H NMR(400MHz, DMSO)δ8.36(s,1H),7.48(qd,J=9.4,4.9Hz,1H),7.27(d,J=7.5Hz,1H),7.21–7.09(m, 2H), 6.94 (d, J = 7.6Hz, 1H), 6.41 (d, J = 7.2Hz, 1H), 2.24 (s, 3H), 1.99 (d, J = 7.2Hz, 3H), 1.91 (s, 3H).

[0173] Compound DA-262: 227 mg, colorless syrup, ESI [M+H] + =381.1.

[0174] 1H NMR (400MHz, DMSO) δ8.41(s,1H),7.49(qd,J=9.5,5.0Hz,1H),7.31(dd,J=8.5,3.2Hz,2H),7.16(t,J =10.7Hz,1H),7.06–6.98(m,1H),6.39(q,J=7.2Hz,1H),1.99(d,J=7.2Hz,3H),1.95(d,J=2.2Hz,3H).

[0175] Compound DA-263: 239 mg, colorless syrup, ESI [M+H] + =397.1.

[0176] 1 H NMR (400MHz, DMSO) δ8.43(s,1H),7.57(dd,J=8.0,0.8Hz,1H),7.50(qd,J=9.5,5.0Hz,1H),7.31 (t,J=7.8Hz,1H),7.20–7.12(m,2H),6.39(q,J=7.2Hz,1H),2.04(s,3H),2.00(d,J=7.2Hz,3H).

[0177] Compound DA-266: 143 mg, colorless syrup, ESI [M+H] + =354.2.

[0178] 1 H NMR (400MHz, DMSO) δ8.21(d,J=1.6Hz,1H),7.28(d,J=7.1Hz,1H),7.15(t,J=7.6Hz,1H),7.09–6.97(m,3H), 6.93(t,J=8.0Hz,1H),6.47(q,J=7.1Hz,1H),2.30(s,3H),2.25(s,3H),1.98(s,3H),1.87(d,J=7.1Hz,3H).

[0179] Compound DA-268: 166 mg, colorless syrup, ESI [M+H] + =375.1.

[0180] 1H NMR (400MHz, DMSO) δ8.27(d,J=1.7Hz,1H),7.60–7.55(m,1H),7.31(t,J=7.8Hz,1H),7.20(d,J=7.6Hz,1H),7. 10–7.00(m,2H),6.94(t,J=8.0Hz,1H),6.45(q,J=7.0Hz,1H),2.31(s,3H),2.09(s,3H),1.88(d,J=7.1Hz,3H).

[0181] Compound DA-282: 137 mg, colorless syrup, ESI [M+H] + =359.1.

[0182] 1 H NMR (400MHz, DMSO) δ8.26(d,J=1.8Hz,1H),7.35–7.27(m,2H),7.26–7.19(m,1H),7.16(t,J=7.6Hz,1H),7.02(d,J=7 .6Hz,1H),6.93(ddd,J=9.0,5.8,3.1Hz,1H),6.47(q,J=7.0Hz,1H),2.26(s,3H),1.98(s,3H),1.90(d,J=7.1Hz,3H).

[0183] Compound DA-283: 159 mg, colorless syrup, ESI [M+H] + =363.1.

[0184] 1 H NMR(400MHz, DMSO)δ8.30(d,J=1.7Hz,1H),7.37–7.29(m,3H),7.27–7.21(m,1H),7.15–7.08(m,1H),6 .96(ddd,J=9.1,5.9,3.2Hz,1H),6.44(q,J=6.9Hz,1H),2.02(d,J=2.2Hz,3H),1.90(d,J=7.1Hz,3H).

[0185] Compound DA-284: 161 mg, colorless syrup, ESI [M+H] + =379.1.

[0186] 1H NMR(400MHz, DMSO)δ8.31(d,J=1.8Hz,1H),7.58(dd,J=8.0,1.0Hz,1H),7.38–7.29(m,2H),7.27–7.20 (m,2H),6.96(ddd,J=9.0,5.8,3.1Hz,1H),6.45(q,J=7.1Hz,1H),2.10(s,3H),1.90(d,J=7.1Hz,3H).

[0187] Compound DA-285: 159 mg, colorless syrup, ESI [M+H] + =359.1.

[0188] 1 H NMR (400MHz, DMSO) δ8.32(d,J=1.7Hz,1H),7.29(d,J=7.4Hz,1H),7.24–7.17(m,1H),7.16(t,J=7.6Hz,1H),7. 04(d,J=7.6Hz,1H),7.02–6.96(m,2H),6.32(q,J=7.1Hz,1H),2.26(s,3H),1.98(s,3H),1.91(d,J=7.2Hz,3H).

[0189] Compound DA-286: 235 mg, colorless syrup, ESI [M+H] + =363.1.

[0190] 1 H NMR (400MHz, DMSO) δ8.35(d,J=1.8Hz,1H),7.32(dd,J=8.4,3.3Hz,2H),7.20(tt,J=9.4,2.3Hz,1H),7. 17–7.10(m,1H),7.06–6.96(m,2H),6.29(q,J=7.2Hz,1H),2.02(d,J=2.2Hz,3H),1.91(d,J=7.2Hz,3H).

[0191] Compound DA-287: 150 mg, colorless syrup, ESI [M+H] + =379.1.

[0192] 1H NMR (400MHz, DMSO) δ8.36(d,J=1.7Hz,1H),7.63–7.56(m,1H),7.32(t,J=7.8Hz,1H),7.25(d,J=7.6Hz ,1H),7.25–7.18(m,1H),7.06–6.98(m,2H),6.30(q,J=7.1Hz,1H),2.11(s,3H),1.91(d,J=7.2Hz,3H).

[0193] Example 5: Preparation of the compounds DA-305 to DA-310 of the present invention

[0194]

[0195] 1. Preparation of DA-305.1

[0196] At room temperature, pyrazole (10.86 g, 149.5 mmol) was dissolved in 150 mL of dry THF. The mixture was cooled to approximately -15 °C with dry ice. NaH (5.9 g, 60% in mineral oil, 147.5 mmol) was slowly added in portions to the reaction mixture, and the mixture was stirred at -15 °C for 30 minutes. A solution of SEMCl (24.7 g, 148.2 mmol) in 10 mL of dry THF was then slowly added dropwise to the reaction mixture, and the mixture was stirred overnight at room temperature. After the reaction was confirmed to be complete by TLC, the reaction solution was slowly poured into ice water and extracted with EtOAc (3 × 30 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 1 / 100–1 / 10). TLC (methanol / dichloromethane (v / v) = 1 / 10) was used to monitor the reaction, and the fraction with Rf = 0.5–0.6 was collected to give a colorless oily compound DA-305.1 (21.9 g, yield 73.9%). (ESI [M+H]) + =199.1.

[0197] 2. Preparation of DA-305.2

[0198] Compound DA-305.1 (4.76 g, 24 mmol) was dissolved in 50 mL of dry THF under an acetone bath on dry ice at -70 °C. Under argon protection, 9.6 mL of n-butyllithium (2.5 mol / L in THF, 24 mmol) was slowly added to the reaction mixture using a syringe, and the mixture was stirred at -70 °C for 2 hours. The reaction mixture was then divided into five equal portions and added to five single-necked reaction flasks purged with argon under argon protection. A 2 mL solution of 1-(2,3-Difluorophenyl)ethan-1-one (624.5 mg, 4 mmol) in THF was slowly added to one of the flasks using a syringe, and the mixture was stirred overnight at room temperature. A 10 mL solution of saturated ammonium chloride was added to the reaction mixture, and the mixture was extracted with EtOAc (3 × 10 mL). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product, compound DA-305.2.

[0199] The crude compound DA-305.2 was dissolved in 4 mL of dry CH2Cl2, and 1 mL of TFA was added. The mixture was stirred overnight at room temperature. After the reaction was completed as monitored by LC-MS, the mixture was concentrated under reduced pressure, alkalized with 5 mL of saturated sodium bicarbonate aqueous solution, extracted with dichloromethane (3 × 5 mL), and the combined organic phases were dried over anhydrous Na2SO4. The mixture was filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain the crude compound DA-305.3 (1 g).

[0200] 3. Preparation of target compound DA-305

[0201] At room temperature, crude compound DA-305.3 (1 g) and 10% wet palladium on carbon (100 mg) were dissolved in MeOH (10 mL). The system was purged three times with hydrogen, and the mixture was stirred overnight under hydrogen atmosphere. After the reaction was monitored by LC-MS to ensure complete reaction, the mixture was filtered. The filter cake was washed with methanol (3 × 5 mL), and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was then subjected to silica gel column chromatography and reverse phase chromatography to prepare a colorless syrupy compound DA-305 (258 mg, overall yield 31.0%). ESI [M+H] + =208.9

[0202] 1 H NMR(400MHz,d6-DMSO)δ12.35(s,1H),7.54(s,1H),7.28–7.17(m,1H),7.17– 7.01(m,2H),6.08(d,J=1.7Hz,1H),4.57–4.42(m,1H),1.62(d,J=7.2Hz,3H).

[0203] 4. Preparation of target compounds DA-306~DA-310

[0204] The remaining four portions of lithium pyrazole salt from the second step were each added to 4 mmol of the following ketone:

[0205]

[0206] Then, the SEM protecting groups were removed by TFA, and the target compounds DA-306 to DA-310 were obtained by 10% wet palladium reduction on carbon.

[0207] Compound DA-306: 76 mg, white solid, ESI [M+H] + =220.9

[0208] 1 H NMR(400MHz,d6-DMSO)δ12.33(s,1H),7.72–7.38(m,1H),7.28–7.01(m,3H), 6.04(d,J=1.7Hz,1H),4.77–4.61(m,1H),2.39(s,3H),1.57(d,J=7.1Hz,3H).

[0209] Compound DA-307: 699 mg, colorless syrup, ESI [M+H] + =204.9

[0210] 1 H NMR(400MHz,d6-DMSO)δ12.30(s,1H),7.50(s,1H),7.18–7.04(m,2H),7.04–6.93(m,1H),6.0 4(d,J=1.8Hz,1H), 4.47(q,J=14.2,7.1Hz,1H), 2.25(d,J=2.0Hz,3H), 1.59(d,J=7.2Hz,3H).

[0211] Compound DA-308: 340 mg, colorless syrup, ESI [M+H] + =224.8

[0212] 1 H NMR (400MHz, d6-DMSO) δ7.54 (s, 1H), 7.40 (t, J = 7.4Hz, 1H), 7.31–7.21 (m, 1H), 7. 20–7.10(m,1H),6.09(d,J=1.6Hz,1H),4.62–4.34(m,1H),1.61(d,J=7.2Hz,3H).

[0213] Compound DA-310: 39 mg, white solid, ESI [M+H] + =187.0

[0214] 1 H NMR(400MHz,d6-DMSO)δ12.45(s,1H),7.58(s,1H),7.24–7.12(m,1H),7.11–6.90(m ,3H),6.06(d,J=1.9Hz,1H),4.23–4.00(m,1H),2.28(s,3H),1.55(d,J=7.3Hz,3H).

[0215] Example 6: Preparation of the compounds DA-311 to DA-317 of the present invention

[0216]

[0217] 1. Preparation of DA-311.1

[0218] At room temperature, 1H-1,2,4-triazole (9.3 g, 134.6 mmol) and DIEA (34.8 g, 269 mmol) were dissolved in 100 mL of dry MeCN and cooled to 0 °C in an ice-salt bath. A 20 mL solution of dry THF containing SEMCl (24.7 g, 114.8 mmol) was slowly added dropwise to the reaction mixture, and the mixture was stirred overnight at room temperature. After the reaction was confirmed to be complete by TLC, the reaction solution was slowly poured into ice water and extracted with EtOAc (3 × 20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 1 / 100–1 / 10). TLC (methanol / dichloromethane (v / v) = 1 / 10) was used to monitor the reaction, and the fraction with Rf = 0.5–0.6 was collected to give a colorless oily compound DA-311.1 (18.38 g, yield 68.5%). + =200.1.

[0219] 2. Preparation of DA-311~DA-317

[0220] The preparation of DA-311 to DA-317 is similar to that of DA-305. Using 24 mmol of DA-311.1 as the starting material, the crude product was obtained by reaction with n-butyllithium, deprotection with TFA, and reduction with 10% wet palladium on carbon. The crude product was purified by silica gel column chromatography and reverse-phase preparation to obtain the corresponding target compounds.

[0221] Compound DA-311: 601 mg, colorless syrup, ESI [M+H] + =202.0

[0222] 1H NMR (400MHz, d6-DMSO) δ13.39(s,1H),8.03(s,1H),7.17–6.91(m,3H),4.57(q,J=7.1Hz,1H),2.28(s,3H),2.27(s,3H),1.60(d,J=7.2Hz,3H).

[0223] Compound DA-312: 334 mg, colorless syrup, ESI [M+H] + =209.9

[0224] 1 H NMR (400MHz, d6-DMSO) δ13.78(s,1H),8.23(s,1H),7.41–7.25(m,1H),7.21–7.07(m,2H),4.57(q,J=7.2Hz,1H),1.62(d,J=7.2Hz,3H).

[0225] Compound DA-313: 334 mg, colorless syrup, ESI [M+H] + =209.9

[0226] 1 H NMR (400MHz, d6-DMSO) δ13.52(s,1H),8.33(s,0.45H),7.82(s,0.38H),7.31–7.04(m,3H),4.90–4.63(m,1H),2.39(s,3H),1.61(d,J=7.1Hz,3H).

[0227] Compound DA-314: 564 mg, colorless syrup, ESI [M+H] + =205.9

[0228] 1 H NMR(400MHz,d6-DMSO)δ13.74(s,1H),8.22(s,1H),7.15(t,J=7.2Hz,1H),7.12– 6.96(m,2H),4.53(q,J=6.9Hz,1H),2.24(d,J=2.0Hz,3H),1.59(d,J=7.2Hz,3H).

[0229] Compound DA-315: 304 mg, colorless syrup, ESI [M+H] + =225.8

[0230] 1H NMR(400MHz,d6-DMSO)δ13.81(s,1H),8.46(s,1H),7.55–7.40(m,1H),7.33 –7.25(m,1H),7.24–7.12(m,1H),4.73–4.42(m,1H),1.62(d,J=5.9Hz,3H).

[0231] Compound DA-316: 67 mg, colorless syrup, ESI [M+H] + =191.9

[0232] 1 H NMR (400MHz, d6-DMSO) δ8.68 (s, 1H), 7.45–7.26 (m, 2H), 7.26–7.11 (m, 2H), 4.63 (q, J = 7.2Hz, 1H), 1.65 (d, J = 7.2Hz, 3H).

[0233] Compound DA-317: 51 mg, colorless syrup, ESI [M+H] + =187.9

[0234] 1 H NMR (400MHz, d6-DMSO) δ8.20(s,1H),7.19(t,J=7.5Hz,1H),7.12–6.97(m,3H),4.26(q,J=7.2Hz,1H),2.28(s,3H),1.60(d,J=7.2Hz,3H).

[0235] Example 7: Preparation of the compounds DA-300, DA-302, DA-318 to DA-322 and DA-318A to DA-320A of the present invention

[0236]

[0237] 1. Preparation of DA-318.2

[0238] At room temperature, 4-Iodo-1-trityl-1H-imidazole (6.54 g, 15 mmol) was dissolved in CH2Cl2 (40 mL). The reaction system was purged three times with argon gas under argon protection and cooled to -10 °C in an ice-salt bath. EtMgBr (7.9 mL, 2 mol / L in Et2O, 15.8 mmol) was slowly added to the system using a syringe, and the mixture was stirred at room temperature for 1 hour. The system was then cooled to -10 °C in an ice-salt bath, and a CH2Cl2 (5 mL) solution of DA-318.1 (1.29 g, 7.5 mmol) was slowly added dropwise to the reaction system, and the mixture was stirred overnight at room temperature. After the reaction was confirmed to be complete by TLC, the system was cooled to 0 °C in an ice-water bath, and a saturated ammonium chloride solution (10 mL) was slowly added to the reaction system. The mixture was extracted with CH2Cl2 (3 × 10 mL), and the combined organic phases were dried over anhydrous Na2SO4. The mixture was filtered and concentrated under reduced pressure to obtain the crude compound DA-318.2.

[0239] The crude compound DA-318.2, iodine (4.76 g, 18.75 mmol), and phosphinic acid (1.92 g, 30 mmol) were dissolved in acetic acid (50 mL) and stirred at 110 °C for 2 hours. After the reaction was complete as monitored by LC-MS, the mixture was concentrated under reduced pressure, cooled to 0 °C in an ice-water bath, and saturated sodium bicarbonate aqueous solution (20 mL) was slowly added to the reaction system. The mixture was extracted with ethyl acetate (3 × 10 mL), and the combined organic phases were dried over anhydrous Na₂SO₄. The mixture was filtered, concentrated under reduced pressure to obtain the crude product, and purified by silica gel column chromatography and reversed-phase chromatography to obtain a white solid, the target compound DA-318 (270 mg). ESI [M+H] + =380.7. DA-318A was also collected.

[0240] Compound DA-318: 270 mg, white solid, ESI [M+H] + =380.7

[0241] 1 H NMR(400MHz,d6-DMSO)δ11.85(s,1H),7.57(s,0.38H),7.54(s,0.67H),7.45–7.18(m,6H),6.8 5(d,J=6.1Hz,1H),4.40–4.20(m,1H),3.23–2.96(m,1H),2.50–2.12(m,2H),1.24–1.14(m,3H).

[0242] Compound DA-318A: 342 mg, white solid, ESI [M+H] + =208.9.

[0243] 1H NMR(400MHz,d6-DMSO)δ11.89(s,1H),7.56(d,J=1.0Hz,1H),7.36–7.21(m,2H) ,7.09(s,1H),6.90(s,1H),4.50(dd,J=13.7,6.7Hz,1H),1.52(d,J=7.1Hz,3H).

[0244] The preparation of compounds DA-319 to DA-322 and DA-319A to DA-320A of the present invention is similar to that of compounds DA-318 and DA-318A of the present invention.

[0245] Compound DA-300: 281 mg, white solid, ESI [M+H] + =226.9.

[0246] 1 H NMR (400MHz, d6-DMSO) δ11.84(s,1H),7.48(d,J=1.0Hz,1H),7.11(t,J=9.0Hz,2H),6.82(s,1H),4.35(q,J=7.2Hz,1H),1.59(d,J=7.3Hz,3H).

[0247] Compound DA-302: 163 mg, colorless syrup, ESI [M+H] + =222.9.

[0248] 1 H NMR (400MHz, d6-DMSO) δ11.82(s,1H),7.47(d,J=1.1Hz,1H),7.17(dd,J=15.1,8.4Hz,1H),6. 96–6.88(m,1H),6.78(s,1H),4.40(q,J=7.2Hz,1H),2.21–2.12(m,3H),1.60(d,J=7.3Hz,3H).

[0249] Compound DA-319: 166 mg, white solid, ESI [M+H] + =348.8

[0250] 1H NMR (400MHz, d6-DMSO) δ11.83 (s, 1H), 7.48 (d, J = 1.1Hz, 0.3H), 7.45 (d, J = 1.1Hz, 0.7H),7.37–7.17(m,2H),7.06–6.96(m,3H),6.92(t,J=9.0Hz,1H),6.76(d,J=11. 7Hz,1H),4.36–4.24(m,0.3H),4.07–3.93(m,0.7H),3.24–3.10(m,0.3H),3.05–2. 92(m,0.7H),2.73–2.55(m,2H),1.32(d,J=7.1Hz,0.9H),1.29(d,J=7.0Hz,2.1H).

[0251] Compound DA-320: 376 mg, white solid, ESI [M+H] + =348.8

[0252] 1 H NMR(400MHz,d6-DMSO)δ12.06–11.65(m,1H),7.60–7.27(m,3H),7.21–6.93(m,4H),6.83(d,J=7.0Hz,1 H),4.16–3.89(m,1H),2.92–2.73(m,1H),2.45–2.26(m,1H),2.25–2.04(m,1H),1.19(d,J=6.9Hz,3H).

[0253] Compound DA-321: 347 mg, white solid, ESI [M+H] + =384.8

[0254] 1 H NMR(400MHz,d6-DMSO)δ11.84(s,1H),7.48(s,0.3H),7.46(s,0.7H),7.19–6.92(m,4H),6.82(d,J=9.8Hz,1H),4.28– 4.17(m,0.3H),3.97–3.85(m,0.7H),3.19–3.06(m,0.3H),3.01–2.84(m,0.7H),2.72–2.37(m,2H),1.33–1.26(m,3H).

[0255] Compound DA-322: 161 mg, white solid, ESI [M+H] + =374.8

[0256] Compound DA-319A: 437 mg, white solid, ESI [M+H] + =208.9.

[0257] 1 H NMR(400MHz,d6-DMSO)δ11.84(s,1H),7.49(d,J=0.9Hz,1H),7.38–7.27(m,1H), 7.04(t,J=8.6Hz,2H),6.80(s,1H),4.41(q,J=7.0Hz,1H),1.62(d,J=7.3Hz,3H).

[0258] Compound DA-320A: 525 mg, colorless oil, ESI [M+H] + =208.9.

[0259] 1 H NMR(400MHz,d6-DMSO)δ11.86(s,1H),7.54(d,J=0.9Hz,1H),7.33–7.21(m,1H),7.21– 7.10(m,1H),7.07–6.94(m,1H),6.83(s,1H),4.39–4.22(m,1H),1.51(d,J=7.2Hz,3H).

[0260] Example 8: Preparation of the compound DA-303 of the present invention

[0261]

[0262] 1. Preparation of DA-303.2

[0263] DA-303.1 (10 g, 56.79 mmol), N,O-dimethylhydroxylamine hydrochloride (16.62 g, 170.36 mmol), and DIEA (22.02 g, 170.36 mmol) were added to DMF (200 mL) and cooled to 0 °C using an ice-water bath. HATU (32.39 g, 85.18 mmol) was added in portions to the reaction mixture, and the mixture was stirred overnight at room temperature. After the reaction was confirmed to be complete by TLC, the reaction system was poured into ice water and extracted with EtOAc (3 × 100 mL). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 20 to 1 / 5). TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5) was used to monitor the reaction, and the fraction with Rf = 0.4–0.5 was collected to give compound DA-303.2 (11.5 g, yield 92.1%). (ESI [M+H]) + =220.1

[0264] 2. Preparation of DA-303.3

[0265] At 0°C in an ice-water bath, methyl magnesium bromide (52 mL, 104.5 mmol, 2.0 M in THF) was slowly added dropwise to DA-303.2 (11.5 g, 52.33 mmol) in 100 mL of THF using a constant-pressure dropping funnel. After the addition was complete, the mixture was slowly brought to room temperature and stirred for 5 hours. After the reaction was confirmed to be complete by TLC, the reaction mixture was poured into ice water and extracted with EtOAc (3 × 100 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound DA-303.3 (6.8 g, yield 74.6%).

[0266] 3. Preparation of DA-303.5

[0267] Tert-butyl 4-iodo-1H-imidazole-1-carboxylate (1.69 g, 5.74 mmol) was dissolved in CH2Cl2 (10 mL) at room temperature. The reaction system was purged three times with nitrogen under nitrogen protection and cooled to -10 °C in an ice-salt bath. EtMgBr (3 mL, 2 mol / L in THF, 6 mmol) was slowly added to the system using a constant-pressure dropping funnel, and the mixture was stirred at room temperature for 1 hour. The system was then cooled to -10 °C in an ice-salt bath, and a CH2Cl2 (2 mL) solution of DA-303.3 (1.0 g, 5.7 mmol) was slowly added dropwise to the reaction system, and the mixture was stirred overnight at room temperature. After the reaction was confirmed to be complete by TLC, the reaction system was cooled to 0 °C in an ice-water bath. A saturated ammonium chloride solution (10 mL) was slowly added to the reaction system, and the mixture was extracted with CH2Cl2 (3 × 10 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product.

[0268] The crude compound DA-303.4 was dissolved in dry CH2Cl2 (4 mL), and TFA (1 mL) was added. The mixture was stirred overnight at room temperature. After the reaction was monitored by LC-MS until complete, the mixture was concentrated under reduced pressure, alkalized with saturated sodium bicarbonate aqueous solution (5 mL), extracted with dichloromethane (3 × 5 mL), and the combined organic phases were dried over anhydrous Na2SO4. The mixture was filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound DA-303.4 (100 mg, two-step yield 7.8%).

[0269] 4. Preparation of target compound DA-303

[0270] At room temperature, crude compound DA-303.4 (100 mg, 0.45 mmol) and 10% wet palladium on carbon (10 mg) were dissolved in MeOH (10 mL). The system was purged three times with hydrogen, and the mixture was stirred overnight under hydrogen atmosphere. After the reaction was monitored by LC-MS to ensure complete reaction, the mixture was filtered. The filter cake was washed with methanol (3 × 5 mL), and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was then subjected to silica gel column chromatography and reversed-phase chromatography to obtain a white solid compound DA-303 (25 mg, yield 24.6%). ESI [M+H] + =226.8

[0271] 1 H NMR(400MHz,d6-DMSO)δ11.84(brs,1H),7.49(s,1H),7.45–7.28(m,1H),7.1 8–7.00(m,1H),6.97–6.79(m,1H),4.55–4.28(m,1H),1.63(d,J=7.2Hz,3H).

[0272] Example 9: Preparation of the present invention compounds DA-440 and DA-441

[0273]

[0274] At room temperature, compound (R)-(1-(1-(2-Chloro-3-methylphenyl)ethyl)-4-fluoro-1H-imidazol-5-yl)(2,3-dimethylphenyl)methanone (200 mg, 0.54 mmol) and 10% wet palladium on carbon (20 mg) were dissolved in MeOH (10 mL). The system was purged three times with hydrogen and stirred overnight under hydrogen atmosphere. After the reaction was monitored by LC-MS to be complete, the mixture was filtered, and the filter cake was washed with methanol (3 × 5 mL). The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was then subjected to silica gel column chromatography and reversed-phase chromatography to prepare white solid compounds DA-440 and DA-441.

[0275] Compound DA-440: 12 mg, white solid, ESI [M+H] + =186.9.

[0276] 1 H NMR (400MHz, d6-DMSO) δ11.77(brs,1H),7.50(s,1H),7.06–6.92(m,3H),6.58(s,1H),3.83(s,2H),2.24(s,3H),2.17(s,3H).

[0277] Compound DA-441: 9 mg, white solid, ESI [M+H] + =204.9.

[0278] 1 H NMR (400MHz, d6-DMSO) δ11.89(brs,1H),7.21(s,1H),7.08–6.98(m,2H),6.96–6.87(m,1H),3.83(s,2H),2.24(s,3H),2.17(s,3H).

[0279] Example 10: Preparation of the present invention compounds DA-270, DA-276 and DA-236

[0280]

[0281] 1. Preparation of DA-270.4

[0282] DA-270.1 (25 g, 120.13 mmol), N,O-dimethylhydroxylamine hydrochloride (35.15 g, 360.4 mmol), and DIEA (23.29 g, 180.2 mmol) were added to DMF (200 mL) and cooled to 0 °C in an ice-water bath. HATU (68.5 g, 180.1 mmol) was added to the reaction system in portions, and the mixture was stirred overnight at room temperature. After the reaction was completed as monitored by TLC, the reaction system was poured into ice water and extracted with EtOAc (3 × 100 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product compound DA-270.2 (28.6 g).

[0283] At 0°C in an ice-water bath, methyl magnesium bromide (85 mL, 171 mmol, 2.0 M in THF) was slowly added dropwise to DA-270.2 (28.6 g, 113.9 mmol) in 100 mL of THF using a constant-pressure dropping funnel. The mixture was stirred at room temperature for 5 hours. After the reaction was completed as monitored by TLC, the reaction mixture was poured into ice water and extracted with EtOAc (3 × 100 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product compound DA-270.3 (24.3 g).

[0284] At room temperature, crude DA-270.3 (24.3 g), formic acid (27.62 g, 600 mmol), and triethylamine (34.43 g, 360 mmol) were added sequentially to isopropanol (250 mL). The reaction system was purged three times with argon. Then, (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropyltoluene)ruthenium chloride (1.53 g, 2.4 mmol) was added to the reaction system. The mixture was stirred overnight at 55 °C under argon protection. The reaction was monitored by TLC until complete. Afterwards, the mixture was cooled to room temperature, filtered, and extracted with EtOAc (3 × 100 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 to 1 / 5). TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5) was used for monitoring. The fraction with Rf = 0.5 to 0.6 was collected to give a light yellow oily compound DA-270.4 (19.18 g, three-step yield 76.7%).

[0285] 2. Preparation of DA-270.5

[0286] At room temperature, Ethyl 4-fluoro-1H-imidazole-5-carboxylate (1.0 g, 6.29 mmol) was dissolved in dry THF (20 mL), and the temperature was lowered to ~-30 °C using a dry ice acetone bath. Then, DA-270.4 (1.45 g, 7.55 mmol) and PPh3 (2.48 g, 9.44 mmol) were added to the reaction system sequentially. DEAD (1.65 g, 9.44 mmol) was slowly added to the reaction system using a syringe, and the mixture was stirred overnight at room temperature. After the reaction was monitored by TLC until complete, the mixture was concentrated under reduced pressure, and EtOAc / PE (10 mL, 1 / 3) was added and stirred. The mixture was then filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10–1 / 3). TLC (ethyl acetate / petroleum ether (v / v) = 1 / 3) was used to monitor the reaction, and the fraction with Rf = 0.5–0.6 was collected to give a colorless oily compound DA-270.5 (2.27 g). ESI [M+H] + =348.8.

[0287] 3. Preparation of DA-270.7

[0288] At room temperature, DA-270.5 (1.88 g, 7.59 mmol) and sodium hydroxide (911 mg, 122.76 mmol) / H2O (5 mL) were dissolved in ethanol (40 mL) and stirred overnight at room temperature. After the reaction was completed as monitored by TLC, the solution was concentrated under reduced pressure, cooled in an ice-water bath, and the pH was adjusted to approximately 7 with 2 M hydrochloric acid solution. The solution was extracted with EtOAc (3 × 10 mL), and the combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude compound DA-270.6.

[0289] At room temperature, DA-270.6, N,O-dimethylhydroxylamine hydrochloride (2.22 g, 22.77 mmol), HATU (4.33 g, 11.39 mmol), and DIEA (2.94 g, 22.77 mmol) were added to DMF (20 mL) and stirred overnight at room temperature. After the reaction was completed as monitored by TLC, the reaction system was poured into ice water and extracted with EtOAc (3 × 10 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 20 to 1 / 3). TLC (ethyl acetate / petroleum ether (v / v) = 1 / 3) was used to monitor the reaction, and the fraction with Rf = 0.4 to 0.5 was collected to give compound DA-270.7 (1.556 g, yield 76.1%).

[0290] 4. Preparation of DA-270

[0291] Compound DA-270.7 (300 mg, 0.82 mmol) was dissolved in 5 mL of dry THF at room temperature. The reaction system was purged three times with nitrogen under nitrogen protection and cooled to -30 °C in a dry ice bath. (2,3-Dimethylphenyl)magnesium bromide (4 mL, 1 mol / L, 4 mmol) was slowly added to the system using a syringe, and the mixture was stirred at room temperature for 5 hours. After the reaction was complete as monitored by TLC, the temperature was lowered to 0 °C in an ice-water bath. A saturated ammonium chloride solution (10 mL) was slowly added to the reaction system, and the mixture was extracted with EtOAc (3 × 10 mL). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography and reversed-phase chromatography to obtain a colorless oily compound DA-270 (265 mg, yield 79.1%) ESI[M+H). + =408.8

[0292] 1H NMR (400MHz, d6-DMSO) δ8.36(d,J=1.7Hz,1H),7.76(dd,J=10.4,1.1Hz,1H),7.60(d,J=8.1Hz,1H),7.27(d,J=7.5Hz,1H),7.20(t, J=7.8Hz,1H),7.14(t,J=7.6Hz,1H),7.00(d,J=7.6Hz,1H),6.51(q,J=7.0Hz,1H),2.24(s,3H),1.92(s,3H),1.92(d,J=7.0Hz,3H).

[0293] 5. Preparation of DA-276 and DA-236

[0294] The preparation of DA-276 and DA-236 is similar to that of DA-270.

[0295] Compound DA-276: 278 mg, white solid, ESI [M+H] + =408.8.

[0296] 1 H NMR (400MHz, d6-DMSO) δ8.36(d,J=1.7Hz,1H),7.76(dd,J=10.4,1.1Hz,1H),7.60(d,J=8.1Hz,1H),7.27(d,J=7.5Hz,1H),7.20(t, J=7.8Hz,1H),7.14(t,J=7.6Hz,1H),7.00(d,J=7.6Hz,1H),6.51(q,J=7.0Hz,1H),2.24(s,3H),1.92(s,3H),1.92(d,J=7.0Hz,3H).

[0297] Compound DA-236: 709 mg, white solid, ESI [M+H] + =358.9.

[0298] 1¹H NMR (400MHz, d⁶-DMSO) δ 8.32 (d, J = 1.6 Hz, 1H), 7.46–7.34 (m, 1H), 7.29 (d, J = 7.5 Hz, 1H), 7.27–7.19 (m, 1H), 7.15 (t, J = 7.6 Hz, 1H), 7.00 (d, J = 7.6 Hz, 1H), 6.82 (t, J = 7.1 Hz, 1H), 6.52 (q, J = 7.1 Hz, 1H), 2.26 (s, 3H), 1.96 (s, 3H), 1.92 (d, J = 7.1 Hz, 3H). Example 11: Preparation of compounds DA-237 and DA-245 of the present invention.

[0299]

[0300] The preparation of DA-237 and DA-245 is similar to that of compound DA-232, using racemic alcohol DA-237.1 and S-alcohol DA-245.1 as starting materials, respectively.

[0301] Compound DA-237: 126 mg, white solid, ESI [M+H] + =359.1.

[0302] 1 H NMR(400MHz,d6-DMSO)δ8.41(s,1H),7.70–7.58(m,1H),7.46–7.28(m,2H),7.2 8–7.18(m,1H),7.15–7.02(m,2H),6.35(q,J=7.1Hz,1H),1.97(d,J=7.2Hz,3H).

[0303] Compound DA-245: 754 mg, white solid, ESI [M+H] + =446.6.

[0304] 1 H NMR(400MHz,d6-DMSO)δ8.18(d,J=1.7Hz,1H),7.36–7.23(m,3H),7.14(t,J=7.6Hz,1H),6.98(d,J=7.5Hz,1 H),6.77–6.68(m,1H),6.55(q,J=6.8Hz,1H),2.37(s,3H),2.25(s,3H),1.97(s,3H),1.87(d,J=7.0Hz,3H).

[0305] The following experimental examples demonstrate the beneficial effects of the present invention.

[0306] Experimental Example 1: Determination of Pharmacological Data of the Compounds of the Invention

[0307] 1. Test Methods

[0308] 1.1 Testing the anesthetic effect of the compound of the present invention after tail vein injection in rats (determination of the minimum effective anesthetic dose):

[0309] Experimental animals were 7-9 week old male SD rats, administered via tail vein (injection rate 0.02 mL / s, volume 0.6 mL / rat). The initial dose of the experimental compound was 1 mg / kg, and the actual dose was calculated based on the rat's pre-experimental body weight. Subsequent dose increases or decreases were determined based on whether the righting reflex disappeared in the rats, and the lowest dose at which the righting reflex disappeared was defined as the minimum effective anesthetic dose.

[0310] While testing whether the compound of this invention has an anesthetic effect after intravenous injection into rats, its analgesic effect was also determined. Once the compound was determined to have an anesthetic effect (loss of righting reflex ≥30s), the rats were immediately observed to respond to a noxious stimulus (alligator clips clamping the outer third of the rat's tail for 30s). If the rats did not respond within 30s, it was considered to have an analgesic effect; otherwise, it was considered not to have an analgesic effect. If the compound did not have an anesthetic effect (loss of righting reflex <30s), one minute after administration, the rats were given a noxious stimulus (alligator clips clamping the outer third of the rat's tail for 30s). If the rats did not respond within 30s, it was considered to have an analgesic effect; otherwise, it was considered not to have an analgesic effect.

[0311] In this invention, the dose at which analgesic effects begin to appear is defined as the minimum effective analgesic dose.

[0312] The minimum effective anesthetic dose in this invention is further classified as follows: A ≤ 5 mg / kg; 5 mg / kg < B ≤ 10 mg / kg; 10 mg / kg <C≤15mg / kg;15mg / kg<D≤20mg / kg;20mg / kg<E≤25mg / kg;F>25mg / kg。

[0313] The most effective analgesic dose in this invention is further classified as follows: A ≤ 10 mg / kg; 10 mg / kg < B ≤ 20 mg / kg; 20 mg / kg <C≤30mg / kg;30mg / kg<D≤40mg / kg;E>40mg / kg。

[0314] 1.2 Determination of the main pharmacological effects of the compounds of this invention

[0315] 1.2.1 The ED of the general anesthesia effect of the compounds of this invention, using the disappearance of the righting reflex in rats as the criterion, 50

[0316] Male SD rats aged 7-9 weeks were selected for the experiment. The median effective dose (EDD) of the compound of this invention for general anesthesia, with the loss of righting reflex as the criterion, was determined using an up-and-down method. 50 During the experiment, the drug was administered via the tail vein of rats, with a volume of 0.6 mL per rat and an administration rate of 0.02 mL / s. The absence of righting reflex (LORR) for ≥30 s was used as the criterion for determining the presence of an anesthetic effect.

[0317] 1.2.2 In rats, the righting reflex was induced to disappear 2 ED. 50 Dosage comparison of the pharmacological effects of the compounds of this invention

[0318] The compound ED was measured. 50 Subsequently, 2ED was used to induce the loss of the righting reflex in rats. 50 Dosage was tested. The drug was administered via the tail vein of rats, with a volume of 0.6 mL per rat and an administration rate of 0.02 mL / s. The time of loss of righting reflex (LORR) was recorded as the time at which the anesthetic effect began. After administration, the time of loss and recovery of the righting reflex, as well as the onset and duration of adverse reactions, were recorded and observed.

[0319] 2ED 50 Pharmacological characteristics of equivalent doses:

[0320] In the above experiments, in addition to recording the dose at which the righting reflex disappeared, the onset and recovery times of the anesthetic effect from the start of administration, the duration of the righting reflex, and the duration of the sedative effect were also recorded. At the dose at which the compound of this invention caused the righting reflex to disappear, the effect of the compound on the respiration of the experimental animals could also be observed.

[0321] 2. Experimental Results

[0322] Table 1. Pharmacological data on the anesthetic effect of a single intravenous injection of the compounds of the present invention.

[0323]

[0324]

[0325] Table 2. Minimum analgesic dose of the compound of the present invention for a single intravenous injection

[0326] Compound numbering Minimum analgesic dose (mg / kg) DA-254 D DA-270 B DA-276 B DA-282 C DA-283 C DA-284 D

[0327] Experimental results show that the compound of the present invention has highly effective anesthetic, sedative and hypnotic effects, can control status epilepticus, and also has analgesic effects.

Claims

1. A compound, its stereoisomer, its pharmaceutically acceptable salt, its solvate, its prodrug, its metabolite, or its deuterated derivative, characterized in that, The structure of the compound is shown in Formula I: in, R x11 Selected from hydrogen, C 1～5 alkyl; R n1 Selected from none or R x6 R x7 R x8 R x9 R x10 Each is independently selected from hydrogen, halogen, halogenated or unhalogenated C 1～5 alkyl; R n2 Selected from hydrogen and halogens; R x1 R x2 R x3 R x4 Each is independently selected from hydrogen, halogen, halogenated or unhalogenated C 1～5 alkyl; When X is F, R n1 For none, R n2 When it is hydrogen, ring A is R x1 R x2 R x3 R x4 Each is independently selected from hydrogen, halogen, and C. 1～5 Alkyl; or, ring A is alkyl; R x4 For F, R x1 R x2 R x3 Each is independently selected from hydrogen, halogen, and C. 1～5 Alkyl, and R x1 R x2 R x3 Not both are hydrogen; or, ring A is R x1 R x2 R x3 R x4 Each is independently selected from hydrogen, halogen, and C. 1～5 alkyl; When X is not F, R n1 for When the compound is: Among them, R q Selected from halogen or C 1～5 alkyl; When X is not F, R n1 None; the compound is: Among them, R n2 R is hydrogen or halogen. k1 Selected from C 1～5 Alkyl, R x1 R x2 R x3 R x4 Selected from hydrogen, halogens, C 1～5 Alkyl; R m1 Selected from hydrogen, chlorine, C 1～5 alkyl.

2. The compound, its stereoisomer, its pharmaceutically acceptable salt, its solvate, its prodrug, its metabolite, or its deuterated derivative according to claim 1, characterized in that, The structure of the compound is shown in Formula II: in, R x5 Selected from hydrogen and halogens; R x6 R x7 R x8 R x9 R x10 Each is independently selected from hydrogen, halogen, halogenated or unhalogenated C 1～5 alkyl; R x11 Selected from hydrogen, C 1～5 alkyl; The Selected from R 12 Selected from hydrogen, F; when R 12 For hydrogen, R x5 For F, R x11 When it is methyl, R x9 R x10 Not both of them are F; R 13 Selected from F, Cl, Br, CH3, CF3, CH2F; R 14 Selected from F, Cl, Br, CH3, CF3, CH2F; R 15 Selected from hydrogen, F, Cl, Br, CH3, CF3, CH2F; when R 15 For hydrogen, R x5 For F, R x11 When it is methyl, R x9 R x10 Not both of them are F; R 16 Selected from CF3 and CH2F; R 17 Selected from F, CF3, CH3, CH2F; When R 17 Selected from F, CH3, R x5 When selected from hydrogen, R x6 R x7 R x8 R x9 R x10 Each is independently selected from hydrogen, halogen, halogenated or unhalogenated C 1～5 alkyl; When R 17 When selected from F and CH3, R x5 When selected from halogens, R x6 R x7 R x8 R x9 R x10 Both are hydrogen; or, when R 17 When selected from F and CH3, R x5 Selected from halogens, R x10 C for halogenation 1～5 When alkyl, R x6 R x7 R x8 R x9 Each is independently selected from hydrogen, halogen, halogenated or unhalogenated C 1～5 Alkyl; or, when R 17 When selected from F and CH3, R x5 Selected from halogens, R x8 R x9 R x10 When both are selected from halogens, R x6 R x7 Each is independently selected from hydrogen, halogen, halogenated or unhalogenated C 1～5 Alkyl; or, when R 17 When selected from F and CH3, R x5 Selected from halogens, R x10 When it is Cl, R x6 R x7 R x8 R x9 Each is independently selected from hydrogen, halogen, halogenated or unhalogenated C 1～5 Alkyl, while R x9 It cannot be F.

3. The compound, its stereoisomer, its pharmaceutically acceptable salt, its solvate, its prodrug, its metabolite, or its deuterated derivative according to claim 2, characterized in that, The Selected from R x5 Selected from hydrogen and halogens; R x6 R x7 R x8 R x9 R x10 Each is independently selected from hydrogen, halogen, halogenated or unhalogenated C 1～5 alkyl; R x11 Selected from hydrogen, C 1～5 alkyl.

4. The compound, its stereoisomer, its pharmaceutically acceptable salt, its solvate, its prodrug, its metabolite, or its deuterated derivative according to claim 2, characterized in that, The Selected from R x5 Selected from hydrogen and halogens; R x6 R x7 R x8 R x9 R x10 Each is independently selected from hydrogen, halogen, halogenated or unhalogenated C 1～5 alkyl; R x11 Selected from hydrogen, C 1～5 alkyl.

5. The compound, its stereoisomer, its pharmaceutically acceptable salt, its solvate, its prodrug, its metabolite, or its deuterated derivative according to claim 1, characterized in that, The structure of the compound is shown in Formula III: R x1 C selected from halogen, halogenated or non-halogenated 1～5 alkyl; R x5 Selected from hydrogen and halogens; R x6 R x7 R x8 R x9 R x10 Each is independently selected from hydrogen, halogen, halogenated or unhalogenated C 1～5 alkyl.

6. The compound, its stereoisomer, its pharmaceutically acceptable salt, its solvate, its prodrug, its metabolite, or its deuterated derivative according to claim 5, characterized in that, The structure of the compound is shown in Formula IV: R x1 C selected from halogen, halogenated or non-halogenated 1～5 alkyl; R x5 Selected from hydrogen and halogens; R x6 R x7 R x8 R x9 R x10 Each is independently selected from hydrogen, halogen, halogenated or unhalogenated C 1～5 alkyl.

7. A compound, its stereoisomer, its pharmaceutically acceptable salt, its solvate, its prodrug, its metabolite, or its deuterated derivative, characterized in that, The compound is selected from:

8. The compound, its stereoisomer, its pharmaceutically acceptable salt, its solvate, its prodrug, its metabolite, or its deuterated derivative according to any one of claims 1-7, characterized in that, The pharmaceutically acceptable salts are citrate, hydrofluoric acid salt, phosphate, propionate, succinate, tartrate, acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate, carbonate, bisulfate, sulfate, borate, camphorsulfonate, citrate, cyclohexanesulfonate, ethanedisulfonate, ethanesulfonate, formate, fumarate, glucohepanoate, glucuronate, glucuronate, hexafluorophosphate, hydrochloride, hydrobromide, hydroiodate, hydroxyethylsulfonate, lactate, malate, maleate, malonate, methanesulfonate, methyl sulfate, naphthate, succinate, nicotinate, nitrate, orotate, oxalate, palmitate, dihydroxynaphthyl salt, phosphate, hydrogen phosphate, dihydrogen phosphate, pyroglutamate, glycoside, stearate, succinate, tannate, tartrate, toluenesulfonate, trifluoroacetate, sine, or p-toluenesulfonate.

9. A pharmaceutical composition, characterized in that, The pharmaceutical composition is a formulation prepared by adding pharmaceutically acceptable excipients to a compound as described in any one of claims 1-7, its stereoisomers, its pharmaceutically acceptable salts, its solvates, its prodrugs, its metabolites or their deuterated derivatives as active ingredients.

10. Use of the compound, its stereoisomer, its pharmaceutically acceptable salt, its solvate, its prodrug, its metabolite or its deuterated derivative according to any one of claims 1-7 in the preparation of a medicament having analgesic effects, and / or having anesthetic, sedative, hypnotic effects and / or being able to control status epilepticus.

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