Heterocyclic compound and use thereof

Abstract

The present invention relates to the technical field of pharmaceutical chemistry, and provides a heterocyclic compound and a use thereof. The structure of the heterocyclic compound is as shown in formula II. The compound of the present invention has efficient sedative, hypnotic and / or anesthetic effects, can control the status epilepticus, further has an analgesic effect, and provides a new option for clinically preparing a drug having an analgesic effect, a drug having anesthetic, sedative and hypnotic effects and / or capable of controlling the status epilepticus, and a drug having anesthetic, sedative and hypnotic effects and / or capable of controlling the status epilepticus and also having the analgesic effect.

Description

A heterocyclic compound and its use Technical Field

[0001] The present invention belongs to the technical field of medicinal chemistry, and in particular relates to a heterocyclic compound and a use thereof. Background Art

[0002] Clinically, anesthetics play an important role in the induction and maintenance of general anesthesia for patients, and in the sedation of critically ill patients in the ICU. Propofol is a fast-acting, short-acting intravenous general anesthetic currently used clinically. It has the advantages of rapid onset of anesthesia induction, rapid awakening and complete functional recovery, and a low incidence of postoperative nausea and vomiting. However, clinically used intravenous general anesthetics, including propofol, etomidate, fospropofol disodium, and propofol, do not have analgesic effects. If a compound has sedative, hypnotic, and / or anesthetic effects that can control status epilepticus while also having analgesic effects, it can achieve more complete analgesia, significantly reduce the use of opioid analgesics, reduce the adverse reactions of opioid analgesics, and make the sedation, hypnosis, and / or anesthesia process more stable. At the same time, it can also reduce the use of other drugs during 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, can control status epilepticus, but also has analgesic effects.

[0003] (±)-5-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole, an imidazole-type α-2-adrenergic receptor agonist, exhibits sedative and analgesic effects. However, the activity of (±)-5-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole remains to be further improved. Therefore, there is an urgent need to develop drugs that not only exhibit highly effective sedative, hypnotic, and / or anesthetic effects, capable of controlling status epilepticus, but also possess analgesic properties. Summary of the Invention

[0004] The object of the present invention is to provide a heterocyclic compound and its use in the preparation of a drug having an analgesic effect, in the preparation of a drug having an anesthetic, sedative, hypnotic effect and / or capable of controlling status epilepticus, and in the preparation of a drug having both an anesthetic, sedative, hypnotic effect and / or capable of controlling status epilepticus and an analgesic effect.

[0005] The present invention provides a compound, its stereoisomer, its pharmaceutically acceptable salt, its solvate, its prodrug, its metabolite or its deuterated derivative, the structure of the compound is shown in Formula II:

[0006] Ring A is selected from substituted or unsubstituted 5-6 membered nitrogen heteroaryl groups, wherein the ring heteroatoms of the 5-6 membered nitrogen heteroaryl groups are all N; the substituents are each independently selected from hydroxyl, halogen, cyano, -O, (CR6R7) m R8,

[0007] The following groups which are unsubstituted or substituted by one or more R9: amino, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, C 1-8 Alkylthio, 3-8 membered saturated cycloalkyl, 3-8 membered saturated heterocyclic group, aryl, heteroaryl;

[0008] m is selected from 0, 1, 2, 3, 4, 5;

[0009] R6, R7 are each independently selected from hydrogen, C 1-8 alkyl;

[0010] R8 is selected from CONR 10 R 11 NR 10 R 11 、COOR 12 、COR 12 , OR 12 , substituted aryl, wherein the substituents are independently selected from halogen, hydroxyl, nitro, cyano, C 1-8 Alkyl, C 1-8 Alkoxy; R 10 、R 11 Each independently selected from hydrogen, C 1-8 Alkyl, C 1-8 Alkoxy, 3-8 membered saturated cycloalkyl, R 12 Selected from C 1-8 Alkyl, 3-8 membered saturated cycloalkyl, 3-8 membered saturated heterocyclic group, 5-6 membered heteroaryl, n is selected from 0, 1, 2, 3, 4, 5; R 13 Selected from hydroxyl, C 1-8 alkoxy;

[0011] The C ring is selected from aryl, 3-8 membered saturated cycloalkyl, aryl and 3-6 membered saturated cycloalkyl;

[0012] e is selected from 0, 1, 2, 3, 4, 5;

[0013] R x1 Each independently selected from hydrogen, hydroxy, halogen, halogenated or unhalogenated C 1-8 Alkyl, halogenated or unhalogenated C 1-8 Alkoxy, L2R2a , L2 is selected from none, C 1-6 Alkylene, R 2a is selected from phenyl, 3-8 membered saturated cycloalkyl, 3-8 membered saturated heterocyclic group;

[0014] R x2 Selected from hydrogen, C 1-8 Alkyl, 3-8 membered saturated cycloalkyl, =CR xa R xb ; R xa Selected from hydrogen, C 1-8 Alkyl, R xb Selected from hydrogen, C 1-8 alkyl;

[0015] R x12 Selected from hydrogen, C 1-8 alkyl;

[0016] f is selected from 0, 1, 2, 3, 4, 5;

[0017] R x6 Each independently selected from hydrogen, halogen, halogenated or unhalogenated C 1-8 alkyl;

[0018] R x5 Selected from C 1-8 alkyl;

[0019] R x7 is selected from hydrogen, halogen, halogenated or unhalogenated C 1-8 alkyl;

[0020] R x8 is selected from hydrogen, halogen, halogenated or unhalogenated C 1-8 Alkyl, CONR x9 R x10 ; R x9 Selected from hydrogen, C 1-8 Alkyl, C 1-8 Alkoxy, R x10 Selected from hydrogen, C 1-8 Alkyl, C 1-8 alkoxy;

[0021] The R9 are independently selected from halogen, hydroxyl, amino, thiol, C 1-8 Alkyl, C 1-8 Alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, OCOR 9a 、SO2R 9a , OR 9c , 3-8 membered saturated cycloalkyl, one or more R 9b Substituted 3-8 membered saturated cycloalkyl, 3-8 membered saturated heterocyclic group, one or more R9b Substituted 3-8 membered saturated heterocyclic group, aryl group, one or more R 9b Substituted aryl, 5-6 membered heteroaryl, one or more R 9b Substituted 5-6 membered heteroaryl; R 9a Selected from C 1-8 Alkyl; R 9b Each independently selected from halogen, C 1-8 Alkyl; R 9c Selected from 3-8 membered saturated cycloalkyl, 3-8 membered saturated heterocyclic group;

[0022] L is selected from None, CR a R b 、C(=CR c R d ),NR e , CO, CS, SO, S, O;

[0023] R a 、R b Each independently selected from hydrogen, halogen, halogenated or unhalogenated C 1-8 Alkyl, halogenated or unhalogenated C 1-8 Alkoxy, OH, OR s , or R a 、R b connected to form a 3-8 membered saturated cycloalkyl group or a 3-8 membered saturated heterocyclic group; R s Selected from 3-8 membered saturated cycloalkyl, 3-8 membered saturated heterocyclic group, benzyl;

[0024] R c 、R d Each independently selected from hydrogen and halogen;

[0025] R e Selected from hydrogen, C 1-8 alkyl;

[0026] Ring B is

[0027] X1 is N or CR1, X2 is N or CR2, X3 is N or CR3, X4 is N or CR4, and X5 is N or CR5, and at least three of X1, X2, X3, X4, and X5 are not N at the same time;

[0028] R1, R2, R3, R4, R5, R 15 Each independently selected from hydrogen, hydroxy, halogen, halogenated or unhalogenated C 1-8 Alkyl, halogenated or unhalogenated C 1-8 Alkoxy, L1R 1a , L1 is selected from none, C 1-6 Alkylene, R 1aSelected from aryl, 3-8 membered saturated cycloalkyl, 3-8 membered saturated heterocyclic group, or two adjacent groups among R1, R2, R3, R4, R5 are connected to form an unsubstituted or substituted group. 14 Substituted benzene ring, the R 14 Each independently selected from halogen, C 1-8 Alkyl, C 1-8 alkoxy;

[0029] Alternatively, the substituent on ring A is connected to R5 to form a ring.

[0030] Furthermore, the A ring is selected from the following structures:

[0031] C ring is selected from aryl, 3-6 membered saturated cycloalkyl, aryl and 3-6 membered saturated cycloalkyl, 3-5 membered unsaturated cycloalkyl, preferably benzene ring, 3-4 membered saturated cycloalkyl,

[0032] e is selected from 0, 1, 2, 3;

[0033] R x1 Each independently selected from hydrogen, hydroxy, halogen, halogenated or unhalogenated C 1-4 Alkyl, halogenated or unhalogenated C 1-4 Alkoxy, L2R 2a , L2 is selected from none, C 1-2 Alkylene, R 2a is selected from phenyl, 3-4 membered saturated cycloalkyl, 3-4 membered saturated heterocyclic group;

[0034] R x2 Selected from hydrogen, C 1-3 Alkyl, 3-4 membered saturated cycloalkyl, =CR xa R xb ; R xa Selected from hydrogen, C 1-4 Alkyl, R xb Selected from hydrogen, C 1-4 alkyl;

[0035] R x12 Selected from hydrogen, C 1-3 alkyl;

[0036] R x3 is selected from hydrogen, halogen, C which is unsubstituted or substituted by one or more halogens 1-3 alkyl,

[0037] R x4 is selected from hydrogen, halogen, C which is unsubstituted or substituted by one or more halogens 1-3 alkyl,

[0038] R x11 is selected from hydrogen, halogen, C which is unsubstituted or substituted by one or more halogens 1-3 alkyl,

[0039] f is selected from 0, 1, 2, 3;

[0040] R x6 Each independently selected from hydrogen, halogen, halogenated or unhalogenated C 1-4 alkyl;

[0041] R x5 Selected from C 1-3 alkyl;

[0042] R x7 is selected from hydrogen, halogen, halogenated or unhalogenated C 1-4 alkyl;

[0043] R x8 is selected from hydrogen, halogen, halogenated or unhalogenated C 1-4 Alkyl, CONR x9 R x10 ; R x9 Selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, R x10 Selected from hydrogen, C 1-4 Alkyl, C 1-4 alkoxy;

[0044] The heterocyclic group contains at least one heteroatom selected from N, O or S.

[0045] Furthermore, the structure of the compound is shown in Formula II-1 or Formula II-2:

[0046] Where Q is selected from none, CR x2 R x12 、CO、CH=CH、

[0047] C ring is selected from aryl, 3-6 membered saturated cycloalkyl, aryl and 3-6 membered saturated cycloalkyl, 3-5 membered unsaturated cycloalkyl, preferably benzene ring, 3-4 membered saturated cycloalkyl,

[0048] e is selected from 0, 1, 2, 3;

[0049] R x1 Each independently selected from hydrogen, hydroxy, halogen, halogenated or unhalogenated C 1-4 Alkyl, halogenated or unhalogenated C 1-4 Alkoxy, L2R 2a , L2 is selected from none, C1-2 Alkylene, R 2a is selected from phenyl, 3-4 membered saturated cycloalkyl, 3-4 membered saturated heterocyclic group;

[0050] R x2 Selected from hydrogen, C 1-3 Alkyl, 3-4 membered saturated cycloalkyl, =CR xa R xb ; R xa Selected from hydrogen, C 1-4 Alkyl, R xb Selected from hydrogen, C 1-4 alkyl;

[0051] R x12 Selected from hydrogen, C 1-3 alkyl;

[0052] R x3 is selected from hydrogen, halogen, C which is unsubstituted or substituted by one or more halogens 1-3 alkyl,

[0053] R x4 is selected from hydrogen, halogen, C which is unsubstituted or substituted by one or more halogens 1-3 alkyl,

[0054] f is selected from 0, 1, 2, 3;

[0055] R x6 Each independently selected from hydrogen, halogen, halogenated or unhalogenated C 1-4 alkyl;

[0056] R x5 Selected from C 1-3 alkyl;

[0057] R x7 is selected from hydrogen, halogen, halogenated or unhalogenated C 1-4 alkyl;

[0058] R x8 is selected from hydrogen, halogen, halogenated or unhalogenated C 1-4 Alkyl, CONR x9 R x10 ; R x9 Selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, R x10 Selected from hydrogen, C 1-4 Alkyl, C 1-4 alkoxy;

[0059] The heterocyclic group contains at least one heteroatom selected from N, O or S;

[0060] L, X1, X2, X3, X4, and X5 are as described above.

[0061] Further, the L is selected from none, CR a R b 、C(=CR c R d ),NR e , CO, CS, SO, S, O;

[0062] R a 、R b Each independently selected from hydrogen, halogen, halogenated or unhalogenated C 1-6 Alkyl, halogenated or unhalogenated C 1-6 Alkoxy, OH, OR s , or R a 、R b Connected to form a 3-6 membered saturated cycloalkyl or a 3-6 membered saturated heterocyclic group; R s Selected from 3-6 membered saturated cycloalkyl, 3-6 membered saturated heterocyclic group, benzyl;

[0063] R c 、R d Each independently selected from hydrogen and halogen;

[0064] R e Selected from hydrogen, C 1-6 alkyl.

[0065] Further, the L is selected from none, CR a R b 、C(=CR c R d ),NR e , CO, CS, SO, S, O;

[0066] R a 、R b Each independently selected from hydrogen, halogen, halogenated or unhalogenated C 1-3 Alkyl, halogenated or unhalogenated C 1-3 Alkoxy, OH, OR s , or R a 、R b Connected to form a 3-4 membered saturated cycloalkyl or a 3-4 membered saturated heterocyclic group; R s Selected from 3-4 membered saturated cycloalkyl, 3-4 membered saturated heterocyclic group, benzyl;

[0067] R c 、R d Each independently selected from hydrogen and halogen;

[0068] R e Selected from hydrogen, C1-3 alkyl.

[0069] Furthermore, the B ring is

[0070] R1, R2, R3, R4, and R5 are each independently selected from hydrogen, hydroxy, halogen, halogenated or unhalogenated C 1-6 Alkyl, halogenated or unhalogenated C 1-6 Alkoxy, L1R 1a , L1 is selected from none, C 1-4 Alkylene, R 1a Selected from aryl, 3-6 membered saturated cycloalkyl, 3-6 membered saturated heterocyclic group.

[0071] Furthermore, the compound is selected from:

[0072] Furthermore, the pharmaceutically acceptable salt is citrate, hydrofluoride, phosphate, propionate, succinate, tartrate, acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate, carbonate, bisulfate, sulfate, borate, camphorsulfonate, citrate, cyclamates, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hydrochloride, hydrobromide, salt, hydroiodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthoate, naphthoate, nicotinate, nitrate, orotate, oxalate, palmitate, dihydroxynaphthoate, phosphate, hydrogen phosphate, dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, toluenesulfonate, trifluoroacetate, xinafoate, methanesulfonate, or p-toluenesulfonate.

[0073] The present invention also provides a pharmaceutical composition, which is a preparation prepared with the above-mentioned compound, its stereoisomer, its pharmaceutically acceptable salt, its solvate, its prodrug, its metabolite or its deuterated derivative as the active ingredient, and pharmaceutically acceptable excipients.

[0074] The present invention also provides the use of the above-mentioned compound, its stereoisomer, its pharmaceutically acceptable salt, its solvate, its prodrug, its metabolite or its deuterated derivative in the preparation of a drug having analgesic effect, and / or anesthetic, sedative, hypnotic effect and / or capable of controlling status epilepticus.

[0075] “Use in drugs having analgesic effect, and / or anesthetic, sedative, hypnotic effect and / or the ability to control status epilepticus” includes the following three situations: (1) having analgesic effect; (2) having anesthetic, sedative, hypnotic effect and / or the ability to control status epilepticus; (3) having both anesthetic, sedative, hypnotic effect and / or the ability to control status epilepticus and analgesic effect.

[0076] The term "having anesthetic, sedative, hypnotic effects and / or being able to control epileptic seizures, and at the same time having analgesic effects" as used in the present invention means that when the compound of the present invention produces sedative, hypnotic and / or anesthetic effects, it does not respond to noxious stimuli or increases the response threshold to noxious stimuli.

[0077] The "drug with sedative effect" mentioned in the present invention refers to a drug that effectively helps sleep and effectively improves sleep. That is, it can avoid the serious harm of insomnia to the human body, treat insomnia, and improve sleep quality.

[0078] The term "drug with hypnotic effect" as used herein refers to a drug that can induce drowsiness and promote sleep. This means that the drug has an inhibitory effect on the central nervous system, causing sedation in small doses and general anesthesia in excessive doses.

[0079] The term "drug with anesthetic effect" as used herein refers to a drug that produces a reversible functional inhibition of the central nervous system and / or peripheral nervous system, wherein the main characteristic of such inhibition is the loss of sensation, especially pain. Preferably, the anesthesia is general anesthesia.

[0080] The "general anesthesia" mentioned in the present invention is referred to as general anesthesia, which refers to the temporary inhibition of the central nervous system after the anesthetic enters the body. The clinical manifestations are loss of consciousness, loss of pain sensation throughout the body, amnesia, reflex inhibition and skeletal muscle relaxation.

[0081] "Status epilepticus," as used herein, refers to frequent recurrences of epileptic seizures with incomplete recovery of consciousness between consecutive seizures, or seizures that persist for more than 30 minutes without spontaneous cessation. Prolonged seizures, if not promptly treated, can lead to irreversible brain damage due to hyperthermia, circulatory failure, or neuronal excitotoxicity, resulting in high disability and mortality rates. Therefore, status epilepticus is a common medical emergency.

[0082] Definitions of terms used in the present invention: Unless otherwise stated, the initial definitions provided for groups or terms in this document apply to the groups or terms throughout the specification; for terms that are not specifically defined herein, they should be given the meaning that a person skilled in the art would give them based on the disclosure and context.

[0083] The minimum and maximum carbon atom content in a hydrocarbon group is indicated by a prefix, for example, the prefix C a～bAlkyl refers to any alkyl group containing from "a" to "b" carbon atoms. For example, C 1～6 Alkyl refers to a straight or branched chain alkyl group containing 1, 2, 3, 4, 5 or 6 carbon atoms. 1～6 Alkoxy refers to a straight or branched chain alkoxy group containing 1, 2, 3, 4, 5 or 6 carbon atoms. 1-4 Alkylene refers to straight or branched chain alkylene groups containing 1, 2, 3 or 4 carbon atoms, and so on.

[0084] The minimum and maximum number of ring atoms in a cyclic group are indicated by prefixes, for example, 3-8 membered saturated cycloalkyl refers to a saturated cycloalkyl group containing 3, 4, 5, 6, 7 or 8 ring atoms, 3-6 membered saturated cycloalkyl refers to a saturated cycloalkyl group containing 3, 4, 5 or 6 ring atoms, 3-8 membered saturated heterocyclyl refers to a saturated heterocyclyl group containing 3, 4, 5, 6, 7 or 8 ring atoms, 3-6 membered saturated heterocyclyl refers to a saturated heterocyclyl group containing 3, 4, 5 or 6 ring atoms, and so on.

[0085] The term "substituted" herein 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 isotopic or ectopic atoms in the molecule.

[0086] "Aryl" refers to an all-carbon monocyclic group with a conjugated π electron system, such as phenyl. The aryl group does not contain heteroatoms such as nitrogen, oxygen, or sulfur, and the point of attachment to the parent moiety must be on a carbon atom on the ring with a conjugated π electron system.

[0087] "Heteroaryl" refers to a heteroaromatic group containing one or more heteroatoms. The heteroatoms referred to herein include, but are not limited to, oxygen, sulfur, and nitrogen. Examples include furyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, thiazolyl, oxazolyl, pyrimidinonyl, pyridonyl, indolyl, tetrazolyl, and the like.

[0088] In some preferred technical embodiments, the heteroaryl group is a 5-6 membered heteroaryl group.

[0089] Heterocyclic compounds are cyclic compounds composed of carbon atoms and non-carbon atoms (heteroatoms) forming a ring. Among the atoms forming the ring, the non-carbon atoms other than carbon atoms are called "ring heteroatoms".

[0090] Halogen is fluorine, chlorine, bromine or iodine.

[0091] Compared with the prior art, the compounds of the present invention have achieved the following beneficial effects:

[0092] On the one hand, compared with (±)-5-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole, the anesthetic activity of the imidazole compounds of the present invention is significantly improved;

[0093] On the other hand, the present invention also provides compounds with other novel core structures in addition to imidazole compounds, and for the first time discovered 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.

[0094] In addition, the present invention also discovered for the first time that the compound of the present invention not only has highly effective sedative, hypnotic and / or anesthetic effects, and can control status epilepticus, but also has analgesic effects. In clinical application, the use of opioid analgesics such as fentanyl, alfentanil, sufentanil or remifentanil can be reduced or eliminated, thereby reducing the occurrence of adverse reactions of opioid analgesics such as circulatory inhibition, respiratory depression, urinary retention, and skin itching.

[0095] Obviously, based on the above contents of the present invention, according to common technical knowledge and customary means in this field, without departing from the above basic technical ideas of the present invention, other various forms of modifications, replacements or changes can be made.

[0096] The following is a further detailed description of the present invention through specific embodiments in the form of examples. However, this should not be construed as limiting the scope of the present invention to the following examples. All technologies implemented based on the above-mentioned content of the present invention fall within the scope of the present invention. DETAILED DESCRIPTION

[0097] The raw materials and equipment used in the specific embodiments of the present invention are all known products and are obtained by purchasing commercial products.

[0098] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6 The unit of measurement is ppm. NMR measurements were performed using a Bruker Avance III 400 nuclear magnetic spectrometer. The solvent used was deuterated dimethyl sulfoxide (d6-DMSO) or deuterated chloroform (CDCl3), and the internal standard was tetramethylsilane (TMS).

[0099] LCMS determination was performed using an Agilent LCMS 1260-6110 (ESI) column using a Waters X-Bridge C18 (50 mm x 4.6 mm x 3.5 μm) column temperature of 40°C; a flow rate of 2.0 mL / min; and a 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] within 3 minutes, followed by a maintenance step of 1 minute, followed by a maintenance step of 0.05 minutes followed by a maintenance step of 0.7 minutes.

[0100] 1) Medicinal materials and reagents

[0101] The thin layer chromatography silica gel plate used was HSGF254 silica gel plate produced by Yantai Xinnuo Chemical Co., Ltd., with a thickness of 1 mm.

[0102] Thin layer chromatography (TLC) was performed using a silica gel product from Yantai Jiangyou Silica Gel Development Co., Ltd. with a specification of 0.2 ± 0.03 mm.

[0103] Column chromatography generally uses 100-200 mesh or 200-300 mesh silica gel produced by Rushan Sun Desiccant Co., Ltd. (Weihai, Shandong) as a carrier.

[0104] 2) Main instruments

[0105] JA2003N electronic balance (Shanghai Youke Instrument Co., Ltd.);

[0106] DF-101S heat-collecting constant temperature heating magnetic stirrer (Zhengzhou Saitelis Biotechnology Co., Ltd.);

[0107] 98-2 magnetic stirrer (Shanghai Silu Instrument Co., Ltd.);

[0108] ZF-2 three-purpose UV instrument (Shanghai Anting Electronic Instrument Factory);

[0109] RE-2000B rotary evaporator (Zhengzhou Ketai Experimental Equipment Co., Ltd.);

[0110] DLSK-5 / 20 low-temperature coolant circulation pump (Zhengzhou Ketai Experimental Equipment Co., Ltd.);

[0111] W201D constant temperature water bath (Shanghai Shenshun Biotechnology Co., Ltd.);

[0112] SHB-III circulating water vacuum pump (Zhengzhou Huicheng Science and Technology Industry and Trade Co., Ltd.);

[0113] SHB-B95 mobile water pump (Zhengzhou Huicheng Science and Technology Industry and Trade Co., Ltd.);

[0114] Ultraviolet high-pressure mercury lamp (Beijing Tianmai Henghui Light Source Electrical Co., Ltd.).

[0115] DGJ-10C vacuum freeze dryer (Shanghai Boden Biotechnology Co., Ltd.);

[0116] KQ5200 ultrasonic cleaner (Kunshan Ultrasonic Instrument Co., Ltd.);

[0117] 2XZ-2 rotary vane vacuum pump (Linhai Tanshi Vacuum Equipment Co., Ltd.);

[0118] Biotage Isolera One (Biotage Sweden AB)

[0119] Example 1 Preparation of compounds DA-6 to DA-8 of the present invention

[0120] 1. Preparation of compound 85-7-1

[0121] Compound 85-6 (7.1 g, 16.8 mmol) was dissolved in THF / MeOH / H₂O (55 mL, v / v / v = 8 / 2 / 1) at room temperature. The reaction system was cooled to 0°C using an ice-salt bath. NaOH (1.3 g, 32.5 mmol) was added portionwise and stirring continued for 30 minutes. After completion of the reaction as monitored by TLC, the reaction system 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 (ethyl acetate / petroleum ether (v / v) = 1 / 10 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5). Fractions with Rf = 0.3 to 0.4 were collected to obtain the target compound 85-7-1 (3.5 g, 77.7% yield) as a white solid. ESI [M+H] + =268.2

[0122] 1 H NMR (400MHz, d6-DMSO) δ12.03(s,1H),7.49(s,1H),7.28(d,J=7.0Hz,1H),7.20–7.09(m,2H),7.01(d,J=1.5Hz,1H),2.28(s,3H),2.09(s,3H).

[0123] 2. Preparation of target compound DA-7

[0124] Compound 85-7-1 (500 mg, 1.87 mmol) was dissolved in dry DMF (10 mL) at room temperature and cooled to 0°C in an ice-salt bath. NaH (88 mg, 60% in mineral oil, 2.2 mmol) was added to the mixture, and the mixture was stirred at 0°C for 10 minutes. BnBr (352 mg, 2.1 mmol) was slowly added to the mixture via syringe, and the mixture was stirred at room temperature for 5 hours. After completion of the reaction as monitored by TLC, the reaction solution was poured into ice water and extracted with EtOAc (3 × 5 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 preparative TLC (ethyl acetate / petroleum ether (v / v) = 1 / 8) and the fractions with Rf = 0.5-0.6 were collected to obtain compound 85-7 (555 mg, 83.0% yield). ESI [M+H] + =358.4.

[0125] At room temperature, 85-7 (555 mg, 1.55 mmol) was dissolved in dry THF (8 mL). The reaction system was purged with nitrogen three times, protected by nitrogen, and cooled to -10°C in an ice-salt bath. MeLi (2.0 mL, 1.3 mol / L in Et2O, 2.6 mmol) was slowly added to the system via syringe and stirring continued for 30 minutes. After completion of the reaction as monitored by TLC, the reaction was quenched with saturated aqueous ammonium chloride (10 mL) and extracted with EtOAc (3 × 5 mL). The combined organic phases were washed with saturated brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and dissolved in dichloromethane (10 mL). TFA (2 mL) was added and stirred at room temperature for 3 hours. After the reaction was completed as monitored by TLC, it was concentrated under reduced pressure, basified with saturated aqueous sodium bicarbonate solution (20 mL), extracted with dichloromethane (3×5 mL), and the combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by preparative TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10), and the Rf = 0.5-0.6 fraction was collected to give the target compound DA-7 (290 mg, two-step yield 52.6%) as a colorless oil.

[0126] 1 H NMR(400MHz,d6-DMSO)δ7.46(d,J=1.7Hz,1H),7.37–7.25(m,3H),7.20–7.14(m,2H),7.12–7.03(m,2H),6 .97–6.93(m,1H),6.39(d,J=2.2Hz,1H),5.47(s,1H),5.06(s,2H),4.93(s,1H),2.21(s,3H),1.96(s,3H).

[0127] 5. Preparation of target compound DA-8

[0128] At room temperature, compound DA-7 (58 mg, 0.16 mmol) and 10% wet palladium on carbon (6 mg) were dissolved in MeOH (5 mL). The system was purged with hydrogen three times and stirred at room temperature under hydrogen for 2 hours. After the reaction was complete as monitored by TLC, 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 purified by preparative TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10), and the fraction with Rf = 0.5-0.6 was collected to obtain the target compound DA-8 (53 mg, 90.9% yield) as a colorless oil.

[0129] 1 H NMR(400MHz,d6-DMSO)δ7.39–7.27(m,4H),7.25–7.19(m,2H),7.00–6.93(m,2H),6.92–6.86(m,1H),6.7 1(d,J=2.1Hz,1H),5.10(s,2H),4.31(q,J=7.1Hz,1H),2.22(s,3H),2.15(s,3H),1.39(d,J=7.1Hz,3H).

[0130] Example 2 Preparation of Compounds DA-5 and DA-9 of the Present Invention

[0131] The target compounds DA-5 and DA-9 are prepared by using compound DA-5-1 as a raw material and reacting it with bromide or iodide through an alkylation reaction.

[0132] Compound DA-5: 11.4 mg, white solid, ESI [M+H] + =282.1.

[0133] Compound DA-9: 36.4 mg, syrupy solid, ESI [M+H] + =318.1.

[0134] 1 H NMR(400MHz,d6-DMSO)δ7.39(t,J=7.6Hz,2H),7.28(dd,J=15.3,7.3Hz,2H),7.20–7.09(m,4H),7.05–7.03(m,1 H),6.29(d,J=4.0Hz,1H),5.97(d,J=4.0Hz,1H),2.29(s,3H),2.10(s,3H),1.99(s,3H),1.94(d,J=7.2Hz,3H).

[0135] Example 3 Preparation of Compound DA-1, Compound DA-2 and Compound DA-3 of the Present Invention

[0136] 1. Preparation of compound DA-1

[0137] At room temperature, an aqueous solution of sodium hydroxide (2 eq) was added to a solution of etomidate (1 eq) in EtOH and stirred at reflux for 2 hours. After the reaction was complete as monitored by TLC, the reaction solution was concentrated under reduced pressure, the pH adjusted to 5-6 with concentrated hydrochloric acid, and extracted with EtOAc. The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain compound DA-1-1 as a gray solid.

[0138] Compound DA-1-1 (1 eq), N,O-dimethylhydroxylamine hydrochloride (2 eq), and DIEA (3 eq) were dissolved in DMF (50 mL) in an ice-water bath at 0°C. HATU (1.5 eq) was added portionwise and stirred at room temperature overnight. After the reaction was complete as monitored by TLC, ice water was added to the reaction system, extracted with EtOAc, and the combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 5 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1). Fractions with Rf = 0.5 to 0.6 were collected to obtain compound DA-1-2 as a colorless oil. ESI [M+H] + =260.2.

[0139] At room temperature, compound DA-1-2 (610 mg, 2.4 mmol) was dissolved in dry THF (5 mL). The reaction system was purged with nitrogen three times, protected by nitrogen, and cooled to 0°C in an ice-salt bath. Grignard reagent A (5 mL, 1 mol / L, 5 mmol) was slowly added to the system using a syringe and stirred at room temperature for 4 hours. After the reaction was complete as monitored by TLC, the solution was cooled to 0°C in an ice-water bath. Saturated aqueous ammonium chloride (10 mL) was slowly added to the reaction system and 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 (ethyl acetate / petroleum ether (v / v) = 1 / 8 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1). The fractions with Rf = 0.5 to 0.6 were collected to obtain compound DA-1 (460 mg, yield 63.0%) as a colorless oil. ESI [M+H] + =305.0

[0140] 1H NMR(400MHz,d6-DMSO)8.50(s,1H),7.38–7.32(m,2H),7.31–7.25(m,2H),7.23–7.17(m,3H),7.14(t,J=7 .6Hz,1H),7.05(d,J=7.3Hz,1H),6.44(q,J=7.0Hz,1H),2.24(s,3H),1.92(s,3H),1.90(d,J=7.3Hz,3H).

[0141] Dissolve compound DA-1 in diethyl ether, add HCl / EtOAc solution at 0°C, filter, wash the solid with Et2O, and dry to obtain compound DA-1 hydrochloride. ESI [M+H] + =305.2

[0142] 1 H NMR(400MHz,d6-DMSO)δ9.36(s,1H),7.76(s,1H),7.44–7.27(m,6H),7.19(t,J=7 .6Hz,1H),7.12(d,J=7.4Hz,1H),6.48(q,J=7.0Hz,1H),2.27(s,3H),1.98(s,6H).

[0143] 2. Preparation of Compound DA-2 and Compound DA-3

[0144] At room temperature, compound DA-1 (330 mg, 1.1 mmol) was dissolved in dry THF (10 mL). The reaction system was purged with nitrogen three times, protected by nitrogen, and cooled to 0°C in an ice-salt bath. MeLi (4 mL, 1.3 mol / L in Et2O, 5.2 mmol) was slowly added to the system via syringe and stirred at room temperature for 4 hours. After completion of the reaction as monitored by TLC, the reaction was quenched with saturated aqueous ammonium chloride (10 mL) and extracted with EtOAc (3 × 5 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, compound DA-2-1. The crude product and TFA (0.5 mL) were dissolved in dichloromethane (5 mL) and stirred at room temperature for 2 hours. After the reaction was complete as monitored by TLC, the mixture was concentrated under reduced pressure, basified with saturated aqueous sodium bicarbonate (10 mL), extracted with dichloromethane (3×5 mL), and the combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative TLC (ethyl acetate / petroleum ether (v / v) = 1 / 6) and fractions with Rf = 0.5-0.6 were collected to give the target compound DA-2 (120 mg, two-step yield 36.1%) as a light yellow oil. ESI [M+H] + =303.1

[0145] 1 H NMR(400MHz,d6-DMSO)δ7.97(s,1H),7.32–7.21(m,3H),7.12(d,J=7.2Hz,1H),7.07(t,J=7.5Hz,1H),6.94–6.87(m,3H),6.80 (s,1H),5.47(d,J=1.2Hz,1H),5.12(q,J=7.5Hz,1H),5.09(d,J=1.3Hz,1H),2.17(s,3H),1.85(s,3H),1.65(d,J=7.1Hz,3H).

[0146] At room temperature, compound DA-2 (80 mg, 0.26 mmol) and 10% wet palladium on carbon (8 mg) were dissolved in MeOH (5 mL). The system was replaced with hydrogen three times and stirred at room temperature under hydrogen for 2 hours. After the reaction was complete as monitored by TLC, the mixture was filtered and the filter cake was washed with methanol (3×5 mL). The filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative TLC (ethyl acetate / petroleum ether (v / v) = 1 / 8), and the fraction with Rf = 0.5-0.6 was collected to obtain the target compound DA-3 (37 mg, yield 46.7%) as a colorless oil. ESI [M+H] + =305.1.

[0147] 1 H NMR(400MHz,d6-DMSO)δ7.93(s,1H),7.70(s,1H),7.36(t,J=7.3Hz,2H),7.29(t,J=7.3Hz,1H),7.15–7.09(m,3H),7.06– 6.95(m,5H),6.89(d,J=7.1Hz,1H),6.84(t,J=7.6Hz,1H),6.81–6.76(m,2H),6.73–6.66(m,2H),6.57(d,J=6.7Hz,1H),5. 11(q, J=7.1Hz,1H),4.64(q, J=6.6Hz,1H),4.31(q, J=6.8Hz,1H),3.93(q, J=6.9Hz,1H),2.16(s,2H),2.13(s,3H),2.02(s,3H),1.70(d, J=7.1Hz,3H),1.49(d, J=7.1Hz,3H),1.46(d, J=7.0Hz,3H),1.29(d, J=7.0Hz,3H). (Due to the presence of diastereomers, two sets of peaks appear in NMR)

[0148] Example 4 Preparation of Compounds DA-10, DA-11, and DA-12 of the Invention

[0149] The preparation methods of the compounds DA-10, DA-11 and DA-12 of the present invention are similar to those of the compounds DA-1, DA-2 and DA-3 of the present invention.

[0150] Compound 211-1 (5.0 g) was reduced with LAH to give compound 211-2 (4.6 g, 89.9% yield). 211-2 was reacted with N-methoxy-N-methyl-1H-imidazole-5-carboxamide to give compound 211-5 (3.3 g, 27.7% yield), which was then reacted with Grignard reagent A to give compound DA-10 (3.0 g, 75.6% yield) as a colorless oil. 1.0 g of compound DA-10 was reacted with methyl lithium and dehydrated with trifluoroacetic acid to give compound DA-11 (580 mg, 58.4% yield over two steps) as a colorless oil. 280 mg of compound DA-11 was reduced with palladium on carbon to give compound DA-12 (120 mg, 42.5% yield) as a white solid.

[0151] Compound DA-10: ESI[M+H] + =269.1

[0152] 1 H NMR(400MHz,d6-DMSO)δ8.40(s,1H),7.34–7.28(m,1H),7.20–7.15(m,2H),7.13(s,1H),4.57–4.45(m,1H),2.29(s,3H),2.12 (s,3H),1.55(d,J=6.8Hz,3H),1.51–1.42(m,1H),0.71–0.62(m,1H),0.54–0.47(m,1H),0.47–0.38(m,1H),0.35–0.26(m,1H).

[0153] Compound DA-11: ESI[M+H] + =267.1

[0154] 1H NMR(400MHz,d6-DMSO)δ7.93(s,1H),7.16(d,J=7.2Hz,1H),7.09(t,J=7.5Hz,1H), 6.95(d,J=7.5Hz,1H),6.81(s,1H),5.56(d,J=1.4Hz,1H),5.17(d,J=1.4Hz,1H),3. 04–2.95(m,1H),2.24(s,3H),2.01(s,3H),1.30–1.22(m,1H),1.21(d,J=6.7Hz,3H ),0.56–0.47(m,1H),0.39–0.31(m,1H),-0.01–-0.08(m,1H),-0.12–-0.20(m,1H).

[0155] Compound DA-12: ESI[M+H] + =269.2

[0156] 1 H NMR(400MHz,d6-DMSO)δ7.82(s,2H),7.03–6.92(m,4H),6.82(d,J=6.1Hz,2H),6.66–6.54(m,2H),4.24( q,J=6.7Hz,2H),3.06–2.94(m,1H),2.86–2.74(m,1H),2.26(s,6H),2.25(s,6H),1.43(d,J=6.9Hz,6H), 1.35 (d, J = 6.7 Hz, 3H), 1.30–1.14 (m, 2H), 0.89 (d, J = 6.7 Hz, 3H), 0.58–0.48 (m, 1H), 0.46–0.34 (m, 2H), 0.26–0.14 (m, 2H), 0.11–0.02 (m, 1H), -0.13–-0.24 (m, 1H), -0.85–-0.96 (m, 1H). (Due to the presence of diastereomers, two groups of peaks appear in NMR)

[0157] Example 5 Preparation of compounds DA-14, DA-15, DA-16, DA-17, DA-18, DA-20, DA-21, DA-22, DA-23, and DA-24 of the present invention

[0158] At room temperature, 4-fluoro-N-methoxy-N-methyl-1H-imidazole-5-carboxamide (952.3 mg, 5.5 mmol) was dissolved in dry THF (10 mL). The temperature was lowered to -30°C with a dry ice acetone bath. (S)-1-phenyl-1-ethanol (806.3 mg, 6.6 mmol) and PPh3 (2.16 g, 8.25 mmol) were added to the reaction system in sequence. DEAD (1.44 g, 8.27 mmol) was slowly added to the reaction system with a syringe, and the mixture was stirred at room temperature overnight. After the reaction was complete as monitored by TLC, ice water was added to the reaction system, extracted with EtOAc, and the combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 5 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1). The fraction with Rf = 0.5 to 0.6 was collected to obtain compound 246-3 (952 mg, yield 62.4%) as a colorless oil. ESI [M+H] + =277.9.

[0159] Compound 246-3 (952 mg, 3.43 mmol) was dissolved in dry THF (10 mL) at room temperature. The reaction system was purged with nitrogen three times under nitrogen protection and cooled to 0°C in an ice-salt bath. A (17.2 mL, 1 mol / L in THF, 17.2 mmol) was slowly added dropwise to the system using a syringe and stirred at room temperature for 4 hours. After the reaction was complete as monitored by TLC, the reaction system was poured into ice water, and saturated aqueous ammonium chloride solution (10 mL) was slowly added to the reaction system. 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 a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 to 1 / 3) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 2). The fractions with Rf = 0.5 to 0.6 were collected to obtain compound DA-21 (805 mg, yield 72.8%) as a colorless oil. ESI [M+H] + =323.0.

[0160] 1H NMR(400MHz,d6-DMSO)δ8.29(d,J=1.7Hz,1H),7.38(t,J=7.4Hz,2H),7.34–7.25(m,2H),7.23(d,J=7.3Hz,2H),7. 13(t,J=7.5Hz,1H),6.98(d,J=7.6Hz,1H),6.34(q,J=7.2Hz,1H),2.25(s,3H),1.94(s,3H),1.90(d,J=7.2Hz,3H).

[0161] The preparation methods of the target compounds DA-14, DA-15, DA-16, DA-17, DA-18, DA-20, DA-22, DA-23, and DA-24 of the present invention are similar to those of compound DA-21.

[0162] Compound DA-14: 629 mg, ESI [M+H] + =319.2

[0163] 1H NMR(400MHz,d6-DMSO)δ8.28(s,1H),7.29(d,J=7.5Hz,1H),7.24–7.10(m,5H),7.02(d,J=7.6Hz,1H),6 .83–6.73(m,1H),6.52(q,J=6.8Hz,1H),2.41(s,3H),2.25(s,3H),1.90(s,3H),1.84(d,J=7.0Hz,3H).

[0164] Compound DA-15: 170 mg, ESI [M+H] + =323.2

[0165] 1H NMR(400MHz,d6-DMSO)δ8.40(s,1H),7.42–7.33(m,1H),7.30(d,J=7.3Hz,1H),7.27–7.14(m,4H),7.06(d ,J=7.5Hz,1H),7.00–6.93(m,1H),6.62(q,J=6.9Hz,1H),2.26(s,3H),1.94(s,3H),1.92(d,J=7.2Hz,3H).

[0166] Compound DA-15 hydrochloride: 878 mg, ESI [M+H] + =323.2

[0167] 1 H NMR(400MHz,d6-DMSO)δ9.15(s,1H),7.69(s,1H),7.45–7.32(m,2H),7.31–7.16( m,3H),7.16–7.06(m,2H),6.63(q,J=7.0Hz,1H),2.27(s,3H),1.99–1.92(m,6H).

[0168] Compound DA-16: 570 mg, ESI [M+H] + =339.1

[0169] 1H NMR(400MHz,d6-DMSO)δ8.33(s,1H),7.54–7.47(m,1H),7.40–7.27(m,3H),7.23(s,1H),7.16(t,J=7.5Hz,1H),7 .05(d,J=7.4Hz,1H),6.90–6.82(m,1H),6.62(q,J=6.8Hz,1H),2.26(s,3H),1.94(s,3H),1.91(d,J=7.1Hz,3H).

[0170] Compound DA-17: 515 mg, ESI [M+H] + =319.2

[0171] 1H NMR(400MHz,d6-DMSO)δ8.43(s,1H),7.31(d,J=7.5Hz,1H),7.25(t,J=7.6Hz,1H),7.22–7.13(m,2H),7.14–7.03( m,3H),7.01(d,J=7.8Hz,1H),6.43(q,J=7.1Hz,1H),2.30(s,3H),2.27(s,3H),1.97(s,3H),1.91(d,J=7.2Hz,3H).

[0172] Compound DA-18: 717 mg, ESI [M+H] + =339.1

[0173] 1H NMR(400MHz,d6-DMSO)δ8.51(s,1H),7.45–7.34(m,2H),7.33–7.25(m,2H),7.21(s,1H),7.20–7.13( m,2H),7.08(d,J=7.4Hz,1H),6.43(q,J=7.1Hz,1H),2.27(s,3H),1.95(s,3H),1.94(d,J=7.2Hz,3H).

[0174] Compound DA-20: 701 mg, ESI [M+H] + =283.2

[0175] 1H NMR(400MHz,d6-DMSO)δ8.38(s,1H),7.33(d,J=7.0Hz,1H),7.24–7.10(m,3H),4.41–4.24(m,1H),2.31(s,3H),2.13(s,3 H),2.06–1.93(m,2H),1.56–1.40(m,1H),0.86(t,J=7.4Hz,3H),0.79–0.71(m,1H),0.54–0.42(m,2H),0.31–0.20(m,1H).

[0176] Example 6 Preparation of Compound DA-33 of the Present Invention

[0177] The preparation of DA-33 was similar to that of compound DA-21 in Example 5.

[0178] DA-33-1 and (S)-1-phenyl-1-ethanol were subjected to Mitsunobu reaction, Grignard reaction, column chromatography and reverse preparation to obtain colorless syrup compound DA-33 (370 mg). ESI [M+H] + =323.0.

[0179] 1 H NMR(400MHz,d6-DMSO)δ7.48–7.40(m,J=7.5Hz,2H),7.39–7.30(m,4H),7.29–7.16(m,2H),7.00 (d,J=1.2Hz,1H),6.66(q,J=7.2Hz,1H),2.31(s,3H),2.13(s,3H),1.95(dd,J=7.2,2.1Hz,3H).

[0180] Example 7 Preparation of compounds of the present invention DA-37~DA-39, DA-44, DA-55~DA-57, DA-62~DA-64, DA-72~DA-80, DA-83, DA-86, DA-119~DA-130, DA-142~DA-147, DA-171

[0181] Compound B-1 was reduced with (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropyltoluene)ruthenium chloride to give B-2. Some of compound B-2 was purchased directly. Ketone compounds were reduced with sodium borohydride to give racemic alcohols.

[0182] The preparation method of the chiral intermediate compound B-1 is as follows:

[0183] At room temperature, 1-(2-fluoro-3-methylphenyl)ethanone (12.8 g, 84.2 mmol), formic acid (19.38 g, 421.1 mmol), and triethylamine (25.56 g, 252.6 mmol) were added to isopropanol (120 mL) in sequence. The reaction system was replaced with argon three times. (S, S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropyltoluene) ruthenium chloride (804 mg, 1.26 mmol) was added to the reaction system. The mixture was stirred at 60 ° C for 4 hours under argon protection and monitored by TLC. After the reaction was complete, the mixture was cooled to room temperature, filtered, extracted with EtOAc (3×50 mL), the combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 to 1 / 3) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10). The fraction with Rf = 0.5 to 0.6 was collected to give (S)-1-(2-fluoro-3-methylphenyl)ethan-1-ol (12.561 g, yield 96.8%) as a light yellow oily compound.

[0184] The preparation of the target compounds DA-37 to DA-39, DA-44, DA-55 to DA-57, DA-62 to DA-64, DA-72 to DA-79, DA-86, and DA-119 to DA-125 of the present invention is similar to that of compound DA-21.

[0185] Compound DA-37: 2.857 g, ESI [M+H] + =322.9

[0186] 1 H NMR(400MHz,d6-DMSO)δ8.45(s,1H),7.34–7.26(m,3H),7.25–7.12(m,4H),7.07(d,J =7.4Hz,1H),6.45(q,J=7.0Hz,1H),2.27(s,3H),1.95(s,3H),1.92(d,J=7.2Hz,3H).

[0187] Compound DA-37 hydrochloride: 1.211 g, ESI [M+H] + =322.9

[0188] 1H NMR(400MHz,d6-DMSO)δ9.33(s,1H),7.75(s,1H),7.43–7.30(m,3H),7.27–7.17(m,3H),7. 14(d,J=7.2Hz,1H),6.48(q,J=7.1Hz,1H),2.28(s,3H),2.00(s,3H),1.96(d,J=7.1Hz,3H).

[0189] Compound DA-38: 3.417 g, ESI [M+H] + =336.9

[0190] 1 H NMR (400MHz, d6-DMSO) δ8.36 (s, 1H), 7.31 (d, J = 7.4Hz, 1H), 7.24 (t, J = 7.3Hz, 1H), 7.21 (s, 1H), 7.17 (t, J = 7.6Hz, 1H), 7.11–7. 02(m,2H),6.77(t,J=7.0Hz,1H),6.62(q,J=7.1Hz,1H),2.27(s,3H),2.26(d,J=1.7Hz,3H),1.96(s,3H),1.90(d,J=7.1Hz,3H).

[0191] Compound DA-39: 596 mg, ESI [M+H] + =337.1

[0192] 1 H NMR(400MHz,d6-DMSO)δ8.37(s,1H),7.31(d,J=7.5Hz,1H),7.23–7.02(m,5H),6.77(d,J=6.9 Hz,1H),6.58(q,J=7.5Hz,1H),2.27(s,3H),2.25(s,3H),1.95(s,3H),1.90(d,J=7.2Hz,3H).

[0193] Compound DA-44: 139 mg, ESI [M+H] + =338.9

[0194] 1H NMR(400MHz,d6-DMSO)δ8.34(s,1H),7.55–7.47(m,1H),7.41–7.28(m,3H),7.24(s,1H),7.16(t,J=7.5Hz,1H),7 .05(d,J=7.3Hz,1H),6.91–6.81(m,1H),6.62(q,J=7.0Hz,1H),2.26(s,3H),1.94(s,3H),1.90(d,J=7.1Hz,3H).

[0195] Compound DA-44 hydrochloride: 461 mg, ESI [M+H] + =338.9

[0196] 1 H NMR(400MHz,d6-DMSO)δ8.94(s,1H),7.64(s,1H),7.57–7.48(m,1H),7.42–7.31(m,3H),7.19(t,J=7.6Hz,1H),7 .10(d,J=7.4Hz,1H),7.00–6.92(m,1H),6.63(q,J=6.9Hz,1H),2.27(s,3H),1.97(s,3H),1.93(d,J=7.0Hz,3H).

[0197] Compound DA-55: 1.26 g, ESI [M+H] + =353.1

[0198] 1 H NMR (400MHz, d6-DMSO) δ8.31(s,1H),7.31(t,J=7.0Hz,2H),7.27–7.22(m,J=9.8,5.4Hz,2H),7.16(t,J=7.6Hz,1H),7.05(d ,J=7.5Hz,1H),6.70(d,J=7.7Hz,1H),6.65(q,J=6.9Hz,1H),2.38(s,3H),2.26(s,3H),1.96(s,3H),1.89(d,J=7.0Hz,3H).

[0199] Compound DA-56: 200 mg, ESI [M+H] + =370.9

[0200] 1H NMR (400MHz, CDCl3) δ7.81(s,1H),7.38(s,1H),7.28(s,1H),7.20–7.11(m,2H),7.02(t,J=8.6Hz,1H),6.91(dd, J=8.6,5.7Hz,1H),6.83(d,J=6.9Hz,1H),2.37(d,J=2.2Hz,3H),2.34(s,3H),2.16(s,3H),1.97(d,J=6.9Hz,3H).

[0201] Compound DA-57: 449 mg, ESI [M+H] + =370.9

[0202] 1 H NMR (400MHz, CDCl3) δ7.80(s,1H),7.37(s,1H),7.28(dd,J=6.3,2.6Hz,1H),7.18–7.10(m,3H),6.84(d,J= 7.8Hz,1H),6.74(q,J=7.0Hz,1H),2.33(s,3H),2.26(d,J=1.6Hz,3H),2.13(s,3H),1.95(d,J=7.0Hz,3H).

[0203] Compound DA-62: 149 mg, ESI [M+H] + =371.1

[0204] 1 H NMR (400MHz, CDCl3) δ7.91 (s, 1H), 7.36 (s, 1H), 7.28 (d, J = 5.2Hz, 1H), 7.16 (dd, J = 8.8, 6.9Hz, 3H), 6. 86(t,J=8.1Hz,1H),6.75(q,J=7.1Hz,1H),2.34(d,J=2.4Hz,6H),2.14(s,3H),1.98(d,J=7.1Hz,3H).

[0205] Compound DA-63: 171 mg, ESI [M+H] + =353.1

[0206] 1H NMR(400MHz, CDCl3)δ7.76(s,1H),7.35(s,1H),7.27–7.19(m,3H),7.14(t,J=4.0Hz,2H),6 .87(dd,J=13.7,6.9Hz,2H),2.43(s,3H),2.33(s,3H),2.14(s,3H),1.97(d,J=7.0Hz,3H).

[0207] Compound DA-64: 1.558 g, ESI [M+H] + =336.9

[0208] 1 H NMR(400MHz,d6-DMSO)δ8.36(s,1H),7.31(d,J=7.5Hz,1H),7.24(t,J=7.2Hz,1H),7.21(d,J=0.7Hz,1H),7.17(t,J=7.6Hz,1H),7.1 2–7.03(m,2H),6.77(t,J=7.4Hz,1H),6.62(q,J=7.0Hz,1H),2.27(s,3H),2.26(d,J=1.8Hz,3H),1.96(s,3H),1.90(d,J=7.1Hz,3H).

[0209] Compound DA-76: 866 mg, ESI [M+H] + =378.9

[0210] 1 H NMR(400MHz,d6-DMSO)δ8.28(s,1H),7.29(s,1H),7.28–7.20(m,2H),7.16(s,1H),7.07(s,1H),7.01–6.96(m,1H),6.73–6.60(m ,2H),2.52(dt,J=3.7,1.8Hz,7H),2.21(ddd,J=10.5,6.8,4.3Hz,1H),1.90(d,J=7.1Hz,3H),1.03(d,J=8.1Hz,2H),0.71(s,2H).

[0211] Compound DA-77: 1.58 g, ESI [M+H] + =362.9

[0212] 1H NMR (400MHz, d6-DMSO) δ8.37(s,1H),7.30(s,1H),7.21(s,1H),7.17(s,1H),7.06(dd,J=7.6,2.9Hz,2H),6.92(t,J=6.9Hz,1H),6.71(t,J=6. 8Hz,1H),6.62(q,J=7.1Hz,1H),2.27(s,3H),2.12–1.99(m,1H),1.95(s,3H),1.91(d,J=7.1Hz,3H),1.04–0.94(m,2H),0.72(d,J=2.2Hz,2H).

[0213] Compound DA-86: 1.83 g, ESI [M+H] + =336.9

[0214] 1 H NMR(400MHz,d6-DMSO)δ8.36(s,1H),7.30(d,J=7.4Hz,1H),7.26–7.21(m,1H),7.20(d,J=0.7Hz,1H),7.16(t,J=7.6Hz,1H),7.11– 7.04(m,2H),6.76(t,J=7.0Hz,1H),6.62(q,J=7.1Hz,1H),2.26(s,3H),2.25(d,J=1.8Hz,3H),1.95(s,3H),1.90(d,J=7.1Hz,3H).

[0215] Compound DA-106: 204 mg, ESI [M+H] + =310.9

[0216] 1 H NMR(400MHz,d6-DMSO)δ8.37(s,1H),7.77–7.69(m,2H),7.69–7.62(m,1H),7.58(d,J=0.7Hz,1H),7.56–7.50(m,2H ),7.51–7.43(m,1H),7.39–7.21(m,2H),6.96(dd,J=7.2,2.3Hz,1H),6.54(q,J=7.1Hz,1H),1.90(d,J=7.1Hz,3H).

[0217] Compound DA-171: 850 mg, colorless syrup, ESI [M+H] + =340.8

[0218] 1H NMR(400MHz,d6-DMSO)δ8.46(s,1H),7.46–7.33(m,1H),7.33–7.26(m,1H),7.23(s,1H),7.23–7.12(m,2H),7. 06(d,J=7.5Hz,1H),6.77–6.71(m,1H),6.61(q,J=7.2Hz,1H),2.26(s,3H),1.94(d,J=5.9Hz,3H),1.93(s,3H).

[0219] Compound B-2 and 1H-imidazole-5-carboxylic acid ethyl ester are subjected to Mitsunobu reaction to prepare intermediate compound B-3, and some isomer compound B-3A is collected. B-3A is hydrolyzed, amidated, and Grignard-reacted to obtain compounds DA-80 and DA-83 of the present invention.

[0220] Compound DA-80: 31.5 mg, ESI [M+H] + =322.9

[0221] 1 H NMR(400MHz,d6-DMSO)δ7.97(d,J=1.0Hz,1H),7.93(d,J=1.1Hz,1H),7.46–7.36(m,2H),7.31–7.23 (m,3H),7.21–7.13(m,2H),5.90(q,J=7.1Hz,1H),2.29(s,3H),2.12(s,3H),1.87(d,J=7.1Hz,3H).

[0222] Compound DA-83: 142 mg, ESI [M+H] + =336.9

[0223] 1 H NMR(400MHz,d6-DMSO)δ7.96(d,J=1.0Hz,1H),7.92(d,J=1.1Hz,1H),7.33–7.25(m,2H),7.23–7.10( m,4H),5.88(q,J=7.1Hz,1H),2.29(s,3H),2.25(d,J=2.0Hz,3H),2.12(s,3H),1.85(d,J=7.1Hz,3H).

[0224] Example 8 Preparation of compounds of the present invention DA-40~DA-43, DA-45, DA-103, DA-105, DA-107~DA-118, DA-148~DA-159, DA-173

[0225] Compound C-1 was reduced with (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropyltoluene)ruthenium chloride to give C-2. Part of compound C-2 was purchased directly. The preparation of compound (S)-1-(2-fluoro-3-methylphenyl)ethan-1-ol was performed in accordance with the method described in Example 4.

[0226] The preparation of the target compounds DA-40 to DA-43, DA-45, DA-103, DA-105, DA-107 to DA-113, DA-155 to DA-159 of the present invention is similar to that of compound DA-21.

[0227] Compound DA-40: 1.587 g, ESI [M+H] + =340.9

[0228] 1 H NMR(400MHz,d6-DMSO)δ8.25(d,J=1.6Hz,1H),7.43–7.33(m,1H),7.29–7.16(m,3H),7.13(t,J=7.6 Hz,1H),7.05–6.90(m,2H),6.50(q,J=7.1Hz,1H),2.24(s,3H),1.95(s,3H),1.90(d,J=7.1Hz,3H).

[0229] Compound DA-41: 1.425 g, ESI [M+H] + =356.9

[0230] 1 H NMR(400MHz,d6-DMSO)δ8.20(d,J=1.6Hz,1H),7.56–7.48(m,1H),7.42–7.31(m,2H),7.28(d,J=7.3Hz,1H),7.14(t,J=7.6Hz,1 H),6.98(d,J=7.6Hz,1H),6.92(dd,J=7.2,1.9Hz,1H),6.52(q,J=7.0Hz,1H),2.25(s,3H),1.96(s,3H),1.89(d,J=7.1Hz,3H).

[0231] Compound DA-42: 22 mg, ESI [M+H] + =337.0

[0232] 1H NMR(400MHz,d6-DMSO)δ8.26(d,J=1.8Hz,1H),7.30–7.23(m,2H),7.13(dd,J=15.1,7.5Hz,2H),7.05(s,1H ),7.03–6.96(m,2H),6.31(q,J=7.3Hz,1H),2.30(s,3H),2.25(s,3H),1.96(s,3H),1.89(d,J=7.2Hz,3H).

[0233] Compound DA-43: 2.534 g, ESI [M+H] + =340.9

[0234] 1 H NMR(400MHz,d6-DMSO)δ8.29(d,J=1.7Hz,1H),7.35–7.26(m,3H),7.25–7.17(m,2H),7.14(t,J=7.6H z,1H),6.99(d,J=7.5Hz,1H),6.34(q,J=7.1Hz,1H),2.25(s,3H),1.95(s,3H),1.90(d,J=7.2Hz,3H).

[0235] Compound DA-45: 1.471 g, ESI [M+H] + =356.9

[0236] 1 H NMR(400MHz,d6-DMSO)δ8.20(d,J=1.7Hz,1H),7.50(dd,J=7.5,1.7Hz,1H),7.43–7.31(m,2H),7.27(d,J=7.5Hz,1H),7.14(t,J=7.6 Hz,1H),6.98(d,J=7.6Hz,1H),6.92(dd,J=7.3,2.1Hz,1H),6.52(q,J=7.0Hz,1H),2.25(s,3H),1.96(s,3H),1.88(d,J=7.1Hz,3H).

[0237] Compound DA-103: 4.564 g, ESI [M+H] + =354.9

[0238] 1H NMR (400MHz, d6-DMSO) δ8.22(d,J=1.4Hz,1H),7.27(d,J=7.5Hz,1H),7.23(t,J=7.6Hz,1H),7.14(t,J=7.6Hz,1H),7.09(t,J=7 .7Hz,1H),6.99(d,J=7.6Hz,1H),6.81(t,J=7.3Hz,1H),6.50(q,J=7.1Hz,1H),2.25(s,6H),1.96(s,3H),1.88(d,J=7.1Hz,3H).

[0239] Compound DA-105: 2.349 g, ESI [M+H] + =370.9

[0240] 1 H NMR(400MHz,d6-DMSO)δ8.16(d,J=1.7Hz,1H),7.35–7.22(m,3H),7.14(t,J=7.6Hz,1H),6.98(d,J=7.7Hz,1H),6 .74(dd,J=7.4,0.9Hz,1H),6.55(q,J=7.0Hz,1H),2.37(s,3H),2.25(s,3H),1.97(s,3H),1.87(d,J=7.0Hz,3H).

[0241] Compound DA-107: 1.554 g, ESI [M+H] + =374.8

[0242] 1H NMR (400MHz, d6-DMSO) δ8.27(d,J=1.6Hz,1H),7.61(dd,J=8.0,1.3Hz,1H),7.39(t,J=8.0Hz,1H),7.27(d,J=7.4Hz,1H),7.13(t,J=7 .6Hz,1H),6.98(d,J=7.6Hz,1H),6.83(dd,J=7.8,1.2Hz,1H),6.50(q,J=7.0Hz,1H),2.24(s,3H),1.95(s,3H),1.88(d,J=7.0Hz,3H).

[0243] Compound DA-109: 1.567 g, ESI [M+H] + =390.8

[0244] 1H NMR (400MHz, d6-DMSO) δ8.27(d,J=1.6Hz,1H),7.61(dd,J=8.0,1.3Hz,1H),7.39(t,J=8.0Hz,1H),7.27(d,J=7.4Hz,1H),7.13(t,J=7 .6Hz,1H),6.98(d,J=7.6Hz,1H),6.83(dd,J=7.8,1.2Hz,1H),6.50(q,J=7.0Hz,1H),2.24(s,3H),1.95(s,3H),1.88(d,J=7.0Hz,3H).

[0245] Compound DA-173: 2180 mg, white solid, ESI [M+H] + =358.8

[0246] 1 H NMR (400MHz, d6-DMSO) δ8.32(d,J=1.7Hz,1H),7.46–7.32(m,1H),7.28(d,J=7.5Hz,1H),7.26–7.19(m,1H),7.14(t,J=7.6 Hz,1H),6.99(d,J=7.6Hz,1H),6.85–6.76(m,1H),6.51(q,J=7.1Hz,1H),2.25(s,3H),1.95(s,3H),1.92(d,J=7.1Hz,3H).

[0247] Compound C-2 and ethyl 4-fluoro-1H-imidazole-5-carboxylate are reacted via Mitsunobu reaction to prepare intermediate compound C-3, and some isomer compound C-3A is collected. C-3A is hydrolyzed, amidated, and Grignard-reacted to obtain compound DA-154 of the present invention.

[0248] Compound DA-154: 201 mg, ESI [M+H] + =370.9

[0249] 1 H NMR(400MHz,d6-DMSO)δ7.81(s,1H),7.40(d,J=7.1Hz,1H),7.34(t,J=7.6Hz,1H),7.28(d,J=6.7Hz,1H),7.24–7 .07(m,J=14.7,7.7Hz,3H),5.87(q,J=7.0Hz,1H),2.38(s,3H),2.28(s,3H),2.12(s,3H),1.86(d,J=7.0Hz,3H).

[0250] Example 9 Preparation of compounds DA-53, DA-58 and DA-59 of the present invention

[0251] Compound (R)-1-(1-(2-chlorophenyl)ethyl)-N-methoxy-N-methyl-1H-imidazole-5-carboxamide was chlorinated under NCS conditions to generate intermediate compounds DA-53-1, DA-58-1 and DA-59-1, and then referring to the preparation method of compound DA-21 in Example 43 to obtain the compounds DA-53, DA-58 and DA-59 of the present invention.

[0252] Compound DA-59: 406 mg, ESI [M+H] + =408.8

[0253] 1 H NMR (400MHz, d6-DMSO) δ7.73–7.65(m,1H),7.51–7.44(m,1H),7.41–7.29(m,3H),7.13(t,J=7.6Hz, 1H), 6.82 (d, J = 7.1Hz, 1H), 6.21 (q, J = 6.9Hz, 1H), 2.26 (s, 3H), 2.09 (s, 3H), 2.08 (d, J = 7.2Hz, 3H).

[0254] Example 10 Preparation of compounds DA-54, DA-60, DA-61, DA-65, DA-67, DA-69 to DA-71, DA-81, DA-82 and DA-84 of the present invention

[0255] Compound (R)-1-(1-(2-chlorophenyl)ethyl)-N-methoxy-N-methyl-1H-imidazole-5-carboxamide was brominated under NBS conditions to generate intermediate compounds DA-54-1, DA-60-1 and DA-61-1, and then referring to the preparation method of compound DA-21 in Example 43 to obtain the compounds DA-54, DA-60 and DA-61 of the present invention.

[0256] Compound DA-60: 42 mg, ESI [M+H] + =418.8

[0257] 1H NMR(400MHz,d6-DMSO)δ8.38(s,1H),7.50–7.45(m,1H),7.42–7.27(m,3H),7.13(t,J=7.6Hz,1H),6.97(dd,J= 7.6,1.7Hz,1H),6.86(d,J=7.7Hz,1H),6.43(q,J=7.1Hz,1H),2.26(s,3H),1.99(s,3H),1.89(d,J=7.1Hz,3H).

[0258] When preparing the compounds DA-65, DA-70, DA-67 and DA-71 of the present invention, by-products DA-69, DA-81, DA-82 and DA-84 were collected respectively.

[0259] Compound DA-69: 488 mg, ESI [M+H] + =538.9

[0260] 1 H NMR(400MHz,d6-DMSO)δ8.41(s,1H),7.75(s,1H),7.46–7.36(m,1H),7.37–7.14(m,7H),7.07–6.98(m,3H),6.87(t,J=7.5H z,1H),6.58(q,J=6.7Hz,1H),6.51(q,J=7.2Hz,1H),2.28(s,3H),2.11(d,J=7.0Hz,3H),1.98(s,3H),1.87(d,J=7.1Hz,3H).

[0261] Compound DA-81: 32 mg, ESI [M+H] + =538.9

[0262] 1 H NMR(400MHz,d6-DMSO)δ8.43(s,1H),8.31(d,J=1.1Hz,1H),7.98(d,J=1.0Hz,1H),7.47–7.31(m,4H),7.29–7.13(m,7H ),6.76(q,J=7.0Hz,1H),5.83(q,J=7.1Hz,1H),2.30(s,3H),2.19(s,3H),1.90(d,J=7.1Hz,3H),1.75(d,J=7.1Hz,3H).

[0263] Compound DA-82: 627 mg, ESI [M+H] + =566.9

[0264] Compound DA-84: 19 mg, ESI [M+H] + =566.9

[0265] 1 H NMR(400MHz,d6-DMSO)δ8.41(s,1H),8.31(d,J=1.1Hz,1H),8.00–7.96(m,1H ),7.40(d,J=7.5Hz,1H),7.35(d,J=7.6Hz,1H),7.32–7.21(m,2H),7.18(t,J= 7.6Hz,1H),7.14–6.94(m,4H),6.81–6.73(m,1H),5.81(q,J=6.9Hz,1H),2.3 1(s,3H),2.24(s,6H),2.19(s,3H),1.91–1.86(m,3H),1.74(d,J=7.1Hz,3H).

[0266] Example 11 Preparation of compounds DA-68, DA-85, DA-87 to DA-89 of the present invention

[0267] At room temperature, compound D-1 (4.89 g, 22.4 mmol), water (0.8 mL), and formamide (10.1 g, 224 mmol) were added sequentially to a 100 mL sealed tube and reacted at 150°C for 2 hours. After the reaction was complete, the reaction solution was adjusted to pH ≈ 8 with a dilute cold aqueous solution of NaHCO₃, extracted with ethyl acetate (3 × 150 mL), washed with saturated brine (100 mL), dried over anhydrous Na₂SO₄, filtered, and the filtrate concentrated to obtain compound D-1 (1.9 g, 41% yield) as a white solid. ESI [M+H] + =209.1

[0268] Referring to the preparation method of compound DA-21 of the present invention, D-2 was hydrolyzed and condensed to obtain compound D-4. D-4 and the corresponding alcohol compound were subjected to Mitsunobu reaction and Grignard reaction to obtain the target compounds DA-68, DA-87 to DA-89 of the present invention.

[0269] The compound DA-85 of the present invention was obtained by collecting during the preparation of the compound DA-68 of the present invention.

[0270] Compound DA-68: 576 mg, ESI [M+H] + =406.8

[0271] 1H NMR(400MHz,CD3OD)δ8.24(s,1H),7.42–7.25(m,4H),7.13–7.07(m,1H),7.04(t,J=7.7Hz,1H) ,6.90(d,J=7.7Hz,1H),6.06(q,J=7.0Hz,1H),2.35(s,3H),2.22(s,3H),1.96(d,J=7.0Hz,3H)

[0272] Compound DA-85: 1.76 g, ESI [M+H] + =661.7

[0273] 1 H NMR (400MHz, CD3OD) δ8.34(d,J=8.2Hz,1H),7.73–7.56(m,1H),7.54–7.29(m,4H),7.25–7.13(m,2H),7.03–6.64(m,2H),6.29–6.08(m ,1H),3.51(s,1H),3.50(s,0.5H),3.12(s,1.5H),3.04(s,0.7H),2.80(s,1.5H),2.46(s,0.8H),2.03–1.95(m,3H),1.93–1.76(m,3H).

[0274] Compound DA-87: 197 mg, ESI [M+H] + =390.9

[0275] 1 H NMR(400MHz,d6-DMSO)δ8.49(s,1H),7.40–7.31(m,2H),7.24–7.12(m,3H),7.07(t,J=7.6Hz,1H ),6.82(d,J=7.6Hz,1H),5.88(q,J=7.1Hz,1H),2.29(s,3H),2.17(s,3H),1.91(d,J=7.1Hz,3H).

[0276] Compound DA-88: ​​176 mg, ESI [M+H] + =404.9

[0277] 1H NMR(400MHz,d6-DMSO)δ8.47(s,1H),7.38(d,J=7.5Hz,1H),7.20(t,J=7.2Hz,1H),7.08(t,J=7.6Hz,2H),7.0 0–6.93(m,1H),6.85(d,J=7.8Hz,1H),5.83(q,J=7.0Hz,1H),2.29(s,3H),2.16(s,6H),1.89(d,J=7.1Hz,3H).

[0278] Compound DA-89: 299 mg, ESI [M+H] + =420.7

[0279] 1 H NMR(400MHz,d6-DMSO)δ8.44(s,1H),7.36(d,J=7.5Hz,1H),7.32–7.20(m,2H),7.06(t,J=7.6Hz,1H),6.89(d,J= 7.4Hz,1H),6.86–6.79(m,1H),5.88(q,J=6.6Hz,1H),2.28(d,J=1.9Hz,6H),2.08(s,3H),1.86(d,J=7.0Hz,3H).

[0280] Example 12 Preparation of compounds DA-90 to DA-93, DA-97 and DA-98 of the present invention

[0281] The target compounds DA-90 to DA-93 of the present invention were prepared by referring to the method for preparing the compound DA-21 of the present invention.

[0282] Compound DA-90: 1.876 g, ESI [M+H] + =322.9

[0283] 1 H NMR(400MHz,d6-DMSO)δ7.65(d,J=2.0Hz,1H),7.40–7.28(m,2H),7.26–7.14(m,3H),7.11(d,J=7.3Hz,1H),7. 09–7.01(m,1H),6.81(q,J=7.0Hz,1H),6.46(d,J=2.0Hz,1H),2.28(s,3H),2.02(s,3H),1.89(d,J=7.0Hz,3H).

[0284] Compound DA-91: 1.614 g, ESI [M+H] + =336.9

[0285] 1 H NMR(400MHz,d6-DMSO)δ7.65(d,J=1.8Hz,1H),7.35(d,J=7.4Hz,1H),7.26–7.16(m,2H),7.11(d,J=7.5Hz,1H),7.05(t ,J=7.6Hz,1H),6.89–6.73(m,2H),6.46(d,J=1.9Hz,1H),2.29(s,3H),2.24(s,3H),2.03(s,3H),1.88(d,J=6.9Hz,3H).

[0286] Compound E-2 and 1H-pyrazole-5-carboxylic acid ethyl ester were subjected to Mitsunobu reaction to prepare intermediate compounds E-3 and E-3A. E-3A was hydrolyzed, amidated, and Grignard-reacted to obtain compounds DA-97 and DA-98 of the present invention.

[0287] Compound DA-97: 2.469 g, ESI [M+H] + =322.9

[0288] 1 H NMR(400MHz,d6-DMSO)δ8.06(d,J=2.4Hz,1H),7.45–7.34(m,1H),7.31(d,J=7.3Hz,1H),7.27–7.12(m,5H ), 6.84 (d, J = 2.4Hz, 1H), 5.96 (q, J = 7.1Hz, 1H), 2.28 (s, 3H), 2.09 (d, J = 4.0Hz, 3H), 1.82 (d, J = 7.1Hz, 3H).

[0289] Compound DA-98: 1.674 g, ESI [M+H] + =336.9

[0290] 1H NMR (400MHz, d6-DMSO) δ8.05(d,J=2.4Hz,1H),7.31(d,J=7.3Hz,1H),7.31(d,J=7.3Hz,1H),7.28–7.20(m,2H),7.17(t,J=7.5Hz,1H),7.09(t,J=7 .6Hz,1H),7.04–6.96(m,1H),6.84(d,J=2.4Hz,1H),5.94(q,J=7.0Hz,1H ),2.29(s,3H),2.24(d,J=1.9Hz,3H),2.09(s,3H),1.81(d,J=7.1Hz,3H).

[0291] Example 13 Preparation of compounds DA-95, DA-99 to DA-102 and DA-104 of the present invention

[0292] Compound DA-15 (1.5 g, 4.65 mmol) was dissolved in anhydrous THF (10 mL) at room temperature. The reaction system was cooled to 0°C using an ice-water bath. Methylmagnesium bromide (4.7 mL, 3 mol / L in THF, 14.1 mmol) was slowly added to the reaction system via syringe and stirred at 0°C for 1 hour. After completion of the reaction as monitored by TLC, the reaction system was cooled to 0°C using an ice-water bath. Saturated aqueous ammonium chloride (20 mL) was slowly added to the reaction system and extracted with ethyl acetate (3 × 20 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. A portion of the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 3). Fractions with Rf = 0.5 to 0.6 were collected to obtain compound DA-99 (70 mg, 64% yield) as a white solid. ESI[M+H] + =338.9.

[0293] 1 H NMR(400MHz,d6-DMSO)δ7.99(s,1H),7.66(d,J=8.2Hz,1H),7.19–7.02(m,3H),6.98–6.85(m,2H),6.82–6.64(m,2H),6 .48(t,J=7.2Hz,1H),5.89(s,1H),5.66(q,J=7.3Hz,1H),1.81(s,3H),1.71(s,3H),1.64(s,3H),1.58(d,J=7.2Hz,3H).

[0294] At room temperature, the crude product, compound DA-99, was dissolved in dichloromethane (5V). The reaction system was cooled to 0°C using an ice-water bath. Trifluoroacetic acid (10V) was added to the reaction system and stirred at room temperature overnight. After the reaction was complete as monitored by TLC, the reaction system was concentrated under reduced pressure. Saturated sodium bicarbonate was slowly added to the reaction system and extracted with ethyl acetate (3×20mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. A portion of the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 3) to obtain compound DA-100 (130mg) as a colorless oil. ESI [M+H] + =320.9.

[0295] 1 H NMR(400MHz,d6-DMSO)δ7.96(d,J=0.7Hz,1H),7.37–7.26(m,1H),7.19–7.06(m,J=16.9,11.9,7.0Hz,3H),7.03(t,J=7.5Hz,1H),6.89(d,J=0.9 Hz,1H),6.86–6.74(m,2H),5.50(d,J=1.5Hz,1H),5.31(q,J=7.1Hz,1H) ,5.09(d,J=1.5Hz,1H),2.16(s,3H),1.87(s,3H),1.64(d,J=7.1Hz,3H).

[0296] At room temperature, compound DA-100 (590 mg, 1.84 mmol) was dissolved in dichloromethane (3 mL). The reaction system was cooled to 0°C using an ice-water bath. Meta-chloroperbenzoic acid (747.7 mg, 3.68 mmol) was added to the reaction system and stirred at room temperature overnight. After the reaction was complete as monitored by TLC, saturated sodium bicarbonate was slowly added to the reaction system. The mixture was extracted with dichloromethane (3 × 20 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. A portion of the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 3) to obtain compound DA-95 as a gray solid and compound DA-104 (13 mg) as a colorless oil.

[0297] Compound DA-95: 63 mg, ESI [M+H] + =336.9

[0298] 1H NMR(400MHz,d6-DMSO)δ8.57(d,J=1.6Hz,1H),7.38–7.29(m,1H),7.25–7.16(m,2H),7.14–6.99(m,4H),6.91(d, J=7.4Hz,1H),5.67(s,1H),5.32(s,1H),5.18(q,J=6.8Hz,1H),2.16(s,3H),1.94(s,3H),1.54(d,J=7.1Hz,3H).

[0299] Compound DA-104: 13 mg, ESI [M+H] + =352.9

[0300] NaH (24 mg, 60% in mineral oil, 0.60 mmol) was slowly added to a DMF (2 mL) solution of DA-99 (170 mg, 0.50 mmol) in an ice-water bath at 0°C. After the addition, stirring was continued at 0°C for 30 minutes. Iodomethane (85.2 mg, 0.60 mmol) was slowly added to the system using a syringe and stirred at room temperature overnight. After the reaction was complete as monitored by TLC, ice water was slowly added to the reaction system. The mixture was extracted with ethyl acetate (3 × 5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, 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 / 1) to obtain compound DA-102 (8 mg).

[0301] At room temperature, DA-99 (170 mg, 0.53 mmol) and 10% wet palladium on carbon (17 mg) were dissolved in MeOH (10 mL). The system was replaced with hydrogen three times and stirred under hydrogen for 2 hours. After the reaction was complete as monitored by TLC, the mixture was filtered and the filter cake was washed with methanol (3 × 5 mL). The filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 5) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1) to obtain a gray solid compound DA-101 (140 mg, yield 81.8%). ESI [M+H] + =322.9

[0302] DA-101 is a diastereomer with two sets of peaks in NMR.

[0303] 1H NMR(400MHz,d6-DMSO)δ7.90(s,1H),7.13–7.06(m,1H),6.91–6.84(m,2H),6.82(s,1H),6.69(d,J=7.3Hz,1H),6.65–6.59(m,2H),6. 54–6.48(m,1H),5.44(q,J=6.9Hz,1H),4.36(q,J=6.8Hz,1H),2.11(s,3H),2.05(s,3H),1.72(d,J=7.1Hz,3H),1.45(d,J=6.9Hz,3H).

[0304] 1 H NMR(400MHz,d6-DMSO)δ7.96(s,1H),7.43–7.34(m,1H),7.28–7.18(m,2H),7.06–6.96(m,3H),6.95–6.90(m,1H),6.57–6.5 4(m,1H),4.91(q,J=6.6Hz,1H),4.00–3.92(m,1H),2.30(s,3H),2.15(s,3H),1.47(d,J=6.6Hz,3H),1.35(d,J=7.0Hz,3H).

[0305] Example 14 Preparation of compounds DA-164, DA-165, DA-166, DA-167 and DA-34 of the present invention

[0306] Dissolve 2-chloro-3-methylbenzoic acid (1.26 g, 7.39 mmol) in thionyl chloride (6.3 mL) at room temperature and stir at 120°C for 2 hours. After the reaction is complete, the reaction mixture is concentrated under reduced pressure to obtain the crude product DA-164-1, which is used directly in the next reaction without purification.

[0307] At room temperature, add a solution of 2-methylpyrrole (500.0 mg, 6.16 mmol) in diethyl ether (5 mL) dropwise to a solution of ethylmagnesium bromide (3.17 mL, 2 mol / L in THF, 6.34 mmol) in diethyl ether (5 mL) and stir at 40°C for 30 minutes. Cool the reaction system to room temperature, add a solution of DA-164-1 in diethyl ether (10 mL) dropwise, and stir at room temperature overnight. After the reaction was complete as monitored by TLC, the reaction system was cooled to 0°C and then poured into a saturated aqueous ammonium chloride solution (20 mL). The mixture was extracted with EtOAc (3×20 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 50 to 1 / 3) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 3). The fractions with Rf = 0.3 to 0.5 were collected to give the white solid compound DA-164-2 (793.9 mg, two-step yield 46.0%). ESI [M+H] + =234.1.

[0308] Compound DA-164-2 (200.0 mg, 0.86 mmol) was dissolved in DCE (5 mL), and cyclopropylboronic acid (147.5 mg, 1.72 mmol), sodium carbonate (181.9 mg, 1.72 mmol), copper acetate (171.5 mg, 0.86 mmol), and 2,2'-bipyridine (134.1 mg, 0.86 mmol) were added. The mixture was stirred at 90°C for 4 hours. After completion of the reaction as monitored by TLC, the reaction solution 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 / 100 to 1 / 10) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10). Fractions with Rf = 0.3 to 0.4 were collected to obtain compound DA-164 (86.3 mg, 36.8% yield) as a white solid. ESI [M+H] + =274.1.

[0309] 1 H NMR (400MHz, d6-DMSO) δ7.50–7.43(m,1H),7.31(t,J=7.5Hz,1H),7.24(dd,J=7.5,1.3Hz,1H),6.19(d,J=4.0H z,1H),5.96–5.88(m,1H),3.36–3.30(m,1H),2.39(s,3H),2.37(s,3H),1.18–1.09(m,2H),0.95–0.81(m,2H).

[0310] The preparation methods of the target compounds DA-165, DA-166, DA-167 and DA-34 are similar to that of the target compound DA-164, and are prepared using different substituted benzoic acids as raw materials.

[0311] Compound DA-165: 78.1 mg, white solid, ESI [M+H] + =258.1.

[0312] 1 H NMR (400MHz, d6-DMSO) δ7.43(t,J=7.0Hz,1H),7.34–7.25(m,1H),7.17(t,J=7.5Hz,1H),6.33(d,J=4.0Hz,1H),5. 93(d,J=4.0Hz,1H),3.36–3.31(m,1H),2.37(s,3H),2.29(d,J=1.8Hz,3H),1.19–1.05(m,2H),0.87–0.75(m,2H).

[0313] Compound DA-166: 64.6 mg, white solid, ESI [M+H] + =278.1.

[0314] 1 H NMR (400MHz, d6-DMSO) δ7.60–7.43(m,2H),7.31(d,J=7.3Hz,1H),6.28(d,J=4.0Hz,1H),5. 95(d,J=4.0Hz,1H),3.38–3.33(m,1H),2.39(s,3H),1.23–1.08(m,2H),0.95–0.81(m,2H).

[0315] Compound DA-167: 67.5 mg, white solid, ESI [M+H] + =278.1.

[0316] 1 H NMR (400MHz, d6-DMSO) δ7.79–7.69(m,1H),7.53–7.44(m,1H),7.32(t,J=7.8Hz,1H),6.41(d,J=4.0H z,1H),5.97(d,J=4.0Hz,1H),3.36–3.31(m,1H),2.38(s,3H),1.15–1.10(m,2H),0.87–0.74(m,2H).

[0317] Compound DA-34: 229.2 mg, white solid, ESI [M+H] +=254.1.

[0318] 1 H NMR(400MHz,d6-DMSO)δ7.26(d,J=6.9Hz,1H),7.17–7.07(m,2H),6.16(d,J=3.9Hz,1H),5.92–5.86(m ,1H),3.36–3.32(m,1H),2.37(s,3H),2.29(s,3H),2.13(s,3H),1.19–1.06(m,2H),0.87–0.76(m,2H).

[0319] Example 15 Preparation of compounds DA-110, DA-130, and DA-157 of the present invention

[0320] The preparation of the target compounds DA-110, DA-130, and DA-157 of the present invention is similar to that of compound DA-21.

[0321] Compound DA-110: 155 mg, white solid, ESI [M+H] + =351.1.

[0322] 1 H NMR (400MHz, d6--DMSO) δ8.11(d,J=1.7Hz,1H),7.27(d,J=7.4Hz,1H),7.14(d,J=7.6Hz,1H),7.10(d,J=5.3Hz,2H),6.95(d,J =7.6Hz,1H),6.66–6.59(m,1H),6.51(d,J=7.0Hz,1H),2.27(d,J=5.1Hz,6H),2.24(s,3H),1.94(s,3H),1.80(d,J=7.0Hz,3H).

[0323] Compound DA-130: 67 mg, white solid, ESI [M+H] + =353.1.

[0324] 1H NMR(400MHz,d6-DMSO)δ8.18(s,1H),7.51(d,J=6.9Hz,1H),7.34(t,J=7.6Hz,1H),7.25(s,1H),7.20(t,J=6.0Hz,1H),7.1 1(t,J=4.7Hz,2H),6.75(d,J=7.0Hz,1H),6.58(d,J=6.9Hz,1H),2.37(s,3H),2.27(d,J=7.0Hz,6H),1.83(d,J=7.0Hz,3H).

[0325] Compound DA-157: 453 mg, colorless oil, ESI [M+H] + =359.1.

[0326] 1 H NMR(400MHz,d6-DMSO)δ8.25(d,J=1.7Hz,1H),7.30(dd,J=14.7,5.1Hz,2H),7.18–7.07(m,3H) ,7.00(d,J=7.6Hz,1H),6.47(d,J=7.1Hz,1H),2.26(s,3H),1.97(s,3H),1.90(d,J=7.1Hz,3H).

[0327] Example 16 Preparation of Compound DA-115 of the Present Invention

[0328] At room temperature, 1-(2,3-methylphenyl)ethanone (20.0 g, 135 mmol), formic acid (31.07 g, 675 mmol), and triethylamine (40.98 g, 405 mmol) were added to isopropanol (200 mL) in sequence, and the reaction system was replaced with argon three times. (S, S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropyltoluene) ruthenium chloride (1.29 g, 2.03 mmol) was added to the reaction system, and stirred at 60 ° C for 4 hours under argon protection. After the reaction was completed as monitored by TLC, the reaction mixture was cooled to room temperature, filtered, extracted with EtOAc (3×50 mL), the combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 to 1 / 3) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10). The Rf = 0.5 to 0.6 fraction was collected to obtain a light yellow oily compound DA-115.2 (19.26 g, yield 95.1%).

[0329] At room temperature, 5-fluoro-1H-imidazole-4-carbaldehyde (1.44 g, 12.58 mmol) was dissolved in dry THF (30 mL). The temperature was lowered to -30°C using a dry ice acetone bath. DA-115.2 (2.44 g, 16.35 mmol) and PBu3 (5.08 g, 25.16 mmol) were then added to the reaction system in sequence. DEAD (4.38 g, 25.16 mmol) was slowly added to the reaction system using a syringe, and the mixture was stirred at room temperature overnight. After the reaction was complete as monitored 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 a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 to 1 / 2) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 2). Fractions with Rf = 0.5 to 0.6 were collected to obtain compound DA-115.3 as a colorless oil (1.54 g, total yield of the two reactions 49.7%). ESI [M+H] + =247.1.

[0330] 3-Chloro-2-fluorobromobenzene (628 mg, 3 mmol) was dissolved in dry THF (10 mL) in a dry ice-acetone bath at -78°C. Under nitrogen, n-butyllithium (0.96 mL, 2.5 mol / L in THF (2.4 mmol)) was added to the reaction system and stirred for 0.5 hour. A solution of compound DA-115.5 (368 mg, 1.5 mmol) in THF (5 mL) was slowly added to the reaction system via syringe and stirred for 1 hour. After completion of the reaction as monitored by TLC, ice water was added to the reaction system and extracted with EtOAc. The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to yield the crude product, compound DA-115.6. This crude product was dissolved in dry DCM (30 mL) and manganese dioxide (2.61 g, 30 mmol) was added to the reaction system. The mixture was stirred at reflux overnight. After the reaction was complete as monitored by TLC, the mixture was filtered and concentrated under reduced pressure to obtain the crude product, which was then purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 to 1 / 2) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 2). Fractions with Rf = 0.5 to 0.6 were collected to obtain compound DA-115 (154 mg, total yield of the two reactions 27.4%) as a white solid. ESI [M+H] + =375.1.

[0331] 1H NMR(400MHz,d6-DMSO)δ8.18(d,J=1.7Hz,1H),7.86–7.74(m,1H),7.43(t,J=6.3Hz,1H),7.34(s,1H),7. 15–7.04(m,2H),6.70–6.61(m,1H),6.44(q,J=6.9Hz,1H),2.28(d,J=3.4Hz,6H),1.79(d,J=7.0Hz,3H).

[0332] Example 17 Preparation of compounds DA-117, DA-127~DA-129, DA-174, DA-175, DA-178~DA-180, DA-182~DA-184, and DA-187~DA-231 of the present invention

[0333] The preparation of the target compounds DA-117, DA-127 to DA-129, DA-174, DA-175, DA-178 to DA-180, DA-182 to DA-184, and DA-187 to DA-231 of the present invention is similar to that of compound DA-115.

[0334] Compound DA-117: 159 mg, white solid, ESI [M+H] + =355.1.

[0335] 1 H NMR (400MHz, d6-DMSO) δ8.11(d,J=1.8Hz,1H),7.48(t,J=6.7Hz,1H),7.23(t,J=6.1Hz,1H),7.19(d,J=7.4Hz,1H),7. 13–7.06(m,2H),6.77–6.62(m,1H),6.46(q,J=6.9Hz,1H),2.27(s,6H),2.25(d,J=1.7Hz,3H),1.79(d,J=7.0Hz,3H).

[0336] Compound DA-127: 221 mg, white solid, ESI [M+H] + =357.1.

[0337] 1H NMR(400MHz,d6-DMSO)δ8.29(s,1H),7.80(td,J=8.0,1.7Hz,1H),7.55(s,1H),7.44(ddd,J=7.8,6.2,1.7Hz,1H),7.34(t ,J=7.9Hz,1H),7.14–7.04(m,2H),6.70–6.63(m,1H),6.52(d,J=7.0Hz,1H),2.27(d,J=3.4Hz,6H),1.81(d,J=7.0Hz,3H).

[0338] Compound DA-128: 111 mg, colorless syrup, ESI [M+H] + =357.1.

[0339] 1 H NMR(400MHz,d6-DMSO)δ8.24(s,1H),7.58(dd,J=13.0,4.8Hz,1H),7.50(td,J=8.0,5.1Hz,1H),7.39(s,1H),7.25(d,J=7 .5Hz,1H),7.15–7.06(m,2H),6.72(d,J=6.8Hz,1H),6.55(q,J=7.1Hz,1H),2.27(d,J=4.6Hz,6H),1.81(t,J=6.4Hz,3H).

[0340] Compound DA-129: 310 mg, colorless syrup, ESI [M+H] + =337.1.

[0341] 1 H NMR (400MHz, d6-DMSO) δ8.23(s,1H),7.48(s,1H),7.44(s,1H),7.25(d,J=6.1Hz,1H),7.19(t,J=7.5Hz,1H),7. 09(d,J=7.1Hz,2H),6.74–6.66(m,1H),6.54(d,J=7.0Hz,1H),2.27(s,6H),2.26(s,3H),1.81(d,J=7.0Hz,3H).

[0342] Compound DA-174: 340 mg, colorless syrup, ESI [M+H] + =341.1.

[0343] 1H NMR(400MHz,d6-DMSO)δ8.29(s,1H),7.70–7.61(m,1H),7.58(s,1H),7.30(s,2H),7.09(d,J=7.1H z,2H),6.67(d,J=6.9Hz,1H),6.52(q,J=7.0Hz,1H),2.27(d,J=2.8Hz,6H),1.81(d,J=7.0Hz,3H).

[0344] Compound DA-175: 134 mg, white solid, ESI [M+H] + =359.1.

[0345] 1 H NMR(400MHz,d6-DMSO)δ8.19(d,J=1.6Hz,1H),7.65(dd,J=17.6,9.2Hz,1H),7.37–7.23(m,2H),7.14–7.0 5(m,2H),6.65(dd,J=6.0,3.0Hz,1H),6.44(q,J=6.9Hz,1H),2.28(d,J=4.4Hz,6H),1.79(d,J=7.0Hz,3H).

[0346] Compound DA-178: 96 mg, white solid, ESI [M+H] + =367.1.

[0347] 1 H NMR(400MHz,d6-DMSO)δ8.40(d,J=1.7Hz,1H),7.66(dd,J=10.3,2.3Hz,1H),7.45–7.36(m,1H),7.36 –7.27(m,2H),7.26–7.18(m,1H),6.85(t,J=7.1Hz,1H),6.44(d,J=7.1Hz,1H),1.91(d,J=7.1Hz,3H).

[0348] Compound DA-179: 142 mg, white solid, ESI [M+H] + =363.1.

[0349] 1H NMR(400MHz,d6-DMSO)δ8.31(d,J=1.7Hz,1H),7.66(dd,J=10.4,2.3Hz,1H),7.39–7.27(m,2H),7.24(d,J=7.1Hz,1H ),7.10(t,J=7.6Hz,1H),6.85(d,J=7.1Hz,1H),6.43(d,J=7.1Hz,1H),2.25(d,J=1.7Hz,3H),1.88(d,J=7.1Hz,3H).

[0350] Compound DA-180: 310 g, white solid, ESI [M+H] + =379.1.

[0351] 1 H NMR(400MHz,d6-DMSO)δ8.26(d,J=1.7Hz,1H),7.66(d,J=8.4Hz,1H),7.40–7.22(m,4 H), 6.76 (d, J = 7.3Hz, 1H), 6.48 (d, J = 7.0Hz, 1H), 2.38 (s, 3H), 1.87 (d, J = 7.0Hz, 3H).

[0352] Compound DA-182: 321 mg, white solid, ESI [M+H] + =349.1.

[0353] 1 H NMR(400MHz,d6-DMSO)δ8.55(d,J=6.4Hz,1H),7.66(ddd,J=10.1,7.8,3.9Hz,1H),7.62(s,1H),7.39(td,J=9.7,1. 5Hz,1H),7.35–7.28(m,2H),7.27–7.18(m,1H),6.79(t,J=7.2Hz,1H),6.53(q,J=7.1Hz,1H),1.93(d,J=7.1Hz,3H).

[0354] Compound DA-183: 226 mg, colorless oil, ESI [M+H] + =345.1.

[0355] 1H NMR(400MHz,d6-DMSO)δ8.44(s,1H),7.66(d,J=5.8Hz,1H),7.59(s,1H),7.39–7.28(m,2H),7.24(s,1H) ,7.09(t,J=7.6Hz,1H),6.80(s,1H),6.53(d,J=7.1Hz,1H),2.25(d,J=1.7Hz,3H),1.89(d,J=7.1Hz,3H).

[0356] Compound DA-184: 101 mg, white solid, ESI [M+H] + =361.1.

[0357] 1 H NMR(400MHz,d6-DMSO)δ8.38(s,1H),7.70–7.61(m,1H),7.60(s,1H),7.37–7.27(m,3H),7.25(t ,J=7.6Hz,1H),6.72(d,J=7.0Hz,1H),6.57(q,J=7.0Hz,1H),2.38(s,3H),1.89(t,J=6.3Hz,3H).

[0358] Compound DA-187: 253 mg, white solid, ESI [M+H] + =365.1.

[0359] 1 H NMR(400MHz,d6-DMSO)δ8.28(d,J=1.5Hz,1H),7.72–7.60(m,1H),7.54–7.48(m,1H),7.36(d dd,J=12.1,5.7,3.5Hz,4H),6.99–6.90(m,1H),6.45(d,J=7.0Hz,1H),1.88(d,J=7.0Hz,3H).

[0360] Compound DA-188: 256 mg, white solid, ESI [M+H] + =383.0.

[0361] 1 H NMR(400MHz,d6-DMSO)δ8.35(d,J=1.5Hz,1H),7.66(dd,J=10.4,2.0Hz,1H),7.45–7.36(m, 2H),7.36–7.26(m,2H),6.77(d,J=6.4Hz,1H),6.43(d,J=7.0Hz,1H),1.89(d,J=7.1Hz,3H).

[0362] Compound DA-189: 178 mg, white solid, ESI [M+H] + =399.0.

[0363] 1 H NMR (400MHz, d6-DMSO) δ8.36 (s, 1H), 7.70–7.64 (m, 1H), 7.62 (d, J = 6.8Hz, 1H), 7.39 (s, 1H) ),7.37–7.26(m,2H),6.86(d,J=6.9Hz,1H),6.44(q,J=7.0Hz,1H),1.88(d,J=7.0Hz,3H).

[0364] Compound DA-190: 223 mg, colorless oil, ESI [M+H] + =349.1.

[0365] 1 H NMR(400MHz,d6-DMSO)δ8.34(d,J=1.5Hz,1H),7.70–7.60(m,1H),7.31(s,3H),7.22( d,J=7.9Hz,2H),7.05(t,J=7.6Hz,1H),6.44(q,J=7.0Hz,1H),1.90(d,J=7.1Hz,3H).

[0366] Compound DA-191: 235 mg, colorless oil, ESI [M+H] + =349.1.

[0367] 1 H NMR(400MHz,d6-DMSO)δ8.37(d,J=1.8Hz,1H),7.66(ddd,J=10.5,7.8,2.2Hz,1H),7. 39–7.29(m,4H),7.21(t,J=8.9Hz,2H),6.27(q,J=7.2Hz,1H),1.90(d,J=7.2Hz,3H).

[0368] Compound DA-192: 291 mg, colorless oil, ESI [M+H] + =367.1.

[0369] 1H NMR(400MHz,d6-DMSO)δ8.33(d,J=1.4Hz,1H),7.67(d,J=8.0Hz,1H),7.42–7 .26(m,3H),7.23–7.06(m,2H),6.39(d,J=7.1Hz,1H),1.89(d,J=7.1Hz,3H).

[0370] Compound DA-212: 188 mg, white solid, ESI [M+H] + =363.1.

[0371] 1 H NMR (400MHz, d6-DMSO) δ8.28(d,J=1.7Hz,1H),7.49(t,J=6.9Hz,1H),7.29(ddd,J=12.2,9.6,4.3Hz,2H),7. 19(t,J=7.5Hz,1H),7.16–7.07(m,2H),6.40(t,J=7.1Hz,1H),2.26(d,J=1.8Hz,3H),1.88(d,J=7.1Hz,3H).

[0372] Compound DA-217: 262 mg, white solid, ESI [M+H] + =367.1.

[0373] 1 H NMR(400MHz,d6-DMSO)δ8.34(d,J=1.8Hz,1H),7.72–7.62(m,1H),7.39–7.28(m,3H),7.23(ddd,J=12 .2,8.2,3.6Hz,1H),6.95(ddd,J=9.0,5.8,3.1Hz,1H),6.39(q,J=7.1Hz,1H),1.90(d,J=7.1Hz,3H).

[0374] Compound DA-218: 138 mg, white solid, ESI [M+H] + =367.1.

[0375] 1H NMR(400MHz,d6-DMSO)δ8.39(d,J=1.8Hz,1H),7.67(ddd,J=10.0,5.6,3.0Hz,1H),7.35(dd,J=6.1,3.0Hz, 2H), 7.20 (tt, J=9.3, 2.3Hz, 1H), 7.01 (dd, J=8.5, 2.0Hz, 2H), 6.24 (d, J=7.1Hz, 1H), 1.90 (d, J=7.2Hz, 3H).

[0376] Compound DA-219: 410 mg, colorless syrup, ESI [M+H] + =367.1.

[0377] 1 H NMR(400MHz,d6-DMSO)δ8.42(s,1H),7.65(dd,J=10.5,1.7Hz,1H),7.40(dd,J=11.7,5.2Hz,1H),7.33(d, J=4.5Hz,1H),7.26(d,J=5.9Hz,1H),7.09(t,J=8.7Hz,2H),6.35(d,J=7.2Hz,1H),1.97(d,J=7.2Hz,3H).

[0378] Compound DA-221: 306 mg, colorless syrup, ESI [M+H] + =367.1.

[0379] 1 H NMR(400MHz,d6-DMSO)δ8.37(d,J=1.8Hz,1H),7.68–7.58(m,1H),7.31(dd,J=15.3,5.9Hz,1H), 7.24(t,J=8.2Hz,2H), 7.11(dd,J=7.6,1.6Hz,2H), 6.40(q,J=7.0Hz,1H), 1.89(d,J=7.1Hz,3H).

[0380] Compound DA-228: 160 mg, colorless syrup, ESI [M+H] + =359.1.

[0381] 1H NMR (400MHz, d6-DMSO) δ8.26(d,J=1.7Hz,1H),7.48(t,J=6.8Hz,1H),7.24(d,J=6.7Hz,2H),7. 20(d,J=7.5Hz,1H),7.09(s,1H),6.81(s,1H),6.44(s,1H),2.25(s,6H),1.87(d,J=7.1Hz,3H).

[0382] The beneficial effects of the present invention are demonstrated by the following test examples.

[0383] Test Example 1 Pharmacological Data Determination of the Compounds of the Invention

[0384] 1. Test methods

[0385] 1.1 Testing the anesthetic effect of the compound of the present invention after tail vein injection in rats (determination of the minimum anesthetic effective dose):

[0386] Experimental animals were 7-9 week old male Sprague-Dawley rats, and administration was performed via the tail vein (dosage rate 0.02 mL / s, dosing volume 0.6 mL / rat). The initial dose of each test compound started at 1 mg / kg, and the actual dose was calculated based on the pre-test body weight of each rat. Subsequent dose increases or decreases were determined based on whether the rats exhibited loss of righting reflex. The lowest dose that resulted in loss of righting reflex was determined as the minimum anesthetic effective dose.

[0387] While testing whether the compound of the present invention has an anesthetic effect after tail vein injection on rats, it is also determined whether the compound has an analgesic effect. Once it is determined that the compound has an anesthetic effect (the righting reflex disappears ≥ 30s), immediately observe whether the rat responds to noxious stimulation (clamping the middle and outer 1 / 3 of the rat's tail with a crocodile clip for 30s) after administration. If the rat does not respond within 30s, it is determined to have an analgesic effect, otherwise it is determined to have no analgesic effect; if the compound has no anesthetic effect (the righting reflex disappears < 30s), 1 minute after administration, give the rat a noxious stimulation (clamping the middle and outer 1 / 3 of the rat's tail with a crocodile clip for 30s). If the rat does not respond within 30s, it is determined to have an analgesic effect; otherwise, it is determined to have no analgesic effect. In the present invention, the dose at which the analgesic effect begins to appear is determined as the minimum analgesic effective dose. The minimum anesthetic effective dose and the minimum analgesic effective dose in the present invention are further classified as: A≤10mg / kg; 10mg / kg<B≤20mg / kg; 20mg / kg <C≤30mg / kg;30mg / kg<D≤40mg / kg;E>40mg / kg。

[0388] 1.2 Determination of the main pharmacological effects of the compounds of the present invention

[0389] 1.2.1 ED of the compounds of the present invention for general anesthetic effect using the loss of righting reflex in rats as the determining indicator 50

[0390] Male SD rats aged 7-9 weeks were selected for the experiment. The median effective dose (ED) of the general anesthetic effect of the compound of the present invention was determined by the up-and-down method with the loss of righting reflex as the evaluation index. 50 The drug was administered via the rat tail vein in a volume of 0.6 mL per rat at a rate of 0.02 mL / s. Anesthetic effect was determined by loss of righting reflex (LORR) ≥ 30 s.

[0391] 1.2.2 Loss of righting reflex in rats 50 Dose comparison of the pharmacological effects of the compounds of the present invention

[0392] The ED of the invented compound was measured 50 Afterwards, 2ED was used to induce loss of righting reflex in rats. 50 The drug was administered via the tail vein of rats in a volume of 0.6 mL per rat at a rate of 0.02 mL / s. The onset of anesthetic effect was determined by the loss of righting reflex (LORR). After administration, the onset and recovery of the righting reflex, as well as adverse reaction symptoms and their onset and end points, were recorded and observed.

[0393] 2ED 50 Pharmacological characteristics of equivalent doses:

[0394] In the above test, in addition to recording the dose at which the righting reflex is lost, the time from the start of administration to the onset and recovery of the anesthetic effect, the duration of the righting reflex, and the duration of the sedative effect can also be recorded. At the dose of the compound of the present invention that causes the righting reflex to be lost, the effect of the compound on the respiration of the experimental animal can also be observed.

[0395] 2. Experimental Results

[0396] Table 1. Pharmacological data of the anesthetic effect of the compounds of the present invention after a single intravenous injection

[0397] Table 2. Minimum analgesic effective dose of the compounds of the present invention for a single intravenous injection

[0398] Table 3. ED of some compounds of the present invention in rats with loss of righting reflex 50 and 2ED 50 Pharmacological characteristics of dosage

[0399] 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.

[0400] Experimental results show that the compound of the present invention has highly effective anesthetic, sedative and hypnotic effects and can control status epilepticus.

Claims

1. A compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, a prodrug thereof, a metabolite thereof, or a deuterated derivative thereof, characterized in that: The structure of the compound is shown in Formula II: Ring A is selected from substituted or unsubstituted 5-6 membered nitrogen heteroaryl groups, wherein the ring heteroatoms of the 5-6 membered nitrogen heteroaryl groups are all N; the substituents are each independently selected from hydroxyl, halogen, cyano, -O, (CR6R7) m R8 The following groups which are unsubstituted or substituted by one or more R9: amino, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-8 Alkoxy, C 1-8 Alkylthio, 3-8 membered saturated cycloalkyl, 3-8 membered saturated heterocyclic group, aryl, heteroaryl; m is selected from 0, 1, 2, 3, 4, 5; R6, R7 are each independently selected from hydrogen, C 1-8 alkyl; R8 is selected from CONR 10 R 11 NR 10 R 11 、COOR 12 、COR 12 , OR 12 , substituted aryl, wherein the substituents are independently selected from halogen, hydroxyl, nitro, cyano, C 1-8 Alkyl, C 1-8 Alkoxy; R 10 、R 11 Each independently selected from hydrogen, C 1-8 Alkyl, C 1-8 Alkoxy, 3-8 membered saturated cycloalkyl, R 12 Selected from C 1-8 Alkyl, 3-8 membered saturated cycloalkyl, 3-8 membered saturated heterocyclic group, 5-6 membered heteroaryl, n is selected from 0, 1, 2, 3, 4, 5; R 13 Selected from hydroxyl, C 1-8 alkoxy; The C ring is selected from aryl, 3-8 membered saturated cycloalkyl, aryl and 3-6 membered saturated cycloalkyl; e is selected from 0, 1, 2, 3, 4, 5; R x1 Each independently selected from hydrogen, hydroxy, halogen, halogenated or unhalogenated C 1-8 Alkyl, halogenated or unhalogenated C 1-8 Alkoxy, L2R 2a , L2 is selected from none, C 1-6 Alkylene, R 2a is selected from phenyl, 3-8 membered saturated cycloalkyl, 3-8 membered saturated heterocyclic group; R x2 Selected from hydrogen, C 1-8 Alkyl, 3-8 membered saturated cycloalkyl, =CR xa R xb ; R xa Selected from hydrogen, C 1-8 Alkyl, R xb Selected from hydrogen, C 1-8 alkyl; R x12 Selected from hydrogen, C 1-8 alkyl; f is selected from 0, 1, 2, 3, 4, 5; R x6 Each independently selected from hydrogen, halogen, halogenated or unhalogenated C 1-8 alkyl; R x5 Selected from C 1-8 alkyl; R x7 is selected from hydrogen, halogen, halogenated or unhalogenated C 1-8 alkyl; R x8 is selected from hydrogen, halogen, halogenated or unhalogenated C 1-8 Alkyl, CONR x9 R x10 ; R x9 Selected from hydrogen, C 1-8 Alkyl, C 1-8 Alkoxy, R x10 Selected from hydrogen, C 1-8 Alkyl, C 1-8 alkoxy; The R9 are independently selected from halogen, hydroxyl, amino, thiol, C 1-8 Alkyl, C 1-8 Alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, OCOR 9a 、SO2R 9a , OR 9c , 3-8 membered saturated cycloalkyl, one or more R 9b Substituted 3-8 membered saturated cycloalkyl, 3-8 membered saturated heterocyclic group, one or more R 9b Substituted 3-8 membered saturated heterocyclic group, aryl group, one or more R 9b Substituted aryl, 5-6 membered heteroaryl, one or more R 9b Substituted 5-6 membered heteroaryl; R 9a Selected from C 1-8 Alkyl; R 9b Each independently selected from halogen, C 1-8 Alkyl; R 9c Selected from 3-8 membered saturated cycloalkyl, 3-8 membered saturated heterocyclic group; L is selected from None, CR a R b 、C(=CR c R d ),NR e , CO, CS, SO, S, O; R a 、R b Each independently selected from hydrogen, halogen, halogenated or unhalogenated C 1-8 Alkyl, halogenated or unhalogenated C 1-8 Alkoxy, OH, OR s , or R a 、R b Connected to form a 3-8 membered saturated cycloalkyl or a 3-8 membered saturated heterocyclic group; R s Selected from 3-8 membered saturated cycloalkyl, 3-8 membered saturated heterocyclic group, benzyl; R c 、R d Each independently selected from hydrogen and halogen; R e Selected from hydrogen, C 1-8 alkyl; Ring B is X1 is N or CR1, X2 is N or CR2, X3 is N or CR3, X4 is N or CR4, and X5 is N or CR5, and at least three of X1, X2, X3, X4, and X5 are not N at the same time; R1, R2, R3, R4, R5, R 15 Each independently selected from hydrogen, hydroxy, halogen, halogenated or unhalogenated C 1-8 Alkyl, halogenated or unhalogenated C 1-8 Alkoxy, L1R 1a , L1 is selected from none, C 1-6 Alkylene, R 1a Selected from aryl, 3-8 membered saturated cycloalkyl, 3-8 membered saturated heterocyclic group, or two adjacent groups among R1, R2, R3, R4, R5 are connected to form an unsubstituted or substituted group. 14 Substituted benzene ring, the R 14 Each independently selected from halogen, C 1-8 Alkyl, C 1-8 alkoxy; Alternatively, the substituent on ring A is connected to R5 to form a ring.

2. The compound according to claim 1, its stereoisomer, its pharmaceutically acceptable salt, its solvate, its prodrug, its metabolite or its deuterated derivative, characterized in that: The A ring is selected from the following structures: C ring is selected from aryl, 3-6 membered saturated cycloalkyl, aryl and 3-6 membered saturated cycloalkyl, 3-5 membered unsaturated cycloalkyl, preferably benzene ring, 3-4 membered saturated cycloalkyl, e is selected from 0, 1, 2, 3; R x1 Each independently selected from hydrogen, hydroxy, halogen, halogenated or unhalogenated C 1-4 Alkyl, halogenated or unhalogenated C 1-4 Alkoxy, L2R 2a , L2 is selected from none, C 1-2 Alkylene, R 2a is selected from phenyl, 3-4 membered saturated cycloalkyl, 3-4 membered saturated heterocyclic group; R x2 Selected from hydrogen, C 1-3 Alkyl, 3-4 membered saturated cycloalkyl, =CR xa R xb ; R xa Selected from hydrogen, C 1-4 Alkyl, R xb Selected from hydrogen, C 1-4 alkyl; R x12 Selected from hydrogen, C 1-3 alkyl; R x3 is selected from hydrogen, halogen, C which is unsubstituted or substituted by one or more halogens 1-3 alkyl, R x4 is selected from hydrogen, halogen, C which is unsubstituted or substituted by one or more halogens 1-3 alkyl, R x11 is selected from hydrogen, halogen, C which is unsubstituted or substituted by one or more halogens 1-3 alkyl, f is selected from 0, 1, 2, 3; R x6 Each independently selected from hydrogen, halogen, halogenated or unhalogenated C 1-4 alkyl; R x5 Selected from C 1-3 alkyl; R x7 is selected from hydrogen, halogen, halogenated or unhalogenated C 1-4 alkyl; R x8 is selected from hydrogen, halogen, halogenated or unhalogenated C 1-4 Alkyl, CONR x9 R x10 ; R x9 Selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, R x10 Selected from hydrogen, C 1-4 Alkyl, C 1-4 alkoxy; The heterocyclic group contains at least one heteroatom selected from N, O or S.

3. The compound according to claim 1, 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 II-1 or Formula II-2: Where Q is selected from none, CR x2 R x12 、CO、CH=CH、 C ring is selected from aryl, 3-6 membered saturated cycloalkyl, aryl and 3-6 membered saturated cycloalkyl, 3-5 membered unsaturated cycloalkyl, preferably benzene ring, 3-4 membered saturated cycloalkyl, e is selected from 0, 1, 2, 3; R x1 Each independently selected from hydrogen, hydroxy, halogen, halogenated or unhalogenated C 1-4 Alkyl, halogenated or unhalogenated C 1-4 Alkoxy, L2R 2a , L2 is selected from none, C 1-2 Alkylene, R 2a is selected from phenyl, 3-4 membered saturated cycloalkyl, 3-4 membered saturated heterocyclic group; R x2 Selected from hydrogen, C 1-3 Alkyl, 3-4 membered saturated cycloalkyl, =CR xa R xb ; R xa Selected from hydrogen, C 1-4 Alkyl, R xb Selected from hydrogen, C 1-4 alkyl; R x12 Selected from hydrogen, C 1-3 alkyl; R x3 is selected from hydrogen, halogen, C which is unsubstituted or substituted by one or more halogens 1-3 alkyl, R x4 is selected from hydrogen, halogen, C which is unsubstituted or substituted by one or more halogens 1-3 alkyl, f is selected from 0, 1, 2, 3; R x6 Each independently selected from hydrogen, halogen, halogenated or unhalogenated C 1-4 alkyl; R x5 Selected from C 1-3 alkyl; R x7 is selected from hydrogen, halogen, halogenated or unhalogenated C 1-4 alkyl; R x8 is selected from hydrogen, halogen, halogenated or unhalogenated C 1-4 Alkyl, CONR x9 R x10 ; R x9 Selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, R x10 Selected from hydrogen, C 1-4 Alkyl, C 1-4 alkoxy; The heterocyclic group contains at least one heteroatom selected from N, O or S; L, X1, X2, X3, X4, X5 are as described in claim 1.

4. The compound according to any one of claims 1 to 3, its stereoisomer, its pharmaceutically acceptable salt, its solvate, its prodrug, its metabolite or its deuterated derivative, characterized in that: The L is selected from none, CR a R b 、C(=CR c R d ),NR e , CO, CS, SO, S, O; R a 、R b Each independently selected from hydrogen, halogen, halogenated or unhalogenated C 1-6 Alkyl, halogenated or unhalogenated C 1-6 Alkoxy, OH, OR s , or R a 、R b Connected to form a 3-6 membered saturated cycloalkyl or a 3-6 membered saturated heterocyclic group; R s Selected from 3-6 membered saturated cycloalkyl, 3-6 membered saturated heterocyclic group, benzyl; R c 、R d Each independently selected from hydrogen and halogen; R e Selected from hydrogen, C 1-6 alkyl.

5. The compound according to claim 4, its stereoisomer, its pharmaceutically acceptable salt, its solvate, its prodrug, its metabolite or its deuterated derivative, characterized in that: The L is selected from none, CR a R b 、C(=CR c R d ),NR e , CO, CS, SO, S, O; R a 、R b Each independently selected from hydrogen, halogen, halogenated or unhalogenated C 1-3 Alkyl, halogenated or unhalogenated C 1-3 Alkoxy, OH, OR s , or R a 、R b Connected to form a 3-4 membered saturated cycloalkyl or a 3-4 membered saturated heterocyclic group; R s Selected from 3-4 membered saturated cycloalkyl, 3-4 membered saturated heterocyclic group, benzyl; R c 、R d Each independently selected from hydrogen and halogen; R e Selected from hydrogen, C 1-3 alkyl.

6. The compound according to any one of claims 1 to 5, its stereoisomer, its pharmaceutically acceptable salt, its solvate, its prodrug, its metabolite or its deuterated derivative, characterized in that: The B ring is R1, R2, R3, R4, and R5 are each independently selected from hydrogen, hydroxy, halogen, halogenated or unhalogenated C 1-6 Alkyl, halogenated or unhalogenated C 1-6 Alkoxy, L1R 1a , L1 is selected from none, C 1-4 Alkylene, R 1a Selected from aryl, 3-6 membered saturated cycloalkyl, 3-6 membered saturated heterocyclic group.

7. The compound according to claim 1, 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 according to any one of claims 1 to 7, its stereoisomer, its pharmaceutically acceptable salt, its solvate, its prodrug, its metabolite or its deuterated derivative, characterized in that: The pharmaceutically acceptable salts are citrate, hydrofluoride, phosphate, propionate, succinate, tartrate, acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate, carbonate, bisulfate, sulfate, borate, camphorsulfonate, citrate, cyclamates, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hydrochloride, hydrobromide, hydroiodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthoate, naphthoate, nicotinate, nitrate, orotate, oxalate, palmitate, dihydroxynaphthoate, phosphate, hydrogen phosphate, dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, toluenesulfonate, trifluoroacetate, xinafoate, methanesulfonate, or p-toluenesulfonate.

9. A pharmaceutical composition, characterized in that The pharmaceutical composition is a preparation prepared with the compound according to any one of claims 1 to 7, its stereoisomers, pharmaceutically acceptable salts, solvates, prodrugs, metabolites or deuterated derivatives thereof as active ingredients, and pharmaceutically acceptable excipients.

10. Use of the compound according to any one of claims 1 to 7, its stereoisomers, pharmaceutically acceptable salts, solvates, prodrugs, metabolites or deuterated derivatives thereof in the preparation of a medicament having analgesic and / or anesthetic, sedative, hypnotic effects and / or capable of controlling status epilepticus.

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