Heterocyclic compound and pharmaceutical use thereof

Abstract

The present invention relates to the technical field of pharmaceutical chemistry, and provides a heterocyclic compound and a pharmaceutical use thereof. The structure of the heterocyclic compound is as shown in formula II. The compound of the present invention has high-efficiency sedative, hypnotic and / or anesthetic effects, can control status epilepticus, and also has an analgesic effect, providing a new choice for clinical preparation of a drug having the analgesic effect, a drug having the anesthetic, sedative, and hypnotic effects and / or capable of controlling status epilepticus, and a drug having both the anesthetic, sedative, and hypnotic effects and / or capable of controlling status epilepticus and also having the analgesic effect.

Description

A heterocyclic compound and its pharmaceutical use Technical Field

[0001] The present invention belongs to the technical field of medicinal chemistry, and in particular relates to a heterocyclic compound and its pharmaceutical use. 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 below:

[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, (CR6R7) m R8, =O, 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;

[0007] m is selected from 0, 1, 2, 3, 4, 5;

[0008] R6, R7 are each independently selected from hydrogen, C 1-8 alkyl;

[0009] 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, 3-8 membered saturated cycloalkyl, R 12 Selected from C 1-8 Alkyl, 3-8 membered saturated cycloalkyl, 3-8 membered saturated heterocyclic group, heteroaryl, n is selected from 0, 1, 2, 3, 4, 5; R 13 Selected from hydroxyl, C 1-8 alkoxy;

[0010] 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 9bSubstituted 3-8 membered saturated heterocyclic group, aryl group, one or more R 9b Substituted aryl, heteroaryl, one or more R 9b Substituted 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;

[0011] L is selected from None, CR a R b 、C(=CR c R d ),NR e , CO, CS, SO, S, O;

[0012] 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;

[0013] R c 、R d Each independently selected from hydrogen and halogen;

[0014] R e Selected from hydrogen, C 1-8 alkyl;

[0015] Ring B is selected from Unsubstituted or replaced by one or more R 15 Substituted rings: 3-5 membered unsaturated carbocyclic ring, 3-5 membered saturated carbocyclic ring, bridged ring;

[0016] 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;

[0017] 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;

[0018] The compound is not

[0019] Furthermore, the A ring is a substituted or unsubstituted 5-membered nitrogen heteroaryl or 6-membered nitrogen heteroaryl, wherein the ring heteroatoms of the 5-membered nitrogen heteroaryl and 6-membered nitrogen heteroaryl are all N; the substituents are each independently selected from hydroxyl, halogen, cyano, (CR6R7) m R8, =O, unsubstituted or substituted by one or more R9: amino, C 1-6 Alkyl, C 1-6 Alkylthio, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, 3-8 membered saturated cycloalkyl, 3-8 membered saturated heterocyclic group, aryl, heteroaryl;

[0020] m is selected from 0, 1, 2, 3;

[0021] R6, R7 are each independently selected from hydrogen, C 1-6 alkyl;

[0022] 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 1-6 Alkyl, 3-6 membered saturated cycloalkyl, R 12 Selected from C 1-6 Alkyl, 3-6 membered saturated cycloalkyl, 3-6 membered saturated heterocyclic group, 5-6 membered heteroaryl, n is selected from 0, 1, 2, 3; R 13 Selected from hydroxyl, C 1-6alkoxy;

[0023] The R9 are independently selected from halogen, hydroxyl, amino, thiol, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, OCOR 9a 、SO2R 9a , OR 9c , 3-6 membered saturated cycloalkyl, one or more R 9b Substituted 3-6 membered saturated cycloalkyl, 3-6 membered saturated heterocyclic group, one or more R 9b Substituted 3-6 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 1-6 Alkyl; R 9b Each independently selected from halogen, C 1-6 Alkyl; R 9c Selected from 3-6 membered saturated cycloalkyl, 3-6 membered saturated heterocyclic group;

[0024] Preferably, the A ring is is a substituted or unsubstituted 5-membered nitrogen heteroaryl group, is a substituted or unsubstituted 6-membered nitrogen heteroaryl group.

[0025] Furthermore, the A ring is a substituted or unsubstituted group: The substituents are independently selected from hydroxyl, halogen, cyano, (CR6R7) m R8, unsubstituted or substituted by one or more R9: amino, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Alkylthio, 3-4 membered saturated cycloalkyl, 3-4 membered saturated heterocyclic group, phenyl, 5-6 membered heteroaryl;

[0026] m is selected from 0, 1, 2, 3;

[0027] R6, R7 are each independently selected from hydrogen, C 1-3 alkyl;

[0028] R8 is selected from CONR 10 R 11 NR 10 R 11、COOR 12 、COR 12 , OR 12 , substituted phenyl, wherein the substituents are independently selected from F, Cl, Br, I, hydroxyl, nitro, cyano, C 1-8 Alkyl, C 1-8 Alkoxy; R 10 、R 11 Each independently selected from hydrogen, C 1-5 Alkyl, 3-4 membered saturated cycloalkyl, R 12 Selected from C 1-5 Alkyl, 3-4 membered saturated cycloalkyl, 3-4 membered saturated heterocyclic group, 5-6 membered heteroaryl, n is selected from 0, 1, 2, 3; R 13 Selected from hydroxyl, C 1-3 alkoxy;

[0029] R 16 Selected from C 1-3 Alkyl, C 1-3 Alkoxy, unsubstituted or substituted by one or more R 18 Substituted groups: 3-4 membered saturated cycloalkyl, 3-4 membered saturated heterocyclic group, phenyl, 5-6 membered heteroaryl; R 18 Each independently selected from halogen, C 1-3 Alkyl; R 17 Selected from hydrogen, C 1-3 Alkyl, hydroxyl;

[0030] The R9 are independently selected from halogen, hydroxyl, amino, thiol, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 Alkenyl, C 2-3 Alkynyl, OCOR 9a 、SO2R 9a , OR 9c , 3-4 membered saturated cycloalkyl, one or more R 9b Substituted 3-4 membered saturated cycloalkyl, 3-4 membered saturated heterocyclic group, one or more R 9b Substituted 3-4 membered saturated heterocyclic group, phenyl group, one or more R 9b Substituted phenyl, 5-6 membered heteroaryl, one or more R 9b Substituted 5-6 membered heteroaryl; R 9a Selected from C 1-3 Alkyl; R 9b Each independently selected from halogen, C 1-3 Alkyl; R 9c is selected from 3-4 membered saturated cycloalkyl, 3-4 membered saturated heterocyclic group;

[0031] The heterocyclic group contains at least one heteroatom selected from N, O or S.

[0032] Furthermore, the A ring is selected from the following substituted or unsubstituted groups:

[0033] Furthermore, the A ring is selected from the following substituted or unsubstituted groups:

[0034] Further, the L is selected from none, CR a R b 、C(=CR c R d ),NR e , CO, CS, SO, S, O;

[0035] 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;

[0036] R c 、R d Each independently selected from hydrogen and halogen;

[0037] R e Selected from hydrogen, C 1-6 alkyl.

[0038] Further, the L is selected from none, CR a R b 、C(=CR c R d ),NR e , CO, CS, SO, S, O;

[0039] 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; Rs Selected from 3-4 membered saturated cycloalkyl, 3-4 membered saturated heterocyclic group, benzyl;

[0040] R c 、R d Each independently selected from hydrogen and halogen;

[0041] R e Selected from hydrogen, C 1-3 alkyl.

[0042] The B ring is Unsubstituted or replaced by one or more R 15 Substituted rings: 3-5 membered unsaturated carbon ring, 3-5 membered saturated carbon ring, 7-8 membered bridged ring, wherein the 3-5 membered unsaturated carbon ring is selected from 7-8 member bridge ring includes R 15 is selected from hydroxy, halogen, halogenated or unhalogenated C 1-3 Alkyl, halogenated or unhalogenated C 1-3 alkoxy;

[0043] 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.

[0044] Furthermore, the compound is selected from:

[0045] 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.

[0046] 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.

[0047] 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.

[0048] “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.

[0049] 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.

[0050] 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.

[0051] 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.

[0052] 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.

[0053] 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.

[0054] "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.

[0055] 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.

[0056] The minimum and maximum carbon atom content in a hydrocarbon group is indicated by a prefix, for example, the prefix C a～b Alkyl 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.

[0057] 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, 3-8 membered saturated heterocyclyl refers to a saturated heterocyclyl group containing 3, 4, 5, 6, 7 or 8 ring atoms, and so on.

[0058] 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.

[0059] "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.

[0060] "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.

[0061] In some preferred technical embodiments, the heteroaryl group is a 5-6 membered heteroaryl group.

[0062] 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".

[0063] Halogen is fluorine, chlorine, bromine or iodine.

[0064] Compared with the prior art, the compounds of the present invention have achieved the following beneficial effects:

[0065] 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;

[0066] 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.

[0067] 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.

[0068] 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.

[0069] 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

[0070] 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.

[0071] 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).

[0072] 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.

[0073] 1) Medicinal materials and reagents

[0074] 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.

[0075] 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.

[0076] 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.

[0077] 2) Main instruments

[0078] JA2003N electronic balance (Shanghai Youke Instrument Co., Ltd.);

[0079] DF-101S heat-collecting constant temperature heating magnetic stirrer (Zhengzhou Saitelis Biotechnology Co., Ltd.);

[0080] 98-2 magnetic stirrer (Shanghai Silu Instrument Co., Ltd.);

[0081] ZF-2 three-purpose UV instrument (Shanghai Anting Electronic Instrument Factory);

[0082] RE-2000B rotary evaporator (Zhengzhou Ketai Experimental Equipment Co., Ltd.);

[0083] DLSK-5 / 20 low-temperature coolant circulation pump (Zhengzhou Ketai Experimental Equipment Co., Ltd.);

[0084] W201D constant temperature water bath (Shanghai Shenshun Biotechnology Co., Ltd.);

[0085] SHB-III circulating water vacuum pump (Zhengzhou Huicheng Science and Technology Industry and Trade Co., Ltd.);

[0086] SHB-B95 mobile water pump (Zhengzhou Huicheng Science and Technology Industry and Trade Co., Ltd.);

[0087] Ultraviolet high-pressure mercury lamp (Beijing Tianmai Henghui Light Source Electrical Co., Ltd.).

[0088] DGJ-10C vacuum freeze dryer (Shanghai Boden Biotechnology Co., Ltd.);

[0089] KQ5200 ultrasonic cleaner (Kunshan Ultrasonic Instrument Co., Ltd.);

[0090] 2XZ-2 rotary vane vacuum pump (Linhai Tanshi Vacuum Equipment Co., Ltd.);

[0091] Biotage Isolera One (Biotage Sweden AB)

[0092] Example 1 Preparation of compounds DEX-2 to DEX-4 of the present invention

[0093] 1. Preparation of Compound 3-1

[0094] At room temperature, 5-amino-1H-imidazole-4-carboxamide hydrochloride (70.0 g, 430.6 mmol), EtOH (300 mL), and methanesulfonic acid (140 mL) were added sequentially to an autoclave (1 L) and reacted at 120°C for 20 hours. After completion of the reaction as monitored by TLC, the reaction solution was concentrated under reduced pressure, the pH was adjusted to ≈ 8 with saturated aqueous NaHCO₃, and extracted with EtOAc (8 × 150 mL). The combined organic phases were washed with saturated brine (2 × 100 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain compound 3-1 (41.0 g, yield 61.4%) as a white solid. ESI [M+H] + =156.1

[0095] 2. Preparation of Compound 3-2

[0096] 3-1 (21.5 g, 138.6 mmol) was dissolved in HBF4 (200 mL, 40% in water) in an ice-salt bath at -10°C. A solution of NaNO2 (10.0 g, 145.5 mmol) in water (15 mL) was added and the mixture was allowed to react under irradiation with a mercury lamp (302 nm) for 8 hours. After completion of the reaction as monitored by TLC, the pH was adjusted to ≈ 7 with a 1N aqueous solution of NaOH in an ice-water bath. The mixture was extracted with EtOAc (3 × 100 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1). Fractions with Rf = 0.4-0.5 were collected to afford compound 3-2 (3.2 g, 14.6% yield) as a colorless oil. ESI [M+H] + =159.1

[0097] 3. Preparation of Compound 3-3

[0098] At room temperature, NaOH (1.2 g, 30.0 mmol) was added to a solution of 3-2 (2.4 g, 15.2 mmol) in EtOH / H2O (80 mL, v / v = 1 / 1) and stirred at 60°C for 6 hours. After completion of the reaction as monitored by TLC, the mixture was concentrated under reduced pressure, cooled in an ice-water bath, and the pH was adjusted to ≈ 5 with 1N HCl. The mixture was extracted with EtOAc (3 × 30 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford compound 3-3 (1.8 g, 91.0% yield) as a gray solid. ESI [M+H] + =131.0

[0099] 4. Preparation of Compound 3-4

[0100] Compound 3-3 (1.8 g, 13.8 mmol), N,O-dimethylhydroxylamine hydrochloride (2.0 g, 20.5 mmol), DIEA (2.7 g, 20.9 mmol), and HATU (7.9 g, 20.8 mmol) were dissolved in DMF (50 mL) at room temperature and stirred overnight. After completion of the reaction as monitored by TLC, H₂O (100 mL) was added to the reaction system and extracted with EtOAc (4 × 30 mL). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 to 1 / 3) 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 3-4 (1.3 g, 54.4% yield) as a white solid. ESI [M+H] + =174.1.

[0101] 5. Preparation of Compound 3-5

[0102] Compound 3-4 (1.3 g, 7.5 mmol) and triphenylmethane (3.1 g, 11.1 mmol) were dissolved in DMF (15 mL) at room temperature. The reaction system was cooled to 5°C in an ice-salt bath. Triethylamine (1.2 g, 11.9 mmol) was slowly added dropwise and stirred at room temperature for 1 hour. After completion of the reaction as monitored by TLC, H₂O (100 mL) was added to the reaction system and extracted with EtOAc (3 × 15 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 / 20 to 1 / 3) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 8). Fractions with Rf = 0.5 to 0.6 were collected to obtain compound 3-5 (2.6 g, 83.4% yield) as a white solid. ESI [M+H] + =416.3.

[0103] 6. Preparation of Compound 3-6

[0104] Compound 3-5 (2.6 g, 6.3 mmol) was dissolved in dry THF (15 mL) at room temperature. The reaction system was purged with nitrogen three times, protected by nitrogen, and cooled to 0°C in an ice-salt bath. MeMgBr (12.5 mL, 1 mol / L in THF, 12.5 mmol) was slowly added dropwise to the system using a syringe and stirred at room temperature for 3 hours. After the reaction was complete as monitored by TLC, the temperature was lowered to 0°C in an ice-water bath. Saturated aqueous ammonium chloride (100 mL) was slowly added to the reaction system. The reaction was extracted with EtOAc (3 × 20 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 / 50 to 1 / 10) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 8). Fractions with Rf = 0.5 to 0.6 were collected to obtain compound 3-6 (1.6 g, 68.6% yield) as a white solid. ESI[M+H] + =371.3.

[0105] 7. Preparation of Compound 3-7

[0106] At room temperature, magnesium turnings (207 mg, 8.5 mmol), iodine (10 mg), and dry THF (5 mL) were added to a 50 mL three-necked reaction flask. The reaction system was purged with nitrogen three times, under nitrogen protection. 2,3-Dimethylbromobenzene (300 mg, 1.6 mmol) was added to the reaction system, and the mixture was heated under reflux until the Grignard reaction initiated. A solution of 2,3-Dimethylbromobenzene (1.0 g, 5.4 mmol) in THF (5 mL) was then added dropwise at a rate of 1.0 mL / min, maintaining the system at reflux. After the additions were complete, the reaction system was refluxed for another 30 minutes, then cooled to room temperature and set aside.

[0107] 3-6 (1.6 g, 4.3 mmol) was dissolved in dry THF (10 mL) at room temperature. 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 was added dropwise to the system at a rate of 1.0 mL / min using a syringe and stirred at room temperature for 4 hours. After the reaction was complete as monitored by TLC, the temperature was lowered to 0°C in an ice-water bath. Saturated aqueous ammonium chloride (50 mL) was slowly added to the reaction system, and the mixture was extracted with EtOAc (3 × 10 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 50 to 1 / 10) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 8). Fractions with Rf = 0.5 to 0.6 were collected to obtain compound 3-7 (0.9 g, 43.9% yield) as a white solid. ESI [M+H] + =477.3.

[0108] 8. Preparation of target compound DEX-4

[0109] At room temperature, 3-7 (95 mg, 0.2 mmol) and TFA (0.5 mL) were dissolved in CH2Cl2 (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 (20 mL), extracted with CH2Cl2 (3 × 5 mL), 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 preparative TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5) and fractions with Rf = 0.5-0.6 were collected to obtain the target compound DEX-4 (30 mg, yield 69.4%). ESI [M+H] + =217.3

[0110] 1 H NMR(400MHz,d6-DMSO)δ12.19(s,1H),7.36(d,J=1.5Hz,1H),7.18–7.06(m,2H ),6.97(d,J=7.1Hz,1H),5.62(s,1H),4.91(s,1H),2.26(s,3H),2.02(s,3H).

[0111] 9. Preparation of target compound DEX-3

[0112] At room temperature, 3-7 (620 mg, 1.3 mmol), triethylsilane (0.5 mL), and TFA (1.5 mL) were dissolved in a sealed tube (10 mL) and stirred at 100°C for 2 hours. After completion of the reaction as monitored by TLC, the mixture was concentrated under reduced pressure, basified with saturated aqueous sodium bicarbonate (20 mL), extracted with EtOAc (3 × 5 mL), and 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 preparative TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5) and fractions with Rf = 0.5-0.6 were collected to obtain the target compound DEX-3 (167 mg, 58.9% yield). ESI [M+H] + =219.3

[0113] 1 H NMR (400MHz, d6-DMSO) δ11.92(s,1H),7.19(s,1H),7.06–6.95(m,3H),4.38(q,J=7.2Hz,1H),2.24(s,3H),2.21(s,3H),1.49(d,J=7.2Hz,3H).

[0114] DEX-3 was resolved to obtain the target compound DEX-2 (31 mg). ESI [M+H] +=219.3

[0115] Example 2 Preparation of compounds DEX-5 to DEX-9 of the present invention

[0116] 1. Preparation of target compound DEX-5

[0117] Intermediates 5-1 to 5-4 were prepared according to the literature method (Synthetic Communications, 1996, vol. 26, #8, 1585–1593).

[0118] DAST (177 mg, 1.1 mmol) was slowly added to a solution of 5-4 (459 mg, 1.0 mmol) in CH2Cl2 (5 mL) in an ice-water bath at 0°C, and the mixture was stirred at 0°C for 2 hours. After the reaction was complete as monitored by TLC, the reaction system was basified with saturated aqueous sodium bicarbonate solution (10 mL), extracted with CH2Cl2 (3 × 5 mL), and the combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was dissolved in CH2Cl2 (5 mL), TFA (0.5 mL) was added in an ice-water bath at -10°C, and stirred at room temperature for 1 hour. After the reaction was completed as monitored by TLC, the reaction system was basified with saturated aqueous sodium bicarbonate (10 mL), extracted with CH2Cl2 (3×5 mL), 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 preparative TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1) and the fractions with Rf = 0.5-0.6 were collected to obtain the target compound DEX-5 (16.2 mg, yield 7.4%). ESI [M+H] + =219.3

[0119] 2. Preparation of Compound 7-1

[0120] Imidazole (8.45 g, 124.1 mmol) and 2,2,2-trifluoro-1-methoxyethan-1-ol (8.84 g, 68.0 mmol) were stirred under reflux for 2 hours. After the reaction was complete as monitored by TLC, the reaction system 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 / 1 to 5 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 5 / 1). The fraction with Rf = 0.5 to 0.6 was collected to obtain compound 7-1 (10.0 g, yield 88.5%). ESI [M+H] + =167.2.

[0121] 3. Preparation of compound 7-2

[0122] Active MnO2 (55.1 g, 577 mmol, 91%) was added to a solution of 7-1 (9.58 g, 57.7 mmol) in CH2Cl2 (100 mL) at room temperature and stirred under reflux for 8 hours. After the reaction was complete as monitored by TLC, the mixture was filtered and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate) and monitored by TLC (ethyl acetate). The fraction with Rf = 0.3-0.4 was collected to obtain compound 7-2 (2.86 g, 30.2% yield) as a white solid. ESI [M+H] + =165.1.

[0123] 4. Preparation of Compound 7-3

[0124] At room temperature, compound 7-2 (2.8 g, 17.1 mmol) and triphenylmethane (5.8 g, 20.8 mmol) were dissolved in CH2Cl2 (30 mL). The reaction system was cooled to 5°C in an ice-salt bath, and triethylamine (2.7 g, 26.7 mmol) was slowly added dropwise. The mixture was stirred at room temperature overnight. After completion of the reaction as monitored by TLC, H2O (50 mL) was added to the reaction system, and the mixture was extracted with CH2Cl2 (3 × 10 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was dispersed with methyl tert-butyl ether, filtered, and the filter cake was washed with methyl tert-butyl ether to obtain compound 7-3 (6.8 g, yield 97.8%). ESI [M+H] + =407.4.

[0125] 5. Preparation of Compound 7-4

[0126] At room temperature, 7-3 (5.0 g, 12.3 mmol) was dissolved in dry THF (10 mL). The reaction system was replaced with nitrogen three times, protected by nitrogen, and cooled to 0°C in an ice-salt bath. A (24 mL, 1 mol / L, 24 mmol) was slowly added dropwise to the system and stirred at room temperature for 4 hours. After the reaction was complete as monitored by TLC, the reaction system was cooled to 0°C in an ice-water bath. Saturated aqueous ammonium chloride (100 mL) was slowly added to the reaction system and extracted with EtOAc (3 × 15 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 (dichloromethane / ethyl acetate (v / v) = 200 / 1 to 40 / 1) and monitored by TLC (dichloromethane / ethyl acetate (v / v) = 40 / 1). Fractions with Rf = 0.4 to 0.5 were collected to obtain compound 7-4 (2.6 g, yield 41.2%) as a white solid. ESI[M+H] + =513.6.

[0127] 6. Preparation of target compounds DEX-7 to DEX-8

[0128] At room temperature, 7-4 (153 mg, 0.3 mmol) and trifluoromethanesulfonic acid (1.5 g, 10.0 mmol) were dissolved in benzene (1 mL) and stirred at 60°C for 1 hour. After the reaction was complete as monitored by TLC, the reaction system was basified with saturated aqueous sodium bicarbonate (10 mL) and extracted with EtOAc (3 × 5 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 preparative TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1) and fractions with Rf = 0.3-0.4 and 0.5-0.6 were collected to obtain the target compounds DEX-7 and DEX-8 as gray solids.

[0129] Compound DEX-7: 35.3 mg, yield 46.6%, ESI [M+H] + =253.2

[0130] 1 H NMR (400MHz, d6-DMSO) δ12.61(s,1H),7.72(s,1H),7.22–7.10(m,2H),4.93–4.83(m,1H),2.29(s,3H),2.26(s,3H).

[0131] Compound DEX-8: 10.3 mg, yield 10.4%, ESI [M+H] + =331.3

[0132] 1 H NMR(400MHz,d6-DMSO)δ12.56(s,1H),7.87–7.75(m,2H),7.52–7.45(m,2H),7.43–7.36(m ,1H),7.34–7.28(m,2H),7.14–7.05(m,2H),5.26–5.14(m,1H),2.25(s,3H),2.11(s,3H).

[0133] 7. Preparation of target compounds DEX-6 and DEX-9

[0134] Phenyl chlorothioformate (177 mg, 1.1 mmol) was slowly added to a solution of 7-4 (1.0 g, 2.0 mmol) and pyridine (316.4 mg, 4.0 mmol) in CHCl (30 mL) in an ice-water bath at 0°C. The mixture was stirred at room temperature for 16 hours. After completion of the reaction as monitored by TLC, the reaction system was basified with saturated aqueous sodium bicarbonate (30 mL), extracted with CHCl (3 × 5 mL), and the combined organic phases were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was dissolved in benzene (5 mL), and AIBN (65.7 mg, 0.4 mmol) and tributyltin hydride (873.2 mg, 3.0 mmol) were added. The mixture was stirred at 50°C for 8 hours. After completion of the reaction as monitored by TLC, saturated brine (30 mL) was added, and the mixture was extracted with EtOAc (3 × 5 mL). The combined organic phases were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was dissolved in CH2Cl2 (10 mL), TFA (0.5 mL) was added, and the mixture was 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 (20 mL), and extracted with CH2Cl2 (3×5 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 preparative TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1) and fractions with Rf = 0.5-0.6 were collected to obtain the target compound DEX-9 (100 mg, three-step yield 19.7%). ESI [M+H] + = 255.3. The target compound DEX-6 was prepared according to the synthesis method in the literature (Synthetic Communications, 1996, vol. 26, #8, p. 1585–1593).

[0135] 1 H NMR (400MHz, d6-DMSO) δ12.10(s,1H),7.60(s,1H),7.52–7.39(m,1H),7.17–7.03(m,3H),5.30–5.19(m,1H),2.28(s,3H),2.27(s,3H).

[0136] Example 3 Preparation of compounds DEX-10 to DEX-11 of the present invention

[0137] 1. Preparation of Compound 10-1

[0138] At room temperature, 2-methyl-1H-imidazole-4-carbaldehyde (1.1 g, 10.0 mmol) and triphenylmethane (4.2 g, 15.1 mmol) were dissolved in DMF (20 mL). The reaction system was cooled to 5°C in an ice-water bath, and triethylamine (1.6 g, 15.8 mmol) was slowly added dropwise. The mixture was stirred at room temperature for 1 hour. After completion of the reaction as monitored by TLC, H₂O (50 mL) was added to the reaction system, and the mixture was extracted with EtOAc (3 × 10 mL). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was dispersed with methyl tert-butyl ether, filtered, and the filter cake was washed with methyl tert-butyl ether to obtain Compound 10-1 (3.1 g, yield 88.0%) as a white solid. ESI [M+H] + =353.5.

[0139] 2. Preparation of Compound 10-2

[0140] At room temperature, 10-1 (2.0 g, 5.7 mmol) was dissolved in dry THF (8 mL). The reaction system was replaced with nitrogen three times, protected by nitrogen, and cooled to 0°C in an ice-salt bath. A (12 mL, 1 mol / L, 12 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 cooled to 0°C in an ice-water bath. Saturated aqueous ammonium chloride (80 mL) was slowly added to the reaction system and extracted with EtOAc (3 × 15 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was used directly in the next reaction without purification. ESI [M+H] + =459.6.

[0141] 3. Preparation of Compound 10-3

[0142] The crude compound 10-2 obtained in the previous step was dissolved in CH2Cl2 (50 mL) at room temperature, and active MnO2 (5.5 g, 57.6 mmol, 91%) was added. The mixture was stirred at reflux for 5 hours. After the reaction was complete as monitored by TLC, the mixture was filtered and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 2). The fraction with Rf = 0.5 to 0.6 was collected to obtain compound 10-3 (1.6 g, two-step yield 61.5%). ESI [M+H] + =457.6

[0143] 4. Preparation of target compound DEX-10

[0144] Compound 10-3 (1.9 g, 4.2 mmol) was dissolved in dry THF (20 mL) at room temperature and cooled to 0°C in an ice-salt bath. MeMgBr (8.4 mL, 1 mol / L in THF, 8.4 mmol) was slowly added dropwise to the system using a syringe and stirred at room temperature for 3 hours. After the reaction was complete as monitored by TLC, the solution was cooled to 0°C in an ice-water bath and saturated aqueous ammonium chloride (20 mL) was slowly added to the reaction system. The reaction 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 and TFA (5 mL) were dissolved in CH2Cl2 (20 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 (20 mL), extracted with CH2Cl2 (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 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 / 1). Fractions with Rf = 0.5 to 0.6 were collected to give the target compound DEX-10 (563 mg, 63.1% yield over two steps) as a white solid. ESI [M+H] + =213.3

[0145] 1 H NMR (400MHz, d6-DMSO) δ11.73(s,1H),7.12(d,J=7.2Hz,1H),7.06(t,J=7.5Hz,1H),6.93(d,J=6. 8Hz,1H),6.17(s,1H),5.75(s,1H),4.71(d,J=2.2Hz,1H),2.26(s,3H),2.25(s,3H),2.03(s,3H).

[0146] 5. Target compound DEX-11

[0147] At room temperature, compound DEX-10 (230 mg, 1.1 mmol) and 10% wet palladium on carbon (23 mg) were dissolved in MeOH (10 mL). The system was replaced with hydrogen three times and stirred at room temperature under hydrogen for 5 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 (dichloromethane / methanol (v / v) = 150 / 1) and the fraction with Rf = 0.5-0.6 was collected to obtain the target compound DEX-11 (160 mg, yield 67.9%) as a white solid. ESI [M+H] + =215.1

[0148] 1H NMR(400MHz,d6-DMSO)δ11.37(s,1H),7.00–6.91(m,3H),6.50(s,1H),4.22(q ,J=7.0Hz,1H),2.23(s,3H),2.20(s,3H),2.17(s,3H),1.41(d,J=7.1Hz,3H).

[0149] Example 4 Preparation of compounds DEX-12 to DEX-13 of the present invention

[0150] Dexmedetomidine hydrochloride (100 mg, 0.42 mmol) was dissolved in DMF (2 mL) at room temperature and cooled to 0°C in an ice-salt bath. NaH (25.3 mg, 60% in mineral oil, 0.63 mmol) was added to the mixture, and the mixture was stirred at 0°C for 10 minutes. MeI (89.4 mg, 0.63 mmol) was slowly added to the mixture via syringe, and stirring was continued for 1 hour. 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 combined organic phases were 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 / 2), and fractions with Rf = 0.5-0.6 were collected to obtain the title compound.

[0151] Compound DEX-12: 28 mg, yield 31.1%, ESI [M+H] + =215.3.

[0152] 1 H NMR(400MHz,d6-DMSO)δ7.54(s,1H),6.99–6.93(m,3H),6.74(s,1H),4.24(q ,J=7.0Hz,1H),3.57(s,3H),2.23(s,3H),2.20(s,3H),1.43(d,J=7.1Hz,3H).

[0153] Compound DEX-13: 36 mg, yield 40.0%, ESI [M+H] + =215.3

[0154] 1H NMR(400MHz,d6-DMSO)δ7.49(s,1H),7.01–6.93(m,2H),6.83(s,1H),6.57(dd,J=7.7,0.9H z,1H),4.35(q,J=6.9Hz,1H),3.15(s,3H),2.28(s,3H),2.26(s,3H),1.42(d,J=7.0Hz,3H).

[0155] Example 5 Preparation of compounds DEX-14 to DEX-17 of the present invention

[0156] 1. Preparation of compound 15-1

[0157] At room temperature, 2-bromo-6-fluoro-3-methylbenzaldehyde (1.09 g, 5.0 mmol), methylboric acid (598.6 mg, 10.0 mmol), Pd(dppf)Cl2.CH2Cl2 (408.3 mg, 0.5 mmol) and K3PO4 (3.2 g, 15.0 mmol) were dissolved in dioxane (20 mL) solution. The reaction system was replaced with nitrogen three times under nitrogen protection and stirred at 110 ° C for 2 hours. After the reaction was complete as monitored by TLC, H2O (30 mL) was added to the reaction system, and the mixture was extracted with EtOAc (3×5 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 / 200 to 1 / 100) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10). The fractions with Rf = 0.5 to 0.6 were collected to obtain compound 15-1 (602.7 mg, yield 79.2%) as a colorless oil. ESI [M+H] + =153.2.

[0158] 2. Preparation of compound 15-3

[0159] At room temperature, 1-trityl-4-iodoimidazole (2.3 g, 5.3 mmol) was dissolved in CH2Cl2 (10 mL). The reaction system was purged with nitrogen three times, protected by nitrogen, and cooled to 0°C in an ice-salt bath. EtMgBr (6 mL, 1 mol / L Et2O, 6.0 mmol) was slowly added dropwise to the reaction system using a syringe and stirred at room temperature for 1 hour. The system was cooled to 0°C in an ice-salt bath and a solution of 15-1 (400 mg, 2.6 mmol) in CH2Cl2 (5 mL) was slowly added dropwise to the reaction system and stirred at room temperature for 1 hour. After the reaction was complete as monitored by TLC, the reaction system was cooled to 0°C in an ice-water bath. Saturated aqueous ammonium chloride (50 mL) was slowly added to the reaction system and extracted with CH2Cl2 (3 × 15 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product.

[0160] The crude product was dissolved in CH2Cl2 (100 mL), and active MnO2 (9.9 g, 104.0 mmol, 91%) was added. The mixture was stirred at reflux for 5 hours. After the reaction was complete as monitored by TLC, the mixture was filtered and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 2). The fraction with Rf = 0.5 to 0.6 was collected to obtain compound 15-3 (576 mg, two-step yield 48.1%). ESI [M+H] + =461.5

[0161] 3. Preparation of target compound DEX-15

[0162] Compound 15-3 (280 mg, 0.61 mmol) and TFA (1 mL) were dissolved in CH2Cl2 (10 mL) at room temperature and stirred at room temperature for 2 hours. After completion of the reaction as monitored by TLC, the mixture was concentrated under reduced pressure, basified with saturated aqueous sodium bicarbonate (20 mL), and extracted with CH2Cl2 (3 × 5 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 preparative TLC (ethyl acetate / petroleum ether (v / v) = 1 / 2) and fractions with Rf = 0.5-0.6 were collected to obtain the target compound DEX-15 (108.6 mg, 81.6% yield) as a white solid. ESI [M+H] + =219.1

[0163] 1 H NMR (400MHz, d6-DMSO) δ12.84(s,1H),7.85(s,1H),7.79(s,1H),7.39–7.18(m,1H),7.10–6.89(m,1H),2.23(s,3H),2.01(s,3H).

[0164] 4. Preparation of target compound DEX-16

[0165] Compound 15-3 (1.1 g, 2.4 mmol) was dissolved in dry THF (15 mL) at room temperature. The reaction system was cooled to 0°C using an ice-salt bath. MeMgBr (5.0 mL, 1 mol / L in THF, 5.0 mmol) was slowly added to the system via syringe and stirred at room temperature 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 EtOAc (3 × 5 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford crude product 15-4. The crude product and TFA (1 mL) were dissolved in C2Cl2 (10 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 (20 mL), extracted with CH2Cl2 (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 / 1) and fractions with Rf = 0.3-0.4 were collected to give the target compound DEX-16 (420 mg, two-step yield 80.9%) as a white solid. ESI [M+H] + =217.1

[0166] 1 H NMR(400MHz,d6-DMSO)δ12.08(s,1H),7.64(s,1H),7.20–7.12(m,1H),6.94(t, J=8.8Hz,1H),6.44(s,1H),6.01(s,1H),4.84(s,1H),2.23(s,3H),2.04(s,3H).

[0167] 5. Preparation of target compound DEX-17

[0168] At room temperature, compound DEX-16 (200 mg, 0.92 mmol) and 10% wet palladium on carbon (20 mg) were dissolved in MeOH (10 mL). The system was replaced with hydrogen three times and stirred at room temperature under hydrogen overnight. After the reaction was complete as monitored by TLC, the mixture was filtered and the filter cake was washed with methanol (3 × 10 mL). The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative TLC (dichloromethane / methanol (v / v) = 20 / 1) and the fraction with Rf = 0.5-0.6 was collected to obtain the target compound DEX-17 (130.4 mg, yield 64.9%) as a white solid. ESI [M+H] + =219.1

[0169] 1 H NMR (400MHz, d6-DMSO) δ11.80 (s, 1H), 7.46 (d, J = 0.9Hz, 1H), 7.02 (dd, J = 8.2, 5.8Hz, 1H), 6.81 (dd, J = 11. 2,8.4Hz,1H),6.70(s,1H),4.43(q,J=7.2Hz,1H),2.19(s,3H),2.15(s,3H),1.56(dd,J=7.2,1.0Hz,3H).

[0170] The preparation method of the target compound DEX-14 is similar to that of the target compound DEX-17, and is prepared using 3,4-dimethylpyridine aldehyde as the starting material.

[0171] Compound DEX-14: 71.3 mg, white solid, ESI [M+H] + =202.1.

[0172] Example 6 Preparation of the compound DEX-1 of the present invention

[0173] The preparation method of intermediate compound 1-6 is similar to that of target compound DEX-11. 1-6 is resolved to obtain target compound DEX-1 (105 mg). ESI[M+H] + =219.3

[0174] Example 7 Preparation of compounds DEX-18 to DEX-21 of the present invention

[0175] The compound 4-(1-(2,3-dimethylphenyl)vinyl)-1-trityl-1H-imidazole was prepared according to the synthesis method in the literature (Synthetic Communications, 1996, vol. 26, #8, p. 1585–1593).

[0176] Target compound DEX-18: 7.2 mg, two-step yield 5.9%, ESI [M+H] + =202.3

[0177] Target compound DEX-19: 13.1 mg, two-step yield 12.0%, ESI [M+H] + =215.3

[0178] Target compound DEX-20: 35.4 mg, two-step yield 26.7%, ESI [M+H] + =213.3

[0179] 1H NMR (400MHz, d6-DMSO) δ11.61 (s, 1H), 7.42 (d, J = 0.9Hz, 1H), 7.20–7.13 (m, 1H), 7.09–7. 01(m,2H),6.15(s,1H),2.22(s,3H),2.17(s,3H),1.39–1.30(m,2H),1.04–0.96(m,2H).

[0180] Target compound DEX-21: 8.9 mg, two-step yield 8.3%, ESI [M+H] + =215.4

[0181] Example 8 Preparation of compounds DEX-22 to DEX-27 of the present invention

[0182] 1. Preparation of Compound 22-1

[0183] At room temperature, (Boc)2O (13.8 g, 63.2 mmol) was slowly added dropwise to a solution of 1H-pyrazole-5-carboxaldehyde (5.0 g, 52.6 mmol) and DMAP (7.8 g, 63.9 mmol) in CH2Cl2 (100 mL). The mixture was stirred at room temperature for 1 hour. After the reaction was complete as monitored by TLC, the reaction solution 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 / 10 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 22-1 (7.2 g, 69.8% yield) as a white solid. ESI [M+H] + =197.3.

[0184] 2. Preparation of Compound 22-2

[0185] At room temperature, 22-1 (7.2 g, 36.7 mmol) was dissolved in dry THF (30 mL). The reaction system was purged with nitrogen three times, protected by nitrogen, and cooled to 0°C in an ice-salt bath. A (80 mL, 1 mol / L in THF, 80 mmol) was slowly added dropwise to the system and stirred at room temperature for 4 hours. After the reaction was complete as monitored by TLC, the reaction system was cooled to 0°C in an ice-water bath. Saturated aqueous ammonium chloride (100 mL) was slowly added to the reaction system and extracted with EtOAc (3 × 50 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was used directly in the next reaction without purification. ESI [M+H] + =303.4.

[0186] 3. Preparation of target compound DEX-22

[0187] The crude compound 22-2 obtained in the previous step was dissolved in CH2Cl2 (100 mL) at room temperature, and activated MnO2 (140.2 g, 1.47 mol, 91%) was added. The mixture was stirred at reflux for 5 hours. After the reaction was complete as monitored by TLC, the mixture was filtered and the filtrate was concentrated under reduced pressure to obtain the crude product. Analysis and identification confirmed that the Boc protecting group had been removed. 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 / 1). Fractions with Rf = 0.5 to 0.6 were collected to obtain the target compound DEX-22 (1.6 g, 21.8% yield for three steps) as a white solid. ESI [M+H] + =201.3

[0188] 1 H NMR (400MHz, d6-DMSO) δ13.48(s,1H),7.88(s,1H),7.30(d,J=6.8Hz,1H),7.26–7.12(m,2H),6.80(s,1H),2.29(s,3H),2.11(s,3H).

[0189] 4. Preparation of Compound 22-3

[0190] Compound DEX-22 (838 mg, 4.2 mmol) was dissolved in dry THF (10 mL) at room temperature. The reaction system was cooled to 0°C using an ice-salt bath. MeMgBr (8.4 mL, 1 mol / L in THF, 8.4 mmol) was slowly added dropwise to the system using a syringe and stirred at room temperature for 3 hours. After the reaction was complete 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 the mixture was extracted with EtOAc (3 × 15 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was used directly in the next reaction without purification.

[0191] 5. Preparation of target compound DEX-23

[0192] The crude product 22-3 obtained in the previous step and TFA (5 mL) were dissolved in CH2Cl2 (20 mL) at room temperature and stirred at room temperature for 2 hours. After completion of the reaction as monitored by TLC, the mixture was concentrated under reduced pressure, basified with saturated aqueous sodium bicarbonate (20 mL), and extracted with CH2Cl2 (3×5 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 / 2). Fractions with Rf = 0.5 to 0.6 were collected to obtain the target compound DEX-23 (655 mg, 78.7% yield over two steps) as a light yellow oil. ESI [M+H] + =199.3

[0193] 1 H NMR(400MHz,d6-DMSO)δ12.70(s,1H),7.59(s,1H),7.16–7.05(m,2H),6.96(d, J=7.0Hz,1H),6.13(s,1H),5.89(s,1H),5.02(s,1H),2.24(s,3H),1.97(s,3H).

[0194] 6. Target compound DEX-24

[0195] At room temperature, compound DEX-23 (400 mg, 2.0 mmol) and 10% wet palladium on carbon (40 mg) were dissolved in MeOH (10 mL). The system was replaced with hydrogen three times and stirred at room temperature under hydrogen overnight. After the reaction was complete as monitored by TLC, the mixture was filtered and the filter cake was washed with methanol (3 × 10 mL). The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative TLC (dichloromethane / methanol (v / v) = 200 / 1) and the fraction with Rf = 0.5-0.6 was collected to obtain the target compound DEX-24 (210.1 mg, 52.4% yield) as a white solid. ESI [M+H] + =201.3

[0196] 1 H NMR(400MHz,d6-DMSO)δ12.44(s,1H),7.45(s,1H),7.05–6.89(m,3H),5.97(d,J=1 .8Hz,1H),4.42(q,J=7.0Hz,1H),2.23(s,3H),2.20(s,3H),1.49(d,J=7.2Hz,3H).

[0197] 8. Target compounds DEX-25~DEX-27

[0198] The preparation of target compounds DEX-25 to DEX-27 was similar to that of target compounds DEX-22 to DEX-24, using 1H-pyrazole-4-carboxaldehyde as the starting material.

[0199] Compound DEX-25: 212.6 mg, ESI [M+H] + =201.2.

[0200] 1 H NMR (400MHz, d6-DMSO) δ13.51(s,1H),8.12(s,1H),7.81(s,1H),7.33–7.27(m,1H),7.22–7.14(m,2H),2.29(s,3H),2.13(s,3H).

[0201] Compound DEX-26: 250.7 mg, ESI [M+H] + =199.2.

[0202] 1 H NMR(400MHz,d6-DMSO)δ12.78(s,1H),7.41(s,2H),7.13(d,J=6.7Hz,1H),7.08(t,J=7.4Hz,1H) ,6.95(d,J=7.3Hz,1H),5.65(d,J=1.7Hz,1H),4.79(d,J=1.8Hz,1H),2.25(s,3H),2.02(s,3H).

[0203] Compound DEX-27: 403 mg, ESI [M+H] + =201.3.

[0204] 1 H NMR (400MHz, d6-DMSO) δ12.53(s,1H),7.33(s,2H),7.04–6.92(m,3H),4.29(q,J=7.1Hz,1H),2.23(s,3H),2.19(s,3H),1.45(d,J=7.1Hz,3H).

[0205] Example 9 Preparation of compounds DEX-28 to DEX-30 of the present invention

[0206] 1. Preparation of Compound 28-1

[0207] At room temperature, propargyl alcohol (7.1 g, 126.7 mmol), TMSN3 (21.9 g, 190.1 mmol), and iodide (1.2 g, 6.3 mmol) were dissolved in DMF / MeOH (64.8 mL, v / v = 35 / 1). The reaction system was purged with nitrogen three times, protected by nitrogen, and stirred at 95°C for 12 hours. After the reaction was complete 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 / 10 to 1 / 5) under TLC (ethyl acetate) monitoring. Fractions with Rf = 0.5 to 0.6 were collected to obtain compound 28-1 (6.8 g, 54.2% yield) as a pale yellow solid. ESI [M+H] + =100.0.

[0208] 2. Preparation of Compound 28-2

[0209] At room temperature, 28-1 (6.8 g, 68.6 mmol) and active MnO2 (65.5 g, 91%, 686 mmol) were dissolved in CH2Cl2 (300 mL) and refluxed with stirring for 5 hours. After the reaction was complete as monitored by TLC, the reaction solution was cooled to room temperature 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 / 20 to 1 / 5) 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 a light yellow solid compound 28-2 (6.3 g, yield 94.6%). ESI [M+H] + =98.1.

[0210] 3. Preparation of Compound 28-3

[0211] Compound 28-2 (6.3 g, 64.9 mmol) and triphenylmethane (21.7 g, 77.9 mmol) were dissolved in DMF (100 mL) at room temperature. The reaction system was cooled to 5°C using an ice-salt bath. Triethylamine (9.9 g, 97.8 mmol) was slowly added dropwise and stirred at room temperature for 1 hour. After completion of the reaction as monitored by TLC, H₂O (200 mL) was added to the reaction system and extracted with EtOAc (3 × 50 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 / 2). Fractions with Rf = 0.5 to 0.6 were collected to obtain compound 28-3 (13.0 g, 59.0% yield) as a white solid. ESI [M+H] + =340.1.

[0212] 4. Preparation of Compound 28-4

[0213] At room temperature, 28-3 (13.0 g, 38.3 mmol) was dissolved in dry THF (50 mL). The reaction system was purged with nitrogen three times, protected by nitrogen, and cooled to 0°C in an ice-salt bath. A (80 mL, 1 mol / L in THF, 80 mmol) was slowly added dropwise to the system and stirred at room temperature for 4 hours. After the reaction was complete as monitored by TLC, the reaction system was cooled to 0°C in an ice-water bath. Saturated aqueous ammonium chloride (100 mL) was slowly added to the reaction system and extracted with EtOAc (3 × 50 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was used directly in the next reaction without purification. ESI [M+H] + =446.5.

[0214] 5. Preparation of Compound 28-5

[0215] The crude product, compound 28-4, obtained in the previous step, was dissolved in CH2Cl2 (100 mL) at room temperature, and activated MnO2 (36.6 g, 383 mmol, 91%) was added. The mixture was stirred at reflux for 5 hours. After the reaction was complete as monitored by TLC, the mixture was filtered and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane / petroleum ether (v / v) = 1 / 10 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 2). The fraction with Rf = 0.6 to 0.7 was collected to obtain compound 28-5 (15 g, 88.3% yield for two steps) as a white solid. ESI [M+H] + =444.6.

[0216] 6. Preparation of target compound DEX-28

[0217] At room temperature, 28-5 (500 mg, 1.1 mmol) and TFA (1 mL) were dissolved in CH2Cl2 (10 mL) and stirred at room temperature for 2 hours. After completion of the reaction as monitored by TLC, the mixture was concentrated under reduced pressure, basified with saturated aqueous sodium bicarbonate (20 mL), and extracted with CH2Cl2 (3 × 5 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 preparative TLC (dichloromethane / petroleum ether (v / v) = 1 / 1) and fractions with Rf = 0.5-0.6 were collected to obtain the target compound DEX-28 (79.2 mg, 35.8% yield) as a white solid. ESI [M+H] + =202.3

[0218] 1H NMR (400MHz, d6-DMSO) δ15.79(s,1H),8.59(s,1H),7.36(d,J=7.4Hz,1H),7.30(d,J=7.5Hz,1H),7.21(t,J=7.5Hz,1H),2.31(s,3H),2.15(s,3H).

[0219] 7. Preparation of Compound 28-6

[0220] Compound 28-5 (8.87 g, 20.0 mmol) was dissolved in dry THF (50 mL) at room temperature. The reaction system was cooled to 0°C using an ice-salt bath. MeMgBr (40 mL, 1 mol / L in THF, 40.0 mmol) was slowly added dropwise to the system, and the mixture was stirred at room temperature for 3 hours. 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 (100 mL) was slowly added to the reaction system, and the mixture was extracted with EtOAc (3 × 50 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was used directly in the next step without purification.

[0221] 8. Preparation of target compound DEX-29

[0222] The crude product 28-6 obtained in the previous step and TFA (10 mL) were dissolved in CH2Cl2 (30 mL) at room temperature and stirred at room temperature for 2 hours. After completion of the reaction as monitored by TLC, the mixture was concentrated under reduced pressure, basified with saturated aqueous sodium bicarbonate (20 mL), and extracted with CH2Cl2 (3×5 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 (dichloromethane / methanol (v / v) = 700 / 1 to 200 / 1) and monitored by TLC (dichloromethane / methanol (v / v) = 50 / 1). Fractions with Rf = 0.5 to 0.6 were collected to obtain the target compound DEX-29 (2.9 g, 72.8% yield over two steps) as a colorless oil. ESI [M+H] + =200.2

[0223] 1 H NMR (400MHz, d6-DMSO) δ14.84(s,1H),7.69(s,1H),7.17(d,J=7.4Hz,1H),7.10(t,J=7 .5Hz,1H),6.99(d,J=7.3Hz,1H),6.05(s,1H),5.15(s,1H),2.26(s,3H),1.96(s,3H).

[0224] 9. Target compound DEX-30

[0225] At room temperature, compound DEX-29 (2.4 g, 12.0 mmol) and 10% wet palladium on carbon (240 mg) were dissolved in MeOH (30 mL). The system was purged with hydrogen three times and stirred at room temperature under hydrogen overnight. After the reaction was complete as monitored by TLC, the mixture was filtered and the filter cake was washed with methanol (3 × 10 mL). The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 2). Fractions with Rf = 0.5 to 0.6 were collected to obtain the target compound DEX-30 (1.3 g, 53.8% yield) as a colorless oil. ESI [M+H] + =202.3.

[0226] 1 H NMR (400MHz, d6-DMSO) δ14.57(s,1H),7.50(s,1H),7.08–6.77(m,3H),4.52(q,J=6.9Hz,1H),2.25(s,3H),2.22(s,3H),1.54(d,J=7.2Hz,3H).

[0227] Example 10 Preparation of compounds DEX-42 to DEX-44, DEX-57 to DEX-59 and DEX-64 of the present invention

[0228] 1. Preparation of target compounds DEX-42 and DEX-57

[0229] 2,3-Dimethylbenzoyl chloride (2.5 g, 14.8 mmol) was slowly added dropwise to a solution of pyrrole (1.5 g, 22.4 mmol) in hexafluoroisopropanol (20 mL) in an ice-salt bath at 0°C. The mixture was stirred overnight at room temperature. After completion of the reaction as monitored by TLC, the reaction system 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 / 20 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5). Two fractions with Rf = 0.5 to 0.7 were collected to obtain the title compound.

[0230] Compound DEX-42: 380 mg, yield 12.9%, ESI [M+H] + =200.2.

[0231] 1H NMR(400MHz,d6-DMSO)δ11.52(s,1H),7.24(d,J=7.1Hz,1H),7.17–7.08(m,J=7.4,6.9Hz,2H),7.05(dt ,J=3.2,1.7Hz,1H),6.87(dd,J=4.7,2.4Hz,1H),6.44(dd,J=4.2,2.5Hz,1H),2.27(s,3H),2.10(s,3H).

[0232] Compound DEX-57: 1.8 g, yield 61.0%, ESI [M+H] + =200.2.

[0233] 1 H NMR (400MHz, d6-DMSO) δ12.07(s,1H),7.31–7.25(m,1H),7.22–7.12(m,3H),6.40–6.35(m,1H),6.21–6.17(m,1H),2.28(s,3H),2.13(s,3H).

[0234] 2. Preparation of target compounds DEX-43~DEX-44, DEX-50 and DEX-58~DEX-59

[0235] Compounds DEX-42 and DEX-57 were protected by Boc2O, subjected to methylmagnesium bromide Grignard reaction, dehydrated and deprotected to obtain target compounds DEX-43 and DEX-58, which were then reduced by palladium carbon hydrogen to obtain target compounds DEX-44 and DEX-59, respectively.

[0236] Compound DEX-43: 230 mg, ESI [M+H] + =198.3.

[0237] 1 H NMR(400MHz,d6-DMSO)δ10.69(s,1H),7.17–7.00(m,2H),6.92(d,J=7.1Hz,1H),6.70(dd,J=4.8,2.4H z,1H),6.19(t,J=2.5Hz,2H),5.46(d,J=2.1Hz,1H),4.60(d,J=2.1Hz,1H),2.24(s,3H),2.03(s,3H).

[0238] Compound DEX-44: 331 mg, ESI [M+H] + =200.3.

[0239] 1H NMR(400MHz,d6-DMSO)δ10.43(s,1H),7.11–6.87(m,3H),6.63–6.59(m,1H),6.46–6.41(m,1H) ),5.83–5.77(m,1H),4.22(q,J=7.1Hz,1H),2.23(s,3H),2.20(s,3H),1.43(d,J=7.1Hz,3H).

[0240] Compound DEX-58: 132 mg, ESI [M+H] + =198.3.

[0241] 1 H NMR (400MHz, d6-DMSO) δ11.03(s,1H),7.13(d,J=7.2Hz,1H),7.07(t,J=7.5Hz,1H),6.94(d,J=7.3Hz,1H),6.78(dd,J=4.1,2 .6Hz,1H),5.93(dd,J=5.6,2.5Hz,1H),5.61(d,J=0.9Hz,1H),5.46(t,J=3.6Hz,1H),4.68(s,1H),2.25(s,3H),2.02(s,3H).

[0242] Compound DEX-59: 133 mg, ESI [M+H] + =200.3.

[0243] 1 H NMR(400MHz,d6-DMSO)δ10.41(s,1H),7.01–6.93(m,2H),6.90–6.82(m,1H),6.56(dd,J=4.2,2.6Hz,1H),5.8 8(dd,J=5.5,2.7Hz,1H),5.75(s,1H),4.32(q,J=7.1Hz,1H),2.24(s,3H),2.21(s,3H),1.43(d,J=7.1Hz,3H).

[0244] Compound DEX-64: 31 mg, ESI [M+H] + =234.1.

[0245] Example 11 Preparation of compounds DEX-41, DEX-46 to DEX-54 and DEX-60 to DEX-63 of the present invention

[0246] 1. Preparation of compound 36-1

[0247] At room temperature, the compound ethyl 2-methyl-1H-pyrrole-3-carboxylate (3.0 g, 19.6 mmol) was dissolved in DMF (30 mL), cooled to 0°C in an ice-salt bath, and NaH (862.4 mg, 60% in mineral oil, 21.6 mmol) was added to the system in batches. The mixture was stirred at 0°C for 10 minutes. Then, p-toluenesulfonyl chloride (5.6 g, 29.4 mmol) was added to the system in batches and stirred at room temperature for 4 hours. After the reaction was complete as monitored by TLC, the reaction solution was poured into ice water and extracted with EtOAc (3×10 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous Na2SO4, 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 / 50 to 1 / 10) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10). The fraction with Rf = 0.5 to 0.6 was collected to obtain compound 36-1 (4.8 g, yield 79.7%). ESI [M+H] + =308.1.

[0248] 2. Preparation of compound 36-3

[0249] At room temperature, 36-1 (4.8 g, 15.6 mmol) was dissolved in CH2Cl2 (30 mL). The temperature was cooled to -78°C in a dry ice-acetone bath. The reaction system was purged with nitrogen three times. Under nitrogen protection, DIBAL-H (32 mL, 1 mol / L in toluene, 32 mmol) was slowly added dropwise to the system and stirred at room temperature for 3 hours. After the reaction was complete as monitored by TLC, saturated aqueous ammonium chloride (100 mL) was slowly added to the reaction system. The product was extracted with CH2Cl2 (3 × 30 mL). The combined organic phases were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and dissolved in CH2Cl2 (100 mL). Active MnO2 (29.8 g, 31.2 mmol, 91%) was added and the mixture was refluxed with stirring for 5 hours. After the reaction was complete as monitored by TLC, the mixture was filtered and 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 / 10 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 3). The fraction with Rf = 0.5 to 0.6 was collected to obtain compound 36-3 (3.4 g, two-step yield 82.8%). ESI [M+H] + =264.3.

[0250] 3. Preparation of compound 36-5

[0251] At room temperature, 36-3 (3.4 g, 12.9 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. A (26 mL, 1 mol / L in THF, 26 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 cooled to 0°C in an ice-water bath. Saturated aqueous ammonium chloride (100 mL) was slowly added to the reaction system, and the reaction system was extracted with EtOAc (3 × 15 mL). The combined organic phases were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and dissolved in CH2Cl2 (100 mL). Active MnO2 (24.6 g, 257.5 mmol, 91%) was added, and the mixture was refluxed with stirring for 5 hours. After the reaction was complete as monitored by TLC, the mixture was filtered and 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 / 10 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 3). The fraction with Rf = 0.5 to 0.6 was collected to obtain compound 36-5 (4.0 g, two-step yield 84.4%). ESI [M+H] + =368.5.

[0252] 4. Preparation of target compound DEX-46

[0253] Compound 36-5 (3.8 g, 10.3 mmol) was dissolved in THF / MeOH / H₂O (22 mL, v / v / v = 8 / 2 / 1) at room temperature. The reaction system was cooled to 0°C using an ice-salt bath. NaOH (412 mg, 10.3 mmol) was added portionwise and stirring continued for 30 minutes. 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 DEX-46 (1.9 g, 86.5% yield) as a white solid. ESI [M+H] + =214.3

[0254] 1 H NMR (400MHz, d6-DMSO) δ11.39(s,1H),7.22(d,J=7.4Hz,1H),7.13(t,J=7.5Hz,1H),7.01(d,J =7.2Hz,1H),6.62–6.59(m,1H),5.97(t,J=2.7Hz,1H),2.29(s,3H),2.28(s,3H),2.08(s,3H).

[0255] 5. Preparation of target compound DEX-47

[0256] DEX-46 (300 mg, 1.4 mmol) was dissolved in dry THF (3 mL) at room temperature. The reaction system was purged with nitrogen three times, protected by nitrogen, and cooled to -10°C in an ice-salt bath. MeLi (2.2 mL, 1.3 mol / L in Et2O, 2.9 mmol) was slowly added to the system via syringe and stirring continued for 30 minutes. After the reaction was complete as monitored by TLC, saturated aqueous ammonium chloride (10 mL) was slowly added to the reaction system. The mixture was 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 and dissolved in CH2Cl2 (10 mL). TFA (1 mL) was added and stirred at room temperature for 1 hour. After the reaction was complete as monitored by TLC, the mixture was concentrated under reduced pressure, basified with saturated aqueous sodium bicarbonate (20 mL), extracted with CH2Cl2 (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 / 5), and fractions with Rf = 0.5-0.6 were collected to give the target compound DEX-47 (182 mg, two-step yield 61.5%) as a gray solid. ESI [M+H] + =212.4

[0257] 1 H NMR(400MHz,d6-DMSO)δ10.52(s,1H),7.12–7.02(m,2H),6.96–6.88(m,1H),6.50(t,J=2.7Hz,1H),5.8 3(t,J=2.8Hz,1H),5.27(d,J=2.3Hz,1H),4.69(d,J=2.3Hz,1H),2.23(s,3H),1.99(s,3H),1.77(s,3H).

[0258] 6. Preparation of target compound DEX-48

[0259] At room temperature, compound F2-D1 (62 mg, 0.29 mmol) and 10% wet palladium on carbon (6 mg) were dissolved in MeOH (5 mL). The system was replaced with hydrogen three times and stirred at room temperature under hydrogen for 30 minutes. After the reaction was complete as monitored by TLC, the mixture was filtered and the filter cake was washed with methanol (3 × 3 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 / 5). Fractions with Rf = 0.5-0.6 were collected to obtain the target compound DEX-48 (47 mg, yield 76.0%) as a gray solid. ESI [M+H] +=214.3.

[0260] 1 H NMR(400MHz, CDCl3)δ7.75(s,1H),7.21–6.92(m,3H),6.71–6.52(m,1H),6.18–5. 96(m,1H),4.32–4.21(m,1H),2.31(s,3H),2.27(s,3H),2.10(s,3H),1.55(s,3H).

[0261] 7. Preparation of Compound 42-2

[0262] In an ice-salt bath at 0°C, MeI (37.3 g, 262.8 mmol) was added to a CH2Cl2 (50 mL) solution of NaOH (569.4 mL, 6 mol / L, 3.42 mol), p-toluenesulfonylmethyl isocyanide (42.8 g, 219.2 mmol) and TEBAC (10.0 g, 43.9 mmol) and stirred at room temperature for 2.5 hours. After the reaction was completed as monitored by TLC, saturated brine (100 mL) was added to the reaction system, extracted with CH2Cl2 (3×30 mL), 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 / 10 to 1 / 3) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5). The Rf = 0.5 to 0.6 fraction was collected to obtain compound 42-1 (25.2 g, yield 54.9%).

[0263] 1 H NMR (400MHz, CDCl3) δ7.90(d,J=8.3Hz,2H),7.46(d,J=8.0Hz,2H),4.61(q,J=6.8Hz,1H),2.52(s,3H),1.77(d,J=6.8Hz,3H).

[0264] NaH (9.6 g, 60% in mineral oil, 240 mmol) was added to a solution of 42-1 (25.2 g, 120.4 mmol) and ethyl acrylate (11.0 g, 109.9 mmol) in Et2O / DMSO (90 mL, v / v = 2 / 1) in an ice-salt bath at 0°C and stirred at room temperature for 2 hours. After the reaction was complete as monitored by TLC, water (100 mL) was slowly added to the reaction system, and the mixture was extracted with EtOAc (3 × 30 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 to 1 / 3) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 4). Fractions with Rf = 0.4 to 0.5 were collected to obtain compound 42-2 (14.0 g, yield 83.2%). ESI [M+H] + =154.2

[0265] 8. Preparation of Compound 52-2

[0266] In a dry ice acetonitrile bath at -10 ° C, AlCl3 (12.5 g, 93.8 mmol) was added to a solution of 1H-pyrrole-2-carboxylic acid methyl ester (4.5 g, 36.0 mmol) in CH2Cl2 / MeNO2 (100 mL, v / v = 1 / 1), and then 1,1-dichlorodimethyl ether (5.4 g, 47.0 mmol) was slowly added to the system and stirred at room temperature overnight. The reaction system was cooled to 0°C in an ice-water bath, and saturated aqueous sodium bicarbonate solution (100 mL) was slowly added. The mixture was extracted with CH2Cl2 (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 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5). The fractions with Rf = 0.5 to 0.6 were collected to obtain compound 52-1 (3.2 g, yield 58.0%). ESI [M+H] + =154.2.

[0267] At room temperature, compound 52-1 (6.1 g, 39.8 mmol) and 10% wet palladium on carbon (600 mg) were dissolved in MeOH (30 mL). The system was replaced with hydrogen three times and stirred at room temperature under hydrogen for 16 hours. After the reaction was complete as monitored by TLC, the mixture was filtered and the filter cake was washed with methanol (3 × 10 mL). The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 20 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5). The fraction with Rf = 0.5 to 0.6 was collected to obtain compound 52-2 (4.5 g, yield 81.3%). ESI [M+H]+ =140.2.

[0268] 9. Preparation of target compounds DEX-41, DEX-49 to DEX-54, DEX-62 to DEX-63

[0269] The preparation methods of the target compounds DEX-49, DEX-52, DEX-62 and DEX-63 are similar to those of the compound DEX-46, the preparation methods of the target compounds DEX-50 and DEX-53 are similar to those of the compound DEX-47, and the preparation methods of the target compounds DEX-41, DEX-51, DEX-54, DEX-60 and DEX-61 are similar to those of the compound DEX-48.

[0270] Compound DEX-41: 12 mg, ESI [M+H] + =225.3

[0271] Compound DEX-49: 219 mg, ESI [M+H] + =214.3

[0272] 1 H NMR (400MHz, d6-DMSO) δ11.17(s,1H),7.22(d,J=7.3Hz,1H),7.12(t,J=7.5Hz,1H),7.05(d,J=6.8Hz, 1H), 6.76 (dd, J=3.2, 2.0Hz, 1H), 6.67–6.62 (m, 1H), 2.27 (s, 3H), 2.23 (d, J=0.9Hz, 3H), 2.08 (s, 3H).

[0273] Compound DEX-50: 37 mg, ESI [M+H] + =212.3

[0274] 1 H NMR(400MHz,d6-DMSO)δ10.43(s,1H),7.10–7.02(m,2H),6.93(dd,J=7.2,0.9Hz,1H),6.51(s,1H),6.0 8(t,J=2.5Hz,1H),5.35(d,J=2.1Hz,1H),4.69(d,J=2.1Hz,1H),2.23(s,3H),2.01(s,3H),2.00(s,3H).

[0275] Compound DEX-51: 121 mg, ESI [M+H] + =214.3

[0276] 1H NMR(400MHz,d6-DMSO)δ10.17(s,1H),6.95–6.89(m,2H),6.87–6.81(m,1H),6. 45–6.39(m,2H),2.23(s,3H),2.22(s,3H),1.66(s,3H),1.36(d,J=7.1Hz,3H).

[0277] Compound DEX-52: 200 mg, ESI [M+H] + =214.3

[0278] 1 H NMR (400MHz, d6-DMSO) δ11.33(s,1H),7.23(d,J=7.3Hz,1H),7.13(t,J=7.5Hz,1H),7.07(d,J =6.9Hz,1H),6.88(dd,J=2.9,1.7Hz,1H),6.13(s,1H),2.27(s,3H),2.17(s,3H),2.09(s,3H).

[0279] Compound DEX-53: 885 mg, ESI [M+H] + =212.2

[0280] 1 H NMR(400MHz,d6-DMSO)δ10.43(s,1H),7.10–7.01(m,2H),6.90(dd,J=7.3,1.0Hz,1H),5.99–5.95(m,1 H),5.89(s,1H),5.37(d,J=2.2Hz,1H),4.54(d,J=2.2Hz,1H),2.24(s,3H),2.12(s,3H),2.03(s,3H).

[0281] Compound DEX-54: 77 mg, ESI [M+H] + =214.3

[0282] Compound DEX-60: 23 mg, ESI [M+H] + =225.3

[0283] Compound DEX-61: 19 mg, ESI [M+H] + =225.3

[0284] Compound DEX-62: 792 mg, ESI [M+H] + =214.3

[0285] 1H NMR (400MHz, d6-DMSO) δ11.74(s,1H),7.30–7.25(m,1H),7.19–7.14(m,2H),6.99(s,1H),6.19(s,1H),2.29(s,3H),2.13(s,3H),2.00(s,3H).

[0286] Compound DEX-63: 460 mg, ESI [M+H] + =214.3

[0287] 1 H NMR(400MHz,d6-DMSO)δ11.48(s,1H),7.26(d,J=7.4Hz,1H),7.17(t,J=7.5Hz,1H) ,7.04–6.98(m,2H),6.03(t,J=2.0Hz,1H),2.28(s,3H),2.07(s,3H),1.69(s,3H).

[0288] Example 12 Preparation of compounds DEX-55 and DEX-56 of the present invention

[0289] At room temperature, tert-butyl 3-(2,3-dimethylbenzoyl)-1H-pyrrole-1-carboxylate (2.0 g, 6.7 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. Ethylmagnesium bromide (20.0 mL, 1.0 mol / L in THF, 20.0 mmol) or cyclopropylmagnesium bromide (20.0 mL, 1.0 mol / L in THF, 20.0 mmol) was slowly added dropwise at a rate of 2 mL / min. The mixture was stirred at room temperature for 3 hours. After completion of the reaction as monitored by TLC, the reaction system was quenched with saturated aqueous ammonium chloride (50 mL) and extracted with EtOAc (3 × 10 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and dissolved in C2Cl2 (10 mL). TFA (2 mL) was added and stirred at room temperature for 2 hours. After the reaction was completed as monitored by TLC, the mixture was concentrated under reduced pressure, basified with saturated aqueous sodium bicarbonate solution (20 mL), extracted with CH2Cl2 (3×5 mL), and the combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a crude product, which was purified by preparative TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5), and the fractions with Rf = 0.5 to 0.6 were collected to give the title compound.

[0290] Compound DEX-55: 600 mg, gray solid, two-step yield 39.4%, ESI [M+H] +=228.3

[0291] 1 H NMR (400MHz, d6-DMSO) δ11.40(s,1H),7.21(d,J=7.4Hz,1H),7.12(t,J=7.5Hz,1H),7.01(d,J=7.2Hz,1H),6.6 3–6.55(m,1H),5.91(t,J=2.7Hz,1H),2.78(q,J=7.5Hz,2H),2.26(s,3H),2.08(s,3H),1.13(t,J=7.5Hz,3H).

[0292] Compound DEX-56: 400 mg, gray solid, two-step yield 24.9%, ESI [M+H] + =240.1

[0293] 1 H NMR (400MHz, d6-DMSO) δ10.95(s,1H),7.21(d,J=7.4Hz,1H),7.12(t,J=7.5Hz,1H),7.03(d,J=7.3Hz,1H),6.52(t,J= 2.7Hz,1H),5.91(t,J=2.7Hz,1H),2.49–2.42(m,2H),2.27(s,3H),2.10(s,3H),0.89–0.82(m,2H),0.82–0.76(m,2H).

[0294] Example 13 Preparation of compounds DEX-65 to DEX-67 and DEX-82 to DEX-85 of the present invention

[0295] Zinc powder (3.9 g, 59.1 mmol) was added portionwise to a solution of 2,3-dimethylbenzoyl chloride (5.0 g, 29.7 mmol) and 2-methyl-1H-pyrrole (2.4 g, 29.7 mmol) in toluene (60 mL) at room temperature and stirred for 2 hours. After completion of the reaction as monitored by TLC, the mixture was filtered and the filtrate was extracted with EtOAc (3 × 10 mL). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to afford the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 20 to 1 / 3) using TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5). Fractions with Rf = 0.5 to 0.6 were collected to afford the target compound DEX-67 (4.0 g, 63.1% yield) as a gray solid. ESI [M+H] + =214.1.

[0296] 1H NMR(400MHz,d6-DMSO)δ11.85(s,1H),7.29–7.24(m,1H),7.18–7.11(m,2H), 6.29–6.24(m,1H),5.96–5.90(m,1H),2.28(s,3H),2.27(s,3H),2.13(s,3H).

[0297] Compound DEX-67 (710 mg, 3.3 mmol) was dissolved in dry THF (10 mL) at room temperature. The reaction system was purged with nitrogen three times, protected by nitrogen, and cooled to -10°C in an ice-salt bath. MeLi (15.0 mL, 1.3 mol / L in Et2O, 19.5 mmol) was added dropwise to the system at a rate of 1.5 mL / min using a syringe. The reaction was stirred at room temperature for 1 hour. 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 and dissolved in CH2Cl2 (10 mL). 100-200 mesh silica gel (5 g) was added and stirred at room temperature for 30 minutes. After the reaction was complete as monitored by TLC, the mixture was filtered and 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 / 20 to 1 / 5) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 8). Fractions with Rf = 0.5 to 0.6 were collected to obtain the target compound DEX-65 (570 mg, yield 81.0%) as a green oil. ESI [M+H] + =212.1.

[0298] 1 H NMR (400MHz, d6-DMSO) δ10.77(s,1H),7.11(d,J=7.0Hz,1H),7.05(t,J=7.5Hz,1H),6.91(d,J=6.6Hz,1H),5.61(t,J=2 .3Hz,1H),5.52(d,J=1.1Hz,1H),5.25(t,J=2.9Hz,1H),4.57(d,J=1.1Hz,1H),2.24(s,3H),2.20(s,3H),2.03(s,3H).

[0299] At room temperature, compound DEX-65 (370 mg, 1.75 mmol) and 10% wet palladium on carbon (37 mg) were dissolved in MeOH (10 mL). The system was replaced with hydrogen three times and stirred at room temperature under hydrogen overnight. 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 / 8), and the fraction with Rf = 0.5-0.6 was collected to obtain the target compound DEX-66 (246 mg, yield 65.9%) as a gray solid. ESI [M+H] + =214.3

[0300] 1 H NMR(400MHz,d6-DMSO)δ10.11(s,1H),6.99–6.93(m,2H),6.91–6.86(m,1H),5.59–5.56(m,1H),5.5 5–5.52(m,1H),4.24(q,J=7.1Hz,1H),2.23(s,3H),2.21(s,3H),2.08(s,3H),1.40(d,J=7.1Hz,3H).

[0301] The preparation methods of compounds DEX-82 to DEX-85 are similar to that of the target compound DEX-67.

[0302] Compound DEX-82: 436 mg, ESI [M+H] + =214.1

[0303] 1 H NMR(400MHz,d6-DMSO)δ12.07(s,1H),7.21–7.17(m,1H),7.12(d,J=7.6Hz,1H),6.98(d,J =7.7Hz,1H),6.30–6.22(m,1H),6.18–6.13(m,1H),2.22(s,3H),2.03(s,3H),1.98(s,3H).

[0304] Compound DEX-83: 78 mg, ESI [M+H] + =268.3

[0305] Compound DEX-84: 54 mg, ESI [M+H] + =240.4

[0306] Compound DEX-85: 11 mg, ESI [M+H] + =268.3

[0307] Example 14 Preparation of compounds DEX-86 to DEX-107 of the present invention

[0308] 1. Preparation of target compound DEX-96

[0309] The preparation method of intermediate compound 85-1 is similar to that of compound 42-2, using ethyl 4,4,4-trifluorocrotonate and TosMic. The preparation methods of compounds 85-2 to 85-6 are similar to those of compounds 36-1 to 36-5.

[0310] 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 DEX-96 (3.5 g, 77.7% yield) as a white solid. ESI [M+H] + =268.2

[0311] 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).

[0312] 2. Preparation of target compound DEX-97-1

[0313] Compound DEX-96 (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 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.

[0314] 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 organic phases were combined, washed with saturated brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and dissolved in CH2Cl2 (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 CH2Cl2 (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 DEX-97-1 (290 mg, two-step yield 52.6%) as a colorless oil.

[0315] 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).

[0316] 3. Preparation of target compounds DEX-97 and DEX-101

[0317] DEX-97-1 (200 mg, 0.56 mmol) and potassium tert-butoxide (555 mg, 1.55 mmol) were dissolved in THF / DMSO (8 mL, v / v = 1 / 1) at room temperature and stirred for 3 hours. After the reaction was complete as monitored by TLC, H₂O (10 mL) was added to the system and extracted with EtOAc (3 × 5 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous Na₂SO₄, filtered, and 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 / 5). Fractions with Rf = 0.5-0.6 were collected to obtain the target compound DEX-97 (122 mg, 81.7% yield) as a white solid. ESI [M+H] + =266.2

[0318] 1 H NMR(400MHz,d6-DMSO)δ11.40(s,1H),7.29(s,1H),7.14–7.03(m,2H),6.96(d, J=7.1Hz,1H),6.23(s,1H),5.49(s,1H),4.91(s,1H),2.22(s,3H),1.99(s,3H).

[0319] Compound DEX-97 (90 mg, 0.34 mmol) and 10% wet palladium on carbon (10 mg) were dissolved in MeOH (5 mL) at room temperature. The system was purged with hydrogen three times and stirred at room temperature under hydrogen overnight. After completion of the reaction as monitored by TLC, the mixture was filtered, the filter cake was washed with methanol (3 × 5 mL), and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5), and the fractions with Rf = 0.5-0.6 were collected to obtain the target compound DEX-101 (82 mg, 90.4% yield) as a white solid.

[0320] 1 H NMR(400MHz,d6-DMSO)δ11.22(s,1H),7.17(s,1H),7.00–6.90(m,3H),6.58(s ,1H),4.33(q,J=7.1Hz,1H),2.23(s,3H),2.15(s,3H),1.41(d,J=7.1Hz,3H).

[0321] 4. Preparation of target compounds DEX-99 and DEX-100

[0322] Compound DEX-97 (200 mg, 0.75 mmol) was dissolved in dry DMF (8 mL) at room temperature and cooled to 0°C in an ice-salt bath. NaH (36.2 mg, 60% in mineral oil, 0.9 mmol) was added to the mixture, and the mixture was stirred at 0°C for 10 minutes. MeI (117.7 mg, 0.83 mmol) was slowly added to the mixture via syringe, and the mixture was stirred at room temperature for 2 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 afford the crude product. The crude product was purified by preparative TLC (ethyl acetate / petroleum ether (v / v) = 1 / 8). Fractions with Rf = 0.5-0.6 were collected to afford the target compound DEX-99 (141 mg, 67.0% yield) as a colorless oil.

[0323] 1 H NMR(400MHz,d6-DMSO)δ7.31(d,J=1.5Hz,1H),7.14–7.04(m,2H),6.98–6.92(m,1H),6 .24(d,J=2.3Hz,1H),5.47(s,1H),4.90(s,1H),3.53(s,3H),2.23(s,3H),2.01(s,3H).

[0324] Compound DEX-99 (80 mg, 0.29 mmol) and 10% wet palladium on carbon (10 mg) were dissolved in MeOH (5 mL) at room temperature. 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 / 5), and the fractions with Rf = 0.5-0.6 were collected to obtain the target compound DEX-100 (55 mg, 68.3% yield) as a white solid.

[0325] 1 H NMR(400MHz,d6-DMSO)δ7.17(d,J=1.0Hz,1H),7.02–6.92(m,3H),6.53(d,J=2.0Hz,1H ), 4.30 (q, J = 7.0Hz, 1H), 3.59 (s, 3H), 2.23 (s, 3H), 2.14 (s, 3H), 1.40 (d, J = 7.1Hz, 3H).

[0326] 5. Preparation of target compound DEX-98

[0327] Compound DEX-96 (100 mg, 0.37 mmol) was dissolved in dry DMF (5 mL) at room temperature and cooled to 0°C in an ice-salt bath. NaH (17.9 mg, 60% in mineral oil, 0.45 mmol) was added to the mixture, and the mixture was stirred at 0°C for 10 minutes. MeI (79.7 mg, 0.56 mmol) was slowly added to the mixture via syringe, and the mixture was stirred at room temperature for 2 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 / 6). Fractions with Rf = 0.5-0.6 were collected to obtain the target compound DEX-98 (63 mg, 59.9% yield) as a white solid. ESI [M+H] + =282.1.

[0328] 1 H NMR(400MHz,d6-DMSO)δ7.52(s,1H),7.29(d,J=7.3Hz,1H),7.18(t,J=7.5Hz,1H),7 .12(d,J=7.1Hz,1H),7.08(d,J=2.0Hz,1H),3.64(s,3H),2.29(s,3H),2.10(s,3H).

[0329] 6. Preparation of target compounds DEX-102 to DEX-104

[0330] In an ice-salt bath at 5°C, N-benzylglycine hydrochloride (50 g, 249 mmol) was dissolved in toluene (500 mL). Ethyl propiolate (37 g, 373 mmol) and trifluoroacetic anhydride (115 g, 547 mmol) were then added to the reaction system in sequence, and the mixture was refluxed and stirred for 5 hours. The reaction system was cooled to 30°C, and trifluoroacetic anhydride (56 g, 273 mmol) was added. The mixture was refluxed and stirred for 5 hours, and then stirred at room temperature for 10 hours. After the reaction was complete as monitored by TLC, ice was added to quench the reaction, water (200 mL) was added to the system, and the mixture was extracted with EtOAc (3×50 mL). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a colorless oily crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 50 to 1 / 20) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5). The fraction with Rf = 0.5 to 0.6 was collected to obtain compound 93-1 (44 g, yield 85%) as a colorless oil. ESI [M+H] + =207.1

[0331] The preparation methods of compounds 93-2 to 93-5 are similar to those of compounds 36-2 to 36-5.

[0332] Compound 93-5 (2 g, 5.6 mmol) was dissolved in MeOH (50 mL). Triethylsilane (35 mL, 224 mmol), triethylamine (39 mL, 280 mmol), and palladium chloride (3.5 g, 19.6 mmol) were then added to the mixture. The mixture was sealed and stirred at 100°C for 3 hours. After completion of the reaction as monitored by TLC, the mixture was 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 / 30 to 1 / 10) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5). Fractions with Rf = 0.5 to 0.6 were collected to obtain the target compound DEX-102 (1.0 g, 67% yield) as a colorless oil. ESI [M+H] + = 267.1 The preparation method of target compounds DEX-103 ~ DEX-104 is similar to that of target compounds DEX-47 ~ DEX-48.

[0333] Compound DEX-103: 39 mg, ESI [M+H] + =266.3

[0334] Compound DEX-104: 12 mg, ESI [M+H] + =268.3.

[0335] The preparation method of the target compounds DEX-86~DEX-95, DEX-97-1, DEX-102~DEX-107 is similar to that of the target compounds DEX-46~DEX-48, using the corresponding substituted pyrrole-3-carboxylate, and undergoing a series of reactions including Tos protection, DIBAL-H reduction, activated MnO2 oxidation, Grignard reaction, activated MnO2 oxidation, and NaOH deprotection.

[0336] Compound DEX-86: 59 mg, ESI [M+H] + =278.1

[0337] Compound DEX-87: 102 mg, ESI [M+H] + =218.1

[0338] Compound DEX-88: 44 mg, ESI [M+H] + =216.2

[0339] Compound DEX-89: 65 mg, ESI [M+H] + =218.2

[0340] Compound DEX-90: 111 mg, ESI [M+H] + =218.1

[0341] Compound DEX-91: 821 mg, ESI [M+H] + =216.1

[0342] Compound DEX-92: 25 mg, ESI [M+H] + =218.1

[0343] Compound DEX-93: 23 mg, ESI [M+H] + =218.1

[0344] Compound DEX-94: 30 mg, ESI [M+H] + =216.1

[0345] Compound DEX-95: 89 mg, ESI [M+H] + =218.1

[0346] Compound DEX-105: 64 mg, ESI [M+H] + =268.1

[0347] Compound DEX-106: 30 mg, ESI [M+H] + =266.1

[0348] Compound DEX-107: 21 mg, ESI [M+H] + =268.1

[0349] Example 15 Preparation of compounds DEX-108 to DEX-122 of the present invention

[0350] 1. Preparation of compound DEX-110

[0351] At room temperature, Et3N (51.4 mL, 369.9 mmol) and MgCl2 (14.3 g, 150 mmol) were added sequentially to a solution of 2,5-dimethylphenol (12.2 g, 100.0 mmol) in MeCN (400 mL), and the mixture was stirred at room temperature for 15 minutes. Paraformaldehyde (20.1 g, 663.2 mmol) was then added to the reaction system, and the mixture was stirred at reflux for 2.5 hours. After the reaction was complete as monitored by TLC, the mixture was concentrated under reduced pressure. A 10% aqueous hydrochloric acid solution (200 mL) was added to the reaction system, stirred at room temperature for 30 minutes, and extracted with CH2Cl2 (2×100 mL). The combined organic phases were washed with saturated brine (100 mL), 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 / 200 to 1 / 100) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 3). The fraction with Rf = 0.5 to 0.6 was collected to obtain compound 101-1 (12.1 g, yield 80%) as a colorless oil. ESI [M+H] + =151.1.

[0352] In an ice-water bath at 0°C, N-phenylbis(trifluoromethanesulfonyl)imide (43.5 g, 120.9 mmol), DMAP (988.2 mg, 8.1 mmol) and Et3N (22.4 mL, 161.2 mmol) were added to a solution of 101-1 (12.1 g, 80.6 mmol) in dry CH2Cl2 (300 mL) and stirred at room temperature for 5 hours. After the reaction was completed as monitored by TLC, H2O (200 mL) was added to the reaction system, extracted with CH2Cl2 (3×50 mL), 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 (dichloromethane / petroleum ether (v / v) = 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 20). The Rf = 0.5-0.6 fraction was collected to obtain compound 101-2 (22 g, yield 96%).

[0353] At room temperature, 101-2 (2.82 g, 10 mmol), K2CO3 (3.97 g, 30.0 mmol), and PdCl2(dppf)-CH2Cl2 (818 mg, 1.0 mmol) were dissolved in THF (50 mL). The reaction system was purged with nitrogen three times, protected by nitrogen, and stirred for 5 minutes. A solution of methylboronic acid (2.55 g, 40.0 mmol) in water (2.5 mL) was then added to the system, and the mixture was refluxed and stirred for 5 hours. After the reaction was completed as monitored by TLC, H2O (100 mL) was added to the reaction system, extracted with EtOAc (2×100 mL), 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 / 200 to 1 / 100) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 30). The Rf = 0.5 to 0.6 fraction was collected to obtain compound 101-3 (1.3 g, yield 87%) as a colorless oil.

[0354] At room temperature, compound B (2.1 g, 7.0 mmol) was dissolved in dry THF (10 mL). The reaction system was purged with nitrogen three times, and then cooled to -78°C in a dry ice / acetone bath under nitrogen protection. n-BuLi (2.8 mL, 2.5 mol / L in Hexane, 7 mmol) was slowly added to the reaction system via syringe, and stirring was continued for 30 minutes. A solution of 101-3 (1.1 g, 7.7 mmol) in THF (5 mL) was slowly added to the reaction system via syringe at a rate of 1.0 mL / min, and stirring was continued for 4 hours. After the reaction was complete as monitored by TLC, saturated aqueous ammonium chloride solution (50 mL) was slowly added to the reaction system, and the mixture was extracted with EtOAc (3×10 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 to 1 / 5) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10). The fraction with Rf = 0.5 to 0.6 was collected to obtain compound 101-4 (680 mg, yield 26%) as a colorless oil. ESI [M+H] + =372.3

[0355] Compound 101-4 (680.0 mg, 1.8 mmol) was dissolved in CH2Cl2 (40 mL) at room temperature, and active MnO2 (1.7 g, 18.0 mmol, 91%) was added to the reaction system. The reaction was stirred at room temperature for 5 hours. After completion of the reaction as monitored by TLC, the mixture was 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 / 100 to 1 / 30) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 15). The fraction with Rf = 0.5 to 0.6 was collected to obtain compound 101-5 (120 mg, 18% yield) as a colorless oil. ESI [M+H] + =370.2

[0356] At room temperature, 101-5 (120 mg, 0.33 mmol) was dissolved in THF (10 mL), and TBAF (95 mg, 0.36 mmol) was added to the reaction system, which was stirred at room temperature for 5 hours. After the reaction was complete as monitored by TLC, H2O (10 mL) was added to the reaction system, and the mixture was extracted with EtOAc (3 × 5 mL). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative TLC (CH2Cl2 / MeOH (v / v) = 50 / 1) to obtain the gray solid compound DEX-110 (65 mg, yield 91%). ESI [M+H] + =214.2

[0357] 1 H NMR(400MHz,d6-DMSO)δ11.49(s,1H),7.10–7.06(m,1H),6.99–6.94(m,2H),6.85(d d,J=4.7,2.3Hz,1H),6.37(d,J=1.0Hz,1H),2.21(s,3H),2.02(s,3H),1.96(s,3H).

[0358] 2. Preparation of target compounds DEX-108~DEX-109, DEX-111~DEX-122

[0359] The preparation methods of target compounds DEX-108~DEX-109, DEX-111~DEX-122 are similar to compound DEX-110. The preparation routes are as follows:

[0360] Compound DEX-108: 57 mg, ESI [M+H] + =214.3

[0361] 1 H NMR(400MHz,d6-DMSO)δ11.50(s,1H),7.08–7.02(m,2H),7.00(d,J=7.7Hz,1H),6.86(dd ,J=4.7,2.4Hz,1H),6.42(dd,J=4.3,2.5Hz,1H),2.29(s,3H),2.17(s,3H),2.12(s,3H).

[0362] Compound DEX-109: 82 mg, ESI [M+H] + =214.3

[0363] 1 H NMR(400MHz,d6-DMSO)δ11.50(s,1H),7.08–7.03(m,2H),6.91(s,1H),6.86(dd,J=4 .6, 2.4Hz, 1H), 6.43 (dd, J = 4.1, 2.5Hz, 1H), 2.25 (s, 3H), 2.23 (s, 3H), 2.04 (s, 3H).

[0364] Compound DEX-111: 54.1 mg, ESI [M+H] + =242.2

[0365] Compound DEX-112: 127.4 mg, ESI [M+H] + =240.3

[0366] 1 H NMR(400MHz,d6-DMSO)δ11.41(s,1H),7.09(d,J=7.7Hz,1H),7.02–6.94(m,2H),6.82(dd,J=4.7,2.3Hz,1H),6.38– 6.33(m,1H),2.36(s,3H),2.00(s,3H),1.63–1.54(m,1H),0.76–0.67(m,1H),0.59–0.49(m,2H),0.32–0.23(m,1H).

[0367] Compound DEX-113: 57 mg, ESI [M+H] + =242.2

[0368] Compound DEX-114: 21 mg, ESI [M+H] + =240.2

[0369] Compound DEX-115: 26 mg, ESI [M+H] +=200.2

[0370] 1 H NMR(400MHz,d6-DMSO)δ11.54(s,1H),7.35(dt,J=3.2,1.7Hz,1H),7.33(s,2H),7 .21(s,1H),6.90(dd,J=4.6,2.4Hz,1H),6.52(dd,J=4.2,2.6Hz,1H),2.34(s,6H).

[0371] Compound DEX-116: 125.9 mg, ESI [M+H] + =226.3

[0372] 1 H NMR(400MHz,d6-DMSO)δ11.48(s,1H),7.08(d,J=7.7Hz,1H),7.02–6.93(m,2H),6.84(dd,J=4.6,2.3Hz, 1H), 6.36 (s, 1H), 2.49–2.40 (m, 1H), 2.38–2.29 (m, 1H), 2.26 (s, 3H), 2.01 (s, 3H), 0.93 (t, J = 7.5Hz, 3H).

[0373] Compound DEX-117: 27 mg, ESI [M+H] + =226.3

[0374] 1 H NMR (400MHz, d6-DMSO) δ11.49(s,1H),7.05(s,1H),7.04(dt,J=3.2,1.7Hz,1H),6.88(s,1H),6.86(dd,J=4.7, 2.3Hz,1H),6.43(dd,J=4.2,2.5Hz,1H),2.53–2.46(m,21H),2.29(s,3H),2.25(s,3H),0.98(t,J=7.5Hz,3H).

[0375] Compound DEX-118: 83 mg, ESI [M+H] + =242.2

[0376] Compound DEX-119: 81 mg, ESI [M+H] + =240.3

[0377] 1H NMR(400MHz,d6-DMSO)δ11.44(s,1H),7.09–7.06(m,1H),7.05(s,1H),6.86–6.81(m,2H),6.42(dd,J =4.1,2.5Hz,1H),2.38(s,3H),2.24(s,3H),1.74–1.66(m,1H),0.71–0.64(m,2H),0.25–0.20(m,2H).

[0378] Compound DEX-120: 115 mg, ESI [M+H] + =226.3

[0379] 1 H NMR(400MHz,d6-DMSO)δ11.49(s,1H),7.06–7.01(m,2H),6.98(d,J=7.6Hz,1H),6.85(dd,J=4.7,2.4Hz, 1H), 6.42 (dd, J = 4.2, 2.5Hz, 1H), 2.57 (q, J = 7.4Hz, 2H), 2.28 (s, 3H), 2.21 (s, 3H), 1.01 (t, J = 7.4Hz, 3H).

[0380] Compound DEX-121: 38 mg, ESI [M+H] + =242.2

[0381] Compound DEX-122: 41 mg, ESI [M+H] + =240.3

[0382] 1 H NMR(400MHz,d6-DMSO)δ11.43(s,1H),7.10–7.03(m,2H),6.95(d,J=7.6Hz,1H),6.83(dd,J=4.6,2.4Hz,1H),6 .42(dd,J=4.1,2.5Hz,1H),2.35(s,3H),2.27(s,3H),1.83–1.75(m,1H),0.76–0.70(m,2H),0.27–0.21(m,2H).

[0383] Example 16 Preparation of the compounds DEX-69, DEX-70, DEX-81, DEX-128 and DEX-129 of the present invention

[0384] 1. Preparation of target compound DEX-70

[0385] At room temperature, 2-methylpyrrole (2.51 g, 31.0 mmol) and potassium thiocyanate (9.03 g, 93.0 mmol) were dissolved in MeCN (30 mL). The mixture was cooled to 0°C in an ice-salt bath. PhI(OAc)2 (10.98 g, 34.1 mmol) was slowly added to the reaction system and stirred at room temperature for 1 hour. After the reaction was complete as monitored by TLC, water (50 mL) was added to the reaction system and the mixture was extracted with EtOAc (3×10 mL). The combined organic phases were washed with saturated brine (50 mL), 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 / 50 to 1 / 20) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10). Fractions with Rf = 0.5 to 0.6 were collected to obtain compound 60-1 (3.66 g, 85% yield) as a white solid.

[0386] Compound 60-1 (3.66 g, 35.6 mmol) was dissolved in dry THF (20 mL) at room temperature. The reaction system was purged with nitrogen three times, protected by nitrogen, and cooled to 0°C in an ice-salt bath. A (70 mL, 1 mol / L in THF, 70 mmol) was slowly added dropwise to the system and stirred at room temperature for 30 minutes. After the reaction was complete as monitored by TLC, saturated aqueous ammonium chloride (50 mL) was slowly added to the reaction system. The mixture was extracted with EtOAc (3 × 15 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 / 30 to 1 / 10) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10). Fractions with Rf = 0.5 to 0.6 were collected to obtain the target compound DEX-70 (5.18 g, 89% yield) as a colorless oil. ESI [M+H] + =218.1.

[0387] 1 H NMR(400MHz,d6-DMSO)δ11.10(s,1H),6.96–6.88(m,2H),6.44(dd,J=7.6,1.2Hz,1H) ,6.26(t,J=2.9Hz,1H),5.88(t,J=2.4Hz,1H),2.24(s,3H),2.23(s,3H),2.19(s,3H).

[0388] 2. Preparation of target compound DEX-69

[0389] NaOH (1.6 g, 40.0 mmol) and TosCl (4.57 g, 24.0 mmol) were added sequentially to a solution of DEX-70 (2.17 g, 10.0 mmol) in DCE (40 mL) in an ice-salt bath at 0°C. The mixture was stirred at room temperature overnight. After completion of the reaction as monitored by TLC, water (50 mL) was added to the reaction system and the mixture was extracted with CH2Cl2 (3 × 15 mL). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 to 1 / 50) using TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10). Fractions with Rf = 0.5 to 0.6 were collected to afford Compound 59-1 (1.9 g, 51% yield) as a white solid. ESI [M+H] + =371.1

[0390] m-CPBA (533 mg, 3.10 mmol) was added to a solution of compound 59-1 (1.0 g, 2.70 mmol) in CH2Cl2 (30 mL) at room temperature and stirred for 2 hours. The reaction was monitored by TLC. Saturated aqueous sodium bicarbonate solution (50 mL) was slowly added to the reaction system, and the mixture was extracted with CH2Cl2 (3 × 15 mL). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, compound 59-2, which was used directly in the next step without purification.

[0391] NaOH (103 mg, 2.58 mmol) was added to a solution of crude compound 59-2 in MeOH / THF / H2O (13.5 mL, v / v / v = 10 / 2.5 / 1) in an ice-salt bath at 0°C and stirred at room temperature overnight. After the reaction was complete as monitored by TLC, water (50 mL) was added to the reaction system, and the mixture was extracted with EtOAc (3 × 5 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 preparative TLC (ethyl acetate / petroleum ether (v / v) = 1 / 3). The fractions with Rf = 0.3-0.4 were collected to obtain the colorless oily compound DEX-69 (210 mg, two-step yield 33%). ESI [M+H] + =234.1.

[0392] 1H NMR (400MHz, d6-DMSO) δ11.47(s,1H),7.85(d,J=7.6Hz,1H),7.39(t,J=7.6Hz,1H),7.32(d, J=7.3Hz,1H),6.16–6.12(m,1H),5.81–5.77(m,1H),2.23(s,3H),2.15(s,3H),2.04(s,3H).

[0393] 3. Preparation of target compound DEX-81

[0394] DEX-69 (354 mg, 1.5 mmol) was dissolved in dry DMF (8 mL) at room temperature and cooled to 0°C in an ice-salt bath. NaH (92.0 mg, 60% in mineral oil, 2.3 mmol) was added to the mixture, and the mixture was stirred at 0°C for 10 minutes. MeI (425.8 mg, 3.0 mmol) was slowly added to the mixture via syringe and stirred at room temperature for 1 hour. After completion of the reaction as monitored by TLC, the reaction mixture was poured into ice water and extracted with EtOAc (3 × 5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford the crude product. The crude product was purified by preparative TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10), and fractions with Rf = 0.5-0.6 were collected to afford the target compound DEX-81 (243 mg, 65.5% yield) as a white solid. ESI [M+H] + =248.2.

[0395] 1 H NMR (400MHz, d6-DMSO) δ7.81(d,J=7.5Hz,1H),7.42(t,J=7.6Hz,1H),7.36(d,J=7.4Hz,1H),5. 90(d,J=3.8Hz,1H),5.86(d,J=3.7Hz,1H),3.60(s,3H),2.25(s,3H),2.18(s,3H),2.01(s,3H).

[0396] 4. Preparation of target compounds DEX-128 and DEX-129

[0397] TFA (2.5 mL) was added to a solution of DEX-70 (200 mg, 0.92 mmol) in DCE (20 mL) in an ice-salt bath at 0°C and stirred at room temperature for 2 hours. After completion of the reaction as monitored by TLC, the mixture was concentrated under reduced pressure, basified with saturated aqueous sodium bicarbonate (30 mL), and extracted with CH2Cl2 (3 x 5 mL). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford the crude product. The crude product was purified by preparative TLC (ethyl acetate / petroleum ether (v / v) = 1 / 20). Fractions with Rf = 0.5-0.6 were collected to afford the title compound DEX-128 (134 mg, 67.0% yield) as a colorless oil. ESI [M+H] + =218.2

[0398] 1 H NMR (400MHz, d6-DMSO) δ11.01(s,1H),6.90(t,J=7.6Hz,1H),6.87–6.82(m,2H),6.67–6.63(m,1H),5.78(s,1H),2.21(s,6H),2.19(s,3H).

[0399] m-CPBA (28 mg, 0.16 mmol) was added to a solution of compound DEX-128 (30 mg, 0.14 mmol) in CH2Cl2 (5 mL) at room temperature and stirred for 2 hours. The reaction was monitored by TLC. Saturated aqueous sodium bicarbonate (10 mL) was slowly added to the reaction system, and the mixture was extracted with CH2Cl2 (3 x 2 mL). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous Na2SO4, filtered, 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 / 10). Fractions with Rf = 0.5-0.6 were collected to obtain the target compound DEX-129 (25 mg, 78% yield) as a colorless oil. ESI [M+H] + =234.2

[0400] 1 H NMR (400MHz, d6-DMSO) δ11.17(s,1H),7.79(d,J=7.4Hz,1H),7.36(t,J=7.6Hz,1H),7.28(d,J=7. 2Hz,1H),7.12(dd,J=2.8,1.8Hz,1H),5.60–5.56(m,1H),2.22(s,3H),2.07(s,3H),2.04(s,3H).

[0401] Example 17 Preparation of compounds DEX-130 to DEX-138 of the present invention

[0402] 1. Preparation of target compounds DEX-130 to DEX-132

[0403] At room temperature, 3-pyridinecarboxaldehyde (2.0 g, 18.7 mmol) was dissolved in dry THF (20 mL). The reaction system was replaced with nitrogen three times, protected by nitrogen, and cooled to 0°C in an ice-salt bath. A (37.4 mL, 1 mol / L in THF, 37.4 mmol) was added to the reaction system at a rate of 2 mL / min and stirred at room temperature for 4 h. After the reaction was complete as monitored by TLC, the reaction system was cooled to 0°C in an ice-water bath, saturated aqueous ammonium chloride solution (100 mL) was slowly added to the reaction system, and the mixture was 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 / 50 to 1 / 10) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5). The fractions with Rf = 0.4 to 0.5 were collected to obtain compound 136-1 (3.5 g, yield 87.9%) as a white solid. ESI [M+H] + =214.2.

[0404] At room temperature, 136-1 (3.5 g, 16.4 mmol) was dissolved in CH2Cl2 (50 mL), and active MnO2 (15.7 g, 164.0 mmol, 91%) was added. The mixture was stirred at reflux for 10 hours. After the reaction was complete as monitored by TLC, the mixture was filtered and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 50 to 1 / 10) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10). The fractions with Rf = 0.5 to 0.6 were collected to obtain the target compound DEX-130 (3.0 g, yield 86.5%) as a colorless oil. ESI [M+H] + =212.2.

[0405] 1 H NMR(400MHz,d6-DMSO)δ8.88–8.76(m,2H),8.06(dt,J=8.0,2.0Hz,1H),7.59(dd,J=7.9,4.8Hz,1 H),7.39(d,J=7.4Hz,1H),7.24(t,J=7.5Hz,1H),7.16(d,J=7.4Hz,1H),2.32(s,3H),2.12(s,3H).

[0406] DEX-130 (1.0 g, 4.74 mmol) was dissolved in dry THF (10 mL) at room temperature. The reaction system was purged with nitrogen three times, protected by nitrogen, and cooled to 0°C in an ice-salt bath. MeLi (3.64 mL, 4.74 mmol in Et2O, 1.3 mol / L) was slowly added to the system via syringe and stirred for 15 minutes. After the reaction was complete as monitored by TLC, the reaction system was cooled to 0°C in an ice-water bath. Saturated aqueous ammonium chloride (30 mL) was slowly added to the reaction system and extracted with EtOAc (3 × 15 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain compound 136-2 (0.9 g, 83.7% yield) as a gray solid. ESI [M+H] + =228.2

[0407] 136-2 (900 mg, 3.96 mmol) was dissolved in TFA (2 mL) at room temperature and stirred at 75°C for 30 minutes. After completion of the reaction as monitored by TLC, the mixture was concentrated under reduced pressure, basified with saturated aqueous sodium bicarbonate (20 mL), and extracted with CH2Cl2 (3 × 5 mL). 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 / 5) and fractions with Rf = 0.5-0.6 were collected to give the target compound DEX-131 (800 mg, 96.5% yield) as a yellow solid. ESI [M+H] + =210.3

[0408] 1 H NMR(400MHz,d6-DMSO)δ8.52–8.39(m,2H),7.59(ddd,J=8.0,2.3,1.7Hz,1H),7.35(ddd,J=8.0,4.7,0.7Hz,1H), 7.22–7.11(m,2H),7.01(d,J=7.1Hz,1H),6.00(d,J=0.9Hz,1H),5.25(d,J=0.8Hz,1H),2.25(s,3H),1.92(s,3H).

[0409] Compound DEX-131 (250 mg, 1.20 mmol) and 10% wet palladium on carbon (25 mg) were dissolved in MeOH (5 mL) at room temperature and stirred for 2 hours. After the reaction was complete as monitored by TLC, the reaction solution was filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5) and the fraction with Rf = 0.5-0.6 was collected to obtain the target compound DEX-132 (172 mg, 68.3% yield) as a white solid. ESI [M+H] +=212.2.

[0410] 1 H NMR (400MHz, d6-DMSO) δ8.43(d,J=1.9Hz,1H),8.37(dd,J=4.7,1.5Hz,1H),7.53(dt,J=7.9,1.8Hz,1H),7.28(ddd,J=7.9,4.8 ,0.4Hz,1H),7.15–7.06(m,2H),7.03(d,J=6.9Hz,1H),4.45(q,J=7.1Hz,1H),2.21(s,3H),2.10(s,3H),1.54(d,J=7.2Hz,3H).

[0411] 2. Preparation of target compounds DEX-133 to DEX-135

[0412] At room temperature, 3-pyridinecarboxaldehyde (2.5 g, 23.1 mmol) was dissolved in dry THF (25 mL). The reaction system was replaced with nitrogen three times, protected by nitrogen, and cooled to 0°C in an ice-salt bath. Grignard reagent A (37.4 mL, 1 mol / L in THF, 37.4 mmol) was slowly added dropwise to the system and stirred at room temperature for 4 hours. After the reaction was complete as monitored by TLC, the reaction system was cooled to 0°C with an ice-water bath, saturated aqueous ammonium chloride solution (50 mL) was slowly added to the reaction system, and the mixture was extracted with EtOAc (3×10 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 50 to 1 / 10) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5). The fractions with Rf = 0.4 to 0.5 were collected to obtain compound 139-1 (3.0 g, yield 61%) as a white solid. ESI [M+H] + =215.2.

[0413] Active MnO2 (13.4 g, 140.0 mmol, 91%) was added to a solution of 139-1 (3.0 g, 14.0 mmol) in CH2Cl2 (40 mL) at room temperature and stirred under reflux for 10 hours. After the reaction was complete as monitored by TLC, the mixture was filtered and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 50 to 1 / 10) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10). Fractions with Rf = 0.5 to 0.6 were collected to obtain the target compound DEX-133 (2.5 g, 84.2% yield) as a white solid. ESI [M+H] + =213.3.

[0414] 1H NMR (400MHz, d6-DMSO) δ9.43(s,1H),9.01(s,2H),7.46–7.39(m,1H),7.29–7.21(m,2H),2.33(s,3H),2.19(s,3H).

[0415] At room temperature, DEX-133 (1.0 g, 4.71 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 (3.63 mL, 4.71 mmol, 1.3 mol / L) was added to the system at a rate of 0.5 mL / min via syringe, and stirring was continued for 15 minutes. After the reaction was complete as monitored by TLC, the reaction system 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 × 5 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain compound 139-2 (210 mg, yield 19.5%) as a gray solid. ESI [M+H] + =229.2

[0416] 139-2 (210 mg, 0.92 mmol) was dissolved in TFA (1 mL) at room temperature and stirred at 75°C for 30 minutes. After completion of the reaction as monitored by TLC, the mixture was concentrated under reduced pressure, basified with saturated aqueous sodium bicarbonate (20 mL), and extracted with CH2Cl2 (3 × 5 mL). 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 / 5) and fractions with Rf = 0.5-0.6 were collected to give the target compound DEX-134 (108 mg, 55.8% yield) as a colorless oil. ESI [M+H] + =211.3

[0417] 1 H NMR(400MHz,d6-DMSO)δ9.10(s,1H),8.65(s,2H),7.24–7.14(m,2H),7.03(d,J=7 .3Hz,1H),6.16(d,J=0.5Hz,1H),5.37(d,J=0.4Hz,1H),2.26(s,3H),1.94(s,3H).

[0418] Compound DEX-134 (62 mg, 0.30 mmol) and 10% wet palladium on carbon (6 mg) were dissolved in MeOH (5 mL) at room temperature and stirred for 2 hours. After completion of the reaction as monitored by TLC, the mixture was filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5) and the fraction with Rf = 0.5-0.6 was collected to obtain the target compound DEX-135 (44 mg, yield 69.6%) as a colorless oil. ESI [M+H] + =213.3.

[0419] 1 H NMR (400MHz, d6-DMSO) δ9.01(s,1H),8.64(s,2H),7.15–7.04(m,3H),4.50(q,J=7.0Hz,1H),2.22(s,3H),2.13(s,3H),1.58(d,J=7.2Hz,3H).

[0420] 3. Preparation of target compound DEX-136

[0421] 4-Methylpyrimidine (2.5 g, 26.6 mmol) was dissolved in 1,4-dioxane (25 mL) at room temperature, and selenium dioxide (2.95 g, 26.6 mmol) was added to the system. The mixture was stirred at 100°C for 5 hours. After completion of the reaction as monitored by TLC, the reaction system was cooled to 0°C in an ice-water bath. The aqueous solution (50 mL) was slowly added to the reaction system, and the mixture was extracted with EtOAc (3 × 50 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 / 50 to 1 / 10) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5). Fractions with Rf = 0.4 to 0.5 were collected to obtain Compound 142-1 (0.5 g, 17.4% yield) as a white solid. ESI [M+H] + =109.1.

[0422] 142-1 (500 mg, 4.62 mmol) was dissolved in dry THF (5 mL) at room temperature. 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 (9.24 mL, 1 mol / L in THF, 9.24 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 ice-water bath was lowered to 0°C, and saturated aqueous ammonium chloride (10 mL) was slowly added to the reaction system. The reaction was extracted with EtOAc (3 × 5 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 / 50 to 1 / 10) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5). Fractions with Rf = 0.4 to 0.5 were collected to obtain compound 142-2 (600 mg, 61% yield) as a white solid. ESI[M+H] + =215.2.

[0423] At room temperature, 142-2 (600 mg, 2.8 mmol) was dissolved in CH2Cl2 (10 mL), and active MnO2 (2.67 g, 28.0 mmol, 91%) was added. The mixture was stirred at reflux for 10 hours. After the reaction was complete as monitored by TLC, the mixture was filtered and 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 / 50 to 1 / 10) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10). The fraction with Rf = 0.5 to 0.6 was collected to obtain compound 142-3 (500 mg, yield 84.2%) as a white solid. ESI [M+H] + =213.3.

[0424] At room temperature, 142-3 (500 mg, 2.36 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. MeLi (1.81 mL, 1.3 mol / L in Et2O, 2.36 mmol) was slowly added to the system via syringe, and stirring was continued for 15 minutes. 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 the reaction was extracted with EtOAc (3 × 5 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was used directly in the next reaction without purification.

[0425] 142-4 and TFA (2 mL) were stirred at 75°C for 30 minutes at room temperature. After the reaction was complete as monitored by TLC, the mixture was concentrated under reduced pressure, basified with saturated aqueous sodium bicarbonate (20 mL), and extracted with CH2Cl2 (3×5 mL). 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 / 5) and fractions with Rf = 0.5-0.6 were collected to give the target compound 142-5 (54 mg, 10.9% yield over two steps). ESI [M+H] + =211.3

[0426] Compound 142-5 (54 mg, 0.26 mmol) and 10% wet palladium on carbon (5 mg) were dissolved in methanol (5 mL) at room temperature and stirred for 2 hours. After the reaction was complete as monitored by TLC, the reaction solution was filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5) and the fraction with Rf = 0.5-0.6 was collected to obtain the target compound DEX-136 (34 mg, yield 62.4%). ESI [M+H] + =213.3.

[0427] 4. Preparation of target compounds DEX-137 to DEX-138

[0428] The target compounds DEX-137 to DEX-138 were prepared by Suzuki coupling reaction using halides and boronic acid according to the synthetic route.

[0429] Compound DEX-137: 75 mg, ESI [M+H] + =201.1.

[0430] Compound DEX-138: 51 mg, ESI [M+H] + =200.1.

[0431] Example 18 Preparation of compounds DEX-45, DEX-123 to DEX-127 of the present invention

[0432] Common operations:

[0433] Dissolve the starting material (1 eq) in dry DMF (5 mL) at room temperature, cool to 0°C in an ice-salt bath, slowly add NaH (1.2 eq, 60% in mineral oil) and continue stirring for 10 minutes. Then slowly add MeI (1.5 eq) via syringe and stir at room temperature for 30 minutes to 2 hours. After completion of the reaction as monitored by TLC, pour the reaction mixture into ice water and extract with EtOAc (3 x 5 mL). The combined organic phases are washed with saturated brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to yield the crude product, which is then purified by preparative TLC to yield the title compound.

[0434] Compound DEX-45: 140 mg, white solid, yield 92%, ESI [M+H] + =228.3.

[0435] 1 H NMR (400MHz, d6-DMSO) δ7.22(d,J=7.4Hz,1H),7.12(t,J=7.5Hz,1H),6.98(d,J=7.3Hz,1H),6. 66(d,J=3.0Hz,1H),5.88(d,J=3.0Hz,1H),3.54(s,3H),2.39(s,3H),2.27(s,3H),2.07(s,3H).

[0436] Compound DEX-123: 49 mg, colorless oil, yield 85.9%, ESI [M+H] + =228.3.

[0437] 1 H NMR(400MHz,d6-DMSO)δ7.22(d,J=7.4Hz,1H),7.12(t,J=7.5Hz,1H),7.04(d,J=7.1Hz,1H) ,6.78(d,J=2.2Hz,1H),6.63–6.60(m,1H),2.27(s,3H),2.21(d,J=0.9Hz,3H),2.08(s,3H).

[0438] Compound DEX-124: 27 mg, white solid, ESI [M+H] + =228.3.

[0439] 1H NMR (400MHz, d6-DMSO) δ7.23(d,J=7.4Hz,1H),7.13(t,J=7.5Hz,1H),7.05(d,J=7.1Hz,1H ),6.99(d,J=1.8Hz,1H),6.18(s,1H),3.51(s,3H),2.27(s,3H),2.16(s,3H),2.08(s,3H).

[0440] Compound DEX-125: 36 mg, yellow solid, ESI [M+H] + =226.3.

[0441] 1 H NMR(400MHz,d6-DMSO)δ7.11–7.01(m,2H),6.92–6.86(m,1H),6.05(d,J=1.9Hz,1H),5.94(d,J=0.9Hz, 1H),5.36(d,J=2.1Hz,1H),4.52(d,J=2.1Hz,1H),3.36(s,3H),2.24(s,3H),2.11(s,3H),2.03(s,3H).

[0442] Compound DEX-126: 115 mg, colorless oil, ESI [M+H] + =214.3.

[0443] 1 H NMR(400MHz,d6-DMSO)δ7.25(d,J=7.4Hz,1H),7.14(t,J=7.5Hz,1H),7.11–7.04(m,2H),6.8 4(dd,J=2.7,2.2Hz,1H),6.41(dd,J=2.8,1.8Hz,1H),3.63(s,3H),2.27(s,3H),2.09(s,3H).

[0444] Compound DEX-127: 83 mg, yellow oil, ESI [M+H] + =282.2.

[0445] 1 H NMR (400MHz, d6-DMSO) δ7.50(d,J=1.8Hz,1H),7.30(d,J=7.0Hz,1H),7.21–7.13(m,2H),6.96(d,J=0.8Hz,1H),3.75(s,3H),2.29(s,3H),2.11(s,3H).

[0446] Example 19 Preparation of compounds of the present invention DEX-179, DEX-184, DEX-187, DEX-188 and DEX-190

[0447] The preparation methods of the target compounds DEX-179, DEX-184, DEX-187, DEX-188 and DEX-190 are similar to that of the target compound DEX-45, using compound DEX-67 as a raw material and reacting them with bromide or iodide through alkylation reaction.

[0448] Compound DEX-179: 281.4 mg, white solid, ESI [M+H] + =228.1.

[0449] 1 H NMR(400MHz,d6-DMSO)δ7.26(d,J=7.3Hz,1H),7.14(t,J=7.5Hz,1H),7.08(d,J=7.3Hz,1 H),6.22(d,J=4.0Hz,1H),5.96(d,J=4.0Hz,1H),3.94(s,3H),2.29(s,6H),2.12(s,3H).

[0450] Compound DEX-184: 4.0 mg, white solid, ESI [M+H] + =256.2.

[0451] 1 H NMR (400MHz, d6-DMSO) δ7.25(d,J=7.6Hz,1H),7.14(t,J=7.5Hz,1H),7.06(d,J=7.3Hz,1H),6.20(d,J=4.0Hz ,1H),5.91(d,J=4.0Hz,1H),5.44–5.25(m,1H),2.40(s,3H),2.29(s,3H),2.10(s,3H),1.56(d,J=7.0Hz,6H).

[0452] Compound DEX-187: 29.3 mg, white solid, ESI [M+H] + =270.2.

[0453] 1H NMR (400MHz, d6-DMSO) δ7.25(d,J=7.3Hz,1H),7.14(t,J=7.6Hz,1H),7.04(d,J=7.3Hz,1H),6.25(d,J=4.0Hz,1H) ,5.96(d,J=4.0Hz,1H),4.26(d,J=7.1Hz,2H),2.31(s,3H),2.29(s,3H),2.12–2.05(m,4H),0.89(d,J=6.7Hz,6H).

[0454] Compound DEX-188: 15.4 mg, white solid, ESI [M+H] + =285.1.

[0455] Compound DEX-190: 38.9 mg, white solid, ESI [M+H] + =242.1.

[0456] Example 20 Preparation of compounds DEX-181 to DEX-183 of the present invention

[0457] Compound DEX-181: 13.6 mg, brown solid, ESI [M+H] + =229.1

[0458] 1 H NMR(400MHz,d6-DMSO)δ12.52(brs,1H),7.85(s,1H),7.13(dd,J=7.6,1.5Hz,1H),7.08–6.94(m,2H),6.7 9(t,J=7.6Hz,1H),5.73(d,J=1.8Hz,1H),5.08(d,J=1.7Hz,1H),3.32–3.28(m,1H),1.17(d,J=6.9Hz,6H).

[0459] Compound DEX-182: 21.7 mg, yellow solid, ESI [M+H] + =231.1

[0460] 1 H NMR(400MHz,d6-DMSO)δ12.19(brs,1H),7.78(s,1H),7.02–6.94(m,2H),6.93–6.85(m,1H),6.70(t ,J=7.6Hz,1H),4.20–4.10(m,1H),3.33–3.27(m,1H),1.52(d,J=7.3Hz,3H),1.13(t,J=6.8Hz,6H).

[0461] Compound DEX-183: 82.23 mg, gray solid, ESI [M+H] + =231.1

[0462] 1 H NMR(400MHz,d6-DMSO)δ13.54(s,1H),13.05(s,1H),8.93(s,1H),8.12(s,1H),7.99(s,1H ),7.48(d,J=7.4Hz,1H),6.94(t,J=7.8Hz,1H),3.32–3.25(m,2H),1.20(d,J=6.9Hz,6H).

[0463] Example 21 Preparation of compounds DEX-206 and DEX-192 of the present invention

[0464] The target compounds DEX-206 and DEX-192 were prepared using methyl 4-fluoropyrrole-2-carboxylate as the starting material.

[0465] DEX-206: 40.8 mg, white solid, ESI [M+H] + =218.1.

[0466] 1 H NMR (400MHz, d6-DMSO) δ11.99(s,1H),7.34–7.30(m,1H),7.25–7.15(m,3H),6.22(s,1H),2.31(s,3H),2.16(s,3H).

[0467] DEX-192: 18.8 mg, white solid, ESI [M+H] + =218.1.

[0468] Example 22 Preparation of the compound DEX-191 of the present invention

[0469] The preparation method of the target compound DEX-191 is similar to that of DEX-3 in Example 1, using ethyl 2-amino-1H-imidazole-5-carboxylate as the starting material. ESI [M+H] + =219.1.

[0470] Example 23 Preparation of compounds of the present invention DEX-193, DEX-194, DEX-195 and DEX-197

[0471] Intermediate 324-1 was prepared similarly to compound DEX-3-2 in Example 1, using ethyl 2-amino-5-methyl-1H-pyrrole-3-carboxylate as the starting material. The target compound DEX-193 was prepared similarly to compound DEX-47 in Example 11, using 324-1 as the starting material.

[0472] The preparation method of the target compound DEX-194 is similar to that of compound DEX-193.

[0473] The preparation method of the target compound DEX-195 is similar to that of compound 324-7.

[0474] The preparation method of the target compound DEX-197 is similar to that of compound 35, and is obtained by alkylation reaction of compound 326 with iodomethane.

[0475] DEX-193: 10.8 mg, white solid, ESI [M+H] + =230.1.

[0476] DEX-194: 15.0 mg, gray solid, ESI [M+H] + =230.1.

[0477] DEX-195: 18.2 mg, white solid, ESI [M+H] + =232.1.

[0478] DEX-197: 11.1 mg, white solid, ESI [M+H] + =246.1.

[0479] Example 24 Preparation of the compound DEX-196 of the present invention

[0480] Compound DEX-67 (100 mg, 0.469 mmol) was dissolved in acetonitrile (2 mL), and a selective fluorine reagent (332.6 mg, 0.939 mmol) was added. The mixture was stirred at 85°C for 6 hours. After the reaction was complete as monitored by TLC, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative TLC to obtain a white solid compound DEX-196 (9.83 mg, 9.1% yield). ESI [M+H] + =232.1.

[0481] Example 25 Preparation of compounds DEX-212 and DEX-213 of the present invention

[0482] At -10°C, Grignard reagent A (27.3 mL, 1 mol / L in THF, 27.3 mmol) was slowly added dropwise to a solution of 2-methylimidazole-4-carbaldehyde (1.0 g, 9.1 mmol) in THF (10 mL). The mixture was allowed to warm to room temperature and stirred for 30 minutes. After completion of the reaction as monitored by TLC, the reaction solution was poured into saturated aqueous ammonium chloride (30 mL) and 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 afford the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 50 to 1 / 5) using TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5). Fractions with Rf = 0.3 to 0.5 were collected to afford DEX-212-1 (552.0 mg, 28.1% yield) as a white solid. ESI [M+H] + =217.1.

[0483] DEX-212-1 (552.0 mg, 2.55 mmol) was dissolved in CH2Cl2 (10 mL), and activated MnO2 (6.4 g, 73.6 mmol) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, as monitored by TLC, the mixture was filtered and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 50 to 1 / 5) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5). Fractions with Rf = 0.4 to 0.6 were collected to obtain the target compound DEX-212-2 (184.1 mg, 33.7% yield) as a white solid. ESI [M+H] + =215.1.

[0484] DEX-212-2 (184.1 mg, 0.86 mmol) was dissolved in DMF (5 mL), and potassium carbonate (112.4 mg, 0.86 mmol) and iodoethane (136.8 mg, 0.88 mmol) were added. The mixture was stirred at room temperature for 12 hours. After completion of the reaction as monitored by TLC, the reaction solution was poured into ice water and extracted with EtOAc (3 × 10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to afford the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 to 1 / 5) to afford the target compound DEX-212 (72.0 mg, 34.7% yield) as a white solid and the target compound DEX-213 (19.0 mg, 9.1% yield) as a syrupy solid.

[0485] Compound DEX-212: ESI[M+H] + =243.1.

[0486] 1 H NMR(400MHz,d6-DMSO)δ7.31(d,J=6.4Hz,1H),7.22–7.13(m,2H),7.03(s,1H),4. 40(q,J=7.1Hz,2H),2.44(s,3H),2.30(s,3H),2.14(s,3H),1.34(t,J=7.1Hz,3H).

[0487] Compound DEX-213: ESI[M+H] + =243.1.

[0488] 1 H NMR(400MHz,d6-DMSO)δ7.70(s,1H),7.31–7.26(m,1H),7.21–7.12(m,2H),3.98 (q,J=7.3Hz,2H),2.35(s,3H),2.30(s,3H),2.12(s,3H),1.32(t,J=7.3Hz,3H).

[0489] Example 26 Preparation of the compounds of the present invention DEX-214, DEX-218 to DEX-222, DEX-236 to DEX-238, DEX-361 to DEX-400, DEX-679 and DEX-680, DEX-697

[0490] A-1 was reduced with sodium borohydride to obtain A-2. Part of the intermediate compound A-2 was purchased directly.

[0491] Preparation of the compound DEX-220 of the present invention

[0492] Compound DEX-220-1 (10 g, 67.47 mmol) was dissolved in dry THF (80 mL) and cooled to 0°C in an ice-salt bath. Sodium borohydride (5.1 g, 134.8 mmol) was added portionwise to the system and stirred at room temperature for 2 hours. After the reaction was complete as monitored by TLC, the reaction was cooled to 0°C in an ice-water bath and poured into saturated aqueous ammonium chloride (100 mL). The mixture was extracted with EtOAc (3 × 10 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 0-20%) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1). Fractions with Rf = 0.5-0.6 were collected to obtain DEX-220-2 (8.27 g, yield 81.6%) as a colorless oil. ESI [M+H] + =305.0

[0493] At room temperature, compound DEX-220-2 (600 mg, 3.99 mmol) was dissolved in dry dichloromethane (10 mL). The temperature was cooled to 0°C in an ice-salt bath. Dichlorothionyl (1.19 g, 10 mmol) was slowly added to the system using a syringe. Two drops of dry DMF were added, and the mixture was refluxed and stirred for 1 hour. The mixture was then concentrated under reduced pressure to obtain the crude compound DEX-220-3. The crude compound DEX-220-3 was dissolved in dry DMF (5 mL), and imidazole (325.97 mg, 4.79 mmol) and potassium carbonate (1.10 g, 7.96 mmol) were added in sequence. The mixture was stirred at 60°C overnight. After the reaction was complete as monitored by TLC, the reaction system was cooled to room temperature and extracted with EtOAc (3×10 mL). The combined organic phases were dried over anhydrous Na 2 SO 4 , 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) = 0-100%) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1) to obtain a light yellow oily compound DEX-220 (455 mg, yield 56.9%). ESI [M+H] + =200.9

[0494] 1 H NMR(400MHz,d6-DMSO)δ7.72(s,1H),7.16(s,1H),7.14–7.05(m,2H),6.97–6.92(m,1H) ),6.90(s,1H),5.80(q,J=7.0Hz,1H),2.27(s,3H),2.21(s,3H),1.74(d,J=7.0Hz,3H).

[0495] The compounds DEX-214, DEX-218, DEX-219, DEX-221, DEX-222, DEX-236 to DEX-238, DEX-361 to DEX-400, DEX-679 and DEX-680 of the present invention were prepared by referring to the method of DEX-220.

[0496] Compound DEX-214: 373 mg, ESI [M+H] + =205.0

[0497] 1H NMR(400MHz,d6-DMSO)δ8.32(s,1H),7.65(t,J=1.4Hz,1H),7.09(d,J=0.5Hz,1H),5.28–5.09(m,1H),2.70–2.55(m,1H), 2.47–2.38(m,1H),2.37–2.25(m,1H),2.05–1.90(m,2H),1.92–1.78(m,1H),1.26(s,3H),1.21–1.16(m,4H),0.98(s,3H).

[0498] Compound DEX-218: 18 mg, ESI [M+H] + =205.0

[0499] 1 H NMR(400MHz,d6-DMSO)δ7.78(s,1H),7.30–7.21(m,2H),7.15–7.04(m,2H),6. 91(s,1H),5.78(q,J=7.2Hz,1H),2.25(d,J=2.1Hz,3H),1.80(d,J=7.1Hz,3H).

[0500] Compound DEX-221: 292 mg, ESI [M+H] + =219.0

[0501] 1 H NMR(400MHz,d6-DMSO)δ7.45(t,J=1.5Hz,1H),7.18–7.07(m,2H),7.03–6.93(m,1H),6.88(d d,J=8.2,1.7Hz,1H),5.73(q,J=6.9Hz,1H),2.27(s,3H),2.22(s,3H),1.72(d,J=7.0Hz,3H).

[0502] Compound DEX-222: 538 mg, ESI [M+H] + =268.9

[0503] 1 H NMR(400MHz,d6-DMSO)δ7.96(s,1H),7.88(s,1H),7.19–7.08(m,2H),7.06–6.96 (m,1H),5.89(q,J=7.0Hz,1H),2.27(s,3H),2.23(s,3H),1.78(d,J=7.0Hz,3H).

[0504] Compound DEX-236: 101 mg, ESI [M+H] + =220.9

[0505] 1 H NMR(400MHz,d6-DMSO)δ7.79(s,1H),7.33(d,J=7.4Hz,1H),7.29–7.21(m,2H),7.06(d ,J=7.7Hz,1H),6.92(s,1H),5.88(q,J=7.0Hz,1H),2.37(s,3H),1.80(d,J=7.0Hz,3H).

[0506] Compound DEX-237: 148 mg, ESI [M+H] + =238.9

[0507] 1 H NMR(400MHz,d6-DMSO)δ7.53(t,J=1.4Hz,1H),7.38–7.32(m,H),7.29(t,J=7.6Hz,1H),7.16–7.0 8(m,1H),6.97(dd,J=8.2,1.7Hz,1H),5.81(q,J=6.9Hz,1H),2.37(s,3H),1.78(d,J=7.0Hz,3H).

[0508] Compound DEX-238: 95 mg, ESI [M+H] + =222.9

[0509] 1 H NMR(400MHz,d6-DMSO)δ7.51(s,1H),7.30–7.23(m,1H),7.15–7.08(m,2H),6.98(dd,J =8.2,1.6Hz,1H),5.71(q,J=6.8Hz,1H),2.25(d,J=2.0Hz,3H),1.78(d,J=7.1Hz,3H).

[0510] Compound DEX-363: 309 mg, white solid, ESI [M+H] + =268.8.

[0511] 1 H NMR (400MHz, d6-DMSO) δ8.13(s,1H),7.45–7.36(m,1H),7.29–7.19(m,2H),7.07–6.97(m,2H),5.70(q,J=7.1Hz,1H),1.86(d,J=7.1Hz,3H).

[0512] Compound DEX-364: 169 mg, colorless oil, ESI [M+H] + =258.9.

[0513] 1 H NMR (400MHz, d6-DMSO) δ8.03(s,1H),7.99(s,1H),7.48–7.32(m,2H),7.31–7.17(m,2H),5.90(q,J=7.1Hz,1H),1.86(d,J=7.1Hz,3H).

[0514] Compound DEX-369: 481 mg, colorless oil, ESI [M+H] + =284.8.

[0515] 1 H NMR(400MHz,d6-DMSO)δ7.82(d,J=1.5Hz,1H),7.55–7.48(m,1H),7.46(d,J= 1.5Hz,1H),7.42–7.30(m,3H),5.85(q,J=7.0Hz,1H),1.81(d,J=7.0Hz,3H).

[0516] Compound DEX-370: 18 mg, colorless oil, ESI [M+H] + =274.8.

[0517] 1 H NMR (400MHz, d6-DMSO) δ8.03(s,1H),8.00–7.96(m,1H),7.54–7.50(m,1H),7.46–7.34(m,3H),5.95(q,J=7.0Hz,1H),1.85(d,J=7.1Hz,3H).

[0518] Compound DEX-374: 139 mg, light yellow oil, ESI [M+H] + =258.8.

[0519] 1 H NMR(400MHz,d6-DMSO)δ7.83(d,J=1.4Hz,1H),7.65–7.53(m,1H),7.45(d,J= 1.5Hz,1H),7.32–7.20(m,2H),5.82(q,J=7.1Hz,1H),1.81(d,J=7.1Hz,3H).

[0520] Compound DEX-375: 137 mg, white solid, ESI [M+H] + =302.8.

[0521] 1 H NMR(400MHz,d6-DMSO)δ7.60(td,J=7.9,1.7Hz,1H),7.56(d,J=1.5Hz,1H),7.28(td,J=7.9,0.8 Hz,1H),7.24–7.17(m,1H),6.99(d,J=1.5Hz,1H),5.81(q,J=7.0Hz,1H),1.81(d,J=7.1Hz,3H).

[0522] Compound DEX-381: 406 mg, colorless oil, ESI [M+H] + =302.7.

[0523] 1 H NMR (400MHz, d6-DMSO) δ7.85(d,J=1.4Hz,1H),7.50–7.41(m,3H),7.20–7.13(m,1H),5.88(q,J=7.0Hz,1H),1.82(d,J=7.0Hz,3H).

[0524] Compound DEX-382: 304 mg, white solid, ESI [M+H] + =292.8.

[0525] 1 H NMR (400MHz, d6-DMSO) δ8.10(s,1H),8.08–8.02(m,1H),7.56–7.41(m,2H),7.26–7.17(m,1H),6.02(q,J=7.0Hz,1H),1.91(d,J=7.1Hz,3H).

[0526] Compound DEX-386: 212 mg, light yellow oil, ESI [M+H] + =224.9.

[0527] 1 H NMR(400MHz,d6-DMSO)δ7.53(d,J=1.5Hz,1H),7.45–7.35(m,1H),7.29–7.18 (m,3H),6.97(d,J=1.5Hz,1H),5.78(q,J=7.1Hz,1H),1.80(d,J=7.1Hz,3H).

[0528] Compound DEX-387: 16 mg, colorless oil, ESI [M+H] + =268.8.

[0529] 1 H NMR(400MHz,d6-DMSO)δ7.58(d,J=1.5Hz,1H),7.45–7.35(m,1H),7.31–7.14 (m,3H),7.03(d,J=1.4Hz,1H),5.75(q,J=7.1Hz,1H),1.80(d,J=7.1Hz,3H).

[0530] Compound DEX-390: 346 mg, light yellow oil, ESI [M+H] + =240.8.

[0531] 1 H NMR (400MHz, d6-DMSO) δ7.56–7.47(m,2H),7.44–7.31(m,2H),7.19–7.09(m,1H),7.05–6.94(m,1H),5.81(q,J=7.0Hz,1H),1.77(d,J=7.0Hz,3H).

[0532] Compound DEX-391: 451 mg, colorless oil, ESI [M+H] + =284.8.

[0533] 1 H NMR(400MHz,d6-DMSO)δ7.54(d,J=1.5Hz,1H),7.54–7.49(m,1H),7.42–7.33(m,2H),7 .11–7.06(m,1H),7.05(d,J=1.4Hz,1H),5.78(q,J=6.8Hz,1H),1.78(d,J=7.0Hz,3H).

[0534] Compound DEX-392: 53 mg, colorless oil, ESI [M+H] + =274.8.

[0535] 1 H NMR(400MHz,d6-DMSO)δ7.79(d,J=1.1Hz,1H),7.56–7.48(m,1H),7.42–7.36(m,2H),7 .23(d,J=1.0Hz,1H),7.15–7.07(m,1H),6.00(q,J=6.9Hz,1H),1.84(d,J=6.9Hz,3H).

[0536] Compound DEX-398: 385 mg, white solid, ESI [M+H] + =258.8.

[0537] 1 H NMR (400MHz, d6-DMSO) δ7.53(d,J=1.5Hz,1H),7.49–7.39(m,2H),7.04–6.91(m,2H),5.83(q,J=7.0Hz,1H),1.79(d,J=7.0Hz,3H).

[0538] Compound DEX-399: 507 mg, white solid, ESI [M+H] + =304.7.

[0539] 1 H NMR(400MHz,d6-DMSO)δ7.57(d,J=1.5Hz,1H),7.49–7.37(m,2H),7.06(d,J= 1.4Hz,1H),6.94–6.85(m,1H),5.79(q,J=7.0Hz,1H),1.79(d,J=7.0Hz,3H).

[0540] Compound DEX-400: 350 mg, white solid, ESI [M+H] + =292.8.

[0541] 1 H NMR(400MHz,d6-DMSO)δ7.82(d,J=1.1Hz,1H),7.51–7.38(m,2H),7.24(d,J=1.0Hz,1H),7. 00–6.91(m,1H),6.02(q,J=6.9Hz,1H),2.52(dt,J=3.5,1.7Hz,2H),1.85(d,J=6.9Hz,3H).

[0542] Compound DEX-679: 54 mg, ESI [M+H] + =205.0

[0543] 1 H NMR(400MHz,d6-DMSO)δ7.78(s,1H),7.28–7.21(m,2H),7.13–7.03(m,2H),6. 92(s,1H),5.78(q,J=7.1Hz,1H),2.25(d,J=2.1Hz,3H),1.80(d,J=7.1Hz,3H).

[0544] Compound DEX-680: 50 mg, ESI [M+H] + =205.0

[0545] 1 H NMR(400MHz,d6-DMSO)δ7.78(s,1H),7.28–7.21(m,2H),7.13–7.03(m,2H),6. 92(s,1H),5.78(q,J=7.1Hz,1H),2.25(d,J=2.1Hz,3H),1.80(d,J=7.1Hz,3H).

[0546] Compound DEX-697: 488 mg, light yellow oil, ESI [M+H] + =208.9.

[0547] 1 H NMR(400MHz,d6-DMSO)δ7.82(s,1H),7.47–7.36(m,1H),7.30(s,1H),7.28–7.19(m ,1H),7.09–6.99(m,1H),6.94(s,1H),5.85(q,J=7.1Hz,1H),1.83(d,J=7.1Hz,3H).

[0548] Example 27 Preparation of the compounds of the present invention DEX-223, DEX-215, DEX-307 and DEX-308

[0549] 4-Iodoimidazole (100 g, 515.5 mmol) and triethylamine (104.3 g, 1032 mmol) were dissolved in CH2Cl2 (500 mL) at room temperature. The reaction system was cooled to 0°C using an ice-salt bath. Triphenylmethane (172.5 g, 618.6 mmol) was added portionwise and stirred at room temperature overnight. After the reaction was complete as monitored by TLC, ice water (1000 mL) was added to the reaction system and extracted with CH2Cl2 (3 × 200 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 / 20 to 1 / 3) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 8). Fractions with Rf = 0.5 to 0.6 were collected to obtain DEX-215-1 (210 g, 93.4% yield) as a white solid.

[0550] At room temperature, DEX-215-1 (54.34 g, 124.5 mmol) was dissolved in CH2Cl2 (150 mL). The reaction system was replaced with nitrogen three times, protected by nitrogen, and cooled to -10°C in an ice-salt bath. EtMgBr (119 mL, 1 mol / L in Et2O, 119 mmol) was slowly added to the system using a constant pressure dropping funnel and stirred at room temperature for 1 hour. The system was cooled to -10°C using an ice-salt bath, and a solution of 1-(2-chloro-3-methylphenyl)ethan-1-one (10 g, 59.3 mmol) in CH2Cl2 (20 mL) was slowly added dropwise to the reaction system and stirred at room temperature overnight. After the reaction was complete as monitored by TLC, the reaction system was cooled to 0°C in an ice-water bath. Saturated aqueous ammonium chloride (200 mL) was slowly added to the reaction system and extracted with CH2Cl2 (3 × 50 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain crude compound DEX-215-2. TFA (40 eq) was added to a solution of crude compound DEX-215-2 in CH2Cl2 (20 mL) at room temperature and stirred overnight at room temperature. After the reaction was complete as monitored by LC-MS, the reaction was concentrated under reduced pressure, basified with saturated aqueous sodium bicarbonate (20 mL), extracted with CH2Cl2 (3 × 5 mL), and 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) to obtain compound DEX-223 as a white solid. ESI [M+H] + =219.0

[0551] 1 H NMR(400MHz,d6-DMSO)δ7.65(s,1H),7.36(d,J=7.4Hz,1H),7.27(t,J=7.5Hz,1H),7 .16(d,J=7.0Hz,1H),6.51(d,J=11.9Hz,1H),5.93(s,1H),4.90(s,1H),2.39(s,3H).

[0552] Compound DEX-223 (2.44 g, 11.16 mmol), iodine (7.08 g, 27.89 mmol), and phosphinic acid (2.86 g, 44.70 mmol) were dissolved in acetic acid (20 mL) at room temperature and stirred at 110°C for 3 hours. After completion of the reaction, as monitored by LC-MS, the mixture was concentrated under reduced pressure. Saturated aqueous sodium bicarbonate (100 mL) was slowly added to the reaction system, and the mixture was extracted with ethyl acetate (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) to afford compound DEX-215 (1.13 g, 45.9% yield) as a white solid. DEX-215 was resolved with either D- or L-tartaric acid to afford compounds DEX-307 and DEX-308.

[0553] Compound DEX-215: white solid, ESI[M+H] + =220.9

[0554] 1 H NMR (400MHz, d6-DMSO) δ7.65(s,1H),7.23–7.10(m,2H),7.09–7.00(m,1H),6.89(s,1H),4.55(q,J=7.1Hz,1H),2.37(s,3H),1.50(d,J=7.1Hz,3H).

[0555] Compound DEX-307: 237 mg, white solid, ESI [M+H] + =220.9

[0556] 1 H NMR (400MHz, d6-DMSO) δ7.67(s,1H),7.32–7.12(m,2H),7.10–6.99(m,1H),6.90(s,1H),4.57(q,J=7.1Hz,1H),2.38(s,3H),1.51(d,J=7.1Hz,3H).

[0557] Compound DEX-308: 167 mg, white solid, ESI [M+H] + =221.0

[0558] 1H NMR (400MHz, d6-DMSO) δ7.66(s,1H),7.31–7.11(m,2H),7.09–7.00(m,1H),6.88(s,1H),4.56(q,J=7.1Hz,1H),2.39(s,3H),1.50(d,J=7.1Hz,3H).

[0559] Example 28 Preparation of the compounds DEX-224, DEX-216, DEX-229 and DEX-230 of the present invention

[0560] 4-Iodoimidazole (100 g, 515.5 mmol) and triethylamine (104.3 g, 1032 mmol) were dissolved in CH2Cl2 (500 mL) at room temperature. The reaction system was cooled to 0°C using an ice-salt bath. Boc2O (172.5 g, 618.6 mmol) was added portionwise and stirred at room temperature overnight. After the reaction was complete as monitored by TLC, ice water (1000 mL) was added to the reaction system and extracted with CH2Cl2 (3 × 200 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 / 20 to 1 / 3) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 8). Fractions with Rf = 0.5 to 0.6 were collected to obtain DEX-216-1 (138 g, 91.0% yield) as a white solid.

[0561] At room temperature, DEX-216-1 (81.17 g, 276 mmol) was dissolved in CH2Cl2 (150 mL). The reaction system was replaced with nitrogen three times, protected by nitrogen, and cooled to -10°C in an ice-salt bath. EtMgBr (263 mL, 1 mol / L in Et2O, 263 mmol) was slowly added to the system using a constant pressure dropping funnel and stirred at room temperature for 1 hour. The system was cooled to -10°C using an ice-salt bath, and a solution of 1-(2-fluoro-3-methylphenyl)ethanone (20 g, 131.4 mmol) in CH2Cl2 (20 mL) was slowly added dropwise to the reaction system and stirred at room temperature overnight. After the reaction was completed as monitored by TLC, the reaction system was cooled to 0°C with an ice-water bath, saturated aqueous ammonium chloride solution (200 mL) was slowly added to the reaction system, and the mixture was extracted with CH2Cl2 (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) to obtain a crude white solid compound DEX-216-2 (58 g).

[0562] DEX-216-2 was deprotected by TFA and dehydrated to give a white solid compound DEX-224 (112 mg). ESI [M+H] + =202.9

[0563] 1H NMR (400MHz, d6-DMSO) δ7.66(s,1H),7.28(s,1H),7.13(dt,J=14.8,7.0Hz,2H),6.69(s,1H),5.93(s,1H),5.02(s,1H),2.27(d,J=2.0Hz,3H).

[0564] Compound DEX-216-2 (5 g, 15.6 mmol), iodine (9.90 g, 39.00 mmol), and phosphinic acid (3.99 g, 62.4 mmol) were dissolved in acetic acid (40 mL) at room temperature and stirred at 110°C for 3 hours. After completion of the reaction, as monitored by LC-MS, the mixture was concentrated under reduced pressure. Saturated aqueous sodium bicarbonate (100 mL) was slowly added to the reaction system, and the mixture was extracted with ethyl acetate (3 × 20 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) to obtain compound DEX-216 as a white solid.

[0565] DEX-216 was resolved with D-tartaric acid or L-tartaric acid to give compounds DEX-229 and DEX-230.

[0566] Compound DEX-216: colorless oil, ESI[M+H] + =204.0

[0567] 1 H NMR (400MHz, d6-DMSO) δ7.52(s,1H),7.10(s,1H),7.00(d,J=7.0Hz,2H),6.80(s,1H),4.41–4.29(m,1H),2.24(d,J=2.0Hz,3H),1.51(d,J=7.2Hz,3H).

[0568] Compound DEX-229: 206 mg, colorless oil, ESI [M+H] + =204.0

[0569] 1H NMR (400MHz, d6-DMSO) δ7.53(s,1H),7.12(s,1H),7.04(d,J=7.0Hz,2H),6.85(s,1H),4.54–4.25(m,1H),2.25(d,J=2.0Hz,3H),1.54(d,J=7.2Hz,3H).

[0570] Compound DEX-230: 142 mg, colorless oil, ESI [M+H] + =204.0

[0571] 1 H NMR (400MHz, d6-DMSO) δ7.51(s,1H),7.10(s,1H),7.02(d,J=7.0Hz,2H),6.82(s,1H),4.47–4.28(m,1H),2.21(d,J=2.0Hz,3H),1.53(d,J=7.2Hz,3H).

[0572] Example 29 Preparation of the compounds of the present invention DEX-217, DEX-225, DEX-231 to DEX-235, DEX-253 to DEX-306, DEX-309 to DEX-329, DEX-401 to DEX-414, DEX-416 to DEX-678, DEX-681 to DEX-696, and DEX-707

[0573] The preparation method of this type of compound is similar to that of Example compounds DEX-215 and DEX-216.

[0574] Compound DEX-217: 167 mg, ESI [M+H] + =238.9

[0575] 1 H NMR(400MHz,d6-DMSO)δ7.55(d,J=1.1Hz,1H),7.38–7.17(m,2H),7.08(t,J=8.3Hz,1 H), 6.84 (s, 1H), 4.32 (q, J = 7.2Hz, 1H), 2.27 (d, J = 2.4Hz, 3H), 1.51 (d, J = 7.2Hz, 3H).

[0576] Compound DEX-225: 66 mg, ESI [M+H] + =237.0

[0577] 1H NMR(400MHz,d6-DMSO)δ7.65(s,1H),7.34(dd,J=12.4,8.5Hz,1H),7.22(q,J=7.7Hz, 1H), 6.82 (s, 1H), 5.97 (d, J = 2.1Hz, 1H), 5.03 (d, J = 2.1Hz, 1H), 2.30 (d, J = 2.4Hz, 3H).

[0578] Compound DEX-231: 99 mg, ESI [M+H] + =218.9

[0579] 1 H NMR (400MHz, d6-DMSO) δ11.79(s,1H),7.53(s,1H),7.25–6.91(m,3H),6.84(s,0.7H),6.69(s,0.3H),4.41(q,J=7.1Hz,0. 3H), 4.32 (q, J=7.1Hz, 0.7H), 2.70–2.58 (m, 2H), 1.53 (d, J=7.2Hz, 0.9H), 1.50 (d, J=7.2Hz, 2.1H), 1.19 (t, J=7.5Hz, 3H).

[0580] Compound DEX-232: 89 mg, ESI [M+H] + =232.9

[0581] 1 H NMR(400MHz,d6-DMSO)δ11.82(s,1H),7.52(d,J=1.0Hz,1H),7.22–7.10(m,1H),7.11–6.91(m,2H),6.80(s,1H),4. 35(q,J=6.6Hz,1H),3.19(hept,J=6.8Hz,1H),1.51(d,J=7.2Hz,3H),1.24(d,J=1.9Hz,3H),1.22(d,J=1.9Hz,3H).

[0582] Compound DEX-253: 189 mg, ESI [M+H] + =204.9

[0583] 1H NMR(400MHz,d6-DMSO)δ11.77(s,1H),7.52(d,J=1.0Hz,1H),7.14(dd,J=14.2,7.8Hz,1H),7.05 –6.88(m,2H),6.76(s,1H),4.29(q,J=6.7Hz,1H),2.25(d,J=2.2Hz,3H),1.49(d,J=7.1Hz,3H).

[0584] Compound DEX-254: 58 mg, ESI [M+H] + =220.9

[0585] 1 H NMR(400MHz,d6-DMSO)δ11.79(s,1H),7.52(d,J=0.9Hz,1H),7.29–7.22(m,1H),7.18 –7.05(m,2H),6.77(s,1H),4.34(q,J=6.8Hz,1H),2.40(s,3H),1.49(d,J=7.1Hz,3H).

[0586] Compound DEX-255: 385 mg, ESI [M+H] + =224.9

[0587] 1 H NMR (400MHz, CD3OD) δ7.62(d,J=1.1Hz,1H),7.38–7.27(m,1H),7.16–7.04(m,2H),6.91(s,1H),4.49(q,J=7.2Hz,1H),1.63(d,J=7.2Hz,3H).

[0588] Compound DEX-277: 466 mg, ESI [M+H] + =218.9

[0589] 1 H NMR(400MHz,d6-DMSO)δ11.58(s,1H),7.39(s,1H),7.31–7.07(m,2H),6.94(s,1 H),4.54–4.06(m,1H),2.21(d,J=1.8Hz,3H),2.00(s,3H),1.49(d,J=7.1Hz,3H).

[0590] Compound DEX-278: 160 mg, ESI [M+H] + =234.9

[0591] 1H NMR(400MHz,d6-DMSO)δ11.59(s,1H),7.39(s,1H),7.31(s,1H),7.24(d,J=7.8Hz,1H),7 .13(t,J=7.7Hz,1H),4.38–4.22(m,1H),2.36(s,3H),1.99(s,3H),1.48(d,J=7.1Hz,3H).

[0592] Compound DEX-279: 17 mg, ESI [M+H] + =238.9

[0593] 1 H NMR(400MHz,d6-DMSO)δ11.70(s,1H),7.42(s,1H),7.41–7.32(m,2H),7.15(td ,J=8.0,0.7Hz,1H),4.39(q,J=7.1Hz,1H),2.07(s,3H),1.53(d,J=7.2Hz,3H).

[0594] Compound DEX-303: 38 mg, ESI [M+H] + =238.9

[0595] 1 H NMR(400MHz,d6-DMSO)δ11.47(s,1H),7.48–7.36(m,1H),7.22(t,J=6.8Hz,1H),7.15(t ,J=7.9Hz,1H),6.69(s,1H),4.29(q,J=7.2Hz,1H),2.21(s,3H),1.50(d,J=7.2Hz,3H).

[0596] Compound DEX-314: 263 mg, ESI [M+H] + =224.9

[0597] 1 H NMR(400MHz,d6-DMSO)δ11.88(s,1H),7.56(d,J=0.9Hz,1H),7.35–7.20(m,2H), 7.08(d,J=7.6Hz,1H),6.88(s,1H),4.51(q,J=7.1Hz,1H),1.52(d,J=7.1Hz,3H).

[0598] Compound DEX-316: 73 mg, ESI [M+H] + =190.9

[0599] 1H NMR(400MHz,d6-DMSO)δ7.53(d,J=1.0Hz,1H),7.25(dt,J=13.3,5.4Hz,2H), 7.18–7.06(m,2H),6.81(s,1H),4.35(q,J=7.2Hz,1H),1.52(d,J=7.2Hz,3H).

[0600] Compound DEX-317: 71 mg, ESI [M+H] + =190.9

[0601] 1 H NMR (400MHz, d6-DMSO) δ7.52(d,J=1.0Hz,1H),7.34–7.22(m,2H),7.18–7.04(m,2H),6.76(s,1H),4.07(q,J=7.1Hz,1H),1.51(d,J=7.2Hz,3H).

[0602] Compound DEX-318: 81 mg, ESI [M+H] + =204.9

[0603] 1 HNMR(400MHz,d6-DMSO)δ7.52(s,1H),7.09(t,J=8.0Hz,1H),6.94(t,J=11.1Hz,2H ),6.77(s,1H),4.29(q,J=6.9Hz,1H),2.28(d,J=6.6Hz,3H),1.50(d,J=7.2Hz,3H).

[0604] Compound DEX-319: 78 mg, ESI [M+H] + =204.9

[0605] 1 H NMR (400MHz, d6-DMSO) δ7.54(s,1H),7.06–6.98(m,3H),6.81(s,1H),4.30(q,J=7.2Hz,1H),2.23(s,3H),1.51(d,J=7.2Hz,3H).

[0606] Compound DEX-421: 114 mg, white solid, ESI [M+H] + =201.1

[0607] 1H NMR (400MHz, d6-DMSO) δ7.54(d,J=0.8Hz,1H),6.84(s,2H),6.80(s,1H),6.76(s,1H),3.96(d,J=7.2Hz,1H),2.23(s,6H),1.49(d,J=7.2Hz,3H).

[0608] Compound DEX-422: 75 mg, yellow syrup, ESI [M+H] + =201.1

[0609] 1 H NMR(400MHz,d6-DMSO)δ7.49(d,J=0.9Hz,1H),7.07–6.99(m,2H),6.94(d,J=7.7Hz,1 H), 6.71 (s, 1H), 3.96 (d, J = 7.1Hz, 1H), 2.18 (d, J = 3.7Hz, 6H), 1.49 (d, J = 7.2Hz, 3H).

[0610] Compound DEX-535: 100 mg, yellow syrup, ESI [M+H] + =209.1

[0611] 1 H NMR(400MHz,d6-DMSO)δ7.54(d,J=1.1Hz,1H),7.33–7.22(m,1H),7.21–7.07(m,1 H),7.05–6.96(m,1H),6.82(s,1H),4.31(q,J=7.2Hz,1H),1.51(d,J=7.2Hz,3H).

[0612] Compound DEX-536: 109 mg, colorless syrup, ESI [M+H] + =225.0

[0613] 1 H NMR(400MHz,d6-DMSO)δ7.54(d,J=1.0Hz,1H),7.35(dd,J=10.3,1.9Hz,1H), 7.31–7.17(m,2H),6.84(s,1H),4.31(q,J=7.2Hz,1H),1.51(d,J=7.2Hz,3H).

[0614] Compound DEX-537: 131 mg, colorless syrup, ESI [M+H] + =269.0

[0615] 1H NMR(400MHz,d6-DMSO)δ7.55(d,J=1.0Hz,1H),7.47(dd,J=9.9,2.0Hz,1H),7.34(dd,J=8.3, 1.8Hz,1H),7.19(t,J=8.3Hz,1H),6.85(s,1H),4.31(q,J=7.2Hz,1H),1.51(d,J=7.2Hz,3H).

[0616] Compound DEX-538: 82 mg, yellow solid, ESI [M+H] + =259.1

[0617] 1 H NMR(400MHz,d6-DMSO)δ7.61(d,J=10.4Hz,1H),7.56(d,J=1.0Hz,1H),7.52(d,J=8.3Hz ,1H),7.47(t,J=7.5Hz,1H),6.91(s,1H),4.41(q,J=6.9Hz,1H),1.55(d,J=7.2Hz,3H).

[0618] Compound DEX-539: 100 mg, yellow solid, ESI [M+H] + =205.1.0

[0619] 1 H NMR (400MHz, d6-DMSO) δ7.54 (s, 1H), 7.09 (t, J = 8.0 Hz, 1H), 6.95 (dd, J = 11.9, 10. 1Hz,2H),6.78(s,1H),4.29(q,J=7.2Hz,1H),2.29(s,3H),1.50(d,J=7.2Hz,3H).

[0620] Compound DEX-541: 90 mg, yellow syrup, ESI [M+H] + =225.1

[0621] 1 H NMR(400MHz,d6-DMSO)δ7.55(s,1H),7.39(d,J=7.1Hz,1H),7.27(s,1H),7.15(t d,J=8.5,2.3Hz,1H),6.86(s,1H),4.45(d,J=6.9Hz,1H),1.49(d,J=7.1Hz,3H).

[0622] Compound DEX-542: 125 mg, yellow solid, ESI [M+H] + =221.0

[0623] 1 H NMR(400MHz,d6-DMSO)δ7.56(dd,J=3.4,1.6Hz,2H),7.35(dd,J=8.4,2.1Hz,1H), 7.24(d,J=8.3Hz,1H),6.88(s,1H),4.45(q,J=7.1Hz,1H),1.49(d,J=7.1Hz,3H).

[0624] Compound DEX-543: 197 mg, yellow solid, ESI [M+H] + =285.0

[0625] 1 H NMR(400MHz,d6-DMSO)δ7.68(d,J=1.6Hz,1H),7.56(d,J=0.9Hz,1H),7.48(dd,J=8.4 ,1.6Hz,1H),7.19(s,1H),6.89(s,1H),4.44(q,J=7.0Hz,1H),1.49(d,J=7.1Hz,3H).

[0626] Compound DEX-544: 56 mg, yellow syrup, ESI [M+H] + =275.0

[0627] 1 H NMR(400MHz,d6-DMSO)δ7.83(s,1H),7.65(d,J=8.2Hz,1H),7.57(d,J=1.0Hz ,1H),7.47(s,1H),6.97(s,1H),4.55(d,J=6.0Hz,1H),1.53(d,J=7.1Hz,4H).

[0628] Compound DEX-545: 121 mg, yellow solid, ESI [M+H] + =221.1

[0629] 1 H NMR(400MHz,d6-DMSO)δ7.54(d,J=0.9Hz,1H),7.24(s,1H),7.08(q,J=8.0Hz ,2H),6.81(s,1H),4.43(q,J=7.1Hz,1H),2.27(s,3H),1.48(d,J=7.1Hz,3H).

[0630] Compound DEX-547: 96 mg, yellow solid, ESI [M+H] + =269.0

[0631] 1 H NMR(400MHz,d6-DMSO)δ7.58(d,J=1.1Hz,1H),7.54(dd,J=8.6,2.6Hz,1H),7.25(dd,J=8.7,6.4 Hz,1H),7.19(td,J=8.5,2.6Hz,1H),6.87(s,1H),4.42(q,J=7.1Hz,1H),1.48(d,J=7.1Hz,3H).

[0632] Compound DEX-548: 103 mg, yellow solid, ESI [M+H] + =285.0

[0633] 1 H NMR(400MHz,d6-DMSO)δ7.56(d,J=1.0Hz,1H),7.33–7.24(m,1H),7.21–7.12(m,1H),7 .00(td,J=8.9,2.1Hz,1H),6.83(s,1H),4.31(q,J=7.2Hz,1H),1.51(d,J=7.2Hz,3H).

[0634] Compound DEX-549: 135 mg, yellow solid, ESI [M+H] + =329.0

[0635] 1 H NMR(400MHz,d6-DMSO)δ7.83(d,J=2.0Hz,1H),7.56(d,J=0.8Hz,1H),7.52(dd,J=8.4,2.0 Hz,1H),7.16(d,J=8.3Hz,1H),6.89(s,1H),4.41(q,J=7.1Hz,1H),1.48(d,J=7.1Hz,3H).

[0636] Compound DEX-550: 252 mg, yellow syrup, ESI [M+H] + =319.0

[0637] 1 H NMR(400MHz,d6-DMSO)δ7.97(s,1H),7.69(d,J=8.2Hz,1H),7.58(d,J=0.9Hz ,1H),7.44(s,1H),6.96(s,1H),4.51(d,J=7.1Hz,1H),1.52(d,J=7.1Hz,3H).

[0638] Compound DEX-551: 92 mg, yellow solid, ESI [M+H] + =265.0

[0639] 1 H NMR (400MHz, d6-DMSO) δ7.54(d,J=1.0Hz,1H),7.42(s,1H),7.17–7.04(m,2H),6.81(s,1H),4.40(q,J=7.1Hz,1H),2.26(s,3H),1.47(d,J=7.1Hz,3H).

[0640] Compound DEX-553: 72 mg, yellow syrup, ESI [M+H] + =259.1

[0641] 1 H NMR(400MHz,d6-DMSO)δ8.87(s,1H),7.67(dd,J=9.3,2.6Hz,1H),7.55(ddd,J=1 4.4,8.5,4.1Hz,2H),7.46(s,1H),4.48(d,J=7.1Hz,1H),1.62(d,J=7.0Hz,3H).

[0642] Compound DEX-559: 153 mg, yellow syrup, ESI [M+H] + =205.1

[0643] 1 H NMR(400MHz,d6-DMSO)δ7.50(d,J=0.9Hz,1H),7.14(s,1H),6.96(ddd,J=11.4,9.3, 2.6Hz,2H),6.72(s,1H),4.22(d,J=7.1Hz,1H),2.35(s,3H),1.47(d,J=7.1Hz,3H).

[0644] Compound DEX-560: 232 mg, yellow syrup, ESI [M+H] + =221.1

[0645] 1 H NMR (400MHz, d6-DMSO) δ7.52(d,J=1.0Hz,1H),7.22(s,1H),7.20–7.09(m,2H),6.75(s,1H),4.23(q,J=7.1Hz,1H),2.35(s,3H),1.47(d,J=7.1Hz,3H).

[0646] Compound DEX-681: 117 mg, ESI [M+H] + =240.8

[0647] 1 H NMR (400MHz, d6-DMSO) δ11.88(s,1H),7.56(s,1H),7.53–7.44(m,1H),7.36–7.20(m,2H),6.94(s,1H),4.63–4.45(m,1H),1.51(d,J=6.9Hz,3H).

[0648] Compound DEX-682: 182 mg, ESI [M+H] + =208.9

[0649] 1 H NMR(400MHz,d6-DMSO)δ11.85(s,1H),7.54(d,J=1.0Hz,1H),7.32–7.18(m,1H), 7.17–6.96(m,2H),6.93–6.71(m,1H),4.37(q,6.8Hz,1H),1.54(d,J=7.2Hz,3H).

[0650] Compound DEX-683: 211 mg, light yellow solid, ESI [M+H] + =258.8.

[0651] 1 H NMR (400MHz, d6-DMSO) δ11.92(s,1H),7.58(d,J=1.1Hz,1H),7.38(t,J=8.8Hz,1 H),7.29–7.22(m,1H),6.91(s,1H),4.50(q,J=7.1Hz,1H),1.51(d,J=7.1Hz,3H).

[0652] Compound DEX-685: 168 mg, ESI [M+H] + =276.89

[0653] 1 H NMR (400MHz, d6-DMSO) δ11.89(s,1H),7.58–7.54(m,2H),7.26(d,J=8.6Hz,1H),6.96(s,1H),4.49(q,J=7.1Hz,1H),1.50(d,J=7.1Hz,3H).

[0654] Compound DEX-696: 153 mg, ESI [M+H] +=222.9

[0655] 1 H NMR (400MHz, d6-DMSO) δ12.10(s,1H),7.66(s,1H),7.64–7.55(m,1H),7.38–7.21(m,2H),6.86(s,1H),5.99(d,J=1.8Hz,1H),5.08(d,J=1.6Hz,1H).

[0656] Compound DEX-707: 96 mg, yellow syrup, ESI [M+H] + =249.1

[0657] 1 H NMR(400MHz,d6-DMSO)δ7.54(d,J=0.9Hz,1H),7.23–7.11(m,2H),7.05(d,J=3.5Hz,1H),6.83(s,1H),4.55(q ,J=7.1Hz,1H),2.71(dd,J=8.8,6.3Hz,2H),1.73–1.55(m,2H),1.49(d,J=7.1Hz,3H),0.96(t,J=7.3Hz,3H).

[0658] Example 30 Preparation of compounds DEX-330 to DEX-360 of the present invention

[0659] DEX-351-1 (25 g, 162 mmol, 1.1 equiv), N,O-dimethylhydroxylamine hydrochloride (47.5 g, 487 mmol, 3.0 equiv) and DIEA (62.9 g, 487 mmol, 3.0 equiv) were added to DMF (250 mL) and the temperature was cooled to 0° C. with an ice-water bath. HATU (92.5 g, 243 mmol, 1.5 equiv) was added portionwise to the reaction system and stirred at room temperature overnight. After the reaction was complete as monitored by TLC, the reaction system was poured into ice water and extracted with EtOAc (3×100 mL). The combined organic phases were dried over anhydrous Na 2 SO 4 and filtered. 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 / 10 to 1 / 3) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5). The fractions with Rf = 0.4 to 0.5 were collected to obtain compound DEX-351-2 (32 g, yield 100%). ESI [M+H] + = 197.9

[0660] Methylmagnesium bromide (108 mL, 324 mmol, 3.0 M in THF, 2.0 equiv) was slowly added dropwise to a solution of DEX-351-2 (32 g, 162 mmol) in THF (250 mL) using a constant pressure dropping funnel at 0°C in an ice-water bath. After the addition was complete, the mixture was slowly warmed to room temperature and stirred overnight. After completion of the reaction as monitored by TLC, the reaction system was poured into ice water and extracted with EtOAc (3 × 100 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 50 to 1 / 20) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 20). Fractions with Rf = 0.4 to 0.5 were collected to obtain compound DEX-351-3 (21.09 g, 89% yield).

[0661] At room temperature, 1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-imidazole (3.98 g, 20 mmol) was dissolved in dry THF (20 mL). The reaction system was purged with nitrogen three times and then cooled to -78°C in a dry ice / acetone bath using a nitrogen blanket. n-BuLi (15 mL, 1.6 mol / L in Hexane, 24 mmol) was slowly added to the reaction system via syringe, and stirring was continued for 30 minutes. A solution of DEX-351-3 (1.52 g, 10 mmol) in THF (5 mL) was slowly added to the reaction system via syringe, and stirring was continued overnight. After completion of the reaction as monitored by TLC, saturated aqueous ammonium chloride (50 mL) was slowly added to the reaction system, and the mixture was extracted with EtOAc (3 × 50 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product DEX-351-4, which was used directly in the next step without purification.

[0662] TFA (10 mL) was added to a solution of the crude compound DEX-351-4 from the previous step in CH2Cl2 (10 mL), and the mixture was stirred at room temperature overnight. After completion of the reaction as monitored by LC-MS, the mixture was concentrated under reduced pressure, neutralized with saturated sodium bicarbonate, and extracted with EtOAc (3 × 100 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product DEX-351-5, which was used directly in the next reaction without purification.

[0663] At room temperature, the crude compound DEX-351-5 and 10% wet palladium on carbon (100 mg) were dissolved in MeOH (10 mL). The system was replaced with hydrogen three times and stirred at room temperature under hydrogen overnight. After the reaction was complete as monitored by LC-MS, 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 (dichloromethane / methanol (v / v) = 150 / 1), and the fraction with Rf = 0.5-0.6 was collected to obtain the target compound DEX-351 (1066 mg, 52.2% yield for three steps) as a light yellow solid. ESI [M+H] + =205.0.

[0664] 1H NMR(400MHz,d6-DMSO)δ11.74(s,1H),7.18–7.07(m,1H),7.03–6.95(m,2H),6. 90(s,2H),4.46(q,J=7.2Hz,1H),2.24(d,J=1.9Hz,3H),1.56(d,J=7.2Hz,3H).

[0665] The preparation methods of the compounds DEX-330 to DEX-360 of the present invention are similar to that of the example compound DEX-351.

[0666] Compound DEX-346: 389 mg, ESI [M+H] + =201.1

[0667] 1 H NMR (400MHz, d6-DMSO) δ11.59(s,1H),7.04–6.80(m,5H),4.46(q,J=7.2Hz,1H),2.26(s,3H),2.26(s,3H),1.53(d,J=7.2Hz,3H).

[0668] Compound DEX-356: 1060 mg, light yellow solid, ESI [M+H] + =220.9.

[0669] 1 H NMR(400MHz,d6-DMSO)δ11.78(s,1H),7.22(d,J=7.4Hz,1H),7.16(t,J=7.6Hz,1H),7.00 (d,J=7.6Hz,1H),6.93(s,2H),4.66(q,J=7.1Hz,1H),2.37(s,3H),1.55(d,J=7.1Hz,3H).

[0670] Example 31 Preparation of compounds DEX-249 to DEX-252 of the present invention

[0671] The preparation method of compound DEX-249-1 is similar to that of DEX-351-2, and it is prepared using 2-chloro-3-methylbenzoic acid as raw material.

[0672] Iodoethane (764.8 mg, 4.90 mmol) and K2CO3 (696.6 mg, 5.04 mmol) were added to a solution of 4-iodo-2-methyl-1H-imidazole (1.0 g, 4.81 mmol) in DMF (10 mL) and stirred at room temperature for 12 hours. After completion of the reaction as monitored by TLC, the reaction solution was poured into ice water (20 mL) and 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 obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 5 to 1 / 1) and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1). Fractions with Rf = 0.3 to 0.5 were collected to obtain DEX-249-2 (571.5 mg, 50.4% yield) as a white solid. ESI [M+H] + =237.1.

[0673] Dissolve DEX-249-2 (130 mg, 0.551 mmol) in CH2Cl2 (2 mL), cool to -10°C, slowly add EtMgBr (1.1 mL, 1 mol / L in Et2O, 1.1 mmol) to the system, naturally warm to room temperature, and stir for 1 hour. Cool to -10°C, and slowly add a solution of DEX-249-1 (234.6 mg, 1.1 mmol) in CH2Cl2 (2 mL) dropwise to the reaction system, stirring at room temperature overnight. After the reaction was complete as monitored by TLC, the reaction system was cooled to 0°C and saturated aqueous ammonium chloride (10 mL) was slowly added to the reaction system. The mixture was extracted with CH2Cl2 (3×10 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 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 = 0.3 to 0.5 were collected to obtain the target compound DEX-249 (80.4 mg, 55.3% yield) as a white solid. ESI [M+H] + =263.1.

[0674] 1H NMR (400MHz, d6-DMSO) δ7.80 (s, 1H), 7.46 (d, J = 6.7Hz, 1H), 7.32 (t, J = 7.5Hz, 1H), 7.2 5–7.20(m,1H),3.98(q,J=7.3Hz,2H),2.39(s,3H),2.33(s,3H),1.31(t,J=7.3Hz,3H).

[0675] The preparation methods of the target compounds DEX-250, DEX-251 and DEX-252 are similar to those of DEX-249, and are prepared using differently substituted benzoic acids as raw materials.

[0676] Compound DEX-250: 188.2 mg, white solid, ESI [M+H] + =267.1.

[0677] 1 H NMR (400MHz, d6-DMSO) δ = 7.90 (s, 1H), 7.52-7.44 (m, 2H), 7.29 (d, J = 7.2, 1H), 3.97 (q, J = 7.3, 2H), 2.32 (s, 3H), 1.30 (t, J = 7.3, 3H).

[0678] Compound DEX-251: 258.9 mg, white solid, ESI [M+H] + =247.1.

[0679] 1 H NMR(400MHz,d6-DMSO)δ7.88(s,1H),7.44(t,J=7.4Hz,1H),7.36(dd,J=10.1,3.9Hz,1H),7.19(t ,J=7.5Hz,1H),3.99(q,J=7.3Hz,2H),2.34(s,3H),2.29(d,J=1.8Hz,3H),1.32(t,J=7.3Hz,3H).

[0680] Compound DEX-252: 317.3 mg, white solid, ESI [M+H] + =267.1.

[0681] 1H NMR(400MHz,d6-DMSO)δ8.00(s,1H),7.79–7.72(m,1H),7.54(ddd,J=7.7,6.1,1.6Hz, 1H),7.35(t,J=7.8Hz,1H),4.01(q,J=7.3Hz,2H),2.35(s,3H),1.34(t,J=7.3Hz,3H).

[0682] The beneficial effects of the present invention are demonstrated by the following test examples.

[0683] Test Example 1 Pharmacological Data Determination of the Compounds of the Invention

[0684] 1. Test methods

[0685] 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):

[0686] 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.

[0687] 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。

[0688] 1.2 Determination of the main pharmacological effects of the compounds of the present invention

[0689] 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

[0690] 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.

[0691] 1.2.2 Loss of righting reflex in rats 50 Dose comparison of the pharmacological effects of the compounds of the present invention

[0692] 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.

[0693] 2ED 50 Pharmacological characteristics of equivalent doses:

[0694] 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.

[0695] 2. Experimental Results

[0696] Table 1. Pharmacological data of the anesthetic effect of the compounds of the present invention after a single intravenous injection

[0697] Table 2. Minimum analgesic effective dose of the compounds of the present invention for a single intravenous injection

[0698] 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

[0699] 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.

[0700] 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 below: 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, (CR6R7) m R8, =O, 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, 3-8 membered saturated cycloalkyl, R 12 Selected from C 1-8 Alkyl, 3-8 membered saturated cycloalkyl, 3-8 membered saturated heterocyclic group, heteroaryl, n is selected from 0, 1, 2, 3, 4, 5; R 13 Selected from hydroxyl, 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, heteroaryl, one or more R 9b Substituted 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 selected from Unsubstituted or replaced by one or more R 15 Substituted rings: 3-5 membered unsaturated carbocyclic ring, 3-5 membered saturated carbocyclic ring, bridged ring; 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; The compound is not 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 a substituted or unsubstituted 5-membered nitrogen heteroaryl or 6-membered nitrogen heteroaryl, wherein the ring heteroatoms of the 5-membered nitrogen heteroaryl and 6-membered nitrogen heteroaryl are all N; the substituents are each independently selected from hydroxyl, halogen, cyano, (CR6R7) m R8, =O, unsubstituted or substituted by one or more R9: amino, C 1-6 Alkyl, C 1-6 Alkylthio, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, 3-8 membered saturated cycloalkyl, 3-8 membered saturated heterocyclic group, aryl, heteroaryl; m is selected from 0, 1, 2, 3; R6, R7 are each independently selected from hydrogen, C 1-6 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 1-6 Alkyl, 3-6 membered saturated cycloalkyl, R 12 Selected from C 1-6 Alkyl, 3-6 membered saturated cycloalkyl, 3-6 membered saturated heterocyclic group, 5-6 membered heteroaryl, n is selected from 0, 1, 2, 3; R 13 Selected from hydroxyl, C 1-6 alkoxy; The R9 are independently selected from halogen, hydroxyl, amino, thiol, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, OCOR 9a 、SO2R 9a , OR 9c , 3-6 membered saturated cycloalkyl, one or more R 9b Substituted 3-6 membered saturated cycloalkyl, 3-6 membered saturated heterocyclic group, one or more R 9b Substituted 3-6 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 1-6 Alkyl; R 9b Each independently selected from halogen, C 1-6 Alkyl; R 9c Selected from 3-6 membered saturated cycloalkyl, 3-6 membered saturated heterocyclic group; Preferably, the A ring is is a substituted or unsubstituted 5-membered nitrogen heteroaryl group, is a substituted or unsubstituted 6-membered nitrogen heteroaryl group.

3. The compound according to claim 2, its stereoisomer, its pharmaceutically acceptable salt, its solvate, its prodrug, its metabolite or its deuterated derivative, characterized in that: The A ring is substituted or unsubstituted by the following groups: The substituents are independently selected from hydroxyl, halogen, cyano, (CR6R7) m R8, unsubstituted or substituted by one or more R9: amino, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Alkylthio, 3-4 membered saturated cycloalkyl, 3-4 membered saturated heterocyclic group, phenyl, 5-6 membered heteroaryl; m is selected from 0, 1, 2, 3; R6, R7 are each independently selected from hydrogen, C 1-3 alkyl; R8 is selected from CONR 10 R 11 NR 10 R 11 、COOR 12 、COR 12 , OR 12 , substituted phenyl, wherein the substituents are independently selected from F, Cl, Br, I, hydroxyl, nitro, cyano, C 1-8 Alkyl, C 1-8 Alkoxy; R 10 、R 11 Each independently selected from hydrogen, C 1-5 Alkyl, 3-4 membered saturated cycloalkyl, R 12 Selected from C 1-5 Alkyl, 3-4 membered saturated cycloalkyl, 3-4 membered saturated heterocyclic group, 5-6 membered heteroaryl, n is selected from 0, 1, 2, 3; R 13 Selected from hydroxyl, C 1-3 alkoxy; R 16 Selected from C 1-3 Alkyl, C 1-3 Alkoxy, unsubstituted or substituted by one or more R 18 Substituted groups: 3-4 membered saturated cycloalkyl, 3-4 membered saturated heterocyclic group, phenyl, 5-6 membered heteroaryl; R 18 Each independently selected from halogen, C 1-3 Alkyl; R 17 Selected from hydrogen, C 1-3 Alkyl, hydroxyl; The R9 are independently selected from halogen, hydroxyl, amino, thiol, C 1-3 Alkyl, C 1-3 Alkoxy, C 2-3 Alkenyl, C 2-3 Alkynyl, OCOR 9a 、SO2R 9a , OR 9c , 3-4 membered saturated cycloalkyl, one or more R 9b Substituted 3-4 membered saturated cycloalkyl, 3-4 membered saturated heterocyclic group, one or more R 9b Substituted 3-4 membered saturated heterocyclic group, phenyl group, one or more R 9b Substituted phenyl, 5-6 membered heteroaryl, one or more R 9b Substituted 5-6 membered heteroaryl; R 9a Selected from C 1-3 Alkyl; R 9b Each independently selected from halogen, C 1-3 Alkyl; R 9c is selected from 3-4 membered saturated cycloalkyl, 3-4 membered saturated heterocyclic group; The heterocyclic group contains at least one heteroatom selected from N, O or S.

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 Unsubstituted or replaced by one or more R 15 Substituted rings: 3-5 membered unsaturated carbon ring, 3-5 membered saturated carbon ring, 7-8 membered bridged ring, wherein the 3-5 membered unsaturated carbon ring is selected from 7-8 member bridge ring includes R 15 is selected from hydroxy, halogen, halogenated or unhalogenated C 1-3 Alkyl, halogenated or unhalogenated C 1-3 alkoxy; 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 8, 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 8, 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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