Ketone heterocyclic compound and use thereof

Abstract

The present invention provides a ketone heterocyclic compound and use thereof, and belongs to the technical field of medicinal chemistry. The structure of the compound is represented by formula I. The compound of the present invention has an efficient sedative, hypnotic, and / or anesthetic effect, can control the persistence of epilepsy, also has an analgesic effect, and provides a new option for the clinical preparation of a drug having an analgesic effect, a drug having an anesthetic, sedative, and hypnotic effect and / or capable of controlling the persistence of epilepsy, and a drug having an anesthetic, sedative, and hypnotic effect and / or capable of controlling the persistence of epilepsy and having an analgesic effect.

Description

A ketone heterocyclic compound and its uses Technical Field

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

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

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

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

[0005] This invention provides a compound, its stereoisomer, its pharmaceutically acceptable salt, its solvate, its prodrug, its metabolite, or its deuterated derivative thereof, said compound being of Formula I:

[0006] Among them, ring A is selected from 3-8 membered saturated cycloalkyl groups and phenyl groups;

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

[0008] R1 is independently selected from hydrogen, C, etc. 1-8 Alkyl, halogen, hydroxyl, 3-8 member saturated cycloalkyl substituted C 1-8 alkyl;

[0009] R2 is selected from C 1-8 Alkyl, C 2-8 Alkenyl, 3-8 membered saturated cycloalkyl;

[0010] R3 is hydrogen;

[0011] L3 is absent;

[0012] The five-membered heteroaryl ring is replaced; among K1, K2, K3, and K4, one is N, and another is either N or CR. a One is CR b One is CR k R k Selected from

[0013] L' is selected from none, C 1-6 Alkylene;

[0014] R0' is selected from C 1-8 Alkyl, C 2-8 Alkyne group, 3-8 membered saturated cycloalkyl group;

[0015] R c Selected from hydrogen, C 1-8 Alkoxy, R d Selected from hydrogen, C 1-8 alkoxy, or R c R d The linkage forms 3-8 member saturated oxygen heterocycles;

[0016] R a Selected from hydrogen and halogens;

[0017] R b Selected from hydrogen and halogens;

[0018] Y is selected from none, CR 10 R 11 ;R 10 Selected from hydrogen, R 11 Selected from hydrogen;

[0019] R e Selected from C 1-10 Alkyl groups, C atoms substituted with one or more halogens 1-10 Alkyl group, with one or more R f Substituted 3-8 saturated cycloalkyl groups, Not replaced or replaced by one or more R h Substituted phenyl;

[0020] R f Each independently selected from C 1-8 alkyl;

[0021] R h Each independently selected from C 1-8 Alkyl groups, halogens;

[0022] R i Selected from 3-8 saturated cycloalkyl groups, C 1-8 alkyl;

[0023] when for When the compound is R is selected from C 1-7 alkyl or halogen-substituted C 1-7 alkyl.

[0024] Furthermore, each of R1 is independently selected from hydrogen, C 1-4 Alkyl, halogen, hydroxyl, 3-6 member saturated cycloalkyl-substituted C 1-4 alkyl;

[0025] R2 is selected from C 1-4 Alkyl, C 2-4 Alkenyl, 3-6 membered saturated cycloalkyl;

[0026] L' is selected from none, C 1-3 Alkylene;

[0027] R0' is selected from C 1-6 Alkyl, C 2-4 Alkyne group, 3-6 membered saturated cycloalkyl group;

[0028] R c Selected from hydrogen, C 1-4 Alkoxy, R d Selected from hydrogen, C 1-4 alkoxy, or R c R d The linkage forms a 5-6 member saturated oxygen heterocycle, preferably a 5-6 member saturated oxygen heterocycle.

[0029] R e Selected from C 1-7 Alkyl groups, C atoms substituted with one or more halogens 1-4 Alkyl group, with one or more R f Substituted 3-6 saturated cycloalkyl groups Not replaced or replaced by one or more R h Substituted phenyl;

[0030] R f Each independently selected from C 1-4 alkyl;

[0031] R h Each independently selected from C 1-4 Alkyl groups, halogens;

[0032] R i Selected from 3-6 saturated cycloalkyl groups, C 1-4 alkyl.

[0033] Furthermore, the compounds are as shown in formula II-1a, II-1b, or II-1c:

[0034] Among them, R1, R2, R3, R a R b R c R d L' and R0' are as described above; m1, m2, and m3 are each independently selected from 0, 1, 2, 3, and 4.

[0035] Furthermore, the compounds are as shown in formula II-2a, II-2b, or II-2c:

[0036] Among them, R1, R2, R3, R a R b R c R d L' and R0' are as described above; m1, m2, and m3 are each independently selected from 0, 1, 2, 3, and 4.

[0037] Furthermore, the compounds are as shown in formula II-3a, II-3b, II-3c, II-3d, or II-3e:

[0038] Among them, R1, R2, R a R b R c R d L' and R0' are as described above; m1, m2, m3, m4, and m5 are each independently selected from 0, 1, 2, 3, and 4.

[0039] Furthermore, the compounds are as shown in formula II-4a, II-4b, II-4c, II-4d, II-4e, or II-4f:

[0040] Among them, R1, R2, R a R b Rc R d L' and R0' are as described above; m1, m2, m3, m4, m5, and m6 are each independently selected from 0, 1, 2, 3, and 4.

[0041] Furthermore, the compound is selected from:

[0042] Further, the pharmaceutically acceptable salts are citrates, hydrofluoric acid salts, phosphates, propionates, succinates, tartrates, acetates, adipates, aspartates, benzoates, benzenesulfonates, bicarbonates, carbonates, bisulfates, sulfates, borates, camphor sulfonates, citrates, cyclohexanesulfonates, ethanedisulfonates, ethanesulfonates, formates, fumarates, glucohepanoates, glucuronates, glucuronates, hexafluorophosphates, hydrochlorides, hydrobromide, hydroiodates, hydroxyethyl sulfonates, lactates, malates, maleic acid esters, malonates, methanesulfonates, methyl sulfates, naphthates, succinates, nicotinates, nitrates, orotates, oxalates, palmitates, dihydroxynaphthyl salts, phosphates, hydrogen phosphates, dihydrogen phosphates, pyroglutamates, glycosides, stearates, succinates, tannates, tartrates, toluenesulfonates, trifluoroacetates, sine salts, or p-toluenesulfonates.

[0043] The present invention also provides a pharmaceutical composition comprising, wherein the pharmaceutical composition is an active ingredient comprising the above-mentioned compound, its stereoisomer, its pharmaceutically acceptable salt, its solvate, its prodrug, its metabolite or its deuterated derivative thereof, and pharmaceutically acceptable excipients.

[0044] The present invention also provides the use of the above-mentioned compounds, their stereoisomers, their pharmaceutically acceptable salts, their solvates, their prodrugs, their metabolites or their deuterated derivatives in the preparation of medicaments having analgesic effects, and / or having anesthetic, sedative, hypnotic effects and / or being able to control status epilepticus.

[0045] Regarding the definition of terms used in this invention: Unless otherwise stated, the initial definitions provided for groups or terms herein apply to the groups or terms used throughout this specification; for terms not specifically defined herein, the meanings that a person skilled in the art would give them should be given based on the disclosure and context.

[0046] The minimum and maximum carbon atom content in hydrocarbon groups are indicated by a prefix, for example, the prefix C. a～b Alkyl groups refer to any alkyl group containing one to two carbon atoms ("a" to "b"). For example, C 1～6 Alkyl groups refer to straight-chain or branched alkyl groups containing 1, 2, 3, 4, 5, or 6 carbon atoms. 1～6 Alkoxy groups are straight-chain or branched alkoxy groups containing 1, 2, 3, 4, 5, or 6 carbon atoms. 1-4 Alkylenes are straight-chain or branched alkylenes containing 1, 2, 3 or 4 carbon atoms, and so on.

[0047] In this invention, This indicates that m hydrogen atoms on ring A are replaced by R1, and the replacement positions can be any position on ring A.

[0048] The minimum and maximum number of ring atoms in a cyclic group are indicated by a prefix. For example, 3-8 saturated cycloalkyl refers to a saturated cycloalkyl group containing 3, 4, 5, 6, 7 or 8 ring atoms, 3-8 saturated heterocyclic group refers to a saturated heterocyclic group containing 3, 4, 5, 6, 7 or 8 ring atoms, and so on.

[0049] In this article, "substitution" refers to the replacement of one, two, or more hydrogen atoms in a molecule by other different atoms or molecules, including one, two, or more substitutions on isotopes or ectopic atoms in the molecule.

[0050] In this article, "halogenation" refers to the replacement of one, two, or more hydrogen atoms in a molecule with other different halogens, including one, two, or more substitutions on isotopes or ectopic atoms in the molecule.

[0051] "Heteroaromatic ring" refers to a heteroaromatic group containing one or more heteroatoms. The heteroatoms referred to here include, but are not limited to, oxygen, sulfur, and nitrogen. Examples include furanyl, thiophene, pyridinyl, pyrazolyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, imidazoleyl, thiazolyl, oxazolyl, pyrimidinoneyl, pyridinoneyl, indolyl, tetrazolyl, etc.

[0052] In some preferred technical solutions, the heteroaryl ring is a 5-6 member heteroaryl ring.

[0053] Heterocyclic compounds are cyclic compounds formed by the combination of carbon atoms and non-carbon atoms (heteroatoms). Among the atoms forming the ring, the non-carbon atoms other than carbon atoms are called "cyclic heteroatoms".

[0054] Halogens are fluorine, chlorine, bromine or iodine.

[0055] In this invention, "pharmaceutically acceptable" means that a carrier, delivery substance, diluent, excipient, and / or the salt formed therefrom is generally chemically or physically compatible with other components constituting a drug dosage form and physiologically compatible with the receptor.

[0056] In this invention, "salt" refers to an acidic and / or basic salt formed by a compound or its stereoisomer with an inorganic and / or organic acid and / or base, including zwitterionic salts (internal salts) and quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly during the final separation and purification of the compound. Alternatively, they can be obtained by mixing the compound, or its stereoisomer, with an appropriate amount (e.g., equimolar amounts) of an acid or base. These salts may precipitate in solution and be collected by filtration, or be recovered after solvent evaporation, or be prepared by freeze-drying after reaction in an aqueous medium. The salts described in this invention can be hydrochlorides, sulfates, citrates, benzenesulfonates, hydrobromides, hydrofluoric acids, phosphates, acetates, propionates, succinates, oxalates, malates, succinates, fumarates, maleates, tartrates, or trifluoroacetates of the compound.

[0057] "Solvate" refers to the solvate formed by the compound of the present invention and a solvent, wherein the solvent includes (but is not limited to): water, ethanol, methanol, isopropanol, propylene glycol, tetrahydrofuran, and dichloromethane.

[0058] "Stereoisomerism" refers to compounds with the same molecular formula in which atoms or groups of atoms are connected in the same order, but arranged in different ways in space.

[0059] Sulphate is 2,4-dimethylbenzenesulfonate.

[0060] Compared with the prior art, the compounds of the present invention have the following beneficial effects:

[0061] The compounds provided by this invention 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.

[0062] Furthermore, this invention is the first to discover that the compound of this invention not only has highly effective sedative, hypnotic, and / or anesthetic effects, which can control status epilepticus, but also has analgesic effects. In clinical applications, it can reduce or eliminate the need for opioid analgesics such as fentanyl, alfentanyl, sufentanil, or remifentanil, thereby reducing the occurrence of adverse reactions such as circulatory depression, respiratory depression, urinary retention, and skin itching caused by opioid analgesics.

[0063] Obviously, based on the above description of the present invention, and according to common technical knowledge and conventional methods in the field, various other modifications, substitutions or alterations can be made without departing from the basic technical concept of the present invention.

[0064] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following embodiments. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention. Detailed Implementation

[0065] The raw materials and equipment used in the specific embodiments of the present invention are all known products, obtained by purchasing commercially available products.

[0066] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ ohms. -6 The unit (ppm) is given. NMR determination was performed using a Bruker Avance III 400 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (d6-DMSO), deuterated methanol (CD3OD), or deuterated chloroform (CDCl3), with tetramethylsilane (TMS) as the internal standard.

[0067] The LCMS determination was performed using an Agilent LCMS 1260 Infinity II-6125B (API-ES). Column: Waters Agilent Eclipse Plus C18 (4.6 mm x 50 mm x 3.5 μm); Column temperature: 45 °C; Flow rate: 2.0 mL / min; Mobile phase: Gradient from 95% [water + 0.1% TFA] and 5% [CH3CN + 0.1% TFA] to 0% [water + 0.1% TFA] and 100% [CH3CN + 0.1% TFA] over 2.5 minutes, held at this condition for 0.5 minutes, then gradient to 95% [water + 0.05% TFA] and 5% [CH3CN + 0.05% TFA] over 0.05 minutes, and held at this condition for 0.45 minutes.

[0068] 1) Medicinal materials and reagents

[0069] The silica gel plates used for thin-layer chromatography are HSGF254 silica gel plates from Yantai Xinnuo Chemical Co., Ltd., with a thickness of 1mm.

[0070] Thin-layer chromatography (TLC) was performed using products from Yantai Jiangyou Silica Gel Development Co., Ltd., with a specification of 0.2±0.03 mm.

[0071] Column chromatography silica gel generally uses 100-200 mesh or 200-300 mesh silica gel from Rushan Taiyang Desiccant Co., Ltd. (Weihai, Shandong) as the carrier.

[0072] 2) Main instruments

[0073] JA2003N Electronic Balance (Shanghai Youke Instrument Co., Ltd.); 98-2 Magnetic Stirrer (Shanghai Sile Instrument Co., Ltd.); DF-101S Thermostatic Heating Magnetic Stirrer (Zhengzhou Setelis Biotechnology Co., Ltd.); ZF-2 Three-Purpose Ultraviolet Analyzer (Shanghai Anting Electronic Instrument Factory); RE-2000B Rotary Evaporator (Zhengzhou Ketai Experimental Equipment Co., Ltd.); SHB-III Circulating Water Vacuum Pump (Zhengzhou Huicheng Science & Technology Co., Ltd.); DLSK-5 / 20 Low Temperature Coolant Circulating Pump (Zhengzhou Ketai Experimental Equipment Co., Ltd.); DGJ-10C Vacuum Freeze Dryer (Shanghai Boden Biotechnology Co., Ltd.); KQ5200 Ultrasonic Cleaner (Kunshan Ultrasonic Instrument Co., Ltd.); 2XZ-2 Rotary Vane Vacuum Pump (Linhai Tanshi Vacuum Equipment Co., Ltd.); Biotage Isolera One (Biotage Sweden AB).

[0074] Example 1: Preparation of the intermediate compound of the present invention

[0075] 1. Preparation of intermediate compounds A-1 to A-4:

[0076] Cyclopropyl methyl ketone (5.0 g, 60.0 mmol) was dissolved in THF (200 mL) and cooled to 0 °C using an ice-water bath. Lithium aluminum hydride (4.56 g, 120.0 mmol) was added in portions to the reaction mixture, and stirring was continued for 4 hours. After the reaction was complete as monitored by TLC, excess sodium sulfate decahydrate was added in portions to the reaction mixture, and stirring was continued for 1 hour. The mixture was then filtered, concentrated under reduced pressure to obtain the crude product, and purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100–1 / 20). TLC (ethyl acetate / petroleum ether (v / v) = 1 / 20) was used to collect the fraction with Rf = 0.5–0.6, yielding compound A-1 (4.16 g, yield 80.6%). ESI [M+H] + =87.1. The preparation method of A-4 is similar to that of compound A-1.

[0077] At 0°C in an ice-water bath, ethyl magnesium bromide (215 mL, 215 mmol, 1 mol / L in THF) was slowly added dropwise to 100 mL of cyclopropylformaldehyde (10.0 g, 143 mmol) in THF using a constant-pressure dropping funnel. After the addition was complete, the mixture was slowly brought to room temperature and stirred for 2 hours. After the reaction was complete as monitored by TLC, the reaction mixture was poured into ice water and extracted with EtOAc (3 × 100 mL). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100–1 / 20), monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 20), and the fraction with Rf = 0.5–0.6 was collected to give compound A-2 (11.03 g, yield 77.2%). ESI[M+H] + =101.1.

[0078] The preparation methods for intermediate compounds A-3 and A-4 are similar to those for compound A-2.

[0079] 2. Preparation of intermediate compounds B-1 to B-3:

[0080] Under constant pressure, magnesium bromide of R2-based (1.5 equivalents) was slowly added dropwise to a THF (20V) solution of cyclobutylformaldehyde (1.0 equivalent) in an ice-water bath at 0°C using a constant pressure dropping funnel. After the addition was complete, the mixture was slowly brought to room temperature and stirred for 2 hours. After the reaction was monitored by TLC until complete, the reaction mixture was poured into ice water and extracted with EtOAc (3×10V). 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 to obtain colorless oily compounds B1–B3.

[0081] 3. Preparation of intermediate compounds CA and CB:

[0082] Some intermediate compounds CA and CB were purchased directly from the supplier, while others were prepared using compound C.3 via chiral reduction or sodium borohydride reduction. Compound C.3, which was not readily available, was prepared via condensation and Grignard synthesis of the corresponding carboxylic acid.

[0083] The preparation of intermediate compounds CA and CB is performed according to the following experimental procedures:

[0084] M-531.1 (25 g, 147 mmol, 1.1 equivalence), N,O-dimethylhydroxylamine hydrochloride (43 g, 439 mmol, 3.0 equivalence), and DIEA (57 g, 439 mmol, 3.0 equivalence) were added to DMF (80 mL) and cooled to 0 °C using an ice-water bath. HATU (84 g, 219 mmol, 1.5 equivalence) was added in portions to the reaction mixture, and the mixture was stirred overnight at room temperature. After the reaction was confirmed to be complete by TLC, the reaction system was poured into ice water and extracted with EtOAc (3 × 100 mL). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 20 to 1 / 5). TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5) was used to monitor the reaction, and the fraction with Rf = 0.4–0.5 was collected to give compound M-531.2 (24 g, yield 76.6%). ESI[M+H] + =214.1

[0085] At 0°C in an ice-water bath, methyl magnesium bromide (75.1 mL, 225.4 mmol, 3.0 M in THF) was slowly added dropwise to a 100 mL THF solution of M-531.2 (24 g, 112.7 mmol) using a constant-pressure dropping funnel. After the addition was complete, the mixture was slowly brought to room temperature and stirred for 4 hours. After the reaction was complete as monitored by TLC, the reaction mixture was poured into ice water and extracted with EtOAc (3 × 100 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100–1 / 20), monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 20), and the fraction with Rf = 0.4–0.5 was collected to give compound M-531.3 (16.1 g, yield 85.5%). ESI [M+H] + =169.1

[0086] Method A for chiral reduction of carbonyl groups:

[0087] At -20°C, (-)-DIP-Chloride (11.55 g, 36.0 mmol) was slowly added dropwise to a 50 mL solution of THF (5.04 g, 30.0 mmol) of M-531.3, and the mixture was stirred at -20°C for 6 hours. MeOH (12.6 mL) was then added to the reaction mixture at -20°C, and stirring continued for 1 hour. The mixture was concentrated under reduced pressure to obtain a crude product, which was dissolved in ethyl acetate (16 mL). Ethanolamine (6.3 mL, 66.3 mmol) was added to the mixture, and the mixture was stirred at room temperature for 2 hours. After the reaction was confirmed to be complete by TLC, the reaction system was poured into ice water and extracted with EtOAc (3 × 50 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 / 10). TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10) was used to monitor the reaction, and the fraction with Rf = 0.4–0.5 was collected to give the chiral compound M-531.4 (2.40 g, yield 47.1%). ESI[M+H] + =171.1

[0088] Chiral reduction of carbonyl group method B:

[0089] At room temperature, M-531.3 (22 g, 130.5 mmol, 1.0 equivalent), formic acid (30 g, 651.7 mmol, 5.0 equivalent), and triethylamine (39.6 g, 391.3 mmol, 3.0 equivalent) were added sequentially to isopropanol (220 mL, 10 V), and stirred at 60 °C for 6 hours. After the reaction was completed as monitored by TLC, the mixture was concentrated under reduced pressure, extracted with EtOAc (3 × 50 mL), and 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 / 10), and the fraction with Rf = 0.4 to 0.5 was collected as monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10) to give the chiral compound M-531.4 (16.8 g, yield 75.4%).

[0090] Chiral reduction carbonyl method:

[0091] M-531.3 (1.0 equivalent) was dissolved in methanol (10V) in an ice-water bath at 0°C. Sodium borohydride (3.0 equivalent) was added to the above system, and the mixture was slowly heated to room temperature and stirred overnight. After the reaction was completed as monitored by TLC, the reaction system was poured into ice water and extracted with EtOAc (3×10V). The organic phases were combined, washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 50 to 1 / 10). TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10) was used to monitor the reaction, and the fraction with Rf = 0.4 to 0.5 was collected to give compound 1-(2-chloro-3-methylphenyl)ethan-1-ol.

[0092] 4. Preparation of intermediate compounds H-1 to H-3:

[0093] At room temperature, H-1.1 (3.0 g, 23.8 mmol), ethanol (30 mL), and methanesulfonic acid (6 mL) were added sequentially to a 200 mL sealed tube, and the reaction was carried out at 120 °C for 10 hours. After concentration, the pH of the reaction solution was adjusted to approximately 8 with a saturated aqueous solution of NaHCO3. The solution was extracted with ethyl acetate (3 × 150 mL), washed with saturated brine (100 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to give a white solid intermediate compound H-1.2 (3.0 g, yield 81%).

[0094] Intermediate compound H-1.2 (250 mg, 1.61 mmol) was dissolved in 40% HBF4 at -10 °C in an ice-salt bath, and 0.15 mL of an aqueous solution of NaNO2 (117 mg, 1.69 mmol) was added. The reaction was carried out under mercury lamp irradiation (302 nm) for 2 hours. After the reaction was complete, the pH was adjusted to approximately 7 with an aqueous solution of 1 N NaOH in an ice-water bath. The aqueous layer was extracted with ethyl acetate (3 × 10 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 1), and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1). The fraction with Rf = 0.4–0.5 was collected to give compound H-1 (100 mg, yield 39%).

[0095] H-2.1 (25 g, 0.192 mol) and imidazole (25 g, 0.349 mol) were reacted in a sealed tube at 150 °C for 2 hours at room temperature. The reaction system was extracted with EtOAc (5 × 30 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain crude product H-2.2.

[0096] At room temperature, crude compound H-2.2 and active manganese dioxide (289.8 g, 2 mol, 60%) were dissolved in CH2Cl2 (100 mL) and refluxed with stirring for 8 hours. After the reaction was complete 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 / 20 to 1 / 2). TLC (ethyl acetate / petroleum ether (v / v) = 1 / 2) was used to collect the fraction with Rf = 0.5 to 0.6, yielding compound H-2 (18.6 g, two-step yield 59.0%). ESI[M+NH4] + =182.3.

[0097] H-3.1 (5 g, 39.65 mmol) and imidazole (4.05 g, 59.48 mmol) were reacted in a sealed tube at 150 °C for 3 hours at room temperature. The reaction system was extracted with EtOAc (5 × 30 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain crude product H-3.2.

[0098] At room temperature, crude compound H-3.2 and active manganese dioxide (86.2 g, 594.8 mmol, 60%) were dissolved in CH2Cl2 (100 mL) and refluxed with stirring overnight. After the reaction was complete 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 / 20 to 1 / 2). TLC (ethyl acetate / petroleum ether (v / v) = 1 / 2) was used to collect the fraction with Rf = 0.5 to 0.6, yielding compound H-3 (911 mg, two-step yield 15.7%). ESI[M+NH4] + =164.1.

[0099] Example 2: Preparation of compounds M-213 to M-226, M-297 to M-345, and M-388 to M-395 of the present invention

[0100] 1. Preparation of compounds M-299 and M-334 of the present invention

[0101] Dicyclopropylmethanol (2.24 g, 20.0 mmol), ethyl 5-fluoro-1H-imidazolium-4-carboxylate (1.58 g, 10.0 mmol), and tri-n-butylphosphine (4.04 g, 20.0 mmol) were dissolved in THF (30 mL) under dry ice / acetonitrile bath at -30 °C. Diethyl azodicarbonate (3.48 g, 20.0 mmol) was slowly added dropwise to the reaction system using a syringe. The mixture was slowly brought to room temperature and stirred overnight. After the reaction was confirmed to be complete by TLC, the reaction system was poured into ice water and extracted with EtOAc (3 × 30 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 to 1 / 2). TLC (ethyl acetate / petroleum ether (v / v) = 1 / 2) was used to monitor the reaction, and the fraction with Rf = 0.4–0.5 was collected to give compound M-299.2 (1.82 g, yield 72.6%). ESI[M+H] + =253.1

[0102] At room temperature, M-299.2 (1.82 g, 7.22 mmol) was dissolved in ethanol (40 mL). Sodium hydroxide (577 mg, 14.44 mmol) was added to the above system, and the mixture was stirred overnight at room temperature. After the reaction was monitored by TLC until complete, the mixture was concentrated under reduced pressure, cooled in an ice-water bath, and concentrated under reduced pressure with 2 M hydrochloric acid at pH ≈ 7 to obtain the crude product compound M-299.3. At room temperature, the crude product compound M-299.3, N,O-dimethylhydroxylamine hydrochloride (2.11 g, 21.66 mmol), HATU (5.48 g, 14.44 mmol), and DIEA (3.72 g, 28.88 mmol) were added to DMF (20 mL), and the mixture was stirred overnight at room temperature. After the reaction was monitored to be complete by TLC, the reaction system was poured into ice water and extracted with EtOAc (3 × 30 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 20 to 1 / 3). TLC (ethyl acetate / petroleum ether (v / v) = 1 / 3) was used to monitor the reaction, and the fraction with Rf = 0.4 to 0.5 was collected to give compound M-299.4 (1.46 g, yield 76.1%). ESI [M+H] + =268.1.

[0103] M-299.4 (1.46 g, 5.46 mmol) was dissolved in THF (30 mL), and the mixture was cooled to 0 °C in an ice-water bath. Methylmagnesium bromide (10.92 mL, 10.92 mmol, 1.0 M in THF) was slowly added to the reaction mixture using a syringe, and the mixture was slowly brought to room temperature and stirred overnight. After the reaction was complete as monitored by TLC, the reaction mixture was poured into ice water and extracted with EtOAc (3 × 50 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 20–1 / 5). TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5) was used to monitor the reaction, and the fraction with Rf = 0.5–0.6 was collected to give compound M-299.5 (981 mg, yield 81.0%). ESI [M+H] + =223.1.

[0104] At -10°C, compound M-299.5 (981 mg, 4.42 mmol) and PhI(OAc)2 (2.13 g, 6.62 mmol) were dissolved in MeOH (20 mL). KOH (2.97 g, 53.04 mol) was added to the reaction system in portions over 30 minutes. After the addition was complete, the mixture was stirred at -10°C for 3 hours. After the reaction was complete as monitored by TLC, saturated brine (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 / 20 to 1 / 10). TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5) was used to monitor the reaction, and the fraction with Rf = 0.5 to 0.6 was collected to obtain compound M-299.6 (879 mg, yield 70%). ESI[M+H] + =285.1, and the compound M-334 of the present invention was collected at the same time.

[0105] NaH (40.0 mg, 60% in mineral oil, 1.0 mmol) was added in a single batch to 5 mL of anhydrous DMF containing compound M-299.6 (142 mg, 0.50 mmol) in an ice-water bath at 0 °C, and the mixture was stirred at 0 °C for 30 minutes. 1-Bromo-2-butyne (132 mg, 1.0 mmol) was slowly added to the system using a syringe, and the mixture was stirred overnight at room temperature. After the reaction was complete as monitored by TLC, 10 mL of ice water was added to the reaction mixture, and the mixture was extracted with EtOAc (3 × 10 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 M-299.7, which was used directly in the next reaction. ESI[M+H] + =337.2.

[0106] At room temperature, PTSA·H₂O (475 mg, 2.5 mmol) was added to a 10 mL acetone solution of the crude compound M-299.7 obtained in the previous step, and the mixture was stirred overnight at room temperature. After the reaction was complete as monitored by TLC, ice water (10 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 (10 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 / 20 to 1 / 5), and the fraction with Rf = 0.5 to 0.6 was collected as monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 3), yielding a colorless oily target compound M-299 (15 mg, two-step yield 10.1%). ESI[M+H] + =291.1

[0107] 1 H NMR (400MHz, CDCl3) δ7.64(s,1H),4.64(d,J=2.3Hz,2H),4.33(q,J=2.3Hz,2H),4.18(s,1H),1.90( t,J=2.3Hz,3H),1.58(s,3H),1.30(s,2H),0.80–0.67(m,2H),0.58–0.46(m,4H),0.46–0.36(m,2H).

[0108] The preparation methods of the target compounds M-301, M-306, M-308~M-310, M-315~M-316, M-322~M-324, M-326~M-327, M-388~M-390 and M-392~M-394 of this invention are similar to those of target compounds M-299 and M-334.

[0109] Compound M-301: 60 mg, colorless oil, ESI [M+H] + =291.1.

[0110] 1H NMR (400MHz, CDCl3) δ7.68(d,J=1.4Hz,1H),4.92(s,1H),4.79(d,J=10.1Hz,1H),4.67(d,J=3.7Hz,1H),4.61(dd,J=10.9,2.2Hz,2H),4.31(q,J=2.3Hz, 2H),1.89(t,J=2.3Hz,3H),1.84(s,3H),1.28–1.20(m,1H),0.98–0.87(m,1H ),0.74–0.65(m,1H),0.65–0.57(m,1H),0.41(ddd,J=10.6,9.6,4.9Hz,1H).

[0111] Compound M-306: 20 mg, white solid, ESI [M+H] + =307.2.

[0112] 1 H NMR (400MHz, CDCl3) δ7.62(s,1H),4.53(d,J=2.4Hz,2H),4.20(s,1H),3.58(d,J=6.9Hz,2H),2.76–2.64(m,1H),2.19–2.08(m,2H) ,2.01–1.88(m,2H),1.88–1.77(m,2H),1.29(s,2H),0.77–0.66(m,2H),0.51(dt,J=10.6,4.3Hz,4H),0.41(dd,J=9.8,4.6Hz,2H).

[0113] Compound M-308: 63 mg, colorless oil, ESI [M+H] + =307.2.

[0114] 1 H NMR(400MHz, CDCl3) δ7.66(d,J=1.3Hz,1H),4.92(s,1H),4.81(d,J=10.1Hz,1H),4 .68(s,1H),4.50(t,J=2.2Hz,2H),3.56(d,J=6.8Hz,2H),2.68(dt,J=14.9,7.5Hz, 1H),2.11(tdd,J=7.5,6.4,2.7Hz,3H),1.98–1.87(m,3H),1.83(s,3H),1.29–1.19 (m,1H),0.97–0.86(m,1H),0.65(dtt,J=15.1,10.5,5.3Hz,2H),0.48–0.30(m,1H).

[0115] Compound M-309: 96 mg, colorless oil, ESI [M+H] + =295.2.

[0116] 1 H NMR (400MHz, CDCl3) δ7.35(s,1H),5.17(dq,J=13.4,6.7Hz,1H),4.54(d,J=2.4Hz,2H),3.61(d,J=6.9Hz,2H),2.8 1–2.64(m,2H),2.24–2.07(m,3H),2.02–1.90(m,4H),1.90–1.78(m,4H),1.77–1.68(m,1H),1.37(d,J=6.6Hz,3H).

[0117] Compound M-310: 18 mg, colorless oil, ESI [M+H] + =322.2.

[0118] 1 H NMR (400MHz, CDCl3) δ7.25 (s, 1H), 5.22 (dd, J = 10.5, 7.0Hz, 1H), 4.57–4.52 (m, 2H),3.61(d,J=6.9Hz,2H),2.83(d,J=8.2Hz,1H),2.77–2.67(m,1H),2.14(ddd, J=15.6,8.3,3.2Hz,3H),1.96(ddd,J=16.6,13.1,5.5Hz,5H),1.83(dd,J=16.5, 7.8Hz, 4H), 1.67 (d, J = 8.7Hz, 1H), 0.93 (d, J = 6.7Hz, 3H), 0.87 (d, J = 6.8Hz, 3H).

[0119] Compound M-315: 42 mg, white solid, ESI [M+H] + =267.1.

[0120] 1H NMR (400MHz, CDCl3) δ7.67(s,1H),4.92(s,1H),4.81(d,J=10.0Hz,1H),4.68(s,1H),4.52(t,J=2.6Hz,2H),3.65(d,J=7.0Hz,2H),1.84(s, 3H),1.30(s,3H),1.27–1.20(m,1H),0.89(d,J=8.1Hz,1H),0.68(dd,J=16.1,11.2Hz,1H),0.61(dt,J=10.5,5.1Hz,1H),0.48–0.36(m,1H).

[0121] Compound M-316: 28 mg, colorless oil, ESI [M+H] + =255.1.

[0122] 1 H NMR (400MHz, CDCl3) δ7.36(d,J=1.1Hz,1H),5.17(dd,J=9.9,6.6Hz,1H),4.56(d,J=2.4Hz,2H),3.69(q,J=7.0Hz,2H),2.81–2.68(m,1H ),2.23–2.12(m,1H),2.01–1.91(m,2H),1.86(tt,J=18.4,6.5Hz,2H),1.79–1.72(m,1H),1.38(d,J=6.7Hz,3H),1.34(t,J=7.0Hz,3H).

[0123] Compound M-322: 59 mg, colorless oil, ESI [M+H] + =321.2.

[0124] 1 H NMR (400MHz, CDCl3) δ7.66(d,J=1.4Hz,1H),4.92(s,1H),4.81(d,J=10.1Hz,1H),4.68(s,1H ),4.48(t,J=2.3Hz,2H),3.50(d,J=6.1Hz,2H),2.49–2.39(m,1H),2.12–2.04(m,3H),1.83( s,3H),1.78(dt,J=7.0,3.9Hz,3H),1.66(d,J=2.3Hz,2H),1.27–1.20(m,1H),0.91(ddd,J=6 .0,4.2,2.3Hz,1H),0.85–0.74(m,1H),0.67(ddd,J=8.7,4.7,2.3Hz,1H),0.46–0.39(m,1H).

[0125] Compound M-323: 100 mg, colorless oil, ESI [M+H] + =309.2.

[0126] 1 H NMR (400MHz, CDCl3) δ7.35(s,1H),5.17(dd,J=10.0,6.6Hz,1H),4.52(d,J=2.4Hz,2H),3.54(t,J=6.9Hz,2H),2.81–2.66(m,1H),2.43(dd, J=15.7,7.8Hz,1H),2.22–2.13(m,1H),2.13–2.05(m,2H),2.01–1.91(m,2H),1.91–1.77(m,6H),1.77–1.63(m,3H),1.37(d,J=6.6Hz,3H).

[0127] Compound M-324: 21 mg, colorless oil, ESI [M+H] + =337.2.

[0128] 1 H NMR (400MHz, CDCl3) δ7.25 (s, 1H), 5.27–5.16 (m, 1H), 4.52 (d, J = 1.3Hz, 2H), 3 .53(t,J=6.9Hz,2H),2.81(s,1H),2.44(dt,J=16.1,8.1Hz,1H),2.18(s,1H),2 .10(dd,J=17.9,9.9Hz,3H),2.01–1.96(m,1H),1.91(dd,J=18.8,10.5Hz,3H) ,1.84–1.79(m,3H),1.68(s,4H),0.92(d,J=6.6Hz,3H),0.86(d,J=6.8Hz,3H).

[0129] Compound M-326: 157 mg, white solid, ESI [M+H] + =283.0.

[0130] 1H NMR(400MHz,d6-DMSO)δ8.32(s,1H),8.02(d,J=0.7Hz,1H),4.34–4.12(m,1H),3.22(s,9H),2.01–1.81(m ,2H),1.51–1.33(m,1H),0.78(t,J=7.4Hz,3H),0.74–0.66(m,1H),0.48–0.37(m,2H),0.18–0.09(m,1H).

[0131] Compound M-327: 111 mg, white solid, ESI [M+H] + =295.0.

[0132] 1 H NMR(400MHz,d6-DMSO)δ8.35(s,1H),8.01(s,1H),4.02–3.78(m,1H),3.23(s,9 H),1.56–1.42(m,2H),0.71–0.61(m,2H),0.52–0.32(m,4H),0.23–0.11(m,2H).

[0133] Compound M-388: 18 mg, colorless oil, ESI [M+H] + =273.0.

[0134] 1 H NMR(400MHz,d6-DMSO)δ8.34(s,1H),7.97(d,J=0.7Hz,1H),4.60(s,2H),4.22(q,J=2.3Hz,2H),3.94–3.78(m,1H),1 .85(t,J=2.4Hz,3H),1.55–1.40(m,2H),0.70–0.55(m,2H),0.51–0.43(m,2H),0.42–0.32(m,2H),0.23–0.10(m,2H).

[0135] Compound M-389: 63 mg, colorless oil, ESI [M+H] + =289.0.

[0136] 1H NMR(400MHz,d6-DMSO)δ8.32(s,1H),7.96(d,J=0.6Hz,1H),4.54(s,2H),3.93–3.79(m,1H),3.46(d,J=6.7Hz,2H), 2.60–2.54(m,1H),2.09–1.67(m,6H),1.57–1.40(m,2H),0.68–0.59(m,2H),0.50–0.33(m,4H),0.23–0.12(m,2H).

[0137] Compound M-390: 15 mg, colorless oil, ESI [M+H] + =249.0.

[0138] 1 H NMR(400MHz,d6-DMSO)δ8.33(s,1H),7.97(d,J=0.7Hz,1H),4.54(s,2H),3.94–3.79(m,1H),3.53(q,J=7.0Hz,2H),1 .56–1.42(m,2H),1.16(t,J=7.0Hz,3H),0.70–0.58(m,2H),0.51–0.42(m,2H),0.42–0.32(m,2H),0.22–0.14(m,2H).

[0139] Compound M-392: 40 mg, colorless oil, ESI [M+H] + =261.1.

[0140] 1 H NMR (400MHz, CDCl3) δ8.73(s,1H),8.42(s,1H),5.38(s,1H),4.51(s,2H),4.31(s,2H),2.31–2.21(m,1H),2.06( s,2H),1.97(s,2H),1.91(s,3H),1.01(t,J=7.0Hz,3H),0.76–0.69(m,1H),0.69–0.61(m,1H),0.32–0.24(m,1H).

[0141] Compound M-393: 10 mg, colorless oil, ESI [M+H] + =277.2.

[0142] 1H NMR (400MHz, CDCl3) δ8.14(s,1H),8.06(s,1H),4.48(s,2H),4.40(s,1H),3.57(d,J=6.8Hz,2H),2.68(s,1H),2.16–2.09(m,2H),1.99–1. 93(m,3H),1.85–1.76(m,3H),1.27–1.20(m,1H),0.95(d,J=7.4Hz,3H),0.90–0.80(m,1H),0.64–0.47(m,2H),0.29(dd,J=9.7,4.8Hz,1H).

[0143] Compound M-394: 63 mg, colorless oil, ESI [M+H] + =236.1.

[0144] 1 H NMR (400MHz, CDCl3) δ7.98(d,J=2.4Hz,2H),4.52(s,2H),4.36(s,1H),3.66(q,J=7.0Hz,2H),2.01–1.90(m,2H),1.32( t,J=7.0Hz,3H),1.27–1.21(m,1H),0.93(t,J=7.4Hz,3H),0.81(d,J=6.4Hz,1H),0.61–0.46(m,2H),0.35–0.24(m,1H).

[0145] Example 3: Compounds of the present invention DA-473, DA-837~DA-840, DA-900~DA-906, DA-927~DA-

[0146] Preparation of 931, DA-993, DA-999~DA-1004, DA-1024, DA-1026, DA-1042, DA-K41, DA-K43 and DA-K45

[0147] At room temperature, H-3 (146 mg, 1 mmol) was dissolved in dry THF (5 mL), and the temperature was lowered to 0 °C using an ice-water bath. Then, (S)-1-(2-fluorophenyl)ethan-1-ol (140 mg, 1 mmol) and PPh3 (393.4 mg, 1.5 mmol) were added sequentially to the reaction system. DEAD (261.2 mg, 1.5 mmol) was slowly added to the reaction system using a syringe, and the mixture was stirred overnight at room temperature. After the reaction was monitored by TLC to indicate completion, ice water was added to the reaction system, and the mixture 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. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give a pale yellow oily compound DA-837 and its isomer DA-929.

[0148] Compound DA-837 (101 mg, yield 37.7%). ESI [M+NH4] + =286.9.

[0149] 1 H NMR(400MHz, CDCl3)δ7.92(s,1H),7.80(s,1H),7.46–7.37(m,1H),7.27–7.10 (m,3H),6.55(t,J=53.7Hz,1H),5.78(q,J=7.1Hz,1H),1.98(d,J=7.0Hz,3H).

[0150] Compound DA-929 (59 mg, yield 22.0%), colorless syrup, ESI [M+NH4] + =286.9.

[0151] 1 H NMR(400MHz, CDCl3)δ8.17(s,1H),8.01(s,1H),7.43–7.32(m,1H),7.24–7.06 (m,3H),6.54(q,J=7.1Hz,1H),6.09(t,J=53.7Hz,1H),1.95(d,J=7.1Hz,3H).

[0152] The preparation of compounds DA-473, DA-839, DA-840, DA-900, DA-902, DA-904, DA-927, DA-928, DA-930, DA-931, DA-1024, DA-1042, DA-K41, DA-K43 and DA-K45 of the present invention is similar to the compounds DA-837 and DA-929 of this example.

[0153] Compound DA-473: 1.76 g, pale yellow oil, ESI [M+NH4] + =304.8.

[0154] 1 H NMR (400MHz, CDCl3) δ8.15(s,1H),8.05(s,1H),7.44–7.33(m,1H),7.22–7.05(m,3H),6.52(q,J=7.0Hz,1H),2.07(s,2H),1.96(d,J=7.0Hz,3H).

[0155] Compound DA-839: 388 mg, white solid, ESI [M+NH4] + =318.9.

[0156] 1 H NMR(400MHz, CDCl3)δ8.14(s,1H),8.00(s,1H),7.27–7.15(m,1H),7.12–7.00(m ,1H),6.99–6.86(m,1H),6.58–6.45(m,1H),2.31(s,3H),1.93(d,J=3.2Hz,3H).

[0157] Compound DA-840: 521 mg, white solid, ESI [M+NH4] + =334.8.

[0158] 1 H NMR (400MHz, CDCl3) δ8.15(s,1H),7.86(s,1H),7.28(d,J=7.8Hz,1H),7.21(t,J=7.6Hz ,1H),6.87(d,J=7.4Hz,1H),6.61(q,J=6.7Hz,1H),2.44(s,3H),1.91(d,J=6.9Hz,3H).

[0159] Compound DA-900: 35 mg, white solid, ESI [M+NH4] + =300.9.

[0160] 1H NMR (400MHz, CDCl3) δ7.91(s,1H),7.77(s,1H),7.28–7.20(m,1H),7.15–7.07(m,1H),7.07–7.00( m,1H),6.55(t,J=53.7Hz,1H),5.76(q,J=7.0Hz,1H),2.32(d,J=2.1Hz,3H),1.96(d,J=7.1Hz,3H).

[0161] Compound DA-902: 57 mg, white solid, ESI [M+NH4] + =316.8.

[0162] 1 H NMR (400MHz, CDCl3) δ7.88(s,1H),7.72(s,1H),7.31(d,J=6.5Hz,1H),7.25(t,J=7.6Hz,1H),7.04( d,J=7.6Hz,1H),6.56(t,J=53.8Hz,1H),5.97(q,J=7.0Hz,1H),2.45(s,3H),1.94(d,J=7.0Hz,3H).

[0163] Compound DA-904: 194 mg, gray solid, ESI [M+NH4] + =320.8.

[0164] 1 H NMR(400MHz, CDCl3)δ8.16(s,1H),7.90(s,1H),7.52–7.40(m,1H),7.38–7. 30(m,2H),7.03–6.93(m,1H),6.58(q,J=6.9Hz,1H),1.93(d,J=7.0Hz,3H).

[0165] Compound DA-927: 310 mg, white solid, ESI [M+NH4] + =334.8.

[0166] 1 H NMR (400MHz, CDCl3) δ8.15(s,1H),7.84(s,1H),7.27(d,J=7.5Hz,1H),7.20(t,J=7.6Hz ,1H),6.85(d,J=7.5Hz,1H),6.61(q,J=6.9Hz,1H),2.44(s,3H),1.91(d,J=6.9Hz,3H).

[0167] Compound DA-928: 81 mg, colorless syrup, ESI [M+NH4] + =316.8.

[0168] 1 H NMR (400MHz, CDCl3) δ8.17(s,1H),7.83(s,1H),7.26(d,J=7.5Hz,1H),7.19(t,J=7.6Hz,1H),6.84( d,J=7.5Hz,1H),6.62(q,J=6.9Hz,1H),6.08(t,J=53.7Hz,1H),2.44(s,3H),1.89(d,J=6.9Hz,3H).

[0169] Compound DA-930: 98 mg, colorless oil, ESI [M+NH4] + =302.8.

[0170] 1 H NMR(400MHz, CDCl3)δ8.19(s,1H),7.91(s,1H),7.51–7.40(m,1H),7.36–7.30(m,2H),7 .04–6.94(m,1H),6.60(q,J=7.0Hz,1H),6.08(t,J=53.7Hz,1H),1.92(d,J=7.0Hz,3H).

[0171] Compound DA-931: 85 mg, white solid, ESI [M+NH4] + =300.9.

[0172] 1 H NMR (400MHz, CDCl3) δ8.16(s,1H),7.97(s,1H),7.20(t,J=7.3Hz,1H),7.05(t,J=7.6Hz,1H),6.92(t,J= 7.0Hz, 1H), 6.54 (q, J = 7.1Hz, 1H), 6.10 (t, J = 53.7Hz, 1H), 2.30 (d, J = 2.0Hz, 3H), 1.92 (d, J = 7.1Hz, 3H).

[0173] Compound DA-993: 35 mg, colorless syrup, ESI [M+NH4] + =320.8.

[0174] 1H NMR(400MHz, CDCl3)δ7.89(s,1H),7.75(s,1H),7.52–7.44(m,1H),7.42–7.33(m, 2H),7.24–7.12(m,1H),5.94(q,J=7.0Hz,1H),1.97(d,J=7.0Hz,3H),1.29(s,3H).

[0175] Compound DA-1024: 54 mg, yellow oil, ESI [M+NH4] + =276.8.

[0176] 1 H NMR (400MHz, CDCl3) δ8.25(s,1H),8.12(s,1H),4.16(t,J=8.5Hz,1H),1.42–1.25(m,2H),0.83–0.71(m,2H),0.63–0.47(m,4H),0.42–0.32(m,2H).

[0177] Compound DA-1042: 174 mg, white solid, ESI [M+NH4] + =322.8.

[0178] 1 H NMR (400MHz, CDCl3) δ8.23–8.11(m,2H),7.25–7.16(m,1H),7.16–7.08(m,1H), 6.84–6.72(m,J=7.5,6.3Hz,1H), 6.53(q,J=7.0Hz,1H), 1.99(d,J=7.1Hz,3H).

[0179] Compound DA-K41: 108 mg, pale yellow oil, ESI [M+H] + =308.9.

[0180] 1 H NMR(400MHz,d6-DMSO)δ8.04(d,J=1.5Hz,1H),7.53–7.45(m,1H),7.36–7.28(m,2H),6.84–6.77(m,1H),6.42(q,J= 7.1Hz,1H),2.66–2.58(m,2H),1.78(d,J=7.1Hz,3H),1.50–1.37(m,2H),1.23–1.09(m,2H),0.80(t,J=7.3Hz,3H).

[0181] Compound DA-K43: 13 mg, colorless syrup, ESI [M+H]+ =346.9.

[0182] 1 H NMR (400MHz, CD3OD) δ7.89(s,1H),7.80(d,J=7.6Hz,1H),7.49–7.36(m,3H),6.86(q,J=7.0Hz,1H),2.93–2.74(m,2H),2.58–2.43(m,1H),2.4 1–2.29(m,1H),1.95(d,J=7.1Hz,3H),1.72–1.61(m,2H),1.50–1.32(m,4H),1.23–1.00(m,2H),0.97(t,J=7.4Hz,3H),0.79(t,J=7.3Hz,3H).

[0183] Compound DA-K45: 73 mg, colorless oil, ESI [M+H] + =290.9.

[0184] 1 H NMR(400MHz,d6-DMSO)δ8.20(s,1H),8.05(s,1H),7.53–7.44(m,1H),7.36–7.24(m,2H),6.82–6.72(m,1H),6.49(q,J= 7.0Hz,1H),2.73(t,J=7.3Hz,2H),1.80(d,J=7.1Hz,3H),1.52–1.39(m,2H),1.24–1.12(m,2H),0.82(t,J=7.3Hz,3H).

[0185] Example 4. Compounds of the present invention DA-841~DA-843, DA-886~DA-899, DA-1005~DA-1008, DA-1013~DA-1014, DA-1027~DA-1029, D Preparation of A-1043~DA-1044, DA-1047~DA-1050, DA-1058~DA-1060, DA-1073~DA-1074, DA-1079~DA-1083, DA-1088

[0186] 1. Preparation of compound DA-841 of the present invention

[0187] Methylmagnesium bromide (1.0 mL, 1.0 mmol, 1.0 M in THF) was added to (R)-1-(1-(2-fluorophenyl)ethyl)-N-methoxy-N-methyl-1H-imidazole-5-carboxamide (200 mg, 0.72 mmol) in THF (3 mL) at 0°C in an ice-water bath. The mixture was slowly heated to room temperature and stirred for 2 hours. After the reaction was completed as monitored by TLC, the reaction mixture 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, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain a colorless oily compound DA-841 (56 mg, yield 33.5%). + =232.9.

[0188] 1 H NMR(400MHz,d6-DMSO)δ8.26(s,1H),8.02(d,J=0.8Hz,1H),7.38–7.29(m,1H),7.24–7.12(m ,2H),6.90(td,J=7.8,1.6Hz,1H),6.50(q,J=7.2Hz,1H),2.37(s,3H),1.81(d,J=7.2Hz,3H).

[0189] The preparation of compounds DA-842~DA-843, DA-886~DA-899, DA-1005~DA-1010 of the present invention is similar to that of compound DA-841 of the present invention.

[0190] Compound DA-842: 68 mg, colorless oil, ESI [M+NH4] + =246.9.

[0191] 1 H NMR(400MHz,d6-DMSO)δ8.26(s,1H),8.02(d,J=0.7Hz,1H),7.38–7.30(m,1H),7.25–7.12(m,2H),6.90(td ,J=7.8,1.6Hz,1H),6.51(q,J=7.2Hz,1H),2.92–2.69(m,2H),1.81(d,J=7.2Hz,3H),0.98(t,J=7.3Hz,3H).

[0192] Compound DA-843: 52 mg, pale yellow oil, ESI [M+NH4] + =260.9.

[0193] 1 H NMR(400MHz,d6-DMSO)δ8.27(s,1H),8.05(d,J=0.6Hz,1H),7.38–7.28(m,1H),7.24–7.11(m,2H),6.87(td,J =7.8,1.6Hz,1H),6.49(q,J=7.2Hz,1H),1.82(d,J=7.2Hz,3H),1.05(d,J=6.8Hz,3H),0.90(d,J=6.9Hz,3H).

[0194] Compound DA-886: 84 mg, colorless syrup, ESI [M+NH4] + =262.9.

[0195] 1 H NMR(400MHz,d6-DMSO)δ8.20(s,1H),8.04(d,J=0.7Hz,1H),7.52–7.45(m,1H),7.36–7.27(m,2H),6.8 3–6.75(m,1H),6.49(q,J=7.1Hz,1H),2.90–2.66(m,2H),1.80(d,J=7.1Hz,3H),0.97(t,J=7.4Hz,3H).

[0196] Compound DA-887: 15 mg, colorless oil, ESI [M+NH4] + =276.9.

[0197] 1 H NMR(400MHz,d6-DMSO)δ8.20(s,1H),8.07(s,1H),7.51–7.42(m,1H),7.36–7.26(m,2H),6.81–6.70(m,1H),6 .47(q,J=7.1Hz,1H),3.31–3.26(m,1H),1.80(d,J=7.1Hz,3H),1.04(d,J=6.7Hz,3H),0.88(d,J=6.9Hz,3H).

[0198] Compound DA-888: 126 mg, white solid, ESI [M+NH4] + =276.9.

[0199] 1H NMR(400MHz,d6-DMSO)δ8.17(s,1H),8.03(d,J=0.6Hz,1H),7.29(d,J=6.9Hz,1H),7.20(t,J=7.6Hz,1H),6.62(d, J=7.2Hz,1H),6.53(q,J=7.1Hz,1H),2.95–2.66(m,2H),2.37(s,3H),1.78(d,J=7.1Hz,3H),0.97(t,J=7.4Hz,3H).

[0200] Compound DA-889: 103 mg, white semi-solid, ESI [M+NH4] + =290.9.

[0201] 1 H NMR (400MHz, d6-DMSO) δ8.17(s,1H),8.07(s,1H),7.29(d,J=6.9Hz,1H),7.20(t,J=7.6Hz,1H),6.63(d,J=7.2Hz,1H),6. 51(q,J=7.0Hz,1H),3.33–3.26(m,1H),2.37(s,3H),1.80(d,J=7.1Hz,3H),1.05(d,J=6.7Hz,3H),0.91(d,J=6.9Hz,3H).

[0202] Compound DA-890: 143 mg, white solid, ESI [M+NH4] + =260.9.

[0203] 1 H NMR (400MHz, d6-DMSO) δ8.22(s,1H),8.02(s,1H),7.21(t,J=7.3Hz,1H),7.04(t,J=7.6Hz,1H),6.71(t,J=7.4Hz, 1H), 6.52 (q, J = 7.2Hz, 1H), 2.94–2.65 (m, 2H), 2.24 (d, J = 1.6Hz, 3H), 1.79 (d, J = 7.2Hz, 3H), 0.99 (t, J = 7.3Hz, 3H).

[0204] Compound DA-891: 118 mg, colorless oil, ESI [M+NH4] + =274.9.

[0205] 1H NMR (400MHz, d6-DMSO) δ8.23(s,1H),8.05(s,1H),7.20(t,J=7.2Hz,1H),7.03(t,J=7.6Hz,1H),6.69(t,J=7.0Hz,1H),6.49(q ,J=7.1Hz,1H),3.39–3.23(m,1H),2.24(d,J=1.9Hz,3H),1.80(d,J=7.2Hz,3H),1.06(d,J=6.8Hz,3H),0.92(d,J=6.9Hz,3H).

[0206] Compound DA-892: 166 mg, pale yellow oil, ESI [M+NH4] + =264.9.

[0207] 1 H NMR(400MHz,d6-DMSO)δ8.10(d,J=1.7Hz,1H),7.41–7.30(m,1H),7.27–7.13(m,2H),6.99–6.90 (m,1H),6.44(q,J=7.2Hz,1H),2.81–2.58(m,2H),1.80(d,J=7.2Hz,3H),0.96(t,J=7.3Hz,3H).

[0208] Compound DA-893: 12 mg, colorless oil, ESI [M+NH4] + =278.9.

[0209] 1 H NMR(400MHz,d6-DMSO)δ8.13(d,J=1.4Hz,1H),7.39–7.30(m,1H),7.25–7.12(m,2H),6.94–6.86(m,1H),6. 41(q,J=7.1Hz,1H),3.14–3.04(m,1H),1.80(d,J=7.2Hz,3H),1.03(d,J=6.7Hz,3H),0.87(d,J=6.9Hz,3H).

[0210] Compound DA-894: 210 mg, colorless oil, ESI [M+NH4] + =280.8.

[0211] 1H NMR(400MHz,d6-DMSO)δ8.15–7.90(m,1H),7.61–7.17(m,3H),6.95–6.68(m,1H ),6.56–6.29(m,1H),2.90–2.62(m,2H),1.95–1.54(m,3H),1.12–0.75(m,3H).

[0212] Compound DA-895: 28 mg, colorless oil, ESI [M+NH4] + =294.9.

[0213] 1 H NMR(400MHz,d6-DMSO)δ8.05(d,J=1.5Hz,1H),7.51–7.44(m,1H),7.36–7.28(m,2H),6.85–6.77(m,1H),6. 41(q,J=7.0Hz,1H),3.17–3.01(m,1H),1.79(d,J=7.1Hz,3H),1.02(d,J=6.7Hz,3H),0.86(d,J=6.8Hz,3H).

[0214] Compound DA-896: 189 mg, white solid, ESI [M+NH4] + =294.9.

[0215] 1 H NMR (400MHz, d6-DMSO) δ8.01(d,J=1.6Hz,1H),7.31(d,J=7.2Hz,1H),7.22(t,J=7.6Hz,1H),6.66(d,J=7.3H z,1H),6.47(q,J=7.0Hz,1H),2.84–2.58(m,2H),2.38(s,3H),1.77(d,J=7.1Hz,3H),0.96(t,J=7.3Hz,3H).

[0216] Compound DA-897: 45 mg, white solid, ESI [M+NH4] + =308.9.

[0217] 1H NMR (400MHz, d6-DMSO) δ8.01(d,J=1.5Hz,1H),7.31(d,J=7.0Hz,1H),7.22(t,J=7.6Hz,1H),6.66(d,J=7.2Hz,1H),6.4 5(q,J=7.1Hz,1H),3.16–3.03(m,1H),2.38(s,3H),1.78(d,J=7.1Hz,3H),1.03(d,J=6.7Hz,3H),0.89(d,J=6.8Hz,3H).

[0218] Compound DA-898: 170 mg, colorless oil, ESI [M+NH4] + =278.9.

[0219] 1 H NMR (400MHz, d6-DMSO) δ8.07(d,J=1.6Hz,1H),7.23(t,J=7.2Hz,1H),7.06(t,J=7.6Hz,1H),6.76(t,J=6.9Hz,1H ),6.45(q,J=7.2Hz,1H),2.81–2.60(m,2H),2.25(d,J=1.8Hz,3H),1.79(d,J=7.2Hz,3H),0.97(t,J=7.3Hz,3H).

[0220] Compound DA-899: 23 mg, colorless oil, ESI [M+NH4] + =292.9.

[0221] 1 H NMR (400MHz, d6-DMSO) δ8.09 (s, 1H), 7.22 (t, J = 7.4Hz, 1H), 7.05 (t, J = 7.6Hz, 1H), 6.72 (t, J = 7.3Hz, 1H), 6.42 (q, J = 7. 1Hz,1H),3.16–3.04(m,1H),2.24(d,J=1.4Hz,3H),1.79(d,J=7.1Hz,3H),1.04(d,J=6.7Hz,3H),0.90(d,J=6.8Hz,3H).

[0222] Compound DA-1005: 163 mg, white solid, ESI [M+NH4] + =314.8.

[0223] 1H NMR (400MHz, d6-DMSO) δ8.13(d,J=1.5Hz,1H),7.59(dd,J=8.0,1.3Hz,1H),7.34(t,J=8.0Hz,1H),6.73(dd ,J=7.9,1.2Hz,1H),6.41(q,J=7.0Hz,1H),2.80–2.57(m,2H),1.79(d,J=7.1Hz,3H),0.94(t,J=7.3Hz,3H).

[0224] Compound DA-1006: 55 mg, colorless syrup, ESI [M+NH4] + =328.8.

[0225] 1 H NMR (400MHz, d6-DMSO) δ8.14(d,J=1.5Hz,1H),7.58(dd,J=8.0,1.3Hz,1H),7.33(t,J=8.0Hz,1H),6.70(dd,J=7.8,1.2 Hz,1H),6.38(q,J=7.1Hz,1H),3.17–2.90(m,1H),1.79(d,J=7.1Hz,3H),1.02(d,J=6.7Hz,3H),0.86(d,J=6.8Hz,3H).

[0226] Compound DA-1007: 167 mg, pale yellow solid, ESI [M+NH4] + =298.8.

[0227] 1 H NMR(400MHz,d6-DMSO)δ8.18(d,J=1.5Hz,1H),7.57–7.47(m,1H),7.24–7.15(m,1H),6.93–6.79 (m,1H),6.41(q,J=7.1Hz,1H),2.80–2.58(m,2H),1.81(d,J=7.2Hz,3H),0.96(t,J=7.3Hz,3H).

[0228] Compound DA-1008: 51 mg, white solid, ESI [M+NH4] + =312.8.

[0229] 1H NMR(400MHz,d6-DMSO)δ8.20(d,J=1.3Hz,1H),7.57–7.50(m,1H),7.20(t,J=8.0Hz,1H),6.88–6.80(m,1H),6 .39(q,J=7.1Hz,1H),3.17–3.01(m,1H),1.82(d,J=7.2Hz,3H),1.04(d,J=6.7Hz,3H),0.88(d,J=6.8Hz,3H).

[0230] Compound DA-1013: 144 mg, white solid, ESI [M+H] + =236.9.

[0231] 1 H NMR(400MHz,d6-DMSO)δ8.11(s,1H),3.99–3.79(m,1H),2.77(qd,J=7.3,2.5Hz,2H),1.60–1 .39(m,2H),1.05(t,J=7.3Hz,3H),0.70–0.57(m,2H),0.52–0.33(m,4H),0.27–0.10(m,2H).

[0232] Compound DA-1014: 87 mg, colorless oil, ESI [M+H] + =264.8.

[0233] 1 H NMR(400MHz,d6-DMSO)δ8.16(d,J=1.7Hz,1H),7.32–7.24(m,2H),7.23–7.14(m,2H),6 .30(q,J=7.2Hz,1H),2.82–2.61(m,2H),1.81(d,J=7.2Hz,3H),0.99(t,J=7.3Hz,3H).

[0234] Compound DA-1027: 170 mg, colorless oil, ESI [M+H] + =218.9.

[0235] 1H NMR(400MHz,d6-DMSO)δ8.29(s,1H),7.94(d,J=0.5Hz,1H),4.04–3.78(m,1H),2.86(q,J=7.3Hz,2H),1.55– 1.40(m,2H),1.06(t,J=7.3Hz,3H),0.68–0.58(m,2H),0.50–0.30(m,4H),0.21–0.11(m,J=9.5,4.9Hz,2H).

[0236] Compound DA-1028: 427 mg, colorless oil, ESI [M+H] + =221.0.

[0237] 1 H NMR(400MHz,d6-DMSO)δ8.09(s,1H),7.94(s,1H),5.37–4.89(m,1H),2.87(q,J=7.4Hz,2H),2.14 –2.00(m,1H),1.90–1.59(m,7H),1.58–1.43(m,1H),1.08(t,J=7.3Hz,3H),0.65(t,J=7.4Hz,3H).

[0238] Compound DA-1029: 50 mg, colorless oil, ESI [M+H] + =207.0.

[0239] 1 H NMR(400MHz,d6-DMSO)δ8.25(s,1H),7.95(s,1H),4.34–4.16(m,1H),2.86(q,J=7.3Hz,2H),1.98–1.81(m,2H),1.47 –1.35(m,1H),1.06(t,J=7.4Hz,3H),0.77(t,J=7.4Hz,3H),0.72–0.65(m,1H),0.46–0.33(m,2H),0.18–0.08(m,1H).

[0240] Compound DA-1043: 99 mg, white solid, ESI [M+H] + =264.9.

[0241] 1H NMR(400MHz,d6-DMSO)δ8.34(s,1H),8.04(s,1H),7.44–7.29(m,1H),7.23–7.11(m,1H),6.71–6. 62(m,1H),6.49(q,J=7.2Hz,1H),2.91–2.66(m,2H),1.83(d,J=7.2Hz,3H),0.98(t,J=7.3Hz,3H).

[0242] Compound DA-1044: 33 mg, white solid, ESI [M+H] + =278.9.

[0243] 1 H NMR(400MHz,d6-DMSO)δ8.35(s,1H),8.08(s,1H),7.42–7.31(m,1H),7.22–7.11(m,1H),6.64(t,J=7.2Hz,1H) ,6.48(q,J=7.2Hz,1H),3.40–3.21(m,1H),1.84(d,J=7.2Hz,3H),1.05(d,J=6.8Hz,3H),0.89(d,J=6.8Hz,3H).

[0244] Compound DA-1047: 382 mg, white solid, ESI [M+H] + =289.2.

[0245] 1 H NMR (400MHz, d6-DMSO) δ8.23(s,1H),8.03(s,1H),7.20(t,J=7.2Hz,1H),7.03(t,J=7.6Hz,1H),6.67(t,J=7.3Hz,1H),6.52(q,J=7.1Hz,1 H),2.61(tt,J=14.6,7.2Hz,2H),2.24(d,J=1.7Hz,3H),2.00(dt,J=13.5,6.8Hz,1H),1.80(d,J=7.2Hz,3H),0.81(dd,J=6.7,2.2Hz,6H).

[0246] Compound DA-1048: 311 mg, white solid, ESI [M+H] + =305.1.

[0247] 1H NMR (400MHz, d6-DMSO) δ8.15(s,1H),8.05(s,1H),7.28(d,J=7.3Hz,1H),7.18(t,J=7.6Hz,1H),6.59(d,J=7.5Hz,1H),6.54( q,J=7.0Hz,1H),2.66–2.54(m,2H),2.36(s,3H),1.97(dt,J=13.6,6.8Hz,1H),1.78(d,J=7.1Hz,3H),0.79(d,J=6.7Hz,6H).

[0248] Compound DA-1049: 25 mg, white solid, ESI [M+H] + =306.9.

[0249] 1 H NMR (400MHz, d6-DMSO) δ8.09(d,J=1.6Hz,1H),7.22(t,J=7.2Hz,1H),7.05(t,J=7.6Hz,1H),6.71(t,J=7.5Hz,1H),6.44(q,J =7.2Hz,1H),2.64–2.41(m,2H),2.24(d,J=1.8Hz,3H),2.04–1.89(m,1H),1.79(d,J=7.2Hz,3H),0.79(dd,J=6.6,4.5Hz,6H).

[0250] Compound DA-1050: 18 mg, white solid, ESI [M+H] + =322.8.

[0251] 1 H NMR (400MHz, d6-DMSO) δ8.01(d,J=1.6Hz,1H),7.30(d,J=6.8Hz,1H),7.21(t,J=7.6Hz,1H),6.63(d,J=6.9Hz,1H),6. 48(q,J=7.0Hz,1H),2.60–2.41(m,2H),2.37(s,3H),2.04–1.89(m,1H),1.78(d,J=7.1Hz,3H),0.78(t,J=6.7Hz,6H).

[0252] Compound DA-1058: 246 mg, white solid, ESI [M+H] + =282.8.

[0253] 1H NMR(400MHz,d6-DMSO)δ8.18(d,J=1.6Hz,1H),7.45–7.32(m,1H),7.24–7.10(m,1H),6.78–6.67 (m,1H),6.43(q,J=7.2Hz,1H),2.82–2.59(m,2H),1.82(d,J=7.2Hz,3H),0.96(t,J=7.3Hz,3H).

[0254] Compound DA-1059: 10 mg, colorless oil, ESI [M+H] + =296.8.

[0255] 1 H NMR(400MHz,d6-DMSO)δ8.20(d,J=1.5Hz,1H),7.42–7.32(m,1H),7.22–7.12(m,1H),6.69(t,J=7.1Hz,1H),6 .40(q,J=7.1Hz,1H),3.17–3.02(m,1H),1.83(d,J=7.2Hz,3H),1.03(d,J=6.7Hz,3H),0.88(d,J=6.8Hz,3H).

[0256] Compound DA-1060: 27 mg, white solid, ESI [M+H] + =310.8.

[0257] 1 H NMR(400MHz,d6-DMSO)δ8.19(d,J=1.6Hz,1H),7.41–7.32(m,1H),7.20–7.12(m,1H),6.71–6.65(m,1H),6.46–6.38 (m,1H),2.49–2.41(m,2H),2.09–1.87(m,1H),1.83(d,J=7.2Hz,3H),0.77(d,J=3.5Hz,3H),0.76(d,J=3.5Hz,3H).

[0258] Compound DA-1073: 182 mg, colorless syrup, ESI [M+H] + =296.9.

[0259] 1H NMR(400MHz,d6-DMSO)δ8.18(d,J=1.6Hz,1H),7.44–7.30(m,1H),7.23–7.10(m,1H),6.70(dd,J=7.8,6.6Hz,1H),6 .42(q,J=7.2Hz,1H),2.63(td,J=7.2,2.2Hz,2H),1.82(d,J=7.2Hz,3H),1.56–1.42(m,2H),0.78(t,J=7.4Hz,3H).

[0260] Compound DA-1074: 139 mg, white solid, ESI [M+H] + =294.8.

[0261] 1 H NMR(400MHz,d6-DMSO)δ8.20(d,J=1.6Hz,1H),7.44–7.28(m,1H),7.26–7.09(m,1H),6.72(t,J=7.2Hz,1H ),6.41(q,J=7.1Hz,1H),2.48–2.38(m,1H),1.81(d,J=7.2Hz,3H),1.04–0.85(m,3H),0.84–0.72(m,1H).

[0262] Compound DA-1079: 353 mg, white solid, ESI [M+H] + =309.1.

[0263] 1 H NMR (400MHz, d6-DMSO) δ8.33(s,1H),8.06(s,1H),7.51(t,J=7.6Hz,1H),7.17(t,J=8.0Hz,1H),6.77(t,J=7.1H z,1H),6.58–6.39(m,1H),2.69–2.57(m,2H),1.97(dt,J=13.7,6.8Hz,1H),1.83(d,J=7.2Hz,3H),0.79(s,6H).

[0264] Compound DA-1080: 144 mg, white solid, ESI [M+H] + =325.1.

[0265] 1H NMR (400MHz, d6-DMSO) δ8.28(s,1H),8.08(s,1H),7.56(d,J=1.3Hz,1H),7.31(s,1H),6.62(d,J=7.8Hz,1H),6.48(q,J =7.0Hz,1H),2.57(d,J=16.6Hz,2H),1.95(dt,J=13.7,6.9Hz,1H),1.81(d,J=7.1Hz,3H),0.77(dd,J=6.6,2.9Hz,6H).

[0266] Compound DA-1081: 241 mg, white solid, ESI [M+H] + =327.1.

[0267] 1 H NMR(400MHz,d6-DMSO)δ8.19(d,J=1.5Hz,1H),7.52(s,1H),7.19(s,1H),6.83(s,1H),6.41(d,J=7.2Hz,1H), 2.59–2.54(m,1H),2.50–2.42(m,1H),2.03–1.89(m,1H),1.82(d,J=7.2Hz,3H),0.77(dd,J=6.6,3.7Hz,6H).

[0268] Compound DA-1082: 164 mg, white solid, ESI [M+H] + =343.1.

[0269] 1 H NMR (400MHz, d6-DMSO) δ8.14(d,J=1.6Hz,1H),7.58(dd,J=8.0,1.4Hz,1H),7.33(t,J=8.0Hz,1H),6.68(dd,J=7.9,1.3Hz,1H),6 .41(d,J=7.1Hz,1H),2.44(ddd,J=15.0,7.2,2.0Hz,1H),2.00–1.89(m,1H),1.80(d,J=7.1Hz,3H),0.76(dd,J=6.5,5.4Hz,6H).

[0270] Compound DA-1083: 215 mg, white solid, ESI [M+H] + =293.2.

[0271] 1H NMR(400MHz,d6-DMSO)δ8.34(s,1H),8.06(s,1H),7.41–7.27(m,1H),7.24–7.11(m,1H),6.62(t,J=7.2Hz,1H),6.50(d,J=7.2Hz,1H), 2.64(dd,J=14.6,6.9Hz,1H), 2.56(d,J=7.2Hz,1H), 1.98(dt,J=13.6,6.8Hz,1H), 1.84(d,J=7.2Hz,3H), 0.79(dd,J=6.6,4.8Hz,6H).

[0272] Compound DA-1088: 445 mg, colorless oil, ESI [M+H] + =285.2.

[0273] 1 H NMR(400MHz,d6-DMSO)δ8.03(d,J=3.4Hz,2H),7.14–6.96(m,2H),6.64(d,J=7.2Hz,1H),6.50(d,J=7.0Hz,1H),2.74(dd,J=13.5,7.3Hz ,2H),2.26(s,3H),2.19(s,3H),1.71(d,J=7.0Hz,3H),1.48(dd,J=8.5,6.5Hz,2H),1.20(dd,J=15.0,7.4Hz,2H),0.83(t,J=7.3Hz,3H).

[0274] Example 5: Preparation of compounds DA-K42, DA-K44 and DA-K46 of the present invention

[0275] At room temperature, A (1.32 g, 3 mmol) was dissolved in anhydrous THF (10 mL), and the reaction system was purged with argon for argon protection. The mixture was cooled to -70 °C in a dry ice / acetone bath, and n-butyllithium (1.5 mL, 2.5 mol / L in pentane, 3.6 mmol) was slowly added to the reaction system using a syringe. The mixture was stirred at -70 °C for 30 minutes. Then, DA-K42.1 (311.7 mg, 1.0 mmol) in anhydrous THF (1 mL) was slowly added to the reaction system using a syringe, and the mixture was stirred overnight at room temperature. The reaction was monitored by TLC until complete. The reaction was terminated with saturated ammonium chloride solution (10 mL), extracted with ethyl acetate (3 × 10 mL), and the combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain a colorless oily compound K42.2 (~10 mg). K42.2 (~10 mg) was dissolved in THF (2 mL), and the solution was cooled to 0 °C using an ice-water bath. TBAF (0.16 mL, 1.0 mol / L in THF, 0.16 mmol) was slowly added to the reaction system using a syringe, and the mixture was stirred at room temperature for 30 minutes. 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 to obtain a white solid compound DA-K42 (3 mg). ESI [M+H] + =454.9.

[0276] 1 H NMR(400MHz,d6-DMSO)δ8.99(s,1H),8.12(s,1H),7.49–7.41(m,2H),7.38–7 .26(m,3H),7.02–6.94(m,1H),6.32(q,J=7.0Hz,1H),3.31–3.23(m,1H),2.5 9–2.55(m,1H),1.87(d,J=7.1Hz,3H),1.20–1.10(m,9H),1.05–0.95(m,1H), 0.58–0.48(m,2H),0.40–0.31(m,1H),0.23–0.13(m,1H),0.12–0.04(m,1H).

[0277] The preparation of compounds DA-K44 and DA-K46 of the present invention is similar to that of compound DA-K42 of the present invention.

[0278] Compound DA-K44: 23 mg, white solid, ESI [M+H] + =492.9.

[0279] 1 H NMR(400MHz,d6-DMSO)δ8.03(d,J=3.4Hz,2H),7.14–6.96(m,2H),6.64(d,J=7.2Hz,1H),6.50(d,J=7.0Hz,1H),2.74(dd,J=13.5,7.3Hz ,2H),2.26(s,3H),2.19(s,3H),1.71(d,J=7.0Hz,3H),1.48(dd,J=8.5,6.5Hz,2H),1.20(dd,J=15.0,7.4Hz,2H),0.83(t,J=7.3Hz,3H).

[0280] Compound DA-K46: 69 mg, pale yellow solid, ESI [M+H] + =436.9.

[0281] 1 H NMR(400MHz,d6-DMSO)δ8.03(d,J=3.4Hz,2H),7.14–6.96(m,2H),6.64(d,J=7.2Hz,1H),6.50(d,J=7.0Hz,1H),2.74(dd,J=13.5,7.3Hz ,2H),2.26(s,3H),2.19(s,3H),1.71(d,J=7.0Hz,3H),1.48(dd,J=8.5,6.5Hz,2H),1.20(dd,J=15.0,7.4Hz,2H),0.83(t,J=7.3Hz,3H).

[0282] Example 6: Preparation of compounds DA-K47 and DA-K48 of the present invention

[0283] 1. Preparation of compound DA-K48 of the present invention:

[0284] Compound A (35.16 g, 80 mmol) was dissolved in anhydrous THF (200 mL) at room temperature. The reaction system was purged with argon for argon protection. The mixture was cooled to -70 °C in a dry ice / acetone bath. Butyllithium (48 mL, 2.5 mol / L in pentane, 120 mmol) was slowly added dropwise to the reaction system using a constant-pressure dropping funnel, and the mixture was stirred at -70 °C for 30 minutes. A solution of dried DMF (11.7 g, 160 mmol) in anhydrous THF (10 mL) was then slowly added dropwise to the reaction system using a constant-pressure dropping funnel, and the mixture was stirred overnight at room temperature. The reaction was monitored by TLC until complete. The reaction was terminated with saturated ammonium chloride solution (100 mL), extracted with ethyl acetate (3 × 50 mL), and the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain a light yellow oily compound DA-K47.1 (26.48 g, yield 85.2%).

[0285] Compound DA-K47.1 (4.58 g, 11.78 mmol) was dissolved in anhydrous THF (50 mL) at room temperature. The reaction system was purged with argon and protected with argon gas. The temperature was lowered to 0 °C using an ice-salt bath. Methylmagnesium bromide (8.9 mL, 2.0 mol / L in THF, 17.8 mmol) was slowly added to the reaction system using a syringe, and the mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC until complete. The reaction was terminated with saturated ammonium chloride solution (50 mL), extracted with ethyl acetate (3 × 10 mL), and the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain a pale yellow oily compound DA-K47.2 (4.54 g, yield 95.2%).

[0286] At room temperature, DA-K47.2 (2.02 g, 5 mmol) and H-1 (870 mg, 5.5 mmol) were dissolved in dry THF (20 mL). The temperature was lowered to -60 °C using a dry ice-ethanol bath. The reaction system was purged with argon and protected with argon gas. PPh3 (1.967 g, 7.5 mmol) was then added sequentially to the reaction system. DEAD (1.306 g, 7.5 mmol) was slowly added to the reaction system using a syringe, and the mixture was stirred overnight at room temperature. After the reaction was complete as monitored by TLC, ice water was added to the reaction system, and the mixture was extracted with EtOAc (3 × 20 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give a pale yellow oily compound DA-K48.3 (762 mg, yield 28.0%).

[0287] Sodium hydroxide (167.8 mg, 14.44 mmol) was added to an ethanol / H₂O (11 mL, V / V = 1 / 1) solution of DA-K48.3 (762 mg, 1.40 mmol) at room temperature and stirred overnight at room temperature. After the reaction was completed as monitored by TLC, the solution was concentrated under reduced pressure to give the crude compound DA-K48.4.

[0288] The crude compound DA-K48.4, N,O-dimethylhydroxylamine hydrochloride (204.8 mg, 2.1 mmol), HATU (798.4 mg, 2.1 mmol), and DIEA (271.4 mg, 2.1 mmol) were added to DMF (10 mL) under an ice-water bath at 0 °C and stirred overnight at room temperature. After the reaction was completed as monitored by TLC, the reaction system was poured into ice water and extracted with EtOAc (3 × 10 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 20 to 1 / 3). TLC (ethyl acetate / petroleum ether (v / v) = 1 / 3) was used to monitor the reaction, and the fraction with Rf = 0.4 to 0.5 was collected to give compound DA-K48.5 (554 mg, two-step yield 70.7%).

[0289] At room temperature, 1-Bromo-3-fluoro-2-methylbenzene (5.0 g, 26.45 mmol) was dissolved in anhydrous THF (13 mL), purged with argon, and cooled to -70 °C under argon protection in a dry ice / acetone bath. Butyllithium (10.6 mL, 2.5 mol / L in pentane, 26.5 mmol) was slowly added dropwise to the reaction system using a constant pressure dropping funnel, and the mixture was stirred at -70 °C for 30 minutes to obtain (3-fluoro-2-methylphenyl)lithium (~1 mmol / mL). DA-K48.5 (554 mg, 0.99 mmol) was dissolved in anhydrous THF (5 mL), purged with argon, and cooled to -70 °C under argon protection in a dry ice / acetone bath. (3-fluoro-2-methylphenyl)lithium (5.0 mL, 1 mmol / mL in THF, 5.0 mmol) was slowly added to the reaction system using a syringe, and the mixture was stirred overnight at room temperature. The reaction was monitored by TLC until complete. The reaction system was terminated with saturated ammonium chloride solution (20 mL), extracted with ethyl acetate (3 × 10 mL), and the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound DA-K48.6 (100 mg).

[0290] DA-K48.6 (100 mg) was dissolved in THF (5 mL), and the solution was cooled to 0 °C using an ice-water bath. TBAF (1 mL, 1.0 mol / L in THF, 1 mmol) was slowly added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete as monitored by TLC, H2O (10 mL) was added to the reaction mixture, 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 then purified by preparative TLC to obtain a gray solid compound, DA-K48 (25 mg). ESI [M+H] + =452.9

[0291] 1 H NMR(400MHz,d6-DMSO)δ8.28(t,J=1.9Hz,1H),8.03(s,1H),7.40–7.26(m,2H),7.11– 6.97(m,2H),6.91(t,J=2.2Hz,1H),6.30–6.16(m,1H),3.31–3.19(m,1H),2.51–2.44 (m,1H),1.94(t,J=1.8Hz,3H),1.90(d,J=7.2Hz,3H),1.19–1.07(m,9H),1.02–0.91( m,1H),0.53–0.41(m,1H),0.31–0.17(m,1H),0.16–0.07(m,1H),0.02–-0.06(m,1H).

[0292] DA-K47 was prepared in a manner similar to that of the compound DA-K48 of this invention.

[0293] Compound DA-K47: 2 mg, white solid, ESI [M+H] + =434.9.

[0294] 1H NMR(400MHz,d6-DMSO)δ8.05(s,1H),8.02(s,1H),8.01(s,1H),7.34–7.27(m,2H),7.26–7.2 1(m,1H),7.12(d,J=2.2Hz,1H),7.01(d,J=1.7Hz,1H),5.52(q,J=7.0Hz,1H),3.31–3.23(m, 1H),2.50–2.43(m,1H),2.13(d,J=2.0Hz,3H),1.83(d,J=7.1Hz,3H),1.22–1.10(m,9H),1.0 7–0.95(m,1H),0.55–0.45(m,1H),0.33–0.22(m,1H),0.20–0.09(m,1H),0.08–0.03(m,1H).

[0295] Example 7: Preparation of compounds DA-K51, DA-K53 to DA-K57 and DA-K59 to DA-K60 of the present invention

[0296] 1. Preparation of compound DA-K54 of the present invention:

[0297] At room temperature, DA-K54.1 (10.245 g, 34 mmol) and Bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methane (18.23 g, 68 mmol) were dissolved in dioxane (166 mL), purged with argon, and protected with argon gas. Pd[P(t-Bu)3]2 (869 mg, 1.7 mmol) and KOH (2.862 g, 51 mmol) in H2O (6.5 mL) were added sequentially to the reaction system, and the reaction was carried out at room temperature for 12 hours. The reaction was monitored by TLC until it was complete. The reaction system was terminated with saturated ammonium chloride solution (100 mL), extracted with ethyl acetate (3 × 30 mL), and the combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound DA-K54.2 (10.54 g, yield 85.6%).

[0298] At room temperature, 2,2,6,6-Tetramethylpiperidine (2.26 g, 16 mmol) was dissolved in anhydrous THF (23 mL), purged with argon, and cooled to 0 °C under argon protection using an ice-salt bath. N-butyllithium (6.4 mL, 2.5 mol / L in pentane, 16 mmol) was slowly added dropwise to the reaction system using a syringe, and the mixture was stirred at 0 °C for 30 minutes. A solution of DA-K54.2 (5.797 g, 16 mmol) in anhydrous THF (2 mL) was slowly added to the reaction system using a syringe, and the mixture was stirred at 0 °C for 30 minutes. The prepared reaction system was divided into two portions, and a solution of H-1 (790.7 mg, 5 mmol) in anhydrous THF (2 mL) was slowly added to one portion using a syringe, and the mixture was stirred overnight at room temperature. The reaction was monitored by TLC until complete. The reaction system was terminated with saturated ammonium chloride solution (20 mL), extracted with ethyl acetate (3 × 20 mL), and the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to obtain compound DA-K54.3 (441 mg).

[0299] At room temperature, DA-K54.3 (220 mg, 0.63 mmol) and (S)-1-(2-Chlorophenyl)ethan-1-ol (119 mg, 0.76 mmol) were dissolved in 5 mL of dry THF. The temperature was lowered to -30 °C using a dry ice-ethanol bath. The reaction system was purged with argon gas and protected with argon atmosphere. Then, PPh3 (248.4 mg, 0.95 mmol) was added sequentially to the reaction system. DEAD (164.9 mg, 0.95 mmol) was slowly added to the reaction system using a syringe, and the mixture was stirred overnight at room temperature. After the reaction was monitored by TLC until it was complete, ice water was added to the reaction system, and the mixture was extracted with EtOAc (3 × 10 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain the colorless oily crude compound DA-K54.4 (233 mg, yield 75.9%).

[0300] At room temperature, the crude compound DA-K54.4 (233 mg, 0.48 mmol) was dissolved in HCl / MeOH (1 mL, 2 mmol / mL, 2 mmol) and stirred at room temperature for 1 hour. After the reaction was complete as monitored by TLC, saturated sodium bicarbonate was added to the reaction system, and the mixture was extracted with EtOAc (3 × 10 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative TLC to obtain the compounds DA-K54 (114 mg, yield 53.6%) and DA-K59 (22 mg) of the present invention.

[0301] Compound DA-K54: 114 mg, white solid, ESI [M+H] + =442.9.

[0302] 1 H NMR(400MHz,d6-DMSO)δ7.99(d,J=1.4Hz,1H),7.92(s,1H),7.51–7.43(m,1H),7.37–7.24(m,2H),6.91–6.85(m,1H),6.71(s,2H),6 .44(q,J=7.1Hz,1H),3.85(q,J=15.4Hz,2H),3.30–3.16(m,2H),1.77(d,J=7.1Hz,3H),1.10(d,J=1.3Hz,6H),1.08(d,J=1.3Hz,6H).

[0303] The preparation of compounds DA-K51, DA-K53, DA-K55 to DA-K57 and DA-K60 of the present invention is similar to that of compounds DA-K54 and DA-K59 of the present invention.

[0304] Compound DA-K51: 16 mg, colorless syrup, ESI [M+H] + =342.9.

[0305] 1 H NMR(400MHz,d6-DMSO)δ8.08(d,J=1.6Hz,1H),7.49–7.45(m,1H),7.36–7.17(m,5H),7.08–7.02(m,2 H), 6.79 (dd, J = 7.4, 1.9Hz, 1H), 6.39 (q, J = 7.1Hz, 1H), 3.99 (d, J = 1.3Hz, 2H), 1.78 (d, J = 7.1Hz, 3H).

[0306] Compound DA-K53: 59 mg, white solid, ESI [M+H] + =424.9.

[0307] 1H NMR(400MHz,d6-DMSO)δ8.18(s,1H),8.13(s,1H),7.90(s,1H),7.47–7.43(m,1H),7.36–7.21(m,2H),6.84(dd,J=7.1,2.2Hz,1H),6.79(s, 2H), 6.49(q,J=6.9Hz,1H),3.93(q,J=14.6Hz,2H),3.30–3.17(m,2H),1.78(d,J=7.1Hz,3H),1.10(d,J=1.6Hz,6H),1.09(d,J=1.6Hz,6H).

[0308] Compound DA-K55: 23 mg, colorless syrup, ESI [M+H] + =376.9.

[0309] 1 H NMR(400MHz,d6-DMSO)δ8.19(d,J=1.3Hz,1H),7.29–7.20(m,1H),7.17–6.93(m,4H),6.88(d,J =7.4Hz, 1H), 6.31 (q, J = 7.2Hz, 1H), 4.12 (s, 2H), 1.84 (d, J = 1.8Hz, 3H), 1.80 (d, J = 7.1Hz, 3H).

[0310] Compound DA-K56: 5 mg, white solid, ESI [M+H] + =380.9.

[0311] 1 H NMR (400MHz, d6-DMSO) δ8.28 (s, 1H), 7.46–7.26 (m, 2H), 7.17–6.91 (m, 4H), 6.25 (q, J = 7.1Hz, 1H), 4.15 (s, 2H), 1.90 (d, J = 7.3Hz, 3H).

[0312] Compound DA-K57: 5 mg, white solid, ESI [M+H] + =378.8.

[0313] 1H NMR(400MHz,d6-DMSO)δ8.12(d,J=1.5Hz,1H),7.51–7.43(m,1H),7.39–7.28(m,3H),7.18–7.06(m,1H ),7.00(t,J=7.0Hz,1H),6.90–6.81(m,1H),6.37(q,J=7.1Hz,1H),4.18(s,2H),1.79(d,J=7.1Hz,3H).

[0314] Compound DA-K59: 22 mg, white solid.

[0315] 1 H NMR(400MHz,d6-DMSO)δ8.17(d,J=1.3Hz,1H),8.10(d,J=1.3Hz,1H),7.56–7.50(m,2H),7.41–7.26(m,4H),7.01(dd,J =5.7,3.6Hz,1H),6.83(dd,J=7.6,1.6Hz,1H),6.58–6.51(m,2H),6.47–6.35(m,2H),6.09(dd,J=2.7,0.8Hz,1H),5.66 (dd,J=2.6,0.6Hz,1H),4.93(d,J=3.4Hz,1H),4.88(d,J=3.1Hz,1H),3.04–2.82(m,3H),2.81–2.60(m,1H),1.87–1.74 (m,6H),1.10–1.02(m,12H),0.96(d,J=6.8Hz,3H),0.88(d,J=6.9Hz,3H),0.78(d,J=6.9Hz,3H),0.67(d,J=6.9Hz,3H).

[0316] Compound DA-K60: 28 mg, white solid, ESI [M+H] + =480.9.

[0317] Example 8: Preparation of compound DA-846 of the present invention

[0318] Compound DA-473 (200 mg, 0.7 mmol), K₂CO₃ (96.7 mg, 0.7 mmol), and 2-Chloroethan-1-ol (56.3 mg, 0.7 mmol) were dissolved in THF (5 mL) at room temperature and stirred overnight at room temperature. After the reaction was monitored by TLC until complete, the mixture was filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography to give a colorless syrupy compound DA-846 (258 mg, yield 78.1%). ESI [M+H]+ =330.9.

[0319] 1 H NMR (400MHz, CDCl3) δ7.88(s,1H),7.35(s,1H),7.33–7.24(m,1H),7.14–7.04(m,2H),6.76(td,J=7.7,1.3Hz,1H),6.04(q,J=7.1Hz, 1H), 4.16 (dd, J=13.6, 6.5Hz, 1H), 4.05 (dd, J=13.7, 6.6Hz, 1H), 3.91 (q, J=6.9Hz, 1H), 3.52 (q, J=6.8Hz, 1H), 1.90 (d, J=7.1Hz, 3H).

[0320] The following experimental examples demonstrate the beneficial effects of the present invention.

[0321] Experimental Example 1: Determination of Pharmacological Data of the Compounds of the Invention

[0322] 1. Experimental Methods

[0323] Testing the anesthetic effect of the compound of this invention after tail vein injection in rats (determination of the minimum effective anesthetic dose):

[0324] Experimental animals were 7-9 week old male SD rats, administered via tail vein (injection rate 0.02 mL / s, volume 0.6 mL / rat). The initial dose of the experimental compound was 1 mg / kg, and the actual dose was calculated based on the rat's pre-experimental body weight. Subsequent dose increases or decreases were determined based on whether the righting reflex disappeared in the rats, and the lowest dose at which the righting reflex disappeared was defined as the minimum effective anesthetic dose.

[0325] While testing whether the compound of this invention has an anesthetic effect after intravenous injection into rats, its analgesic effect was also determined. Once the compound was confirmed to have an anesthetic effect (loss of righting reflex ≥30s), the rats were immediately observed for any response to a noxious stimulus (alligator clips clamping the outer third of the rat's tail for 30s). If the rats did not respond within 30s, it was considered to have an analgesic effect; otherwise, it was considered not to have an analgesic effect. If the compound did not have an anesthetic effect (loss of righting reflex <30s), one minute after administration, the rats were given a noxious stimulus (alligator clips clamping the outer third of the rat's tail for 30s). If the rats did not respond within 30s, it was considered to have an analgesic effect; otherwise, it was considered not to have an analgesic effect. In this invention, the dose at which analgesic effect begins to appear is defined as the minimum effective analgesic dose.

[0326] The minimum effective anesthetic dose of the compounds in this invention is further classified as follows: A ≤ 10 mg / kg; 10 mg / kg < B ≤ 20 mg / kg; 20 mg / kg <C≤30mg / kg;30mg / kg<D≤40mg / kg;E>40mg / kg。

[0327] The most effective analgesic dose in the compounds of this invention is further classified as follows: A ≤ 10 mg / kg; 10 mg / kg < B ≤ 20 mg / kg; 20 mg / kg <C≤30mg / kg;30mg / kg<D≤40mg / kg;E>40mg / kg。

[0328] Pharmacological characteristics of equivalent doses:

[0329] In the above experiments, in addition to recording the dose at which the righting reflex disappeared, the onset and recovery times of the anesthetic effect from the start of administration, the duration of the righting reflex, and the duration of the sedative effect were also recorded. At the dose at which the compound of this invention caused the righting reflex to disappear, the effect of the compound on the respiration of the experimental animals could also be observed.

[0330] 2. Experimental Results

[0331] Table 1. Pharmacological data of the compounds of the present invention after a single intravenous injection.

[0332] Table 2. Minimum analgesic dose of the compound of the present invention for a single intravenous injection

[0333] Experimental results show that the compound of the present invention has a rapid onset of anesthesia and a clear sedative effect after intravenous injection, and also has an analgesic effect.

Claims

1. A compound, its stereoisomer, its pharmaceutically acceptable salt, its solvate, its prodrug, its metabolite, or its deuterated derivative, characterized in that, The compound is shown in Formula I: Among them, ring A is selected from 3-8 membered saturated cycloalkyl groups and phenyl groups; m is selected from 0, 1, 2, 3, and 4; R1 is independently selected from hydrogen, C, etc. 1-8 Alkyl, halogen, hydroxyl, 3-8 member saturated cycloalkyl-substituted C 1-8 alkyl; R2 is selected from C 1-8 Alkyl, C 2-8 Alkenyl, 3-8 membered saturated cycloalkyl; R3 is hydrogen; L3 is absent; The five-membered heteroaryl ring is replaced; among K1, K2, K3, and K4, one is N, and another is either N or CR. a One is CR b One is CR k R k Selected from L' is selected from none, C 1-6 Alkylene; R0' is selected from C 1-8 Alkyl, C 2-8 Alkyne group, 3-8 membered saturated cycloalkyl group; R c Selected from hydrogen, C 1-8 Alkoxy, R d Selected from hydrogen, C 1-8 alkoxy, or R c R d The linkage forms 3-8 member saturated oxygen heterocycles; R a Selected from hydrogen and halogens; R b Selected from hydrogen and halogens; Y is selected from none, CR 10 R 11 ;R 10 Selected from hydrogen, R 11 Selected from hydrogen; R e Selected from C 1-10 Alkyl groups, C atoms substituted with one or more halogens 1-10 Alkyl group, with one or more R f Substituted 3-8 saturated cycloalkyl groups, Not replaced or replaced by one or more R h Substituted phenyl; R f Each independently selected from C 1-8 alkyl; R h Each independently selected from C 1-8 Alkyl groups, halogens; R i Selected from 3-8 saturated cycloalkyl groups, C 1-8 alkyl; when for When the compound is R is selected from C 1-7 alkyl or halogen-substituted C 1-7 alkyl.

2. The compound, its stereoisomer, its pharmaceutically acceptable salt, its solvate, its prodrug, its metabolite, or its deuterated derivative according to claim 1, characterized in that, Each of R1 is independently selected from hydrogen, C 1- 4-alkyl, halogen, hydroxyl, 3-6 member saturated cycloalkyl substituted C 1-4 alkyl; R2 is selected from C 1-4 Alkyl, C 2-4 Alkenyl, 3-6 membered saturated cycloalkyl; L' is selected from none, C 1-3 Alkylene; R0' is selected from C 1-6 Alkyl, C 2-4 Alkyne group, 3-6 membered saturated cycloalkyl group; R c Selected from hydrogen, C 1-4 Alkoxy, R d Selected from hydrogen, C 1-4 alkoxy, or R c R d The linkage forms a 5-6 member saturated oxygen heterocycle, preferably a 5-6 member saturated oxygen heterocycle. R e Selected from C 1-7 Alkyl groups, C atoms substituted with one or more halogens 1-4 Alkyl group, with one or more R f Substituted 3-6 saturated cycloalkyl groups Not replaced or replaced by one or more R h Substituted phenyl; R f Each independently selected from C 1-4 alkyl; R h Each independently selected from C 1-4 Alkyl groups, halogens; R i Selected from 3-6 saturated cycloalkyl groups, C 1-4 alkyl.

3. The compound, its stereoisomer, its pharmaceutically acceptable salt, its solvate, its prodrug, its metabolite, or its deuterated derivative according to claim 2, characterized in that, The compounds are shown as those of formula II-1a, II-1b or II-1c: Among them, R1, R2, R3, R a R b R c R d L' and R0' are as described in claim 2; m1, m2, and m3 are each independently selected from 0, 1, 2, 3, and 4.

4. The compound, its stereoisomer, its pharmaceutically acceptable salt, its solvate, its prodrug, its metabolite, or its deuterated derivative according to claim 2, characterized in that, The compounds are shown as those of formula II-2a, II-2b or II-2c: Among them, R1, R2, R3, R a R b R c R d L' and R0' are as described in claim 2; m1, m2, and m3 are each independently selected from 0, 1, 2, 3, and 4.

5. The compound, its stereoisomer, its pharmaceutically acceptable salt, its solvate, its prodrug, its metabolite, or its deuterated derivative according to claim 2, characterized in that, The compounds are shown as those of formula II-3a, II-3b, II-3c, II-3d, or II-3e: Among them, R1, R2, R a R b R c R d L' and R0' are as described in claim 2; m1, m2, m3, m4, and m5 are each independently selected from 0, 1, 2, 3, and 4.

6. The compound, its stereoisomer, its pharmaceutically acceptable salt, its solvate, its prodrug, its metabolite, or its deuterated derivative according to claim 2, characterized in that, The compounds are shown as those of formula II-4a, II-4b, II-4c, II-4d, II-4e, or II-4f: Among them, R1, R2, R a R b R c R d L' and R0' are as described in claim 2; m1, m2, m3, m4, m5, and m6 are each independently selected from 0, 1, 2, 3, and 4.

7. The compound, its stereoisomer, its pharmaceutically acceptable salt, its solvate, its prodrug, its metabolite, or its deuterated derivative according to claim 1, characterized in that, The compound is selected from:

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

9. A pharmaceutical composition, characterized in that, The pharmaceutical composition is a formulation prepared by adding pharmaceutically acceptable excipients to a compound as described in any one of claims 1-8, its stereoisomers, its pharmaceutically acceptable salts, its solvates, its prodrugs, its metabolites or their deuterated derivatives as active ingredients.

10. Use of the compound, its stereoisomer, its pharmaceutically acceptable salt, its solvate, its prodrug, its metabolite or its deuterated derivative according to any one of claims 1-8 in the preparation of a medicament having analgesic effects, and / or having anesthetic, sedative, hypnotic effects and / or being able to control status epilepticus.

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