Ester heterocyclic compound and use thereof

Abstract

The present invention belongs to the technical field of pharmaceutical chemistry. Provided in the present invention are an ester heterocyclic compound and the use thereof. The structure of the compound is represented by formula I. The compound of the present invention has efficient sedative, hypnotic and / or anesthetic effects, is capable of controlling status epilepticus, and has an analgesic effect. The present invention provides a new option for the clinical preparation of a drug that has an analgesic effect, a drug that has an anesthetic, sedative or hypnotic effect and / or is capable of controlling status epilepticus, and a drug that not only has an anesthetic, sedative or hypnotic effect and / or is capable of controlling the status epilepticus, but also has an analgesic effect.

Description

An ester heterocyclic compound and its uses Technical Field

[0001] This invention belongs to the field of medicinal chemistry technology, specifically relating to an ester 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 groups, halogens;

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

[0010] R3 is hydrogen;

[0011] L3 is absent;

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

[0013] L4 is selected from none, C 1-6 Alkylene;

[0014] L is selected from none, C 1-6 Alkylene, =CO;

[0015] R0 is selected from C that is either unsubstituted or substituted by one or more R8 molecules. 1-8 Alkyl, C 2-8 alkenyl, C 2-8 Alkyne group, unsubstituted or substituted C with one or more R8 groups 1-6 Alkoxy, C 2-8 alkenyl-substituted C 2-8 alkynyl group, C 2-8 alkynyl-substituted C 2-8 alkenyl, hydroxyl group;

[0016] R8 is independently selected from hydroxyl, C 2-8 alkenyl, C 2-8 Alkyne group, =O, OR, C 1-6 Alkoxy, C 2-8 alkenyl-substituted C 2-8 alkynyl group, C 2-8 alkynyl-substituted C 2-8 Alkenyl group; R is a hydroxyl protecting group;

[0017] Ring B is selected from 3-8 membered saturated cycloalkyl groups, 3-8 membered saturated heterocyclic groups, and 3-6 membered unsaturated cycloalkyl groups;

[0018] R6 is selected from hydrogen, C 1-8 Alkyl, C1-8 Alkoxy, C 2-8 alkenyl,

[0019] R a Selected from hydrogen and halogens;

[0020] R b Selected from hydrogen and halogens;

[0021] The compound is not

[0022] Furthermore, each of R1 is independently selected from hydrogen, C 1-4 Alkyl groups, halogens;

[0023] R2 is selected from C 1-4 Alkyl, C 2-4 Alkenyl, 3-6 membered saturated cycloalkyl;

[0024] L4 is selected from none, C 1-3 Alkylene;

[0025] L is selected from none, C 1-3 Alkylene, =CO;

[0026] R0 is selected from C that is either unsubstituted or substituted by one or more R8 molecules. 1-6 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, unsubstituted or substituted C with one or more R8 groups 1-4 Alkoxy, C 2-4 alkenyl-substituted C 2-4 alkynyl group, C 2-4 alkynyl-substituted C 2-4 alkenyl, hydroxyl group;

[0027] R8 is independently selected from hydroxyl, C 2-4 alkenyl, C 2-4 Alkyne group, =O, OR, C 1-4 Alkoxy, C 2-4 alkenyl-substituted C 2-4 alkynyl group, C 2-4 alkynyl-substituted C 2-4 Alkenyl group; R is a hydroxyl protecting group;

[0028] Ring B is selected from 3-6 membered saturated cycloalkyl groups, 3-6 membered saturated heterocyclic groups, and 3-6 membered unsaturated cycloalkyl groups;

[0029] R6 is selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 alkenyl,

[0030] Furthermore, the compounds are as shown in formula II-1a, II-1b, II-1c, or II-1d:

[0031] Among them, R1, R2, R3, L, R0, R b As mentioned above, m1, m2, m3, and m4 are each independently selected from 0, 1, 2, 3, and 4.

[0032] Furthermore, the aforementioned Each is selected independently from:

[0033] R1 is as described above.

[0034] Furthermore, the compounds are as shown in formula II-2a, II-2b, II-2c, II-2d, or II-2e:

[0035] Among them, R1, R2, R3, L, R0, R b As mentioned above, m1, m2, m3, m4, and m5 are each independently selected from 0, 1, 2, 3, and 4.

[0036] Furthermore, the aforementioned Each is selected independently from:

[0037] R1 is as described above.

[0038] Furthermore, the compound is selected from:

[0039] 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.

[0040] 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.

[0041] The present invention 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.

[0042] 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.

[0043] 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.

[0044] 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.

[0045] 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.

[0046] 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.

[0047] 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.

[0048] "Aryl" refers to a monocyclic group consisting entirely of carbon atoms 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 compound must be on a carbon atom of a ring with a conjugated π-electron system.

[0049] "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.

[0050] In some preferred technical solutions, the heteroaryl ring is a 5-6 member heteroaryl ring.

[0051] 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".

[0052] Halogens are fluorine, chlorine, bromine or iodine.

[0053] "Hydroxyprotecting groups" include triethoxysilyl (TES) and tert-butyldimethylsilyl (TBS).

[0054] 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.

[0055] 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.

[0056] "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.

[0057] "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.

[0058] Sulphate is 2,4-dimethylbenzenesulfonate.

[0059] Compared with the prior art, the compounds of the present invention have the following beneficial effects:

[0060] 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.

[0061] 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.

[0062] 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.

[0063] 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

[0064] The raw materials and equipment used in the specific embodiments of the present invention are all known products, obtained by purchasing commercially available products.

[0065] 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.

[0066] The LCMS determination was performed using an Agilent LCMS1260 InfinityⅡ-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.

[0067] 1) Medicinal materials and reagents

[0068] Thin-layer chromatography silica gel plates used were HSGF254 silica gel plates from Yantai Xinnuo Chemical Co., Ltd., with a thickness of 1 mm; thin-layer chromatography (TLC) used products from Yantai Jiangyou Silica Gel Development Co., Ltd., with a specification of 0.2±0.03 mm; column chromatography silica gel generally used 100-200 mesh or 200-300 mesh silica gel from Rushan Taiyang Desiccant Co., Ltd. (Weihai, Shandong) as the carrier.

[0069] 2) Main instruments

[0070] 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).

[0071] Example 1: Preparation of compound M-178 of the present invention

[0072] 1. Preparation of compound M-178.2

[0073] Compound M-178.1 (10.00 g, 119.0 mmol) and lithium aluminum hydride (9.04 g, 238.0 mmol) were dissolved in THF (300 mL) at 0 °C and stirred for 4 hours. After the reaction was complete as monitored by TLC, excess sodium sulfate decahydrate was added to the reaction system, and the mixture was stirred for 1 hour. The mixture was then 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). TLC (ethyl acetate / petroleum ether (v / v) = 1 / 20) was used to monitor the reaction, and the fraction with Rf = 0.5–0.6 was collected to give compound M-178.2 (8.45 g, yield 82.6%). ESI [M+H] + =87.1.

[0074] 2. Preparation of compound M-178.3

[0075] At 0°C, M-178.2 (4.61 g, 53.57 mmol), ethyl imidazole-4-carboxylate (5.00 g, 35.71 mmol), and tributylphosphine (14.43 g, 71.42 mmol) were dissolved in THF (100 mL), and diethyl azodicarbonate (12.43 g, 71.42 mmol) was added dropwise to the above system. The mixture was then allowed to warm naturally 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 × 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 / 20–1 / 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-178.3 (4.98 g, yield 67.06%). ESI[M+H] + =209.1

[0076] 3. Preparation of compound M-178.4

[0077] M-178.3 (4.98 g, 23.94 mmol) was dissolved in ethanol (60 mL) at room temperature. Lithium hydroxide (1.15 g, 47.88 mmol) was added to the mixture, and the mixture was stirred overnight at room temperature. After the reaction was completed as monitored by TLC, the mixture was concentrated under reduced pressure, cooled in an ice-water bath, and the pH was adjusted to 7 with 2 M hydrochloric acid solution. The crude product was then concentrated under reduced pressure and purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 1 / 20–1 / 5). TLC (methanol / dichloromethane (v / v) = 1 / 5) was used to collect the fraction with Rf = 0.4–0.5, yielding compound M-178.4 (2.63 g, yield 61.2%). ESI [M+H] + =181.1

[0078] 4. Preparation of target compound M-178

[0079] Compound M-178.4 (180 mg, 1.0 mmol) was dissolved in DCM (10 mL) at room temperature. DCC (309 mg, 1.5 mmol) and DMAP (183 mg, 1.5 mmol) were added to the system, and the mixture was stirred at room temperature for 15 minutes. 3-propadienyloxetane-3-ol (224 mg, 2.0 mmol) was added to the system. The mixture was stirred overnight at room temperature. 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 / 20–1 / 5). TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5) was used to collect the fraction with Rf = 0.4–0.5, yielding a colorless oily compound M-178 (116 mg, yield 42.3%). ESI [M+H] + =275.1

[0080] 1 H NMR (400MHz, CDCl3) δ7.60(d,J=1.9Hz,1H),6.90(d,J=2.0Hz,1H),5.75(t,J=6.6Hz,1H),5.09(d,J=6.6Hz,2H),4.96(d,J=7.9Hz,2H),4.85(dd,J =8.4,1.2Hz,2H),4.66(dq,J=9.2,6.7Hz,1H),1.63(d,J=6.7Hz,3H),1.5 5–1.41(m,1H),0.74–0.63(m,1H),0.52–0.41(m,1H),0.41–0.25(m,2H).

[0081] Example 2: Preparation of compounds M-179~191, M-602~621, M-657~658, M-662~664, M-668~670, M-677~680 and M-685~687 of the present invention

[0082] The preparation methods of target compounds M-179~191, M-602~621, M-657~658, M-662~664, M-668~670, M-677~680, and M-685~687 are similar to those of target compound M-178.

[0083] Compound M-179: 99 mg, colorless oil, ESI [M+H] + =289.1

[0084] 1H NMR (400MHz, CDCl3) δ7.63(d,J=1.8Hz,1H),6.90(d,J=1.9Hz,1H),5.75(t,J=6.6Hz,1H),5.09(d,J=6.7Hz,2H),4.96(d,J=7.6Hz,2H),4.85(d,J=7.9Hz ,2H),4.47(td,J=9.5,5.3Hz,1H),2.26–1.99(m,2H),1.53–1.42(m,1H),0.8 0(t,J=7.4Hz,3H),0.76–0.67(m,1H),0.48–0.36(m,2H),0.34–0.22(m,1H).

[0085] Compound M-180: 100 mg, colorless oil, ESI [M+H] + =301.1

[0086] 1 H NMR (400MHz, CDCl3) δ7.63(d,J=1.9Hz,1H),6.90(d,J=2.0Hz,1H),5.73(t,J=6.6Hz,1H),5.09(d,J=6.6Hz,2H),4.94(d,J=7.8H z,2H),4.83(d,J=7.9Hz,2H),4.00(t,J=9.1Hz,1H),1.64–1.56(m,3H),0.79–0.66(m,2H),0.51–0.38(m,4H),0.31–0.19(m,2H).

[0087] Compound M-181: 90 mg, colorless oil, ESI [M+H] + =337.1

[0088] 1 H NMR (400MHz, CDCl3) δ7.65 (d, J=1.8Hz, 1H), 7.39–7.31 (m, 4H), 7.29–7.26 (m, 1H) ,6.93(d,J=1.8Hz,1H),5.69(t,J=6.6Hz,1H),5.59(d,J=9.8Hz,1H),5.00(tt,J=1 1.6,5.8Hz,2H),4.95–4.86(m,2H),4.81(t,J=6.6Hz,2H),2.10–1.98(m,2H),0.8 5–0.76(m,1H),0.77–0.66(m,1H),0.54(td,J=9.5,4.8Hz,1H),0.50–0.41(m,1H).

[0089] Compound M-182: 58 mg, colorless oil, ESI [M+H] + =301.1

[0090] 1 H NMR (400MHz, CDCl3) δ7.63(d,J=1.7Hz,1H),6.93(d,J=1.7Hz,1H),5.74(t,J=6.6Hz,1H),5.08(d,J=6.7Hz,2H),5.04(s,1H),5.00–4.92( m,4H),4.84(d,J=7.6Hz,2H),1.78–1.70(m,1H),1.67(s,3H),0.88–0.79(m,1H),0.63–0.52(m,1H),0.51–0.42(m,1H),0.40–0.30(m,1H).

[0091] Compound M-183: 84 mg, colorless oil, ESI [M+H] + =289.1

[0092] 1 H NMR (400MHz, CDCl3) δ7.56(d,J=1.8Hz,1H),6.88(d,J=1.8Hz,1H),5.78(t,J=6.6Hz,1H),5.36–5.27(m,1H),5.10(d,J=6.6Hz,2H),4.98(d,J =7.5Hz,2H),4.87(dd,J=7.4,2.8Hz,2H),2.99–2.86(m,1H),2.19–2.09(m,1H),1.87–1.73(m,4H),1.70–1.59(m,1H),1.42(d,J=6.6Hz,3H).

[0093] Compound M-184: 106 mg, colorless oil, ESI [M+H] + =317.1

[0094] 1H NMR (400MHz, CDCl3) δ7.57(d,J=1.4Hz,1H),6.87(d,J=1.7Hz,1H),5.79(t,J= 6.7Hz,1H),5.10(d,J=6.7Hz,2H),5.05–4.97(m,3H),4.87(d,J=7.7Hz,2H),3. 16–3.03(m,1H),2.31–2.21(m,1H),2.20–2.10(m,1H),2.09–2.01(m,1H),1.93 –1.78(m,2H),1.76–1.67(m,2H),0.97(d,J=6.8Hz,3H),0.72(d,J=6.7Hz,3H).

[0095] Compound M-185: 108 mg, colorless oil, ESI [M+H] + =265.1

[0096] 1 H NMR (400MHz, CDCl3) δ7.58(d,J=1.9Hz,1H),6.86(d,J=1.9Hz,1H),4.85(p,J=7.3Hz,1H),4.70(dq,J=9.2,6.7Hz,1H),3.69(p,J=6.9Hz,1H),3.31 (s,3H),2.96–2.82(m,2H),2.28–2.10(m,2H),1.62(d,J=6.7Hz,3H),1.5 4–1.42(m,1H),0.70–0.65(m,1H),0.52–0.40(m,1H),0.40–0.27(m,2H).

[0097] Compound M-186: 84 mg, colorless oil, ESI [M+H] + =279.1

[0098] 1 H NMR(400MHz, CDCl3) δ7.65(d,J=1.8Hz,1H),6.88(d,J=1.9Hz,1H),4.92–4.7 9(m,1H),4.53(td,J=9.5,5.3Hz,1H),3.69(p,J=6.8Hz,1H),3.31(s,3H),2. 99–2.83(m,2H),2.28–2.13(m,3H),2.12–1.99(m,1H),1.58–1.45(m,1H),0. 80(t,J=7.4Hz,3H),0.75–0.67(m,1H),0.47–0.38(m,2H),0.35–0.25(m,1H).

[0099] Compound M-187: 74 mg, colorless oil, ESI [M+H] + =291.1

[0100] 1 H NMR (400MHz, CDCl3) δ7.61(d,J=1.9Hz,1H),6.86(d,J=1.9Hz,1H),4.82(p,J=7.3Hz,1H),4.04(t,J=9.2Hz,1H),3.68(p,J=6.8Hz,1 H),3.30(s,3H),2.96–2.81(m,2H),2.22–2.11(m,2H),1.65–1.57(m,2H),0.77–0.68(m,2H),0.54–0.36(m,4H),0.32–0.21(m,2H).

[0101] Compound M-188: 92 mg, colorless oil, ESI [M+H] + =327.1

[0102] 1 H NMR(400MHz, CDCl3)δ7.63(d,J=1.8Hz,1H),7.42–7.31(m,4H),7.29–7.24(m,1H) ,6.90(d,J=1.8Hz,1H),5.65(d,J=10.0Hz,1H),4.83(p,J=7.3Hz,1H),3.66(p,J=6 .8Hz,1H),2.97–2.78(m,2H),2.21–2.10(m,2H),2.07–1.96(m,1H),0.86–0.77(m ,1H),0.74–0.65(m,1H),0.55(td,J=9.7,4.9Hz,1H),0.46(td,J=9.7,4.9Hz,1H).

[0103] Compound M-189: 67 mg, colorless oil, ESI [M+H] + =291.1

[0104] 1H NMR(400MHz, CDCl3) δ7.61(d,J=1.9Hz,1H),6.90(d,J=1.9Hz,1H),5.05–4.96 (m,3H),4.94–4.77(m,1H),3.76–3.61(m,1H),3.31(s,3H),2.95–2.85(m,2H) ,2.24–2.12(m,2H),1.76–1.68(m,1H),1.67(s,3H),0.88–0.77(m,1H),0.56( ddd,J=16.9,8.5,4.9Hz,1H),0.50–0.43(m,1H),0.36(td,J=9.8,4.9Hz,1H).

[0105] Compound M-190: 76 mg, colorless oil, ESI [M+H] + =279.1

[0106] 1 H NMR (400MHz, CDCl3) δ7.54(d,J=1.8Hz,1H),6.85(d,J=1.8Hz,1H),5.37(dq,J=9.7,6.5Hz,1H),4.89(p,J=7.3Hz,1H) ,3.71(p,J=7.1Hz,1H),3.32(s,3H),3.00–2.82(m,3H),2.31–2.00(m,4H),1.93–1.73(m,4H),1.42(d,J=6.6Hz,3H).

[0107] Compound M-191: 109 mg, colorless oil, ESI [M+H] + =307.1

[0108] 1 H NMR (400MHz, CDCl3) δ7.54(d,J=1.7Hz,1H),6.83(d,J=1.9Hz,1H),5.09–5.01(m,1H),4.94–4.82(m,1H),3.71(p,J=6.9Hz,1H),3.3 2(s,3H),3.16–2.99(m,1H),3.00–2.85(m,2H),2.36–2.10(m,4H),1.92–1.62(m,5H),0.96(d,J=6.8Hz,3H),0.72(d,J=6.7Hz,3H).

[0109] Compound M-602: 34 mg, colorless oil, ESI [M+H] + =223.1

[0110] 1 H NMR (400MHz, CDCl3) δ7.62(d,J=1.7Hz,1H),6.86(d,J=1.9Hz,1H),4.56(td,J=9.5,5.3Hz,1H),4.36(q,J=7.1Hz,2H),2.23–2.03 (m,2H),1.57–1.47(m,1H),1.41(t,J=7.1Hz,3H),0.80(t,J=7.4Hz,3H),0.75–0.67(m,1H),0.47–0.37(m,2H),0.36–0.28(m,1H).

[0111] Compound M-603: 28 mg, colorless oil, ESI [M+H] + =235.1

[0112] 1 H NMR (400MHz, CDCl3) δ7.61(d,J=1.9Hz,1H),6.86(d,J=1.9Hz,1H),4.33(q,J=7.1Hz,2H),4.08(t,J=9.1Hz,1H ),1.73–1.56(m,2H),1.40(t,J=7.1Hz,3H),0.77–0.69(m,2H),0.54–0.37(m,4H),0.28(td,J=9.7,4.8Hz,2H).

[0113] Compound M-604: 76 mg, colorless oil, ESI [M+H] + =271.1

[0114] 1 H NMR(400MHz, CDCl3) δ7.64(d,J=1.9Hz,1H),7.44–7.31(m,4H),7.29–7.25(m,1H),6.90(d,J=1.9Hz,1H),5.70(d,J=10.0Hz,1H),4.3 9–4.26(m,2H),2.11–1.97(m,1H),1.38(t,J=7.1Hz,3H),0.86–0.79(m,1H),0.73–0.66(m,1H),0.59–0.53(m,1H),0.51–0.43(m,1H).

[0115] Compound M-605: 144 mg, colorless oil, ESI [M+H] + =235.1

[0116] 1H NMR (400MHz, CDCl3) δ7.61(d,J=1.8Hz,1H),6.89(d,J=1.9Hz,1H),5.06(d,J=8.6Hz,2H),4.99(s,1H),4.35(q,J=7.0Hz,2H),1. 77–1.70(m,1H),1.68(s,3H),1.40(t,J=7.1Hz,3H),0.87–0.78(m,1H),0.60–0.52(m,1H),0.50–0.45(m,1H),0.43–0.32(m,1H).

[0117] Compound M-606: 106 mg, colorless oil, ESI [M+H] + =223.1

[0118] 1 H NMR (400MHz, CDCl3) δ7.54(d,J=1.8Hz,1H),6.84(d,J=1.9Hz,1H),5.48–5.31(m,1H),4.39(q,J=7.1Hz,2H),3.00 –2.88(m,1H),2.22–2.09(m,1H),1.90–1.77(m,4H),1.74–1.60(m,1H),1.44(d,J=3.3Hz,3H),1.43–1.40(m,3H).

[0119] Compound M-607: 48 mg, colorless oil, ESI [M+H] + =251.1

[0120] 1 H NMR (400MHz, CDCl3) δ7.60(d,J=1.6Hz,1H),6.85(d,J=1.6Hz,1H),4.40(q,J=7.1Hz,2H),3.18–3.06(m,1H),2.37–2. 24(m,1H),2.21–2.12(m,1H),1.90–1.56(m,6H),1.43(t,J=7.1Hz,3H),0.98(d,J=6.8Hz,3H),0.72(d,J=6.7Hz,3H).

[0121] Compound M-608: 88 mg, colorless oil, ESI [M+H] + =263.1

[0122] 1H NMR(400MHz, CDCl3) δ7.62(d,J=1.9Hz,1H),6.94(d,J=2.0Hz,1H),6.35(dd,J=1 7.4,10.9Hz,1H),5.42(dd,J=17.5,14.2Hz,2H),4.98(dd,J=7.4,2.0Hz,2H),4. 86–4.77(m,2H),4.66(dq,J=9.2,6.7Hz,1H),1.62(d,J=6.7Hz,3H),1.53–1.41( m,1H),0.74–0.62(m,1H),0.45(tdd,J=8.1,4.6,3.6Hz,1H),0.41–0.26(m,2H).

[0123] Compound M-609: 56 mg, colorless oil, ESI [M+H] + =277.1

[0124] 1 H NMR (400MHz, CDCl3) δ7.64(d,J=1.8Hz,1H),6.93(d,J=1.9Hz,1H),6.35(dd,J =17.4,10.9Hz,1H),5.41(t,J=14.0Hz,2H),4.98(d,J=7.9Hz,2H),4.81(d,J=7 .9Hz,2H),4.45(td,J=9.5,5.2Hz,1H),2.22–1.95(m,2H),1.52–1.41(m,1H),0 .78(t,J=7.4Hz,3H),0.74–0.66(m,1H),0.49–0.34(m,2H),0.34–0.21(m,1H).

[0125] Compound M-610: 79 mg, colorless oil, ESI [M+H] + =289.1

[0126] 1 H NMR (400MHz, CDCl3) δ7.65(d,J=1.9Hz,1H),6.94(d,J=2.0Hz,1H),6.34(dd,J=17.3,10.9Hz,1H),5.41(t,J=13.8Hz,2H),4.97(d,J= 7.9Hz,2H),4.80(d,J=7.9Hz,2H),3.99(t,J=9.2Hz,1H),1.66–1.56(m,2H),0.76–0.70(m,2H),0.47–0.40(m,4H),0.29–0.18(m,2H).

[0127] Compound M-611: 64 mg, colorless oil, ESI [M+H] + =325.1

[0128] 1 H NMR (400MHz, CDCl3) δ7.66 (d, J=1.9Hz, 1H), 7.39–7.31 (m, 4H), 7.28–7.25 (m, 1H), 6. 96(d,J=1.9Hz,1H),6.30(dd,J=17.4,10.9Hz,1H),5.59(d,J=9.9Hz,1H),5.34(dd,J =14.2,3.2Hz,2H),4.92(dd,J=17.9,7.5Hz,2H),4.78(dd,J=7.5,2.1Hz,2H),2.08–1 .96(m,1H),0.86–0.77(m,1H),0.71(ddd,J=13.6,9.1,4.8Hz,1H),0.57–0.41(m,2H).

[0129] Compound M-612: 52 mg, colorless oil, ESI [M+H] + =289.1

[0130] 1 H NMR (400MHz, CDCl3) δ7.64(d,J=1.9Hz,1H),6.96(d,J=1.9Hz,1H),6.35(dd,J=17.4,10.9Hz,1H),5.40(dd,J=14.1,12.6Hz,2H),5.06–4.92(m ,5H),4.80(dd,J=7.2,4.4Hz,2H),1.77–1.71(m,1H),1.67(s,3H),0.86 –0.80(m,1H),0.61–0.55(m,1H),0.50–0.40(m,1H),0.39–0.29(m,1H).

[0131] Compound M-613: 46 mg, colorless oil, ESI [M+H] + =277.1

[0132] 1H NMR (400MHz, CDCl3) δ7.57(d,J=1.9Hz,1H),6.91(d,J=2.0Hz,1H),6.38(dd,J=17.4,10.9Hz,1H),5.43(dd,J=18.6,14.2Hz,2H),5 .00(d,J=7.7Hz,2H),4.83(dd,J=7.4,3.2Hz,2H),2.97–2.84(m,1H),2.18–2.08(m,1H),1.93–1.62(m,6H),1.42(d,J=6.6Hz,3H).

[0133] Compound M-614: 95 mg, colorless oil, ESI [M+H] + =305.1

[0134] 1 H NMR (400MHz, CDCl3) δ7.58(d,J=1.7Hz,1H),6.91(d,J=1.9Hz,1H),6.38(dd,J=17.4,10.9Hz,1H),5.42(t,J=14.1Hz,2H),5.01(dd,J=7.7,3.9Hz,2 H),4.83(d,J=7.9Hz,2H),3.13–3.00(m,1H),2.30–2.20(m,1H),2.16–2.0 9(m,1H),1.91–1.61(m,6H),0.95(d,J=6.8Hz,3H),0.71(d,J=6.7Hz,3H).

[0135] Compound M-615: 29 mg, colorless oil, ESI [M+H] + =251.1

[0136] 1 H NMR (400MHz, CDCl3) δ7.60(d,J=1.9Hz,1H),6.86(d,J=2.0Hz,1H),4.91(d,J=7.3Hz,2H),4.67(dq,J=9.3,6.7Hz,1H),4.61(d, J=7.9Hz,2H),1.85(s,3H),1.63(d,J=6.7Hz,3H),1.57–1.42(m,1H),0.72–0.65(m,1H),0.48–0.43(m,1H),0.40–0.29(m,2H).

[0137] Compound M-616: 48 mg, colorless oil, ESI [M+H] + =265.1

[0138] 1 H NMR (400MHz, CDCl3) δ7.64(d,J=1.8Hz,1H),6.87(d,J=2.0Hz,1H),4.90(d,J=7.3Hz,2H),4.61(d,J=7.8Hz,2H),4.48(td,J=9.4,5.3Hz, 1H),2.24–2.02(m,2H),1.85(s,3H),1.55–1.44(m,1H),0.80(t,J=7.4Hz,3H),0.76–0.67(m,1H),0.49–0.35(m,2H),0.31–0.24(m,1H).

[0139] Compound M-617: 59 mg, colorless oil, ESI [M+H] + =277.1

[0140] 1 H NMR (400MHz, CDCl3) δ7.62(d,J=1.8Hz,1H),6.86(d,J=1.9Hz,1H),4.89(d,J=7.3Hz,2H),4.60(d,J=7.8Hz,2H),4.00 (t,J=9.2Hz,1H),1.84(s,3H),1.68–1.56(m,2H),0.81–0.65(m,2H),0.45(pd,J=10.1,5.5Hz,4H),0.35–0.19(m,2H).

[0141] Compound M-618: 70 mg, colorless oil, ESI [M+H] + =313.1

[0142] 1 H NMR (400MHz, CDCl3) δ7.64(d,J=1.8Hz,1H),7.35(dd,J=17.7,7.7Hz,4H),7.29–7.26(m,1H),6.89(d,J=1.8Hz,1H),5.60(d,J=10.0Hz,1H),4.85(dd ,J=14.3,7.3Hz,2H),4.62–4.53(m,2H),2.08–2.01(m,1H),1.79(s,3H),0 .86–0.78(m,1H),0.75–0.67(m,1H),0.59–0.50(m,1H),0.50–0.43(m,1H).

[0143] Compound M-619: 50 mg, colorless oil, ESI [M+H] + =277.1

[0144] 1 H NMR (400MHz, CDCl3) δ7.63(d,J=1.7Hz,1H),6.89(d,J=1.7Hz,1H),5.04(s,1H),4.97(d,J=10.1Hz,2H),4.90(d,J=6.8Hz,2H),4.61(d,J=7.5Hz,2 H),1.84(s,3H),1.79–1.69(m,1H),1.68(s,3H),0.88–0.77(m,1H),0.62 –0.54(m,1H),0.46(dt,J=10.0,4.9Hz,1H),0.35(td,J=9.8,4.9Hz,1H).

[0145] Compound M-620: 47 mg, colorless oil, ESI [M+H] + =265.1

[0146] 1 H NMR (400MHz, CDCl3) δ7.55(d,J=1.5Hz,1H),6.84(d,J=1.2Hz,1H),4.93(d,J=7.2Hz,2H),4.64(d,J=7.7Hz,2H), 2.99–2.86(m,1H),2.20–2.09(m,1H),1.88(s,3H),1.87–1.72(m,4H),1.70–1.64(m,2H),1.43(d,J=6.6Hz,3H).

[0147] Compound M-621: 91 mg, colorless oil, ESI [M+H] + =293.1

[0148] 1 H NMR (400MHz, CDCl3) δ7.56(d,J=1.7Hz,1H),6.83(d,J=1.9Hz,1H),4.93(dd,J=7.1,3.1Hz,2H),4.64(d,J=7.7Hz,2H),3.14–3. 01(m,1H),2.31–2.20(m,1H),2.19–2.10(m,1H),1.88(s,3H),1.88–1.59(m,6H),0.96(d,J=6.8Hz,3H),0.72(d,J=6.7Hz,3H).

[0149] Compound M-657: 168 mg, colorless oil, ESI [M+H] + =309.1

[0150] 1 H NMR(400MHz, CDCl3)δ7.63(d,J=1.9Hz,1H),7.44–7.31(m,4H),7.29–7.26(m,1H),6.9 0(t,J=1.7Hz,1H),5.69(dd,J=10.0,2.4Hz,1H),5.60–5.48(m,1H),5.36(ddd,J=17.7 ,12.6,6.6Hz,1H),4.98–4.82(m,2H),2.08–1.97(m,1H),1.45(dd,J=10.8,6.4Hz,3H) ,0.86–0.77(m,1H),0.74–0.64(m,1H),0.55(td,J=9.6,4.9Hz,1H),0.52–0.43(m,1H).

[0151] Compound M-658: 181 mg, colorless oil, ESI [M+H] + =321.1

[0152] 1 H NMR (400MHz, CDCl3) δ7.64(t,J=1.9Hz,1H),7.44–7.37(m,2H),7.33(t,J=7.4Hz,2H),7.28–7.22(m,1H),6.94(t,J=1.4Hz,1H),5.90–5.80(m,1H) ,5.80–5.64(m,3H),5.59–5.51(m,1H),2.09–1.97(m,1H),1.61(dd,J=11 .0,6.7Hz,3H),0.86–0.75(m,1H),0.74–0.63(m,1H),0.59–0.44(m,2H).

[0153] Compound M-662: 145 mg, colorless oil, ESI [M+H] + =263.1

[0154] 1 H NMR (400MHz, CDCl3) δ7.62(d,J=1.9Hz,1H),7.28–7.21(m,1H),7.11–7.02(m,3H),6.93(d,J=1. 9Hz, 1H), 6.89 (q, J = 7.1Hz, 1H), 4.41–4.25 (m, 2H), 1.94 (d, J = 7.0Hz, 3H), 1.35 (t, J = 7.1Hz, 3H).

[0155] Compound M-663: 76 mg, colorless oil, ESI [M+H] +=277.1

[0156] 1 H NMR (400MHz, CDCl3) δ7.61(d,J=1.9Hz,1H),7.10(t,J=6.9Hz,1H),6.97(t,J=7.6Hz,1H),6.92(d,J=1.9Hz,1 H), 6.91–6.86 (m, 2H), 4.41–4.26 (m, 2H), 2.30 (d, J = 2.1Hz, 3H), 1.93 (d, J = 7.0Hz, 3H), 1.36 (t, J = 7.1Hz, 3H).

[0157] Compound M-664: 110 mg, white solid, ESI [M+H] + =311.1

[0158] 1 H NMR(400MHz, CDCl3)δ7.62(d,J=1.9Hz,1H),6.95(d,J=1.9Hz,1H),6.93–6.85(m,2H),6.83–6.8 0(m,1H),4.41–4.24(m,2H),2.36(d,J=2.3Hz,3H),1.91(d,J=6.9Hz,3H),1.35(t,J=7.1Hz,3H).

[0159] Compound M-668: 112 mg, colorless oil, ESI [M+H] + =311.1

[0160] 1 H NMR (400MHz, CDCl3) δ7.43 (d, J = 2.4Hz, 1H), 6.97 (s, 1H), 6.95 (s, 1H), 6.85 (d, J = 2.4Hz, 1H), 6.07 (q, J = 7. 0Hz, 1H), 4.44 (qd, J = 7.1, 0.9Hz, 2H), 2.36 (d, J = 2.3Hz, 3H), 1.94 (d, J = 7.0Hz, 3H), 1.43 (t, J = 7.1Hz, 3H).

[0161] Compound M-669: 72 mg, colorless oil, ESI [M+H] + =276.1

[0162] 1H NMR (400MHz, CDCl3) δ7.48(d,J=2.4Hz,1H),7.16(dd,J=7.3,6.3Hz,1H),7.02(t,J=7.6Hz,1H),7.00–6.95(m,1H),6.84(d,J= 2.4Hz,1H),5.96(q,J=7.1Hz,1H),4.43(q,J=7.1Hz,2H),2.31(d,J=2.1Hz,3H),1.96(d,J=7.1Hz,3H),1.42(t,J=7.1Hz,3H).

[0163] Compound M-670: 76 mg, colorless oil, ESI [M+H] + =263.1

[0164] 1 H NMR(400MHz, CDCl3) δ7.50(d,J=2.3Hz,1H),7.35–7.30(m,1H),7.17–7.05(m,3H),6.85(d,J=2.3H z,1H),5.97(q,J=7.1Hz,1H),4.43(q,J=7.1Hz,2H),1.97(d,J=7.1Hz,3H),1.42(t,J=7.1Hz,3H).

[0165] Compound M-677: 182 mg, colorless oil, ESI [M+H] + =279.1

[0166] 1 H NMR (400MHz, DMSO) δ7.72(d,J=1.9Hz,1H),7.46(dd,J=7.3,1.9Hz,1H),7.34–7.25(m,2H),6.98(d,J=1.9Hz,1H),6 .89(dd,J=7.1,2.3Hz,1H),6.73(q,J=6.9Hz,1H),4.32–4.16(m,2H),1.82(d,J=6.9Hz,3H),1.24(t,J=7.1Hz,3H).

[0167] Compound M-678: 213 mg, white solid, ESI [M+H] + =293.1

[0168] 1H NMR (400MHz, DMSO) δ7.72(d,J=1.9Hz,1H),7.28(d,J=7.3Hz,1H),7.17(t,J=7.6Hz,1H),6.99(d,J=1.9Hz,1H),6.76( q,J=6.9Hz,1H),6.69(d,J=7.6Hz,1H),4.33–4.14(m,2H),2.37(s,3H),1.82(d,J=6.9Hz,3H),1.24(t,J=7.1Hz,3H).

[0169] Compound M-679: 213 mg, colorless oil, ESI [M+H] + =289.1

[0170] 1 H NMR (400MHz, DMSO) δ7.67(d,J=1.9Hz,1H),7.56(dd,J=7.7,6.2Hz,1H),7.40–7.31(m,1H),7.25–7.13(m,2H),6.91(d,J=1.9Hz,1H),5.95(d, J=9.9Hz,1H),4.29(tt,J=7.1,3.6Hz,2H),1.97–1.80(m,1H),1.28(t,J=7.1Hz,3H),0.76–0.67(m,1H),0.67–0.57(m,1H),0.54–0.39(m,2H).

[0171] Compound M-680: 211 mg, yellow solid, ESI [M+H] + =303.1

[0172] 1 H NMR (400MHz, DMSO) δ7.65(d,J=1.8Hz,1H),7.39(t,J=7.1Hz,1H),7.22(t,J=7.2Hz,1H),7.09(t,J=7.6Hz,1H),6.90(d,J=1.9Hz,1H),5.96(d,J=9. 9Hz,1H),4.36–4.22(m,2H),2.21(d,J=1.5Hz,3H),1.94–1.83(m,1H),1. 32–1.23(m,3H),0.76–0.67(m,1H),0.65–0.56(m,1H),0.53–0.37(m,2H).

[0173] Compound M-685: 234 mg, colorless oil, ESI [M+H] + =279.1

[0174] 1 H NMR (400MHz, DMSO) δ8.06 (d, J = 2.4Hz, 1H), 7.55–7.48 (m, 1H), 7.40–7.33 (m, 2H), 7.17–7.11 (m, 1H), 6.81 ( d,J=2.4Hz,1H),6.04(q,J=7.0Hz,1H),4.28(q,J=7.1Hz,2H),1.85(d,J=7.0Hz,3H),1.29(t,J=7.1Hz,3H).

[0175] Compound M-686: 342 mg, colorless oil, ESI [M+H] + =292.1

[0176] 1 H NMR (400MHz, DMSO) δ8.04(d,J=2.4Hz,1H),7.34(d,J=6.7Hz,1H),7.25(t,J=7.6Hz,1H),6.99–6.89(m,1H),6.80(d,J =2.4Hz,1H),6.07(q,J=7.0Hz,1H),4.28(q,J=7.1Hz,2H),2.38(s,3H),1.84(d,J=7.0Hz,3H),1.29(t,J=7.1Hz,3H).

[0177] Compound M-687: 189 mg, colorless oil, ESI [M+H] + =303.1

[0178] 1 H NMR (400MHz, DMSO) δ8.14(d,J=2.4Hz,1H),7.37–7.32(m,1H),7.29–7.24(m,1H),7.13(t,J=7.6Hz,1H),6.78(d,J=2.4Hz,1H),5.03(d,J=10. 1Hz,1H),4.26(tt,J=7.2,3.6Hz,2H),2.24(d,J=1.9Hz,3H),1.91–1.78(m,1H),1.28(t,J=7.1Hz,3H),0.77–0.63(m,2H),0.58–0.39(m,2H).

[0179] Example 3: Preparation of compounds M-624 and M-201 of the present invention

[0180] 1. Preparation of compound M-624.2

[0181] Compound M-624.1 (50 g, 318.4 mmol) was dissolved in ethanol (200 mL) at 0 °C, and thionyl chloride (75.8 mL, 636.8 mmol) was added dropwise. After the addition was complete, the mixture was heated to reflux and stirred for 8 hours. After the reaction was complete as monitored by LCMS, 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 to 1 / 10). TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10) was used to monitor the reaction, and the fraction with Rf = 0.5 to 0.6 was collected to give the gray solid compound M-624.2 (42.4 g, yield 72.0%). ESI [M+H] + =186.1.

[0182] 2. Preparation of target compound M-624.3

[0183] M-624.2 (42.4 g, 229.1 mmol) was dissolved in methanol (200 mL) at room temperature. Palladium on carbon (8.5 g, 10% PD) was added to the above system, and the mixture was purged with hydrogen three times. The mixture was stirred at room temperature for 18 hours. After the reaction was completed as monitored by TLC, the reaction system was filtered through diatomaceous earth and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 to 1 / 2). TLC (ethyl acetate / petroleum ether (v / v) = 1 / 2) was used to monitor the reaction, and the fraction with Rf = 0.4 to 0.5 was collected to give a gray solid compound M-624.3 (32.0 g, yield 90.1%). ESI [M+H] + =156.1.

[0184] 3. Preparation of compound M-624.4

[0185] Compound M-624.3 (32.0 g, 206.4 mmol) was dissolved in tetrafluoroboric acid solution (2000 mL) at 0 °C. Sodium nitrite (28.4 g, 412.8 mmol) was added to the system. The reaction mixture was placed under a 302 nm lamp and stirred at room temperature for 14 days. After the reaction was completed as monitored by TLC, the mixture was poured into an ice-water solution of sodium hydroxide and extracted with EtOAc (5 × 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 / 100–1 / 5). TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5) was used to monitor the reaction. The fraction with Rf = 0.5–0.6 was collected to give compound M-624.4 (2.16 g, yield 6.0%). ESI [M+H] + =159.1.

[0186] 4. Preparation of target compound M-624

[0187] At 0 °C, M-624.4 (1.11 g, 7.0 mmol), dicyclopropylmethanol (1.18 g, 10.5 mmol), and tributylphosphine (2.83 g, 14.0 mmol) were dissolved in THF (20 mL), and diethyl azodicarbonate (2.44 g, 14.0 mmol) was added dropwise to the above system. The mixture was then allowed to warm naturally 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 × 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 / 8). TLC (ethyl acetate / petroleum ether (v / v) = 1 / 8) was used to monitor the reaction, and the fraction with Rf = 0.4–0.5 was collected to give a colorless oily compound M-624 (1.00 g, yield 57.1%). ESI[M+H] + =253.1.

[0188] 1 H NMR (400MHz, CDCl3) δ7.48(d,J=4.6Hz,1H),4.38(q,J=7.1Hz,2H),3.95(t,J=9.2Hz,1H),1.61 –1.52(m,2H),1.41(t,J=7.1Hz,3H),0.76–0.69(m,2H),0.50–0.38(m,4H),0.32–0.24(m,2H).

[0189] 5. Preparation of compound M-201.1

[0190] Compound M-624 (880 mg, 3.50 mmol) was dissolved in ethanol (20 mL) at room temperature. Sodium hydroxide (280 mg, 7.00 mmol) was added to the system, and the mixture was stirred overnight at room temperature. After the reaction was completed as monitored by TLC, the solution was concentrated under reduced pressure, cooled in an ice-water bath, and the pH was adjusted to 7 with 2 M hydrochloric acid solution. The crude product was then concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 1 / 20 to 1 / 10). TLC (methanol / dichloromethane (v / v) = 1 / 10) was used to monitor the reaction, and the fraction with Rf = 0.4 to 0.5 was collected to obtain compound M-201.1 (680 mg, yield 86.7%). ESI [M+H] + =225.1.

[0191] 6. Preparation of target compound M-201

[0192] Compound M-201.1 (224 mg, 1.0 mmol) was dissolved in DCM (10 mL) at room temperature. DCC (309 mg, 1.5 mmol) and DMAP (183 mg, 1.5 mmol) were added to the system, and the mixture was stirred at room temperature for 15 minutes. 3-propadienyloxetane-3-ol (224 mg, 2.0 mmol) was added to the system. The mixture was stirred overnight at room temperature. 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 / 20–1 / 5). TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5) was used to collect the fraction with Rf = 0.4–0.5, yielding a white solid compound M-201 (56 mg, yield 17.6%). ESI [M+H] + =319.1

[0193] 1 H NMR (400MHz, CDCl3) δ7.50(d,J=4.5Hz,1H),5.73(t,J=6.6Hz,1H),5.10(d,J=6.6Hz,2H),4.95(d,J=7.8Hz,2H),4.84 (d,J=8.1Hz,2H),3.87(t,J=9.2Hz,1H),1.58–1.51(m,2H),0.80–0.68(m,2H),0.53–0.38(m,4H),0.33–0.15(m,2H).

[0194] Example 4: Preparation of compounds M-203, M-631, M-633, M-638 and M-640 of the present invention

[0195] The preparation methods of target compounds M-203, M-631, M-633, M-638 and M-640 are similar to those of target compound M-201.

[0196] Compound M-203: 48 mg, colorless oil, ESI [M+H] + =319.1

[0197] 1 H NMR (400MHz, CDCl3) δ7.51(d,J=4.5Hz,1H),5.73(t,J=6.7Hz,1H),5.10(d,J=6.7Hz,2H),5.02–4.91(m,4H),4.89–4.77(m, 3H),1.68(s,3H),1.67–1.62(m,1H),0.88–0.78(m,1H),0.60(qd,J=8.8,4.6Hz,1H),0.52–0.42(m,1H),0.40–0.29(m,1H).

[0198] Compound M-631: 38 mg, colorless oil, ESI [M+H] + =307.1

[0199] 1 H NMR (400MHz, CDCl3) δ7.51 (d, J=4.6Hz, 1H), 6.34 (dd, J=17.4, 10.9Hz, 1H), 5.43 (t, J=14.5Hz, 2H), 4.98 (d, J=8.0Hz, 2H), 4.80(d,J=8.1Hz,2H),3.85(t,J=9.3Hz,1H),1.57–1.51(m,2H),0.77–0.68(m,2H),0.50–0.37(m,4H),0.31–0.20(m,2H).

[0200] Compound M-633: 36 mg, white solid, ESI [M+H] + =307.1

[0201] 1H NMR (400MHz, CDCl3) δ7.52(d,J=4.5Hz,1H),6.34(dd,J=17.4,10.9Hz,1H),5.42(t,J=13.8Hz,2H),5.02–4.95(m,4H),4.81(dd,J=11.6,5. 8Hz,3H),1.67(s,3H),1.67–1.62(m,1H),0.88–0.74(m,1H),0.66–0.54(m,1H),0.44(dq,J=10.0,5.2Hz,1H),0.34(td,J=9.8,4.9Hz,1H).

[0202] Compound M-638: 29 mg, white solid, ESI [M+H] + =295.1

[0203] 1 H NMR (400MHz, CDCl3) δ7.49(d,J=4.6Hz,1H),4.90(d,J=7.4Hz,2H),4.60(d,J=7.9Hz,2H),3.87(t,J= 9.2Hz,1H),1.85(s,3H),1.60–1.53(m,2H),0.78–0.68(m,2H),0.51–0.39(m,4H),0.30–0.21(m,2H).

[0204] Compound M-640: 39 mg, white solid, ESI [M+H] + =295.1

[0205] 1 H NMR (400MHz, CDCl3) δ7.50(d,J=4.5Hz,1H),4.99(d,J=6.6Hz,2H),4.91(dd,J=7.1,2.9Hz,2H),4.84(d,J=9.9Hz,1H),4.61(d,J=7.7Hz,2H), 1.86(s,3H),1.68(s,3H),1.67–1.62(m,1H),0.87–0.82(m,1H),0.64– 0.56(m,1H),0.46(td,J=10.0,5.0Hz,1H),0.35(td,J=9.8,5.0Hz,1H).

[0206] Example 5: Preparation of compounds M-665, M-671, M-681 and M-683 of the present invention

[0207] 1. Preparation of compound M-665.2

[0208] At room temperature, 2-fluoroacetophenone (10.0 g, 72.5 mmol), formic acid (10.0 g, 217.5 mmol), and triethylamine (36.6 g, 362.5 mmol) were added sequentially to isopropanol (200 mL). The reaction system was purged three times with argon. Then, (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropyltoluene)ruthenium chloride (922 mg, 1.45 mmol) was added to the reaction system. The mixture was stirred at 60 °C for 4 hours under argon protection. After the reaction was complete under C monitoring, the mixture was cooled to room temperature, filtered, and extracted with EtOAc (3 × 100 mL). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 20–1 / 10). TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10) was used to monitor the reaction, and the fraction with Rf = 0.5–0.6 was collected to give a wine-red oily compound M-665.2 (9.1 g, yield 89.6%). ESI[M+H] + =141.1.

[0209] 2. Preparation of target compounds M-655 and M-671

[0210] At 0 °C, ethyl imidazole-4-carboxylate (5.0 g, 35.7 mmol), M-665.2 (7.5 g, 53.6 mmol), and tributylphosphine (14.1 g, 70.1 mmol) were dissolved in THF (30 mL), and diethyl azodicarbonate (12.2 g, 70.1 mmol) was added dropwise to the above system. The mixture was then allowed to warm naturally 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 × 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 / 20–1 / 4). TLC (ethyl acetate / petroleum ether (v / v) = 1 / 4) was used to monitor the reaction. The fraction with Rf = 0.4–0.5 was collected to give a colorless oily compound M-665 (5.1 g, yield 54.2%). ESI[M+H] + =263.1.

[0211] 1H NMR (400MHz, CDCl3) δ7.62(d,J=1.9Hz,1H),7.29–7.21(m,1H),7.11–7.02(m,3H),6.93(d,J=1. 9Hz, 1H), 6.89 (q, J = 7.0Hz, 1H), 4.42–4.20 (m, 2H), 1.94 (d, J = 7.0Hz, 3H), 1.36 (t, J = 7.1Hz, 3H).

[0212] TLC (ethyl acetate / petroleum ether (v / v) = 1 / 4) monitoring was performed, and the fraction with Rf = 0.2–0.3 was collected to give a colorless oily compound M-671 (2.3 g, yield 24.4%). ESI [M+H] + =263.1.

[0213] 1 H NMR(400MHz, CDCl3) δ7.50(d,J=2.4Hz,1H),7.35–7.31(m,1H),7.17–7.06(m,3H),6.86(d,J=2.4H z,1H),5.97(d,J=7.1Hz,1H),4.44(q,J=7.1Hz,2H),1.98(d,J=7.1Hz,3H),1.43(t,J=7.1Hz,3H).

[0214] 3. Preparation of compound M-681.1

[0215] Compound M-665 (5.1 g, 19.5 mmol) was dissolved in ethanol (40 mL) at room temperature. Sodium hydroxide (1.56 g, 39.0 mmol) was added to the mixture, and the solution was stirred overnight at room temperature. After the reaction was completed as monitored by TLC, the solution was concentrated under reduced pressure, cooled in an ice-water bath, and the pH was adjusted to 7 with 2 M hydrochloric acid solution. The crude product was then concentrated under reduced pressure and purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 1 / 20–1 / 5). TLC (methanol / dichloromethane (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-681.1 (3.04 g, yield 66.7%). ESI [M+H] + =235.1.

[0216] 4. Preparation of target compound M-681

[0217] Compound M-681.1 (351 mg, 1.5 mmol) was dissolved in DCM (10 mL) at room temperature. DCC (618 mg, 3.0 mmol) and DMAP (366 mg, 3.0 mmol) were added to the system, and the mixture was stirred at room temperature for 15 minutes. 3-propadienyloxetane-3-ol (336 mg, 3.0 mmol) was added to the system. The mixture was stirred overnight at room temperature. 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 / 5). TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5) was used to collect the fraction with Rf = 0.4 to 0.5, yielding a colorless oily compound M-681 (224 mg, yield 45.5%). ESI [M+H] + =329.1

[0218] 1 H NMR (400MHz, DMSO) δ7.72 (d, J=2.0Hz, 1H), 7.34 (tdd, J=7.3, 5.5, 1.7Hz, 1H), 7.24–7. 12(m,2H),7.05(d,J=2.0Hz,1H),6.99(td,J=7.8,1.6Hz,1H),6.68(q,J=6.9Hz,1H),5 .78(t,J=6.7Hz,1H),5.09(dd,J=12.0,6.7Hz,1H),4.96(dd,J=12.0,6.6Hz,1H),4.87 (d,J=7.5Hz,1H),4.75(d,J=7.4Hz,1H),4.68(t,J=7.2Hz,2H),1.82(d,J=7.0Hz,3H).

[0219] 5. Preparation of compound M-683.1

[0220] Compound M-671 (2.3 g, 8.8 mmol) was dissolved in ethanol (20 mL) at room temperature. Sodium hydroxide (704 mg, 17.6 mmol) was added to the system, and the mixture was stirred overnight at room temperature. After the reaction was completed as monitored by TLC, the solution was concentrated under reduced pressure, cooled in an ice-water bath, and the pH was adjusted to 7 with 2 M hydrochloric acid solution. The crude product was then concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 1 / 20–1 / 5). TLC (methanol / dichloromethane (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-681.1 (1.44 g, yield 69.9%). ESI [M+H] + =235.1.

[0221] 6. Preparation of target compound M-683

[0222] Compound M-683.1 (351 mg, 1.5 mmol) was dissolved in DCM (10 mL) at room temperature. DCC (618 mg, 3.0 mmol) and DMAP (366 mg, 3.0 mmol) were added to the system, and the mixture was stirred at room temperature for 15 minutes. 3-propadienyloxetane-3-ol (336 mg, 3.0 mmol) was added to the system. The mixture was stirred overnight at room temperature. 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 / 5). TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5) was used to collect the fraction with Rf = 0.2 to 0.3, yielding a colorless oily compound M-683 (55 mg, yield 11.1%). ESI [M+H] + =329.1

[0223] 1 H NMR (400MHz, DMSO) δ8.07(d,J=2.4Hz,1H),7.46–7.36(m,1H),7.30–7.20(m,3H),6.84(d,J=2.4Hz,1H),6.00(q,J=7.0H z,1H),5.84(t,J=6.7Hz,1H),5.17(d,J=6.7Hz,2H),4.84(d,J=7.7Hz,2H),4.69(d,J=7.9Hz,2H),1.86(d,J=7.1Hz,3H).

[0224] Example 6: Preparation of compounds M-666~667, M-672~673, M-682, M-684, M-688~691, M-701~707, M-728~730, M-734~736, M-740~742, M-746~761 and M-837~864 of the present invention

[0225] The preparation methods for target compounds M-666~667, M-672~673, M-682, M-684, M-688~691, M-701~707, M-728~730, M-734~736, M-740~742, M-746~761 and M-837~864 are similar to those for target compound M-681.

[0226] Compound M-666: 100 mg, colorless oil, ESI [M+H] + =277.1

[0227] 1 H NMR (400MHz, CDCl3) δ7.61(d,J=1.3Hz,1H),7.10(t,J=7.2Hz,1H),6.97(t,J=7.6Hz,1H),6.93(d,J=1.4Hz,1H) ,6.89(t,J=6.7Hz,2H),4.42–4.25(m,2H),2.30(d,J=2.0Hz,3H),1.93(d,J=7.0Hz,3H),1.36(t,J=7.1Hz,3H).

[0228] Compound M-667: 68 mg, colorless oil, ESI [M+H] + =311.1

[0229] 1 H NMR (400MHz, CDCl3) δ7.62(d,J=1.8Hz,1H),6.94(d,J=1.8Hz,1H),6.90(t,J=8.7Hz,1H),6.87–6. 79(m,2H),4.41–4.24(m,2H),2.35(d,J=2.2Hz,3H),1.91(d,J=6.9Hz,3H),1.35(t,J=7.1Hz,3H).

[0230] Compound M-672: 106 mg, colorless oil, ESI [M+H] + =277.1

[0231] 1 H NMR (400MHz, CDCl3) δ7.44(d,J=2.3Hz,1H),7.12(t,J=7.0Hz,1H),6.99(t,J=7.6Hz,1H),6.96–6.91(m,1H),6.81(d,J=2. 4Hz, 1H), 5.92 (q, J = 7.0Hz, 1H), 4.40 ( q, J = 7.1Hz, 2H), 2.27 ( d, J = 2.1Hz, 3H), 1.92 ( d, J = 7.1Hz, 3H), 1.39 ( t, J = 7.1Hz, 3H).

[0232] Compound M-673: 101 mg, colorless oil, ESI [M+H] + =311.1

[0233] 1H NMR (400MHz, CDCl3) δ7.43(d,J=2.4Hz,1H),6.97(s,1H),6.95(s,1H),6.84(d,J=2.3Hz,1H),6.07(q,J =7.0Hz, 1H), 4.44 (q, J = 7.0Hz, 2H), 2.36 (d, J = 2.3Hz, 3H), 1.94 (d, J = 7.0Hz, 3H), 1.43 (t, J = 7.1Hz, 3H).

[0234] Compound M-682: 255 mg, colorless oil, ESI [M+H] + =342.1

[0235] 1 H NMR (400MHz, DMSO) δ7.69(d,J=2.0Hz,1H),7.18(t,J=7.1Hz,1H),7.05–6.98(m,2 H),6.76(t,J=7.4Hz,1H),6.65(q,J=6.9Hz,1H),5.76(t,J=6.7Hz,1H),5.07(dd, J=12.0,6.7Hz,1H),4.95(dd,J=12.0,6.6Hz,1H),4.84(d,J=7.5Hz,1H),4.73(d, J=7.4Hz,1H),4.66(t,J=6.6Hz,2H),2.22(d,J=1.8Hz,3H),1.79(d,J=7.0Hz,3H).

[0236] Compound M-684: 39 mg, colorless oil, ESI [M+H] + =343.1

[0237] 1 H NMR (400MHz, DMSO) δ8.05(d,J=2.4Hz,1H),7.26(t,J=6.5Hz,1H),7.22–7.03(m,3H),6.84(d,J=2.4Hz,1H),5.98(q,J=7.0Hz,1H),5. 84(t,J=6.7Hz,1H),5.17(d,J=6.7Hz,2H),4.84(d,J=7.7Hz,2H),4.69(d,J=7.9Hz,2H),2.25(d,J=1.9Hz,3H),1.85(d,J=7.1Hz,3H).

[0238] Compound M-688: 252 mg, colorless oil, ESI [M+H] + =305.1

[0239] 1 H NMR(400MHz, DMSO)δ7.71(d,J=2.0Hz,1H),7.34(tdd,J=7.3,5.5,1.7Hz,1H),7.24–7.12(m,2H),7.05–6.98(m,2H),6.6 8(q,J=6.9Hz,1H),4.76(d,J=7.3Hz,1H),4.64(d,J=7.2Hz,1H),4.53–4.46(m,2H),1.83(d,J=7.0Hz,3H),1.65(s,3H).

[0240] Compound M-689: 268 mg, colorless oil, ESI [M+H] + =317.1

[0241] 1 H NMR(400MHz,DMSO)δ7.73(d,J=1.9Hz,1H),7.38–7.28(m,1H),7.17(dt,J=15.3,8 .3Hz,2H),7.08(d,J=1.9Hz,1H),6.99(td,J=7.8,1.4Hz,1H),6.67(q,J=7.0Hz,1 H),6.26(dd,J=17.4,11.0Hz,1H),5.25(dd,J=14.0,12.7Hz,2H),4.86(d,J=7.4H z, 1H), 4.73 (d, J = 7.5Hz, 1H), 4.69 (dd, J = 7.3, 3.3Hz, 2H), 1.82 (d, J = 7.0Hz, 3H).

[0242] Compound M-690: 93 mg, colorless oil, ESI [M+H] + =319.1

[0243] 1 H NMR (400MHz, DMSO) δ7.70(d,J=2.0Hz,1H),7.20(t,J=7.5Hz,1H),7.04(t,J=6.0Hz,1H),7.01(d,J=2.0Hz,1H),6.80(t,J=6.9Hz,1H),6.67(q,J= 7.0Hz,1H),4.76(d,J=7.2Hz,1H),4.64(d,J=7.2Hz,1H),4.50(dd,J=7.1,3.6Hz,2H),2.24(d,J=1.9Hz,3H),1.81(d,J=7.0Hz,3H),1.65(s,3H).

[0244] Compound M-691: 92 mg, colorless oil, ESI [M+H] + =331.1

[0245] 1 H NMR (400MHz, DMSO) δ7.73(d,J=2.0Hz,1H),7.20(t,J=7.2Hz,1H),7.08(d,J=2.0Hz, 1H),7.03(t,J=7.7Hz,1H),6.77(t,J=7.8Hz,1H),6.65(q,J=6.9Hz,1H),6.26(dd,J= 17.4,10.9Hz,1H),5.24(dd,J=16.7,14.2Hz,2H),4.86(d,J=7.4Hz,1H),4.74(d,J=7 .5Hz,1H),4.70(dd,J=7.3,2.9Hz,2H),2.23(d,J=1.8Hz,3H),1.81(d,J=6.9Hz,3H).

[0246] Compound M-701: 228 mg, colorless oil, ESI [M+H] + =281.1

[0247] 1 H NMR (400MHz, DMSO) δ7.71(d,J=2.0Hz,1H),7.40–7.32(m,1H),7.19–7.13(m,1H),6.97(d,J=2.0Hz,1H) ,6.79(ddd,J=21.3,10.1,4.0Hz,2H),4.34–4.19(m,2H),1.84(d,J=7.0Hz,3H),1.26(t,J=7.1Hz,3H).

[0248] Compound M-702: 123 mg, white solid, ESI [M+H] + =323.1

[0249] 1 H NMR (400MHz, DMSO) δ7.73(d,J=1.9Hz,1H),7.37(td,J=9.5,1.1Hz,1H),7.21–7.13(m,1H),7.03(d,J=1.9Hz,1H),6.83(t,J=7.1H z,1H),6.69(q,J=6.9Hz,1H),4.77(d,J=7.2Hz,1H),4.65(d,J=7.2Hz,1H),4.54–4.47(m,2H),1.83(d,J=7.0Hz,3H),1.66(s,3H).

[0250] Compound M-703: 144 mg, white solid, ESI [M+H] + =335.1

[0251] 1 H NMR (400MHz, DMSO) δ7.76(d,J=1.9Hz,1H),7.42–7.31(m,1H),7.21–7.14(m,1H),7.11(d,J=1.9Hz,1H),6.80(t,J=7.1Hz,1H),6.67(q,J=7.0Hz ,1H),6.27(dd,J=17.4,11.0Hz,1H),5.24(dd,J=18.0,14.2Hz,2H),4.87(d,J=7.4Hz,1H),4.72(dt,J=15.0,7.4Hz,3H),1.84(d,J=6.9Hz,3H).

[0252] Compound M-704: 157 mg, colorless oil, ESI [M+H] + =347.1

[0253] 1 H NMR(400MHz,DMSO)δ7.74(d,J=1.9Hz,1H),7.38(td,J=9.4,1.2Hz,1H),7.21–7.14 (m,1H),7.07(d,J=1.9Hz,1H),6.81(t,J=7.1Hz,1H),6.69(q,J=6.9Hz,1H),5.81(t ,J=6.7Hz,1H),5.10(dd,J=12.0,6.7Hz,1H),4.98(dd,J=12.0,6.7Hz,1H),4.88(d ,J=7.4Hz,1H),4.76(d,J=7.4Hz,1H),4.68(t,J=7.7Hz,2H),1.84(d,J=7.0Hz,3H).

[0254] Compound M-705: 162 mg, white solid, ESI [M+H] + =311.1

[0255] 1H NMR (400MHz, DMSO) δ7.73(d,J=1.9Hz,1H),7.37(dtd,J=9.4,8.3,1.3Hz,1H),7.22–7.11(m,1H),6.98(d,J= 1.9Hz,1H),6.82–6.71(m,2H),4.40–4.30(m,2H),3.60(t,J=4.6Hz,2H),3.27(s,3H),1.84(d,J=7.0Hz,3H).

[0256] Compound M-706: 167 mg, colorless oil, ESI [M+H] + =337.1

[0257] 1 H NMR (400MHz, DMSO) δ7.72(d,J=1.9Hz,1H),7.36(td,J=9.5,1.2Hz,1H),7.19–7.13(m,1H),7.01(d,J=1.9Hz,1H),6.77(t,J=7.2Hz,1H),6.7 2(q,J=6.9Hz,1H),4.84–4.71(m,1H),3.68–3.55(m,1H),3.16(d,J=3.2Hz,3H),2.81–2.68(m,2H),2.05–1.88(m,2H),1.83(d,J=7.0Hz,3H).

[0258] Compound M-707: 189 mg, colorless oil, ESI [M+H] + =281.1

[0259] 1 H NMR (400MHz, DMSO) δ8.07(d,J=2.4Hz,1H),7.42(dtd,J=9.6,8.2,1.4Hz,1H),7.28–7.19(m,1H),7.05(dd,J=7.7,6.6Hz ,1H),6.80(d,J=2.4Hz,1H),6.03(q,J=7.0Hz,1H),4.28(q,J=7.1Hz,2H),1.87(d,J=7.1Hz,3H),1.29(t,J=7.1Hz,3H).

[0260] Compound M-728: 67 mg, colorless oil, ESI [M+H] + =347.1

[0261] 1H NMR (400MHz, DMSO) δ7.73(d,J=1.9Hz,1H),7.40(dt,J=10.7,8.5Hz,1H),7.27(ddd,J =11.7,7.8,2.2Hz,1H),7.04(d,J=2.0Hz,1H),7.03–6.98(m,1H),6.42(q,J=6.8Hz,1H ),5.84(t,J=6.6Hz,1H),5.12(dd,J=12.0,6.7Hz,1H),5.03(dd,J=12.0,6.7Hz,1H),4 .90(d,J=7.5Hz,1H),4.82(d,J=7.3Hz,1H),4.73–4.64(m,2H),1.82(d,J=7.0Hz,3H).

[0262] Compound M-729: 106 mg, colorless oil, ESI [M+H] + =311.1

[0263] 1 H NMR (400MHz, DMSO) δ7.71(d,J=1.9Hz,1H),7.39(dt,J=10.7,8.5Hz,1H),7.30(ddd,J=11.8,7.8,2.1Hz,1H),7.07–7.00(m,1H ),6.95(d,J=2.0Hz,1H),6.49(q,J=7.0Hz,1H),4.43–4.32(m,2H),3.63(t,J=4.6Hz,2H),3.30(s,3H),1.83(d,J=7.0Hz,3H).

[0264] Compound M-730: 151 mg, colorless oil, ESI [M+H] + =337.1

[0265] 1 H NMR (400MHz, DMSO) δ7.71(d,J=1.9Hz,1H),7.39(dt,J=10.7,8.5Hz,1H),7.27(ddd,J=11.7,7.8,2.1Hz,1H),7.01–6.99(m,1H),6.98(d,J=1.9Hz, 1H),6.47(q,J=6.9Hz,1H),4.79(p,J=7.2Hz,1H),3.64(p,J=6.8Hz,1H), 3.17(s,3H),2.84–2.72(m,2H),2.06–1.92(m,2H),1.82(d,J=7.0Hz,3H).

[0266] Compound M-734: 115 mg, colorless oil, ESI [M+H] + =347.1

[0267] 1 H NMR (400MHz, DMSO) δ8.09(d,J=2.4Hz,1H),7.44(dt,J=10.9,8.7Hz,2H),7.18–7.10(m,1H),6.85(d,J=2.4Hz,1H),5.84(t,J=6.7 Hz,1H),5.79(dd,J=14.8,7.8Hz,1H),5.17(d,J=6.7Hz,2H),4.84(d,J=7.6Hz,2H),4.69(d,J=7.8Hz,2H),1.84(d,J=7.1Hz,3H).

[0268] Compound M-735: 164 mg, colorless oil, ESI [M+H] + =311.1

[0269] 1 H NMR (400MHz, DMSO) δ8.07(d,J=2.4Hz,1H),7.49–7.37(m,2H),7.16–7.08(m,1H),6.80(d,J=2.4Hz,1 H),5.79(d,J=7.1Hz,1H),4.39–4.32(m,2H),3.66–3.60(m,2H),3.33(s,3H),1.84(d,J=7.1Hz,3H).

[0270] Compound M-736: 150 mg, colorless oil, ESI [M+H] + =337.1

[0271] 1 H NMR(400MHz, DMSO)δ8.06(d,J=2.4Hz,1H),7.49–7.36(m,2H),7.16–7.09(m,1H),6.81(d,J=2.4Hz,1H),5.78(q,J=7.1Hz,1H),4 .78(p,J=7.3Hz,1H),3.64(p,J=6.8Hz,1H),3.17(d,J=4.4Hz,3H),2.85–2.72(m,2H),2.04–1.93(m,2H),1.84(d,J=7.1Hz,3H).

[0272] Compound M-740: 166 mg, colorless oil, ESI [M+H] + =359.1

[0273] 1 H NMR (400MHz, DMSO) δ7.74(d,J=1.9Hz,1H),7.30(d,J=7.5Hz,1H),7.20(t,J=7.7H z,1H),7.07(d,J=1.8Hz,1H),6.72(d,J=7.8Hz,1H),6.68(dd,J=14.5,7.6Hz,1H), 5.74(t,J=6.7Hz,1H),5.07(dd,J=11.9,6.7Hz,1H),4.94(dd,J=12.0,6.7Hz,1H) ,4.87(d,J=7.4Hz,1H),4.68(q,J=7.6Hz,3H),2.37(s,3H),1.82(d,J=6.9Hz,3H).

[0274] Compound M-741: 186 mg, colorless oil, ESI [M+H] + =323.1

[0275] 1 H NMR (400MHz, DMSO) δ7.71(d,J=1.9Hz,1H),7.27(d,J=6.8Hz,1H),7.17(t,J=7.7Hz,1H),6.97(d,J=2.0Hz,1H),6.76(q,J= 6.9Hz,1H),6.71(d,J=7.7Hz,1H),4.39–4.26(m,2H),3.63–3.52(m,2H),3.25(s,3H),2.36(s,3H),1.81(d,J=6.9Hz,3H).

[0276] Compound M-742: 201 mg, colorless oil, ESI [M+H] + =349.1

[0277] 1 H NMR (400MHz, DMSO) δ7.71(d,J=1.9Hz,1H),7.27(d,J=7.0Hz,1H),7.16(t,J=7. 6Hz,1H),7.01(d,J=1.9Hz,1H),6.69(q,J=6.9Hz,1H),6.64(d,J=8.2Hz,1H),4. 75(p,J=7.3Hz,1H),3.59(p,J=6.8Hz,1H),3.15(d,J=2.7Hz,3H),2.80–2.66(m ,2H),2.36(s,3H),2.03–1.91(m,1H),1.90–1.83(m,1H),1.81(d,J=6.9Hz,3H).

[0278] Compound M-746: 39 mg, colorless oil, ESI [M+H] + =359.1

[0279] 1 H NMR (400MHz, DMSO) δ8.08(d,J=2.5Hz,1H),7.35(d,J=7.2Hz,1H),7.26(t,J=7.7Hz,1H),6.98(d,J=7.9Hz,1H),6.86(d,J=2.4Hz,1H),6.09(q ,J=6.9Hz,1H),5.84(t,J=6.7Hz,1H),5.18(d,J=6.6Hz,2H),4.85(d,J=7.5Hz,2H),4.69(d,J=7.8Hz,2H),2.39(s,3H),1.84(d,J=7.0Hz,3H).

[0280] Compound M-747: 40 mg, colorless oil, ESI [M+H] + =323.1

[0281] 1 H NMR (400MHz, DMSO) δ8.05(d,J=2.4Hz,1H),7.34(d,J=7.1Hz,1H),7.25(t,J=7.6Hz,1H),6.95(d,J=9.0Hz,1H),6.81(d,J= 2.4Hz,1H),6.08(q,J=7.0Hz,1H),4.39–4.31(m,2H),3.66–3.60(m,2H),3.30(s,3H),2.38(s,3H),1.84(d,J=7.0Hz,3H).

[0282] Compound M-748: 82 mg, colorless oil, ESI [M+H] + =349.1

[0283] 1H NMR (400MHz, DMSO) δ8.04(d,J=2.4Hz,1H),7.34(d,J=6.8Hz,1H),7.25(t,J=7.6Hz,1H),6.95(d,J=7.0Hz,1H),6.81(d,J=2.4Hz,1H),6.07(q,J= 7.0Hz,1H),4.78(p,J=7.3Hz,1H),3.64(p,J=6.8Hz,1H),3.17(s,3H),2 .84–2.72(m,2H),2.38(s,3H),2.07–1.92(m,2H),1.84(d,J=7.0Hz,3H).

[0284] Compound M-749: 221 mg, colorless oil, ESI [M+H] + =273.1

[0285] 1 H NMR (400MHz, DMSO) δ7.69(d,J=1.9Hz,1H),7.04(d,J=7.0Hz,1H),7.01–6.92(m,2H),6.68(q,J=6.9Hz,1 H),6.58(d,J=7.6Hz,1H),4.33–4.10(m,2H),2.26(s,6H),1.74(d,J=6.9Hz,3H),1.23(t,J=7.1Hz,3H).

[0286] Compound M-750: 222 mg, white solid, ESI [M+H] + =315.1

[0287] 1 H NMR(400MHz, DMSO) δ7.70(d,J=2.0Hz,1H),7.11–6.92(m,3H),6.65–6.49(m,2H),4.73(d,J=7.1Hz,1H),4.55 (d,J=7.1Hz,1H),4.47(dd,J=10.2,7.1Hz,2H),2.25(s,3H),2.21(s,3H),1.74(d,J=6.9Hz,3H),1.58(s,3H).

[0288] Compound M-751: 192 mg, white solid, ESI [M+H] + =327.1

[0289] 1H NMR (400MHz, DMSO) δ7.73(d,J=2.0Hz,1H),7.09(d,J=2.0Hz,1H),7.05(d,J=7.2Hz,1H),6.99(t,J=7.6Hz,1H),6.60–6.53(m,2H),6.20(dd,J= 17.4,10.9Hz,1H),5.13(dd,J=41.8,14.2Hz,2H),4.76(dd,J=65.4,7.4Hz,2H),4.65(s,2H),2.24(s,3H),2.19(s,3H),1.75(d,J=6.9Hz,3H).

[0290] Compound M-752: 220 mg, white solid, ESI [M+H] + =339.1

[0291] 1 H NMR (400MHz, DMSO) δ7.71(d,J=2.0Hz,1H),7.06(d,J=5.9Hz,1H),7.05(d,J=1.9Hz,1H),6.99(t,J=7.6Hz,1H),6.63–6.55(m,2H),5.72(t,J=6.7H z,1H),5.03(dd,J=12.0,6.7Hz,1H),4.86(dd,J=12.1,6.8Hz,2H),4.65(dd,J=14.4,7.7Hz,3H),2.26(s,3H),2.21(s,3H),1.74(d,J=6.9Hz,3H).

[0292] Compound M-753: 202 mg, colorless oil, ESI [M+H] + =303.1

[0293] 1 H NMR (400MHz, DMSO) δ7.70(d,J=1.9Hz,1H),7.04(d,J=7.2Hz,1H),7.00–6.93(m,2H),6.67(q,J=6.9Hz,1H),6.59( d,J=7.6Hz,1H),4.39–4.21(m,2H),3.56(dt,J=5.6,3.9Hz,2H),3.25(s,3H),2.26(s,6H),1.74(d,J=6.9Hz,3H).

[0294] Compound M-754: 238 mg, colorless oil, ESI [M+H] + =329.1

[0295] 1 H NMR (400MHz, DMSO) δ7.70(d,J=2.0Hz,1H),7.04(d,J=7.1Hz,1H),7.00(d,J=2.0Hz,1H),6.97(t,J=7.6Hz,1H),6.62(q,J=6.9Hz,1H),6.54(d, J=7.6Hz,1H),4.86–4.60(m,1H),3.59(p,J=6.8Hz,1H),3.14(s,3H),2. 78–2.64(m,2H),2.26(s,6H),1.97–1.82(m,2H),1.74(d,J=6.9Hz,3H).

[0296] Compound M-755: 200 mg, white solid, ESI [M+H] + =272.1

[0297] 1 H NMR (400MHz, DMSO) δ7.90(d,J=2.4Hz,1H),7.16–7.03(m,2H),6.87(d,J=7.3Hz,1H),6.77(d,J=2.4Hz,1H),5.99 (q,J=7.0Hz,1H),4.27(q,J=7.1Hz,2H),2.27(s,3H),2.22(s,3H),1.78(d,J=7.0Hz,3H),1.29(t,J=7.1Hz,3H).

[0298] Compound M-756: 246 mg, colorless oil, ESI [M+H] + =315.1

[0299] 1 H NMR (400MHz, DMSO) δ7.94(d,J=2.4Hz,1H),7.16–7.04(m,2H),6.90(d,J=7.4Hz,1H),6.81(d,J=2.4Hz,1H),6.00(q,J= 6.9Hz,1H),4.75(d,J=7.3Hz,2H),4.52(d,J=7.7Hz,2H),2.27(s,3H),2.23(s,3H),1.78(d,J=7.0Hz,3H),1.73(s,3H).

[0300] Compound M-757: 218 mg, colorless oil, ESI [M+H] + =327.1

[0301] 1H NMR (400MHz, DMSO) δ7.95(d,J=2.4Hz,1H),7.15–7.04(m,2H),6.92(s,1H),6.85(d,J=2.4Hz,1H),6.35(dd,J=17.4,10.9Hz,1H),6.01(q,J =7.0Hz,1H),5.36(dd,J=19.6,14.2Hz,2H),4.84(d,J=7.8Hz,2H),4.71(d,J=7.9Hz,2H),2.27(s,3H),2.24(s,3H),1.79(d,J=7.0Hz,3H).

[0302] Compound M-758: 136 mg, colorless oil, ESI [M+H] + =339.1

[0303] 1 H NMR (400MHz, DMSO) δ7.94(d,J=2.4Hz,1H),7.16–7.04(m,2H),6.90(d,J=7.4Hz,1H),6.83(d,J=2.4Hz,1H),6.01(q,J=7.0Hz,1H),5.84 (t,J=6.7Hz,1H),5.17(d,J=6.7Hz,2H),4.84(d,J=7.7Hz,2H),4.69(d,J=7.9Hz,2H),2.27(s,3H),2.23(s,3H),1.78(d,J=7.0Hz,3H).

[0304] Compound M-759: 162 mg, colorless oil, ESI [M+H] + =303.1

[0305] 1 H NMR (400MHz, DMSO) δ7.91(d,J=2.4Hz,1H),7.15–7.03(m,2H),6.88(d,J=7.5Hz,1H),6.78(d,J=2.4Hz,1H),6.00(q ,J=7.0Hz,1H),4.40–4.31(m,2H),3.67–3.56(m,2H),3.30(s,3H),2.27(s,3H),2.23(s,3H),1.78(d,J=7.0Hz,3H).

[0306] Compound M-760: 239 mg, colorless oil, ESI [M+H] + =329.1

[0307] 1H NMR (400MHz, DMSO) δ7.90(d,J=2.4Hz,1H),7.16–7.04(m,2H),6.88(d,J=7.3Hz,1H),6.78(d,J=2.4Hz,1H),5.99(q,J=6.9Hz,1H),4.89– 4.66(m,1H),3.64(p,J=6.9Hz,1H),3.16(s,3H),2.83–2.73(m,2H),2.27(s,3H),2.22(s,3H),2.03–1.92(m,2H),1.78(d,J=7.0Hz,3H).

[0308] Compound M-761: 155 mg, colorless oil, ESI [M+H] + =325.1

[0309] 1 H NMR (400MHz, DMSO) δ7.74(d,J=1.9Hz,1H),7.37(dd,J=17.2,8.3Hz,1H),7.17(dd,J=13.2,6.8Hz,1H),7.04(d,J=1.9Hz,1H),6 .81(t,J=7.2Hz,1H),6.71(q,J=6.9Hz,1H),5.72(p,J=7.8Hz,1H),3.57–3.48(m,2H),3.35–3.30(m,2H),1.83(d,J=7.0Hz,3H).

[0310] Compound M-837: 255 mg, colorless oil, ESI [M+H] + =281.1

[0311] 1 H NMR(400MHz, CDCl3) δ7.61(d,J=1.7Hz,1H),7.18–7.06(m,1H),6.93(d,J=1.7Hz,1H) ,6.89–6.75(m,3H),4.44–4.25(m,2H),1.92(d,J=7.0Hz,3H),1.37(t,J=7.1Hz,3H).

[0312] Compound M-838: 35 mg, colorless oil, ESI [M+H] + =323.1

[0313] 1H NMR (400MHz, DMSO) δ7.71(d,J=2.0Hz,1H),7.29–7.20(m,1H),7.14(td,J=8.6,6.6Hz,1H),7.06(td,J=8.6,2.5Hz,1H),7.01(d,J=2.0Hz, 1H), 6.65 (q, J = 6.8Hz, 1H), 4.78 (d, J = 7.2Hz, 1H), 4.67 (d, J = 7.2Hz, 1H), 4.51 (dd, J = 6.8, 4.6Hz, 2H), 1.81 (d, J = 7.0Hz, 3H), 1.68 (s, 3H).

[0314] Compound M-839: 61 mg, colorless oil, ESI [M+H] + =335.1

[0315] 1 H NMR (400MHz, DMSO) δ7.73(d,J=1.9Hz,1H),7.29–7.20(m,1H),7.16–7.02(m,3H),6.64(q,J=6.9Hz,1H),6.29(dd,J=17.4,11.0 Hz,1H),5.28(dd,J=14.2,10.4Hz,2H),4.88(d,J=7.4Hz,1H),4.77(d,J=7.5Hz,1H),4.74–4.64(m,2H),1.81(d,J=6.9Hz,3H).

[0316] Compound M-840: 84 mg, colorless oil, ESI [M+H] + =347.1

[0317] 1 H NMR (400MHz, DMSO) δ7.72(d,J=2.0Hz,1H),7.30–7.21(m,1H),7.17–7.05(m,2H),7.04(d,J=2.0Hz,1H),6.65(q,J=7.0Hz,1H),5.81(t,J=6.7Hz,1H), 5.12(dd,J=12.0,6.7Hz,1H),5.01(dd,J=12.0,6.6Hz,1H),4.88(d,J=7.5H z, 1H), 4.78 (d, J = 7.5Hz, 1H), 4.69 (t, J = 6.6Hz, 2H), 1.81 (d, J = 7.0Hz, 3H).

[0318] Compound M-841: 203 mg, colorless oil, ESI [M+H] + =311.1

[0319] 1 H NMR(400MHz,DMSO)δ7.70(d,J=2.0Hz,1H),7.29–7.20(m,1H),7.15–7.00(m,2H),6.96(d,J=2.0Hz,1 H),6.72(q,J=6.9Hz,1H),4.42–4.30(m,2H),3.65–3.56(m,2H),3.28(s,3H),1.81(d,J=7.0Hz,3H).

[0320] Compound M-842: 120 mg, colorless oil, ESI [M+H] + =337.1

[0321] 1 H NMR(400MHz, DMSO)δ7.70(d,J=1.9Hz,1H),7.29–7.20(m,1H),7.13–7.01(m,2H),6.98(d,J=2.0Hz,1H),6.68(q,J=6.9Hz,1H),4 .78(p,J=7.2Hz,1H),3.62(p,J=6.9Hz,1H),3.16(d,J=3.0Hz,3H),2.82–2.67(m,2H),2.05–1.88(m,2H),1.80(d,J=7.0Hz,3H).

[0322] Compound M-843: 66 mg, colorless oil, ESI [M+H] + =281.1

[0323] 1 H NMR(400MHz, CDCl3)δ7.50(d,J=2.4Hz,1H),7.14(td,J=8.8,6.4Hz,1H),6.93–6.78(m,3H) ,5.91(q,J=7.1Hz,1H),4.43(q,J=7.1Hz,2H),1.95(d,J=7.1Hz,3H),1.42(t,J=7.1Hz,3H).

[0324] Compound M-844: 191 mg, white solid, ESI [M+H] + =323.1

[0325] 1H NMR(400MHz,DMSO)δ8.06(d,J=2.4Hz,1H),7.42–7.26(m,2H),7.13(td,J=8.9,2.6Hz,1H),6.82(d,J=2.4Hz, 1H), 5.97 (q, J = 7.0Hz, 1H), 4.74 (d, J = 7.3Hz, 2H), 4.51 (d, J = 7.8Hz, 2H), 1.84 (d, J = 7.1Hz, 3H), 1.73 (s, 3H).

[0326] Compound M-845: 159 mg, colorless oil, ESI [M+H] + =334.1

[0327] 1 H NMR (400MHz, DMSO) δ8.08(d,J=2.4Hz,1H),7.42–7.27(m,2H),7.18–7.09(m,1H),6.87(d,J=2.4Hz,1H),6.34(dd,J=17.4,10.9H z,1H),5.98(q,J=7.1Hz,1H),5.36(dd,J=20.5,14.1Hz,2H),4.84(d,J=7.9Hz,2H),4.71(d,J=8.0Hz,2H),1.85(d,J=7.1Hz,3H).

[0328] Compound M-846: 176 mg, colorless oil, ESI [M+H] + =347.1

[0329] 1 H NMR (400MHz, DMSO) δ8.08(d,J=2.4Hz,1H),7.41–7.26(m,2H),7.14(td,J=8.7,2.4Hz,1H),6.85(d,J=2.4Hz,1H),5.98(q,J= 7.1Hz, 1H), 5.84 (t, J = 6.7Hz, 1H), 5.18 (d, J = 6.7Hz, 2H), 4.84 (d, J = 7.6Hz, 2H), 4.69 (d, J = 7.8Hz, 2H), 1.85 (d, J = 7.1Hz, 3H).

[0330] Compound M-847: 169 mg, colorless oil, ESI [M+H] + =311.1

[0331] 1H NMR (400MHz, DMSO) δ8.04(d,J=2.4Hz,1H),7.32(tdd,J=11.1,9.0,4.6Hz,2H),7.13(td,J=8.8,2.5Hz,1H),6.80( d,J=2.4Hz,1H),5.97(q,J=7.0Hz,1H),4.40–4.31(m,2H),3.66–3.59(m,2H),3.30(s,3H),1.85(d,J=7.1Hz,3H).

[0332] Compound M-848: 134 mg, colorless oil, ESI [M+H] + =337.1

[0333] 1 H NMR (400MHz, DMSO) δ8.04(d,J=2.4Hz,1H),7.40–7.24(m,2H),7.12(td,J=9.3,3.0Hz,1H),6.80(d,J=2.4Hz,1H),5.96(q,J=7.0 Hz,1H),4.77(p,J=7.3Hz,1H),3.64(p,J=6.8Hz,1H),3.16(s,3H),2.86–2.74(m,2H),2.04–1.93(m,2H),1.84(d,J=7.1Hz,3H).

[0334] Compound M-849: 298 mg, colorless oil, ESI [M+H] + =277.1

[0335] 1 H NMR (400MHz, CDCl3) δ7.62(d,J=1.9Hz,1H),7.14–7.06(m,1H),6.99–6.91(m,2H),6.81(d,J=7.8Hz,1H),6. 73(q,J=7.0Hz,1H),4.41–4.20(m,2H),2.33(d,J=2.0Hz,3H),1.88(d,J=7.0Hz,3H),1.35(t,J=7.1Hz,3H).

[0336] Compound M-850: 149 mg, colorless oil, ESI [M+H] + =319.1

[0337] 1H NMR (400MHz, DMSO) δ7.73(d,J=2.0Hz,1H),7.16(dd,J=14.0,8.0Hz,1H),7.07(d,J=8.7Hz,1H),7.04(d,J=2.0Hz,1H),6.64(d,J=7.6Hz,1H),6.53(q ,J=6.9Hz,1H),4.75(d,J=7.1Hz,1H),4.57(d,J=7.1Hz,1H),4.48(dd,J=1 0.6,7.1Hz,2H),2.23(d,J=2.0Hz,3H),1.77(d,J=6.9Hz,3H),1.61(s,3H).

[0338] Compound M-851: 114 mg, colorless oil, ESI [M+H] + =331.1

[0339] 1 H NMR(400MHz,DMSO)δ7.75(d,J=2.0Hz,1H),7.20–7.12(m,1H),7.11(d,J=2.0Hz,1H) ,7.06(t,J=8.6Hz,1H),6.60(d,J=7.7Hz,1H),6.51(q,J=6.9Hz,1H),6.23(dd,J=17 .4,10.9Hz,1H),5.20(d,J=10.9Hz,1H),5.11(d,J=17.4Hz,1H),4.86(d,J=7.2Hz,1 H), 4.69 (d, J = 7.3Hz, 1H), 4.66 (s, 2H), 2.20 (d, J = 1.9Hz, 3H), 1.77 (d, J = 6.9Hz, 3H).

[0340] Compound M-852: 113 mg, white solid, ESI [M+H] + =343.1

[0341] 1 H NMR (400MHz, DMSO) δ7.74(d,J=2.0Hz,1H),7.16(dd,J=14.0,7.9Hz,1H),7.11–7.03(m,2H),6.64(d,J=7.6Hz,1H),6.53(q,J=6.9Hz,1H),5.76 (t,J=6.7Hz,1H),5.05(dd,J=12.0,6.7Hz,1H),4.95–4.83(m,2H),4.67(dt,J=16.1,6.1Hz,3H),2.23(d,J=1.9Hz,3H),1.77(d,J=6.9Hz,3H).

[0342] Compound M-853: 150 mg, white solid, ESI [M+H] + =307.1

[0343] 1 H NMR (400MHz, DMSO) δ7.72(d,J=2.0Hz,1H),7.18–7.11(m,1H),7.05(t,J=8.6Hz,1H),6.98(d,J=2.0Hz,1H),6.65(d,J=7.7Hz ,1H),6.60(q,J=6.9Hz,1H),4.38–4.26(m,2H),3.63–3.52(m,2H),3.25(s,3H),2.27(d,J=2.0Hz,3H),1.77(d,J=6.9Hz,3H).

[0344] Compound M-854: 120 mg, colorless oil, ESI [M+H] + =333.1

[0345] 1 H NMR (400MHz, DMSO) δ7.72(d,J=2.0Hz,1H),7.18–7.10(m,1H),7.05(t,J=8.6Hz,1H),7.01(d,J=2.0Hz,1H),6.61(d,J=7.8Hz,1H),6.56(q,J=6. 9Hz,1H),4.80–4.69(m,1H),3.66–3.55(m,1H),3.14(s,3H),2.80–2.66 (m,2H),2.27(d,J=1.9Hz,3H),1.97–1.85(m,2H),1.76(d,J=6.9Hz,3H).

[0346] Compound M-855: 81 mg, colorless oil, ESI [M+H] + =277.1

[0347] 1 H NMR (400MHz, CDCl3) δ7.22(p,J=8.0Hz,2H),7.06(t,J=7.4Hz,2H),6.81(d,J=2.4Hz,1H),5.90(q,J=7 .0Hz,1H),4.45(q,J=7.1Hz,2H),2.17(d,J=2.0Hz,3H),1.92(d,J=7.0Hz,3H),1.43(t,J=7.1Hz,3H).

[0348] Compound M-856: 123 mg, colorless oil, ESI [M+H] + =319.1

[0349] 1 H NMR (400MHz, DMSO) δ8.00(d,J=2.4Hz,1H),7.25(dd,J=14.0,8.0Hz,1H),7.13(t,J=8.7Hz,1H),6.94(d,J=7.8Hz,1H),6.83(d,J=2.4H z,1H),5.98(q,J=6.9Hz,1H),4.75(d,J=7.3Hz,2H),4.52(d,J=7.7Hz,2H),2.25(d,J=2.0Hz,3H),1.81(d,J=7.0Hz,3H),1.74(s,3H).

[0350] Compound M-857: 139 mg, colorless oil, ESI [M+H] + =331.1

[0351] 1 H NMR (400MHz, DMSO) δ8.02(d,J=2.4Hz,1H),7.25(dd,J=14.0,8.0Hz,1H),7.13( t,J=8.7Hz,1H),6.95(d,J=7.7Hz,1H),6.87(d,J=2.4Hz,1H),6.35(dd,J=17.4 ,10.9Hz,1H),5.99(q,J=7.0Hz,1H),5.37(dd,J=20.4,14.1Hz,2H),4.84(d,J= 7.8Hz, 2H), 4.72 (d, J = 7.9Hz, 2H), 2.26 (d, J = 2.0Hz, 3H), 1.81 (d, J = 7.0Hz, 3H).

[0352] Compound M-858: 126 mg, colorless oil, ESI [M+H] + =343.1

[0353] 1H NMR (400MHz, DMSO) δ8.01(d,J=2.4Hz,1H),7.29–7.21(m,1H),7.13(t,J=8.7Hz,1H),6.94(d,J=7.7Hz,1H),6.85(d,J=2.4Hz,1H),5.99(q,J=7.0 Hz,1H),5.85(t,J=6.7Hz,1H),5.17(d,J=6.7Hz,2H),4.85(d,J=7.7Hz,2H),4.69(d,J=7.9Hz,2H),2.26(d,J=2.0Hz,3H),1.81(d,J=7.0Hz,3H).

[0354] Compound M-859: 118 mg, colorless oil, ESI [M+H] + =307.1

[0355] 1 H NMR (400MHz, DMSO) δ7.98(d,J=2.4Hz,1H),7.29–7.18(m,1H),7.12(t,J=8.8Hz,1H),6.92(d,J=7.7Hz,1H),6.80(d,J=2.4Hz,1H) ,5.97(q,J=7.0Hz,1H),4.36(dd,J=5.4,3.9Hz,2H),3.69–3.57(m,2H),3.30(s,3H),2.25(d,J=2.1Hz,3H),1.81(d,J=7.0Hz,3H).

[0356] Compound M-860: 162 mg, colorless oil, ESI [M+H] + =333.1

[0357] 1 H NMR (400MHz, DMSO) δ7.97(d,J=2.4Hz,1H),7.24(dd,J=14.0,7.9Hz,1H),7.12(t ,J=8.9Hz,1H),6.91(d,J=7.8Hz,1H),6.80(d,J=2.4Hz,1H),5.97(q,J=7.0Hz,1H ),4.78(p,J=7.3Hz,1H),3.64(p,J=6.8Hz,1H),3.16(s,3H),2.84–2.71(m,2H), 2.25(d,J=2.0Hz,3H), 1.98(dtd,J=10.0,7.4,2.7Hz,2H), 1.80(d,J=7.0Hz,3H).

[0358] Compound M-861: 121 mg, colorless oil, ESI [M+H] + =293.1

[0359] 1 H NMR (400MHz, DMSO) δ7.71(d,J=2.0Hz,1H),7.33(tdd,J=7.3,5.4,1.7Hz,1H),7.24–7.11(m,2H),6.99(td,J=7.9,1.8Hz,1 H),6.96(d,J=2.0Hz,1H),6.76(q,J=7.0Hz,1H),4.43–4.28(m,2H),3.68–3.53(m,2H),3.27(s,3H),1.82(d,J=7.0Hz,3H).

[0360] Compound M-862: 181 mg, colorless oil, ESI [M+H] + =293.1

[0361] 1 H NMR(400MHz,DMSO)δ8.05(d,J=2.4Hz,1H),7.43–7.35(m,1H),7.28–7.18(m,3H),6.80(d,J=2.4Hz,1 H),5.99(q,J=7.1Hz,1H),4.39–4.30(m,2H),3.67–3.56(m,2H),3.29(s,3H),1.85(d,J=7.1Hz,3H).

[0362] Compound M-863: 152 mg, colorless oil, ESI [M+H] + =307.1

[0363] 1 H NMR (400MHz, DMSO) δ7.70(d,J=1.5Hz,1H),7.20(t,J=7.4Hz,1H),7.02(t,J=7.7Hz,1H),6.96(d,J=1.6Hz,1H ),6.84–6.70(m,2H),4.43–4.28(m,2H),3.69–3.52(m,2H),3.28(s,3H),2.24(s,3H),1.81(d,J=6.9Hz,3H).

[0364] Compound M-864: 154 mg, colorless oil, ESI [M+H] + =307.1

[0365] 1H NMR (400MHz, DMSO) δ8.04(d,J=2.3Hz,1H),7.26(t,J=7.3Hz,1H),7.10(t,J=7.6Hz,1H),7.03(t,J=6.9Hz,1H),6.79(d,J= 2.4Hz,1H),5.97(d,J=7.1Hz,1H),4.39–4.31(m,2H),3.66–3.57(m,2H),3.29(s,3H),2.24(s,3H),1.84(d,J=7.1Hz,3H).

[0366] Example 7: Preparation of compounds M-713, M-717, M-719 and M-723 of the present invention

[0367] The preparation methods of target compounds M-713, M-717, M-719 and M-723 are similar to those of target compound M-681.

[0368] Compound M-713: 183 mg, colorless oil, ESI [M+H] + =263.1

[0369] 1 H NMR (400MHz, DMSO) δ8.50(s,1H),7.91(s,1H),7.39(ddd,J=15.4,5.5,1.8Hz,1H),7.29(td,J=7.7,1.6Hz,1H),7.22 (dd,J=15.2,7.9Hz,2H),5.95(q,J=7.0Hz,1H),4.23(q,J=7.1Hz,2H),1.85(d,J=7.1Hz,3H),1.28(t,J=7.1Hz,3H).

[0370] Compound M-717: 295 mg, colorless oil, ESI [M+H] + =293.1

[0371] 1 H NMR(400MHz, CDCl3)δ8.05(s,1H),8.02(s,1H),7.42–7.31(m,1H),7.22–7.03(m,3H),5.89 (q,J=7.0Hz,1H),4.48–4.40(m,2H),3.76–3.67(m,2H),3.45(s,3H),1.96(d,J=7.0Hz,3H).

[0372] Compound M-719: 233 mg, white solid, ESI [M+H] +=277.1

[0373] 1 H NMR (400MHz, DMSO) δ8.48(s,1H),7.89(s,1H),7.28–7.22(m,1H),7.12–7.05(m,2H),5.93(q,J=7.0 Hz, 1H), 4.23 (q, J = 7.1Hz, 2H), 2.24 (d, J = 1.8Hz, 3H), 1.83 (d, J = 7.1Hz, 3H), 1.28 (t, J = 7.1Hz, 3H).

[0374] Compound M-723: 222 mg, colorless oil, ESI [M+H] + =307.1

[0375] 1 H NMR (400MHz, CDCl3) δ8.03(s,1H),8.00(s,1H),7.17(td,J=7.3,1.2Hz,1H),7.04(t,J=7.5Hz,1H),7.02–6.97(m,1H),5.86(q,J =7.1Hz,1H),4.42(dd,J=5.4,4.1Hz,2H),3.71(dd,J=5.4,4.1Hz,2H),3.44(s,3H),2.30(d,J=2.1Hz,3H),1.93(d,J=7.1Hz,3H).

[0376] Example 8: Compounds of the present invention M-1001~1004, M-1006, M-1008~1015, M-1017, M-1019~1026, M-1028, M-1032~1033, M-1043, M-1759~1761, M-1765~1767, M-1769~1770, M-1773, M-1777, M-1781~1782, M-1784, M-1786~1787, M-1789, M-1791, M-1797~1799, M-1801, M-1803, M-1805 ~1833,M-1840,M-1843,M-1845~1846,M-1849,M-1851~1852,M-1855,M-1857~1858,M-1861~1864,M-1867~1870,M-1873~1877,M - Preparation of 1879~1882, M-1885, M-1887, M-1889, M-1891, M-1893~1895, M-1897~1901, M-1903~1905, M-1924~1925, M-1927 and M-1934~1936

[0377] Target compounds M-1001~1004, M-1006, M-1008~1015, M-1017, M-1019~1026, M-1028, M-1032~1033, M-1043, M-1759~1761, M-1765~1767, M-1769~1770, M-1773, M-1777, M-1781~1782, M-1784, M-1786~1787, M-1789, M-1791, M-1797~1799, M-1801, M-1803, M-1805~1833, M-1840 The preparation methods for compounds M-1843, M-1845~1846, M-1849, M-1851~1852, M-1855, M-1857~1858, M-1861~1864, M-1867~1870, M-1873~1877, M-1879~1882, M-1885, M-1887, M-1889, M-1891, M-1893~1895, M-1897~1901, M-1903~1905, M-1924~1925, M-1927, and M-1934~1936 are similar to those for the target compound M-681.

[0378] Compound M-1001: 138 mg, colorless oil, ESI [M+H] + =319.1

[0379] 1 H NMR (400MHz, DMSO) δ7.70(d,J=2.0Hz,1H),7.36–7.29(m,1H),7.22–7.11(m,2H),6.99(d,J=2.0Hz,1H),6.98–6.93(m,1H),6.71(q,J =7.0Hz,1H),4.76(p,J=7.3Hz,1H),3.61(p,J=6.8Hz,1H),3.15(s,3H),2.82–2.66(m,2H),2.03–1.87(m,2H),1.81(d,J=7.0Hz,3H).

[0380] Compound M-1002: 150 mg, colorless oil, ESI [M+H] + =319.1

[0381] 1H NMR (400MHz, DMSO) δ8.05(d,J=2.4Hz,1H),7.46–7.34(m,1H),7.30–7.16(m,3H),6.81(d,J=2.4Hz,1H),5.99(q,J=7.1Hz,1 H),4.77(p,J=7.3Hz,1H),3.64(p,J=6.8Hz,1H),3.16(s,3H),2.83–2.74(m,2H),2.03–1.93(m,2H),1.85(d,J=7.1Hz,3H).

[0382] Compound M-1003: 124 mg, colorless oil, ESI [M+H] + =333.1

[0383] 1 H NMR (400MHz, DMSO) δ7.70(d,J=2.0Hz,1H),7.20(t,J=7.5Hz,1H),7.02(d,J=7.7Hz,1H),6.99(d,J=2.0Hz,1H),6.70(dt,J=10.8,7.1Hz,2H),4.77(p,J =7.3Hz,1H),3.62(p,J=6.8Hz,1H),3.16(s,3H),2.81–2.68(m,2H),2.24(d ,J=1.9Hz,3H),2.03–1.93(m,1H),1.92–1.84(m,1H),1.80(d,J=7.0Hz,3H).

[0384] Compound M-1004: 150 mg, colorless oil, ESI [M+H] + =333.1

[0385] 1 H NMR (400MHz, DMSO) δ8.03(d,J=2.4Hz,1H),7.26(t,J=7.0Hz,1H),7.10(t,J= 7.6Hz,1H),7.04(dd,J=10.3,4.4Hz,1H),6.79(d,J=2.4Hz,1H),5.97(q,J=7 .0Hz,1H),4.77(p,J=7.3Hz,1H),3.64(p,J=6.8Hz,1H),3.16(s,3H),2.83–2 .73(m,2H),2.25(d,J=1.9Hz,3H),2.02–1.93(m,2H),1.83(d,J=7.1Hz,3H).

[0386] Compound M-1006: 184 mg, colorless oil, ESI [M+H] + =311.1

[0387] 1 H NMR (400MHz, DMSO) δ8.55(s,1H),7.92(s,1H),7.41(dtd,J=9.8,8.2,1.5Hz,1H),7.27–7.18(m,1H),7.11(dd,J= 7.8, 6.5Hz, 1H), 6.01 (q, J = 7.0Hz, 1H), 4.34–4.29 (m, 2H), 3.67–3.55 (m, 2H), 3.30 (s, 3H), 1.87 (d, J = 7.1Hz, 3H).

[0388] Compound M-1008: 150 mg, colorless oil, ESI [M+H] + =281.1

[0389] 1 H NMR (400MHz, DMSO) δ7.61 (d, J=1.9Hz, 1H), 7.41 (tt, J=8.4, 6.4Hz, 1H), 7.12–7.03 (m, 2H), 6.92 (d, J= 2.0Hz,1H),6.69(q,J=7.1Hz,1H),4.27(q,J=7.1Hz,2H),1.90(d,J=7.1Hz,3H),1.26(t,J=7.1Hz,3H).

[0390] Compound M-1009: 186 mg, colorless oil, ESI [M+H] + =347.1

[0391] 1 H NMR (400MHz, DMSO) δ7.65(d,J=2.0Hz,1H),7.46–7.37(m,1H),7.12–7.03(m,2H),7.01(d,J=2.0Hz,1H),6.62(q,J=7.1Hz,1H),5.77(t,J=6.7Hz,1H), 5.12(dd,J=12.0,6.7Hz,1H),5.02(dd,J=12.0,6.6Hz,1H),4.87(d,J=7.4H z, 1H), 4.73 (d, J = 7.4Hz, 1H), 4.68 (t, J = 7.5Hz, 2H), 1.90 (d, J = 7.0Hz, 3H).

[0392] Compound M-1010: 126 mg, colorless oil, ESI [M+H] +=311.1

[0393] 1 H NMR (400MHz, DMSO) δ7.62(d,J=1.9Hz,1H),7.46–7.35(m,1H),7.11–7.03(m,2H),6.93(d,J=1.9Hz,1H ),6.69(q,J=7.1Hz,1H),4.36(t,J=4.6Hz,2H),3.66–3.55(m,2H),3.28(s,3H),1.90(d,J=7.1Hz,3H).

[0394] Compound M-1011: 144 mg, colorless oil, ESI [M+H] + =337.1

[0395] 1 H NMR (400MHz, DMSO) δ7.62(d,J=1.9Hz,1H),7.46–7.35(m,1H),7.11–7.03(m,2H),6.95(d,J=2.0Hz,1H),6.65(q,J=7.1Hz,1 H),4.78(p,J=7.3Hz,1H),3.63(p,J=6.8Hz,1H),3.16(s,3H),2.84–2.67(m,2H),2.07–1.92(m,2H),1.89(d,J=7.1Hz,3H).

[0396] Compound M-1012: 88 mg, white solid, ESI [M+H] + =281.1

[0397] 1 H NMR (400MHz, DMSO) δ8.06(d,J=2.4Hz,1H),7.47(tt,J=8.4,6.6Hz,1H),7.20–7.10(m,2H),6.78(d,J =2.5Hz,1H),5.98(q,J=7.1Hz,1H),4.34–4.18(m,2H),1.95(d,J=7.2Hz,3H),1.27(t,J=7.1Hz,3H).

[0398] Compound M-1013: 166 mg, colorless oil, ESI [M+H] + =347.1

[0399] 1H NMR (400MHz, DMSO) δ8.10(d,J=2.4Hz,1H),7.52–7.42(m,1H),7.22–7.09(m,2H),6.84(d,J=2.5Hz,1H),6.00(q,J=7.1H z,1H),5.83(t,J=6.7Hz,1H),5.16(d,J=6.7Hz,2H),4.83(d,J=7.6Hz,2H),4.67(d,J=7.7Hz,2H),1.96(d,J=7.2Hz,3H).

[0400] Compound M-1014: 125 mg, colorless oil, ESI [M+H] + =311.1

[0401] 1 H NMR (400MHz, DMSO) δ8.07(d,J=2.4Hz,1H),7.52–7.42(m,1H),7.20–7.08(m,2H),6.78(d,J=2.4Hz,1H ),5.99(q,J=7.1Hz,1H),4.40–4.27(m,2H),3.61(t,J=4.7Hz,2H),3.28(s,3H),1.96(d,J=7.2Hz,3H).

[0402] Compound M-1015: 147 mg, colorless oil, ESI [M+H] + =337.1

[0403] 1 H NMR (400MHz, DMSO) δ8.06(d,J=2.3Hz,1H),7.54–7.41(m,1H),7.23–7.05(m,2H),6.79(d,J=2.4Hz,1H),5.99(q ,J=7.2Hz,1H),4.75(p,J=7.3Hz,1H),3.63(p,J=6.9Hz,1H),3.16(s,3H),2.87–2.70(m,2H),2.07–1.90(m,5H).

[0404] Compound M-1017: 129 mg, colorless oil, ESI [M+H] + =311.1

[0405] 1H NMR(400MHz, DMSO)δ8.49(s,1H),7.87(s,1H),7.46(tt,J=8.4,6.5Hz,1H),7.18–7.08(m,2H),5 .95(q,J=7.1Hz,1H),4.38–4.25(m,2H),3.68–3.57(m,2H),3.30(s,3H),1.96(d,J=7.2Hz,3H).

[0406] Compound M-1019: 137 mg, colorless oil, ESI [M+H] + =299.1

[0407] 1 H NMR (400MHz, DMSO) δ7.62(d,J=2.0Hz,1H),7.23–7.13(m,2H),6.93(d,J=2.0Hz,1H),6. 65(q,J=7.1Hz,1H), 4.29(q,J=7.1Hz,2H), 1.88(d,J=7.1Hz,3H), 1.28(t,J=7.1Hz,3H).

[0408] Compound M-1020: 211 mg, colorless oil, ESI [M+H] + =365.1

[0409] 1 H NMR (400MHz, DMSO) δ7.65(d,J=2.0Hz,1H),7.23–7.14(m,2H),7.02(d,J=2.0Hz,1H),6.58(q,J=7.0Hz,1H),5.80(t,J=6.7Hz,1H),5.14(dd, J=12.0,6.7Hz,1H),5.06(dd,J=12.0,6.6Hz,1H),4.88(d,J=7.5Hz,1H),4.77(d,J=7.5Hz,1H),4.69(t,J=7.1Hz,2H),1.88(d,J=7.0Hz,3H).

[0410] Compound M-1021: 162 mg, colorless oil, ESI [M+H] + =329.1

[0411] 1H NMR (400MHz, DMSO) δ7.62(d,J=2.0Hz,1H),7.24–7.12(m,2H),6.93(d,J=2.0Hz,1H),6.65( q,J=7.1Hz,1H),4.41–4.33(m,2H),3.67–3.55(m,2H),3.28(s,3H),1.87(d,J=7.1Hz,3H).

[0412] Compound M-1022: 132 mg, white solid, ESI [M+H] + =355.1

[0413] 1 H NMR (400MHz, DMSO) δ7.62(d,J=1.8Hz,1H),7.22–7.12(m,2H),6.95(d,J=1.8Hz,1H),6.62(q,J=7.1Hz,1H),4.7 9(p,J=7.2Hz,1H),3.69–3.58(m,1H),3.16(s,3H),2.84–2.71(m,2H),2.03–1.91(m,2H),1.87(d,J=7.0Hz,3H).

[0414] Compound M-1023: 95 mg, colorless oil, ESI [M+H] + =299.1

[0415] 1 H NMR(400MHz,DMSO)δ8.06(d,J=2.4Hz,1H),7.36–7.21(m,2H),6.78(d,J=2.5Hz,1H),5 .95(q,J=7.2Hz,1H),4.35–4.18(m,2H),1.93(d,J=7.2Hz,3H),1.27(t,J=7.1Hz,3H).

[0416] Compound M-1024: 128 mg, colorless oil, ESI [M+H] + =365.1

[0417] 1H NMR (400MHz, DMSO) δ8.09(d,J=2.4Hz,1H),7.32–7.22(m,2H),6.83(d,J=2.5Hz,1H),5.96(q,J=7.2Hz,1H),5. 82(t,J=6.7Hz,1H), 5.16(d,J=6.7Hz,2H), 4.82(d,J=7.7Hz,2H), 4.67(d,J=7.9Hz,2H), 1.94(d,J=7.2Hz,3H).

[0418] Compound M-1025: 128 mg, colorless oil, ESI [M+H] + =329.1

[0419] 1 H NMR (400MHz, DMSO) δ8.07(d,J=2.4Hz,1H),7.31–7.21(m,2H),6.78(d,J=2.4Hz,1H),5.96(q ,J=7.2Hz,1H),4.41–4.28(m,2H),3.61(t,J=4.7Hz,2H),3.29(s,3H),1.94(d,J=7.2Hz,3H).

[0420] Compound M-1026: 182 mg, white solid, ESI [M+H] + =355.1

[0421] 1 H NMR (400MHz, DMSO) δ8.06(d,J=2.4Hz,1H),7.31–7.21(m,2H),6.79(d,J=2.4Hz,1H),5.95(q,J=7.1Hz ,1H),4.75(p,J=7.3Hz,1H),3.63(p,J=6.8Hz,1H),3.16(s,3H),2.85–2.73(m,2H),2.04–1.90(m,5H).

[0422] Compound M-1028: 161 mg, white solid, ESI [M+H] + =329.1

[0423] 1H NMR(400MHz,DMSO)δ8.50(s,1H),7.87(s,1H),7.29–7.19(m,2H),5.92(q,J=7.1Hz,1H ),4.32(dd,J=5.4,3.9Hz,2H),3.66–3.56(m,2H),3.30(s,3H),1.94(d,J=7.1Hz,3H).

[0424] Compound M-1032: 210 mg, colorless oil, ESI [M+H] + =315.1

[0425] 1 H NMR (400MHz, DMSO) δ7.69(t,J=1.7Hz,1H),7.20(t,J=7.2Hz,1H),7.02(t,J=7.5Hz,1H),6.97–6.92(m,1H),6.8 0–6.66(m,2H),5.54–5.38(m,2H),5.04–4.88(m,2H),2.24(s,3H),1.81(d,J=7.0Hz,3H),1.36(t,J=6.4Hz,3H).

[0426] Compound M-1033: 31 mg, colorless oil, ESI [M+H] + =345.1

[0427] 1 H NMR (400MHz, DMSO) δ7.70(d,J=1.8Hz,1H),7.20(t,J=7.2Hz,1H),7.03(t,J=7.6Hz,1H),6.95(d,J=1.9Hz,1H),6.83–6.68(m,2H),5.58–5.49(m,1H ),5.44–5.33(m,1H),5.00(dd,J=6.7,2.4Hz,1H),4.98–4.83(m,1H),3.6 2–3.49(m,2H),3.27(d,J=2.2Hz,3H),2.24(s,3H),1.81(d,J=7.0Hz,3H).

[0428] Compound M-1043: 69 mg, colorless oil, ESI [M+H] + =349.1

[0429] 1H NMR (400MHz, DMSO) δ7.72(d,J=1.5Hz,1H),7.37(dd,J=17.0,8.1Hz,1H),7.16(dd,J=13.2,8.2Hz,1H),6.97(d,J=2.0Hz,1H),6.83–6.68(m,2H),5. 59–5.49(m,1H),5.44–5.35(m,1H),5.00(dd,J=6.7,2.5Hz,1H),4.98–4.8 2(m,1H),3.61–3.51(m,2H),3.27(d,J=5.8Hz,3H),1.84(d,J=7.0Hz,3H).

[0430] Compound M-1759: 133 mg, colorless oil, ESI [M+H] + =342.1

[0431] 1 H NMR (400MHz, DMSO) δ8.05(d,J=2.4Hz,1H),7.27(d,J=7.6Hz,1H),7.19–7.10(m,2H),6.83(d,J=2.4Hz,1H),5.84(t,J=6.7Hz,1H),5. 72(q,J=7.1Hz,1H),5.17(d,J=6.7Hz,2H),4.84(d,J=7.6Hz,2H),4.69(d,J=7.8Hz,2H),2.23(d,J=1.6Hz,3H),1.83(d,J=7.1Hz,3H).

[0432] Compound M-1760: 139 mg, colorless oil, ESI [M+H] + =307.1

[0433] 1 H NMR (400MHz, DMSO) δ8.02(d,J=2.4Hz,1H),7.25(d,J=7.7Hz,1H),7.17–7.07(m,2H),6.78(d,J=2.4Hz,1H),5.71( q,J=7.1Hz,1H),4.38–4.31(m,2H),3.67–3.57(m,2H),3.29(s,3H),2.22(d,J=1.6Hz,3H),1.82(d,J=7.1Hz,3H).

[0434] Compound M-1761: 145 mg, colorless oil, ESI [M+H] + =333.1

[0435] 1 H NMR (400MHz, DMSO) δ8.02(d,J=2.4Hz,1H),7.25(d,J=7.6Hz,1H),7.19–7.06(m,2H),6.79(d,J=2.3Hz,1H),5.71(q,J=7.0Hz,1H),4.78(p,J=7.3 Hz,1H),3.65(p,J=6.8Hz,1H),3.17(s,3H),2.85–2.73(m,2H),2.23(d, J=1.7Hz,3H),1.98(dtd,J=10.0,7.4,2.7Hz,2H),1.83(d,J=7.1Hz,3H).

[0436] Compound M-1765: 40 mg, colorless oil, ESI [M+H] + =343.1

[0437] 1 H NMR (400MHz, DMSO) δ7.70 (d, J=1.9Hz, 1H), 7.18–7.13 (m, 1H), 7.12–7.03 (m, 2H) ,7.01(d,J=1.9Hz,1H),6.40(q,J=6.9Hz,1H),5.84(t,J=6.7Hz,1H),5.12(dd,J= 12.0,6.7Hz,1H),5.02(dd,J=12.0,6.6Hz,1H),4.89(d,J=7.5Hz,1H),4.81(d,J =7.6Hz, 1H), 4.70 (t, J = 6.4Hz, 2H), 2.20 (d, J = 1.4Hz, 3H), 1.81 (d, J = 7.0Hz, 3H).

[0438] Compound M-1766: 115 mg, colorless oil, ESI [M+H] + =307.1

[0439] 1 H NMR (400MHz, DMSO) δ7.68(d,J=1.9Hz,1H),7.17(d,J=7.7Hz,1H),7.07(dd,J=6.7,1.9Hz,2H),6.92(d,J=2.0Hz,1H),6. 47(q,J=6.9Hz,1H),4.45–4.29(m,2H),3.63(t,J=4.6Hz,2H),3.29(s,3H),2.20(d,J=1.6Hz,3H),1.81(d,J=7.0Hz,3H).

[0440] Compound M-1767: 67 mg, colorless oil, ESI [M+H] + =333.1

[0441] 1 H NMR (400MHz, DMSO) δ7.68(d,J=1.9Hz,1H),7.16(dd,J=7.5,1.8Hz,1H),7.10–6.99(m,2H),6.96(d,J=2.0Hz,1H),6.44(q,J=7.0Hz,1H),4. 80(p,J=7.2Hz,1H),3.64(p,J=6.8Hz,1H),3.17(s,3H),2.85–2.72(m,2H),2.20(d,J=1.6Hz,3H),2.07–1.92(m,2H),1.80(d,J=7.0Hz,3H).

[0442] Compound M-1769: 216 mg, white solid, ESI [M+H] + =341.1

[0443] 1 H NMR (400MHz, DMSO) δ7.71(d,J=1.9Hz,1H),7.07–7.02(m,1H),7.01–6.94(m,2H),6.73–6.55(m,2H),5.70–5.54(m,1H) ,3.65–3.52(m,2H),3.26(d,J=20.4Hz,3H),2.27(d,J=3.4Hz,6H),1.82(dd,J=18.0,2.2Hz,3H),1.76(d,J=6.9Hz,3H).

[0444] Compound M-1770: 116 mg, colorless oil, ESI [M+H] + =343.1

[0445] 1 H NMR (400MHz, DMSO) δ7.71–7.65(m,1H),7.04(d,J=7.5Hz,1H),7.01–6.92(m,2H),6.69–6.55(m,2H),5.76–5.62(m,1H),5.86–5.32(m,1H), 5.52–5.43(m,1H),3.56–3.36(m,2H),3.24(dd,J=19.4,5.4Hz,3H),2.24(dd,J=10.1,4.1Hz,6H),1.75(d,J=6.9Hz,3H),1.72–1.59(m,3H).

[0446] Compound M-1773: 196 mg, colorless oil, ESI [M+H] + =331.1

[0447] 1 H NMR (400MHz, DMSO) δ7.72(t,J=1.9Hz,1H),7.38–7.30(m,1H),7.25–7.10(m,2H),7.04–6.93(m,2H),6.73(qd,J=6.9,3 .8Hz,1H),5.71–5.58(m,1H),3.68–3.55(m,2H),3.28(d,J=14.8Hz,3H),1.84(d,J=2.3Hz,3H),1.82(d,J=2.0Hz,3H).

[0448] Compound M-1777: 270 mg, colorless oil, ESI [M+H] + =349.1

[0449] 1 H NMR (400MHz, DMSO) δ7.72(t,J=2.1Hz,1H),7.30–7.20(m,1H),7.15–7.03(m,2H),6.99(dd,J=4.5,2.0Hz,1H),6.69(t t,J=6.9,3.6Hz,1H),5.66(ttt,J=8.1,4.2,2.0Hz,1H),3.69–3.56(m,2H),3.32(d,J=8.4Hz,3H),1.86–1.79(m,6H).

[0450] Compound M-1781: 261 mg, colorless oil, ESI [M+H] + =349.1

[0451] 1 H NMR (400MHz, DMSO) δ7.74(t,J=2.0Hz,1H),7.43–7.31(m,1H),7.21–7.11(m,1H),7.01(dd,J=4.6,2.0Hz, 1H),6.85–6.67(m,2H),5.70–5.62(m,1H),3.68–3.55(m,2H),3.28(d,J=14.0Hz,3H),1.88–1.80(m,6H).

[0452] Compound M-1782: 69 mg, colorless oil, ESI [M+H] + =351.1

[0453] 1 H NMR (400MHz, DMSO) δ7.72 (dt, J=4.5, 2.3Hz, 1H), 7.36 (q, J=10.2Hz, 1H), 7.16 (dd, J=13.5, 7.2Hz, 1H), 6.98 (ddd, J=7.2, 5.4, 2.0Hz, 1H),6.83–6.68(m,2H),5.92–5.30(m,3H),3.60–3.40(m,2H),3.26(dd,J=7.6,5.4Hz,3H),1.84(d,J=6.9Hz,3H),1.75–1.61(m,3H).

[0454] Compound M-1784: 226 mg, colorless oil, ESI [M+H] + =345.1

[0455] 1 H NMR(400MHz, DMSO)δ7.71(s,1H),7.20(dd,J=11.4,7.5Hz,1H),7.06–6.96(m,2H),6.83–6.67(m,2 H),5.70–5.60(m,1H),3.69–3.55(m,2H),3.29(d,J=11.9Hz,3H),2.24(s,3H),1.87–1.77(m,6H).

[0456] Compound M-1786: 174 mg, colorless oil, ESI [M+H] + =347.1

[0457] 1 H NMR (400MHz, DMSO) δ7.74(t,J=2.3Hz,1H),7.28(t,J=6.0Hz,1H),7.18(dd,J=14.1,7.5Hz,1H),7.02(dd,J=4.3,2.0Hz,1H),6 .79–6.67(m,2H),5.72–5.60(m,1H),3.72–3.58(m,3H),3.29(d,J=12.5Hz,3H),2.37(d,J=3.0Hz,3H),1.82(d,J=6.9Hz,3H).

[0458] Compound M-1787: 106 mg, white solid, ESI [M+H] + =341.1

[0459] 1H NMR (400MHz, DMSO) δ7.92(dd,J=5.6,2.4Hz,1H),7.09(ddd,J=10.3,9.0,4.3Hz,2H),6.94–6.87(m,1H),6.80(dd,J=2.3,1.2Hz,1H),6.01(q,J=6.9Hz,1H ),5.73–5.64(m,1H),3.64(ddd,J=15.0,11.1,5.7Hz,2H),3.32(d,J=1.4Hz, 3H), 2.27 (s, 3H), 2.23 (s, 3H), 1.85 (t, J = 2.2Hz, 3H), 1.79 (d, J = 7.0Hz, 3H).

[0460] Compound M-1789: 222 mg, colorless oil, ESI [M+H] + =331.1

[0461] 1 H NMR(400MHz, DMSO)δ8.06(dd,J=4.3,2.4Hz,1H),7.44–7.34(m,1H),7.30–7.17(m,3H),6.82(dd,J=2.3,1.2Hz,1H),6.00(q ,J=7.0Hz,1H),5.72–5.61(m,1H),3.64(ddd,J=15.0,11.1,5.7Hz,2H),3.32(d,J=1.4Hz,3H),1.85(dd,J=7.1,4.9Hz,6H).

[0462] Compound M-1791: 61 mg, white solid, ESI [M+H] + =349.1

[0463] 1 H NMR (400MHz, DMSO) δ8.06(dd,J=4.3,2.4Hz,1H),7.40–7.25(m,2H),7.13(t,J=8.6Hz,1H),6.81(dd,J=2.3,1.2Hz,1H),5.97 (q,J=7.1Hz,1H),5.72–5.62(m,1H),3.64(ddd,J=15.0,11.1,5.7Hz,2H),3.31(d,J=0.5Hz,3H),1.85(dd,J=4.4,2.4Hz,6H).

[0464] Compound M-1797: 146 mg, colorless oil, ESI [M+H] + =349.1

[0465] 1 H NMR (400MHz, DMSO) δ7.64(t,J=2.3Hz,1H),7.48–7.35(m,1H),7.07(td,J=8.6,4.6Hz,2H),6.95(dd,J=7.1,2.0Hz,1H),6.67(qd,J=7.0,2. 9Hz,1H),5.66(dtd,J=11.2,4.0,2.1Hz,1H),3.73–3.55(m,2H),3.32(d,J=3.0Hz,3H),1.90(d,J=7.1Hz,3H),1.84(dd,J=9.4,2.2Hz,3H).

[0466] Compound M-1798: 111 mg, colorless oil, ESI [M+H] + =349.1

[0467] 1 H NMR (400MHz, DMSO) δ8.08(t,J=2.8Hz,1H),7.55–7.42(m,1H),7.22–7.06(m,2H),6.81(dd,J=2.4,1.1Hz,1H),6.00(q,J=7.1H z,1H),5.66(dtd,J=7.5,3.9,2.2Hz,1H),3.71–3.55(m,2H),3.30(d,J=3.1Hz,3H),1.96(d,J=7.2Hz,3H),1.88–1.79(m,3H).

[0468] Compound M-1799: 148 mg, white solid, ESI [M+H] + =381.1

[0469] 1 H NMR (400MHz, DMSO) δ7.76(s,1H),7.58(ddd,J=7.7,4.9,1.0Hz,1H),7.32(dd,J=14.4,7.9Hz,1H),7.03(dd,J=5.3,1.9Hz,1H),6.81(dd,J =23.6,7.3Hz,1H),6.70(p,J=7.1Hz,1H),5.65(d,J=2.6Hz,1H),3.68–3.52(m,2H),3.26(d,J=14.3Hz,3H),1.82(dd,J=11.0,2.3Hz,6H).

[0470] Compound M-1801: 150 mg, colorless oil, ESI [M+H] + =361.1

[0471] 1 H NMR (400MHz, DMSO) δ7.73(d,J=1.4Hz,1H),7.33–7.24(m,1H),7.17(dd,J=13.9,7.5Hz,1H),7.00(dd,J=4.1,1.9Hz,1H),6.78– 6.63(m,2H),5.70–5.57(m,1H),3.69–3.53(m,2H),3.26(d,J=13.6Hz,3H),2.37(d,J=3.8Hz,3H),1.82(dd,J=10.7,2.2Hz,6H).

[0472] Compound M-1803: 157 mg, colorless oil, ESI [M+H] + =345.1

[0473] 1 H NMR(400MHz, DMSO)δ7.74(d,J=1.7Hz,1H),7.18–7.10(m,1H),7.09–6.97(m,2H),6.68–6.53(m,2H),5 .69–5.57(m,1H),3.67–3.51(m,2H),3.26(d,J=23.9Hz,3H),2.29(d,J=1.9Hz,3H),1.86–1.75(m,6H).

[0474] Compound M-1805: 95 mg, colorless oil, ESI [M+H] + =367.1

[0475] 1 H NMR (400MHz, DMSO) δ7.64(t,J=2.2Hz,1H),7.17(td,J=9.0,4.2Hz,2H),6.95(dd,J=7.7,1.9Hz,1H),6.62(qd,J= 7.0,2.4Hz,1H),5.67(dtd,J=6.0,4.0,2.1Hz,1H),3.73–3.55(m,2H),3.32(d,J=1.1Hz,3H),1.93–1.78(m,6H).

[0476] Compound M-1806: 201 mg, colorless oil, ESI [M+H] + =367.1

[0477] 1H NMR (400MHz, DMSO) δ8.08(t,J=2.7Hz,1H),7.26(t,J=9.0Hz,2H),6.81(dd,J=2.3,1.0Hz,1H),5.97(q,J=7.1Hz,1H),5.7 4–5.60(m,1H),3.63(ddd,J=15.1,11.2,5.8Hz,2H),3.31(d,J=2.2Hz,3H),1.94(d,J=7.2Hz,3H),1.84(d,J=1.3Hz,3H).

[0478] Compound M-1807: 258 mg, colorless oil, ESI [M+H] + =307.1

[0479] 1 H NMR (400MHz, DMSO) δ7.69(t,J=2.1Hz,1H),7.37–7.28(m,1H),7.24–7.10(m,2H),7.03–6.91(m,2H),6.74(q,J=6.9Hz ,1H),5.22–5.09(m,1H),3.53–3.37(m,2H),3.25(d,J=2.7Hz,3H),1.82(d,J=7.0Hz,3H),1.20(dd,J=6.5,1.9Hz,3H).

[0480] Compound M-1808: 148 mg, white solid, ESI [M+H] + =325.1

[0481] 1 H NMR (400MHz, DMSO) δ7.71(d,J=1.5Hz,1H),7.41–7.31(m,1H),7.21–7.10(m,1H),6.97–6.92(m,1H),6.83–6.68( m,2H),5.23–5.10(m,1H),3.50–3.40(m,2H),3.24(d,J=2.4Hz,3H),1.83(d,J=7.0Hz,3H),1.20(d,J=6.5Hz,3H).

[0482] Compound M-1809: 181 mg, colorless oil, ESI [M+H] + =343.1

[0483] 1H NMR (400MHz, DMSO) δ7.65–7.56(m,1H),7.17(t,J=9.1Hz,2H),6.90(dd,J=4.9,1.9Hz,1H),6.65(q,J=7.0Hz,1H), 5.25–5.13(m,1H),3.56–3.39(m,2H),3.27(d,J=14.1Hz,3H),1.88(d,J=6.9Hz,3H),1.23(dd,J=12.5,6.5Hz,3H).

[0484] Compound M-1810: 107 mg, colorless oil, ESI [M+H] + =325.1

[0485] 1 H NMR (400MHz, DMSO) δ7.60(t,J=1.7Hz,1H),7.47–7.35(m,1H),7.12–7.01(m,2H),6.89(dd,J=7.0,1.9Hz,1H),6.68(q,J=7.1Hz,1H) ,5.18(dtq,J=9.8,6.5,3.3Hz,1H),3.52–3.40(m,2H),3.27(d,J=14.7Hz,3H),1.90(d,J=6.9Hz,3H),1.22(dd,J=14.3,6.5Hz,3H).

[0486] Compound M-1811: 237 mg, white solid, ESI [M+H] + =321.1

[0487] 1 H NMR (400MHz, DMSO) δ7.68(t,J=2.0Hz,1H),7.19(t,J=7.2Hz,1H),7.02(t,J=7.7Hz,1H),6.93(dd,J=4.1,2.0Hz,1H),6.82–6.68 (m,2H),5.22–5.10(m,1H),3.53–3.39(m,2H),3.25(s,3H),2.24(d,J=1.9Hz,3H),1.81(d,J=7.0Hz,3H),1.20(t,J=6.4Hz,3H).

[0488] Compound M-1812: 223 mg, white solid, ESI [M+H] + =317.1

[0489] 1H NMR (400MHz, DMSO) δ7.68(t,J=1.8Hz,1H),7.05(d,J=7.3Hz,1H),6.98(td,J=7.7,1.5Hz,1H),6.93(t,J=2.2Hz,1H),6.72–6.58(m,2H), 5.20–5.05(m,1H),3.48–3.36(m,2H),3.24(d,J=17.1Hz,3H),2.26(d,J=4.2Hz,6H),1.75(d,J=6.9Hz,3H),1.18(dd,J=14.1,6.5Hz,3H).

[0490] Compound M-1813: 153 mg, white solid, ESI [M+H] + =321.1

[0491] 1 H NMR (400MHz, DMSO) δ7.71(s,1H),7.16(dd,J=14.2,7.2Hz,1H),7.07(t,J=9.0Hz,1H),6.96(d,J=1.4Hz,1H),6.67(t,J=6.9Hz,1H),6.64–6 .57(m,1H),5.22–5.06(m,1H),3.50–3.38(m,2H),3.25(d,J=21.8Hz,3H),2.28(s,3H),1.79(d,J=6.9Hz,3H),1.20(dd,J=18.8,6.5Hz,3H).

[0492] Compound M-1814: 163 mg, white solid, ESI [M+H] + =337.1

[0493] 1 H NMR (400MHz, CDCl3) δ7.62(d,J=1.7Hz,1H),7.16(d,J=7.4Hz,1H),7.09(td,J=7 .6,2.9Hz,1H),6.96(dd,J=4.5,1.7Hz,1H),6.91–6.83(m,1H),6.79(dd,J=17.1, 7.4Hz,1H),5.34–5.22(m,1H),3.48(dqd,J=14.6,10.5,6.4Hz,2H),3.36(d,J=2 .0Hz,3H),2.43(s,3H),1.94(dd,J=6.9,2.6Hz,3H),1.28(dd,J=8.2,6.6Hz,3H).

[0494] Compound M-1815: 149 mg, white solid, ESI [M+H] + =323.1

[0495] 1 H NMR (400MHz, DMSO) δ7.71(d,J=1.5Hz,1H),7.50–7.43(m,1H),7.35–7.25(m,2H),6.96(dd,J=3.5,2.0Hz,1H),6.94–6.86(m,1H),6. 71(qd,J=7.0,2.5Hz,1H),5.21–5.09(m,1H),3.51–3.37(m,2H),3.23(d,J=2.0Hz,3H),1.82(d,J=6.9Hz,3H),1.19(d,J=6.5Hz,3H).

[0496] Compound M-1816: 139 mg, colorless oil, ESI [M+H] + =291.1

[0497] 1 H NMR (400MHz, DMSO) δ7.75 (d, J=1.9Hz, 1H), 7.34 (ddd, J=15.1, 5.6, 1.6Hz, 1H), 7.24–7.12 (m, 2H) ,7.10–7.00(m,2H),6.74(q,J=6.9Hz,1H),5.09–4.92(m,2H),2.14(s,3H),1.83(d,J=7.0Hz,3H).

[0498] Compound M-1817: 148 mg, colorless oil, ESI [M+H] + =309.1

[0499] 1 H NMR (400MHz, DMSO) δ7.76(d,J=1.9Hz,1H),7.36(dtd,J=9.6,8.2,1.4Hz,1H),7.21–7.13(m,1H),7.05(d,J=2.0H z,1H),6.84(dd,J=7.7,6.5Hz,1H),6.73(q,J=7.0Hz,1H),5.09–4.91(m,2H),2.14(s,3H),1.84(d,J=7.0Hz,3H).

[0500] Compound M-1818: 188 mg, white solid, ESI [M+H] + =327.1

[0501] 1 H NMR (400MHz, DMSO) δ7.66(d,J=1.9Hz,1H),7.17(t,J=9.1Hz,2H),7.01(d,J=2.0 Hz,1H),6.62(q,J=7.1Hz,1H),5.01(s,2H),2.15(s,3H),1.87(d,J=7.1Hz,3H).

[0502] Compound M-1819: 138 mg, colorless oil, ESI [M+H] + =309.1

[0503] 1 H NMR(400MHz,DMSO)δ7.65(d,J=2.0Hz,1H),7.45–7.35(m,1H),7.10–7.02(m,2H),7.00( d,J=2.0Hz,1H),6.66(q,J=7.1Hz,1H),4.99(s,2H),2.13(s,3H),1.88(d,J=7.1Hz,3H).

[0504] Compound M-1820: 154 mg, colorless oil, ESI [M+H] + =305.1

[0505] 1 H NMR (400MHz, DMSO) δ7.73(d,J=2.0Hz,1H),7.20(t,J=7.1Hz,1H),7.07–6.99(m,2H),6.82(t,J=7.4Hz,1 H),6.72(q,J=6.9Hz,1H),5.07–4.91(m,2H),2.23(d,J=1.8Hz,3H),2.13(s,3H),1.80(d,J=7.0Hz,3H).

[0506] Compound M-1821: 159 mg, colorless oil, ESI [M+H] + =301.1

[0507] 1 H NMR (400MHz, DMSO) δ7.73 (d, J=2.0Hz, 1H), 7.08–7.02 (m, 2H), 6.98 (t, J=7.6Hz, 1H), 6.64 (dd, J= 13.7,7.0Hz,2H),5.03–4.86(m,2H),2.24(d,J=13.0Hz,6H),2.11(s,3H),1.75(d,J=6.9Hz,3H).

[0508] Compound M-1822: 163 mg, colorless oil, ESI [M+H] + =305.1

[0509] 1 H NMR (400MHz, CDCl3) δ7.65(d,J=1.9Hz,1H),7.09(dd,J=13.8,7.9Hz,1H),7.03(d,J=2.0Hz,1H),6.94(t,J=8.8Hz,1H),6.78(d ,J=7.8Hz,1H),6.66(q,J=6.9Hz,1H),4.79(dd,J=46.8,16.8Hz,2H),2.31(d,J=1.9Hz,3H),2.18(s,3H),1.89(d,J=7.0Hz,3H).

[0510] Compound M-1823: 152 mg, colorless oil, ESI [M+H] + =321.1

[0511] 1 H NMR (400MHz, CDCl3) δ7.66(d,J=1.9Hz,1H),7.16(d,J=6.7Hz,1H),7.09(t,J=7.6Hz,1H),7.05(d,J=2.0Hz,1H),6. 86(q,J=6.9Hz,1H),6.79(d,J=6.7Hz,1H),4.80(q,J=16.8Hz,2H),2.42(s,3H),2.16(s,3H),1.93(d,J=6.9Hz,3H).

[0512] Compound M-1824: 147 mg, white solid, ESI [M+H] + =307.1

[0513] 1 H NMR (400MHz, DMSO) δ7.75(d,J=2.0Hz,1H),7.48–7.41(m,1H),7.34–7.26(m,2H),7.06(d,J=2.0Hz,1H ),6.98–6.92(m,1H),6.71(q,J=6.9Hz,1H),4.97(d,J=1.9Hz,2H),2.11(s,3H),1.81(d,J=6.9Hz,3H).

[0514] Compound M-1825: 106 mg, colorless oil, ESI [M+H] + =307.1

[0515] 1 H NMR(400MHz,DMSO)δ7.74(d,J=1.9Hz,1H),7.36–7.30(m,1H),7.21–7.12(m,2H),7.07 –7.00(m,2H),6.72(q,J=6.9Hz,1H),4.90(s,2H),3.68(s,3H),1.82(d,J=7.0Hz,3H).

[0516] Compound M-1826: 153 mg, colorless oil, ESI [M+H] + =325.1

[0517] 1 H NMR (400MHz, DMSO) δ7.77(d,J=1.9Hz,1H),7.38(dd,J=17.7,9.0Hz,1H),7.18(dd,J=13.4,6.8Hz,1H),7.07(d ,J=1.9Hz,1H),6.86(t,J=7.1Hz,1H),6.73(q,J=6.9Hz,1H),4.92(s,2H),3.70(s,3H),1.85(d,J=7.0Hz,3H).

[0518] Compound M-1827: 132 mg, colorless oil, ESI [M+H] + =343.1

[0519] 1 H NMR (400MHz, DMSO) δ7.67(d,J=1.9Hz,1H),7.17(t,J=9.1Hz,2H),7.02(d,J=1.9 Hz,1H),6.62(q,J=7.0Hz,1H),4.92(s,2H),3.70(s,3H),1.88(d,J=7.0Hz,3H).

[0520] Compound M-1828: 102 mg, colorless oil, ESI [M+H] + =325.1

[0521] 1 H NMR(400MHz,DMSO)δ7.67(d,J=1.9Hz,1H),7.47–7.38(m,1H),7.08(t,J=8.6Hz,2H),7.03 (d,J=1.9Hz,1H),6.67(q,J=7.0Hz,1H),4.92(s,2H),3.70(s,3H),1.90(d,J=7.0Hz,3H).

[0522] Compound M-1829: 132 mg, colorless oil, ESI [M+H] + =321.1

[0523] 1 H NMR (400MHz, DMSO) δ7.75 (d, J=1.9Hz, 1H), 7.21 (t, J=7.3Hz, 1H), 7.04 (dd, J=9.7, 4.8Hz, 2H), 6.84 (t, J= 7.1Hz, 1H), 6.73 (q, J = 6.9Hz, 1H), 4.92 (s, 2H), 3.70 (s, 3H), 2.24 (d, J = 1.5Hz, 3H), 1.82 (d, J = 7.0Hz, 3H).

[0524] Compound M-1830: 153 mg, white solid, ESI [M+H] + =317.1

[0525] 1 H NMR (400MHz, DMSO) δ7.74(d,J=2.0Hz,1H),7.09–7.02(m,2H),6.99(t,J=7.6Hz,1H),6.65(dd,J=1 4.9,7.7Hz,2H),4.87(d,J=1.9Hz,2H),3.67(s,3H),2.24(d,J=11.7Hz,6H),1.75(d,J=6.9Hz,3H).

[0526] Compound M-1831: 101 mg, colorless oil, ESI [M+H] + =321.1

[0527] 1 H NMR (400MHz, CDCl3) δ7.65(d,J=2.0Hz,1H),7.14–7.06(m,1H),7.04(d,J=2.0Hz,1H),6.94(t,J=8.8Hz,1H),6.81(d,J=7. 8Hz, 1H), 6.68 (q, J = 6.9Hz, 1H), 4.78 (dd, J = 49.0, 15.9Hz, 2H), 3.79 (s, 3H), 2.31 (d, J = 2.0Hz, 3H), 1.89 (d, J = 7.0Hz, 3H).

[0528] Compound M-1832: 120 mg, white solid, ESI [M+H] + =337.1

[0529] 1H NMR (400MHz, CDCl3) δ7.66(d,J=1.9Hz,1H),7.16(d,J=7.0Hz,1H),7.10(t,J=7.6Hz,1H),7.05(d,J=1.9Hz,1H),6.88( q,J=6.9Hz,1H),6.82(d,J=6.7Hz,1H),4.79(dd,J=40.5,15.9Hz,2H),3.78(s,3H),2.43(s,3H),1.94(d,J=6.9Hz,3H).

[0530] Compound M-1833: 173 mg, white solid, ESI [M+H] + =323.1

[0531] 1 H NMR(400MHz, DMSO) δ7.76(d,J=2.0Hz,1H),7.50–7.43(m,1H),7.35–7.27(m,2H),7.08(d,J=1.9Hz,1H ),6.98(dd,J=6.1,3.4Hz,1H),6.72(q,J=6.9Hz,1H),4.90(s,2H),3.68(s,3H),1.83(d,J=6.9Hz,3H).

[0532] Compound M-1840: 210 mg, white solid, ESI [M+H] + =341.1

[0533] 1 H NMR(400MHz, CDCl3)δ7.61(d,J=1.9Hz,1H),6.98–6.84(m,3H),6.79(q,J=7.0Hz,1H),4.89(d ,J=7.3Hz,1H),4.83(d,J=7.3Hz,1H),4.65–4.55(m,2H),1.92(d,J=7.0Hz,3H),1.81(s,3H).

[0534] Compound M-1843: 190 mg, colorless oil, ESI [M+H] + =339.1

[0535] 1H NMR (400MHz, CDCl3) δ7.63(d,J=1.9Hz,1H),7.33(td,J=7.7,1.7Hz,1H),7.04(t,J=7.9Hz,1H),7.02–6.96(m,1H),6.94(d,J=1 .9Hz,1H),6.81(q,J=7.0Hz,1H),4.85(dd,J=31.4,7.3Hz,2H),4.60(dd,J=6.8,4.2Hz,2H),1.95(d,J=7.0Hz,3H),1.79(s,3H).

[0536] Compound M-1845: 174 mg, colorless oil, ESI [M+H] + =355.1

[0537] 1 H NMR (400MHz, CDCl3) δ7.64(d,J=1.8Hz,1H),7.40(dd,J=8.0,1.0Hz,1H),7.16(t,J=7.9Hz,1H),6.96(d,J=1.9Hz,1H),6.86(d ,J=7.9Hz,1H),6.77(q,J=6.9Hz,1H),4.81(dd,J=53.5,7.3Hz,2H),4.57(t,J=6.5Hz,2H),1.94(d,J=6.9Hz,3H),1.74(s,3H).

[0538] Compound M-1846: 142 mg, colorless oil, ESI [M+H] + =352.1

[0539] 1 H NMR (400MHz, CDCl3) δ7.63(d,J=1.9Hz,1H),6.99(d,J=2.0Hz,1H),6.97–6.83(m,2H),6.78(q,J=7.0Hz,1H),6.30( dd,J=17.3,11.0Hz,1H),5.40–5.28(m,2H),4.94(dd,J=25.8,7.6Hz,2H),4.83–4.77(m,2H),1.92(d,J=7.0Hz,3H).

[0540] Compound M-1849: 121 mg, colorless oil, ESI [M+H] + =350.1

[0541] 1H NMR (400MHz, CDCl3) δ7.64(d,J=1.9Hz,1H),7.35–7.30(m,1H),7.04(t,J=7.9Hz,1H),7.00(d,J=1.9Hz,1H),6.99–6.94(m,1H),6.80(q,J=7.0Hz, 1H), 6.28 (dd, J=17.4, 11.0Hz, 1H), 5.32 (dd, J=14.2, 7.5Hz, 2H), 4.92 (dd, J=31.8, 7.5Hz, 2H), 4.79 (dd, J=7.4, 3.8Hz, 2H), 1.94 (d, J=7.0Hz, 3H).

[0542] Compound M-1851: 136 mg, colorless oil, ESI [M+H] + =366.1

[0543] 1 H NMR (400MHz, CDCl3) δ7.65(d,J=2.0Hz,1H),7.40(dd,J=8.0,1.5Hz,1H),7.16(t,J=7.9Hz,1H),7.02(d,J=2.0Hz,1H),6.86(dd,J=7.9,1.3Hz,1H),6.78( q,J=6.9Hz,1H),6.23(dd,J=17.4,10.9Hz,1H),5.26(dd,J=20.6,14.2Hz,2H ), 4.89 (dd, J = 51.9, 7.6 Hz, 2H), 4.77 ( d, J = 7.8 Hz, 2H), 1.94 ( d, J = 6.9 Hz, 3H).

[0544] Compound M-1852: 130 mg, colorless oil, ESI [M+H] + =365.1

[0545] 1 H NMR (400MHz, CDCl3) δ7.62 (d, J=1.9Hz, 1H), 6.99–6.82 (m, 3H), 6.78 (q, J=7.0Hz, 1H), 5.70 (t, J= 6.6Hz,1H),5.09–4.98(m,2H),4.88(ddd,J=29.3,14.6,7.1Hz,4H),1.93(dd,J=8.4,4.1Hz,3H).

[0546] Compound M-1855: 196 mg, colorless oil, ESI [M+H] + =363.1

[0547] 1 H NMR (400MHz, CDCl3) δ7.63(d,J=1.9Hz,1H),7.36–7.31(m,1H),7.04(t,J=8.0Hz,1H),7.00–6.94(m,2H),6.81( q,J=7.0Hz,1H),5.68(t,J=6.6Hz,1H),5.02(qd,J=11.7,6.7Hz,2H),4.96–4.79(m,4H),1.94(d,J=7.0Hz,3H).

[0548] Compound M-1857: 183 mg, colorless oil, ESI [M+H] + =379.1

[0549] 1 H NMR (400MHz, CDCl3) δ7.65(d,J=1.8Hz,1H),7.40(dd,J=8.0,1.2Hz,1H),7.15(t,J=7.9Hz,1H),6.99(d,J=1.9Hz,1H),6.85 (d,J=7.9Hz,1H),6.78(q,J=7.0Hz,1H),5.63(t,J=6.6Hz,1H),5.07–4.87(m,3H),4.84–4.74(m,3H),1.94(d,J=6.9Hz,3H).

[0550] Compound M-1858: 189 mg, white solid, ESI [M+H] + =355.1

[0551] 1 H NMR (400MHz, CDCl3) δ7.61(d,J=1.8Hz,1H),6.93(d,J=1.8Hz,1H),6.93–6.86(m,1H),6.86–6.79(m,2H),4.86(p ,J=7.3Hz,1H),3.67(p,J=6.9Hz,1H),3.30(s,3H),2.96–2.80(m,2H),2.21–2.07(m,2H),1.92(d,J=7.0Hz,3H).

[0552] Compound M-1861: 153 mg, colorless oil, ESI [M+H] + =353.1

[0553] 1H NMR(400MHz, CDCl3)δ7.62(d,J=1.8Hz,1H),7.34–7.30(m,1H),7.02(t,J=8.0Hz,1H),6.97–6.91(m,2H),6.86(q,J=7.0Hz,1H), 4.85(p,J=7.3Hz,1H),3.66(p,J=6.9Hz,1H),3.29(d,J=2.7Hz,3H),2.94–2.78(m,2H),2.19–2.05(m,2H),1.93(d,J=7.0Hz,3H).

[0554] Compound M-1862: 68 mg, colorless oil, ESI [M+H] + =353.1

[0555] 1 H NMR (400MHz, CDCl3) δ7.60 (d, J=1.9Hz, 1H), 7.12 (td, J=8.0, 5.4Hz, 1H), 7.0 3(td,J=8.5,1.5Hz,1H),6.92(d,J=1.9Hz,1H),6.79(q,J=7.0Hz,1H),6.70( d,J=7.8Hz,1H),4.79(p,J=7.3Hz,1H),3.60(p,J=6.9Hz,1H),3.25(s,3H),2 .89–2.74(m,2H),2.07(dtd,J=11.3,7.4,3.8Hz,2H),1.89(d,J=7.0Hz,3H).

[0556] Compound M-1863: 109 mg, colorless oil, ESI [M+H] + =369.1

[0557] 1 H NMR (400MHz, CDCl3) δ7.64(d,J=1.9Hz,1H),7.39(dd,J=8.0,1.4Hz,1H),7.13(t,J=7.9Hz,1H),6.96(d,J=2.0Hz,1H),6.88–6.80(m, 2H),4.83(p,J=7.3Hz,1H),3.64(p,J=6.9Hz,1H),3.28(d,J=3.3Hz,3H),2.94–2.76(m,2H),2.19–2.04(m,2H),1.93(d,J=7.0Hz,3H).

[0558] Compound M-1864: 179 mg, colorless oil, ESI [M+H] + =329.1

[0559] 1 H NMR (400MHz, DMSO) δ7.71(d,J=1.9Hz,1H),7.28(td,J=9.7,2.1Hz,1H),6.97(d,J=2.0Hz,1H),6.94–6.86( m,1H),6.72(q,J=6.9Hz,1H),4.42–4.29(m,2H),3.60(t,J=4.6Hz,2H),3.27(s,3H),1.82(d,J=7.0Hz,3H).

[0560] Compound M-1867: 160 mg, colorless oil, ESI [M+H] + =327.1

[0561] 1 H NMR (400MHz, CDCl3) δ7.62(d,J=1.9Hz,1H),7.35–7.30(m,1H),7.02(t,J=8.0Hz,1H),6.98(d,J=1.9Hz,1H),6.97 –6.92(m,1H),6.89(q,J=7.0Hz,1H),4.51–4.35(m,2H),3.69(t,J=4.7Hz,2H),3.42(s,3H),1.94(d,J=7.0Hz,3H).

[0562] Compound M-1868: 59 mg, white solid, ESI [M+H] + =327.1

[0563] 1 H NMR (400MHz, CDCl3) δ7.60(d,J=1.9Hz,1H),7.12(td,J=8.0,5.4Hz,1H),7.03(td,J=8.5,1.4Hz,1H),6.96(d,J=1.9Hz,1H ),6.82(q,J=6.9Hz,1H),6.70(d,J=7.8Hz,1H),4.45–4.28(m,2H),3.71–3.55(m,2H),3.37(s,3H),1.90(d,J=7.0Hz,3H).

[0564] Compound M-1869: 100 mg, colorless oil, ESI [M+H] + =342.1

[0565] 1H NMR (400MHz, CDCl3) δ7.64(d,J=1.9Hz,1H),7.38(dd,J=8.0,1.5Hz,1H),7.13(t,J=7.9Hz,1H),7.00(d,J =2.0Hz,1H),6.91–6.80(m,2H),4.49–4.32(m,2H),3.72–3.61(m,2H),3.40(s,3H),1.93(d,J=6.9Hz,3H).

[0566] Compound M-1870: 194 mg, white solid, ESI [M+H] + =342.1

[0567] 1 H NMR (400MHz, DMSO) δ7.72(d,J=2.0Hz,1H),7.34–7.24(m,1H),6.97(d,J=2.0Hz,1H),6.91(ddd,J=16.7,5.8,2.4Hz,1H),6.7 3(q,J=7.0Hz,1H),4.40–4.32(m,2H),3.69–3.61(m,2H),3.47(q,J=7.0Hz,2H),1.83(d,J=7.0Hz,3H),1.08(t,J=7.0Hz,3H).

[0568] Compound M-1873: 159 mg, colorless oil, ESI [M+H] + =341.1

[0569] 1 H NMR (400MHz, CDCl3) δ7.62(d,J=1.9Hz,1H),7.34–7.30(m,1H),7.05–6.99(m,1H),6.99–6.93(m,2H),6.89(q,J=7.0Hz, 1H), 4.49–4.36 (m, 2H), 3.72 (dd, J=7.1, 2.6Hz, 2H), 3.57 (q, J=7.0Hz, 2H), 1.94 (d, J=7.0Hz, 3H), 1.23 (t, J=7.0Hz, 3H).

[0570] Compound M-1874: 68 mg, white solid, ESI [M+H] + =341.1

[0571] 1H NMR (400MHz, CDCl3) δ7.64(d,J=1.9Hz,1H),7.16(td,J=8.0,5.4Hz,1H),7.07(td,J=8.5,1.4Hz,1H),7.00(d,J=1.9Hz,1H),6.87(q,J=6. 9Hz,1H),6.75(d,J=7.8Hz,1H),4.48–4.33(m,2H),3.78–3.65(m,2H),3.56(q,J=7.0Hz,2H),1.94(d,J=7.0Hz,3H),1.22(t,J=7.0Hz,3H).

[0572] Compound M-1875: 175 mg, colorless oil, ESI [M+H] + =357.1

[0573] 1 H NMR (400MHz, CDCl3) δ7.64(d,J=1.9Hz,1H),7.38(dd,J=8.0,1.4Hz,1H),7.13(t,J=7.9Hz,1H),7.00(d,J=2.0Hz,1H),6.9 2–6.81(m,2H),4.48–4.31(m,2H),3.78–3.64(m,2H),3.55(q,J=7.0Hz,2H),1.93(d,J=7.0Hz,3H),1.21(t,J=7.0Hz,3H).

[0574] Compound M-1876: 101 mg, colorless oil, ESI [M+H] + =343.1

[0575] 1 H NMR(400MHz, CDCl3)δ7.57(d,J=1.9Hz,1H),6.91–6.77(m,4H),4.42–4.29(m,2H) ,3.46(t,J=6.2Hz,2H),3.33(s,3H),1.98(p,J=6.3Hz,2H),1.89(d,J=7.0Hz,3H).

[0576] Compound M-1877: 89 mg, colorless oil, ESI [M+H] + =343.1

[0577] 1H NMR (400MHz, CDCl3) δ7.64(d,J=1.9Hz,1H),6.94(d,J=2.0Hz,1H),6.92–6.87(m,1H),6.87–6.80(m,1H),6.59–6 .53(m,1H),4.46–4.32(m,2H),3.50(t,J=6.2Hz,2H),3.36(s,3H),2.01(p,J=6.3Hz,2H),1.93(d,J=7.0Hz,3H).

[0578] Compound M-1879: 123 mg, colorless oil, ESI [M+H] + =341.1

[0579] 1 H NMR(400MHz, CDCl3)δ7.58(d,J=1.9Hz,1H),7.31–7.26(m,1H),6.99(t,J=8.1Hz,1H),6.95–6.90(m,1H),6.89(d,J=1.9Hz,1H),6 .84(dd,J=12.8,5.8Hz,1H),4.40–4.28(m,2H),3.45(t,J=6.2Hz,2H),3.32(s,3H),1.96(p,J=6.3Hz,2H),1.90(d,J=7.0Hz,3H).

[0580] Compound M-1880: 60 mg, white solid, ESI [M+H] + =341.1

[0581] 1 H NMR (400MHz, CDCl3) δ7.60(d,J=1.9Hz,1H),7.13(td,J=8.0,5.4Hz,1H),7.03(td,J=8.5,1.4Hz,1H),6.91(d,J=1.9Hz,1H),6.83(q,J=6.9 Hz,1H),6.72(d,J=7.8Hz,1H),4.38–4.25(m,2H),3.42(t,J=6.2Hz,2H),3.31(s,3H),1.95(dd,J=12.7,6.4Hz,2H),1.90(d,J=7.0Hz,3H).

[0582] Compound M-1881: 143 mg, colorless oil, ESI [M+H] + =357.1

[0583] 1H NMR (400MHz, CDCl3) δ7.60(d,J=1.9Hz,1H),7.35(dd,J=8.0,1.4Hz,1H),7.09(t,J=7.9Hz,1H),6.91(d,J=1.9Hz,1H),6.87–6.78( m,2H),4.32(qt,J=11.0,6.5Hz,2H),3.41(td,J=6.3,0.9Hz,2H),3.30(s,3H),1.95(dd,J=12.7,6.3Hz,2H),1.90(d,J=7.0Hz,3H).

[0584] Compound M-1882: 103 mg, colorless oil, ESI [M+H] + =343.1

[0585] 1 H NMR (400MHz, CDCl3) δ7.57(d,J=1.9Hz,1H),6.90(t,J=2.0Hz,1H),6.89–6.75(m,3H),5.32–5.18(m ,1H),3.56–3.41(m,2H),3.36(d,J=5.4Hz,3H),1.89(d,J=7.0Hz,3H),1.29(dd,J=6.5,2.1Hz,3H).

[0586] Compound M-1885: 151 mg, colorless oil, ESI [M+H] + =341.1

[0587] 1 H NMR (400MHz, CDCl3) δ7.58 (d, J=1.7Hz, 1H), 7.31–7.26 (m, 1H), 6.98 (td, J=7.9, 1.0Hz, 1H), 6.94–6.86 (m, 2H), 6.86–6. 79(m,1H),5.30–5.19(m,1H),3.56–3.40(m,2H),3.35(s,3H),1.90(dd,J=7.0,1.7Hz,3H),1.28(dd,J=9.3,6.5Hz,3H).

[0588] Compound M-1887: 188 mg, white solid, ESI [M+H] + =357.1

[0589] 1H NMR (400MHz, CDCl3) δ7.59(d,J=1.9Hz,1H),7.35(d,J=7.9Hz,1H),7.09(td,J=7.9,1.7Hz,1H),6.93(t,J=2.0Hz,1H),6.80(ddd,J=1 0.9,9.0,4.2Hz,2H),5.30–5.17(m,1H),3.54–3.36(m,2H),3.32(d,J=2.9Hz,3H),1.90(dd,J=6.9,2.4Hz,3H),1.25(t,J=6.4Hz,3H).

[0590] Compound M-1889: 71 mg, colorless oil, ESI [M+H] + =343.1

[0591] 1 H NMR(400MHz, CDCl3)δ7.65(d,J=1.9Hz,1H),7.00–6.97(m,1H),6.93–6.88(m,1H),6.88–6.80(m,1H),6.60–6.52(m, 1H), 4.36–4.18 (m, 2H), 3.73–3.62 (m, 1H), 3.43 (d, J = 2.9Hz, 3H), 1.94 (d, J = 7.0Hz, 3H), 1.24 (dd, J = 6.4, 1.6Hz, 3H).

[0592] Compound M-1891: 197 mg, colorless oil, ESI [M+H] + =341.1

[0593] 1 H NMR(400MHz, CDCl3)δ7.62(d,J=1.8Hz,1H),7.35–7.30(m,1H),7.01(dd,J=14.7,6.9Hz,1H),6.99–6.93(m,2H),6.93–6.8 6(m,1H),4.36–4.17(m,2H),3.72–3.59(m,1H),3.42(d,J=6.6Hz,3H),1.94(d,J=7.0Hz,3H),1.22(dd,J=6.4,1.3Hz,3H).

[0594] Compound M-1893: 179 mg, colorless oil, ESI [M+H] + =357.1

[0595] 1H NMR (400MHz, CDCl3) δ7.60(d,J=1.9Hz,1H),7.35(dd,J=8.0,1.3Hz,1H),7.09(t,J=7.9Hz,1H),6.94(d,J=1.5Hz,1H),6. 89–6.79(m,2H),4.30–4.10(m,2H),3.65–3.54(m,1H),3.36(d,J=10.3Hz,3H),1.90(d,J=7.0Hz,3H),1.20–1.12(m,3H).

[0596] Compound M-1894: 156 mg, colorless oil, ESI [M+H] + =342.1

[0597] 1 H NMR (400MHz, CDCl3) δ7.60(d,J=1.9Hz,1H),7.00(d,J=2.0Hz,1H),6.92–6.74(m,3H),4.78(q,J=15.8Hz,2H),3.77(s,3H),1.89(d,J=7.0Hz,3H).

[0598] Compound M-1895: 165 mg, colorless oil, ESI [M+H] + =343.1

[0599] 1 H NMR(400MHz, CDCl3)δ7.67(d,J=2.0Hz,1H),7.05(d,J=2.0Hz,1H),6.89–6.80(m,2H), 6.61–6.54(m,1H),4.82(dd,J=37.8,15.8Hz,2H),3.81(s,3H),1.94(d,J=7.0Hz,3H).

[0600] Compound M-1897: 141 mg, white solid, ESI [M+H] + =341.1

[0601] 1 H NMR(400MHz, CDCl3)δ7.61(d,J=1.9Hz,1H),7.31–7.27(m,1H),7.02–6.96(m,2H),6.96–6.91(m ,1H),6.82(q,J=7.0Hz,1H),4.78(dd,J=39.2,15.8Hz,2H),3.77(s,3H),1.91(d,J=7.0Hz,3H).

[0602] Compound M-1898: 101 mg, colorless oil, ESI [M+H] + =341.1

[0603] 1 H NMR (400MHz, CDCl3) δ7.63 (s, 1H), 7.14 (dd, J=13.5, 7.9Hz, 1H), 7.07–7.00 (m, 2H), 6.80 (q, J= 6.9Hz, 1H), 6.73 (d, J = 7.8Hz, 1H), 4.76 (q, J = 15.8Hz, 2H), 3.75 (s, 3H), 1.91 (d, J = 7.0Hz, 3H).

[0604] Compound M-1899: 118 mg, colorless oil, ESI [M+H] + =357.1

[0605] 1 H NMR (400MHz, CDCl3) δ7.63(d,J=1.9Hz,1H),7.35(dd,J=8.0,1.3Hz,1H),7.10(t,J=7.9Hz,1H),7. 03(d,J=1.9Hz,1H),6.85–6.78(m,2H),4.76(q,J=15.8Hz,2H),3.74(s,3H),1.90(d,J=6.9Hz,3H).

[0606] Compound M-1900: 129 mg, white solid, ESI [M+H] + =327.1

[0607] 1 H NMR (400MHz, CDCl3) δ7.61(d,J=2.0Hz,1H),6.99(d,J=2.0Hz,1H),6.92–6.73(m,3H),4.82(q,J=16.8Hz,2H),2.19(s,3H),1.89(d,J=7.0Hz,3H).

[0608] Compound M-1901: 75 mg, colorless oil, ESI [M+H] + =327.1

[0609] 1H NMR(400MHz, CDCl3)δ7.63(d,J=2.0Hz,1H),7.01(d,J=2.0Hz,1H),6.85–6.75(m,2H), 6.57–6.50(m,1H),4.81(dd,J=37.9,16.8Hz,2H),2.19(s,3H),1.90(d,J=7.0Hz,3H).

[0610] Compound M-1903: 168 mg, white solid, ESI [M+H] + =325.1

[0611] 1 H NMR(400MHz, CDCl3)δ7.62(d,J=1.9Hz,1H),7.31–7.27(m,1H),7.03–6.97(m,2H),6.96–6.9 1(m,1H),6.81(q,J=7.0Hz,1H),4.80(q,J=16.8Hz,2H),2.18(s,3H),1.91(d,J=7.0Hz,3H).

[0612] Compound M-1904: 71 mg, white solid, ESI [M+H] + =325.1

[0613] 1 H NMR (400MHz, CDCl3) δ7.67(d,J=2.0Hz,1H),7.17(td,J=8.0,5.4Hz,1H),7.11–7.03(m,2H),6.82( q,J=7.0Hz,1H),6.75(d,J=7.9Hz,1H),4.82(q,J=16.8Hz,2H),2.19(s,3H),1.94(d,J=7.0Hz,3H).

[0614] Compound M-1905: 139 mg, white solid, ESI [M+H] + =341.1

[0615] 1 H NMR (400MHz, CDCl3) δ7.63(d,J=1.9Hz,1H),7.35(dd,J=8.0,1.3Hz,1H),7.10(t,J=7.9Hz,1H),7. 02(d,J=1.9Hz,1H),6.85–6.75(m,2H),4.78(q,J=16.8Hz,2H),2.15(s,3H),1.90(d,J=6.9Hz,3H).

[0616] Compound M-1924: 101 mg, colorless oil, ESI [M+H] + =367.1

[0617] 1 H NMR(400MHz, CDCl3) δ7.58(s,1H),6.96(dd,J=3.3,2.0Hz,1H),6.92–6.70(m,3H),5.68(ddd,J=5.7,4.7,2. 5Hz,1H),3.76–3.57(m,2H),3.39(d,J=7.1Hz,3H),1.89(dd,J=7.0,2.4Hz,3H),1.84(dd,J=5.5,2.0Hz,3H).

[0618] Compound M-1925: 82 mg, colorless oil, ESI [M+H] + =367.1

[0619] 1 H NMR (400MHz, CDCl3) δ7.65(d,J=1.7Hz,1H),7.02(t,J=1.9Hz,1H),6.88(dd,J=14.0,7.1Hz,1H),6.85–6.79(m,1H),6.59–6.49 (m,1H),5.77–5.66(m,1H),3.77–3.63(m,2H),3.42(d,J=5.3Hz,3H),1.94(dd,J=7.0,2.4Hz,3H),1.88(dd,J=5.7,2.2Hz,3H).

[0620] Compound M-1927: 95 mg, colorless oil, ESI [M+H] + =365.1

[0621] 1 H NMR (400MHz, CDCl3) δ7.59 (d, J = 1.8Hz, 1H), 7.31–7.27 (m, 1H), 7.02–6.95 (m, 2H), 6.95–6.80 (m, 2H), 5.73–5. 63(m,1H),3.73–3.57(m,2H),3.38(d,J=5.5Hz,3H),1.90(dd,J=7.0,2.4Hz,3H),1.84(dd,J=3.8,2.2Hz,3H).

[0622] Compound M-1934: 59 mg, colorless oil, ESI [M+H] + =323.1

[0623] 1 H NMR(400MHz, CDCl3)δ7.59(d,J=1.8Hz,1H),7.09–7.01(m,1H),7.01–6.94( m,1H),6.90(d,J=1.7Hz,1H),6.86(q,J=7.1Hz,1H),6.82–6.75(m,1H),4.48 –4.34(m,2H),3.06–2.96(m,1H),2.77(dt,J=9.2,4.5Hz,1H),2.50(dt,J=4 .8,2.3Hz,1H),2.07–1.96(m,1H),1.91(d,J=7.0Hz,3H),1.90–1.83(m,1H).

[0624] Compound M-1935: 19 mg, colorless oil, ESI [M+H] + =309.1

[0625] 1 H NMR(400MHz, CDCl3)δ7.56(d,J=1.9Hz,1H),7.24–7.17(m,1H),6.92(d,J=1.9H z,1H),6.85(t,J=8.4Hz,2H),6.77(q,J=7.1Hz,1H),4.56(ddd,J=12.2,7.2,3.1 Hz,1H),4.11(ddd,J=12.3,6.2,2.5Hz,1H),3.27(ddt,J=9.3,6.2,3.1Hz,1H), 2.87(td,J=4.5,1.9Hz,1H), 2.67(td,J=5.3,2.6Hz,1H), 2.00(d,J=7.0Hz,3H).

[0626] Compound M-1936: 88 mg, colorless oil, ESI [M+H] + =323.1

[0627] 1 H NMR(400MHz, CDCl3)δ7.58(d,J=1.9Hz,1H),7.29–7.21(m,1H),6.95–6.85(m,3H),6.82(q,J=7.1Hz,1H),4.50–4.39(m,2H),3 .10–3.03(m,1H),2.85–2.78(m,1H),2.55(dt,J=4.9,2.4Hz,1H),2.03(d,J=7.1Hz,3H),2.01–1.98(m,1H),1.98–1.88(m,1H).

[0628] Example 9: Preparation of compounds DA-2048, DA2074 to DA-2077, M-2229, DA-2050, DA-2070 to DA-2073 and DA-2118 of the present invention

[0629] At -78°C, DIP-Chloride (22.5 g, 70.1 mmol) was added dropwise to 80 mL of THF containing 10 g, 64.0 mmol of 2,3-difluoroacetophenone. The mixture was allowed to warm naturally to room temperature and stirred overnight. The reaction mixture was then cooled to -20°C, methanol (16 mL) was added, and the mixture was warmed to room temperature and stirred for 1 hour. After the reaction was completed as monitored by TLC, the reaction mixture was concentrated under reduced pressure. EtOAc (20 mL) and ethanolamine (8 mL) were added to the residue, and the mixture was stirred at room temperature for 2 hours. Saturated brine (150 mL) was added to the reaction system, and the mixture was extracted with EtOAc (3 × 100 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 / 20–1 / 2). TLC (ethyl acetate / petroleum ether (v / v) = 1 / 2) was used for monitoring, and the fraction with Rf = 0.5–0.6 was collected to give compound DA-2048-1 (7.24 g, yield 71.5%). (ESI [M+H]) + =159.1.

[0630] At 0°C, DA-2048-1 (7.24 g, 45.8 mmol) and PPh3 (24.0 g, 91.6 mmol) were dissolved in THF (75 mL). Then, a solution of DEAD (15.9 g, 91.3 mmol) in THF (10 mL) was added dropwise to the reaction system at a rate of 10 mmol / min. Next, DPPA (15.1 g, 54.9 mmol) was added dropwise to the system at a rate of 6 mmol / min. After the addition was complete, the temperature was slowly raised to room temperature and stirred overnight. After the reaction was monitored by TLC until complete, saturated brine (150 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (3 × 100 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 DA-2048-2. The crude product was used directly in the next reaction without further purification. ESI[M+H] + =184.1.

[0631] At room temperature, the crude product DA-2048-2 and ethyl propargyl acid (17.0 g, 173.4 mmol) were dissolved in toluene (100 mL) and refluxed with stirring for 2 hours. After the reaction was complete as monitored by TLC, saturated brine (100 mL) was added to the reaction system and extracted with EtOAc (3 × 100 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 / 1) to give syrupy solid compound DA-2048-3 (1.38 g, two-step yield 10.7%) and syrupy solid compound DA-2048-4 (7.78 g, two-step yield 60.4%).

[0632] DA-2048-3: ESI[M+H] + =282.1.

[0633] DA-2048-4: ESI[M+H] + =282.1.

[0634] At room temperature, LiOH·H₂O (411.4 mg, 9.8 mmol) was added to a MeOH / THF / H₂O (15 mL, v / v / v = 1 / 1 / 1) solution of compound DA-2048-3 (1.38 g, 4.91 mmol), and the mixture was stirred at room temperature for 2 hours. After the reaction was completed as monitored by TLC, the reaction solution was concentrated under reduced pressure. H₂O (50 mL) was added to the concentrate, and the solution was washed with EtOAc (3 × 20 mL). The aqueous phase was adjusted to pH 4–5 with 1 N hydrochloric acid, and then extracted with EtOAc (3 × 15 mL). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give a white solid compound DA-2048-5 (692 mg, yield 55.7%). ESI [M+H] + =254.1.

[0635] Under nitrogen protection, oxalyl chloride (136.5 mg, 1.08 mmol) was added dropwise to DA-2048-5 (136.0 mg, 0.537 mmol) in 2 mL of CH2Cl2, and the reaction was carried out at room temperature for 30 minutes. After the reaction was completed as monitored by TLC, the reaction solution was concentrated under reduced pressure, and the residue was used directly for the next reaction without purification.

[0636] Dissolve 3-(propa-1,2-dien-1-yl)oxetan-3-ol (120.4 mg, 1.07 mmol) and triethylamine (162 mg, 1.60 mmol) in CH2Cl2 (2 mL), and add DA-2048-6 CH2Cl2 (2 mL) solution dropwise at 0 °C, stirring for 10 minutes. After the reaction was completed as monitored by TLC, saturated brine (10 mL) was added to the reaction system, and the mixture was extracted with CH2Cl2 (3 × 10 mL). The combined organic phases were washed with saturated brine (20 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 / 10 to 1 / 1), and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1). The fraction with Rf = 0.4 to 0.6 was collected to give compound DA-2048 (146.1 mg, two-step yield 78.3%). ESI [M+H] + =348.1.

[0637] 1 H NMR (400MHz, d6-DMSO) δ8.48 (s, 1H), 7.44 (dd, J = 17.3, 8.4Hz, 1H), 7.31–7. 15(m,1H),6.88(t,J=7.1Hz,1H),6.70(q,J=7.0Hz,1H),5.80(t,J=6.6Hz,1H ),5.10(dd,J=12.1,6.7Hz,1H),4.98(dd,J=12.1,6.6Hz,1H),4.91(d,J=7.4 Hz, 1H), 4.79 (d, J = 7.4Hz, 1H), 4.68 (t, J = 8.1Hz, 2H), 1.96 (d, J = 7.0Hz, 3H).

[0638] 2. The preparation methods of target compounds DA-2074, DA-2075, DA-2076, DA-2077 and M-2229 are similar to those of DA-2048, and they are prepared using DA-2048-5 as the raw material.

[0639] Compound DA-2074: 28.6 mg, white solid, ESI [M+H] + =324.1.

[0640] 1H NMR (400MHz, d6-DMSO) δ8.42(s,1H),7.42(d,J=8.8Hz,1H),7.21(dd,J=5.1,1.5Hz,1H),6.87(t,J=7.1Hz,1H),6.69(d,J= 7.0Hz, 1H), 4.78 (d, J = 7.3Hz, 1H), 4.65 (d, J = 7.2Hz, 1H), 4.49 (dd, J = 6.8, 4.7Hz, 2H), 1.95 (d, J = 7.0Hz, 3H), 1.64 (s, 3H).

[0641] Compound DA-2075: 53.4 mg, syrupy solid, ESI [M+H] + =336.1.

[0642] 1 H NMR(400MHz,d6-DMSO)δ8.48(s,1H),7.44–7.34(m,1H),7.18(dd,J=13.3,6.6Hz,1H),6.83(t,J=7.2Hz,1H),6.66(q,J=7.0Hz ,1H),6.23(dd,J=17.4,11.0Hz,1H),5.23(t,J=14.3Hz,2H),4.86(d,J=7.4Hz,1H),4.77–4.62(m,3H),1.93(d,J=7.0Hz,3H).

[0643] Compound DA-2076: 101.4 mg, syrupy solid, ESI [M+H] + =312.1.

[0644] 1 H NMR(400MHz,d6-DMSO)δ8.39(s,1H),7.42(dd,J=17.8,8.8Hz,1H),7.20(dd,J=13.3,7.7Hz,1H),6.85(t,J=7.1Hz ,1H),6.75(q,J=7.0Hz,1H),4.45–4.32(m,2H),3.59(dd,J=10.4,5.8Hz,2H),3.26(s,3H),1.96(d,J=7.0Hz,3H).

[0645] Compound DA-2077: 111.7 mg, white solid, ESI [M+H] + =338.1.

[0646] 1H NMR(400MHz,d6-DMSO)δ8.42(s,1H),7.47–7.38(m,1H),7.21(dt,J=12.0,4.1Hz,1H),6.82(t,J=7.1Hz,1H),6.72 (q,J=7.0Hz,1H),4.81(p,J=7.3Hz,1H),3.61(p,J=6.8Hz,1H),3.15(s,3H),2.81–2.71(m,2H),2.02–1.92(m,5H).

[0647] Compound M-2229: 161.6 mg, syrupy solid, ESI [M+H] + =324.1.

[0648] 1 H NMR (400MHz, d6-DMSO) δ8.42–8.41(m,1H),7.46–7.39(m,1H),7.31–7.16(m,1H),6.90(t,J=7.1Hz,1H),6.77(q,J=7.0Hz, 1H),4.48–4.31(m,2H),3.04–2.99(m,1H),2.76–2.64(m,1H),2.52–2.49(m,1H),1.97(d,J=7.0Hz,3H),1.95–1.78(m,2H).

[0649] LiOH·H₂O (2.32 g, 55.3 mmol) was added to a MeOH / THF / H₂O (70 mL, v / v / v = 1 / 1 / 1) solution of compound DA-2048-4 (7.78 g, 27.7 mmol), and stirred at room temperature for 2 hours. After the reaction was complete as monitored by TLC, the reaction solution was concentrated under reduced pressure. H₂O (150 mL) was added to the concentrate, and the solution was washed with EtOAc (3 × 50 mL). The aqueous phase was adjusted to pH 4–5 with 1 N hydrochloric acid, extracted with EtOAc (3 × 100 mL), and the combined organic phases were dried over anhydrous Na₂SO₄. The mixture was filtered and concentrated under reduced pressure to give a white solid compound DA-2050-1 (3.89 g, yield 55.5%). ESI [M+H] + =254.1.

[0650] DA-2050-1 (200 mg, 0.79 mmol), DCC (244 mg, 1.18 mmol), and DMAP (144.6 mg, 1.18 mmol) were dissolved in dichloromethane (4 mL) and stirred at room temperature for 15 minutes. 3-(propa-1,2-dien-1-yl)oxetan-3-ol (167.55 mg, 1.49 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 12 hours. After the reaction was complete as monitored by TLC, methyl tert-butyl ether (4 mL) was added to the reaction mixture, and after stirring for 5 minutes, the mixture was filtered. The filter cake was washed with methyl tert-butyl ether. The filtrate was concentrated under reduced pressure to obtain a crude product, which was then purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 to 1 / 1). TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1) was used for monitoring, and the fraction with Rf = 0.4–0.6 was collected to give a syrupy solid compound DA-2050 (80.2 mg, yield 29.2%). (ESI [M+H]) + =348.1.

[0651] 1 H NMR(400MHz,d6-DMSO)δ9.08(s,1H),7.58–7.36(m,1H),7.35–7.14(m,2H),6.33(q,J=7.0Hz,1H),5.88(t ,J=6.7Hz,1H),5.18(d,J=6.7Hz,2H),4.88(d,J=7.6Hz,2H),4.72(d,J=7.7Hz,2H),1.98(d,J=7.1Hz,3H).

[0652] 4. The preparation methods for target compounds DA-2070, DA-2071, DA-2072, and DA-2073 are similar to those for DA-2050, using DA-2050-1 as the raw material.

[0653] Compound DA-2070: 73.5 mg, white solid, ESI [M+H] + =324.1.

[0654] 1 H NMR(400MHz,d6-DMSO)δ9.05(s,1H),7.51–7.41(m,1H),7.32–7.20(m,2H),6.31(q,J=7.1 Hz,1H),4.77(d,J=7.3Hz,2H),4.53(d,J=7.7Hz,2H),1.95(d,J=7.1Hz,3H),1.74(s,3H).

[0655] Compound DA-2071: 74.7 mg, white solid, ESI [M+H] + =336.1.

[0656] 1 H NMR(400MHz,d6-DMSO)δ9.08(s,1H),7.51–7.40(m,1H),7.32–7.19(m,2H),6.42–6.26(m,2H),5. 37(dd,J=24.5,14.2Hz,2H), 4.86(d,J=7.7Hz,2H), 4.72(d,J=7.8Hz,2H), 1.96(d,J=7.1Hz,3H).

[0657] Compound DA-2072: 81.4 mg, white solid, ESI [M+H] + =312.1.

[0658] 1 H NMR(400MHz,d6-DMSO)δ9.02(s,1H),7.53–7.39(m,1H),7.36–7.18(m,2H),6.32(q,J=7.1H z,1H),4.42(dd,J=5.3,3.9Hz,2H),3.69–3.60(m,2H),3.31(s,3H),1.97(d,J=7.1Hz,3H).

[0659] Compound DA-2073: 94.6 mg, syrupy solid, ESI [M+H] + =338.1.

[0660] 1 H NMR (400MHz, d6-DMSO) δ9.00 (s, 1H), 7.50–7.40 (m, 1H), 7.31–7.17 (m, 2H), 6.29 (q, J = 7.1Hz, 1H), 4. 82(t,J=7.2Hz,1H),3.70–3.58(m,1H),3.16(d,J=4.4Hz,3H),2.85–2.74(m,2H),2.05–1.93(m,5H).

[0661] The preparation method of compound DA-2118A-1 is similar to that of DA-2048-4.

[0662] Silver fluoride (4.98 g, 39.3 mmol) and N,N,N',N'-tetramethylethylenediamine (456.5 mg, 3.93 mmol) were added to a toluene (50 mL) solution of DA-2118A-1 (3.19 g, 7.83 mmol), and the mixture was stirred at 100 °C for 12 hours. After the reaction was complete as monitored by TLC, saturated brine (100 mL) was added to the reaction system, and the mixture was extracted with EtOAc (3 × 50 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 / 1) to give a colorless oily compound DA-2118 (723.7 mg, yield 30.9%). + =300.1.

[0663] 1 H NMR(400MHz,d6-DMSO)δ7.49(ddd,J=10.2,7.3,3.6Hz,1H),7.33–7.26(m,2H),6.1 7(q,J=7.0Hz,1H),4.36–4.24(m,2H),1.96(d,J=7.0Hz,3H),1.28(t,J=7.1Hz,3H).

[0664] Example 10: Preparation of compounds DA-2056, DA2086, DA-2088, DA-2089, DA-2058, DA-2092 and DA-2093 of the present invention

[0665] The preparation of compounds DA-2056-3 and DA-2056-4 is similar to that of compounds DA-2048-3 and DA-2048-4.

[0666] The preparation of target compounds DA-2056, DA-2086, DA-2088, DA-2089, DA-2058, DA-2092 and DA-2093 is similar to that of target compound DA-2048, and they are prepared from DA-2056-3 or DA-2056-4, respectively.

[0667] Compound DA-2056: 31.9 mg, syrupy solid, ESI [M+H] + =360.1.

[0668] 1H NMR(400MHz,d6-DMSO)δ8.49(s,1H),7.35(d,J=7.5Hz,1H),7.25(t,J=7.7Hz,1H),6.72(dt,J=13.8,6.9Hz,2H),5.74(t,J=6.7Hz,1H ),5.08(dd,J=12.1,6.6Hz,1H),4.97–4.87(m,2H),4.72(d,J=7.3Hz,1H),4.67(t,J=7.9Hz,2H),2.38(s,3H),1.93(d,J=6.9Hz,3H).

[0669] Compound DA-2058: 13.8 mg, syrupy solid, ESI [M+H] + =360.1.

[0670] 1 H NMR(400MHz,d6-DMSO)δ9.05(s,1H),7.38(d,J=7.1Hz,1H),7.30(t,J=7.6Hz,1H),7.16(d,J=7.2Hz,1H),6.38(q,J=6.9Hz,1H) ,5.87(t,J=6.6Hz,1H),5.18(d,J=6.7Hz,2H),4.87(d,J=7.7Hz,2H),4.71(d,J=7.8Hz,2H),2.38(s,3H),1.92(t,J=5.5Hz,3H).

[0671] Compound DA-2086: 6.7 mg, syrupy solid, ESI [M+H] + =336.1.

[0672] 1 H NMR(400MHz,d6-DMSO)δ8.44(s,1H),7.34(d,J=7.5Hz,1H),7.23(t,J=7.7Hz,1H),6.70(dt,J=14.0,6.8Hz,2H), 4.76(d,J=7.0Hz,1H),4.57(d,J=7.1Hz,1H),4.51–4.45(m,2H),2.37(s,3H),1.93(d,J=6.9Hz,3H),1.59(s,3H).

[0673] Compound DA-2088: 53.0 mg, syrupy solid, ESI [M+H] + =324.1.

[0674] 1H NMR(400MHz,d6-DMSO)δ8.39(s,1H),7.34(d,J=7.1Hz,1H),7.23(t,J=7.7Hz,1H),6.82–6.72( m,2H),4.43–4.31(m,2H),3.64–3.52(m,2H),3.25(s,3H),2.38(s,3H),1.93(d,J=7.0Hz,3H).

[0675] Compound DA-2089: 46.5 mg, syrupy solid, ESI [M+H] + =350.1.

[0676] 1 H NMR (400MHz, d6-DMSO) δ8.42(s,1H),7.32(d,J=7.3Hz,1H),7.21(t,J=7.7Hz,1H),6.68(dt,J=18.6,7.0H z,2H),4.78(t,J=7.3Hz,1H),3.62–3.54(m,1H),3.13(s,3H),2.71(dt,J=11.2,6.7Hz,2H),2.37(s,3H).

[0677] Compound DA-2092: 104.4 mg, syrupy solid, ESI [M+H] + =324.1.

[0678] 1 H NMR(400MHz,d6-DMSO)δ8.99(s,1H),7.38(d,J=6.8Hz,1H),7.30(t,J=7.7Hz,1H),7.15(d,J=6.8Hz,1H),6. 38(q,J=7.0Hz,1H),4.44–4.39(m,2H),3.66–3.62(m,2H),3.30(s,3H),2.38(s,3H),1.93(d,J=7.1Hz,3H).

[0679] Compound DA-2093: 50.3 mg, syrupy solid, ESI [M+H] + =350.1.

[0680] 1H NMR(400MHz,d6-DMSO)δ8.99(s,1H),7.38(d,J=6.8Hz,1H),7.29(t,J=7.7Hz,1H),7.14(d,J=6.9Hz,1H),6.37(q,J=7.1Hz,1H),4.8 9–4.79(m,1H),3.70–3.61(m,1H),3.17(s,3H),2.85–2.76(m,2H),2.38(s,3H),2.01(dt,J=9.8,7.4Hz,2H),1.93(d,J=7.0Hz,3H).

[0681] Example 11: Preparation of compounds DA-2064, DA-2078 to DA-2081, DA-2066, DA-2082 to DA-2085 of the present invention

[0682] The preparation of compounds DA-2064-3 and DA-2064-4 is similar to that of compounds DA-2048-3 and DA-2048-4.

[0683] The preparation of target compounds DA-2064, DA-2078 to DA-2081 is similar to that of target compound DA-2048, and they are prepared using DA-2064-3 as the raw material.

[0684] Compound DA-2064: 176.1 mg, syrupy solid, ESI [M+H] + =380.1.

[0685] 1 H NMR (400MHz, d6-DMSO) δ8.51(s,1H),7.66(dd,J=8.0,1.2Hz,1H),7.38(t,J=8.0Hz,1H),6.88(dd,J=7.9,1.1Hz,1H),6.70(q,J=6.9Hz,1H),5.7 7(t,J=6.6Hz,1H),5.09(dd,J=12.1,6.7Hz,1H),5.00–4.88(m,2H),4.74(d,J=7.3Hz,1H),4.67(dd,J=10.3,7.5Hz,2H),1.94(d,J=6.9Hz,3H).

[0686] Compound DA-2078: 26.5 mg, syrupy solid, ESI [M+H] + =356.1.

[0687] 1H NMR (400MHz, d6-DMSO) δ8.46(s,1H),7.64(dd,J=8.0,1.3Hz,1H),7.37(t,J=8.0Hz,1H),6.87(d,J=7.9Hz,1H),6.68( d,J=6.9Hz,1H),4.78(d,J=7.4Hz,1H),4.58(d,J=7.3Hz,1H),4.52–4.45(m,2H),1.93(d,J=6.9Hz,3H),1.61(s,3H).

[0688] Compound DA-2079: 56.5 mg, white solid, ESI [M+H] + =368.1.

[0689] 1 H NMR (400MHz, d6-DMSO) δ8.54(s,1H),7.65(dd,J=8.0,1.4Hz,1H),7.38(t,J=8.0Hz,1H),6.86(dd,J=7.9,1.3Hz,1H),6.69(q,J=6.9H z,1H),6.23(dd,J=17.4,11.0Hz,1H),5.22(dd,J=26.8,14.2Hz,2H),4.89(d,J=7.3Hz,1H),4.74–4.65(m,3H),1.95(d,J=6.9Hz,3H).

[0690] Compound DA-2080: 144.0 mg, syrupy solid, ESI [M+H] + =344.1.

[0691] 1 H NMR (400MHz, d6-DMSO) δ8.41(s,1H),7.64(dd,J=8.0,1.3Hz,1H),7.36(t,J=8.0Hz,1H),6.87(dd,J=7.9,1.2Hz,1H),6.75(q,J=6.9Hz,1H),4.43– 4.32(m,2H),3.66–3.52(m,2H),3.24(s,3H),1.94(d,J=7.0Hz,3H).

[0692] Compound DA-2081: 165.5 mg, white solid, ESI [M+H] + =370.1.

[0693] 1H NMR (400MHz, d6-DMSO) δ8.42(s,1H),7.61(dd,J=8.0,1.3Hz,1H),7.34(t,J=8.0Hz,1H),6.79(dd,J=7.9,1.3Hz,1H),6.68( q,J=6.9Hz,1H),4.76(p,J=7.2Hz,1H),3.57(p,J=6.8Hz,1H),3.12(s,3H),2.70(tt,J=11.8,5.9Hz,2H),1.97–1.85(m,5H).

[0694] The preparation of target compounds DA-2066, DA-2082 to DA-2085 is similar to that of target compound DA-2050, and they are prepared using DA-2064-4 as the raw material.

[0695] Compound DA-2066: 58.7 mg, syrupy solid, ESI [M+H] + =380.1.

[0696] 1 H NMR(400MHz,d6-DMSO)δ9.08(s,1H),7.69(dd,J=8.0,1.3Hz,1H),7.44(t,J=8.0Hz,1H),7.32(dd,J=7.9,1.1Hz,1H),6.39(q,J =7.0Hz,1H),5.88(t,J=6.7Hz,1H),5.19(d,J=6.7Hz,2H),4.88(d,J=7.6Hz,2H),4.72(d,J=7.7Hz,2H),1.96(d,J=7.0Hz,3H).

[0697] Compound DA-2082: 83.2 mg, white solid, ESI [M+H] + =356.1.

[0698] 1 H NMR(400MHz,d6-DMSO)δ9.05(s,1H),7.69(dd,J=8.0,1.4Hz,1H),7.44(t,J=8.0Hz,1H),7.32(dd,J=7.9,1.2H z,1H),6.39(q,J=7.0Hz,1H),4.79(d,J=7.3Hz,2H),4.55(d,J=7.6Hz,2H),1.95(d,J=7.0Hz,3H),1.76(s,3H).

[0699] Compound DA-2083: 103.0 mg, syrupy solid, ESI [M+H]+ =368.1.

[0700] 1 H NMR (400MHz, d6-DMSO) δ9.11(s,1H),7.70(dd,J=8.0,1.3Hz,1H),7.45(t,J=8.0Hz,1H),7.34(dd,J=7.9,1.2Hz,1H),6.39( dt,J=17.4,9.2Hz,2H),5.40(dd,J=24.8,14.2Hz,2H),4.88(d,J=7.7Hz,2H),4.75(d,J=7.8Hz,2H),1.97(d,J=7.0Hz,3H).

[0701] Compound DA-2084: 137.9 mg, syrupy solid, ESI [M+H] + =344.1.

[0702] 1 H NMR(400MHz,d6-DMSO)δ9.06(s,1H),7.70(dd,J=8.0,1.2Hz,1H),7.45(t,J=8.0Hz,1H),7.31(dd,J=7.9,1 .0Hz,1H),6.40(q,J=7.0Hz,1H),4.46–4.40(m,2H),3.69–3.62(m,2H),3.32(s,3H),1.97(d,J=7.0Hz,3H).

[0703] Compound DA-2085: 132.6 mg, syrupy solid, ESI [M+H] + =370.1.

[0704] 1 H NMR(400MHz,d6-DMSO)δ9.02(s,1H),7.68(dd,J=8.0,1.4Hz,1H),7.43(t,J=8.0Hz,1H),7.29(dd,J=7.9,1.3Hz,1H),6.37(q,J=7 .0Hz,1H),4.84(p,J=7.3Hz,1H),3.66(p,J=6.8Hz,1H),3.17(s,3H),2.85–2.76(m,2H),2.06–1.97(m,2H),1.95(d,J=7.0Hz,3H).

[0705] Example 12: Preparation of compounds DA-2052, DA-2095 to DA-2097, DA-2160H(cis), DA-2162(trans) and M-2230 of the present invention.

[0706] The preparation of target compounds DA-2052, DA-2095~DA-2097, DA-2160H(cis), DA-2162(trans) and M-2230 is similar to that of target compound DA-2048.

[0707] Compound DA-2052: 54.4 mg, syrupy solid, ESI [M+H] + =344.1.

[0708] 1 H NMR (400MHz, d6-DMSO) δ8.44(s,1H),7.25(t,J=7.3Hz,1H),7.07(t,J=7.6Hz,1H ),6.82(t,J=7.3Hz,1H),6.66(q,J=7.0Hz,1H),5.77(t,J=6.7Hz,1H),5.08(dd,J =12.1,6.7Hz,1H),4.95(dd,J=12.1,6.6Hz,1H),4.87(d,J=7.5Hz,1H),4.76(d,J =7.5Hz, 1H), 4.66 (t, J = 6.9Hz, 2H), 2.23 (d, J = 1.8Hz, 3H), 1.92 (d, J = 7.0Hz, 3H).

[0709] Compound DA-2095: 52.6 mg, syrupy solid, ESI [M+H] + =332.1.

[0710] 1 H NMR(400MHz,d6-DMSO)δ8.50(s,1H),7.26(t,J=7.2Hz,1H),7.08(t,J=7.7Hz,1H) ,6.83(t,J=7.1Hz,1H),6.67(q,J=7.0Hz,1H),6.25(dd,J=17.4,11.0Hz,1H),5.2 8(d,J=11.0Hz,1H),5.23(d,J=17.4Hz,1H),4.88(d,J=7.5Hz,1H),4.76(d,J=7.5 Hz, 1H), 4.70 (dd, J = 7.1, 4.8Hz, 2H), 2.24 (d, J = 1.7Hz, 3H), 1.94 (d, J = 7.0Hz, 3H).

[0711] Compound DA-2096: 70.6 mg, syrupy solid, ESI [M+H] + =308.1.

[0712] 1 H NMR (400MHz, d6-DMSO) δ8.37(s,1H),7.26(t,J=7.2Hz,1H),7.08(t,J=7.7Hz,1H),6.86(t,J=7.4Hz,1H),6.74(q ,J=7.0Hz,1H),4.47–4.30(m,2H),3.67–3.53(m,2H),3.27(s,3H),2.25(d,J=1.9Hz,3H),1.93(d,J=7.0Hz,3H).

[0713] Compound DA-2097: 52.3 mg, syrupy solid, ESI [M+H] + =334.1.

[0714] 1 H NMR (400MHz, d6-DMSO) δ8.40(s,1H),7.24(t,J=7.3Hz,1H),7.05(t,J=7.6Hz,1H),6.74(t,J=7.1Hz,1H),6.68(q,J=7.0Hz,1H),4.79(p,J=7.3Hz ,1H),3.59(p,J=6.9Hz,1H),3.13(s,3H),2.75-2.67(m,2H),2.24(d,J= 1.5Hz,3H),2.02-1.94(m,1H),1.91(d,J=7.0Hz,3H),1.87-1.82(m,1H).

[0715] Compound DA-2160H(cis): 57.2 mg, syrupy solid, ESI [M+H] + =334.1.

[0716] 1 H NMR(400MHz,d6-DMSO)δ8.40(s,1H),7.25(t,J=7.5Hz,1H),7.06(td,J=7.7,3.0Hz,1H),6.78(dd,1H),6.70(q,1H),4.99–4 .93(m,1H),3.89–3.80(m,1H),3.15(s,3H),2.24(s,3H),2.20–2.04(m,2H),1.92(dd,J=7.0,2.1Hz,3H),1.60–1.38(m,2H).

[0717] Compound DA-2162(trans): 50.1 mg, syrupy solid, ESI [M+H] + =348.1.

[0718] 1 H NMR(400MHz,d6-DMSO)δ8.39(s,1H),7.26(t,J=7.4Hz,1H),7.07(t,J=7.6Hz,1H),6.76(t,J=7.5Hz,1H),6.73–6.65(m,1H),5.15–5.10(m,1H),3 .75–3.66(m,1H),3.23(d,J=5.0Hz,3H),2.25(s,3H),2.00(dd,J=14.0, 6.8Hz,1H),1.94(t,J=7.1Hz,3H),1.91–1.79(m,1H),1.73–1.49(m,4H).

[0719] Compound M-2230: 152.7 mg, syrupy solid, ESI [M+H] + =320.1.

[0720] 1 H NMR (400MHz, d6-DMSO) δ8.40–8.38(m,1H),7.26(t,J=7.2Hz,1H),7.08(t,J=7.6Hz,1H),6.86(t,J=7.0Hz,1H),6.82–6.71(m,1H),4.5 1–4.24(m,2H),3.08–2.95(m,1H),2.81–2.65(m,1H),2.51–2.47(m,1H),2.26–2.24(m,3H),1.94(d,J=7.0Hz,3H),1.92–1.78(m,2H).

[0721] Example 13: Preparation of compounds DA-2164, DA-2165, DA-2167H(cis) and M-2231 of the present invention

[0722] The preparation of target compounds DA-2164, DA-2165, DA-2167H(cis) and M-2231 is similar to that of target compound DA-2048.

[0723] Compound DA-2164: 23.3 mg, syrupy solid, ESI [M+H] + =312.1.

[0724] 1H NMR(400MHz,d6-DMSO)δ8.38(s,1H),7.36–7.28(m,1H),7.21(td,J=8.7,6.5Hz,1H),7.12(td,J=8.4,2.0Hz,1 H),6.72(q,J=7.0Hz,1H),4.41(td,J=4.1,2.2Hz,2H),3.64–3.60(m,2H),3.29(s,3H),1.95(d,J=7.0Hz,3H).

[0725] Compound DA-2165: 30.2 mg, syrupy solid, ESI [M+H] + =338.1.

[0726] 1 H NMR(400MHz,d6-DMSO)δ8.38(s,1H),7.29(ddd,J=11.5,9.3,2.5Hz,1H),7.15(td,J=8.6,6.5Hz,1H),7.08(td,J=8.7,2.4Hz,1H),6.66(q,J=7.0Hz,1 H),4.80(p,J=7.2Hz,1H),3.61(p,J=6.8Hz,1H),3.14(s,3H),2.75(dt,J=1 1.0, 6.8Hz, 2H), 1.98 (ddd, J=13.0, 8.2, 4.0Hz, 2H), 1.91 (d, J=7.0Hz, 3H).

[0727] Compound DA-2167H(cis): 22.6 mg, syrupy solid, ESI [M+H] + =338.1.

[0728] 1 H NMR(400MHz,d6-DMSO)δ8.40(d,J=1.2Hz,1H),7.31(tt,J=11.1,2.2Hz,1H),7.21–7.13(m,1H),7.10(td,J=8.9,2.4Hz,1H),6.68(q,J =7.0Hz,1H),5.03–4.90(m,1H),3.96–3.84(m,1H),3.18(d,J=6.4Hz,3H),2.21–2.04(m,2H),1.93(d,J=7.0Hz,3H),1.61–1.39(m,2H).

[0729] Compound M-2231: 126.7 mg, syrupy solid, ESI [M+H] + =324.1.

[0730] 1 H NMR(400MHz,d6-DMSO)δ8.40–8.38(m,1H),7.35–7.26(m,1H),7.25–7.19(m,1H),7.13–7.08(m,1H),6.72(q,J=7.0Hz,1H ),4.42–4.37(m,2H),3.08–2.96(m,1H),2.77–2.65(m,1H),2.53–2.49(m,1H),1.94(d,J=7.0Hz,3H),1.93–1.81(m,2H).

[0731] Example 14: Preparation of compounds DA-2170 to DA-2173, DA-2174, DA-2175(trans), M-2232, M-2015 and M-2016 of the present invention

[0732] The preparation of target compounds DA-2170 to DA-2173, DA-2174, DA-2175(trans) and M-2232 is similar to that of target compound DA-2048.

[0733] Compound DA-2170: 38.7 mg, syrupy solid, ESI [M+H] + =348.1.

[0734] 1 H NMR (400MHz, d6-DMSO) δ8.43(s,1H),7.44(dt,J=14.9,4.2Hz,1H),7.11(t,J=8.6Hz,2H),6.57(q,J=7.1Hz,1H),5.71( t,J=6.6Hz,1H),5.07(dd,J=12.1,6.7Hz,1H),4.97–4.82(m,2H),4.66(dt,J=12.6,7.4Hz,3H),2.01(d,J=7.0Hz,3H).

[0735] Compound DA-2171: 31.6 mg, syrupy solid, ESI [M+H] + =312.1.

[0736] 1H NMR(400MHz,d6-DMSO)δ8.35(s,1H),7.49–7.41(m,1H),7.15–7.08(m,2H),6.63(q,J=7 .1Hz,1H),4.36(t,J=4.6Hz,2H),3.61–3.53(m,2H),3.24(s,3H),2.02(d,J=7.1Hz,3H).

[0737] Compound DA-2172: 41.4 mg, white solid, ESI [M+H] + =338.1.

[0738] 1 H NMR (400MHz, d6-DMSO) δ8.37(s,1H),7.44(m,1H),7.09(dd,J=14.7,6.1Hz,2H),6.59(q,J=7.0Hz,1H),4. 75(p,J=7.3Hz,1H),3.59(p,J=6.9Hz,1H),3.14(s,3H),2.72(m,2H),2.01(d,J=7.1Hz,3H),1.92(m,2H).

[0739] Compound DA-2173: 16.1 mg, white solid, ESI [M+H] + =336.1.

[0740] 1 H NMR (400MHz, d6-DMSO) δ8.49 (s, 1H), 7.45 (m, 1H), 7.11 (m, 2H), 6.58 (q, J = 7.0Hz, 1H), 6.20 (dd, J = 17.4, 11. 0Hz, 1H), 5.20 (dd, J = 25.9, 14.2Hz, 2H), 4.86 (d, J = 7.6Hz, 1H), 4.68 (d, J = 2.7Hz, 3H), 2.04 (d, J = 7.1Hz, 3H).

[0741] Compound DA-2174: 71.5 mg, syrupy solid, ESI [M+H] + =338.1.

[0742] 1H NMR(400MHz,d6-DMSO)δ8.40–8.38(m,1H),7.49–7.42(m,1H),7.14–7.09(m,2H),6.64–6.59(m,1H),5.05–4.83(m ,1H),3.99–3.80(m,1H),3.19(s,1.5H),3.11(s,1.5H),2.19–2.07(m,2H),2.04–2.02(m,3H),1.57–1.36(m,2H).

[0743] Compound DA-2175(trans): 7.6 mg, syrupy solid, ESI [M+H] + =352.1.

[0744] 1 H NMR(400MHz,d6-DMSO)δ8.37–8.35(m,1H),7.53–7.38(m,1H),7.15–7.10(m,2H),6.71–6.56(m,1H),5.16–5.04(m, 1H),3.79–3.62(m,1H),3.25(s,1.5H),3.21(s,1.5H),2.03(d,J=7.1Hz,3H),1.99–1.83(m,2H),1.73–1.49(m,4H).

[0745] Compound M-2232: 116.4 mg, syrupy solid, ESI [M+H] + =324.1.

[0746] 1 H NMR(400MHz,d6-DMSO)δ8.38–8.36(m,1H),7.52–7.40(m,1H),7.18–7.03(m,2H),6.64(q,J=7.0Hz,1H),4.36(t, J=6.3Hz,2H),3.01–2.99(m,1H),2.75–2.63(m,1H),2.50–2.46(m,1H),2.03(d,J=7.1Hz,3H),1.97–1.70(m,2H).

[0747] At 0°C, DA-2170-1 (9.808 g, 62.0 mmol) and PPh3 (32.55 g, 124.1 mmol) were dissolved in THF (98 mL). Then, a solution of DEAD (21.62 g, 124.1 mmol) in THF (10 mL) was added dropwise to the reaction system at a rate of 10 mmol / min. Next, DPPA (20.5 g, 74.5 mmol) was added dropwise to the system at a rate of 6 mmol / min. After the addition was complete, the temperature was slowly raised to room temperature and stirred overnight. After the reaction was monitored by TLC until complete, saturated brine (150 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (3 × 100 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 DA-2170-2. The crude product was used directly in the next reaction without further purification. ESI[M+H] + =184.1.

[0748] At room temperature, triethylamine (6.62 g, 65.4 mmol) and ethyl 3-oxo-4-(triphenylphosphine-1,2-ethyl)butyrate (25.6 g, 65.6 mmol) were added to a toluene (100 mL) solution of the crude product DA-2170-2, and the mixture was stirred at 120 °C for 8 hours. After the reaction was completed as monitored by TLC, saturated brine (100 mL) was added to the reaction system, and the mixture was extracted with EtOAc (3 × 100 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 / 20 to 2 / 1) to give a syrupy solid compound M-2015-1 (3.85 g, two-step yield 21.0%). ESI[M+H] + =296.1.

[0749] NaOH (1.41 g, 35.3 mmol) was added to a MeOH / THF / H₂O (40 mL, v / v / v = 1 / 1 / 1) solution of compound M-2015-1 (3.85 g, 13.0 mmol) and stirred at room temperature for 2 hours. After the reaction was completed as monitored by TLC, the reaction solution was concentrated under reduced pressure. H₂O (100 mL) was added to the concentrate, and the solution was washed with EtOAc (3 × 50 mL). The aqueous phase was adjusted to pH 4–5 with 1 N hydrochloric acid, and then extracted with EtOAc (3 × 15 mL). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give a white solid compound M-2015-2 (2.37 g, yield 68.0%). ESI [M+H] + =268.1.

[0750] M-2015-2 (171.3 mg, 0.64 mmol), DCC (198.3 mg, 0.96 mmol), and DMAP (234.8 mg, 1.92 mmol) were dissolved in dichloromethane (4 mL) and stirred at room temperature for 15 minutes. Ethylene glycol methyl ether (73.1 mg, 0.96 mmol) was added to the reaction system, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete as monitored by TLC, methyl tert-butyl ether (4 mL) was added to the reaction system, and the mixture was stirred for 5 minutes and then filtered. The filter cake was washed with methyl tert-butyl ether, 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). TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1) was used to monitor the reaction, and the fraction with Rf = 0.2 to 0.4 was collected to give a colorless oily compound M-2015 (36.8 mg, yield 17.6%). ESI[M+H] + =326.1.

[0751] 1 H NMR(400MHz,d6-DMSO)δ7.66(s,1H),7.47(tt,J=8.4,6.5Hz,1H),7.21–7.06(m,2H),6.10(q,J=7.0H z,1H),4.13–4.03(m,2H),3.96–3.79(m,2H),3.55–3.43(m,2H),3.26(s,3H),2.03(d,J=7.0Hz,3H).

[0752] At 0°C, a solution of DCC (131.6 mg, 0.64 mmol) and DMAP (5.13 mg, 0.042 mmol) in dichloromethane (2 mL) was added dropwise to a solution of M-2015-2 (163.7 mg, 0.61 mmol) and glycidyl (227 mg, 3.07 mmol) in dichloromethane (2 mL). After the addition was complete, the mixture was stirred at 0°C for 2 hours. After the reaction was confirmed to be complete by TLC, 4 mL of methyl tert-butyl ether was added to the reaction system. The mixture was stirred for 5 minutes and then filtered. The filter cake was washed with methyl tert-butyl ether, 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). TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1) was used to monitor the reaction, and the fraction with Rf = 0.2–0.4 was collected to give a syrupy solid compound M-2016 (49.0 mg, yield 24.7%). ESI[M+H] + =324.1.

[0753] 1H NMR(400MHz,d6-DMSO)δ7.67(s,1H),7.54–7.42(m,1H),7.22–7.07(m,2H),6.10(q,J=7.0Hz,1H),4.33–4.28(m,1H), 4.02–3.85(m,2H),3.78–3.73(m,1H),3.18–3.14(m,1H),2.82–2.78(m,1H),2.64–2.59(m,1H),2.03(d,J=7.0Hz,3H).

[0754] Example 15: Preparation of compounds DA-2177 to DA-2180, DA-2181, DA-2182(trans), M-2001, M-2002, M-2006, M-2009 to M-2014 and M-2018 of the present invention.

[0755] The preparation of target compounds DA-2177 to DA-2180, DA-2181, DA-2182(trans), M-2001, M-2002, M-2014 and M-2018 is similar to that of target compound DA-2048.

[0756] Compound DA-2177: 58.7 mg, syrupy solid, ESI [M+H] + =366.1.

[0757] 1 H NMR(400MHz,d6-DMSO)δ8.45(s,1H),7.25(t,J=9.1Hz,2H),6.54(q,J=7.0Hz,1H),5.76(t,J=6.6Hz,1H),5.11(dd,J=12.1,6.7Hz,1 H), 4.98 (dd, J = 12.1, 6.6Hz, 1H), 4.88 (d, J = 7.4Hz, 1H), 4.75 (d, J = 7.4Hz, 1H), 4.67 (dd, J = 11.6, 7.4Hz, 2H), 2.00 (d, J = 7.0Hz, 3H).

[0758] Compound DA-2178: 56.7 mg, syrupy solid, ESI [M+H] + =330.1.

[0759] 1H NMR(400MHz,d6-DMSO)δ8.34(s,1H),7.23(t,J=9.1Hz,2H),6.57(q,J=7.1Hz ,1H),4.36(t,J=4.5Hz,2H),3.57(m,2H),3.24(s,3H),1.99(d,J=7.1Hz,3H).

[0760] Compound DA-2179: 59.8 mg, white solid, ESI [M+H] + =356.1.

[0761] 1 H NMR (400MHz, d6-DMSO) δ8.38(s,1H),7.23(t,J=9.1Hz,2H),6.55(q,J=7.1Hz,1H),4.78(p,J=7.2Hz,1H),3.60(p,J=6.8Hz, 1H), 3.15 (d, J = 3.5Hz, 3H), 2.74 (ddt, J = 15.7, 13.3, 6.6Hz, 2H), 1.99 (d, J = 7.1Hz, 3H), 1.93 (ddd, J = 11.8, 7.5, 5.2Hz, 2H).

[0762] Compound DA-2180: 32.8 mg, syrupy solid, ESI [M+H] + =354.1.

[0763] 1 H NMR (400MHz, d6-DMSO) δ8.47(s,1H),7.22(t,J=9.2Hz,2H),6.52(q,J=7.0Hz,1H),6.23(dd,J=17.4,1 1.0Hz, 1H), 5.22 (dd, J=21.5, 14.2Hz, 2H), 4.86 (d, J=7.4Hz, 1H), 4.69 (m, 3H), 1.99 (d, J=7.0Hz, 3H).

[0764] Compound DA-2181: 36.6 mg, syrupy solid, ESI [M+H] + =356.1.

[0765] 1H NMR(400MHz,d6-DMSO)δ8.40–8.38(m,1H),7.27–7.22(m,2H),6.61–6.56(m,1H),5.08–4.83(m,1H),4.02 –3.79(m,1H),3.21(s,1.5H),3.14(s,1.5H),2.20–2.06(m,2H),2.01(d,J=6.9Hz,3H),1.62–1.38(m,2H).

[0766] Compound DA-2182(trans): 64.5 mg, white solid, ESI [M+H] + =370.1.

[0767] 1 H NMR(400MHz,d6-DMSO)δ8.37–8.35(m,1H),7.32–7.16(m,2H),6.66–6.52(m,1H),5.14–5.10(m ,1H),3.85–3.66(m,1H),3.27(s,1.5H),3.23(s,1.5H),2.09–1.86(m,5H),1.75–1.54(m,4H).

[0768] Compound M-2001: 40.7 mg, syrupy solid, ESI [M+H] + =344.1.

[0769] 1 H NMR(400MHz,d6-DMSO)δ8.32(s,1H),7.24(td,J=9.2,1.1Hz,2H),6.59(q,J=7.0Hz,1H),5.22–5.16 (m,1H),3.50–3.38(m,2H),3.26(s,1.5H),3.22(s,1.5H),2.01(d,J=7.0Hz,3H),1.23–1.18(m,3H).

[0770] Compound M-2002: 37.2 mg, syrupy solid, ESI [M+H] + =344.1.

[0771] 1H NMR(400MHz,d6-DMSO)δ8.37(s,1H),7.31–7.14(m,2H),6.60(q,J=7.0Hz,1H),4.36–4.25(m,1H),4.22– 4.16(m,1H),3.68–3.53(m,1H),3.26(s,1.5H),3.24(s,1.5H),2.01(d,J=7.1Hz,3H),1.13–1.09(m,3H).

[0772] Compound M-2014: 53.4 mg, white solid, ESI [M+H] + =328.1.

[0773] 1 H NMR(400MHz,d6-DMSO)δ8.42–8.41(m,1H),7.34–7.11(m,2H),6.59(q,J=7.0Hz,1H),4.66–4.61(m,1H ),4.11–4.04(m,1H),3.32–3.22(m,1H),2.89–2.79(m,1H),2.73–2.69(m,1H),2.01(d,J=7.0Hz,3H).

[0774] Compound M-2018: 31.6 mg, syrupy solid, ESI [M+H] + =342.1.

[0775] 1 H NMR (400MHz, d6-DMSO) δ8.38(d,J=1.0Hz,1H),7.24(t,J=9.1Hz,2H),6.61(q,J=7.0Hz,1H),4.38(t,J=6.2 Hz,2H),3.09–2.96(m,1H),2.79–2.66(m,1H),2.51–2.48(m,1H),2.01(d,J=7.1Hz,3H),1.97–1.76(m,2H).

[0776] Dissolve 2-methoxycarbonylcyclopentanone (62.3 mg, 0.438 mmol) and triethylamine (89.4 mg, 0.88 mmol) in CH2Cl2 (2 mL). Add DA-2177-5 (86.0 mg, 0.297 mmol) in CH2Cl2 (2 mL) dropwise at 0 °C. Allow the mixture to warm naturally to room temperature and stir for 2 hours. After the reaction was completed as monitored by TLC, saturated brine (10 mL) was added to the reaction system, and the mixture was extracted with CH2Cl2 (3 × 10 mL). The combined organic phases were washed with saturated brine (20 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 / 10 to 1 / 1). TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1) was used to monitor the reaction, and the fraction with Rf = 0.4–0.6 was collected to obtain a syrupy solid target compound M-2009 (56.7 mg, yield 48.3%). ESI[M+H] + =396.1.

[0777] 1 H NMR (400MHz, d6-DMSO) δ8.51 (s, 1H), 7.24 (t, J = 9.1Hz, 2H), 6.55 (q, J = 7.0Hz, 1H), 3.49 (s, 3H), 2.73–2.57 (m, 4H), 2.04 (d, J = 7.1Hz, 3H), 2.01–1.89 (m, 2H).

[0778] Dissolve DA-2177-4 (94.5 mg, 0.348 mmol) in acetone (2 mL), add potassium carbonate (52.96 mg, 0.383 mmol), potassium iodide (5.81 mg, 0.035 mmol), and methyl bromoacetate (58.8 mg, 0.384 mmol), and stir at 50 °C for 12 hours. After the reaction was completed as monitored by TLC, saturated brine (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 (20 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 / 10 to 1 / 1), and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1). The fraction with Rf = 0.4 to 0.6 was collected to obtain the syrupy solid target compound M-2006 (56.6 mg, yield 47.3%). ESI[M+H] + =344.1.

[0779] 1H NMR (400MHz, d6-DMSO) δ8.46 (s, 1H), 7.24 (t, J = 9.1Hz, 2H), 6.57 (q, J = 7.0Hz, 1H), 4.94 (s, 2H), 3.68 (s, 3H), 2.02 (d, J = 7.0Hz, 3H).

[0780] The preparation method of the target compound M-2010 is similar to that of M-2006, and it is prepared using DA-2177-4 and bromoacetone as raw materials.

[0781] Compound M-2010: 95.1 mg, white solid, ESI [M+H] + =328.1.

[0782] 1 H NMR (400MHz, d6-DMSO) δ8.44(s,1H),7.30–7.16(m,2H),6.57(q,J=7.1Hz,1H),5.04(s,2H),2.14(s,3H),2.02(d,J=7.1Hz,3H).

[0783] DA-2177-4 (450 mg, 1.66 mmol), DCC (513.1 mg, 2.49 mmol), and DMAP (303.7 mg, 2.49 mmol) were dissolved in dichloromethane (4 mL) and stirred at room temperature for 15 minutes. This mixture was then added dropwise to a solution of ethylene glycol (3.089 g, 49.8 mmol) in dichloromethane (4 mL) and stirred at room temperature for 12 hours. After the reaction was confirmed to be complete by TLC, 4 mL of methyl tert-butyl ether was added to the reaction system. The mixture was stirred for 5 minutes and then filtered. The filter cake was washed with methyl tert-butyl ether, 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). TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1) was used to monitor the reaction, and the fraction with Rf = 0.2–0.3 was collected to give a white solid compound M-2012 (242 mg, yield 46.3%). ESI [M+H] + =316.1.

[0784] 1 H NMR(400MHz,d6-DMSO)δ8.37(s,1H),7.23(t,J=9.1Hz,2H),6.61(q,J=7.1Hz,1H), 4.92(t,J=5.8Hz,1H),4.34–4.17(m,2H),3.67–3.63(m,2H),2.01(d,J=7.1Hz,3H).

[0785] Imidazole (13.47 mg, 0.198 mmol) and tert-butyldimethylchlorosilane (27.1 mg, 0.18 mmol) were added to a 2 mL DMF solution of compound M-2012 (57.0 mg, 0.18 mmol) and stirred at room temperature for 5 hours. After the reaction was complete as monitored by TLC, the reaction solution was poured into ice water and extracted with EtOAc (3 × 30 mL). The combined organic phases were washed with saturated brine (20 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 / 2). TLC (ethyl acetate / petroleum ether (v / v) = 1 / 2) was used to monitor the reaction, and the fraction with Rf = 0.4 to 0.6 was collected to give a syrupy solid compound M-2011 (29.7 mg, yield 38.2%). ESI[M+H] + =430.2.

[0786] 1 H NMR (400MHz, d6-DMSO) δ8.30 (s, 1H), 7.29–7.17 (m, 2H), 6.60 (q, J = 7.1Hz, 1H), 4.40 (ddd, J = 11.5, 5.7, 3.8Hz, 1H), 4. 28(ddd,J=11.6,5.5,3.7Hz,1H),3.93–3.76(m,2H),2.01(d,J=7.1Hz,3H),0.82–0.80(m,9H),-0.00(d,J=2.4Hz,6H).

[0787] M-2012 (102 mg, 0.32 mmol) and triethylamine (76.9 mg, 0.76 mmol) were dissolved in CH2Cl2 (2 mL). A CH2Cl2 solution of acetyl chloride (28.3 mg, 0.36 mmol) was added dropwise at -20 °C, and the mixture was stirred for 30 minutes. After the reaction was completed as monitored by TLC, saturated brine (10 mL) was added to the reaction system, and the mixture was extracted with CH2Cl2 (3 × 10 mL). The combined organic phases were washed with saturated brine (20 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 / 10 to 1 / 1). TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1) was used to monitor the reaction, and the fraction with Rf = 0.4–0.6 was collected to give a white solid compound M-2013 (49.7 mg, yield 43.0%). ESI[M+H] + =358.1.

[0788] 1H NMR (400MHz, d6-DMSO) δ8.35(s,1H),7.26–7.21(m,2H),6.59(q,J=7.1Hz,1H),4.54–4.38(m,2H),4.29–4.27(m,2H),2.02–2.00(m,6H).

[0789] Example 16: Preparation of compounds M-2019 to M-2021, M-2023, M-2025(trans), M-2026 to M-2031, M-2041 and M-2045 of the present invention.

[0790] The preparation of target compound M-2026 is similar to that of target compound DA-2048-3.

[0791] Compound M-2026: 122.6 mg, syrupy solid, ESI [M+H] + =300.1.

[0792] 1 H NMR(400MHz,d6-DMSO)δ8.36(s,1H),7.54(qd,J=9.4,5.0Hz,1H),7.17(tdd,J=9.8,3.8,2.2H z,1H),6.64(q,J=7.1Hz,1H),4.38–4.19(m,2H),2.05(d,J=7.1Hz,3H),1.25(t,J=7.1Hz,3H).

[0793] The preparation of target compounds M-2019~M-2021, M-2023, M-2025(trans), M-2027~M-2031 is similar to that of target compound DA-2048.

[0794] Compound M-2019: 48.8 mg, syrupy solid, ESI [M+H] + =366.1.

[0795] 1H NMR(400MHz,d6-DMSO)δ8.46(s,1H),7.55(qd,J=9.4,4.9Hz,1H),7.26–7.10(m,1H),6.60(q,J=7.1Hz,1H),5.76(t,J=6.7Hz,1H),5.10( dd,J=12.1,6.7Hz,1H),4.96(dd,J=12.1,6.6Hz,1H),4.89(d,J=7.4Hz,1H),4.81–4.71(m,1H),4.71–4.60(m,2H),2.05(d,J=7.0Hz,3H).

[0796] Compound M-2020: 110.1 mg, syrupy solid, ESI [M+H] + =330.1.

[0797] 1 H NMR(400MHz,d6-DMSO)δ8.36(s,1H),7.53(ddd,J=19.1,9.4,5.0Hz,1H),7.17(tdd,J=9.8,3.9,2.2Hz ,1H),6.64(q,J=7.1Hz,1H),4.43–4.35(m,2H),3.67–3.52(m,2H),3.26(s,3H),2.05(d,J=7.1Hz,3H).

[0798] Compound M-2021: 88.4 mg, syrupy solid, ESI [M+H] + =356.1.

[0799] 1 H NMR(400MHz,d6-DMSO)δ8.40(s,1H),7.54(qd,J=9.4,5.0Hz,1H),7.23–7.07(m,1H),6.62(q,J=7.1Hz,1H),4.79( p,J=7.2Hz,1H),3.62(p,J=6.8Hz,1H),3.16(s,3H),2.83–2.68(m,2H),2.04(d,J=7.1Hz,3H),2.00–1.88(m,2H).

[0800] Compound M-2023: 117.9 mg, syrupy solid, ESI [M+H] + =356.1.

[0801] 1H NMR(400MHz,d6-DMSO)δ8.41–8.39(m,1H),7.58–7.49(m,1H),7.25–7.09(m,1H),6.63(q,J=7.0Hz,1H),5.05–4 .85(m,1H),4.00–3.79(m,1H),3.20–3.13(m,3H),2.20–2.08(m,2H),2.04(d,J=7.1Hz,3H),1.59–1.34(m,2H).

[0802] Compound M-2025(trans): 54.2 mg, syrupy solid, ESI [M+H] + =370.1.

[0803] 1 H NMR(400MHz,d6-DMSO)δ8.38–8.36(m,1H),7.59–7.51(m,1H),7.21–7.16(m,1H),6.73–6.58(m,1H),5.15–5. 10(m,1H),3.78–3.67(m,1H),3.27–3.22(m,3H),2.05(d,J=7.1Hz,3H),2.02–1.86(m,2H),1.74–1.53(m,4H).

[0804] Compound M-2027: 89.4 mg, white solid, ESI [M+H] + =342.1.

[0805] 1 H NMR(400MHz,d6-DMSO)δ8.42(s,1H),7.55(qd,J=9.4,5.0Hz,1H),7.24–7.11(m,1H),6.61(q,J=7.1Hz,1 H),4.78(d,J=7.2Hz,1H),4.62(d,J=7.2Hz,1H),4.56–4.40(m,2H),2.05(d,J=7.1Hz,3H),1.62(s,3H).

[0806] Compound M-2028: 94.5 mg, syrupy solid, ESI [M+H] + =344.1.

[0807] 1H NMR(400MHz,d6-DMSO)δ8.36(s,1H),7.54(qd,J=9.4,5.0Hz,1H),7.25–7.10(m,1H),6.65(q,J=7.1Hz,1H) ,4.51–4.28(m,2H),3.70–3.54(m,2H),3.45(q,J=7.0Hz,2H),2.05(d,J=7.1Hz,3H),1.07(t,J=7.0Hz,3H).

[0808] Compound M-2029: 98.8 mg, white solid, ESI [M+H] + =344.1.

[0809] 1 H NMR(400MHz,d6-DMSO)δ8.38(s,1H),7.54(qd,J=9.4,5.0Hz,1H),7.24–7.10(m,1H),6.64(q,J=7.1Hz,1H ), 4.29 (t, J = 6.5Hz, 2H), 3.38 (t, J = 6.2Hz, 2H), 3.22 (s, 3H), 2.05 (d, J = 7.1Hz, 3H), 1.87 (p, J = 6.4Hz, 2H).

[0810] Compound M-2030: 49.4 mg, syrupy solid, ESI [M+H] + =328.1.

[0811] 1 H NMR(400MHz,d6-DMSO)δ8.44–8.42(m,1H),7.58–7.49(m,1H),7.26–7.10(m,1H),6.64(q,J=7.1Hz,1H),4.70–4 .56(m,1H),4.11–4.04(m,1H),3.31–3.18(m,1H),2.87–2.79(m,1H),2.77–2.65(m,1H),2.05(d,J=7.1Hz,3H).

[0812] Compound M-2031: 62.7 mg, syrupy solid, ESI [M+H] + =342.1.

[0813] 1H NMR(400MHz,d6-DMSO)δ8.40–8.38(m,1H),7.58–7.49(m,1H),7.24–7.10(m,1H),6.65(q,J=7.1Hz,1H),4.37(t, J=6.2Hz,2H),3.06–2.93(m,1H),2.76–2.66(m,1H),2.51–2.47(m,1H),2.05(d,J=7.1Hz,3H),1.96–1.72(m,2H).

[0814] Compound M-2041: 152.1 mg, syrupy solid, ESI [M+H] + =368.1.

[0815] 1 H NMR(400MHz,d6-DMSO)δ8.37–8.35(m,1H),7.59–7.51(m,1H),7.20–7.15(m,1H),6.63(q,J=7.0Hz,1H),5.63–5.51(m,1H),5.4 7–5.34(m,1H),5.04–5.02(m,1H),4.97–4.81(m,1H),3.61–3.49(m,2H),3.29(s,1.5H),3.23(s,1.5H),2.05(d,J=7.1Hz,3H).

[0816] Compound M-2045: 53.5 mg, white solid, ESI [M+H] + =358.1.

[0817] 1 H NMR(400MHz,d6-DMSO)δ8.42(s,1H),7.55(qd,J=9.4,5.0Hz,1H),7.24–7.12(m,1H),6.61(q,J=7.1Hz,1H ), 4.78 (d, J = 7.2Hz, 1H), 4.62 (d, J = 7.2Hz, 1H), 4.50 (t, J = 7.3Hz, 2H), 2.05 (d, J = 7.1Hz, 3H), 1.62 (s, 3H).

[0818] Example 17: Preparation of compounds M-2141, M-2148, M-2155 and M-2166 of the present invention

[0819] The preparation of target compounds M-2141, M-2148, M-2155 and M-2166 is similar to that of target compound DA-2048.

[0820] Compound M-2141: 54.4 mg, syrupy solid, ESI [M+H] + =328.1.

[0821] 1 H NMR(400MHz,d6-DMSO)δ8.40(s,1H),7.47–7.33(m,2H),6.79–6.72(m,2H) ,4.47–4.26(m,2H),3.68–3.51(m,2H),3.25(s,3H),1.95(d,J=7.0Hz,3H).

[0822] Compound M-2148: 34.8 mg, syrupy solid, ESI [M+H] + =340.1.

[0823] 1 H NMR(400MHz,d6-DMSO)δ8.44–8.43(m,1H),7.48–7.34(m,2H),6.80–6.73(m,2H),4.46–4.30(m,2H) ,3.05–2.94(m,1H),2.74–2.60(m,1H),2.50–2.47(m,1H),1.95(d,J=7.0Hz,3H),1.93–1.77(m,2H).

[0824] Compound M-2155: 20.2 mg, syrupy solid, ESI [M+H] + =340.1.

[0825] 1 H NMR(400MHz,d6-DMSO)δ8.35(s,1H),7.47–7.35(m,2H),6.80(dd,J=6.2,2.7Hz,1H),6.73(q ,J=6.8Hz,1H),4.52–4.33(m,2H),2.89(t,J=6.1Hz,2H),2.13(s,3H),1.94(d,J=7.0Hz,3H).

[0826] Compound M-2166: 28.0 mg, syrupy solid, ESI [M+H] + =366.1.

[0827] 1H NMR(400MHz,d6-DMSO)δ8.45–8.44(m,1H),7.49–7.27(m,2H),6.78–6.70(m,2H),5.70–5 .67(m,1H),3.72–3.54(m,2H),3.28–3.25(m,3H),1.97–1.95(m,3H),1.84–1.81(m,3H).

[0828] Example 18: Preparation of compounds DA-2048, DA2074 to DA-2077, M-2229, DA-2050, DA-2070 to DA-2073 and DA-2118A of the present invention

[0829] At -78°C, DIP-Chloride (22.5 g, 70.1 mmol) was added dropwise to 80 mL of THF containing 10 g, 64.0 mmol of 2,3-difluoroacetophenone. The mixture was allowed to warm naturally to room temperature and stirred overnight. The reaction mixture was then cooled to -20°C, methanol (16 mL) was added, and the mixture was warmed to room temperature and stirred for 1 hour. After the reaction was completed as monitored by TLC, the reaction mixture was concentrated under reduced pressure. EtOAc (20 mL) and ethanolamine (8 mL) were added to the residue, and the mixture was stirred at room temperature for 2 hours. Saturated brine (150 mL) was added to the reaction system, and the mixture was extracted with EtOAc (3 × 100 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 / 20–1 / 2). TLC (ethyl acetate / petroleum ether (v / v) = 1 / 2) was used for monitoring, and the fraction with Rf = 0.5–0.6 was collected to give compound DA-2048-1 (7.24 g, yield 71.5%). (ESI [M+H]) + =159.1.

[0830] At 0°C, DA-2048-1 (7.24 g, 45.8 mmol) and PPh3 (24.0 g, 91.6 mmol) were dissolved in THF (75 mL). Then, a solution of DEAD (15.9 g, 91.3 mmol) in THF (10 mL) was added dropwise to the reaction system at a rate of 10 mmol / min. Next, DPPA (15.1 g, 54.9 mmol) was added dropwise to the system at a rate of 6 mmol / min. After the addition was complete, the temperature was slowly raised to room temperature and stirred overnight. After the reaction was monitored by TLC until complete, saturated brine (150 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (3 × 100 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 DA-2048-2. The crude product was used directly in the next reaction without further purification. ESI[M+H] + =184.1.

[0831] At room temperature, the crude product DA-2048-2 and ethyl propargyl acid (17.0 g, 173.4 mmol) were dissolved in toluene (100 mL) and refluxed with stirring for 2 hours. After the reaction was complete as monitored by TLC, saturated brine (100 mL) was added to the reaction system and extracted with EtOAc (3 × 100 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 / 1) to give syrupy solid compound DA-2048-3 (1.38 g, two-step yield 10.7%) and syrupy solid compound DA-2048-4 (7.78 g, two-step yield 60.4%).

[0832] DA-2048-3: ESI[M+H] + =282.1.

[0833] DA-2048-4: ESI[M+H] + =282.1.

[0834] At room temperature, LiOH·H₂O (411.4 mg, 9.8 mmol) was added to a MeOH / THF / H₂O (15 mL, v / v / v = 1 / 1 / 1) solution of compound DA-2048-3 (1.38 g, 4.91 mmol), and the mixture was stirred at room temperature for 2 hours. After the reaction was completed as monitored by TLC, the reaction solution was concentrated under reduced pressure. H₂O (50 mL) was added to the concentrate, and the solution was washed with EtOAc (3 × 20 mL). The aqueous phase was adjusted to pH 4–5 with 1 N hydrochloric acid, and then extracted with EtOAc (3 × 15 mL). The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give a white solid compound DA-2048-5 (692 mg, yield 55.7%). ESI [M+H] + =254.1.

[0835] Under nitrogen protection, oxalyl chloride (136.5 mg, 1.08 mmol) was added dropwise to DA-2048-5 (136.0 mg, 0.537 mmol) in 2 mL of CH2Cl2, and the reaction was carried out at room temperature for 30 minutes. After the reaction was completed as monitored by TLC, the reaction solution was concentrated under reduced pressure, and the residue was used directly for the next reaction without purification.

[0836] Dissolve 3-(propa-1,2-dien-1-yl)oxetan-3-ol (120.4 mg, 1.07 mmol) and triethylamine (162 mg, 1.60 mmol) in CH2Cl2 (2 mL), and add DA-2048-6 CH2Cl2 (2 mL) solution dropwise at 0 °C, stirring for 10 minutes. After the reaction was completed as monitored by TLC, saturated brine (10 mL) was added to the reaction system, and the mixture was extracted with CH2Cl2 (3 × 10 mL). The combined organic phases were washed with saturated brine (20 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 / 10 to 1 / 1), and monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1). The fraction with Rf = 0.4 to 0.6 was collected to give compound DA-2048 (146.1 mg, two-step yield 78.3%). ESI [M+H] + =348.1.

[0837] 1H NMR (400MHz, d6-DMSO) δ8.48 (s, 1H), 7.44 (dd, J = 17.3, 8.4Hz, 1H), 7.31–7. 15(m,1H),6.88(t,J=7.1Hz,1H),6.70(q,J=7.0Hz,1H),5.80(t,J=6.6Hz,1H ),5.10(dd,J=12.1,6.7Hz,1H),4.98(dd,J=12.1,6.6Hz,1H),4.91(d,J=7.4 Hz, 1H), 4.79 (d, J = 7.4Hz, 1H), 4.68 (t, J = 8.1Hz, 2H), 1.96 (d, J = 7.0Hz, 3H).

[0838] 2. The preparation methods of target compounds DA-2074, DA-2075, DA-2076, DA-2077 and M-2229 are similar to those of DA-2048, and they are prepared using DA-2048-5 as the raw material.

[0839] Compound DA-2074: 28.6 mg, white solid, ESI [M+H] + =324.1.

[0840] 1 H NMR (400MHz, d6-DMSO) δ8.42(s,1H),7.42(d,J=8.8Hz,1H),7.21(dd,J=5.1,1.5Hz,1H),6.87(t,J=7.1Hz,1H),6.69(d,J= 7.0Hz, 1H), 4.78 (d, J = 7.3Hz, 1H), 4.65 (d, J = 7.2Hz, 1H), 4.49 (dd, J = 6.8, 4.7Hz, 2H), 1.95 (d, J = 7.0Hz, 3H), 1.64 (s, 3H).

[0841] Compound DA-2075: 53.4 mg, syrupy solid, ESI [M+H] + =336.1.

[0842] 1H NMR(400MHz,d6-DMSO)δ8.48(s,1H),7.44–7.34(m,1H),7.18(dd,J=13.3,6.6Hz,1H),6.83(t,J=7.2Hz,1H),6.66(q,J=7.0Hz ,1H),6.23(dd,J=17.4,11.0Hz,1H),5.23(t,J=14.3Hz,2H),4.86(d,J=7.4Hz,1H),4.77–4.62(m,3H),1.93(d,J=7.0Hz,3H).

[0843] Compound DA-2076: 101.4 mg, syrupy solid, ESI [M+H] + =312.1.

[0844] 1 H NMR(400MHz,d6-DMSO)δ8.39(s,1H),7.42(dd,J=17.8,8.8Hz,1H),7.20(dd,J=13.3,7.7Hz,1H),6.85(t,J=7.1Hz ,1H),6.75(q,J=7.0Hz,1H),4.45–4.32(m,2H),3.59(dd,J=10.4,5.8Hz,2H),3.26(s,3H),1.96(d,J=7.0Hz,3H).

[0845] Compound DA-2077: 111.7 mg, white solid, ESI [M+H] + =338.1.

[0846] 1 H NMR(400MHz,d6-DMSO)δ8.42(s,1H),7.47–7.38(m,1H),7.21(dt,J=12.0,4.1Hz,1H),6.82(t,J=7.1Hz,1H),6.72 (q,J=7.0Hz,1H),4.81(p,J=7.3Hz,1H),3.61(p,J=6.8Hz,1H),3.15(s,3H),2.81–2.71(m,2H),2.02–1.92(m,5H).

[0847] Compound M-2229: 161.6 mg, syrupy solid, ESI [M+H] + =324.1.

[0848] 1H NMR (400MHz, d6-DMSO) δ8.42–8.41(m,1H),7.46–7.39(m,1H),7.31–7.16(m,1H),6.90(t,J=7.1Hz,1H),6.77(q,J=7.0Hz, 1H),4.48–4.31(m,2H),3.04–2.99(m,1H),2.76–2.64(m,1H),2.52–2.49(m,1H),1.97(d,J=7.0Hz,3H),1.95–1.78(m,2H).

[0849] LiOH·H₂O (2.32 g, 55.3 mmol) was added to a MeOH / THF / H₂O (70 mL, v / v / v = 1 / 1 / 1) solution of compound DA-2048-4 (7.78 g, 27.7 mmol), and stirred at room temperature for 2 hours. After the reaction was complete as monitored by TLC, the reaction solution was concentrated under reduced pressure. H₂O (150 mL) was added to the concentrate, and the solution was washed with EtOAc (3 × 50 mL). The aqueous phase was adjusted to pH 4–5 with 1 N hydrochloric acid, extracted with EtOAc (3 × 100 mL), and the combined organic phases were dried over anhydrous Na₂SO₄. The mixture was filtered and concentrated under reduced pressure to give a white solid compound DA-2050-1 (3.89 g, yield 55.5%). ESI [M+H] + =254.1.

[0850] DA-2050-1 (200 mg, 0.79 mmol), DCC (244 mg, 1.18 mmol), and DMAP (144.6 mg, 1.18 mmol) were dissolved in dichloromethane (4 mL) and stirred at room temperature for 15 minutes. 3-(propa-1,2-dien-1-yl)oxetan-3-ol (167.55 mg, 1.49 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 12 hours. After the reaction was complete as monitored by TLC, methyl tert-butyl ether (4 mL) was added to the reaction mixture, and after stirring for 5 minutes, the mixture was filtered. The filter cake was washed with methyl tert-butyl ether. The filtrate was concentrated under reduced pressure to obtain a crude product, which was then purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 to 1 / 1). TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1) was used for monitoring, and the fraction with Rf = 0.4–0.6 was collected to give a syrupy solid compound DA-2050 (80.2 mg, yield 29.2%). (ESI [M+H]) + =348.1.

[0851] 1H NMR(400MHz,d6-DMSO)δ9.08(s,1H),7.58–7.36(m,1H),7.35–7.14(m,2H),6.33(q,J=7.0Hz,1H),5.88(t ,J=6.7Hz,1H),5.18(d,J=6.7Hz,2H),4.88(d,J=7.6Hz,2H),4.72(d,J=7.7Hz,2H),1.98(d,J=7.1Hz,3H).

[0852] 4. The preparation methods for target compounds DA-2070, DA-2071, DA-2072, and DA-2073 are similar to those for DA-2050, using DA-2050-1 as the raw material.

[0853] Compound DA-2070: 73.5 mg, white solid, ESI [M+H] + =324.1.

[0854] 1 H NMR(400MHz,d6-DMSO)δ9.05(s,1H),7.51–7.41(m,1H),7.32–7.20(m,2H),6.31(q,J=7.1 Hz,1H),4.77(d,J=7.3Hz,2H),4.53(d,J=7.7Hz,2H),1.95(d,J=7.1Hz,3H),1.74(s,3H).

[0855] Compound DA-2071: 74.7 mg, white solid, ESI [M+H] + =336.1.

[0856] 1 H NMR(400MHz,d6-DMSO)δ9.08(s,1H),7.51–7.40(m,1H),7.32–7.19(m,2H),6.42–6.26(m,2H),5. 37(dd,J=24.5,14.2Hz,2H), 4.86(d,J=7.7Hz,2H), 4.72(d,J=7.8Hz,2H), 1.96(d,J=7.1Hz,3H).

[0857] Compound DA-2072: 81.4 mg, white solid, ESI [M+H] + =312.1.

[0858] 1H NMR(400MHz,d6-DMSO)δ9.02(s,1H),7.53–7.39(m,1H),7.36–7.18(m,2H),6.32(q,J=7.1H z,1H),4.42(dd,J=5.3,3.9Hz,2H),3.69–3.60(m,2H),3.31(s,3H),1.97(d,J=7.1Hz,3H).

[0859] Compound DA-2073: 94.6 mg, syrupy solid, ESI [M+H] + =338.1.

[0860] 1 H NMR (400MHz, d6-DMSO) δ9.00 (s, 1H), 7.50–7.40 (m, 1H), 7.31–7.17 (m, 2H), 6.29 (q, J = 7.1Hz, 1H), 4. 82(t,J=7.2Hz,1H),3.70–3.58(m,1H),3.16(d,J=4.4Hz,3H),2.85–2.74(m,2H),2.05–1.93(m,5H).

[0861] The preparation method of compound DA-2118A-1 is similar to that of DA-2048-4.

[0862] Silver fluoride (4.98 g, 39.3 mmol) and N,N,N',N'-tetramethylethylenediamine (456.5 mg, 3.93 mmol) were added to a toluene (50 mL) solution of DA-2118A-1 (3.19 g, 7.83 mmol), and the mixture was stirred at 100 °C for 12 hours. After the reaction was completed as monitored by TLC, saturated brine (100 mL) was added to the reaction system, and the mixture was extracted with EtOAc (3 × 50 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 / 1) to give a colorless oily compound DA-2118A (723.7 mg, yield 30.9%). + =300.1.

[0863] 1H NMR(400MHz,d6-DMSO)δ7.49(ddd,J=10.2,7.3,3.6Hz,1H),7.33–7.26(m,2H),6.1 7(q,J=7.0Hz,1H),4.36–4.24(m,2H),1.96(d,J=7.0Hz,3H),1.28(t,J=7.1Hz,3H).

[0864] Example 19: Preparation of compounds DA-2056, DA2086, DA-2088, DA-2089, DA-2058, DA-2092 and DA-2093 of the present invention

[0865] The preparation of compounds DA-2056-3 and DA-2056-4 is similar to that of compounds DA-2048-3 and DA-2048-4.

[0866] The preparation of target compounds DA-2056, DA-2086, DA-2088, DA-2089, DA-2058, DA-2092 and DA-2093 is similar to that of target compound DA-2048, and they are prepared from DA-2056-3 or DA-2056-4, respectively.

[0867] Compound DA-2056: 31.9 mg, syrupy solid, ESI [M+H] + =360.1.

[0868] 1 H NMR(400MHz,d6-DMSO)δ8.49(s,1H),7.35(d,J=7.5Hz,1H),7.25(t,J=7.7Hz,1H),6.72(dt,J=13.8,6.9Hz,2H),5.74(t,J=6.7Hz,1H ),5.08(dd,J=12.1,6.6Hz,1H),4.97–4.87(m,2H),4.72(d,J=7.3Hz,1H),4.67(t,J=7.9Hz,2H),2.38(s,3H),1.93(d,J=6.9Hz,3H).

[0869] Compound DA-2058: 13.8 mg, syrupy solid, ESI [M+H] + =360.1.

[0870] 1H NMR(400MHz,d6-DMSO)δ9.05(s,1H),7.38(d,J=7.1Hz,1H),7.30(t,J=7.6Hz,1H),7.16(d,J=7.2Hz,1H),6.38(q,J=6.9Hz,1H) ,5.87(t,J=6.6Hz,1H),5.18(d,J=6.7Hz,2H),4.87(d,J=7.7Hz,2H),4.71(d,J=7.8Hz,2H),2.38(s,3H),1.92(t,J=5.5Hz,3H).

[0871] Compound DA-2086: 6.7 mg, syrupy solid, ESI [M+H] + =336.1.

[0872] 1 H NMR(400MHz,d6-DMSO)δ8.44(s,1H),7.34(d,J=7.5Hz,1H),7.23(t,J=7.7Hz,1H),6.70(dt,J=14.0,6.8Hz,2H), 4.76(d,J=7.0Hz,1H),4.57(d,J=7.1Hz,1H),4.51–4.45(m,2H),2.37(s,3H),1.93(d,J=6.9Hz,3H),1.59(s,3H).

[0873] Compound DA-2088: 53.0 mg, syrupy solid, ESI [M+H] + =324.1.

[0874] 1 H NMR(400MHz,d6-DMSO)δ8.39(s,1H),7.34(d,J=7.1Hz,1H),7.23(t,J=7.7Hz,1H),6.82–6.72( m,2H),4.43–4.31(m,2H),3.64–3.52(m,2H),3.25(s,3H),2.38(s,3H),1.93(d,J=7.0Hz,3H).

[0875] Compound DA-2089: 46.5 mg, syrupy solid, ESI [M+H] + =350.1.

[0876] 1H NMR (400MHz, d6-DMSO) δ8.42(s,1H),7.32(d,J=7.3Hz,1H),7.21(t,J=7.7Hz,1H),6.68(dt,J=18.6,7.0H z,2H),4.78(t,J=7.3Hz,1H),3.62–3.54(m,1H),3.13(s,3H),2.71(dt,J=11.2,6.7Hz,2H),2.37(s,3H).

[0877] Compound DA-2092: 104.4 mg, syrupy solid, ESI [M+H] + =324.1.

[0878] 1 H NMR(400MHz,d6-DMSO)δ8.99(s,1H),7.38(d,J=6.8Hz,1H),7.30(t,J=7.7Hz,1H),7.15(d,J=6.8Hz,1H),6. 38(q,J=7.0Hz,1H),4.44–4.39(m,2H),3.66–3.62(m,2H),3.30(s,3H),2.38(s,3H),1.93(d,J=7.1Hz,3H).

[0879] Compound DA-2093: 50.3 mg, syrupy solid, ESI [M+H] + =350.1.

[0880] 1 H NMR(400MHz,d6-DMSO)δ8.99(s,1H),7.38(d,J=6.8Hz,1H),7.29(t,J=7.7Hz,1H),7.14(d,J=6.9Hz,1H),6.37(q,J=7.1Hz,1H),4.8 9–4.79(m,1H),3.70–3.61(m,1H),3.17(s,3H),2.85–2.76(m,2H),2.38(s,3H),2.01(dt,J=9.8,7.4Hz,2H),1.93(d,J=7.0Hz,3H).

[0881] Example 20: Preparation of compounds DA-2064, DA-2078 to DA-2081, DA-2066, DA-2082 to DA-2085 of the present invention

[0882] The preparation of compounds DA-2064-3 and DA-2064-4 is similar to that of compounds DA-2048-3 and DA-2048-4.

[0883] The preparation of target compounds DA-2064, DA-2078 to DA-2081 is similar to that of target compound DA-2048, and they are prepared using DA-2064-3 as the raw material.

[0884] Compound DA-2064: 176.1 mg, syrupy solid, ESI [M+H] + =380.1.

[0885] 1 H NMR (400MHz, d6-DMSO) δ8.51(s,1H),7.66(dd,J=8.0,1.2Hz,1H),7.38(t,J=8.0Hz,1H),6.88(dd,J=7.9,1.1Hz,1H),6.70(q,J=6.9Hz,1H),5.7 7(t,J=6.6Hz,1H),5.09(dd,J=12.1,6.7Hz,1H),5.00–4.88(m,2H),4.74(d,J=7.3Hz,1H),4.67(dd,J=10.3,7.5Hz,2H),1.94(d,J=6.9Hz,3H).

[0886] Compound DA-2078: 26.5 mg, syrupy solid, ESI [M+H] + =356.1.

[0887] 1 H NMR (400MHz, d6-DMSO) δ8.46(s,1H),7.64(dd,J=8.0,1.3Hz,1H),7.37(t,J=8.0Hz,1H),6.87(d,J=7.9Hz,1H),6.68( d,J=6.9Hz,1H),4.78(d,J=7.4Hz,1H),4.58(d,J=7.3Hz,1H),4.52–4.45(m,2H),1.93(d,J=6.9Hz,3H),1.61(s,3H).

[0888] Compound DA-2079: 56.5 mg, white solid, ESI [M+H] + =368.1.

[0889] 1H NMR (400MHz, d6-DMSO) δ8.54(s,1H),7.65(dd,J=8.0,1.4Hz,1H),7.38(t,J=8.0Hz,1H),6.86(dd,J=7.9,1.3Hz,1H),6.69(q,J=6.9H z,1H),6.23(dd,J=17.4,11.0Hz,1H),5.22(dd,J=26.8,14.2Hz,2H),4.89(d,J=7.3Hz,1H),4.74–4.65(m,3H),1.95(d,J=6.9Hz,3H).

[0890] Compound DA-2080: 144.0 mg, syrupy solid, ESI [M+H] + =344.1.

[0891] 1 H NMR (400MHz, d6-DMSO) δ8.41(s,1H),7.64(dd,J=8.0,1.3Hz,1H),7.36(t,J=8.0Hz,1H),6.87(dd,J=7.9,1 .2Hz,1H),6.75(q,J=6.9Hz,1H),4.43–4.32(m,2H),3.66–3.52(m,2H),3.24(s,3H),1.94(d,J=7.0Hz,3H).

[0892] Compound DA-2081: 165.5 mg, white solid, ESI [M+H] + =370.1.

[0893] 1 H NMR (400MHz, d6-DMSO) δ8.42(s,1H),7.61(dd,J=8.0,1.3Hz,1H),7.34(t,J=8.0Hz,1H),6.79(dd,J=7.9,1.3Hz,1H),6.68( q,J=6.9Hz,1H),4.76(p,J=7.2Hz,1H),3.57(p,J=6.8Hz,1H),3.12(s,3H),2.70(tt,J=11.8,5.9Hz,2H),1.97–1.85(m,5H).

[0894] The preparation of target compounds DA-2066, DA-2082 to DA-2085 is similar to that of target compound DA-2050, and they are prepared using DA-2064-4 as the raw material.

[0895] Compound DA-2066: 58.7 mg, syrupy solid, ESI [M+H]+ =380.1.

[0896] 1 H NMR(400MHz,d6-DMSO)δ9.08(s,1H),7.69(dd,J=8.0,1.3Hz,1H),7.44(t,J=8.0Hz,1H),7.32(dd,J=7.9,1.1Hz,1H),6.39(q,J =7.0Hz,1H),5.88(t,J=6.7Hz,1H),5.19(d,J=6.7Hz,2H),4.88(d,J=7.6Hz,2H),4.72(d,J=7.7Hz,2H),1.96(d,J=7.0Hz,3H).

[0897] Compound DA-2082: 83.2 mg, white solid, ESI [M+H] + =356.1.

[0898] 1 H NMR(400MHz,d6-DMSO)δ9.05(s,1H),7.69(dd,J=8.0,1.4Hz,1H),7.44(t,J=8.0Hz,1H),7.32(dd,J=7.9,1.2H z,1H),6.39(q,J=7.0Hz,1H),4.79(d,J=7.3Hz,2H),4.55(d,J=7.6Hz,2H),1.95(d,J=7.0Hz,3H),1.76(s,3H).

[0899] Compound DA-2083: 103.0 mg, syrupy solid, ESI [M+H] + =368.1.

[0900] 1 H NMR (400MHz, d6-DMSO) δ9.11(s,1H),7.70(dd,J=8.0,1.3Hz,1H),7.45(t,J=8.0Hz,1H),7.34(dd,J=7.9,1.2Hz,1H),6.39( dt,J=17.4,9.2Hz,2H),5.40(dd,J=24.8,14.2Hz,2H),4.88(d,J=7.7Hz,2H),4.75(d,J=7.8Hz,2H),1.97(d,J=7.0Hz,3H).

[0901] Compound DA-2084: 137.9 mg, syrupy solid, ESI [M+H] + =344.1.

[0902] 1 H NMR(400MHz,d6-DMSO)δ9.06(s,1H),7.70(dd,J=8.0,1.2Hz,1H),7.45(t,J=8.0Hz,1H),7.31(dd,J=7.9,1.0Hz,1H),6.40(q,J=7.0Hz,1H),4.46– 4.40(m,2H),3.69–3.62(m,2H),3.32(s,3H),1.97(d,J=7.0Hz,3H).

[0903] Compound DA-2085: 132.6 mg, syrupy solid, ESI [M+H] + =370.1.

[0904] 1 H NMR(400MHz,d6-DMSO)δ9.02(s,1H),7.68(dd,J=8.0,1.4Hz,1H),7.43(t,J=8.0Hz,1H),7.29(dd,J=7.9,1.3Hz,1H),6.37(q,J=7 .0Hz,1H),4.84(p,J=7.3Hz,1H),3.66(p,J=6.8Hz,1H),3.17(s,3H),2.85–2.76(m,2H),2.06–1.97(m,2H),1.95(d,J=7.0Hz,3H).

[0905] Example 21: Preparation of compounds DA-2052, DA-2095 to DA-2097, DA-2160H(cis), DA-2162(trans) and M-2230 of the present invention.

[0906] The preparation of target compounds DA-2052, DA-2095~DA-2097, DA-2160H(cis), DA-2162(trans) and M-2230 is similar to that of target compound DA-2048.

[0907] Compound DA-2052: 54.4 mg, syrupy solid, ESI [M+H] + =344.1.

[0908] 1H NMR (400MHz, d6-DMSO) δ8.44(s,1H),7.25(t,J=7.3Hz,1H),7.07(t,J=7.6Hz,1H ),6.82(t,J=7.3Hz,1H),6.66(q,J=7.0Hz,1H),5.77(t,J=6.7Hz,1H),5.08(dd,J =12.1,6.7Hz,1H),4.95(dd,J=12.1,6.6Hz,1H),4.87(d,J=7.5Hz,1H),4.76(d,J =7.5Hz, 1H), 4.66 (t, J = 6.9Hz, 2H), 2.23 (d, J = 1.8Hz, 3H), 1.92 (d, J = 7.0Hz, 3H).

[0909] Compound DA-2095: 52.6 mg, syrupy solid, ESI [M+H] + =332.1.

[0910] 1 H NMR(400MHz,d6-DMSO)δ8.50(s,1H),7.26(t,J=7.2Hz,1H),7.08(t,J=7.7Hz,1H) ,6.83(t,J=7.1Hz,1H),6.67(q,J=7.0Hz,1H),6.25(dd,J=17.4,11.0Hz,1H),5.2 8(d,J=11.0Hz,1H),5.23(d,J=17.4Hz,1H),4.88(d,J=7.5Hz,1H),4.76(d,J=7.5 Hz, 1H), 4.70 (dd, J = 7.1, 4.8Hz, 2H), 2.24 (d, J = 1.7Hz, 3H), 1.94 (d, J = 7.0Hz, 3H).

[0911] Compound DA-2096: 70.6 mg, syrupy solid, ESI [M+H] + =308.1.

[0912] 1 H NMR (400MHz, d6-DMSO) δ8.37(s,1H),7.26(t,J=7.2Hz,1H),7.08(t,J=7.7Hz,1H),6.86(t,J=7.4Hz,1H),6.74(q ,J=7.0Hz,1H),4.47–4.30(m,2H),3.67–3.53(m,2H),3.27(s,3H),2.25(d,J=1.9Hz,3H),1.93(d,J=7.0Hz,3H).

[0913] Compound DA-2097: 52.3 mg, syrupy solid, ESI [M+H] + =334.1.

[0914] 1 H NMR (400MHz, d6-DMSO) δ8.40(s,1H),7.24(t,J=7.3Hz,1H),7.05(t,J=7.6Hz,1H),6.74(t,J=7.1Hz,1H),6.68(q,J=7.0Hz,1H),4.79(p,J=7.3Hz ,1H),3.59(p,J=6.9Hz,1H),3.13(s,3H),2.75-2.67(m,2H),2.24(d,J= 1.5Hz,3H),2.02-1.94(m,1H),1.91(d,J=7.0Hz,3H),1.87-1.82(m,1H).

[0915] Compound DA-2160H(cis): 57.2 mg, syrupy solid, ESI [M+H] + =334.1.

[0916] 1 H NMR(400MHz,d6-DMSO)δ8.40(s,1H),7.25(t,J=7.5Hz,1H),7.06(td,J=7.7,3.0Hz,1H),6.78(dd,1H),6.70(q,1H),4.99–4 .93(m,1H),3.89–3.80(m,1H),3.15(s,3H),2.24(s,3H),2.20–2.04(m,2H),1.92(dd,J=7.0,2.1Hz,3H),1.60–1.38(m,2H).

[0917] Compound DA-2162(trans): 50.1 mg, syrupy solid, ESI [M+H] + =348.1.

[0918] 1H NMR(400MHz,d6-DMSO)δ8.39(s,1H),7.26(t,J=7.4Hz,1H),7.07(t,J=7.6Hz,1H),6.76(t,J=7.5Hz,1H),6.73–6.65(m,1H),5.15–5.10(m,1H),3 .75–3.66(m,1H),3.23(d,J=5.0Hz,3H),2.25(s,3H),2.00(dd,J=14.0, 6.8Hz,1H),1.94(t,J=7.1Hz,3H),1.91–1.79(m,1H),1.73–1.49(m,4H).

[0919] Compound M-2230: 152.7 mg, syrupy solid, ESI [M+H] + =320.1.

[0920] 1 H NMR (400MHz, d6-DMSO) δ8.40–8.38(m,1H),7.26(t,J=7.2Hz,1H),7.08(t,J=7.6Hz,1H),6.86(t,J=7.0Hz,1H),6.82–6.71(m,1H),4.5 1–4.24(m,2H),3.08–2.95(m,1H),2.81–2.65(m,1H),2.51–2.47(m,1H),2.26–2.24(m,3H),1.94(d,J=7.0Hz,3H),1.92–1.78(m,2H).

[0921] Example 22: Preparation of compounds DA-2164, DA-2165, DA-2167H(cis) and M-2231 of the present invention

[0922] The preparation of target compounds DA-2164, DA-2165, DA-2167H(cis) and M-2231 is similar to that of target compound DA-2048.

[0923] Compound DA-2164: 23.3 mg, syrupy solid, ESI [M+H] + =312.1.

[0924] 1H NMR(400MHz,d6-DMSO)δ8.38(s,1H),7.36–7.28(m,1H),7.21(td,J=8.7,6.5Hz,1H),7.12(td,J=8.4,2.0Hz,1 H),6.72(q,J=7.0Hz,1H),4.41(td,J=4.1,2.2Hz,2H),3.64–3.60(m,2H),3.29(s,3H),1.95(d,J=7.0Hz,3H).

[0925] Compound DA-2165: 30.2 mg, syrupy solid, ESI [M+H] + =338.1.

[0926] 1 H NMR(400MHz,d6-DMSO)δ8.38(s,1H),7.29(ddd,J=11.5,9.3,2.5Hz,1H),7.15(td,J=8.6,6.5Hz,1H),7.08(td,J=8.7,2.4Hz,1H),6.66(q,J=7.0Hz,1 H),4.80(p,J=7.2Hz,1H),3.61(p,J=6.8Hz,1H),3.14(s,3H),2.75(dt,J=1 1.0, 6.8Hz, 2H), 1.98 (ddd, J=13.0, 8.2, 4.0Hz, 2H), 1.91 (d, J=7.0Hz, 3H).

[0927] Compound DA-2167H(cis): 22.6 mg, syrupy solid, ESI [M+H] + =338.1.

[0928] 1 H NMR(400MHz,d6-DMSO)δ8.40(d,J=1.2Hz,1H),7.31(tt,J=11.1,2.2Hz,1H),7.21–7.13(m,1H),7.10(td,J=8.9,2.4Hz,1H),6.68(q,J =7.0Hz,1H),5.03–4.90(m,1H),3.96–3.84(m,1H),3.18(d,J=6.4Hz,3H),2.21–2.04(m,2H),1.93(d,J=7.0Hz,3H),1.61–1.39(m,2H).

[0929] Compound M-2231: 126.7 mg, syrupy solid, ESI [M+H] + =324.1.

[0930] 1 H NMR(400MHz,d6-DMSO)δ8.40–8.38(m,1H),7.35–7.26(m,1H),7.25–7.19(m,1H),7.13–7.08(m,1H),6.72(q,J=7.0Hz,1H ),4.42–4.37(m,2H),3.08–2.96(m,1H),2.77–2.65(m,1H),2.53–2.49(m,1H),1.94(d,J=7.0Hz,3H),1.93–1.81(m,2H).

[0931] Example 23: Preparation of compounds M-2019 to M-2021, M-2023, M-2025(trans), M-2026 to M-2031, M-2041 and M-2045 of the present invention.

[0932] The preparation of target compound M-2026 is similar to that of target compound DA-2048-3.

[0933] Compound M-2026: 122.6 mg, syrupy solid, ESI [M+H] + =300.1.

[0934] 1 H NMR(400MHz,d6-DMSO)δ8.36(s,1H),7.54(qd,J=9.4,5.0Hz,1H),7.17(tdd,J=9.8,3.8,2.2H z,1H),6.64(q,J=7.1Hz,1H),4.38–4.19(m,2H),2.05(d,J=7.1Hz,3H),1.25(t,J=7.1Hz,3H).

[0935] The preparation of target compounds M-2019~M-2021, M-2023, M-2025(trans), M-2027~M-2031 is similar to that of target compound DA-2048.

[0936] Compound M-2019: 48.8 mg, syrupy solid, ESI [M+H] + =366.1.

[0937] 1H NMR(400MHz,d6-DMSO)δ8.46(s,1H),7.55(qd,J=9.4,4.9Hz,1H),7.26–7.10(m,1H),6.60(q,J=7.1Hz,1H),5.76(t,J=6.7Hz,1H),5.10( dd,J=12.1,6.7Hz,1H),4.96(dd,J=12.1,6.6Hz,1H),4.89(d,J=7.4Hz,1H),4.81–4.71(m,1H),4.71–4.60(m,2H),2.05(d,J=7.0Hz,3H).

[0938] Compound M-2020: 110.1 mg, syrupy solid, ESI [M+H] + =330.1.

[0939] 1 H NMR(400MHz,d6-DMSO)δ8.36(s,1H),7.53(ddd,J=19.1,9.4,5.0Hz,1H),7.17(tdd,J=9.8,3.9,2.2Hz ,1H),6.64(q,J=7.1Hz,1H),4.43–4.35(m,2H),3.67–3.52(m,2H),3.26(s,3H),2.05(d,J=7.1Hz,3H).

[0940] Compound M-2021: 88.4 mg, syrupy solid, ESI [M+H] + =356.1.

[0941] 1 H NMR(400MHz,d6-DMSO)δ8.40(s,1H),7.54(qd,J=9.4,5.0Hz,1H),7.23–7.07(m,1H),6.62(q,J=7.1Hz,1H),4.79( p,J=7.2Hz,1H),3.62(p,J=6.8Hz,1H),3.16(s,3H),2.83–2.68(m,2H),2.04(d,J=7.1Hz,3H),2.00–1.88(m,2H).

[0942] Compound M-2023: 117.9 mg, syrupy solid, ESI [M+H] + =356.1.

[0943] 1H NMR(400MHz,d6-DMSO)δ8.41–8.39(m,1H),7.58–7.49(m,1H),7.25–7.09(m,1H),6.63(q,J=7.0Hz,1H),5.05–4 .85(m,1H),4.00–3.79(m,1H),3.20–3.13(m,3H),2.20–2.08(m,2H),2.04(d,J=7.1Hz,3H),1.59–1.34(m,2H).

[0944] Compound M-2025(trans): 54.2 mg, syrupy solid, ESI [M+H] + =370.1.

[0945] 1 H NMR(400MHz,d6-DMSO)δ8.38–8.36(m,1H),7.59–7.51(m,1H),7.21–7.16(m,1H),6.73–6.58(m,1H),5.15–5. 10(m,1H),3.78–3.67(m,1H),3.27–3.22(m,3H),2.05(d,J=7.1Hz,3H),2.02–1.86(m,2H),1.74–1.53(m,4H).

[0946] Compound M-2027: 89.4 mg, white solid, ESI [M+H] + =342.1.

[0947] 1 H NMR(400MHz,d6-DMSO)δ8.42(s,1H),7.55(qd,J=9.4,5.0Hz,1H),7.24–7.11(m,1H),6.61(q,J=7.1Hz,1 H),4.78(d,J=7.2Hz,1H),4.62(d,J=7.2Hz,1H),4.56–4.40(m,2H),2.05(d,J=7.1Hz,3H),1.62(s,3H).

[0948] Compound M-2028: 94.5 mg, syrupy solid, ESI [M+H] + =344.1.

[0949] 1H NMR(400MHz,d6-DMSO)δ8.36(s,1H),7.54(qd,J=9.4,5.0Hz,1H),7.25–7.10(m,1H),6.65(q,J=7.1Hz,1H) ,4.51–4.28(m,2H),3.70–3.54(m,2H),3.45(q,J=7.0Hz,2H),2.05(d,J=7.1Hz,3H),1.07(t,J=7.0Hz,3H).

[0950] Compound M-2029: 98.8 mg, white solid, ESI [M+H] + =344.1.

[0951] 1 H NMR(400MHz,d6-DMSO)δ8.38(s,1H),7.54(qd,J=9.4,5.0Hz,1H),7.24–7.10(m,1H),6.64(q,J=7.1Hz,1H ), 4.29 (t, J = 6.5Hz, 2H), 3.38 (t, J = 6.2Hz, 2H), 3.22 (s, 3H), 2.05 (d, J = 7.1Hz, 3H), 1.87 (p, J = 6.4Hz, 2H).

[0952] Compound M-2030: 49.4 mg, syrupy solid, ESI [M+H] + =328.1.

[0953] 1 H NMR(400MHz,d6-DMSO)δ8.44–8.42(m,1H),7.58–7.49(m,1H),7.26–7.10(m,1H),6.64(q,J=7.1Hz,1H),4.70–4 .56(m,1H),4.11–4.04(m,1H),3.31–3.18(m,1H),2.87–2.79(m,1H),2.77–2.65(m,1H),2.05(d,J=7.1Hz,3H).

[0954] Compound M-2031: 62.7 mg, syrupy solid, ESI [M+H] + =342.1.

[0955] 1H NMR(400MHz,d6-DMSO)δ8.40–8.38(m,1H),7.58–7.49(m,1H),7.24–7.10(m,1H),6.65(q,J=7.1Hz,1H),4.37(t, J=6.2Hz,2H),3.06–2.93(m,1H),2.76–2.66(m,1H),2.51–2.47(m,1H),2.05(d,J=7.1Hz,3H),1.96–1.72(m,2H).

[0956] Compound M-2041: 152.1 mg, syrupy solid, ESI [M+H] + =368.1.

[0957] 1 H NMR(400MHz,d6-DMSO)δ8.37–8.35(m,1H),7.59–7.51(m,1H),7.20–7.15(m,1H),6.63(q,J=7.0Hz,1H),5.63–5.51(m,1H),5.4 7–5.34(m,1H),5.04–5.02(m,1H),4.97–4.81(m,1H),3.61–3.49(m,2H),3.29(s,1.5H),3.23(s,1.5H),2.05(d,J=7.1Hz,3H).

[0958] Compound M-2045: 53.5 mg, white solid, ESI [M+H] + =358.1.

[0959] 1 H NMR(400MHz,d6-DMSO)δ8.42(s,1H),7.55(qd,J=9.4,5.0Hz,1H),7.24–7.12(m,1H),6.61(q,J=7.1Hz,1H ), 4.78 (d, J = 7.2Hz, 1H), 4.62 (d, J = 7.2Hz, 1H), 4.50 (t, J = 7.3Hz, 2H), 2.05 (d, J = 7.1Hz, 3H), 1.62 (s, 3H).

[0960] Example 24: Preparation of compounds M-2141, M-2148, M-2155 and M-2166 of the present invention

[0961] The preparation of target compounds M-2141, M-2148, M-2155 and M-2166 is similar to that of target compound DA-2048.

[0962] Compound M-2141: 54.4 mg, syrupy solid, ESI [M+H] + =328.1.

[0963] 1 H NMR(400MHz,d6-DMSO)δ8.40(s,1H),7.47–7.33(m,2H),6.79–6.72(m,2H) ,4.47–4.26(m,2H),3.68–3.51(m,2H),3.25(s,3H),1.95(d,J=7.0Hz,3H).

[0964] Compound M-2148: 34.8 mg, syrupy solid, ESI [M+H] + =340.1.

[0965] 1 H NMR(400MHz,d6-DMSO)δ8.44–8.43(m,1H),7.48–7.34(m,2H),6.80–6.73(m,2H),4.46–4.30(m,2H) ,3.05–2.94(m,1H),2.74–2.60(m,1H),2.50–2.47(m,1H),1.95(d,J=7.0Hz,3H),1.93–1.77(m,2H).

[0966] Compound M-2155: 20.2 mg, syrupy solid, ESI [M+H] + =340.1.

[0967] 1 H NMR(400MHz,d6-DMSO)δ8.35(s,1H),7.47–7.35(m,2H),6.80(dd,J=6.2,2.7Hz,1H),6.73(q ,J=6.8Hz,1H),4.52–4.33(m,2H),2.89(t,J=6.1Hz,2H),2.13(s,3H),1.94(d,J=7.0Hz,3H).

[0968] Compound M-2166: 28.0 mg, syrupy solid, ESI [M+H] + =366.1.

[0969] 1H NMR(400MHz,d6-DMSO)δ8.45–8.44(m,1H),7.49–7.27(m,2H),6.78–6.70(m,2H),5.70–5 .67(m,1H),3.72–3.54(m,2H),3.28–3.25(m,3H),1.97–1.95(m,3H),1.84–1.81(m,3H).

[0970] The following experimental examples demonstrate the beneficial effects of the present invention.

[0971] Experimental Example 1: Determination of Pharmacological Data of the Compounds of the Invention

[0972] 1. Experimental Methods

[0973] Testing the anesthetic effect of the compound of this invention after tail vein injection in rats (determination of the minimum effective anesthetic dose):

[0974] 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.

[0975] 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.

[0976] 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。

[0977] 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;40mg / kg<E≤50mg / kg;50mg / kg<F≤60mg / kg;60mg / kg<G≤70mg / kg;70mg / kg<H≤80mg / kg;80mg / kg<I≤90mg / kg;90mg / kg<J≤100mg / kg;K>100mg / kg。

[0978] Pharmacological characteristics of equivalent doses:

[0979] 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.

[0980] 2. Experimental Results

[0981] Table 1. Pharmacological data of the compounds of the present invention after a single intravenous injection.

[0982] Table 2. Minimum analgesic dose of the compound of the present invention for a single intravenous injection

[0983] 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 groups, halogens; R2 is selected from C 1-8 Alkyl, C 2-8 Alkenyl, 3-8 member saturated cycloalkyl; R3 is hydrogen; L3 is absent; The five-membered heteroaryl ring is replaced; K4 is N, and one of K1, K2, and K3 is either N or CR. a One is CR b One is CR k R k for L4 is selected from none, C 1-6 Alkylene; L is selected from none, C 1-6 Alkylene, =CO; R0 is selected from C that is either unsubstituted or substituted by one or more R8 molecules. 1-8 Alkyl, C 2-8 alkenyl, C 2-8 Alkyne group, unsubstituted or substituted C with one or more R8 groups 1-6 Alkoxy, C 2-8 alkenyl-substituted C 2-8 alkynyl group, C 2-8 alkynyl-substituted C 2-8 alkenyl, hydroxyl group; R8 is independently selected from hydroxyl, C 2-8 alkenyl, C 2-8 Alkyne group, =O, OR, C 1-6 Alkoxy, C 2-8 alkenyl-substituted C 2-8 alkynyl group, C 2-8 alkynyl-substituted C 2-8 Alkenyl group; R is a hydroxyl protecting group; Ring B is selected from 3-8 membered saturated cycloalkyl groups, 3-8 membered saturated heterocyclic groups, and 3-6 membered unsaturated cycloalkyl groups; R6 is selected from hydrogen, C 1-8 Alkyl, C 1-8 Alkoxy, C 2-8 alkenyl, R a Selected from hydrogen and halogens; R b Selected from hydrogen and halogens; The compound is not 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 groups, halogens; R2 is selected from C 1-4 Alkyl, C 2-4 Alkenyl, 3-6 membered saturated cycloalkyl; L4 is selected from none, C 1-3 Alkylene; L is selected from none, C 1-3 Alkylene, =CO; R0 is selected from C that is either unsubstituted or substituted by one or more R8 molecules. 1-6 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, unsubstituted or substituted C with one or more R8 groups 1-4 Alkoxy, C 2-4 alkenyl-substituted C 2-4 alkynyl group, C 2-4 alkynyl-substituted C 2-4 alkenyl, hydroxyl group; R8 is independently selected from hydroxyl, C 2-4 alkenyl, C 2-4 Alkyne group, =O, OR, C 1-4 Alkoxy, C 2-4 alkenyl-substituted C 2-4 alkynyl group, C 2-4 alkynyl-substituted C 2-4 Alkenyl group; R is a hydroxyl protecting group; Ring B is selected from 3-6 membered saturated cycloalkyl groups, 3-6 membered saturated heterocyclic groups, and 3-6 membered unsaturated cycloalkyl groups; R6 is selected from hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 alkenyl, 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, II-1c or II-1d: Among them, R1, R2, R3, L, R0, R b As described in claim 2; m1, m2, m3, and m4 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 3, characterized in that, The Each is selected independently from: Wherein, R1 is as described in claim 2.

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-2a, II-2b, II-2c, II-2d, or II-2e: Among them, R1, R2, R3, L, R0, R b 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 5, characterized in that, The Each is selected independently from: Wherein, R1 is as described in claim 2.

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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