Heterocyclic compound and use thereof

Abstract

Provided in the present invention are a heterocyclic compound and the use thereof, belonging to the technical field of pharmaceutical chemistry. A series of heterocyclic compounds prepared in the present invention have highly efficient sedative, hypnotic, and / or anesthetic effects, can control status epilepticus, and also have analgesic effects, thus providing a new option for the clinical preparation of a drug having analgesic effects, a drug having anesthetic, sedative, and hypnotic effects and / or capable of controlling status epilepticus, and a drug having anesthetic, sedative, and hypnotic effects and / or capable of controlling status epilepticus which also has analgesic effects.

Description

Heterocyclic compound and use thereof TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical chemistry, and particularly relates to a heterocyclic compound and use thereof. BACKGROUND

[0002] Clinically, anesthetic drugs play an important role in the induction of general anesthesia, the maintenance of general anesthesia, and the sedation of ICU critical patients. Propofol is a fast-acting and short-acting intravenous general anesthetic drug currently used in clinical practice. It has the advantages of fast onset of anesthetic induction, rapid recovery, perfect functional recovery, and low incidence of postoperative nausea and vomiting. However, none of the intravenous general anesthetic drugs used in clinical practice, including propofol, etomidate, fospropofol disodium, and cyclopropofol, has analgesic effect. If a compound has sedative, hypnotic, and / or anesthetic effect, can control status epilepticus, and also has analgesic effect, it can achieve more perfect analgesia, significantly reduce the use amount of opioid analgesic drugs, reduce the adverse reactions of opioid analgesic drugs, and make the sedation, hypnotic, and / or anesthesia process more stable. At the same time, it can also reduce the use amount of other drugs in combined anesthesia, speed up the recovery of the patient's self-sedation, hypnotic, and / or anesthesia state, and increase the safety of the patient. Therefore, there is an urgent need to develop a drug that not only has sedative, hypnotic, and / or anesthetic effect, can control status epilepticus, but also has analgesic effect.

[0003] (±)-5-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole is an imidazole alpha-2-adrenergic receptor agonist with sedative and analgesic effects. However, the activity of (±)-5-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole needs to be further improved. Therefore, there is an urgent need to develop a drug that not only has high sedative, hypnotic, and / or anesthetic effect, can control status epilepticus, but also has analgesic effect. SUMMARY

[0004] The purpose of the present application is to provide a heterocyclic compound and its use in the preparation of a drug with analgesic effect, in the preparation of a drug with anesthetic, sedative, hypnotic effect and / or capable of controlling status epilepticus, and in the preparation of a drug with anesthetic, sedative, hypnotic effect and / or capable of controlling status epilepticus, and also with analgesic effect.

[0005] The present application provides a compound represented by formula I, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, a prodrug thereof, a metabolite thereof, or a deuterated derivative thereof:

[0006] selected from the following groups which are substituted or unsubstituted: each of said substituents is independently selected from the group consisting of hydroxy, halogen, cyano, (CR6R7)n m R8, mercapto, amino, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 alkoxy, C 1-8 alkylthio, L-Cring, Cring is selected from the group consisting of 3-8 membered saturated cycloalkyl, 3-8 membered saturated heterocyclyl, phenyl, 5-6 membered heteroaromatic ring;

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

[0008] R6, R7are each independently selected from the group consisting of hydrogen, C 1-8 alkyl;

[0009] R8is selected from CONR 10 R 11 , NR 10 R 11 , COOR 12 , COR 12 , OR 12 , phenyl substituted with one or two substituents each independently selected from the group consisting of halogen, hydroxy, nitro, cyano, C 1-8 alkyl, C 1-8 alkoxy;

[0010] L is selected from nothing, O, S, NR 10 R 11 , (CR 15 R 16 ) p , 3-6 membered saturated cycloalkyl, 3-6 membered saturated heterocyclyl, C(=CR c R d ), CO;

[0011] p is selected from 0, 1, 2, 3, 4, 5;

[0012] R 15 , R 16 are each independently selected from the group consisting of hydrogen, halogen, halogenated or unhalogenated C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkenyl substituted C 1-8 alkyl, C 1-8 alkoxy, OH, 3-8 membered saturated cycloalkyl, OCOR 12 , SO2R 17 ; R 17 is selected from C 1-8 alkyl;

[0013] R9is each independently selected from NR 10 R 11 , C 2-8 enyl, C 1-8 alkyl, halo, hydroxyl, amino, thiol, C 1-8 alkyl, C 1-8 alkoxy, C 2-8 enyl, C 2-8 ynyl, OCOR 9a , SO2R 9a , OR 9c , 3-8 membered saturated cycloalkyl, one or two R 9b substituted 3-8 membered saturated cycloalkyl, 3-8 membered saturated heterocyclyl, one or two R 9b substituted 3-8 membered saturated heterocyclyl, phenyl, one or two R 9b substituted phenyl, 5-6 membered heteroaromatic ring, one or two R 9b substituted 5-6 membered heteroaromatic ring;

[0014] R 9a is selected from C 1-5 alkyl; R 9b is each independently selected from hydroxyl, halo, halo or unhalo C 1-5 alkyl, halo or unhalo C 1-5 alkyl, 3-6 membered saturated cycloalkyl, 3-6 membered saturated heterocyclyl; R 9c is selected from 3-6 membered saturated cycloalkyl, 3-6 membered saturated heterocyclyl;

[0015] R 10 , R 11 is each independently selected from hydrogen, OH, C 1-8 alkyl, 3-8 membered saturated cycloalkyl, R 12 is selected from C 1-8 alkyl, 3-8 membered saturated cycloalkyl, 3-8 membered saturated heterocyclyl, 5-6 membered heteroaromatic ring, n is selected from 0, 1, 2, 3, 4, 5; R 13 is selected from hydroxyl, C 1-8 alkoxy;

[0016] R C , R D is each independently selected from hydrogen, halo, halo or unhalo C 1-6 alkyl, halo or unhalo C 1-6 alkyl, OH, OR s , or R C , R D are joined to form a 3-6 membered saturated cycloalkyl or 3-6 membered saturated heterocyclyl, or RC R D and the C atom therebetween forms C(=CR c R d ), CO; R s is selected from 3-6 membered saturated cycloalkyl, 3-6 membered saturated heterocyclyl, benzyl;

[0017] R c , R d each independently is selected from hydrogen, halogen;

[0018] R1, R2, R3, R4, R5are each independently selected from hydrogen, hydroxyl, halogen, halo- or unhalo-genated C 1-8 alkyl, halo- or unhalo-genated C 1-8 alkoxy, L1R 1a , L1is selected from null, C 1-4 alkylene, R 1a is selected from phenyl, 3-6 membered saturated cycloalkyl, 3-6 membered saturated heterocyclyl.

[0019] Further, the structure of the compound is shown as Formula II-a, II-b, III-a, III-b:

[0020] z is selected from 0, 1, 2;

[0021] R E each independently is selected from hydroxyl, halogen, cyano, the following groups unsubstituted or substituted with one or two or more R9: amino, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 alkoxy, C 1-3 alkylthio, 3-4 membered saturated cycloalkyl, 3-4 membered saturated heterocyclyl, phenyl, 5-6 membered heteroaromatic ring;

[0022] R9is each independently selected from halogen, hydroxyl, amino, mercapto, C 1-3 alkyl, C 1-3 alkoxy, C 2-3 alkenyl, C 2-3 alkynyl, OCOR 9a , SO2R 9a , OR 9c , 3-4 membered saturated cycloalkyl, 3-4 membered saturated cycloalkyl substituted with one or two or more R 9b , 3-4 membered saturated heterocyclyl, 3-4 membered saturated heterocyclyl substituted with one or two or more R 9b , phenyl, phenyl substituted with one or two or more R 9b , 5-6 membered heteroaromatic ring, 5-6 membered heteroaromatic ring substituted with one or two or more R 9bsubstituted 5-6 membered heteroaromatic ring;

[0023] R 9a selected from C 1-3 alkyl; R 9b each independently selected from hydroxy, halogen, halogenated or unhalogenated C 1-3 alkyl, halogenated or unhalogenated C 1-3 alkoxy, 3-4 membered saturated cycloalkyl, 3-4 membered saturated heterocyclyl; R 9c selected from 3-4 membered saturated cycloalkyl, 3-4 membered saturated heterocyclyl;

[0024] R C , R D each independently selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy, or R C , R D together with the C atom in between form C=CH2, CO;

[0025] R1, R2, R3, R4, R5are each independently selected from hydrogen, hydroxy, halogen, halogenated or unhalogenated C 1-3 alkyl, halogenated or unhalogenated C 1-3 alkoxy.

[0026] Further, the structure of the compound is shown as formula V:

[0027] z is selected from 0, 1, 2;

[0028] R E each independently selected from hydroxy, halogen, cyano, the following groups which are unsubstituted or substituted with one or more than two R9: amino, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 alkoxy, C 1-3 alkylthio, L-C ring, C ring selected from 3-4 membered saturated cycloalkyl, 3-4 membered saturated heterocyclyl, phenyl, 5-6 membered heteroaromatic ring;

[0029] L is selected from nothing, O, S, NR 10 R 11 , (CR 15 R 16 ) p , 3-4 membered saturated cycloalkyl, 3-4 membered saturated heterocyclyl, C(=CR c R d ), CO;

[0030] p is selected from 0, 1, 2, 3;

[0031] R 15 , R 16 each independently selected from the group consisting of hydrogen, halogen, halogenated or unhalogenated C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkenyl substituted with C 1-3 alkyl, C 1-3 alkoxy, OH, 3-4 membered saturated cycloalkyl, OCOR 12 , SO2R 17 ; R 17 is selected from the group consisting of C 1-3 alkyl;

[0032] R9is each independently selected from the group consisting of halogen, hydroxyl, amino, thiol, C 1-3 alkyl, C 1-3 alkoxy, C 2-3 alkenyl, C 2-3 alkynyl, OCOR 9a , SO2R 9a , OR 9c , 3-4 membered saturated cycloalkyl, one or two R 9b substituted 3-4 membered saturated cycloalkyl, 3-4 membered saturated heterocyclyl, one or two R 9b substituted 3-4 membered saturated heterocyclyl, phenyl, one or two R 9b substituted phenyl, 5-6 membered heteroaromatic ring, one or two R 9b substituted 5-6 membered heteroaromatic ring;

[0033] R 9a is selected from the group consisting of C 1-3 alkyl; R 9b is each independently selected from the group consisting of hydroxyl, halogen, halogenated or unhalogenated C 1-3 alkyl, halogenated or unhalogenated C 1-3 alkoxy, 3-4 membered saturated cycloalkyl, 3-4 membered saturated heterocyclyl; R 9c is selected from the group consisting of 3-4 membered saturated cycloalkyl, 3-4 membered saturated heterocyclyl;

[0034] R 10 , R 11 is each independently selected from the group consisting of hydrogen, OH, C 1-5 alkyl, 3-6 membered saturated cycloalkyl, R 13 is selected from the group consisting of C 1-5 alkyl, 3-6 membered saturated cycloalkyl, 3-6 membered saturated heterocyclyl, 5-6 membered heteroaromatic ring, n is selected from 0, 1, 2, 3, 4, 5; R 13 is selected from the group consisting of hydroxyl, C 1-5 alkoxy;

[0035] R C , R D each independently selected from the group consisting of hydrogen, C 1-3 alkyl, C 1-3 alkoxy, or R C , R D and the C-atoms between them form together C=CH2, CO;

[0036] R c , R d each independently selected from the group consisting of hydrogen, halogen;

[0037] R1, R2, R3, R4, R5are each independently selected from the group consisting of hydrogen, hydroxyl, halogen, halogenated or unhalogenated C 1-3 alkyl, halogenated or unhalogenated C 1-3 alkoxy.

[0038] Further, the structure of the compound is shown in formula V-a, V-b, V-c:

[0039] z, R E , R C , R D , R1, R2, R3, R4, R5are as described above.

[0040] Further, the structure of the compound is shown in formula VI-a, VI-b, VI-c, VI-d:

[0041] X is selected from the group consisting of halogen, hydrogen, halogenated or unhalogenated C 1-3 alkyl;

[0042] R C , R D , R1, R2, R3, R4, R5are as described above.

[0043] Further, the structure of the compound is shown in formula VII-a, VII-b:

[0044] q is selected from 1, 2, 3;

[0045] R 91 selected from the group consisting of hydrogen, halogen, hydroxyl, amino, thiol, C 1-3 alkyl, C 1-3 alkoxy, C 2-3 alkenyl, C 2-3 alkynyl, OCOR 9a , SO2R 9a , OR 9c , 3-4 membered saturated cycloalkyl, one or two R 9bsubstituted 3-4 membered saturated cycloalkyl, 3-4 membered saturated heterocyclyl, one or two R 9b substituted 3-4 membered saturated heterocyclyl, phenyl, one or two R 9b substituted phenyl, 5-6 membered heteroaromatic ring, one or two R 9b substituted 5-6 membered heteroaromatic ring;

[0046] R 9a selected from C 1-3 alkyl; R 9b each independently selected from hydroxyl, halogen, halo or unhalo genated C 1-3 alkyl, halo or unhalogenated C 1-3 alkoxy, 3-4 membered saturated cycloalkyl, 3-4 membered saturated heterocyclyl; R 9c selected from 3-4 membered saturated cycloalkyl, 3-4 membered saturated heterocyclyl;

[0047] R C , R D , R1, R2, R3, R4, R5, L, X are as described above.

[0048] The present application also provides the following compound, stereoisomer thereof, pharmaceutically acceptable salt thereof, solvate thereof, prodrug thereof, metabolite thereof or deuterated derivative thereof, the compound is selected from one of the following compounds:

[0049] Further, the pharmaceutically acceptable salt is citrate, hydrofluoric acid salt, phosphate, propionic acid salt, succinate, tartrate, acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate, carbonate, bisulfate, sulfate, borate, camphorsulfonate, citrate, cyclamate, edisylate, ethanesulfonate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hydrochloride, hydrobromide, hydroiodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthalene-2-carboxylate, oxalate, palmitate, pamoate, phosphate, hydrogen phosphate, dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, xinafoate or p-toluenesulfonate.

[0050] The present application also provides a pharmaceutical composition, which is a preparation prepared from the above-mentioned compound, stereoisomer thereof, pharmaceutically acceptable salt thereof, solvate thereof, prodrug thereof, metabolite thereof or deuterated derivative thereof as an active ingredient, and a pharmaceutically acceptable adjuvant.

[0051] The present application also provides the use of the above-mentioned compound, stereoisomer thereof, pharmaceutically acceptable salt thereof, solvate thereof, prodrug thereof, metabolite thereof or deuterated derivative thereof in the preparation of a drug having analgesic effect, and / or, having anesthetic, sedative, hypnotic effect and / or being able to control status epilepticus.

[0052] The "use in a drug having analgesic effect, and / or, having anesthetic, sedative, hypnotic effect and / or being able to control status epilepticus" includes the following three cases: (1) having analgesic effect; (2) having anesthetic, sedative, hypnotic effect and / or being able to control status epilepticus; (3) having both anesthetic, sedative, hypnotic effect and / or being able to control status epilepticus and analgesic effect.

[0053] The "having both anesthetic, sedative, hypnotic effect and / or being able to control status epilepticus and analgesic effect" in the present application refers to no response to noxious stimuli or increasing the response threshold to noxious stimuli when the compound in the present application produces sedative, hypnotic and / or anesthetic effect.

[0054] The "drug having sedative effect" in the present application refers to a drug that can effectively help sleep and effectively improve sleep. That is, it can avoid the serious harm of insomnia to the human body, treat insomnia, and improve sleep quality.

[0055] The "drug having hypnotic effect" in the present application refers to a drug that can induce sleepiness and promote sleep. That is, it has an inhibitory effect on the central nervous system, causes sedation at a small dose, and causes general anesthesia in excess.

[0056] The "drug having anesthetic effect" in the present application refers to a reversible inhibition of central nervous and / or peripheral nervous system function produced by a drug. The main feature of this inhibition is the loss of sensation, especially pain sensation. Preferably, the anesthetic is general anesthesia.

[0057] The "general anesthesia" in the present application, referred to as general anesthesia, refers to the temporary inhibition of the central nervous system produced by anesthetic drugs after entering the body, and the clinical manifestations are loss of consciousness, loss of general pain sensation, amnesia, reflex inhibition and skeletal muscle relaxation.

[0058] The "status epilepticus" according to the present application means that the consciousness is not completely recovered between successive seizures of epilepsy, or the seizures frequently recur, or the seizures last for more than 30 minutes and do not stop by themselves. If the long-time seizures are not treated in time, irreversible brain damage can be caused due to high fever, circulatory failure or toxic damage of neurons, and the disability rate and mortality rate are very high, so the status epilepticus is a common emergency in internal medicine.

[0059] Definitions of terms used in connection with the present application: Unless otherwise indicated, the initial definition of a group or term provided herein is intended to apply throughout the description in this document to that group or term; to the extent a term is not specifically defined in this document, it should be given the meaning that would be given by one of ordinary skill in the art to which it belongs based on the disclosure and context.

[0060] The minimum and maximum number of carbon atoms in a hydrocarbon group is indicated by a prefix, e.g., the prefix C a～b Alkyl means any alkyl group containing "a" to "b" carbon atoms. For example, C 1～6 Alkyl means any alkyl group containing "a" to "b" carbon atoms. For example, C 1～6 Alkyl means any alkyl group containing "a" to "b" carbon atoms. For example, C 1-4 Alkyl means any alkyl group containing "a" to "b" carbon atoms. For example, C

[0061] The minimum and maximum number of ring atoms in a cyclic group is indicated by a prefix, e.g., 3-8 membered saturated cycloalkyl means a saturated cycloalkyl group containing 3, 4, 5, 6, 7, or 8 ring atoms, 3-8 membered saturated heterocyclyl means a saturated heterocyclyl group containing 3, 4, 5, 6, 7, or 8 ring atoms, and so on.

[0062] "Substituted" herein means that 1, 2, or more hydrogen atoms in a molecule are replaced by other different atoms or molecules, including 1, 2, or more substitutions on the same atom or different atoms in the molecule.

[0063] "Substituted" herein means that 1, 2, or more hydrogen atoms in a molecule are replaced by other different atoms or molecules, including 1, 2, or more substitutions on the same atom or different atoms in the molecule.

[0064] "Aryl" means a fully carbon monocyclic group having a conjugated pi electron system, e.g., phenyl. The aryl group does not contain heteroatoms, such as nitrogen, oxygen, or sulfur, and the point of attachment to the parent must be on a carbon atom in the ring having the conjugated pi electron system.

[0065] "Heteroaromatic ring" means a heteroaromatic group containing one to several heteroatoms. The heteroatoms herein include, but are not limited to, oxygen, sulfur, and nitrogen. Examples include furanyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkyl pyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, thiazolyl, oxazolyl, pyrimidinonyl, pyridinonyl, indolyl, tetrazolyl, and the like.

[0066] In some preferred embodiments, the heteroaromatic ring is a 5-6 membered heteroaromatic ring.

[0067] A heterocyclic compound is a cyclic compound composed of carbon atoms and non-carbon atoms (heteroatoms) combined to form a ring. The non-carbon atoms other than carbon atoms in the ring are referred to as "ring heteroatoms".

[0068] Halogen is fluorine, chlorine, bromine, or iodine.

[0069] In the present application, "pharmaceutically acceptable" means that a carrier, vehicle, diluent, adjuvant, and / or a formed salt is generally chemically or physically compatible with other ingredients constituting a pharmaceutical dosage form, and is physiologically compatible with a recipient.

[0070] In the present application, "salt" means an acid and / or a base salt of a compound or its stereoisomer formed with inorganic and / or organic acids and / or bases, and also includes a zwitterionic salt (internal salt), and further includes a quaternary ammonium salt, such as an alkylammonium salt. These salts can be obtained directly in the final isolation and purification of the compound. Alternatively, they can be obtained by mixing a compound, or its stereoisomer, with an appropriate amount (e.g., equivalent amount) of an acid or a base. These salts can be collected by filtration as a precipitate in a solution, or recovered after evaporation of a solvent, or prepared by freeze-drying after reaction in an aqueous medium. The salt described in the present application can be a hydrochloride, a sulfate, a citrate, a besylate, a hydrobromide, a hydrofluoride, a phosphate, an acetate, a propionate, a succinate, an oxalate, a malate, a succinate, a fumarate, a maleate, a tartrate, or a trifluoroacetate of the compound.

[0071] "Solvate thereof" means a solvate of a compound of the present application formed with a solvent, wherein the solvent includes, but is not limited to, water, ethanol, methanol, isopropanol, propylene glycol, tetrahydrofuran, dichloromethane.

[0072] "Stereoisomer" means a compound of the same molecular formula but different spatial arrangement of atoms.

[0073] Benzene sulfonate is 2,4-dimethylbenzene sulfonate.

[0074] Compared with the prior art, the compound of the present application has the following beneficial effects:

[0075] The present application provides compounds with other novel parent nucleus structures except imidazole compounds, and it is first discovered that the compounds have sedative, hypnotic and / or narcotic effects and can control status epilepticus, thereby providing a new choice for preparing drugs with sedative, hypnotic and / or narcotic effects and control of status epilepticus in clinic.

[0076] In addition, it is first discovered in the present application that the compounds not only have high sedative, hypnotic and / or narcotic effects and can control status epilepticus, but also have analgesic effects, so that the use of opioid analgesic drugs such as fentanyl, alfentanil, sufentanil or remifentanil can be reduced or not used in clinical application, thereby reducing the occurrence of adverse reactions such as circulatory depression, respiratory depression, urinary retention and skin itching of opioid analgesic drugs.

[0077] Obviously, according to the above content of the present application, according to the ordinary technical knowledge and conventional means in the art, other various forms of modifications, substitutions or changes can be made without departing from the above basic technical idea of the present application.

[0078] The above content of the present application will be further described in detail through the specific embodiments in the form of examples. However, this should not be understood as the scope of the above subject matter of the present application being limited to the following examples. Any technology realized based on the above content of the present application belongs to the scope of the present application. DETAILED DESCRIPTION

[0079] The raw materials and equipment used in the present application are known products, which are obtained by purchasing commercially available products. The raw materials and equipment used in the specific embodiments of the present application are known products, which are obtained by purchasing commercially available products.

[0080] The structure of the compound is determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). The NMR shift (δ) is given in units of 10 -6 (ppm). The determination of NMR is carried out by using a (Bruker Avance III 400) nuclear magnetic instrument, the determination solvent is deuterated dimethyl sulfoxide (d6-DMSO), and the internal standard is tetramethylsilane (TMS).

[0081] LCMS determination with Agilent LCMS1260-6110 (ESI), column: Waters X-Bridge C18 (50 mm x 4.6 mm x 3.5 μm); column temperature: 40 °C; flow rate: 2.0 mL / min; mobile phase: gradient from 95% [water + 0.05% TFA] and 5% [CH3CN + 0.05% TFA] to 0% [water + 0.05% TFA] and 100% [CH3CN + 0.05% TFA] in 3 min, hold for 1 min, gradient to 95% [water + 0.05% TFA] and 5% [CH3CN + 0.05% TFA] in 0.05 min, hold for 0.7 min.

[0082] 1) Medicinal materials and reagents

[0083] Thin layer chromatography silica gel plate uses Yantai Xinuo Chemical Co., Ltd. HSGF254 silica gel plate, thickness of 1 mm. Thin layer chromatography (TLC) uses the product of Yantai Jiangyou Silica Gel Development Co., Ltd., with a specification of 0.2 ± 0.03 mm. Column chromatography generally uses 100-200 mesh or 200-300 mesh silica gel as a carrier from Laoshan Taiyang Drying Agent Co., Ltd. (Weihai, Shandong).

[0084] 2) Main instruments

[0085] JA2003N electronic balance (Shanghai Youke Instruments Co., Ltd.);

[0086] DF-101S heat collecting constant temperature heating magnetic stirrer (Zhengzhou Setils Biological Technology Co., Ltd.);

[0087] 98-2 magnetic stirrer (Shanghai Sile Instrument Co., Ltd.);

[0088] ZF-2 three-purpose ultraviolet instrument (Shanghai Anting Electronic Instrument Factory);

[0089] RE-2000B rotary evaporator (Zhengzhou Ketai Experimental Equipment Co., Ltd.);

[0090] DLSK-5 / 20 low-temperature cooling liquid circulating pump (Zhengzhou Ketai Experimental Equipment Co., Ltd.);

[0091] W201D constant temperature water bath (Shanghai Shenshun Biological Technology Co., Ltd.);

[0092] SHB-III circulating water type vacuum pump (Zhengzhou Huitong Science and Technology Co., Ltd.);

[0093] SHB-B95 mobile water pump (Zhengzhou Huitong Science and Technology Co., Ltd.);

[0094] Ultraviolet high-pressure mercury lamp (Beijing Tianli Hengguang Light Source Electric Co., Ltd.).

[0095] DGJ-10C vacuum freeze dryer (Shanghai Bioden Biotech Co., Ltd.);

[0096] KQ5200 ultrasonic cleaner (Kunshan Ultrasonic Instrument Co., Ltd.);

[0097] 2XZ-2 rotary vane vacuum pump (Linhai Tan Vacuum Equipment Co., Ltd.);

[0098] Biotage Isolera One (Biotage Sweden AB)

[0099] Example 1, Preparation of compounds SZ-1-SZ-4 and SZ-24-SZ-25 of the present application

[0100] 1. Preparation of compound SZ-3-2

[0101] Ethyl oxazole-4-carboxylate (5.0 g, 35.4 mmol) was dissolved in dry THF (50 mL) at room temperature, and lithium aluminum hydride (1.3 g, 34.3 mmol) was slowly added in batches under dry ice cooling to -20 °C. The stirring was continued for 1 hour. After the reaction was completed by TLC monitoring, the reaction system was terminated with sodium sulfate decahydrate, and was suction filtered. The filter cake was washed with tetrahydrofuran (3 x 20 mL). The filtrate was concentrated under reduced pressure, and was dissolved in CH2Cl2(50 mL). Activated MnO2(33.8 g, 354 mmol, 91%) was added, and the stirring was continued at reflux for 5 hours. After the reaction was completed by TLC monitoring, the suction filtration was performed, 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 / 10-1 / 1), and TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1) monitoring was performed. The fraction with Rf= 0.6-0.7 was collected to obtain compound SZ-3-2 (680 mg, two-step yield 19.8%). ESI [M+H] + = 98.1.

[0102] 2. Preparation of target compound SZ-1

[0103] To a 250 mL three-necked flask, was added magnesium turnings (2.63 g, 109.5 mmol), iodine (30 mg) at room temperature, the reaction system was replaced with nitrogen for three times. Dry THF (1 mL) and 2,3-dimethylbromobenzene (200 mg, 1.08 mmol) were added to the reaction system. After the Grignard reaction was initiated, dry THF (90 mL) was added, and then 2,3-dimethylbromobenzene (17.68 g, 95.5 mmol) was added dropwise to the system at a rate of 0.15 mL / min. After the dropwise addition was completed, the reaction system was stirred at room temperature for 1 h to obtain Grignard reagent A.

[0104] To a 250 mL three-necked flask, was added magnesium turnings (2.63 g, 109.5 mmol), iodine (30 mg) at room temperature, the reaction system was replaced with nitrogen for three times. Dry THF (1 mL) and 2,3-dimethylbromobenzene (200 mg, 1.08 mmol) were added to the reaction system. After the Grignard reaction was initiated, dry THF (90 mL) was added, and then 2,3-dimethylbromobenzene (17.68 g, 95.5 mmol) was added dropwise to the system at a rate of 0.15 mL / min. After the dropwise addition was completed, the reaction system was stirred at room temperature for 1 h to obtain Grignard reagent A. + = 202.3.

[0105] 1 H NMR (400 MHz, d6-DMSO) δ 8.69 (d, J = 0.8 Hz, 1H), 8.58 (d, J = 0.8 Hz, 1H), 7.36 (d, J = 7.4 Hz, 1H), 7.29 (d, J = 7.0 Hz, 1H), 7.21 (t, J = 7.5 Hz, 1H), 2.30 (s, 3H), 2.15 (s, 3H).

[0106] 2. Preparation of target compound SZ-2

[0107] Compound SZ-1 (428 mg, 2.12 mmol) was dissolved in dry THF (10 mL) at room temperature, the reaction system was reduced to 0 °C with ice-salt bath, MeMgBr (3.2 mL, 1 mol / L in THF, 3.2 mmol) was added to the system at a rate of 1.0 mmol / min with a syringe, stirred at room temperature for 3 hours. After monitoring the reaction was complete by TLC, the reaction system was reduced to 0 °C with ice water bath, saturated aqueous ammonium chloride solution (30 mL) was slowly added to the reaction system, extracted with EtOAc (3 x 5 mL), combined organic phase was dried over anhydrous Na2SO4, suction filtration, concentrated under reduced pressure to obtain the crude product.

[0108] The crude product SZ-3-4 obtained in the previous step and TFA (1 mL) were dissolved in CH2Cl2(10 mL), stirred at room temperature for 2 hours. After monitoring the reaction was complete by TLC, concentrated under reduced pressure, saturated aqueous sodium bicarbonate solution (20 mL) was alkalized, extracted with CH2Cl2(3 x 5 mL), combined organic phase was dried over anhydrous Na2SO4, suction filtration, concentrated under reduced pressure to obtain the crude product, the crude product was purified by preparative TLC (dichloromethane / petroleum ether (v / v) = 1 / 3), the Rf= 0.5-0.6 part was collected to obtain the target compound SZ-2 (350 mg, two-step yield 82.9%) as a light yellow oil. ESI [M+H] + = 200.2

[0109] 1 H NMR (400 MHz, d6-DMSO) δ 8.39 (d, J = 0.9 Hz, 1H), 7.48 (s, 1H), 7.17 (d, J = 7.1 Hz, 1H), 7.11 (t, J = 7.5 Hz, 1H), 6.99 (d, J = 6.9 Hz, 1H), 6.05 (d, J = 2.1 Hz, 1H), 5.07 (d, J = 2.2 Hz, 1H), 2.26 (s, 3H), 2.04 (s, 3H).

[0110] 3. Preparation of the target compound SZ-3

[0111] Compound SZ-2 (200 mg, 1.0 mmol) and 10% wet Pd-C (20 mg) were dissolved in MeOH (10 mL) at room temperature, the system was replaced with hydrogen gas three times, stirred at room temperature under hydrogen gas overnight. After monitoring the reaction was complete by TLC, suction filtration, the filter cake was washed with methanol (3 x 10 mL), the filtrate was concentrated under reduced pressure to obtain the crude product, the crude product was purified by preparative TLC (ethyl acetate / petroleum ether (v / v) = 1 / 20), the Rf= 0.5-0.6 part was collected to obtain the target compound SZ-3 (128.3 mg, yield 63.7%) as a colorless oil. ESI [M+H] + = 202.3.

[0112] 1 H NMR (400 MHz, d6-DMSO) δ 8.24 (d, J = 0.7 Hz, 1H), 7.81 (t, J = 1.0 Hz, 1H), 7.02 - 6.97 (m, 2H), 6.96 - 6.91 (m, 1H), 4.29 (q, J = 7.0 Hz, 1H), 2.24 (s, 3H), 2.22 (s, 3H), 1.46 (d, J = 7.1 Hz, 3H).

[0113] 4. Preparation of target compounds SZ-4, SZ-24-SZ-25

[0114] The preparation method of target compound SZ-4 is similar to that of target compound SZ-1, using ethyl oxazole-5-carboxylate (1.0 g, 7.1 mmol) as the starting material, reduced by sodium borohydride, oxidized by pyridine sulfur trioxide, subjected to Grignard reaction, and oxidized by active MnO2 to obtain. The crude product was purified by preparative TLC (ethyl acetate / petroleum ether (v / v) = 1 / 20), and the Rf= 0.5-0.6 part was collected to obtain target compound SZ-4 (20 mg, total yield 1.4%). ESI [M+H] + = 202.1.

[0115] 1 H NMR (400 MHz, d6-DMSO) δ 8.77 (s, 1H), 7.78 (s, 1H), 7.40 (d, J = 7.7 Hz, 1H), 7.37 (d, J = 7.6 Hz, 1H), 7.24 (t, J = 7.6 Hz, 1H), 2.31 (s, 3H), 2.18 (s, 3H).

[0116] The preparation method of target compound SZ-24 is similar to that of target compound SZ-1, and the preparation method of target compound SZ-25 is similar to that of target compound SZ-3.

[0117] Compound SZ-24: 78 mg, ESI [M+H] + = 216.3

[0118] 1 H NMR (400 MHz, d6-DMSO) δ 8.77 (s, 1H), 7.78 (s, 1H), 7.40 (d, J = 7.7 Hz, 1H), 7.37 (d, J = 7.6 Hz, 1H), 7.24 (t, J = 7.6 Hz, 1H), 2.31 (s, 3H), 2.18 (s, 3H).

[0119] Compound SZ-25: 37 mg, ESI [M+H] += 216.3

[0120] 1 H NMR (400 MHz, d6-DMSO) d 7.06 - 6.99 (m, 2H), 6.89 - 6.83 (m, 1H), 6.77 (d, J = 0.7 Hz, 1H), 4.42 (q, J = 7.2 Hz, 1H), 2.30 (s, 3H), 2.26 (s, 3H), 2.22 (s, 3H), 1.46 (d, J = 7.1 Hz, 3H).

[0121] Example 2, Preparation of the compounds of the application SZ-5 to SZ-8 and SZ-26 to SZ-27

[0122] 1. Preparation of the target compound SZ-5

[0123] thiazole-4-carbaldehyde (1.78 g, 15.7 mmol) was dissolved in dry THF (10 mL), the reaction system was replaced with nitrogen three times, and then protected with nitrogen. The ice-salt bath was cooled to 0 °C, and A (30 mL, 1 mol / L in THF, 30 mmol) was added to the system at a rate of 2.5 mmol / min. After stirring at room temperature for 4 h, the reaction was monitored by TLC. After the reaction was completed, the reaction system was cooled to 0 °C with an ice-water bath, and saturated aqueous ammonium chloride solution (100 mL) was slowly added to the reaction system. The organic phase was extracted with EtOAc (3 x 15 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was dissolved in CH2Cl2(50 mL), and activated MnO2(15.0 g, 157 mmol, 91%) was added. After refluxing and stirring for 5 h, the reaction was monitored by TLC. After filtration, the filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 to 1 / 1), monitored by TLC (dichloromethane), and the fraction with Rf = 0.4 to 0.5 was collected to obtain the white solid target compound SZ-5 (2.4 g, two-step yield 70.4%). ESI [M+H] + = 218.1.

[0124] 1 H NMR (400 MHz, d6-DMSO) d 9.19 (d, J = 1.9 Hz, 1H), 8.51 (d, J = 1.9 Hz, 1H), 7.36 - 7.31 (m, 1H), 7.24 - 7.17 (m, 2H), 2.30 (s, 3H), 2.11 (s, 3H).

[0125] 2. Preparation of the target compound SZ-6

[0126] Compound SZ-5 (1.0 g, 4.6 mmol) was dissolved in dry THF (10 mL) at room temperature, the reaction system was reduced to 0 °C with ice-salt bath, MeMgBr (9.0 mL, 1 mol / L in THF, 9.0 mmol) was added to the system at a rate of 1.0 mmol / min with a syringe, and stirred at room temperature for 3 hours. After the reaction was completed by TLC monitoring, the reaction system was reduced to 0 °C with an ice-water bath, saturated aqueous ammonium chloride solution (30 mL) was slowly added to the reaction system, extracted with EtOAc (3 x 5 mL), the combined organic phase was dried over anhydrous Na2SO4, suction filtered, and concentrated under reduced pressure to obtain the crude product, which was directly used in the next step reaction without purification.

[0127] The crude product SZ-7-2 obtained in the previous step and TFA (2 mL) were dissolved in CH2Cl2(20 mL) at room temperature, and stirred at room temperature for 2 hours. After the reaction was completed by TLC monitoring, it was concentrated under reduced pressure, alkalized with saturated aqueous sodium bicarbonate solution (20 mL), extracted with CH2Cl2(3 x 5 mL), the combined organic phase was dried over anhydrous Na2SO4, suction filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by preparative TLC (ethyl acetate / petroleum ether (v / v) = 1 / 30), and the Rf = 0.5-0.6 fraction was collected to obtain the target compound SZ-6 (919 mg, two-step yield 92.7%) as a colorless oil. ESI [M+H] + = 216.3

[0128] 1 H NMR (400 MHz, d6-DMSO) δ 9.12 (d, J = 1.9 Hz, 1H), 7.18 (d, J = 7.2 Hz, 1H), 7.13 (t, J = 7.5 Hz, 1H), 7.01 (d, J = 6.8 Hz, 1H), 6.91 (d, J = 1.9 Hz, 1H), 6.27 (d, J = 2.3 Hz, 1H), 5.19 (d, J = 2.3 Hz, 1H), 2.27 (s, 3H), 2.00 (s, 3H).

[0129] 3. Preparation of the target compound SZ-7

[0130] Compound SZ-6 (468 mg, 2.17 mmol) and 10% wet palladium on carbon (50 mg) were dissolved in MeOH (15 mL) at room temperature, the system was replaced by hydrogen gas for three times, stirred under hydrogen gas at room temperature overnight. After the reaction was monitored to be completed by TLC, filtered, the filter cake was washed with methanol (3 x 10 mL), the filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by preparative TLC (ethyl acetate / petroleum ether (v / v) = 1 / 15), the Rf= 0.5-0.6 fraction was collected to obtain the target compound SZ-7 (169 mg, yield 35.8%) as a light brown oil. ESI [M+H] + = 218.2.

[0131] 1 H NMR (400 MHz, d6-DMSO) δ 8.99 (d, J = 1.9 Hz, 1H), 7.29 (dd, J = 1.9, 0.8 Hz, 1H), 7.02 - 6.97 (m, 2H), 6.96 - 6.91 (m, 1H), 4.59 (q, J = 7.0 Hz, 1H), 2.24 (s, 3H), 2.21 (s, 3H), 1.55 (d, J = 7.1 Hz, 3H).

[0132] 4. Preparation of target compounds SZ-8 and SZ-26-SZ-27

[0133] The preparation method of target compound SZ-8 is similar to that of target compound SZ-5, using thiazole-5-carbaldehyde (500 mg, 4.4 mmol) as the starting material, and obtaining through Grignard reaction and oxidation reaction. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 20-1 / 1), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 3) monitoring, and the Rf= 0.4-0.5 fraction was collected to obtain the target compound SZ-8 (850 mg, total yield 88.9%) as a yellow oil. ESI [M+H] + = 218.1.

[0134] 1 H NMR (400 MHz, d6-DMSO) δ 9.49 (s, 1H), 8.12 (d, J = 0.4 Hz, 1H), 7.39 (d, J = 7.4 Hz, 1H), 7.33 (d, J = 7.1 Hz, 1H), 7.25 (t, J = 7.6 Hz, 1H), 2.31 (s, 3H), 2.16 (s, 3H).

[0135] The preparation method of target compound SZ-26 is similar to that of target compound SZ-5, and the preparation method of target compound SZ-27 is similar to that of target compound SZ-7.

[0136] Compound SZ-26: 160 mg, ESI [M+H] + = 232.1

[0137] 1 H NMR (400 MHz, d6-DMSO) δ 7.84 (s, 1H), 7.37 (d, J = 7.4 Hz, 1H), 7.29 (d, J = 6.6 Hz, 1H), 7.23 (t, J = 7.5 Hz, 1H), 2.75 (s, 3H), 2.30 (s, 3H), 2.15 (s, 3H).

[0138] Compound SZ-27: 37 mg, ESI [M+H] + = 232.1

[0139] 1 H NMR (400 MHz, d6-DMSO) δ 7.35 (s, 1H), 7.10 - 7.00 (m, 3H), 4.62 (q, J = 7.2 Hz, 1H), 2.54 (s, 3H), 2.24 (s, 3H), 2.19 (s, 3H), 1.57 (d, J = 7.0 Hz, 3H).

[0140] Example 3, Preparation of compounds SZ-9~SZ-12 of the present application

[0141] 1. Preparation of compound SZ-12-1

[0142] To a solution of 2-(triphenylphosphoranylidene)propanal (50 g, 157.2 mmol) in dry CH2Cl2(100 mL) was added 3-oxetanone (10.0 g, 138.9 mmol) slowly at room temperature and stirred at room temperature for 16 hours. After the reaction was completed by TLC monitoring, water (100 mL) was added to the reaction system, extracted with CH2Cl2(2 x 100 mL), the combined organic phase was washed with saturated brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (methyl tert-butyl ether / petroleum ether (v / v) = 1 / 10~1 / 1), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1) monitoring, and the fraction with Rf= 0.5~0.6 was collected to obtain compound SZ-12-1 (15.0 g, yield 96%) as colorless oil.

[0143] 2. Preparation of compound SZ-12-2

[0144] To a solution of SZ-12-2 (5.0 g, 45.5 mmol) in CH2Cl2(100 mL) was added boron trifluoride etherate (0.17 mL, 1.34 mmol) slowly at room temperature and stirred for 1 min at room temperature. After the reaction was completed by TLC, water (50 mL) was added to the reaction system, extracted with CH2Cl2(2 x 50 mL), the combined organic phase was washed with saturated brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product SZ-12-3, which was used directly in the next step without purification.

[0145] 3. Preparation of compound SZ-12-3

[0146] To a solution of crude compound SZ-12-2 and MnO2(81.0 g, 847.8 mmol, 91%) in CH2Cl2(200 mL) was added at room temperature and stirred overnight at room temperature. After the reaction was completed by TLC, filtered, and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 40 ~ 1 / 20), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10) monitoring, and the fraction with Rf= 0.5 ~ 0.6 was collected to give compound SZ-12-3 (5.0 g, yield 33%) as colorless oil. ESI [M+H] + = 110.1

[0147] 4. Preparation of compound SZ-12-4

[0148] To a solution of SZ-12-3 (5.0 g, 45.5 mmol) in dry THF (30 mL) was added A (90 mL, 1 mol / L, 90 mmol) dropwise at a rate of 5.0 mmol / min under nitrogen protection at 0°C in an ice-salt bath, and stirred at room temperature for 4 h. After the reaction was completed by TLC, the reaction system was cooled to 0°C with an ice-water bath, and saturated aqueous ammonium chloride solution (100 mL) was slowly added to the reaction system, extracted with EtOAc (3 x 15 mL), the combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product compound SZ-12-4 as colorless oil, which was used directly in the next step without purification.

[0149] 5. Preparation of target compound SZ-11

[0150] The crude compound SZ-12-4 (10 g) was dissolved in CH2Cl2(50 mL) at room temperature, activated MnO2(43.5 g, 455 mmol, 91%) was added, and stirring was performed at reflux for 10 h. After the reaction was completed by TLC monitoring, it was filtered under suction, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100~1 / 50), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10) monitoring, and the fraction with Rf= 0.5~0.6 was collected to obtain the target compound SZ-11 (3.8 g, two-step yield 39%) in the form of colorless oil. ESI [M+H] + = 215.21

[0151] 1 H NMR (400 MHz, d6-DMSO) δ 7.84 (d, J = 0.8 Hz, 1H), 7.35-7.28 (m, J = 8.4, 4.6 Hz, 1H), 7.23-7.14 (m, 2H), 6.51-6.43 (m, 1H), 2.31 (d, J = 0.9 Hz, 3H), 2.28 (s, 3H), 2.12 (s, 3H).

[0152] 6, Preparation of the target compound SZ-12

[0153] SZ-11 (300 mg, 1.4 mmol) was dissolved in dry THF (10 mL) at room temperature, the reaction system was replaced with nitrogen three times, and the nitrogen protection was performed. The ice-salt bath was cooled to 0°C, MeLi (10.8 mL, 1.3 mol / L in Et2O, 14.0 mmol) was slowly added to the system by using a syringe, and stirring was performed at room temperature for 1 h. After the reaction was completed by TLC monitoring, the reaction was terminated with saturated aqueous ammonium chloride solution (10 mL), extracted with EtOAc (3 x 5 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous Na2SO4, filtered under suction, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative TLC (ethyl acetate / petroleum ether (v / v) = 1 / 50), and the fraction with Rf= 0.5~0.6 was collected to obtain the target compound SZ-12 (200 mg, yield 67%) in the form of colorless oil. ESI [M+H] + = 213.4.

[0154] 1 H NMR (400 MHz, CDCl3) δ 7.18-7.04 (m, 3H), 6.75 (s, 1H), 6.22 (s, 1H), 5.54 (d, J = 1.5 Hz, 1H), 4.95 (d, J = 1.5 Hz, 1H), 2.32 (s, 3H), 2.30 (s, 3H), 2.14 (s, 3H).

[0155] 7. Preparation of target compound SZ-9

[0156] Compound SZ-12 (89 mg, 0.42 mmol) and 10% wet Pd-C (9 mg) were dissolved in MeOH (5 mL) at room temperature, the system was replaced by hydrogen gas for three times, stirred for 30 minutes under hydrogen gas at room temperature. After the reaction was completed by TLC monitoring, the filter cake was washed with methanol (3 x 5 mL), and the filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by preparative TLC (ethyl acetate / petroleum ether (v / v) = 1 / 30) and the Rf = 0.5-0.6 fraction was collected to obtain the target compound SZ-9 (9.0 mg, yield 10%). ESI [M+H] + = 215.2

[0157] 8. Preparation of target compound SZ-10

[0158] Compound SZ-12-4 (55 mg, 0.25 mmol) was dissolved in dry DMF (3 mL) at room temperature, and the temperature was lowered to 0°C in an ice-salt bath, NaH (12.0 mg, 60% in mineral oil, 0.3 mmol) was added to the system, and stirred for 10 minutes at 0°C, MeI (43 mg, 0.3 mmol) was slowly added to the system with a syringe, and stirred for 30 minutes at room temperature. After the reaction was completed by TLC monitoring, the reaction liquid was poured into ice water, extracted with EtOAc (3 x 5 mL), the organic phase was combined, washed with saturated brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product, which was purified by preparative TLC (ethyl acetate / petroleum ether (v / v) = 1 / 6) and the Rf = 0.5-0.6 fraction was collected to obtain the target compound SZ-10 (47 mg, yield 80%).

[0159] 1 H NMR (400 MHz, d6-DMSO) δ 7.34 (s, 1H), 7.25 (dd, J = 6.9, 2.0 Hz, 1H), 7.12-7.05 (m, 2H), 5.87 (s, 1H), 5.36 (s, 1H), 3.21 (s, 3H), 2.23 (s, 3H), 2.18 (s, 3H), 2.12 (s, 3H).

[0160] Example 4, Preparation of compounds SZ-13-SZ-22, SZ-28-SZ-30 of the application

[0161] 1. Preparation of target compound SZ-13

[0162] At room temperature, 5-methylfuran-2-carbaldehyde (500 mg, 4.54 mmol) was dissolved in dry THF (30 mL), the reaction system was replaced with nitrogen for three times, and then protected with nitrogen. The ice-salt bath was cooled to 0 °C, and A (12 mL, 1 mol / L, 12 mmol) was added dropwise into the system at a rate of 2.0 mmol / min. After stirring at room temperature for 4 h, the reaction was monitored by TLC. After the reaction was completed, the reaction system was cooled to 0 °C with an ice-water bath, and saturated aqueous ammonium chloride solution (10 mL) was slowly added into the reaction system. The organic phase was extracted with EtOAc (3 x 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was directly used in the next reaction without purification.

[0163] At room temperature, the crude compound SZ-13-1 obtained in the previous step was dissolved in CH2Cl2(20 mL), and active MnO2(8.6 g, 90.0 mmol, 91%) was added. After stirring at room temperature for 10 h, the reaction was monitored by TLC. After the reaction was completed, the reaction system was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by preparative TLC (ethyl acetate / petroleum ether (v / v) = 1 / 8). The fraction with Rf = 0.5-0.6 was collected to obtain compound SZ-13 (670 mg, 69% yield over two steps). ESI [M+H] + = 215.2

[0164] 1 H NMR (400 MHz, d6-DMSO) δ 7.35-7.30 (m, 1H), 7.23-7.17 (m, 2H), 6.93 (d, J = 3.4 Hz, 1H), 6.39 (d, J = 3.0 Hz, 1H), 2.40 (s, 3H), 2.29 (s, 3H), 2.13 (s, 3H).

[0165] The preparation method of the target compounds SZ-14-SZ-20 is similar to that of the target compound SZ-13.

[0166] Compound SZ-14: 64 mg, ESI [M+H] + = 229.1

[0167] Compound SZ-15: 30 mg, ESI [M+H] + = 229.2

[0168] Compound SZ-16: 57 mg, ESI [M+H] + = 229.1

[0169] Compound SZ-17: 12 mg, ESI [M+H] + = 257.2

[0170] Compound SZ-18: 32 mg, ESI [M+H] + = 255.2

[0171] Compound SZ-19: 9 mg, ESI [M+H] + = 257.2

[0172] Compound SZ-20: 28 mg, ESI [M+H] + = 255.2

[0173] 2, Preparation of target compound SZ-21

[0174] At room temperature, 5-methylthiophene-2-carbaldehyde (500 mg, 3.97 mmol) was dissolved in dry THF (10 mL), the reaction system was replaced with nitrogen for three times, nitrogen protection, ice salt bath cooling to 0 °C, A (12 mL, 1 mol / L, 12 mmol) was added to the system at a rate of 1.0 mmol / min with a syringe, and stirred at room temperature for 4 hours. After the reaction was completed by TLC monitoring, the reaction system was reduced to 0 °C with an ice water bath, saturated aqueous ammonium chloride solution (10 mL) was slowly added to the reaction system, extracted with EtOAc (3×10 mL), the combined organic phase was dried over anhydrous Na2SO4, suction filtered, and concentrated under reduced pressure to obtain the crude product, which was directly used in the next step reaction without purification.

[0175] At room temperature, the crude compound SZ-21-1 obtained in the previous step was dissolved in CH2Cl2(20 mL), and active MnO2(7.6 g, 79.5 mmol, 91%) was added, and stirred at room temperature for 10 hours. After the reaction was completed by TLC monitoring, suction filtration was performed, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by preparative TLC (ethyl acetate / petroleum ether (v / v)=1 / 8), and the Rf=0.5-0.6 fraction was collected to obtain compound SZ-21 (247 mg, two-step yield 27%). ESI [M+H] + = 231.1

[0176] 1 H NMR (400 MHz, d6-DMSO) δ 7.35-7.30 (m, 1H), 7.23-7.16 (m, 3H), 6.95 (dd, J = 3.8, 1.0 Hz, 1H), 2.54 (s, 3H), 2.29 (s, 3H), 2.12 (s, 3H).

[0177] 3, Preparation of target compound SZ-22

[0178] At room temperature, 4-bromo-2-methylthiophene (5.0 g, 28.4 mmol) was dissolved in dry Et2O (50 mL), the reaction system was replaced with nitrogen for three times, protected with nitrogen, cooled to -78 °C with dry ice acetone bath, n-BuLi (22.7 mL, 2.5 mmol / mL in the Hexanes, 56.8 mmol) was added to the system at a rate of 1.0 mmol / min with a syringe, stirring continued for 30 min, DMF (2.41 mL, 31.2 mmol) was added to the system, stirring at room temperature for 2 h. After the reaction was completed by TLC monitoring, the reaction system was reduced to 0 °C with ice water bath, saturated aqueous ammonium chloride solution (10 mL) was slowly added to the reaction system, extracted with EtOAc (3 x 10 mL), the combined organic phase was washed with saturated brine (30 mL), dried over anhydrous Na2SO4, filtered under suction, concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 ~ 1 / 50), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10) monitoring, the Rf = 0.5 ~ 0.6 part was collected to obtain compound SZ-22-1 (3.1 g, yield 86.5%) as colorless oil. ESI [M+H] + = 126.1

[0179] At room temperature, compound SZ-22-1 (3.1 g, 24.6 mmol) was dissolved in dry THF (20 mL), the reaction system was replaced with nitrogen for three times, protected with nitrogen, cooled to 0 °C with ice salt bath, A (50 mL, 1 mol / L in THF, 50 mmol) was added to the system at a rate of 1.2 mmol / min, stirring at room temperature for 4 h. After the reaction was completed by TLC monitoring, the reaction system was reduced to 0 °C with ice water bath, saturated aqueous ammonium chloride solution (50 mL) was slowly added to the reaction system, extracted with EtOAc (3 x 15 mL), the combined organic phase was dried over anhydrous Na2SO4, filtered under suction, concentrated under reduced pressure to obtain the crude product.

[0180] The crude product obtained in the above step was dissolved in CH2Cl2(150 mL), MnO2(47.0 g, 491.9 mmol, 91%) was added to the reaction system, stirring at room temperature for 10 h. After the reaction was completed by TLC monitoring, filtered under suction, concentrated under reduced pressure to obtain the crude product, which 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 / 10) monitoring, the Rf = 0.5 ~ 0.6 part was collected to obtain the target compound SZ-22 (3.6 g, two-step yield 64%) as colorless oil. ESI [M+H] + = 231.1

[0181] 1H NMR (400 MHz, d6-DMSO) δ 7.73 (d, J = 1.4 Hz, 1H), 7.32 (d, J = 7.4 Hz, 1H), 7.24 - 7.12 (m, 3H), 2.47 (d, J = 0.8 Hz, 3H), 2.30 (s, 3H), 2.11 (s, 3H).

[0182] The intermediate compound SZ-29-4 was prepared according to the literature method (Angewandte Chemie, International Edition, 55(5), 1820-1824; 2016).

[0183] The preparation method of the target compounds SZ-28 to SZ-30 is similar to that of the target compound SZ-21.

[0184] Compound SZ-28: 27 mg, ESI [M+H] + = 269.1

[0185] Compound SZ-29: 308 mg, ESI [M+H] + = 215.1

[0186] 1 H NMR (400 MHz, d6-DMSO) δ 7.86 (s, 1H), 7.37 - 7.31 (m, 1H), 7.26 - 7.17 (m, 2H), 6.96 (s, 1H), 2.30 (s, 3H), 2.13 (s, 3H), 2.02 (s, 3H).

[0187] Compound SZ-30: 211 mg, ESI [M+H] + = 215.1

[0188] 1 H NMR (400 MHz, d6-DMSO) δ 7.85 (d, J = 1.4 Hz, 1H), 7.31 (d, J = 7.3 Hz, 1H), 7.20 (t, J = 7.5 Hz, 1H), 7.13 (d, J = 7.2 Hz, 1H), 6.67 (d, J = 1.4 Hz, 1H), 2.29 (s, 3H), 2.20 (s, 3H), 2.08 (s, 3H).

[0189] Example 5, Preparation of the compound SZ-23 of the application

[0190] LiAlH4(1.25 g, 32.9 mmol) was added portionwise to ethyl 2,3-dimethylbenzoate (3.5 g, 19.7 mmol) in dry THF (30 mL) at 0 °C in an ice-salt bath and stirred at room temperature for 1 h. After the reaction was completed by TLC monitoring, quenched with sodium sulfate decahydrate, water (20 mL) was added to the system, extracted with EtOAc (3 x 10 mL), the combined organic phase was washed with saturated brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product, which was used directly in the next step without purification.

[0191] The crude compound SZ-23-1 and MnO2(37.6 g, 393.6 mmol, 91%) were dissolved in CH2Cl2(100 mL) at room temperature and stirred at room temperature for 30 min. After the reaction was completed by TLC monitoring, filtered, and concentrated under reduced pressure to give the crude product, which was used directly in the next step without purification.

[0192] Compound SZ-23-2 was dissolved in dry THF (20 mL) at room temperature, the reaction system was replaced with nitrogen for three times, protected with nitrogen, cooled to 0 °C in an ice-water bath, MeMgBr (40 mL, 1 mol / L in THF, 40 mmol) was added to the system at a rate of 1.2 mmol / min, and stirred at room temperature for 30 min. After the reaction was completed by TLC monitoring, cooled to 0 °C in an ice-water bath, saturated aqueous ammonium chloride solution (50 mL) was slowly added to the reaction system, extracted with EtOAc (3 x 15 mL), the combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100~1 / 50), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 20) monitoring, and the fraction with Rf= 0.5~0.6 was collected to give the target compound SZ-23-3 (2.46 g, 83% yield for three steps) as colorless oil. ESI [M+H]=150.1 + = 150.1

[0193] Compound SZ-23-3 (332 mg, 2.21 mmol), 2-methylfuran (362 mg, 4.42 mmol), and Yb(OTf)3(274 mg, 0.44 mmol) were dissolved in MeNO2(5 mL) at room temperature, and stirred at room temperature overnight. After the reaction was completed by TLC monitoring, water (20 mL) was added to the system, extracted with n-hexane (2 x 20 mL), the combined organic phase was washed with saturated brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product as colorless oil, which was purified by preparative TLC (n-hexane) to give the target compound SZ-23 (288 mg, yield 61%) as colorless oil.

[0194] 1 H NMR (400 MHz, d6-DMSO) δ 7.03 - 6.95 (m, 2H), 6.86 - 6.79 (m, 1H), 6.02 - 5.98 (m, 1H), 5.97 - 5.92 (m, 1H), 4.33 (q, J = 7.1 Hz, 1H), 2.24 (s, 3H), 2.21 (s, 3H), 2.16 (s, 3H), 1.42 (d, J = 7.1 Hz, 3H).

[0195] Example 6, Preparation of compounds SZ-38, SZ-42, SZ-43 and SZ-48 of the present application

[0196] The preparation method of compound SZ-38-2 is similar to that of target compound SZ-5, using the corresponding aldehyde as the raw material, reacting with Grignard reagent A, and being oxidized by active manganese dioxide to obtain.

[0197] Compound SZ-38-2: 818.7 mg, white solid, ESI [M+H] + = 232.1.

[0198] 1 H NMR (400 MHz, d6-DMSO) δ 7.03 - 6.95 (m, 2H), 6.86 - 6.79 (m, 1H), 6.02 - 5.98 (m, 1H), 5.97 - 5.92 (m, 1H), 4.33 (q, J = 7.1 Hz, 1H), 2.24 (s, 3H), 2.21 (s, 3H), 2.16 (s, 3H), 1.42 (d, J = 7.1 Hz, 3H).

[0199] Compound SZ-38-2 (2.45 g, 10.6 mmol) was dissolved in dry THF (30 mL) at room temperature, and an ice-salt bath was used to cool the system to 0 °C. MeMgBr (16.1 mL, 1 mol / L in THF, 16.1 mmol) was added to the system at a rate of 1.0 mmol / min using a syringe, and the system was stirred at room temperature for 3 hours. After the reaction was completed as monitored by TLC, the system was cooled to 0 °C using an ice-water bath, and saturated aqueous ammonium chloride solution (30 mL) was slowly added to the reaction system. The organic phase was extracted with EtOAc (3 x 30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 ~ 1 / 5), and the target compound SZ-38-3 (2.61 g, yield 99.6%) was obtained as a white solid after TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5) monitoring and collection of the Rf = 0.2 ~ 0.3 fraction. ESI [M+H] + = 248.1.

[0200] SZ-38-3 (550 mg, 2.22 mmol), triethylsilane (1.5 mL) and TFA (4.5 mL) were added into a sealed tube at room temperature, stirred at 100 °C for 2 hours. The reaction solution was concentrated under reduced pressure, the residue was alkalized with saturated aqueous sodium bicarbonate solution (20 mL), extracted with EtOAc (3 x 15 mL), the combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 ~ 1 / 30) to obtain syrup solid target compound SZ-38 (138.2 mg, yield 26.8%) and syrup solid target compound SZ-42 (130.5 mg, yield 25.6%).

[0201] Compound SZ-38: ESI [M+H] + = 232.1.

[0202] 1 H NMR (400 MHz, d6-DMSO) δ 7.07 - 6.93 (m, 4H), 4.50 (q, J = 7.1 Hz, 1H), 2.60 (s, 3H), 2.26 (s, 3H), 2.23 (s, 3H), 1.53 (d, J = 7.1 Hz, 3H).

[0203] Compound SZ-42: ESI [M+H] + = 230.1.

[0204] 1 H NMR (400 MHz, d6-DMSO) δ 7.19 (d, J = 7.3 Hz, 1H), 7.14 (t, J = 7.5 Hz, 1H), 7.00 (d, J = 7.3 Hz, 1H), 6.64 (s, 1H), 6.21 (d, J = 2.3 Hz, 1H), 5.15 (d, J = 2.3 Hz, 1H), 2.69 (s, 3H), 2.29 (s, 3H), 2.03 (s, 3H).

[0205] The target compound SZ-43 was prepared using compound SZ-42 as raw material, which was oxidized by an oxidant.

[0206] Compound SZ-43: 18.7 mg, white solid, ESI [M+H] + = 246.1.

[0207] The preparation method of compound SZ-48 was similar to that of target compound SZ-5, using 2-isopropylthiazole-4-carboxaldehyde as raw material, which was reacted with Grignard reagent A and oxidized by active manganese dioxide.

[0208] Compound SZ-48: 490.5 mg, white solid, ESI [M+H] + = 260.1.

[0209] 1 H NMR (400 MHz, d6-DMSO) d 8.24 (s, 1H), 7.38 - 7.32 (m, 1H), 7.28 - 7.14 (m, 2H), 3.35 - 3.29 (m, 1H), 2.31 (s, 3H), 2.14 (s, 3H), 1.35 (d, J = 6.9 Hz, 6H).

[0210] Example 7, Preparation of compounds SZ-45, SZ-49, SZ-380, SZ-381, SZ-382, SZ-383, SZ-384 and SZ-385 of the present application

[0211] To a solution of 2-ethylthiazole-4-carboxylic acid (250 mg, 1.59 mmol), N, O-dimethylhydroxylamine hydrochloride (232.7 mg, 2.39 mmol), HATU (906.5 mg, 2.38 mmol) and DIEA (615.5 mg, 4.76 mmol) in DMF (2.5 mL) was stirred at room temperature for 5 hours. After the reaction was completed by TLC, ice water (10 mL) was added to the reaction system, extracted with EtOAc (3 x 15 mL), the combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, the filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 ~ 1 / 1), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1) monitoring, the fraction with Rf = 0.2 ~ 0.3 was collected to obtain compound SZ-45-1 (183.0 mg, yield 57.5%). ESI [M+H] + = 201.1.

[0212] To a solution of SZ-45-1 (183.0 mg, 0.91 mmol) in THF (3 mL) was added format reagent A (1.36 mL, 1 mol / L in THF, 1.36 mmol) dropwise at room temperature, and the mixture was stirred at 80 °C for 30 min. After the reaction was completed by TLC, the reaction mixture was cooled to 0 °C, then poured into saturated aqueous ammonium chloride solution (10 mL), extracted with EtOAc (3 x 20 mL), the combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (ethyl acetate / petroleum ether (v / v) = 1 / 50 ~ 1 / 10), monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10), and the fraction with Rf = 0.2 ~ 0.3 was collected to give the target compound SZ-45 (160.6 mg, yield 71.6%) as a white solid. ESI [M+H] + = 246.1.

[0213] 1 H NMR (400 MHz, d6-DMSO) δ 8.25 (s, 1H), 7.36 - 7.32 (m, 1H), 7.25 - 7.16 (m, 2H), 3.03 (q, J = 7.5 Hz, 2H), 2.32 (s, 3H), 2.13 (s, 3H), 1.32 (t, J = 7.5 Hz, 3H).

[0214] Format reagents B, C and D were prepared by the same method as format reagent A in Example 1, using 2-bromo-6-fluorotoluene, 2-bromo-6-chlorotoluene and 2,3-difluorobromobenzene as raw materials, respectively.

[0215] The preparation methods of target compounds SZ-49, SZ-380, SZ-381, SZ-382, SZ-383, SZ-384 and SZ-385 are similar to those of target compound SZ-45.

[0216] Compound SZ-49: 253.4 mg, white solid, ESI [M+H] + = 258.1.

[0217] 1 H NMR (400 MHz, d6-DMSO) δ 8.25 (s, 1H), 7.36 - 7.32 (m, 1H), 7.25 - 7.16 (m, 2H), 3.03 (q, J = 7.5 Hz, 2H), 2.32 (s, 3H), 2.13 (s, 3H), 1.32 (t, J = 7.5 Hz, 3H).

[0218] Compound SZ-380: 64.9 mg, syrup solid, ESI [M+H]+ = 262.1.

[0219] 1 H NMR (400 MHz, d6-DMSO) δ 8.23 (s, 1H), 7.38 - 7.33 (m, 2H), 7.32 - 7.27 (m, 1H), 2.49 - 2.43 (m, 1H), 2.14 (d, J = 2.4 Hz, 3H), 1.18 - 1.09 (m, 2H), 1.01 - 0.92 (m, 2H).

[0220] Compound SZ-381 : 56.2 mg, syrupy solid, ESI [M+H] + = 278.1.

[0221] 1 H NMR (400 MHz, d6-DMSO) δ 8.24 (s, 1H), 7.61 (dd, J = 7.7, 1.5 Hz, 1H), 7.40 - 7.31 (m, 2H), 2.49 - 2.43 (m, 1H), 2.22 (s, 3H), 1.19 - 1.12 (m, 2H), 0.98 - 0.92 (m, 2H).

[0222] Compound SZ-382: 21.9 mg, syrupy solid, ESI [M+H] + = 266.1.

[0223] 1 H NMR (400 MHz, d6-DMSO) δ 8.44 (s, 1H), 7.70 (dtd, J = 9.7, 8.1, 1.6 Hz, 1H), 7.53 - 7.44 (m, 1H), 7.37 (tdd, J = 8.2, 4.7, 1.4 Hz, 1H), 2.49 - 2.46 (m, 1H), 1.21 - 1.13 (m, 2H), 1.01 - 0.95 (m, 2H).

[0224] Compound SZ-383: 214.8 mg, syrupy solid, ESI [M+H] + = 264.1.

[0225] 1 H NMR (400 MHz, d6-DMSO) δ 8.38 (s, 1H), 7.42 - 7.29 (m, 3H), 3.38 - 3.32 (m, 1H), 2.17 (d, J = 2.4 Hz, 3H), 1.35 (d, J = 6.9 Hz, 6H).

[0226] Compound SZ-384: 187.9 mg, white solid, ESI [M+H] += 280.1.

[0227] 1 H NMR (400 MHz, d6-DMSO) δ 8.39 (s, 1H), 7.64 (dd, J = 7.8, 1.1 Hz, 1H), 7.42 (dd, J = 7.6, 1.3 Hz, 1H), 7.37 (t, J = 7.7 Hz, 1H), 3.35 - 3.29 (m, 1H), 2.25 (s, 3H), 1.35 (d, J = 6.9 Hz, 6H).

[0228] Compound SZ-385: 136.9 mg, syrup solid, ESI [M+H] + = 268.1.

[0229] 1 H NMR (400 MHz, d6-DMSO) δ 8.39 (s, 1H), 7.64 (dd, J = 7.8, 1.1 Hz, 1H), 7.42 (dd, J = 7.6, 1.3 Hz, 1H), 7.37 (t, J = 7.7 Hz, 1H), 3.35 - 3.29 (m, 1H), 2.25 (s, 3H), 1.35 (d, J = 6.9 Hz, 6H).

[0230] Example 8, Preparation of compound SZ-46 of the present application

[0231] -5-amino-2-methyl-l,3-thiazole-4-carboxylic acid ethyl ester (1.0 g, 5.37 mmol) was dissolved in HBF4(70 mL, 40% in water) at -10 °C, an aqueous solution of NaNO2(1.889 g, 27.4 mmol) (2.38 mL) was added, and the reaction was carried out under irradiation with a mercury lamp (254 nm) for 8 h. After the reaction was completed by TLC monitoring, the pH was adjusted to 7 with an aqueous solution of 1 N NaOH under an ice water bath, and the organic phase was extracted with EtOAc (3 x 50 mL), washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 ~ 1 / 3), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5) monitoring, and the fraction with Rf = 0.4 ~ 0.5 was collected to obtain compound SZ-46-1 (155 mg, yield 15.3%) as a white solid. ESI [M+H] + = 190.1.

[0232] NaOH (63.6 mg, 1.59 mmol) was added to a solution of SZ-46-1 (150 mg, 0.793 mmol) in THF / MeOH / H2O (2 mL, v / v / v = 1 / 1 / 1) at room temperature, stirred at 60 °C for 2 h. After the reaction was monitored to be completed by TLC, cooled with ice water bath, adjusted pH = 5 with 1 N HC1, extracted with EtOAc (3 x 30 mL), combined organic phase was washed with saturated brine, dried over anhydrous Na2S04, suction filtered, concentrated under reduced pressure to give compound SZ-46-2 (145 mg, crude) as a white solid. ESI [M+H] + = 162.1.

[0233] The preparation method of target compound SZ-46 is similar to that of target compound SZ-45, which is prepared using SZ-46-2 as the raw material.

[0234] Compound SZ-46: 20.1 mg, white solid, ESI [M+H] + = 250.0.

[0235] 1 H NMR (400 MHz, d6-DMSO) δ 7.34 (d, J = 6.7 Hz, 1H), 7.26 - 7.12 (m, 2H), 2.58 (d, J = 2.0 Hz, 3H), 2.31 (s, 3H), 2.16 (s, 3H).

[0236] Example 9, Preparation of compounds SZ-47, SZ-50 and SZ-53 of the application

[0237] The preparation method of target compound SZ-47 is similar to that of target compound SZ-5, which is prepared using 2-bromo-4-formylthiazole as the raw material.

[0238] Compound SZ-47: 17.6 g, white solid, ESI [M+H] + = 295.9.

[0239] 1 H NMR (400 MHz, d6-DMSO) δ 8.41 (s, 1H), 7.40 - 7.34 (m, 1H), 7.29 - 7.18 (m, 2H), 2.32 (s, 3H), 2.15 (s, 3H).

[0240] SZ-47 (100 mg, 0.338 mmol), isopropenylboronic acid pinacol ester (362.1 mg, 2.15 mmol), Pd(dppf)Cl2.CH2Cl2(69.9 mg, 0.086 mmol) and NaHCO3(54.3 mg, 0.646 mmol) were dissolved in DMF / H2O (2 mL / 0.2 mL), protected by nitrogen, stirred at 90 °C for 4 h. After the reaction was monitored to be completed by TLC, the reaction was poured into ice water, extracted with EtOAc (3 x 20 mL), the combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 30 ~ 1 / 10), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10) monitoring, the fraction with Rf= 0.2 ~ 0.3 was collected to give the white solid target compound SZ-50 (52.1 mg, yield 60.0%). ESI [M+H] + = 258.1.

[0241] 1 H NMR (400 MHz, d6-DMSO) δ 8.32 (s, 1H), 7.37 (d, J = 7.3 Hz, 1H), 7.28 (d, J = 6.6 Hz, 1H), 7.22 (t, J = 7.5 Hz, 1H), 5.90 (s, 1H), 5.52 (d, J = 1.3 Hz, 1H), 2.33 (s, 3H), 2.18 (s, 3H), 2.17 (s, 3H).

[0242] SZ-47 (400.0 mg, 1.35 mmol), isobutylboronic acid (310.6 mg, 3.05 mmol), Pd(OAc)2(50.0 mg, 0.22 mmol), BIDIME (145.4 mg, 0.44 mmol) and K3PO4(862.4 mg, 4.06 mmol) were dissolved in toluene (5 mL), protected by nitrogen, stirred at 110 °C for 2 h. After the reaction was monitored to be completed by TLC, the reaction was concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 30 ~ 1 / 10), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10) monitoring, the fraction with Rf= 0.2 ~ 0.3 was collected to give the white solid target compound SZ-53 (26.0 mg, yield 7.0%). ESI [M+H] + = 274.1.

[0243] 1H NMR (400 MHz, d6-DMSO) δ 8.29 (s, 1H), 7.36 - 7.33 (m, 1H), 7.26 - 7.09 (m, 2H), 2.90 (d, J = 7.1 Hz, 2H), 2.31 (s, 3H), 2.13 (s, 3H), 2.04 (dt, J = 13.5, 6.7 Hz, 1H), 0.96 (d, J = 6.6 Hz, 6H).

[0244] Example 10, Preparation of compounds SZ-51, SZ-52 and SZ-56 of the present application

[0245] SZ-47-1 (11.004 g, 36.9 mmol) was dissolved in dry THF (100 mL) at room temperature, cooled to 0 °C, NaH (3.7 g, 60% in mineral oil, 92.5 mmol) was added to the system in batches, and after the addition was completed, the stirring was continued for 10 minutes. TIPSCl (16.424 g, 85.2 mmol) was slowly added dropwise to the system, and after the dropwise addition was completed, the stirring was continued for 2 hours. After the reaction was completed by TLC monitoring, the reaction liquid was poured into ice water, extracted with EtOAc (3 x 100 mL), and the combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 ~ 1 / 20), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10) monitoring, and the Rf = 0.4 ~ 0.6 part was collected to obtain the white solid target compound SZ-52-1 (11.877 g, yield 70.8%). ESI [M+H] + = 454.1.

[0246] Compound SZ-52-1 (4.0 g, 8.80 mmol) was dissolved in dry THF (40 mL) under nitrogen protection, the reaction system was cooled to -78 °C with dry ice / acetone bath. n-BuLi (5.57 mL, 1.6 mol / L in Hexane, 8.91 mmol) was added slowly to the reaction system with a syringe, and stirred for another 10 minutes after the addition was completed. Cyclopropylmethanone (2.23 g, 26.5 mmol) was added slowly to the reaction system with a syringe, and stirred for 30 minutes. After the reaction was completed by TLC monitoring, saturated aqueous ammonium chloride solution was slowly added to the reaction system, extracted with EtOAc (3 x 100 mL), the combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 ~ 1 / 10), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10) monitoring, and the Rf = 0.4 ~ 0.5 part was collected to obtain white solid compound SZ-52-2 (3.955 g, yield 97.8%). ESI [M+H] + = 460.1.

[0247] SZ-52-2 (3.955 g, 8.60 mmol) was dissolved in THF (40 mL), and TBAF (21.3 mL, 1 mol / L in THF, 21.3 mmol) was added dropwise, and stirred at room temperature for 30 minutes. After the reaction was completed by TLC monitoring, H2O (40 mL) was added to the reaction system, extracted with EtOAc (3 x 50 mL), the combined organic phase was washed with saturated brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product SZ-52-3 (4.405 g). The crude product was directly used in the next reaction without purification. ESI [M+H] + = 304.1.

[0248] The crude compound SZ-52-3 (4.405 g) was dissolved in CH2Cl2(50 mL), and active MnO2(36.6 g, 421.0 mmol) was added, and stirred at room temperature for 5 hours. After the reaction was completed by TLC monitoring, it was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 ~ 1 / 3), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 3) monitoring, and the Rf = 0.3 ~ 0.5 part was collected to obtain syrup solid compound SZ-56 (2.17 g, two-step yield 83.7%). ESI [M+H] + = 302.1.

[0249] 1H NMR (400 MHz, d6-DMSO) δ 8.19 (s, 1H), 7.35 (d, J = 6.4 Hz, 1H), 7.29 - 7.16 (m, 2H), 5.87 (s, 1H), 2.31 (s, 3H), 2.14 (s, 3H), 1.57 (s, 3H), 1.28 - 1.23 (m, 1H), 0.46 - 0.42 (m, 3H), 0.29 - 0.25 (m, 1H).

[0250] SZ-56 (2.17 g, 7.20 mmol), triethylsilane (10 mL) and TFA (10 mL) were added into the reaction flask in turn, and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, the residue was alkalized with saturated aqueous sodium bicarbonate solution, extracted with EtOAc (3 x 30 mL), the combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 ~ 1 / 10) to obtain the syrup solid target compound SZ-52 (1.2 g, yield 58.4%) and the syrup solid target compound SZ-51 (29.0 mg, yield 1.4%).

[0251] Compound SZ-51: ESI [M+H] + = 286.1.

[0252] 1 H NMR (400 MHz, d6-DMSO) δ 8.45 (s, 1H), 7.35 (d, J = 7.4 Hz, 1H), 7.28 (d, J = 7.2 Hz, 1H), 7.21 (t, J = 7.5 Hz, 1H), 5.93 (t, J = 7.3 Hz, 1H), 2.49 - 2.39 (m, 2H), 2.32 (s, 3H), 2.16 (s, 3H), 2.15 (s, 3H), 0.99 (t, J = 7.5 Hz, 3H).

[0253] Compound SZ-52: ESI [M+H] + = 286.1.

[0254] 1 H NMR (400 MHz, d6-DMSO) δ 8.25 (s, 1H), 7.35 (d, J = 6.6 Hz, 1H), 7.28 - 7.17 (m, 2H), 2.53 - 2.46 (m, 1H), 2.32 (s, 3H), 2.14 (s, 3H), 1.40 (d, J = 7.0 Hz, 3H), 1.06 - 1.02 (m, 1H), 0.66 - 0.52 (m, 2H), 0.41 - 0.23 (m, 2H).

[0255] Example 11, Preparation of compounds SZ-54, SZ-55, SZ-57, SZ-58, SZ-95 and SZ-139 of the present application

[0256] Compound SZ-52-1 (4.0 g, 8.8 mmol) was dissolved in dry THF (40 mL) under nitrogen protection, the reaction system was cooled to -78 °C with dry ice / acetone bath. n-BuLi (5.57 mL, 1.6 mol / L in Hexane, 8.91 mmol) was slowly added to the reaction system with a syringe, and stirring was continued for 10 minutes. Cyclopropylcarboxaldehyde (1.86 g, 26.5 mmol) was slowly added dropwise to the reaction system with a syringe, and stirring was continued for 30 minutes. After the reaction was completed by TLC monitoring, saturated aqueous ammonium chloride solution was slowly added to the reaction system, extracted with EtOAc (3 x 30 mL), the combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered under suction, and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 ~ 1 / 10), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 0) monitoring, and the fraction with Rf = 0.2 ~ 0.3 was collected to obtain compound SZ-54-1 (3.469 g, yield 88.4%) as a white solid. ESI [M+H] + = 446.1.

[0257] DCC (2.40 g, 11.6 mmol) and DMAP (1.90 g, 15.6 mmol) were added to a solution of acetic acid (702.2 mg, 11.7 mmol) in dichloromethane (24 mL), stirred at room temperature for 15 minutes, and then SZ-54-1 (3.469 g, 7.78 mmol) was added to the reaction system, and stirred at room temperature for 3 hours. After the reaction system was completed by TLC monitoring, methyl tert-butyl ether (24 mL) was added, and stirred for 15 minutes. The reaction system was filtered under suction, the filter cake was washed with methyl tert-butyl ether, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 ~ 1 / 3), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 3) monitoring, and the fraction with Rf = 0.3 ~ 0.5 was collected to obtain compound SZ-54-2 (3.581 g, yield 94.3%) as a syrup. ESI [M+H] + = 488.2.

[0258] SZ-54-2 (3.581 g, 7.34 mmol) was dissolved in THF (40 mL), TBAF (15.5 mL, 1 mol / L in THF, 15.5 mmol) was added dropwise, and the mixture was stirred at room temperature for 30 min. After the reaction was completed by TLC monitoring, H2O (40 mL) was added to the reaction system, and the mixture was extracted with EtOAc (3 x 30 mL), and the combined organic phase was washed with saturated brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product SZ-54-3 (4.40 g). The crude product was used directly in the next step without purification. ESI [M+H] + = 332.1.

[0259] The crude compound SZ-54-3 (4.40 g) was dissolved in CH2Cl2(50 mL), and active MnO2(19.6 g, 225.4 mmol) was added, and the mixture was stirred at room temperature for 5 h. After the reaction was completed by TLC monitoring, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 ~ 1 / 10), and the product was collected by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10) monitoring, and the Rf = 0.3 ~ 0.5 fraction was collected to obtain the syrupy compound SZ-58 (2.20 g, 91.0% yield for two steps). ESI [M+H] + = 330.1.

[0260] 1 H NMR (400 MHz, d6-DMSO) δ 8.41 (s, 1H), 7.41-7.32 (m, 1H), 7.30-7.16 (m, 2H), 5.44 (d, J = 8.7 Hz, 1H), 2.32 (s, 3H), 2.13 (s, 3H), 2.11 (s, 3H), 1.47-1.41 (m, 1H), 0.67-0.62 (m, 2H), 0.61-0.34 (m, 2H).

[0261] NaOH (405.0 mg, 10.1 mmol) was added to a solution of SZ-58 (2.20 g, 6.68 mmol) in THF / H2O (20 mL, v / v = 1 / 1) at room temperature, and stirred at room temperature for 12 h. After the reaction was monitored to be completed by TLC, the reaction solution was concentrated under reduced pressure, cooled with ice water bath, adjusted to pH = 5 with 1 N HC1, extracted with EtOAc (3 x 30 mL), the combined organic phase was washed with saturated brine, dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 30 ~ 1 / 1) to give compound SZ-57 (1.902 g, yield 99.1%) as a syrup solid. ESI [M+H] + = 288.1.

[0262] 1 H NMR (400 MHz, d6-DMSO) δ 8.29 (s, 1H), 7.40 - 7.30 (m, 1H), 7.28 - 7.17 (m, 2H), 6.24 (d, J = 4.9 Hz, 1H), 4.54 - 4.43 (m, 1H), 2.31 (s, 3H), 2.13 (s, 3H), 1.23 - 1.18 (m, 1H), 0.56 - 0.31 (m, 4H).

[0263] SZ-57 (900.0 mg, 3.13 mmol), triethylsilane (10 mL) and TFA (10 mL) were added to the reaction bottle in turn, and stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure, the residue was basified with saturated aqueous sodium bicarbonate solution, extracted with EtOAc (3 x 30 mL), the combined organic phase was washed with saturated brine, dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 ~ 1 / 10) to give target compound SZ-54 (315.7 mg, yield 37.1%) as a syrup solid and target compound SZ-55 (42.4 mg, yield 4.99%) as a syrup solid.

[0264] Compound SZ-54: ESI [M+H] + = 272.0.

[0265] 1H NMR (400 MHz, d6-DMSO) δ 8.27 (s, 1H), 7.36 - 7.32 (m, 1H), 7.25 - 7.17 (m, 2H), 2.92 (d, J = 7.2 Hz, 2H), 2.31 (s, 3H), 2.13 (s, 3H), 1.16 - 1.10 (m, 1H), 0.67 - 0.49 (m, 2H), 0.43 - 0.28 (m, 2H).

[0266] Compound SZ-55: ESI [M+H] + = 272.0.

[0267] 1 H NMR (400 MHz, d6-DMSO) δ 8.27 (s, 1H), 7.36 - 7.32 (m, 1H), 7.25 - 7.17 (m, 2H), 2.92 (d, J = 7.2 Hz, 2H), 2.31 (s, 3H), 2.13 (s, 3H), 1.16 - 1.10 (m, 1H), 0.67 - 0.49 (m, 2H), 0.43 - 0.28 (m, 2H).

[0268] Compound SZ-57 (33.3 mg, 0.116 mmol) was dissolved in dry DMF (2 mL), cooled to 0 °C, NaH (6.96 mg, 60% in mineral oil, 0.174 mmol) was added to the system, stirred for 10 min, CH3I (24.7 mg, 0.174 mmol) was slowly added to the system by syringe, naturally warmed to room temperature, stirred for 2 h. After the reaction was monitored to be complete by TLC, the reaction was poured into ice water, extracted with EtOAc (3 x 15 mL), the combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, suction filtered, concentrated under reduced pressure to obtain the crude product, which 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) monitoring, the fraction with Rf = 0.4 ~ 0.5 was collected to obtain the syrup solid target compound SZ-95 (22.6 mg, yield 64.7%). ESI [M+H] + = 302.1.

[0269] 1 H NMR (400 MHz, d6-DMSO) δ 8.27 (s, 1H), 7.36 - 7.32 (m, 1H), 7.25 - 7.17 (m, 2H), 2.92 (d, J = 7.2 Hz, 2H), 2.31 (s, 3H), 2.13 (s, 3H), 1.16 - 1.10 (m, 1H), 0.67 - 0.49 (m, 2H), 0.43 - 0.28 (m, 2H).

[0270] The preparation method of target compound SZ-139-5 is similar to that of target compound SZ-57, which is prepared using SZ-52-1 as the raw material. ESI [M+H] + = 302.1.

[0271] SZ-139-5 (305.0 mg, 1.01 mmol) was dissolved in dichloromethane (5 mL) at room temperature, and a drop of DMF was added. Then, a solution of thionyl chloride (592.9 mg, 4.98 mmol) in dichloromethane (2 mL) was added dropwise. The reaction was stirred at room temperature for 30 minutes. After the reaction was completed by TLC monitoring, the reaction solution was poured into ice water (10 mL) and extracted with EtOAc (3 x 15 mL). The combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 ~ 1 / 10) and TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10) monitoring. The fraction with Rf = 0.3 ~ 0.4 was collected to obtain compound SZ-139-6 (290.8 mg, yield 89.8%) in the form of a syrup solid. ESI [M+H] + = 320.1.

[0272] Zinc powder (100.4 mg, 1.54 mmol) and ammonium chloride (82.1 mg, 1.53 mmol) were added to a solution of SZ-139-6 (244.8 mg, 0.865 mmol) in methanol (5 mL), and the reaction was stirred at room temperature for 12 hours. After the reaction was completed by TLC monitoring, the reaction system was filtered, the filter cake was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 ~ 1 / 10) and TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10) monitoring. The fraction with Rf = 0.3 ~ 0.4 was collected to obtain compound SZ-139 (107.3 mg, yield 49.1%) in the form of a syrup solid. ESI [M+H] + = 286.1.

[0273] 1 H NMR (400 MHz, d6-DMSO) δ 8.26 (s, 1H), 7.35 - 7.32 (m, 1H), 7.26 - 7.14 (m, 2H), 3.11 (d, J = 7.6 Hz, 2H), 2.67 (dt, J = 15.3, 7.7 Hz, 1H), 2.31 (s, 3H), 2.12 (s, 3H), 2.11 - 2.04 (m, 2H), 1.92 - 1.71 (m, 4H).

[0274] Example 12, Preparation of compounds SZ-59, SZ-60, SZ-61 and SZ-63 of the present application

[0275] SZ-54-1 (862.0 mg, 1.93 mmol), triethylsilane (5 mL) and TFA (5 mL) were added into a sealed tube, stirred at 60 °C for 2 h. The reaction was concentrated under reduced pressure, the residue was basified with saturated aqueous sodium bicarbonate solution, extracted with EtOAc (3 x 30 mL), the combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (ethyl acetate / petroleum ether (v / v) = 1 / 30 ~ 1 / 3) to give the target compound SZ-59 (239.1 mg, yield 42.7%) as a white solid and the target compound SZ-60 (181.5 mg, yield 34.3%) as a white solid.

[0276] Compound SZ-59: ESI [M+H] + = 290.1.

[0277] 1 H NMR (400 MHz, d6-DMSO) δ 7.27 - 7.15 (m, 2H), 7.07 - 7.02 (m, 2H), 6.00 - 5.94 (m, 2H), 5.79 (dd, J = 6.0, 4.9 Hz, 1H), 4.50 - 4.33 (m, 1H), 2.25 - 2.20 (m, 6H), 1.18 - 1.12 (m, 1H), 0.52 - 0.31 (m, 4H).

[0278] Compound SZ-60: ESI [M+H] + = 274.1.

[0279] 1 H NMR (400 MHz, d6-DMSO) δ 7.27 - 7.15 (m, 2H), 7.07 - 7.02 (m, 2H), 6.00 - 5.94 (m, 2H), 5.79 (dd, J = 6.0, 4.9 Hz, 1H), 4.50 - 4.33 (m, 1H), 2.25 - 2.20 (m, 6H), 1.18 - 1.12 (m, 1H), 0.52 - 0.31 (m, 4H).

[0280] Active MnO2(1.35 g, 15.5 mmol) was added to a solution of SZ-59 (150.6 mg, 0.52 mmol) in CH2Cl2(10 mL) and stirred at room temperature for 5 h. After the reaction was monitored to be complete by TLC, it was filtered and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by column chromatography on silica gel (ethyl acetate / petroleum ether (v / v) = 1 / 100 ~ 1 / 10), monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10), and the fraction with Rf= 0.3 ~ 0.5 was collected to give compound SZ-63 (87.0 mg, yield 58.6%) as a syrup solid. ESI [M+H] + = 286.1.

[0281] 1 H NMR (400 MHz, d6-DMSO) δ 8.82 (s, 1H), 7.39 (d, J = 7.4 Hz, 1H), 7.35 (d, J = 7.5 Hz, 1H), 7.25 (t, J = 7.6 Hz, 1H), 3.09 - 2.94 (m, 1H), 2.34 (s, 3H), 2.21 (s, 3H), 1.29 - 1.13 (m, 4H).

[0282] The preparation method of target compound SZ-61 is similar to that of target compound SZ-63, which is prepared from SZ-60 as a raw material by oxidation with active MnO2.

[0283] Compound SZ-61: 51.9 mg, white solid, ESI [M+H] + = 272.1.

[0284] 1 H NMR (400 MHz, d6-DMSO) δ 7.65 (s, 1H), 7.12 - 7.02 (m, 3H), 4.22 (s, 2H), 3.21 - 3.04 (m, 1H), 2.27 (s, 3H), 2.21 (s, 3H), 1.25 - 1.01 (m, 4H).

[0285] Example 13, Preparation of Compounds SZ-62 and SZ-64 of the Invention

[0286] Active Mn02(1.76 g, 20.2 mmol) was added to a solution of SZ-54-1 (300.0 mg, 0.67 mmol) in CH2CI2(10 mL) and stirred at room temperature for 5 h. After the reaction was completed by TLC, it was filtered and the filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 ~ 1 / 10), monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10), and the fraction with Rf= 0.3 ~ 0.5 was collected to obtain compound SZ-64-1 (271.3 mg, yield 90.8%) as a white solid. ESI [M+H] + = 444.1.

[0287] SZ-64-1 (271.3 mg, 0.61 mmol) was dissolved in THF (4 mL), and TBAF (1.22 mL, 1 mol / L in THF, 1.22 mmol) was added to the reaction system, which was stirred at room temperature for 30 min. After the reaction was completed by TLC, H2O (10 mL) was added to the reaction system, which was extracted with EtOAc (3 x 10 mL), and the combined organic phase was washed with saturated brine (10 mL), dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 30 ~ 1 / 3), monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 3), and the fraction with Rf= 0.5 ~ 0.6 was collected to obtain compound SZ-62 (136.2 mg, yield 77.5%) as a white solid. ESI [M+H] + = 288.1.

[0288] 1 H NMR (400 MHz, d6-DMSO) d 7.91 (d, J = 0.6 Hz, 1H), 7.25 - 7.22 (m, 1H), 7.09 - 7.06 (m, 2H), 6.15 (d, J = 4.7 Hz, 1H), 6.07 (d, J = 4.7 Hz, 1H), 3.11 - 2.96 (m, 1H), 2.26 (s, 6H), 1.24 - 0.94 (m, 4H).

[0289] Compound SZ-62 (77.5 mg, 0.27 mmol) was dissolved in dry DMF (2 mL), cooled to 0 °C, NaH (16.2 mg, 60% in mineral oil, 0.405 mmol) was added to the system, stirred for 10 min, CH3I (57.5 mg, 0.405 mmol) was slowly added to the system by syringe, naturally warmed to room temperature, stirred for 2 h. After the reaction was monitored to be complete by TLC, the reaction was poured into ice water, extracted with EtOAc (3 x 15 mL), the combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, suction filtered, concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 ~ 1 / 10), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10) monitoring, the fraction with Rf= 0.4 ~ 0.5 was collected to obtain the syrup solid target compound SZ-64 (42.8 mg, yield 52.7%). ESI [M+H] + = 302.1.

[0290] 1 H NMR (400 MHz, d6-DMSO) d 7.96 (s, 1H), 7.24 (t, J = 4.6 Hz, 1H), 7.12 (t, J = 6.3 Hz, 2H), 5.81 (s, 1H), 3.31 (s, 3H), 3.10 - 2.96 (m, 1H), 2.24 (s, 3H), 2.23 (s, 3H), 1.22 - 1.06 (m, 4H).

[0291] Example 14, Preparation of compounds SZ-65, SZ-67, SZ-68 and SZ-88 of the present application

[0292] Compound SZ-47 (600 mg, 2.03 mmol) was dissolved in dry THF (6 mL) under nitrogen protection, the reaction system was cooled to -78 °C with dry ice / acetone bath. n-BuLi (1.3 mL, 1.6 mol / L in Hexane, 2.08 mmol) was slowly added to the reaction system with a syringe, and stirring was continued for 5 min. A solution of acetophenone (488.8 mg, 4.07 mmol) in THF (5 mL) was slowly added to the reaction system with a syringe at a rate of 1.0 mL / min, and stirring was continued for 30 min. After the reaction was completed by TLC monitoring, saturated aqueous ammonium chloride solution was slowly added to the reaction system, extracted with EtOAc, and the combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 ~ 1 / 3), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 3) monitoring, and the Rf = 0.2 ~ 0.3 part was collected to obtain white solid compound SZ-65-1 (183.0 mg, yield 26.8%). ESI [M+H] + = 338.1.

[0293] SZ-65-1 (175.0 mg, 0.519 mmol), triethylsilane (1.5 mL), and TFA (7.5 mL) were added to a sealed tube, and stirring was continued at 80 °C for 2 h. The reaction solution was concentrated under reduced pressure, the residue was basified with saturated aqueous sodium bicarbonate solution, extracted with EtOAc (3 x 15 mL), and the combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 30 ~ 1 / 3) to obtain the target compound SZ-65 as a syrup solid (64.2 mg, yield 38.5%). ESI [M+H] + = 322.1.

[0294] 1 H NMR (400 MHz, d6-DMSO) δ 8.22 (s, 1H), 7.40 - 7.34 (m, 5H), 7.33 - 7.26 (m, 1H), 7.26 - 7.18 (m, 2H), 4.61 (q, J = 7.1 Hz, 1H), 2.31 (s, 3H), 2.12 (s, 3H), 1.70 (d, J = 7.2 Hz, 3H).

[0295] The preparation method of the target compound SZ-67 is similar to that of compound SZ-65-1, which is prepared using SZ-47 and o-chloroacetophenone as raw materials.

[0296] Compound SZ-67: 612.5 mg, syrup solid, ESI [M+H]+ = 372.1.

[0297] 1 H NMR (400 MHz, d6-DMSO) δ 8.31 (s, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.47 - 7.35 (m, 3H), 7.32 (d, J = 6.3 Hz, 1H), 7.24 - 7.12 (m, 2H), 6.73 (s, 1H), 2.27 (s, 3H), 2.10 (s, 3H), 2.00 (s, 3H).

[0298] SZ-67 (602.5 mg, 1.62 mmol) and TFA (5 mL) were added into a sealed tube, stirred at 90 °C for 2 hours. The reaction was concentrated under reduced pressure, the residue was basified with saturated aqueous sodium bicarbonate solution, extracted with EtOAc (3 x 15 mL), the combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (ethyl acetate / petroleum ether (v / v) = 1 / 30 ~ 1 / 3) to give the target compound SZ-68-1 (42.0 mg, yield 7.3%) as a syrup solid. ESI [M+H] + = 354.1.

[0299] Compound SZ-68-1 (42.0 mg, 0.12 mmol), zinc bromide (26.9 mg, 0.12 mmol) and 10% wet Pd-C (88.2 mg) were dissolved in MeOH (2 mL), the system was replaced with hydrogen gas for three times, stirred at room temperature for 12 hours under hydrogen gas. After the reaction was completed by TLC monitoring, the filter cake was washed with methanol (3 x 5 mL), and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by preparative TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5), and the Rf = 0.4 ~ 0.5 part was collected to give the target compound SZ-68 (20.6 mg, yield 48.8%) as a syrup solid. ESI [M+H] + = 356.1.

[0300] 1 H NMR (400 MHz, d6-DMSO) δ 8.25 (s, 1H), 7.52 (dd, J = 7.7, 1.5 Hz, 1H), 7.48 (dd, J = 7.6, 1.8 Hz, 1H), 7.41 (td, J = 7.6, 1.6 Hz, 1H), 7.38 - 7.33 (m, 2H), 7.27 - 7.15 (m, 2H), 4.95 (q, J = 7.1 Hz, 1H), 2.30 (s, 3H), 2.12 (s, 3H), 1.72 (d, J = 7.1 Hz, 3H).

[0301] The preparation method of target compound SZ-88 is similar to that of target compound SZ-65, and the target compound SZ-88 is prepared from SZ-47 and a corresponding ketone.

[0302] Compound SZ-88: 22.7 mg, syrup solid, ESI [M+H] + = 312.1.

[0303] 1 H NMR (400 MHz, d6-DMSO) δ 8.27 (s, 1H), 7.34 (d, J = 6.8 Hz, 1H), 7.27-7.16 (m, 2H), 2.31 (s, 3H), 2.13 (s, 3H), 2.02 (t, J = 8.8 Hz, 1H), 1.25-1.02 (m, 2H), 0.65-0.52 (m, 2H), 0.51-0.38 (m, 4H), 0.28-0.12 (m, 2H).

[0304] Example 15, Preparation of Compounds SZ-66, SZ-99, SZ-103 and SZ-117 of the Invention

[0305] Compound SZ-47-1 (4.624 g, 15.5 mmol) was dissolved in dry DMF (40 mL), cooled to 0 °C, NaH (933.9 mg, 60% in mineral oil, 23.3 mmol) was added to the system, stirred for 10 minutes, and benzyl bromide (3.986 g, 23.3 mmol) was slowly added to the system, and the temperature was allowed to rise to room temperature naturally, and stirred for 2 hours. After the reaction was completed by TLC monitoring, the reaction liquid was poured into ice water, extracted with EtOAc (3 x 50 mL), the combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered under suction, and concentrated under reduced pressure to obtain a crude product, which 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) monitoring, and the Rf= 0.5~0.6 part was collected to obtain the white solid target compound SZ-103-1 (4.8 g, yield 79.7%). ESI [M+H] + = 388.1.

[0306] Compound SZ-103-1 (600 mg, 1.55 mmol) was dissolved in dry THF (10 mL) under nitrogen protection, the reaction system was cooled to -78 °C with dry ice / acetone bath. n-BuLi (1.01 mL, 1.6 mol / L in Hexane, 1.616 mmol) was slowly added to the reaction system with a syringe, and the stirring was continued for 10 minutes. Cyclopropylcarboxaldehyde (543.3 mg, 7.75 mmol) was slowly added to the reaction system dropwise with a syringe, and the stirring was continued for 30 minutes. After the reaction was completed by TLC monitoring, saturated aqueous ammonium chloride solution was slowly added to the reaction system, extracted with EtOAc (3 x 30 mL), the combined organic phase was 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 / 30 ~ 1 / 2), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 2) monitoring, and the Rf = 0.3 ~ 0.4 part was collected to obtain compound SZ-103 (183.9 mg, yield 31.4%) in syrup solid. ESI [M+H] + = 380.1.

[0307] 1 H NMR (400 MHz, d6-DMSO) δ 7.39 - 7.34 (m, 5H), 7.33 - 7.29 (m, 2H), 7.16 - 7.07 (m, 2H), 5.99 (dd, J = 4.8, 2.6 Hz, 1H), 5.88 (s, 1H), 4.58 - 4.48 (m, 2H), 4.48 - 4.33 (m, 1H), 2.26 (d, J = 2.9 Hz, 3H), 2.19 (d, J = 6.6 Hz, 3H), 1.21 - 1.10 (m, 1H), 0.53 - 0.36 (m, 4H).

[0308] The preparation method of target compound SZ-99 is similar to that of target compound SZ-103, which is prepared using SZ-103-1 and benzaldehyde as raw materials.

[0309] Compound SZ-99: 142.3 mg, syrup solid, ESI [M+H] + = 416.1.

[0310] 1H NMR (400 MHz, d6-DMSO) δ 7.46 - 7.41 (m, 2H), 7.39 - 7.25 (m, 10H), 7.15 - 7.06 (m, 2H), 6.74 (d, J = 4.4 Hz, 1H), 5.90 (dd, J = 9.4, 4.4 Hz, 1H), 5.85 (d, J = 1.8 Hz, 1H), 4.57 - 4.44 (m, 2H), 2.24 (d, J = 11.2 Hz, 3H), 2.15 (d, J = 22.4 Hz, 3H).

[0311] Compound SZ-103-1 (400 mg, 1.03 mmol) was dissolved in dry THF (4 mL) under nitrogen protection, the reaction system was cooled to -78 °C with dry ice / acetone bath. n-BuLi (0.68 mL, 1.6 mol / L in Hexane, 1.09 mmol) was slowly added to the reaction system with a syringe, and stirring was continued for 10 minutes. o-Chloroacetophenone (799.0 mg, 5.17 mmol) was slowly added dropwise to the reaction system with a syringe, and stirring was continued for 30 minutes. After the reaction was completed by TLC monitoring, saturated aqueous ammonium chloride solution was slowly added to the reaction system, extracted with EtOAc (3 x 30 mL), the combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 ~ 1 / 10), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10) monitoring, and the Rf= 0.3 ~ 0.4 part was collected to obtain white solid compound SZ-66-1 (430.0 mg, yield 90.0%). ESI [M+H] + = 464.1.

[0312] SZ-66-1 (430.0 mg, 0.927 mmol), triethylsilane (3 mL) and TFA (3 mL) were sequentially added to a sealed tube, and stirred at 80 °C for 1 hour. The reaction solution was concentrated under reduced pressure, the residue was basified with saturated aqueous sodium bicarbonate solution, extracted with EtOAc (3 x 30 mL), the combined organic phase was 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 / 30 ~ 1 / 3), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 3) monitoring, and the Rf= 0.3 ~ 0.5 part was collected to obtain the target compound SZ-66 (43.5 mg, yield 13.1%) as a syrup solid. ESI [M+H] + = 358.1.

[0313] 1H NMR (400 MHz, d6-DMSO) δ 7.90 (dd, J = 7.8, 1.4 Hz, 1H), 7.43 - 7.28 (m, 3H), 7.08 - 6.93 (m, 3H), 6.89 (s, 1H), 6.46 (s, 1H), 4.01 (s, 2H), 2.24 (s, 3H), 2.13 (s, 3H), 1.99 (s, 3H).

[0314] The preparation method of target compound SZ-117 is similar to that of target compound SZ-66, which is prepared by using SZ-103-1 as the raw material.

[0315] Compound SZ-117: 27.2 mg, colorless oily compound, ESI [M+H] + = 272.1.

[0316] 1 H NMR (400 MHz, d6-DMSO) δ 7.05 - 7.02 (m, 3H), 6.84 (s, 1H), 4.05 (s, 2H), 2.41 (dq, J = 13.8, 6.9 Hz, 1H), 2.26 (s, 3H), 2.18 (s, 3H), 1.38 (d, J = 6.9 Hz, 3H), 1.06 - 0.94 (m, 1H), 0.63 - 0.44 (m, 2H), 0.34 - 0.30 (m, 2H).

[0317] Example 16, Preparation of Compounds SZ-69, SZ-70, SZ-71 and SZ-72 of the Invention

[0318] Compound SZ-103-1 (400 mg, 1.03 mmol) was dissolved in dry THF (4 mL) under nitrogen protection, and the reaction system was cooled to -78 °C with dry ice / acetone bath. n-BuLi (0.68 mL, 1.6 mol / L in Hexane, 1.09 mmol) was slowly added to the reaction system with a syringe, and stirring was continued for 10 minutes. o-Fluoroacetophenone (713.9 mg, 5.17 mmol) was slowly added dropwise to the reaction system with a syringe, and stirring was continued for 30 minutes. After the reaction was completed by TLC monitoring, saturated aqueous ammonium chloride solution was slowly added to the reaction system, and the organic phase was extracted with EtOAc (3 x 30 mL), washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 ~ 1 / 10), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10) monitoring, and the Rf = 0.3 ~ 0.4 part was collected to obtain compound SZ-69-1 (363.0 mg, yield 78.7%). ESI [M+H]+ = 448.1.

[0319] To a sealed tube was added SZ-69-1 (363.0 mg, 0.811 mmol), triethylsilane (3 mL) and TFA (3 mL) sequentially, and stirred at 80 °C for 1 h. The reaction was concentrated under reduced pressure, the residue was basified with saturated aqueous NaHC03solution, extracted with EtOAc (3 x 30 mL), the combined organic phase was washed with saturated brine, dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to give a dark brown solid residue. The residue was dissolved in CH2C12(10 mL), activated Mn02(2.7 g, 31.1 mmol) was added, and stirred at room temperature for 5 h. After the reaction was completed by TLC monitoring, it was filtered and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 ~ 1 / 3) to give SZ-69 (24.3 mg, 8.8% yield), SZ-70 (42.1 mg, 15.2% yield), SZ-71 (53.1 mg, 18.4% yield) and SZ-72 (25.5 mg, 9.3% yield).

[0320] Compound SZ-69: 24.3 mg, syrupy solid, ESI [M+H] + = 340.1.

[0321] 1 H NMR (400 MHz, d6-DMSO) δ 8.24 (s, 1H), 7.48 - 7.46 (m, 1H), 7.42 - 7.32 (m, 2H), 7.27 - 7.19 (m, 4H), 4.81 (q, J = 7.1 Hz, 1H), 2.30 (s, 3H), 2.11 (s, 3H), 1.72 (d, J = 7.1 Hz, 3H).

[0322] Compound SZ-70: 42.1 mg, white solid, ESI [M+H] + = 342.1.

[0323] 1 H NMR (400 MHz, d6-DMSO) δ 7.67 (td, J = 8.0, 1.7 Hz, 1H), 7.39 - 7.32 (m, 1H), 7.21 (td, J = 7.6, 1.2 Hz, 1H), 7.13 - 7.08 (m, 1H), 7.06 - 6.94 (m, 3H), 6.87 (s, 1H), 6.55 (s, 1H), 4.02 (s, 2H), 2.25 (s, 3H), 2.15 (s, 3H), 1.96 (s, 3H).

[0324] Compound SZ-71 : 53.1 mg, syrup solid, ESI [M+H] + = 356.1.

[0325] 1 H NMR (400 MHz, d6-DMSO) δ 8.28 (s, 1H), 7.69 (td, J = 8.0, 1.7 Hz, 1H), 7.44 - 7.35 (m, 1H), 7.33 (d, J = 6.3 Hz, 1H), 7.26 - 7.17 (m, 3H), 7.17 - 7.11 (m, 1H), 6.83 (s, 1H), 2.28 (s, 3H), 2.09 (s, 3H), 1.96 (s, 3H).

[0326] Compound SZ-72: 25.5 mg, light yellow oil, ESI [M+H] + = 338.1.

[0327] 1 H NMR (400 MHz, d6-DMSO) δ 8.38 (s, 1H), 7.55 - 7.46 (m, 2H), 7.36 - 7.24 (m, 4H), 7.19 (t, J = 7.5 Hz, 1H), 6.33 (s, 1H), 5.77 (s, 1H), 2.30 (s, 3H), 2.15 (s, 3H).

[0328] Example 17, Preparation of compounds SZ-75, SZ-77 and SZ-81 of the present application

[0329] Compound SZ-177-1 (4.0 g, 17.1 mmol) was dissolved in dry DMF (40 mL), cooled to -10 °C, NaH (824 mg, 60% in mineral oil, 20.6 mmol) was added to the system, stirred for 10 minutes, 4-methoxychlorobenzene (3.2 g, 20.5 mmol) was slowly added to the system, and the temperature was allowed to rise to room temperature naturally, and stirred for 2 hours. After the reaction was completed by TLC monitoring, the reaction liquid was poured into ice water, extracted with EtOAc (3 x 30 mL), the combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered under suction, 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 / 10) monitoring, and the Rf = 0.5 ~ 0.6 part was collected to obtain compound SZ-75-1 (5.112 g, yield 84.5%) as a colorless oil. ESI [M+H] + = 354.2.

[0330] Compound SZ-75-1 (1 g, 2.83 mmol) was dissolved in dry THF (20 mL) under nitrogen protection, the reaction system was cooled to -78 °C with dry ice / acetone bath. n-BuLi (1.24 mL, 2.5 mol / L in Hexane, 3.1 mmol) was slowly added to the reaction system with a syringe, and the stirring was continued for 10 minutes. 2-Chloro-3-methylbenzaldehyde (520 mg, 3.37 mmol) was slowly added dropwise to the reaction system with a syringe, and the stirring was continued for 30 minutes. After the reaction was completed by TLC monitoring, saturated aqueous ammonium chloride solution was slowly added to the reaction system, and the organic phase was extracted with EtOAc (3 x 30 mL), 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 / 30 ~ 1 / 2), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 2) monitoring, and the Rf = 0.3 ~ 0.4 part was collected to obtain compound SZ-75-2 (420.4 mg, yield 35%) as a syrup solid. ESI [M+H] + = 430.1.

[0331] DCC (303.3 mg, 1.47 mmol) and DMAP (239.4 mg, 1.96 mmol) were added to a solution of acetic acid (88.96 mg, 1.47 mmol) in dichloromethane (5 mL) at 0 °C, and stirred for 15 minutes. SZ-75-2 (420.4 mg, 0.98 mmol) was added to the reaction system, and stirred for 3 hours. After the reaction system was completed by TLC monitoring, methyl tert-butyl ether (5 mL) was added to the reaction system, and stirred for 5 minutes. The reaction system was 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 ~ 1 / 3), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 3) monitoring, and the Rf = 0.3 ~ 0.5 part was collected to obtain compound SZ-75-3 (415.2 mg, yield 90%) as a syrup. ESI [M+H] + = 472.0.

[0332] SZ-75-3 (415.2 mg, 0.88 mmol) was dissolved in CH2Cl2(10 mL) at room temperature, TFA (1 mL) was added, and stirring was performed for 2 h. After the reaction was completed as monitored by TLC, it was basified with saturated aqueous NaHC03solution (20 mL), extracted with CH2Cl2(3 x 20 mL), the organic phase was combined and dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (ethyl acetate / petroleum ether (v / v) = 1 / 10 ~ 1 / 3) with TLC (ethyl acetate / petroleum ether (v / v) = 1 / 3) monitoring, and the fraction with Rf= 0.3 ~ 0.5 was collected to give the target compound SZ-75-4 (285.6 mg, yield 92%) as a yellow oil. ESI [M+H]+= 352.0.

[0333] SZ-75-4 (285.6 mg, 0.82 mmol) was dissolved in CH2Cl2(10 mL), and active Mn02(1.36 g, 14.2 mmol, 91%) was added, and stirring was performed at room temperature for 5 h. After the reaction was completed as monitored by TLC, it was filtered, and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (ethyl acetate / petroleum ether (v / v) = 1 / 10 ~ 1 / 1) with TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1) monitoring, and the fraction with Rf= 0.7 ~ 0.8 was collected to give compound SZ-75-5 (215.3 mg, yield 76%) as a white solid. ESI [M+H]+= 350.0.

[0334] NaOH (49.3 mg, 1.23 mmol) was added to a solution of SZ-75-5 (215.3 mg, 0.62 mmol) in THF / H20 (3 mL, v / v = 1 / 1) at room temperature, and stirring was performed for 12 h. After the reaction was completed as monitored by TLC, it was concentrated under reduced pressure, cooled with an ice water bath, adjusted to pH = 5 with 1N HC1, extracted with EtOAc (3 x 30 mL), the organic phase was combined and washed with saturated brine, dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (ethyl acetate / petroleum ether (v / v) = 1 / 30 ~ 1 / 1) with TLC (ethyl acetate / petroleum ether (v / v) = 1 / 1) monitoring, and the fraction with Rf= 0.3 ~ 0.5 was collected to give compound SZ-75-6 (154.3 mg, yield 81%) as a white solid. ESI [M+H]+= 308.1. +

[0335] ​SZ-75-6 (154.3 mg, 0.50 mmol), triethylsilane (1 mL) and TFA (1 mL) were added to a sealed tube in turn, and stirred at 90 °C for 1 h. The reaction was concentrated under reduced pressure, the residue was basified with saturated aqueous NaHC03solution, extracted with EtOAc (3 x 30 mL), the combined organic phase was washed with saturated brine, dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (EtOAc / petroleum ether (v / v) = 1 / 100 ~ 1 / 10) to give the target compound SZ-75-7 (111.4 mg, yield 76%) as a white solid. ESI [M+H] + = 292.1.

[0336] Compound SZ-75-7 (111.4 mg, 0.38 mmol) was dissolved in dry THF (2 mL), cooled to -10 °C, and LAH (0.76 mL, 1 mol / L in THF, 0.76 mmol) was added to the system, and the temperature was allowed to rise to room temperature, and stirred for 2 h. After TLC monitoring showed that the reaction was complete, Na2S04.10H20 was added to the reaction system in batches, filtered, and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (EtOAc / petroleum ether (v / v) = 1 / 100 ~ 1 / 20), TLC (EtOAc / petroleum ether (v / v) = 1 / 20) monitoring, and the fraction with Rf = 0.5 ~ 0.6 was collected to give the target compound SZ-75 (52.6 mg, yield 46.9%) as a white solid. ESI [M+H] + = 294.1.

[0337] 1 H NMR (400 MHz, d6-DMSO) δ 7.45 (s, 1H), 7.27 - 7.16 (m, 3H), 5.89 (d, J = 4.9, 1H), 4.27 (dd, J = 6.4, 4.9, 1H), 4.23 (s, 2H), 2.33 (s, 3H), 1.15 - 1.06 (m, 1H), 0.49 - 0.32 (m, 4H).

[0338] The preparation method of the target compounds SZ-77 and SZ-81 is similar to that of compound SZ-75.

[0339] Compound SZ-77: 65.6 mg, syrup solid, ESI [M+H] + = 278.1.

[0340] 1H NMR (400 MHz, d6-DMSO) δ 7.45 (s, 1H), 7.17 (t, J = 7.4 Hz, 2H), 7.04 (t, J = 7.5 Hz, 1H), 5.91 (d, J = 4.9 Hz, 1H), 4.29 (dd, J = 6.2, 5.1 Hz, 1H), 4.14 (s, 2H), 2.23 (d, J = 1.5 Hz, 3H), 1.19 - 1.04 (m, 1H), 0.50 - 0.34 (m, 4H).

[0341] Compound SZ-81 : 34.8 mg, syrup solid, ESI [M+H] + = 314.1.

[0342] 1 H NMR (400 MHz, d6-DMSO) δ 7.56 (dd, J = 7.9, 1.6 Hz, 1H), 7.49 (s, 1H), 7.43 (dd, J = 7.7, 1.6 Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H), 5.93 (d, J = 4.8 Hz, 1H), 4.35 - 4.26 (m, 3H), 1.20 - 1.05 (m, 1H), 0.50 - 0.36 (m, 4H).

[0343] Example 18, Preparation of compounds SZ-89, SZ-98, SZ-108, SZ-109, SZ-111, SZ-119, SZ-120, SZ-121 and SZ-123 of the present application

[0344] General procedure:

[0345] Compound SZ-47 (1 eq) was dissolved in dry THF under nitrogen protection, the reaction system was cooled to -78 °C with dry ice / acetone bath. n-BuLi (1 eq, 2.5 mol / L in Hexane) was slowly added to the reaction system with a syringe, and stirring was continued for 2 minutes. The THF solution of the corresponding aldehyde or ketone (1 eq) was slowly added to the reaction system with a syringe at a rate of 1.0 mL / min, and stirring was continued for 30 minutes. After the reaction was completed by TLC monitoring, saturated aqueous ammonium chloride solution was slowly added to the reaction system, extracted with EtOAc, the combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography to obtain the target compound.

[0346] Compound SZ-89: 65.8 mg, white solid, ESI [M+H] + = 262.1.

[0347] 1H NMR (400 MHz, d6-DMSO) δ 8.27 (s, 1H), 7.36 - 7.32 (m, 1H), 7.26 - 7.13 (m, 2H), 6.29 (d, J = 5.0 Hz, 1H), 5.11 - 4.87 (m, 1H), 2.31 (s, 3H), 2.13 (s, 3H), 1.46 (d, J = 6.5 Hz, 3H).

[0348] Compound SZ-98: 62.0 mg, white solid, ESI [M+H] + = 324.1.

[0349] 1 H NMR (400 MHz, d6-DMSO) δ 8.29 (s, 1H), 7.46 (d, J = 7.1 Hz, 2H), 7.38 (t, J = 7.4 Hz, 2H), 7.35 - 7.28 (m, 2H), 7.22 - 7.15 (m, 2H), 6.98 (d, J = 4.4 Hz, 1H), 5.98 (d, J = 4.4 Hz, 1H), 2.29 (s, 3H), 2.05 (s, 3H).

[0350] Compound SZ-108: 37.1 mg, syrup-like solid, ESI [M+H] + = 290.1.

[0351] 1 H NMR (400 MHz, d6-DMSO) δ 8.32 (s, 1H), 7.35 - 7.32 (m, 1H), 7.25 - 7.14 (m, 2H), 6.27 (d, J = 5.1 Hz, 1H), 4.63 (t, J = 4.8 Hz, 1H), 2.31 (s, 3H), 2.13 (s, 3H), 2.11 - 1.98 (m, 1H), 0.93 (d, J = 6.9 Hz, 3H), 0.84 (d, J = 6.8 Hz, 3H).

[0352] Compound SZ-109: 85.6 mg, syrup-like solid, ESI [M+H] + = 288.1.

[0353] 1 H NMR (400 MHz, d6-DMSO) δ 8.32 (s, 1H), 7.36 - 7.34 (m, 1H), 7.24 - 7.14 (m, 2H), 6.57 (d, J = 4.3 Hz, 1H), 5.28 (d, J = 4.2 Hz, 1H), 5.15 (s, 1H), 4.95 (s, 1H), 2.31 (s, 3H), 2.12 (s, 3H), 1.68 (s, 3H).

[0354] Compound SZ-111: 18.5 mg, syrup solid, ESI [M+H] + = 276.1.

[0355] 1 H NMR (400 MHz, d6-DMSO) δ 8.30 (s, 1H), 7.35 - 7.32 (m, 1H), 7.28 - 7.15 (m, 2H), 6.27 (d, J = 5.2 Hz, 1H), 4.75 (dt, J = 7.3, 4.9 Hz, 1H), 2.31 (s, 3H), 2.13 (s, 3H), 1.92 - 1.76 (m, 1H), 1.78 - 1.57 (m, 1H), 0.93 (t, J = 7.4 Hz, 3H).

[0356] Compound SZ-119: 45.7 mg, white solid, ESI [M+H] + = 356.1.

[0357] 1 H NMR (400 MHz, d6-DMSO) δ 8.31 (s, 1H), 7.35 - 7.31 (m, 1H), 7.28 (dd, J = 14.5, 7.4 Hz, 2H), 7.21 - 7.16 (m, 2H), 7.15 - 7.08 (m, 1H), 7.01 (d, J = 4.8 Hz, 1H), 6.15 (d, J = 4.7 Hz, 1H), 2.27 (s, 3H), 2.25 (d, J = 1.6 Hz, 3H), 2.04 (s, 3H).

[0358] Compound SZ-120: 60.4 mg, white solid, ESI [M+H] + = 342.1.

[0359] 1 H NMR (400 MHz, d6-DMSO) δ 8.31 (s, 1H), 7.53 - 7.46 (m, 1H), 7.44 - 7.36 (m, 1H), 7.34 - 7.30 (m, 1H), 7.26 - 7.21 (m, 2H), 7.19 - 7.15 (m, 2H), 7.06 (d, J = 4.8 Hz, 1H), 6.17 (d, J = 4.7 Hz, 1H), 2.27 (s, 3H), 2.04 (s, 3H).

[0360] Compound SZ-121: 66.7 mg, white solid, ESI [M+H] + = 358.1.

[0361] 1H NMR (400 MHz, d6-DMSO) δ 8.32 (s, 1H), 7.55 (dd, J = 7.3, 2.1 Hz, 1H), 7.48 (dd, J = 7.4, 1.8 Hz, 1H), 7.44 - 7.35 (m, 2H), 7.33 (d, J = 6.8 Hz, 1H), 7.23 - 7.14 (m, 2H), 7.09 (d, J = 4.9 Hz, 1H), 6.26 (d, J = 4.9 Hz, 1H), 2.28 (s, 3H), 2.05 (s, 3H).

[0362] Compound SZ-123: 35.1 mg, white solid, ESI [M+H] + = 372.1.

[0363] 1 H NMR (400 MHz, d6-DMSO) δ 8.32 (s, 1H), 7.55 (dd, J = 7.3, 2.1 Hz, 1H), 7.48 (dd, J = 7.4, 1.8 Hz, 1H), 7.44 - 7.35 (m, 2H), 7.33 (d, J = 6.8 Hz, 1H), 7.23 - 7.14 (m, 2H), 7.09 (d, J = 4.9 Hz, 1H), 6.26 (d, J = 4.9 Hz, 1H), 2.28 (s, 3H), 2.05 (s, 3H).

[0364] Example 19, Preparation of Compounds SZ-93, SZ-96, SZ-100, SZ-142 and SZ-174 of the Invention

[0365] SZ-47 (500.0 mg, 1.69 mmol) was dissolved in DMSO (5 mL), cyclopropylamine (387.1 mg, 6.78 mmol) and triethylamine (513.6 mg, 5.08 mmol) were added, and stirring was carried out at 70 °C for 3 hours. After the reaction was completed by TLC monitoring, the reaction solution was poured into ice water (20 mL), extracted with EtOAc (3 x 15 mL), and the combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 50 ~ 1 / 10), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10) monitoring, and the fraction with Rf = 0.3 ~ 0.4 was collected to obtain the white solid target compound SZ-93 (434.0 mg, yield 94.4%). ESI [M+H] + = 273.1.

[0366] 1H NMR (400 MHz, d6-DMSO) δ 13.02 (s, 1H), 7.36 (d, J = 7.5 Hz, 1H), 7.31 - 7.25 (m, 2H), 7.20 (t, J = 7.5 Hz, 1H), 3.54 - 3.39 (m, 1H), 2.30 (s, 3H), 2.16 (s, 3H), 0.95 - 0.94 (m, 4H).

[0367] Compound SZ-93 (260 mg, 0.95 mmol) was dissolved in dry DMF (3 mL) at room temperature, cooled to -10 °C, NaH (46.0 mg, 60% in mineral oil, 1.15 mmol) was added to the system, stirred for 10 min, CH3I (149.2 mg, 1.05 mmol) was slowly added to the system by syringe, continue to stir for 1 h. After the reaction was monitored to be complete by TLC, the reaction was poured into ice water, extracted with EtOAc (3 x 15 mL), the combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 30 ~ 1 / 3), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 3) monitoring, the fraction with Rf = 0.2 ~ 0.4 was collected to give the white solid target compound SZ-96 (167.5 mg, yield 61.3%). ESI [M+H] + = 287.1.

[0368] 1 H NMR (400 MHz, d6-DMSO) δ 7.60 (s, 1H), 7.32 - 7.28 (m, 1H), 7.22 - 7.14 (m, 2H), 3.31 - 3.22 (m, 1H), 2.60 (s, 3H), 2.30 (s, 3H), 2.14 (s, 3H), 1.09 - 0.96 (m, 4H).

[0369] SZ-47 (500 mg, 1.69 mmol) was dissolved in ethanol (5 mL), sodium hydrosulfide (379.6 mg, 6.77 mmol) was added, stirred at 80 °C for 2 h. After the reaction was monitored to be complete by TLC, the reaction was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 ~ 1 / 2), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 2) monitoring, the fraction with Rf = 0.3 ~ 0.4 was collected to give the white solid compound SZ-100 (395.0 mg, yield 93.8%). ESI [M+H] + = 250.1.

[0370] 1H NMR (400 MHz, d6-DMSO) δ 13.87 (s, 1H), 7.44 (s, 1H), 7.40 (d, J = 7.5 Hz, 1H), 7.35 (d, J = 7.3 Hz, 1H), 7.24 (t, J = 7.6 Hz, 1H), 2.32 (s, 3H), 2.18 (s, 3H).

[0371] NaH (39.8 mg, 60% in mineral oil, 0.995 mmol) was added to a solution of cyclopropanol (121.9 mg, 2.10 mmol) in THF (3 mL) at 0 °C and stirred for 10 min. A solution of SZ-47 (267.5 mg, 0.903 mmol) in THF (1 mL) was added and the reaction was allowed to warm to room temperature naturally and stirred for 2 h. After the reaction was completed by TLC monitoring, the reaction was poured into ice water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 ~ 1 / 5) to give syrup solid target compound SZ-142 (80.8 mg, yield 32.7%) and white solid target compound SZ-174 (100.0 mg, yield 33.4%).

[0372] Compound SZ-142: ESI [M+H] + = 274.1.

[0373] 1 H NMR (400 MHz, d6-DMSO) δ 7.76 (s, 1H), 7.35 - 7.31 (m, 1H), 7.25 - 7.13 (m, 2H), 4.36 (tt, J = 5.7, 3.0 Hz, 1H), 2.31 (s, 3H), 2.13 (s, 3H), 0.98 - 0.77 (m, 4H).

[0374] Compound SZ-174: ESI [M+H] + = 332.1.

[0375] 1 H NMR (400 MHz, d6-DMSO) δ 13.49 (s, 1H), 7.35 (d, J = 7.4 Hz, 1H), 7.22 (t, J = 7.6 Hz, 1H), 7.15 (d, J = 7.3 Hz, 1H), 5.26 (s, 1H), 3.56 - 3.46 (m, 2H), 2.32 (s, 3H), 2.15 (s, 3H), 0.60 - 0.43 (m, 8H).

[0376] Example 20, Preparation of compound SZ-112 of the present application

[0377] Active MnO2(4.68 g, 53.8 mmol) was added to a solution of SZ-111 (511 mg, 1.86 mmol) in CH2Cl2(20 mL) and stirred at room temperature for 5 h. After the reaction was completed by TLC monitoring, it was filtered and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 30 ~ 1 / 5) with TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5) monitoring, and the fraction with Rf= 0.3 ~ 0.5 was collected to give compound SZ-112-1 (193.2 mg, yield 38.1%) as a white solid. ESI [M+H] + = 274.1.

[0378] Potassium tert-butoxide (75.2 mg, 0.67 mmol) was added to a solution of methyltriphenylphosphonium bromide (239.4 mg, 0.67 mmol) in THF (5 mL) at 0 °C, and allowed to warm to room temperature and stirred for 1 h. The reaction was cooled to 0 °C, and a solution of SZ-112-1 (183.0 mg, 0.67 mmol) in THF (3 mL) was added dropwise, and allowed to warm to room temperature and stirred for 8 h. After the reaction was completed by TLC monitoring, the reaction was poured into ice water and extracted with EtOAc (3 x 20 mL), and the combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 30 ~ 1 / 10) with TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10) monitoring, and the fraction with Rf= 0.2 ~ 0.3 was collected to give the target compound SZ-112 (27.0 mg, yield 14.9%) as a syrup solid. ESI [M+H] + = 272.1.

[0379] 1 H NMR (400 MHz, d6-DMSO) δ 8.34 (s, 1H), 7.37 (d, J = 7.3 Hz, 1H), 7.28 (d, J = 6.9 Hz, 1H), 7.22 (t, J = 7.5 Hz, 1H), 5.90 (s, 1H), 5.48 (s, 1H), 2.61 - 2.54 (m, 2H), 2.33 (s, 3H), 2.17 (s, 3H), 1.15 (t, J = 7.4 Hz, 3H).

[0380] Example 21, Preparation of compounds SZ-114, SZ-115 and SZ-116 of the present application

[0381] The preparation method of target compound SZ-114 and SZ-115 is similar to that of target compound SZ-89, which is prepared using SZ-47 and the corresponding ketone as raw materials.

[0382] Compound SZ-114: 80.4 mg, white solid, ESI [M+H] + = 290.1.

[0383] 1 H NMR (400 MHz, d6-DMSO) δ 8.34 (s, 1H), 7.46 (s, 1H), 7.37 (d, J = 7.2 Hz, 1H), 7.28 (d, J = 6.9 Hz, 1H), 7.23 (t, J = 7.5 Hz, 1H), 4.88 (d, J = 6.5 Hz, 2H), 4.73 (d, J = 6.5 Hz, 2H), 2.33 (s, 3H), 2.17 (s, 3H).

[0384] Compound SZ-115: 120.4 mg, white solid, ESI [M+H] + = 288.1.

[0385] 1 H NMR (400 MHz, d6-DMSO) δ 8.25 (s, 1H), 7.36 (d, J = 7.4 Hz, 1H), 7.28 (d, J = 6.6 Hz, 1H), 7.22 (t, J = 7.5 Hz, 1H), 6.65 (s, 1H), 2.52-2.48 (m, 2H), 2.41-2.30 (m, 5H), 2.16 (s, 3H), 1.95-1.84 (m, 2H).

[0386] SZ-115 (84.0 mg, 0.29 mmol), triethylsilane (5 mL) and TFA (1 mL) were added to a sealed tube, and stirred at 80°C for 2 hours. The reaction solution was concentrated under reduced pressure, the residue was alkalized with saturated aqueous sodium bicarbonate solution, extracted with EtOAc (3 x 15 mL), the combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, suction filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 30~1 / 3) to obtain the target compound SZ-116 (16.5 mg, yield 20.6%) in the form of a syrup solid. ESI [M+H] + = 274.1.

[0387] 1H NMR (400 MHz, d6-DMSO) δ 7.10 - 7.00 (m, 3H), 6.87 (s, 1H), 6.35 (s, 1H), 4.07 (s, 2H), 2.52 - 2.47 (m, 2H), 2.35 - 2.27 (m, 2H), 2.26 (s, 3H), 2.20 (s, 3H), 1.97 - 1.78 (m, 2H).

[0388] Example 22, Preparation of compounds SZ-118 and SZ-124 of the present application

[0389] To a solution of compound SZ-118-1 (3.74 g, 19.0 mmol) in THF (30 mL) was added methyl magnesium bromide (29.1 mL, 1 mol / L in THF, 29.1 mmol) dropwise at 0 °C. The reaction was stirred for 30 min. After the reaction was completed by TLC, the reaction was poured into saturated aqueous ammonium chloride solution (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 ~ 1 / 20) with TLC (ethyl acetate / petroleum ether (v / v) = 1 / 20) monitoring. The fractions with Rf = 0.5 ~ 0.6 were collected to give compound SZ-118-2 (2.2 g, yield 76.2%) as a white solid. ESI [M+H] + = 198.1.

[0390] To a solution of compound SZ-118-1 (3.74 g, 19.0 mmol) in THF (30 mL) was added methyl magnesium bromide (29.1 mL, 1 mol / L in THF, 29.1 mmol) dropwise at 0 °C. The reaction was stirred for 30 min. After the reaction was completed by TLC, the reaction was poured into saturated aqueous ammonium chloride solution (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 ~ 1 / 20) with TLC (ethyl acetate / petroleum ether (v / v) = 1 / 20) monitoring. The fractions with Rf = 0.5 ~ 0.6 were collected to give compound SZ-118-2 (2.2 g, yield 76.2%) as a white solid. ESI [M+H] + = 153.1.

[0391] The preparation method of target compound SZ-118 is similar to that of target compound SZ-65, which is prepared using SZ-47 and SZ-118-2 as raw materials.

[0392] Compound SZ-118: 30.7 mg, syrupy solid, ESI [M+H] + = 354.1.

[0393] 1 H NMR (400 MHz, d6-DMSO) δ 8.24 (s, 1H), 7.35 (d, J = 7.1 Hz, 1H), 7.29 - 7.17 (m, 4H), 7.12 (t, J = 7.6 Hz, 1H), 4.79 (q, J = 7.2 Hz, 1H), 2.30 (s, 3H), 2.25 (d, J = 1.9 Hz, 3H), 2.11 (s, 3H), 1.70 (d, J = 7.1 Hz, 3H).

[0394] The preparation method of compound SZ-124-2 is similar to that of compound SZ-118-2, using 2-chloro-3-methylbenzoic acid as the raw material to prepare.

[0395] The preparation method of target compound SZ-124 is similar to that of target compound SZ-68, using SZ-47 as the raw material to prepare.

[0396] Compound SZ-124: 37.4 mg, syrupy solid, ESI [M+H] + = 370.1.

[0397] 1 H NMR (400 MHz, d6-DMSO) δ 8.24 (s, 1H), 7.35 (d, J = 7.1 Hz, 1H), 7.29 - 7.17 (m, 4H), 7.12 (t, J = 7.6 Hz, 1H), 4.79 (q, J = 7.2 Hz, 1H), 2.30 (s, 3H), 2.25 (d, J = 1.9 Hz, 3H), 2.11 (s, 3H), 1.70 (d, J = 7.1 Hz, 3H).

[0398] Example 23, Preparation of compound SZ-131 of the application

[0399] Under nitrogen protection, 5-bromothiazole (1.0 g, 6.1 mmol) was dissolved in dry THF (10 mL), the reaction system was cooled to -78 °C with dry ice / acetone bath. n-BuLi (3.8 mL, 1.6 mol / L in Hexane, 6.1 mmol) was slowly added to the reaction system with syringe, stirred for 10 minutes. The solution of SZ-118-2 (926.8 mg, 6.1 mmol) in THF (2 mL) was slowly added to the reaction system with syringe at a rate of 1.0 mL / min, stirred for 30 minutes. After the reaction was completed by TLC monitoring, saturated aqueous ammonium chloride solution was slowly added to the reaction system, extracted with EtOAc (3 x 30 mL), the combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure to obtain the crude product, which 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) monitoring, the Rf= 0.3 ~ 0.5 part was collected to obtain white solid compound SZ-131-1 (320.0 mg, yield 22.1%). ESI [M+H] + = 238.1.

[0400] SZ-131-1 (320.0 mg, 1.35 mmol), triethylsilane (3 mL) and TFA (3 mL) were added to a sealed tube, stirred at 80 °C for 1 hour. The reaction solution was concentrated under reduced pressure, the residue was basified with saturated aqueous sodium bicarbonate solution, extracted with EtOAc (3 x 15 mL), the combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 ~ 1 / 5) to obtain a white solid mixture of SZ-131 and SZ-131-2 (128.7 mg).

[0401] Compound SZ-131: ESI [M+H] + = 222.1.

[0402] Compound SZ-131-2: ESI [M+H] + = 220.1.

[0403] A mixture of the above SZ-131 and SZ-131-2 (128.7 mg), zinc bromide (132.3 mg, 0.587 mmol) and 10% wet Pd-C (270.3 mg) was dissolved in MeOH (2 mL) at room temperature, the system was replaced by hydrogen gas for three times, stirred under hydrogen gas for 12 hours at room temperature. After the reaction was monitored to be completed by TLC, it was suction filtered, the filter cake was washed with methanol (3 x 5 mL), the filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by preparative TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10) and the Rf = 0.3-0.5 fraction was collected to obtain the target compound SZ-131 (16.5 mg, 5.5% yield for two steps) in the form of a syrup solid. ESI [M+H] + = 222.1.

[0404] 1 H NMR (400 MHz, d6-DMSO) δ 7.73 (d, J = 3.3 Hz, 1H), 7.61 (d, J = 3.3 Hz, 1H), 7.22 (t, J = 7.4 Hz, 2H), 7.14 - 7.05 (m, 1H), 4.77 (q, J = 7.1 Hz, 1H), 2.25 (d, J = 2.1 Hz, 3H), 1.71 (d, J = 7.2 Hz, 3H).

[0405] Example 24, Preparation of the compound SZ-132 of the present application

[0406] The preparation method of the target compound SZ-132 is similar to that of the target compound SZ-5.

[0407] Compound SZ-132: 60.4 mg, white solid, ESI [M+H] + = 222.1.

[0408] 1 H NMR (400 MHz, d6-DMSO) δ 9.53 (s, 1H), 8.37 (s, 1H), 7.59 (t, J = 7.4 Hz, 1H), 7.53 (t, J = 6.4 Hz, 1H), 7.30 (t, J = 7.6 Hz, 1H), 2.34 (d, J = 1.9 Hz, 3H).

[0409] Example 25, Preparation of the compounds SZ-133, SZ-146, SZ-136 and SZ-147 of the present application

[0410] Format reagent A (15.7 mL, 1 mol / L in THF, 15.7 mmol) was added slowly dropwise to 5-thiazolyl ethanone (1 g, 7.86 mmol) in THF (10 mL) at 0 °C, and the temperature was allowed to rise to room temperature, and stirred for 4 h. After the reaction was completed by TLC monitoring, the reaction was poured into saturated aqueous ammonium chloride solution (20 mL), extracted with EtOAc (3 x 20 mL), the combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 50 ~ 1 / 3), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 3) monitoring, and the fraction with Rf = 0.3 ~ 0.5 was collected to obtain white solid compound SZ-133-1 (914.1 mg, yield 49.8%). ESI [M+H] + = 234.1.

[0411] SZ-133-1 (914.0 mg, 3.92 mmol), triethylsilane (5 mL) and TFA (5 mL) were added to a reaction bottle, and stirred at room temperature for 2 h. The reaction was concentrated under reduced pressure, basified with saturated aqueous sodium bicarbonate solution, extracted with EtOAc (3 x 15 mL), the combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 ~ 1 / 30) to obtain syrup solid target compound SZ-133 (147.1 mg, yield 17.3%) and syrup solid target compound SZ-146 (275.7 mg, yield 32.7%).

[0412] Compound SZ-133: ESI [M+H] + = 218.1.

[0413] 1 H NMR (400 MHz, d6-DMSO) δ 8.92 (s, 1H), 7.69 (s, 1H), 7.13 - 7.02 (m, 3H), 4.74 (q, J = 7.0 Hz, 1H), 2.27 (s, 3H), 2.21 (s, 3H), 1.63 (d, J = 7.1 Hz, 3H).

[0414] Compound SZ-146: ESI [M+H] + = 216.1.

[0415] 1H NMR (400 MHz, d6-DMSO) δ 9.02 (s, 1H), 7.45 (s, 1H), 7.22 (d, J = 7.4 Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H), 7.04 (d, J = 7.3 Hz, 1H), 5.86 (s, 1H), 5.16 (s, 1H), 2.29 (s, 3H), 2.05 (s, 3H).

[0416] The preparation method of target compounds SZ-136 and SZ-147 is similar to that of target compounds SZ-133 and SZ-146, which is prepared using 4-acetylthiazole as raw material.

[0417] Compound SZ-136: 179.7 mg, syrupy solid, ESI [M+H] + = 218.1.

[0418] 1 H NMR (400 MHz, d6-DMSO) δ 9.01 (d, J = 1.9 Hz, 1H), 7.30 (d, J = 1.2 Hz, 1H), 7.06 - 6.94 (m, 3H), 4.61 (q, J = 7.1 Hz, 1H), 2.26 (s, 3H), 2.24 (s, 3H), 1.58 (d, J = 7.1 Hz, 3H).

[0419] Compound SZ-147: 13.0 mg, syrupy solid, ESI [M+H] + = 216.1.

[0420] 1 H NMR (400 MHz, d6-DMSO) δ 9.14 (d, J = 1.8 Hz, 1H), 7.20 (d, J = 7.4 Hz, 1H), 7.15 (t, J = 7.4 Hz, 1H), 7.03 (d, J = 7.4 Hz, 1H), 6.93 (d, J = 1.7 Hz, 1H), 6.29 (d, J = 2.2 Hz, 1H), 5.21 (d, J = 2.2 Hz, 1H), 2.29 (s, 3H), 2.02 (s, 3H).

[0421] Example 26, Preparation of compounds SZ-134, SZ-152, SZ-153, SZ-155, SZ-158, SZ-159, SZ-160 and SZ-175 of the application

[0422] Under nitrogen protection, 2,3-dimethylbromobenzene (16.357 g, 88.4 mmol) was dissolved in dry THF (160 mL), the reaction system was cooled to -78 °C with dry ice / acetone bath. n-BuLi (55.26 mL, 1.6 mol / L in Hexane, 88.4 mmol) was slowly added to the reaction system with syringe, stirred for 10 min. 5-thiazolecarboxaldehyde (5.0 g, 44.2 mmol) in THF (25 mL) was slowly added to the reaction system at a rate of 1.0 mL / min, naturally warmed to -40 °C, stirred for 30 min. Another 5-thiazolecarboxaldehyde (5.0 g, 44.2 mmol) in THF (25 mL) was slowly added to the reaction system at a rate of 1.0 mL / min, continued to stir for 30 min at -40 °C. After the reaction was completed by TLC monitoring, saturated aqueous ammonium chloride solution was slowly added to the reaction system, extracted with EtOAc (3 x 150 mL), the combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, suction filtered, concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 1 / 100 ~ 1 / 10), TLC (methanol / dichloromethane (v / v) = 1 / 10) monitoring, the Rf = 0.4 ~ 0.6 part was collected to obtain white solid compound SZ-152 (10.2 g, yield 34.7%). ESI [M+H] + = 333.1.

[0423] 1 H NMR (400 MHz, d6-DMSO) δ 9.02 (d, J = 5.8 Hz, 1H), 7.86 (d, J = 2.7 Hz, 1H), 7.46 - 7.38 (m, 2H), 7.17 - 7.10 (m, 3H), 6.26 - 6.20 (m, 1H), 6.19 (dd, J = 4.4, 1.7 Hz, 1H), 6.15 (d, J = 4.1 Hz, 1H), 2.24 (s, 3H), 2.14 (s, 3H).

[0424] SZ-152 (1.1 g, 3.31 mmol) was dissolved in CH2Cl2(20 mL), activated MnO2(1.57 g, 31.7 mmol) was added, stirred at room temperature for 5 hours. After the reaction was completed by TLC monitoring, suction filtered, the filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 ~ 1 / 1) to obtain white solid compound SZ-134 (553.0 mg, yield 50.9%) and yellow solid compound SZ-155 (429.0 mg, yield 39.2%).

[0425] Compound SZ-134: ESI [M+H] += 329.1.

[0426] 1 H NMR (400 MHz, d6-DMSO) δ 9.59 (s, 1H), 9.19 (s, 1H), 8.44 (s, 1H), 7.51 - 7.42 (m, 2H), 7.31 (t, J = 7.7 Hz, 1H), 2.36 (s, 3H), 2.24 (s, 3H).

[0427] Compound SZ-155: ESI [M+H] + = 331.1.

[0428] 1 H NMR (400 MHz, d6-DMSO) δ 9.52 (s, 1H), 9.11 (s, 1H), 7.97 (s, 1H), 7.41 - 7.38 (m, 1H), 7.18 - 7.15 (m, 2H), 6.59 (d, J = 4.5 Hz, 1H), 6.33 (d, J = 4.5 Hz, 1H), 2.27 (s, 3H), 2.22 (s, 3H).

[0429] SZ-152 (332 mg, 1.0 mmol) was dissolved in dichloromethane (3 mL), TFA (3 mL) and methanol (3 mL) were added successively, stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, the residue was alkalized with saturated aqueous sodium bicarbonate solution, extracted with EtOAc (3 x 15 mL), the combined organic phase was washed with saturated brine, dried over anhydrous Na2S04, suction filtered, concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 ~ 1 / 10), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10) monitoring, the Rf = 0.3 ~ 0.5 part was collected to obtain white solid compound SZ-175 (78.2 mg, yield 22.7%). ESI [M+H] + = 345.1.

[0430] 1 H NMR (400 MHz, d6-DMSO) δ 9.52 (s, 1H), 9.11 (s, 1H), 8.05 (s, 1H), 7.39 - 7.30 (m, 1H), 7.23 - 7.13 (m, 2H), 6.04 (s, 1H), 3.36 (s, 3H), 2.26 (s, 3H), 2.21 (s, 3H).

[0431] SZ-152 (1.056 g, 3.18 mmol), triethylsilane (5 mL) and TFA (5 mL) were added into a sealed tube successively, and stirred at 100 °C for 30 min. The reaction solution was concentrated under reduced pressure, the residue was basified with saturated aqueous sodium bicarbonate solution, extracted with EtOAc (3 x 15 mL), the combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (ethyl acetate / petroleum ether (v / v) = 1 / 10 ~ 1 / 1) to give the target compound SZ-153 (267.4 mg, yield 28.0%) as a white solid and the target compound SZ-158 (212.3 mg, yield 21.1%) as a syrup solid.

[0432] Compound SZ-153: ESI [M+H] + = 301.1.

[0433] 1 H NMR (400 MHz, d6-DMSO) δ 8.99 (s, 1H), 7.80 (s, 1H), 7.44 (s, 1H), 7.10 - 6.99 (m, 3H), 4.55 (s, 2H), 4.14 (s, 2H), 2.23 (s, 3H), 2.15 (s, 3H).

[0434] Compound SZ-158: ESI [M+H] + = 317.1.

[0435] 1 H NMR (400 MHz, d6-DMSO) δ 9.02 (s, 1H), 7.86 (s, 1H), 7.46 (s, 1H), 7.13 (d, J = 4.9 Hz, 1H), 7.11 - 7.03 (m, 3H), 6.23 (d, J = 4.8 Hz, 1H), 4.17 (s, 2H), 2.25 (s, 3H), 2.17 (s, 3H).

[0436] Methylmagnesium bromide (2.1 mL, 1 mol / L in THF, 2.1 mmol) was added slowly to SZ-134 (345.0 mg, 1.05 mmol) in THF (4 mL) at 0 °C and stirred for 30 min. After the reaction was completed by TLC, the reaction was poured into saturated aqueous ammonium chloride solution (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 ~ 1 / 2) and TLC (ethyl acetate / petroleum ether (v / v) = 1 / 2) monitoring. The fraction with Rf = 0.3 ~ 0.4 was collected to give compound SZ-160-1 (234.8 mg, yield 64.9%) as a syrup solid. ESI [M+H] + = 345.1.

[0437] Iodine (125.5 mg, 0.49 mmol) and hypophosphorous acid (0.17 mL) were added successively to a solution of SZ-160-1 (170 mg, 0.49 mmol) in acetic acid (2.55 mL) and stirred at 110 °C for 8 h. After the reaction was completed by TLC, the reaction was concentrated under reduced pressure. The residue was adjusted to pH = 7 with saturated aqueous sodium bicarbonate solution and extracted with EtOAc (3 x 10 mL). The combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 ~ 1 / 10) and TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10) monitoring. The fraction with Rf = 0.2 ~ 0.3 was collected to give compound SZ-160 (71.2 mg, yield 43.9%) as a syrup solid. ESI [M+H] + = 329.1.

[0438] 1 H NMR (400 MHz, d6-DMSO) δ 9.07 (s, 1H), 7.98 (s, 1H), 7.93 (s, 1H), 7.39 (d, J = 7.4 Hz, 1H), 7.33 (d, J = 7.1 Hz, 1H), 7.24 (t, J = 7.6 Hz, 1H), 5.13 (q, J = 7.0 Hz, 1H), 2.32 (s, 3H), 2.17 (s, 3H), 1.80 (d, J = 7.1 Hz, 3H).

[0439] Active Mn02(5.859 g, 67.4 mmol) was added to a solution of SZ-158 (532.0 mg, 1.68 mmol) in CH2CI2(10 mL) and stirred at room temperature for 5 h. After the reaction was completed by TLC, it was filtered and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (ethyl acetate / petroleum ether (v / v) = 1 / 100 ~ 1 / 10), monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10), and the fraction with Rf= 0.3 ~ 0.5 was collected to give compound SZ-159 (168.1 mg, yield 31.8%) as a white solid. ESI [M+H] + = 315.1.

[0440] 1 H NMR (400 MHz, d6-DMSO) δ 9.52 (s, 1H), 9.10 (s, 1H), 8.04 (s, 1H), 7.20 - 7.02 (m, 3H), 4.37 (s, 2H), 2.26 (s, 3H), 2.19 (s, 3H).

[0441] Example 27, Preparation of compound SZ-138 of the present application

[0442] Cyclopropylacetic acid (5.0 g, 49.9 mmol) was dissolved in thionyl chloride (5 mL) and stirred at 80 °C for 2 h. After the reaction was completed by TLC, the reaction was concentrated under reduced pressure to give the crude product SZ-138-1 (2.16 g), which was used directly in the next step without purification.

[0443] A solution of SZ-138-1 (2.16 g, crude) in CH2CI2(10 mL) was added dropwise to a solution of ammonia (100 mL, 0.4 mol / L in THF, 40.0 mmol) in CH2CI2(10 mL) at 0 °C, and the temperature was allowed to rise to room temperature and stirred for 2 h. After the reaction was completed by TLC, it was filtered and the filtrate was concentrated under reduced pressure to give the crude product SZ-138-2 (987 mg), which was used directly in the next step without purification.

[0444] Lawesson's reagent (3.87 g, 9.57 mmol) was added to a solution of SZ-138-2 (987 mg, crude) in THF (10 mL) and stirred at room temperature for 16 h. After the reaction was completed by TLC, the reaction was filtered and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 50 ~ 1 / 5), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10) monitoring, and the fraction with Rf= 0.3 ~ 0.4 was collected to obtain compound SZ-138-3 (599.7 mg, 10.4% yield for three steps) as a colorless oil. ESI [M+H] + = 116.1.

[0445] Ethyl (chloroformyl)acetate (1.18 g, 7.82 mmol) was dissolved in DMF (2 mL) and adjusted to pH = 2 with concentrated sulfuric acid, and a solution of SZ-138-3 (599.7 mg, 5.21 mmol) in DMF (2 mL) was added to the system, which was stirred at 100°C for 20 h. After the reaction was completed by TLC, the reaction was poured into water (10 mL) and extracted with EtOAc (3 x 15 mL), and the combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 50 ~ 1 / 5), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5) monitoring, and the fraction with Rf= 0.3 ~ 0.4 was collected to obtain compound SZ-138-4 (532.9 mg, yield 48.4%) as a colorless oil. ESI [M+H] + = 212.1.

[0446] NaBH4(303.4 mg, 8.02 mmol) was added to a solution of SZ-138-4 (423.1 mg, 2.0 mmol) in ethanol (6 mL) at 0°C, and stirred for 12 h. After the reaction was completed by TLC, the reaction was poured into water (10 mL) and extracted with EtOAc (3 x 15 mL), and the combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product SZ-138-5 (319 mg), which was used directly in the next reaction without purification. ESI [M+H] + = 170.1.

[0447] The crude compound SZ-138-5 (319 mg) obtained in the previous step was dissolved in CH2Cl2(10 mL), activated MnO2(3.18 g, 36.6 mmol) was added, and the mixture was stirred at room temperature for 5 h. After the reaction was completed by TLC monitoring, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography on silica gel (ethyl acetate / petroleum ether (v / v) = 1 / 30-1 / 5), and TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5) monitoring was performed. The fractions with Rf = 0.4-0.6 were collected to obtain the target compound SZ-138-6 (172.0 mg, 40.8% yield for two steps) in the form of a white solid. ESI [M+H] + = 168.1.

[0448] Format reagent A (1.54 mL, 1 mol / L in THF, 1.54 mmol) was slowly added to SZ-138-6 (172.0 mg, 1.03 mmol) in THF (2 mL) at 0°C, and the mixture was allowed to naturally warm to room temperature and stirred for 4 h. After the reaction was completed by TLC monitoring, the reaction system was poured into saturated aqueous ammonium chloride solution (10 mL), extracted with EtOAc (3 x 20 mL), and the combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography on silica gel (ethyl acetate / petroleum ether (v / v) = 1 / 30-1 / 3), and TLC (ethyl acetate / petroleum ether (v / v) = 1 / 3) monitoring was performed. The fractions with Rf = 0.2-0.3 were collected to obtain compound SZ-138-7 (256.6 mg, 91.3% yield) in the form of a syrup solid. ESI [M+H] + = 274.1.

[0449] SZ-138-7 (256.6 mg, 0.94 mmol) was dissolved in CH2Cl2(10 mL), and activated MnO2(1.579 g, 18.2 mmol) was added. The mixture was stirred at room temperature for 5 h. After the reaction was completed by TLC monitoring, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography on silica gel (ethyl acetate / petroleum ether (v / v) = 1 / 100-1 / 10), and TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10) monitoring was performed. The fractions with Rf = 0.4-0.6 were collected to obtain the target compound SZ-138 (184.7 mg, 72.5% yield) in the form of a syrup solid. ESI [M+H] + = 272.1.

[0450] 1H NMR (400 MHz, d6-DMSO) δ 7.91 (s, 1H), 7.39 (d, J = 7.4 Hz, 1H), 7.32 (d, J = 6.9 Hz, 1H), 7.25 (t, J = 7.5 Hz, 1H), 2.97 (d, J = 7.1 Hz, 2H), 2.33 (s, 3H), 2.18 (s, 3H), 1.26 - 1.04 (m, 1H), 0.70 - 0.56 (m, 2H), 0.42 - 0.29 (m, 2H).

[0451] Example 28, Preparation of compounds SZ-144, SZ-145 and SZ-156 of the present application

[0452] Compound 4-bromothiazole (2.59 g, 15.8 mmol) was dissolved in dry THF (20 mL) under nitrogen protection, the reaction system was cooled to -78 °C with dry ice / acetone bath. n-BuLi (9.87 mL, 1.6 mol / L in Hexane, 15.8 mmol) was slowly added to the reaction system with a syringe, stirred for 10 minutes. The solution of SZ-118-2 (2 g, 13.1 mmol) in THF (5 mL) was slowly added to the reaction system with a syringe at a rate of 1.0 mL / min, stirred for 30 minutes. After the reaction was completed by TLC monitoring, saturated aqueous ammonium chloride solution was slowly added to the reaction system, extracted with EtOAc (3 x 30 mL), the combined organic phase was dried over anhydrous Na2SO4, suction filtered, concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography to obtain compounds SZ-144-1 (716.0 mg, yield 18.6%), SZ-145-1 (2.07 g, yield 53.7%) and SZ-156-1 (467.7 mg, yield 8.2%).

[0453] Compound SZ-144-1: white solid, ESI [M+H] + = 316.1.

[0454] Compound SZ-145-1: white solid, ESI [M+H] + = 316.1.

[0455] Compound SZ-156-1: white solid, ESI [M+H] + = 468.1.

[0456] SZ-144-1 (416.9 mg, 1.32 mmol), triethylsilane (5 mL) and TFA (5 mL) were added into a sealed tube, stirred at 80 °C for 1 h. The reaction was concentrated under reduced pressure, the residue was basified with saturated aqueous NaHC03solution, extracted with EtOAc (3 x 15 mL), the combined organic phase was washed with saturated brine, dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (EtOAc / petroleum ether (v / v) = 1 / 50 ~ 1 / 5), monitored by TLC (EtOAc / petroleum ether (v / v) = 1 / 5), the fractions with Rf= 0.4 ~ 0.6 were collected to give the target compound SZ-144 (298.7 mg, yield 75.5%) as a syrup solid. ESI [M+H] + = 300.1.

[0457] 1 H NMR (400 MHz, d6-DMSO) δ 9.06 (s, 1H), 7.19 (dd, J = 14.9, 7.3 Hz, 2H), 7.10 (t, J = 7.6 Hz, 1H), 4.68 (q, J = 7.2 Hz, 1H), 2.23 (d, J = 2.1 Hz, 3H), 1.63 (d, J = 7.2 Hz, 3H).

[0458] The preparation method of the target compounds SZ-145 and SZ-156 is similar to that of the target compound SZ-144, which are prepared using SZ-145-1 and SZ-156-1 as raw materials, respectively.

[0459] Compound SZ-145: 80.5 mg, syrup solid, ESI [M+H] + = 300.1.

[0460] 1 H NMR (400 MHz, d6-DMSO) δ 9.06 (s, 1H), 7.19 (dd, J = 14.9, 7.3 Hz, 2H), 7.10 (t, J = 7.6 Hz, 1H), 4.68 (q, J = 7.2 Hz, 1H), 2.23 (d, J = 2.1 Hz, 3H), 1.63 (d, J = 7.2 Hz, 3H).

[0461] Compound SZ-156: 106.8 mg, syrup solid, ESI [M+H] + = 436.1.

[0462] 1H NMR (400 MHz, d6-DMSO) δ 7.23 (t, J = 7.4 Hz, 2H), 7.17 (t, J = 7.2 Hz, 2H), 7.13 - 7.07 (m, 2H), 4.70 (q, J = 7.0 Hz, 1H), 4.61 (q, J = 7.1 Hz, 1H), 2.24 (s, 3H), 2.23 (s, 3H), 1.65 (dd, J = 7.1, 1.5 Hz, 3H), 1.57 (dd, J = 7.1, 3.1 Hz, 3H).

[0463] Example 29, Preparation of compounds SZ-157, SZ-184 and SZ-185 of the present application

[0464] To a solution of compound SZ-157-1 (820.1 mg, 2.6 mmol) in THF (10 mL) was added 2,2-dimethylpropanal (0.3 mL, 2.6 mmol) at 0 °C, stirred for 1 h at 0 °C, then stirred for 5 h at room temperature. The reaction was monitored by TLC (methanol / dichloromethane (v / v) = 1 / 10). The reaction mixture was poured into ice water (10 mL), extracted with EtOAc (3 x 20 mL), the combined organic phase was washed with saturated brine, dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 1 / 100 ~ 1 / 10), monitored by TLC (methanol / dichloromethane (v / v) = 1 / 10), the fraction with Rf = 0.4 ~ 0.5 was collected to give compound SZ-157 (520.1 mg, yield 58.2%). ESI [M+H] = 342.1. + = 158.1.

[0465] Compound SZ-52-1 (453.3 mg, 0.997 mmol) was dissolved in dry THF (4 mL) under nitrogen protection, the reaction system was cooled to -78 °C with dry ice / acetone bath. n-BuLi (0.656 mL, 1.6 mol / L in Hexane, 1.05 mmol) was slowly added to the reaction system with a syringe, and after the addition was completed, it was continuously stirred for 10 minutes. The solution of SZ-157-1 (314.0 mg, 2.0 mmol) in THF (4 mL) was slowly added to the reaction system with a syringe, and stirred for 30 minutes. After the reaction was completed by TLC monitoring, saturated aqueous ammonium chloride solution was slowly added to the reaction system, extracted with EtOAc (3 x 20 mL), the combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 ~ 1 / 10), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10) monitoring, and the Rf = 0.4 ~ 0.5 part was collected to obtain white solid compound SZ-157-2 (456 mg, yield 96.9 %). ESI [M+H] + = 472.1.

[0466] The preparation method of target compound SZ-157 is similar to that of target compound SZ-58, using SZ-157-2 as raw material, deprotection and oxidation to prepare.

[0467] Compound SZ-157: 43.5 mg, syrup solid, ESI [M+H] + = 314.1.

[0468] 1 H NMR (400 MHz, d6-DMSO) δ 8.75 (s, 1H), 7.40 (d, J = 7.4 Hz, 1H), 7.36 (d, J = 7.4 Hz, 1H), 7.24 (t, J = 7.5 Hz, 1H), 2.99 (dd, J = 7.6, 5.7 Hz, 1H), 2.34 (s, 3H), 2.20 (s, 3H), 1.38 (dd, J = 5.5, 3.8 Hz, 1H), 1.28 (s, 3H), 1.27 - 1.23 (m, 1H), 1.15 (s, 3H).

[0469] LiAlH4(1.62 mL, 1 mol / L in THF, 1.62 mmol) was added dropwise to a solution of SZ-157-2 (714.2 mg, 1.51 mmol) in THF (7 mL) at 10 °C and stirred for 1 h. After the reaction was completed by TLC, the reaction was poured into water (7 mL) and extracted with EtOAc (3 x 15 mL). The combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 ~ 1 / 2), monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 2), and the fraction with Rf = 0.5 ~ 0.6 was collected to give compound SZ-184-1 (407.0 mg, yield 56.7%) as a white solid. ESI [M+H] + = 474.2.

[0470] The preparation method of target compound SZ-184 was similar to that of target compound SZ-57, which was prepared using SZ-184-1 as the raw material.

[0471] Compound SZ-184: 73.8 mg, syrup solid, ESI [M+H] + = 316.1.

[0472] 1 H NMR (400 MHz, d6-DMSO) δ 8.42 - 8.29 (m, 1H), 7.36 - 7.33 (m, 1H), 7.28 - 7.10 (m, 2H), 6.18 - 6.15 (m, 1H), 4.43 - 4.38 (m, 1H), 2.31 (s, 3H), 2.13 (s, 3H), 1.21 (s, 3H), 1.08 (s, 3H), 0.97 - 0.91 (m, 1H), 0.50 - 0.45 (m, 1H), 0.38 (t, J = 4.9 Hz, 1H).

[0473] -10 °C, BAST (115.9 mg, 1.51 mmol) was added to a solution of SZ-184 (200.0 mg, 0.63 mmol) in dichloromethane (3 mL) and stirred for 1 h. After the reaction was completed by TLC monitoring, the reaction was poured into water (7 mL) and extracted with EtOAc (3 x 15 mL), the combined organic phase was washed with saturated brine, dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 ~ 1 / 10), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10) monitoring, and the fraction with Rf= 0.3 ~ 0.4 was collected to give compound SZ-185 (70.3 mg, yield 34.9%) as a syrup solid. ESI [M+H] + = 318.1.

[0474] 1 H NMR (400 MHz, d6-DMSO) δ 8.30 (s, 1H), 7.36 (d, J = 5.9 Hz, 1H), 7.29 - 7.18 (m, 2H), 6.82 (d, J = 15.8 Hz, 1H), 6.69 - 6.57 (m, 1H), 2.61 (dd, J = 19.6, 7.9 Hz, 2H), 2.32 (s, 3H), 2.15 (s, 3H), 1.40 (s, 3H), 1.35 (s, 3H).

[0475] Example 30, Preparation of compounds SZ-149 and SZ-336 of the application

[0476] At room temperature, 3,3-dimethylcyclobutane carboxylic acid (1 g, 7.80 mmol), HATU (4.4 g, 11.6 mmol) and DIEA (3.01 g, 23.3 mmol) were added to DMF (10 mL), stirred for 15 min, then N, O-dimethylhydroxylamine hydrochloride (1.14 g, 11.7 mmol) was added, stirred at room temperature for 12 h. After the reaction was completed by TLC monitoring, the reaction was poured into ice water (10 mL) and extracted with EtOAc (3 x 20 mL), the combined organic phase was washed with saturated brine, dried over anhydrous Na2S04, filtered and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 ~ 1 / 1), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 2) monitoring, and the fraction with Rf= 0.3 ~ 0.5 was collected to give compound SZ-336-1 (1.1291 g, yield 84.5%) as a colorless oil. ESI [M+H] + = 172.1.

[0477] Compound SZ-52-1 (676.6 mg, 1.49 mmol) was dissolved in dry THF (10 mL) under nitrogen protection, the reaction system was cooled to -78 °C with dry ice / acetone bath. n-BuLi (0.597 mL, 2.5 mol / L in Hexane, 1.49 mmol) was added slowly to the reaction system with a syringe, and after the addition was completed, the stirring was continued for 10 minutes. A solution of SZ-336-1 (280.9 mg, 1.64 mmol) in THF (2 mL) was slowly added to the reaction system with a syringe, and stirred for 30 minutes. After the reaction was completed by TLC monitoring, saturated aqueous ammonium chloride solution was slowly added to the reaction system, extracted with EtOAc (3 x 30 mL), the combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 ~ 1 / 10), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10) monitoring, and the Rf = 0.4 ~ 0.5 part was collected to obtain white solid compound SZ-336-2 (674.3 mg, yield 93.0%). ESI [M+H] + = 486.2.

[0478] Compound SZ-336-2 (674.3 mg, 1.38 mmol) was dissolved in dry THF (7 mL) and cooled to -10 °C, and LAH (1.38 mL, 1 mol / L in THF, 1.38 mmol) was slowly added dropwise to the system, and stirred for 2 hours. After the reaction was completed by TLC monitoring, Na2SO4.10H2O was added to the reaction system in batches, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 ~ 1 / 20), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 20) monitoring, and the Rf = 0.5 ~ 0.6 part was collected to obtain white solid target compound SZ-336-3 (564.2 mg, yield 83.2%). ESI [M+H] + = 488.2.

[0479] SZ-336-3 (489.0 mg, 1.01 mmol) was dissolved in dichloromethane (10 mL), triethylamine (442.7 mg, 4.02 mmol) and a drop of DMF were added, and the solution was cooled to -10 °C. A solution of thionyl chloride (239.4 mg, 2.02 mmol) was added dropwise, and the mixture was stirred for 30 min. After the reaction was completed as monitored by TLC, the reaction mixture was poured into ice water (10 mL) and extracted with EtOAc (3 x 15 mL). The combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography on silica gel (ethyl acetate / petroleum ether (v / v) = 1 / 100 ~ 1 / 10) with TLC (ethyl acetate / petroleum ether (v / v) = 1 / 50) monitoring. The fraction with Rf = 0.3 ~ 0.4 was collected to give compound SZ-336-4 (237.6 mg, yield 46.7%) as a syrup solid. ESI [M+H] + = 506.2.

[0480] Zinc powder (184.5 mg, 2.82 mmol) and acetic acid (1 mL) were added to a solution of SZ-336-4 (237.6 mg, 0.47 mmol) in methanol (4 mL), and the mixture was stirred at 60 °C for 1 h. After the reaction was completed as monitored by TLC, the reaction mixture was filtered, and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography on silica gel (ethyl acetate / petroleum ether (v / v) = 1 / 100 ~ 1 / 10) with TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10) monitoring. The fraction with Rf = 0.3 ~ 0.4 was collected to give compound SZ-336-5 (219.8 mg, yield 99%) as a syrup solid. ESI [M+H] + = 472.3.

[0481] SZ-336-5 (219.8 mg, 0.47 mmol) was dissolved in THF (5 mL) at room temperature, and TBAF (0.93 mL, 1 mol / L in THF, 0.93 mmol) was added dropwise. The mixture was stirred for 30 min. After the reaction was completed as monitored by TLC, H2O (10 mL) was added to the reaction mixture, and the mixture was extracted with EtOAc (3 x 10 mL). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product SZ-336-6. The crude product was used directly in the next reaction without purification. ESI [M+H] + = 316.1.

[0482] The crude compound SZ-336-6 obtained in the previous step was dissolved in CH2Cl2(20 mL), activated MnO2(779.2 mg, 8.96 mmol) was added, and the mixture was stirred at room temperature for 5 h. After the reaction was completed by TLC, the mixture was filtered and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by column chromatography on silica gel (ethyl acetate / petroleum ether (v / v) = 1 / 10 ~ 1 / 3), monitored by TLC (ethyl acetate / petroleum ether (v / v) = 1 / 3), and the fraction with Rf= 0.3 ~ 0.5 was collected to give syrupy compound SZ-336 (90.7 mg, 62.3% yield over two steps). ESI [M+H] + = 314.1.

[0483] 1 H NMR (400 MHz, d6-DMSO) δ 8.23 (s, 1H), 7.33 - 7.31 (m, 1H), 7.21 - 7.15 (m, 2H), 3.07 (d, J = 7.6 Hz, 2H), 2.66 - 2.53 (m, 1H), 2.29 (s, 3H), 2.10 (s, 3H), 1.90 - 1.80 (m, 2H), 1.57 (td, J = 9.0, 2.4 Hz, 2H), 1.11 (s, 3H), 1.05 (s, 3H).

[0484] The method for preparing compound SZ-149 was similar to that for preparing target compound SZ-336, which was prepared using 1-methylcyclobutane carboxylic acid as a raw material.

[0485] Compound SZ-149: 47.0 mg, syrupy solid, ESI [M+H] + = 300.1.

[0486] 1 H NMR (400 MHz, d6-DMSO) δ 8.23 (s, 1H), 7.33 - 7.31 (m, 1H), 7.21 - 7.15 (m, 2H), 3.07 (d, J = 7.6 Hz, 2H), 2.66 - 2.53 (m, 1H), 2.29 (s, 3H), 2.10 (s, 3H), 1.90 - 1.80 (m, 2H), 1.57 (td, J = 9.0, 2.4 Hz, 2H), 1.11 (s, 3H), 1.05 (s, 3H).

[0487] Example 31, Preparation of compounds SZ-151 and SZ-170 of the application

[0488] SZ-98 (387 mg, 1.20 mmol), triethylsilane (3 mL) and TFA (3 mL) were added into a sealed tube successively, and stirred at 100 °C for 30 min. The reaction solution was concentrated under reduced pressure, the residue was basified with saturated aqueous sodium bicarbonate solution, extracted with EtOAc (3 x 15 mL), the combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a crude product, which was purified by column chromatography on silica gel (ethyl acetate / petroleum ether (v / v) = 1 / 100 ~ 1 / 10) to give the target compound SZ-151 (201.5 mg, yield 54.8%) as a syrup solid and the target compound SZ-170 (40.3 mg, yield 11.5%) as a white solid.

[0489] Compound SZ-151: ESI [M+H] + = 308.1.

[0490] 1 H NMR (400 MHz, d6-DMSO) δ 8.24 (s, 1H), 7.40 - 7.29 (m, 6H), 7.26 - 7.13 (m, 2H), 4.38 (s, 2H), 2.31 (s, 3H), 2.12 (s, 3H).

[0491] Compound SZ-170: ESI [M+H] + = 294.1.

[0492] 1 H NMR (400 MHz, d6-DMSO) δ 7.39 - 7.31 (m, 4H), 7.30 - 7.24 (m, 1H), 7.09 - 7.00 (m, 3H), 6.88 (s, 1H), 4.29 (s, 2H), 4.05 (s, 2H), 2.25 (s, 3H), 2.17 (s, 3H).

[0493] Example 32, Preparation of the compounds SZ-162, SZ-166, SZ-167, SZ-168, SZ-169 and SZ-173 of the present application

[0494] Under nitrogen protection, 5-bromothiazole (3.28 g, 20.0 mmol) was dissolved in dry THF (20 mL) and the reaction system was cooled to -78 °C with dry ice / acetone bath. n-BuLi (12.5 mL, 1.6 mol / L in Hexane, 20.0 mmol) was slowly added to the reaction system with a syringe, and stirred for 15 minutes. A solution of 2-fluorobenzaldehyde (2.48 g, 20.0 mmol) in THF (25 mL) was slowly added to the reaction system at a rate of 1.0 mL / min, and stirred for 15 minutes. The temperature was raised to -40 °C, and phenyllithium (10.5 mL, 1.9 mol / L in THF, 20.0 mmol) was slowly added to the reaction system with a syringe, and stirred for 15 minutes. A solution of 5-thiazolecarboxaldehyde (2.26 g, 20.0 mmol) in THF (25 mL) was slowly added to the reaction system at a rate of 1.0 mL / min, and stirred for 15 minutes. After the reaction was monitored to be complete, saturated aqueous ammonium chloride solution was slowly added to the reaction system, extracted with EtOAc (3 x 30 mL), and the organic phase was combined and washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 1 / 100 ~ 1 / 10) to obtain the target compound SZ-162 (600.0 mg, yield 9.3%) as a syrup solid and the target compound SZ-169 (1.0 g, yield 23.9%) as a white solid.

[0495] Compound SZ-162: ESI [M+H] + = 323.1.

[0496] 1 H NMR (400 MHz, d6-DMSO) δ 9.04 (s, 1H), 7.80 (s, 1H), 7.54 (d, J = 5.2 Hz, 1H), 7.49-7.45 (m, 1H), 7.39-7.34 (m, 1H), 7.24-7.16 (m, 2H), 6.83 (d, J = 4.9 Hz, 1H), 6.79 (dd, J = 4.5, 1.9 Hz, 1H), 6.39 (d, J = 4.5 Hz, 1H), 6.10 (d, J = 4.9 Hz, 1H).

[0497] Compound SZ-169: ESI [M+H] + = 210.1.

[0498] 1H NMR (400 MHz, d6-DMSO) δ 7.71 (d, J = 3.2 Hz, 1H), 7.67 (d, J = 3.2 Hz, 1H), 7.47 (td, J = 7.5, 1.6 Hz, 1H), 7.40 - 7.34 (m, 1H), 7.24 - 7.17 (m, 2H), 6.85 (d, J = 4.9 Hz, 1H), 6.19 (d, J = 4.9 Hz, 1H).

[0499] SZ-162 (600.0 mg, 1.86 mmol) was dissolved in CH2Cl2(20 mL), activated MnO2(3.036 g, 34.9 mmol) was added, and stirring was performed at room temperature for 5 hours. After the reaction was completed by TLC monitoring, suction filtration was performed, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 ~ 1 / 1) to obtain white solid compound SZ-166 (113.7 mg, yield 19.2%), syrupy compound SZ-167 (125.6 mg, yield 21.1%), and syrupy compound SZ-168 (26.8 mg, yield 4.5%).

[0500] Compound SZ-166: ESI [M+H] + = 319.0.

[0501] 1 H NMR (400 MHz, d6-DMSO) δ 9.60 (s, 1H), 9.04 (s, 1H), 8.96 (s, 1H), 8.00 (td, J = 7.6, 1.7 Hz, 1H), 7.81 - 7.75 (m, 1H), 7.53 - 7.40 (m, 2H).

[0502] Compound SZ-167: ESI [M+H] + = 321.0.

[0503] 1 H NMR (400 MHz, d6-DMSO) δ 9.10 (d, J = 0.6 Hz, 1H), 8.05 (d, J = 0.7 Hz, 1H), 7.91 (s, 1H), 7.87 (td, J = 7.5, 1.7 Hz, 1H), 7.75 - 7.67 (m, 1H), 7.45 - 7.36 (m, 2H), 7.20 (d, J = 4.7 Hz, 1H), 6.60 (d, J = 4.7 Hz, 1H).

[0504] Compound SZ-168: ESI [M+H] + = 321.0.

[0505] 1H NMR (400 MHz, d6-DMSO) δ 9.51 (s, 1H), 8.86 (s, 1H), 8.66 (s, 1H), 7.52-7.49 (m, 1H), 7.44-7.39 (m, 1H), 7.29-7.16 (m, 3H), 6.23 (d, J = 4.8 Hz, 1H).

[0506] The preparation method of the target compound SZ-173 is similar to that of the target compound SZ-166, which is prepared from SZ-169 as the raw material by manganese dioxide oxidation.

[0507] Compound SZ-173: 73.2 mg, white solid, ESI [M+H] + = 208.1.

[0508] 1 H NMR (400 MHz, d6-DMSO) δ 8.36 (d, J = 3.0 Hz, 1H), 8.22 (d, J = 3.0 Hz, 1H), 7.94-7.85 (m, 1H), 7.75-7.70 (m, 1H), 7.43-7.39 (m, 2H).

[0509] Example 33, Preparation of the compound SZ-172 of the application

[0510] SZ-109 (286.5 mg, 1.0 mmol), triethylsilane (3 mL) and TFA (3 mL) were added into a sealed tube in turn, and stirred at 100°C for 1 hour. The reaction solution was concentrated under reduced pressure, the residue was alkalized with saturated aqueous sodium bicarbonate solution, extracted with EtOAc (3 x 20 mL), the combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100~1 / 10), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10) monitoring, and the fraction with Rf = 0.4~0.6 was collected to obtain the target compound SZ-172 (46.0 mg, yield 17.0%) in the form of syrup solid. ESI [M+H] + = 272.1.

[0511] 1 H NMR (400 MHz, d6-DMSO) δ 8.33 (s, 1H), 7.35 (d, J = 7.2 Hz, 1H), 7.26 (d, J = 6.7 Hz, 1H), 7.20 (t, J = 7.5 Hz, 1H), 6.57 (s, 1H), 2.32 (s, 3H), 2.15 (s, 3H), 2.11 (s, 3H), 1.97 (s, 3H).

[0512] Example 34, Preparation of compounds SZ-177, SZ-180 and SZ-181 of the present application

[0513] Cyclopropyl magnesium bromide (27.5 mL, 1 mol / L in THF, 27.5 mmol) was slowly added to 4-bromo-2-thiazolecarboxaldehyde (4.8 g, 25.0 mmol) in THF (70 mL) at -10 °C and stirred for 1 h. After the reaction was completed by TLC, the reaction was poured into saturated aqueous ammonium chloride solution (70 mL) and extracted with EtOAc (3 x 60 mL). The combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 ~ 1 / 5) with TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5) monitoring. The fractions with Rf = 0.4 ~ 0.6 were collected to give compound SZ-177-1 (4.5 g, yield 76.9%) as colorless oil. ESI [M+H] = 234.0. +

[0514] SZ-177-1 (4.5 g, 19.2 mmol), triethylsilane (20 mL) and TFA (20 mL) were added to a sealed tube successively and stirred at 50 °C for 1 h. The reaction was concentrated under reduced pressure. The residue was basified with saturated aqueous sodium bicarbonate solution and extracted with EtOAc (3 x 50 mL). The combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 ~ 1 / 30) with TLC (ethyl acetate / petroleum ether (v / v) = 1 / 30) monitoring. The fractions with Rf = 0.4 ~ 0.6 were collected to give compound SZ-177-2 (3.19 g, yield 76.1%) as colorless oil. ESI [M+H] = 218.0. +

[0515] ​​Under nitrogen protection, SZ-177-2 (500 mg, 2.29 mmol) was dissolved in dry THF (7 mL), the reaction system was cooled to -78 °C with dry ice / acetone bath. n-BuLi (1.01 mL, 2.5 mol / L in Hexane, 2.52 mmol) was slowly added to the reaction system with a syringe, and stirred for 30 minutes. A solution of SZ-118-2 (420.3 mg, 2.76 mmol) in THF (2 mL) was slowly added to the reaction system at a rate of 1.0 mL / min, and stirred for 30 minutes. After the reaction was completed by TLC monitoring, saturated aqueous ammonium chloride solution was slowly added to the reaction system, extracted with EtOAc (3 x 15 mL), the combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography to obtain compounds SZ-177-3 (258.2 mg, yield 38.7%) and SZ-177-4 (235.0 mg, yield 27.7%).

[0516] Compound SZ-177-3: syrup solid, ESI [M+H] + = 292.1.

[0517] Compound SZ-177-4: syrup solid, ESI [M+H] + = 370.1.

[0518] The preparation method of target compounds SZ-177 and SZ-180 is similar to that of target compounds SZ-133 and SZ-146, which is prepared using SZ-177-3 as raw material.

[0519] Compound SZ-177: 125.5 mg, colorless oil, ESI [M+H] + = 276.1.

[0520] 1 H NMR (400 MHz, d6-DMSO) δ 7.45 (d, J = 0.8 Hz, 1H), 7.19 (t, J = 7.4 Hz, 2H), 7.11 - 7.06 (m, 1H), 4.66 (q, J = 7.1 Hz, 1H), 2.79 (d, J = 7.1 Hz, 2H), 2.24 (d, J = 2.0 Hz, 3H), 1.65 (d, J = 7.2 Hz, 3H), 1.16 - 0.98 (m, 1H), 0.61 - 0.50 (m, 2H), 0.31 - 0.20 (m, 2H).

[0521] Compound SZ-180: 23.4 mg, colorless oil, ESI [M+H] + = 274.1.

[0522] 1 H NMR (400 MHz, d6-DMSO) d 7.41 - 7.31 (m, 2H), 7.25 - 7.14 (m, 2H), 5.80 (s, 1H), 5.31 (s, 1H), 2.87 (d, J = 7.1 Hz, 2H), 2.29 (d, J = 2.0 Hz, 3H), 1.15 - 1.08 (m, 1H), 0.62 - 0.55 (m, 2H), 0.36 - 0.29 (m, 2H).

[0523] The preparation method of the target compound SZ-181 is similar to that of the target compound SZ-144, which is prepared using SZ-177-4 as the raw material.

[0524] Compound SZ-181: 149.4 mg, white solid, ESI [M+H] + = 354.1.

[0525] 1 H NMR (400 MHz, d6-DMSO) d 7.29 - 7.17 (m, 2H), 7.17 - 7.07 (m, 1H), 4.64 (q, J = 7.2 Hz, 1H), 2.83 (d, J = 7.1 Hz, 2H), 2.24 (d, J = 2.0 Hz, 3H), 1.62 (d, J = 7.2 Hz, 3H), 1.10 - 1.03 (m, 1H), 0.60 - 0.54 (m, 2H), 0.34 - 0.22 (m, 2H).

[0526] Example 35, Preparation of the compounds SZ-178 and SZ-182 of the application

[0527] The preparation method of the target compounds SZ-178-1 and SZ-178-2 is similar to that of the target compounds SZ-177-3 and SZ-177-4, which is prepared using SZ-177-2 as the raw material.

[0528] Compound SZ-178-1: 169.0 mg, syrup solid, ESI [M+H] + = 308.1.

[0529] Compound SZ-178-2: 173.9 mg, syrup solid, ESI [M+H] + = 386.1.

[0530] The preparation method of the target compounds SZ-178 and SZ-182 is similar to that of the target compound SZ-131, which is prepared using SZ-178-1 and SZ-178-2 as the raw material, respectively.

[0531] Compound SZ-178: 53.1 mg, syrup solid, ESI [M+H] + = 292.1.

[0532] 1 H NMR (400 MHz, d6-DMSO) δ 7.46 (s, 1H), 7.28 - 7.21 (m, 3H), 4.85 (q, J = 7.1 Hz, 1H), 2.79 (d, J = 7.1 Hz, 2H), 2.37 (s, 3H), 1.64 (d, J = 7.1 Hz, 3H), 1.07 - 1.01 (m, 1H), 0.59 - 0.44 (m, 2H), 0.27 - 0.23 (m, 2H).

[0533] Compound SZ-182: 22.4 mg, white solid, ESI [M+H] + = 370.0.

[0534] 1 H NMR (400 MHz, d6-DMSO) δ 7.37 - 7.18 (m, 3H), 4.78 (q, J = 7.1 Hz, 1H), 2.82 (d, J = 7.1 Hz, 2H), 2.36 (s, 3H), 1.60 (d, J = 7.1 Hz, 3H), 1.13 - 1.00 (m, 1H), 0.57 - 0.53 (m, 2H), 0.29 - 0.25 (m, 2H).

[0535] Example 36, Preparation of compounds SZ-183, SZ-186, SZ-338 and SZ-339 of the present application

[0536] SZ-177-2 (350 mg, 1.60 mmol) was dissolved in dry THF (5 mL) under nitrogen protection, the reaction system was cooled to -78 °C with dry ice / acetone bath. n-BuLi (0.71 mL, 2.5 mol / L in Hexane, 1.77 mmol) was slowly added to the reaction system with a syringe, stirred for 30 minutes. The THF (2 mL) solution of SZ-124-1 (412.0 mg, 1.93 mmol) was slowly added to the reaction system at a rate of 1.0 mL / min, stirred for 30 minutes. After the reaction was completed by TLC monitoring, saturated aqueous ammonium chloride solution was slowly added to the reaction system, extracted with EtOAc (3 x 15 mL), the combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered under suction, concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 ~ 1 / 10) to obtain the white solid target compound SZ-183 (252.7 mg, yield 42.5%).

[0537] Compound SZ-183: ESI [M+H] + = 370.0.

[0538] 1 H NMR (400 MHz, d6-DMSO) δ 7.61 - 7.55 (m, 1H), 7.46 - 7.40 (m, 2H), 2.97 (d, J = 7.1 Hz, 2H), 2.42 (s, 3H), 1.19 - 1.11 (m, 1H), 0.69 - 0.51 (m, 2H), 0.40 - 0.24 (m, 2H).

[0539] The preparation method of compound SZ-186-1 is similar to that of compound SZ-118-1, which is prepared using the corresponding substituted benzoic acid as the raw material.

[0540] The preparation method of the target compound SZ-186 is similar to that of compound SZ-183, which is prepared using SZ-177-2 and SZ-186-1 as the raw materials.

[0541] Compound SZ-186: 20.0 mg, white solid, ESI [M+H] + = 296.1.

[0542] 1 H NMR (400 MHz, d6-DMSO) δ 8.57 (s, 1H), 7.88 - 7.80 (m, 1H), 7.67 - 7.60 (m, 1H), 7.40 (t, J = 7.9 Hz, 1H), 2.93 (d, J = 7.1 Hz, 2H), 1.22 - 1.06 (m, 1H), 0.67 - 0.53 (m, 2H), 0.34 (q, J = 4.4 Hz, 2H).

[0543] Under nitrogen protection, SZ-177-2 (1.40 g, 6.42 mmol) was dissolved in dry THF (15 mL) and the reaction system was cooled to -78 °C with dry ice / acetone bath. n-BuLi (2.58 mL, 2.5 mol / L in Hexane, 6.45 mmol) was slowly added to the reaction system with a syringe, and stirred for 30 min. The prepared lithium salt was added to a THF (5 mL) solution of N-methoxy-N-methyl-2,2,2-trifluoroacetamide (1.013 g, 6.45 mmol) at 80 °C, and stirred for 5 min. After the reaction was completed by TLC monitoring, the reaction was cooled, poured into saturated aqueous ammonium chloride solution, extracted with EtOAc (3 x 15 mL), and the combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 ~ 1 / 10) to obtain the target compound SZ-338 (22.0 mg, yield 1.46%) as a white solid and the target compound SZ-339 (14.7 mg, yield 0.73%) as a syrup solid.

[0544] Compound SZ-338: ESI [M+H] + = 236.0.

[0545] 1 H NMR (400 MHz, d6-DMSO) δ 8.72-7.69 (m, 1H), 3.05-2.86 (m, 2H), 1.24-1.05 (m, 1H), 0.71-0.50 (m, 2H), 0.46-0.11 (m, 2H).

[0546] Compound SZ-339: ESI [M+H] + = 313.9.

[0547] 1 H NMR (400 MHz, MeOD) δ 2.88 (t, J = 7.3 Hz, 2H), 1.23-1.08 (m, 1H), 0.71-0.67 (m, 2H), 0.39-0.35 (m, 2H).

[0548] Example 37, Preparation of Compounds SZ-188, SZ-189, SZ-190 and SZ-84 of the Invention

[0549] The preparation method of compound SZ-189-2 is similar to that of compound SZ-177-2, which is prepared using 5-bromothiazole-2-carboxaldehyde as the starting material.

[0550] Under nitrogen protection, SZ-189-2 (200 mg, 0.917 mmol) was dissolved in dry THF (5 mL), and the reaction system was cooled to -78 °C with dry ice / acetone bath. n-BuLi (0.479 mL, 2.5 mol / L in Hexane, 1.20 mmol) was slowly added to the reaction system with a syringe, and stirred for 30 min. A solution of SZ-118-1 (272.4 mg, 1.38 mmol) in THF (2 mL) was slowly added to the reaction system at a rate of 1.0 mL / min, and stirred for 30 min. After the reaction was completed by TLC monitoring, saturated aqueous ammonium chloride solution was slowly added to the reaction system, extracted with EtOAc (3 x 15 mL), and the combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 ~ 1 / 10) to obtain the white solid target compound SZ-188 (75.4 mg, yield 29.9%).

[0551] Compound SZ-188: 75.4 mg, syrup solid, ESI [M+H] + = 276.1.

[0552] 1 H NMR (400 MHz, d6-DMSO) δ 8.14 (d, J = 1.3 Hz, 1H), 7.58 (t, J = 7.4 Hz, 1H), 7.51 (t, J = 7.1 Hz, 1H), 7.29 (t, J = 7.6 Hz, 1H), 2.99 (d, J = 7.1 Hz, 2H), 2.33 (d, J = 2.0 Hz, 3H), 1.26 - 1.10 (m, 1H), 0.70 - 0.59 (m, 2H), 0.44 - 0.27 (m, 2H).

[0553] The preparation method of compound SZ-84-1 is similar to that of compound SZ-118-1, which is prepared from 2,3-dichlorobenzoic acid.

[0554] The preparation methods of target compounds SZ-189, SZ-190 and SZ-84 are similar to those of compound SZ-188, which are prepared from SZ-189-2.

[0555] Compound SZ-189: 10.3 mg, syrup solid, ESI [M+H] + = 292.1.

[0556] 1H NMR (400 MHz, d6-DMSO) δ 7.96 (s, 1H), 7.59 (d, J = 5.9 Hz, 1H), 7.48 - 7.39 (m, 2H), 2.98 (d, J = 7.1 Hz, 2H), 2.43 (s, 3H), 1.20 - 1.16 (m, 1H), 0.65 - 0.60 (m, 2H), 0.38 - 0.35 (m, 2H).

[0557] Compound SZ-190: 167.3 mg, syrupy solid, ESI [M+H] + = 296.1.

[0558] 1 H NMR (400 MHz, d6-DMSO) δ 8.23 (s, 1H), 7.93 - 7.85 (m, 1H), 7.76 - 7.64 (m, 1H), 7.44 (t, J = 7.9 Hz, 1H), 3.01 (d, J = 7.1 Hz, 2H), 1.23 - 1.14 (m, 1H), 0.72 - 0.58 (m, 2H), 0.39 - 0.36 (m, 2H).

[0559] Compound SZ-84: 58.2 mg, syrupy solid, ESI [M+H] + = 312.1.

[0560] 1 H NMR (400 MHz, d6-DMSO) δ 8.23 (s, 1H), 7.93 - 7.85 (m, 1H), 7.76 - 7.64 (m, 1H), 7.44 (t, J = 7.9 Hz, 1H), 3.01 (d, J = 7.1 Hz, 2H), 1.23 - 1.14 (m, 1H), 0.72 - 0.58 (m, 2H), 0.39 - 0.36 (m, 2H).

[0561] Example 38, Preparation of compound SZ-187 of the present application

[0562] LiAlH4(10.25 mL, 1 mol / L in THF, 10.25 mmol) was added dropwise to SZ-54 (2.778 g, 10.2 mmol) in dry THF (30 mL) at 0 °C and stirred for 1 h. After the reaction was completed by TLC, it was quenched with sodium sulfate decahydrate, suction filtered, and the filter cake was washed with THF. The filtrate was concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 ~ 1 / 5) with TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5) monitoring, and the fraction with Rf = 0.4 ~ 0.6 was collected to give compound SZ-187-1 (2.546 g, yield 91.0%) as a white solid. ESI [M+H] + = 274.1.

[0563] Compound SZ-187-1 (2.546 g, 9.31 mmol) was dissolved in dry DMF (30 mL) at room temperature, and the system was cooled to -10 °C in an ice-salt bath. NaH (0.448 g, 60% in mineral oil, 11.2 mmol) was added to the system, which was stirred at -10 °C for 10 min. 4-Methoxychlorobenzene (2.191 g, 14.0 mmol) was slowly added to the system using a syringe, and it was stirred for 30 min. After the reaction was completed by TLC, the reaction solution was poured into ice water, extracted with EtOAc (3 x 50 mL), and the combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 ~ 1 / 10) with TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10) monitoring, and the fraction with Rf = 0.4 ~ 0.6 was collected to give compound SZ-187-2 (2.851 g, yield 77.8%) as a white solid. ESI [M+H] + = 394.2.

[0564] SZ-187-2 (1.4695 g, 3.73 mmol) was dissolved in dry THF (16 mL) under nitrogen protection, the reaction system was cooled to -78 °C with dry ice / acetone bath. n-BuLi (1.64 mL, 2.5 mol / L in Hexane, 4.11 mmol) was added slowly into the reaction system by syringe, stirred for 30 min. A solution of N-fluorobenzenesulfonimide (1.415 g, 4.49 mmol) in THF (10 mL) was added slowly into the reaction system, stirred for 3 h. After the reaction was completed by TLC monitoring, saturated aqueous ammonium chloride solution was slowly added to the reaction system, extracted with EtOAc (3 x 30 mL), the combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, suction filtered, concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 50 ~ 1 / 5), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5) monitoring, the Rf = 0.4 ~ 0.6 part was collected to obtain white solid compound SZ-187-3 (836 mg, yield 54.4%). ESI [M+H] + = 412.2.

[0565] Trifluoroacetic acid (2.318 g, 20.3 mmol) was added to SZ-187-3 (836 mg, 2.03 mmol) in dichloromethane (10 mL) at 0 °C, stirred for 3 h. After the reaction was completed by TLC monitoring, the reaction liquid was concentrated under reduced pressure, the residue was alkalized with saturated aqueous sodium bicarbonate solution (20 mL), extracted with EtOAc (3 x 30 mL), the combined organic phase was dried over anhydrous Na2SO4, suction filtered, concentrated under reduced pressure to obtain the crude product, which was directly used in the next step reaction without purification. ESI [M+H] + = 292.2.

[0566] The crude product obtained in the previous step was dissolved in CH2Cl2(20 mL) at room temperature, activated MnO2(3.677 g, 38.5 mmol, 91%) was added, stirred for 12 h. After the reaction was completed by TLC monitoring, suction filtered, the filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 50 ~ 1 / 5), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5) monitoring, the Rf = 0.3 ~ 0.5 part was collected to obtain the target compound SZ-187 (346 mg, two-step yield 58.9%) as syrup. ESI [M+H] + = 290.1.

[0567] 1H NMR (400 MHz, d6-DMSO) δ 7.34 (d, J = 7.0 Hz, 1H), 7.26 - 7.16 (m, 2H), 2.79 (dd, J = 7.2, 2.1 Hz, 2H), 2.30 (s, 3H), 2.16 (s, 3H), 1.15 - 0.98 (m, 1H), 0.64 - 0.54 (m, 2H), 0.37 - 0.23 (m, 2H).

[0568] Example 39, Preparation of compounds SZ-191, SZ-333 and SZ-357 of the present application

[0569] SZ-177-2 (1 g, 4.58 mmol) was dissolved in dry THF (10 mL) under nitrogen protection, the reaction system was cooled to -78 °C with dry ice / acetone bath. n-BuLi (1.94 mL, 2.5 mol / L in Hexane, 4.85 mmol) was slowly added to the reaction system with a syringe, stirred for 30 min. 2,3-Dimethylbenzaldehyde (680.2 mg, 5.07 mmol) was slowly added to the reaction system at a rate of 0.2 mL / min, stirred for 30 min. After the reaction was completed by TLC monitoring, saturated aqueous ammonium chloride solution was slowly added to the reaction system, extracted with EtOAc (3 x 30 mL), the combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered under suction, concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 ~ 1 / 2) to obtain compound SZ-333-1 (727.0 mg, yield 44.9%) and compound SZ-357-1 (472.0 mg, yield 37.7%) as colorless oil.

[0570] SZ-333-1: ESI [M+H] + = 352.1.

[0571] SZ-357-1: ESI [M+H] + = 274.1.

[0572] SZ-333-1 (727 mg, 2.06 mmol) was dissolved in CH2Cl2(20 mL) at room temperature, activated MnO2(5.40 g, 56.5 mmol, 91%) was added, and stirred for 12 h. After the reaction was completed by TLC monitoring, it was filtered under reduced pressure, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 50~1 / 5), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5) monitoring, and the Rf=0.3~0.5 part was collected to obtain the white solid target compound SZ-333 (630.3 mg, yield 87.2%). ESI [M+H] + = 350.1.

[0573] 1 H NMR (400 MHz, d6-DMSO) δ 7.39-7.35 (m, 1H), 7.29-7.19 (m, 2H), 2.95 (d, J = 7.1 Hz, 2H), 2.32 (s, 3H), 2.16 (s, 3H), 1.17-1.10 (m, 1H), 0.70-0.52 (m, 2H), 0.43-0.27 (m, 2H).

[0574] The preparation method of compound SZ-191-1 is similar to that of compound SZ-187-2, which is prepared using SZ-333-1 as the raw material.

[0575] SZ-191-1 (1.771 g, 3.75 mmol) was dissolved in dry THF (17 mL) under nitrogen protection, and the reaction system was cooled to -78°C with an ice / acetone bath. n-BuLi (1.88 mL, 2.5 mol / L in Hexane, 4.70 mmol) was slowly added to the reaction system with a syringe, and stirred for 30 min. A solution of N-fluorobenzene sulfonamide (2.023 g, 6.42 mmol) in THF (8 mL) was slowly added to the reaction system, and stirred for 3 h. After the reaction was completed by TLC monitoring, saturated aqueous ammonium chloride solution was slowly added to the reaction system, extracted with EtOAc (3 x 30 mL), and the combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered under reduced pressure, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 50~1 / 5), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5) monitoring, and the Rf=0.4~0.6 part was collected to obtain the white solid compound SZ-191-2 (140 mg, yield 9.1%). ESI [M+H] + = 412.2.

[0576] The preparation method of compound SZ-191 is similar to that of compound SZ-187, and SZ-191-2 is used as the raw material to prepare by deprotection and oxidation.

[0577] Compound SZ-191: 6.5 mg, yellow syrup solid, ESI [M+H] + = 290.1.

[0578] 1 H NMR (400 MHz, d6-DMSO) δ 7.38-7.32 (m, 2H), 7.25-7.21 (m, 1H), 2.92 (d, J = 7.1 Hz, 2H), 2.32 (s, 3H), 2.19 (s, 3H), 1.17-1.10 (m, 1H), 0.68-0.58 (m, 2H), 0.37-0.33 (m, 2H).

[0579] The preparation method of compound SZ-357-2 is similar to that of compound SZ-187-2, and SZ-357-1 is used as the raw material to prepare.

[0580] Under nitrogen protection, SZ-357-2 (4.023 g, 10.2 mmol) was dissolved in dry THF (40 mL), and the reaction system was cooled to -78 °C with an ice / acetone bath. n-BuLi (4.10 mL, 2.5 mol / L in Hexane, 10.2 mmol) was slowly added to the reaction system with a syringe, and stirred for 30 minutes. A solution of N-fluorobenzene sulfonamide (3.228 g, 10.2 mmol) in THF (20 mL) was slowly added to the reaction system, and the temperature was allowed to rise to room temperature naturally, and stirred for 3 hours. After the reaction was completed by TLC monitoring, saturated aqueous ammonium chloride solution was slowly added to the reaction system, extracted with EtOAc (3 x 50 mL), the combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 50 ~ 1 / 5), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5) monitoring, and the Rf = 0.4 ~ 0.6 part was collected to obtain white solid compound SZ-357-3 (34.3 mg, yield 0.82 %). ESI [M+H] + = 412.2.

[0581] The preparation method of target compound SZ-357 is similar to that of compound SZ-187, and SZ-357-3 is used as the raw material to prepare by deprotection and oxidation.

[0582] Compound SZ-357: 9.5 mg, yellow syrup, ESI [M+H] + = 290.1.

[0583] 1 H NMR (400 MHz, d6-DMSO) δ 8.09 (d, J = 2.0 Hz, 1H), 7.41 (dd, J = 13.7, 7.4 Hz, 2H), 7.28 (t, J = 7.6 Hz, 1H), 5.37 (dd, J = 46.2, 8.7 Hz, 1H), 2.34 (s, 3H), 2.21 (s, 3H), 1.63 - 1.45 (m, 1H), 0.80 - 0.68 (m, 3H), 0.63 - 0.61 (m, 1H).

[0584] Example 40, Preparation of the compound SZ-340 of the present application

[0585] Under nitrogen protection, SZ-177-2 (1 g, 4.58 mmol) was dissolved in dry THF (10 mL), the reaction system was cooled to -78 °C with dry ice / acetone bath. n-BuLi (1.84 mL, 2.5 mol / L in Hexane, 4.60 mmol) was slowly added to the reaction system with a syringe, stirred for 30 minutes. Propionaldehyde (401.4 mg, 6.91 mmol) in THF (2 mL) was added to the reaction system, stirred for 30 minutes. After the reaction was completed by TLC monitoring, saturated aqueous ammonium chloride solution was slowly added to the reaction system, extracted with EtOAc (3 x 15 mL), the combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered under suction, concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 ~ 1 / 10) to obtain compound SZ-340-1 (358.0 mg, yield 39.6%) as colorless oil. ESI [M+H] + = 198.1.

[0586] SZ-340-1 (358.0 mg, 1.81 mmol) was dissolved in CH2Cl2(20 mL), activated MnO2(4.5 g, 47.1 mmol, 91%) was added, stirred at room temperature for 5 hours. After the reaction was completed by TLC monitoring, filtered under suction, the filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 ~ 1 / 3), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 3) monitoring, the Rf = 0.3 ~ 0.5 part was collected to obtain compound SZ-340 (95.1 mg, yield 26.7%) as syrup. ESI [M+H] + = 196.1.

[0587] 1H NMR (400 MHz, d6-DMSO) δ 8.49 (s, 1H), 2.99 (q, J = 7.3, 2H), 2.91 (d, J = 7.1, 2H), 1.16 - 1.06 (m, 4H), 0.61 - 0.55 (m, 2H), 0.35 - 0.28 (m, 2H).

[0588] Example 41, Preparation of compounds SZ-347 ~ SZ-350 of the present application

[0589] The preparation method of compound SZ-347-2 is similar to that of target compound SZ-5, which is prepared from 2-bromo-4-formylthiazole as a raw material.

[0590] Dry KF (167.2 mg, 2.86 mmol), Kryptofix 222 (1.0 g, 2.65 mmol) were added to a solution of SZ-347-2 (672.0 mg, 2.21 mmol) in DMSO (10 mL) in turn, and the mixture was stirred at 130 °C for 3 h. After the reaction was completed by TLC monitoring, the reaction solution was poured into ice water, extracted with EtOAc (3 x 20 mL), and the combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 ~ 1 / 10), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5) monitoring, and the fraction with Rf = 0.4 ~ 0.6 was collected to obtain the white solid target compound SZ-347-3 (398.5 mg, yield 73.8%). ESI [M+H] + = 244.0.

[0591] Methylmagnesium bromide (2.46 mL, 1 mol / L in THF, 2.46 mmol) was slowly added to a solution of SZ-347-3 (398.5 mg, 1.64 mmol) in THF (5 mL) at 0 °C, and stirred for 30 min. After the reaction was completed by TLC monitoring, the reaction solution was poured into saturated aqueous ammonium chloride solution (10 mL), extracted with EtOAc (3 x 20 mL), and the combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 ~ 1 / 2), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 2) monitoring, and the fraction with Rf = 0.3 ~ 0.4 was collected to obtain the syrup solid compound SZ-347-4 (331.7 mg, yield 78.2%). ESI [M+H] + = 260.1.

[0592] SZ-347-4 (331.7 mg, 1.28 mmol), triethylsilane (2 mL) and TFA (2 mL) were added into a sealed tube successively, and stirred at 35 °C for 30 min. The reaction was concentrated under reduced pressure, and the residue was basified with saturated aqueous NaHC03solution and extracted with EtOAc (3 x 15 mL). The combined organic phase was washed with saturated brine, dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (EtOAc / petroleum ether (v / v) = 1 / 10 ~ 1 / 1) to give the target compound SZ-347 (63.1 mg, yield 19%) as colorless oil. ESI [M+H] + = 244.1.

[0593] 1 H NMR (400 MHz, d6-DMSO) δ 7.30 (m, 1H), 7.21 - 7.14 (m, 1H), 7.12 - 7.07 (m, 2H), 4.41 (q, J = 7.1 Hz, 1H), 1.55 (d, J = 7.2 Hz, 3H).

[0594] Compound 2,4-dibromothiazole (2.0 g, 8.2 mmol) was dissolved in dry THF (20 mL) under nitrogen protection, and the reaction system was cooled to -50 °C with dry ice / acetone bath. n-BuLi (3.62 mL, 2.5 mol / L in Hexane, 9.05 mmol) was slowly added to the reaction system with a syringe, and stirred for 15 min. A solution of 2,3-difluoroacetophenone (1.67 g, 10.7 mmol) in THF (5 mL) was slowly added to the reaction system with a syringe at a rate of 1.0 mL / min, and stirred for 30 min. After the reaction was completed by TLC monitoring, saturated aqueous ammonium chloride solution was slowly added to the reaction system, extracted with EtOAc (3 x 30 mL), and the combined organic phase was dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel to give compound SZ-348-1 (746 mg, yield 28%) and a mixture of SZ-349-1 and SZ-349-2 (938 mg).

[0595] Compound SZ-348-1: syrup solid, ESI [M+H] + = 319.9.

[0596] Compound SZ-349-1: ESI [M+H] + = 319.9.

[0597] Compound SZ-349-2: ESI [M+H] + = 397.9.

[0598] SZ-348-1 (746 mg, 2.34 mmol), triethylsilane (5 mL) and TFA (5 mL) were added into a sealed tube, stirred at 80 °C for 1 h. The reaction was concentrated under reduced pressure, the residue was basified with saturated aqueous NaHC03solution, extracted with EtOAc (3 x 15 mL), the combined organic phase was washed with saturated brine, dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography on silica gel (ethyl acetate / petroleum ether (v / v) = 1 / 50 ~ 1 / 5), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5) was used to monitor the purification, the fractions with Rf= 0.4 ~ 0.6 were collected to give the target compound SZ-348 (221.7 mg, yield 31.3%) as a syrup solid. ESI [M+H] + = 303.9.

[0599] 1H NMR (400 MHz, d6-DMSO) d 7.76 (s, 1H), 7.42 - 7.34 (m, 1H), 7.27 - 7.21 (m, 2H), 4.83 (q, J = 7.1 Hz, 1H), 1.70 (d, J = 7.1 Hz, 3H).

[0600] A mixture of SZ-349-1 and SZ-349-2 (938 mg), triethylsilane (5 mL) and TFA (5 mL) were added into a sealed tube, stirred at 80 °C for 1 h. The reaction was concentrated under reduced pressure, the residue was basified with saturated aqueous NaHC03solution, extracted with EtOAc (3 x 15 mL), the combined organic phase was washed with saturated brine, dried over anhydrous Na2S04, filtered, and concentrated under reduced pressure to give the crude product. The crude product was dissolved in MeOH (5 mL) with zinc bromide (272.1 mg, 1.21 mmol) and 10% wet Pd-C (840.4 mg) at room temperature, the system was replaced with hydrogen gas for three times, stirred at room temperature under hydrogen gas for 12 h. After the reaction was monitored to be complete by TLC, filtered, the filter cake was washed with methanol (3 x 5 mL), the filtrate was concentrated under reduced pressure to give the crude product, which was purified by preparative TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10) to give the target compound SZ-349 (95.8 mg, 3.83% yield for two steps) as a syrup solid and the target compound SZ-350 (8.4 mg, 0.45% yield for two steps) as a yellow syrup solid.

[0601] Compound SZ-349: ESI [M+H] + = 303.9.

[0602] 1H NMR (400 MHz, d6-DMSO) δ 9.09 (s, 1H), 7.40 - 7.33 (m, 1H), 7.27 - 7.16 (m, 2H), 4.73 (q, J = 7.2 Hz, 1H), 1.67 (d, J = 7.2 Hz, 3H).

[0603] Compound SZ-350: ESI [M+H] + = 226.0.

[0604] 1 H NMR (400 MHz, d6-DMSO) δ 8.98 (s, 1H), 7.76 (s, 1H), 7.39 - 7.30 (m, 1H), 7.26 - 7.17 (m, 2H), 4.80 (q, J = 7.1 Hz, 1H), 1.70 (d, J = 7.2 Hz, 3H).

[0605] Example 42, Preparation of compound SZ-356 of the present application

[0606] Compound SZ-103-1 (1.3 g, 3.35 mmol) was dissolved in dry THF (20 mL) under nitrogen protection, the reaction system was cooled to -78 °C with dry ice / acetone bath. n-BuLi (1.41 mL, 2.5 mol / L in Hexane, 3.52 mmol) was slowly added to the reaction system with a syringe, stirred for 15 min. The solution of SZ-157-1 (580.1 mg, 3.69 mmol) in THF (5 mL) was slowly added to the reaction system with a syringe at a rate of 1.0 mL / min, stirred for 30 min. After the reaction was completed by TLC monitoring, saturated aqueous ammonium chloride solution was slowly added to the reaction system, extracted with EtOAc (3 x 30 mL), the combined organic phase was dried over anhydrous Na2SO4, suction filtered, concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 ~ 1 / 10), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10) monitoring, the fraction with Rf = 0.3 ~ 0.5 was collected to obtain compound SZ-356-1 (1.187 g, yield 87.3%). ESI [M+H] + = 406.1.

[0607] Compound SZ-356-1 (1.187 g, 2.93 mmol) was dissolved in dry THF (10 mL), cooled to -10 °C, LAH (2.93 mL, 1 mol / L in THF, 2.93 mmol) was added to the system, stirred for 2 hours. After the reaction was completed by TLC monitoring, Na2SO4.10H2O was added to the reaction system in batches, suction filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 ~ 1 / 10), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 5) monitoring, and the Rf = 0.4 ~ 0.6 part was collected to obtain white solid compound SZ-356-2 (1.03 g, yield 86.5%). ESI [M+H] + = 408.1.

[0608] Iodine (641 mg, 2.52 mmol) and hypophosphorous acid (2.5 mL) were added to the solution of SZ-356-2 (1.03 g, 2.53 mmol) in acetic acid (15 mL) in turn, and stirred at 110 °C for 8 hours. After the reaction was completed by TLC monitoring, the reaction liquid was concentrated under reduced pressure, the residue was adjusted to pH = 7 with saturated aqueous sodium bicarbonate solution, extracted with EtOAc (3 x 30 mL), the combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, suction 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 / 10), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10) monitoring, and the Rf = 0.2 ~ 0.3 part was collected to obtain syrup solid compound SZ-356-3 (132 mg, yield 17.3%). ESI [M+H] + = 302.1

[0609] SZ-356-3 (132 mg, 0.44 mmol) was dissolved in CH2Cl2(20 mL), and active MnO2(4.5 g, 47.1 mmol, 91%) was added, and stirred at room temperature for 5 hours. After the reaction was completed by TLC monitoring, the reaction liquid was suction filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 ~ 1 / 3), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 3) monitoring, and the Rf = 0.3 ~ 0.5 part was collected to obtain syrup compound SZ-356 (69.5 mg, yield 53%). ESI [M+H] + = 300.1.

[0610] 1H NMR (400 MHz, d6-DMSO) δ 7.55 (s, 1H), 7.10 - 7.03 (m, 3H), 4.21 (s, 2H), 3.05 (dd, J = 7.7, 5.7 Hz, 1H), 2.26 (s, 3H), 2.21 (s, 3H), 1.33 (dd, J = 5.6, 3.7 Hz, 1H), 1.29 (s, 3H), 1.20 (dd, J = 7.7, 3.6 Hz, 1H), 1.13 (s, 3H).

[0611] Example 43, Preparation of compound SZ-359 of the present application

[0612] The preparation method of compound SZ-359-1 is similar to that of compound SZ-187-2, which is prepared from SZ-47-1. ESI [M+H] + = 418.1.

[0613] Compound SZ-359-1 (417 mg, 1.0 mmol) was dissolved in dry THF (5 mL) under nitrogen protection, and the reaction system was cooled to -78 °C with dry ice / acetone bath. n-BuLi (0.4 mL, 2.5 mol / L in Hexane, 1.0 mmol) was slowly added to the reaction system with a syringe, and stirred for 30 min. (2-Iodoethyl)cyclopropane (392.06 mg, 2.0 mmol) in THF (5 mL) was slowly added to the reaction system at a rate of 1.0 mL / min with a syringe, and the temperature was allowed to rise to room temperature naturally, and stirred for 2 h. After the reaction was completed by TLC monitoring, saturated aqueous ammonium chloride solution was slowly added to the reaction system, extracted with EtOAc (3 x 30 mL), the combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 ~ 1 / 10), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 10) monitoring, and the fraction with Rf = 0.3 ~ 0.5 was collected to obtain compound SZ-359-2 (171 mg, yield 42.0%). ESI [M+H] + = 408.1.

[0614] The preparation method of target compound SZ-359 is similar to that of target compound SZ-187, which is prepared from SZ-359-2 by deprotection and oxidation.

[0615] Compound SZ-359: 77.4 mg, white solid, ESI [M+H] + = 286.1.

[0616] 1H NMR (400 MHz, d6-DMSO) δ 8.25 (s, 1H), 7.37 - 7.32 (m, 1H), 7.23 - 7.19 (m, 2H), 3.12 - 3.05 (m, 2H), 2.31 (s, 3H), 2.13 (s, 3H), 1.64 (dd, J = 14.9, 7.2 Hz, 2H), 0.82 - 0.72 (m, 1H), 0.46 - 0.38 (m, 2H), 0.13 - 0.06 (m, 2H).

[0617] Example 44, Preparation of compound SZ-360 of the present application

[0618] The preparation method of target compound SZ-360 is similar to that of target compound SZ-131, which is prepared by using 4-bromothiazole as raw material.

[0619] Compound SZ-360: 93.3 mg, syrup solid, ESI [M+H] + = 226.1.

[0620] 1 H NMR (400 MHz, d6-DMSO) δ 7.76 (d, J = 3.3 Hz, 1H), 7.67 (d, J = 3.3 Hz, 1H), 7.43 - 7.34 (m, 1H), 7.27 - 7.22 (m, 2H), 4.86 (q, J = 7.2 Hz, 1H), 1.75 (d, J = 7.2 Hz, 3H).

[0621] Example 45, Preparation of compounds SZ-361 and SZ-362 of the present application

[0622] Under nitrogen protection, SZ-177-2 (366.8 mg, 1.68 mmol) was dissolved in dry THF (5 mL), and the reaction system was cooled to -78 °C with dry ice / acetone bath. n-BuLi (0.676 mL, 2.5 mol / L in Hexane, 1.69 mmol) was slowly added to the reaction system with a syringe, and stirred for 30 min. A solution of 2,3-difluorobenzaldehyde (312.3 mg, 2.20 mmol) in THF (2 mL) was slowly added to the reaction system at a rate of 1.0 mL / min, and stirred for 30 min. After the reaction was completed by TLC monitoring, saturated aqueous ammonium chloride solution was slowly added to the reaction system, extracted with EtOAc (3 x 15 mL), and the combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 50 ~ 1 / 2) to obtain white solid target compound SZ-361-1 (263.0 mg, yield 43.4%) and white solid target compound SZ-362-1 (148.0 mg, yield 31.3%).

[0623] Compound SZ-361-1: ESI [M+H] + = 359.9.

[0624] Compound SZ-362-1: ESI [M+H] + = 282.1.

[0625] SZ-361-1 (263.0 mg, 0.73 mmol) was dissolved in CH2Cl2(20 mL), and active MnO2(1.85 g, 19.4 mmol, 91%) was added, and stirred at room temperature for 5 h. After the reaction was completed by TLC monitoring, the reaction liquid was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 ~ 1 / 3), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 3) monitoring, and the Rf = 0.3 ~ 0.5 part was collected to obtain white solid compound SZ-361 (164.3 mg, yield 62.4%). ESI [M+H] + = 358.1.

[0626] 1 H NMR (400 MHz, d6-DMSO) δ 7.78 - 7.71 (m, 1H), 7.54 - 7.48 (m, 1H), 7.45 - 7.39 (m, 1H), 2.98 (d, J = 7.1 Hz, 2H), 1.20 - 1.11 (m, 1H), 0.66 - 0.57 (m, 2H), 0.37 - 0.31 (m, 2H).

[0627] The preparation method of the target compound SZ-362 is similar to that of the compound SZ-361, which is prepared using SZ-362-1 as the raw material.

[0628] Compound SZ-362: 110.7 mg, white solid, ESI [M+H] + = 280.1.

[0629] 1 H NMR (400 MHz, d6-DMSO) δ 8.23 (d, J = 1.3 Hz, 1H), 7.72 (dtd, J = 9.7, 8.1, 1.5 Hz, 1H), 7.53 (dd, J = 7.6, 6.0 Hz, 1H), 7.40 (tdd, J = 8.2, 4.7, 1.3 Hz, 1H), 2.98 (d, J = 7.1 Hz, 2H), 1.23 - 1.10 (m, 1H), 0.66 - 0.58 (m, 2H), 0.41 - 0.31 (m, 2H).

[0630] Example 46, Preparation of the compounds SZ-363~SZ-368, SZ-395~SZ-396, SZ-436~SZ-440 and SZ-479~SZ-484 of the application

[0631] The preparation methods of the target compounds SZ-363~SZ-368, SZ-395~SZ-396, SZ-436~SZ-440 and SZ-479~SZ-484 are similar to those of the compounds SZ-361 or SZ-362, which are prepared using different substituted benzaldehyde and SZ-177-2 as the raw materials, respectively.

[0632] Compound SZ-363: 120.8 mg, syrup solid, ESI [M+H] + = 354.1.

[0633] 1 H NMR (400 MHz, d6-DMSO) δ 8.23 (d, J = 1.3 Hz, 1H), 7.72 (dtd, J = 9.7, 8.1, 1.5 Hz, 1H), 7.53 (dd, J = 7.6, 6.0 Hz, 1H), 7.40 (tdd, J = 8.2, 4.7, 1.3 Hz, 1H), 2.98 (d, J = 7.1 Hz, 2H), 1.23 - 1.10 (m, 1H), 0.66 - 0.58 (m, 2H), 0.41 - 0.31 (m, 2H).

[0634] Compound SZ-364: 168.4 mg, syrup solid, ESI [M+H] + = 354.1.

[0635] 1 H NMR (400 MHz, d6-DMSO) d 7.47 - 7.39 (m, 2H), 7.36 (dd, J = 8.7, 4.9 Hz, 1H), 2.97 (d, J = 7.1 Hz, 2H), 2.19 (d, J = 2.2 Hz, 3H), 1.15 (qd, J = 7.5, 3.8 Hz, 1H), 0.66 - 0.58 (m, 2H), 0.39 - 0.32 (m, 2H).

[0636] Compound SZ-365: 63.3 mg, syrupy solid, ESI [M+H] + = 276.1.

[0637] 1 H NMR (400 MHz, d6-DMSO) d 7.99 (s, 1H), 7.41 (dd, J = 6.5, 4.5 Hz, 3H), 2.97 (d, J = 7.1 Hz, 2H), 2.19 (d, J = 2.2 Hz, 3H), 1.20 - 1.10 (m, 1H), 0.64 - 0.56 (m, 2H), 0.38 - 0.31 (m, 2H).

[0638] Compound SZ-366: 178.4 mg, white solid, ESI [M+H] + = 374.1.

[0639] 1 H NMR (400 MHz, d6-DMSO) d 7.91 - 7.85 (m, 1H), 7.69 - 7.62 (m, 1H), 7.43 (t, J = 7.9 Hz, 1H), 2.97 (d, J = 7.1 Hz, 2H), 1.14 (ddd, J = 12.4, 7.6, 4.9 Hz, 1H), 0.64 - 0.57 (m, 2H), 0.34 (q, J = 4.5 Hz, 2H).

[0640] Compound SZ-367: 139.9 mg, syrupy solid, ESI [M+H] + = 358.1.

[0641] 1 H NMR (400 MHz, d6-DMSO) d 7.79 (td, J = 8.4, 6.6 Hz, 1H), 7.55 - 7.47 (m, 1H), 7.31 (td, J = 8.5, 2.2 Hz, 1H), 2.97 (d, J = 7.1 Hz, 2H), 1.19 - 1.10 (m, 1H), 0.65 - 0.58 (m, 2H), 0.37 - 0.31 (m, 2H).

[0642] Compound SZ-368: 99.6 mg, white solid, ESI [M+H] + = 280.1.

[0643] 1 H NMR (400 MHz, d6-DMSO) δ 8.18 (d, J = 1.4 Hz, 1H), 7.81 (td, J = 8.4, 6.6 Hz, 1H), 7.54 - 7.46 (m, 1H), 7.28 (td, J = 8.5, 2.4 Hz, 1H), 2.97 (d, J = 7.1 Hz, 2H), 1.22 - 1.12 (m, 1H), 0.65 - 0.58 (m, 2H), 0.39 - 0.31 (m, 2H).

[0644] Compound SZ-395: 44.8 mg, white solid, ESI [M+H] + = 292.1.

[0645] 1 H NMR (400 MHz, d6-DMSO) δ 8.00 (s, 1H), 7.69 (d, J = 7.2 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.41 (t, J = 7.8 Hz, 1H), 2.99 (d, J = 7.1 Hz, 2H), 2.30 (s, 3H), 1.23 - 1.14 (m, 1H), 0.67 - 0.60 (m, 2H), 0.41 - 0.32 (m, 2H).

[0646] Compound SZ-396: 77.5 mg, white solid, ESI [M+H] + = 370.1.

[0647] 1 H NMR (400 MHz, d6-DMSO) δ 7.67 (dd, J = 7.9, 1.1 Hz, 1H), 7.46 (dd, J = 7.6, 1.2 Hz, 1H), 7.40 (t, J = 7.7 Hz, 1H), 2.96 (d, J = 7.1 Hz, 2H), 2.28 (s, 3H), 1.20 - 1.09 (m, 1H), 0.65 - 0.58 (m, 2H), 0.37 - 0.32 (m, 2H).

[0648] Compound SZ-436: 34.3 mg, syrup-like solid, ESI [M+H] + = 296.1.

[0649] 1H NMR (400 MHz, d6-DMSO) δ 8.08 (s, 1H), 7.67 (ddd, J = 9.5, 8.2, 1.7 Hz, 1H), 7.59 (td, J = 7.9, 5.0 Hz, 1H), 7.55 - 7.50 (m, 1H), 3.00 (d, J = 7.1 Hz, 2H), 1.18 (ddd, J = 7.8, 4.7, 3.0 Hz, 1H), 0.71 - 0.54 (m, 2H), 0.41 - 0.29 (m, 2H).

[0650] Compound SZ-437: 25.0 mg, white solid, ESI [M+H] + = 276.1.

[0651] 1 H NMR (400 MHz, d6-DMSO) δ 8.14 (s, 1H), 7.61 (t, J = 7.7 Hz, 1H), 7.27 (d, J = 11.5 Hz, 1H), 7.22 (d, J = 7.9 Hz, 1H), 2.99 (d, J = 7.1 Hz, 2H), 2.44 (s, 3H), 1.21 - 1.15 (m, 1H), 0.75 - 0.59 (m, 2H), 0.36 (q, J = 4.8 Hz, 2H).

[0652] Compound SZ-438: 57.5 mg, white solid, ESI [M+H] + = 298.1.

[0653] 1 H NMR (400 MHz, d6-DMSO) δ 8.30 (d, J = 1.7 Hz, 1H), 7.69 - 7.59 (m, 1H), 7.56 - 7.49 (m, 1H), 3.00 (d, J = 7.1 Hz, 2H), 1.27 - 1.10 (m, 1H), 0.73 - 0.55 (m, 2H), 0.45 - 0.31 (m, 2H).

[0654] Compound SZ-439: 46.0 mg, syrup solid, ESI [M+H] + = 298.1.

[0655] 1 H NMR (400 MHz, d6-DMSO) δ 8.40 (s, 1H), 7.80 (ddd, J = 19.4, 9.4, 5.1 Hz, 1H), 7.46 - 7.34 (m, 1H), 3.02 (d, J = 7.1 Hz, 2H), 1.27 - 1.10 (m, 1H), 0.71 - 0.58 (m, 2H), 0.45 - 0.30 (m, 2H).

[0656] Compound SZ-440: 46.0 mg, yellowish solid, ESI [M+H] + = 280.1.

[0657] 1 H NMR (400 MHz, d6-DMSO) δ 8.26 (s, 1H), 7.73 (tt, J = 8.5, 6.7 Hz, 1H), 7.47 - 7.27 (m, 2H), 3.01 (d, J = 7.1 Hz, 2H), 1.29 - 1.09 (m, 1H), 0.68 - 0.58 (m, 2H), 0.46 - 0.30 (m, 2H).

[0658] Compound SZ-479: 74.9 mg, syrupy solid, ESI [M+H] + = 374.1.

[0659] 1 H NMR (400 MHz, d6-DMSO) δ 7.70 - 7.64 (m, 1H), 7.60 (td, J = 8.0, 5.1 Hz, 1H), 7.50 (d, J = 7.5 Hz, 1H), 2.98 (d, J = 7.1 Hz, 2H), 1.20 - 1.08 (m, 1H), 0.64 - 0.59 (m, 2H), 0.40 - 0.30 (m, 2H).

[0660] Compound SZ-480: 68.0 mg, white solid, ESI [M+H] + = 354.1.

[0661] 1 H NMR (400 MHz, d6-DMSO) δ 7.56 (t, J = 7.7 Hz, 1H), 7.23 (t, J = 10.6 Hz, 2H), 2.96 (d, J = 7.1 Hz, 2H), 2.43 (d, J = 6.0 Hz, 3H), 1.20 - 1.09 (m, 1H), 0.65 - 0.55 (m, 2H), 0.40 - 0.29 (m, 2H).

[0662] Compound SZ-481: 90.3 mg, syrupy solid, ESI [M+H] + = 376.1.

[0663] 1 H NMR (400 MHz, d6-DMSO) δ 7.68 - 7.52 (m, 2H), 2.99 (d, J = 7.1 Hz, 2H), 1.20 - 1.14 (m, 1H), 0.67 - 0.59 (m, 2H), 0.38 - 0.34 (m, 2H).

[0664] Compound SZ-482: 68.2 mg, syrupy solid, ESI [M+H] + = 376.1.

[0665] 1 1H NMR (400 MHz, d6-DMSO) d 7.85 (ddd, J = 19.4, 9.4, 5.2 Hz, 1H), 7.49 - 7.36 (m, 1H), 3.01 (d, J = 7.1 Hz, 2H), 1.23 - 1.14 (m, 1H), 0.68 - 0.60 (m, 2H), 0.44 - 0.32 (m, 2H).

[0666] Compound SZ-483: 77.3 mg, syrupy solid, ESI [M+H] + = 358.1.

[0667] 1H NMR (400 MHz, d6-DMSO) d 7.77 - 7.70 (m, 1H), 7.38 - 7.31 (m, 2H), 2.98 (d, J = 7.1 Hz, 2H), 1.20 - 1.10 (m, 1H), 0.66 - 0.56 (m, 2H), 0.37 - 0.31 (m, 2H).

[0668] Compound SZ-484: 92.3 mg, white solid, ESI [M+H] + = 376.1.

[0669] 1 1H NMR (400 MHz, d6-DMSO) d 7.56 - 7.46 (m, 2H), 2.98 (d, J = 7.1 Hz, 2H), 1.22 - 1.11 (m, 1H), 0.64 - 0.58 (m, 2H), 0.37 - 0.34 (m, 2H).

[0670] Example 47, Preparation of Compounds SZ-369 ~ SZ-375, SZ-377 ~ SZ-379 and SZ-473 ~ SZ-477 of the Invention

[0671] Under nitrogen protection, 2-bromo-4-chlorothiazole (10.0 g, 50.4 mmol) was dissolved in dry THF (100 mL), the reaction system was cooled to -78 °C with dry ice / acetone bath. n-BuLi (20.2 mL, 2.5 mol / L in Hexane, 50.5 mmol) was slowly added to the reaction system with syringe, stirring for 5 minutes. Cyclopropylcarboxaldehyde (7.97 g, 113.7 mmol) was slowly added to the reaction system with syringe, stirring for 30 minutes. After the reaction was completed by TLC monitoring, saturated aqueous ammonium chloride solution was slowly added to the reaction system, extracted with EtOAc (3 x 100 mL), the combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 10 ~ 1 / 3), TLC (ethyl acetate / petroleum ether (v / v) = 1 / 3) monitoring, the Rf = 0.4 ~ 0.6 part was collected to obtain compound SZ-369-1 (2.59 g, yield 27.1%) as colorless oil. ESI [M+H] + = 190.0.

[0672] SZ-369-1 (2.50 g, 13.2 mmol), triethylsilane (15.38 g, 132.3 mmol) and TFA (25 mL) were added to a sealed tube, stirring at 80 °C for 2 hours. The reaction was concentrated under reduced pressure, the residue was basified with saturated aqueous sodium bicarbonate solution, extracted with EtOAc (3 x 50 mL), the combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 ~ 1 / 10) to obtain compound SZ-369-2 (1.885 g, yield 82.3%) as colorless oil. ESI [M+H] + = 174.1.

[0673] General operation for target compounds SZ-369 ~ SZ-375, SZ-377 ~ SZ-379 and SZ-473 ~ SZ-477:

[0674] Under nitrogen protection, SZ-369-2 (1 eq) was dissolved in dry THF, and the reaction system was cooled to -78 °C with dry ice / acetone bath. n-BuLi (1 eq) was slowly added to the reaction system with a syringe, and stirred for 30 min. The THF solution of different substituted benzaldehyde (1.3 eq) was slowly added to the reaction system at a rate of 1.0 mL / min, and stirred for 30 min. After the reaction was completed by TLC monitoring, saturated aqueous ammonium chloride solution was slowly added to the reaction system, extracted with EtOAc, and the combined organic phase was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The above crude product was dissolved in CH2Cl2, and active MnO2 (30 eq) was added, and stirred at room temperature for 5 h. After the reaction was completed by TLC monitoring, the reaction liquid was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography to obtain the corresponding target compound.

[0675] Compound SZ-369: 101.7 mg, white solid, ESI [M+H] + = 306.1.

[0676] 1 H NMR (400 MHz, d6-DMSO) δ 7.38-7.35 (m, 1H), 7.28-7.20 (m, 2H), 2.92 (d, J = 7.1 Hz, 2H), 2.32 (d, J = 6.9 Hz, 3H), 2.16 (s, 3H), 1.19-1.07 (m, 1H), 0.63-0.56 (m, 2H), 0.37-0.30 (m, 2H).

[0677] Compound SZ-370: 51.7 mg, white solid, ESI [M+H] + = 326.1.

[0678] 1 H NMR (400 MHz, d6-DMSO) δ 7.56 (t, J = 4.7 Hz, 1H), 7.41 (d, J = 4.7 Hz, 2H), 2.93 (d, J = 7.2 Hz, 2H), 2.40 (s, 3H), 1.18-1.09 (m, 1H), 0.62-0.56 (m, 2H), 0.33 (q, J = 4.6 Hz, 2H).

[0679] Compound SZ-371: 191.3 mg, syrup solid, ESI [M+H] + = 314.1.

[0680] 1H NMR (400 MHz, d6-DMSO) δ 7.75 (dtd, J = 9.7, 8.1, 1.6 Hz, 1H), 7.52 (tt, J = 5.8, 1.5 Hz, 1H), 7.42 (tdd, J = 8.2, 4.6, 1.3 Hz, 1H), 2.97 (d, J = 7.1 Hz, 2H), 1.21 - 1.10 (m, 1H), 0.66 - 0.58 (m, 2H), 0.38 - 0.32 (m, 2H).

[0681] Compound SZ-372: 229.0 mg, syrup solid, ESI [M+H] + = 310.0.

[0682] 1 H NMR (400 MHz, d6-DMSO) δ 7.55 (t, J = 7.3 Hz, 1H), 7.45 (t, J = 6.9 Hz, 1H), 7.30 - 7.23 (m, 1H), 2.93 (d, J = 7.1 Hz, 2H), 2.29 (d, J = 1.6 Hz, 3H), 1.13 (ddd, J = 12.4, 7.6, 4.8 Hz, 1H), 0.63 - 0.56 (m, 2H), 0.33 (q, J = 4.6 Hz, 2H).

[0683] Compound SZ-373: 42.2 mg, syrup solid, ESI [M+H] + = 310.0.

[0684] 1 H NMR (400 MHz, d6-DMSO) δ 7.53 - 7.26 (m, 3H), 2.94 (d, J = 7.1 Hz, 2H), 2.18 (d, J = 2.2 Hz, 3H), 1.20 - 1.08 (m, 1H), 0.65 - 0.56 (m, 2H), 0.38 - 0.29 (m, 2H).

[0685] Compound SZ-374: 89.5 mg, syrup solid, ESI [M+H] + = 330.1.

[0686] 1 H NMR (400 MHz, d6-DMSO) δ 7.78 (td, J = 8.4, 6.6 Hz, 1H), 7.50 (ddd, J = 10.8, 9.6, 2.4 Hz, 1H), 7.30 (td, J = 8.4, 2.0 Hz, 1H), 2.95 (d, J = 7.1 Hz, 2H), 1.19 - 1.10 (m, 1H), 0.64 - 0.56 (m, 2H), 0.39 - 0.30 (m, 2H).

[0687] Compound SZ-375: 103.1 mg, white solid, ESI [M+H] + = 314.1.

[0688] 1 H NMR (400 MHz, d6-DMSO) δ 7.78 (td, J = 8.4, 6.6 Hz, 1H), 7.50 (ddd, J = 10.8, 9.6, 2.4 Hz, 1H), 7.30 (td, J = 8.4, 2.0 Hz, 1H), 2.95 (d, J = 7.1 Hz, 2H), 1.19 - 1.10 (m, 1H), 0.64 - 0.56 (m, 2H), 0.39 - 0.30 (m, 2H).

[0689] Compound SZ-377: 149.3 mg, white solid, ESI [M+H] + = 326.0.

[0690] 1 H NMR (400 MHz, d6-DMSO) δ 7.65 (d, J = 7.9 Hz, 1H), 7.46 (d, J = 7.5 Hz, 1H), 7.38 (t, J = 7.8 Hz, 1H), 2.93 (d, J = 7.1 Hz, 2H), 2.26 (s, 3H), 1.13 (ddd, J = 12.5, 7.7, 4.8 Hz, 1H), 0.63 - 0.56 (m, 2H), 0.33 (q, J = 4.9 Hz, 2H).

[0691] Compound SZ-378: 139.9 mg, white solid, ESI [M+H] + = 314.0.

[0692] 1 H NMR (400 MHz, d6-DMSO) δ 7.84 - 7.69 (m, 1H), 7.46 - 7.32 (m, 2H), 3.00 (d, J = 7.1 Hz, 2H), 1.26 - 1.14 (m, 1H), 0.70 - 0.59 (m, 2H), 0.38 (q, J = 4.4 Hz, 2H).

[0693] Compound SZ-379: 146.2 mg, white solid, ESI [M+H] + = 332.1.

[0694] 1H NMR (400 MHz, d6-DMSO) δ 7.54 - 7.44 (m, 2H), 2.95 (d, J = 7.1 Hz, 2H), 1.18 - 1.09 (m, 1H), 0.65 - 0.57 (m, 2H), 0.38 - 0.31 (m, 2H).

[0695] Compound SZ-473: 75.9 mg, syrup solid, ESI [M+H] + = 346.1.

[0696] 1 H NMR (400 MHz, d6-DMSO) δ 7.89 (dd, J = 7.9, 1.7 Hz, 1H), 7.65 (dd, J = 7.6, 1.7 Hz, 1H), 7.59 (t, J = 7.8 Hz, 1H), 2.99 (d, J = 7.1 Hz, 2H), 1.21 - 1.12 (m, 1H), 0.69 - 0.59 (m, 2H), 0.40 - 0.35 (m, 2H).

[0697] Compound SZ-474: 37.2 mg, syrup solid, ESI [M+H] + = 330.1.

[0698] 1 H NMR (400 MHz, d6-DMSO) δ 7.71 - 7.65 (m, 1H), 7.61 (td, J = 7.9, 5.1 Hz, 1H), 7.53 (d, J = 7.5 Hz, 1H), 2.98 (d, J = 7.1 Hz, 2H), 1.22 - 1.12 (m, 1H), 0.68 - 0.60 (m, 2H), 0.40 - 0.32 (m, 2H).

[0699] Compound SZ-475: 79.8 mg, white solid, ESI [M+H] + = 310.1.

[0700] 1 H NMR (400 MHz, d6-DMSO) δ 7.56 (t, J = 7.7 Hz, 1H), 7.22 (t, J = 10.8 Hz, 2H), 2.95 (d, J = 7.2 Hz, 2H), 2.42 (s, 3H), 1.16 - 1.11 (m, 1H), 0.65 - 0.56 (m, 2H), 0.36 - 0.29 (m, 2H).

[0701] Compound SZ-476: 51.5 mg, white solid, ESI [M+H] + = 332.1.

[0702] 1 H NMR (400 MHz, d6-DMSO) δ 7.67 - 7.60 (m, 1H), 7.59 - 7.51 (m, 1H), 2.97 (d, J = 7.1 Hz, 2H), 1.20 - 1.10 (m, 1H), 0.66 - 0.57 (m, 2H), 0.40 - 0.32 (m, 2H).

[0703] Compound SZ-477: 91.0 mg, syrup solid, ESI [M+H] + = 332.1.

[0704] 1 H NMR (400 MHz, d6-DMSO) δ 7.83 (ddd, J = 19.4, 9.4, 5.1 Hz, 1H), 7.46 - 7.38 (m, 1H), 2.98 (d, J = 7.1 Hz, 2H), 1.25 - 1.11 (m, 1H), 0.66 - 0.58 (m, 2H), 0.39 - 0.33 (m, 2H).

[0705] Example 48, Preparation of Compounds SZ-386, SZ-387, SZ-391 and SZ-397 of the Invention

[0706] The preparation method of compound SZ-386-1 is similar to that of compound SZ-7-1.

[0707] The preparation method of compound SZ-386-2 is similar to that of compound SZ-52-1, using SZ-386-1 as the raw material to prepare.

[0708] The preparation method of target compound SZ-397 is similar to that of target compound SZ-57, using SZ-386-2 as the raw material to prepare.

[0709] Compound SZ-397: 150.9 mg, syrup solid, ESI [M+H] + = 292.1.

[0710] 1 H NMR (400 MHz, d6-DMSO) δ 8.43 (s, 1H), 7.41 - 7.31 (m, 3H), 6.28 (d, J = 4.9 Hz, 1H), 4.49 (dd, J = 6.2, 5.0 Hz, 1H), 2.17 (d, J = 2.3 Hz, 3H), 1.21 (dt, J = 18.9, 6.3 Hz, 1H), 0.54 - 0.40 (m, 4H).

[0711] The preparation method of target compounds SZ-386, SZ-387 and SZ-391 is similar to that of target compound SZ-54, which is prepared using SZ-386-2 as raw material.

[0712] Compound SZ-386: 145.2 mg, syrupy solid, ESI [M+H] + = 290.1.

[0713] 1 H NMR (400 MHz, d6-DMSO) δ 8.38 (s, 1H), 7.36 (ddd, J = 15.4, 7.2, 4.6 Hz, 3H), 2.49 (dd, J = 11.6, 4.7 Hz, 1H), 2.17 (d, J = 2.3 Hz, 3H), 1.40 (d, J = 6.9 Hz, 3H), 1.09 - 0.97 (m, 1H), 0.65 - 0.53 (m, 2H), 0.41 - 0.32 (m, 2H).

[0714] Compound SZ-387: 58.4 mg, syrupy solid, ESI [M+H] + = 288.1.

[0715] 1 H NMR (400 MHz, d6-DMSO) δ 8.47 (s, 1H), 7.41 - 7.34 (m, 3H), 5.84 (s, 1H), 5.28 (s, 1H), 2.19 (d, J = 2.0 Hz, 3H), 1.92 (td, J = 8.3, 4.2 Hz, 1H), 0.90 - 0.83 (m, 2H), 0.71 - 0.63 (m, 2H).

[0716] Compound SZ-391: 181.3 mg, white solid, ESI [M+H] + = 276.1.

[0717] 1 H NMR (400 MHz, d6-DMSO) δ 8.40 (s, 1H), 7.40 - 7.35 (m, 2H), 7.35 - 7.30 (m, 1H), 2.93 (d, J = 7.2 Hz, 2H), 2.16 (d, J = 2.3 Hz, 3H), 1.17 - 1.09 (m, 1H), 0.65 - 0.54 (m, 2H), 0.37 - 0.29 (m, 2H).

[0718] Example 49, Preparation of compounds SZ-388, SZ-392 and SZ-398 of the application

[0719] The preparation method of compound SZ-388-1 is similar to that of compound SZ-7-1.

[0720] The preparation method of target compound SZ-388 is similar to that of target compound SZ-52, using SZ-388-1 as the raw material to prepare.

[0721] The preparation methods of target compounds SZ-398 and SZ-392 are similar to those of target compounds SZ-57 and SZ-54, respectively, using SZ-388-2 as the raw material to prepare.

[0722] Compound SZ-388: 177.6 mg, syrupy solid, ESI [M+H] + = 306.1.

[0723] 1 H NMR (400 MHz, d6-DMSO) δ 8.39 (s, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.45 - 7.40 (m, 1H), 7.36 (t, J = 7.8 Hz, 1H), 2.50 - 2.45 (m, 1H), 2.25 (s, 3H), 1.39 (d, J = 6.9 Hz, 3H), 1.08 - 0.98 (m, 1H), 0.64 - 0.52 (m, 2H), 0.41 - 0.30 (m, 2H).

[0724] Compound SZ-392: 170.7 mg, white solid, ESI [M+H] + = 292.1.

[0725] 1 H NMR (400 MHz, d6-DMSO) δ 8.42 (s, 1H), 7.63 (dd, J = 7.7, 1.4 Hz, 1H), 7.43 - 7.33 (m, 2H), 2.92 (d, J = 7.2 Hz, 2H), 2.25 (s, 3H), 1.18 - 1.08 (m, 1H), 0.64 - 0.57 (m, 2H), 0.36 - 0.30 (m, 2H).

[0726] Compound SZ-398: 194.1 mg, syrupy solid, ESI [M+H] + = 308.1.

[0727] 1H NMR (400 MHz, d6-DMSO) δ 8.44 (s, 1H), 7.63 (dd, J = 7.8, 1.3 Hz, 1H), 7.44 - 7.33 (m, 2H), 6.27 (d, J = 4.9 Hz, 1H), 4.48 (dd, J = 6.2, 5.0 Hz, 1H), 2.25 (s, 3H), 1.24 - 1.13 (m, 1H), 0.54 - 0.38 (m, 4H).

[0728] Example 50, Preparation of compounds SZ-389, SZ-390, SZ-393 and SZ-399 of the present application

[0729] The preparation method of compound SZ-389-1 is similar to that of compound SZ-7-1.

[0730] The preparation method of compound SZ-389-2 is similar to that of compound SZ-52-1, using SZ-389-1 as the raw material.

[0731] The preparation method of target compound SZ-399 is similar to that of target compound SZ-57, using SZ-389-2 as the raw material.

[0732] Compound SZ-399: 146.7 mg, syrupy solid, ESI [M+H] + = 296.1.

[0733] 1 H NMR (400 MHz, d6-DMSO) δ 8.44 (s, 1H), 7.63 (dd, J = 7.8, 1.3 Hz, 1H), 7.44 - 7.33 (m, 2H), 6.27 (d, J = 4.9 Hz, 1H), 4.48 (dd, J = 6.2, 5.0 Hz, 1H), 2.25 (s, 3H), 1.24 - 1.13 (m, 1H), 0.54 - 0.38 (m, 4H).

[0734] The preparation method of target compounds SZ-389, SZ-390, and SZ-393 is similar to that of target compound SZ-54, using SZ-389-2 as the raw material.

[0735] Compound SZ-389: 70.1 mg, syrupy solid, ESI [M+H] + = 294.1.

[0736] 1H NMR (400 MHz, d6-DMSO) δ 8.58 (s, 1H), 7.70 (dtd, J = 9.7, 8.1, 1.6 Hz, 1H), 7.51 (dd, J = 7.5, 5.9 Hz, 1H), 7.42 - 7.35 (m, 1H), 2.49 (t, J = 4.7 Hz, 1H), 1.40 (d, J = 6.9 Hz, 3H), 1.10 - 0.99 (m, 1H), 0.65 - 0.52 (m, 2H), 0.40 - 0.32 (m, 2H).

[0737] Compound SZ-390: 20.8 mg, syrup solid, ESI [M+H] + = 292.1.

[0738] 1 H NMR (400 MHz, d6-DMSO) δ 8.67 (s, 1H), 7.72 (dtd, J = 9.7, 8.1, 1.5 Hz, 1H), 7.55 (dd, J = 7.6, 6.0 Hz, 1H), 7.40 (ddd, J = 8.2, 6.0, 2.9 Hz, 1H), 5.85 (s, 1H), 5.30 (s, 1H), 1.96 - 1.88 (m, 1H), 0.91 - 0.83 (m, 2H), 0.71 - 0.65 (m, 2H).

[0739] Compound SZ-393: 84.2 mg, white solid, ESI [M+H] + = 280.1.

[0740] 1 H NMR (400 MHz, d6-DMSO) δ 8.58 (s, 1H), 7.70 (dtd, J = 9.7, 8.1, 1.6 Hz, 1H), 7.49 (tt, J = 5.7, 1.5 Hz, 1H), 7.38 (tdd, J = 8.1, 4.6, 1.3 Hz, 1H), 2.94 (d, J = 7.2 Hz, 2H), 1.19 - 1.07 (m, 1H), 0.64 - 0.56 (m, 2H), 0.37 - 0.31 (m, 2H).

[0741] The advantageous effects of the present application are demonstrated by the following test examples.

[0742] Test Example 1, Pharmacological data measurement of the compounds of the present application

[0743] 1. Test method

[0744] 1.1 Test of the anesthetic effect of the compounds of the present application after intravenous injection in rats (measurement of the minimum anesthetic effective dose):

[0745] The experimental animals are 7-9 week old male SD rats, and the drug is given through the tail vein (the speed of administration is 0.02 mL / s, and the volume of administration is 0.6 mL per rat). The initial dose of each test compound is 1 mg / kg, and the actual dose is calculated according to the weight of each rat before the test. According to whether the experimental rats appear righting reflex loss, the subsequent dose is increased or decreased, and the lowest dose at which the righting reflex loss occurs is determined as the minimum anesthetic effective dose.

[0746] While testing whether the compounds of the present application have an anesthetic effect after being injected into the tail vein of rats, it is also determined whether the compounds have analgesic effect. Once it is determined that the compound has an anesthetic effect (righting reflex loss ≥ 30 s), the reaction of the rat to a noxious stimulus (holding the middle and outer 1 / 3 of the rat's tail with an alligator clip for 30 s) after administration is observed. If the rat does not react within 30 s, it is determined to have analgesic effect, otherwise it does not. If the compound has no anesthetic effect (righting reflex loss < 30 s), the rat is given a noxious stimulus (holding the middle and outer 1 / 3 of the rat's tail with an alligator clip for 30 s) 1 min after administration. If the rat does not react within 30 s, it is determined to have analgesic effect, otherwise it does not. In the present application, the dose at which analgesic effect begins to appear is determined as the minimum analgesic effective dose. In the present application, the minimum anesthetic effective dose and the minimum analgesic effective dose are further classified as: A ≤ 10 mg / kg; 10 mg / kg < B ≤ 20 mg / kg; 20 mg / kg < C ≤ 30 mg / kg; 30 mg / kg < D ≤ 40 mg / kg; E > 40 mg / kg.

[0747] 1.2 Determination of the main pharmacological effects of the compounds of the present application

[0748] 1.2.1 ED of the compounds of the present application for general anesthetic effect with righting reflex loss of rats as the determination index 50 Seven to nine week old male SD rats are selected for the test. The median effective dose (ED 50 ) of the compounds of the present application for general anesthetic effect with righting reflex loss as the determination index is determined by using the up-and-down method. The drug is administered through the tail vein of the rats during the test, and the volume of administration for each rat is 0.6 mL, and the speed of administration is 0.02 mL / s. Righting reflex loss (LORR) ≥ 30 s is used as the determination standard for anesthetic effect.

[0749] 1.2.2 2ED of the compounds of the present application for righting reflex loss of rats 50 Comparison of the pharmacological effects of the compounds of the present application

[0750] After the ED 50 of the compounds of the present application is determined, the 2ED 50The test was carried out in a dose-dependent manner. The test was carried out by administering the drug through the tail vein of the rat, with a volume of 0.6 mL and a speed of 0.02 mL / s. The time of loss of righting reflex (LORR) was recorded as the time of onset of anesthetic effect. After administration, the time of loss of righting reflex, the time of recovery of righting reflex, and the symptoms of adverse reactions and their onset and termination time were recorded and observed.

[0751] 2ED 50 Pharmacological characteristics of the equivalent dose of the compound of the present application:

[0752] In the above test, in addition to recording the dose at which the loss of righting reflex occurs, the onset and recovery times of anesthetic effect, the duration of righting reflex and the duration of sedative effect since administration were also recorded. In the dose at which the compound of the present application caused the loss of righting reflex, the effect of the compound on the respiration of the experimental animal was also observed.

[0753] 2、Experimental results

[0754] Table 1. Pharmacological data of single intravenous injection of the compound of the present application with anesthetic effect

[0755] Table 2. Minimum analgesic effective dose of single intravenous injection of the compound of the present application

[0756] Table 3. ED of some compounds of the present application in rats with loss of righting reflex 50 and 2ED 50 Pharmacological characteristics of the equivalent dose of the compound of the present application: " / " indicates that the experiment of 2ED50 was not done.

[0757] The experimental results show that the compound of the present application has high anesthetic, sedative, hypnotic effect, can control status epilepticus, and also has analgesic effect.

Claims

a compound represented by Formula I, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, a prodrug thereof, a metabolite thereof, or a deuterated derivative thereof: selected from substituted or unsubstituted: Each of the substituents is independently selected from hydroxyl, halogen, cyano, (CR6R7) m R8, mercapto, unsubstituted or substituted with one or more R9 groups: amino, C 1-8 Alkyl, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-8 Alkoxy, C 1-8 Alkylthio group, LC ring, C ring selected from 3-8 membered saturated cycloalkyl group, 3-8 membered saturated heterocyclic group, phenyl group, 5-6 membered heteroaromatic ring; m is selected from 0, 1, 2, 3, 4, 5; R6, R7are each independently selected from the group consisting of hydrogen, C 1-8 alkyl; R8is selected from CONR 10 R 11 , NR 10 R 11 , COOR 12 , COR 12 , OR 12 , phenyl substituted with one or two substituents each independently selected from halo, hydroxy, nitro, cyano, C 1-8 alkyl, C 1-8 alkoxy; L is selected from the group consisting of none, O, S, NR 10 R 11 、 (CR 15 R 16 ) p , 3-6 membered saturated cycloalkyl, 3-6 membered saturated heterocyclyl, C(=CR c R d ), CO; p is selected from 0, 1, 2, 3, 4, 5; R 15 , R 16 each independently is selected from hydrogen, halogen, halogenated or unhalogenated C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkenyl substituted with C 1-8 alkyl, C 1-8 alkoxy, OH, 3-8 membered saturated cycloalkyl, OCOR 12 , SO2R 17 ; R 17 is selected from C 1-8 alkyl; R9 is selected independently from NR 10 R 11 C 2-8 alkenyl-substituted C 1-8 Alkyl, halogen, hydroxyl, amino, mercapto, C 1-8 Alkyl, C 1-8 Alkoxy, C 2-8 alkenyl, C 2-8 Alkyne group, OCOR 9a SO2R 9a OR 9c 3-8 saturated cycloalkyl groups, one or more R 9b Substituted 3-8 saturated cycloalkyl groups, 3-8 saturated heterocyclic groups, one or more R groups 9b Substituted 3-8 membered saturated heterocyclic groups, phenyl groups, one or more R groups 9b Substituted phenyl groups, 5-6 membered heteroaryl rings, one or more R groups 9b Substituted 5-6 membered heteroaryl rings; R 9a Selected from C 1-5 Alkyl; R 9b Each C is independently selected from hydroxyl, halogen, halogenated or non-halogenated. 1-5 Alkyl, halogenated or unhalogenated C 1-5 Alkoxy, 3-6 membered saturated cycloalkyl, 3-6 membered saturated heterocyclic group; R 9c Selected from 3-6 membered saturated cycloalkyl groups and 3-6 membered saturated heterocyclic groups; R 10 , R 11 each independently is selected from hydrogen, OH, C 1-8 alkyl, 3- to 8-membered saturated cycloalkyl, R 12 selected from C 1-8 alkyl, 3-8 membered saturated cycloalkyl, 3-8 membered saturated heterocyclyl, 5-6 membered heteroaromatic, n is selected from 0, 1, 2, 3, 4, 5; R 13 selected from hydroxy, C 1-8 alkoxy; R C , R D each independently is selected from hydrogen, halogen, halo- or unhalo-genated C 1-6 alkyl, halo- or unhalogenated C 1-6 alkoxy, OH, OR s , or R C , R D are linked to form a 3-6 membered saturated cycloalkyl or 3-6 membered saturated heterocyclyl, or R C , R D together with the C atom in between form C(=CR c R d ), CO; R s is selected from 3-6 membered saturated cycloalkyl, 3-6 membered saturated heterocyclyl, benzyl; R c , R d each independently is selected from hydrogen, halogen; R1, R2, R3, R4, R5are each independently selected from the group consisting of hydrogen, hydroxyl, halogen, halo or unhalo genated C 1-8 alkyl, halo or unhalogenated C 1-8 alkyl, halo or unhalogenated C 1a alkyl, halo or unhalogenated C 1-4 alkyl, halo or unhalogenated C 1a selected from the group consisting of phenyl, 3-6 membered saturated cycloalkyl, 3-6 membered saturated heterocyclyl. The compound of claim 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, a prodrug thereof, a metabolite thereof, or a deuterated derivative thereof, characterized in that, The structure of the compound is shown as formula II-a, II-b, III-a, III-b: z is selected from 0, 1, 2; R E each independently selected from the group consisting of hydroxyl, halogen, cyano, unsubstituted or substituted with one or more R9, amino, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 alkoxy, C 1-3 alkylthio, 3-4 membered saturated cycloalkyl, 3-4 membered saturated heterocyclyl, phenyl, 5-6 membered heteroaromatic ring; R9is each independently selected from the group consisting of halogen, hydroxyl, amino, thiol, C 1-3 alkyl, C 1-3 alkoxy, C 2-3 alkenyl, C 2-3 alkynyl, OCOR 9a , SO2R 9a , OR 9c , 3-4 membered saturated cycloalkyl, one or two R 9b substituted 3-4 membered saturated cycloalkyl, 3-4 membered saturated heterocyclyl, one or two R 9b substituted 3-4 membered saturated heterocyclyl, phenyl, one or two R 9b substituted phenyl, 5-6 membered heteroaromatic ring, one or two R 9b substituted 5-6 membered heteroaromatic ring; R 9a selected from C 1-3 alkyl; R 9b each independently selected from hydroxy, halogen, halo- or unhalo- genated C 1-3 alkyl, halo- or unhalogenated C 1-3 alkoxy, 3-4 membered saturated cycloalkyl, 3-4 membered saturated heterocyclyl; R 9c selected from 3-4 membered saturated cycloalkyl, 3-4 membered saturated heterocyclyl; R C , R D each independently is selected from the group consisting of hydrogen, C 1-3 1-6alkyl, C 1-3 1-6alkoxy, or R C , R D and the C-atoms between them form together C=CH2, CO; R1, R2, R3, R4, R5are each independently selected from the group consisting of hydrogen, hydroxyl, halogen, halogenated or unhalogenated C 1-3 alkyl, halogenated or unhalogenated C 1-3 alkoxy. The compound of claim 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, a prodrug thereof, a metabolite thereof, or a deuterated derivative thereof, characterized in that, The structure of the compound is shown in formula V: z is selected from 0, 1, 2; R E each independently selected from the group consisting of hydroxy, halogen, cyano, unsubstituted or substituted with one or more R9, amino, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 alkoxy, C 1-3 alkylthio, L-Cring, Cring is selected from the group consisting of 3-4 membered saturated cycloalkyl, 3-4 membered saturated heterocyclyl, phenyl, 5-6 membered heteroaromatic ring; L is selected from the group consisting of none, O, S, NR 10 R 11 、 (CR 15 R 16 ) p , 3-4 membered saturated cycloalkyl, 3-4 membered saturated heterocyclyl, C(=CR c R d ), CO; p is selected from 0, 1, 2, 3; R 15 , R 16 each independently is selected from the group consisting of hydrogen, halogen, halogenated or unhalogenated C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkenyl substituted with C 1-3 alkyl, C 1-3 alkoxy, OH, 3-4 membered saturated cycloalkyl, OCOR 12 , SO2R 17 ; R 17 is selected from the group consisting of C 1-3 alkyl; R9is each independently selected from the group consisting of halogen, hydroxyl, amino, thiol, C 1-3 alkyl, C 1-3 alkoxy, C 2-3 alkenyl, C 2-3 alkynyl, OCOR 9a , SO2R 9a , OR 9c , 3-4 membered saturated cycloalkyl, one or two R 9b substituted 3-4 membered saturated cycloalkyl, 3-4 membered saturated heterocyclyl, one or two R 9b substituted 3-4 membered saturated heterocyclyl, phenyl, one or two R 9b substituted phenyl, 5-6 membered heteroaromatic ring, one or two R 9b substituted 5-6 membered heteroaromatic ring; R 9a selected from C 1-3 alkyl; R 9b each independently selected from hydroxy, halogen, halo- or unhalo- genated C 1-3 alkyl, halo- or unhalogenated C 1-3 alkoxy, 3-4 membered saturated cycloalkyl, 3-4 membered saturated heterocyclyl; R 9c selected from 3-4 membered saturated cycloalkyl, 3-4 membered saturated heterocyclyl; R 10 , R 11 each independently is selected from hydrogen, OH, C 1-5 alkyl, 3- to 6-membered saturated cycloalkyl, R 13 selected from C 1-5 alkyl, 3-6 membered saturated cycloalkyl, 3-6 membered saturated heterocyclyl, 5-6 membered heteroaromatic, n is selected from 0, 1, 2, 3, 4, 5; R 13 selected from hydroxy, C 1-5 alkoxy; R C , R D each independently is selected from the group consisting of hydrogen, C 1-3 1-6alkyl, C 1-3 1-6alkoxy, or R C , R D and the C-atoms between them form together C=CH2, CO; R c , R d each independently is selected from hydrogen, halogen; R1, R2, R3, R4, R5are each independently selected from the group consisting of hydrogen, hydroxyl, halogen, halogenated or unhalogenated C 1-3 alkyl, halogenated or unhalogenated C 1-3 alkoxy. The compound, stereoisomer, pharmaceutically acceptable salt, solvate, prodrug, metabolite, or deuterated derivative thereof according to claim 3, characterized in that, The structure of the compound is shown as formula V-a, V-b, V-c: z, R E , R C , R D , R1, R2, R3, R4, R5 are as described in claim 3. The compound, stereoisomer, pharmaceutically acceptable salt, solvate, prodrug, metabolite, or deuterated derivative thereof according to claim 4, characterized in that, The structure of the compound is shown as formula VI-a, VI-b, VI-c, VI-d: X is selected from halogen, hydrogen, halo- or unhalo- genated C 1-3 alkyl; R C , R D , R1, R2, R3, R4, R5 are as defined in claim 4. The compound, stereoisomer, pharmaceutically acceptable salt, solvate, prodrug, metabolite, or deuterated derivative thereof according to claim 5, characterized in that, The structure of the compound is shown in formula VII-a, VII-b: q is selected from 1, 2, 3; R 91 selected from hydrogen, halogen, hydroxyl, amino, thiol, C 1-3 alkyl, C 1-3 alkoxy, C 2-3 alkenyl, C 2-3 alkynyl, OCOR 9a , SO2R 9a , OR 9c , 3-4 membered saturated cycloalkyl, one or two R 9b substituted 3-4 membered saturated cycloalkyl, 3-4 membered saturated heterocyclyl, one or two R 9b substituted 3-4 membered saturated heterocyclyl, phenyl, one or two R 9b substituted phenyl, 5-6 membered heteroaromatic ring, one or two R 9b substituted 5-6 membered heteroaromatic ring; R 9a selected from C 1-3 alkyl; R 9b each independently selected from hydroxy, halogen, halo- or unhalo- genated C 1-3 alkyl, halo- or unhalogenated C 1-3 alkoxy, 3-4 membered saturated cycloalkyl, 3-4 membered saturated heterocyclyl; R 9c selected from 3-4 membered saturated cycloalkyl, 3-4 membered saturated heterocyclyl; R C , R D , R1, R2, R3, R4, R5, L, X are as defined in claim 5. The following compounds, stereoisomers thereof, pharmaceutically acceptable salts thereof, solvates thereof, prodrugs thereof, metabolites thereof, or deuterated derivatives thereof, characterized in that, The compound is selected from one of the following compounds: The compound, stereoisomer, pharmaceutically acceptable salt, solvate, prodrug, metabolite, or deuterated derivative thereof according to any one of claims 1-7, wherein, the pharmaceutically acceptable salt is citrate, hydrofluoride, phosphate, propionate, succinate, tartrate, acetate, adipate, aspartate, benzoate, besylate, bicarbonate, carbonate, bisulfate, sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hydrochloride, hydrobromide, hydroiodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate, hydrogen phosphate, dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, xinafoate, or p-toluenesulfonate. A pharmaceutical composition, characterized by The pharmaceutical composition is a preparation prepared by adding a pharmaceutically acceptable adjuvant to the compound, the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the solvate thereof, the prodrug thereof, the metabolite thereof, or the deuterated derivative thereof of any one of claims 1 to 8 as an active ingredient. The use of the compound, the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the solvate thereof, the prodrug thereof, the metabolite thereof, or the deuterated derivative thereof of any one of claims 1 to 8 in the manufacture of a medicament having analgesic effect, and / or, having anesthetic, sedative, hypnotic effect and / or being able to control status epilepticus.

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